3-(2-(dimethylamino)ethyl)-1H-indol-4-yl derivatives

Abstract

As used herein, the formula (I) [Formula 1] JPEG2026503411000111.jpg45165 or a compound selected from any of the compounds of Table 1, Table 2, Table 3, Table 4, or Table 5, or a pharmaceutically acceptable salt or deuterated form thereof, wherein R 1 , R 2 , R 3 , and R 4 is defined herein. Also provided herein are pharmaceutical compositions comprising a compound of formula (I), or a compound selected from any of the compounds in Table 1, Table 2, Table 3, Table 4, or Table 5, or a pharmaceutically acceptable salt or deuterated form thereof, and methods of using a compound of formula (I), or a pharmaceutically acceptable salt or deuterated form thereof, for example, in the treatment of a 5-HT2A receptor-associated disease or disorder.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Application No. 63 / 481,385, filed January 24, 2023, and U.S. Provisional Application No. 63 / 457,469, filed April 6, 2023, the disclosures of each of which are incorporated by reference in their entirety for all purposes. [Background technology]

[0002] In the United States, over 50% of adults will be diagnosed with a mental disorder at some point in their lifetime. Approximately 1 in 5 people suffer from a mental illness, and approximately 1 in 25 people suffer from a severe mental illness such as major depression, schizophrenia, or bipolar disorder.

[0003] Hallucinogens show promising activity in the treatment of psychiatric disorders. Novel psychedelic compounds are needed to treat psychiatric disorders. Summary of the Invention

[0004] In some embodiments, the present disclosure provides a compound of formula (I)

[0005] [ka] or a pharmaceutically acceptable salt or deuterated form thereof, wherein R 1 , R 2 , R 3 , and R 4 is defined herein.

[0006] In some embodiments, the disclosure provides a compound selected from any of the compounds in Table 1, Table 2, Table 3, Table 4, or Table 5, or a pharmaceutical salt or deuterated form thereof. DETAILED DESCRIPTION OF THE INVENTION

[0007] The following terms, as used herein, have the following meanings unless otherwise indicated:

[0008] "Cyano" refers to the -CN radical.

[0009] "Hydroxy" or "hydroxyl" refers to the --OH radical.

[0010] "Oxo" refers to the =O substituent.

[0011] "Alkyl" or "alkyl group" refers to a fully saturated straight or branched hydrocarbon chain radical having from 1 to 12 carbon atoms, which is attached to the rest of the molecule by a single bond. Alkyl groups containing any number of carbon atoms from 1 to 12 are included. Alkyl groups containing up to 12 carbon atoms include C1-C 12 Alkyl groups containing up to 10 carbon atoms are C1-C 10 An alkyl group containing up to 6 carbon atoms is a C1-C6 alkyl, and an alkyl group containing up to 5 carbon atoms is a C1-C5 alkyl. C1-C5 alkyl includes C5 alkyl, C4 alkyl, C3 alkyl, C2 alkyl, and C1 alkyl (i.e., methyl). C1-C6 alkyl includes all of the moieties described above for C1-C5 alkyl, but also includes C6 alkyl. C1-C 10 Alkyl includes all of the above C1-C5 alkyl and C1-C6 alkyl moieties, as well as C7, C8, C9 and C 10 Also includes alkyl. Similarly, C1-C 12 Alkyl includes all of the above moieties, but C 11 and C 12 Includes alkyl. C1-C 12Non-limiting examples of alkyl include methyl, ethyl, n-propyl, i-propyl, sec-propyl, n-butyl, i-butyl, sec-butyl, t-butyl, n-pentyl, t-amyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, n-undecyl, and n-dodecyl. Unless stated otherwise specifically in the specification, an alkyl group can be optionally substituted.

[0012] "Alkylene" or "alkylene chain" refers to a fully saturated, straight or branched divalent hydrocarbon chain radical having from 1 to 12 carbon atoms. 12 Non-limiting examples of alkylene include methylene, ethylene, propylene, n-butylene, etc. The alkylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond. The points of attachment of the alkylene chain to the rest of the molecule and to the radical group can be through one carbon or any two carbons within the chain. Unless stated otherwise specifically in the specification, an alkylene chain can be optionally substituted.

[0013] "Alkenyl" or "alkenyl group" refers to a straight or branched hydrocarbon chain radical having from 2 to 12 carbon atoms and having one or more carbon-carbon double bonds. Each alkenyl group is attached to the rest of the molecule by a single bond. Alkenyl groups containing any number of carbon atoms from 2 to 12 are included. Alkenyl groups containing up to 12 carbon atoms are C2-C 12 Alkenyl containing up to 10 carbon atoms is C2-C 10 An alkenyl group containing up to 6 carbon atoms is C2-C6 alkenyl, and an alkenyl containing up to 5 carbon atoms is C2-C5 alkenyl. C2-C5 alkenyl includes C5 alkenyl, C4 alkenyl, C3 alkenyl, and C2 alkenyl. C2-C6 alkenyl includes all of the moieties described above for C2-C5 alkenyl, but also includes C6 alkenyl. C2-C 10Alkenyl includes all of the moieties described above for C2-C5 alkenyl and C2-C6 alkenyl, but also includes C7, C8, C9 and C 10 Also includes alkenyl. Similarly, C2-C 12 Alkenyl includes all of the above moieties, but C 11 and C 12 Includes alkenyl. C2-C 12 Non-limiting examples of alkenyl include ethenyl (vinyl), 1-propenyl, 2-propenyl (allyl), isopropenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1-heptenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 5-heptenyl, 6-heptenyl, 1-octenyl, 2-octenyl, 3-octenyl, 4-octenyl, 5-octenyl, 6-octenyl, 7-octenyl, 1-nonenyl, 2-nonenyl, and 3-nonenyl. , 4-nonenyl, 5-nonenyl, 6-nonenyl, 7-nonenyl, 8-nonenyl, 1-decenyl, 2-decenyl, 3-decenyl, 4-decenyl, 5-decenyl, 6-decenyl, 7-decenyl, 8-decenyl, 9-decenyl, 1-undecenyl, 2-undecenyl, 3-undecenyl, 4-undecenyl, 5-undecenyl, 6-undecenyl, 7-undecenyl, 8-undecenyl, 9-undecenyl, 10-undecenyl, 1-dodecenyl, 2-dodecenyl, 3-dodecenyl, 4-dodecenyl, 5-dodecenyl, 6-dodecenyl, 7-dodecenyl, 8-dodecenyl, 9-dodecenyl, 10-dodecenyl, and 11-dodecenyl. Unless stated otherwise in the specification, an alkenyl group may be optionally substituted.

[0014] "Alkoxy" is a group of formulas -OR a where R a is an alkyl, alkenyl, or alkynyl radical, as defined above, containing 1 to 12 carbon atoms. Unless stated otherwise specifically in the specification, an alkoxy group can be optionally substituted.

[0015] "Alkylamino" refers to a group of the formula -NHR a or -NR a R a where each R a is independently an alkyl, alkenyl, or alkynyl radical, as defined above, containing 1 to 12 carbon atoms. Unless stated otherwise specifically in the specification, an alkylamino group can be optionally substituted.

[0016] "Aryl" refers to a hydrocarbon ring system radical containing hydrogen, 6 to 18 carbon atoms, and at least one aromatic ring. For purposes of the present invention, an aryl radical can be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which can include fused or bridged 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 otherwise specifically stated in this specification, the term "aryl" is intended to include aryl radicals that are optionally substituted.

[0017] An "aralkyl", "arylalkyl", or "alkylene-aryl" is an alkylene group of the formula -R b -R c where R b is an alkylene group as defined above, and R c is one or more aryl radicals as defined above, e.g., benzyl, diphenylmethyl, etc. Unless stated otherwise specifically in the specification, an aralkyl group may be optionally substituted.

[0018] "Carbocyclyl," "carbocyclyl ring," or "carbocycle" refers to a non-aromatic cyclic structure in which each atom forming the ring is carbon. A carbocyclic ring can contain from 3 to 20 carbon atoms within the ring. Carbocyclic rings include cycloalkyl, cycloalkenyl, and cycloalkynyl, as defined herein. Unless otherwise specifically stated in the specification, a carbocyclyl group can be optionally substituted.

[0019] "Cycloalkyl" refers to a stable non-aromatic monocyclic or polycyclic fully saturated hydrocarbon radical, consisting solely of carbon and hydrogen atoms, having from 3 to 20 carbon atoms, and may include fused or bridged ring systems, e.g., from 3 to 10 carbon atoms, which are attached to the remainder 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 specifically stated in the specification, cycloalkyl groups can be optionally substituted.

[0020] "Cycloalkenyl" refers to a stable non-aromatic monocyclic or polycyclic hydrocarbon radical, consisting solely of carbon and hydrogen atoms, having one or more carbon-carbon double bonds, and may include fused or bridged ring systems having 3 to 20 carbon atoms, e.g., 3 to 10 carbon atoms, which are attached to the remainder of the molecule by a single bond. Monocyclic cycloalkenyl radicals include, for example, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, and the like. Polycyclic cycloalkenyl radicals include, for example, bicyclo[2.2.1]hept-2-enyl, and the like. Unless otherwise specifically stated in the specification, a cycloalkenyl group can be optionally substituted.

[0021] "Cycloalkynyl" refers to a stable non-aromatic monocyclic or polycyclic hydrocarbon radical, consisting solely of carbon and hydrogen atoms, having one or more carbon-carbon triple bonds, and having from 3 to 20 carbon atoms, for example, from 3 to 10 carbon atoms, which may include fused or bridged ring systems, which are attached to the remainder of the molecule by a single bond. Monocyclic cycloalkynyl radicals include, for example, cycloheptynyl, cyclooctynyl, and the like. Unless otherwise specifically stated in the specification, a cycloalkynyl group can be optionally substituted.

[0022] "Haloalkyl" refers to an alkyl radical, as defined above, that is substituted by one or more halo radicals, as defined above, such as, for example, trifluoromethyl, difluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, etc. Unless stated otherwise specifically in the specification, a haloalkyl group can be optionally substituted.

[0023] "Haloalkenyl" refers to an alkenyl radical, as defined above, that is substituted by one or more halo radicals, as defined above, such as, for example, 1-fluoropropenyl, 1,1-difluorobutenyl, etc. Unless stated otherwise specifically in the specification, a haloalkenyl group can be optionally substituted.

[0024] "Haloalkynyl" refers to an alkynyl radical, as defined above, that is substituted by one or more halo radicals, as defined above, such as, for example, 1-fluoropropynyl, 1-fluorobutynyl, etc. Unless stated otherwise specifically in the specification, a haloalkynyl group can be optionally substituted.

[0025] "Heterocyclyl," "heterocyclic ring," or "heterocycle" refers to a stable 3- to 20-membered non-aromatic radical, consisting of 2 to 12 carbon atoms and 1 to 6 heteroatoms selected from nitrogen, oxygen, sulfur, or silicon. Unless stated otherwise specifically in the specification, the heterocyclyl radical can be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which can include fused or bridged ring systems; the nitrogen, carbon, or sulfur atoms in the heterocyclyl radical can be optionally oxidized; the nitrogen atom can be optionally quaternized; and the heterocyclyl radical can be partially saturated or fully saturated. Examples of such heterocyclyl radicals include, but are not limited to, dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, and 1,1-dioxo-thiomorpholinyl. Unless stated otherwise specifically in the specification, heterocyclyl groups may be optionally substituted.

[0026] A "heterocyclylalkyl" or "alkylene-heterocyclyl" is a heterocyclyl group of the formula -R b -R e where R b is an alkylene group as defined above, and R e is a heterocyclyl radical as defined above. Unless stated otherwise specifically in the specification, a heterocycloalkyl group may be optionally substituted.

[0027] "N-heterocyclyl" refers to a heterocyclyl radical, as defined above, containing at least one nitrogen, and the point of attachment of the heterocyclyl radical to the rest of the molecule is through a nitrogen atom in the heterocyclyl radical. Unless stated otherwise specifically in the specification, an N-heterocyclyl group can be optionally substituted.

[0028] "Heteroaryl" refers to a 5- to 20-membered ring system radical containing a hydrogen atom, 1 to 13 carbon atoms, 1 to 6 heteroatoms selected from nitrogen, oxygen, and sulfur, and at least one aromatic ring containing at least one heteroatom selected from nitrogen, oxygen, and sulfur. For purposes of this invention, a heteroaryl radical can be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which can include fused or bridged ring systems, and the nitrogen, carbon, or sulfur atoms in the heteroaryl radical can be optionally oxidized, and the nitrogen atom can be optionally quaternized. Examples include azepinyl, acridinyl, benzimidazolyl, benzothiazolyl, benzoindolyl, benzodioxolyl, benzofuranyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophene), benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophene, furanyl, furanonyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, and indophenyl. linyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl, 1-oxidopyridinyl, 1-oxidopyrimidinyl, 1-oxidopyrazinyl, 1-oxidopyridazinyl, 1-phenyl-1H-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 may be optionally substituted.

[0029] "N-heteroaryl" refers to a heteroaryl radical, as defined above, containing at least one nitrogen, and the point of attachment of the heteroaryl radical to the rest of the molecule is through a nitrogen atom in the heteroaryl radical. Unless stated otherwise specifically in the specification, an N-heteroaryl group can be optionally substituted.

[0030] A "heteroarylalkyl" or "alkylene-heteroaryl" is a heteroaryl group of the formula -R b -R f where R b is an alkylene chain as defined above, and R f is a heteroaryl radical as defined above. Unless stated otherwise specifically in the specification, a heteroarylalkyl group may be optionally substituted.

[0031] "Thioalkyl" is -SR a where R a is an alkyl, alkenyl, or alkynyl radical, as defined above, containing 1 to 20 carbon atoms. Unless stated otherwise specifically in the specification, a thioalkyl group may be optionally substituted.

[0032] The term "substituted," as used herein, means any of the above groups (e.g., alkyl, alkylene, alkenyl, alkenylene, alkynyl, alkynylene, alkoxy, alkylamino, thioalkyl, aryl, aralkyl, carbocyclyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, haloalkyl, heterocyclyl, N-heterocyclyl, heterocyclylalkyl, heteroaryl, N-heteroaryl, and / or heteroarylalkyl) wherein at least one hydrogen atom is replaced with a non-hydrogen atom, such as, but not limited to, F, Cl, Br, and and halogen atoms such as I; oxygen atoms in groups such as hydroxyl, alkoxy, and ester groups; sulfur atoms in groups such as thiol, thioalkyl, sulfone, sulfonyl, and sulfoxide groups; nitrogen atoms in groups such as amine, amide, alkylamine, dialkylamine, arylamine, alkylarylamine, diarylamine, N-oxide, imide, and enamine; silicon atoms in groups such as trialkylsilyl, dialkylarylsilyl, alkyldiarylsilyl, and triarylsilyl groups; and other heteroatoms in various other groups.

[0033] "Substituted" also refers to any of the above groups in which one or more hydrogen atoms are replaced by a higher 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 imine, oxime, hydrazone, and nitrile. For example, "substituted" includes any of the above groups in which one or more hydrogen atoms are replaced by a higher 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 imine, oxime, hydrazone, and nitrile. g R h , -NR g C(=O)R h , -NR g C(=O)NR g R h , -NR g C(=O)OR h , -NR g SO2R h , -OC(=O)NR g Rh , -OR g , -SR g , -SOR g , -SO2R g , -OSO2R g , -SO2OR g , =NSO2R g , and -SO2NR g R h Also, "substituted" means any of the above groups in which one or more hydrogen atoms are replaced by -C(=O)R g , -C(=O)OR g , -C(=O)NR g R h , -CH2SO2R g , -CH2SO2NR g R h In the previous example, R g and R h are the same or different and are independently hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylamino, thioalkyl, aryl, aralkyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, haloalkyl, haloalkenyl, haloalkynyl, heterocyclyl, N-heterocyclyl, heterocyclylalkyl, heteroaryl, N-heteroaryl and / or heteroarylalkyl.

[0034] "Substituted" further includes any of the above groups in which 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, cycloalkynyl, cycloalkylalkyl, haloalkyl, haloalkenyl, haloalkynyl, heterocyclyl, N-heterocyclyl, heterocyclylalkyl, heteroaryl, N-heteroaryl and / or heteroarylalkyl group.

[0035] As used herein, unless otherwise specified, the term "pharmaceutically acceptable" is used to characterize a moiety (e.g., a salt, dosage form, or excipient) as being suitable for therapeutic use. Generally, a pharmaceutically acceptable moiety has one or more benefits that outweigh any adverse effects that the moiety may have. Adverse effects may include, for example, excessive toxicity, irritation, allergic responses, and other problems and complications.

[0036] The term "pharmaceutically acceptable salts" includes both acid addition salts and base addition salts. Pharmaceutically acceptable salts include those obtained by reacting an active compound that functions as a base with an inorganic or organic acid to form a salt, such as, 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, and the like. Those skilled in the art will further recognize that acid addition salts may be prepared by reacting the compound with an appropriate inorganic or organic acid by any of several known methods.

[0037] The compounds of the present disclosure, or pharmaceutically acceptable salts thereof, can contain one or more asymmetric centers, i.e., can give rise to enantiomers, diastereomers, and other stereoisomers that can be defined in terms of absolute stereochemistry as (R)- or (S)-, or, for amino acids, as (D)- or (L)-. The present disclosure is intended to include all such possible isomers, as well as their racemic and optically pure forms, whether or not specifically depicted herein. Optically active (+)- and (-), (R)- and (S)-, or (D)- and (L)-isomers can be prepared using chiral synthons or chiral reagents or resolved using conventional techniques, such as chromatography and fractional crystallization. Conventional techniques for the preparation / isolation of individual enantiomers include chiral synthesis from suitable optically pure precursors, or resolution of the racemate (or racemate of a salt or derivative) using, for example, chiral high-pressure liquid chromatography (HPLC). When compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, unless otherwise specified, the compounds are intended to include both E and Z geometric isomers, as well as all tautomeric forms. compound

[0038] In embodiments, the present disclosure provides a compound of formula (I)

[0039] [ka] or a pharmaceutically acceptable salt thereof.

[0040] In embodiments, R 1 is NR 5 R 6 , alkyl, haloalkyl, alkenyl, alkylene-NR 5 R 6 , alkylene-C(═O)O-alkyl, alkylene-C(═O)O-heteroaryl, where heteroaryl is alkyl or alkylene-NR 5 R6 , alkylene-O-alkyl, alkylene-OC(=O)alkyl, alkylene-O-haloalkyl, alkylene-O-alkylene-O-alkyl, alkylene-C(=O)NR 5 R 6 , 1, 2, 3, or 4 R 7 alkylene-aryl, alkylene-heteroaryl, alkylene-carbocyclyl, alkylene-heterocyclyl optionally substituted with 1, 2, 3, or 4 R 7 aryl substituted with 1, 2, 3, or 4 R 7 heteroaryl optionally substituted with O-alkyl, O-alkylene-heterocyclyl, O-heterocyclyl, O-alkylene-carbocyclyl, 1, 2, 3, or 4 R 7 Optionally substituted by O-aryl, O-alkylene-heteroaryl, or carbocyclyl optionally substituted by Si(alkyl)3.

[0041] In embodiments, R 2 and R 3 is independently alkyl.

[0042] In embodiments, R 4 is H or C(=O)Oalkyl.

[0043] In embodiments, R 5 and R 6 are independently H, OH, alkyl, C(=O)alkyl, or C(=O)Oalkyl.

[0044] In embodiments, R 7 OH, halo, alkyl, NR 5 R 6 , OC(=O)alkyl, or O-alkyl.

[0045] In embodiments, the present disclosure provides a compound of formula (II)

[0046] [ka] or a pharmaceutically acceptable salt thereof.

[0047] In embodiments, R 2 and R 3 is independently alkyl.

[0048] In embodiments, R 4 is H or C(=O)Oalkyl.

[0049] In embodiments, R 8 is alkylene-carbocyclyl, alkylene-heterocyclyl, 1, 2, 3, or 4 R 7 alkylene-heterocyclyl, alkylene-C(=O)NR 5 R 6 , alkylene-C(=O)aryl, alkylene-OC(=O)alkyl, alkylene-N + (C 1-6 alkyl)3, alkylene-NR 5 R 6 , alkylene-S(O)2(alkyl), alkylene-S(O)2(NR 5 R 6 ), alkylene-Si(alkyl)3, (CH2CH2O) m alkyl, heterocyclyl, or 1, 2, 3, or 4 R 7 Examples of aryl substituted with include, but are not limited to, aryl substituted with

[0050] In embodiments, R 5 and R 6 are independently H, alkyl, C(=O)alkyl, alkylene-aryl, or S(O)alkyl.

[0051] In embodiments, R 7 is halo, alkyl, or O-alkyl.

[0052] In embodiments, m is 2, 3, 4, 5, 6, 7, or 8.

[0053] Compound of formula (III)

[0054] [ka] or a pharmaceutically acceptable salt thereof, R 9A is -O-aryl or -OC(=O)C 1-6 Alkyl-substituted branched C 1-6 Alkyl, 1 to 4 R 7 aryl optionally substituted by, 5-10 membered heteroaryl optionally substituted by OH; 3-10 membered heterocyclyl optionally substituted by C(=O)O alkyl or haloalkyl; 3-8 membered carbocyclyl; 3-8 membered carbocyclyl substituted by aryl or Si(alkyl)3; -CH(R A )-C 1-6 Alkyl, -CH(R A )NR 5 R 6 , -CH(R A )-O-aryl, -CH(R A )-aryl, -CH(R A )-5 to 10-membered heteroaryl, C(R A )2-Si(C 1-3 alkyl)3, Each R A are independently H, OH, halo, C 1-6 Alkyl, or C 1-6 alkylene-OH, R 2 and R 3 independently C 1-4 is alkyl, R 4 is H or C(=O)OC 1-4 is alkyl, R 5 and R 6 are independently H, C 1-6 Alkyl, C(=O)C 1-6 Alkyl, C(=O)aryl, C(=O)OC 1-6 Alkyl, S(O)2-C 1-6 Alkyl, C1-6 alkylene-3 to 10-membered heterocyclyl; R 7 is OH, halo, alkyl, O-alkyl, OC(=O)C 1-6 Alkyl, Si(C 1-3 alkyl), aryl, or a 3- to 10-membered heterocycle; However, R 9A teeth,

[0055] [ka] isn't it.

[0056] In embodiments, the present disclosure provides a compound of formula (IV)

[0057] [ka] or a pharmaceutically acceptable salt thereof.

[0058] In embodiments, R 1 is branched alkyl, haloalkyl, alkylene -OH, NR 5 R 6 , S(O)NR 5 R 6 , S(O)2 alkyl, alkylene-NR 5 R 6 , C(=O)O-alkyl, C(=O)NR 5 R 6 , alkyl or alkylene-NR 5 R 6 C(═O)O-heteroaryl, alkenylene-NR optionally substituted with 5 R 6 , alkenylene-aryl, alkenylene(OH)(aryl), alkylene-OC(═O)alkyl, 1, 2, 3, or 4 R 7 alkylene-O-aryl, O-alkyl, O-haloalkyl, O-alkenylene-NR 5 R 6, O-alkylene-O-alkyl, O-aryl, OC(=O)alkyl, OC(=O)haloalkyl, Si(alkyl)3, haloalkylSi(alkyl)3, 1, 2, 3, or 4 R 7 C(═O)O is an optionally substituted aryl, heteroaryl, C(═O)O is an optionally substituted heterocyclyl with alkyl, carbocyclyl, carbocyclyl substituted with aryl.

[0059] In embodiments, R 4 is H or C(=O)Oalkyl.

[0060] In embodiments, R 5 and R 6 are independently H, alkyl, C(=O)alkyl, C(=O)aryl, C(=O)Oalkyl, S(O)2alkyl, alkylene-heterocyclyl.

[0061] In embodiments, R 7 is OH, halo, alkyl, O-alkyl, OC(=O)alkyl, or aryl.

[0062] In embodiments, n is 1, 2, 3, 4, 5, or 6.

[0063] In embodiments, R 1 NR 5 R 6 If n is not 1 or R 5 and R 6 is not H. In an embodiment, R 9 When is aryl, n is not 1.

[0064] In embodiments, the present disclosure provides a compound of formula (V)

[0065] [ka] or a pharmaceutically acceptable salt thereof.

[0066] In embodiments, R2 and R 3 is independently alkyl.

[0067] In embodiments, R 4 is H or C(=O)Oalkyl.

[0068] In embodiments, R 5 and R 6 is independently aryl optionally substituted with H, OH, alkyl, haloalkyl, C(=O)alkyl, C(=O)Oalkyl, Oalkyl, or C(=O)NH(alkyl). 5 and R 6 together with the atoms to which they are attached form a heterocyclyl.

[0069] In embodiments, the present disclosure provides a compound of formula (VI)

[0070] [ka] or a pharmaceutically acceptable salt thereof.

[0071] In embodiments, R 2 and R 3 is independently alkyl.

[0072] In embodiments, R 10 is alkyl, alkylene-C(=O)Oalkyl, 1, 2, 3, or 4 R 7 is O-alkylene-aryl optionally substituted with

[0073] In embodiments, R 7 is OH, halo, alkyl, O-alkyl, OC(O)alkyl, alkylene-OC(=O)alkyl.

[0074] In some embodiments, the present disclosure provides a compound of formula (I)

[0075] [ka] or a pharmaceutically acceptable salt thereof, wherein: R 2 and R 3 are independently alkyl; R 4 is H or C(=O)Oalkyl, R 1 is defined according to i, ii, iii, or iv.

[0076] R 1 In an embodiment of formula (I), where R 1 -OR 8 where: R 8 is alkylene-carbocyclyl, alkylene-heterocyclyl (heterocyclyl is 1 to 4 R 7 substituted with 1 to 4 R 7 substituted with 1 to 4 R 7 substituted with), alkylene-C(=O)NR 5 R 6 , alkylene-C(=O)aryl, alkylene-OC(=O)alkyl, alkylene-OH, alkylene-N + (C 1-6 alkyl)3, alkylene-NR 5 R 6 , alkylene-S(O)2(alkyl), alkylene-S(O)2(NR 5 R 6 ), alkylene-Si(alkyl)3, (CH2CH2O) m Alkyl, -C(=O)alkyl, or 1 to 4 R 7 is an aryl substituted with R 5 and R 6 are independently H, alkyl, C(═O)alkyl, alkylene-aryl, or S(O)alkyl; R 7is OH, halo, alkyl, haloalkyl, O-alkyl, OC(=O)alkyl, Si(alkyl)3, aryl, -NH(C=O)alkyl, -N(alkyl)2, or heterocyclyl; m is 2, 3, 4, 5, 6, 7, or 8; or

[0077] R 1 In an embodiment of formula (I), R 1 is R 9A where: R 9A is a branched alkyl substituted with -OC(=O) alkyl or 1 to 4 R 7 -O-aryl optionally substituted with aryl, alkenyl substituted with aryl, 1 to 4 R 7 aryl optionally substituted with 1 to 4 R 7 heteroaryl optionally substituted with 1 to 4 R 7 heterocyclyl optionally substituted with 1 to 4 R 7 carbocyclyl optionally substituted with -C(R A )2-alkyl, -C(R A )2NR 5 R 6 , -C(R A )2-O-aryl, -C(R A )2-aryl, -C(R A )2-heteroaryl, or C(R A )2-Si(alkyl)3, Each R A are independently H, OH, halo, unsubstituted alkyl, or alkylene-OH, provided that at least one R A But it's not H, it's R 9A -C(R A ) 2-alkyl, two R A cannot both be CH3, R 5 and R 6 are independently H, alkyl, C(=O)alkyl, C(=O)aryl, C(=O)Oalkyl, S(O)alkyl, alkylene-heterocyclyl; R7 is OH, halo, alkyl, haloalkyl, O-alkyl, OC(=O)alkyl, Si(alkyl), aryl, -NH(C=O)alkyl, -N(alkyl), or heterocyclyl, provided that R 9A teeth,

[0078] [ka] or

[0079] R 1 In an embodiment of formula (I), wherein R 1 is -(CH2) n -R 9B where: n is 1, 2, 3, 4, 5, or 6; R 9B is haloalkyl, alkylene-OH, alkenyl, NR 5 R 6 , S(O)NR 5 R 6 , S(O)2 alkyl, C(=O)O alkyl, C(=O)NR 5 R 6 , alkyl or alkylene-NR 5 R 6 C(═O) optionally substituted with O-heteroaryl, O-alkyl, O-haloalkyl, O-alkenylene-NR 5 R 6 , O-Alkylene-O-alkyl, O-Aryl, OC(=O)Alkyl, OC(=O)Haloalkyl, Si(Alkyl)3, 1 to 4 R 7 aryl optionally substituted with C(═O)Oalkyl, heterocyclyl optionally substituted with C(═O)Oalkyl, carbocyclyl, aryl-substituted carbocyclyl, provided that R 9B is C(═O)Oalkyl, n is less than 5, and R 9B NR 5 R 6 If n is not 1 or R 5 and R 6Both are H, not R 9A is aryl, n is not 1, and R 9B teeth,

[0080] [ka] Not only that, R 7 is OH, halo, alkyl, haloalkyl, O-alkyl, OC(=O)alkyl, Si(alkyl)3, aryl, -NH(C=O)alkyl, -N(alkyl)2, or heterocyclyl;

[0081] R 1 In an embodiment of formula (I), where R is defined according to iv 1 Ha-NR 5A R 6A where: R 5A and R 6A are independently H, OH, unsubstituted C 1-6 aryl substituted with alkyl, haloalkyl, C(=O)alkyl, C(=O)Oalkyl, O-alkyl, or C(=O)NH(alkyl), provided that R 5A and R 6A and R cannot both be H. 5A and R 6A is CH3, then the other cannot be H, CH3, or CH2CH3; Alternatively, R 5A and R 6A together with the atoms to which they are attached form a heterocyclyl.

[0082] In some embodiments, the present disclosure provides a compound of formula (II)

[0083] [ka] or a pharmaceutically acceptable salt thereof, wherein: R 8is alkylene-heterocyclyl, alkylene-heterocyclyl (heterocyclyl is 1 to 4 R 7 substituted with 1 to 4 R 7 substituted with 1 to 4 R 7 substituted with), alkylene-C(=O)NR 5 R 6 , alkylene-C(=O)aryl, alkylene-OC(=O)alkyl, alkylene-OH, alkylene-N + (C 1-6 alkyl)3, alkylene-NR 5 R 6 , alkylene-S(O)2(alkyl), alkylene-S(O)2(NR 5 R 6 ), alkylene-Si(alkyl)3, (CH2CH2O) m Alkyl or 1 to 4 R 7 is an aryl substituted with R 2 and R 3 are independently alkyl; R 4 is H or C(=O)Oalkyl, R 5 and R 6 are independently H, alkyl, C(═O)alkyl, alkylene-aryl, or S(O)alkyl; R 7 is halo, alkyl, OH, or O-alkyl; m is 2, 3, 4, 5, 6, 7, or 8.

[0084] Compound of formula (II)

[0085] [ka] or a pharmaceutically acceptable salt thereof, R 8 is the unsubstituted C 1-6Alkylene-C 3-10 Carbocyclyl, C 1-6 alkylene-3 to 10-membered heterocyclyl (heterocycle having 1 to 4 R 7 substituted with), C 1-6 Alkylene-aryl (aryl is 1 to 4 R 7 substituted with), C 1-6 Alkylene-5 to 10-membered heteroaryl, C 1-6 alkylene-5 to 10-membered heteroaryl (heteroaryl is 7 substituted with), C 1-6 Alkylene-C(=O)NR 5 R 6 , C 1-6 Alkylene-C(=O)aryl, C 1-6 Alkylene-OC(=O)-C 1-6 Alkyl, C 1-6 Alkylene-OH, C 1-6 Alkylene-N + (C 1-6 Alkyl)3, C 1-6 Alkylene-NR 5 R 6 , C 1-6 Alkylene-S(O)2(C 1-6 alkyl), C 1-6 Alkylene-S(O)2(NR 5 R 6 ), alkylene-Si(C 1-3 alkyl)3, (CH2CH2O) m Alkyl, -C(=O)-C 1-6 Alkyl or 1 to 4 R 7 is an aryl substituted with R 2 and R 3 independently C 1-3 is alkyl, R 4 is H or C(=O)OC 1-6 is alkyl, R 5 and R 6 are independently H, C 1-6 Alkyl, C(=O)C 1-6 Alkyl, C 1-6Alkylene-aryl, or S(O)2-C 1-6 is alkyl, R 7 Ha, Halo, C 1-6 Alkyl, OH, or OC 1-6 is alkyl, m is 2, 3, 4, 5, 6, 7, or 8.

[0086] In some embodiments of the compound of Formula (II), R 2 and R 3 independently C 1-3 is alkyl, R 4 is H or C(=O)OC 1-6 is alkyl, R 8 is C 1-6 Alkylene-C 3-10 Carbocyclyl or 1, 2, 3, or 4 R 7 is an aryl substituted with R 7 Ha, Halo, C 1-6 Alkyl, OC 1-6 It is alkyl.

[0087] In some embodiments, the present disclosure provides a compound of formula (III)

[0088] [ka] or a pharmaceutically acceptable salt thereof, wherein: R 9A is a branched alkyl substituted with -OC(=O) alkyl or 1 to 4 R 7 -O-aryl optionally substituted with 1 to 4 R 7 aryl optionally substituted with 1 to 4 R 7 heteroaryl optionally substituted with 1 to 4 R 7 heterocyclyl optionally substituted with 1 to 4 R 7 carbocyclyl optionally substituted with -C(R A)2-alkyl, -C(R A )2NR 5 R 6 , -C(R A )2-O-aryl, -C(R A )2-aryl, -C(R A )2-heteroaryl, or C(R A )2-Si(alkyl)3, Each R A are independently H, OH, halo, unsubstituted alkyl, or alkylene-OH, provided that at least one R A But it's not H, it's R 9A -C(R A ) 2-alkyl, two R A cannot both be CH3, R 2 and R 3 are independently alkyl; R 4 is H or C(=O)Oalkyl, R 5 and R 6 are independently H, alkyl, C(=O)alkyl, C(=O)aryl, C(=O)Oalkyl, S(O)alkyl, alkylene-heterocyclyl; R 7 is OH, halo, alkyl, haloalkyl, O-alkyl, OC(=O)alkyl, Si(alkyl)3, aryl, -NH(C=O)alkyl, -N(alkyl)2, or heterocyclyl; However, R 9A teeth,

[0089] [ka] isn't it.

[0090] In some embodiments of the compound of Formula (III), R 9A is a branched alkyl substituted with -O-aryl or -OC(=O)alkyl, 1 to 3 R 7aryl optionally substituted with , heteroaryl optionally substituted with OH, heterocyclyl optionally substituted with C(=O)Oalkyl, carbocyclyl optionally substituted with haloalkyl, aryl or Si(alkyl)3, -CH(R A )-alkyl, -CH(R A )NR 5 R 6 , -CH(R A )-O-aryl, -CH(R A )-aryl, -CH(R A )-heteroaryl, C(R A )2-Si(alkyl)3, R A each one of is independently H, OH, halo, unsubstituted alkyl, or alkylene-OH; R 2 and R 3 independently C 1-4 is alkyl, R 4 is H or C(=O)OC 1-4 is alkyl, R 5 and R 6 are independently H, alkyl, C(=O)alkyl, C(=O)aryl, C(=O)Oalkyl, S(O)alkyl, alkylene-heterocyclyl; R 7 is OH, halo, alkyl, haloalkyl, O-alkyl, OC(=O)alkyl, Si(alkyl)3, aryl, -N(alkyl)2, or heterocycle, provided that R 9A teeth,

[0091] [ka] isn't it.

[0092] Compound of formula (III)

[0093] [ka] or a pharmaceutically acceptable salt thereof, R 9A is -O-aryl or -OC(=O)C 1-6 Alkyl-substituted branched C 1-6 Alkyl, 1 to 4 R 7 aryl optionally substituted by, 5-10 membered heteroaryl optionally substituted by OH; 3-10 membered heterocyclyl optionally substituted by C(=O)O alkyl or haloalkyl; 3-8 membered carbocyclyl; 3-8 membered carbocyclyl substituted by aryl or Si(alkyl)3; -CH(R A )-C 1-6 Alkyl, -CH(R A )NR 5 R 6 , -CH(R A )-O-aryl, -CH(R A )-aryl, -CH(R A )-5 to 10-membered heteroaryl, C(R A )2-Si(C 1-3 alkyl)3, Each R A are independently H, OH, halo, C 1-6 Alkyl, or C 1-6 alkylene-OH, R 2 and R 3 independently C 1-4 is alkyl, R 4 is H or C(=O)OC 1-4 is alkyl, R 5 and R 6 are independently H, C 1-6 Alkyl, C(=O)C 1-6 Alkyl, C(=O)aryl, C(=O)OC 1-6 Alkyl, S(O)2-C 1-6 Alkyl, C 1-6 alkylene-3 to 10-membered heterocyclyl; R 7 is OH, halo, alkyl, O-alkyl, OC(=O)C 1-6 Alkyl, Si(C 1-3alkyl), aryl, or a 3- to 10-membered heterocycle; However, R 9A teeth,

[0094] [ka] isn't it.

[0095] In some embodiments, the present disclosure provides a compound of formula (IV)

[0096] [ka] or a pharmaceutically acceptable salt thereof, wherein: n is 1, 2, 3, 4, 5, or 6; R 9B is haloalkyl, alkylene -OH, NR 5 R 6 , S(O)NR 5 R 6 , S(O)2 alkyl, C(=O)O alkyl, C(=O)NR 5 R 6 , alkyl or alkylene-NR 5 R 6 C(═O) optionally substituted with O-heteroaryl, O-alkyl, O-haloalkyl, O-alkenylene-NR 5 R 6 , O-Alkylene-O-alkyl, O-Aryl, OC(=O)Alkyl, OC(=O)Haloalkyl, Si(Alkyl)3, 1 to 4 R 7 aryl optionally substituted with C(═O)Oalkyl, heterocyclyl optionally substituted with C(═O)Oalkyl, carbocyclyl, aryl-substituted carbocyclyl, provided that R 9B is C(═O)Oalkyl, then n is less than 5; R 2 and R 3 are independently alkyl; R 4 is H or C(=O)Oalkyl, R 5 and R 6 are independently H, alkyl, C(=O)alkyl, C(=O)aryl, C(=O)Oalkyl, S(O)alkyl, alkylene-heterocyclyl; R 7 is OH, halo, alkyl, O-alkyl, OC(=O)alkyl, Si(alkyl)3, aryl, heterocyclyl; However, R 9 NR 5 R 6 If n is not 1, or R 5 and R 6 Both are H, not R 9 is aryl, n is not 1, and R 9B teeth,

[0097] [ka] isn't it.

[0098] Compound of formula (IV)

[0099] [ka] or a pharmaceutically acceptable salt thereof, n is 1, 2, 3, 4, 5, or 6; R 9B is C 1-6 Haloalkyl, C 1-6 Alkylene-OH, NR 5 R 6 , S(O)NR 5 R 6 , S(O)2C 1-6 Alkyl, C(=O)NR 5 R 6 , C 1-6 Alkyl or C 1-6 Alkylene-NR 5 R 6 C(=O)O-5 to 10 membered heteroaryl optionally substituted with OC1-6 Alkyl, OC 1-6 Haloalkyl, OC 1-6 Alkenylene-NR 5 R 6 , O.C. 1-6 Alkylene-OC 1-6 Alkyl, O-aryl, OC(=O)C 1-6 Alkyl, OC(=O)C 1-6 Haloalkyl, Si(C 1-3 alkyl)3, 1 to 4 R 7 aryl optionally substituted with, 5-10 membered heteroaryl, C(=O)OC 1-6 a 3- to 10-membered heterocyclyl optionally substituted with alkyl, a 3- to 10-membered carbocyclyl, or an aryl-substituted 3- to 10-membered carbocyclyl; R 2 and R 3 independently C 1-3 is alkyl, R 4 is H or C(=O)OC 1-6 is alkyl, R 5 and R 6 are independently H, C 1-6 Alkyl, C(=O)C 1-6 Alkyl, C(=O)aryl, C(=O)OC 1-6 Alkyl, S(O)2-C 1-6 Alkyl, C 1-6 alkylene-3 to 10-membered heterocyclyl; R 7 OH, halo, C 1-6 Alkyl, OC 1-6 Alkyl, OC(=O) C1-6 Alkyl, Si(C 1-3 alkyl), aryl, or heterocyclic; However, R 9 NR 5 R 6 If n is not 1, or R 5 and R 6 Both are H, not R 9 is aryl, n is not 1, and R 9B teeth,

[0100] [ka] isn't it.

[0101] In some embodiments, the present disclosure provides a compound of formula (V)

[0102] [ka] or a pharmaceutically acceptable salt thereof, wherein: R 2 and R 3 are independently alkyl; R 4 is H or C(=O)Oalkyl, R 5A and R 6A are independently H, OH, unsubstituted C 1-6 aryl substituted with alkyl, haloalkyl, C(=O)alkyl, C(=O)Oalkyl, O-alkyl, or C(=O)NH(alkyl), provided that R 5A and R 6A and R cannot both be H. 5A and R 6A is CH3, then the other cannot be H, CH3, or CH2CH3; Alternatively, R 5A and R 6A together with the atoms to which they are attached form a heterocyclyl.

[0103] Compound of formula (V)

[0104] [ka] or a pharmaceutically acceptable salt thereof, R 2 and R 3 independently C 1-3 is alkyl, R 4 is H or C(=O)OC 1-6 is alkyl, R 5A and R 6A are independently H, OH, unsubstituted C 3-6 Alkyl, haloalkyl, C(=O)C 1-6 Alkyl, C(=O)OC 1-6 Alkyl, OC 1-6 Alkyl, or C(=O)NH(C 1-6 alkyl), where R 5A and R 6A and R cannot both be H. 5A and R 6A is CH3, then the other cannot be H, CH3, or CH2CH3; Alternatively, R 5A and R 6A together with the atoms to which they are attached form a 3- to 10-membered heterocyclyl.

[0105] In some embodiments, the present disclosure provides a compound of formula (VI)

[0106] [ka] or a pharmaceutically acceptable salt thereof, wherein: R 2 and R 3 are independently alkyl; R 10 is O-linear alkyl, alkylene-C(=O)Oalkyl, 1, 2, 3, or 4 R 7 O-alkylene-aryl optionally substituted with R 7 is OH, halo, alkyl, O-alkyl, OC(=O)alkyl, alkylene-OC(=O)alkyl.

[0107] Compound of formula (VI)

[0108] [ka] or a pharmaceutically acceptable salt thereof, R 2 and R 3 independently C 1-3 is alkyl, R 10 is O-linear C 1-6 Alkyl, C 1-6 Alkylene-C(=O)OC 1-6 Alkyl, 1, 2, 3, or 4 R 7 OC optionally replaced by 1-6 alkylene-aryl, R 7 OH, halo, C 1-6 Alkyl, O-alkyl, OC(=O)-C 1-6 Alkyl, alkylene -OC(=O)C 1-6 It is alkyl.

[0109] In some embodiments, the present disclosure provides a compound selected from any of the compounds in Table 1, Table 2, Table 3, Table 4, or Table 5, or a pharmaceutical salt or deuterated form thereof. In some embodiments, the present disclosure provides a compound selected from any of the compounds in Table 1, Table 2, Table 3, Table 4, or Table 5, or a pharmaceutically acceptable salt thereof.

[0110] [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] Table 1-6 Table 1-7 Table 1-8 Table 1-9

[0111] Table 2-1 Table 2-2 Table 2-3 Table 2-4 Table 2-5 Table 2-6

[0112] Table 3-1 Table 3-2 Table 3-3 Table 3-4 Table 3-5 Table 3-6 Table 3-7 Table 3-8 Table 3-9

[0113] Table 4-1 Table 4-2 Table 4-3

[0114] Table 5-1 Table 5-2 Table 5-3

[0115] Medical ingredients The present invention provides pharmaceutical compositions comprising at least one compound disclosed herein and one or more pharmaceutically acceptable excipients.

[0116] The compounds provided herein may be administered as the compounds themselves or may be formulated as pharmaceutical compositions, which may include one or more pharmaceutically acceptable excipients such as carriers, diluents, fillers, disintegrants, lubricants, binders, colorants, pigments, stabilizers, preservatives, and / or antioxidants.

[0117] Pharmaceutical compositions are described in "Remington: The Science and Practice of Pharmacy," Pharmaceutical Press, 22 nd Pharmaceutical compositions can be formulated by techniques known to those skilled in the art, such as those published in the "Publications of the American Pharmaceutical Association" edition. Pharmaceutical compositions can be formulated for oral, parenteral, e.g., intramuscular, intravenous, subcutaneous, intradermal, intraarterial, intracardiac, rectal, nasal, topical, aerosol, or vaginal administration. Oral dosage forms include coated and uncoated tablets, soft and hard gelatin capsules, lozenges, troches, solutions, emulsions, suspensions, syrups, elixirs, powders and granules for reconstitution, dispersible powders and granules, medicated gums, gum tablets, and effervescent tablets. Parenteral dosage forms include solutions, emulsions, suspensions, dispersions, and powders and granules for reconstitution. Emulsions are preferred dosage forms for parenteral administration. Rectal and vaginal dosage forms include suppositories and pessaries. Nasal dosage forms can be administered via inhalation and insufflation, for example, by a metered-dose inhaler. Dosage forms for topical administration include creams, gels, ointments, salves, patches, and transdermal delivery systems.

[0118] Treatment method The present disclosure further relates to a compound disclosed herein, or a pharmaceutical composition comprising at least one compound disclosed herein, for use in the treatment of a serotonin 5-HT2A receptor-associated disease / disorder. In embodiments, the compounds may be used to treat anxiety disorders, attention deficit hyperactivity disorder (ADHD), depression (including treatment-resistant depression), cluster headache, demotivation, burnout, boredom syndrome, migraine, Parkinson's disease, schizophrenia, eating disorders (including anorexia nervosa), psychotic disorders, schizophrenia, schizophreniform disorder, schizoaffective disorder, bipolar I disorder, bipolar II disorder, major depressive disorder, psychotic depression, delusional disorder, shared psychotic disorder, dyadic psychosis, brief psychotic disorder, suspicious personality disorder, schizotypal personality disorder, schizotypal personality disorder, social anxiety disorder, substance-induced anxiety disorder, selective mutism, panic disorder, panic attacks, agoraphobia, post-traumatic stress disorder (PTSD), premenstrual dysphoric disorder (PMDD), and premenstrual syndrome (PMS).

[0119] In an embodiment, the 5-HT2A receptor-related disease or disorder is depression. In an embodiment, the depression is treatment-resistant depression.

[0120] In embodiments, the 5-HT2A receptor-associated disease or disorder is an eating disorder. In embodiments, the eating disorder is anorexia nervosa.

[0121] In embodiments, the 5-HT2A receptor-associated disease or disorder is an anxiety disorder.

[0122] In embodiments, the 5-HT2A receptor-associated disease or disorder is bipolar I disorder.

[0123] In embodiments, the 5-HT2A receptor-associated disease or disorder is bipolar II disorder.

[0124] In embodiments, the 5-HT2A receptor-associated disease or disorder is major depressive disorder.

[0125] In embodiments, the 5-HT2A receptor-associated disease or disorder is post-traumatic stress disorder (PTSD). [Example]

[0126] Example 1. Synthesis of Compound 100: 3-(2-(dimethylamino)ethyl)-1H-indol-4-yl 4-pivalamidobutanoate, formic acid

[0127] [ka]

[0128] To a stirred solution of 4-[(2,2-dimethylpropionyl)amino]butyric acid (187 mg, 1.1 equiv., 999 μmol) in dry DCM (4 mL) at room temperature under a nitrogen atmosphere, oxalyl chloride (173 mg, 120 μL, 1.5 equiv., 1.37 mmol) and one drop of DMF were added. The reaction mixture was stirred at room temperature for 3 hours. The volatiles were removed in vacuo. The residue was redissolved in DCM (2 mL) and added to a solution of psilocin (204.6 mg, 1 equiv., 942 μmol) and triethylamine (363 mg, 500 μL, 3.8 equiv., 3.59 mmol) in DCM (2 mL) at 0°C. The resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with water (10 mL) and extracted with DCM (3 × 10 mL). The combined organic layers were collected, dried (NaSO), filtered, and concentrated in vacuo. The crude product was purified by chromatography on silica gel (24 g cartridge, 0-20% MeOH / DCM) to give partially purified product. This material was dissolved in DMSO (1.94 mL), filtered, and loaded onto a Waters X-Select CSH C18 ODB preparative column, 130 Å, 5 μm, 30 mm × 100 mm, flow rate 40 mL min -1The above was purified by reversed-phase preparative HPLC (Waters 2767 Sample Manager, Waters 2545 Binary Gradient Module, Waters Systems Fluidics Organiser, Waters 515 ACD pump, Waters 515 Makeup pump, Waters 2998 Photodiode Array Detector, Waters QDa) eluting with 0.1% formic acid in a water-MeCN gradient over 8.5 min using UV across all wavelengths with PDA, QDa and ELS detectors. The column dilution pump was used to pump 2 mL of water throughout the method. -1 of MeCN was obtained, which contained the following percentages of MeCN. Gradient information: 0.0-0.5 min, 10% MeCN; 0.5-5.5 min, increasing from 10% MeCN to 40% MeCN; 5.5-5.6 min, increasing from 40% MeCN to 100% MeCN; 5.6-8.5 min, holding at 100% MeCN. The clean fractions were evaporated in a Genevac to give the title compound (25.7 mg, 52 μmol, 6%) as a yellow oil. m / z 374.3 (M+H) + (ES+)

[0129] 1 H NMR (500 MHz, DMSO-d6) δ 11.02 (s, 1H), 8.17 (s, 1H), 7.55 (t, J = 5.7 Hz, 1H), 7.22 (dd, J = 8.1, 0.8 Hz, 1H), 7.14 (d, J = 2.3 Hz, 1H), 7.03 (t, J = 7.9 Hz, 1H), 6.67 (dd, J = 7.6, 0.8 Hz, 1H), 3.16 (q, J = 6.5 Hz, 2H), 2.79 - 2.71 (m, 2H), 2.64 (t, J = 7.6 Hz, 2H), 2.23 (s, 6H), 1.85 - 1.77 (m, 2H), 1.10 (s, 9H). Two H's are missing - the signal overlaps with the DMSO solvent peak. One exchangeable H is missing.

[0130] Example 2. Synthesis of Compound 105: 3-(2-(dimethylamino)ethyl)-1H-indol-4-yl 2-(pyridin-2-yl)acetate, formic acid

[0131] [ka]

[0132] A mixture of psilocin (200.0 mg, 1 equiv., 960 μmol), 2-(pyridin-2-yl)acetic acid, HCl (168 mg, 1 equiv., 960 μmol), HATU (525 mg, 1.4 equiv., 1.38 mmol), and DIPEA (417 mg, 557 μL, 3.4 equiv., 3.22 mmol) in dry DMF (2.5 mL) was stirred at room temperature for 16 h. The reaction mixture was diluted with saturated NaHCO (25 mL) and extracted with EtOAc (3 × 25 mL). The combined organic layers were washed with water (3 × 20 mL) and brine (25 mL), dried (NaSO), filtered, and concentrated in vacuo. The crude product was loaded onto Celite and purified by chromatography on a RP Flash C18 (12 g cartridge, 0–100% (0.1% formic acid in MeCN) / (0.1% formic acid in water)). The partially purified sample was dissolved in DMSO (1.8 mL), filtered, and then loaded onto a Waters X-Select CSH C18 ODB preparative column, 130 Å, 5 μm, 30 mm × 100 mm, at a flow rate of 40 mL min -1 The above was purified by reversed-phase preparative HPLC (Waters 2767 Sample Manager, Waters 2545 Binary Gradient Module, Waters Systems Fluidics Organiser, Waters 515 ACD pump, Waters 515 Makeup pump, Waters 2998 Photodiode Array Detector, Waters QDa) eluting with 0.1% formic acid in a water-MeCN gradient over 12.5 min using UV across all wavelengths with PDA, QDa and ELS detectors. The column dilution pump was used to pump 2 mL of water throughout the method. -1of MeCN was obtained, which contained the following percentages of MeCN. Gradient information: 0.0-0.5 min, 5% MeCN; 0.5-10.5 min, increasing from 5% MeCN to 22.5% MeCN; 10.5-10.6 min, increasing from 22.5% MeCN to 100% MeCN; 10.6-12.5 min, holding at 100% MeCN. The clean fractions were evaporated in a Genevac to give the title compound (7.0 mg, 17 μmol, 2%) as a brown solid.

[0133] m / z 324.1 (M+H) + (ES+)

[0134] 1 H NMR (500 MHz, DMSO-d6) δ 11.08 (s, 1H), 8.56 (dd, J = 5.1, 1.8 Hz, 1H), 8.24 (s, 1H), 7.85 - 7.78 (m, 1H), 7.50 (d, J = 7.8 Hz, 1H), 7.33 (dd, J = 7.6, 4.9 Hz, 1H), 7.24 (d, J = 8.1 Hz, 1H), 7.17 (d, J = 2.3 Hz, 1H), 7.07 - 7.01 (m, 1H), 6.69 (d, J = 7.6 Hz, 1H), 4.23 (s, 2H), 2.87 - 2.81 (m, 2H), 2.68 - 2.62 (m, 2H), 2.35 (s, 6H). (One exchangeable hydrogen not observed).

[0135] Example 3. Synthesis of Compound 107: 3-(2-(dimethylamino)ethyl)-1H-indol-4-yl(thiazol-5-ylmethyl)carbonate, 0.5 fumaric acid

[0136] [ka]

[0137] To a stirred solution of thiazol-5-ylmethanol (114 mg, 1 equiv., 990 μmol) and bis(4-nitrophenyl)carbonate (361 mg, 1.2 equiv., 1.19 mmol) in dry DCM (8 mL) at 20°C under a nitrogen atmosphere, triethylamine (220 mg, 304 μL, 2.2 equiv., 2.18 mmol) was added. The reaction mixture was stirred at room temperature for 1 hour. To the reaction mixture at 20°C under a nitrogen atmosphere, a DMF solution (2 mL) of psilocin (202.2 mg, 1 equiv., 990 μmol) was added. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was then heated at 38°C overnight. The reaction mixture was diluted with DCM (10 mL), poured into ice / water (20 mL), and transferred to a separatory funnel. The aqueous layer was extracted with DCM (3 × 10 mL). The combined organic layers were washed with brine (15 mL), dried (NaSO), filtered, and concentrated in vacuo. The crude product was purified by chromatography on a RP Flash C18 (24 g cartridge, 5–50% (0.1% formic acid in MeCN) / (0.1% formic acid in water)) to afford 3-(2-(dimethylamino)ethyl)-1H-indol-4-yl(thiazol-5-ylmethyl)carbonate, formic acid (94.7 mg, 242 μmol, 24%) as a pale yellow oil. This material was dissolved in acetone (5 mL) and a solution of fumaric acid (28 mg, 0.24 equiv., 242 μmol) in acetone (5 mL) was added. The resulting solid was filtered, washed with acetone, and dried in vacuo for 24 h to afford the title compound (48.7 mg, 0.12 mmol, 12%) as an off-white solid.

[0138] m / z 346.1 (M+H) + (ES+)

[0139] 1H NMR (500 MHz, DMSO-d6) δ 11.13 (s, 1H), 9.18 (s, 1H), 8.05 (s, 1H), 7.30–7.25 (m, 1H), 7.19 (d, J = 2.3 Hz, 1H), 7.09–7.02 (m, 1H), 6.79 (d, J = 7.6 Hz, 1H), 6.54 (s, 1H), 5.56 (s, 2H), 2.75–2.69 (m, 2H), 2.56–2.51 (m, 2H), 2.20 (s, 6H). One exchangeable hydrogen was not observed.

[0140] Example 4. Synthesis of Compound 109: 3-(2-(dimethylamino)ethyl)-1H-indol-4-yl phenethyl carbonate, fumaric acid

[0141] [ka]

[0142] To a stirred solution of 2-phenylethan-1-ol (121.8 mg, 1 equiv., 996.7 μmol) and bis(4-nitrophenyl)carbonate (363.9 mg, 1.2 equiv., 1.196 mmol) in dry DCM (8.00 mL) at 20°C under a nitrogen atmosphere, EtN (221.9 mg, 306 μL, 2.2 equiv., 2.193 mmol) was added. The reaction mixture was stirred at room temperature for 1 hour. To the reaction mixture at 20°C under a nitrogen atmosphere, a DMF solution (2.00 mL) of psilocin (203.6 mg, 1 equiv., 996.7 μmol) was added. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was then heated at 38°C for 17 hours. The reaction mixture was cooled to room temperature, diluted with DCM (10 mL), poured into ice / water (30 mL), and transferred to a separatory funnel. The aqueous layer was extracted with DCM (3 × 15 mL). The combined organic layers were washed with water (3 × 20 mL) and brine (20 mL), dried (NaSO), filtered, and concentrated in vacuo. The crude product was purified by chromatography on a RP Flash C18 (12 g cartridge, 5–35% (0.1% formic acid in MeCN) / (0.1% formic acid in water)) to give the formate salt (173.1 mg, 0.35 mmol, 35%, 80% purity) as a brown oil. This material was dissolved in acetone (8 mL) and a solution of fumaric acid (50.42 mg, 0.4358 equiv., 434.4 μmol) in acetone (6 mL) was added. The resulting solid was filtered, washed with acetone, and dried in a vacuum oven over the weekend to give the title compound (111.5 mg, 0.23 mmol, 23%, 95% purity) as a brown solid.

[0143] m / z 353.15 (M+H) + (ES+);307.80 (M-NMe2-H) - (ES-)

[0144] 1H NMR (500 MHz, DMSO) δ 11.17 (d, J = 2.7 Hz, 1H), 7.36 - 7.22 (m, 6H), 7.20 (d, J = 2.4 Hz, 1H), 7.05 (t, J = 7.9 Hz, 1H), 6.75 (dd, J = 7.7, 0.9 Hz, 1H), 6.54 (d, J = 1.4 Hz, 2H), 4.46 (t, J = 6.8 Hz, 2H), 3.01 (t, J = 6.8 Hz, 2H), 2.84 (dd, J = 10.0, 5.6 Hz, 2H), 2.74 (dd, J = 9.2, 6.1Hz, 2H), 2.38 (s, 6H). Two H's are absent (exchangeable protons of fumaric acid).

[0145] Example 5. Synthesis of Compound 110: 3-(2-(dimethylamino)ethyl)-1H-indol-4-yl(2-(pyridin-2-yl)ethyl)carbonate, diformic acid

[0146] [ka]

[0147] To a solution of 2-(pyridin-2-yl)ethan-1-ol (116 mg, 1 eq., 920 μmol) and bis(4-nitrophenyl)carbonate (297 mg, 1.1 eq., 966 μmol) in dry DMF (2 mL) at room temperature under a nitrogen atmosphere, DIPEA (742 mg, 1.0 mL, 6.2 eq., 5.74 mmol) was added. The reaction mixture was stirred at room temperature for 2 hours. To the reaction mixture was added a DMF solution (2 mL) of psilocin (200 mg, 1 eq., 920 μmol). The reaction mixture was stirred at 40° C. for 48 hours. The reaction mixture was diluted with distilled water (25 mL). The layers were extracted with DCM (3×20 mL). The combined organic layers were collected, dried (NaSO), filtered, and concentrated in vacuo. The crude product was loaded onto Celite and purified by chromatography on RP Flash C18 (12 g cartridge, 5-20% (0.1% formic acid in MeCN) / (0.1% formic acid in water)) to give the title compound (196 mg, 0.38 mmol, 42%) as a dark brown oil.

[0148] m / z 354.2 (M+H) + (ES+)

[0149] 1 H NMR (500 MHz, DMSO-d6) δ 11.13 (s, 1H), 8.53 (ddd, J = 4.9, 1.9, 0.9 Hz, 1H), 8.21 (s, 2H), 7.75 (td, J = 7.6, 1.9 Hz, 1H), 7.35 (dt, J = 7.8, 1.1 Hz, 1H), 7.29 - 7.24 (m, 2H), 7.19 (d, J = 2.3 Hz, 1H), 7.07 - 7.01 (m, 1H), 6.74 (dd, J = 7.7, 0.8 Hz, 1H), 4.63 (t, J = 6.6 Hz, 2H), 3.17 (d, J = 13.1 Hz, 2H), 2.78 (dd, J = 9.2, 6.5 Hz, 2H), 2.63 (dd, J = 9.2, 6.5 Hz, 2H), 2.30 (s, 6H). Two exchangeable hydrogens were not observed.

[0150] Example 6. Synthesis of Compound 113: 3-(2-(dimethylamino)ethyl)-1H-indol-4-yl 5-methylpicolinic acid, 0.5 fumaric acid

[0151] [ka]

[0152] A mixture of psilocin (202.0 mg, 1 equiv., 930 μmol), 5-methylpicolinic acid (130 mg, 1 equiv., 930 μmol), HATU (509 mg, 1.4 equiv., 1.34 mmol), and DIPEA (284 mg, 379 μL, 2.4 equiv., 2.19 mmol) in dry DMF (2.5 mL) was stirred at room temperature for 7 days. The reaction mixture was diluted with saturated NaHCO (25 mL) and extracted with EtOAc (3 × 25 mL). The combined organic layers were washed with water (3 × 20 mL) and brine (25 mL), dried (NaSO), filtered, and concentrated in vacuo. The crude product was loaded onto Celite and purified by chromatography on a RP Flash C18 (12 g cartridge, 5–30% (0.1% formic acid in MeCN) / (0.1% formic acid in water)) to afford 3-(2-(dimethylamino)ethyl)-1H-indol-4-yl 5-methylpicolinate, formate (42 mg) as a glassy oil. To a solution of this material (40.0 mg, 1 equiv., 103 μmol) in acetone (2 mL) was added a solution of fumaric acid (13 mg, 1.05 equiv., 108 μmol) in acetone (2 mL). This was stored at −20° C. for 64 hours. The resulting solid was isolated by filtration and dried in vacuo at 45° C. for 2 hours to afford the title compound (35.2 mg, 90 μmol, 10%) as an off-white solid.

[0153] m / z 324.6 (M+H) + (ES+)

[0154] 1H NMR (500 MHz, DMSO-d6) δ 1H NMR (500 MHz, DMSO) δ 11.19 - 11.05 (m, 1H), 8.70 - 8.65 (m, 1H), 8.20 (d, J = 7.9 Hz, 1H), 7.93 - 7.88 (m, 1H), 7.29 (dd, 1H), 7.18 (d, J = 2.3 Hz, 1H), 7.12 - 7.08 (m, 1H), 6.81 (dd, 1H), 6.52 (s, 1H), 2.77 - 2.71 (m, 2H), 2.56 - 2.52 (m, 2H), 2.45 (s, 3H), 2.04 (s, 6H). (One exchangeable H not recognized).

[0155] Example 7. Synthesis of Compound 117: 3-(2-(dimethylamino)ethyl)-1H-indol-4-ylthiazole-5-carboxylate, formic acid

[0156] [ka]

[0157] To a stirred solution of thiazole-5-carboxylic acid (135 mg, 1.1 equiv., 1.04 mmol) in dry DCM (4 mL) at room temperature under a nitrogen atmosphere, oxalyl chloride (173 mg, 120 μL, 1.5 equiv., 1.37 mmol) and one drop of DMF were added. The reaction mixture was stirred at room temperature for 3 hours. The resulting mixture was stirred at room temperature for 3 hours. The volatiles were removed in vacuo. The residue was redissolved in DCM (2 mL) and added to a solution of psilocin (200.1 mg, 1 equiv., 921 μmol) and triethylamine (363 mg, 500 μL, 3.9 equiv., 3.59 mmol) in DCM (2 mL) at 0° C. The resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with water (10 mL) and extracted with DCM (3 × 10 mL). The combined organic layers were collected, dried (NaSO), filtered, and concentrated in vacuo. The crude product was purified by chromatography on RP Flash C18 (24 g cartridge, 5-40% (0.1% formic acid in MeCN) / (0.1% formic acid in water) to give the partially purified title compound (224.1 mg) as a brown oil. 101.9 mg of this material was triturated with diethyl ether and dried in a vacuum oven at 40° C. for 72 h to give the title compound (66.4 mg, 0.18 mmol, 20%) as a light brown solid.

[0158] m / z 316.1 (M+H) + (ES+)

[0159] 1H NMR (500 MHz, DMSO-d6) δ 11.15 (s, 1H), 9.51 (d, J = 0.8 Hz, 1H), 8.83 (d, J = 0.8 Hz, 1H), 8.17 (s, 1H), 7.31 (dd, J = 8.2, 0.8 Hz, 1H), 7.20 (d, J = 2.3 Hz, 1H), 7.10 (t, J = 7.9 Hz, 1H), 6.85 (dd, J = 7.7, 0.8 Hz, 1H), 2.79–2.72 (m, 2H), 2.07 (s, 6H). Two protons from CH2 were not observed. The signal overlapped with the DMSO solvent peak. One exchangeable hydrogen was not observed.

[0160] Example 8. Synthesis of Compound 118: 3-(2-(dimethylamino)ethyl)-1H-indol-4-ylbenzo[d]thiazole-2-carboxylate, fumaric acid

[0161] [ka]

[0162] To a stirred solution of lithium benzo[d]thiazole-2-carboxylate (184.2 mg, 1 equiv., 994.8 μmol) in dry DCM (4.00 mL) at room temperature under a N atmosphere, oxalyl chloride (265.1 mg, 182.9 μL, 2.1 equiv., 2.089 mmol) and one drop of DMF (72.72 mg, 77.0 μL, 1 equiv., 994.8 μmol) were added. The reaction mixture was stirred at room temperature for 2 hours. The volatiles were removed in vacuo. The residue was dissolved in DCM (2.00 mL) and added to a solution of psilocin (203.2 mg, 1 equiv., 994.8 μmol) and EtN (362.4 mg, 499 μL, 3.6 equiv., 3.581 mmol) in DCM (2.00 mL) at 0°C. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated in vacuo. The crude product was purified by chromatography on RP Flash C18 (24 g cartridge, 5–40% (0.1% formic acid in MeCN) / (0.1% formic acid in water)) to give 3-(2-(dimethylamino)ethyl)-1H-indol-4-ylbenzo[d]thiazole-2-carboxylate, formic acid (199.4 mg, 0.35 mmol, 35%, 72% purity) as a dark yellow oil. This material was dissolved in acetone (8 mL) and a solution of fumaric acid (46 mg, 0.40 equiv., 0.40 mmol) in acetone (6 mL) was added. The resulting solid was filtered, washed with acetone, and dried overnight in a vacuum oven to give the title compound (92.2 mg, 0.17 mmol, 17%, 88% purity) as a light brown solid.

[0163] m / z 366.14 (M+H) + (ES+);319.88 (M-NMe2-H) - (ES-)

[0164] 1H NMR (500 MHz, DMSO) δ 11.24 (s, 1H), 8.37–8.29 (m, 2H), 7.77–7.67 (m, 2H), 7.36 (d, J = 8.1 Hz, 1H), 7.25 (d, J = 2.3 Hz, 1H), 7.18–7.11 (m, 1H), 6.99 (d, J = 7.6 Hz, 1H), 6.56 (s, 2H), 2.90–2.84 (m, 2H), 2.73 (s, 2H), 2.17 (s, 6H). Two Hs are missing (exchangeable protons of fumaric acid).

[0165] Example 9. Synthesis of Compound 123: 3-(2-(dimethylamino)ethyl)-1H-indol-4-yl 4-acetamidobutanoate, 0.2 HPF, 0.8 formic acid

[0166] [ka]

[0167] A mixture of 4-acetamidobutanoic acid (141 mg, 1 equiv., 969 μmol), HATU (516 mg, 1.4 equiv., 1.36 mmol), DIPEA (301 mg, 405 μL, 2.4 equiv., 2.33 mmol), and psilocin (200 mg, 1 equiv., 969 μmol) in DMF (4 mL) was stirred overnight at room temperature. The reaction mixture was loaded directly onto an 80 g C18 reverse column and purified (80 g cartridge, 0–100% (0.1% formic acid in MeCN) / (0.1% formic acid in water)) to give the desired product as an amber glass with DMF impurity. Upon standing, the desired product crystallized from the amber glass. The amber glass / crystalline product was triturated with diethyl ether to give the title compound (25.0 mg, 63.1 μmol, 7%) as a beige solid.

[0168] m / z 332.2 (M+H) + (ES+)

[0169] 1H NMR (500 MHz, DMSO-d6) δ 11.23 (d, J = 2.5 Hz, 1H), 9.26 (s, 1H), 7.96 (s, 1H), 7.28–7.26 (m, 2H), 7.08 (dd, J = 7.9 Hz, 1H), 6.75 (d, J = 7.6 Hz, 1H), 3.16 (q, J = 6.6 Hz, 2H), 3.02 (t, J = 7.9 Hz, 2H), 2.84 (s, 6H), 2.74–2.67 (m, 2H), 1.83 (s, 3H), 1.82–1.78 (m, 2H). Two Hs are obscured by water peaks. One exchangeable H was not recognized.

[0170] Example 10. Synthesis of Compound 126: 2-acetoxyethyl 3-(2-(dimethylamino)ethyl)-4-hydroxy-1H-indole-1-carboxylate, formic acid

[0171] [ka]

[0172] Step 1: 2-(((4-nitrophenoxy)carbonyl)oxy)ethyl acetate To a solution of ethylene glycol monoacetate (100 mg, 90.0 μL, 1 equiv., 961 μmol) and carbonic acid, bis(4-nitrophenyl) ester (315.5 mg, 1.08 equiv., 1.037 mmol) in anhydrous DMF (3.0 mL) at room temperature, DIPEA (742 mg, 1.00 mL, 5.98 equiv., 5.74 mmol) was added. The reaction mixture was stirred at room temperature for 3 h. The reaction mixture was diluted with distilled water (5 mL) and extracted with DCM (3 × 5 mL). The combined organic layers were collected, dried (NaSO), filtered, and concentrated in vacuo. The crude product was purified by chromatography on silica gel (12 g cartridge, 0–50% EtOAc / isohexane) to afford the subtitle compound (351.7 mg, 0.61 mmol, 64%, 47% purity) as a yellow oil.

[0173] 1 H NMR (500 MHz, DMSO) δ 8.35 - 8.29 (m, 2H), 7.60 - 7.53 (m, 2H), 4.48 - 4.41 (m, 2H), 4.34 - 4.29 (m, 2H), 2.06 (s, 3H).

[0174] Step 2: 2-Acetoxyethyl-4-(benzyloxy)-3-(2-(dimethylamino)ethyl)-1H-indole-1-carboxylate

[0175] To a solution of 2-(4-(benzyloxy)-1H-indol-3-yl)-N,N-dimethylethan-1-amine (145.5 mg, 95 wt%, 1 eq, 469.5 μmol) in DMF (5.00 mL) was added NaH (21.8 mg, 60 wt%, 1.16 eq, 545 μmol) at 0° C., and the reaction was stirred at 0° C. for 10 min. The product of Step 1 above (351.7 mg, 47 wt%, 1.308 eq, 614.0 μmol) was added at 0° C., followed by stirring at room temperature for 3 h. The reaction mixture was diluted with distilled water (5 mL) and extracted with DCM (3×5 mL). The combined organic layers were collected, dried (NaSO), filtered, and concentrated in vacuo. The crude product was purified by chromatography on silica gel (24 g cartridge, 0-10% MeOH / DCM) to give the subtitle compound (142.6 mg, 0.29 mmol, 62%, 86% purity) as a pale yellow oil.

[0176] m / z 425.2 (M+H) + (ES+)

[0177] 1H NMR (500 MHz, DMSO) δ 7.69 (d, J = 8.3 Hz, 1H), 7.54 - 7.49 (m, 2H), 7.43 - 7.39 (m, 2H), 7.38 - 7.31 (m, 2H), 7.24 (t, J = 8.2 Hz, 1H), 6.90 (d, J = 8.0 Hz, 1H), 5.22 (s, 2H), 4.58 - 4.54 (m, 2H), 4.42 - 4.37 (m, 2H), 2.92 - 2.86 (m, 2H), 2.06 (s, 6H), 2.05 (s, 3H). Two protons from CH2 were not observed. The signal overlaps with the DMSO solvent peak.

[0178] Step 3: 2-Acetoxyethyl 3-(2-(dimethylamino)ethyl)-4-hydroxy-1H-indole-1-carboxylate, formic acid

[0179] A solution of the product of Step 2 above (142.6 mg, 86 wt %, 1 equiv, 288.9 μmol) in EtOH (20 mL) was hydrogenated on an H-Cube (Pd / C catalyst cartridge) at 5 bar, 60° C., and 1 mL / min for 30 min (recirculation). The mixture was concentrated in vacuo to give impure product. The crude material was dissolved in DMSO (1.91 mL), filtered, and purified by reverse-phase preparative HPLC (Waters 2767 Sample Manager, Waters 2545 Binary Gradient Module, Waters Systems Fluidics Organizer, Waters 515 ACD pump, Waters 515 Makeup pump, Waters 2998 Photodiode Array Detector, Waters QDa) on a Waters X-Select CSH C18 ODB preparative column, 130 Å, 5 μm, 30 mm × 100 mm, flow rate 40 mL min eluting with 0.1% formic acid in a water-MeCN gradient over 17.5 min using UV across all wavelengths with PDA, QDa, and ELS detectors. The column dilution pump provided 2 mL min throughout the procedure, which was included in the MeCN ratio below. Gradient information: 0.0–0.5 min, 5% MeCN; 0.5–15.5 min, increasing from 5% MeCN to 22.5% MeCN; 15.5–15.6 min, increasing from 22.5% MeCN to 100% MeCN; 15.6–17.5 min, hold at 100% MeCN. Clean fractions were evaporated in a Genevac to give the title compound (35.4 mg, 92 μmol, 32%, 99% purity) as a light brown oil.

[0180] m / z 335.2 (M+H) + (ES+)

[0181] 1H NMR (500 MHz, DMSO) δ 8.18 (s, 1H), 7.52 (d, J = 8.2 Hz, 1H), 7.32 (s, 1H), 7.09 (t, J = 8.0 Hz, 1H), 6.60 (dd, J = 7.9, 0.8 Hz, 1H), 4.57 - 4.52 (m, 2H), 4.40 - 4.36 (m, 2H), 2.94 - 2.89 (m, 2H), 2.66 - 2.60 (m, 2H), 2.26 (s, 6H), 2.05 (s, 3H). No exchangeable protons observed.

[0182] Example 11. Synthesis of Compound 129: 3-(2-(dimethylamino)ethyl)-1H-indol-4-yl 2,3-dimethylbutanoate, fumaric acid

[0183] [ka]

[0184] To a stirred solution of 2,3-dimethylbutyric acid (123 mg, 1.1 equiv., 1.06 mmol) in dry DCM (4 mL) at room temperature under a nitrogen atmosphere, oxalyl chloride (146 mg, 101 μL, 1.2 equiv., 1.15 mmol) and one drop of DMF were added. The reaction mixture was stirred at room temperature for 3 hours. The volatiles were removed in vacuo. The residue was redissolved in DCM (2 mL) and added to a solution of psilocin (200 mg, 1 equiv., 960 μmol) and triethylamine (485 mg, 669 μL, 5 equiv., 4.80 mmol) in DCM (2 mL) at 0° C. The resulting mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with water (25 mL) and extracted with DCM (3×25 mL). The combined organic layers were collected, dried (NaSO), filtered, and concentrated in vacuo. The crude product was loaded onto Celite and purified by chromatography on RP Flash C18 (24 g cartridge, 0–30% (0.1% formic acid in MeCN) / (0.1% formic acid in water)) to give 3-(2-(dimethylamino)ethyl)-1H-indol-4-yl 2,3-dimethylbutanoate, formate (110 mg, 364 μmol, 38%). This material was dissolved in acetone (6 mL) and a solution of fumaric acid (43 mg, 1.02 equiv., 370 μmol) in acetone (6 mL) was added. The mixture was cooled to −20° C. for 60 h. The resulting solid was isolated by filtration and washed with MeCN (2×2 mL) to give the title compound (52.3 mg, 0.12 mmol, 13%) as a tan solid.

[0185] m / z 303.5 (M+H) + (ES+)

[0186] 1H NMR (500 MHz, DMSO-d6) δ 12.85 (s, 2H), 11.07 (s, 1H), 7.23 (d, J = 8.1 Hz, 1H), 7.16 (d, J = 2.4 Hz, 1H), 7.04 (dd, J = 7.9, 7.9 Hz, 1H), 6.61 (d, J = 7.6 Hz, 1H), 6.56 (s, 2H), 2.89 - 2.76 (m, 2H), 2.73 - 2.60 (m, 4H), 2.32 (s, 6H), 2.14 - 2.04 (m, 1H), 1.22 (d, J = 7.0 Hz, 3H), 1.02 (dd, J = 21.7, 6.8 Hz, 6H).

[0187] Example 12 Synthesis of Compound 135: 3-(2-(dimethylamino)ethyl)-1H-indol-4-ylisopropyl(methyl)carbamate, 0.63 formic acid, 0.37 HCl

[0188] [ka]

[0189] To a solution of N-methylpropan-2-amine (59 mg, 84 μL, 1.1 equiv., 808 μmol) and triethylamine (149 mg, 205 μL, 2 equiv., 1.47 mmol) in THF (4 mL) was added triphosgene (113 mg, 0.5 equiv., 367 μmol) at 0° C. The reaction was stirred at 0° C. for 20 minutes. A suspension of psilocin (150 mg, 1 equiv., 734 μmol) in THF (3 mL) was added at 0° C. The mixture was stirred at room temperature for 48 hours. The reaction was stirred at 40° C. for an additional 4 days. The reaction was quenched with ice-cold water (10 mL) and diluted with ethyl acetate (10 mL). The phases were separated, and the aqueous phase was further extracted with ethyl acetate (10 mL). The combined organics were washed with brine (20 mL), dried (NaSO), and concentrated in vacuo. This crude material (211 mg) was dissolved in DMSO (2.7 mL), filtered, and purified using a Waters X-Select CSH C18 ODB preparative column, 130 Å, 5 μm, 30 mm × 100 mm, at a flow rate of 40 mL / min. -1 The above was purified by reversed-phase preparative HPLC (Waters 2767 Sample Manager, Waters 2545 Binary Gradient Module, Waters Systems Fluidics Organiser, Waters 515 ACD pump, Waters 515 Makeup pump, Waters 2998 Photodiode Array Detector, Waters QDa) eluting with 0.1% formic acid in a water-MeCN gradient over 8.5 min using UV across all wavelengths with PDA, QDa and ELS detectors. The column dilution pump was used to pump 2 mL of water throughout the method. -1 of MeCN was obtained, which contained the following percentages of MeCN. Gradient information: 0.0-0.5 min, 7.5% MeCN; 0.5-5.5 min, increasing from 7.5% MeCN to 37.5% MeCN; 5.5-5.6 min, increasing from 37.5% MeCN to 100% MeCN; 5.6-8.5 min, holding at 100% MeCN. The clean fractions were evaporated in a Genevac to give the title compound (50.0 mg, 145 μmol, 20%) as a light brown solid.

[0190] m / z 304.2 (M+H) + (ES+)

[0191] 1 H NMR (500 MHz, DMSO-d6) δ 11.03 (s, 1H), 8.15 (s, 0.63 H), 7.20 (dd, J = 8.1, 0.8 Hz, 1H), 7.15 (d, J = 2.3 Hz, 1H), 7.04 - 6.98 (m, 1H), 6.65 - 6.58 (m, 1H), 4.57 - 4.48 (m, 0.33H), 4.31 (p, J = 6.6 Hz, 0.67H), 2.97 (s, 2H), 2.90 - 2.82 (m, 2H), 2.80 (s, 1H), 2.79 - 2.71 (m, 2H), 2.38 (s, 6H), 1.24 (d, J = 6.7 Hz, 2H), 1.15 (d, J = 6.8 Hz, 4H). One exchangeable hydrogen was not observed.

[0192] Example 13. Synthesis of Compound 137: 3-(2-(dimethylamino)ethyl)-1H-indol-4-yl isobutylcarbamate, HCl

[0193] [ka]

[0194] To a suspension of psilocin (205.0 mg, 88 wt%, 1 equiv, 883.1 μmol) in MeCN (5.00 mL) was added DABCO (118.9 mg, 1.2 equiv, 1.060 mmol) in DCM and 1 M 1-isocyanato-2-methylpropane (131.3 mg, 1.325 mL, 1.00 molar, 1.5 equiv, 1.325 mmol). The reaction was stirred at room temperature for 16 h. Volatiles were removed in vacuo. The crude product was loaded onto Celite and purified by chromatography on a RP Flash C18 (24 g cartridge, 0–20% (0.1% formic acid in MeCN) / (0.1% formic acid in water)) to give an oil. Trituration of the sample with acetone afforded the title compound (9.20 mg, 26 μmol, 2.3%, 95% purity) as a dark brown solid.

[0195] m / z 304.2 (M+H) + (ES+)

[0196] 1 H NMR (500 MHz, DMSO) δ 11.21 - 11.10 (m, 1H), 10.98-10.10 (br s, 1H), 7.94 (m, 1H), 7.25 - 7.18 (m, 2H), 7.06 - 7.00 (m, 1H), 6.71 (d, J = 7.6 Hz, 1H), 3.24 - 3.17 (m, 2H), 3.11 - 3.04 (m, 2H), 2.93 (t, J = 6.4 Hz, 2H), 2.75 (s, 6H), 1.78 (hept, J = 6.7 Hz, 1H), 0.91 (d, J = 6.7 Hz, 6H).

[0197] Example 14. Synthesis of Compound 139: 3-(2-(dimethylamino)ethyl)-1H-indol-4-yl 2-isopropoxyacetate, fumaric acid

[0198] [ka]

[0199] To a stirred solution of 2-(1-methylethoxy)-acetic acid (143 mg, 1.4 equiv., 1.21 mmol) in dry DCM (4 mL) at room temperature under a nitrogen atmosphere, oxalyl chloride (233 mg, 161 μL, 2.1 equiv., 1.84 mmol) and one drop of DMF were added. The reaction mixture was stirred at room temperature for 2 hours. The volatiles were removed in vacuo, and the residue was dissolved in DCM (2 mL) and added to a solution of psilocin (179.0 mg, 1 equiv., 876 μmol) and triethylamine (323 mg, 445 μL, 3.6 equiv., 3.19 mmol) in DCM (2 mL) at 0° C. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with water (5 mL). The aqueous layer was extracted with DCM (3 × 5 mL). The combined organic layers were collected, dried (NaSO), filtered, and concentrated in vacuo. The crude product was purified by chromatography on RP Flash C18 (24 g cartridge, 5-50% (0.1% formic acid in MeCN) / (0.1% formic acid in water)) to give 3-(2-(dimethylamino)ethyl)-1H-indol-4-yl 2-isopropoxyacetate (187 mg, 614 μmol) as a brown oil. This material was dissolved in acetone (10 mL) and a solution of fumaric acid (71 mg, 0.7 equiv., 614 μmol) in acetone (10 mL) was added. The resulting solid was isolated by filtration, washed with acetone, and dried in vacuo to give the title compound (130 mg, 309 μmol, 35%) as an off-white solid.

[0200] m / z 305.2 (M+H) + (ES+)

[0201] 1H NMR (500 MHz, DMSO-d6) δ 11.10 (s, 1H), 7.25 (dd, J = 8.1, 0.8 Hz, 1H), 7.18 (d, J = 2.3 Hz, 1H), 7.09 - 7.02 (m, 1H), 6.72 (dd, J = 7.6, 0.8 Hz, 1H), 6.56 (s, 2H), 4.48 (s, 2H), 3.75 (hept, J = 6.0 Hz, 1H), 2.86 - 2.78 (m, 2H), 2.70 - 2.60 (m, 2H), 2.35 (s, 6H), 1.17 (d, J = 6.1 Hz, 6H). (Two exchangeable H's are not recognized).

[0202] Example 15. Synthesis of Compound 168: 3-(2-(dimethylamino)ethyl)-1H-indol-4-yl 3-bromobenzoate, formic acid

[0203] [ka]

[0204] A mixture of psilocin (200.0 mg, 1 equiv., 881 μmol), 3-bromobenzoic acid (181 mg, 1 equiv., 881 μmol), HATU (483 mg, 1.4 equiv., 1.27 mmol), and diisopropylethylamine (269 mg, 359 μL, 2.4 equiv., 2.08 mmol) in dry DMF (2.5 mL) was stirred at room temperature for 16 h. The reaction mixture was diluted with saturated aqueous NaHCO (25 mL) and extracted with EtOAc (3 × 25 mL). The combined organic layers were washed with water (3 × 20 mL) and brine (25 mL), dried (NaSO), filtered, and concentrated in vacuo. The crude product was loaded onto silica gel and purified by chromatography on silica gel (12 g cartridge, 2–10% (0.7 M ammonia / MeOH) / DCM) to give the partially purified title compound. The material was loaded onto Celite and purified by chromatography on RP Flash C18 (24 g cartridge, 5-50% (0.1% formic acid in MeCN) / (0.1% formic acid in water)) to give the title compound (29.2 mg, 67 μmol, 8%) as a light brown solid.

[0205] m / z 387.1 / 389.0 (M+H) + (ES+)

[0206] 1 H NMR (500 MHz, DMSO-d6) δ 11.21 - 11.10 (m, 1H), 8.36 - 8.29 (m, 1H), 8.26 - 8.17 (m, 2H), 8.03 - 7.95 (m, 1H), 7.63 - 7.57 (m, 1H), 7.31 (d, J = 8.1 Hz, 1H), 7.20 (d, J = 2.3 Hz, 1H), 7.14 - 7.08 (m, 1H), 6.83 (d, J = 7.6 Hz, 1H), 2.78 - 2.70 (m, 2H), 2.61 - 2.55 (m, 2H), 2.10 (s, 6H). One exchangeable H was not found.

[0207] Example 16. Synthesis of Compound 169: 3-(2-(dimethylamino)ethyl)-1H-indol-4-yl 3-bromo-2-methylbenzoate, fumaric acid

[0208] [ka]

[0209] To a stirred solution of 3-bromo-2-methylbenzoic acid (249 mg, 1.2 equiv., 1.16 mmol) in dry DCM (4 mL) at room temperature under a nitrogen atmosphere, oxalyl dichloride (260 mg, 180 μL, 2.1 equiv., 2.05 mmol) and one drop of DMF were added. The reaction mixture was stirred at room temperature for 2 hours. The volatiles were removed in vacuo. The residue was redissolved in DCM (2 mL) and added to a solution of psilocin (200.9 mg, 1 equiv., 964 μmol) and triethylamine (290 mg, 400 μL, 3 equiv., 2.87 mmol) in DCM (2 mL) at 0° C. The resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with water (5 mL) and extracted with DCM (3×5 mL). The combined organic layers were collected, dried (NaSO), filtered, and concentrated in vacuo. The crude product was purified by chromatography on silica gel (24 g cartridge, 0-20% MeOH / DCM). The purified product was dissolved in acetone (15 mL). Fumaric acid (88 mg, 756 μmol) in acetone (20 mL) was added. The precipitate that formed was collected by filtration to give the title compound (283.2 mg, 0.54 mmol, 56%) as a white solid.

[0210] m / z 401.1 / 403.4 (M+H) + (ES+)

[0211] 1H NMR (500 MHz, DMSO-d6) δ 11.15 (s, 1H), 8.16 (dd, J = 7.8, 1.3 Hz, 1H), 7.95 (dd, J = 8.0, 1.3 Hz, 1H), 7.38 (dd, J = 7.9 Hz, 1H), 7.31 (dd, J = 8.1, 0.8 Hz, 1H), 7.20 (d, J = 2.3 Hz, 1H), 7.11 (dd, J = 7.9 Hz, 1H), 6.87 (dd, J = 7.6, 0.8 Hz, 1H), 6.56 (s, 2H), 2.80 - 2.73 (m, 2H), 2.67 (s, 3H), 2.60 (t, J = 8.1 Hz, 2H), 2.11 (s, 6H). Two exchangeable protons not observed.

[0212] Example 17. Synthesis of Compound 171: 3-(2-(dimethylamino)ethyl)-1H-indol-4-yl 3-bromo-5-isopropylbenzoate, fumaric acid

[0213] [ka]

[0214] To a stirred solution of psilocin (79.4 mg, 1.1 equiv., 338 μmol) and 3-bromo-5-isopropylbenzoic acid (76 mg, 1 equiv., 311 μmol) in dry DMF (2 mL) at room temperature, DMAP (121 mg, 3.2 equiv., 990 μmol) and EDCI (91 mg, 1.5 equiv., 472 μmol) were added. The reaction mixture was stirred at room temperature for 72 h. The reaction mixture was diluted with EtOAc (5 mL), washed with 5% citric acid solution (5 mL), water (5 mL), and saturated aqueous NaHCO (5 mL), dried (NaSO), filtered, and concentrated in vacuo. The crude product was purified by chromatography on silica gel (12 g cartridge, 0–10% MeOH / DCM) to give a light brown oil.

[0215] Separately, to a stirred solution of psilocin (124.2 mg, 1.1 equiv., 529 μmol) and 3-bromo-5-isopropylbenzoic acid (120 mg, 1 equiv., 494 μmol) in dry DMF (2.5 mL) at room temperature, DMAP (102 mg, 1.7 equiv., 837 μmol) and DCC (181 mg, 157 μL, 1.8 equiv., 867 μmol) were added. The reaction mixture was stirred at room temperature for 72 h. The reaction mixture was diluted with EtOAc (5 mL), washed with 5% citric acid solution (5 mL), water (5 mL), and saturated aqueous NaHCO (5 mL), dried (NaSO), filtered, and concentrated in vacuo. The crude product was purified by chromatography on silica gel (12 g cartridge, 0–10% MeOH / DCM) to give a light brown oil.

[0216] The two oils were dissolved in acetone (1 mL) and combined. A solution of fumaric acid (7 mg, 0.20 equiv., 64 μmol) in acetone (1 mL) was added. The precipitate that formed was collected by filtration to give the title compound (12.2 mg, 22 μmol, 3%) as a beige solid.

[0217] m / z 429.5 / 431.6 (M+H) + (ES+)

[0218] 1 H NMR (500 MHz, DMSO-d6) δ 11.16 (s, 1H), 8.14 (dd, J = 1.7 Hz, 1H), 8.05 (dd, J = 1.6 Hz, 1H), 7.87 (dd, J = 1.8 Hz, 1H), 7.31 (dd, J = 8.1, 0.8 Hz, 1H), 7.20 (d, J = 2.4 Hz, 1H), 7.10 (dd, J = 7.9 Hz, 1H), 6.83 (dd, J = 7.7, 0.8 Hz, 1H), 6.55 (s, 2H), 3.11 - 3.02 (m, 1H), 2.79 - 2.72 (m, 2H), 2.66 - 2.59 (m, 2H), 2.12 (s, 6H), 1.26 (d, J = 6.9 Hz, 6H). Two exchangeable protons not observed.

[0219] Example 18 Synthesis of Compound 176: 3-(2-(dimethylamino)ethyl)-1H-indol-4-yl 2-phenylacetate, 0.8 fumaric acid, 0.2 HCl

[0220] [ka]

[0221] To a stirred solution of 2-phenylacetic acid (117 mg, 1 equiv., 857 μmol) in dry DCM (4 mL) at room temperature under a nitrogen atmosphere, oxalyl chloride (228 mg, 158 μL, 2.1 equiv., 1.80 mmol) and one drop of DMF were added. The reaction mixture was stirred at room temperature for 2 hours. The volatiles were removed in vacuo. The residue was dissolved in DCM (2 mL) and added to a solution of psilocin (198.9 mg, 1 equiv., 857 μmol) and triethylamine (312 mg, 430 μL, 3.6 equiv., 3.09 mmol) in DCM (2 mL) at 0° C. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with water (5 mL) and transferred to a separatory funnel. The aqueous layer was extracted with DCM (3 × 5 mL). The combined organic layers were collected, dried (NaSO), filtered, and concentrated in vacuo. The crude product was purified by chromatography on RP Flash C18 (24 g cartridge, 5–40% (0.1% formic acid in MeCN) / (0.1% formic acid in water)) to give 3-(2-(dimethylamino)ethyl)-1H-indol-4-yl 2-phenylacetate, formic acid (84.6 mg, 0.18 mmol, 21%) as a brown oil. This partially purified material was dissolved in acetone (3 mL) and a solution of fumaric acid (21 mg, 0.21 equiv., 0.18 mmol) in acetone (4 mL) was added. The resulting solid was filtered, washed with acetone (2 mL), and dried in a vacuum oven for 24 h to give the title compound (32.8 mg, 70 μmol, 8%) as a brown solid.

[0222] m / z 323.1 (M+H) + (ES+)

[0223] 1 H NMR (500 MHz, DMSO) δ 11.07 (s, 1H), 7.43–7.35 (m, 4H), 7.33–7.26 (m, 1H), 7.23 (d, J = 8.1 Hz, 1H), 7.16 (d, J = 2.3 Hz, 1H), 7.06–6.99 (m, 1H), 6.65 (d, J = 7.6 Hz, 1H), 6.52 (s, 1.6H), 4.06 (s, 2H), 2.80 (t, J = 7.8 Hz, 2H), 2.66–2.59 (m, 2H), 2.32 (s, 6H). (Two exchangeable hydrogens not observed.)

[0224] Example 19. Synthesis of Compound 185: tert-butyl 2-(3-((3-(2-(dimethylamino)ethyl)-1H-indol-4-yl)oxy)-3-oxopropyl)pyrrolidine-1-carboxylate, fumaric acid

[0225] [ka]

[0226] 3-(1-(tert-butoxycarbonyl)pyrrolidin-2-yl)propanoic acid (155 mg, 1.3 equivalents, 636 μmol), DMAP (12.0 mg, 0.2 equivalents, 97.9 μmol), and CDI (159 mg, 2 equivalents, 979 μmol) were stirred at room temperature for 1 hour. Then, psilocin (100 mg, 1 equivalent, 490 μmol) was added, and the mixture was stirred at room temperature overnight. Another solution of 3-(1-(tert-butoxycarbonyl)pyrrolidin-2-yl)propanoic acid (119 mg, 1 equivalent, 490 μmol), CDI (87.3 mg, 1.1 equivalents, 539 μmol), and DMAP (5.98 mg, 0.1 equivalents, 49.0 μmol) in THF (2.00 mL), which had been previously stirred at room temperature for 1 hour, was added to this mixture. The reaction mixture was allowed to stir at room temperature for 24 hours. The mixture was heated at 40°C for 24 hours. The mixture was then heated at 55°C over the weekend. The reaction mixture was cooled to room temperature, diluted with distilled water (10 mL), and transferred to a separatory funnel. The organic layer was extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine (1 x 15 mL), dried (NaSO), filtered, and concentrated in vacuo. The crude product was purified by chromatography on a RP Flash C18 (12 g cartridge, 5-50% (0.1% formic acid in MeCN) / (0.1% formic acid in water)) to give the desired product (89.4 mg, 0.16 mmol, 33%, 85% purity) as a brown oil. This material was dissolved in acetone (5 mL), and a solution of fumaric acid (19 mg, 0.33 equiv, 0.16 mmol) in acetone (5 mL) was added. The resulting solid was filtered, washed with acetone, and dried in a vacuum oven over the weekend to give the title compound (29.9 mg, 49.6 μmol, 10.1%, 90.6% purity) as a brown solid.

[0227] m / z 430.36 (M+H) + (ES+)

[0228] 1H NMR (500 MHz, DMSO) δ 11.10 (s, 1H), 7.23 (dd, J = 8.1, 0.8 Hz, 1H), 7.18 (d, J = 2.4 Hz, 1H), 7.08 - 7.01 (m, 1H), 6.73 - 6.66 (m, 1H), 6.57 (s, 2H), 3.81 (s, 1H, rotamer), 3.32 - 3.19 (m, 2H, rotamer), 2.86 (s, 1H, rotamer), 2.78 (s, 2H, rotamer), 2.70 - 2.65 (m, 1H, rotamer), 2.45 (s, 3H, rotamer), 2.42 (s, 3H, rotamer), 1.97 - 1.65 (m, 9H, rotamer), 1.40 (s, 9H). Two H's are absent (exchangeable protons of fumaric acid).

[0229] Example 20. Synthesis of Compound 188: 3-(2-(dimethylamino)ethyl)-1H-indol-4-yl 2-(4-isobutylphenyl)propanoate, 0.75 fumaric acid

[0230] [ka]

[0231] To a stirred solution of 2-(4-isobutylphenyl)propionic acid (124 mg, 1.2 equiv., 593 μmol) in dry DCM (4 mL) at room temperature under a nitrogen atmosphere, oxalyl chloride (130 mg, 90 μL, 2.1 equiv., 1.02 mmol) and one drop of DMF were added. The reaction mixture was stirred at room temperature for 2 hours. The volatiles were removed in vacuo. The residue was redissolved in DCM (2 mL) and added to a solution of psilocin (102.6 mg, 1 equiv., 492 μmol) and triethylamine (182 mg, 250 μL, 3.6 equiv., 1.79 mmol) in DCM (2 mL) at 0° C. The resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with water (5 mL) and extracted with DCM (3×5 mL). The combined organic layers were collected, dried (NaSO), filtered, and concentrated in vacuo. The crude product was purified by chromatography on silica gel (12 g cartridge, 0-20% MeOH / DCM) to give a light brown oil. The product was dissolved in acetone (2 mL). Fumaric acid (34 mg, 293 μmol) in acetone (2 mL) was added. The precipitate that formed was collected by filtration to give the title compound (51.4 mg, 0.11 mmol, 22%) as a beige solid.

[0232] m / z 393.3 (M+H) + (ES+)

[0233] 1H NMR (500 MHz, DMSO-d6) δ 11.04 (s, 1H), 7.36 - 7.32 (m, 2H), 7.23 - 7.16 (m, 3H), 7.14 (d, J = 2.3 Hz, 1H), 7.00 (t, J = 7.9 Hz, 1H), 6.55 (s, 1.5H), 6.50 (dd, J = 7.6, 0.8 Hz, 1H), 4.13 (q, J = 7.1 Hz, 1H), 2.72 - 2.65 (m, 2H), 2.61 - 2.52 (m, 2H), 2.45 (d, J = 7.1 Hz, 2H), 2.28 (s, 6H), 1.83 (dq, J = 13.5, 6.7 Hz, 1H), 1.55 (d, J = 7.1 Hz, 3H), 0.87 (d, J = 6.6 Hz, 6H). 1.5 exchangeable protons not observed.

[0234] Example 21. Synthesis of Compound 189: 3-(2-(dimethylamino)ethyl)-1H-indol-4-yl((trimethylsilyl)methyl)carbonate, formic acid

[0235] [ka] To a solution of (trimethylsilyl)methanol (148 mg, 1.3 equiv., 1.42 mmol) and triethylamine (174 mg, 240 μL, 1.6 equiv., 1.72 mmol) in THF (6 mL) at 0° C. was added triphosgene (160 mg, 0.5 equiv., 518 μmol). The reaction was stirred at 0° C. for 3 h. A suspension of psilocin (227.2 mg, 1 equiv., 1.11 mmol) and triethylamine (145 mg, 200 μL, 1.3 equiv., 1.43 mmol) in THF (5 mL) was added at 0° C. The mixture was stirred at 0° C. for 30 min and then at room temperature for 40 h. The reaction was quenched with ice-cold water (10 mL) and diluted with ethyl acetate (10 mL). The phases were separated, and the aqueous phase was further extracted with ethyl acetate (10 mL). The combined organics were washed with brine (20 mL), dried (NaSO), and concentrated in vacuo. The crude product was purified by chromatography on a RP Flash C18 (4 g cartridge, 5-50% (0.1% formic acid in MeCN) / 0.1% formic acid in water) (elution approximately 25%) to give the title compound (12.4 mg, 31 μmol, 3%) as a sticky brown gum after trituration with diethyl ether (3 × 5 mL).

[0236] m / z 335.2 (M+H) + (ES+)

[0237] 1 H NMR (500 MHz, DMSO-d6) δ 11.07 (s, 1H), 8.19 (s, 1H), 7.25 (d, J = 8.1 Hz, 1H), 7.17 (d, J = 2.3 Hz, 1H), 7.04 (dd, J = 7.9, 7.9 Hz, 1H), 6.73 (d, J = 7.6 Hz, 1H), 3.95 (s, 2H), 2.81 - 2.72 (m, 2H), 2.48 (s, 2H), 2.21 (s, 6H), 0.10 (s, 9H). One exchangeable hydrogen was not observed.

[0238] Example 22. Synthesis of Compound 191: 3-(2-(dimethylamino)ethyl)-1H-indol-4-yl(3-(trimethylsilyl)propyl)carbonate, formic acid

[0239] [ka]

[0240] To a solution of 3-(trimethylsilyl)propan-1-ol (179 mg, 1.1 equiv., 1.35 mmol) and triethylamine (174 mg, 240 μL, 1.4 equiv., 1.72 mmol) in THF (6 mL) at 0° C. was added triphosgene (189 mg, 0.5 equiv., 612 μmol). The reaction was stirred at 0° C. for 20 minutes. A suspension of psilocin (250.8 mg, 1 equiv., 1.23 mmol) in THF (5 mL) was added at 0° C. The mixture was stirred at room temperature for 16 hours. The reaction was quenched with ice-cold water (10 mL) and diluted with ethyl acetate (10 mL). The phases were separated and the aqueous phase was further extracted with ethyl acetate (10 mL). The combined organics were washed with brine (20 mL), dried (Na2SO4), and concentrated in vacuo. The crude product was partially purified by chromatography on silica gel (4 g cartridge, 0-10% (0.7 M ammonia / MeOH) / DCM) (approximately 2% eluted). The partially purified crude product was purified by chromatography on RP Flash C18 (4 g cartridge, 10-100% (0.1% formic acid in MeCN) / (0.1% formic acid in water)) (approximately 25% eluted) to give the title compound (92.0 mg, 0.22 mmol, 18%) as an off-white solid after trituration with diethyl ether (2 × 5 mL).

[0241] m / z 363.2 (M+H) + (ES+) 1H NMR (500 MHz, DMSO-d6) δ 11.09 (s, 1H), 8.17 (s, 1H), 7.26 (d, J = 8.1 Hz, 1H), 7.18 (d, J = 2.3 Hz, 1H), 7.04 (dd, J = 7.9, 7.9 Hz, 1H), 6.75 (d, J = 7.6 Hz, 1H), 4.17 (t, J = 6.8 Hz, 2H), 2.83 - 2.73 (m, 2H), 2.55 - 2.51 (m, 2H), 2.23 (s, 6H), 1.72 - 1.60 (m, 2H), 0.61 - 0.48 (m, 2H), 0.01 (s, 9H). One exchangeable H was not observed.

[0242] Example 23 Synthesis of Compound 195: 1-(3-(2-(dimethylamino)ethyl)-4-hydroxy-1H-indol-1-yl)-3-methylbutan-1-one, formic acid

[0243] [ka]

[0244] Step 1: 2-(4-(benzyloxy)-1H-indol-3-yl)-N,N-dimethyl-2-oxoacetamide

[0245] Oxalyl chloride (3.13 g, 2.2 mL, 1.1 equiv., 24.6 mmol) was added portionwise to a stirred solution of 4-(benzyloxy)-1H-indole (5.00 g, 1 equiv., 22.4 mmol) in MTBE (100 mL) and stirred at room temperature for 90 minutes. The reaction mixture was then cooled to 0° C., and dimethylamine in THF (5.55 g, 61.6 mL, 2.0 M, 5.5 equiv., 123 mmol) was added portionwise over 5 minutes. The reaction mixture was placed in an ice bath, which allowed it to slowly warm to room temperature over an additional 90 minutes. The resulting suspension was filtered, and the filtered solid was partitioned between EtOAc (300 mL) and water (200 mL). The organic layer was separated, washed with saturated aqueous NaHCO3 (200 ml) and concentrated in vacuo to give 2-(4-(benzyloxy)-1H-indol-3-yl)-N,N-dimethyl-2-oxoacetamide (4.76 g, 14.8 mmol, 66%) as a beige foam.

[0246] m / z 323.5 (M+H) + (ES+)

[0247] 1 H NMR (500 MHz, DMSO-d6) δ 12.26 (s, 1H), 8.06 (s, 1H), 7.64 - 7.58 (m, 2H), 7.37 (dd, J = 8.3, 6.9 Hz, 2H), 7.28 (t, J = 7.3 Hz, 1H), 7.14 - 7.06 (m, 2H), 6.69 (dd, J = 7.2, 1.5 Hz, 1H), 5.26 (s, 2H), 2.90 (d, J = 16.8 Hz, 6H).

[0248] Step 2: 2-(4-(benzyloxy)-1H-indol-3-yl)-N,N-dimethylethan-1-amine

[0249] To a stirred suspension of the product of Step 1 above (4.76 g, 1 equiv., 14.8 mmol) in 2-MeTHF (100 mL) was added lithium aluminum hydride in THF (1.96 g, 21.5 mL, 2.4 molar, 3.5 equiv., 51.7 mmol) in portions under nitrogen at 0°C. The mixture continued to stir while the ice bath warmed to room temperature over 30 minutes, then stirred at 80°C for 4 hours. The reaction mixture was cooled to room temperature, after which sodium sulfate decahydrate was added in small portions until the resulting effervescence subsided. The reaction mixture was filtered, the solid plug was washed with MeOH (30 mL), and the collected clear filtrate was allowed to stand at room temperature overnight. The resulting dark green solution was concentrated under reduced pressure to give a dark green oil that solidified on standing. The solid was partitioned between EtOAc (200 mL) and water (100 mL). The organic layer was separated and concentrated in vacuo to give the subtitle compound (4.16 g, 13 mmol, 90%) as a brown solid which solidified on standing.

[0250] m / z 295.2 (M+H) + (ES+)

[0251] 1 H NMR (500 MHz, DMSO-d6) δ 10.75 (s, 1H), 7.56 - 7.50 (m, 2H), 7.39 (dd, J = 8.3, 6.8 Hz, 2H), 7.36 - 7.29 (m, 1H), 6.97 (d, J = 2.3 Hz, 1H), 6.96 - 6.89 (m, 2H), 6.53 (dd, J = 6.0, 2.5 Hz, 1H), 5.16 (s, 2H), 2.94 - 2.87 (m, 2H), 2.50 - 2.42 (m, 2H), 2.05 (s, 6H).

[0252] Step 3: 1-(4-(benzyloxy)-3-(2-(dimethylamino)ethyl)-1H-indol-1-yl)-3-methylbutan-1-one

[0253] CDI (214 mg, 1.7 equiv., 1.32 mmol) was added to a solution of 3-methylbutyric acid (122 mg, 1.5 equiv., 1.20 mmol) in DCM (3.00 mL) and stirred for 2 h. Separately, potassium tert-butoxide (148 mg, 1.7 equiv., 1.32 mmol) was added to a solution of the product of Step 2 above (250 mg, 1 equiv., 798 μmol) in DMF (5 mL) and stirred at room temperature for 90 min. The DCM solution was added to the DMF solution and stirring was continued at room temperature for 20 h. The reaction mixture was partitioned between EtOAc (20 mL) and brine (20 mL). The organic layer was separated and concentrated in vacuo. The crude product was purified by chromatography on RP Flash C18 (12 g cartridge, 0-100% (0.1% formic acid in MeCN) / (0.1% formic acid in water)) to give the subtitle compound (102 mg, 269 μmol, 34%) as a colourless gum.

[0254] m / z 379.2 (M+H) + (ES+)

[0255] Step 4: 1-(3-(2-(dimethylamino)ethyl)-4-hydroxy-1H-indol-1-yl)-3-methylbutan-1-one, formic acid

[0256] The product of Step 3 above (102 mg, 1 equiv., 256 μmol) in methanol (10 mL) was passed through a 10% Pd / C catalyst cartridge (H-cube, recirculation) at 1 mL / min, 60°C, and 1 bar for 90 min. The bulk solvent was removed in vacuo. The crude product was dissolved in DMSO (2 mL), filtered, and purified by chromatography on a Waters X-Select CSH C18 ODB preparative column, 130 Å, 5 μm, 30 mm x 100 mm, with a flow rate of 40 mL min. -1The above was purified by reverse-phase preparative HPLC (Waters 2767 Sample Manager, Waters 2545 Binary Gradient Module, Waters Systems Fluidics Organiser, Waters 515 ACD pump, Waters 515 Makeup pump, Waters 2998 Photodiode Array Detector, Waters QDa) eluting with 0.1% formic acid in a water-MeCN gradient over 8.5 min using UV across all wavelengths with PDA, QDa and ELS detectors. The column dilution pump was used to pump 2 mL of water throughout the method. -1 of MeCN was obtained, which contained the following percentages of MeCN: Gradient information: 0.0-0.5 min, 12.5% ​​MeCN; 0.5-5.5 min, increasing from 12.5% ​​MeCN to 42.5% MeCN; 5.5-5.6 min, increasing from 42.5% MeCN to 100% MeCN; 5.6-8.5 min, holding at 100% MeCN. The clean fractions were evaporated in a Genevac to give the title compound (37.0 mg, 0.11 mmol, 43%) as colorless flakes.

[0257] m / z 289.2 (M+H) + (ES+)

[0258] 1 H NMR (500 MHz, DMSO-d₆) δ 8.19 (s, 1H), 7.82 (d, J = 8.1 Hz, 1H), 7.53 (s, 1H), 7.08–7.05 (m, 1H), 6.61 (d, J = 7.8 Hz, 1H), 2.92 (t, J = 7.1 Hz, 2H), 2.82 (d, J = 7.0 Hz, 2H), 2.69 (t, J = 7.1 Hz, 2H), 2.30 (s, 6H), 2.18 (dq, J = 13.4, 6.7 Hz, 1H), 0.99 (d, J = 6.7 Hz, 6H). (Two exchangeable hydrogens not observed.)

[0259] Example 24. Synthesis of Compound 197: Ethyl 3-(2-(dimethylamino)ethyl)-4-hydroxy-1H-indole-1-carboxylate, formic acid

[0260] [ka]

[0261] Step 1: 2-(4-(benzyloxy)-1H-indol-3-yl)-N,N-dimethyl-2-oxoacetamide

[0262] Oxalyl chloride (3.13 g, 2.2 mL, 1.1 equiv., 24.6 mmol) was added portionwise to a stirred solution of 4-(benzyloxy)-1H-indole (5.00 g, 1 equiv., 22.4 mmol) in MTBE (100 mL) and stirred at room temperature for 90 minutes. The reaction mixture was then cooled to 0° C., and dimethylamine in THF (5.55 g, 61.6 mL, 2.0 M, 5.5 equiv., 123 mmol) was added portionwise over 5 minutes. The reaction mixture was placed in an ice bath, which allowed it to slowly warm to room temperature over an additional 90 minutes. The resulting suspension was filtered, and the filtered solid was partitioned between EtOAc (300 mL) and water (200 mL). The organic layer was separated, washed with saturated aqueous NaHCO3 (200 ml) and concentrated in vacuo to give 2-(4-(benzyloxy)-1H-indol-3-yl)-N,N-dimethyl-2-oxoacetamide (4.76 g, 14.8 mmol, 66%) as a beige foam.

[0263] m / z 323.5 (M+H) + (ES+)

[0264] 1H NMR (500 MHz, DMSO-d6) δ 12.26 (s, 1H), 8.06 (s, 1H), 7.64 - 7.58 (m, 2H), 7.37 (dd, J = 8.3, 6.9 Hz, 2H), 7.28 (t, J = 7.3 Hz, 1H), 7.14 - 7.06 (m, 2H), 6.69 (dd, J = 7.2, 1.5 Hz, 1H), 5.26 (s, 2H), 2.90 (d, J = 16.8 Hz, 6H).

[0265] Step 2: 2-(4-(benzyloxy)-1H-indol-3-yl)-N,N-dimethylethan-1-amine

[0266] To a stirred suspension of the product of Step 1 above (4.76 g, 1 equiv., 14.8 mmol) in 2-MeTHF (100 mL) was added lithium aluminum hydride in THF (1.96 g, 21.5 mL, 2.4 molar, 3.5 equiv., 51.7 mmol) in portions under nitrogen at 0°C. The mixture continued to stir while the ice bath warmed to room temperature over 30 minutes, then stirred at 80°C for 4 hours. The reaction mixture was cooled to room temperature, after which sodium sulfate decahydrate was added in small portions until the resulting effervescence subsided. The reaction mixture was filtered, the solid plug was washed with MeOH (30 mL), and the collected clear filtrate was allowed to stand at room temperature overnight. The resulting dark green solution was concentrated under reduced pressure to give a dark green oil that solidified on standing. The solid was partitioned between EtOAc (200 mL) and water (100 mL). The organic layer was separated and concentrated in vacuo to give the subtitle compound (4.16 g, 13 mmol, 90%) as a brown solid which solidified on standing.

[0267] m / z 295.2 (M+H) + (ES+)

[0268] 1H NMR (500 MHz, DMSO-d6) δ 10.75 (s, 1H), 7.56 - 7.50 (m, 2H), 7.39 (dd, J = 8.3, 6.8 Hz, 2H), 7.36 - 7.29 (m, 1H), 6.97 (d, J = 2.3 Hz, 1H), 6.96 - 6.89 (m, 2H), 6.53 (dd, J = 6.0, 2.5 Hz, 1H), 5.16 (s, 2H), 2.94 - 2.87 (m, 2H), 2.50 - 2.42 (m, 2H), 2.05 (s, 6H).

[0269] Step 3: Ethyl 3-(2-(dimethylamino)ethyl)-4-hydroxy-1H-indole-1-carboxylate, formic acid

[0270] To a solution of the product of Step 2 above (53.9 mg, 1 equiv., 183 μmol) in DMF (1 mL) at 0° C. was added sodium hydride (9 mg, 60 wt %, 1.2 equiv., 220 μmol) and the reaction was stirred for 10 minutes at 0° C. Ethyl chloroformate (34 mg, 30 μL, 1.7 equiv., 312 μmol) was added at 0° C., followed by stirring at room temperature for 22 hours.

[0271] In a separate vial, to a solution of the product from Step 1 above (252.9 mg, 1 equiv., 859 μmol) in DMF (5 mL) at 0° C. was added sodium hydride (48.0 mg, 1.4 equiv., 1.20 mmol), and the reaction was stirred at 0° C. for 10 minutes. Ethyl chloroformate (170 mg, 150 μL, 1.8 equiv., 1.56 mmol) was added at 0° C., followed by stirring at room temperature for 18 hours. The mixture was combined with the above mixture, diluted with ethyl acetate (15 mL), and poured into water / brine (4:1, 50 mL). The phases were separated, and the aqueous phase was further extracted with ethyl acetate (20 mL). The combined organics were washed with brine (50 mL), dried (NaSO), and concentrated in vacuo. The crude product was purified by chromatography on RP Flash C18 (12 g cartridge, 5-50% (0.1% formic acid in MeCN) / (0.1% formic acid in water)) (elution 20%) to give the subtitle compound (163 mg, 0.34 mmol, 32%) as a bright yellow oil.

[0272] m / z 367.3 (M+H) + (ES+)

[0273] 1 H NMR (500 MHz, DMSO-d6) δ 8.20 (s, 1H), 7.71 (d, J = 8.3 Hz, 1H), 7.57 - 7.51 (m, 2H), 7.45 - 7.31 (m, 4H), 7.25 (dd, J = 8.2, 8.2 Hz, 1H), 6.90 (d, J = 8.1 Hz, 1H), 5.22 (s, 2H), 4.42 (q, J = 7.1 Hz, 2H), 2.99 - 2.89 (m, 2H), 2.69 (q, J = 5.5 Hz, 2H), 2.19 (s, 6H), 1.38 (t, J = 7.1 Hz, 3H) (One exchangeable H was not recognized).

[0274] Step 4: Ethyl 3-(2-(dimethylamino)ethyl)-4-hydroxy-1H-indole-1-carboxylate, formic acid

[0275] A solution of the product of Step 3 above (163 mg, 1 equiv., 395 μmol) in ethanol (5 mL) was hydrogenated on an H-Cube (10% Pd / C catalyst cartridge, batch: N0755, ID, THS-01131) at 5 bar and 1 mL / min for 1 h (recycle). The solution was then hydrogenated at 15 bar and 1 mL / min for 1 h (recycle). The collected mixture was concentrated in vacuo. The resulting material was triturated with acetonitrile (5 mL) and diethyl ether (5 mL) to afford the title compound (78.0 mg, 0.24 mmol, 60%) as a white solid.

[0276] m / z 277.2 (M+H) + (ES+)

[0277] 1 H NMR (500 MHz, DMSO-d₆) δ 11.95 (br, 1H), 8.19 (s, 1H), 7.54 (d, J = 8.2 Hz, 1H), 7.34 (s, 1H), 7.08 (dd, J = 8.1, 8.1 Hz, 1H), 6.59 (d, J = 7.9 Hz, 1H), 4.39 (q, J = 7.1 Hz, 2H), 2.92 (t, J = 7.0 Hz, 2H), 2.66 (t, J = 7.0 Hz, 2H), 2.28 (d, J = 1.5 Hz, 6H), 1.37 (t, J = 7.1 Hz, 3H) (one exchangeable hydrogen missing).

[0278] Example 25. Synthesis of Compound 199: isobutyl 3-(2-(dimethylamino)ethyl)-4-hydroxy-1H-indole-1-carboxylate, 0.5 fumaric acid.

[0279] [ka]

[0280] Step 1: 2-(4-(benzyloxy)-1H-indol-3-yl)-N,N-dimethyl-2-oxoacetamide

[0281] Oxalyl chloride (3.13 g, 2.2 mL, 1.1 equiv., 24.6 mmol) was added portionwise to a stirred solution of 4-(benzyloxy)-1H-indole (5.00 g, 1 equiv., 22.4 mmol) in MTBE (100 mL) and stirred at room temperature for 90 minutes. The reaction mixture was then cooled to 0° C., and dimethylamine in THF (5.55 g, 61.6 mL, 2.0 M, 5.5 equiv., 123 mmol) was added portionwise over 5 minutes. The reaction mixture was placed in an ice bath, which allowed it to slowly warm to room temperature over an additional 90 minutes. The resulting suspension was filtered, and the filtered solid was partitioned between EtOAc (300 mL) and water (200 mL). The organic layer was separated, washed with saturated aqueous NaHCO3 (200 ml) and concentrated in vacuo to give 2-(4-(benzyloxy)-1H-indol-3-yl)-N,N-dimethyl-2-oxoacetamide (4.76 g, 14.8 mmol, 66%) as a beige foam.

[0282] m / z 323.5 (M+H) + (ES+)

[0283] 1 H NMR (500 MHz, DMSO-d6) δ 12.26 (s, 1H), 8.06 (s, 1H), 7.64 - 7.58 (m, 2H), 7.37 (dd, J = 8.3, 6.9 Hz, 2H), 7.28 (t, J = 7.3 Hz, 1H), 7.14 - 7.06 (m, 2H), 6.69 (dd, J = 7.2, 1.5 Hz, 1H), 5.26 (s, 2H), 2.90 (d, J = 16.8 Hz, 6H).

[0284] Step 2: 2-(4-(benzyloxy)-1H-indol-3-yl)-N,N-dimethylethan-1-amine

[0285] To a stirred suspension of the product of Step 1 above (4.76 g, 1 equiv., 14.8 mmol) in 2-MeTHF (100 mL) was added lithium aluminum hydride in THF (1.96 g, 21.5 mL, 2.4 molar, 3.5 equiv., 51.7 mmol) in portions under nitrogen at 0°C. The mixture continued to stir while the ice bath warmed to room temperature over 30 minutes, then stirred at 80°C for 4 hours. The reaction mixture was cooled to room temperature, after which sodium sulfate decahydrate was added in small portions until the resulting effervescence subsided. The reaction mixture was filtered, the solid plug was washed with MeOH (30 mL), and the collected clear filtrate was allowed to stand at room temperature overnight. The resulting dark green solution was concentrated under reduced pressure to give a dark green oil that solidified on standing. The solid was partitioned between EtOAc (200 mL) and water (100 mL). The organic layer was separated and concentrated in vacuo to give the subtitle compound (4.16 g, 13 mmol, 90%) as a brown solid which solidified on standing.

[0286] m / z 295.2 (M+H) + (ES+)

[0287] 1 H NMR (500 MHz, DMSO-d6) δ 10.75 (s, 1H), 7.56 - 7.50 (m, 2H), 7.39 (dd, J = 8.3, 6.8 Hz, 2H), 7.36 - 7.29 (m, 1H), 6.97 (d, J = 2.3 Hz, 1H), 6.96 - 6.89 (m, 2H), 6.53 (dd, J = 6.0, 2.5 Hz, 1H), 5.16 (s, 2H), 2.94 - 2.87 (m, 2H), 2.50 - 2.42 (m, 2H), 2.05 (s, 6H).

[0288] Step 3: Isobutyl 4-(benzyloxy)-3-(2-(dimethylamino)ethyl)-1H-indole-1-carboxylate, formic acid

[0289] To a solution of 2-(4-(benzyloxy)-1H-indol-3-yl)-N,N-dimethylethan-1-amine (257.5 mg, 1 equiv., 875 μmol) in DMF (5 mL) at 0° C. was added sodium hydride (45 mg, 60 wt %, 1.3 equiv., 1.13 mmol), and the reaction was stirred at 0° C. for 10 min. Isobutyl carbonochloridate (263 mg, 250 μL, 2.2 equiv., 1.93 mmol) was added at 0° C., followed by stirring at room temperature for 2 h. The mixture was diluted with ethyl acetate (20 mL). Water / brine (1:1, 50 mL) was added, and the phases were separated. The aqueous phase was extracted with EtOAc (20 mL). The combined organics were washed sequentially with water / brine (1:1, 50 mL), brine (50 mL), dried (NaSO), and concentrated in vacuo. The crude product was purified by chromatography on RP Flash C18 (24 g cartridge, 5-50% (0.1% formic acid in MeCN) / (0.1% formic acid in water)) to give the subtitle compound (161 mg, 0.30 mmol, 35%) as a viscous brown oil.

[0290] m / z 395.3 (M+H) + (ES+)

[0291] 1 H NMR (500 MHz, DMSO-d6) δ 8.19 (s, 1H), 7.70 (d, J = 8.3 Hz, 1H), 7.55 - 7.50 (m, 2H), 7.46 - 7.39 (m, 3H), 7.38 - 7.32 (m, 1H), 7.25 (dd, J = 8.2, 8.2 Hz, 1H), 6.91 (d, J = 8.1 Hz, 1H), 5.23 (s, 2H), 4.18 (d, J = 6.5 Hz, 2H), 3.01 - 2.93 (m, 2H), 2.73 - 2.64 (m, 2H), 2.19 (s, 6H), 2.12 - 2.03 (m, 1H), 1.00 (d, J = 6.7 Hz, 6H). (One exchangeable hydrogen not observed).

[0292] Step 4: Isobutyl 3-(2-(dimethylamino)ethyl)-4-hydroxy-1H-indole-1-carboxylate, 0.5 fumaric acid

[0293] A solution of the product of Step 3 (161 mg, 1 equiv., 303 μmol) in ethanol (5 mL) was hydrogenated in an H-Cube (Pd / C catalyst cartridge) at 1 bar, 60°C, and 1 mL / min for 90 min (recycle). The mixture was concentrated in vacuo. The crude product was purified by chromatography on an RP Flash C18 (12 g cartridge, 5–50% (0.1% formic acid in MeCN) / (0.1% formic acid in water)) to give isobutyl 3-(2-(dimethylamino)ethyl)-4-hydroxy-1H-indole-1-carboxylate, formic acid (47.0 mg, 134 μmol, 44%) as a light brown oil. To a solution of this oil in acetone (2 mL) was added a solution of fumaric acid (17 mg, 1.1 equiv., 146 μmol) in acetone (3 mL). The mixture was cooled to −20°C for 1 h. The resulting solid was isolated by filtration and dried in vacuo to give the title compound (30.1 mg, 81 μmol, 61%) as a white solid.

[0294] m / z 305.2 (M+H) + (ES+)

[0295] 1 H NMR (500 MHz, DMSO-d₆) δ 11.62 (1H, br), 7.53 (d, J = 8.2 Hz, 1H), 7.37 (s, 1H), 7.09 (dd, J = 8.1, 8.1 Hz, 1H), 6.60 (d, J = 7.8 Hz, 1H), 6.53 (s, 1H), 4.16 (d, J = 6.5 Hz, 2H), 2.94 (t, J = 7.0 Hz, 2H), 2.74–2.68 (m, 2H), 2.32 (s, 6H), 2.12–2.02 (m, 1H), 1.00 (d, J = 6.7 Hz, 6H). (One exchangeable hydrogen was not observed.)

[0296] Example 26. Synthesis of Compound 52: Ethyl 3-(2-(dimethylamino)ethyl)-4-((ethoxycarbonyl)oxy)-1H-indole-1-carboxylate

[0297] [ka]

[0298] To a suspension of 3-(2-(dimethylamino)ethyl)-1H-indol-4-ol (25.0 mg, 99 wt%, 1 equiv., 121 μmol) and NaCO (128 mg, 10 equiv., 1.21 mmol) in anhydrous MeCN (1.00 mL) at 0 °C was added 1-chloroethyl ethyl carbonate (21.3 mg, 18.7 μL, 1.15 equiv., 139 μmol). The reaction mixture was allowed to warm to room temperature and then stirred at 50 °C for 72 h. The reaction mixture was poured into water (20 mL) and diluted with EtOAc (20 mL). The organic layer was collected and the aqueous layer was extracted with EtOAc (2 × 10 mL). The combined extracts were collected, dried (MgSO), filtered, and concentrated in vacuo. The crude product was purified by chromatography on silica gel (4 g cartridge, 0-10% EtOAc / isohexane) to give the title compound (20.5 mg, 51 μmol, 42%, 87% purity) as a yellow oil.

[0299] m / z 349.07 (M+H) + (ES+)

[0300] 1H NMR (500 MHz, CDCl3) δ 8.08 (d, J = 8.3 Hz, 1H), 7.40 (s, 1H), 7.30 (t, J = 8.2 Hz, 1H), 7.06 (dd, J = 8.0, 0.8 Hz, 1H), 4.47 (q, J = 7.1 Hz, 2H), 4.35 (q, J = 7.1 Hz, 2H), 2.93 - 2.86 (m, 2H), 2.65 - 2.59 (m, 2H), 2.32 (s, 6H), 1.46 (t, J = 7.1 Hz, 3H), 1.40 (t, J = 7.1 Hz, 3H).

[0301] Example 27. Synthesis of Compound 78: 3-(2-(dimethylamino)ethyl)-1H-indol-4-yl 2-(4-chlorophenoxy)-2-methylpropanoate, fumaric acid

[0302] [ka]

[0303] To a stirred solution of clofibric acid (381 mg, 1.4 equiv., 1.78 mmol) in anhydrous DCM (5 mL) at room temperature under a nitrogen atmosphere, oxalyl chloride (338 mg, 233 μL, 2.1 equiv., 2.67 mmol) and one drop of DMF were added. The reaction mixture was stirred at room temperature for 2 hours. The volatiles were removed in vacuo. The residue was dissolved in DCM (3 mL) and added to a solution of psilocin (259.3 mg, 1 equiv., 1.27 mmol) and triethylamine (462 mg, 637 μL, 3.6 equiv., 4.57 mmol) in DCM (3 mL) at 0° C. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with water (5 mL) and transferred to a separatory funnel. The aqueous layer was extracted with DCM (3 × 5 mL). The combined organic layers were collected, dried (NaSO), filtered, and concentrated in vacuo. The crude product was purified by chromatography on RP Flash C18 (24 g cartridge, 5-50% (0.1% formic acid in MeCN) / (0.1% formic acid in water)) to afford 3-(2-(dimethylamino)ethyl)-1H-indol-4-yl 2-(4-chlorophenoxy)-2-methylpropanoate, formic acid (322 mg, 720 μmol, 57%) as a brown oil. This material was dissolved in acetone (10 mL) and a solution of fumaric acid (84 mg, 0.720 mmol) in acetone (10 mL) was added. The resulting solid was filtered, washed with acetone, and dried in vacuo to afford the title compound (85.0 mg, 0.16 mmol, 13%) as a beige solid.

[0304] m / z 401.2 / 403.5 (M+H) + (ES+)

[0305] 1H NMR (500 MHz, DMSO-d6) δ 11.13 (s, 1H), 7.43–7.36 (m, 2H), 7.26 (dd, J = 8.2, 0.8 Hz, 1H), 7.18 (d, J = 2.3 Hz, 1H), 7.08–7.00 (m, 3H), 6.64 (dd, J = 7.7, 0.8 Hz, 1H), 6.56 (s, 2H), 2.86–2.79 (m, 2H), 2.70–2.64 (m, 2H), 2.29 (s, 6H), 1.76 (s, 6H). (Two exchangeable hydrogens not observed.)

[0306] Example 28. Synthesis of Compound 79: 2-(dimethylamino)-2-oxoethyl (3-(2-(dimethylamino)ethyl)-1H-indol-4-yl) carbonate, formic acid

[0307] [ka]

[0308] To a stirred solution of 2-hydroxy-N,N-dimethylacetamide (103 mg, 1.04 equiv., 997 μmol) and bis(4-nitrophenyl)carbonate (357 mg, 1.22 equiv., 1.18 mmol) in dry DMF (3 mL) at room temperature under a nitrogen atmosphere, triethylamine (218 mg, 300 μL, 2.23 equiv., 2.15 mmol) was added. The reaction mixture was stirred at room temperature for 2 hours. A DMF solution (1 mL) of psilocin (200.8 mg, 1 equiv., 963 μmol) was added. The reaction mixture was heated at 40° C. overnight. The reaction mixture was cooled to room temperature, diluted with DCM (10 mL), and water (10 mL) was added. The aqueous layer was extracted with DCM (3×25 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by chromatography on RP Flash C18 (24 g cartridge, 0-30% (0.1% formic acid in MeCN) / (0.1% formic acid in water)) to give the partially purified title compound (96.6 mg, 0.22 mmol, 22%) as a brown oil. The product was dissolved in acetone (5 mL). Fumaric acid (34 mg, 0.306 equiv., 295 μmol) in acetone (5 mL) was added. The mixture was left in the freezer for 1 week, but no solids formed. The volatiles were removed in vacuo, and the residue was dissolved in DMSO (1.93 mL), filtered, and purified using a Waters X-Select CSH C18 ODB preparative column, 130 Å, 5 μm, 30 mm × 100 mm, flow rate 40 mL min -1 The above was purified by reversed-phase preparative HPLC (Waters 2767 Sample Manager, Waters 2545 Binary Gradient Module, Waters Systems Fluidics Organiser, Waters 515 ACD pump, Waters 515 Makeup pump, Waters 2998 Photodiode Array Detector, Waters QDa) eluting with 0.1% formic acid in a water-MeCN gradient over 12.5 min using UV across all wavelengths with PDA, QDa and ELS detectors. The column dilution pump was used to pump 2 mL of water throughout the method.-1 of MeCN was obtained, which contained the following percentages of MeCN. Gradient information: 0.0-0.5 min, 5% MeCN; 0.5-10.5 min, increasing from 5% MeCN to 22.5% MeCN; 10.5-10.6 min, increasing from 22.5% MeCN to 100% MeCN; 10.6-12.5 min, holding at 100% MeCN. The clean fractions were evaporated in a Genevac to give the title compound (61.7 mg, 0.15 mmol, 15%) as a brown oil.

[0309] m / z 334.2 (M+H) + (ES+)

[0310] 1 H NMR (500 MHz, DMSO-d6) δ 11.11 (s, 1H), 8.22 (s, 1H), 7.26 (d, J = 8.2 Hz, 1H), 7.19 (s, 1H), 7.06 (dd, J = 7.9, 7.9 Hz, 1H), 6.76 (d, J = 7.8 Hz, 1H), 4.95 (s, 2H), 2.94–2.90 (m, 5H), 2.85 (s, 3H), 2.70–2.59 (m, 2H), 2.34 (s, 6H). One exchangeable hydrogen was not observed.

[0311] Example 29. Synthesis of Compound 82: 2-(benzyl(methyl)amino)ethyl (3-(2-(dimethylamino)ethyl)-1H-indol-4-yl)carbonate, formic acid

[0312] [ka]

[0313] To a solution of 2-(benzyl(methyl)amino)ethan-1-ol (125 mg, 0.8 equiv., 755 μmol) and bis(4-nitrophenyl)carbonate (301 mg, 1.1 equiv., 990 μmol) in dry DMF (2 mL) at room temperature under a nitrogen atmosphere was added DIPEA (742 mg, 1.0 mL, 6.1 equiv., 5.74 mmol). The reaction mixture was stirred at room temperature for 1.5 hours. To the reaction mixture was added a DMF solution (2 mL) of psilocin (202.8 mg, 1 equiv., 943 μmol), followed by DMAP (12 mg, 0.1 equiv., 98.2 μmol). The reaction mixture was stirred at room temperature and monitored for 5 days. The reaction mixture was diluted with water (25 mL). The layers were extracted with DCM (3×20 mL). The combined organic layers were collected, dried (NaSO), filtered, and concentrated in vacuo. The crude product was loaded onto Celite and purified by chromatography on RP Flash C18 (12 g cartridge, 5-30% (0.1% formic acid in MeCN) / (0.1% formic acid in water)) to give the partially purified target compound (307 mg). The sample was dissolved in DMSO (3.32 mL), filtered, and purified on a Waters X-Select CSH C18 ODB preparative column, 130 Å, 5 μm, 30 mm × 100 mm, flow rate 40 mL min -1 The above was purified by reversed-phase preparative HPLC (Waters 2767 Sample Manager, Waters 2545 Binary Gradient Module, Waters Systems Fluidics Organiser, Waters 515 ACD pump, Waters 515 Makeup pump, Waters 2998 Photodiode Array Detector, Waters QDa) eluting with 0.1% formic acid in a water-MeCN gradient over 12.5 min using UV across all wavelengths with PDA, QDa and ELS detectors. The column dilution pump was used to pump 2 mL of water throughout the method. -1of MeCN was obtained, which contained the following percentages of MeCN: Gradient information: 0.0–0.5 min, 5% MeCN; 0.5–10.5 min, increasing from 5% MeCN to 20% MeCN; 10.5–10.6 min, increasing from 20% MeCN to 100% MeCN; 10.6–12.5 min, holding at 100% MeCN. Clean fractions were evaporated in a Genevac. The partially purified sample was dissolved in DMSO (2 mL), filtered, and eluted with a 0.1% formic acid-water MeCN gradient over 15 min on a Phenomenex Gemini NC-C18 preparative column, 110 Å, 5 μm, 30 mm × 150 mm, flow rate 42 mL min -1 The column was purified by reverse-phase preparative HPLC (Gilson) using a column dilution pump. -1 Inject 10% MeCN in water at RT for 1.2 min. Gradient information: 0.0–0.5 min, 1% MeCN; 0.5–15.0 min, increasing from 1% MeCN to 14.9% MeCN; 15.0–15.1 min, increasing from 14.9% MeCN to 100% MeCN; 15.1–17.0 min, hold at 100% MeCN. Evaporation of clean fractions in a Genevac afforded the title compound (16.0 mg, 31 μmol, 3%) as a brown sticky gum.

[0314] m / z 396.5 (M+H) + (ES+)

[0315] 1H NMR (500 MHz, DMSO-d6) δ 11.18 - 11.05 (m, 1H), 8.25 (s, 1H), 7.32 - 7.30 (m, 4H), 7.29 - 7.22 (m, 2H), 7.19 (d, J = 2.3 Hz, 1H), 7.05 (dd, J = 7.9 Hz, 1H), 6.76 (dd, J = 7.7, 0.8 Hz, 1H), 4.34 (t, J = 5.7 Hz, 2H), 3.54 (s, 2H), 2.82 (dd, J = 9.2, 6.7 Hz, 2H), 2.70 (t, J = 5.7 Hz, 2H), 2.60 - 2.55 (m, 2H), 2.26 (s, 6H), 2.19 (s, 3H). One exchangeable hydrogen was not observed.

[0316] Example 30 Synthesis of Compound 83: 3-(2-(dimethylamino)ethyl)-1H-indol-4-yl(2,5,8,11-tetraoxatridecan-13-yl)carbonate, 0.9 formic acid, 0.1 fumaric acid

[0317] [ka]

[0318] To a solution of 2,5,8,11-tetraoxatridecan-13-ol (310 mg, 1.5 equiv., 1.49 mmol) and triethylamine (0.7 g, 1 mL, 7 equiv., 7 mmol) in THF (3 mL) at 0° C. was added triphosgene (160 mg, 0.5 equiv., 518 μmol). The reaction was stirred at 0° C. for 2 h. A suspension of psilocin (202.5 mg, 1 equiv., 991 μmol) in THF (3 mL) was added at 0° C. The mixture was stirred at 0° C. for 2 h and then at room temperature for an additional 16 h. The mixture was diluted with EtOAc (10 mL) and water (10 mL). The phases were separated and the aqueous phase was further extracted with EtOAc (10 mL). The combined organics were washed with brine (20 mL), dried (Na2SO4), and concentrated in vacuo. The crude product was purified by chromatography on RP Flash C18 (24 g cartridge, 5-10% (0.1% formic acid in MeCN) / (0.1% formic acid in water)) (elution with 10%) to give 3-(2-(dimethylamino)ethyl)-1H-indol-4-yl(2,5,8,11-tetraoxatridecan-13-yl)carbonate, formic acid (55.0 mg, 103 μmol, 10%) as a viscous brown oil. This material was dissolved in acetone (3 mL) and a solution of fumaric acid (16 mg, 1.2 equiv., 138 μmol) in acetone (3 mL). The mixture was cooled to −20° C. for 100 h. The mixture was concentrated in vacuo. This crude material was dissolved in DMSO (2.1 mL), filtered, and purified using a Waters X-Select CSH C18 ODB preparative column, 130 Å, 5 μm, 30 mm × 100 mm, at a flow rate of 40 mL / min. -1The above was purified by reverse-phase preparative HPLC (Waters 2767 Sample Manager, Waters 2545 Binary Gradient Module, Waters Systems Fluidics Organiser, Waters 515 ACD pump, Waters 515 Makeup pump, Waters 2998 Photodiode Array Detector, Waters QDa) eluting with 0.1% formic acid in a water-MeCN gradient over 8.5 min using UV across all wavelengths with PDA, QDa and ELS detectors. The column dilution pump was used to pump 2 mL of water throughout the method. -1 of MeCN was obtained, which contained the following percentages of MeCN: Gradient information: 0.0-0.5 min, 7.5% MeCN; 0.5-5.5 min, increasing from 7.5% MeCN to 37.5% MeCN; 5.5-5.6 min, increasing from 37.5% MeCN to 100% MeCN; 5.6-8.5 min, holding at 100% MeCN. The clean fractions were evaporated in a Genevac to give the title compound (33.0 mg, 66 μmol, 7%) as a brown oil.

[0319] m / z 439.2 (M+H) + (ES+)

[0320] 1H NMR (500 MHz, DMSO-d6) δ 11.10 (s, 1H), 8.18 (s, 0.9H), 7.26 (d, J = 8.1 Hz, 1H), 7.18 (d, J = 2.3 Hz, 1H), 7.05 (dd, J = 7.9, 7.9 Hz, 1H), 6.77 (d, J = 7.6 Hz, 1H), 6.50 (s, 0.2H), 4.34 (dd, J = 5.7, 3.4 Hz, 2H), 3.73 - 3.65 (m, 2H), 3.60 - 3.48 (m, 10H), 3.42 (dd, J = 5.9, 3.7 Hz, 2H), 3.23 (s, 3H), 2.82 - 2.76 (m, 2H), 2.57 - 2.52 (m, 2H), 2.26 (s, 6H). Two exchangeable hydrogens were not observed.

[0321] Example 31 Synthesis of Compound 87: 3-(2-(dimethylamino)ethyl)-1H-indol-4-yl(2-(N-methylacetamido)ethyl)carbonate, formic acid

[0322] [ka]

[0323] To a stirred solution of N-(2-hydroxyethyl)-N-methylacetamide (136 mg, 1.2 equiv., 1.16 mmol) and bis(4-nitrophenyl)carbonate (411 mg, 1.4 equiv., 1.35 mmol) in dry DCM (8 mL) at 20 °C under a nitrogen atmosphere, triethylamine (234 mg, 323 μL, 2.4 equiv., 2.31 mmol) was added. The reaction mixture was stirred at room temperature for 1 hour. To the reaction mixture at 20 °C under a nitrogen atmosphere, a DMF solution (2 mL) of psilocin (197 mg, 1 equiv., 964 μmol) was added. The reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was then heated at 40 °C for 24 hours. The reaction mixture was cooled to room temperature, diluted with DCM (10 mL), poured into ice / water (20 mL), and transferred to a separatory funnel. The aqueous layer was extracted with DCM (3 × 10 mL). The combined organic layers were washed with brine (15 mL), dried (NaSO), filtered, and concentrated in vacuo. This material was dissolved in DMSO (5.1 mL), filtered, and purified by elution on a Waters X-Select CSH C18 ODB preparative column, 130 Å, 5 μm, 30 mm × 100 mm, flow rate 40 mL min -1 The above was purified by reverse-phase preparative HPLC (Waters 2767 Sample Manager, Waters 2545 Binary Gradient Module, Waters Systems Fluidics Organiser, Waters 515 ACD pump, Waters 515 Makeup pump, Waters 2998 Photodiode Array Detector, Waters QDa) eluting with 0.1% formic acid in a water-MeCN gradient over 17.5 min using UV across all wavelengths with PDA, QDa and ELS detectors. The column dilution pump was used to pump 2 mL of water throughout the method. -1of MeCN was obtained, which contained the following percentages of MeCN. Gradient information: 0.0-0.5 min, 5% MeCN; 0.5-15.5 min, increasing from 5% MeCN to 17.5% MeCN; 15.5-15.6 min, increasing from 17.5% MeCN to 100% MeCN; 15.6-17.5 min, holding at 100% MeCN. The clean fractions were evaporated in a Genevac to give the title compound (74.0 mg, 0.18 mmol, 19%) as a brown oil.

[0324] m / z 348.1 (M+H) + (ES+)

[0325] 1 H NMR (500 MHz, DMSO-d6) δ 11.10 (s, 1H), 8.20 (s, 1H), 7.26 (dd, J = 7.9, 2.5 Hz, 1H), 7.18 (d, J = 2.1 Hz, 1H), 7.08 - 7.01 (m, 1H), 6.80 - 6.73 (m, 1H), 4.38 (t, J = 5.3 Hz, 1H), 4.29 (t, J = 5.5 Hz, 1H), 3.60 (t, J = 5.5 Hz, 1H), 3.65 (t, J = 5.3 Hz, 1H), 3.00 (s, 2H), 2.83 (s, 1H), 2.81 - 2.76 (m, 2H), 2.55 - 2.51 (m, 2H), 2.24 (s, 3H), 2.22 (s, 3H), 2.00 (d, J = 3.3 Hz, 3H). One exchangeable hydrogen was not observed.

[0326] Example 32 Synthesis of Compound 89: 2,4-dichlorobenzyl (3-(2-(dimethylamino)ethyl)-1H-indol-4-yl) carbonate, formic acid

[0327] [ka]

[0328] To a stirred solution of (2,4-dichlorophenyl)methanol (200 mg, 1.1 equiv., 1.13 mmol) and bis(4-nitrophenyl)carbonate (376 mg, 1.2 equiv., 1.23 mmol) in dry DCM (8 mL) at 20 °C under a nitrogen atmosphere, triethylamine (229 mg, 316 μL, 2.2 equiv., 2.26 mmol) was added. The reaction mixture was stirred at room temperature for 1 hour. To the reaction mixture at 20 °C under a nitrogen atmosphere, a DMF solution (2 mL) of psilocin (210.2 mg, 1 equiv., 1.03 mmol) was added. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was then heated at 38 °C for 18 hours. The reaction mixture was diluted with DCM (10 mL), poured into ice / water (20 mL), and transferred to a separatory funnel. The aqueous layer was extracted with DCM (3 × 10 mL). The combined organic layers were washed with brine (15 mL), dried (NaSO), filtered, and concentrated in vacuo. The crude product was purified by chromatography on silica gel (12 g cartridge, 0-20% MeOH / DCM) to give a brown oil. The partially purified material was purified by chromatography on RP Flash C18 (12 g cartridge, 0-50% (0.1% formic acid in MeCN) / (0.1% formic acid in water)) to give the title compound (69.1 mg, 156 μmol, 15%) as a brown oil.

[0329] m / z 407.2 / 409.2 (M+H) + (ES+)

[0330] 1H NMR (500 MHz, DMSO-d6) δ 11.12 (s, 1H), 8.19 (s, 1H), 7.74 (d, J = 2.1 Hz, 1H), 7.64 (d, J = 8.3 Hz, 1H), 7.52 (dd, J = 8.2, 2.2 Hz, 1H), 7.27 (dd, J = 8.1, 0.8 Hz, 1H), 7.18 (d, J = 2.3 Hz, 1H), 7.09 - 7.02 (m, 1H), 6.80 (dd, J = 7.7, 0.8 Hz, 1H), 5.36 (s, 2H), 2.78 - 2.71 (m, 2H), 2.56 - 2.51 (m, 2H), 2.19 (s, 6H). One exchangeable hydrogen was not observed.

[0331] Example 33. Synthesis of Compound 91: 3-(2-(dimethylamino)ethyl)-1H-indol-4-yl nicotinate, formic acid

[0332] [ka]

[0333] A mixture of psilocin (200.0 mg, 1 equiv., 852 μmol), nicotinic acid (106 mg, 1 equiv., 852 μmol), HATU (466 mg, 1.4 equiv., 1.23 mmol), and diisopropylethylamine (260 mg, 347 μL, 2.4 equiv., 2.01 mmol) in dry DMF (2.5 mL) was stirred at room temperature for 16 hours. The reaction mixture was diluted with saturated aqueous NaHCO (25 mL) and extracted with EtOAc (3 × 25 mL). The combined organic layers were washed with water (3 × 20 mL) and brine (25 mL), dried (NaSO), filtered, and concentrated in vacuo. The crude product was loaded onto Celite and purified by chromatography on RP Flash C18 (12 g cartridge, 0-100% (0.1% formic acid in MeCN) / (0.1% formic acid in water)) to give the title compound (150.6 mg, 0.41 mmol, 48%) as a light brown solid.

[0334] m / z 310.1 (M+H) + (ES+)

[0335] 1 H NMR (500 MHz, DMSO-d6) δ 11.16 (s, 1H), 9.35 (d, J = 2.2 Hz, 1H), 8.92 (dd, J = 4.8, 1.7 Hz, 1H), 8.62 - 8.51 (m, 1H), 8.21 (s, 1H), 7.68 (dd, J = 8.0, 4.8 Hz, 1H), 7.32 (d, J = 8.1 Hz, 1H), 7.20 (d, J = 2.3 Hz, 1H), 7.16 - 7.08 (m, 1H), 6.86 (d, J = 7.6 Hz, 1H), 2.79 - 2.72 (m, 2H), 2.60 - 2.53 (m, 2H), 2.06 (s, 6H). One exchangeable hydrogen was not observed.

[0336] Example 34. Synthesis of Compound 96: 3-(2-(dimethylamino)ethyl)-1H-indol-4-yl 4-phenylbutanoate, 0.5 fumaric acid

[0337] [ka]

[0338] To a stirred solution of 4-phenylbutyric acid (141 mg, 1 equiv., 860 μmol) in dry DCM (4 mL) at room temperature under a nitrogen atmosphere, oxalyl chloride (229 mg, 158 μL, 2.1 equiv., 1.81 mmol) and one drop of DMF were added. The reaction mixture was stirred at room temperature for 2 hours. The volatiles were removed in vacuo. The residue was dissolved in DCM (2 mL) and added to a solution of psilocin (199.6 mg, 1 equiv., 860 μmol) and triethylamine (313 mg, 431 μL, 3.6 equiv., 3.10 mmol) in DCM (2 mL) at 0° C. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with water (5 mL) and transferred to a separatory funnel. The aqueous layer was extracted with DCM (3 × 5 mL). The combined organic layers were collected, dried (NaSO), filtered, and concentrated in vacuo. The crude product was purified by chromatography on RP Flash C18 (24 g cartridge, 5–50% (0.1% formic acid in MeCN) / (0.1% formic acid in water)) to afford 3-(2-(dimethylamino)ethyl)-1H-indol-4-yl 4-phenylbutanoate, formic acid (144 mg, 0.30 mmol, 35%) as a brown oil. This material was dissolved in acetone (2 mL) and a solution of fumaric acid (35 mg, 0.35 equiv., 0.30 mmol) in acetone (4 mL) was added. The resulting solid was filtered, washed with acetone (2 mL), and dried in a vacuum oven overnight to afford the title compound (56.8 mg, 137 μmol, 16%) as a light brown solid.

[0339] m / z 351.0 (M+H) + (ES+)

[0340] 1H NMR (500 MHz, DMSO) δ 11.08 (d, J = 2.5 Hz, 1H), 7.34 - 7.27 (m, 2H), 7.26 - 7.18 (m, 4H), 7.16 (d, J = 2.3 Hz, 1H), 7.04 (dd, J = 7.9 Hz, 1H), 6.66 (dd, J = 7.6, 0.8 Hz, 1H), 6.53 (s, 1H), 2.81 (dd, J = 9.4, 6.6 Hz, 2H), 2.73 - 2.67 (m, 4H), 2.64 (dd, J = 9.6, 6.3 Hz, 2H), 2.31 (s, 6H), 1.99 (app. p, J = 7.6 Hz, 2H). (2 × 0.5 exchangeable H not observed)

[0341] Example 35. Synthesis of Compound 97: 3-(2-(dimethylamino)ethyl)-1H-indol-4-yl 4-acetamidobenzoate, 0.5 fumaric acid

[0342] [ka]

[0343] To a stirred solution of 4-acetamidobenzoic acid (182.6 mg, 1 equiv., 1.019 mmol) in dry DCM (4.00 mL) at room temperature under a N atmosphere, oxalyl chloride (271.7 mg, 187.4 μL, 2.1 equiv., 2.140 mmol) and one drop of DMF (74.51 mg, 78.9 μL, 1 equiv., 1.019 mmol) were added. The reaction mixture was stirred at room temperature for 2 hours. The volatiles were removed in vacuo. The residue was dissolved in DCM (2.00 mL) and added to a solution of psilocin (208.2 mg, 1 equiv., 1.019 mmol) and EtN (371.3 mg, 511 μL, 3.6 equiv., 3.669 mmol) in DCM (2.00 mL) at 0°C. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated in vacuo. The crude product (diluted with 1.5 mL of DMF) was purified by chromatography on a RP Flash C18 column (12 g cartridge, 5-50% (0.1% formic acid in MeCN) / (0.1% formic acid in water)) to give the impure material (220 mg, 0.40 mmol, 39%, 75% purity) as a brown oil. This material was subjected to a second purification on a RP Flash C18 column (12 g cartridge, 5-50% (0.1% formic acid in MeCN) / (0.1% formic acid in water)) to give the desired material as the formate salt (76.0 mg, 0.15 mmol, 14%, 80% purity (20% acetonitrile)) as a brown oil. This material was dissolved in acetone (5 mL) and a solution of fumaric acid (17 mg, 0.15 equiv., 0.15 mmol) in acetone (5 mL) was added. The resulting solid was filtered, washed with acetone, and dried in a vacuum oven over the weekend to give the title compound (44.7 mg, 97.6 μmol, 9.58%, 92.5% purity) as a yellow solid.

[0344] m / z 366.19 (M+H) + (ES+);364.19 (MH) - (ES-)

[0345] 1H NMR (500 MHz, DMSO) δ 11.11 (s, 1H), 10.38 (s, 1H), 8.16 - 8.12 (m, 2H), 7.84 - 7.78 (m, 2H), 7.28 (dd, J = 8.1, 0.8 Hz, 1H), 7.17 (d, J = 2.3 Hz, 1H), 7.12 - 7.05 (m, 1H), 6.77 (dd, J = 7.6, 0.8 Hz, 1H), 6.53 (s, 1H), 2.77 - 2.70 (m, 2H), 2.58 - 2.51 (m, 2H), 2.11 (s, 3H), 2.06 (s, 6H). One H is not recognized (exchangeable proton of fumaric acid)

[0346] Example 36. Synthesis of Compound 99: 3-(2-(dimethylamino)ethyl)-1H-indol-4-yl 2-acetoxybenzoate, fumaric acid

[0347] [ka]

[0348] To a stirred solution of 2-acetoxybenzoic acid (210 mg, 1.2 equiv., 1.17 mmol) in dry DCM (2 mL) at room temperature under a nitrogen atmosphere, oxalyl chloride (149 mg, 103 μL, 1.2 equiv., 1.17 mmol) and one drop of DMF were added. The reaction mixture was stirred at room temperature for 2 hours. The volatiles were removed in vacuo. The residue was redissolved in DCM (2 mL) and added to a solution of psilocin (202.9 mg, 1 equiv., 973 μmol) and triethylamine (218 mg, 300 μL, 2.2 equiv., 2.15 mmol) in DCM (2 mL) at 0° C. The resulting mixture was stirred at room temperature for 18 hours. The mixture was diluted with DCM (10 mL) and poured into ice / water (20 mL). The phases were separated and the aqueous phase was extracted with additional DCM (10 mL). The combined organics were washed with brine (20 mL), dried (NaSO), and concentrated in vacuo. The crude product was purified by chromatography on a RP Flash C18 (12 g cartridge, 5–50% (0.1% formic acid in MeCN) / (0.1% formic acid in water)) (elution approximately 20%) to give 3-(2-(dimethylamino)ethyl)-1H-indol-4-yl 2-acetoxybenzoate, formic acid (244 mg, 592 μmol, 61%) as a viscous orange oil. To a solution of the resulting oil in acetone (2 mL) was added a solution of fumaric acid (240 mg, 2.12 equiv., 2.1 mmol) in acetone (12 mL). The mixture was stored at −20° C. for 16 h. The resulting crystalline solid was isolated by filtration and washed with cold acetone (2×5 mL) to afford the title compound (164.9 mg, 0.32 mmol, 33%) as a white crystalline solid.

[0349] m / z 367.4 (M+H) + (ES+)

[0350] 1H NMR (500 MHz, DMSO-d6) δ 12.84 (s, 2H), 11.14 (s, 1H), 8.29 (dd, J = 7.8, 1.7 Hz, 1H), 7.80 (ddd, J = 7.8, 7.8, 1.7 Hz, 1H), 7.52 (dd, J = 7.6, 7.6 Hz, 1H), 7.32 (dd, J = 24.2, 8.1 Hz, 2H), 7.19 (d, J = 2.4 Hz, 1H), 7.10 (dd, J = 7.9, 7.9 Hz, 1H), 6.74 (d, J = 7.6 Hz, 1H), 6.56 (s, 2H), 2.78 - 2.69 (m, 2H), 2.58 (t, J = 8.0 Hz, 2H), 2.21 (s, 3H), 2.09 (s, 6H).

[0351] Example 37. Human hepatocyte clearance and human plasma stability Human plasma stability overview

[0352] Plasma stability of the compounds was assessed using a positive (propantheline), negative (pepstatin), and solvent control (DMSO) in plasma in duplicate at 37°C by monitoring the disappearance of the parent compound for up to 2 hours to confirm assay suitability. Psilocin was also run as a control to semiquantitatively monitor psilocin formation.

[0353] Samples were analyzed by UHPLC-MS / MS-Sciex™ MS500 Triple Quad QTRAP UHPLC system equipped with a Waters™ Acquity UPLC™ HSS T3 column (1.8 μm, 2.1 mm × 50 mm) and a HESI-II electrospray source, and the mobile phases were water + 0.1% formic acid and methanol + 0.1% formic acid phases.

[0354] The elimination rate constant and half-life (t) were determined using Ln(MS response) versus time plots. Additionally, the appearance of psilocin from the test compounds was monitored and assessed (as a percentage) relative to the peak of control psilocin (time 0) to provide a semi-quantitative measure of psilocin release. Human plasma stability data are included in Table A.

[0355] Human hepatocyte clearance

[0356] The metabolic stability of the compounds was assessed by monitoring the disappearance of the parent compound in cryopreserved hepatocytes for up to 1 hour at 37°C using established controls (diltazem and naloxone) to confirm the suitability of the assay. Psilocin was also run as an additional control to semiquantitatively monitor psilocin formation.

[0357] Samples were analyzed by UHPLC-MS / MS-Waters™ Acquity UPLC system, Waters™ Xevo TQ-XS on a Waters™ Acquity UPLC® HSS T3 column (1.8 μm, 2.1 mm × 30 mm), and the mobile phases were water + 0.1% formic acid and methanol + 0.1% formic acid.

[0358] Elimination rate constant, half-life (t1 / 2), and intrinsic clearance (CL Int ,μL / min / 10 6 Cells) was determined using Ln(MS response) versus time plots. Additionally, the appearance of psilocin by the test compound was monitored and assessed (as a percentage) relative to the peak control psilocin (time 0) to provide a semi-quantitative measure of psilocin release. Human hepatocyte clearance plasma data is included in Table A.

[0359] [Table 6-1] [Table 6-2]

Claims

1. The following structure: 【Chemistry 1-1】 [Chemistry 1-2] [Chemistry 1-3] [Chemistry 1-4] [Chemistry 1-5] [Chemistry 1-6] [Chemistry 1-7] [Chemistry 1-8] [Chemistry 1-9] 【Chemistry 1-10】 【Chemistry 1-11】 【Chemistry 1-12】 【Chemistry 1-13】 or a pharmaceutically acceptable salt or deuterated form thereof.

2. The following structure: 【Chemistry 2-1】 【Chemistry 2-2】 or a pharmaceutically acceptable salt or deuterated form thereof.

3. 10. A pharmaceutical composition comprising the compound of claim 1, or a pharmaceutically acceptable salt or deuterated form thereof.

4. 5-HT agonists, comprising administering a compound of claim 1 or 2, or a pharmaceutically acceptable salt or deuterated form thereof. ２ A method for treating an A receptor-related disease or disorder.

5. The 5-HT ２ 5. The method of claim 4, wherein the A receptor-related disease or disorder can be used to treat anxiety disorders, attention deficit hyperactivity disorder (ADHD), depression, cluster headache, loss of motivation, burnout syndrome, boredom syndrome, migraine, Parkinson's disease, schizophrenia, eating disorders, psychotic disorders, schizophreniform disorder, schizoaffective disorder, bipolar I disorder, bipolar II disorder, major depressive disorder, psychotic depression, delusional disorder, shared psychotic disorder, dyadic psychosis, brief psychotic disorder, suspicious personality disorder, schizotypal personality disorder, schizotypal personality disorder, social anxiety disorder, substance-induced anxiety disorder, selective mutism, panic disorder, panic attacks, agoraphobia, post-traumatic stress disorder (PTSD), premenstrual dysphoric disorder (PMDD), and premenstrual syndrome (PMS).

6. The 5-HT ２ 6. The method of claim 5, wherein the A receptor-related disease or disorder is depression.

7. 7. The method of claim 6, wherein the depression is treatment-resistant depression.

8. The 5-HT ２ 6. The method of claim 5, wherein the A receptor-related disease or disorder is an eating disorder.

9. 9. The method of claim 8, wherein the eating disorder is anorexia nervosa.

10. The 5-HT ２ 6. The method of claim 5, wherein the A receptor-related disease or disorder is an anxiety disorder.

11. The 5-HT ２ 6. The method of claim 5, wherein the A receptor-related disease or disorder is bipolar I disorder.

12. The 5-HT ２ 6. The method of claim 5, wherein the A receptor-related disease or disorder is bipolar II disorder.

13. The 5-HT ２ 6. The method of claim 5, wherein the A receptor-related disease or disorder is major depressive disorder.

14. The 5-HT ２ 6. The method of claim 5, wherein the A receptor-related disease or disorder is post-traumatic stress disorder (PTSD).

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