Novel benzyltryptamines

Abstract

Compounds of Formula I and pharmaceutical compositions containing compounds of Formula I are provided herein. Methods of using the compounds and pharmaceutical compositions described herein to treat diseases and disorders, such as neurological and / or psychiatric diseases and disorders, are also provided.

Description

NOVEL BENZYLTRYPTAMINESCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of priority to U. S. Provisional Patent Application No. 63 / 729,830, filed on December 9, 2024, the contents of which are incorporated herein by reference in their entirety.BACKGROUND

[0002] Psilocybin is a naturally occurring psychedelic prodrug compound produced by more than 200 species of mushrooms which are collectively known as psilocybin mushrooms. Psilocybin has mind-altering effects not unlike those produced by lysergic acid diethylamide (LSD), mescaline, and N, N-dimethyl tryptamine (DMT). These effects include, inter alia, euphoria, visual and mental hallucinations, changes in perception, a distorted sense of time, and spiritual experiences, and can also include possible adverse reactions such as nausea and panic attacks.

[0003] While psilocybin and its therapeutic potential, along with that of other psychedelic drugs like LSD in psychiatry, was recognized and explored over 50 years ago by Hofmann and co-workers at Sandoz (see, for example, Hofmann, A., Troxler, F. U. S. Patent Nos. 3,075,992 and 3,078,214), subsequent investigation into the recreational use of psilocybin and related psychedelic drugs (e.g., LSD) was curtailed in the early 1970s. Since then, psilocybin has remained classified as a scheduled drug of abuse in most countries by many national drug laws. However, clinical investigations have recently led to increased awareness of the potential for psychedelic drugs and psilocybin, in particular as breakthrough therapies to treat CNS diseases of unmet medical need. These diseases that may be addressed include both difficult to treat mental health disorders (Daniel J, Haberman M. Clinical potential of psilocybin as a treatment for mental health conditions. Merit. Health Clin. 2017, 7(1), 24-8) associated with significant morbidity such as treatment resistant depression (TRD), along with alcoholism and cocaine and tobacco addiction, as well as neurological disorders such as cluster headache, which is also associated with morbidity.

[0004] As a prodrug, psilocybin is quickly metabolized by the body to generate the bioactive compound psilocin:4938-1723-0719.1Psilocybin Psilocin

[0005] Psilocin acts on serotonin receptors, also known as 5 -hydroxytryptamine receptors (5-HT) receptors, in the brain, which mediate both excitatory and inhibitory neurotransmission. Psilocin has been shown to act at a number of serotonin receptor subtypes from in vitro receptor binding and functional assays, in line with its structural resemblance to serotonin (Geiger H. A., Wurst M. G., Daniels R. N., “DARK Classics in Chemical Neuroscience: Psilocybin,” ACS Chem. Neurosci. 2018, 9 (10), 2438-2447). Psilocin exhibited no significant effect on dopamine receptors (unlike LSD) and appears to only act upon the noradrenergic system at very high dosages. The diverse pharmacological effects of particular relevance to therapeutic utility and limitations can be ascribed to psilocin’s activation of 5-HT2A, 5-HT2B, and 5-HT2C receptors specifically as a functional agonist.

[0006] Psilocin’s potent agonist activity at 5-HT2B receptors, which can result in toxicological issues such as cardiac valvulopathy, represents a limitation for therapeutic development. Thus, previous drugs with 5-HT2B receptor agonist activity have been found to have life threatening side effects such as cardiac valvulopathy (Rothman, R., Baumann, M., Savage, J., Rauser, L, McBride, A., Hufeisen, S., Roth, B. L. “Evidence for Possible Involvement of 5-HT2B Receptors in the Cardiac Valvulopathy Associated with Fenfluramine and other Serotonergic Medications” Circulation 2000, 102, 2836; Fitzgerald, L., Bum, T., Brown, B., Patterson, J., Corjay, M., Valentine, P., Sun, J-H., Link, J., Abbaszade, I., Hollis, J., Largent, B., Hartig, P., Hollis, G., Meunier, P., Robichaud, A., Robertson, D. “Possible Role of Valvular Serotonin 5-HT2B Receptors in the Cardiopathy Associated with Fenfluramine” Mol. Pharmacol. 2000, 57, 75) and pulmonary hypertension (Launay, J., Herve, P., Peoc'h, K., Toumois, C., Callebert, J., Nebigil, C., Etienne, N., Drouet, L., Humbert, M., Simonneau, G., Maroteaux, L. “Function of the Serotonin 5 -Hydroxytryptamine 2B Receptor in Pulmonary Hypertension” Nature Med. 2002, 8, 1129).

[0007] W02023070228 describes benzyltryptamine compounds for the treatment of CNSdisorders.

[0008] There remains a need for safer drugs and analogs of psilocin that maintain 5-HT2A receptor agonist activity but that lack cardiotoxic 5-HT2B agonist activity.SUMMARY

[0009] In one aspect, the present disclosure provides compounds that are represented by Formula I or are pharmaceutically acceptable salts thereof:wherein:Ring A is an optionally substituted group selected from saturated C3-C10 carbocyclyl, Ce-Cio aryl, 5-10 membered heterocyclyl, and 5-10 membered heteroaryl;Rais selected from halogen, hydroxyl, and C1-6 alkoxyl;q is an integer from 0 to 4;RNis hydrogen or optionally substituted C1-6 aliphatic;Rpis a lone electron pair or optionally substituted C1-6 aliphatic; andRcland Rc2are each independently hydrogen or C1-6 aliphatic.

[0010] In certain embodiments, the compounds of the present disclosure do not include the following compounds of Table 1:Table 1Compound Structure1-200CH3I I 0 CH3H3C~ { / \ / \ / / = / \ / \ 0 O 0== d N-\ / # # / O p 4 °10— - 1-20ch3\ \ I f T) >00 O- OA H Y I / o Zz —- Qoz I \- O-CH ) 03Z 3I / CHZCH3° \ \ J co / 1 / 1^ / XZ X1-202 A Y Y / sY / / xiT° / ^ °^X^ <?h= r "ir°'cH3\J / O -"w1HN-^, CH31-203HNO^ CuH3 1-2041-205Compound Structure1-207co T1-208 Qy^N^XjA^C OHa \ £ OHNJ°' / (C o=H3CH3[^>1 QX^ > co1-209 T / N^AJoz-HNJ°'CH31-210 \ r^HN-^1-211 O HN-^^ XK CH3H3C111-212HN—JCH31-213HN-^ CH3 / CH31-214HN—JCH31-215 Q^JX l,HN— CH3Compound Structure1-216HN-J1-217 Q HN-^rJXk1-218 Z / TJ z z y=HN-^1-219 Q HyJoo z z-- ZE / N-^HAw\ CH3H o; y \ / / \< o=1-220 QT~"-O? oX <o o o HN-- / T I I 1-221 Q HVrJ^ O-Z1-222OCH31-223 Qp Zc:Compound Structuref i3\ T1-225^\ ll ^ y ocHj HN-^ OCH3co co co co X X X / o o o ZE co > co 1-226 oo \ \ / ZE- )\ o o o.-= <>« / \ \\ / / / / ^\ O G O-= <>—\ co \ oI co \ \ #\ °r ZE co \ / o X oz oz ) > ZE / CO coz X / / -- - oz oz-- v r°^1-227 / x i o \A Z ZE=\ co / 1c>' / / X x 1^ co / Xx Lx1° J\J kJ^1o z- 1-2281^11-229 \ F HN-71-2301-2311-232Compound Structure1-233I0 r> r>\ T I2 4 / T I u= O1- 3 / < o o 00=6 O AO——I / I / oz- oz- 1-235zHN-^\ j rz^CH31-236 Of* zo- / iHN-71-237

[0011] In a second aspect, the present disclosure provides pharmaceutical compositions comprising a compound described herein and a pharmaceutically acceptable excipient.

[0012] In a third aspect, the present disclosure provides methods of administering compounds described herein, comprising orally, rectally, topically, buccally, or parenterally (e.g., subcutaneously, intramuscularly, intradermally, or intravenously) administering to a subject a compound described herein, or a pharmaceutical composition described herein.

[0013] In a fourth aspect, the present disclosure provides methods of treating a disease or disorder in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound described herein or a pharmaceutical composition described herein, optionally wherein the disease or disorder is a neurological and / or psychiatric disease or disorder, such as generalized anxiety disorder, depression including postpartum depression, adjustment disorder, addiction, anxiety, post-traumatic stress disorder (PTSD), a neurodegenerative disease, suicidal ideation, bipolar disorder, schizophrenia, a mood disorder, a psychotic disorder, a personality disorder, an eating disorder, a sleep disorder, animpulse control disorder, a gambling disorder, a movement disorder, a memory disorder, a substance use disorder (e.g., alcohol dependence, nicotine dependence, opioid dependence, and cocaine dependence), a dissociative disorder, a cognitive disorder, a developmental disorder, a factitious disorder, obsessive compulsive disorder, a body dysmorphic disorder, chronic pain, and chronic fatigue.

[0014] In another aspect, the compounds of the present disclosure may be used in the manufacture of a medicament for the treatment of a disease mediated by 5-HT2A receptor activity in a subject, e.g., a neurological and / or psychiatric disease or disorder, such as generalized anxiety disorder, depression including postpartum depression, adjustment disorder, addiction, anxiety, post-traumatic stress disorder (PTSD), a neurodegenerative disease, suicidal ideation, bipolar disorder, schizophrenia, a mood disorder, a psychotic disorder, a personality disorder, an eating disorder, a sleep disorder, an impulse control disorder, a gambling disorder, a movement disorder, a memory disorder, a substance use disorder (e.g., alcohol dependence, nicotine dependence, opioid dependence, and cocaine dependence), a dissociative disorder, a cognitive disorder, a developmental disorder, a factitious disorder, obsessive compulsive disorder, a body dysmorphic disorder, chronic pain, and chronic fatigue.BRIEF DESCRIPTION OF THE DRAWINGS

[0015] These and other features, aspect, and advantages of the present disclosure will become better understood with regard to the following description, and accompanying drawings, where:

[0016] Figure 1A shows a single non-psychedelic dose comparison of compounds 1-6 and 1-219. Figure IB shows a single non-psychedelic dose comparison of compounds 1-6 and I-219 seven days post-dose in the rat forced swim test (FST).

[0017] Figure 2A shows a plasma concentration of compounds 1-6 and 1-219 following subcutaneous and oral administration to rats. Figure 2B shows cortex concentration of 1-6 and 1-219 following subcutaneous and oral administration to rats.

[0018] Figure 3 shows the 5-HT2B (A) ICso curve of exemplary compound 1-34.

[0019] Figure 4 shows the 5-HT2A(A) ECSO curve of exemplary compound 1-33.

[0020] Figure 5 shows a histogram of head twitch response (HTR) counts over 60 minutes in rats following administration of compounds of the present disclosure.

[0021] Figure 6A shows a graph of average HTR over 60 minutes in rats against the cortical concentration of compounds described herein, i.e., 1-6, 2,5-dimethoxy-4-iodoamphetamine (DOI), and 4-OH-DiPT. Figure 6B shows the cortical concentration of compounds of the present disclosure in rats when measured approximately 1.25 hours postdose.

[0022] Figure 7 shows the X-ray diffraction pattern (XRPD) of 1-6 HC1.DETAILED DESCRIPTION1. Definitions

[0023] When describing the embodiments of the present disclosure, which may include compounds and pharmaceutically acceptable salts thereof, pharmaceutical compositions containing such compounds and methods of using such compounds and compositions, the following terms, if present, have the following meanings unless otherwise indicated.

[0024] In general, terms used herein are intended as “open” terms (e.g., the term “including” should be interpreted as “including but not limited to,” the term “having” should be interpreted as “having at least,” the term “includes” should be interpreted as “includes but is not limited to,” etc.). As such, indefinite articles such as “a,” “an,” and “the” should be interpreted as singular or plural (e.g., referring one or more), unless the context plainly dictates otherwise. Moreover, the use of introductory phrases such as “at least one” and “one or more” in some instances should not be understood to indicate that the use of “a” or “an” or “the” in other instances is meant to refer to the singular (e.g., only one). Further, if a specific number of features, elements, steps (etc.) is intended, such a number will be explicitly stated.

[0025] As used herein, phrases such as “at least one of A, B, and C, etc.” should be interpreted as referring to one or more of the listed options (e.g., “a system having at least one of A, B, and C” would include but not be limited to systems that have A alone, B alone, C alone, A and B together, A and C together, B and C together, and / or A, B, and C together, etc.).

[0026] In addition, where features or aspects of the disclosure are described in terms of Markush groups, the disclosure should be interpreted as including any individual member of the Markush group and any and all permutations and combinations of subgroups of members of the Markush group.

[0027] All ranges disclosed herein should be interpreted as disclosing each individual value within the range (including the endpoints thereof) as well as any and all possible sub-ranges and combinations of sub-ranges thereof, including subranges of equal halves, thirds, quarters, fifths, tenths, etc., unequal subranges, and nested ranges, such as nested ranges centered around a midpoint of a range. Likewise, language such as “up to,” “at least,” “greater than,’ “less than,” and the like may be interpreted as open-ended ranges which include a disclosure of sub-ranges as discussed above.

[0028] Compounds of this disclosure include those described generally above, and are further illustrated by the classes, subclasses, and species disclosed herein. As used herein, the following definitions shall apply unless otherwise indicated. For purposes of this disclosure, the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75thEd. Additionally, general principles of organic chemistry are described in “Organic Chemistry”, Thomas Sorrell, University Science Books, Sausalito: 1999, and “March’s Advanced Organic Chemistry”, 5thEd., Ed.: Smith, M. B. and March, J., John Wiley & Sons, New York: 2001, the entire contents of which are hereby incorporated by reference.

[0029] The abbreviations used herein have their conventional meaning within the chemical and biological arts. The chemical structures and formulae set forth herein are constructed according to the standard rules of chemical valency known in the chemical arts.

[0030] A dash (“-”) that is not between two letters or symbols is used to indicate a point of attachment for a substituent. For example, -CN is attached through the carbon atom.

[0031] When a range of values is listed, it is intended to encompass each value and subrange within the range. For example, “Ci-Ce alkyl” or “Ci-6 alkyl” is intended to encompass Ci, C2, C3, C4, Cs, Ce, C1-6, C1-5, C1-4, C1-3, C1-2, C2-6, C2-5, C2-4, C2-3, C3-6, C3-5, C3-4, C4-6, C4-5, and C5-6 alkyl.

[0032] The term “about,” as used herein will be understood by persons of ordinary skill in the art and will vary to some extent depending upon the context in which it is used. If there are uses of the term which are not clear to persons of ordinary skill in the art given the context in which it is used, “about” will mean up to plus or minus 10% of the particular term.

[0033] The term “aliphatic” or “aliphatic group”, as used herein, means a straight-chain (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is completely saturated or that contains one or more units of unsaturation, or a monocyclic hydrocarbon or bicyclic hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic (also referred to herein as “carbocyclyl”,“cycloaliphatic”, or “cycloalkyl”), that has a single point of attachment to the rest of the molecule. Unless otherwise specified, aliphatic groups contain 1-6 aliphatic carbon atoms. In some embodiments, aliphatic groups contain 1-5 aliphatic carbon atoms. In some embodiments, aliphatic groups contain 1-4 aliphatic carbon atoms. In some embodiments, aliphatic groups contain 1-3 aliphatic carbon atoms. In some embodiments, aliphatic groups contain 1-2 aliphatic carbon atoms. In some embodiments, “cycloaliphatic” (or “carbocyclyl” or “cycloalkyl”) refers to a monocyclic C3-C10 hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic, that has a single point of attachment to the rest of the molecule. Suitable aliphatic groups include, but are not limited to, linear or branched, substituted or unsubstituted alkyl, alkenyl, alkynyl groups and hybrids thereof such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or (cycloalkyl)alkenyl.

[0034] The term “alkyl,” as used herein, refers to a saturated straight or branched hydrocarbon, such as a straight or branched group of 1 to 8 carbon atoms, referred to herein as C1-8 alkyl. Exemplary alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, 2-methyl-l -propyl, 2-methyl-2-propyl, 2-methyl-l -butyl, 3 methyl- 1 -butyl, 2-methyl-3 -butyl, 2,2-dimethyl-l -propyl, 2-methyl-l -pentyl, 3 methyl- 1 -pentyl, 4-m ethyl- 1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4 methyl-2-pentyl, 2,2-dimethyl-l -butyl, 3,3-dimethyl-1 -butyl, 2-ethyl-l -butyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, and octyl. In some embodiments, “alkyl” is a straight-chain hydrocarbon. In some embodiments, “alkyl” is a branched hydrocarbon.

[0035] The term “alkylene” refers to a divalent alkyl group. An “alkylene chain” is a polymethylene group, i.e., -(CH2)n-, wherein n is a positive integer, for example, from 1 to 6, from 1 to 4, from 1 to 3, from 1 to 2, or from 2 to 3. A substituted alkylene chain is a polymethylene group in which one or more methylene hydrogen atoms are replaced with a substituent. Suitable substituents include those described below for a substituted aliphatic group.

[0036] The term “alkoxyl” means a group that consists of a straight chain or branched hydrocarbon containing 1-12 carbon atoms containing a terminal “O” in the chain, e.g., -O(alkyl). Examples of alkoxyl groups include, without limitation, methoxy, ethoxy, propoxy, butoxy, t-butoxy, or pentoxy groups.

[0037] The term “aryl,” as used herein, refers to an all carbon monocyclic or fused-ring polycyclic (i.e., rings which share adjacent pairs of carbon atoms) groups / systems having acompletely conjugated pi-electron system without any heteroatom ring atoms. An aryl group may be selected from: monocyclic carbocyclic aromatic rings, for example, phenyl; bicyclic ring systems such as 7-12 membered, e.g., 9-10 membered (e.g., naphthalenyl), bicyclic ring systems wherein at least one ring is carbocyclic and aromatic, selected, for example, from naphthalene, indane, and 1,2,3,4-tetrahydroquinoline; and tricyclic ring systems such as 10-15 membered tricyclic ring systems wherein at least one ring is carbocyclic and aromatic, for example, fluorene.

[0038] For example, the aryl group may be a 6-membered carbocyclic aromatic ring fused to a 5- to 7-membered cycloalkyl or heterocyclic ring optionally comprising at least one heteroatom selected from N, O, and S, provided that the point of attachment is at the carbocyclic aromatic ring when the carbocyclic aromatic ring is fused with a heterocyclic ring, and the point of attachment can be at the carbocyclic aromatic ring or at the cycloalkyl group when the carbocyclic aromatic ring is fused with a cycloalkyl group. Divalent radicals formed from substituted benzene derivatives and having the free valences at ring atoms are named as substituted phenylene radicals. Divalent radicals derived from univalent polycyclic hydrocarbon radicals whose names end in “-yl” by removal of one hydrogen atom from the carbon atom with the free valence are named by adding “-idene” to the name of the corresponding univalent radical, e.g., a naphthyl group with two points of attachment is termed naphthylidene.

[0039] The term “cyano,” as used herein, refers to CN.

[0040] The term “cycloalkyl,” as used herein, refers to a saturated or unsaturated cyclic, bicyclic, or bridged bicyclic hydrocarbon group of 3-16 carbons, or 3-8 carbons, referred to herein as “(Cs-Csjcycloalkyl,” derived from a cycloalkane. Exemplary cycloalkyl groups include, but are not limited to, cyclohexanes, cyclohexenes, cyclopentanes, and cyclopentenes. Cycloalkyl groups may be substituted with alkoxy, aryloxy, alkyl, alkenyl, alkynyl, amide, amino, aryl, arylalkyl, carbamate, carboxy, cyano, cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclyl, hydroxyl, ketone, nitro, phosphate, sulfide, sulfinyl, sulfonyl, sulfonic acid, sulfonamide, and thioketone. Cycloalkyl groups can be fused to other cycloalkyl (saturated or partially unsaturated), aryl, or heterocyclyl groups, to form a bicycle, tetracycle, etc. The term “cycloalkyl” also includes bridged and spiro-fused cyclic structures which may or may not contain heteroatoms.

[0041] The term “heteroatom” means one or more of oxygen, sulfur, nitrogen, phosphorus,or silicon (including, any oxidized form of nitrogen, sulfur, phosphorus, or silicon; the quatemized form of any basic nitrogen or; a substituted nitrogen of a heterocyclic ring, for example N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) or NR+(as in N-substituted pyrrolidinyl)).

[0042] The term “hallucinogen,” as used herein, refers to a substance that can produce an altered state of consciousness characterized by major alterations in thought, mood, and perception.

[0043] The terms “halo” or “halogen,” as used herein, refer to -F, -Cl, -Br, and / or -I.

[0044] The term “haloalkyl,” as used herein, means an alkyl group substituted with one or more halogens. Examples of haloalkyl groups include, but are not limited to, trifluoromethyl, difluoromethyl, pentafluoroethyl, trichloromethyl, etc.The terms “heteroaryl” and “heteroar-”, used alone or as part of a larger moiety, e.g., “heteroaralkyl”, or “heteroaralkoxy”, refer to monocyclic or bicyclic ring groups having 5 to 10 ring atoms (e.g., 5- to 6-membered monocyclic heteroaryl or 9- to 10-membered bicyclic heteroaryl); having 6, 10, or 14 ^-electrons shared in a cyclic array; and having, in addition to carbon atoms, from one to five heteroatoms. Heteroaryl groups include, without limitation, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl, pteridinyl, imidazo[l,2-a]pyrimidinyl, imidazo[l,2-a]pyridyl, imidazo[4,5-b]pyridyl, imidazo[4,5-c]pyridyl, pyrrolopyridyl, pyrrolopyrazinyl, thienopyrimidinyl, tri azol opyridyl, and benzoisoxazolyl. The terms “heteroaryl” and “heteroar-”, as used herein, also include groups in which a heteroaromatic ring is fused to one or more aryl, cycloaliphatic, or heterocyclyl rings, where the radical or point of attachment is on the heteroaromatic ring (i.e., a bicyclic heteroaryl ring having 1 to 3 heteroatoms). Nonlimiting examples include indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzotri azolyl, benzothiazolyl, benzothiadiazolyl, benzoxazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H-quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, pyrido[2,3-b]-l,4-oxazin-3(4H)-one, 4H-thieno[3,2-b]pyrrole, and benzoisoxazolyl. The term “heteroaryl” may be used interchangeably with the terms “heteroaryl ring”, “heteroaryl group”, or “heteroaromatic”, any of which terms include rings that are optionally substituted. Exemplary monocyclic and

[0045] The term “heterocyclyl” or “heterocyclic” group, as used herein, refers to a ring structure having from 3 to 12 atoms, for example 5 to 10 atoms or 4 to 8 atoms, wherein one or more atoms are selected from the group consisting of N, O, and S wherein the ring N atom may be oxidized to N-O, and the ring S atom may be oxidized to SO or SO2, the remainder of the ring atoms being carbon. The heterocyclyl can be completely saturated or contain one or more units of unsaturation, but is not aromatic, and has a single point of attachment to the rest of the molecule. The heterocyclyl may be a monocyclic, a bicyclic, a spirocyclic, or a bridged ring system. The heterocyclyl is independently optionally substituted on a ring nitrogen atom with alkyl, aralkyl, alkylcarbonyl, or on sulfur with lower alkyl. Examples of heterocyclic groups include, without limitation, epoxy, azetidinyl, aziridinyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, pyrrolidinonyl, piperidinyl, piperazinyl, imidazolidinyl, imidazopyridinyl, thiazolidinyl, dithianyl, trithianyl, dioxolanyl, oxazolidinyl, oxazolidinonyl, decahydroquinolinyl, piperidonyl, 4-piperidinonyl, quinuclidinyl, thiomorpholinyl, morpholinyl, azepanyl, oxazepanyl, azabicyclohexanyls, azabicycloheptanyl, azabicyclooctanyls, azabicyclononanyls (e.g., octahydroindolizinyl), azaspiroheptanyls, dihydro-lH,3H,5H-oxazolo[3,4-c]oxazolyl, tetrahydro- 1'H, 3 'H- spiro[cyclopropane-l,2'-pyrrolizine], hexahydro- IH-pyrrolizinyl, hexahydro-lH-pyrrolo[2, 1- c][l,4]oxazinyl, octahydroindolizinyl, oxaazaspirononanyls, oxaazaspirooctanyls, diazaspirononanyls, oxaazabiocycloheptanyls, hexahydropyrrolizinyl 4(lH)-oxide, tetrahydro- 2H-thiopyranyl 1 -oxide and tetrahydro-2H-thiopyranyl 1,1 -di oxide. Specifically excluded from the scope of this term are compounds having adjacent annular O and / or S atoms.

[0046] The term “heteroaliphatic” or “heteroaliphatic group”, as used herein, denotes an optionally substituted hydrocarbon moiety having, in addition to carbon atoms, from one to five heteroatoms, that may be straight-chain (i.e., unbranched), branched, or cyclic (“heterocyclic”) and may be completely saturated or may contain one or more units of unsaturation, but which is not aromatic. The term “heteroatom” refers to nitrogen, oxygen, or sulfur, and includes any oxidized form of nitrogen or sulfur, and any quaternized form of a basic nitrogen. The term “nitrogen” also includes a substituted nitrogen. Unless otherwisespecified, heteroaliphatic groups contain 1-10 carbon atoms wherein 1-3 carbon atoms are optionally and independently replaced with heteroatoms selected from oxygen, nitrogen, and sulfur. In some embodiments, heteroaliphatic groups contain 1-4 carbon atoms, wherein 1-2 carbon atoms are optionally and independently replaced with heteroatoms selected from oxygen, nitrogen, and sulfur. In some embodiments, heteroaliphatic groups contain 1-3 carbon atoms, wherein 1 carbon atom is optionally and independently replaced with a heteroatom selected from oxygen, nitrogen, and sulfur. Suitable heteroaliphatic groups include, but are not limited to, linear or branched, heteroalkyl, heteroalkenyl, and heteroalkynyl groups. For example, a 1- to 10-atom heteroaliphatic group includes the following exemplary groups: -O-CH3, -CH2-O-CH3,-O-CH2- CH2-O-CH2-CH2-O-CH3, and the like.

[0047] The terms “hydroxy” and “hydroxyl” as used herein refer to -OH.

[0048] The term “mental disorder,” as used herein, includes those disorders which may be diagnosed by a mental health professional as a psychological or psychiatric disorder, including those which may be diagnosed by reference to Diagnostic and Statistical Manual of Mental Disorders (DSM-5). In some embodiments, the mental disorder is a depressive condition, including unipolar and bipolar depressive conditions, such as but not limited to depression, depression from generalized anxiety, major depression, treatment resistant depression and postpartum depression.

[0049] The term “neuroplastogen,” as used herein, includes the classic psychedelics, such as psilocybin and LSD, and glutamatergic compounds, such as ketamine. Many known neuroplastogens are also psychedelics (e.g., compounds that induce hallucinations or compounds that ‘manifest the mind.’) Compounds of the present disclosure can be characterized as compounds that induce neuroplastogenic effects in a subject, yet are without hallucinogenic or psychedelic effects.

[0050] The term “partially unsaturated,” as used herein, refers to a ring moiety that includes at least one double or triple bond. The term “partially unsaturated” is intended to encompass rings having multiple sites of unsaturation but is not intended to include aryl or heteroaryl moieties, as herein defined.

[0051] The term “pharmaceutically acceptable composition,” as used herein, refers to a composition comprising at least one compound as disclosed herein formulated together with one or more pharmaceutically acceptable carriers.

[0052] The term “pharmaceutically acceptable excipient,” as used herein, refers to those substances that are well accepted by the industry and regulatory agencies such as those listed in monographs published in compendia such as USP-NF, Food Chemicals Codex, Code of Federal Regulations (CFR), FDA Inactive Ingredients Guide and in 21 CFR parts 182 and 184 that lists substances that are generally regarded as safe (GRAS) food ingredients.

[0053] The term “pharmaceutically acceptable salt,” as used herein, refers to salts of a compound, which salts are suitable for pharmaceutical use and are derived from a variety of organic and inorganic counter ions well known in the art. See Stahl and Wermuth, eds., “Handbook of Pharmaceutically Acceptable Salts,” (2002), Verlag Helvetica Chimica Acta, Zurich, Switzerland), for a discussion of pharmaceutical salts, their selection, preparation, and use.

[0054] Pharmaceutically acceptable salts include acid addition salts formed with inorganic acids or organic acids. Inorganic acids suitable for forming pharmaceutically acceptable acid addition salts include, by way of example and not limitation, hydrohalide acids (e.g., hydrochloric acid), sulfuric acid, and the like.

[0055] The term “psychedelic state,” as used herein, refers to an altered state of consciousness experienced by a person, which may include intensified sensory perception, perceptual distortion or hallucinations, and / or feelings of euphoria or despair. Psychedelic states have been described as resulting from psychedelic drugs such as DMT (dimethyltryptamine), LSD, mescaline or psilocybin. Other known psychedelic drugs include the 4-hydroxy analogs of N-Methyl-N-isopropyl-tryptamine (MiPT) and N, N-diisopropyltryptamine (DiPT).

[0056] The term “subject,” as used herein, refers to an animal. Typically, the animal is a mammal. A subject also refers to for example, primates (e.g., humans, male or female), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds, and the like. In certain embodiments, the subject is a primate. In some embodiments, the subject is a human.

[0057] The term “therapeutically effective amount,” as used herein, refers to an amount of a therapeutic agent (e.g., a compound of the present disclosure) that confers a therapeutic effect in a target patient population. The therapeutic effect may be objective (i.e., measurable by some test or marker) or subjective (i.e., subject gives an indication of or feels an effect). A “therapeutically effective amount” may be an amount effective to treat, ameliorate, or prevent a disease or condition, or to exhibit a detectable therapeutic or preventive effect, such as byameliorating symptoms associated with the disease, preventing or delaying the onset of the disease or condition, and / or also lessening the severity or frequency of symptoms of the disease or condition. It should be understood that a therapeutically effective amount may not necessarily be effective in every subject treated with that amount. A therapeutically effective amount may be administered in a dosing regimen that comprises multiple doses. For any particular therapeutic agent, a therapeutically effective amount (and / or an appropriate unit dose within an effective dosing regimen) may vary, for example, depending on route of administration, or use in combination with other pharmaceutical agents. Also, the specific therapeutically effective amount (and / or unit dose) for any particular subject or patient population may depend upon a variety of factors including the disorder being treated and the severity of the disorder; the activity of the specific therapeutic agent employed; the specific composition employed; the age, body weight, general health, sex and diet of the subject; the time of administration, route of administration, and / or rate of excretion or metabolism of the specific therapeutic agent employed; the duration of the treatment; and like factors as is well known in the medical arts.

[0058] The term “treat,” “treating,” or “treatment,” as used herein, refers to ameliorating the disease or disorder (i.e., slowing or arresting or reducing the development of the disease or at least one of the clinical symptoms thereof). In another embodiment “treat,” “treating,” or “treatment” refers to alleviating or ameliorating at least one physical parameter including those which may not be discernible by the patient. In yet another embodiment, “treat,” “treating,” or “treatment” refers to modulating the disease or disorder, either physically (e.g., through stabilization of a discernible symptom), physiologically, (e.g., through stabilization of a physical parameter), or both. In yet another embodiment, “treat,” “treating,” or “treatment” refers to reducing the risk of or delaying the onset or development or progression of the disease or disorder.

[0059] There term “in need of,” as used herein, refers to a subject for which a treatment would benefit biologically, medically or in quality of life.

[0060] Additionally, unless otherwise stated, structures described herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures except for the replacement of hydrogen by deuterium (2H) or tritium (3H), or the replacement of a carbon by a13C- or14C-carbon atom are within the scope of this disclosure. Such compounds may be useful as, for example, analytical tools, probes in biological assays, or therapeutic agents.

[0061] Unless otherwise indicated, variable groups of Formula I are presented in the same orientation, e.g., left to right, as is Formula I and subgenera thereof. The compounds of the disclosure may contain one or more chiral centers and / or double bonds and, therefore, exist as stereoisomers, such as geometric isomers, enantiomers or diastereomers. The term “stereoisomers” when used herein consist of all geometric isomers, enantiomers or diastereomers. These compounds may be designated by the symbols “R” or “S,” depending on the configuration of substituents around the stereogenic carbon atom. The present disclosure encompasses various stereoisomers of these compounds and mixtures thereof. Stereoisomers include enantiomers and diastereomers. Mixtures of enantiomers or diastereomers may be designated “(±)” in nomenclature, but the skilled artisan will recognize that a structure may denote a chiral center implicitly. In some embodiments, an enantiomer or stereoisomer may be provided substantially free of the corresponding enantiomer.

[0062] As described herein, compounds of the disclosure may, when specified, contain “optionally substituted” moieties. In general, the term “substituted,” whether preceded by the term “optionally” or not, means that one or more hydrogens of the designated moiety are replaced with a suitable substituent. “Substituted” applies to one or more hydrogens that areaddition, in a polycyclic ring system (any grouping of atoms that together form a cyclic structure), substituents may, unless otherwise indicated, replace a hydrogen on any individualsuitable substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at every position. Combinations of substituents envisioned by this disclosure are those that result in the formation of stable or chemically feasible compounds.

[0063] Suitable monovalent substituents on a substitutable carbon atom of an “optionally substituted” group are independently halogen; -(CH2)o-4R°; -(CH2)0-4ORO; -0(CH2)O-4R°; -0(CH2)O-4C(0)OR°; -0(CH2)O-40R°; -(CH2)O-4CH(OR°)2; -(CH2)O-4SR°; -(CH2)o-4Ph, which may be substituted with R°; -(CH2)o-40(CH2)o-iPh, which may be substituted with R°, -CH=CHPh, which may be substituted with R°; -(CH2)o-40(CH2)o-i-pyridyl which may be substituted with R°; -NO2; -CN; -N3; -(CH2)o-4N(R°)2; -(CH2)o-4N(R0)C(0)R°; -N(R°)C(S)R°; -(CH2)O-4N(R0)C(0)N(R°)2; -N(RO)C(S)N(R°)2; -(CH2)O-4N(R0)C(S)N(R°)2; -(CH2)O-4N(R0)C(0)OR°; -N(R°)N(R°)C(O)R°; -N(RO)N(RO)C(O)N(RO)2; -N(R°)N(R°)C(O)OR°; -(CH2)o-4C(0)R°; -C(S)R°; -(CH2)o-4C(0)OR°; -(CH2)o-4C(0)SR°; -(CH2)o-4C(0)OSi(R°)3; -(CH2)o-40C(0)R°; -OC(0)(CH2)o-4SR°; -SC(S)SR°; -(CH2)o-4SC(O)R°; -(CH2)O-4C(0)N(R°)2; -C(S)N(RO)2; -C(S)SR°; -SC(S)SR°; -(CH2)O-4OC(O)N(RO)2; -C(O)N(OR°)R°; -C(O)C(O)R°; -C(O)CH2C(O)RO; -C(NOR°)R°; -(CH2)O-4SSR°; -(CH2)O-4S(0)2R°; -(CH2)O-4S(0)20R°; -(CH2)O-40S(0)2R°; -S(O)2NRO; -(CH2)O-4S(O)RO; -N(RO)S(O)2N(R°)2; -N(RO)S(O)2R°; -N(OR°)R°; -C(NH)N(RO)2; -P(ORO)2; -P(O)(R°)2; -OP(O)(RO)2; -OP(O)(ORO)2; -SiR°3; -(Ci-4 straight or branched alkylene)O-N(R°)2; or -(Ci-4 straight or branched alkylene)C(O)O-N(R°)2, wherein each R° may be substituted as defined below and is independently hydrogen, C1-6 aliphatic, -CH2Ph, -0(CH2)o-iPh, -CH2-(5- to 6-membered heteroaryl ring), or a 5- to 6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or, notwithstanding the definition above, two independent occurrences of R°, taken together with their intervening atoms(s), form a 3- to 12-membered saturated, partially unsaturated, or aryl mono- or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, which may be substituted as defined below.

[0064] Suitable monovalent substituents on R° (or the ring formed by taking two independent occurrences of R° together with their intervening atoms), are independently halogen; -(CH2)o-2R*; -(haloR*), -(CH2)o-2OH; -(CH2)o-20R*; -(CH2)o-2CH(OR*)2; -O(haloR’); -CN; -N3; -(CH2)o-2C(0)R*; -(CH2)o-2C(0)OH; -(CH2)o-2C(0)OR*; -(CH2)o-2SR*; -(CH2)O-2SH; -(CH2)O-2NH2; -(CH2)O-2NHR*; -(CH2)O-2NR*2; -NO2, -SiR*3; -OSiR*3; -C(O)SR*; -(Ci-4 straight or branched alkylene)C(O)OR*, or -SSR* wherein each R* is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently selected from Ci-4 aliphatic, -CH2Ph, -0(CH2)o-iPh, or a 5- to 6-memebered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selectedfrom nitrogen, oxygen, and sulfur. Suitable divalent substituents on a saturated carbon atom of R° include =0 and =S.

[0065] Suitable divalent substituents on a saturated carbon atom of an “optionally substituted” group include the following: =0; =S; =NNR#2; =NNHC(0)R#2;=NNHC(0)0R#2; =NNHS(O)2R#2; =NR#; =N0R#; -O(C(R#2))2-3O-; or -S(C(R#2))2-3S-; wherein each independent occurrence of R#is selected from hydrogen, Ci-6 aliphatic which may be substituted as defined below, or an unsubstituted 5- to 6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. Suitable divalent substituents that are bound to vicinal substitutable carbons of an “optionally substituted” group include: -O(CR#2)2-3O-, wherein each independent occurrence of R#is selected from hydrogen, Ci-6 aliphatic which may be substituted as defined below, or an unsubstituted 5- to 6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0066] Suitable substituents on the aliphatic group of R#include halogen, -R*, -(haloR*), -OH, -OR’, -O(haloR’), -CN, -C(O)OH, -C(O)OR*, -NH2, -NHR*, -NR*2, or -NO2, wherein each R* is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently Ci-4 aliphatic, -CH2PI1, -0(CH2)o-iPh, or a 5- to 6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0067] Suitable substituents on a substitutable nitrogen of an “optionally substituted” group include -Rt, -NR^, -C(O)Rt, -C(O)ORt, -C(O)C(O)Rt, -C(O)CH2C(O)Rt, -S(O)2Rt, -S(O)2NRt2, -C(S)NR1'2, -C(NH)NR1'2, or -N(R1')S(O)2R^2; wherein each R1' is independently hydrogen, C1-6 aliphatic which may be substituted as defined below, unsubstituted -OPh, or an unsubstituted 5- to 6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or, notwithstanding the definition above, two independent occurrences or R1', taken together with their intervening atom(s) form an unsubstituted 3- to 12-membered saturated, partially unsaturated, or aryl mono- or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0068] Suitable substituents on the aliphatic group of RJ are independently halogen, -R*, -(haloR*), -OH, -OR’, -O(haloR’), -CN, -C(O)OH, -C(O)OR*, -NH2, -NHR*, -NR*2, or -NO2,wherein each R* is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently Ci-4 aliphatic, -CEEPh, -0(CH2)o-iPh, or a 5- to 6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0069] Those skilled in the art will appreciate that a bond designated as — in a small molecule structure, as used herein, refers to a bond that, in some embodiments, is a single (e.g., saturated) bond, and in some embodiments, is a double (e.g., unsaturated) bond. ForJHNf j Jexample the following structure: H is intended to encompass both Hand H

[0070] Some of the compounds may exist with different points of attachment of hydrogen, referred to as “tautomers.” For example, compounds including carbonyl -CH2C(O)- groups (keto forms) may undergo tautomerism to form hydroxyl -CH=C(OH)- groups (enol forms). Both keto and enol forms, individually as well as mixtures thereof, are also intended to be included where applicable.

[0071] The compounds, tautomers, solvates, or pharmaceutically acceptable salts of the disclosure may contain an asymmetric center and may thus exist as enantiomers. For example, where the compounds possess two or more asymmetric centers, they may additionally exist as diastereoisomers. Enantiomers and diastereoisomers fall within the broader class of stereoisomers. All such possible stereoisomers as substantially pure resolved enantiomers, racemic mixtures thereof, as well as mixtures of diastereoisomers are intended to be included in this disclosure. All stereoisomers of the compounds, tautomers, solvates, and pharmaceutically acceptable salts thereof are intended to be included. Unless specifically mentioned otherwise, reference to one isomer applies to any of the possible isomers.Whenever the isomeric composition is unspecified, all possible isomers are included.

[0072] Diastereomeric mixtures can be separated into their individual diastereoisomers on the basis of their physical chemical differences by methods well known to those skilled in the art, such as by chromatography and / or fractional crystallization. Enantiomers can be separated by converting the enantiomeric mixture into a diastereomeric mixture by reaction with an appropriate optically active compound (e.g., chiral auxiliary such as a chiral alcoholor Mosher's acid chloride), separating the diastereoisomers and converting (e.g., hydrolyzing) the individual diastereoisomers to the corresponding pure enantiomers. Enantiomers can also be separated by use of a chiral HPLC column.

[0073] “ Stereoisomer” or “optical isomer” means a stable isomer that has at least one chiral atom or restricted rotation giving rise to perpendicular dissymmetric planes (e.g., certain biphenyls, allenes, and spiro compounds) and can rotate plane-polarized light.Because asymmetric centers and other chemical structure exist in the compounds of the disclosure which may give rise to stereoisomerism, the disclosure contemplates stereoisomers and mixtures thereof. The compounds of the disclosure and their salts include asymmetric carbon atoms and may therefore exist as single stereoisomers, racemates, and as mixtures of enantiomers and diastereomers. Typically, such compounds will be prepared as a racemic mixture. If desired, however, such compounds can be prepared or isolated as pure stereoisomers, i.e., as individual enantiomers or diastereomers, or as stereoisomer-enriched mixtures. Individual stereoisomers of compounds are prepared by synthesis from optically active starting materials containing the desired chiral centers or by preparation of mixtures of enantiomeric products followed by separation or resolution, such as conversion to a mixture of diastereomers followed by separation or recrystallization, chromatographic techniques, use of chiral resolving agents, or direct separation of the enantiomers on chiral chromatographic columns. Starting compounds of particular stereochemistry are either commercially available or are made by the methods described below and resolved by techniques well-known in the art.

[0074] It is well-known in the art that the biological and pharmacological activity of a compound is sensitive to the stereochemistry of the compound. Thus, for example, enantiomers often exhibit strikingly different biological activity including differences in pharmacokinetic properties, including metabolism, protein binding, and the like, and pharmacological properties, including the type of activity displayed, the degree of activity, toxicity, and the like. Thus, one skilled in the art will appreciate that one enantiomer may be more active or may exhibit beneficial effects when enriched relative to the other enantiomer or when separated from the other enantiomer. Additionally, one skilled in the art would know how to separate, enrich, or selectively prepare the enantiomers of the compounds of this disclosure and the knowledge of the prior art.

[0075] Thus, although the racemic form of drug may be used, it is often less effective than administering an equal amount of enantiomerically pure drug; indeed, in some cases, oneenantiomer may be pharmacologically inactive and would merely serve as a simple diluent. For example, although ibuprofen had been previously administered as a racemate, it has been shown that only the S-isomer of ibuprofen is effective as an anti-inflammatory agent (in the case of ibuprofen, however, although the R-isomer is inactive, it is converted in vivo to the S-isomer, thus, the rapidity of action of the racemic form of the drug is less than that of the pure S-isomer). Furthermore, the pharmacological activities of enantiomers may have distinct biological activity. For example, S-penicillamine is a therapeutic agent for chronic arthritis, while R-penicillamine is toxic. Indeed, some purified enantiomers have advantages over the racemates, as it has been reported that purified individual isomers have faster transdermal penetration rates compared to the racemic mixture.

[0076] In some embodiments, the compound is a racemic mixture of (S)- and (R)-isomers. In other embodiments, provided herein is a mixture of compounds wherein individual compounds of the mixture exist predominately in an (S)- or (R)-isomeric configuration. For example, the compound mixture has an (S)-enantiomeric excess of greater than 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, 99.5%, or more. In other embodiments, the compound mixture has an (S)-enantiomeric excess of greater than 55% to 99.5%, greater than 60% to 99.5%, greater than 65% to 99.5%, greater than 70% to 99.5%, greater than 75% to 99.5%, greater than 80% to 99.5%, greater than 85% to 99.5%, greater than 90% to 99.5%, greater than 95% to 99.5%, greater than 96% to 99.5%, greater than 97% to 99.5%, greater than 98% to greater than 99.5%, greater than 99% to 99.5%, or more. In other embodiments, the compound mixture has an (R)-enantiomeric purity of greater than 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, 99.5% or more. In some other embodiments, the compound mixture has an (R)-enantiomeric excess of greater than 55% to 99.5%, greater than 60% to 99.5%, greater than 65% to 99.5%, greater than 70% to 99.5%, greater than 75% to 99.5%, greater than 80% to 99.5%, greater than 85% to 99.5%, greater than 90% to 99.5%, greater than 95% to 99.5%, greater than 96% to 99.5%, greater than 97% to 99.5%, greater than 98% to greater than 99.5%, greater than 99% to 99.5% or more.

[0077] Individual stereoisomers of compounds of the present disclosure can be prepared synthetically from commercially available starting materials that contain asymmetric or stereogenic / chiral centers, or by preparation of racemic mixtures followed by resolution methods well known to those of ordinary skill in the art. These methods of resolution are exemplified by: (1) attachment of a mixture of enantiomers to a chiral auxiliary, separation ofthe resulting mixture of diastereomers by recrystallization or chromatography and liberation of the optically pure product from the auxiliary; (2) salt formation employing an optically active resolving agent; or (3) direct separation of the mixture of optical enantiomers on chiral chromatographic columns. Stereoisomeric mixtures can also be resolved into their component stereoisomers by well-known methods, such as chiral-phase gas chromatography, chiral-phase high performance liquid chromatography, crystallizing the compound as a chiral salt complex, or crystallizing the compound in a chiral solvent. Stereoisomers can also be obtained from stereomerically-pure intermediates, reagents, and catalysts by well-known asymmetric synthetic methods.

[0078] Thus, if one enantiomer is pharmacologically more active, less toxic, or has a preferred disposition in the body than the other enantiomer, it would be therapeutically more beneficial to administer that enantiomer preferentially.2. Compounds

[0079] In one aspect of the present disclosure, a compound is provided, wherein the compound is represented by Formula I:or is a pharmaceutically acceptable salt thereof, wherein:Ring A is an optionally substituted group selected from saturated C3-C10 carbocyclyl, Ce-Cio aryl, 5-10 membered heterocyclyl, and 5-10 membered heteroaryl;Rais selected from halogen, hydroxyl, and C1-6 alkoxyl;q is an integer from 0 to 4;RNis hydrogen or optionally substituted C1-6 aliphatic;Rpis a lone electron pair or optionally substituted C1-6 aliphatic; andRcland Rc2are each independently hydrogen or C1-6 aliphatic;

[0080] In some embodiments of Formula I, q is 0. In some embodiments of Formula I, q is 1, 2, 3, or 4. In some embodiments of Formula I, q is 1. In some embodiments of Formula I, q is 2. In some embodiments of Formula I, q is 3. In some embodiments of Formula I, q is 4.

[0081] In some embodiments of Formula I, Rais selected from halogen, hydroxyl, and C1-6 alkoxyl.

[0082] In some embodiments of Formula I, Rais halogen. In some embodiments of Formula I, Rais halogen and q is 1, 2, 3, or 4. In some embodiments of Formula I, Rais halogen and q is 1, 2, or 3. In some embodiments of Formula I, Rais halogen and q is 1. In some embodiments of Formula I, Rais halogen and q is 2. In some embodiments of Formula 1, Rais halogen and q is 3. In some embodiments of Formula I, Rais halogen and q is 4.

[0083] In some embodiments of Formula I, Rais fluoro, chloro, bromo, or iodo and q is 1, 2, 3, or 4. In some embodiments of Formula I, Rais fluoro, chloro, bromo, or iodo and q is 1, 2, or 3. In some embodiments of Formula I, Rais fluoro, chloro, bromo, or iodo and q is 1. In some embodiments of Formula I, Rais fluoro, chloro, bromo, or iodo and q is 2. In some embodiments of Formula I, Rais fluoro, chloro, bromo, or iodo and q is 3. In some embodiments of Formula I, Rais fluoro, chloro, bromo, or iodo and q is 4.

[0084] In some embodiments of Formula I, Rais hydroxyl. In some embodiments of Formula I, Rais hydroxyl and q is 1, 2, 3, or 4. In some embodiments of Formula I, Rais hydroxyl and q is 1, 2, or 3. In some embodiments of Formula I, Rais hydroxyl and q is 1. In some embodiments of Formula I, Rais hydroxyl and q is 2. In some embodiments of Formula I, Rais hydroxyl and q is 3. In some embodiments of Formula I, Rais hydroxyl and q is 4.

[0085] In some embodiments of Formula I, Rais Ci-6 alkoxyl. In some embodiments of Formula I, Rais Ci-6 alkoxyl and q is 1, 2, 3, or 4. In some embodiments of Formula I, Rais Ci-6 alkoxyl and q is 1, 2, or 3. In some embodiments of Formula I, Rais Ci-6 alkoxyl and q is 1. In some embodiments of Formula I, Rais Ci-6 alkoxyl and q is 2. In some embodiments of Formula I, Rais Ci-6 alkoxyl and q is 3. In some embodiments of Formula I, Rais Ci-6 alkoxyl and q is 4.

[0086] In some embodiments of Formula I, Rais methoxy. In some embodiments of Formula I, Rais methoxy and q is 1, 2, 3, or 4. In some embodiments of Formula I, Rais methoxy and q is 1, 2, or 3. In some embodiments of Formula I, Rais methoxy and q is 1. In some embodiments of Formula I, Rais methoxy and q is 2. In some embodiments of Formula I, Rais methoxy and q is 3. In some embodiments of Formula I, Rais methoxy and q is 4.

[0087] In some embodiments of Formula I, Rais bonded to the benzene ring of the 1H-indole such that compound is represented by Formula la:or is a pharmaceutically acceptable salt thereof, wherein Ra, q, RN, Rp, Rcl, Rc2, and A are defined as above for Formula I.

[0088] In some embodiments of Formula la, q is 1 and Rais at the 4-position of the 1H-indole. In some embodiments of Formula la, q is 1 and Rais at the 5-position of the 1H-indole. In some embodiments of Formula la, q is 1 and Rais at the 6-position of the 1H-indole.

[0089] In some embodiments of Formula la, q is 1 and Rais a halogen at the 4-position of the IH-indole. In some embodiments of Formula la, q is 1 and Rais a fluoro, chloro, bromo, or iodo at the 4-position of the IH-indole.

[0090] In some embodiments of Formula la, q is 1 and Rais a hydroxyl at the 4-position of the IH-indole. In some embodiments of Formula la, q is 1 and Rais a Ci-6 alkoxyl at the 4-position of the IH-indole. In some embodiments of Formula la, q is 1 and Rais a methoxy at the 4-position of the IH-indole.

[0091] In some embodiments of Formula la, q is 1 and Rais a halogen at the 5-position of the IH-indole. In some embodiments of Formula la, q is 1 and Rais a fluoro, chloro, bromo, or iodo at the 5-position of the IH-indole. In some embodiments of Formula la, q is 1 and Rais a hydroxyl at the 5-position of the IH-indole. In some embodiments of Formula la, q is 1 and Rais a Ci-6 alkoxyl at the 5-position of the IH-indole. In some embodiments of Formula la, q is 1 and Rais a methoxy at the 5-position of the IH-indole.

[0092] In some embodiments of Formula la, q is 1 and Rais a halogen at the 6-position of the IH-indole. In some embodiments of Formula la, q is 1 and Rais a fluoro, chloro, bromo, or iodo at the 6-position of the IH-indole. In some embodiments of Formula la, q is 1 and Rais a hydroxyl at the 6-position of the IH-indole. In some embodiments of Formula la, q is 1 and Rais a Ci-6 alkoxyl at the 6-position of the IH-indole. In some embodiments of Formula la, q is 1 and Rais a methoxy at the 6-position of the IH-indole.

[0093] In some embodiments of Formula la, q is 1 and Rais a halogen at the 7-position of the IH-indole. In some embodiments of Formula la, q is 1 and Rais a fluoro, chloro, bromo, or iodo at the 7-position of the IH-indole. In some embodiments of Formula la, q is 1 and Rais a hydroxyl at the 7-position of the IH-indole. In some embodiments of Formula la, q is 1 and Rais a Ci-6 alkoxyl at the 7-position of the IH-indole. In some embodiments of Formula la, q is 1 and Rais a methoxy at the 7-position of the IH-indole.

[0094] In some embodiments of Formula I, q is 1 and Rais at the 2-position of the IH-indole, i.e., on the pyrrole. In some embodiments of Formula I, q is 1 and Rais a halogen at the 2-position of the IH-indole. In some embodiments of Formula I, q is 1 and Rais a fluoro, chloro, bromo, or iodo at the 2-position of the IH-indole. In some embodiments of Formula I, q is 1 and Rais a hydroxyl at the 2-position of the IH-indole. In some embodiments of Formula I, q is 1 and Rais a Ci-6 alkoxyl at the 2-position of the IH-indole. In some embodiments of Formula I, q is 1 and Rais a methoxy at the 2-position of the IH-indole.

[0095] In some embodiments of Formula I, RNis hydrogen. In some embodiments of Formula I, RNis optionally substituted Ci-6 aliphatic. In some embodiments of Formula I, RNis optionally substituted Ci-4 aliphatic. In some embodiments of Formula I, RNis optionally substituted C1-3 aliphatic.

[0096] In some embodiments of Formula I, RNis an optionally substituted group selected from C1-6 alkyl, C1-6 alkenyl, Ci-ealkynyl, and C1-6 alkylaryl.

[0097] In some embodiments of Formula I, RNis optionally substituted C1-6 alkyl. In some embodiments of Formula I, RNis optionally substituted linear C1-6 alkyl. In some embodiments of Formula I, RNis optionally substituted branched C1-6 alkyl. In some embodiments of Formula I, RNis optionally substituted C1-6 cycloalkyl. In some embodiments of Formula I, RNis methyl, ethyl, or isopropyl. In some embodiments of Formula I, RNis C1-6 hydroxyalkyl, e.g., -(CH2)nOH, where n is 1, 2, 3, 4, 5, or 6. In some embodiments of Formula I, RNis hydroxy ethyl.

[0098] In some embodiments of Formula I, RNis optionally substituted C1-6 alkenyl. In some embodiments of Formula I, RNis optionally substituted C1-3 alkenyl. In some embodiments of Formula I, RNis optionally substituted linear C1-6 alkenyl. In some embodiments of Formula I, RNis optionally substituted linear C1-3 alkenyl. In some embodiments of Formula I, RNis optionally substituted branched C1-6 alkenyl. In some embodiments of Formula I, RNis optionally substituted branched C1-3 alkenyl. In some embodiments of Formula I, RNis optionally substituted C1-6 cycloalkenyl. In some embodiments of Formula I, RNis -CH=CH2; -(CH2)nCH=CH2 wherein n is 1, 2, 3, or 4; or -CH=CH-(CH2)nCH3 wherein n is 1, 2, or 3.

[0099] In some embodiments of Formula I, RNis optionally substituted Ci-6 alkylaryl. In some embodiments of Formula I, RNis optionally substituted -(CH2)n-Ar, wherein n is 1-6 and Ar is an optionally substituted benzene, e.g., a benzene substituted with one or more halogen or Ci-6 alkyoxyl.

[0100] In some embodiments of Formula I, Rpis a lone pair of electrons. In some embodiments of Formula I, Rpis a lone pair of electrons and RNis optionally substituted Ci-6 aliphatic. In some embodiments of Formula I, Rpis a lone pair of electrons and RNis optionally substituted Ci-4 aliphatic. In some embodiments of Formula I, Rpis a lone pair of electrons and RNis optionally substituted C1-3 aliphatic.

[0101] In some embodiments of Formula I, Rpis a lone pair of electrons and RNis optionally substituted C1-6 alkyl, C1-6 alkenyl, Ci-ealkynyl, or C1-6 alkylaryl.

[0102] In some embodiments of Formula I, Rpis a lone pair of electrons and RNis optionally substituted C1-6 alkyl. In some embodiments of Formula I, Rpis a lone pair of electrons and RNis optionally substituted linear C1-6 alkyl. In some embodiments of Formula 1, Rpis a lone pair of electrons and RNis optionally substituted branched C1-6 alkyl. In some embodiments of Formula I, Rpis a lone pair of electrons and RNis optionally substituted C1-6 cycloalkyl. In some embodiments of Formula I, Rpis a lone pair of electrons and RNis methyl, ethyl, or isopropyl. In some embodiments of Formula I, Rpis a lone pair of electrons and RNis C1-6 alkylhydroxyl, e.g., -(CH2)nOH, where n is 1, 2, 3, 4, 5, or 6.

[0103] In some embodiments of Formula I, Rpis a lone pair of electrons and RNis optionally substituted C1-6 alkenyl. In some embodiments of Formula I, Rpis a lone pair of electrons and RNis optionally substituted C1-3 alkenyl. In some embodiments of Formula I, Rpis a lone pair of electrons and RNis optionally substituted linear C1-6 alkenyl. In some embodiments of Formula I, Rpis a lone pair of electrons and RNis optionally substituted linear C1-3 alkenyl. In some embodiments of Formula I, Rpis a lone pair of electrons and RNis optionally substituted branched C1-6 alkenyl. In some embodiments of Formula I, Rpis a lone pair of electrons and RNis optionally substituted branched C1-3 alkenyl. In some embodiments of Formula I, Rpis a lone pair of electrons and RNis optionally substituted C1-6 cycloalkenyl. In some embodiments of Formula I, Rpis a lone pair of electrons and RNis -CH=CH2; -(CH2)nCH=CH2 wherein n is 1, 2, 3, or 4; or -CH=CH-(CH2)nCH3 wherein n is 1, 2, or 3.

[0104] In some embodiments of Formula I, Rpis optionally substituted C 1-6 aliphatic. Insome embodiments of Formula I, Rpis optionally substituted Ci-4 aliphatic. In some embodiments of Formula I, Rpis optionally substituted C1-3 aliphatic. In some embodiments of Formula I, Rpis optionally substituted C1-6 alkyl. In some embodiments of Formula I, Rpis optionally substituted linear C1-6 alkyl. In some embodiments of Formula I, Rpis optionally substituted branched C1-6 alkyl. In some embodiments of Formula I, Rpis optionally substituted C1-6 cycloalkyl. In some embodiments of Formula I, Rpis methyl.

[0105] In some embodiments of Formula I, RNis optionally substituted C1-6 aliphatic and Rpis optionally substituted C1-6 aliphatic. In some embodiments of Formula I, RNis optionally substituted Ci-4 aliphatic and Rpis optionally substituted Ci-4 aliphatic. In some embodiments of Formula I, RNis optionally substituted C1-3 aliphatic and Rpis optionally substituted C1-3 aliphatic. In each instance, RNand Rpcan be the same or different.

[0106] In some embodiments of Formula I, RNis optionally substituted C1-6 alkyl and Rpis optionally substituted C1-6 alkyl. In some embodiments of Formula I, RNis optionally substituted linear C1-6 alkyl and Rpis optionally substituted linear C1-6 alkyl. In some embodiments of Formula I, RNis optionally substituted branched C1-6 alkyl and Rpis optionally substituted branched C1-6 alkyl. In some embodiments of Formula I, RNis optionally substituted C1-6 cycloalkyl andRpis optionally substituted C1-6 cycloalkyl. In each instance, RNand Rpcan be the same or different. In some embodiments of Formula I, RNis methyl and Rpis methyl.

[0107] In some embodiments of Formula I, Rclis hydrogen. In some embodiments of Formula I, Rclis optionally substituted C1-6 aliphatic. In some embodiments of Formula I, Rclis an optionally substituted group selected from C1-6 alkyl, C1-6 alkenyl, and Ci-ealkynyl. In some embodiments of Formula I, Rclis optionally substituted C1-6 alkyl. In some embodiments of Formula I, Rclis optionally substituted linear C1-6 alkyl. In some embodiments of Formula I, Rclis optionally substituted branched C1-6 alkyl. In some embodiments of Formula I, Rclis optionally substituted C1-6 cycloalkyl. In some embodiments of Formula I, Rclis methyl.

[0108] In some embodiments of Formula I, Rc2is hydrogen. In some embodiments of Formula I, Rc2is optionally substituted C1-6 aliphatic. In some embodiments of Formula I, Rc2is an optionally substituted group selected from C1-6 alkyl, C1-6 alkenyl, and Ci-ealkynyl. In some embodiments of Formula I, Rc2is optionally substituted C1-6 alkyl. In some embodiments of Formula I, Rc2is optionally substituted linear C1-6 alkyl. In someembodiments of Formula I, Rc2is optionally substituted branched Ci-6 alkyl. In some embodiments of Formula I, Rc2is optionally substituted Ci-6 cycloalkyl. In some embodiments of Formula I, Rc2is methyl.

[0109] In some embodiments of Formula I, Rclis hydrogen and Rc2is hydrogen. In some embodiments of Formula I, Rclis optionally substituted Ci-6 aliphatic and Rc2is hydrogen. In some embodiments of Formula I, Rclis an optionally substituted group selected from Ci-6 alkyl, Ci-6 alkenyl, and Ci-6 alkynyl, and Rc2is hydrogen. In some embodiments of Formula I, Rclis optionally substituted Ci-6 alkyl and Rc2is hydrogen. In some embodiments of Formula I, Rclis optionally substituted linear Ci-6 alkyl and Rc2is hydrogen. In some embodiments of Formula I, Rclis optionally substituted branched Ci-6 alkyl and Rc2is hydrogen 1. In some embodiments of Formula I, Rclis optionally substituted Ci-6 cycloalkyl and Rc2is hydrogen. In some embodiments of Formula I, Rclis methyl and Rc2is hydrogen.

[0110] In some embodiments of Formula I, Ring A is an optionally substituted group selected from saturated C3-C10 carbocyclyl, Ce-Cio aryl, 5-10 membered heterocyclyl, and 5-10 membered heteroaryl; Rais selected from halogen, hydroxyl, and C1-6 alkoxyl; q is an integer from 0 to 4; RNis hydrogen or optionally substituted C1-6 aliphatic; Rpis a lone electron pair or optionally substituted C1-6 aliphatic; and one of Rclor Rc2is C1-6 alkyl and the other is hydrogen.

[0111] In some embodiments of Formula I, Ring A is an optionally substituted group selected from saturated C3-C10 carbocyclyl, Ce-Cio aryl, 5-10 membered heterocyclyl, and 5-10 membered heteroaryl; Rais selected from halogen, hydroxyl, and C1-6 alkoxyl; q is an integer from 0 to 4; RNis hydrogen or optionally substituted C1-6 aliphatic; Rpis a lone electron pair or optionally substituted C1-6 aliphatic; and one of Rclor Rc2is methyl and the other is hydrogen.

[0112] In some embodiments of Formula I, Ring A is an optionally substituted group selected from Ce-Cio aryl and 5-10 membered heteroaryl; Rais selected from halogen, hydroxyl, and C1-6 alkoxyl; q is an integer from 0 to 4; RNis C1-6 aliphatic; Rpis a lone electron pair; and one of Rclor Rc2is C1-6 alkyl and the other is hydrogen.

[0113] In some embodiments of Formula I, Ring A is an optionally substituted group selected from Ce-Cio aryl and 5-10 membered heteroaryl; Rais selected from halogen, hydroxyl, and C1-6 alkoxyl; q is an integer from 0 to 4; RNis C1-6 alkyl; Rpis a lone electron pair; and one of Rclor Rc2is C1-6 alkyl and the other is hydrogen.

[0114] In some embodiments of Formula I, Ring A is an optionally substituted group selected from Ce-Cio aryl and 5-10 membered heteroaryl; Rais selected from halogen, hydroxyl, and Ci-6 alkoxyl; q is an integer from 0 to 4; RNis methyl; Rpis a lone electron pair; and one of Rclor Rc2is methyl and the other is hydrogen.

[0115] In some embodiments of Formula I, Ring A is an optionally substituted group selected from saturated C3-C10 carbocyclyl, Ce-Cio aryl, 5-10 membered heterocyclyl, and 5-10 membered heteroaryl; Rais selected from halogen, hydroxyl, and C1-6 alkoxyl; q is 1; RNis hydrogen or optionally substituted C1-6 aliphatic; Rpis a lone electron pair or optionally substituted C1-6 aliphatic; and one of Rclor Rc2is methyl and the other is hydrogen.

[0116] In some embodiments of Formula I, Ring A is an optionally substituted group selected from Ce-Cio aryl and 5-10 membered heteroaryl; Rais selected from halogen, hydroxyl, and C1-6 alkoxyl; q is 1; RNis C1-6 aliphatic; Rpis a lone electron pair; and one of Rclor Rc2is C1-6alkyl and the other is hydrogen.

[0117] In some embodiments of Formula I, Ring A is an optionally substituted group selected from Ce-Cio aryl and 5-10 membered heteroaryl; Rais selected from halogen, hydroxyl, and C1-6 alkoxyl; q is 1; RNis C1-6 alkyl; Rpis a lone electron pair; and one of Rclor Rc2is C1-6 alkyl and the other is hydrogen.

[0118] In some embodiments of Formula I, Ring A is an optionally substituted group selected from Ce-Cio aryl and 5-10 membered heteroaryl; Rais selected from halogen, hydroxyl, and C1-6 alkoxyl; q is an integer from 0 to 4; RNis methyl; Rpis a lone electron pair; and one of Rclor Rc2is methyl and the other is hydrogen.

[0119] In some embodiments of Formula I, Ring A is an optionally substituted saturated C3-C10 carbocyclyl, e.g., optionally substituted C3 carbocyclyl, optionally substituted C4 carbocyclyl, optionally substituted Cs carbocyclyl, optionally substituted Ce carbocyclyl, optionally substituted C7 carbocyclyl, optionally substituted Cs carbocyclyl, optionally substituted C9 carbocyclyl, and optionally substituted C10 carbocyclyl. In some embodiments of Formula I, Ring A is an optionally substituted cyclohexane.

[0120] In some embodiments of Formula I, Ring A is an optionally substituted Ce-Cio aryl, e.g., optionally substituted Ce aryl, optionally substituted C7 aryl, optionally substituted Cs aryl, optionally substituted C9 aryl, and optionally substituted C10 aryl. In some embodiments of Formula I, Ring A is an optionally substituted benzene.

[0121] In some embodiments of Formula I, Ring A is an optionally substituted 5-10membered heterocyclyl, e.g., optionally substituted 5-membered heterocyclyl, optionally substituted 6-membered heterocyclyl, optionally substituted 7-membered heterocyclyl, optionally substituted 8-membered heterocyclyl, optionally substituted 9-membered heterocyclyl, and optionally substituted 10-membered heterocyclyl.

[0122] In some embodiments of Formula I, Ring A is an optionally substituted 5-10 membered heteroaryl, e.g., optionally substituted 5-membered heteroaryl, optionally substituted 6-membered heteroaryl, optionally substituted 7-membered heteroaryl, optionally substituted 8-membered heteroaryl, optionally substituted 9-membered heteroaryl, and optionally substituted 10-membered heteroaryl.

[0123] In some embodiments of Formula I, Ring A is an optionally substituted group selected from furan, pyrrole, pyridine, thiophene, thiazole, isothiazole, oxazole, isoxazole, benzofuran, indole, indazole, benzothiophene, benzimidazole, benzoxazole, benzothiazole, benzo[ ][l,3]dioxole, 2,2-dimethylbenzo[ ][l,3]dioxole, and 2,3-dihydrobenzo[Z>] [ 1,4]di oxine.

[0124] In some embodiments of Formula I, Ring A is an optionally substituted furan. In some embodiments of Formula I, Ring A is an optionally substituted pyrrole. In some embodiments of Formula I, Ring A is an optionally substituted pyridine. In some embodiments of Formula I, Ring A is an optionally substituted thiophene. In some embodiments of Formula I, Ring A is an optionally substituted thiazole. In some embodiments of Formula I, Ring A is an optionally substituted isothiazole. In some embodiments of Formula I, Ring A is an optionally substituted oxazole. In some embodiments of Formula I, Ring A is an optionally substituted isoxazole. In some embodiments of Formula I, Ring A is an optionally substituted benzofuran. In some embodiments of Formula I, Ring A is an optionally substituted indole. In some embodiments of Formula I, Ring A is an optionally substituted indazole. In some embodiments of Formula I, Ring A is an optionally substituted benzothiophene. In some embodiments of Formula I, Ring A is an optionally substituted benzimidazole, benzoxazole. In some embodiments of Formula I, Ring A is an optionally substituted benzothiazole, benzo[ ][l,3]dioxole. In some embodiments of Formula I, Ring A is an optionally substituted 2,2-dimethylbenzo[ ][l,3]dioxole. In some embodiments of Formula I, Ring A is an optionally substituted 2,3-dihydrobenzo[Z>][l,4]dioxine.

[0125] In some embodiments of Formula I, Ring A is selected from:of Formula I, Ring A isIn some embodiments of Formula I, Ring A isIn some embodiments of Formula I, Ring A issome embodiments of Formula I, Ring A is. In some embodiments of FormulaIn some embodiments of Formula I, Ring A is

[0127] In some embodiments of Formula I, Ring A is selected from:

[0128] In some embodiments of Formula I, RingA is. In some embodimentsof Formula I, Ring A isIn some embodiments of Formula I, Ring A isIn some embodiments of Formula I, Ring A isembodiments of Formula I, Ring A is. In some embodiments of FormulaIn some embodiments of Formula I, Ring A issome embodiments of Formula I, Ring A is. In some embodiments of Formula II J CH3I, Ring A is '. In some embodiments of Formula I, Ring A is(Rf)m

[0129] In some embodiments of Formula I, Ring A is selected from:Neach Rfis independently selected from hydrogen, hydroxyl, Ci-6 aliphatic, and Ci-6 heteroaliphatic; and m is an integer from 0 to 4. In some embodiments, Rfis Ci-6 alkyl, e.g., linear or branched Ci-6 alkyl. In some embodiments, Rfis Ci-6 alkylhydroxyl. In some embodiments, Rfis Ci-6 alkylalkoxy. In some embodiments, Rfis Ci-6 aminoalkyl.t(RAi

[0130] In some embodiments of Formula I, Ring A is N In some embodimentsof Formula I, RingA is In some embodiments of Formula I, RingA issome embodiments of Formula I, RingA is In some embodiments of Formula I,Ring Ais In some embodiments of Formula I, RingA isembodiments of Formula I, RingA is In some embodiments of Formula I, Ring AIn some embodiments of Formula I, RingA is. In some embodimentsof Formula I, RingA is In some embodiments of Formula I, RingA issome embodiments of Formula I, RingA is In these embodiments, Rfand m are defined as above.

[0131] In some embodiments of Formula I, Ring A is selected fromFormula I, Ring A isIn some embodiments of Formula I, Ring A issome embodiments of Formula I, Ring A isIn some embodiments of Formula I, Ring A isIn some embodiments of Formula I, Ring A is. In some embodiments of Formula I, Ring A isIn some embodiments of Formula I, Ring AIn some embodiments of Formula I, Ring A isembodiments of Formula I, Ring A isIn some embodiments of Formula I,Ring Ais In some embodiments of Formula I, RingA isIL z- CH3embodiments of Formula I, Ring A is0. In some embodiments of Formula I,Ring A is In some embodiments of Formula I, Ring A isIn some embodiments of Formula I, Ring A is. In some CH3embodiments of Formula I, Ring Ais CH3

[0133] In some embodiments, a compound of the present disclosure is represented by Formula II:or is a pharmaceutically acceptable salt thereof, wherein:R8, R9, R10, R11, and R12are each independently selected from hydrogen, halogen, cyano, hydroxyl, -S(O)2R’, -S(O)2NR’R”, -C(O)NHR’, -C(O)OR’, and an optionally substituted group selected from C1-6 aliphatic and C1-6 heteroaliphatic; wherein R’ and R” are each independently C1-6 aliphatic; ortwo adjacent groups from among R8, R9, R10, R11, and R12, together with the atoms to which they are bound, form a 5-membered heterocycle; andRa, q, RN, RC1, and Rc2are defined as for Formula I.

[0134] In some embodiments of Formula II, q is 0. In some embodiments of Formula II, q is 0; RNis C1-6 aliphatic; Rclis C1-6 aliphatic; and Rc2is H. In some embodiments of Formula II, q is 0; RNis C1-6 aliphatic; Rclis H; and Rc2is H.

[0135] In some embodiments of Formula II, q is 0; RNis C1-6 alkyl; Rclis C1-6 alkyl; and Rc2is H. In some embodiments of Formula II, q is 0; RNis C1-6 alkyl; Rclis H; and Rc2is H.

[0136] In some embodiments of Formula II, q is 0; RNis methyl; Rclis methyl; and Rc2isH. In some embodiments of Formula II, q is 0; RNis methyl; Rclis H; and Rc2is H.

[0137] In some embodiments of Formula II, q is 0; RNis ethyl; Rclis H; and Rc2is H. In some embodiments of Formula II, q is 0; RNis iso-propyl; Rclis H; and Rc2is H.

[0138] In some embodiments of Formula II, q is 0; RNis Ci-6 hydroxyalkyl; Rclis H; and Rc2is H. In some embodiments of Formula II, q is 0; RNis hydroxy ethyl; Rclis H; and Rc2is H.

[0139] In some embodiments of Formula II, q is 0; RNis optionally substituted Ci-6 alkylaryl; Rclis H; and Rc2is H. In some embodiments of Formula II, q is 0; RNis optionally substituted -(CH2)n-Ar, wherein n is an integer from 1 to 6 and Ar is an optionally substituted benzene; Rclis H; and Rc2is H. In some embodiments of Formula II, q is 0; RNis -(CH2)n-Ar, wherein n is i and Ar is a benzene substituted with one or more halogen or Ci-6 alkyoxyl (e.g., methoxy); Rclis H; and Rc2is H.

[0140] In some embodiments of Formula II, q is 1; Rais selected from halogen, hydroxyl, and Ci-6 alkoxyl; RNis Ci-6 aliphatic; Rclis Ci-6 aliphatic; and Rc2is H. In some embodiments of Formula II, q is 1; Rais selected from halogen, hydroxyl, and Ci-6 alkoxyl; RNis Ci-6 alkyl; Rclis Ci-6 alkyl; and Rc2is H. In some embodiments of Formula II, q is 1; Rais selected from halogen, hydroxyl, and Ci-6 alkoxyl; RNis methyl; Rclis methyl; and Rc2is H.

[0141] In some embodiments of Formula II, q is 1; Rais Ci-6 alkoxyl (e.g., methoxy); RNis Ci-6 aliphatic; Rclis H; and Rc2is H. In some embodiments of Formula II, q is 1; Rais Ci-6 alkoxyl (e.g., methoxy); RNis Ci-6 alkyl; Rclis H; and Rc2is H. In some embodiments of Formula II, q is 1; Rais Ci-6 alkoxyl (e.g., methoxy); RNis methyl; Rclis H; and Rc2is H. In some embodiments of Formula II, q is 1; Rais Ci-6 alkoxyl (e.g., methoxy); RNis ethyl; Rclis H; and Rc2is H. In some embodiments of Formula II, q is 1; Rais Ci-6 alkoxyl (e.g., methoxy); RNis iso-propyl; Rclis H; and Rc2is H.

[0142] In some embodiments of Formula II, q is 1; Rais halogen; RNis Ci-6 aliphatic; Rclis H; and Rc2is H. In some embodiments of Formula II, q is 1; Rais bromo or fluoro; RNis Ci-6 alkyl; Rclis H; and Rc2is H. In some embodiments of Formula II, q is 1; Rais bromo or fluoro; RNis methyl; Rclis H; and Rc2is H.

[0143] In some embodiments of Formula II, q is 1; Rais hydroxyl; RNis Ci-6 aliphatic; Rclis H; and Rc2is H. In some embodiments of Formula II, q is 1; Rais hydroxyl; RNis Ci-6 alkyl; Rclis H; and Rc2is H. In some embodiments of Formula II, q is 1; Rais hydroxyl; RNis methyl; Rclis H; and Rc2is H.

[0144] In some embodiments of Formula II, q is 1; Rais Ci-6 alkoxyl (e.g., methoxy); RNis Ci-6 alkenyl; Rclis H; and Rc2is H. In some embodiments of Formula II, q is 1; Rais Ci-6 alkoxyl (e.g., methoxy); RNis -(CH)2C=CH2; Rclis H; and Rc2is H. In some embodiments of Formula II, q is 1; Rais methoxy; RNis -(CH)2C=CH2; Rclis H; and Rc2is H.

[0145] In some embodiments of Formula II, R8, R9, R10, R11, and R12are each independently selected from hydrogen, hydroxyl, and Ci-6 alkoxyl; or R9and R10, together with the atoms to which they are bound, form a 5 -membered heterocycle.

[0146] In some embodiments of Formula II, R8is selected from halogen, cyano, hydroxyl, Ci-6 alkyl, and Ci-6 alkoxyl. In some embodiments of Formula II, R8is selected from halogen, cyano, hydroxyl, Ci-6 alkyl, and Ci-6 alkoxyl; and at least one of R9, R10, R11, and R12is hydrogen. In some embodiments of Formula II, R8is selected from halogen, cyano, hydroxyl, Ci-6 alkyl, and Ci-6 alkoxyl; and all of R9, R10, R11, and R12are hydrogen.

[0147] In some embodiments of Formula II, R8is halogen and at least one of R9, R10, R11, and R12is hydrogen. In some embodiments of Formula II, R8is cyano and at least one of R9, R10, R11, and R12is hydrogen. In some embodiments of Formula II, R8is hydroxyl and at least one of R9, R10, R11, and R12is hydrogen. In some embodiments of Formula II, R8is Ci-6 alkyl and at least one of R9, R10, R11, and R12is hydrogen. In some embodiments of Formula II, R8is Ci-6 alkoxyl and at least one of R9, R10, R11, and R12is hydrogen.

[0148] In some embodiments of Formula II, R8is halogen and all of R9, R10, R11, and R12are hydrogen. In some embodiments of Formula II, R8is cyano and all of R9, R10, R11, and R12are hydrogen. In some embodiments of Formula II, R8is hydroxyl and all of R9, R10, R11, and R12are hydrogen. In some embodiments of Formula II, R8is Ci-6 alkyl and all of R9, R10, R11, and R12are hydrogen. In some embodiments of Formula II, R8is Ci-6 alkoxyl and all of R9, R10, R11, and R12are hydrogen.

[0149] In some embodiments of Formula II, R8is selected from bromo, cyano, hydroxyl, methyl, and methoxy. In some embodiments of Formula II, R8is selected from bromo, cyano, hydroxyl, methyl, and methoxy; and at least one of R9, R10, R11, and R12is hydrogen. In some embodiments of Formula II, R8is selected from bromo, cyano, hydroxyl, methyl, and methoxy; and all of R9, R10, R11, and R12are hydrogen.

[0150] In some embodiments of Formula II, R8is bromo and at least one of R9, R10, R11, and R12is hydrogen. In some embodiments of Formula II, R8is cyano and at least one of R9, R10, R11, and R12is hydrogen. In some embodiments of Formula II, R8is hydroxyl and atleast one of R9, R10, R11, and R12is hydrogen. In some embodiments of Formula II, R8is methyl and at least one of R9, R10, R11, and R12is hydrogen. In some embodiments of Formula II, R8is methoxy and at least one of R9, R10, R11, and R12is hydrogen.

[0151] In some embodiments of Formula II, R8is bromo and all of R9, R10, R11, and R12are hydrogen. In some embodiments of Formula II, R8is cyano and all of R9, R10, R11, and R12are hydrogen. In some embodiments of Formula II, R8is hydroxyl and all of R9, R10, R11, and R12are hydrogen. In some embodiments of Formula II, R8is methyl and all of R9, R10, R11, and R12are hydrogen. In some embodiments of Formula II, R8is methoxy and all of R9, R10, R11, and R12are hydrogen.

[0152] In some embodiments of Formula II, R9is selected from halogen, C(O)OR’, -C(O)NHR’, -S(O)2R’, -S(O)2NR’R”, CI-6 hydroxyalkyl, Ci-6 alkoxyl, Ci-6 alkyl, and cyano, wherein R’ and R” are each independently Ci-6 alkyl. In some embodiments of Formula II, R9is selected from C(O)OR’, -C(O)NHR’, -S(O)2R’, -S(O)2NR’R”, Ci-6 hydroxyalkyl, Ci-6 alkoxyl, Ci-6 alkyl, and cyano, wherein R’ and R” are each independently Ci-6 alkyl; and at least one of R8, R10, R11, and R12is hydrogen. In some embodiments of Formula II, R9is selected from C(O)OR’, -C(O)NHR’, -S(O)2R’, -S(O)2NR’R”, Ci-6 hydroxyalkyl, Ci-6 alkoxyl, Ci-6 alkyl, and cyano, wherein R’ and R” are each independently Ci-6 alkyl; and all of R8, R10, R11, and R12are hydrogen.

[0153] In some embodiments of Formula II, R9is halogen (e.g., bromo) and at least one of R8, R10, R11, and R12is hydrogen. In some embodiments of Formula II, R9is C(O)OR’, wherein R’ is Ci-6 alkyl (e.g., methyl); and at least one of R8, R10, R11, and R12is hydrogen. In some embodiments of Formula II, R9is -C(O)NHR’, wherein R’ is Ci-6 alkyl (e.g., methyl); and at least one of R8, R10, R11, and R12is hydrogen. In some embodiments of Formula II, R9is -S(O)2R’, wherein R’ is Ci-6 alkyl (e.g., methyl); and at least one of R8, R10, R11, and R12is hydrogen. In some embodiments of Formula II, R9is -S(O)2NR’R”, wherein R’ and R” are Ci-6 alkyl (e.g., methyl); and at least one of R8, R10, R11, and R12is hydrogen. In some embodiments of Formula II, R9is Ci-6 hydroxyalkyl (e.g., hydroxymethyl); and at least one of R8, R10, R11, and R12is hydrogen. In some embodiments of Formula II, R9is Ci-6 alkoxyl (e.g., methoxy and ethoxy); and at least one of R8, R10, R11, and R12is hydrogen. In some embodiments of Formula II, R9is Ci-6 alkyl (e.g., methyl); and at least one of R8, R10, R11, and R12is hydrogen. In some embodiments of Formula II, R9is cyano; and at least one of R8, R10, R11, and R12is hydrogen.

[0154] In some embodiments of Formula II, R9is halogen and all of R8, R10, R11, and R12are hydrogen. In some embodiments of Formula II, R9is C(O)OR’, wherein R’ is Ci-6 alkyl (e.g., methyl); and all of R8, R10, R11, and R12are hydrogen. In some embodiments of Formula II, R9is -C(O)NHR’, wherein R’ is Ci-6 alkyl (e.g., methyl); and all of R8, R10, R11, and R12are hydrogen. In some embodiments of Formula II, R9is -S(O)2R’, wherein R’ is Ci-6 alkyl (e.g., methyl); and all of R8, R10, R11, and R12are hydrogen. In some embodiments of Formula II, R9is -S(O)2NR’R”, wherein R’ and R” are Ci-6 alkyl (e.g., methyl); and all of R8, R10, R11, and R12are hydrogen. In some embodiments of Formula II, R9is Ci-6 hydroxyalkyl (e.g., hydroxymethyl); and all of R8, R10, R11, and R12are hydrogen. In some embodiments of Formula II, R9is Ci-6 alkoxyl (e.g., methoxy and ethoxy); and all of R8, R10, R11, and R12are hydrogen. In some embodiments of Formula II, R9is Ci-6 alkyl (e.g., methyl); and all of R8, R10, R11, and R12are hydrogen. In some embodiments of Formula II, R9is cyano; and all of R8, R10, R11, and R12are hydrogen.

[0155] In some embodiments of Formula II, R9and R10, together with the atoms to which they are bound, form an optionally substituted 5-membered heterocycle, e.g., comprising 1 or 2 heteroatoms selected from O and N. In some embodiments of Formula II, R9and R10, together with the atoms to which they are bound, form an optionally substituted 5-membered heterocycle, e.g., comprising 1 or 2 heteroatoms selected from O and N, and at least one of R8, R11, and R12is hydrogen. In some embodiments of Formula II, R9and R10, together with the atoms to which they are bound, form an optionally substituted 5-membered heterocycle, e.g., comprising 1 or 2 heteroatoms selected from O and N, and all of R8, R11, and R12are hydrogen. In some embodiments of Formula II, the substitution on the 5-membered heterocycle includes Ci-6 alkyl (e.g., methyl).

[0156] In some embodiments of Formula II, R9and R10, together with the atoms to which they are bound, form an optionally substituted heterocycle selected from dioxolane, oxazole, furan, dihydrofuran, and dioxane. In some embodiments of Formula II, R9and R10, together with the atoms to which they are bound, form an optionally substituted heterocycle selected from di oxolane, oxazole, furan, dihydrofuran, and dioxane; and at least one of R8, R11, and R12is hydrogen. In some embodiments of Formula II, R9and R10, together with the atoms to which they are bound, form an optionally substituted heterocycle selected from dioxolane, oxazole, furan, dihydrofuran, and dioxane; and all of R8, R11, and R12are hydrogen. In some embodiments of Formula II, the substitution on the 5-membered heterocycle includes Ci-6 alkyl (e.g., methyl).

[0157] In some embodiments of Formula II, R10is selected from Ci-6 alkyl and Ci-6 alkoxyl. In some embodiments of Formula II, R10is selected from Ci-6 alkyl and Ci-6 alkoxyl, and at least one of R8, R9, R11, and R12is hydrogen. In some embodiments of Formula II, R10is selected from Ci-6 alkyl and Ci-6 alkoxyl, and all of R8, R9, R11, and R12are hydrogen.

[0158] In some embodiments of Formula II, R10is selected from methyl and methoxy. In some embodiments of Formula II, R10is selected from methyl and methoxy, and at least one of R8, R9, R11, and R12is hydrogen. In some embodiments of Formula II, R10is selected from methyl and methoxy, and all of R8, R9, R11, and R12are hydrogen.

[0159] In some embodiments of Formula I or Formula II, the compound is represented by Formula lib:or is a pharmaceutically acceptable salt thereof, wherein:one of Rclor Rc2is selected from Ci-6 alkyl, Ci-6 alkenyl, and Ci-6 alkynyl, and the other is hydrogen; andone of R8or R9is Ci-6 alkoxyl and the other is hydrogen.

[0160] In some embodiments of Formula lib, one of Rclor Rc2is Ci-6 alkyl and the other is hydrogen. In some embodiments of Formula lib, one of Rclor Rc2is methyl and the other is hydrogen.

[0161] In some embodiments of Formula lib, one of Rclor Rc2is Ci-6 alkyl and the other is hydrogen, R8is Ci-6 alkoxyl, and R9is hydrogen. In some embodiments of Formula lib, one of Rclor Rc2is C1-3 alkyl and the other is hydrogen, R8is Ci-6 alkoxyl, and R9is hydrogen. In some embodiments of Formula lib, one of Rclor Rc2is methyl and the other is hydrogen, R8is Ci-6 alkoxyl, and R9is hydrogen.

[0162] In some embodiments of Formula lib, one of Rclor Rc2is Ci-6 alkyl and the other is hydrogen, R8is C1-3 alkoxyl, and R9is hydrogen. In some embodiments of Formula lib, one of Rclor Rc2is Ci-6 alkyl and the other is hydrogen, R8is methoxy, and R9is hydrogen. In some embodiments of Formula lib, one of Rclor Rc2is methyl and the other is hydrogen, R8is methoxy, and R9is hydrogen.

[0163] In some embodiments of Formula lib, one of Rclor Rc2is Ci-6 alkyl and the other ishydrogen, R8is hydrogen, and R9is Ci-6 alkoxyl. In some embodiments of Formula lib, one of Rclor Rc2is C1-3 alkyl and the other is hydrogen, R8is hydrogen, and R9is C1-6 alkoxyl. In some embodiments of Formula lib, one of Rclor Rc2is methyl and the other is hydrogen, R8is hydrogen, and R9is C1-6 alkoxyl.

[0164] In some embodiments of Formula lib, one of Rclor Rc2is C1-6 alkyl and the other is hydrogen, R8is hydrogen, and R9is C1-3 alkoxyl. In some embodiments of Formula lib, one of Rclor Rc2is C1-6 alkyl and the other is hydrogen, R8is hydrogen, and R9is methoxy. In some embodiments of Formula lib, one of Rclor Rc2is methyl and the other is hydrogen, R8is hydrogen, and R9is methoxy.

[0165] In some embodiments of Formula I or Formula II, the compound is represented by Formula lie:or is a pharmaceutically acceptable salt thereof, wherein:X and Y are each selected from O and CH2;Rcland Rc2are each independently hydrogen or C1-6 aliphatic; andRxand RYare each selected from hydrogen, and C1-6 aliphatic.

[0166] In some embodiments of Formula lie, Rcland Rc2are both hydrogen. In some embodiments of Formula lie, Rclis hydrogen and Rc2is C1-6 aliphatic. In some embodiments of Formula lie, Rclis hydrogen and Rc2is C1-6 alkyl. In some embodiments of Formula lie, Rclis hydrogen and Rc2is C1-6 alkyl.

[0167] In some embodiments of Formula lie, Rclis C1-6 aliphatic and Rc2is hydrogen. In some embodiments of Formula lie, Rclis C1-6 alkyl and Rc2is hydrogen. In some embodiments of Formula lie, Rclis hydrogen and Rc2is methyl.

[0168] In some embodiments of Formula lie, Rcland Rc2are both C1-6 aliphatic. In some embodiments of Formula lie, Rcland Rc2are both C1-6 alkyl. In some embodiments of Formula lie, Rcland Rc2are both methyl.

[0169] In some embodiments of Formula lie, X and Y are both O. In some embodiments of Formula lie, Rcland Rc2are both hydrogen, and X and Y are both O. In some embodiments of Formula lie, Rclis hydrogen, Rc2is C1-6 aliphatic, and X and Y are both O. In some embodiments of Formula lie, Rclis hydrogen, Rc2is C1-6 alkyl, and X and Y are bothO. In some embodiments of Formula lie, Rclis Ci-6 aliphatic, Rc2is hydrogen, and X and Y are both O. In some embodiments of Formula lie, Rclis Ci-6 alkyl, Rc2is hydrogen, and X and Y are both O. In some embodiments of Formula lie, Rclis methyl, Rc2is hydrogen, and X and Y are both O. In the above embodiments of Formula lie, Rxand RYare each selected from hydrogen, and Ci-6 aliphatic (e.g., methyl).

[0170] In some embodiments of Formula lie, X and Y are CH2. In some embodiments of Formula lie, Rcland Rc2are both hydrogen, and X and Y are both CH2. In some embodiments of Formula lie, Rclis hydrogen, Rc2is C1-6 aliphatic, and X and Y are both CH2. In some embodiments of Formula lie, Rclis hydrogen, Rc2is C1-6 alkyl, and X and Y are both CH2. In some embodiments of Formula lie, Rclis C1-6 aliphatic, Rc2is hydrogen, and X and Y are both CH2. In some embodiments of Formula lie, Rclis C1-6 alkyl, Rc2is hydrogen, and X and Y are both CH2. In some embodiments of Formula lie, Rclis methyl, Rc2is hydrogen, and X and Y are both CH2. In the above embodiments of Formula lie, Rxand RYare each selected from hydrogen, and C1-6 aliphatic (e.g., methyl).

[0171] In some embodiments of Formula lie, X is O and Y is CH2. In some embodiments of Formula lie, Rcland Rc2are both hydrogen, X is O, and Y is CH2. In some embodiments of Formula lie, Rclis hydrogen, Rc2is C1-6 aliphatic, X is O, and Y is CH2. In some embodiments of Formula lie, Rclis hydrogen, Rc2is C1-6 alkyl, X is O, and Y is CH2. In some embodiments of Formula lie, Rclis C1-6 aliphatic, Rc2is hydrogen, X is O, and Y is CH2. In some embodiments of Formula lie, Rclis C1-6 alkyl, Rc2is hydrogen, X is O, and Y is CH2. In some embodiments of Formula lie, Rclis methyl, Rc2is hydrogen, X is O, and Y is CH2. In the above embodiments of Formula lie, Rxand RYare each selected from hydrogen, and C1-6 aliphatic (e.g., methyl).

[0172] In some embodiments of Formula lie, X is CH2 and Y is O. In some embodiments of Formula lie, Rcland Rc2are both hydrogen, X is CH2, and Y is O. In some embodiments of Formula lie, Rclis hydrogen, Rc2is C1-6 aliphatic, X is CH2, and Y is O. In some embodiments of Formula lie, Rclis hydrogen, Rc2is C1-6 alkyl, X is CH2, and Y is O. In some embodiments of Formula lie, Rclis C1-6 aliphatic, Rc2is hydrogen, X is CH2, and Y is O. In some embodiments of Formula lie, Rclis C1-6 alkyl, Rc2is hydrogen, X is CH2, and Y is O. In some embodiments of Formula lie, Rclis methyl, Rc2is hydrogen, X is CH2, and Y is O. In the above embodiments of Formula lie, Rxand RYare each selected from hydrogen, and C1-6 aliphatic (e.g., methyl).

[0173] In some embodiments of Formula I or Formula II, the compound is represented by Formula lid:or is a pharmaceutically acceptable salt thereof, wherein:Y is selected from CH and N; andRYis selected from hydrogen and Ci-6 aliphatic.

[0174] In some embodiments of Formula lid, Y is CH. In some embodiments of Formula lid, Y is CH and RYis hydrogen. In some embodiments of Formula lid, Y is CH and RYis Ci-6 aliphatic. In some embodiments of Formula lid, Y is CH and RYis Ci-6 alkyl. In some embodiments of Formula lid, Y is CH and RYis methyl.

[0175] In some embodiments of Formula lid, Y is N. In some embodiments of Formula lid, Y is N and RYis hydrogen. In some embodiments of Formula lid, Y is N and RYis Ci-6 aliphatic. In some embodiments of Formula lid, Y is N and RYis Ci-6 alkyl. In some embodiments of Formula lid, Y is N and RYis methyl.

[0176] In some embodiments of Formula I or Formula II, the compound is represented by Formula lie:or is a pharmaceutically acceptable salt thereof, wherein RNis Ci-6 aliphatic.

[0177] In some embodiments of Formula lie, RNis C1-3 aliphatic. In some embodiments of Formula lie, RNis C1-3 alkyl. In some embodiments of Formula lie, RNis methyl.

[0178] In some embodiments of Formula I, the compound is represented by Formula III:or is a pharmaceutically acceptable salt thereof, wherein:Rais Ci-6 alkoxyl, andRcyis C1-6 alkoxyl.

[0179] In some embodiments of Formula III, Rais C1-3 alkoxyl and Rcyis C1-3 alkoxyl. In some embodiments of Formula III, both Raand Rcyare methoxy.

[0180] In some embodiments, a compound of the present disclosure is represented in Table 2 or is a pharmaceutically acceptable salt thereof.Table 2Compound StructureA\ CH31-1HN-^ CH3(XGH31-2 n cH30HN-^ dH3OGI-I31-3 C AA^ CHJ A3JHN"7C IH3T CLfx1-4 nA T?HN"7CH3CH3A1-5 A / N A n AHN—7CH3CH3A\ CH3A1-6 C AAHN7A^A Al" CH3CH31-7HN-^ CH31-8A J £HN-7CH31-9 A / A^^AX, XAAHN-^ CH3Compound Structure1-10QA kHN'-JCH3Br1-11 co Qr-A ZE HN-JCH3Br / o £ O _> / \ / y\-= <>1-12 4 h o—Qy-A ) co I7\ / ZEHN- £ )Q O- CH3Broz- 1-13H \ J coN-^ CH3x / Y * °1-14 QA A,HN-^ CH31-15 QA AHN-J CH31-16HN- Br1-17CH31-18HNJ°'CH3n 'H3A1-19 Aj -" "^ -^'0HNACompound StructureZCH31-20HN— ' k CH3OH1-21 'H3A XjA"HN— ' CH31-22O zHN— / A3CH3H3%zo- 1-23 / Iw\C N. JL^C H30 V 7—\ HN—A7 / > o= / IOw\ o I w 1-241-25Qy^A^XX0'CH3HN-JA? H3O1-26 ^yvw v*’HN-^1-27 Qy^N^CX^CHa HN-JO^CH31-28 QY^AHN-7NNCompound StructureCH31-29QX A HN-^1-30 Q HN-AJA.CH3 / X CH3r=\1-31 N ~^UyN~CH3 HX CH3CH A^CH3 f IH3\ T1-32A / / HN-7(O 9H3rv / 0H1-330HIA / A CH3r-A O-CH31-340HN-71-35 Q^:oCX> HN-^1-36HN-^1-37 Q HN-^^ X Q1-381-39i.:'V "Compound Structure1-40HN-^1-41HlA' 0^1-42Qy-AHN-7CH3A.1-43 r\HN—7( / A 9H3 (ps1-44HN''J1-45HN-^1-46O HN-r7A CH3AA CH31-47AJ HN—7?H3r°v1-48 L 1 ACH3HN— 'C\ f z>1-49HN-^ CH3CH3K-S, CH31-50 \ A N A A~NHNHN"'1-51HN-^Compound Structure'H3O1-52 L _ N^ / A J HN—7CH3ZX CH3X1-53QHN—11-54 f H \xN J—7'H31-55 A?H3rv.HN J— ■01-56 Q HN-^7^ V 0 'CH31-57HN-J1-58 HN-^1-59 Q HN"r / jzrj OH1-60HN—7OH H3C^CH3^1-61 X HN- - X OH1-62X HN-^ " X >".Compound StructureZCH31-63HN-^H3C\^CH3p\X1-64 m o HN-^ZCH3\ ZE0 7 o1 H3C CH^1-65 V f\ / XT& ~z / coI. N. A> A0-CH300 / co ZE / ) o1 / ZE / HN-^\ J I co / co > TY / ^ A L / A1^ / w< o1-66 AAA °^'HN-^co 1-67 -1-68 Qv-IJXHN-^1-691-70QP -0-" HN-^1-71Compound Structure1-72HN-^1-73 o ZE_CH30J\ ZE7 O1-74cp / co > O{ )-XX / HN-^0, CH3\ co / _, CH3r\^z ZE==1-75?HN-^^CH30JHsC^CH^k1-76^>y^N^AA0XH3HN-^, CH3, CH30?HsC^CH^k1-77^>y^N^AA0XH3HN-^OH1-78 Qr^Xlo HN-^ CH31-79 fx 'H3AHN-\ CH3F CH31-80HN-A CH3BrCompound Structure1-81CH3f^Y%H31-82 L N. / V Jk^xCH3CO ZE HN'-J00-1-83 A 'H3rr°xCH3X / HN-J oz- 1-84 QyXtWA V HN-J1-85 Q HN-^^ A CH301-86 QyXAHISA CH31-87HN-^ CH31-88 A 'H3A°XCH3HN-^ CH31-89HN-^ CH31-90 QyJ^jOQHN-^ CH31-91 CX^^ o>HNA CH3coI / \ / / \ O=# 4 °) ( co\ I f)00- \ coI \1 / coJx / T'T°

[0181] In some embodiments, the compound of the present disclosure is not a compound of Table 1.Table 1Compound Structure1-200CH3CH3H3C— (N— X O-CH31-201\=zHHsCO-CH3Compound StructureO, CH31-202 A r Y°'CH3HN-^co ZEI o co co co ZE ZE / / \ o O / / \ / / \ / \--= <= <>>= u ° \ / \ / / 1-203 #\ # N 4O O4\ ZE> O\ Y Z > co\ / —ZE / ~ / / co CO > ) O o Oz- I / ZE / 1 co / \ 1 J / CO co1-204 Y JL r Y Yx L L^^ °AJZ oY^-^TW11-2051-206UK^? NH^3HrAi0, CH31-207HN-^ CLCH31-208 CK^N^)AO, CH3HNJ°'CH3CH31-209 CK^N^JUHNJ°'CH3Compound Structure1-210 QyJtO HN"'1-211HN— ' CH H3C.3Il1-212HN— ' CH31-213HaCi AHN—JCH3 / CH31-214HN- ' ' CH31-215HN-^ CH31-216 Q^ X LOH HN-''1-217 Q HN-^' XJO.1-218 Qv^“X l„ HN-^Compound Structure1-219 QrX -a,HN-^ CH3co co 1-220 T I \ / o o 07 £ O O -> ^ 5 O=o £ h —r1-221oz I / - oz > co- H z y HV QZ- 0- / . I J 07x / Y / * °X.^zo- 1-222? (o o <- C / 1\ / xw— A noy vOC oH?3o < / o 1-223 T GJ O HNH M ' 1-224,y^OCH3f \\ iH3\ T1-225 X / X. A A. / / 7 OCH3HN— ' OCH31-226Compound Structure1-227co co X co ZE o o ZE \ t5 co co* >\ o o O= oo \ \ / ZE X X \ z 0- -= <>1-228 > Z O G o——\ co \ oX # N ° °> > I co \ co co co \>o ozz > ZE / co I / X / ZE X co / / X / oz oz---- oz- oz- V r°c / 41■ <>1-229 \ ZJ ZE=- I00 / X / x / X^^ 1 co / CJ / x^o w k CJX1x 1C / 11o z- 1-23081-2311-232Q^ ZV ”'' HN-^ CXCuH31-2331-234

[0182] In some embodiments, the compound of the present disclosure is not a compound of Formula Ila:R11wherein:Rais hydrogen or methoxy;q is 1;RNis selected from methyl, 2-propenyl, cz.s-2-butenyl, trazz -2-butenyl, 2- methyl-2-propenyl and z-propyl;R12is hydrogen or methoxy; andR11is hydroxyl, halogen, methoxy, ethynyl, ethyl, or methyl substituted with hydroxyl.

[0183] In some embodiments, the compound of the present disclosure is a hydrogen chloride salt of 1-3:

[0184] In some embodiments, the compound of the present disclosure is a hydrogenchloride salt of 1-6:CH3oCH3

[0185] In many embodiments, 1-6 or the HC1 salt thereof is amorphous. In some embodiments, 1-6 or the HC1 salt thereof is crystalline.3. Pharmaceutical Compositions

[0186] In one aspect of the present disclosure, a pharmaceutical composition is provided comprising a compound described herein formulated together with a pharmaceutically acceptable excipient. In some embodiments, the pharmaceutical composition is formulated for oral, rectal, topical, buccal or parenteral (e.g., subcutaneous, intramuscular, intradermal, or intravenous) administration. The most suitable form of administration in any given case will depend on the degree and severity of the condition being treated and on the nature of the particular compound being used.

[0187] Pharmaceutical compositions provided by the present disclosure include compositions wherein the compound is contained in a therapeutically effective amount. The actual amount effective for a particular application will depend, inter alia, on the condition being treated. For example, when administered in methods to treat neurological and / or psychiatric diseases or disorders, such compositions will contain an amount of active ingredient effective to achieve the desired result, e.g., treatment of generalized anxiety disorder, depression including postpartum depression, adjustment disorder, addiction, anxiety, post-traumatic stress disorder (PTSD), a neurodegenerative disease, suicidal ideation, bipolar disorder, schizophrenia, a mood disorder, a psychotic disorder, a personality disorder, an eating disorder, a sleep disorder, an impulse control disorder, a gambling disorder, a movement disorder, a memory disorder, a substance use disorder (e.g., alcohol dependence, nicotine dependence, opioid dependence, and cocaine dependence), a dissociative disorder, a cognitive disorder, a developmental disorder, a factitious disorder, obsessive compulsive disorder, a body dysmorphic disorder, chronic pain, and chronic fatigue. in a subject.

[0188] Therapeutically effective amounts for use in a subject (e.g., a human) may be determined from animal models. For example, a dose for humans can be formulated to achieve a concentration that has been found to be effective in animals. The dosage in humanscan be adjusted by monitoring physiological effects and / or subjective mental effects and adjusting the dosage upwards or downwards.

[0189] Dosages may be varied depending upon the requirements of the subject and the compound being employed. The dose administered to a subject, in the context of the present disclosure, should be sufficient to effect a beneficial therapeutic response in the subject over time. The size of the dose also will be determined by the existence, nature, and extent of any adverse side effects.4. Methods of Treatment

[0190] In another aspect, the present disclosure provides a method of administering a compound of the present disclosure, the method comprising orally, rectally, topically, buccally or parenterally (e.g., subcutaneously, intramuscularly, intradermally, or intravenously) administering to a subject a compound or pharmaceutical composition described herein.

[0191] In another aspect, the present disclosure provides a method of modulating the activity of 5-HT2A receptors in a subject, the method comprising administering to the subject a compound or pharmaceutical composition described herein.

[0192] In another aspect, the present disclosure provides a method of treating a disease or disorder in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound or pharmaceutical composition described herein. In certain embodiments, the compound or pharmaceutical composition is administered orally, rectally, topically, buccally, or parenterally (e.g., subcutaneously, intramuscularly, intradermally, or intravenously.

[0193] In another aspect, the compounds of the present disclosure may be used in the manufacture of a medicament for the treatment of a disease mediated by 5-HT2A receptor activity in a subject, e.g., a neurological and / or psychiatric disease or disorder.

[0194] In some embodiments, the disease or disorder is a neurological and / or psychiatric disease or disorder. In some embodiments, the disease or disorder is a neurological disease or disorder. In some embodiments, the disease or disorder is a psychiatric disease or disorder.

[0195] In some embodiments, the disease or disorder is selected from generalized anxiety disorder, depression including postpartum depression, adjustment disorder, addiction, anxiety, post-traumatic stress disorder (PTSD), a neurodegenerative disease, suicidalideation, bipolar disorder, schizophrenia, a mood disorder, a psychotic disorder, a personality disorder, an eating disorder, a sleep disorder, an impulse control disorder, a gambling disorder, a movement disorder, a memory disorder, a substance use disorder (e.g., alcohol dependence, nicotine dependence, opioid dependence, and cocaine dependence), a dissociative disorder, a cognitive disorder, a developmental disorder, a factitious disorder, obsessive compulsive disorder, a body dysmorphic disorder, chronic pain, and chronic fatigue.

[0196] In some embodiments, the disease or disorder is selected from treatment-resistant depression, suicidal ideation, major depressive disorder, bipolar disorder, schizophrenia, and substance use disorder.

[0197] In some embodiments, the disease or disorder is mediated by the loss of synaptic connectivity, plasticity, or a combination thereof.ENUMERATED EMBODIMENTSEmbodiment 1. A compound, wherein the compound is represented by Formula (I) or is a pharmaceutically acceptable salt thereof:wherein R8, R9, R10, R11, and R12is each independently hydrogen, halogen, alkoxy, cyano, hydroxyl, or an optionally substituted group selected from Ci-6 aliphatic, Ci-ehaloalkyl, Ci-6 cycloalkyl, and Ci-6 heterocyclic;Rcland Rc2is each independently hydrogen or an optionally substituted group selected from Ci-6 aliphatic, Ci-ehaloalkyl, Ci-6 cycloalkyl, and Ci-6 heterocyclic; andRNis hydrogen or an optionally substituted group selected from Ci-6 aliphatic, Ci-6 cycloalkyl, Ci-ehaloalkyl, and Ci-6 heterocyclic.Embodiment 2. The compound according to Embodiment 1, wherein the compound is represented by Formula (la) or a is a pharmaceutically acceptable salt thereof:Embodiment 3. The compound of Embodiment 1, wherein the compound is selected from:or a pharmaceutically acceptable salt thereof.Embodiment 4. The compound according to Embodiment 3, wherein the compound is a hydrogen chloride salt ofEmbodiment 5. The compound according to Embodiment 3, wherein the compound is a hydrogen chloride salt ofEmbodiment 6. A pharmaceutical composition comprising a compound according to any one of Embodiments 1-5, and a pharmaceutically acceptable carrier, pharmaceutically acceptable vehicle, or pharmaceutically acceptable excipient.Embodiment 7. A method of treating a neurological and / or psychiatric disease or disorder in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound according to any one of Embodiments 1-5 or a pharmaceutical composition according to Embodiment 6.Embodiment 8. The method of Embodiment 7, wherein the disease or disorder is a neurological disease or disorder.Embodiment 9. The method of Embodiment 7, wherein the disease or disorder is a psychiatric disease or disorder.Embodiment 10. The method of Embodiment 7, wherein the disease or disorder is aneurological and psychiatric disease or disorder.Embodiment 11. The method according to Embodiment 7, wherein the disease or disorder is selected from depression, addiction, anxiety, post-traumatic stress disorder, a neurodegenerative disease, suicidal ideation, bipolar disorder, schizophrenia, a mood disorder, a psychotic disorder, a personality disorder, an eating disorder, a sleep disorder, an impulse control disorder, a movement disorder, a memory disorder, a substance use disorder, a dissociative disorder, a cognitive disorder, a developmental disorder, and a factitious disorder.Embodiment 12. The method according to Embodiment 7, wherein the disease or disorder is selected from treatment-resistant depression, suicidal ideation, major depressive disorder, bipolar disorder, schizophrenia, and substance use disorder.Embodiment 13. The method of Embodiment 7, wherein the neurological and / or psychiatric disease or disorder is mediated by the loss of synaptic connectivity, plasticity, or a combination thereof.Embodiment 14. A method of modulating the activity of 5-HT2A receptors in a subject, the method comprising administering a compound according to any one of Embodiments 1-5 or a pharmaceutical composition according to Embodiment 6.EXAMPLES

[0198] The examples and preparations provided below further illustrate and exemplify the compounds as disclosed herein and methods of preparing such compounds. It is to be understood that the scope of the present disclosure is not limited in any way by the scope of the following examples and preparations.

[0199] The compounds of the disclosure can be made by one or more of the illustrative schemes herein.

[0200] Unless specified to the contrary, the reactions described herein take place at atmospheric pressure, generally within a temperature range from -10°C to 200°C. Further, except as otherwise specified, reaction times and conditions are intended to be approximate, e.g., taking place at atmospheric pressure within a temperature range of -10°C to 200°C over a period that can be, for example, 1 to 24 hours; reactions left to run overnight in some embodiments can average a period of 16 hours.

[0201] Isolation and purification of the chemical entities and intermediates described herein can be effected, if desired, by any suitable separation or purification procedure such as, for example, filtration, extraction, crystallization, column chromatography, thin-layer chromatography or thick-layer chromatography, or a combination of these procedures. See, e.g., Carey et al. Advanced Organic Chemistry, 3rdEd., 1990 New York: Plenum Press;Mundy et al., Name Reaction and Reagents in Organic Synthesis, 2ndEd., 2005 Hoboken, NJ: J. Wiley & Sons. Specific illustrations of suitable separation and isolation procedures are given by reference to the examples hereinbelow. However, other equivalent separation or isolation procedures can also be used.

[0202] In all of the methods, it is well understood that protecting groups for sensitive or reactive groups may be employed where necessary, in accordance with general principles of chemistry. Protecting groups are manipulated according to standard methods of organic synthesis (T. W. Greene and P. G. M. Wuts (1999) Protective Groups in Organic Synthesis, 3rdEd., John Wiley & Sons). These groups may be removed at a convenient stage of the compound synthesis using methods that are readily apparent to those skilled in the art.

[0203] When desired, the (R)- and (S)-isomers of the nonlimiting exemplary compounds, if present, can be resolved by methods known to those skilled in the art, for example, by formation of diastereoisomeric salts or complexes which can be separated, e.g., by crystallization; via formation of diastereoisomeric derivatives which can be separated, e.g., by crystallization, gas-liquid or liquid chromatography; selective reaction of one enantiomer with an enantiomer-specific reagent, e.g., enzymatic oxidation or reduction, followed by separation of the modified and unmodified enantiomers; or gas-liquid or liquid chromatography in a chiral environment, e.g., on a chiral support, such as silica with a bound chiral ligand or in the presence of a chiral solvent. Alternatively, a specific enantiomer can be synthesized by asymmetric synthesis using optically active reagents, substrates, catalysts or solvents, or by converting one enantiomer to the other by asymmetric transformation.

[0204] The compounds described herein can be optionally contacted with a pharmaceutically acceptable acid to form the corresponding acid addition salts. Also, the compounds described herein can be optionally contacted with a pharmaceutically acceptable base to form the corresponding basic addition salts.

[0205] In some embodiments, disclosed compounds can generally be synthesized by an appropriate combination of generally well-known synthetic methods. Techniques useful insynthesizing these chemical entities are both readily apparent and accessible to those of skill in the relevant art, based on the instant disclosure. Many of the optionally substituted starting compounds and other reactants are commercially available, e.g., from Millipore Sigma or can be readily prepared by those skilled in the art using commonly employed synthetic methodology.

[0206] The discussion below is offered to illustrate certain of the diverse methods available for use in making the disclosed compounds and is not intended to limit the scope of reactions or reaction sequences that can be used in preparing the compounds provided herein. The skilled artisan will understand that standard atom valences apply to all compounds disclosed herein in genus or named compound for unless otherwise specified.Example 1. General Synthetic Method I

[0207] In some embodiments, compounds described herein were prepared according to one or more steps of the following scheme:amide formation3reduction

[0208] The variables in the scheme above are the same as those defined for Formula I herein, i.e.,:Ring A is an optionally substituted group selected from saturated C3-C10 carbocyclyl, Ce-Cio aryl, 5-10 membered heterocyclyl, and 5-10 membered heteroaryl;Rais selected from halogen, hydroxyl, and C1-6 alkoxyl;q is an integer from 0 to 4;RNis hydrogen or optionally substituted C1-6 aliphatic;Rpis a lone electron pair or optionally substituted C1-6 aliphatic; andRcland Rc2are each independently hydrogen or Ci-6 aliphatic.

[0209] In this method, carboxylic acid 1 and amine 2 (wherein RNis hydrogen or optionally substituted Ci-6 aliphatic) are coupled to form amide 3. The carbonyl of amide 3 is then reduced to provide amine 4. Amine 4 is converted to salt 5, e.g., by treatment with an acid such as HCI. In some instances, the amine of 4 is functionalized (e.g., by methylation) to provide 6 (wherein Rpis optionally substituted Ci-6 aliphatic), which is then converted to salt 7.

[0210] This general method was used to prepare compounds described herein, e.g., 1-3 HCI, 1-6 HCI, and 1-67 formate. Exemplary procedures for certain compounds are described herein. A person of skill in art will recognize that the synthetic procedure can be adapted to prepare other compounds based on appropriate selection of starting materials e.g., 1 and 2, and reactants.Example 2. Preparation of (R)-N-(2-(lH-indol-3-yl)ethyl)-l-(2-methoxyphenyl)-N-methylethan-l-amine (1-3) hydrogen chloride

[0211] 1-3 HC1 was prepared according to General Synthetic Method I and the scheme below.4M HCIEtOAc

[0212] Step 1. Preparation of methyl (R)-(l-(2-methoxyphenyl)ethyl)carbamate

[0213] To a stirred solution of (R)-l-(2-methoxyphenyl)ethan-l -amine (4.50 g, 1.0 equiv) in dichloromethane (DCM) (100 mL) were added methyl carbonochloridate (3.66 g, 1.3 equiv) and triethylamine (12.4 mL, 3.0 equiv) at room temperature. The reaction mixture was stirred at room temperature for 16h. The progress of the reaction was monitored by thin layer chromatography (TLC). After completion, the reaction mixture was concentrated in vacuo, diluted with water (50 mL), and extracted with DCM (2 x 150 mL). The separated organic layer was dried over anhydrous Na2SC>4, filtered and concentrated in vacuo. The crude material obtained was purified by combi flash chromatography (20 - 40% ethyl acetate (EtOAc) in heptane) to provide methyl (R)-(l-(2-methoxyphenyl)ethyl)carbamate (2.52 g, 40.5% yield) as a pale yellow liquid.

[0214] Step 2. Preparation of (R)-l-(2-methoxyphenyl)-N-methylethan-l -amine

[0215] To a stirred solution of methyl (R)-(l-(2-methoxyphenyl)ethyl)carbamate (1.0 g, 1.0 equiv) in tetrahydrofuran (THF) (10 mL) was added a solution of 2M lithium aluminium hydride (LAH) (7.2 mL, 3.0 equiv) dropwise. The reaction mixture was stirred at refluxed for 5 h under N2 atmosphere. The progress of the reaction was monitored by TLC. After completion, the reaction mixture was cooled to 0°C, quenched with 15% NaOH solution (ImL), then washed with water (3 mL), followed by the addition of EtOAc (20mL). The white precipitate and solution was filtered through pad of Celite and the pad was washed with EtOAc (100 mL). The filtrate (biphasic EtOAc and water) was washed with water (30 mL), then the organic phase was dried over anhydrous Na2SO4, filtered and concentrated in vacuo to afford crude compound (R)-l-(2-methoxyphenyl)-N-methylethan-l -amine (0.89 g, crude) as a brown liquid.

[0216] Step 3. Preparation of (R)-2-(lH-indol-3-yl)-N-(l-(2-methoxyphenyl)ethyl)-N-methylacetamide

[0217] To a stirred solution of (R)-l-(2-methoxyphenyl)-N-methylethan-l -amine (0.8 g, 1.0 equiv) and 2-(lH-indol-3-yl)acetic acid (0.85 g, 1.0 equiv) in acetonitrile (MeCN) (25 mL) was added triethylamine (2.03 mL, 3.0 equiv) at room temperature. The reaction mixture was cooled to 0°C, stirred for 5 min and 50% propanephosphonic acid anhydride (T3P) solution in EtOAc (4.63 g, 1.5 equiv) was added dropwise. The reaction mixture was stirred at room temperature for 16 h. The progress of the reaction was monitored by TLC. After completion, the reaction mixture was concentrated in vacuo to afford crude material, which was diluted with water (50 mL), and extracted with EtOAc (2 x 100 mL). The separated organic layer was dried over anhydrous Na2SO4, filtered and concentrated in vacuo to afford crude material. The crude material was purified by combi flash chromatography (20 to 40% EtOAc in heptane) to afford (R)-2-(lH-indol-3-yl)-N-(l-(2-methoxyphenyl)ethyl)-N-methylacetamide (0.91 g, 58.17%) as brown sticky oil.

[0218] Step 4. Preparation of (R)-N-(2-(lH-indol-3-yl)ethyl)-l-(2-methoxyphenyl)-N-methylethan- 1 -amine

[0219] To a stirred solution of (R)-2-(lH-indol-3-yl)-N-(l-(2-methoxyphenyl)ethyl)-N-methylacetamide (0.8 g, 1.0 equiv) in THF (10 mL) was added a solution of 2M LAH (2.48 mL, 2.0 equiv) dropwise. The reaction mixture was stirred at 65°C for 12h under N2 atmosphere. The progress of the reaction was monitored by TLC. After completion, the reaction mixture was quenched with a saturated Na2SC>4 solution (20 mL), and the white precipitate was filtered through pad of Celite and washed with EtOAc (100 mL). The filtrate was washed with water (30 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude material was purified by Prep-HPLC purification to afford (R)-N-(2-(lH-indol-3-yl)ethyl)-l-(2-methoxyphenyl)-N-methylethan-l -amine (0.23 g, 30.06%) as a pale yellow gummy liquid. MS (ESI) m / e [M+H]+: 309.29; HPLC purity: 98.65% (retention time= 9.25 min), 1.28 (d, 7=6.63 Hz, 3H, CH3CH), 2.26 (s, 3H, NMe), 2.52 - 2.57 (m, 1H, CH2), 2.58 - 2.68 (m, 1H, CH2), 2.74 - 2.89 (m, 2H, CH2), 3.60 (q, 7=6.63 Hz, 1H, CH), 3.72 (s, 3H, OMe), 6.76 - 6.82 (m, 1H, aromCH), 6.86 - 6.92 (m, 3H, aromCH), 6.99 - 7.04 (m, 1H, aromCH), 7.07 (d, J=2.13 Hz, 1H, aromCH), 7.21 (t, 7=8.07 Hz, 1H, aromCH), 7.30 (dd, 7=8.13, 3.25 Hz, 2H, aromCH), 10.71 (S, 1H, indole-NH).

[0220] Step 5. Preparation of (R)-N-(2-(lH-indol-3-yl)ethyl)-l-(2-methoxyphenyl)-N-methylethan-1 -amine hydrogen chloride4M HCIEtOAc

[0221] To a stirred solution of (R)-N-(2-(lH-indol-3-yl)ethyl)-l-(2-methoxyphenyl)-N-methylethan-1 -amine (120 mg, 1.0 equiv) in EtOAc (1 mL) was added 4M HCI in EtOAc (0.2 mL, 1.7 equiv) at 0°C. The reaction mixture was stirred at room temperature for 30 min. Volatiles were removed under reduced pressure. The crude residue was triturated with diethyl ether and concentrated under reduced pressure to afford (R)-N-(2-(lH-indol-3-yl)ethyl)-l-(2-methoxyphenyl)-N-methylethan-l -amine hydrochloride (39 mg, 29.21% yield) as an off-white solid. MS (ESI) m / e [M+H]+: 309.0; HPLC purity: 96.19% (retention time = 5.790 min), 'H NMR (400 MHz, DMSO-r / r,) 6 ppm 1.68 (dd, 7=13.88, 6.88 Hz, 3H, NMe), 2.69 -2.92 (m, 3H, CH2), 2.95 - 3.27 (m, 3H, CH2), 3.36 - 3.42 (m, 1H, CH2), 3.79 (d, 7=1.63 Hz, 3H, CH3), 4.54 - 4.70 (m, 1H, CH), 6.89 - 7.12 (m, 3H, aromCH), 7.15 - 7.59 (m, 6H, aromCH), 10.40 - 10.59 (m, 1H, HCI salt), 10.95 (d, 7=17.26 Hz, 1H, Indole-NH).Example 3. Preparation of (R)-N-(2-(lH-indol-3-yl)ethyl)-l-(3-methoxyphenyl)-N-methylethan-l-amine (1-6) hydrochloride

[0222] 1-6 HCI was prepared according to General Synthetic Method I and the scheme below.O4M HCIEtOAc

[0223] Step 1. Preparation of methyl (R)-(l-(3-methoxyphenyl)ethyl)carbamateOCH3CH3(X,J JCH3

[0224] To a stirred solution of (R)-l-(3-methoxyphenyl)ethan-l-amine (1.0 g, 1.0 equiv) in DCM (10 mL) were added methyl carbonochloridate (0.75 g, 1.2 equiv) and N, N-diisopropylethylamine (DIPEA) (0.2.56 g, 3.0 equiv) at room temperature. The reaction mixture was stirred at room temperature for 16h. The progress of the reaction was monitored by TLC. After completion, the reaction mixture was concentrated in vacuo, diluted with water (30 mL), and extracted with DCM (2 x 50 mL). The separated organic layer was dried over anhydrous Na2SC>4, filtered and concentrated in vacuo. The crude material was purified by combi flash chromatography (20 to 40% EtOAc in heptane) to provide methyl (R)-(l-(3-methoxyphenyl)ethyl)carbamate (1.2 g, 86% yield) as a colourless liquid.

[0225] Step 2. Preparation of (R)-l-(3-methoxyphenyl)-N-methylethan-l-amine■CH3O 0, CH3CH3%H3CH3

[0226] To a stirred solution of methyl (R)-(l-(3-methoxyphenyl)ethyl)carbamate (1.2 g, 1.0 equiv) in THF (10 mL) was added a solution of 2M LAH (6.6 mL, 2.0 equiv) dropwise. The reaction mixture was stirred at 65°C for 16h under N2 atmosphere. The progress of the reaction was monitored by TLC. After completion, the reaction mixture was quenched with a saturated aqueous Na2SC>4 solution (10 mL). The white precipitate and solution was filtered through a pad of Celite and washed with EtOAc (100 mL). The biphasic filtrate was washed with water (30 mL), and the organic phase was collected and dried over anhydrous Na2SC>4, filtered and concentrated in vacuo. The crude obtained was purified by combi flash chromatography (20 to 50% EtOAc in heptane) to afford (R)-l-(3-methoxyphenyl)-N-methylethan-1 -amine (0.7 g, 63%) as a brown liquid.

[0227] Step 3. Preparation of (R)-2-(lH-indol-3-yl)-N-(l-(3-methoxyphenyl)ethyl)-N-methylacetamideCH3

[0228] To a stirred solution of (R)-l-(3-methoxyphenyl)-N-methylethan-l-amine (0.7 g, 1.0 equiv) and 2-(lH-indol-3-yl)acetic acid (0.74 g, 1.0 equiv) in MeCN (10 mL) was added triethylamine (1.8 mL, 2.0 equiv) at room temperature. The reaction mixture was cooled to 0 °C, stirred for 5 min and then 50% T3P solution in EtOAc (2.57 mL, 2.0 equiv) was added dropwise. The reaction mixture was stirred at room temperature for 16h. The progress of the reaction was monitored by TLC. After completion, the reaction mixture was concentrated in vacuo to afford crude, diluted with water (50 mL), and extracted with EtOAc (2 x 100 mL). The separated organic layer was dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The material was purified by combi flash chromatography (20 to 40% EtOAc in heptane) to afford (R)-2-(lH-indol-3-yl)-N-(l-(3-methoxyphenyl)ethyl)-N-methylacetamide (0.6 g, 44%) as brown sticky oil.

[0229] Step 4. Preparation of (R)-N-(2-(lH-indol-3-yl)ethyl)-l-(3-methoxyphenyl)-N-methylethan- 1 -amine

[0230] To a stirred solution of (R)-2-(lH-indol-3-yl)-N-(l-(3-methoxyphenyl)ethyl)-N-methylacetamide (0.6 g, 1.0 equiv) in THF (10 mL) was added a solution of 2M LAH (0.14 mL, 2.0 equiv) dropwise. The reaction mixture was stirred at 65°C for 16h under N2 atmosphere. The progress of the reaction was monitored by TLC. After completion, the reaction mixture was quenched with a saturated aqueous Na2SC>4 solution (20 mL). The white precipitate was filtered through pad of Celite and the pad washed with EtOAc (100 mL). The biphasic filtrate was washed with water (30 mL), then dried over anhydrous Na2SC>4, then filtered and concentrated in vacuo. The material was purified by combi flash chromatography to afford (R)-N-(2-(lH-indol-3-yl)ethyl)-l-(3-methoxyphenyl)-N-methylethan-l-amine (0.1 g, 21%) as a brown liquid. MS (ESI) m / e [M+H]+: 309.2; HPLC purity: 97.81 % (retention time = 5.026 min); 'HNMR (400 MHz, DMSO-fifc) 8 ppm 2.37 (s, 3H, NCH3), 2.60 - 2.66 (m, 2H, -CH2-), 2.69 - 2.76 (m, 4H, -CH2CH2-), 2.81 - 2.86 (m, 2H, CH2), 3.78 (s, 3H, OMe), 6.85 (dd, J=7.38, 1.00 Hz, 1H, aromCH),6.92 - 6.99 (m, 2H),7.05 (dd, J=7.47, 1.06 Hz, 1H, aromCH), 7.12 - 7.20 (m, 2H, aromCH), 7.32 (d, J=8.00 Hz, 1H),7.51 (d, J=8.00 Hz, 1H, aromCH), 8.16 (s, 1H, aromCH), 10.76 (S, 1H, indole-NH).

[0231] Step 5. Preparation of (R)-N-(2-(lH-indol-3-yl)ethyl)-l-(3-methoxyphenyl)-N-methylethan- 1 -amine hydrochloride

[0232] To a stirred solution (R)-N-(2-(lH-indol-3-yl)ethyl)-l-(3-methoxyphenyl)-N-methylethan-1 -amine (200 mg, 1 equiv) in 1,4-di oxane (2 mL) was added 1,4-di oxane HC1 (4M, 0.4 mL) at 0 °C. The reaction mixture was stirred at room temperature for 45 minutes After completion, the reaction mixture was concentrated under reduced pressure and triturated with diethyl ether (2 x 10 mL). The compound was dried to afford (R)-N-(2-(lH-indol-3-yl)ethyl)-l-(3-methoxyphenyl)-N-methylethan-l-amine HC1 (200 mg, 90.9%) as an off-white solid. MS (ESI) m / e [M+H]+: 309.0; HPLC purity: 96.19% (retention time = 5.790 min); 'HNMR (400 MHz, DMSO-tL) 6 ppm 1.68 (dd, 7=13.88, 6.88 Hz, 3H, NMe), 2.69 -2.92 (m, 3H, CH2), 2.95 - 3.27 (m, 3H, CH2), 3.36 - 3.42 (m, 1H, CH2), 3.79 (d, 7=1.63 Hz, 3H, CH3), 4.54 - 4.70 (m, 1H, CH), 6.89 - 7.12 (m, 3H, aromCH), 7.15 - 7.59 (m, 6H, aromCH), 10.40 - 10.59 (m, 1H, HC1 salt), 10.95 (d, 7=17.26 Hz, 1H, Indole-NH).Example 4. Alternative preparation of (R)-N-(2-(lH-indol-3-yl)ethyl)-l-(3-methoxyphenyl)-N-methylethan-l-amine (1-6) hydrochloride

[0233] Step 1. Preparation of (R)-l-(3-methoxyphenyl)-N-methylethan-l-amineCH32. NaBH4CH3

[0234] To a stirred solution of (R)-l-(3-methoxyphenyl)ethan-l-amine (2.8 g, 1.0 equiv) in methanol (70 mL) were added sodium methoxide (1.5 g, 1.5 equiv) and formaldehyde (37% in H2O, 2.45 mL, 1.5 equiv) at room temperature. The reaction mixture was stirred at 90°C for 16h. The reaction mixture was cooled 0°C and to it was added sodium borohydride (1.05 g, 3 equiv) at the same temperature and stirred at room temperature for 2h. The progress of the reaction was monitored by TLC. After completion, the reaction mixture was concentrated in vacuo, diluted with water (30 mL), and extracted with DCM (2 x 50 mL). The separated organic layer was dried over anhydrous Na2SC>4, filtered and concentrated in vacuo. The material was purified by combi flash chromatography (20 to 40% EtOAc in heptane to get methyl (R)-(l-(3-methoxyphenyl)ethyl)carbamate (1.3 g, 42% yield) as a colourless liquid.

[0235] Step 2. Preparation of (R)-N-(2-(lH-indol-3-yl)ethyl)-l-(3-methoxyphenyl)-N-methylethan- 1 -amineDMF

[0236] To a stirred solution of methyl (R)-(l-(3-methoxyphenyl)ethyl)carbamate (1.3 g, 1.0 equiv) in N, N-dimethylformamide (DMF) (10 mL) were added 3 -(2 -bromoethyl)- 1H-indole (1.76 g, 1.0 equiv), potassium carbonate (1.41 g, 1.3 equiv) and potassium iodide (0.26 g, 0.2 equiv) at room temperature. The reaction mixture was stirred at 100 °C for 16h under N2 atmosphere. The progress of the reaction was monitored by TLC. After completion, the reaction mixture was quenched with a saturated aqueous Na2SC>4 solution (20 mL). The white precipitate was filtered through pad of Celite and washed with EtOAc (100 mL). The filtrate was washed with water (30 mL), and then dried over anhydrous Na2SC>4, filtered and concentrated in vacuo. The material was purified by combi flash chromatography to afford (R)-N-(2-(lH-indol-3-yl)ethyl)-l-(3-methoxyphenyl)-N-methylethan-l-amine (0.87 g, 36%) as a brown liquid. MS (ESI) m / e [M+H]+: 309.2; HPLC purity: 97.81 % (retention time = 5.026 min); 'H NMR (400 MHz, DMSO-tL) 6 ppm 2.37 (s, 3H, NCH3),2.60 - 2.66 (m, 2H, -CH2-), 2.69 - 2.76 (m, 4H, -CH2CH2-), 2.81 - 2.86 (m, 2H, CH2), 3.78 (s, 3H, OMe), 6.85 (dd, J=7.38, 1.00 Hz, 1H, aromCH),6.92 - 6.99 (m, 2H),7.05 (dd, J=7.47, 1.06 Hz, 1H, aromCH), 7.12 - 7.20 (m, 2H, aromCH), 7.32 (d, J=8.00 Hz, 1H),7.51 (d, J=8.00 Hz, 1H, aromCH), 8.16 (s, 1H, aromCH), 10.76 (S, 1H, indole-NH).

[0237] Step 3. Preparation of (R)-N-(2-(lH-indol-3-yl)ethyl)-l-(3-methoxyphenyl)-N-methylethan- 1 -amine hydrochloride

[0238] To a stirred solution (R)-N-(2-(lH-indol-3-yl)ethyl)-l-(3-methoxyphenyl)-N-methylethan-1 -amine (200 mg, 1 equiv) in 1,4-di oxane (2 mL) was added 1,4-dioxane. HCl (4M, 0.4 mL) at 0°C. The reaction mixture was stirred at room temperature for 45 minutes.After completion, the reaction mixture was concentrated under reduced pressure and triturated with diethyl ether (2 x 10 mL). The compound was dried to afford (R)-N-(2-(lH-indol-3-yl)ethyl)-l-(3-methoxyphenyl)-N-methylethan-l-amine HC1 (200 mg, 90.9%) as an off-white solid. MS (ESI) m / e [M+H]+: 309.0; HPLC purity: 96.19% (retention time = 5.790 min); 'HNMR (400 MHz, DMSO-fifc) 6 ppm 1.68 (dd, J=13.88, 6.88 Hz, 3H, NMe), 2.69 -2.92 (m, 3H, CH2), 2.95 - 3.27 (m, 3H, CH2), 3.36 - 3.42 (m, 1H, CH2), 3.79 (d, J=1.63 Hz, 3H, CH3), 4.54 - 4.70 (m, 1H, CH), 6.89 - 7.12 (m, 3H, aromCH), 7.15 - 7.59 (m, 6H, aromCH), 10.40 - 10.59 (m, 1H, HC1 salt), 10.95 (d, J= 17.26 Hz, 1H, Indole-NH).

[0239] In a larger batch procedure, to a stirred solution of (R)-N-(2-(lH-indol-3-yl)ethyl)-l-(3-methoxyphenyl)-N-methylethan-l-amine (3.17 g, 10.3 mmol, 100 mass%) in 1,4-dioxane (31.7 mL, 99.8 mass%) was added hydrochloric acid (4 mol / L) in dioxane (3 equiv., 30.8 mmol, 4 mol / L) at 0°C. The reaction mixture was stirred at room temperature for Ih. The reaction mixture was evaporated under reduced pressure to afford residue. The residue was triturated with diethyl ether (100 mL), and the solid was filtered and washed with diethyl ether wash. The solid was dissolved in methanol and concentrated under reduced pressure, dissolved in water and acetonitrile mixture (3:1), and dried over freeze dryer lyophilizer to afford (R)-N-(2-(lH-indol-3-yl)ethyl)-l-(3-methoxyphenyl)-N-methylethan-l-amine. hydrochloride (1-6 HC1, 3 g, 8.698 mmol, 100 mass%, 84.6% yield) as a pale brown solid. The X-ray diffraction pattern (XRPD) of the solid indicated the material was amorphous (Figure 7).Example 5. In vitro pharmacological investigation - General agonist and antagonist

[0240] Compounds were tested several concentrations to determine ICso and ECso values. Compound binding was calculated as % inhibition of the binding of a ligand specific for each target (e.g., a neuronal transmembrane receptor).

[0241] Cellular agonist effect was calculated as a % of control response to a known reference agonist for each target and cellular antagonist effect was calculated as a % inhibition of control reference agonist response for each target.

[0242] Results showing an inhibition (or stimulation for assays run in basal conditions) higher than 50% represent significant effects of the test compounds. 50% is generally the cutoff value for further investigation (determination of ICso or ECso values from concentrationresponse curves).

[0243] Results showing an inhibition (or stimulation) between 25% and 50% representweak to moderate effects.

[0244] Results showing an inhibition (or stimulation) lower than 25% are not considered significant and mostly attributable to variability of the signal around the control level.

[0245] Low to moderate negative values are also not considered significant and are attributable to variability of the signal around the control level. High negative values (> 50%) that are sometimes obtained with high concentrations of test compounds are generally attributable to non-specific effects of the test compounds in the assays. In some embodiments, the results suggest an allosteric effect of the test compound.Materials and Methods - Experimental ConditionsIn Vitro Pharmacology: Binding AssayAssay Source Agonist Cone. Kd Non Incubation Specific5-HT2B (h) human [125I](±)DOI 0.2 nM 0.2 nM (±)DOI 60 min (agonist recombinant (I pM) roomradioligand) (CHO cells) temperature In Vitro Pharmacology Binding AssaysAssay Source Stimulus Incubation Measured Component 5-HT2A (h) human none 30 min IPi(agonist effect) recombinant (10 pM serotonin 37°C(HEK-293 cells) for control)5-HT2A (h) human serotonin 30 min IPi (antagonist recombinant (100 nM) 37°Ceffect) (HEK-293 cells)5-HT2B(h) human none 30 min IPi(agonist effect) recombinant ( 1 pM serotonin 37°C(CHO cells) for control)5-HT2B(h) human serotonin 30 min IPi (antagonist recombinant (30 nM) 37°Ceffect) (CHO cells)IPi = inositol monophosphate biomarker

[0246] Pharmacological, biological, and other such examples of the present disclosure employed control compounds. Some of them are displayed here.Name Action Structure5-HT (serotonin; 5- EndogenousNH2hydroxytryptamine) neurotransmitterH'"'O(±)DOI5-HT2A and 5- HT2B receptor(2,5-dimethoxy-4- agonistiodoamphetamine)°\5-HT2A and 5- HT2B receptor[125I](±)DOIagonist... Xrr" radioligand°\o5-HT2A receptorketanserin uantagonistH HN— / '5-HT2B andSB-206553 5HT2C receptorV zantagonist < II [ >N\\l-"DLX-001 5-HT2B receptor(zalsupindole) antagonist5.15-HTIB (h) against radioligand agonist ([125I](±)DOI)

[0247] Binding data, including ICso values of compounds of the disclosure for 5-HT2B (A) against radioligand agonist [125I](±)DOI, are provided in Table 3.Table 3 - 5-HT2B( I (agonist radioligand)Cpd # ICso(M) Ki(M) nH1-35 8.7E-08 M 4.3E-08 M 0.81-34 1.2E-07 M 5.8E-08 M 0.81-19 4.3E-08 M 2.1E-08 M 0.71-59 2.0E-07 M 1.0E-07 M 0.91-41 1.1E-07 M 5.3E-08 M 1.01-43 3.9E-08 M 2.0E-08 M 1.0

[0248] nH refers to the Hill coefficient, a measure of ligand-receptor cooperativity, and is derived from the Hill equation. A nH value of 1 indicates a non-cooperative binding process, i.e., each agonist molecule binds independently to a single binding site on the receptor. nH values greater than 1 indicate positive cooperativity, i.e., binding of one agonist increases theaffinity of the receptor for subsequent agonist molecules. nH values less than 1 indicate negative cooperativity, i.e., binding of 1 agonist reduces the affinity of the receptor for the other agonist molecules.IC50 and Ki determination

[0249] Receptor binding data was measured at multiple concentrations of a given compound. The compound’s inhibition was calculated as a percentage of inhibition of a control reference agonist’s binding. This is exemplified below for compound 1-34 (5-HT2B (Ji) receptors), where compounds 1-34’ s percent inhibition of [125I](±)DOI’s (the control agonist) binding was measured.1-34 Test % Inhibition of Control Specific Binding Concentration 1st2ndMean1.0E-09 M -18.3 -0.5 -9.43.0E-09 M -9.8 -9.6 -9.71.0E-08 M -2.4 2.3 0.03.0E-08 M 19.5 17.0 18.31.0E-07 M 39.0 36.5 37.83.0E-07 M 62.3 65.3 63.81.0E-06 M 84.2 84.6 84.43.0E-06 M 92.6 82.5 87.51.0E-05 M 97.6 99.5 98.63.0E-05 M 97.4 99.8 98.6

[0250] The compound’s inhibitory concentration (logarithmic) against mean percent inhibition of control agonist was plotted, as shown in Figure 3 for 1-34. Non-linear regression analysis was performed to fit a dose-response curve to the plotted data. The compound’s IC50 was then calculated from the curve as the concentration of compound that produces 50% of the maximal inhibition. This value is reported in Table 3 for 1-34.

[0251] The inhibition constant (Ki) was calculated using the Cheng Prusoff equation IC50Ki=(1+LKD)where L = concentration of ligand in the assay, and KD = affinity of the ligand for the receptor. Here, the ligand was [125I](±)DOI. This value is reported in Table 3 for 1-34.

[0252] Similar experiments were conducted to determine the IC50 and Ki values reported inTable 3 and the tables below that report IC50 and Ki values. The same methodology was used in different receptor assays with different control compounds.5-HTIB (h) (agonist radioligand) IC50(M) Ki(M) nH125I(±)DOI 1.6E-09 M 8.2E-10 M 0.7125I(±)DOI 2.7E-09 M 1.3E-09 M 1.2 5.25-HTIA (h) and 5-HTIB (h) agonism against serotonin

[0253] 5 -HT2A (A) (agonist effect) and 5-HT2B (A) (agonist effect) values for compounds of the present disclosure against serotonin are provided in Table 4.Table 4Cpd # Test % of Control Agonist Response Concentration J st 2ndMean 5-HT2A(A) (agonist effect)1-23 1.0E-05 M 13.8 15.5 14.6 1-42 1.0E-05 M 53.4 54.5 54.0 1-32 1.0E-05 M 9.5 10.0 9.7 1-29 1.0E-05 M 87.7 88.8 88.2 5-HT2B(A) (agonist effect)1-35 1.0E-05 M 18.1 19.2 18.6 1-34 1.0E-05 M 26.2 28.0 27.1 1-19 1.0E-05 M 13.3 14.2 13.81-59 1.0E-05 M 12.8 12.9 12.9Reference Agonists5-HT2A (h) (agonist effect) ECso(M) nH serotonin 1.3E-08 M n / a5-HT2B (h) (agonist effect)serotonin 4.2E-09 M n / a

[0254] Human 5-HT2A and human 5-HT2B EC50 and Emax concentrations for compounds disclosed herein against serotonin are provided in Table 5A and Table 5B.Table 5 A - 5-HT2A / ?) (agonist effect)Compound EC5o(M) nH Emax(%)1-35 > 3.0E-05 n / a 381-34 N. C. n / a N. C.1-19 N. C. n / a N. C.1-59 N. C. n / a N. C.1-207 N. C. n / a N. C.1-39 N. C. n / a N. C.1-16 3.2E-06 M n / a 57Compound ECso(M) nH Emax(%)1-6 N. C. n / a N. C.1-33 3.5E-07 M n / a 33Table 5B - 5-HT2B(7Z (agonist effect)Compound ECso(M) nH Emax(%)1-41 N. C. n / a N. C.1-42 N. C. n / a N. C.1-32 N. C. n / a N. C.1-29 N. C. n / a N. C.1-16 N. C. n / a N. C.1-33 3.1E-07 M n / a 32> Cone.: ECso value above the highest test concentration. Concentration-response curve shows less than 50 % effect at the highest validated testing concentrationN. C.: ECso value not calculable. Concentration-response curve shows less than 25% effect at the highest validated testing concentration.ECso and E max determination

[0255] Receptor response data was measured at multiple concentrations of a given compound. The compound’s response was calculated as a percentage of a control reference agonist’s response. This is exemplified in the table below for 1-33 (5-HT2A( / Z) receptors), where compound 1-33 ’s percent response of serotonin’s (the control agonist) response was measured. Similar data are provided for additional compounds in Table 4 for 5-HT2A(A) and 5-HT2B (A) receptors.1-33 Test % of Control Agonist Response Concentration 1st2ndMean 1.0E-09 M 1.8 2.0 1.9 3.0E-09 M 0.8 1.7 1.2 1.0E-08 M 6.0 3.7 4.9 3.0E-08 M 6.3 4.6 5.5 1.0E-07 M 8.1 9.6 8.8 3.0E-07 M 17.2 15.6 16.4 1.0E-06 M 25.5 23.8 24.7 3.0E-06 M 29.4 29.1 29.2 1.0E-05 M 32.9 32.4 32.63.0E-05 M 31.4 31.6 31.5

[0256] The compound’s response concentration (logarithmic) against mean percent response of control agonist response was plotted, as shown in Figure 4 for 1-33. Non-linear regression analysis was performed to fit a dose-response curve to the plotted data. The compound’s ECso was then calculated from the curve as the concentration of compound that produces 50% of the maximal effective concentration. This value is reported in Table 5B for 1-33.

[0257] Emax may be roughly estimated as the maximum percentage agonist response on a compound’s ECso curve and / or the highest mean percent of control agonist response measured (e.g., in Table 4 or the table for 1-33 above). For 5-HT2A(A), 1-33 ’S Emax can be estimated as -33%.

[0258] Similar experiments were conducted to determine the ECso and Emax values reported in Table 5 A and Table 5B. The same methodology can be used to determine ECso and Emax values in different receptor assays with different control compounds.Reference Agonist5-HT2A( / I) (agonist effect) ECSo(M) nH serotonin 1.3E-08 M n / a serotonin 1.3E-08 M n / a serotonin 1.6E-08 M n / a5-HT21 / / 7) (agonist effect)serotonin 4.8E-09 M n / aserotonin 5.5E-09 M n / a5.35-HTIA (h) antagonism against ketanserin and 5-HTIB (h) antagonism against SB-206553

[0259] Table 6 provides in vitro 5-HT2A (A) (antagonist effect) inhibition of compounds described herein against ketanserin and 5-HT2B (Ji) (antagonist effect) inhibition of compounds described herein against SB-206553. The data in Table 6 may be used to calculate ICso.Table 6Compound Test % Inhibition of Control Agonist Response Concentration 1st2ndMean 5-HT2AW (antagonist effect)1-35 1.0E-05 M 52.2 50.3 51.31-34 1.0E-05 M 85.8 82.6 84.21-19 1.0E-05 M 88.7 88.1 88.4 1-59 1.0E-05 M 60.7 59.4 60.0 1-209 1.0E-05 M 38.1 33.5 35.8 1-213 1.0E-05 M 34.3 52.3 43.3 1-17 1.0E-05 M 1.4 10.4 5.9 1-207 1.0E-05 M 61.7 62.2 61.9 1-204 1.0E-05 M -20.0 -17.5 -18.8 1-206 1.0E-05 M 58.1 60.2 59.2 1-54 1.0E-05 M 28.1 34.7 31.4 1-222 1.0E-05 M 53.9 57.5 55.7 1-202 1.0E-05 M -4.0 3.0 -0.5 1-223 1.0E-05 M 56.7 60.4 58.5 1-45 1.0E-05 M 20.6 29.5 25.0 1-97 1.0E-05 M 10.2 17.7 14.0 1-28 1.0E-05 M 57.0 54.8 55.9 1-22 1.0E-05 M -3.9 -4.0 -4.0 S-HTii / / / ) (antagonist effect)1-35 1.0E-05 M 70.0 62.6 66.3 1-34 1.0E-05 M 57.8 52.6 55.2 1-19 1.0E-05 M 78.1 76.5 77.3 1-59 1.0E-05 M 65.8 60.8 63.3 1-40 1.0E-05 M 75.2 75.5 75.4 1-41 1.0E-05 M 67.7 70.8 69.31-43 1.0E-05 M 15.7 11.0 13.4 Reference Antagonists5-HT2A( / 7) (antagonist effect) ICSo(M) KB(M) nH ketanserin 2.0E-08 M 4.1E-09 M n / a 5-HT2BW (antagonist effect)SB-206553 3.1E-08 M 4.7E-09 M n / a Example 6. In vitro pharmacological investigation

[0260] IC50 or EC50 characteristics at serotonin receptors (5-HT2A and / or 5-HT2B) were determined for several compounds of the present disclosure. Compound binding was calculated as a % inhibition of the binding of a ligand specific for each target. Cellular agonist effect was calculated as a % of control response to a known reference agonist for each target and cellular antagonist effect was calculated as a % inhibition of control reference agonist response for each target.Materials and Methods - Experimental ConditionsIn Vitro Pharmacology: Binding AssayAssay Source Ligand Cone. Kd Non-Specific Receptors5-HT2A (h) human recombinant [125I](±)DOI 0.1 nM 0.3 nM (±)DOI (agonist (HEK-293 cells) (I pM)radioligand)5-HT2B(h) human recombinant [125I](±)DOI 0.2 nM 0.2 nM (±)DOI (agonist (CHO cells) (I pM)radioligand)In Vitro Pharmacology Binding AssaysReceptor Measured Source Stimulus IncubationAssay Component 5-HT; A (ll) human recombinant (HEK- None (10 pM 30 min 37°C IPi W‘ 293 cells) serotonin forcontrol)5-HT2A (h) human recombinant (HEK- serotonin 30 min 37°C IPi (antagonist 293 cells) (100 nM)effect)5-HT? B(h) human recombinant (CHO None ( 1 pM 30 min 37°C IPI cells) serotonin forcontrol)5-HT2B (h) human recombinant (CHO serotonin (30 30 min 37°C IPi (antagonist cells) nM)effect)IPi = inositol monophosphate biomarker

[0261] Results showing inhibition or stimulation higher than 50% represent significant effects of the test compounds. Such effects were observed here and are listed in the following tables.

[0262] Results showing an inhibition (or stimulation) between 25% and 50% represent weak to moderate effects.

[0263] Results showing an inhibition (or stimulation) lower than 25% are not considered significant and mostly attributable to variability of the signal around the control level.

[0264] Low to moderate negative values are also not considered significant and are attributable to variability of the signal around the control level. High negative values (> 50%) that are sometimes obtained with high concentrations of test compounds are generally attributable to non-specific effects of the test compounds in the assays. In some embodiments, the results suggest an allosteric effect of the test compound.

[0265] Minor variations to the experimental protocol described below may have occurred during the testing, they have no impact on the quality of the results obtained.6.1 - 5-HTIA (h) and 5-HTIB (h) agonism against [125I](±)DOI

[0266] The 5-HT2A (h) (agonist effect) and 5-HT2B (h) (agonist effect) ICso (M)concentrations of compounds described herein against radioligand [125I](±)DOI are provided in Table 7A and Table 7B.Table 7A - 5HT2A / 7?) (agonist radioligand)Compound ICSo(M) K(M) nH1-43 7.4E-08 M 5.6E-08 M 1.01-33 1.9E-07 M 1.4E-07 M 0.9Table 7B - 5HT2B(7?) (agonist radioligand)Compound ICSo(M) K(M) nH1-213 2.1E-07 M 1.0E-07 M 0.61-42 3.1E-07 M 1.5E-07 M 0.81-32 1.6E-08 M 8.1E-09 M 1.31-29 1.6E-08 M 7.8E-09 M 1.01-16 3.4E-07 M 1.7E-07 M 0.91-33 6.5E-08 M 3.2E-08 M 0.81-215 1.0E-08 M 5.1E-09 M 0.9Reference Agonists5-HTIA(A) (agonist radioligand IC50(M) Ki(M) nH [125I](±)DOI 2.5E-10 M 1.9E-10 M 0.8 5-HTIB(A) (agonist radioligand)[125I](±)DOI 2.0E-09 M 1.0E-09 M 2.0[125I](±)DOI 1.7E-09 M 8.3E-10 M 1.0 6.25-HTIA (h) and 5-HTIB (h) agonism against serotonin

[0267] The 5-HT2A (h) (agonist effect) and 5-HT2B (h) (agonist effect) ECso (M) concentrations of compounds described herein are provided in Table 8A and Table 8B.Table 8A - 5-HT2A(7?) (agonist effect)Compound ECSo(M) nH Emax(%)1-209 N. C. n / a N. C.1-213 > 1.0E-05 n / a 321-41 N. C. n / a N. C.1-42 5.0E-07 M n / a 461-17 1.9E-06 M n / a 751-206 N. C. n / a N. C.1-210 4.7E-07 M n / a 61-215 N. C. n / a N. C.1-216 N. C. n / a N. C.1-24 N. C. n / a N. C.1-27 4.4E-07 M n / a 53Compound ECSo(M) nH Emax(%)1-30 N. C. n / a N. C.1-36 N. C. n / a N. C.1-217 1.8E-07 M n / a 351-38 N. C. n / a N. C.1-93 N. C. n / a N. C.1-221 N. C. n / a N. C.1-53 N. C. n / a N. C.Table 8B - 5-HT2B(7? (agonist effect)Compound ECSo(M) nH Emax(%)1-35 N. C. n / a N. C.1-34 N. C. n / a N. C.1-19 N. C. n / a N. C.1-59 N. C. n / a N. C.1-209 N. C. n / a N. C.1-213 N. C. n / a N. C.1-40 N. C. n / a N. C.1-17 N. C. n / a N. C.1-204 1.5E-05 M n / a 561-39 N. C. n / a N. C.1-6 N. C. n / a N. C.1-203 1.2E-06 M n / a 391-205 4.9E-07 M n / a 601-208 1.2E-06 M n / a 511-201 N. C. n / a N. C.1-210 7.8E-07 M n / a 291-211 1.8E-06 M n / a 511-214 2.0E-07 M n / a 321-215 N. C. n / a N. C.1-216 N. C. n / a N. C.1-24 N. C. n / a N. C.1-27 N. C. n / a N. C.1-30 N. C. n / a N. C.1-36 N. C. n / a N. C.1-217 N. C. n / a N. C.1-38 N. C. n / a N. C.1-93 N. C. n / a N. C.1-221 N. C. n / a N. C.1-53 2.2E-07 M n / a 53N. C.: ECso value not calculable. Concentration-response curve shows less than 25% effect at the highest validated testing concentration.> Cone.: EC50 value above the highest test concentration. Concentration-response curve shows less than 50 % effect at the highest validated testing concentrationReference Agonist ResultsCompound I. D. ECso(M) nH5-HTiA(Zt) (agonist effect)serotonin 1.2E-08 M n / a serotonin 1.2E-08 M n / a serotonin 1.1E-08 M n / a serotonin 9.2E-09 M n / a serotonin 1.3E-08 M n / a serotonin 1.1E-08 M n / a5-HT2B(ZI) (agonist effect)serotonin 3.8E-09 M n / a serotonin 5.3E-09 M n / a serotonin 3.5E-09 M n / a serotonin 5.4E-09 M n / a serotonin 4.2E-09 M n / a serotonin 4.0E-09 M n / a serotonin 3.7E-09 M n / a serotonin 4.3E-09 M n / a serotonin 8.6E-09 M n / aserotonin 8.0E-09 M n / a6.35-HTIA (h) antagonism against ketanserin and 5HTIB (h) antagonism against SB-206553

[0268] Table 9A and Table 9B provide in vitro 5-HT2A (A) (antagonist effect) inhibition of compounds described herein against ketanserin and 5-HT2B (Ji) (antagonist effect) inhibition of compounds described herein against SB-206553. IC50 (M) concentrations are also provided.Table 9A - 5-HT2 / / 7 (antagonist effect)Compound ICSo(M) KB(M) nH1-42 2.3E-05 M 4.6E-06 M n / a1-32 1.3E-06 M 2.5E-07 M n / a1-207 4.1E-06 M 8.2E-07 M n / a1-220 7.7E-06 M 1.5E-06 M n / aTable 9B - 5-HT? B ^) (antagonist effect)Compound ICSo(M) KB(M) nH1-43 > 3.0E-05 n / a n / aCompound ICSo(M) KB(M) nH1-16 3.7E-06M 5.6E-07M n / a> Cone.: IC50 value above the highest test concentration. Concentration-response curve shows less than 50 % effect at the highest validated testing concentrationReference Antagonists5-HTIA(A) (antagonist effect) IC50(M) KB(M) nH ketanserin 1.5E-08 M 3.0E-09M n / a ketanserin 1.3E-08 M 2.6E-09 M n / a 5-HT2B(A) (antagonist effect)SB-206553 5.2E-08 M 8.0E-09 M n / a Example 7. Gq Cellular Functional Assays - 5-HTIA antagonist and 5-HTIB antagonist assays

[0269] Compounds were tested at several concentrations for IC50 or EC50 determination in cellular and nuclear receptor functional assays. Cellular agonist effect was calculated as a % of control response to a known reference agonist for each target and cellular antagonist effect was calculated as a % inhibition of control reference agonist response for each target.

[0270] Results showing a stimulation or an inhibition higher than 50% represent significant effects of the test compounds. 50% is generally the cut-off value for further investigation (determination of EC50 or IC50 values from concentration-response curves).

[0271] Results showing a stimulation or an inhibition between 25% and 50% represent weak to moderate effects.

[0272] Results showing a stimulation or an inhibition lower than 25% are not considered significant and mostly attributable to variability of the signal around the control level.7.15-HTIA (h) antagonism against ketanserin and 5-HTIB (h) antagonism against SB-206553

[0273] The 5-HT2A (Ji) (antagonist effect) against ketanserin and 5-HT2B (Ji) (antagonist effect) against SB-206533 for compounds described herein are provided in Table 10A and Table 10B. IC50 (M) concentrations are also provided.Table 10A - 5HT2A / 7I) (antagonist effect)Compound ICso(M) KB(M) nH1-6 4.7E-07 M 9.3E-08 M n / a1-215 4.5E-07M 9.1E-08 M n / aCompound IC5o(M) KB(M) nH1-23 N. C. n / a n / a1-225 7.5E-06M 1.5E-06M n / a1-210 N. C. n / a n / a1-211 6.0E-06 M 1.2E-06M n / aTable 10B - 5HT21 / 7J (antagonist effect)Compound ICso(M) KB(M) nH1-225 4.5E-06M 6.8E-07M n / a1-210 4.1E-06M 6.3E-07M n / a1-211 2.4E-06 M 3.6E-07M n / aN. C.: IC50 value not calculable. Concentration-response curve shows less than 25% effect at the highest validated testing concentration.Reference Antagonists5-HT2A(7Z) (antagonist effect) ICso(M) KB(M) nH ketanserin 1.6E-08 M 3.3E-09 M n / a ketanserin 1.6E-08 M 3.2E-09 M n / a 5-HT2B( / 7) (antagonist effect)SB-206553 4.0E-08 M 6.1E-09 M n / aSB-206553 2.8E-08 M 4.2E-09 M n / aAssay Source Stimulus Incubation Measured Component 5-HT2A (h) human recombinant serotonin 30 min IPi(antagonist effect) (HEK-293 cells) (100 nM) 37°C5-HT2B (h) human recombinant serotonin 30 min IPi(antagonist effect) (CHO cells) (30 nM) 37°CIPi = inositol monophosphate biomarkerExample 8. Human 5-HTIA receptor binding assay

[0274] Compounds of the present disclosure were evaluated in the 5-HT2A (Ji) (agonist radioligand) assay. Compounds were tested at several concentrations for IC50 or EC50 determination. Compound binding was calculated as a % inhibition of the binding of a ligand specific for each target.

[0275] Results showing an inhibition (or stimulation for assays run in basal conditions) higher than 50% represent significant effects of the test compounds. 50% is generally the cutoff value for further investigation (determination of IC50 or EC50 values from concentration-response curves).

[0276] Results showing an inhibition (or stimulation) between 25% and 50% represent weak to moderate effects. Results showing an inhibition (or stimulation) lower than 25% are not considered significant and mostly attributable to variability of the signal around the control level. Low to moderate negative values are also not considered significant and are attributable to variability of the signal around the control level. High negative values (> 50%) that are sometimes obtained with high concentrations of test compounds are generally attributable to non- specific effects of the test compounds in the assays. In some embodiments, the results suggest an allosteric effect of the test compound.8.1 - 5-HTIA (h) agonism against ([125I](±)DOI

[0277] The 5-HT2A (h) (agonism effect) ICso (M) concentrations of compounds of the present disclosure against [125I](±)DOI are provided in Table 11.Table 11 - 5HT2A^1 - (agonist radioligand)Compound ICS0(M) Ki(M) nH1-6 1.5E-08 M 1.1E-08 M 0.81-19 4.4E-06 M 3.3E-06 M 1.01-20 3.2E-08 M 2.4E-08 M 0.91-212 2.1E-08 M 1.6E-08 M 0.71-213 1.8E-07 M 1.3E-07 M 0.71-215 7.1E-09 M 5.3E-09 M 1.21-22 1.2E-06 M 8.6E-07 M 0.61-24 8.7E-08 M 6.5E-08 M 0.9Reference Agonist5-HTIA(A) (agonist radioligand) IC50(M) Ki(M) nH [125I](±)DOI 2.2E-10 M 1.7E-10 M 0.7 [125I](±)DOI 2.6E-10 M 1.9E-10 M 1.09.4E-11 M 7.1E-11 M 0.9[125I](±)DOIAssay Source Ligand Cone. Kd Non Incubation Specific5-HT2A (h) human [125I](±)DOI 0.1 0.3 (±)DOI 60 min (agonist recombinant nM nM (I pM) room radioligand) (HEK-293 cells)temperature Example 9. Human 5-HTIB receptor binding assay

[0278] Compounds of the present disclosure were evaluated in the 5-HT2B (h) (antagonisteffect) assay. Compounds were tested at several concentrations for IC50 or EC50 determination.

[0279] Cellular agonist effects were calculated as a % of control response to a known reference agonist for each target and cellular antagonist effect was calculated as a % inhibition of control reference agonist response for each target.

[0280] Results showing a stimulation or an inhibition higher than 50% represent significant effects of the test compounds. 50% is generally the cut-off value for further investigation (determination of ECso or ICso values from concentration-response curves).

[0281] Results showing stimulation or an inhibition between 25% and 50% represent weak to moderate effects.

[0282] Results showing stimulation or an inhibition lower than 25% are not considered significant and mostly attributable to variability of the signal around the control level.9.15-HTIB (h) antagonism against SB-206553

[0283] The ICso (M) concentrations and 5-HT2B (A) (antagonism effect) of compounds described herein against SB-206553 are provided in Table 12.Table 12 - 5HT2i / b (antagonist effect)Compound ICS0(M) KB(M) nH1-6 1.4E-07 M 2.1E-08 M n / a1-20 > 3.0E-06 n / a n / a1-212 2.8E-06 M 4.3E-07 M n / a1-215 6.9E-07 M 1.0E-07 M n / a> Cone.: IC50 value above the highest test concentration. Concentration-response curve shows less than 50 % effect at the highest validated testing concentrationReference Antagonist5-HT2B(A) (antagonist effect) IC5O(M) KB(M) nHSB-206553 3.7E-08 M 5.6E-09 M n / aSB-206553 2.8E-08 M 4.2E-09 M n / aSB-206553 4.2E-08 M 6.3E-09 Mn / aExample 10. Mouse Head Twitch Response (HTR) Study

[0284] HC1 salts of compounds of the present disclosure were prepared for injection as 0.1 mg / kg doses for delivery as a standard injection volume of 5 mL / kg in 5% DMSO + 95% normal saline.

[0285] Fifteen groups of eight male C57BL / 6 mice (age: 8-10 weeks; weight: 25-30 g; 130 (120 + 10 extra)) were selected as the test system to evaluate the effect of test compound on head twitch response (HTR).

[0286] A total of 130 (120 + 10 extra) male C57BL / 6 mice were allowed to quarantine for 3 days and acclimatized for 1 day in an experimental lab prior to study initiation. During this period, the mice were observed daily for clinical signs. Animals with any abnormalities, ill health, or poor physical condition were excluded from the study. 130 (120 + 10 extra) male C57BL / 6 mice were randomized based on their body weight into 15 groups with 8 animals per group. All the extra animals were euthanized. Each dose (5 mL / kg) was administered as a single dose, subcutaneously, according to Table 13.Table 13Dose ConcentrationGroup Treatment (mg / kg) (mg / mL)G1 Vehicle - 0ControlG2 1-67 HC1 0.1 0.02G3 1-217 HC1 0.1 0.02G4 1-6 HC1 0.1 0.02G5 1-6 HC1 0.03 0.006G6 1-40 HC1 0.1 0.02G7 1-15 HC1 0.1 0.02G8 1-36 HC1 0.1 0.02G9 1-56 HC1 0.1 0.02G10 1-42 HC1 0.1 0.02Gil 1-23 HC1 0.1 0.02G12 1-216 HC1 0.1 0.02G13 1-210 HC1 0.1 0.02G14 1-35 HC1 0.1 0.02G15 1-219 HC1 0.1 0.02Experimental Protocol and Dose Administration

[0287] All male C57BL / 6 mice 130 (120+10 extra) were quarantined for 3 days and acclimatized for 1 day prior to experiment initiation. During this period, all the mice were observed daily for clinical signs.

[0288] All the animals were weighed and randomized into 15 different groups based onbody weight. All the test compounds were freshly formulated, within 15 minutes of dose administration to respective animals of each group as per the body weight. Animals of Gl, Vehicle control group, were administered with vehicle. G2, G3, G4, G5, G6, G7, G8, G9, GIO, Gl 1, G12, G13, G14 & G15 groups were administered with single dose of 1-67 HC1, 1-217 HC1, 1-6 HC1, 1-40 HC1, 1-15 HC1, 1-36 HC1, 1-56 HC1, 1-42 HC1, 1-23 HC1, 1-216 HC1, 1-35 HC1, and 1-219 HC1 O.lmg / kg and 1-6 HC10.03 mg / kg respectively. The study was conducted in two cohorts with equal distribution of animals (4+4) in all the two cohorts. Scheduled time points for Head Twitch Response for different groups are provided below.Day / Group Gl G2 G3 G4 G5 G6 G7 G8 G9Day 1y y y y y y y y yDay / Group G10 Gil G12 G13 G14 G15Day 1y y y y y yHead Twitch Response

[0289] The head-twitch response (HTR) is a rhythmic paroxysmal rotational head movement that occurs in mice and rats in response to 5-HT2A receptor activation. The HTR was first observed in mice after administration of the 5-HT precursor 5-hydroxytryptophan and was later shown to be induced by a variety of serotonergic hallucinogens, including LSD and DOI. Most importantly, selective 5-HT2A antagonists block the HTR induced by DOI and other hallucinogens. Most commonly, a trained person observes the animals directly and counts the number of head twitches. Alternatively, the behavior of the test animals is video recorded for off-line assessment. Head twitch response was counted by a blinded observer from recorded videos for the entire Ih session.

[0290] All data was expressed as Mean ± SEM. Data on each parameter was summarized in tabular form. Appropriate graphical representation was done using suitable method.Statistical analysis was done with GraphPad Prism-9 using one-way ANOVA followed by Dunnetts’s post hoc test. Data were considered statistically significant if P value is less than 0.05.Body weight

[0291] The effect of compounds of the disclosure on body weight of mice is shown in Table 14. The body weight was recorded on the day of randomization and dosing with test compounds. All the treatment groups did not show any significant difference in the bodyweights when compared to G1 vehicle control group.Table 14: Body WeightTreatment Group Day 1 Weight (g)Gl, Vehicle Control, 2 mL / kg, SC 22.39 ± 0.98G2, 1-67 HC1 O.lmg / kg, SC, QD 22.31 ± 0.81G3, 1-217 HC1 O.lmg / kg, SC, QD. 22.24 ± 0.75G4, 1-6 HC1 O.lmg / kg, SC, QD 22.20 ± 0.68G5, 1-6 HC10.03mg / kg, SC, QD 22.14 ± 0.63G6, 1-40 HC1 O.lmg / kg, SC, QD. 22.13 ± 0.59G7, 1-15 HC1 O.lmg / kg, SC, QD. 22.10 ± 0.57G8, 1-36 HC1 O.lmg / kg, SC, QD 22.10 ± 0.55G9, 1-56 HC1 O.lmg / kg, SC, QD. 22.13 ± 0.52GIO, 1-42 HC1 O.lmg / kg, SC, QD 22.10 ± 0.52Gil, 1-23 HC1 O.lmg / kg, SC, QD 22.09 ± 0.48G12, 1-216 HC1 O.lmg / kg, SC, QD 22.09 ± 0.48G13, 1-210 HC1 O.lmg / kg, SC, QD 22.09± 0.48G14, 1-35 HC1 O.lmg / kg, SC, QD 22.10 ± 0.49G15, 1-219 HC1 O.lmg / kg, SC, QD. 22.13 ± 0.49Data is shown as Mean ± S. E. M (n=8)Head Twitch Response

[0292] Head twitch response counts for each group are shown in Table 15.Table 15: Effect of compounds on HTR on Dav 1 (60 minutes)Treatment Group HTR Count (Sec) Gl, Vehicle Control, 2 mL / kg, SC 1.25 ± 0.16 G2, 1-67 HC1 O.lmg / kg, SC, QD 4.25 ± 0.25**G3, 1-217 HC1 O.lmg / kg, SC, QD. 5.25 ± 0.62****G4, 1-6 HC1 O.lmg / kg, SC, QD 5.75 ± 0.73**** G5, 1-6 HC1 0.03mg / kg, SC, QD 4.13 ± 0.88** G6, 1-40 HC1 O.lmg / kg, SC, QD. 3.00 ± 0.38 G7, 1-15 HC1 O.lmg / kg, SC, QD. 3.75 ± 0.53* G8, 1-36 HC1 O.lmg / kg, SC, QD 4.50 ± 0.73*** G9, 1-56 HC1 O.lmg / kg, SC, QD. 4.63 ± 0.53*** G10, 1-42 HC1 O.lmg / kg, SC, QD 4.25 ± 0.37** Gil, 1-23 HC1 O.lmg / kg, SC, QD 5.00 ± 0.38**** G12, 1-216 HC1 O.lmg / kg, SC, QD 5.38 ± 0.46**** G13, 1-210 HC1 O.lmg / kg, SC, QD 5.13 ± 0.48**** G14, 1-35 HC1 O.lmg / kg, SC, QD 5.50 ± 0.73**** G15, 1-219 HC1 O.lmg / kg, SC, QD. 10.50 ± 0.63****Data is shown as Mean ± SEM, n=8* Significant difference as compared to Gl, Vehicle ControlOne-way ANOVA followed by Dunnett’s Multiple Comparison Test.*P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001.Example 11. Rat Head Twitch Response and Forced Swim Test Study

[0293] Vehicle (Test & Reference Compound): 5% DMSO + 95% normal saline.Quarantine and Acclimatization

[0294] A total of 116 (96 + 12 extra) male Wistar rats were allowed to quarantine for 3 days and acclimatized for 1 day in an experimental lab prior to study initiation. During this period, the rats were observed daily for clinical signs. Animals with any abnormalities, ill health or poor physical condition were excluded from the study.

[0295] Rats were randomized based on their body weight into 12 groups with 8 animals in a group as shown in Table 16.Table 16Route ofDose Dose administration, ConcentrationGroup Treatment (mg / kg) Volume Dosing (mg / mL)(mL / kg) frequency,Regimen VehicleG1 - 0 2 Single dose, SC ControlG2 1-219 0.3 0.15 2 Single dose, SC G3 1-67 0.03 0.015 2 Single dose, SC G4 1-67 0.3 0.15 2 Single dose, SC G5 1-42 0.03 0.015 2 Single dose, SC G6 1-42 0.3 0.15 2 Single dose, SC G7 1-216 0.03 0.015 2 Single dose, SC G8 1-216 0.3 0.15 2 Single dose, SC G9 1-217 0.03 0.015 2 Single dose, SC G10 1-217 0.3 0.15 2 Single dose, SC Gil 1-6 0.03 0.015 2 Single dose, SCG12 1-6 0.3 0.15 2 Single dose, SC

[0296] On Day -4, Pre-swim FST were performed for all the animals for 15 minutes. Again, on day -3 FST were performed for 5 minutes. On Day 0 all the animals were randomized based on FST outcome and body weights into 12 different groups.

[0297] On Day 1, an exemplary compound of the present disclosure was formulated and administered to respective animals of each group.

[0298] On Day 1 after dosing, HTR was performed and recorded for 1 Hour. On Day 7, animals were subjected to FST in a glass cylinder for the duration of 5 minutes.

[0299] The cages were transferred from the holding room to the experiment room 1 hour before the start of experiment to acclimatize the animals. For HTR, the set up was built using a camera to record each animal. Immediately after drug administration, all the animals were transferred to the transparent observational chamber. Animals were observed for 1 hour and observation was recorded by using a camera. The number of head twitches in Ih (60 min) was counted from the video recording. (The observer was blinded to the treatment groups).

[0300] For FST all animals were placed individually in a glass cylinder (20 cm in diameter X 45 cm in height) containing 35 cm of water, with water temperature being maintained at 25±1°C. A camera located directly in front of the cylinder, records the session of 5 minutes. Predominant behaviors such as immobility time, swimming time (Sec.) and climbing time (Sec.) were measured by blinded observer from recorded videos using a stopwatch for theentire 5 min session. After FST recording, all the animals were handed over to PK team for bioanalysis.

[0301] Note: The study was conducted in four cohorts with equal distribution of animals (2+2+2+2) in all the four cohorts.Scheduled time points for Head Twitch Response for different groups Head Twitch Response (HTR)Day / Group G1 G2 G3 G4 G5 G6Day 1 y y y y y y Day / Group G7 G8 G9 G10 Gil G12Day 1 y y y y y yScheduled time points for Forced Swim test for different groups Forced Swim Test (FST)Day / Group G1 G2 G3 G4 G5 G6 Day -4 (Pre-swim) y y y y y yDay -3 (FST Basal) y y y y y yDay 7 (FST Final) y y y y y yDay / Group G7 G8 G9 G10 Gil G12 Day -4 (Pre-swim) y y y y y y Day -3 (FST Basal) y y y y y yDay 7 (FST Final) y y y y y yBody Weight

[0302] The body weight of each animal was recorded on Day 0, 3 and 7.Forced Swim Test

[0303] Immobility time (seconds), swimming time (seconds), and climbing time (seconds) were measured by a blinded observer from recorded videos during a forced-swim test using a stopwatch for the entire 5-minute session.Head Twitch Response

[0304] Immediately after drug administration, all the animals were transferred to the transparent observational chamber. Head Twitch Response were recorded using camera for 1 hour. The number of head twitches in Ih (60 min) were counted from the video recording in 10 min bins. Rapid rhythmic reciprocal head movement that occurred in mice during observation was considered as head twitch response. Head twitch response was counted by ablinded observer from recorded videos for the entire Ih session.

[0305] All data was expressed as the Mean ± SEM. Data on each parameter was summarized in tabular form. Appropriate graphical representation was done using suitable method. Statistical analysis was done with GraphPad Prism-9 using one-way ANOVA followed by Dunnetts’s post hoc test. Data were considered statistically significant if P value is less than 0.05.

[0306] The body weight was recorded on the day of randomization, day 0, day 3 and on day 7. The results are summarized in Table 17. All the treatment groups did not show any significant difference in the body weights when compared to G1 vehicle control group.Table 17: Body Weight (grams)Treatment Group Day 0 Day 3 Day 7 Gl, Vehicle Control (2 mL / kg,265.74 ± 8.07 284.20 ± 9.06 330.64 ± 10.69 SC, Single Dose)G2, 1-219 (0.3 mg / kg, SC, Single262.94 ± 6.04 281.88 ± 5.91 318.39 ± 6.18 Dose)G3, 1-67 (0.03 mg / kg, SC, Single275.56 ± 9.98 296.35 ± 11.26 336.95 ± 7.95 Dose)G4, 1-67 (0.3 mg / kg, SC, Single272.65 ± 8.77 291.84 ± 10.29 329.88 ± 9.47 Dose)G5, 1-42 (0.03 mg / kg, SC, Single278.49 ± 11.16 299.43 ± 11.32 334.73 ± 10.97 Dose)G6, 1-42 (0.3 mg / kg, SC, Single260.54 ± 6.12 274.03 ± 4.43 314.13 ± 6.30 Dose)G7, 1-216 (0.03 mg / kg, SC,272.69 ± 7.46 286.16 ± 5.64 325.05 ± 9.25 Single Dose)G8, 1-216 (0.3 mg / kg, SC, Single272.13 ± 5.13 287.53 ± 5.34 332.91 ± 8.02 Dose)G9, 1-217 (0.03 mg / kg, SC,269.79 ± 8.61 290.20 ± 7.48 332.63 ± 8.60 Single Dose)G10, 1-217 (0.3 mg / kg, SC,257.19 ± 10.24 278.85 ± 9.11 317.45 ± 8.87 Single Dose)Gil, 1-6 (0.03 mg / kg, SC, Single268.43 ± 5.41 286.46 ± 6.09 325.35 ± 6.77 Dose)G12, 1-6 (0.3 mg / kg, SC, Single272.40 ± 5.52 292.79 ± 7.07 334.10 ± 8.62Dose)Data is shown as Mean ± S. E. M (n=8)Forced Swim Test

[0307] Results of the FST are provided in Table 18 (Day -1) and Table 19 (Day 7).Table 18: Effect of Test Compounds on FST at Day (-1)Cumulative Scoring (MEAN± SEM) Treatment Group ImmobilitySwimming time Climbing time time(Sec) (Sec) (Sec)Gl, Vehicle Control (2 mL / kg, SC, SingleDose) 45.75 ± 8.39 89.25 ± 4.08 165.00 ± 8.24 G2, 1-219 (0.3 mg / kg, SC, Single Dose) 55.75 ± 6.39 75.50 ± 10.30 168.75 ± 7.14 G3, 1-67 (0.03 mg / kg, SC, Single Dose) 60.75 ± 9.67 75.00 ± 12.24 164.25 ± 9.65 G4, 1-67 (0.3 mg / kg, SC, Single Dose) 54.50 ± 5.62 82.50 ± 6.44 163.00 ± 9.13 G5, 1-42 (0.03 mg / kg, SC, Single Dose) 41.75 ± 5.68 105.75 ± 9.92 152.50 ± 7.79 G6, 1-42 (0.3 mg / kg, SC, Single Dose) 57.50 ± 4.94 88.63 ± 9.77 153.88 ± 7.27 G7, 1-216 (0.03 mg / kg, SC, Single Dose) 62.75 ± 7.63 84.25 ± 8.48 153.00 ± 7.33 G8, 1-216 (0.3 mg / kg, SC, Single Dose) 73.88 ± 7.93 80.88 ± 11.49 145.25 ± 6.41 G9, 1-217 (0.03 mg / kg, SC, Single Dose) 64.25 ± 7.47 90.13 ± 10.94 145.63 ± 7.77 G10, 1-217 (0.3 mg / kg, SC, Single Dose) 52.00 ± 8.07 103.63 ± 8.39 144.38 ± 6.90 Gil, 1-6 (0.03 mg / kg, SC, Single Dose) 36.75 ± 3.50 118.75 ± 5.70 144.50 ± 5.04G12, 1-6 (0.3 mg / kg, SC, Single Dose) 48.38 ± 7.15 105.25 ± 7.38 146.38 ± 4.07Data is shown as Mean ± S. E. M (n=8)Table 19: Effect of Test Compounds on FST at Day 7Cumulative Scoring (MEAN± SEM) Treatment Group ImmobilitySwimming time Climbing time time(Sec) (Sec) (Sec)Gl, Vehicle Control(2 mL / kg, SC, Single Dose) 66.13 ± 5.95 101.88 ± 8.97 132.00 ± 10.45 G2, 1-219(0.3 mg / kg, SC, Single Dose) 75.88 ± 7.16 144.13 ± 9.18 80.00 ± 5.97 G3, 1-67(0.03 mg / kg, SC, Single Dose) 53.88 ± 8.83 161.13 ± 6.93 85.00 ± 3.80 G4, 1-67(0.3 mg / kg, SC, Single Dose) 78.88 ± 8.93 153.75 ± 8.86 67.38 ± 7.36 G5, 1-42(0.03 mg / kg, SC, Single Dose) 38.50 ± 6.38 143.38 ± 10.25 118.13 ± 7.47 G6, 1-42(0.3 mg / kg, SC, Single Dose) 78.25 ± 8.72 110.50 ± 4.98 111.25 ± 8.71 G7, 1-216(0.03 mg / kg, SC, Single Dose) 78.50 ± 10.10 160.00 ± 7.71 61.50 ± 6.84 G8, 1-216(0.3 mg / kg, SC, Single Dose) 76.63 ± 7.52 151.88 ± 6.96 71.50 ± 9.42G9, 1-217(0.03 mg / kg, SC, Single Dose) 75.38 ± 17.23 124.50 ± 14.30 100.13 ± 11.19 G10, 1-217 (0.3 mg / kg, SC, SingleDose) 63.88 ± 8.94 162.75 ± 14.08 73.38 ± 11.71 Gil, 1-6(0.03 mg / kg, SC, Single Dose) 73.63 ± 7.35 155.00 ± 3.81 71.38 ± 8.52 G12, 1-6(0.3 mg / kg, SC, Single Dose) 91.25 ± 12.21 135.13 ± 8.25 73.63 ± 10.94Data is shown as Mean ± S. E. M (n=8)Head Twitch Response

[0308] The results of the HTR test are shown in Table 20.Table 20: Effect of Test compounds on HTR on Day 1 (60 minutes)Treatment Group HTR Count (Sec) Gl, Vehicle Control (2 mL / kg, SC, Single Dose) 1.38 ± 0.18G2, 1-219 (0.3 mg / kg, SC, Single Dose) 4.50 ± 4.00G3, 1-67 (0.03 mg / kg, SC, Single Dose) 2.75 ± 0.37G4, 1-67 (0.3 mg / kg, SC, Single Dose) 3.13 ± 0.48G5, 1-42 (0.03 mg / kg, SC, Single Dose) 3.25 ± 0.31G6, 1-42 (0.3 mg / kg, SC, Single Dose) 3.75 ± 0.31G7, 1-216 (0.03 mg / kg, SC, Single Dose) 3.25 ± 0.37G8, 1-216 (0.3 mg / kg, SC, Single Dose) 3.75 ± 0.45G9, 1-217 (0.03 mg / kg, SC, Single Dose) 2.63 ± 0.46G10, 1-217 (0.3 mg / kg, SC, Single Dose) 2.38 ± 0.42Gil, 1-6 (0.03 mg / kg, SC, Single Dose) 2.88 ± 0.23G12, 1-6 (0.3 mg / kg, SC, Single Dose) 2.63 ± 0.56Example 12. Rat Head Twitch Response and Forced Swim Test Study II

[0309] Vehicle (Test & Reference Compound): 10 mM Sodium Citrate Buffer, pH 4.5.Formulation DetailsPreparation of 10 mM Citrate buffer (pH 4.5):

[0310] 1355.45mg of sodium citrate dihydrate (5.45mM) and 1136.35mg citric acid monohydrate (4.55mM) were weighed in clean volumetric flask. 3 / 4th volume of distilled water was added and subject to vortex and sonication (water bath) till solid chemical completely get solubilized and form a clear solution. The volume was made up to 1000 mL volume till the mark with distilled water and vortexed. The pH was checked for 4.45.Test Compound I 1-6 HC1Dose: 0.3 mg / kg & 30 mg / kgRoute of Administration: Subcutaneous and PeroralDose volume: 2 mL / kg & 5 mL / kg

[0311] Formulations of 1-6 HC1 were prepared as follows: 1.14 mg and 21.58mg of 1-6 HC1 were weighed and transferred to separate amber colored schott bottles. Then, 6.458mL and 3.056mL of 10 mM citrate buffer were added, respectively, and vortex mixed to provide a clear solution at a concentration of 0.15 mg / mL and 6 mg / mL. The formulation was prepared fresh before administration.Test Compound II: 1-59 Free baseDose: 0.3 mg / kg & 30 mg / kgRoute of Administration: Subcutaneous and PeroralDose volume: 2 mL / kg & 5 mL / kg

[0312] Formulations of 1-59 were prepared as follows: 1.08 mg and 21.12mg of 1-59 were weighed and transferred to separate amber colored schott bottles. Then, 7.074mL and 3.458mL of 10 mM citrate buffer were added, respectively, and vortex mixed to provide a clear solution at a concentration of 0.15 mg / mL and 6 mg / mL. The formulation was prepared fresh before administration.Test Compound III: 1-36 HC1Dose: 0.03 mg / kgRoute of Administration: SubcutaneousDose volume: 2 mL / kg

[0313] A formulation of 1-36 HC1 was prepared as follows: 0.6mg 1-36 HC1 was weighed and transferred to an amber colored schott bottle. Then, 34.768 mL of 10 mM citrate buffer was added, and vortex mixed to provide a clear solution at a concentration of 0.015 mg / mL test compound. The formulation was prepared fresh before administration.Test Compound IV: 1-24 HC1Dose: 0.03 mg / kgRoute of Administration: SubcutaneousDose volume: 2 mL / kg

[0314] A formulation of 1-24 HC1 was prepared as follows: 0.77mg 1-24 HC1 was weighed and transferred to an amber colored schott bottle. Then, 45.035 mL of 10 mM citrate buffer was added, and vortex mixed to provide a clear solution at a concentration of 0.015 mg / mL test compound. The formulation was prepared fresh before administration.Test Compound V 1-226Dose 0.03 mg / kgRoute of Administration SubcutaneousDose volume 2 mL / kg

[0315] A formulation of 1-226 was prepared as follows: 0.45 mg 1-226 was weighed and transferred to an amber colored schott bottle. Then, 26.440 mL of 10 mM citrate buffer was added, and vortex mixed to provide a clear solution at a concentration of 0.015 mg / mL test compound. The formulation was prepared fresh before administration.Reference compound 1-219 HC1Dose 0.3 mg / kg & 30 mg / kgDose volume 2 mL / kg & 5 mL / kg

[0316] Formulations of 1-219 were prepared as follows: 1.07mg and 21.38mg of 1-219 HC1 were weighed and transferred to separate amber colored schott bottles. Then, 6.112mL and 3.053mL of 10 mM citrate buffer were added, respectively, and vortex mixed to provide a clear solution at concentrations of 0.15mg / mL and 6mg / mL test compound. The formulation was prepared fresh before administration.Test System DetailsSpecies: RatStrain: WistarSex: MaleAge: 8-10 weeksBody weight: 200-300 gTotal no. of animals: 120 (96+24 extra)No. of animals / group: 7-8Quarantine and Acclimatization

[0317] A total of 120 (96 + 24 extra) male Wistar rats were allowed to quarantine for 3 days and acclimatized for 1 days in an experimental lab prior to study initiation. During this period, the rats were observed daily for clinical signs.Animal Randomization

[0318] 120 (96 + 24 extra) male Wistar rats were randomized based on their body weight and immobility time into groups with 7-8 animals in a group as shown in Table 21. Extra animals were used for blank sample preparation.Table 21DoseDose ConcentrationVolumeGroup Treatment (mg / kg) (mg / mL)(mL / kg)VehicleG1 - 0 2ControlVehicleG2 - 0 5ControlG3 1-219 HC1 30 6 5G4 1-219 HC1 0.3 0.15 2G5 1-6 HC1 30 6 5G6 1-6 HC1 0.3 0.15 2G7 1-59 30 6 5G8 1-59 0.3 0.15 2G10 1-36 HC1 0.03 0.015 2Gil 1-24 HC1 0.03 0.015 2G12 1-224 HC1 0.03 0.015 2

[0319] After quarantine and acclimatization, on day -4, Pre-swim FST was performed for all the animals for 15 minutes. Then, on day -3 FST was performed for 5 minutes. On Day 0 all the animals were randomized based on FST outcome (immobility) and body weights into 13 different groups.

[0320] On Day 1 test compounds were formulated and administered to respective animals of each group according to the body weight.

[0321] Animals of G1 and G2, Vehicle control groups, were administered with vehicle SC and PO respectively. On Day 1 immediately after dosing, animals were recorded for HTR for 1 Hour. On Day 7 animals were subjected to FST in a glass cylinder for the duration of 5 minutes.

[0322] The cages were transferred from the holding room to the experiment room 1 hour before the start of the experiment to acclimatize the animals. For HTR, the set up was built using a camera to record each animal. Immediately after drug administration, all the animals were transferred to the transparent observational chamber. Animals were observed for 1 hour and observations were recorded by using a camera. The number of head twitches in Ih (60 min) were counted from the video recording (The observer was blinded to the treatment groups).

[0323] For FST all animals were placed individually in a glass cylinder (20 cm in diameter X 45 cm in height) containing 35 cm of water, with water temperature being maintained at 25+1 °C. A camera located directly in front of the cylinder, records the session for 5 minutes. Predominant behaviors such as immobility time, swimming time (Sec.) and climbing time (Sec.) were measured by blinded observer from recorded videos using a stopwatch for the entire 5 min session. After FST recording, all the animals were handed over to PK team for bioanalysis.Note: The study were conducted in four cohorts with equal distribution of animals (2+2+2+1) / (2+2+2+ 1) in all the four cohorts.Scheduled time points for Head Twitch Response for different groups Head Twitch Response (HTR)Day / Group G1 G2 G3 G4 G5 G6 G7 G8Day 1 y y y y y y y yDay / Group G10 Gil G12Day 1 y y yScheduled time points for Forced Swim test for different groups Forced Swim Test (FST)Day / Group G1 G2 G3 G4 G5 G6 Day -4 (Pre-swim) y y y y y y Day -3 (FST Basal) y y y y y yDay 7 (FST Final) y y y y y yDay / Group G7 G8 G10 Gil G12 Day -4 (Pre-swim) y y y y y Day -3 (FST Basal) y y y y yDay 7 (FST Final) y y y y yForced Swim Test

[0324] Immobility time (Sec.), swimming time (Sec.) and climbing time (Sec.) were measured by blinded observer from recorded videos during forced swim test using a stopwatch for the entire 5 min session.Head Twitch Response

[0325] Immediately after drug administration, all the animals were transferred to thetransparent observational chamber. Head Twitch Response were recorded using camera for 1 hour. The number of head twitches in Ih (60 min) were counted from the video recording in 10 min bins. Rapid rhythmic reciprocal head movement that occurred in rats during observation was considered as Head twitch response. Head twitch response was counted by blinded observer from recorded videos for the entire Ih session.

[0326] All data was expressed as the Mean ± SEM. Data on each parameter was summarized in tabular form. Appropriate graphical representation was done using suitable method. Statistical analysis was done with GraphPad Prism-9 using one-way ANOVA followed by Dunnetts’s post hoc test. Data were considered statistically significant if P value is less than 0.05.Body Weight

[0327] The body weight of each animal was recorded on Day 0, 3 and 7. The results are shown in Table 22.Table 22: Body Weight (grams)Treatment Group Day 0 Day 3 Day 7302.28 ± 323.98 ± 346.09 ± Gl, Vehicle Control, (2mL / kg, SC, Single dose) 7.76 9.46 7.52300.40 ± 320.39 ± 344.31 ± G2, Vehicle Control, (5mL / kg, PO, Single dose) 5.18 5.80 5.12302.13 ± 322.00 ± 344.13 ± G3, 1-219 HC1 (30 mg / kg, PO Single Dose) 5.68 5.39 7.33298.14 ± 317.80 ± 333.83 ± G4, 1-219 HC1 (0.3mg / kg, SC, Single Dose) 5.01 7.76 7.71296.43 ± 312.04 ± 336.06 ± G5, 1-6 HC1 (30, mg / kg, PO, Single Dose) 9.02 8.58 8.11299.83 ± 322.06 ± 345.71 ± G6, 1-6 HC1 (0.3 mg / kg, SC, Single Dose) 6.29 5.21 6.68299.21 ± 325.46 ± 349.13 ± G7, 1-59 (30 mg / kg, PO, Single Dose) 5.42 7.50 7.84300.83 ± 321.33 ± 346.93 ± G8, 1-59 (0.3 mg / kg, SC, Single Dose) 9.15 10.17 10.48292.74 ± 313.27± 333.71 ± G10, 1-36 HC1 (0.03 mg / kg, SC, Single Dose) 7.62 7.36 8.43299.97 ± 321.80± 343.56 ± Gl 1, 1-24 HC1 (0.03 mg / kg, SC, Single Dose) 5.76 5.15 3.80315.71 ± 335.80 ± 364.63 ± G12, 1-224 (0.03 mg / kg, SC, Single Dose) 10.70 11.81 13.34Rat FST

[0328] The results from the forced swim test are shown in Table 23 (Day 0) and Table 24 (Day 7).Table 23: Effect of Test Compounds on FST at Dav (0)Cumulative Scoring (MEAN± SEM) Treatment Group Immobility Climbing time Swimming timetime (Sec) (Sec)(Sec) Gl, Vehicle Control,(2mL / kg, SC, Single dose) 84.75 ± 5.01 68.38 ± 3.79 146.88 ± 2.40 G2, Vehicle Control,(5mL / kg, PO, Single dose) 92.63 ± 5.30 62.13 ± 3.58 145.25 ± 3.41 G3, 1-219 HC1 (30 mg / kg,PO Single Dose) 85.38 ± 2.96 68.00 ± 4.26 146.63 ± 2.98 G4, 1-219 HC1 (0.3mg / kg,SC, Single Dose) 88.29 ± 4.01 65.86 ± 3.51 145.86 ± 3.97 G5, 1-6 HC1 (30, mg / kg, PO,Single Dose) 88.88 ± 4.79 66.88 ± 3.60 144.25 ± 2.74 G6, 1-6 HC1 (0.3 mg / kg, SC,Single Dose) 78.29 ± 3.71 75.00 ± 3.67 146.71 ± 2.15 G7, 1-59 (30, mg / kg, PO,Single Dose) 91.38 ± 5.04 62.00 ± 3.25 146.63 ± 2.81 G8, 1-59 (0.3 mg / kg, SC,Single Dose) 80.71 ± 5.06 72.43 ± 3.62 146.86 ± 3.28 G10, 1-36 HC1 (0.03 mg / kg,SC, Single Dose) 76.57 ± 4.63 76.71 ± 4.33 146.71 ± 3.00 Gi l, 1-24 HC1 (0.03 mg / kg,SC, Single Dose) 76.43 ± 3.08 77.14 ± 3.69 146.43 ± 3.37 G12, 1-224 HC1 (0.03 mg / kg,SC, Single Dose) 87.00 ± 3.20 67.57 ± 2.82 145.43 ± 2.14Data is shown as Mean ± S. EM (n=7-8)Table 24: Effect of Test Compounds on FST at Dav 7 Cumulative Scoring (MEAN± SEM) Treatment Group Climbing time Swimming time Immobility time (Sec) (Sec) (Sec) Gl, Vehicle Control,(2mL / kg, SC, Single dose) 85.50 ± 3.64 63.50 ± 2.46 151.00 ± 4.64 G2, Vehicle Control,(5mL / kg, PO, Single dose) 91.00 ± 3.89 62.50 ± 2.61**** 146.50 ± 4.09**** G3, 1-219 HC1(30 mg / kg, PO Single Dose) 115.63 ± 3.62****** 107.75 ± 3.09******** 76.63 ± 2.65******** G4, 1-219 HC1(0.3mg / kg, SC, Single Dose) 107.00 ± 3.94* 104.86 ± 4.47**** 88.14 ± 2.81****G5, 1-6 HC1 114.88 ± 4.25****** 103.13 ± 3.61******** 82.00 ± 3.42********(30, mg / kg, PO, Single Dose)G6, 1-6 HC1(0.3 mg / kg, SC, Single Dose) 137.86 ± 6.49*** 83.14 ± 3.23**** 79.00 ± 5.30**** G7, 1-59(30, mg / kg, PO, Single Dose) 105.50 ± 3.48#113.25 ± 3.45*^ 81.25 ± 2.93^ G8, 1-59(0.3 mg / kg, SC, Single Dose) 104.00 ± 4.38* 102.86 ± 4.06**** 93.14 ± 2.93**** G10, 1-36 HC1(0.03 mg / kg, SC, Single Dose) 127.14 ± 5.99*** 90.71 ± 3.24**** 82.14 ± 2.91**** Gil, 1-24 HC1(0.03 mg / kg, SC, Single Dose) 117.00 ± 3.02*** 75.43 ± 2.77**** 107.57 ± 2.69**** G12, 1-224 HC1(0.03 mg / kg, SC, Single Dose) 96.43 ± 4.68 103.29 ± 3.54**** 100.29 ± 3.21****Data is shown as Mean ± S. E. M (n=7-8). * Significant difference as compared to Gl, Vehicle Control SC, # significant difference as compared to G2, Vehicle Control PO. One-way ANOVA followed by Dunnett’s Multiple Comparison Test.# / *P < 0.05, < 001### / ***p < o 001#### / ****p < o 0001Head Twitch Response

[0329] The results of the head twitch response test are shown in Table 25.Table 25: Effect of Test compounds on HTR Count on Dav 1 (60 minutes)Treatment Group HTR Count (Sec) Gl, Vehicle Control (2 mL / kg, SC, Single Dose) 1.25 ± 0.25G2, Vehicle Control (5 mL / kg, PO, Single Dose) 0.88 ± 0.23G3, 1-219 HC1 (30 mg / kg, PO Single Dose) 5.75 ± 0.65G4, 1-219 HC1 (0.3mg / kg, SC, Single Dose) 6.71 ± 0.52G5, 1-6 HC1 (30, mg / kg, PO, Single Dose) 3.13 ± 0.44G6, 1-6 HC1 (0.3 mg / kg, SC, Single Dose) 3.14 ± 0.40G7, 1-59 (30, mg / kg, PO, Single Dose) 5.50 ± 0.50 G8, 1-59 (0.3 mg / kg, SC, Single Dose) 4.71 ± 0.36 G10, 1-36 HC1 (0.03 mg / kg, SC, Single Dose) 2.86 ± 0.51Gl 1, 1-24 HC1 (0.03 mg / kg, SC, Single Dose) 2.86 ± 0.40G12, 1-224 HC1 (0.03 mg / kg, SC, Single Dose) 4.71 ± 0.75Example 13. Evaluation of Dose Dependent Effect of Compounds Described Herein on Head Twitch Response in Wistar ratsFormulation Preparation

[0330] 1-6 HC1 was evaluated using a 10 mM sodium citrate buffer, pH 4.5 vehicle (Vehicle 1). The buffer was prepared using the following procedure:

[0331] 1353.47mg of sodium citrate dihydrate (5.45mM) and 1135.22mg of citric acid monohydrate (4.55mM) were weighed in clean volumetric flask. 3 / 4th volume of distilledwater was added and subjected to vortex and sonication (water bath) until the solid was solubilized and formed a clear solution. The volume was made up to lOOmL with distilled water and vortexed. The pH was checked and adjusted to 4.49.

[0332] DOI and 4-OH-DiPT were evaluated using a normal saline vehicle (Vehicle 2).

[0333] Samples of the test compounds were prepared using the following procedures. For each, the planned dose volume was 2 mL / kg

[0334] 1-6 HC1 (10 mg / kg): 5.97mg of 1-6 HC1 was weighed and transferred to an amber colored schott bottle. 1.0259ml of sodium citrate buffer was added, and the mixture was vortexed until the compound dissolved, and a clear solution was observed at a concentration of 5mg / mL. This solution was used as a stock for corresponding dilutions to prepare formulations of 1-6 HC1 for dosing at 0.03 mg / kg, 0.1 mg / kg, 0.3 mg / kg, Img / kg and 3 mg / kg.

[0335] DOI (1 mg / kg): 1.94 mg of DOI was weighed and transferred to an amber colored schott bottle. 3.415 mL of saline was added, and the mixture was vortexed until the compound dissolved, and a clear solution was observed at a concentration of 0.5 mg / mL. The formulation was prepared fresh before administration.

[0336] 4-OH-DiPT HC1 (1 mg / kg): 2.19 mg of 4-OH DiPT was weighed into an amber colored schott bottle. 3.649mL of saline was added, and the mixture was vortexed until the compound dissolved, and a clear solution was observed at a concentration of 0.5 mg / mL. The formulation was prepared fresh before administration.Animal Details

[0337] For this study, male Wistar rats 8-10 weeks of age (Hylasco Bio-Technology Pvt. Ltd., Hyderabad) were used, each 200-300 g weight. A total of 90 (80 + 10 extra) rats were quarantined for 3 days and acclimatized for 1 day in an experimental lab prior to study initiation. During this period, the rats were observed daily for clinical signs. Animals with any abnormalities, ill health or poor physical condition were excluded from the study.Animal Randomization and Dosing

[0338] Rats were randomized based on their body weight into groups with 8 animals in a group according to Table 28.Table 28Group TreatmentDose Concentration Dose Route of (mg / kg) (mg / ml) Volume administration,(mL / kg) Dosing frequency, RegimenG1 Vehicle - 0 2 Single dose, SC ControlG2 4-OH-DiPT 1 0.5 2 Single dose, SC G3 DOI 1 0.5 2 Single dose, IP G4 1-6 HC1 0.03 0.015 2 Single dose, SC G5 1-6 HC1 0.1 0.05 2 Single dose, SC G6 1-6 HC1 0.3 0.15 2 Single dose, SC G7 1-6 HC1 1 0.5 2 Single dose, SC G8 1-6 HC1 3 1.5 2 Single dose, SC G9 1-6 HC1 10 5 2 Single dose, SC

[0339] All test compounds were freshly formulated within 15 minutes of dose administration to respective animals of each group as per the body weight. Following administration, the cages were transferred from the holding room to the experiment room 1 hour before the start of the experiment to acclimatize the animals. The setup was built using a camera to record each animal. Immediately after drug administration, all the animals were transferred to the transparent observational chamber. Animals were observed for 1 hour and observation was recorded by using a camera. The number of head twitches in 1 hr (60 min) were counted from the video recording. (The observer was blinded to the treatment groups).1.25 hr post recording the animals were sacrificed by carbon dioxide anaphylaxis, and their brain cortex was isolated. Blood was centrifuged at 4°C and 5000 RPM for 10 minutes to separate the plasma. Cortex and plasma samples were submitted for bioanalysis. The study was conducted in two cohorts with equal distribution of animals (4+4) in all the two cohorts.Results

[0340] All data was expressed as Mean ± SEM. Statistical analysis was done with GraphPad Prism-9 using one-way ANOVA and Two way ANOVA followed by Dunnetts’s post hoc test. Data were considered statistically significant if P value was less than 0.05.Body Weight

[0341] The body weight of each animal was recorded on the day of randomization and dosing. No treatment groups showed any significant difference in body weight when compared to G1 vehicle control group.Head Twitch Response

[0342] Immediately after drug administration, all the animals were transferred to the transparent observational chamber. Head Twitch Response (HTR) were recorded using a camera for 1 hour. The number of head twitches in 1 hr (60 min) were counted from the video recording in 10 min bins. Rapid rhythmic reciprocal head movement that occurred in rats during observation was considered as HTR. HTR was counted by a blinded observer from recorded videos for the entire Ih session. The results are shown in Table 29 and Figure 5.Table 29: Head Twitch Response (HTR) on Dav 1HTR Count Treatment Group(Sec)1.25 ± 0.31Gl, Vehicle Control, 2 ml / kg, SC17.38 ± 0.98****G2, 4-OH-DiPT HC1 1 mg / kg, SC, QD26.88 ± 1.99****G3, DOI Img / kg, IP, QD.2.75 ± 0.41G4, 1-6 HC10.03mg / kg, SC, QD3.75 ± 0.59G5, 1-6 HC10. Img / kg, SC, QD3.50 ± 0.46G6, 1-6 HC10.3mg / kg, SC, QD.4.50 ± 0.50G7, 1-6 HC1 Img / kg, SC, QD.4.38 ± 0.84G8, 1-6 HC13mg / kg, SC, QD4.88 ± 0.85G9, 1-6 HC1 lOmg / kg, SC, QD.Data is shown as Mean ± SEM, n=8* Significant difference as compared to Gl, Vehicle Control One-way ANOVA followed by Dunnett’s Mult iple Comparison Test.*P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001

[0343] G2 (4-OH-DiPT) (1 mg / kg, SC, single dose) group showed a significant increase in head twitch response compared to Gl, Vehicle control. G3 (DOI) (Img / kg IP, single dose) group showed a significant increase in head twitch response compared to Gl, Vehicle control. Groups G4 to G9 (1-6 HC1) (0.03, 0.1,0.3, 1,3, and 10 mg / kg, SC, single dose) groups did not show any significant difference in the average mean head twitch response (0-60min) compared to Gl, Vehicle control.

[0344] Dose-responsive HTR is indicative of 5HT2A (h) receptor engagement. Figure 6A illustrates average HTR counts over 60 minutes against the cortical concentration for the compounds evaluated. The lack of a significant increase in HTR versus vehicle control is predictive of a lack of psychoactivity / hallucinogenicity in the clinic. 1-6 HC1 provided HTR counts of less than 5 per 60 minutes observed even when present in cortical concentrations greater than 200-fold the compound’s Ki (5HT2A (h) Figure 6B provides the cortical concentration of the compounds -1.25 h post dose.Example 14. In-vivo pharmacological investigation

[0345] Male Wistar rats were quarantined for 3 days and acclimatize for 1 days prior to experiment initiation. During this period, the rats were observed daily for clinical signs.

[0346] On Day -4, Pre-swim FST were performed for all the animals for 15 minutes. Again, on day -3 FST were performed for 5 minutes. On Day 0, all the animals were randomized based on FST outcome and body weights into 12 different groups.

[0347] On Day 1, an exemplary compound of the present disclosure (1-6) and a comparative compound (1-219) were formulated and administered to respective animals of each group as per the body weight.

[0348] The cages were transferred from the holding room to the experiment room 1 hour before the start of experiment to acclimatize the animals. For HTR, the set-up was built using a camera to record each animal. Immediately after drug administration, all the animals were transferred to the transparent observational chamber. Animals were observed for 1 hour and observation was recorded by using a camera. The number of head twitches in Ih (60 min) was counted from the video recording. (The observer was blinded to the treatment groups).

[0349] For FST all animals were placed individually in a glass cylinder (20 cm in diameter X 45 cm in height) containing 35 cm of water, with water temperature being maintained at 25±1 °C. A camera located directly in front of the cylinder recorded the session of 5 minutes. Predominant behaviors such as immobility time, swimming time (Sec.) and climbing time (Sec.) were measured by a blinded observer from recorded videos using a stopwatch for the entire 5 min session. After FST recording, all the animals were handed over to PK team for bioanalysis.

[0350] The results are shown in Table 26 and Table 27 as well as Figures 1A-1B and Figures 2A-2B. FST results for compounds are reported as % higher than the FST for the vehicle (“VEH”). 5-HT2A receptor and 5-HT2C receptor Emax values were determined bymeasuring inositol monophosphate (IPi) biomarker. “RLM” refers to rat liver microsomes. “HLM” refers to human liver microsomes, “mpk” refers to milligrams per kilogram (mg / kg).Table 26[Brain] 5- Rat HTR Rat HTRDay 7 FST @lhr / 5- 5-HT2A Day 1 FSTHT2AAverage AverageCpd. No. % 0.03 mpk 0.3 mpk %Ki count count HT2A Ki Emax % VEH VEH 0.03, 0.3 (nM) 0.03 mpk 0.3 mpkmpk 1-6 11 25 2.9 2.6 46% 44% 3x; 62x 1-219 14 25 4.8 4.5 43% 39% 5x; 20xTable 27Metab Metab 5-HT2A 5-HT2B 5-HT2BK (nM) %max RLM HLMpd. 5-HTIA 5-HT2C 5-HT2C P- K (nM) % Emax K arrestin inhibition No. ti / 2 (min) ti / 2 (min)%Emax8 90 1 7 1-6 103 100 1800 2120 90 1 7219 32 104 713 60[00351 ing (Ki) with partial agonism ] The compounds showed potent 5-HT2A receptor bine(25% 5-HT2A Emax) and full 5-HT2C agonism (-100% 5-HT2C Emax), and about lOx less binding potency (Ki) for 5-HT2C than 5-HT2A. The compounds exhibited strong antagonist activity at 5-HT2B receptors (90% max 5-HT2B inhibition), indicative of lower cardiac toxicity risk. The compounds exhibited modest P-arrestin biased agonism.

[0352] Behavioral assays, PK and CNS penetration confirmed no substantial HTR, indicating lack of psychedelic psychoactivity; robust antidepressive effects in FST, durable to at least 7 days at a non-psychoactive dose; and CNS concentrations in excess of 5-HT2A binding constants.Example 15. Preparation of (R)-3-(l-((2-(lH-indol-3- yl)ethyl)(methyl)amino)ethyl)phenol (1-94).

[0353] Compound 1-94 was prepared according to the following scheme:BBr3, CH2CI21-94

[0354] To a stirred solution of (R)-N-(2-(lH-indol-3-yl)ethyl)-l-(3-methoxyphenyl)-N- methylethan-1 -amine (1-6) (0.428 g, 1.0 eq) in dichloromethane (20 mL) was added boron tribromide (IM in DCM) (6.9 mL, 5eq) dropwise at 0°C. The reaction mixture was stirred atroom temperature for 3h. Progress of the reaction was monitored by TLC and Liquid Chromatograph - Mass Spectrometry (LCMS). After completion, the reaction mixture was cooled to 0°C and quenched with saturated sodium bicarbonate solution, and extracted with di chloromethane (3x50 mL). The di chloromethane layer was washed with water (100 mL).The organic layers were dried over anhydrous Na2SC>4, filtered, and concentrated in vacuum to afford crude product The crude was purified by Combi-Flash column chromatography using 3.5-4% methanol in dichloromethane to afford (R)-3-(l-((2-(lH-indol-3-yl)ethyl)(methyl)amino)ethyl)phenol (1-94) (0.15 g, 36%) as an off white solid. MS (ESI) m / e [M+H]+: 295.1; HPLC purity: 95.55% (Retention Time) = 3.92 min); 'HNMR (400 MHz, DMSO-tL) 6 ppm 10.63 - 10.78 (m, 1 H) 9.07 - 9.32 (m, 1 H) 7.27 - 7.37 (m, 2 H) 6.99 - 7.16 (m, 3 H) 6.83 - 6.93 (m, 1 H) 6.71 - 6.82 (m, 2 H) 6.53 - 6.65 (m, 1 H) 3.48 - 3.58 (m, 1 H) 2.73 - 2.93 (m, 2 H) 2.58 - 2.71 (m, 2 H) 2.18 - 2.29 (m, 3 H) 1.20 - 1.31 (m, 3 H).Example 16. Preparation of (R)-3-(2-((l-(3-methoxyphenyl)ethyl)amino)ethyl)-lH-indol-5-ol (1-95).

[0355] Compound 1-95 was prepared according to the following scheme:

[0356] Step-1: Synthesis of 2-(5-(benzyloxy)-lH-indol-3-yl)ethan-l-ol (2): To a stirred solution of 2-(5-(benzyloxy)-lH-indol-3-yl)acetic acid (1, 3 g, 10.66 mmol) in diethyl ether (DEE) (50 mL) was added lithium aluminum hydride (LAH) (2M in THF, 16 mL, 31.99mmol) at O°C. The reaction mixture was stirred at room temperature for 3h. The progress of the reaction was monitored by LCMS and TLC. After completion of reaction, the reaction mixture was quenched with ice cold water (100 mL) and extracted with ethyl acetate (2 x 100 mL). The combined organic layers were dried over anhydrous Na2SC>4, filtered, and concentrated to obtain 2-(5-(benzyloxy)-lH-indol-3-yl)ethan-l-ol (2) (2.9 g, 100% yield) as a colorless liquid. MS (ESI) m / e [M+H]+: 268.24.

[0357] Step-2: Synthesis of 5-(benzyloxy)-3-(2-bromoethyl)-lH-indole (3): To a stirred solution of 2-(5-(benzyloxy)-lH-indol-3-yl)ethan-l-ol (2, 2.9 g, 11 mmol) indi chloromethane (40 mL) were added triphenylphosphine (TPP) (4.2 g, 16 mmol) and carbon tetrabromide (5.3 g, 16 mmol) at 0°C. The reaction mass was stirred at room temperature for 2h. The progress of the reaction was monitored by LCMS and TLC. After completion of reaction, the reaction mass was evaporated under reduced pressure to afford crude product. The crude product was purified by combi flash column chromatography using 15% ethyl acetate in heptane as eluent to obtain 5-(benzyloxy)-3-(2-bromoethyl)-lH-indole (3) (1.5 g, 42% yield) as a pale-yellow liquid. MS (ESI) m / e [M+H]+: 332.15.

[0358] Step-3: Synthesis of (R)-2-(5-(benzyloxy)-lH-indol-3-yl)-N-(l-(3-methoxyphenyl)ethyl)ethan-l-amine (5): To a stirred solution of (R)-l-(3-methoxyphenyl)ethan-l -amine (4, 0.68 g, 4.54 mmol) in N, N-dimethylformamide (DMF) (10 mL) were added 5-(benzyloxy)-3-(2-bromoethyl)-lH-indole (3, 1.50 g, 4.54 mmol) and potassium carbonate (0.94 g, 6.81 mmol) followed by potassium iodide (0.15 g, 0.909 mmol). The reaction mass was stirred at 80°C for 16h. The progress of the reaction was monitored by LCMS. After completion of the reaction, the reaction mass was diluted with water (70 mL) and extracted with ethyl acetate (2 x 50 mL). The combined organic layer was washed with brine solution, dried over anhydrous Na2SC>4, filtered, and concentrated to afford crude product which was purified by combi-flash column chromatography using 75% ethyl acetate in heptane as eluent to afford (R)-2-(5-(benzyloxy)-lH-indol-3-yl)-N-(l-(3-methoxyphenyl)ethyl)ethan-l -amine (5) (1.5 g, 83.3% yield) as an off-white solid. MS (ESI) m / e [M+H]+: 401.37.

[0359] Step 4: Synthesis of (R)-3-(2-((l-(3-methoxyphenyl)ethyl)amino)ethyl)-lH-indol-5-ol (1-95): To a stirred solution of (R)-2-(5-(benzyloxy)-lH-indol-3-yl)-N-(l-(3-methoxyphenyl)ethyl)ethan-l -amine (5, 600 mg, 1.49 mmol) in ethyl acetate (30 mL) were added 10% Palladium on Carbon (Pd / C) (300 mg, 2.819 mmol), and the resulting solution was hydrogenated under hydrogen bladder pressure at room temperature for 16h. Theprogress of the reaction was monitored by LCMS. After completion of the reaction, the reaction mixture was filtered through celite pad, and filtrate was concentrated to obtain crude which was triturated with diethyl ether (5 mL) and pentane (2 x 10 mL) and dried under reduced pressure to obtain (R)-3-(2-((l-(3-methoxyphenyl)ethyl)amino)ethyl)-lH-indol-5-ol (1-95) (300 mg, 64.51% yield) as an off-white solid. MS (ESI) m / e [M+H]+: 311.0; HPLC purity: 97.16% (Retention Time (RT) = 2.96 min);JH NMR (400 MHz, DMSO-tL) 8 ppm 10.31 - 10.52 (m, 1 H) 8.39 - 8.61 (m, 1 H) 7.15 - 7.23 (m, 1 H) 7.03 - 7.11 (m, 1 H) 6.91 -6.99 (m, 1 H) 6.84 - 6.91 (m, 2 H) 6.70 - 6.76 (m, 2 H) 6.48 - 6.59 (m, 1 H) 3.66 - 3.77 (m, 4 H) 2.56 - 2.84 (m, 4 H) 0.99 - 1.28 (m, 3 H).Example 17. Preparation of (R)-3-(2-((l-(3-hydroxyphenyl)ethyl)(methyl)amino)ethyl)-lH-indol-5-ol (1-96).

[0360] Compound 1-96 was prepared according to the following scheme:

[0361] Step-1: Synthesis of 2-(5-methoxy-lH-indol-3-yl)ethan-l-ol (2): To a stirred solution of 2-(5-(methoxy)-lH-indol-3-yl)acetic acid (1, 3 g, 10.66 mmol) in diethyl ether (DEE) (50 mL) was added lithium aluminum hydride (LAH) (2M in THF, 16 mL, 31.99 mmol) at 0°C. The reaction mixture was stirred at room temperature for 3h. The progress of the reaction was monitored by LCMS and TLC. After completion of reaction, the reaction mixture was quenched with ice cold water (100 mL), extracted with ethyl acetate (2 x 100 mL). The combined organic layers were dried over anhydrous Na2SC>4, filtered, and concentrated to obtain 2-(5-methoxy-lH-indol-3-yl)ethan-l-ol (2) (2.9 g, 100% Yield) as a colorless liquid. MS (ESI) m / e [M+H]+: 191.2.

[0362] Step-2: Synthesis of 5-(methoxy)-3-(2-bromoethyl)-lH-indole (3): To a stirred solution of 2-(5-methoxy-lH-indol-3-yl)ethan-l-ol (2, 1 g, 5.22 mmol) in dichloromethane (DCM) (20 mL) were added carbon tetrabromide (2.07 g, 6.2752 mmol) and triphenylphosphine (TPP) (2.05 g, 7.84 mmol) at 0°C. The reaction mixture was stirred at room temperature for 3h. The progress of the reaction was monitored by LCMS and TLC. After completion of reaction, the reaction mass was evaporated under reduced pressure to afford crude product. The crude product was purified by combi flash column chromatography using 15% ethyl acetate in heptane as eluent to obtain 5 -(methoxy)-3 -(2 -bromoethyl)- 1H-indole (3) (1.32 g, 99% yield) as a pale yellow liquid. MS (ESI) m / e [M+H]+: 254.2.

[0363] Step-3: synthesis of (R)-2-(5-methoxy-lH-indol-3-yl)-N-(l-(3-methoxyphenyl)ethyl)-N-methylethan-l-amine (5): To a stirred solution of (R)-l-(3-methoxyphenyl)-N-methylethan-l -amine (4, 0.5 g, 3 mmol) in A A -di methyl form am ide (DMF) (10 ml) were added 3-(2-bromoethyl)-5-methoxy-lH-indole (3, 0.76 g, 3 mmol) and potassium carbonate (0.69 g, 5 mmol), potassium iodide (50 mg, 0.3 mmol). The reaction mass was stirred at 70°C for 16h. After completion of the reaction, the reaction mass was diluted with water (50 mL) and extracted with ethyl acetate (2 x 70 mL). The combined organic layer was dried over Na2SC>4 and concentrated under reduced pressure to afford crude product which was purified by combi flash column chromatography using 50% ethyl acetate in heptane as eluent to obtain (A)-2-(5-methoxy-lH-indol-3-yl)-N-(l-(3-methoxyphenyl)ethyl)-N-methylethan-l -amine (5) (0.3 g, 30% yield) as an off-white solid. MS (ESI) m / e [M+H]+: 325.1

[0364] Step-4: synthesis of (R)-3-(2-((l-(3-hydroxyphenyl)ethyl)(methyl)amino)ethyl)-lH-indol-5-ol (1-96): To a stirred solution of (R)-2-(5-methoxy-lH-indol-3-yl)-N-(l-(3-methoxyphenyl)ethyl)-N-methylethan-l -amine (5, 0.58 g, 1.7 mmol) in dichloromethane (30 mL) was added BBri (8.6 mL, 8.5 mmol) at 0°C. The reaction mixture was stirred at room temperature for 3h. The progress of the reaction was monitored by LCMS. After the completion of reaction, the reaction mass was quenched with saturated sodium bicarbonate solution at 0°C and extracted with di chloromethane (3 x 50 mL). The combined organic layer was washed with water (100 mL), dried over sodium sulphate, and concentrated under reduced pressure to afford crude product which was purified by column chromatography using 8% methanol in dichloromethane as eluent to afford (R)-3-(2-((l-(3-hydroxyphenyl)ethyl)(methyl)amino)ethyl)-lH-indol-5-ol (1-96) (135 mg, 25% yield) as an off white solid. MS (ESI) m / e [M+H]+: 311.0; HPLC purity: 96.42% (RT = 3.44 min); 'HNMR (400 MHz, DMSO-tL) 6 ppm 10.23 - 10.49 (m, 1 H) 9.08 - 9.28 (m, 1 H) 8.44 - 8.56 (m, 1 H) 7.04 - 7.11 (m, 2 H) 6.92 - 6.98 (m, 1 H) 6.70 - 6.78 (m, 3 H) 6.51 - 6.62 (m, 2 H) 3.48 - 3.63 (m, 1 H) 2.52 - 2.82 (m, 4 H) 2.17 - 2.26 (m, 3 H) 1.25 - 1.32 (m, 3 H).Example 18. Rat Head Twitch Response and Forced Swim Test III

[0365] Compounds 1-6 HC1, 1-94 HC1, 1-95 HC1, and 1-96 HC1 were evaluated in the forced swim test and for head twitch response in Wistar rats as described for other compounds in Example 11, Example 12, and Example 14. 1-6 HC1 showed antidepressive effect 7 and 28 days following a single subcutaneous dose (0.3 mg / kg) in the forced swim test. Additional anti-depressive efficacy for 1-6 HC1 was demonstrated in the mouse and rat chronic unpredictable mild stress (CUMS) models of depression and in a rat inflammatory depression model using the sucrose preference test and forced swim tests as behavioral measures of anhedonia and depressive-like behavior, respectively.Example 20. Preparation of N-(3-bromobenzyl)-N-ethyl-2-(5-methoxy-lH-indol-3-yl)ethan-l-amine formic acid (1-67 formate)

[0366] 1-67 was prepared according to General Synthetic Method I and the scheme below.2Botgfte-DMS, TSP, TEA, ACN Step-1 Step-2

[0367] Step-1: Synthesis of N-(3-bromobenzyl)-N-ethyl-2-(5-methoxy-lH-indol-3-yl)acetamide

[0368] To a stirred solution of 2-(5-methoxy-lH-indol-3-yl)acetic acid (1) (1.0 g, 1.0 equiv) in acetonitrile (ACN) (20 mL) were added triethylamine (TEA) (2.72 mL, 4.0 equiv), N-(3-bromobenzyl)ethanamine (2) (1.3g, 1.20 equiv) followed by 50% propylphosphonic anhydride (T3P) (4.25 g, 4.0 equiv) and at 0 °C. The reaction mixture was stirred at room temperature for 16h. Progress of the reaction was monitored by TLC. After completion, the reaction mixture was concentrated in vacuo, diluted with water (100 mL), and extracted with EtOAc (2 x 100 mL). The separated organic layers were washed with brine solution, driedover anhydrous Na2SC>4, filtered, and concentrated in vacuo. The crude material obtained was purified by combi flash chromatography using 2-5% methanol in DCM to afford N-(3-bromobenzyl)-N-ethyl-2-(5-methoxy-lH-indol-3-yl)acetamide (3) (1.85 g, 94.6%) as a semisolid.

[0369] Step-2: Synthesis of N-(3-bromobenzyl)-N-ethyl-2-(5-methoxy-lH-indol-3-yl)ethan-l-amine Formic acid (1-67)

[0370] To a stirred solution of N-(3-bromobenzyl)-N-ethyl-2-(5-methoxy-lH-indol-3-yl)acetamide (3) (0.25 g, 1.0 equiv) in THF (2 mL) was added a solution of 2M borane dimethylsulfide complex (Borane-DMS) in THF (3.37 mmol, 5.0 equiv) dropwise at 0 °C. The reaction mixture was stirred at room temperature for 16h under N2 atmosphere. Progress of the reaction was monitored by TLC. After completion, the reaction mixture was quenched with a 20% NaOH solution (10 mL) followed by water (20 mL) and EtOAc (10 mL) and stirred for 30 min. The white precipitate was filtered through pad of Celite and washed with EtOAc (20 mL). The filtrate was washed with water (10 mL) and brine (10 mL). The separated organic layer was dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The crude obtained was purified by combi-flash chromatography using 2-5% MeOH in DCM to afford N-(3-bromobenzyl)-N-ethyl-2-(5-methoxy-lH-indol-3-yl)ethan-l-amine formic acid (1-67 formic acid) (90 mg, 9.33%) as a brown liquid. MS (ESI) m / e [M+H]+: 387.51; HPLC purity: 99.62% (retention time = 5.342 min),JH NMR (400 MHz, DMSO-de) 5 ppm 1.04 (t, J=7.07 Hz, 3H, CH3), 2.61 (q, J=7.05 Hz, 2H, CH2), 2.67 - 2.72 (m, 2H, CH2), 2.78 - 2.84 (m, 2H, CH2), 3.67 (s, 2H, CH2), 3.70 (s, 3H, OCH3), 6.68 (dd, J=8.76, 2.38 Hz, 1H, aromCH), 6.83 (d, J=2.25 Hz, 1H, aromCH), 7.06 (d, J=2.25 Hz, 1H, aromCH), 7.20 (d, J=8.76 Hz, 1H, aromCH), 7.23 - 7.32 (m, 1H, aromCH), 7.36 (d, J=7.63 Hz, 1H, aromCH), 7.43 (d, J=7.75 Hz, 1H, aromCH), 7.55 (s, 1H, aromCH), 8.15 (formate salt), 10.50 - 10.68 (s, indole-NH, 1H).Example 19. General Synthetic Method II

[0371] In some embodiments, compounds described herein were prepared according to one or more steps of the following scheme:acid salt formation

[0372] The variables in the scheme above are the same as those defined for Formula I herein, i.e.,:Ring A is an optionally substituted group selected from saturated C3-C10 carbocyclyl, Ce-Cio aryl, 5-10 membered heterocyclyl, and 5-10 membered heteroaryl;Rais selected from halogen, hydroxyl, and C1-6 alkoxyl;q is an integer from 0 to 4;RNis hydrogen or optionally substituted C1-6 aliphatic; andRpis a lone electron pair or optionally substituted Ci-6 aliphatic.

[0373] In this method, amine 1 is coupled with carboxylic acid 2a to form amide 3a. The carbonyl of 3a is reduced to provide amine 3, which is converted to salt 6, e.g., by treatment with an acid such as HC1. In some instances, the amine of 3 is functionalized (e.g., by methylation) to provide 4 (wherein Rpis optionally substituted Ci-6 aliphatic), which is then converted to salt 5.

[0374] This general method was used to prepare compounds described herein, e.g., 1-27, and 1-57. Exemplary procedures for certain compounds are described herein. A person of skill in art will recognize that the synthetic procedure can be adapted to prepare other compounds based on appropriate selection of starting materials e.g., 1 and 2a, and reactants.Example 21. Preparation of 2-(lH-indol-3-yl)-N-(((lS,3R)-3-methoxycyclohexyl)methyl)-N-methylethan-l-amine (1-27)

[0375] 1-27 was prepared according to General Synthetic Method II and the scheme below.

[0376] Step-1: Synthesis of (lS,4S,5S)-4-iodo-6-oxabicyclo[3.2.1]octan-7-one (2):

[0377] To a stirred solution of (S)-cyclohex-3-ene-l -carboxylic acid (1) (5.0 g, 1.0 equiv) in water (80 mL) were added NaHCO3 (12.0 g, 3.0 equiv) followed by potassium iodide(47.35 g, 6.0 equiv) and Iodine (L) in water (80 mL) (12.7 g, 2.1 equiv) at 0°C. The reaction mixture was stirred at room temperature for 16h. Progress of the reaction was monitored by TLC. After completion, the reaction mixture was concentrated in vacuo, diluted with water(100 mL), and extracted with DCM (2 x 350 mL). The separated organic layer was washed with saturated sodium thiosulfate solution and brine solution, dried over anhydrous Na2SC>4, filtered, and concentrated in vacuo to afford (lS,4S,5S)-4-iodo-6-oxabicyclo[3.2.1]octan-7-one (2) (11.82 g, 98%) as a pale yellow solid.

[0378] Step-2: Synthesis of (lS,5S)-6-oxabicyclo[3.2.1]oct-3-en-7-one (3)

[0379] To a stirred solution of (lS,4S,5S)-4-iodo-6-oxabicyclo[3.2.1]octan-7-one (2) (11.8 g, 1.0 equiv) in THF (120 mL) were added l,8-Diazabicyclo[5.4.0]undec-7-ene (DBU) (98 mL, 1.4 equiv) at room temperature. The reaction mixture was stirred at 70 °C for 16h.Progress of the reaction was monitored by TLC. After completion, the reaction mixture was concentrated in vacuo, diluted with water (150 mL), and extracted with ethyl acetate (2 x 450 mL). The separated organic layer was dried over anhydrous Na2SC>4, filtered, and concentrated in vacuo to provide (lS,5S)-6-oxabicyclo[3.2.1]oct-3-en-7-one (3) (5.6 g, crude) as a pale yellow oil. The crude compound was used in the next step without purification.

[0380] Step-3: Synthesis of methyl (lS,5S)-5-hydroxycyclohex-3-ene-l-carboxylate (4)

[0381] To a stirred solution of (lS,5S)-6-oxabicyclo[3.2.1]oct-3-en-7-one (3) (5.6 g, 1.0 equiv) in MeOH (80 mL) was added NaHCOs (4.24 g, 1.12 equiv) at room temperature. The reaction mixture was stirred at 65°C for 3h. Progress of the reaction was monitored by TLC. After completion, the reaction mixture was filtered through a pad of Celite and washed with MeOH (100 mL). The filtrate was concentrated, and the crude residue was diluted water (200 mL) and extracted with ethyl acetate (2 x 300 mL). The separated organic layer was dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The crude compound was purified by Flash Combi flash column chromatography using 50% EtOAc in heptane to afford methyl (lS,5S)-5-hydroxycyclohex-3-ene-l-carboxylate (4) (4.21 g, 59%) as a pale yellow oil.

[0382] Step-4: Synthesis of methyl (lS,3R)-3-hydroxycyclohexane-l-carboxylate (5)

[0383] To a stirred solution of (lS,5S)-5-hydroxycyclohex-3-ene-l-carboxylate (4) (4.2 g, 1.0 equiv) in MeOH (60 mL) was added 10% Palladium on carbon (0.84 g) and stirred at room temperature for 16 hours under hydrogen atmosphere with 100 psi pressure in autoclave. Progress of the reaction was monitored by TLC. After completion, the reaction mixture was filtered through celite pad and washed with ethyl acetate. The organic layer was concentrated under in vacuo. The crude compound was purified by Flash Combi flash column chromatography using 50% EtOAc in heptane to afford methyl (lS,3R)-3-hydroxycyclohexane-1 -carboxylate (5) (2.25 g, 52%) as a pale yellow liquid.

[0384] Step-5: Synthesis of methyl (lS,3R)-3-methoxycyclohexane-l-carboxylate (6)

[0385] To a stirred solution of methyl (lS,3R)-3-hydroxycyclohexane-l-carboxylate (5) (2.2 g, 1.0 equiv) in DCM (50 mL) were added silver oxide (Ag2O) (3.22 g, 1.0 equiv) and methyl iodide (9.0 mL, 10 equiv) at 0°C and then reaction mixture stirred at roomtemperature for 72 hours. Progress of the reaction was monitored by TLC. After completion, the reaction mixture was filtered through celite pad and washed with ethyl acetate. The organic layer was concentrated under in vacuo. The crude compound was purified by Flash Combi flash column chromatography using 30% EtOAc in heptane to afford methyl (lS,3R)-3-m ethoxy cyclohexane-1 -carboxylate (6) (1.05 g, 44%) as a pale yellow liquid.

[0386] Step-6: Synthesis of (lS,3R)-3-methoxycyclohexane-l-carboxylic acid (7)

[0387] To a stirred solution of methyl (lS,3R)-3-methoxycyclohexane-l-carboxylate (6) (1.0 g, 1.0 equiv) in THF: Water(7:3) (20 mL) were added LiOEEEhO (0.73 g, 3.0 equiv) at room temperature and then reaction mixture stirred at room temperature for 16 hours. Progress of the reaction was monitored by TLC. After completion, the reaction mixture was concentrated in vacuo, diluted with water (10 mL), and acidified with 2N HC1 solution. The aqueous layer was extracted with ethyl acetate (2 x 100 mL). The separated organic layer was dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to afford (lS,3R)-3-m ethoxy cyclohexane-1 -carboxylic acid (7) (0.90 g, 98%) as an off white solid.

[0388] Step-7: Synthesis of (lS,3R)-N-(2-(lH-indol-3-yl)ethyl)-3-methoxy-N-methylcyclohexane-l-carboxamide (9)

[0389] To a stirred solution of (lS,3R)-3-methoxycyclohexane-l-carboxylic acid (7) (0.9 g, 1.0 equiv), 2-(lH-indol-3-yl)-N-methylethan-l-amine (Int-8) (1.19 g, 1.2 equiv) in 20 ml of ACN were added T3P (5.4 mL, 1.5 equiv) and Et3N (2.40 mL, 3.0 equiv) at 0°C. The reaction mixture was stirred at room temperature for 16h. The progress of the reaction was monitored by TLC. After completion, the reaction mixture was concentrated in vacuo, diluted with water (100 mL), and extracted with EtOAc (2 x 200 mL). The separated organic layer was dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The crude obtained was purified by combi flash chromatography to afford (lS,3R)-N-(2-(lH-indol-3-yl)ethyl)-3-m ethoxy -N-methylcy cl ohexane-1 -carboxamide (9)(0.65 g, 36%) as an off white solid.

[0390] Step-8: Synthesis of 2-(lH-indol-3-yl)-N-(((lS,3R)-3-methoxycyclohexyl)methyl)-N-methylethan-l-amine (1-27)

[0391] To a stirred solution of (lS,3R)-N-(2-(lH-indol-3-yl)ethyl)-3-methoxy-N-methylcy cl ohexane-1 -carboxamide (9) (0.65 g, 1.0 equiv) in THF (20 mL) was added a solution of 2M LAH (2.06 mL, 2.0 equiv) dropwise. The reaction mixture was stirred at 70°C for 16 h under N2atmosphere. Progress of the reaction was monitored by TLC. Aftercompletion, the reaction mixture was quenched with a saturated 20% NaOH solution (20 mL). The white precipitate was filtered through pad of Celite and washed with EtOAc (200 mL). The filtrate was washed with water (40 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The crude obtained was purified by Flash Combi flash column chromatography using 70% EtOAc in heptane to afford 2-(lH-indol-3-yl)-N-(((lS,3R)-3-methoxycyclohexyl)methyl)-N-methylethan-l -amine (I-27)( 0.105 g, 16%) as a pale yellow gummy syrup. MS (ESI) m / e [M+H]+: 301.5; HPLC purity: 99.08% (retention time = 8.529 min), 'H NMR (400 MHz, DMSO-t / „) 8 ppm 0.59 (br d, 7=14.67 Hz, 2 H), 0.89 - 1.02 (m, 2 H), 1.10 - 1.23 (m, 2 H), 1.47 (br s, 1 H), 1.61 - 1.73 (m, 2 H), 1.91 - 1.97 (m, 1 H), 2.07 (br d, 7=12.23 Hz, 1 H), 2.22 (br s, 5 H), 2.79 (br t, 7=7.09 Hz, 2 H), 3.00 - 3.08 (m,l H), 3.19 (s, 3H), 6.91 - 6.97 (m, 1H, aromCH), 7.03 (t, 7=7.34 Hz, 1H, aromCH), 7.12 (s, 1H, aromCH), 7.30 (d, 7=7.82 Hz, 1H, aromCH), 7.47 (d, 7=7.82 Hz, 1H, aromCH), 10.74 (s, 1H, Indole-NH).Example 22. General Synthetic Method III

[0392] In some embodiments, compounds described herein were formed according to one or more steps of the following scheme:red,uct „ive ami.nation i: OKA!| R0’ 2ci / amine functionalization / acid sait formation / i acid salt formationi

[0393] The variables in the scheme above are the same as those defined for Formula I herein, i.e.,:Ring A is an optionally substituted group selected from saturated C3-C10 carbocyclyl, Ce-Cio aryl, 5-10 membered heterocyclyl, and 5-10 membered heteroaryl;Rais selected from halogen, hydroxyl, and C1-6 alkoxyl;q is an integer from 0 to 4;RNis hydrogen or optionally substituted C1-6 aliphatic;Rpis a lone electron pair or optionally substituted C1-6 aliphatic; andRclis hydrogen or C1-6 aliphatic.

[0394] In this method, amine 3 is prepared in a one-pot process via reductive amination of2c and amine 1. Amine 3 is converted to salt 6, e.g., by treatment with an acid such as HC1. In some instances, the amine of 3 is functionalized (e.g., by methylation) to provide 4 (wherein Rpis optionally substituted Ci-6 aliphatic), which is then converted to salt 5.

[0395] This general method was used to prepare compounds described herein, e.g., 1-34, 1-59 HC1, 1-41, 1-43, 1-20, 1-31 HC1, and 1-89. Exemplary procedures for certain compounds are described herein. A person of skill in art will recognize that the synthetic procedure can be adapted to prepare other compounds based on appropriate selection of starting materials e.g., 1 and 2c, and reactants.Example 23. Preparation of N-((2,3-dihydrobenzo[b][l,4]dioxin-5-yl)methyl)-2-(lH-indol-3-yl)-N-methylethan-l-amine (1-41)

[0396] 1-41 was prepared according to General Synthetic Method III and the scheme below.

[0397] Step-1: Synthesis of methyl (2-(lH-indol-3-yl)ethyl)carbamate (3)

[0398] To a stirred solution of 2-(lH-indol-3-yl)ethan-l-amine (1) (5.0 g, 1.0 equiv) in DCM (50 mL) were added methyl carbonochloridate (2) (2.9 mL, 1.2 equiv) and triethylamine (13 mL, 3.0 equiv) at room temperature. The reaction mixture was stirred at room temperature for 16h. Progress of the reaction was monitored by TLC. After completion, the reaction mixture was concentrated in vacuo, diluted with water (150 mL), and extracted with ethyl acetate (2 x 300 mL). The separated organic layer was dried over anhydrous Na2SC>4, filtered, and concentrated in vacuo. The crude obtained was purified by combi flash chromatography using 50% EtOAc in heptane to afford methyl (2-(lH-indol-3-yl)ethyl)carbamate (3) (4.05 g, 59.50%) as an off white solid.

[0399] Step-2: Synthesis of 2-(lH-indol-3-yl)-N-methylethan-l-amine (4)

[0400] To a stirred solution of methyl (2-(lH-indol-3-yl)ethyl)carbamate (3) (4.0 g, 1.0 equiv) in THF (80 mL) was added a solution of 2M LAH (27 mL, 3.0 equiv) dropwise. The reaction mixture was stirred at 70°C for 5 h under N2atmosphere. Progress of the reaction was monitored by TLC. After completion, the reaction mixture was quenched with asaturated Na2SO4 solution (20 mL), and the white precipitate was filtered through pad of Celite and washed with EtOAc (300 mL). The filtrate was washed with water (40 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo to afford 2-(lH-indol-3-yl)-N-methylethan-1 -amine (3.2 g, 100%) as a pale brown solid. A crude was forwarded to next step without purification.

[0401] Step-3: Synthesis of N-((2,3-dihydrobenzo[b][l,4]dioxin-5-yl)methyl)-2-(lH-indol-3-yl)-N-methylethan-l-amine (1-41)

[0402] To a stirred solution of 2-(lH-indol-3-yl)-N-methylethan-l-amine (0.7 g, 1.0 equiv) in 1,2-di chloroethane (DCE) (25 mL) were added 2,3-dihydrobenzo[b][l,4]dioxine-5-carbaldehyde (5) (0.66 g, 1.0 equiv) and NaBH(OAc)3(1.7 g, 2.0 equiv). The reaction mixture was stirred at room temperature for 16h. The progress of reaction was monitored by TLC. After completion, the reaction mixture was diluted with DCM and quenched with saturated NaHCOs solution. The organic layer was separated, and aqueous layer was extracted with DCM (50 ml x 2). Then organic layer was washed with brine solution and dried over anhydrous Na2SO4, and filtered, concentrated in vacuo. The crude was purified by Flash chromatography (Combi-Flash Column, 12 g redisep cartridge) using 70% EtOAc in heptane to afford N-((2,3-dihydrobenzo[b][l,4]dioxin-5-yl)methyl)-2-(lH-indol-3-yl)-N-methylethan-1 -amine (1-41, 0.55 g, 42%) as a brown gummy syrup. MS (ESI) m / e [M+H]+: 323.3; HPLC purity: 95.387% (RT = 8.624 min), 'H NMR (400 MHz, DMSO-d6) 8 ppm 'H NMR (400 MHz, DMSO-t / ,) 6 ppm 2.23 (s, 3H, NMe), 2.57 - 2.66 (m, 2H, CH2), 2.83 - 2.89 (m, 2H, CH2), 3.51 (s, 2H, CEL), 4.19-4.24 (m, 4H, OCH2CH2O), 6.71-6.78 (m, 2H, aromCH), 6.84 - 6.87 (m, 1H, aromCH), 6.91 (t, J=7.34 Hz, 1H, aromCH), 7.02 (t, J=7.34 Hz, 1H, aromCH), 7.12 (s, 1H, aromCH), 7.31 (d, J=7.83 Hz, 1H, aromCH), 7.44 (d, J=7.82 Hz, 1H, aromCH), 10.73 (s, 1H, indole-NH).Example 24. Preparation of N-(3-ethoxybenzyl)-N-(2-(5-methoxy-lH-indol-3-yl)ethyl)prop-2-en-l-amine (1-20)

[0403] 1-20 was prepared according to General Synthetic Method III and the scheme below.oet EtOOB 5 MeO I" > MeO 'NEton. 65°C,? h K2CO3>DMF..,. N..-NH H then, NaSH.,;, rt. 4 h Stap-2 1Step-1 i-20

[0404] Step 1: Synthesis of N-(3-ethoxybenzyl)-2-(5-methoxy-lH-indol-3-yl)ethan-l-amine (3)

[0405] To a stirred solution of 2-(5-methoxy-lH-indol-3-yl)ethan-l-amine (1.0 g, 1.0 equiv) in ethanol (25 mL) was added 3 -ethoxybenzaldehyde (2) (0.948 g, 1.2 equiv) at room temperature. The reaction mixture was stirred at 75 °C for 7 hours. Then, the reaction mixture was allowed to cool at 0 °C followed by addition of NaBH4 (0.397 g, 2.0 equiv) at 0 °C. The reaction mixture was stirred further at room temperature for 4 hours. The progress of reaction was monitored by TLC. After completion, the reaction mixture was quenched with ice-cold water, diluted with water (30 mL), and extracted with EtOAc (2 x 100 mL). The organic layers were washed with brine (30 mL). The organic layer was separated, dried over Na2SO4, filtered, and concentrated to dryness to give an orange gummy mass. Flash Chromatography (Combi-Flash Column, 12 g redisep cartridge) using 0-3% MeOH in DCM toN-(3-ethoxybenzyl)-2-(5-methoxy-lH-indol-3-yl)ethan-l-amine (1.3 g, 76%) as an orange gummy liquid.

[0406] Step 2: Synthesis of N-(3-ethoxybenzyl)-N-(2-(5-methoxy-lH-indol-3-yl)ethyl)prop-2-en-l-amine (1-20)

[0407] To a stirred solution of N-(3-ethoxybenzyl)-2-(5-methoxy-lH-indol-3-yl)ethan-l-amine (0.85 g, 1. equiv) in DMF (10 mL) was added K2CO3 (0.724 g, 2.0 equvi) followed by 3 -bromoprop- 1-ene drop-wise at room temperature. The reaction mixture was stirred at room temperature for 2 hours and monitored by TLC. The reaction mixture was diluted with water (30 mL) and extracted with EtOAc (2 x 40 mL). The organic layer was washed with brine (30 mL). The organic layer was separated, dried over Na2SO4, filtered, and concentrated to dryness to give an orange gummy mass. Flash Chromatography (Combi-Flash Column, 12 g redisep cartridge) using 0-5% MeOH in DCM to afford N-(3-ethoxybenzyl)-N-(2-(5-methoxy-lH-indol-3-yl)ethyl)prop-2-en-l-amine (1-20, 0.61 g, 63%) as an orange sticky solid. MS (ESI) m / e [M+H]+: 365.2; Purity HPLC = 99.39% (RT = 5.95 min), 'H NMR (DMSO-de) 6:ppm 1.30 (t, J=6.9 Hz, 3H, CH2Me). 2.68 (m, 2H, CH2), 2.83 (m, 2H, NCH2-),3.18 (d, J=6.3 Hz, 2H, OCH2-),3.63 (s, 2H, NCH2PI1), 3.69 (s, 3H, OMe), 3.95 (q,.7=7.0 Hz, 2H, -CH3), 5.14 (m, 1H, alkeneCH), 5.25 (m, 1H, alkeneCH), 5.90 (m, 1H, alkeneCH), 6.67 (dd, J=8.8, 1H, aromCH), 6.77 (dd, 1H, aromCH), 6.82 (d,.7=2,4 Hz, 1H, aromCH), ), 6.90 (m, 2H, aromCH), 7.03 (d,.7=2,3 Hz, 1H, aromCH), 7.19 (d, J=8.3 Hz, 2H, aromCH), 10.56 ppm (s, 1H, Indole-NH).Example 25. Preparation of 2-(lH-indol-3-yl)-N-methyl-N-((l,2,5-trimethyl-lH-pyrrol-3-yl)methyl)ethan-l-amine hydrochloride (1-31 HC1).

[0408] 1-31 HC1 was prepared according to General Synthetic Method III and the scheme below.HN"' 2 NaBH3CN, MeOH Dioxane. HC!Step-2 H1-31 1-31 HCi

[0409] Step-1: 2-(lH-indol-3-yl)-N-methyl-N-((l,2,5-trimethyl-lH-pyrrol-3-yl)methyl)ethan-l-amine (1-31)

[0410] To a stirred solution of 2-(lH-indol-3-yl)-N-methylethan-l-amine (1, 0.5 g, 1 equiv) in methanol (10 mL) was added l,2,5-trimethyl-lH-pyrrole-3-carbaldehyde (2, 0.4 g, 1 equiv) and acetic acid (1 drop). The reaction was stirred at room temperature for 1 h. Then, the reaction was cooled to 0°C and sodium cyanoborohydride (0.9 g, 5 equiv) was added. The reaction mixture was stirred at room temperature for 16 h. The progress of the reaction was monitored by TLC. After completion, the reaction mixture was concentrated under reduced pressure, diluted with water (50 mL), and extracted with ethyl acetate (3 x 150 mL). The combined organic layers were dried over sodium sulphate and concentrated under reduced pressure to afford crude which was purified by preparative HPLC to afford 2-(lH-indol-3-yl)-N-methyl-N-((l,2,5-trimethyl-lH-pyrrol-3-yl)methyl)ethan-l-amine (1-31, 0.46 g, 50% yield) as a colorless gummy liquid.

[0411] Step-2: 2-(lH-indol-3-yl)-N-methyl-N-((l,2,5-trimethyl-lH-pyrrol-3-yl)methyl)ethan-l-amine hydrochloride (1-31 HC1)

[0412] To a stirred solution of 1-31 (0.45 g, 1.0 equiv) in dioxane (5 mL) was added 4MHC1 in dioxane (1 mL) at 0°C. The reaction mixture was stirred at room temperature for 1 h.Volatiles were removed under reduced pressure. The crude residue was triturated with diethyl ether and concentrated under reduced pressure to afford 2-(lH-indol-3-yl)-N-methyl-N-((1, 2, 5-trimethyl-lH-pyrrol-3-yl)methyl)ethan-l-amine hydrochloride (1-31 HC1, 0.41 g, 81% yield) as a brown semisolid. MS (ESI) m / e [M+H]+: 296.4; HPLC purity: 90.46% (retention time = 5.574min).'H NMR (400 MHz, DMSO4) 6 ppm 10.90 - 11.03 (m, 1 H) 9.39 - 9.73 (m, 1 H) 7.53 (d, J=7.88 Hz, 1 H) 7.36 (d, J=8.13 Hz, 1 H) 7.21 (d, J=2.13 Hz, 1 H) 7.10 (t, J=7.13 Hz, 1 H) 6.97 - 7.04 (m, 1 H) 5.87 (s, 1 H) 4.11 - 4.18 (m, 1 H) 3.99 - 4.08 (m, l H) 3.39 (br s, 3 H) 3.07 - 3.20 (m, 4 H) 2.72 (d, J=4.88 Hz, 3 H), 2.15 (d, J=8.25 Hz, 6 H).Example 26. Preparation of 2-(lH-indol-3-yl)-N-methyl-N-((l,2,5-trimethyl-lH-pyrrol-3-yl)methyl)ethan-l-amine hydrochloride (1-85) and 1-89.

[0413] 1-85 HC1 was prepared according to General Synthetic Method III and the scheme below.P-;Ij ' * TiH1-85 ' H 1-89 H

[0414] Step-1: Synthesis of N-(2-(lH-indol-3-yl)ethyl)-l-(2,3-dihydrobenzofuran-5-yl)ethan-l-amine (3)

[0415] To a stirred solution of 2-(lH-indol-3-yl)ethan-l -amine (1, 1 g, 1.0 eq) in methanol (50 mL) were added l-(2,3-dihydrobenzofuran-5-yl)ethan-l-one (2, 1.21 g, 1.2 eq) followed by acetic acid (1.13 g,3 eq) at room temperature. The reaction mixture was stirred at room temperature for 2h. Then, polymer supported cyanoborohydride (MP-NaCNBHs) (1.2 g) was added. The reaction mixture was stirred at 75 °C for 36h. The progress of the reaction was monitored by TLC and LCMS. After completion, the reaction mass was filtered, and the unwanted solid was washed with 10% methanol in di chloromethane. The organic layer was dried over anhydrous Na2SC>4, filtered, and concentrated in vacuo. The crude material obtained was purified by combi flash chromatography using 10% methanol in dichloromethane to afford N-(2-(lH-indol-3-yl)ethyl)-l-(2,3-dihydrobenzofuran-5-yl)ethan- 1-amine (3) (0.7 g, 36.6%) as an off -white gummy solid.

[0416] Step-2: Synthesis of N-(2-(lH-indol-3-yl)ethyl)-l-(2,3-dihydrobenzofuran-5-yl)-N-methylethan-l-amine (1-85)

[0417] To a stirred solution of N-(2-(lH-indol-3-yl)ethyl)-l-(2,3-dihydrobenzofuran-5-yl)ethan-l -amine (3, 0.7 g, 1.0 equiv) in methanol (28 mL) and tetrahydrofuran (14 mL) were added sodium methoxide (0.25 g, 2 eq), followed by para formaldehyde (0.28 g,4 eq) at room temperature. The reaction mixture was stirred at room temperature for 48 h. Sodium borohydride (0.26 g, 3 eq) was added at 0 °C. The reaction mixture was stirred at room temperature for 5 h. The progress of the reaction was monitored by LCMS. After completion, the reaction mixture was concentrated, diluted with water (150 mL), and extracted with ethyl acetate (3 x 80 mL). The separated organic layer was dried over anhydrous Na2SC>4, filtered, and concentrated in vacuo. The crude product (630 mg) was purified by preparative column chromatography to afford N-(2-(lH-indol-3-yl)ethyl)-l-(2,3-dihydrobenzofuran-5-yl)-N-methylethan-1 -amine (1-85) (0.21 g, 28.69%) as a brown gummy liquid. MS (ESI) m / e [M+H]+: 321.44; HPLC purity: 96.89% (RT = 4.6 min).JH NMR (400 MHz, DMSO-tL) 6 ppm 10.72 (br s, 1 H) 7.27 - 7.33 (m, 2 H) 7.16 (s, 1 H) 7.07 (d, J=2.25 Hz, 1 H) 6.98 - 7.05 (m, 2 H) 6.90 (ddd, J=7.91, 6.97, 0.88 Hz, 1 H) 6.66 (d, J=8.13 Hz, 1 H) 4.48 (t, J=8.69 Hz, 2 H) 3.58 (q, J=6.50 Hz, 1 H) 3.12 (t, J=8.69 Hz, 2 H) 2.73 - 2.87 (m, 2 H) 2.54 (br s, 2 H) 2.24 (s, 3 H) 1.27 (d, J=6.63 Hz, 3 H).

[0418] Chiral purification: The racemic compound (210 mg) was chirally separated to afford 70 mg of each isomer a pale brown gummy liquid. 1-89 (arbitrary): MS (ESI) m / e [M+H]+: 321.44; HPLC purity: 96.89% (RT = 4.6 min). 'H NMR (400 MHz, DMSO-tL) 6 ppm 10.72 (br s, 1 H) 7.27 - 7.33 (m, 2 H) 7.16 (s, 1 H) 7.07 (d,. / =2,25 Hz, 1 H) 6.98 - 7.05 (m, 2 H) 6.90 (ddd, J=7.91, 6.97, 0.88 Hz, 1 H) 6.66 (d, J=8.13 Hz, 1 H) 4.48 (t, J=8.69 Hz, 2 H) 3.58 (q, J=6.50 Hz, 1 H) 3.12 (t, J=8.69 Hz, 2 H) 2.73 - 2.87 (m, 2 H) 2.54 (br s, 2 H) 2.24 (s, 3 H) 1.27 (d, J=6.63 Hz, 3 H). Isomer of 1-89 (arbitrary): (ESI) m / e [M+H]+: 321.1;HPLC purity: 96.89% (RT = 4.6 min). 'HNMR (400 MHz, DMSO4) 6 ppm 10.72 (br s, 1 H) 7.27 - 7.33 (m, 2 H) 7.16 (s, 1 H) 7.07 (d, J=2.25 Hz, 1 H) 6.98 - 7.05 (m, 2 H) 6.90 (ddd, <7=7.91, 6.97, 0.88 Hz, 1 H) 6.66 (d, <7=8.13 Hz, 1 H) 4.48 (t, J=8.69 Hz, 2 H) 3.58 (q, J=6.50 Hz, 1 H) 3.12 (t, J=8.69 Hz, 2 H) 2.73 - 2.87 (m, 2 H) 2.54 (br s, 2 H) 2.24 (s, 3 H) 1.27 (d, <7=6.63 Hz, 3 H).Example 27. Preparation of N-(3-ethoxybenzyl)-2-(lH-indol-3-yl)-N-methylethan-l-amine (1-19).

[0419] 1-19 may be prepared according to General Synthetic Method I and the scheme below, where “rt” refer to room temperature.2^NH2LiAIH4MeOH, rt, 7 h T3P. Et then, NaBH4, rt, 4 h3N THE, rt. 16 h THF, rt, 16 h Step-1 Step-3 Step-2Example 28. Preparation of 2-(lH-indol-3-yl)-N-methyl-N-(thiazol-2-ylmethyl)ethan-l-amine (1-51).

[0420] 1-51 may be prepared according to General Synthetic Method I and the scheme below.LAH / l'Hf N" - *. j Step-22 3Example 29. Preparation of N-((lH-pyrrol-l-yl)methyl)-2-(lH-indol-3-yl)-N-methylethan-l-amine (1-52).

[0421] 1-52 may be prepared according to General Synthetic Method I and the scheme below. “TBA. HSO4” refers to tetrabutylammonium hydrogen sulfate.SQaOH. TBA. HS04,CH3CN 3C mm. f.t,24 fi, refluxStep-4s lnt-2Step 4 - PCT lot Appt 2014048165. 63 Apr 2014EQUIVALENTS AND INCORPORATION BY REFERENCE

[0422] While aspects of this disclosure have been particularly shown and described with reference to a preferred embodiment and various alternate embodiments, it will be understood by persons skilled in the relevant art that various changes in form and details can be made therein without departing from the scope of the disclosure.

[0423] All references, issued patents and patent applications cited within the body of the instant specification, particularly WO2023070228, are hereby incorporated by reference in their entirety, for all purposes.

Claims

WHAT IS CLAIMED IS:

1. A compound, wherein the compound is represented by Formula I:or is a pharmaceutically acceptable salt thereof, wherein:Ring A is an optionally substituted group selected from saturated C3-C10 carbocyclyl, Ce-Cio aryl, 5-10 membered heterocyclyl, and 5-10 membered heteroaryl;Rais selected from halogen, hydroxyl, and C1-6 alkoxyl;q is an integer from 0 to 4;RNis hydrogen or optionally substituted C1-6 aliphatic;Rpis a lone electron pair or optionally substituted C1-6 aliphatic; andRcland Rc2are each independently hydrogen or C1-6 aliphatic;with the provisos that the compound does not include:(1) a compound of Formula Ila:R11wherein:Rais hydrogen or methoxy;q is 1;RNis selected from methyl, 2-propenyl, c / .s-2-butenyf / ra / 7.s-2-butenyl, 2- methyl-2-propenyl and z-propyl;R11is hydroxyl, halogen, methoxy, ethynyl, ethyl, or methyl substituted with hydroxyl; andR12is hydrogen or methoxy; or(2) any one of the following compounds:Table 1Compound Structure1-200 co ZEO co co co T / I I / \ / \ O O 0= / \ / / \ / \ / / / \-= <>=# 4 °) ( coX # N \ #\ °0CH3\ \ I f ICH3H3C-( ) )000- y Z > co —\ ZE / coo _ / N~\ y°~1-201CH3 / co > 0 oz I \- I / | 1 / co / co \ co / / x^z / ^xH^XZX^H3O-CH3ZJx / Txy / °xCJ O / X''^H'T°03XH3w0 1V1-202 9^3 CH3HN--JZCH30V H3C.1-203HNJ°'CH31-2041-2051-206Compound Structure1-207co T1-208 Qy^N^XjA^C OHa \ £ OHNJ°' / (C o= H3CH3[^>11 QX^ N > co-209 T / ^AJoz-HNJ°'CH31-210 \ r^HN-^1-211Qr^X KHN-^ CH3H3C111-212HN—JCH31-213HN-^ CH3 / CH31-214HN—JCH31-215 Q^ JX l,HN— CH3Compound Structure1-216HN-J1-217 Q rJX kHN-^1-218Z / T4 z z y=HN-^1-219 QyJoo z z--HAZE? / HN-^ / O o <w— \ \ / T CH3H o o; y y v— \ / \ / \ / \< o=° / X1-220 QyJtCy?? o o o < <\ / / o o o HN-- / T I I co co co 1-221Q HVrJ^ O-Z1-222OCH31-223Qp Z c:HN-^1-224Compound Structuref i3\ T1-225^\ ll ^ y ocHj HN-^ OCH3co co co co X X X / o o o ZE co > co 1-226 oo \ \ / ZE- )\ o o o.-= <>« / \ \\ / / / / ^\ O G O-= <>—\ co \ oI co \ \ #\ °r ZE co \ / o X oz oz ) > ZE / CO coz X / / -- - oz oz-- v r°^1-227 / x i o \A Z ZE=\ co / 1c>' / / X x 1^ co / Xx Lx1° J\J kJ^1o z- 1-2281^11-229 \ F HN-71-2301-2311-2322. The compound according to claim 1, wherein q is 1, 2, or 3.

3. The compound according to claim 1 or claim 2, wherein Rais methoxy and q is 1.

4. The compound according to claim 1 or claim 2, wherein Rais hydroxyl and q is 1.

5. The compound according to claim 1 or claim 2, wherein Rais halogen and q is 1.

6. The compound according to any one of claims 1-5, wherein RNis an optionally substituted C1-3 aliphatic.

7. The compound according to any one of claims 1-5, wherein RNis an optionally substituted group selected from C1-6 alkyl, C1-6 alkenyl, C1-6 alkynyl, and C1-6 alkylaryl.

8. The compound according to any one of claims 1-7, wherein Rcland Rc2are bothhydrogen.

9. The compound according to any one of claims 1-7, wherein Rclis methyl and Rc2is hydrogen.

10. The compound according to any one of claims 1-7, wherein Rclis hydrogen and Rc2is methyl.

11. The compound according to any one of claims 1-10, wherein Ring A is optionally substituted C3-C10 saturated carbocyclyl.

12. The compound according to any one of claims 1-10, wherein Ring A is optionally substituted C5-C10 partially unsaturated carbocyclyl.

13. The compound according to any one of claims 1-10, wherein Ring A is optionally substituted 5- to 10-membered partially unsaturated heterocyclyl.

14. The compound according to any one of claims 1-10, wherein Ring A is optionally substituted Ce-Cio aryl.

15. The compound according to any one of claims 1-10, wherein Ring A is optionally substituted 5- to 10-membered heteroaryl.

16. The compound according to claim 15, wherein Ring A is an optionally substituted group selected from furan, pyrrole, pyridine, thiophene, thiazole, isothiazole, oxazole, isoxazole, benzofuran, indole, indazole, benzothiophene, benzimidazole, benzoxazole, benzothiazole, benzo [ ] [1,3] di oxole, 2,2-dimethylbenzo[ ][l,3]dioxole, and 2,3- dihydrobenzo[Z>] [ 1, 4] di oxine.

17. The compound according to claim 15 or 16, wherein Ring A is selected from:

18. The compound according to any one of claims 15-17, wherein Ring A is selected from:

19. The compound according to claim 15 or 16, wherein Ring A is selected from:wherein each Rfis independently selected from hydrogen, hydroxyl, Ci-6 aliphatic, and Ci-6 heteroaliphatic; andm is an integer from 0 to 4.

20. The compound according to claim 15 or 16, wherein Ring A is selected from21. The compound according to any one of claims 1-10, wherein the compound isrepresented by Formula II:(II)or is a pharmaceutically acceptable salt thereof, wherein:R8, R9, R10, R11, and R12are each independently selected from hydrogen, halogen, cyano, hydroxyl, -S(O)2R’, -S(0)2NR’R”, -C(O)NHR’, -C(O)OR’, and an optionally substituted group selected from Ci-6 aliphatic and Ci-6 heteroaliphatic, wherein R’ and R” are each independently Ci-6 aliphatic; ortwo adjacent groups from among R8, R9, R10, R11, and R12, together with the atoms to which they are bound, form a 5-membered heterocycle; andRa, q, RN, RC1, and Rc2are defined as for Formula I of claim 1.

22. The compound according to claim 21, wherein R8, R9, R10, R11, and R12are each independently selected from hydrogen, hydroxyl, and Ci-6 alkoxyl; orwherein R9and R10, together with the atoms to which they are bound, form a 5- membered heterocycle.

23. The compound according to claim 21, wherein R8is selected from halogen, cyano, hydroxyl, Ci-6 alkyl (e.g., methyl), and Ci-6 alkoxyl (e.g., methoxy).

24. The compound according to claim 23, wherein at least one or all of R9, R10, R11, and R12are hydrogen.

25. The compound according to claim 21, wherein R9is selected from halogen, C(O)OR’, -C(O)NHR’, -S(O)2R’, -S(0)2NR’R”, CI-6 hydroxyalkyl (e.g., hydroxymethyl), Ci-6 alkoxyl (e.g., methoxy and ethoxy), Ci-6 alkyl (e.g., methyl), and cyano, wherein R’ and R” are each independently Ci-6 alkyl (e.g., methyl).

26. The compound according to claim 21 or 25, wherein R9is methoxy.

27. The compound according to claim 25 or 26, wherein at least one or all of R8, R10, R11, and R12are hydrogen.

28. The compound according to claim 21, wherein R9and R10, together with the atoms to which they are bound, form an optionally substituted 5-membered heterocycle comprising 1 or 2 heteroatoms selected from O and N.

29. The compound according to claim 28, wherein at least one or all of R8, R11, and R12are hydrogen.

30. The compound according to claim 21, wherein R10is selected from Ci-6 alkyl (e.g., methyl) and Ci-6 alkoxyl (e.g., methoxy).

31. The compound according to claim 30, wherein at least one or all of R8, R9, R11, and R12are hydrogen.

32. The compound according to claim 21, wherein the compound is represented by Formula lib:or is a pharmaceutically acceptable salt thereof, wherein:one of Rclor Rc2is selected from Ci-6 alkyl, Ci-6 alkenyl, and Ci-6 alkynyl, and the other is hydrogen, andone of R8or R9is Ci-6 alkoxyl and the other is hydrogen.

33. The compound according to claim 32, wherein one of Rclor Rc2is methyl and the other is hydrogen, and one of R8or R9is methoxy and the other is hydrogen.

34. The compound according to claim 32, wherein Rclis Ci-6 alkyl and Rc2is hydrogen.

35. The compound according to claim 34, wherein Rclis methyl and Rc2is hydrogen.

36. The compound according to any one of claims 33- 35, wherein R8is hydrogen and R9is Ci-6 alkoxyl.

37. The compound according to claim 36, wherein R8is hydrogen and R9is methoxy.

38. The compound according to claim 21, wherein the compound is represented by Formula lie:or is a pharmaceutically acceptable salt thereof, wherein:X and Y are each independently O or CH2;Rcland Rc2are each independently hydrogen or C1-6 aliphatic; andRxand RYare each selected from hydrogen and C1-6 aliphatic.

39. The compound according to claim 38, wherein Rcland Rc2are both hydrogen.

40. The compound according to claim 38, wherein Rclis hydrogen and Rc2is C1-6 aliphatic.

41. The compound according to claim 38, wherein Rclis C1-6 aliphatic and Rc2is hydrogen.

42. The compound according to any one of claims 38, 40, or 41, wherein the C1-6 aliphatic is C1-6 alkyl (e.g., methyl).

43. The compound according to any one of claims 38-42, wherein X is O and Y is CH2.

44. The compound according to any one of claims 38-42, wherein X is CH2 and Y is O.

45. The compound according to any one of claims 38-42, wherein X is O and Y is O.

46. The compound according to any one of claims 38-45, wherein Rxand RYare both hydrogen.

47. The compound according to any one of claims 38-45, wherein Rxand RYare both Ci- 6 alkyl.

48. The compound according to any one of claims 38-45, wherein Rxand RYare both methyl.

49. The compound according to claim 21, wherein the compound is represented by Formula lid:or is a pharmaceutically acceptable salt thereof, wherein:Y is selected from CH and N; andRYis selected from hydrogen and Ci-6 aliphatic.

50. The compound according to claim 49, wherein Y is CH.

51. The compound according to claim 49, wherein Y is N.

52. The compound according to any one of claims 49-51, wherein RYis hydrogen.

53. The compound according to any one of claims 49-51, wherein RYis Ci-6 aliphatic.

54. The compound according to any one of claims 49-51, wherein RYis methyl.

55. The compound according to claim 21, wherein the compound is represented by Formula lie:or is a pharmaceutically acceptable salt thereof, wherein RNis Ci-6 aliphatic.

56. The compound according to claim 55, wherein RNis C1-3 alkyl (e.g., methyl).

57. The compound according to any one of claims 1-11, wherein the compound is represented by Formula III:or is a pharmaceutically acceptable salt thereof, wherein:Rais Ci-6 alkoxyl, andRcyis Ci-6 alkoxyl.

58. The compound according to claim 57, wherein Rais methoxy.

59. The compound according to claim 57 or 58, wherein Rcyis methoxy.

60. The compound according to claim 1, wherein the compound is selected from:Compound StructureCH3A1-1HN-^ CH3(XI^H31-2 CX? H3OHN— 6H3O UI-I3CH3A1-3 CA^AJA J I A CH3T CLA1-4 nA HN" A7A CH3CH31-5 A X / N A A AHN—7CH3CH3AX CH3AX1-6 CA XAXX JA HN-7A CH3A CH3(Ax 9H31-7HN-^ CH3(X 9H3''cHs1-8 L AA J £HN-7CH3Compound Structure1-9HN-^ CH31-10 co co X X HNr CH3Br / / o o £g o O. _>\ / \ / \ / / ^\ \ o O=1-11 / / ) ( > co c\ X # 4 °(o °=HN-J \ ' '££ 2 )O oO O>-- CH3Br u ozz-- 1-12 Q 1 co / HN"r7X CXH3Br / ^ / XXzx^^w11-13HN-^ CH31-14 Q HNv-^-m CH3.1-15HN-^ CH31-16 Q Hhrr--^ Br1-171-18Compound Structure1-19co co co 1-20 ZE ZE ZE Q— \ o O O £ _ O>? / \ \ / ( O= OH x / ° <—.AA CHco3A>1-21 ZE / ^Cj / O ozZ. Z--—"HN"7CH31-22 1 co / AX iQA A C C / / 11HN"7 3CH3H3%1-23C / N. JL^C H3HN—71-241-25 QY^N^JCX0--CH’HN^1-26 A? H3O ^X^Nx''''XvCH3HN^1-27 Qy^N^XX0XH3HN-JCompound Structure^CH3od1-28HNJI I N CH31-29HN-^> coZE / oz- 1-30HN--JCH / X^3CH3r==\1-31 Qj1NHN-^ CH3CHf I3\ ||1-32HN-7fx 'H3rVv0H1-33°HN—7<^\?H3 / TV / 0-CH3 1-34°HN-71-35HN"1-361-371-38 X " X lrCompound Structure1-39A o''b1-40HN-J1-41QrAHN—1-42QA " AHN-JCH3A. 'H3A1-43\ jA^' o HN-J< T\?H3 O1-44 A A AA JSHN-J1-45 (L x OHN-J1-46Qr-AHN-J CH3CH3rA1-47A J HN-J?H3r°v1-48A J HN—7(A. 'H3A1-49HN— CH3CH3 rTS\ CH31-50 \ K^. N X >-NH Aj '-' NHN—7Compound Structure1-51HN—XX 'H3O1-52X J HN-J CH31-53 XX 9H3 rC°HN—11-54\ JHN—7?H3rv.1-55 V / Xr / CH3X Jj01-56Q^ *^ V 'CH3HN-701-57HN- ■1-58 C^ xCx>HN-^1-59Q r-XHN- '1OH1-60HN—7OHH3C CHvx1-61 Qp U?HN— ' OH1-62 QP A -HN-^Compound StructureZCH31-63HN-^1-64 m HN-^ZCH3\ ZE0 7 OV H3c CHo ^1-65 V fo Y / op / Z ZE z & / co1 ° / ZE / 100 / HN-^I co / > T / > w ZEo \Yx / * ° / <>*< o1-66HN-^p co 1-67 - ZE^ ^1-68O p AHN-^1-691-70 QP -JX..HN-^1-71Compound Structure1-81A A A HN--JCH3Aft CH3AAA 1-82 L N. / A. Jk^CH3HN— 'A 'HsA A1-83 ^A / A\A^CI A HN--J1-84 Q ^ XCiQHN--'1-85QY A HN— CH31-86QY A HN- CH31-87 Q ^ ^ °> HN- CH3A1-88 'v-pzYHSA °X ^oC^H3i HN— CH31-89HN— CH31-90HN— CH31-91HN— CH3or is a pharmaceutically acceptable salt thereof.

61. A compound, wherein the compound is of Formula I:or is a pharmaceutically acceptable salt thereof, wherein:Ring A is an optionally substituted group selected from saturated C3-C10 carbocyclyl, Ce-Cio aryl, saturated 5-10 membered heterocyclyl, and 5-10 membered heteroaryl;Rais selected from halogen, hydroxyl, and C1-6 alkloxyl;q is an integer from 0 to 4;RNis hydrogen or optionally substituted Ci-6 aliphatic;Rpis a lone electron pair or optionally substituted Ci-6 aliphatic; andone of Rclor Rc2is methyl and the other is hydrogen.

62. The compound according to claim 61, wherein the compound is represented by Formula II:or is a pharmaceutically acceptable salt thereof, wherein:R8, R9, R10, R11, and R12are each independently selected from hydrogen, halogen, cyano, hydroxyl, -S(O)2R’, -S(0)2NR’R”, -C(O)NHR’, -C(O)OR’, and an optionally substituted group selected from Ci-6 aliphatic, and Ci-6 heteroaliphatic; wherein R’ and R” are each independently Ci-6 aliphatic; ortwo adjacent groups from among R8, R9, R10, R11, and R12, together with the atoms to which they are bound, form a 5-membered heterocycle; andRa, q, RN, RC1, and Rc2are defined as for Formula I of claim 61.

63. The compound according to claim 62, wherein the compound is represented by Formula lib:(lib)or is a pharmaceutically acceptable salt thereof, wherein:one of R8or R9is Ci-6 alkoxyl and the other is hydrogen.

64. A compound, wherein the compound is selected from:Compound StructureA. 'Han1-1A J I I HN— ' CH3OXCH3n A co1-2 TN 63 / O H — H OO Ul-I3CH3AA< co1-3 \ ZEX J I I T HN"7QZ- CH3OUrl31-4?AxH3AHzN— ' ^ CAH3A CH31-5 n AAjA^A CH3YY1-6HN—JCH3CH31-7 V. N. JJA J 1HN—1CH3A 9H3 ^CH31-8HN CH3 ancj1-9or is a pharmaceutically acceptable salt thereof.

65. A pharmaceutical composition comprising a compound according to any one of claims 1-64, and a pharmaceutically acceptable excipient.

66. A method of administering a compound, the method comprising orally, rectally, topically, buccally or parenterally (e.g., subcutaneously, intramuscularly, intradermally, or intravenously) administering to a subject a compound according to any one of claims 1-64, or a pharmaceutical composition according to claim 65.

67. A method of treating a disease or disorder in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound according to any one of claims 1-64 or a pharmaceutical composition according to claim 65.

68. The method according to claim 67, wherein the disease or disorder is neurological and / or psychiatric disease or disorder.

69. The method according to claim 67 or 68, wherein the disease or disorder is selected from generalized anxiety disorder, depression including postpartum depression, adjustment disorder, addiction, anxiety, post-traumatic stress disorder (PTSD), a neurodegenerative disease, suicidal ideation, bipolar disorder, schizophrenia, a mood disorder, a psychotic disorder, a personality disorder, an eating disorder, a sleep disorder, an impulse control disorder, a gambling disorder, a movement disorder, a memory disorder, a substance use disorder (e.g., alcohol dependence, nicotine dependence, opioid dependence, and cocaine dependence), a dissociative disorder, a cognitive disorder, a developmental disorder, a factitious disorder, obsessive compulsive disorder, a body dysmorphic disorder, chronic pain, and chronic fatigue.

70. The method according to claim 67 or 68, wherein the disease or disorder is selected from treatment-resistant depression, suicidal ideation, major depressive disorder, bipolar disorder, schizophrenia, and substance use disorder.

71. The method according to any one of claims 67-70, wherein the disease or disorder is mediated by the loss of synaptic connectivity, plasticity, or a combination thereof.

72. A method of modulating the activity of 5-HT2A receptors in a subject, the method comprising administering to the subject a compound according to any one of claims 1-64 or a pharmaceutical composition according to claim 65.

73. A compound according to any one of claims 1-64 or a pharmaceutical composition according to claim 65, for use as a medicament.

74. A compound according to any one of claims 1-64 or a pharmaceutical composition according to claim 65, for use in the treatment of a neurological and / or psychiatric disease or disorder.

75. Use of a compound according to any one of claims 1-64 or a pharmaceutical composition according to claim 65, in the manufacture of a medicament for the treatment of a neurological and / or psychiatric disease or disorder.

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