Novel tetrahydro pyridine substituted indole and azaindoles, compositions of matter and pharmaceutical compositions

Abstract

Provided herein are compounds which overcome solubility and oral bioavailability issues to act as (partial) agonists of the CNS serotonin receptor, 5-HT2A.

Description

NOVEL TETRAHYDRO PYRIDINE SUBSTITUTED INDOLE AND AZAINDOLES, COMPOSITIONS OF MATTER AND PHARMACEUTICAL COMPOSITIONSCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority from U.S. Provisional Application No. 63 / 613,504, filed December 21, 2023, which is hereby incorporated by reference in its entirety.BACKGROUND

[0002] G protein-coupled receptors, or GPCRs, are a major class of membrane proteins. Approximately 800 different GPCRs are encoded by the human genome and when expressed are located in the plasma membrane to act as the ‘eyes and ears’ of the cell. Gurevich, V.V. et al. GPCR Signaling Regulation: The Role of GRKs and Arrestins. Front Pharmacol 10: 125 (2019). Structurally they are composed of seven transmembrane alpha helices connected by intra- and inter-cellular loops of various lengths. These helices and loops play important roles in binding effectors, and / or other proteins, which often results in a signaling or communication event. Signaling of GPCRs produces cellular responses crucial for the health and benefit of the cell and organism.

[0003] Several GPCRs are expressed in the central nervous system, or CNS. One example is the serotonin family of receptors. The serotonin family is divided into subfamilies, 5-HT1 to 5-HT7 (note: 5-HT3 is a non-GPCR subfamily) and further into subtypes, e.g.: the 5-HT2 subfamily is composed of 5-HT2A, 5-HT2B and 5-HT2C. Pandy-Szekeres, G., et al. The G protein database, GproteinDb. Nucleic acids research, 50:D518-D525 (2022). Twelve serotonin GPCR subtypes have been identified. Serotonin receptors bind serotonin (or 5- hydroxytryptamine) triggering signal transduction, the downstream effects of which modulate a variety of processes such as: memory, sleep, mood, and vision among others. Sizemore, T.R., et al. Serotonergic modulation across sensory modalities. J Neurophysiol, 123, 2406 (2020). In addition to serotonin, serotonin receptors are known to bind other endogenous neurotransmitters as well as exogenous small molecules. Indeed, many small molecule drugs have been developed that either activate or deactivate serotonin receptors leading to positive outcomes for a variety of neuropsychiatric disorders. Terry, A. V. Drugs that target serotonergic receptors. In: Buccafusco, J. J. (eds) Cognitive Enhancing Drugs. Milestones in Drug Therapy MDT. Birkhauser, Basel, https: / / doi.org / 10.1007 / 978-3-0348-7867-8_6.

[0004] Compounds such as the classic psychedelic tryptamines including N, N- dimethyltryptamine (DMT), 5-methoxy-DMT (5-MeO-DMT) and psilocybin (specifically psilocin or 4-hydroxy-DMT) bind select serotonin receptors in the active state and are known to be agonists or partial agonists. McClure-Begley, T.D. et al. The promises and perils of psychedelic pharmacology for psychiatry. Nat Rev Drug Discov 21, 463-473 (2022). These compounds have attracted increasing attention as they are thought to be therapeutically efficacious for various mental health disorders such as MDD, TRD, SUD, as well as compulsive, anxiety, stress, and eating disorders. Mertens, L.J. et al. Classical Psychedelics as Therapeutics in Psychiatry - Current Clinical Evidence and Potential Therapeutic Mechanisms in Substance Use and Mood Disorders. Pharmacopsychiatry, 54(4), 176 (2021).

[0005] However, many classic psychedelic tryptamines suffer from poor oral bioavailability due to metabolism by monoamine oxidases (MAOs) and are therefore not suitable as oral therapeutic agents. For example, a strong first pass effect oxidizes 100% of DMT after oral administration and therefore DMT must be administered with a MOA-A inhibitor to bez orally active. Riba, J., et al. Metabolism and urinary disposition of N, N -dimethyltryptamine after oral and smoked administration: a comparative study. Drug Test Anal, 7(5), 401 (2015). Furthermore, classic psychedelic tryptamine solubility and duration of target engagement may not be ideal for many therapeutic purposes.

[0006] There remains a need for improved compounds to overcome solubility and oral bioavailability issues to act as full (partial) agonists of the CNS serotonin receptor, 5-HT2A.SUMMARY

[0007] In an aspect, the present disclosure relates to compounds which overcome solubility and oral bioavailability issues to act as (partial) agonists of the CNS serotonin receptor, 5- HT2A. These compounds persist through first pass metabolism and cross the blood brain barrier, resulting in therapeutically effective concentrations at the site of action.

[0008] In embodiments, the present disclosure provides a compound having the formula of Formula (I):pharmaceutically acceptable salt thereof; wherein: each of Yi and Y2 is independently C or N, wherein when Yi is N, Re is absent and Xi is C; when Y2 is N, A and R4 are absent and X2 is C; each A is independently absent, O, NRi, or S;Xi, X2 and X3 are independently C or N;W is NRi, O, or S; each Ri, R2, and R3 are independently H, D, alkyl, cycloalkyl, aromatic, or heteroaromatic, wherein when X3 is N, R3 is absent;R4 and Rs are independently H, D, alkyl, cycloalkyl, aromatic or heteroaromatic, wherein when X2 is N, Rs is absent, or R4 and Rs are prodrugs, or R4 and Rs are joined together with the nitrogen to which they are attached to form a 4 member or 5-member ring.Re is halogen, alkyl, cycloalkyl, aromatic, or heteroaromatic;R7 and Rs are independently H, D, alkyl, cycloalkyl, aromatic or heteroaromatic; or R7 and Rs together with the atoms to which they are attached form a heterocyclic ring; and wherein each alkyl, cycloalkyl, aromatic and heteroaromatic is optionally substituted.

[0009] In embodiments, the present disclosure provides a compound having the formula of Formula (la):r pharmaceutically acceptable salt thereof; wherein: each A is independently absent, O, NRi, or S;Xi, X2 and X3 are independently C or N;W is NRi, O, or S; each Ri, R2, and R3 are independently H, D, alkyl, cycloalkyl, aromatic, or heteroaromatic, wherein when X3 is N, R3 is absent;R4 and Rs are independently H, D, alkyl, cycloalkyl, aromatic or heteroaromatic, wherein when X2 is N, Rs is absent, or R4 and Rs are prodrugs, or R4 and Rs are joined together with the nitrogen to which they are attached to form a 4 member or 5-member ring.Re is halogen, alkyl, cycloalkyl, aromatic, or heteroaromatic;R7 and Rs are independently H, D, alkyl, cycloalkyl, aromatic or heteroaromatic; or R7 and Rs together with the atoms to which they are attached form a heterocyclic ring; and wherein each alkyl, cycloalkyl, aromatic and heteroaromatic is optionally substituted.

[0010] In embodiments the present disclosure provides a compound according to Formula (II):whereinYi and Y2 are independently hydrogen, deuterium, alkyl, ORi, C(O)ORi, or NR1R2; n is 0, 1, or 2 carbon atoms;Zi is independently SH, SD, ORi, Ri, or NRiR2; each A is independently absent, O, NRi, or S;Xi, X2, and X3 are independently C or N;M is absent, CF2, C=O, C=N, or CR1R2;W is NRi, O, or S; each Ri, R2, and R3 are independently H, D, alkyl, cycloalkyl, aromatic, or heteroaromatic;Re is independently F, Cl, Br, I, alkyl, cycloalkyl, or heteroaromatic; andR4 and Rs are independently H, D, alkyl, cycloalkyl, aromatic, or heteroaromatic, wherein when X2 is N, Rs is absent; wherein each alkyl, cycloalkyl, aromatic and heteroaromatic is optionally substituted.DETAILED DESCRIPTION

[0011] Throughout this disclosure, various patents, patent applications and publications are referenced. The disclosures of these patents, patent applications and publications in their entireties are incorporated into this disclosure by reference for all purposes in order to more fully describe the state of the art as known to those skilled therein as of the date of this disclosure. This disclosure will govern in the instance that there is any inconsistency between the patents, patent applications, and publications cited and this disclosure.Definitions

[0012] For convenience, certain terms employed in the specification, examples and claims are collected here. Unless defined otherwise, all technical and scientific terms used in this disclosure have the same meanings as commonly understood by one of ordinary skill in the art to which this disclosure belongs.

[0013] The term “about” when immediately preceding a numerical value means a range (e.g., plus or minus 10% of that value). For example, “about 50” can mean 45 to 55, “about 25,000” can mean 22,500 to 27,500, etc., unless the context of the disclosure indicates otherwise, or is inconsistent with such an interpretation. For example, in a list of numerical values such as “about 49, about 50, about 55, ...”, “about 50” means a range extending to less than half the interval(s) between the preceding and subsequent values, e.g., more than 49.5 to less than 50.5. Furthermore, the phrases “less than about” a value or “greater than about” a value should be understood in view of the definition of the term “about” provided herein. Similarly, the term “about” when preceding a series of numerical values or a range of values (e.g., “about 10, 20, 30” or “about 10-30”) refers, respectively, to all values in the series, or the endpoints of the range.

[0014] In this specification, unless stated otherwise, the term “pharmaceutically acceptable” is used to characterize a moiety (e.g., a salt, dosage form, or excipient) as being appropriate for use in accordance with sound medical judgment. In general, a pharmaceutically acceptable moiety has one or more benefits that outweigh any deleterious effect that the moiety may have. Deleterious effects may include, for example, excessive toxicity, irritation, allergic response, and other problems and complications.

[0015] The term “pharmaceutically acceptable salt” includes both acid and base addition salts. Pharmaceutically acceptable salts include those obtained by reacting the active compound functioning as a base, with an inorganic or organic acid to form a salt, for example, salts of hydrochloric acid, sulfuric acid, phosphoric acid, methanesulfonic acid, camphorsulfonic acid, oxalic acid, maleic acid, succinic acid, citric acid, formic acid, hydrobromic acid, benzoic acid, tartaric acid, fumaric acid, salicylic acid, mandelic acid, carbonic acid, etc. Those skilled in the art will further recognize that acid addition salts may be prepared by reaction of the compounds with the appropriate inorganic or organic acid via any of a number of known methods.

[0016] When a range of values is listed, it is intended to encompass each value and sub-range within the range. For example, “Ci-Ce alkyl” is intended to encompass Ci, C2, C3, C4, Cs, Ce, C1-6, C1-5, Ci-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.

[0017] “Alkyl” or “alkyl group” refers to a fully saturated, straight or branched hydrocarbon chain having from one to twelve carbon atoms, and which is attached to the rest of the molecule by a single bond. Alkyls comprising any number of carbon atoms from 1 to 12 are included.An alkyl comprising up to 12 carbon atoms is a C1-C12 alkyl, an alkyl comprising up to 10 carbon atoms is a C1-C10 alkyl, an alkyl comprising up to 6 carbon atoms is a Ci-Ce alkyl and an alkyl comprising up to 5 carbon atoms is a C1-C5 alkyl. A C1-C5 alkyl includes C5 alkyls, C4 alkyls, C3 alkyls, C2 alkyls and Ci alkyl (z.e., methyl). A Ci-Ce alkyl includes all moieties described above for C1-C5 alkyls but also includes Ce alkyls. A C1-C10 alkyl includes all moieties described above for C1-C5 alkyls and Ci-Ce alkyls, but also includes C7, Cs, C9 and C10 alkyls. Similarly, a C1-C12 alkyl includes all the foregoing moieties, but also includes C11 and C12 alkyls. Non-limiting examples of C1-C12 alkyl include methyl, ethyl, zz-propyl, z-propyl, sec-propyl, zz-butyl, z-butyl, sec-butyl, / -butyl, zz-pentyl, / -amyl, zz-hexyl, zz-heptyl, zz-octyl, n- nonyl, zz-decyl, zz-undecyl, and zz-dodecyl. Unless stated otherwise specifically in the specification, an alkyl group can be optionally substituted.

[0018] “Aryl” or “aromatic” refers to a hydrocarbon ring system radical comprising hydrogen, 6 to 18 carbon ring atoms and at least one aromatic ring. For purposes of this disclosure, the aryl radical can be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which can include fused, bridged, or spiro ring systems. Aryl radicals include, but are not limited to, aryl radicals derived from aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, fluoranthene, fluorene, as-indacene, s-indacene, indane, indene, naphthalene, phenalene, phenanthrene, pleiadene, pyrene, and triphenylene. Unless stated otherwise specifically in the specification, the term “aryl” or “aromatic” is meant to include aryl radicals that are optionally substituted.

[0019] “Carbocyclyl,” “carbocyclic ring” or “carbocycle” refers to a rings structure, wherein the atoms which form the ring are each carbon. Carbocyclic rings can comprise from 3 to 20 carbon atoms in the ring. Carbocyclic rings include cycloalkyl, cycloalkenyl and cycloalkynyl as defined herein. Unless stated otherwise specifically in the specification, a carbocyclyl group can be optionally substituted.

[0020] “Cycloalkyl” refers to a stable non-aromatic monocyclic or polycyclic fully saturated hydrocarbon radical consisting solely of carbon and hydrogen atoms, which can include fused, bridged, or spiro ring systems, having from three to twenty carbon atoms, e.g., having from three to ten carbon atoms, and which is attached to the rest of the molecule by a single bond. Monocyclic cycloalkyl radicals include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic cycloalkyl radicals include,for example, adamantyl, norbornyl, decalinyl, 7,7-dimethyl-bicyclo[2.2.1]heptanyl, and the like. Unless otherwise stated specifically in the specification, a cycloalkyl group can be optionally substituted.

[0021] “Heterocyclyl,” “heterocyclic ring” or “heterocycle” refers to a stable saturated, unsaturated, or aromatic 3- to 20-membered ring which consists of two to nineteen carbon atoms and from one to six heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, and which is attached to the rest of the molecule by a single bond. Heterocyclyl or heterocyclic rings include heteroaryls, heterocyclylalkyls, heterocyclylalkenyls, and hetercyclylalkynyls. Unless stated otherwise specifically in the specification, the heterocyclyl can be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which can include fused, bridged, or spirocyclic ring systems; and the nitrogen, carbon or sulfur atoms in the heterocyclyl can be optionally oxidized; the nitrogen atom can be optionally quaternized; and the heterocyclyl can be partially or fully saturated. Examples of such heterocyclyl include, but are not limited to, dioxolanyl, thienyl[l,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, azetidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, and 1,1-dioxo-thiomorpholinyl. Unless stated otherwise specifically in the specification, a heterocyclyl group can be optionally substituted.

[0022] “Heteroaryl” or “heteroaromatic” refers to a 5- to 20-membered ring system radical comprising one to thirteen carbon ring atoms, one to six heteroatoms as ring atoms selected from nitrogen, oxygen and sulfur, and at least one aromatic ring containing at least one heteroatom as a ring atom. For purposes of this disclosure, the heteroaryl radical can be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which can include fused, bridged, or spiro ring systems; and the nitrogen, carbon or sulfur atoms in the heteroaryl radical can be optionally oxidized; the nitrogen atom can be optionally quaternized. Examples include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzodi oxolyl, benzofuranyl, benzooxazolyl, benzothiazolyl, benzothiadiazolyl, benzo[b][l,4]dioxepinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodi oxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl,benzothienyl (benzothiophene), benzotriazolyl, benzo[4,6]imidazo[l,2-a]pyridinyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophene, furanyl, furanonyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl, 1- oxidopyridinyl, 1-oxidopyrimidinyl, 1-oxidopyrazinyl, 1-oxidopyridazinyl, 1 -phenyl- IH-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxalinyl, quinolinyl, quinuclidinyl, isoquinolinyl, tetrahydroquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, and thiophene (i.e. thienyl). Unless stated otherwise specifically in the specification, a heteroaryl group can be optionally substituted.

[0023] The term “substituted” used herein means any of the groups described herein (e.g., alkyl, heterocyclyl, and / or heteroaryl) wherein at least one hydrogen atom is replaced by a bond to a non-hydrogen atoms such as, but not limited to: a halogen atom such as F, Cl, Br, and I; an oxygen atom in groups such as hydroxyl groups, alkoxy groups, and ester groups; a sulfur atom in groups such as thiol groups, thioalkyl groups, sulfone groups, sulfonyl groups, and sulfoxide groups; a nitrogen atom in groups such as amines, amides, alkylamines, dialkylamines, arylamines, alkylarylamines, diarylamines, N-oxides, imides, and enamines; a silicon atom in groups such as trialkylsilyl groups, dialkylarylsilyl groups, alkyldiarylsilyl groups, and triarylsilyl groups; and other heteroatoms in various other groups. “Substituted” also means any of the above groups in which one or more hydrogen atoms are replaced by a higher-order bond (e.g., a double- or triple-bond) to a heteroatom such as oxygen in oxo, carbonyl, carboxyl, and ester groups; and nitrogen in groups such as imines, oximes, hydrazones, and nitriles. For example, “substituted” includes any of the above groups in which one or more hydrogen atoms are replaced with -NRgRh, -NRgC(=O)Rh, -NRgC(=O)NRgRh, -NRgC(=O)ORh, -NRgSO2Rh, -OC(=O)NRgRh, -ORg, -SRg, -SORg, -SChRg, -OSO2Rg, -SO2ORg, =NSO2Rg, and -SO2NRgRh. “Substituted” also means any of the above groups in which one or more hydrogen atoms are replaced with -C(=O)Rg, -C(=O)ORg, -C(=O)NRgRh, -CH2SO2Rg, -CH2SO2NRgRh. In the foregoing, Rgand Rh are the same or different and independently hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylamino, thioalkyl, aryl, aralkyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, haloalkyl, haloalkenyl, haloalkynyl, heterocyclyl, 7V-heterocyclyl, heterocyclylalkyl, heteroaryl, N- heteroaryl and / or heteroarylalkyl. “Substituted” further means any of the above groups inwhich one or more hydrogen atoms are replaced by a bond to an amino, cyano, hydroxyl, imino, nitro, oxo, thioxo, halo, alkyl, alkenyl, alkynyl, alkoxy, alkylamino, thioalkyl, aryl, aralkyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, haloalkyl, haloalkenyl, haloalkynyl, heterocyclyl, N- heterocyclyl, heterocyclylalkyl, heteroaryl, Wheteroaryl and / or heteroarylalkyl group.

[0024] The compounds of the disclosure, or their pharmaceutically acceptable salts can contain one or more asymmetric centers and can thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that can be defined, in terms of absolute stereochemistry, such as (R)- or (5)-. The present disclosure is meant to include all such possible isomers, as well as their racemic and optically pure forms whether or not they are specifically depicted herein. Optically active (+) and (-), or (R)- and (5)-, isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques, for example, chromatography and fractional crystallization. Conventional techniques for the preparation / isolation of individual enantiomers include chiral synthesis from a suitable optically pure precursor or resolution of the racemate (or the racemate of a salt or derivative) using, for example, chiral high pressure liquid chromatography (HPLC).

[0025] Where a particular stereoisomer is expressly depicted, it is to be understood to refer to only that particular stereoisomer.Compounds of the Present Disclosure

[0026] In an aspect, the present disclosure relates to compounds which overcome solubility and oral bioavailability issues to act as (partial) agonists of the CNS serotonin receptor, 5- HT2A. These compounds persist through first pass metabolism and cross the blood brain barrier, resulting in therapeutically effective concentrations at the site of action.

[0027] In embodiments the present disclosure provides a compound having the formula of Formula (I):wherein: each of Yi and Y2 is independently C or N, wherein when Yi is N, Re is absent and Xi is C; when Y2 is N, A and R4 are absent and X2 is C; each A is independently absent, O, NRi, or S;Xi, X2 and X3 are independently C or N;W is NRi, O, or S; each Ri, R2, and R3 are independently H, D, alkyl, cycloalkyl, aromatic, or heteroaromatic, wherein when X3 is N, R3 is absent;R4 and Rs are independently H, D, alkyl, cycloalkyl, aromatic or heteroaromatic, wherein when X2 is N, Rs is absent, or R4 and Rs are prodrugs, or R4 and Rs are joined together with the nitrogen to which they are attached to form a 4 member or 5-member ring.Re is halogen, alkyl, cycloalkyl, aromatic, or heteroaromatic;R7 and Rs are independently H, D, alkyl, cycloalkyl, aromatic or heteroaromatic; or R7 and Rs together with the atoms to which they are attached form a heterocyclic ring; and wherein each alkyl, cycloalkyl, aromatic and heteroaromatic is optionally substituted.

[0028] In embodiments, Yi and Y2 are both N. In embodiments, one of Yi and Y2 is N and the other C. In embodiments, both Yi and Y2 are C.

[0029] In embodiments, the compound according to Formula (I) is selected from:or pharmaceutically acceptable salt thereof.

[0030] In embodiments the present disclosure provides a compound according to Formulawherein each A is independently absent, O, NRi, or S;Xi, X2 and X3 are independently C or N;W is NRi, O, or S; each Ri, R2, and R3 are independently H, D, alkyl, cycloalkyl, aromatic, or heteroaromatic, wherein when X3 is N, R3 is absent;R4 and Rs are independently H, D, alkyl, cycloalkyl, aromatic or heteroaromatic, wherein when X2 is N, Rs is absent, or R4 and Rs are prodrugs, or R4 and Rs are joined together with the nitrogen to which they are attached to form a 4 member or 5-member ring.Re is halogen, alkyl, cycloalkyl, aromatic, or heteroaromatic;R7 and Rs are independently H, D, alkyl, cycloalkyl, aromatic or heteroaromatic; or R7 and Rs together with the atoms to which they are attached form a heterocyclic ring; and wherein each alkyl, cycloalkyl, aromatic and heteroaromatic is optionally substituted.

[0031] In embodiments, R4 and Rs are alkyl, cycloalkyl, aromatic, heteroaromatic esters, aminal, hemiaminal, -CH2-OPO3H2, or -CH alkyl-OPChft and its salt.

[0032] In embodiments, at least one of Ri is a prodrug.

[0033] In embodiments, each A is independently absent or O.

[0034] In embodiments, W is NH, each of Xi, X2, and X3 is C, and each Ri and R2 is hydrogen or deuterium. In embodiments, Re is Br. In embodiments, W is NH, each of Xi, X2, and X3 is C, and each Ri and R2 is hydrogen or deuterium, and Re is Br.

[0035] In embodiments, R3 is H, D, Br, Cl, F, or CH3.

[0036] In embodiments, the A attached to Rs is absent and Rs is H or F, or the A attached to Rs is O and Rs is H or CH3. In embodiments, the A attached to Rs is absent and Rs is H.

[0037] In embodiments, the A attached to R4 is O and R4 is CH3.

[0038] In embodiments, the A attached to R4 is absent and R4 is H.

[0039] In embodiments, Re is Cl, F, or CF3. In embodiments, Re is Cl. In embodiments, Re is F or CF3.

[0040] In embodiments, R7 and Rs are independently H, D, alkyl, cycloalkyl, aromatic or heteroaromatic.

[0041] In embodiments, R7 and Rs taken together form a ring

[0042] In embodiments, the compound persists (e.g., substantially persists) through a first pass metabolism of a mammal. In embodiments, the compound acts as a partial agonist of a CNS serotonin receptor.

[0043] In embodiments, the compound is selected from:

[0044] In embodiments, the compound is selected from:

[0045] In embodiments the present disclosure provides a compound according to Formula (II):pharmaceutically acceptable salt thereof, whereinYi and Y2 are independently hydrogen, deuterium, alkyl, ORi, C(O)ORi, or NR1R2; n is 0, 1, or 2 carbon atoms;Zi is independently SH, SD, ORi, Ri, or NRiR2;each A is independently absent, O, NRi, or S;Xi, X2, and X3 are independently C or N;M is absent, CF2, C=O, C=N, or CR1R2;W is NRi, O, or S; each Ri, R2, and R3 are independently H, D, alkyl, cycloalkyl, aromatic, or heteroaromatic;Re is independently F, Cl, Br, I, alkyl, cycloalkyl, or heteroaromatic; andR4 and Rs are independently H, D, alkyl, cycloalkyl,, aromatic, or heteroaromatic, wherein when X2 is N, Rs is absent; wherein each alkyl, cycloalkyl, aromatic and heteroaromatic is optionally substituted

[0046] In embodiments, the compound is selected from compounds according to Formulae (Ila), (lib), (lie), or (lid):

[0047] In embodiments, R4 and Rs are alkyl, cycloalkyl, aromatic, heteroaromatic esters, aminal, hemiaminal, -CH2-OPO3H2, or -CH alkyl-OPO3H2 and its salt.

[0048] In embodiments at least one of Ri and Zi are a prodrug.

[0049] In embodiments, Zi is independently OH, OD, H, SD, or NR1R2. In embodiments, each A is independently absent or O.

[0050] In embodiments, W is NH, each of Xi, X2,, and X3 is C, each Ri and R2 is hydrogen or deuterium. In embodiments, Y1 and Y2 are hydrogen or deuterium. In embodiments, M is CH2. In embodiments, Zi is OH. In embodiments, Re is Br.

[0051] In embodiments, W is NH, each of Xi, X2,, and X3 is C, each Ri and R2 is hydrogen or deuterium, Y1 and Y2 are hydrogen or deuterium, M is CH2, Zi is OH, and Re is Br.

[0052] In embodiments, R3 is H, D, Br, Cl, F, or CH3.

[0053] In embodiments, the A attached to R4 is absent and R4 is H. In embodiments, the A attached to Rs is absent Rs is F, or the A attached to Rs is O and Rs is H or CH3.

[0054] In embodiments the A attached to R4 is O and R4 is CH3. In embodiments, the A attached to R4 is absent and R4 is H.

[0055] In embodiments, Re is Cl, F, or CF3. In embodiments, Re is Cl. In embodiments, Re is F or CF3.

[0056] In embodiments, the compound persists (e.g., substantially persists) through a first pass metabolism of a mammal. In embodiments, the compound acts as a partial agonist of a CNS serotonin receptor.

[0057] In embodiments, the compound is selected from:

[0058] In embodiments, the compound according to Formula (I), Formula (la), or Formula(II) is a compounds selected from Table 1:or a pharmaceutically acceptable salt thereof

[0059] In embodiments, the compounds of Formula (I), Formula (la), or Formula (II) comprise the (R) enantiomer thereof, or the (S) enantiomer thereof. In embodiment, the compound is substantially enantiomerically pure (e.g., comprises at least 80% of the (R) enantiomer thereof, or at least 80% of the (S) enantiomer thereof).NUMBERED EMBODIMENTS

[0060] The present disclosure provides for the following numbered embodiments:Embodiment 1. A compound of Formula (la):r pharmaceutically acceptable salt thereof; wherein each A is independently absent, O, NRi, or S;Xi, X2 and X3 are independently C or N;W is NRi, O, or S; each Ri, R2, and R3 are independently H, D, alkyl, cycloalkyl, aromatic, or heteroaromatic, wherein when X3 is N, R3 is absent ;R4 and Rs are independently H, D, alkyl, cycloalkyl, aromatic or heteroaromatic, or R4 and Rs are prodrugs, wherein when X2 is N, Rs is absent;Re is halogen, alkyl, cycloalkyl, aromatic, or heteroaromatic;R7 and Rs are independently H, D, alkyl, cycloalkyl, aromatic or heteroaromatic; or R7 and Rs together with the atoms to which they are attached form a heterocyclic ring; and wherein each alkyl, cycloalkyl, aromatic and heteroaromatic is optionally substituted.Embodiment 2. The compound of embodiment 1, wherein R4 and Rs are alkyl, cycloalkyl, aromatic, heteroaromatic esters, aminal, hemiaminal, -CH2-OPO3H2, or -CH alkyl-OPC>3H2 and its salt.Embodiment 3. The compound of embodiment 1 or embodiment 2, wherein at least one Ri is a prodrug.Embodiment 4. The compound of any of embodiments 1-3, wherein Re is Br.Embodiment 5. The compound of any of embodiments 1-4, wherein W is NH, each of Xi, X2, and X3 is C, and each Ri and R2 is hydrogen or deuterium.Embodiment 6. The compound of any of embodiments 1-5, wherein the A attached to Rs is absent and Rs is H.Embodiment 7. The compound of any of embodiments 1-6, wherein R3 is H, D, Br, Cl, F, or CEE.Embodiment 8. The compound of any of embodiments 1-7, wherein the A attached to R4 is O and R4 is CEE.Embodiment 9. The compound of any of embodiments 1-7, wherein the A attached to R4 is absent and R4 is H.Embodiment 10. The compound of any of embodiments 1-9, wherein the A attached to Rs is absent and Rs is F, or the A attached to Rs is O and Rs is H or CEE.Embodiment 11. The compound of any of embodiments 1-10, wherein Re is Cl.Embodiment 12. The compound of any of embodiments 1-10, wherein Re is F or CF3.Embodiment 13. The compound of any of embodiments 1-12, wherein the compound persists through a first pass metabolism of a mammal.Embodiment 14. The compound of any of embodiments 1-13, wherein the compound acts as a partial agonist of a CNS serotonin receptor.Embodiment 15. The compound of any of embodiments 1-14, wherein R7 and Rs are independently H, D, alkyl, cycloalkyl, aromatic or heteroaromatic.Embodiment 16. The compound of any of embodiments 1-15, wherein the compound is selected from:r pharmaceutically acceptable salt thereof.Embodiment 17. The compound of any of embodiments 1-15, wherein the compound is selected from:r pharmaceutically acceptable salt thereof.Embodiment 18. The compound of any of embodiments 1-15 or embodiment 17, whereinR.7 and Rs taken together form a ring.Embodiment 19. A composition comprising a pharmaceutical carrier and a compound ofFormula (II):(II), or a pharmaceutically acceptable salt thereof; whereinYi and Y2 are independently hydrogen, deuterium, alkyl, ORi, C(O)ORi, orNR1R2; n is 0, 1, or 2 carbon atoms;Zi is independently SH, SD, ORi, Ri, or NRiR?; each A is independently absent, O, NRi, or S;Xi, X2, and X3 are independently C or N;M is absent, CF2, C=O, C=N, or CR1R2;W is NRi, O, or S; each Ri, R2, and R3 are independently H, D, alkyl, cycloalkyl, aromatic, or heteroaromatic;Re is independently F, Cl, Br, I, alkyl, cycloalkyl, heteroatom substituted or halogen substituted alkyl or cycloalkyl, aromatic, or heteroaromatic and its salt; andR4 and Rs are independently H, D, alkyl, cycloalkyl,, aromatic, or heteroaromatic; or R4 and Rs are prodrugs, wherein when X2 is N, Rs is absent; wherein each alkyl, cycloalkyl, aromatic and heteroaromatic is optionally substituted.Embodiment 20. The composition of embodiment 19, wherein R4 and Rs are alkyl, cycloalkyl, aromatic, heteroaromatic esters, aminal, hemiaminal, -CH2-OPO3H2, or -CH alkyl-OPO3H2 and its salt.Embodiment 21. The composition of embodiment 19 or embodiment 20, wherein at least one of Ri and Zi are a prodrug.Embodiment 22. The composition of any of embodiments 19-21, wherein Zi is independently OH, OD, H, SD, or NR1R2.Embodiment 23. The composition of any of embodiments 19-22, wherein W is NH, each of Xi, X2,, and X3 is C, and each Ri and R2 is hydrogen or deuterium.Embodiment 24. The composition of any of embodiments 19-23, wherein Yi and Y2 are hydrogen or deuterium.Embodiment 25. The composition of any of embodiments 19-24, wherein M is CH2.Embodiment 26. The composition of any of embodiments 19-25, wherein Zi is OH.Embodiment 27. The composition of any of embodiments 19-26, wherein Re is Br.Embodiment 28. The composition of any of embodiments 19-27, wherein the A attached to Rs is absent and Rs is H.Embodiment 29. The composition of any of embodiments 19-28, wherein R3 is H, D, Br, Cl, F, or CH3.Embodiment 30. The composition of any of embodiments 19-29, wherein the A attached to R4 is O and R4 is CH3.Embodiment 31. The composition of any of embodiments 19-29, wherein the A attached to R4 is absent and R4 is H.Embodiment 32. The composition of any of embodiments 19-31, wherein the A attached to Rs is absent Rs is F, or the A attached to Rs is O and Rs is H or CH3.Embodiment 33. The composition of any of embodiments 19-32, wherein Re is Cl.Embodiment 34. The composition of any of embodiments 19-32, wherein Re is F or CF3.Embodiment 35. The composition of any of embodiments 19-34, wherein the pharmaceutical carrier is a bulking agent.Embodiment 36. The composition of any of embodiments 19-35, wherein the compound persists through a first pass metabolism of a mammal.Embodiment 37. The composition of any of embodiments 19-36, wherein the compound acts as a partial agonist of a CNS serotonin receptor.Embodiment 38. The composition of any of embodiments 19-37, wherein the compound is selected from:orpharmaceutically acceptable salt thereof.EXAMPLES

[0061] Compounds of the present disclosure can be synthesized using the following exemplary methods or other methods that are known to those skilled in the art.

[0062] General reaction conditions are provided, and reaction products can be purified by known methods including silica gel chromatography using various organic solvents such as hexane, di chloromethane, ethyl acetate, methanol and the like or preparative reverse phase high pressure liquid chromatography.

[0063] Preparation of compounds can involve the protection and deprotection of various chemical groups. The need for protection and deprotection, and the selection of appropriate protecting groups can be readily determined by one skilled in the art. The chemistry of protecting groups can be found, for example, in Greene and Wuts, Protective Groups in Organic Synthesis, 44th. Ed., Wiley & Sons, 2006, as well as in Jerry March, Advanced Organic Chemistry, 4thedition, John Wiley & Sons, publisher, New York, 1992 which are incorporated herein by reference in their entirety.General Synthesis of Cyclic Amines

[0064] All compounds of Table 1 and Table 2 can be synthesized by the following method:Synthesis of Example 1.0: (l-(2-(7-bromo-4-methoxy-lH-indol-3-yl)ethyl)pyrrolidin-2- yl)methanol

[0065] The compound of Example 1.0 was synthesized from commercially available 4- methoxy-lH-indole by the four steps shown in Scheme 1.Scheme 1

[0066] To a stirred solution of 4-methoxy-lH-indole, 1.1 (200 mg, 1.36 mmol, 1.0 equiv) in diethyl ether (5.0 mL) was added oxalyl chloride (0.18 g, 1.36 mmol, 1.0 equiv) dropwise at 0°C under nitrogen atmosphere. The resulting mixture was stirred for an additional 3 h at room temperature. The resulting mixture 1.2 was used in the next step directly without further purification.

[0067] To a solution of 1.2 (100 mg, 0.42 mmol, 1.00 equiv) in tetrahydrofuran (2 mL) was added 2-(Hydroxymethyl)pyrrolidine (212.1 mg, 2.10 mmol, 5.00 equiv) and triethylamine (212.1 mg, 2.10 mmol, 5.00 equiv) at 0°C. The resulting mixture was stirred for 1 h at 25°C under nitrogen atmosphere. The reaction was diluted with 20 mL of ethyl acetate. The organic layer was washed with 2 x 20 mL saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate. The resulting solution was concentrated under reduced pressure and purified by reverse-phase flash with the following conditions: Column, C18 silica gel; mobile phase, water (with 0.05% NH4HCO3), 10% to 100% gradient in 20 min; detector, UV 254 nm. 100 mg of 1.3 was obtained. MS m / z [M+H]+(ESI): 303.20.

[0068] To a solution of 1.3 (100 mg, 0.33 mmol, 1.00 equiv) in tetrahydrofuran (2 mL) were added lithium aluminum hydride (31.5 mg, 0.83 mmol, 2.50 equiv) at 0°C for 10 min. Then the reaction was stirred for 16 h at 66°C. The reaction was diluted with 20 mL of ethyl acetate. The organic layer was washed with 2 x 20 mL saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. The resulting solution was concentrated under reduced pressure and purified by reverse-phase flash with the following conditions: Column, Cl 8 silica gel; mobile phase, water (with 0.05% NH4HCO3), 10% to 100% gradient in 20 min; detector, UV 254 nm. 50 mg of 1.4 was obtained. MS m / z [M+H]+(ESI): 275.10.

[0069] To a solution of 1.4 (300 mg, 1.093 mmol, 1 equiv) in 1,2-di chloroethane (3.00 mL, 34.66 equiv) was added the solution of dibromocopper (0.73 g, 3.279 mmol, 3 equiv) in acetonitrile (3 mL) by dropwise at 0°C. Then, the mixture was stirred for one hour at room temperature. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, acetonitrile in water (0.1% NHs.tLO+ I Omrnol / L NH4HCO3), 5% to 50% gradient in 12 min; detector, UV 254 nm. This resulted in a crude product. The residue was purified by column: XB ridge Prep OBD C18 Column, 30*150 mm, 5pm; Mobile Phase A: Water (lOmmol / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL / min mL / min; Gradient: 35% B to 55% B in 12min; Wave Length: 220nm nm; RTl(min): 7.52. This resulted in 19.1 mg of 1.0, (1 -(2-(7-bromo-4-m ethoxy- 1H- indol-3-yl)ethyl)pyrrolidin-2-yl)methanol as a white solid. MS m / z [M+H]+(ESI):353.15, 355.15. 'H NMR (300 MHz, Methanol -d4) 5 7.13 (d, J = 8.1 Hz, 1H), 7.00 (s, 1H), 6.42 (d, J = 8.1 Hz, 1H), 3.91 (s, 3H), 3.69-3.61 (m, 1H), 3.58-3.50 (m, 1H), 3.40-3.33 (m, 1H), 3.29-3.18 (m, 1H), 3.15-2.97 (m, 2H), 2.86-2.63 (m, 2H), 2.63-2.50 (m, 1H), 2.10-1.96 (m, 1H), 1.91- 1.79 (m, 2H), 1.78-1.64 (m, 1H).

[0070] The compound of Example 2.0 was synthesized from commercially available 5- methoxy-U / -pyrrolo[2,3-Z>]pyridine by the four steps shown in Scheme 2.Scheme 2Synthesis of intermediate 3-iodo-5-methoxy-lH-pyrrolo [2, 3-b] pyridine, 2.2:To a solution of 5-methoxy-lH-pyrrolo[2,3-b]pyridine (1 g, 6.749 mmol, 1 equiv) in EtOH (40 mL) was added KI (1.68 g, 10.123 mmol, 1.5 equiv), iodine (2.57 g, 10.123 mmol, 1.5 equiv) followed by NaOH (10.12 mL, 10.123 mmol, 1.5 equiv) at 25°C. Then the mixture was stirred at 25°C for 4 h. The reaction mixture was quenched with sat.Na2S2C>4 solution (50 mL) and then concentrated in vacuum to remove most of the solvent. The aqueous was extracted with EtOAc (50 mL x 2). The combined organic phase was concentrated in vacuum to give a crude product. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (10 mmol / L NH4HCO3), 40% to 60% gradient in 10 min; detector, UV 220 nm. to give 3-iodo-5-methoxy-lH-pyrrolo[2,3-b]pyridine (1.3 g) as a yellow solid. MS m / z [M+H]+(ESI): 275.00.Synthesis of 3-[(E)-2-ethoxyethenyl]-5-methoxy-lH-pyrrolo[2,3-b]pyridine, 2.3:To a solution of 3-iodo-5-methoxy-lH-pyrrolo[2,3-b]pyridine (1.15 g, 4.196 mmol, 1 equiv) and 2-[(E)-2-ethoxyethenyl]-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (1.66 g, 8.392 mmol, 2 equiv) in Dioxane (12 mL) and H2O (3 mL) was added Na2COs (1.33 g, 12.588 mmol, 3 equiv) followed by XPhos Pd G2 (330.16 mg, 0.420 mmol, 0.1 equiv) at 25°C under N2. Then the mixture was degassed and purged with N2 for three times and then heated to 80°C and stirred for 24 h. The reaction mixture was diluted with water (20 mL) and extracted with EtOAc(30 mL x 2). The combined organic phase was concentrated in vacuum to give a crude product. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (10 mmol / L NH4HCO3), 40% to 70% gradient in 10 min; detector, UV 220 nm. twice to give 3-[(E)-2-ethoxyethenyl]- 5-methoxy-lH-pyrrolo[2,3-b]pyridine (130 mg) as a brown solid. MS m / z [M+H]+(ESI): 219.10.Synthesis of 2-(5-methoxy-lH-pyrrolo[2,3-b]pyridin-3-ylacetaldehyde, 2.4:A solution of 3-[(E)-2-ethoxyethenyl]-5-methoxy-lH-pyrrolo[2,3-b]pyridine (130 mg, 0.595 mmol, 1 equiv) in HCOOH (1.5 mL, 0.041 mmol) was stirred at 25°C for 1 h. The reaction mixture was concentrated in vacuo to give a crude product. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (0.1% FA), 30% to 60% gradient in 10 min; detector, UV 220 nm. to give 2-(5-methoxy-lH-pyrrolo[2,3-b]pyridin-3-ylacetaldehyde (100 mg) as an oil. MS m / z [M+H]+(ESI): 191.00.Synthesis of (S)-( l-(2-(5-methoxy-l / / -pyrrolo|2.3- / flpyridin-3-yl)ethyl)pyrrolidin-2- yl)methanol, 2.0:To a solution of 2-{5-methoxy-lH-pyrrolo[2,3-b]pyridin-3-yl}acetaldehyde (50 mg, 0.263 mmol, 1 equiv) and (2S)-pyrrolidin-2-ylmethanol (53.18 mg, 0.526 mmol, 2 equiv) in methanol (1 mL) was added HO Ac (1.58 mg, 0.026 mmol, 0.1 equiv) followed by Sodium cyanoborohydride (49.56 mg, 0.789 mmol, 3 equiv) at 0°C. Then the mixture was stirred at 25°C for 2 h. The reaction mixture was concentrated in vacuum to give a residue. The crude product was purified by Prep-HPLC with the following conditions (Column: SunFire Prep Cl 8 OBD Column, 19*250 mm, 5pm; Mobile Phase A: Water(0.05% HC1), Mobile Phase B: ACN; Flow rate: 20ml / min mL / min; Gradient (B%): 1% B to 6% B in 12 min; Wave Length: 254nm / 220nm nm; RTl(min): 10.42) to afford (5)-( l-(2-(5 -methoxy- UT-pyrrolo [2,3- Z>]pyridin-3-yl)ethyl)pyrrolidin-2-yl)methanol (10.8 mg) as a solid. MS m / z [M+H]+(ESI):276.10.'H NMR (300 MHz, Methanol^) 8 8.52 (d, J= 2.4 Hz, 1H), 8.23 (d, J= 2.2 Hz, 1H), 7.69 (s, 1H), 4.05 (s, 3H), 3.99 - 3.65 (m, 5H), 3.55 - 3.45 (m, 1H), 3.42 - 3.29 (m, 3H), 2.36 - 1.89 (m, 4H).Synthesis of 3-{2-[(2S)-2-(hydroxymethyl)pyrrolidin-l-yl]ethyl}-lH-pyrrolo[2,3- b]pyridin-5-ol hydrochloride, 3.0:Scheme 3A mixture of [(2S)-l-(2-{5-methoxy-lH-pyrrolo[2,3-b]pyridin-3-yl}ethyl)pyrrolidin- 2-yl]methanol hydrochloride (100 mg, 0.321 mmol, 1 equiv) in DCM (5 mL) was added BBn (1.60 mL, 1.605 mmol, 5.0 equiv) at 0°C. Then the mixture was stirred at room temperature for 2 h under nitrogen atmosphere. The reaction was quenched with MeOH (1 mL) at 0°C. The resulting mixture was concentrated under reduced pressure to give a residue. The crude product was purified by Prep-HPLC with the following conditions (Column: XBridge Shield RP18 OBD Columnl9*250 mm, 5pm; Mobile Phase A: Water(0.05% HCL), Mobile Phase B: ACN; Flow rate: 20ml / min mL / min; Gradient (B%): 1% B to 6% B in 12 min; Wave Length:254nm / 220nm nm; RTl(min): 5.42) to afford 3-{2-[(2S)-2- (hydroxymethyl)pyrrolidin-l-yl]ethyl}-lH-pyrrolo[2,3-b]pyridin-5-ol hydrochloride (15.3 mg) as a solid. MS m / z [M+H]+(ESI):262.00.'H NMR (300 MHz, Methanol^) 5 8.32 (s, 1H), 8.03 (s, 1H), 7.68 (s, 1H), 3.96 (d, J= 10.5 Hz, 1H), 3.89 - 3.60 (m, 4H), 3.49 - 3.34 (m, 4H), 2.38 - 1.92 (m, 4H).Synthesis of [(2R)-l-(2-(5-methoxy-lH-pyrrolo[2,3-b]pyridin-3-ylethyl)pyrrolidin-2- yljmethanol hydrochloride, 4.0:Scheme 4To a solution of 2-(5-methoxy-lH-pyrrolo[2,3-b]pyridin-3-ylacetaldehyde (100 mg, 0.526 mmol, 1 equiv) and (2S)-pyrrolidin-2-ylmethanol (53.18 mg, 0.526 mmol, 1 equiv) in methanol (1 mL) was added HO Ac (31.57 mg, 0.526 mmol, 1 equiv) followed by Sodium cyanoborohydride (66.08 mg, 1.052 mmol, 2 equiv) at 0°C. Then the mixture was stirred at 25°C for 2 h. The crude product was purified by Prep-HPLC with the following conditions (Column: Xbridge Prep C18 OBD, 30*150mm, 5.0um; Mobile Phase A: Water(10mmol / L NH4HC03+0.05%NH3.H20), Mobile Phase B: ACN; Flow rate: 60 mL / min mL / min; Gradient (B%): 11% B to 24% B in 10 min; Wave Length: 254nm / 220nm nm; RTl(min): 9.38). The fractions were concentrated in vacuum to give free base product, which was further treated with 4 M HC1 in MeOH (0.2 mL) then dried by lyophilization to afford [(2R)-l-(2-(5-methoxy-lH-pyrrolo[2,3-b]pyridin-3-ylethyl)pyrrolidin-2-yl]methanol hydrochloride (26.0 mg) as a solid. MS m / z [M+H]+(ESI):276.10.‘H NMR (300 MHz, Methanol^) 5 8.60 (d, J= 2.3 Hz, 1H), 8.24 (d, J= 2.1 Hz, 1H), 7.72 (s, 1H), 4.06 (s, 3H), 4.02 - 3.91 (m, 1H), 3.89 - 3.70 (m, 4H), 3.49 - 3.42 (m, 1H), 3.41 - 3.32 (m, 3H), 2.24 - 2.01 (m, 3H), 1.96 - 1.86 (m, 1H).Synthesis of [(2S)-l-(2-{5-methoxy-lH-pyrrolo[3,2-b]pyridin-3-yl}ethyl)pyrrolidin-2- yl|methanol hydrochloride, 5.0: It was synthesized in 3 steps reaction (scheme 5).Scheme 5Synthesis of intermediate 2-{5-methoxy-lH-pyrrolo[3,2-b]pyridin-3-yl}ethanol, 5.2:To a solution of 5-hydrazinyl-2-methoxypyridine dihydrochloride (4 g, 18.862 mmol, 1.00 equiv) and 2-(3-chloropropyl)-l,3-dioxolane (2.84 g, 18.862 mmol, 1 equiv) in H2SO4 (200 mL, 4%) was heated to 100°C and stirred for 12 h. The reaction mixture was cooled and then basified with sat.NaHCCh solution until pH = 8-9. The resulting mixture was extracted with EtOAc (150 mL x 2). The combined organic phase was concentrated in vacuum to give a crude product. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (10 mmol / L NH4HCO3), 20% to 40% gradient in 8 min; detector, UV 220 nm. to give 2-{5-methoxy-lH- pyrrolo[3,2-b]pyri din-3 -yl} ethanol (1 g) as a solid. MS m / z [M+H]+(ESI): 193.10.Synthesis of intermediate 2-{5-methoxy-lH-pyrrolo[3,2-b]pyridin-3-yl}ethyl methanesulfonate, 5.3:To a solution of 2-{5-methoxy-lH-pyrrolo[3,2-b]pyridin-3-yl}ethanol (500 mg, 2.601 mmol, 1 equiv) in DCM (5 mL) was added EtiN (1.81 mL, 13.005 mmol, 5 equiv) followed by methanesulfonyl methanesulfonate (1.36 g, 7.803 mmol, 3 equiv) at 25°C. Then the mixture was stirred at 25°C for 1 h. The reaction was quenched with sat.NaHCCh solution (20 mL) and extracted with DCM (20 mL x 2). The combined organic phase was washed with brine (10 mL) and dried over Na2SC>4. Filtered and the filtrate was concentrated in vacuum to give 2-{5- methoxy-lH-pyrrolo[3,2-b]pyridin-3-yl}ethyl methanesulfonate (700 mg) as an oil. MS m / z [M+H]+(ESI):271.10.Synthesis of final product [(2S)-l-(2-{5-methoxy-lH-pyrrolo[3,2-b]pyridin-3- yl}ethyl)pyrrolidin-2-yl]methanol hydrochloride, 5.0:To a solution of 3-(2-chloroethyl)-5-methoxy-lH-pyrrolo[3,2-b]pyridine (100 mg, 0.332 mmol, 1 equiv, 90% purity) and (2S)-pyrrolidin-2-ylmethanol (50.42 mg, 0.498 mmol, 1.5 equiv) in MeCN (2 mL) was added K2CO3 (91.85 mg, 0.664 mmol, 2 equiv) at 25°C. Then the mixture was heated to 80°C and stirred for 2 h. The reaction mixture was filtered and the filtrate was concentrated in vacuum to give a crude product. The crude product was purified by Prep-HPLC with the following conditions (Column: XBridge Shield RP18 OBD Columnl9*250 mm, 5pm; Mobile Phase A: Water(0.05% HCL), Mobile Phase B: ACN; Flow rate: 20ml / min mL / min; Gradient: 26% B to 47% B in 10 min; Wave Length: 254nm / 220nm nm; RTl(min): 8.26) to afford [(2S)-l-(2-{5-methoxy-lH-pyrrolo[3,2-b]pyridin-3- yl}ethyl)pyrrolidin-2-yl]methanol hydrochloride (25.1 mg) as a solid. MS m / z [M+H]+(ESI): 276.10'H NMR (300 MHz, Methanol-d4) 5 8.46 (d, J= 9.0 Hz, 1H), 7.93 (s, 1H), 7.21 (d, J= 9.0 Hz, 1H), 4.23 (s, 3H), 4.00 - 3.88 (m, 1H), 3.87 - 3.70 (m, 4H), 3.50 - 3.31 (m, 3H), 2.35 - 1.84 (m, 5H)Synthesis of [(2R)-l-(2-{5-methoxy-lH-pyrrolo[3,2-b]pyridin-3-yl}ethyl)pyrrolidin-2- yljmethanol hydrochloride, 6.0:Scheme 6To a solution of 3-(2-chloroethyl)-5-methoxy-lH-pyrrolo[3,2-b]pyridine (150 mg, 0.5 mmol, 1 equiv, 90% purity) and (2R)-pyrrolidin-2-ylmethanol (75.75 mg, 0.75 mmol, 1.5 equiv) in MeCN (2 mL) was added K2CO3 (196.82 mg, 1.424 mmol, 2 equiv) at 25°C. Then the mixture was heated to 80°C and stirred for 2 h. The reaction mixture was filtered and the filtrate was concentrated in vacuum to give a crude product. The crude product (mg) was purified by Prep-HPLC with the following conditions (Column: XBridge Shield RP18 OBD Columnl9*250 mm, 5pm; Mobile Phase A: Water(0.05% HCL), Mobile Phase B: ACN; Flow rate: 20ml / min mL / min; Gradient: 16% B to 37% B in 10 min; Wave Length: 254nm / 220nmnm; RTl(min): 8.05) to afford [(2R)-l-(2-{5-methoxy-lH-pyrrolo[3,2-b]pyridin-3- yl}ethyl)pyrrolidin-2-yl]methanol hydrochloride (36.5 mg) as a solid. MS m / z [M+H]+(ESI): 276.10'H NMR (300 MHz, Methanol-d4) 5 8.46 (d, J= 9.0 Hz, 1H), 7.93 (s, 1H), 7.21 (d, J= 9.0 Hz, 1H), 4.23 (s, 3H), 4.00 - 3.88 (m, 1H), 3.87 - 3.70 (m, 4H), 3.50 - 3.31 (m, 3H), 2.35 - 1.84 (m, 5H)Synthesis of (5)-( l-(2-(7-bromo-4-methoxy-LH-indol-3-yl)ethyl)pyrrolidin-2- yl)methanol, 7.0: It was synthesized in 3 steps reaction (scheme 7).Scheme 7To a solution of 4-methoxy-lH-indole (10 g, 67.945 mmol, 1 equiv) in diethyl ether (100 mL) was added oxalyl chloride (8.62 g, 67.945 mmol, 1 equiv) at 0°C. The mixture was stirred for 1 hour at 0°C. The resulting mixture was used in the next step directly without further purification. MS m / z [M+H]+(ESI):238.02.To a solution of prolinol (10.64 g, 105.200 mmol, 2.5 equiv) and TEA (21.29 g, 210.400 mmol, 5 equiv) in tetrahydrofuran (100 mL) was added 7.2 (10 g, 42.080 mmol, 1 equiv) dropwise at 0°C. The resulting mixture was stirred for 2 h at room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, Cl 8 silica gel; mobile phase,MeCN in Water (lOmmol / L NH4HCO3), 10% to 50% gradient in 10 in; detector, UV 220 nm.to afford 7.3 (4 g) as a solid. MS m / z [M+H]+(ESI):303.13.To a stirred solution of 7.3 (4 g, 13.231 mmol, 1 equiv) in tetrahydrofuran (40 mL) was added LiAlH4 (2.51 g, 66.155 mmol, 5 equiv) at 0 °C. The resulting mixture was stirred for overnight at 65°C. The reaction was quenched with potassium sodium tartrate at 0°C. The resulting mixture was filtered and the filter cake was washed with tetrahydrofuran (3 x 50 mL). The filtrate was concentrated under reduced pressure. The residue was purified by reversed- phase flash chromatography with the following conditions: column, Cl 8 silica gel; mobile phase, MeCN in Water (0.1% NH3.H2O+10mmol / L NH4HCO3), 10% to 50% gradient in 10 min; detector, UV 220 nm.to afford 7.4 (2 g) as a solid. MS m / z [M+H]+(ESI):275.17.Synthesis of final product (S)-(l-(2-(7-bronio-4-niethoxy-l / / -indol-3- yl)ethyl)pyrrolidin-2-yl)methanol, 7.0To a stirred solution of 7.4 (100 mg, 0.364 mmol, 1 equiv) in DCE (4 mL) was added dibromocopper (244.22 mg, 1.092 mmol, 3 equiv) in acetonitrile (2 mL, 0.728 mmol) at 0°C under nitrogen atmosphere. The resulting mixture was stirred for 3 h at 25°C under nitrogen atmosphere. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (0.1% NH3.H2O+10mmol / L NH4HCO3), 10% to 50% gradient in 10 min; detector, UV 220 nm.to afford (5)-(l-(2-(7-bromo-4-methoxy-U / -indol-3-yl)ethyl)pyrrolidin-2-yl)methanol, 7.0 (20 mg) as a solid. MS m / z [M+H]+(ESI):353.00, 354.95. 'H NMR (300 MHz, DMSO-t / e) 5 10.90 (s, 1H), 7.14 (d, J= 8.4 Hz, 1H), 7.04 (d, = 2.4 Hz, 1H), 6.42 (d, J= 8.3 Hz, 1H), 4.26 (t, J= 5.5 Hz, 1H), 3.84 (s, 3H), 3.48 - 3.38 (m, 1H), 3.24- 3.06 (m, 2H), 3.06 - 2.75 (m, 3H), 2.47 - 2.39 (m, 2H), 2.29 - 2.18 (m, 1H), 1.86 - 1.72 (m, 1H), 1.71 - 1.48 (m, 3H).METHODSGPCR Arrestin Assay Methods

[0071] Arrestin Pathway (Performed by DiscoverX Eurofins)

[0072] The PathHunter® P-Arrestin assay monitors the activation of a GPCR in a homogenous, non-imaging assay format using a technology developed by DiscoverX called Enzyme Fragment Complementation (EFC) with P-galactosidase (P-Gal) as the functional reporter. The enzyme is split into two inactive complementary portions (EA for EnzymeAcceptor and PK for ProLink) expressed as fusion proteins in the cell. EA is fused to P-Arrestin and PK is fused to the GPCR of interest.

[0073] When the GPCR is activated and P-Arrestin is recruited to the receptor, ED and EA complementation occurs, restoring P-Gal activity which is measured using chemiluminescent PathHunter® Detection Reagents.

[0074] PathHunter® cell lines (DiscoveRx Eurofins) were expanded from freezer stocks according to standard procedures. Cells were seeded in a total volume of 20 pL into white walled, 384-well microplates and incubated at 37°C for the appropriate time prior to testing.

[0075] For agonist determination, cells were incubated with sample to induce response. Intermediate dilution of sample stocks was performed to generate 5X sample in assay buffer. 5 pL of 5X sample was added to cells and incubated at 37°C or room temperature for 90 to 180 minutes. Vehicle concentration was 1%.

[0076] b-Arrestin assay signal was generated through a single addition of 12.5 or 15 pL (50% v / v) of PathHunter® Detection reagent cocktail, followed by a one-hour incubation at room temperature. Microplates were read following signal generation with a PerkinElmer Envision™ instrument for chemiluminescent signal detection.

[0077] Compound activity was analyzed using CBIS data analysis suite (Chemlnnovation, CA). For agonist mode assays, percentage activity was calculated using the following formula:% Activity = 100%

[0078] In these studies, the MAX control ligand response was generated using 10 mM serotonin.Calcium Mobilization Assay Method (Performed by DiscoveRx Eurofins)

[0079] The Calcium No-WashPLUSassay monitors the activation of a GPCR via Gq secondary messenger signaling in a live cell, non-imaging assay format. Calcium mobilization in PathHunter® cell lines or other cell lines stably expressing Gq-coupled GPCRs is monitored using a calcium-sensitive dye that is loaded into cells. GPCR activation by a compound results in the release of calcium from intracellular stores and an increase in dye fluorescence that is measured in real-time.

[0080] Cell lines expressing the GPCR of interest were expanded from freezer stocks according to standard procedures. Cells were seeded in a total volume of 20 pL into blackwalled, clear-bottom, Poly-D-lysine coated 384-well microplates and incubated at 37°C for the appropriate time prior to testing.

[0081] Assays were performed in 1 x Dye Loading Buffer consisting of lx Dye, lx Additive A and 2.5 mM Probenecid in HBSS / 20 mM Hepes. Probenicid was prepared fresh. Cells were loaded with dye prior to testing. Media was aspirated from cells and replaced with 20 pL Dye Loading Buffer. Cells were incubated for 30-60 minutes at 37°C.

[0082] For agonist determination, cells were incubated with sample to induce response. After dye loading, cells were removed from the incubator and 10 pL HBSS / 20 mM Hepes was added. 3x vehicle was included in the buffer when performing agonist dose curves to define the EC80 for subsequent antagonist assays. Cells were incubated for 30 minutes at room temperature in the dark to equilibrate plate temperature.

[0083] Intermediate dilution of sample stocks was performed to generate 4X sample in assay buffer. Compound agonist activity was measured on a FLIPR Tetra (MDS). Calcium mobilization was monitored for 2 minutes and 10 pL 4X sample in HBSS / 20 mM Hepes was added to the cells 5 seconds into the assay.

[0084] Compound activity data was analyzed using CBIS data analysis suite (Chemlnnovation, CA). For agonist mode assays, percentage activity is calculated using the following formula:% Activity = 100%

[0085] In these studies, the MAX RFU was generated by using 0.1 mM serotonin for the calcium mobilization assay.IPOne Assay Method

[0086] IPOne assays were performed using stably-transfected cell lines (CHO-K1) expressing human 5-HT2A or 5-HT2B receptors. Upon activation of these receptors, Gq- mediated myo-Inositol 1 phosphate (IP1) production is detected by a Homogeneous Time- Resolved Fluorescence (HTRF) competitive immunoassay, whereby an IP1 analog coupled toa fluorophore (acceptor) competes with endogenous IP1 for binding to a labeled anti -IP 1 antibody (donor). The resulting signal is inversely proportional to the concentration of IP1 in the sample. Cells were incubated with an IP1 inhibitor (to prevent degradation and allow detection) and either reference compound or test compound. a-Me-5-HT was used as the assay reference agonist. Activation of 5-HT2A or 5-HT2B receptors was measured via accumulation of IP1 detected by HTRF. Agonist activity of test compounds was expressed as a percentage of the activity of the reference agonist at its EC100 concentration. For primary screening, test compounds were screened at 0.3 and 30pM, in duplicate. Follow-up screening had test compounds tested at 10 concentrations, in duplicate, ranging from 0.03-10pM for 5-HT2A receptor screening and 1.0-30pM for 5-HT2B receptor screening. Concentration-response curves were calculated from the test compound agonist activity data using XLfit (IDBS) software using the XL Fit Model 203 : 4 Parameter Logistic Model. Results are shown in Table 2 using the IPOne assay:* ECso is the half maximal effective concentration.

Claims

CLAIMS1. A compound of Formula (la):r pharmaceutically acceptable salt thereof; wherein each A is independently absent, O, NRi, or S;Xi, X2 and X3 are independently C or N;W is NRi, O, or S; each Ri, R2, and R3 are independently H, D, alkyl, cycloalkyl, aromatic, or heteroaromatic, wherein when X3 is N, R3 is absent;R4 and Rs are independently H, D, alkyl, cycloalkyl, aromatic or heteroaromatic, wherein when X2 is N, Rs is absent;Re is halogen, alkyl, cycloalkyl, aromatic, or heteroaromatic;R7 and Rs are independently H, D, alkyl, cycloalkyl, aromatic or heteroaromatic; or R7 and Rs together with the atoms to which they are attached form a heterocyclic ring; and wherein each alkyl, cycloalkyl, aromatic and heteroaromatic is optionally substituted.

2. The compound of claim 1, wherein R4 and Rs are alkyl, cycloalkyl, aromatic, heteroaromatic esters, aminal, hemiaminal, -CH2-OPO3H2, or -CH alkyl-OPO3H2 and its salt.

3. The compound of claim 1, wherein Re is Br.

4. The compound of claim 1, wherein W is NH, each of Xi, X2, and X3 is C, and each Ri and R2 is hydrogen or deuterium.

5. The compound of claim 1, wherein the A attached to Rs is absent and Rs is H.

6. The compound of claim 1, wherein R3 is H, D, Br, Cl, F, or CH3.

7. The compound of claim 1, wherein the A attached to R4 is O and R4 is CH3.

8. The compound of claim 1, wherein the A attached to R4 is absent and R4 is H.

9. The compound of claim 1, wherein the A attached to Rs is absent and Rs is F, or the A attached to Rs is O and Rs is H or CH3.

10. The compound of claim 1, wherein Re is Cl.

11. The compound of claim 1, wherein Re is F or CF3.

12. The compound of claim 1, wherein the compound persists through a first pass metabolism of a mammal.

13. The compound of claim 1, wherein the compound acts as a partial agonist of a CNS serotonin receptor.

14. The compound of claim 1, wherein R? and Rs are independently H, D, alkyl, cycloalkyl, aromatic or heteroaromatic.

15. The compound of claim 1, wherein the compound is selected from:

17. The compound of claim 1, wherein R7 and Rs taken together form a ring.

18. A composition comprising a pharmaceutical carrier and a compound of Formula (II):or a pharmaceutically acceptable salt thereof; whereinYi and Y2 are independently hydrogen, deuterium, alkyl, ORi, C(O)ORi, or NR1R2; n is 0, 1, or 2 carbon atoms;Zi is independently SH, SD, ORi, Ri, or NRiR2; each A is independently absent, O, NRi, or S;Xi, X2, and X3 are independently C or N;M is absent, CF2, C=O, C=N, or CR1R2;W is NRi, O, or S; each Ri, R2, and R3 are independently H, D, alkyl, cycloalkyl, aromatic, or heteroaromatic;Re is independently F, Cl, Br, I, alkyl, cycloalkyl, or heteroaromatic; andR4 and Rs are independently H, D, alkyl, cycloalkyl,, aromatic, or heteroaromatic, wherein when X2 is N, Rs is absent; wherein each alkyl, cycloalkyl, aromatic and heteroaromatic is optionally substituted.

19. The composition of claim 18, wherein R4 and Rs are alkyl, cycloalkylalkyl, cycloakyl, aromatic, heteroaromatic esters, aminal, hemiaminal, -CH2-OPO3H2, or -CH alkyl- OPO3H2 and its salt.

20. The composition of claim 18, wherein Zi is independently OH, OD, H, SD, or NR1R2.

21. The composition of claim 18, wherein W is NH, each of Xi, X2,, and X3 is C, and each Ri and R2 is hydrogen or deuterium.

22. The composition of claim 18, wherein Yi and Y2 are hydrogen or deuterium.

23. The composition of claim 18, wherein M is CH2.

24. The composition of claim 18, wherein Zi is OH.

25. The composition of claim 18, wherein Re is Br.

26. The composition of claim 18, wherein the A attached to Rs is absent and Rs is H.

27. The composition of claim 18, wherein R3 is H, D, Br, Cl, F, or CH3.

28. The composition of claim 18, wherein the A attached to R4 is O and R4 is CH3.

29. The composition of claim 18, wherein the A attached to R4 is absent and R4 is H.

30. The composition of claim 18, wherein the A attached to Rs is absent Rs is F, or the A attached to Rs is O and Rs is H or CH3.

31. The composition of claim 18, wherein Re is Cl.

32. The composition of claim 18, wherein Re is F or CF3.

33. The composition of claim 18, wherein the pharmaceutical carrier is a bulking agent.

34. The composition of claim 18, wherein the compound persists through a first pass metabolism of a mammal.

35. The composition of claim 18, wherein the compound acts as a partial agonist of a CNS serotonin receptor.

36. The composition of claim 18, wherein the compound is selected from:

Images