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

Abstract

Provided herein are compounds of Formula (I), Formula (II), Formula (III), a compound selected from any of the compounds in Table 1, Table 2, Table 3, Table 4, or a pharmaceutically acceptable salt or deuterated form thereof, wherein R1, R2, R3, R4, RD, RG, p, and q are defined herein. Also provided herein are pharmaceutical compositions comprising a compound of Formula (I), or a compound selected from any of Table 1, Table 2, Table 3, Table 4, or a pharmaceutically acceptable salt or deuterated form thereof, and methods of using a compound of Formula (I), Formula (II), Formula (III), or a pharmaceutically acceptable salt or deuterated form thereof, e.g., in the treatment of a 5-HT2A receptor associated disease or disorder. (I), (II), and (III).

Description

Cross-references to related applications

[0001] This application claims priority to U.S. Provisional Application No. 63 / 578,799, filed August 25, 2023, the disclosure of which is incorporated herein by reference in its entirety for all purposes. Background Technology

[0002] More than 50% of American adults will be diagnosed with a mental illness at some point in their lives. Nearly one in five suffers from a mental illness, and nearly one in twenty-five suffers from a serious mental illness, such as major depressive disorder, schizophrenia, or bipolar disorder.

[0003] Hallucinogens have shown promising activity in the treatment of mental illnesses. Novel hallucinogen compounds are needed for the treatment of mental illnesses. Attached Figure Description

[0004] Figure 1 This shows the pharmacokinetic data for compound 122 administered subcutaneously. Summary of the Invention

[0005] In some embodiments, this disclosure provides a compound of formula (I): Or, or a pharmaceutically acceptable salt thereof or its deuterated form, wherein: R 2 and R 3 Independently alkyl; R 4 It is an H or C(=O)O alkyl group; p is 2 or 3; R D It is a divalent or trivalent group selected from the following: alkylene, alkenylene, alkylene-O-alkylene, -(CH2) n -(OCH2CH2) m -, cycloalkylene, or arylene, or Each of them is optionally substituted by 1 to 4 groups selected from the following: halogen, OH, O-alkyl, alkyl, NH2, NH(alkyl), N(alkyl)2, C(=O)OH, C(=O)Oalkyl, OC(=O)alkyl, C(=O)alkyl or cycloalkyl; n is 1, 2, 3, 4, 5, 6, 7 or 8; m is 1, 2, 3, 4, 5, 6, 7 or 8; r is 1, 2, or 3; The condition is when R 2 and R 3 When each is an alkyl group, then R DNot CH2, (CH2)2, (CH2)3, (CH2)4, (CH2)5, (CH2)8 , , , or , And the condition is that when R 2 and R 3 When each is a deuterated alkyl group, then R D It is not (CH2)3.

[0006] In some embodiments, this disclosure provides a compound of formula (II): , Or its pharmaceutically acceptable salt or deuterated form, in: R 2 and R 3 Independently alkyl; R 4 It is an H or C(=O)O alkyl group; q is 2, 3, or 4; R G -(CH2) n -(OCH2CH2) m - or divalent, trivalent or tetravalent alkylene or alkenylene; n is 1, 2, 3, 4, 5, 6, 7, or 8; and m is 0, 1, 2, 3, 4, 5, 6, 7 or 8; The condition is when q is 2 and R 2 and R 3 When each is CH3, then R G It is neither -(CH2)2- nor -(CH2)3-.

[0007] In some embodiments, this disclosure provides a compound of formula (III): Or, or a pharmaceutically acceptable salt thereof or its deuterated form, wherein: R 2 and R 3 Independently alkyl; R 4 It is an H or C(=O)O alkyl group; R 1The alkylene group is -C(=O)OH, wherein the alkylene group is optionally substituted with OH, C(=O)OH, -OC(=O)alkyl, or NH2, or alkenyl-C(=O)OH, wherein the alkenyl group is optionally substituted with C(=O)OH, or cycloalkyl-C(=O)OH, wherein the cycloalkyl group is optionally substituted with C(=O)OH, or aryl-C(=O)OH, wherein the aryl group is optionally substituted with alkyl, Oalkyl, or C(=O)OH, or -(CH2CH2O). m -(CH2CH2) n -C(=O)OH, alkylene-O-alkylene-C(=O)OH, arylene-O(C=O)-alkylene-C(=O)O-arylene-C(=O)OH, O-alkylene-OH, wherein the alkylene group is optionally replaced by OH or -(OCH2CH2). m -OH substitution; m is 1, 2, or 3. n is 1, 2, or 3. The condition is when R 2 and R 3 When each is an alkyl group, then R 1 Not (CH2)2, (CH2)3, -CH=CH-, . Detailed Implementation

[0008] definition Unless otherwise specified, the following terms as used herein have the following meanings: “Cyano” refers to the -CN group.

[0009] "Hydroxy (hydroxy / hydroxyl)" refers to the -OH group.

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

[0011] "alkyl" or "alkyl group" refers to a fully saturated, straight-chain or branched hydrocarbon chain group having one to twelve carbon atoms, and which is connected to the rest of the molecule by a single bond. This includes alkyl groups containing any number of carbon atoms from 1 to 12. Alkyl groups containing up to 12 carbon atoms are C1-C2. 12 Alkyl groups, alkyl groups containing up to 10 carbon atoms, are C1-C6. 10 Alkyl groups, specifically C1-C6 alkyl groups containing up to six carbon atoms, and C1-C5 alkyl groups containing up to five carbon atoms, are defined as alkyl groups. C1-C5 alkyl groups include C5 alkyl, C4 alkyl, C3 alkyl, C2 alkyl, and C1 alkyl (i.e., methyl). C1-C6 alkyl groups include all the portions described above for C1-C5 alkyl groups but also include C6 alkyl groups. C1-C10 Alkyl groups include all the portions described above for C1-C5 and C1-C6 alkyl groups, but also include C7, C8, C9, and C6 alkyl groups. 10 Alkyl group. Similarly, C1-C 12 Alkyl groups include all the foregoing portions, but also include C. 11 and C 12 Alkyl group. C1-C 12 Non-limiting examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, sec-propyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, tert-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, n-undecyl, and n-dodecyl. Unless otherwise specified in this specification, the alkyl group may optionally be substituted.

[0012] "alkylene" or "alkylene chain" refers to a fully saturated, straight-chain or branched polyvalent (e.g., divalent, trivalent, or tetravalent) hydrocarbon chain group having one to twelve carbon atoms. (C1-C) 12 Non-limiting examples of alkylene groups include methylene, ethylene, propylene, n-butylene, etc. As a non-limiting example, the alkylene chain is attached to the remainder of the molecule by a single bond and to a group by a single bond. The points of attachment of the alkylene chain to the remainder of the molecule and to the group can be one carbon or any two or more carbons within the chain. Unless otherwise specifically stated in this specification, the alkylene chain may optionally be substituted.

[0013] "Alkenyl" or "alkenyl group" refers to a straight-chain or branched hydrocarbon chain group having two to twelve carbon atoms and one or more carbon-carbon double bonds. Each alkenyl group is connected to the rest of the molecule by a single bond. This includes alkenyl groups containing any number of carbon atoms from 2 to 12. Alkenyl groups containing up to 12 carbon atoms are C2-C. 12 Alkenyl groups, specifically those containing up to 10 carbon atoms, are C2-C. 10 Alkenyl groups, comprising up to 6 carbon atoms, are C2-C6 alkenyl groups, and alkenyl groups comprising up to 5 carbon atoms are C2-C5 alkenyl groups. C2-C5 alkenyl groups include C5 alkenyl, C4 alkenyl, C3 alkenyl, and C2 alkenyl. C2-C6 alkenyl groups include all the portions described above for C2-C5 alkenyl groups but also include C6 alkenyl groups. C2-C 10 The alkenyl group includes all the portions described above for C2-C5 alkenyl and C2-C6 alkenyl groups, but also includes C7, C8, C9 and C6 alkenyl groups. 10 Alkenyl. Similarly, C2-C 12 The alkenyl group includes all the aforementioned parts, but also includes C. 11 and C12 Alkenyl. C2-C 12 Non-limiting examples of alkenyl groups include ethenyl, 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, 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, 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 otherwise specified in this specification, the alkenyl group may optionally be substituted.

[0014] "Alkenylene" or "alkenylene chain" refers to a straight-chain or branched polyvalent (e.g., divalent, trivalent, or tetravalent) hydrocarbon chain group having two to twelve carbon atoms and one or more carbon-carbon double bonds. (C2-C) 12 Non-limiting examples of alkenyl groups include vinylene, propenylene, butenylene, etc. As a non-limiting example, the alkenyl chain is attached to the remainder of the molecule and to a group via a single bond. The points of attachment of the alkenyl chain to the remainder of the molecule and to the group can be one carbon or any two or more carbons within the chain. Unless otherwise specifically stated in this specification, the alkenyl chain may optionally be substituted.

[0015] "Alkynyl" or "alkynyl group" refers to a straight-chain or branched hydrocarbon chain group having two to twelve carbon atoms and one or more carbon-carbon triple bonds. Each alkynyl group is attached to the rest of the molecule by a single bond. It includes alkynyl groups containing any number of carbon atoms from 2 to 12. Alkynyl groups containing up to 12 carbon atoms are C2-C. 12 The alkynyl group, which contains up to 10 carbon atoms, is C2-C.10 The alkynyl group, comprising up to 6 carbon atoms, is C2-C6 alkynyl, and comprising up to 5 carbon atoms, is C2-C5 alkynyl. C2-C5 alkynyl groups include C5, C4, C3, and C2 alkynyl groups. C2-C6 alkynyl groups include all the portions described above for C2-C5 alkynyl groups but also include C6 alkynyl groups. C2-C 10 The ynyl group includes all the portions described above for C2-C5 and C2-C6 ynyl groups, but also includes C7, C8, C9, and C6 ynyl groups. 10 Alkyne group. Similarly, C2-C 12 The alkynyl group includes all the aforementioned parts, but also includes C. 11 and C 12 Alkyne group. C2-C 12 Non-limiting examples of alkenyl groups include ethynyl, propynyl, butynyl, pentyynyl, etc. Unless otherwise specified in this specification, the alkynyl group may optionally be substituted.

[0016] "alkynylene" or "alkynylene chain" refers to a straight-chain or branched polyvalent (e.g., divalent, trivalent, or tetravalent) hydrocarbon chain group having two to twelve carbon atoms and one or more carbon-carbon triple bonds. (C2-C) 12 Non-limiting examples of ynylene groups include ethynylene, propynylene, etc. The ynylene chain and the points where it is attached to the rest of the molecule and to the group can be one carbon or any two or more carbons within the chain. Unless otherwise specified in this specification, the ynylene chain may optionally be substituted.

[0017] "alkoxy" refers to the compound with the formula -OR a The group, wherein R a The alkyl, alkenyl, or alkynyl group containing one to twelve carbon atoms as defined above. Unless otherwise specified in this specification, the alkoxy group may optionally be substituted.

[0018] "alkylamino" refers to the formula -NHR a or -NR a R a The groups, wherein each R a Independently, it refers to an alkyl, alkenyl, or alkynyl group containing one to twelve carbon atoms as defined above. Unless otherwise specified in this specification, the alkylamino group may optionally be substituted.

[0019] "Aryl" refers to a hydrocarbon cyclic group comprising hydrogen, 6 to 18 carbon atoms, and at least one aromatic ring. For the purposes of this invention, the aryl group may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused or bridged ring systems. The aryl group includes, but is not limited to, aryl groups derived from the following: aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, fluoranthene, fluorene, as-indacene, s-indacene, indane, indene, naphthalene, phenalene, phenanthrene, pleiadene, pyrene, and triphenylene. Unless otherwise specified in this specification, the term "aryl" is intended to include aryl groups that are optionally substituted.

[0020] "Arylene" refers to a polyvalent (e.g., divalent, trivalent, or tetravalent) hydrocarbon ring system comprising hydrogen, 6 to 18 carbon atoms, and at least one aromatic ring, which is connected to the remainder of the molecule by two or more single bonds. For the purposes of this disclosure, the aryl group can be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused or bridged ring systems. Arylene includes, but is not limited to, arylene derived from the following: acetane, acenaphthene, phenanthrene, anthracene, azulene, benzene, phenanthrene, fluorene, asymmetric indole, symmetric indole, dihydroindene, indene, naphthalene, phenanthrene, heptamethrin, pyrene, and benzo[a]phenanthrene. Unless otherwise specifically stated in this specification, "arylene" may optionally be substituted.

[0021] "aralkyl" or "arylalkyl" or "alkyene-aryl" refers to an alkyl group having the formula -R b -R c The group, wherein R b For alkylene groups as defined above and R c It is one or more aryl groups as defined above, such as benzyl, diphenylmethyl, etc. Unless otherwise specified in this specification, the aryl group may optionally be substituted.

[0022] "Carbocyclyl" or "carbocyclic ring / carbocycle" refers to a non-aromatic ring structure in which each atom forming the ring is carbon. A carbocyclic ring can contain 3 to 20 carbon atoms. Carbocyclic rings include cycloalkyl, cycloalkenyl, and cycloynyl groups as defined herein. Unless otherwise specified in this specification, the carbocyclic group may optionally be substituted.

[0023] “Cycloalkyl” refers to a stable, non-aromatic, monocyclic or polycyclic, fully saturated hydrocarbon group consisting only of carbon and hydrogen atoms. It may include fused or bridged ring systems having three to twenty carbon atoms (e.g., three to ten carbon atoms) and being connected to the rest of the molecule by single bonds. Monocyclic cycloalkyl groups include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic cycloalkyl groups include, for example, adamantyl, norcamphenyl, decalinyl, 7,7-dimethyl-bicyclo[2.2.1]heptyl, etc. Unless otherwise specified in this specification, cycloalkyl groups may optionally be substituted.

[0024] “Cycloalkene” refers to a polyvalent (e.g., divalent, trivalent, or tetravalent) non-aromatic monocyclic or polycyclic fully saturated hydrocarbon ring consisting only of carbon and hydrogen atoms. It may include fused, spiro, or bridged ring systems having three to twenty carbon atoms (e.g., three to ten carbon atoms) and being connected to the remainder of the molecule by one or more single bonds. Monocyclic cycloalkylene groups include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic cycloalkylene groups include, for example, bicyclic [2.2.2]octylene, cubanylene, bicyclic (1.1.1)pentylene, adamantylene, norbornylene, decalinylene, 7,7-dimethyl-bicyclic [2.2.1]heptylene, etc. Unless otherwise specified in this specification, the cycloalkylene groups may optionally be substituted.

[0025] "Cycloalkenyl" refers to a stable non-aromatic monocyclic or polycyclic hydrocarbon group consisting only of carbon and hydrogen atoms and having one or more carbon-carbon double bonds. It may include fused or bridging ring systems having three to twenty carbon atoms (e.g., three to ten carbon atoms) and being connected to the rest of the molecule by single bonds. Monocyclic cycloalkenyl groups include, for example, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, etc. Polycyclic cycloalkenyl groups include, for example, bicyclic [2.2.1]hept-2-enyl, etc. Unless otherwise specified in this specification, cycloalkenyl groups may optionally be substituted.

[0026] "Cycloalkynyl" refers to a stable non-aromatic monocyclic or polycyclic hydrocarbon group consisting only of carbon and hydrogen atoms and having one or more carbon-carbon triple bonds. It may include fused or bridging ring systems having three to twenty carbon atoms (e.g., three to ten carbon atoms) and being connected to the rest of the molecule by single bonds. Monocyclic cycloalkynyl groups include, for example, cycloheptynyl, cyclooctyynyl, etc. Unless otherwise specified in this specification, cycloalkynyl groups may optionally be substituted.

[0027] "Haloalkyl" means an alkyl group as defined above that has been substituted with one or more halogen groups as defined above, such as trifluoromethyl, difluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, etc. Unless otherwise specified in this specification, the haloalkyl group may optionally be substituted.

[0028] "Haloalkenyl" refers to an alkenyl group as defined above, which is substituted with one or more halogen groups as defined above, such as 1-fluoropropenyl, 1,1-difluorobutenyl, etc. Unless otherwise specified in this specification, the haloalkenyl group may optionally be substituted.

[0029] "Haloalkynyl" refers to an alkynyl group as defined above, which is substituted with one or more halogen groups as defined above, such as 1-fluoropropynyl, 1-difluorobutynyl, etc. Unless otherwise specified in this specification, the haloalkynyl group may optionally be substituted.

[0030] "Heterocyclyl" or "heterocyclic ring / heterocycle" refers to a stable 3- to 20-membered non-aromatic group consisting of two to twelve carbon atoms and one to six heteroatoms selected from nitrogen, oxygen, sulfur, or silicon. Unless otherwise specified in this specification, the heterocyclic group may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused or bridged ring systems; and the nitrogen, carbon, or sulfur atom in the heterocyclic group may optionally be oxidized; the nitrogen atom may optionally be quaternized; and the heterocyclic group may be partially or fully saturated. Examples of such heterocyclic groups include, but are not limited to, dioxolanyl, thiophene[1,3]dithiohexacyclohexyl, decahydroisoquinolinyl, imidazolinyl, imidazoalkyl, isothiazolyl, and isoxazole. Alkyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopiperidylalkyl, oxazolylalkyl, piperidinyl, piperazinyl, 4-piperidinoneyl, pyrrolylalkyl, pyrazolylalkyl, quinuclidinyl, thiazolidinyl, tetrahydrofuranyl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, and 1,1-dioxo-thiomorpholinyl. Unless otherwise specified in this specification, heterocyclic groups may optionally be substituted.

[0031] "Heterocyclylene" refers to a polyvalent (e.g., divalent, trivalent, or tetravalent) 3 to 20-membered non-aromatic, partially aromatic, or aromatic cyclic group, consisting of two to twelve carbon atoms and one to six heteroatoms selected from nitrogen, oxygen, or sulfur. Unless otherwise specified in this specification, the heterocyclylene group may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused, spiro, or bridged ring systems; and the nitrogen, carbon, or sulfur atoms in the heterocyclylene group may optionally be oxidized; the nitrogen atom may optionally be quaternized; and the heterocyclylene group may be partially or fully saturated. Examples of such heterocyclic groups include, but are not limited to, dioxolanylene, decahydroisoquinolinyl, imidazolinyl, imidazoalkyl, isothiazolyl, isoxazolyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinylene, 2-oxopiperidinylene, and 2-oxopyrrolidinylene. The heterocyclic groups may be optionally substituted unless otherwise specified in this specification.

[0032] "Heterocyclylalkyl" or "alkylene-heterocyclyl" refers to a compound with the formula -R b -R e The group, wherein R b For alkylene groups as defined above and R e The heterocyclic alkyl group is as defined above. Unless otherwise specified in this specification, the heterocyclic alkyl group may optionally be substituted.

[0033] “N-heterocyclyl” means a heterocyclic group containing at least one nitrogen atom as defined above, wherein the point by which the heterocyclic group is connected to the remainder of the molecule is through the nitrogen atom in the heterocyclic group. Unless otherwise specified in this specification, the N-heterocyclyl group may optionally be substituted.

[0034] "Heteroaryl" refers to a 5- to 20-membered ring group comprising a hydrogen atom, one to thirteen carbon atoms, one to six heteroatoms selected from nitrogen, oxygen, and sulfur, and at least one aromatic ring comprising at least one heteroatom selected from nitrogen, oxygen, and sulfur. For the purposes of this invention, the heteroaryl group may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused or bridged ring systems; and the nitrogen, carbon, or sulfur atoms in the heteroaryl group may optionally be oxidized; the nitrogen atom may optionally be quaternized. Examples include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzothiazolyl, benzoindolyl, benzodioxolyl, benzofuranyl, benzooxazolyl, benzothiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, and benzo[b][1,4]dioxepinyl. Azolyl, benzodioxanepentyl, benzodioxanehexenyl, benzopyranyl, benzopyranoneyl, benzofuranyl, benzofuranoneyl, benzothiophene, benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophene, furanyl, furanoneyl nyl), isothiazolyl, imidazolyl, indazole, indole, indazole, isoindole, indololinyl, isoindololinyl, isoquinolinyl, indolizinyl, isoxazolyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, ethylene oxide, 1-oxidopyridinyl, 1-pyrimidinyl, 1-pyrazinyl, 1-pyridazinyl, 1-phenyl-1 H-pyrrole, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purine, pyrrole, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxolinyl, quinolinyl, quininecycloyl, isoquinolinyl, tetrahydroquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, and thiophene (i.e., thiophene group). Unless otherwise specified in this specification, heteroaryl groups may optionally be substituted.

[0035] “N-heteroaryl” means a heteroaryl group containing at least one nitrogen atom as defined above, wherein the point by which the heteroaryl group is connected to the remainder of the molecule is through the nitrogen atom in the heteroaryl group. Unless otherwise specified in this specification, the N-heteroaryl group may optionally be substituted.

[0036] "Heteroarylalkyl" or "alkylene-heteroaryl" refers to a compound with the formula -R b -R f The group, wherein R b For alkylene chains as defined above and R f The heteroaryl group is defined above. Unless otherwise specified in this specification, the heteroarylalkyl group may optionally be substituted.

[0037] "Thioalkyl" refers to the formula -SR a The group, wherein R a The alkyl, alkenyl, or alkynyl group containing one to twelve carbon atoms as defined above. Unless otherwise specified in this specification, the thioalkyl group may optionally be substituted.

[0038] As used herein, the term "substituted" means that at least one hydrogen atom of any of the above groups (e.g., alkyl, alkylene, alkenyl, alkyne, alkyne, alkoxy, alkylamino, thioalkyl, aryl, aralkyl, carbocyclic, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, haloalkyl, heterocyclic, N-heterocyclic, heterocyclic alkyl, heteroaryl, N-heteroaryl and / or heteroarylalkyl) is replaced by a bond to a non-hydrogen atom, said non-hydrogen atom being, for example, but not limited to, halogen atoms such as F, Cl, Br, and 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 amines, amides, alkylamines, dialkylamines, arylamines, alkylarylamines, diarylamines, N-oxides, imides, and enamines; silicon atoms in groups such as trialkylsilyl, dialkylarylsilyl, alkyldiarylsilyl, and triarylsilyl groups; and other heteroatoms in various other groups.

[0039] "Substituted" also means that one or more hydrogen atoms in any of the above groups are replaced by a higher-order bond (e.g., a double or triple bond) attached 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 one or more hydrogen atoms in any of the above groups being replaced by the following: -NR 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 R h -OR g -SR g -SOR g -SO2R g -OSO2R g -SO2OR g =NSO2R g and -SO2NR g R h "Substituted" also means that one or more hydrogen atoms in any of the above groups are replaced by the following: -C(=O)R g -C(=O)OR g -C(=O)NR g R h -CH2SO2R g -CH2SO2NR g R h In the foregoing, R g and R h They are the same or different, and are independently hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylamino, thioalkyl, aryl, aralkyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, haloalkyl, haloalkenyl, haloalkynyl, heterocyclic, N-heterocyclic, heterocyclic alkyl, heteroaryl, N-heteroaryl and / or heteroarylalkyl.

[0040] "Substituted" also includes the substitution of one or more hydrogen atoms of any of the above groups by bonds attached to the following groups: amino, cyano, hydroxy, imino, nitro, oxo, thionyl, halogen, alkyl, alkenyl, alkynyl, alkoxy, alkylamino, thioalkyl, aryl, aralkyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkylalkyl, haloalkyl, haloalkenyl, haloalkynyl, heterocyclic, N-heterocyclic, heterocyclic alkyl, heteroaryl, N-heteroaryl and / or heteroarylalkyl groups.

[0041] In this specification, unless otherwise stated, the term "pharmaceutically acceptable" is used to characterize a portion (e.g., salt, dosage form, or excipient) suitable for therapeutic use. Generally, a pharmaceutically acceptable portion has one or more benefits that outweigh any potentially harmful effects that the portion might have. Harmful effects may include, for example, excessive toxicity, irritation, allergic reactions, and other problems and complications.

[0042] The term "pharmaceutically acceptable salt" includes both acid addition salts and base addition salts. Pharmaceutically acceptable salts include salts obtained by reacting an active compound acting as a base with an inorganic or organic acid to form a salt, such as hydrochlorides, sulfates, phosphates, methanesulfonates, camphorsulfonates, oxalates, maleates, succinates, citrates, formates, hydrobroms, benzoates, tartrates, fumarates, salicylates, amygdalinates, carbonates, etc. Those skilled in the art will further recognize that acid addition salts can be prepared by reacting a compound with a suitable inorganic or organic acid via any of many known methods.

[0043] The compounds disclosed herein, or pharmaceutically acceptable salts thereof, may contain one or more asymmetric centers, and thus produce enantiomers, diastereomers, and other stereoisomers, which can be defined by absolute stereochemistry as ( R )-or( S (D)- or (L)- for amino acids. This disclosure is intended to include all such possible isomers, as well as their racemic and optically pure forms, whether or not they are specifically illustrated herein. Optically active (+) and (-), ( R )-and( S(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 / separation of individual enantiomers include chiral synthesis from suitable optically pure precursors, or resolution of racemic mixtures (or racemic mixtures of salts or derivatives) using, for example, chiral high-performance liquid chromatography (HPLC). When compounds described herein contain olefinic double bonds or other geometrically asymmetric centers, unless otherwise specified, it is intended that the compounds include both E and Z geometrical isomers. Similarly, all tautomeric forms are intended to be included.

[0044] In some embodiments, “substituted” further means any alkyl, cycloalkyl, or heterocyclic alkyl in which one or more hydrogen atoms are replaced by an isotope (e.g., deuterium). Furthermore, each of the aforementioned substituents may optionally be substituted by one or more of the substituents listed above.

[0045] The compounds disclosed herein may also contain atomic isotopes in non-natural proportions at one or more of the atoms constituting such compounds. For example, the compounds may be radioactive isotopes (e.g., deuterium). 2 H), tritium ( 3 H), Iodine-125 ( 125 I) or carbon-14 ( 14 C) Radioactive labeling. All isotopic variations of the compounds disclosed herein (whether radioactive or not) are intended to be covered within the scope of this disclosure.

[0046] In some embodiments, unless otherwise specified, “rt” or “rt” means room temperature, “h” or “h.” means hour, “min” or “min.” means minute, and “eq.” means equivalent.

[0047] compound This disclosure provides dimers, trimers, and tetramers of psilocin. The disclosed compounds are designed to release psilocin upon administration to a subject in need. In embodiments, the disclosed compounds have a psilocin release efficacy in the range of about 7% to about 100% (as described in Example 14), including about 25% to about 100%, about 50% to about 100%, about 75% to about 100%, about 80% to about 100%, about 85% to about 100%, about 90% to about 100%, or about 95% to about 100%. In embodiments, the disclosed compounds have a release efficacy of about 80% to about 100%. In some embodiments, this disclosure provides compounds of formula (I). Or, or a pharmaceutically acceptable salt thereof or its deuterated form, wherein: R2 and R 3 Independently alkyl; R 4 It is an H or C(=O)O alkyl group; p can be 2 (dimer), 3 (trimer), or 4 (tetramer); R D It is a divalent, trivalent, or tetravalent group selected from the following: alkylene, alkenylene, alkylene-O-alkylene, -(CH2) n -(OCH2CH2) m -, cycloalkylene, heterocyclic, aryl, heteroaryl or Each of these groups may optionally be substituted with one of the following groups: OH, O-alkyl, alkyl, NH2, NH(alkyl), N(alkyl)2, C(=O)OH, C(=O)Oalkyl, OC(=O)alkyl, cycloalkyl or C(=O)alkyl; n is 1, 2, 3, 4, 5, 6, 7 or 8; m is 1, 2, 3, 4, 5, 6, 7, or 8; or r can be 1, 2, or 3.

[0048] In some implementations of equation (I), when R 2 and R 3 When each is a non-deuterated alkyl group, then R D Not CH2, (CH2)2, (CH2)3, (CH2)4, (CH2)5, (CH2)8 , , , or .

[0049] In some implementations of equation (I), when R 2 and R 3 When each is a deuterated alkyl group, then R D It is not (CH2)3.

[0050] In some implementations of equation (I), when R 2 and R 3 When each is CD3, then R D It is not (CH2)3.

[0051] R D It can be conjugated with 2, 3, or 4 dephosphorylated psilocybin residues to form any suitable portion of a dephosphorylated psilocybin dimer, trimer, or tetramer. In some embodiments, R D It is a divalent or trivalent group selected from the following: alkylene, alkylene-O-alkylene, -(CH2) n -(OCH2CH2)m -, cycloalkylene, heterocyclic, aryl, heteroaryl or Each of these can be optionally substituted with OH, OCH3, NH2, COOH, cycloalkyl, or C(=O)alkyl. In some embodiments, R D It is a divalent or trivalent group selected from the following: alkylene, -O-alkylene, -(CH2) n -(OCH2CH2) m -, cycloalkylene, heterocyclic, aryl, heteroaryl or Each of these can be optionally substituted with OH, OCH3, NH2, COOH, cycloalkyl, or C(=O)alkyl. In some embodiments, R D It is a divalent alkylene group. In some embodiments, R D It is a trivalent alkylene group. In some embodiments, R D It is a divalent alkylene-O-alkylene. In some embodiments, R D -(CH2) n -(OCH2CH2) m - where n is 1-8 and m is 1-8. In some implementations, R D It is a divalent cycloalkylene group. In some embodiments, R D It is a trivalent cycloalkylene group. In some embodiments, R D It is a divalent arylene. In some implementations, R D It is a trivalent aryl group. In some implementations, R D for Where r is 1-3. In some implementations, R D Optionally substituted with OH, OCH3, NH2, COOH, cycloalkyl or C(=O)alkyl.

[0052] In some embodiments, when the compound of formula (I) is deuterated, the compound has the formula (DI). The structure of, or a pharmaceutically acceptable salt thereof, wherein R D R 2 R 3 and R 4 As defined in equation (I).

[0053] In some implementation schemes, R D For R E And R E It is a divalent group. In some embodiments, the compound of formula (I) is a compound of formula (Ia). , Or its pharmaceutically acceptable salt or deuterated form, in: Each R 2 and R 3 Independently alkyl; Each R 4 Independently, it is an H or C(=O)O alkyl group; R E The divalent group is selected from the following: alkylene, cycloalkylene, arylene, alkylene-O-alkylene, -(CH2) n -(OCH2CH2) m -or Each of them may optionally be substituted by one or more groups selected from the following: O-alkyl, NH2, NHC 1-6 Alkyl, N(C) 1-6 Alkyl)2, COOH, cycloalkyl and C(=O)O alkyl; n is 1, 2, 3, 4, 5, 6, 7 or 8; m is 1, 2, or 3; and r can be 1, 2, or 3.

[0054] In some implementation schemes, R E It is a divalent alkylene group. In some embodiments, the alkylene group is straight-chain or branched. In some embodiments, the alkylene group is straight-chain. In some embodiments, the straight-chain alkylene group is C3-C7 alkylene. In some embodiments, the straight-chain alkylene group is substituted with -NH2, OH, or C(O)OH. In some embodiments, the alkylene group is branched. In some embodiments, the branched alkylene group is C3-C5 alkylene. In some embodiments, the branched alkylene group is a C3-C5 alkylene group substituted with -NH2, OH, or C(O)OH.

[0055] In some implementation schemes, R E It is a divalent group selected from the following: cycloalkylene, arylene, alkylene-O-alkylene, -(CH2) n -(OCH2CH2) m -or Each of them may optionally be substituted by one or more groups selected from the following: O-alkyl, NH2, NHC 1-6 Alkyl, N(C) 1-6 Alkyl)2, COOH, cycloalkyl, and C(=O)O alkyl. In some embodiments, R E It is a divalent cycloalkylene group. In some embodiments, R E It is a divalent C3-C8 cycloalkylene group. In some embodiments, R E It is a divalent C4 cycloalkylene group. In some embodiments, R E It is a divalent C6 cycloalkylene group. In some embodiments, R E for In some implementations, R E for .

[0056] In some implementation schemes, R E It is a divalent arylene. In some implementations, R E It is a divalent phenylene. In embodiments, the phenylene is substituted with O-alkyl, alkyl, or C(=O)OH. In embodiments, the divalent phenylene is substituted with OCH3, CH3, or C(=O)OH. In some embodiments, R E for In some implementations, R D Or R E for In some implementations, R D Or R E for In some implementations, R D Or R E for In some implementations, R D Or R E for In some implementations, R D Or R E for .

[0057] In some implementation schemes, R E It is a divalent alkylene-O-alkylene. In some embodiments, R E for , , or In some implementations, R E for In some implementations, R E for In some implementations, R E for In some implementations, R E for .

[0058] In some implementation schemes, R E -(CH2) n -(OCH2CH2) m- In some implementations, n is 1. In some implementations, n is 2. In some implementations, n is 3. In some implementations, n is 4. In some implementations, n is 5. In some implementations, n is 6. In some implementations, n is 7. In some implementations, n is 8. In some implementations, m is 1. In some implementations, m is 2. In some implementations, m is 3. In some implementations, n is 1-3 and m is 1-4. In some implementations, n is 2 and m is 2 or 3. In some implementations, R E It is -(CH2)2-(OCH2CH2)2-. In some implementations, R E It is -(CH2)2-(OCH2CH2)3-.

[0059] In some implementation schemes, R E for In some implementations, r is 1. In some implementations, r is 2. In some implementations, r is 3. In some implementations, R E for .

[0060] In some implementation schemes, R D Or R E For (CH2)6, (CH2)7, , , , , , , , , -(CH2)2-(OCH2CH2)2-, -(CH2)2-(OCH2CH2)3-, , , , , , , , , or In some implementations, R D Or R E It is (CH2)6. In some implementations, R D Or R E It is (CH2)7. In some implementations, R D Or R E for In some implementations, R D Or R E for In some implementations, R D Or R E for In some implementations, R D Or R E for In some implementations, R D Or R E for In some implementations, R D Or R E for In some implementations, R D Or R E for In some implementations, R D Or R E for In some implementations, R D Or R E for In some implementations, R D Or R E It is -(CH2)2-(OCH2CH2)2-. In some implementations, R D Or R E It is -(CH2)2-(OCH2CH2)3-. In some implementations, R D Or R E for In some implementations, R D Or R E for In some implementations, R D Or R E for In some implementations, R D Or R E for In some implementations, R D Or R E for In some implementations, R D Or R E for In some implementations, R D Or R E for In some implementations, R D Or R E for In some implementations, R D Or R E for In some implementations, R D Or RE for .

[0061] In some embodiments, when the compound of formula (Ia) is deuterated, the compound has the formula (D-Ia). The structure of, or a pharmaceutically acceptable salt thereof, wherein R E R 2 R 3 and R 4 As defined in equation (Ia).

[0062] In some embodiments, the compound of formula (I) is a compound of formula (Ib). , Or its pharmaceutically acceptable salt or deuterated form, wherein Each R 2 and R 3 Independently alkyl; Each R 4 Independently, it is an H or C(=O)O alkyl group; R F It is a trivalent group selected from alkylene, alkenylene, cycloalkylene, or arylene groups substituted with OH or C(=O) alkyl.

[0063] In some implementation schemes, R F It is a trivalent alkylene group. In some embodiments, R F It is a trivalent C3-C8 alkylene group. In some embodiments, R F It is a trivalent C3-C6 alkylene group. In some embodiments, the trivalent alkylene group is substituted with -OH or C(=O) alkyl. In some embodiments, the trivalent alkylene group is substituted with -OH or C(=O)CH3. In some embodiments, R F for In some implementations, R F for .

[0064] In some implementation schemes, R F It is a trivalent alkenyl group. In some embodiments, R F It is a trivalent C3-C8 alkenyl group. In some embodiments, R F It is a trivalent C3-C6 alkenyl group. In some embodiments, R F It is a trivalent C3-C5 alkenyl group. In some embodiments, R F for .

[0065] In some implementation schemes, R F It is a trivalent cycloalkylene group. In some embodiments, R FIt is a trivalent C3-C8 cycloalkylene group. In some embodiments, R F It is a trivalent C3-C6 cycloalkylene group. In some embodiments, R F It is a trivalent C6 cycloalkylene group. In some embodiments, R F for .

[0066] In some implementation schemes, R F It is a trivalent aryl group. In the implementation scheme, R... F It is a trivalent phenylene oxide. In the implementation scheme, R... F for .

[0067] In some embodiments, when a compound of formula (Ib) is deuterated, the compound has the formula (D-Ib). The structure of, or a pharmaceutically acceptable salt thereof, wherein R F R 2 R 3 and R 4 As defined in equation (Ib).

[0068] In some embodiments, this disclosure provides compounds of formula (II), , Or its pharmaceutically acceptable salt or deuterated form, in: R 2 and R 3 Independently alkyl; R 4 It is an H or C(=O)O alkyl group; q is 2, 3, or 4; R G -(CH2) n -(OCH2CH2) m - or divalent, trivalent, or tetravalent alkylene or alkenylene; n is 1, 2, 3, 4, 5, 6, 7, or 8; and m can be 0, 1, 2, 3, 4, 5, 6, 7 or 8.

[0069] In some implementations of equation (II), when q is 2 and R 2 and R 3 When each is CH3, then R G It is neither -(CH2)2- nor -(CH2)3-.

[0070] In some implementation schemes, R G -(CH2) n -(OCH2CH2) m- or trivalent or tetravalent alkylene, or divalent, trivalent or tetravalent alkenylene.

[0071] In some implementation schemes, R G -(CH2) n -(OCH2CH2) m - In some implementations, n is 1. In some implementations, n is 2. In some implementations, n is 3. In some implementations, n is 4. In some implementations, n is 5. In some implementations, n is 6. In some implementations, n is 7. In some implementations, n is 8. In some implementations, m is 1. In some implementations, m is 2. In some implementations, m is 3. In some implementations, n is 1-3 and m is 1-4. In some implementations, n is 2 and m is 2 or 3. In some implementations, n is 2 and m is 2. In some implementations, R G It is -(CH2)2-(OCH2CH2)2-.

[0072] In some implementation schemes, R G It is a divalent alkylene group. In some embodiments, R G divalent C1-C 12 Alkylene. Some embodiments, R G divalent C1-C 10 Alkylene. In some embodiments, R G It is a divalent C1-C8 alkylene group. In the embodiment, R G For -CH2-. In the implementation scheme, R G It is -(CH2)4-. In the implementation scheme, R G It is -(CH2)5-. In the implementation scheme, R G It is -(CH2)6-. In the implementation scheme, R G It is -(CH2)7-. In the implementation scheme, R G It is -(CH2)8-.

[0073] In some implementation schemes, R G It is a trivalent alkylene group. In the embodiment, R... G It is a trivalent C1-C8 alkylene group. In the embodiment, R G It is a trivalent C1-C8 alkylene group. In the embodiment, R G It is a trivalent C1-C6 alkylene group. In the embodiment, R G It is a trivalent C2-C6 alkylene group. In the embodiment, R G It is a trivalent C1-C5 alkylene group. In the embodiment, R G It is a trivalent C2-C5 alkylene group. In the embodiment, RG It is a trivalent C2-C4 alkylene group. In the embodiment, R G for or In the implementation plan, R G for In the implementation plan, R G for .

[0074] In some implementation schemes, R G It is a tetravalent alkylene group. In the embodiment, R... G It is a tetravalent C1-C8 alkylene group. In the embodiment, R G It is a tetravalent C3-C8 alkylene group. In the embodiment, R G It is a tetravalent C3-C6 alkylene group. In the embodiment, R G It is a tetravalent C5 alkylene group. In the embodiment, R G for .

[0075] In some implementation schemes, R G -CH2-, -(CH2)4-, -(CH2)5-, -(CH2)6-, -(CH2)7-, -(CH2)8-, -(CH2)2-(OCH2CH2)2-, , or .

[0076] In some embodiments, when the compound of formula (II) is deuterated, the compound has the formula (D-II). The structure of, or a pharmaceutically acceptable salt thereof, wherein R G R 2 R 3 and R 4 As defined in equation (II).

[0077] In some embodiments, the compound of formula (II) is the same as the compound of formula (IIa). , Or its pharmaceutically acceptable salt or deuterated form, in: Each R 2 and R 3 Independently alkyl; Each R 4 Independently, it is an H or C(=O)O alkyl group; R H -(CH2) n -(OCH2CH2) m -; n is 1, 2, 3, 4, 5, 6, 7, or 8; and m can be 0, 1, 2, or 3.

[0078] In the implementation scheme, the compound of formula (IIa) is the compound of formula (IIa-D) is... .

[0079] In some implementation schemes, R H -(CH2) n -(OCH2CH2) m - In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4. In some embodiments, n is 5. In some embodiments, n is 6. In some embodiments, n is 7. In some embodiments, n is 8. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3. In some embodiments, n is 1-3 and m is 1-4. In some embodiments, n is 2 and m is 2 or 3. In some embodiments, n is 2 and m is 2.

[0080] In some implementation schemes, R H It is -(CH2)2-(OCH2CH2)2-.

[0081] In some implementation schemes, R G Or R H It is -(CH2)2-, -(CH2)4-, -(CH2)5-, -(CH2)6-, -(CH2)7-, -(CH2)8- or -(CH2)2-(OCH2CH2)2-.

[0082] In the embodiments, when the compound of formula (IIa) is a deuterated compound, the compound has formula (D-IIa). The structure of (D-IIa), or a pharmaceutically acceptable salt thereof, wherein R H R 2 R 3 and R 4 As defined in equation (IIa).

[0083] In some embodiments, the compound of formula (II) is a compound of formula (IIb). Or its pharmaceutically acceptable salt or deuterated form, in: Each R 2 and R 3 Independently alkyl; Each R 4Independently, it is an H or C(=O)O alkyl group; R I It is a trivalent alkylene group.

[0084] In some implementation schemes, R G Or R I Trivalent C 1-6 Alkylene group. In some embodiments, R G Or R I Trivalent C 2-6 Alkylene group. In some embodiments, R G Or R I Trivalent C 2-5 Alkylene group. In some embodiments, R G Or R I Trivalent C 2-4 Alkylene group. In some embodiments, R G Or R I It is a trivalent C2 alkylene group. In some embodiments, R G Or R I It is a trivalent C4 alkylene group. In some embodiments, R G Or R I for In some implementations, R G Or R I for .

[0085] In some implementation schemes, R G Or R I for or .

[0086] In some embodiments, when a compound of formula (IIb) is deuterated, the compound has the formula (D-IIb). The structure of (D-IIb), or a pharmaceutically acceptable salt thereof, wherein R I R 2 R 3 and R 4 As defined in equation (IIb).

[0087] In some embodiments, the compound is a compound of formula (IIc). (IIc), Or its pharmaceutically acceptable salt or deuterated form, in: R 2 and R 3 Independently alkyl; R 4It is an H or C(=O)O alkyl group; R J It is a tetravalent alkylene group.

[0088] In some implementation schemes, R G Or R J It is tetravalent C 1-6 Alkylene group. In some embodiments, R G Or R J It is tetravalent C 2-6 Alkylene group. In some embodiments, R G Or R J It is tetravalent C 2-5 Alkylene group. In some embodiments, R G Or R J It is a tetravalent C5 alkylene group.

[0089] In some implementation schemes, R G Or R J for .

[0090] In some embodiments, when a compound of formula (IIc) is deuterated, the compound has the formula (D-IIc). The structure of (D-IIc), or a pharmaceutically acceptable salt thereof, wherein G J R 2 R 3 and R 4 As defined in equation (IIc).

[0091] In some embodiments, this disclosure provides compounds of formula (III), (III), or a pharmaceutically acceptable salt thereof or its deuterated form, wherein: R 2 and R 3 Independently alkyl; R 4 It is an H or C(=O)O alkyl group; R 1 The alkylene group is -C(=O)OH, wherein the alkylene group is optionally substituted with OH, C(=O)OH, -OC(=O)alkyl, or NH2, or alkenyl-C(=O)OH, wherein the alkenyl group is optionally substituted with C(=O)OH, or cycloalkyl-C(=O)OH, wherein the cycloalkyl group is optionally substituted with C(=O)OH, or aryl-C(=O)OH, wherein the aryl group is optionally substituted with alkyl, Oalkyl, or C(=O)OH, or -(CH2CH2O). m -(CH2CH2) n-C(=O)OH, alkylene-O-alkylene-C(=O)OH, arylene-O(C=O)-alkylene-C(=O)O-arylene-C(=O)OH, O-alkylene-OH, wherein the alkylene group is optionally replaced by OH or -(OCH2CH2). m -OH substitution; m is 1, 2, 3; and n is 1, 2, or 3.

[0092] In some implementations of formula (III), when R 2 and R 3 When each is an alkyl group, then R 1 Not (CH2)2C(=O)OH, (CH2)3C(=O)OH, -CH=CHC(=O)OH or .

[0093] In some implementation schemes, R 1 The alkyl group is an alkenyl-C(=O)OH, wherein the alkenyl group is optionally substituted with C(=O)OH or a cycloalkyl-C(=O)OH, wherein the cycloalkyl group is optionally substituted with C(=O)OH or an aryl-C(=O)OH, wherein the aryl group is optionally substituted with an alkyl group, an O-alkyl group, or a C(=O)OH group, or -(CH2CH2O). m -(CH2CH2) n -C(=O)OH, alkylene-O-alkylene-C(=O)OH, arylene-O(C=O)-alkylene-C(=O)O-arylene-C(=O)OH, O-alkylene-OH, wherein the alkylene group is optionally replaced by OH or -(OCH2CH2). m -OH substitution. In some implementations, R 1 C 1-10 Alkylene -C(=O)OH, wherein the alkylene is optionally replaced by OH, C(=O)OH, -OC(=O)alkyl or NH2, C 1-6 Substitution of the imidene group with -C(=O)OH, wherein the imidene group is optionally replaced by C(=O)OH, C 3-6 The cycloalkyl group is substituted with -C(=O)OH, wherein the cycloalkyl group is optionally substituted with C(=O)OH or arylene-C(=O)OH, wherein the arylene group is optionally substituted with alkyl, O-alkyl, or C(=O)OH or -(CH2CH2O). m -(CH2CH2) n -C(=O)OH、C 1-6 Alkylene-OC 1-6 Alkylene-C(=O)OH, arylene-O(C=O)-alkylene-C(=O)O-arylene-C(=O)OH, OC 1-10Alkylene-OH substitution, wherein the alkylene is optionally replaced by OH or -(OCH2CH2). m -OH substitution.

[0094] In some implementation schemes, R 1 C 1-10 Alkylene -C(=O)OH, wherein the alkylene is optionally substituted with OH, C(=O)OH, -OC(=O)alkyl or NH2.

[0095] In some implementation schemes, R 1 C 1-6 The alkenyl group is substituted with C(=O)OH, wherein the alkenyl group is optionally replaced with C(=O)OH.

[0096] In some implementation schemes, R 1 C 3-6 Cycloalkylene-C(=O)OH, wherein the cycloalkylene is optionally substituted with C(=O)OH.

[0097] In some implementation schemes, R 1 It is arylene-C(=O)OH, wherein the arylene group is optionally substituted with an alkyl group, an O-alkyl group, or a C(=O)OH group.

[0098] In some implementation schemes, R 1 -(CH2CH2O) m -(CH2CH2) n -C(=O)OH. In some implementations, m is 1, 2, 3 and n is 1.

[0099] In some implementation schemes, R 1 C 1-6 Alkylene-OC 1-6 Alkylene-C(=O)OH. In some embodiments, R 1 C 1-5 Alkylene-OC 1-5 Alkylene-C(=O)OH. In some embodiments, R 1 C 1-4 Alkylene-OC 1-4 Alkylene-C(=O)OH.

[0100] In some implementation schemes, R 1 It is arylene-O(C=O)-alkylene-C(=O)O-arylene-C(=O)OH.

[0101] In some implementation schemes, R 1 For OC 1-10 Alkylene -OH, wherein the alkylene group is optionally replaced by OH or -(OCH2CH2).m -OH substitution.

[0102] In the implementation plan, R 1 -(OCH2CH2) m -OH.

[0103] In some implementation schemes, R 1 for , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or .

[0104] In some implementation schemes, R 1 for In some implementations, R 1 for In some implementations, R 1 for In some implementations, R 1 for In some implementations, R 1 for In some implementations, R 1 for In some implementations, R 1 for In some implementations, R 1 for In some implementations, R 1 for In some implementations, R 1 for In some implementations, R 1 for In some implementations, R 1 for In some implementations, R 1 for In some implementations, R 1 for In some implementations, R 1 for In some implementations, R 1 for In some implementations, R 1 for In some implementations, R 1 for In some implementations, R 1 for In some implementations, R 1 for In some implementations, R 1 for In some implementations, R 1 for In some implementations, R 1 for In some implementations, R 1 for In some implementations, R 1 for In some implementations, R 1 for In some implementations, R 1 for In some implementations, R 1 for In some implementations, R 1 for In some implementations, R 1 for In some implementations, R 1 for In some implementations, R 1 for In some implementations, R 1 for In some implementations, R 1 for In some implementations, R 1 for In some implementations, R 1 for In some implementations, R 1 for In some implementations, R 1 for In some implementations, R 1 for In some implementations, R 1 for In some implementations, R 1 for In some implementations, R 1 for In some implementations, R 1 for .

[0105] In some embodiments, when the compound of formula (III) is deuterated, the compound has the formula (D-III). The structure of (D-III), or a pharmaceutically acceptable salt thereof, wherein R 1 R 2 R 3 and R 4 As defined in equation (III).

[0106] In some embodiments of formulas (I), (Ia), (Ib), (II), (Iia), (Iib), (IIc), (III), (DI), (D-Ia), (D-Ib), (D-II), (D-Iia), (D-Iib), (D-IIc), or (D-III), R 2 and R 3 Independently for C 1-6 alkyl.

[0107] In some embodiments of formulas (I), (Ia), (Ib), (II), (Iia), (Iib), (IIc), (III), (DI), (D-Ia), (D-Ib), (D-II), (D-Iia), (D-Iib), (D-IIc), or (D-III), R 2 and R 3 Independent for deuterated C 1-6 alkyl.

[0108] In some embodiments of formulas (I), (Ia), (Ib), (II), (Iia), (Iib), (IIc), (III), (DI), (D-Ia), (D-Ib), (D-II), (D-Iia), (D-Iib), (D-IIc), or (D-III), R 2 and R 3 Independently for fully deuterated C 1-6 alkyl.

[0109] In some embodiments of formulas (I), (Ia), (Ib), (II), (Iia), (Iib), (IIc), (III), (DI), (D-Ia), (D-Ib), (D-II), (D-Iia), (D-Iib), (D-IIc), or (D-III), R 2 and R 3 It is -CH3.

[0110] In some embodiments of formulas (I), (Ia), (Ib), (II), (Iia), (Iib), (IIc), (III), (DI), (D-Ia), (D-Ib), (D-II), (D-Iia), (D-Iib), (D-IIc), or (D-III), R 2 and R 3 It is deuterated -CH3.

[0111] In some embodiments of formulas (I), (Ia), (Ib), (II), (Iia), (Iib), (IIc), (III), (DI), (D-Ia), (D-Ib), (D-II), (D-Iia), (D-Iib), (D-IIc), or (D-III), R 2 and R 3 It is deuterated-CD3.

[0112] In some embodiments of formulas (I), (Ia), (Ib), (II), (Iia), (Iib), (IIc), (III), (DI), (D-Ia), (D-Ib), (D-II), (D-Iia), (D-Iib), (D-IIc), or (D-III), R 4 For H or C (=O)OC 1-6 alkyl.

[0113] In some embodiments of formulas (I), (Ia), (Ib), (II), (Iia), (Iib), (IIc), (III), (DI), (D-Ia), (D-Ib), (D-II), (D-Iia), (D-Iib), (D-IIc), or (D-III), R 4 It is H or C(=O)OCH3.

[0114] In some embodiments of formulas (I), (Ia), (Ib), (II), (Iia), (Iib), (IIc), (III), (DI), (D-Ia), (D-Ib), (D-II), (D-Iia), (D-Iib), (D-IIc), or (D-III), R 4 For H.

[0115] In some embodiments of formulas (I), (Ia), (Ib), (II), (Iia), (Iib), (IIc), (III), (DI), (D-Ia), (D-Ib), (D-II), (D-Iia), (D-Iib), (D-IIc), or (D-III), R 2 and R 3 Independently CH3, and R 4 For H.

[0116] In some embodiments, this disclosure provides compounds selected from Tables 1, 2, and 3, or pharmaceutically acceptable salts thereof, or deuterated forms thereof.

[0117] In some embodiments, this disclosure provides compounds selected from Tables 1 and 2, or pharmaceutically acceptable salts thereof, or deuterated forms thereof.

[0118] In some embodiments, this disclosure provides compounds selected from Table 1, their pharmaceutically acceptable salts, or their deuterated forms.

[0119] In some embodiments, this disclosure provides compounds selected from Table 4, their pharmaceutically acceptable salts, or their deuterated forms.

[0120] In some embodiments, this disclosure provides a method for treating a disease, the method comprising subcutaneous administration of a pharmaceutical composition comprising a compound selected from Tables 1, 2, 3, and 4, or a pharmaceutically acceptable salt thereof, or a deuterated form thereof.

[0121] In some embodiments, this disclosure provides a method of treating a disease, the method comprising subcutaneous administration of a pharmaceutical composition comprising a compound of formula (I), formula (II), or formula (III) or a pharmaceutically acceptable salt thereof, or a deuterated form thereof. , in R 2 and R 3 Independently alkyl; R 4 It is an H or C(=O)O alkyl group; p is 2 or 3; R D It is a divalent or trivalent group selected from the following: alkyl, alkenyl, alkylene, -O-alkylene, -(CH2) n -(OCH2CH2) m - cycloalkyl, heterocyclic, aryl, heteroaryl or Each of these groups may optionally be substituted with one of the following groups: OH, O-alkyl, NH2, NH(alkyl), N(alkyl)2, cycloalkyl, COOH, C(=O)Oalkyl or C(=O)alkyl; n is 1, 2, 3, 4, 5, 6, 7, or 8; m is 1, 2, or 3; and r is 1, 2, or 3; or , Or its pharmaceutically acceptable salt or deuterated form, in: R 2 and R 3 Independently alkyl; R 4 It is an H or C(=O)O alkyl group; q is 2, 3, or 4; R G -(CH2) n -(OCH2CH2) m - or trivalent or tetravalent alkyl groups; wherein n is 1, 2, 3, 4, 5, 6, 7 or 8, and m is 0, 1, 2 or 3. or (III) or its pharmaceutically acceptable salt or its deuterated form, wherein: R 2 and R 3 Independently alkyl; R 4 It is an H or C(=O)O alkyl group; R 1The alkylene group is -C(=O)OH, wherein the alkylene group is optionally substituted with OH, C(=O)OH, -OC(=O)alkyl, or NH2, or alkenyl-C(=O)OH, wherein the alkenyl group is optionally substituted with C(=O)OH, or cycloalkyl-C(=O)OH, wherein the cycloalkyl group is optionally substituted with C(=O)OH, or aryl-C(=O)OH, wherein the aryl group is optionally substituted with alkyl, Oalkyl, or C(=O)OH, or -(CH2CH2O). m -(CH2CH2) n -C(=O)OH, alkylene-O-alkylene-C(=O)OH, arylene-O(C=O)-alkylene-C(=O)O-arylene-C(=O)OH, O-alkylene-OH, wherein the alkylene group is optionally replaced by OH or -(OCH2CH2). m -OH substitution; m is 1, 2, or 3. n is 1, 2, or 3.

[0122] In some embodiments, this disclosure provides compounds of formula (I): (I), or a pharmaceutically acceptable salt thereof or its deuterated form, wherein: R 2 and R 3 Independently alkyl; R 4 It is an H or C(=O)O alkyl group; p is 2 or 3; R D It is a divalent or trivalent group selected from the following: alkylene, alkenylene, alkylene-O-alkylene, -(CH2) n -(OCH2CH2) m -, cycloalkylene, or arylene, or Each of them is optionally substituted by 1 to 4 groups selected from the following: halogen, OH, O alkyl, alkyl, NH2, NH (alkyl), N (alkyl)2, C(=O)OH, C(=O)O alkyl, OC (=O) alkyl, cycloalkyl or C(=O) alkyl; n is 1, 2, 3, 4, 5, 6, 7 or 8; m is 1, 2, 3, 4, 5, 6, 7 or 8; r is 1, 2, or 3; The condition is when R 2 and R 3 When each is an alkyl group, then R D Not CH2, (CH2)2, (CH2)3, (CH2)4, (CH2)5, (CH2)8 , , , or .

[0123] In some implementations of equation (I), when R 2 and R 3 When each is an alkyl group, then R D Not CH2, (CH2)2, (CH2)3, (CH2)4, (CH2)5, (CH2)8 , , , or .

[0124] In some implementation schemes, R D The following are divalent or trivalent groups: C 1-12 Alkylene, C 1-6 Alkylene-OC 1-6 Alkylene, -(CH2) n -(OCH2CH2) m -、C 3-8 Cycloalkylene, arylene or Each of them is optionally substituted by 1 to 4 groups selected from the following: C 1-3 Alkyl, OH, OCH3, NH2, cycloalkyl, COOH, or C(=O)alkyl.

[0125] In some embodiments, the compound is a compound of formula (Ia). Or its pharmaceutically acceptable salt or deuterated form, in: Each R 2 and R 3 Independently alkyl; Each R 4 Independently, it is an H or C(=O)O alkyl group; R E The divalent group is selected from the following: alkylene, cycloalkylene, arylene, alkylene-O-alkylene, -(CH2) n -(OCH2CH2) m -or Each of these groups may optionally be substituted by one or more groups selected from the following: halogen, alkyl, Oalkyl, NH2, NHC 1-6 Alkyl, NC ( 1-6 Alkyl)2, COOH and C(=O)O alkyl; n is 1, 2, or 3; m is 1, 2, or 3; and r can be 1, 2, or 3.

[0126] In the implementation plan, R E The divalent group is selected from the following: C 1-12 Alkylene, C 3-8 Cycloalkylene, arylene, C 1-6 Alkylene-OC 1-6 Alkylene, -(CH2) n -(OCH2CH2) m -or Each of these groups is optionally substituted by one or more groups selected from the following: halogen, C 1-3 Alkyl, O-alkyl, NH2, NHC 1-6 Alkyl, NC ( 1-6 Alkyl)2, COOH and C(=O)O alkyl.

[0127] In some implementation schemes, R D Or R E for , , , , , -(CH2)2-(OCH2CH2)2-, -(CH2)2-(OCH2CH2)3-, , , , , or .

[0128] In some embodiments, the compound of formula (I) is a compound of formula (Ib). , Or its pharmaceutically acceptable salt or deuterated form, wherein Each R 2 and R 3 Independently alkyl; Each R 4 Independently, it is an H or C(=O)O alkyl group; R F It is a trivalent cycloalkyl or alkylene group.

[0129] In some implementation schemes, R F Trivalent C 3-8 Cycloalkylene.

[0130] In some implementation schemes, R F for In some implementations, R F for .

[0131] In some embodiments, this disclosure provides compounds of formula (II), , Or its pharmaceutically acceptable salt or deuterated form, in: Each R 2 and R 3 Independently alkyl; Each R 4 Independently, it is an H or C(=O)O alkyl group; R H For --(CH2) n -(OCH2CH2) m -or alkylene; n is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12, and m is 1, 2, or 3; The condition is when q is 2 and R 2 and R 3 When each is CH3, then R H Not --(CH2)3-.

[0132] In some implementations of equation (II), n is 1, 2, 3, 4, 5, 6, 7, 8, and m can be 1, 2, or 3.

[0133] In some implementation schemes, R H It is --(CH2)5-, --(CH2)8- or --(CH2)2-(OCH2CH2)2-.

[0134] In some implementation schemes, R 2 and R 3 Independently for C 1-6 alkyl.

[0135] In some implementation schemes, R 2 and R 3 It is -CH3.

[0136] In some implementation schemes, R 4 For H or C (=O)OC 1-6 alkyl.

[0137] In some implementation schemes, R 4 It is H or C(=O)OCH3.

[0138] In some implementation schemes, R 4 For H.

[0139] In some implementations, R2 and R 3 Independently CH3, and R 4 For H.

[0140] In the embodiments, the present disclosure provides the compounds listed in Table 1.

[0141] In the embodiments, this disclosure provides compounds listed in Tables 1 and 2.

[0142] In the implementation scheme, the compounds listed in Table 4 are provided in this disclosure.

[0143] In some embodiments, the compounds disclosed herein have a human plasma dephosphorylated psilocybin release efficiency greater than 50%. In some embodiments, the compounds disclosed herein have a human plasma dephosphorylated psilocybin release efficiency greater than 60%. In some embodiments, the compounds disclosed herein have a human plasma dephosphorylated psilocybin release efficiency greater than 70%. In some embodiments, the compounds disclosed herein have a human plasma dephosphorylated psilocybin release efficiency greater than 80%. In some embodiments, the compounds disclosed herein have a human plasma release efficiency of 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% (inclusive of all values ​​and ranges therein).

[0144] Table 1.

[0145] Table 2.

[0146] Table 3.

[0147] Table 4.

[0148] Pharmaceutical Composition This disclosure provides pharmaceutical compositions comprising at least one compound disclosed herein and one or more pharmaceutically acceptable excipients.

[0149] The compounds described herein may be administered as compounds on their own or formulated into pharmaceutical compositions. Pharmaceutical compositions may contain one or more pharmaceutically acceptable excipients, such as carriers, diluents, fillers, disintegrants, lubricants, binders, colorants, pigments, stabilizers, preservatives, and / or antioxidants.

[0150] Pharmaceutical compositions can be formulated using techniques known to those skilled in the art, such as those disclosed in "Remington: The Science and Practice of Pharmacy," Pharmaceutical Press, 22nd edition. Pharmaceutical compositions can be formulated into dosage forms for oral, parenteral (e.g., intramuscular, intravenous, subcutaneous, intradermal, intraarterial, intracardiac, rectal, nasal, topical, aerosol, or vaginal) administration. Dosage forms for oral administration include coated and uncoated tablets, soft gelatin capsules, hard gelatin capsules, sugar tablets, lozenges, solutions, emulsions, suspensions, syrups, elixirs, powders and granules for reconstitution, dispersible powders and granules, pharmaceutical gum, chewable tablets, and effervescent tablets. Dosage forms for parenteral administration include solutions, emulsions, suspensions, dispersibles, and powders and granules for reconstitution. Emulsions are a preferred dosage form for parenteral administration. Dosage forms for rectal and vaginal administration include suppositories and vaginal suppositories (ovula). Dosage forms for nasal administration can be administered via inhalation and blowing, for example, through a metered inhaler. Dosage forms for topical administration include creams, gels, ointments, balms, patches, and transdermal delivery systems.

[0151] Treatment This disclosure further relates to the compounds disclosed herein, or pharmaceutical compositions comprising at least one of the compounds disclosed herein, for the treatment of serotonin 5-HT2A receptor-related diseases / conditions. In embodiments, the compounds may be used to treat anxiety disorders, attention deficit hyperactivity disorder (ADHD), depression (including treatment-resistant depression), cluster headaches, decreased motivation, fatigue, boredom, migraines, Parkinson's disease, schizophrenia, eating disorders (including anorexia nervosa), mental illnesses, schizophrenia, schizophrenia-like disorders, schizoaffective disorder, type I bipolar disorder, type II bipolar disorder, major depressive disorder, psychotic depression, paranoia, common psychotic disorders, common paranoia, transient psychotic disorders, paranoid personality disorder, schizoaffective 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).

[0152] In some embodiments, one or more of the compounds of formula (I), (Ia), (Ib), (II), (iIa), (iIb), (IIc), (III), (DI), (D-Ia), (D-Ib), (D-II), (D-iIa), (D-iIb), (D-IIc), or (D-III), or their deuterated form or pharmaceutically acceptable salt, are administered to a subject to treat the disease disclosed herein.

[0153] In some implementations, one or more of the compounds in Table 1, or their deuterated forms or pharmaceutically acceptable salts, are administered to a subject to treat the disease disclosed herein.

[0154] In some implementations, one or more of the compounds in Table 2, or their deuterated forms or pharmaceutically acceptable salts, are administered to a subject to treat the disease disclosed herein.

[0155] In some implementations, one or more of the compounds in Table 3, or their deuterated forms or pharmaceutically acceptable salts, are administered to a subject to treat the disease disclosed herein.

[0156] In some implementations, one or more of the compounds in Table 4, or their deuterated forms or pharmaceutically acceptable salts, are administered to a subject to treat the disease disclosed herein.

[0157] Numbering Implementation Plan 1. A compound of formula (I), (I), or a pharmaceutically acceptable salt thereof or its deuterated form, wherein: R 2 and R 3 Independently alkyl; R 4 It is an H or C(=O)O alkyl group; p is 2 or 3; R D It is a divalent or trivalent group selected from the following: alkylene, alkenylene, alkylene-O-alkylene, -(CH2) n -(OCH2CH2) m -, cycloalkylene, or arylene, or Each of them is optionally substituted by 1 to 4 groups selected from the following: halogen, OH, O alkyl, alkyl, NH2, NH (alkyl), N (alkyl)2, C(=O)OH, C(=O)O alkyl, OC(=O) alkyl or C(=O) alkyl; n is 1, 2, 3, 4, 5, 6, 7 or 8; m is 1, 2, 3, 4, 5, 6, 7 or 8; r is 1, 2, or 3; The condition is when R 2 and R 3 When each is a non-deuterated alkyl group, then R D Not (CH2)2, (CH2)3, (CH2)4, (CH2)5, (CH2)8. , , or .

[0158] 2. The compound as described in embodiment 1, wherein R D The following are divalent or trivalent groups: C 1-12 Alkylene, C 1-6 Alkylene-OC 1-6 Alkylene, -(CH2) n -(OCH2CH2) m -、C 3-8 Cycloalkylene, arylene or Each of them is optionally substituted by 1 to 4 groups selected from the following: C 1-3 Alkyl, OH, OCH3, NH2, COOH or C(=O) alkyl.

[0159] 3. The compound as described in embodiment 1, wherein the compound is a compound of formula (Ia). , Or its pharmaceutically acceptable salt or deuterated form, in: Each R 2 and R3 Independently alkyl; Each R 4 Independently, it is an H or C(=O)O alkyl group; R E The divalent group is selected from the following: alkylene, cycloalkylene, arylene, alkylene-O-alkylene, -(CH2) n -(OCH2CH2) m -or Each of these groups may optionally be substituted by one or more groups selected from the following: halogen, alkyl, Oalkyl, NH2, NHC 1-6 Alkyl, NC ( 1-6 Alkyl)2, COOH, cycloalkyl and C(=O)O alkyl; n is 1, 2, or 3; m is 1, 2, or 3; and r can be 1, 2, or 3.

[0160] 4. The compound as described in embodiment 3, wherein R E The divalent group is selected from the following: C 1-12 Alkylene, C 3-8 Cycloalkylene, arylene, C 1-6 Alkylene-OC 1-6 Alkylene, -(CH2) n -(OCH2CH2) m -or Each of these groups is optionally substituted by one or more groups selected from the following: halogen, C 1-3 Alkyl, O-alkyl, NH2, NHC 1-6 Alkyl, NC ( 1-6 Alkyl)2, COOH, C 3-8 Cycloalkyl and C(=O)Oalkyl.

[0161] 5. The compound of any one of embodiments 3-4, wherein the alkylene group is straight-chain or branched.

[0162] 6. The compound of any one of embodiments 3-5, wherein the alkylene group is branched.

[0163] 7. The compound as described in any one of embodiments 1-6, wherein R D Or R E for , , , , , , -(CH2)2-(OCH2CH2)2-, -(CH2)2-(OCH2CH2)3-, , , , , or .

[0164] 8. The compound as described in embodiment 1, wherein the compound is a compound of formula (Ib). , Or its pharmaceutically acceptable salt or deuterated form, wherein Each R 2 and R 3 Independently alkyl; Each R 4 Independently, it is an H or C(=O)O alkyl group; R F It is a trivalent cycloalkyl or alkylene group.

[0165] 9. The compound as described in embodiment 8, wherein R F Trivalent C 3-8 Cycloalkylene.

[0166] 10. The compound as described in embodiment 8 or 9, wherein R F for .

[0167] 11. A compound of formula (iIa), , Or its pharmaceutically acceptable salt or deuterated form, in: Each R 2 and R 3 Independently alkyl; Each R 4 Independently, it is an H or C(=O)O alkyl group; R H For --(CH2) n -(OCH2CH2) m -or alkylene; n is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12, and m is 1, 2, or 3; The condition is when q is 2 and R 2 and R 3 When each is CH3, then R H Not --(CH2)3-.

[0168] 12. The compound as described in embodiment 11, wherein, n is 1, 2, 3, 4, 5, 6, 7, 8, and m can be 1, 2, or 3.

[0169] 13. The compound as described in embodiment 11 or 12, wherein R H It is -(CH2)5-, -(CH2)8- or --(CH2)2-(OCH2CH2)2.

[0170] 14. The compound as described in any one of embodiments 1-13, wherein R 2 and R 3 Independently for C 1-6 alkyl.

[0171] 15. The compound as described in any one of embodiments 1-14, wherein R 2 and R 3 It is -CH3.

[0172] 16. The compound as described in any one of embodiments 1-15, wherein R 4 For H or C (=O)OC 1-6 alkyl.

[0173] 17. The compound as described in any one of embodiments 1-16, wherein R 4 It is H or C(=O)OCH3.

[0174] 18. The compound as described in any one of embodiments 1-17, wherein R 4 For H.

[0175] 19. The compound as described in any one of embodiments 1-18, wherein R 2 and R 3 Independently CH3, and R 4 For H.

[0176] 20. A compound selected from Table 1, or a pharmaceutically acceptable salt thereof, or a deuterated form thereof.

[0177] 21. A pharmaceutical composition comprising the compound described in embodiments 1-20, or a pharmaceutically acceptable salt thereof.

[0178] 22. A method of treating a disease, the method comprising administering the pharmaceutical composition described in embodiment 21.

[0179] 23. A method of treating a disease, the method comprising subcutaneously administering the pharmaceutical composition described in embodiment 21.

[0180] 24. A method of treating a disease, the method comprising subcutaneously administering a pharmaceutical composition comprising a compound selected from Tables 1, 2, and 3, a pharmaceutically acceptable salt thereof, or a deuterated form thereof.

[0181] 25. A method of treating a disease, the method comprising subcutaneous administration of a pharmaceutical composition comprising a compound of formula (I) or formula (II), or a pharmaceutically acceptable salt thereof, or a deuterated form thereof. , in R 2 and R 3 Independently alkyl; R 4 It is an H or C(=O)O alkyl group; p is 2 or 3; R D It is a divalent or trivalent group selected from the following: alkyl, alkenyl, alkylene, -O-alkylene, -(CH2) n -(OCH2CH2) m -, cycloalkyl, aryl or Each of these groups may optionally be substituted with one of the following groups: OH, O-alkyl, NH2, NH(alkyl), N(alkyl)2, COOH, C(=O)Oalkyl, COOH, cycloalkyl or C(=O)alkyl; n is 1, 2, 3, 4, 5, 6, 7, or 8; m is 1, 2, or 3; and r is 1, 2, or 3; or , Or its pharmaceutically acceptable salt or deuterated form, in: Each R 2 and R 3 Independently alkyl; Each R 4 Independently, it is an H or C(=O)O alkyl group; R H -(CH2) n -(OCH2CH2) m -or alkylene; n is 1, 2, or 3, and m is 1, 2, or 3; 26. The method of any one of embodiments 22-25, wherein the disease is a 5-HT2A receptor-related disease or condition.

[0182] 27. The method as described in embodiment 26, wherein the neuropsychiatric disorder is selected from anxiety disorders, attention deficit hyperactivity disorder (ADHD), depression (including treatment-resistant depression), cluster headaches, decreased motivation, fatigue, boredom, migraines, Parkinson's disease, schizophrenia, eating disorders (including anorexia nervosa), mental illness, schizophrenia, schizophrenia-like disorder, schizoaffective disorder, type I bipolar disorder, type II bipolar disorder, major depressive disorder, psychotic depression, paranoia, common mental disorder, common paranoia, transient psychotic disorder, paranoid personality disorder, schizoaffective personality disorder, schizotypal personality disorder, anxiety disorder, social anxiety disorder, substance-induced anxiety disorder, selective mutism, panic disorder, panic attacks, agoraphobia, attention deficit syndrome, post-traumatic stress disorder (PTSD), premenstrual dysphoric disorder (PMDD), and premenstrual syndrome (PMS).

[0183] Example Example 1. Synthesis of compound 101: (trans)-cyclohexane-1,4-dicarboxylic acid bis(3-(2-(dimethylamino)ethyl)-1H-indole-4-yl) ester, 2-formic acid Oxaloyl chloride (278 mg, 192 μL, 4.2 equivalents, 2.19 mmol) and one drop of DMF were added to a stirred solution of (trans)cyclohexane-1,4-dicarboxylic acid (89.9 mg, 1 equivalent, 522 μmol) in anhydrous DCM (3 mL) at room temperature under a nitrogen atmosphere. The reaction mixture was stirred at room temperature for 2 h. Volatile substances were removed under vacuum. The residue was dissolved in DCM (2 mL) and added at 0 °C to a solution of dephosphorylated psilocybin (217.7 mg, 2 equivalents, 1.04 mmol) and triethylamine (370 mg, 510 μL, 7 equivalents, 3.66 mmol) in DCM (2 mL). The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was diluted with water (5 mL) and transferred to a separatory funnel. The aqueous layer was extracted with DCM (3 x 10 mL). The combined organic layers were washed with brine (20 mL), dried (Na₂SO₄), filtered, and concentrated under vacuum. The crude product was purified by chromatography on an RPFlash C18 filter (24 g filter cartridge, 5–30% (0.1% formic acid in MeCN) / (0.1% formic acid in water)) to give a yellow solid (1r,4r)-cyclohexane-1,4-dicarboxylic acid bis(3-(2-(dimethylamino)ethyl)-1H-indol-4-yl) ester, 2-formic acid (90.9 mg, 0.11 mmol, 20%). The substance was dissolved in acetone (5 mL) and a solution of fumaric acid (26 mg, 2 equivalents, 0.22 mmol) was added to the acetone (5 mL) solution. The resulting solid was filtered, washed with acetone (2 x 5 mL), and dried in a vacuum desiccator for 24 h to give the title compound (58.3 mg, 86 μmol, 16%) as a beige solid.

[0184] m / z 546.7 (M+H) + (ES+) 1 H NMR (500 MHz, DMSO- d 6) δ 11.10 (s, 2H), 8.22 (s, 2H), 7.25 (dd, J =8.1, 0.8 Hz, 2H), 7.17 (d, J = 2.3 Hz, 2H), 7.08 - 7.02 (m, 2H), 6.66 (dd, J= 7.6, 0.8 Hz, 2H), 2.87 - 2.82 (m, 4H), 2.77 (s, 2H), 2.73 - 2.66 (m, 4H), 2.36 (s, 12H), 2.31 - 2.26 (m, 4H), 2.08 (s, 1H), 1.68 (td, J = 9.1, 3.2 Hz, 4H). No 2x interchangeable 0.5H was observed.

[0185] Example 2. Synthesis of compound 102: rac-(trans)-cyclobutane-1,2-dicarboxylic acid bis(3-(2-(dimethylamino)ethyl)-1H-indole-4-yl) ester, 2-formic acid Oxaloyl chloride (41 mg, 28 μL, 1.3 equivalents, 327 μmol) and one drop of DMF were added to a stirred solution of trans-cyclobutane-1,2-dicarboxylic acid (14.0 mg, 0.4 equivalents, 97.1 μmol) in anhydrous DCM (2 mL) at room temperature under a nitrogen atmosphere. The reaction mixture was stirred at room temperature for 2 h. Volatile substances were removed under vacuum. The residue was redissolved in DCM (1 mL) and added to a solution of dephosphorylated psilocybin (50.4 mg, 1 equivalent, 247 μmol) and triethylamine (247 mg, 340 μL, 10 equivalents, 2.44 mmol) in DMF (2 mL) at room temperature. The resulting mixture was stirred at room temperature for 2 h. The reaction mixture was diluted with ethyl acetate (10 mL), then with water: saline (1:1, 40 mL), and the phases were separated. The organic layer was further washed with water:salt (1:1, 40 mL) and saline (20 mL), dried (Na₂SO₄), filtered, and concentrated under vacuum. The crude product was purified by chromatography on an RP Flash C18 filter (12 g filter cartridge, 5–50% (0.1% formic acid in MeCN) / (0.1% formic acid in water)) to give the title compound (13.8 mg, 19 μmol, 20%) as a brown gel.

[0186] m / z 517.2 (M+H) + (ES+) 1H NMR (500 MHz, DMSO- d 6 δ 11.05 (s, 2H), 8.19 (s, 2H), 7.24 (d, J = 8.1 Hz, 2H), 7.15 (d, J = 2.3 Hz, 2H), 7.04 (dd, J = 7.9, 7.9 Hz, 2H), 6.70 (d, J = 7.6 Hz, 2H), 3.99 - 3.90 (m, 2H), 2.79 (dd, J = 9.4, 6.3 Hz, 4H), 2.55 - 2.51 (m, 3H), 2.47 - 2.42 (m, 2H), 2.40 - 2.34 (m, 2H), 2.20 (s, 12H). No 2x exchangeable H was observed.

[0187] Example 3. Synthesis of the salt of compound 103: bis(3-(2-(dimethylamino)ethyl)-1H-indol-4-yl) ester of 2,6-dimethylterephthalate, 0.75 formic acid, 1.25 HCl Oxaloyl dichloride (145 mg, 100 μL, 2.7 equivalents, 1.14 mmol) was added to a stirred suspension of 2,6-dimethylterephthalic acid (86 mg, 1 equivalent, 422 μmol) and one drop of DMF in DCM (4 mL) and stirred under nitrogen for 3 h. The volatile components were then removed under vacuum, and the residue was redissolved in DCM (4 mL). Dephosphorylated psilocybin (200 mg, 2.2 equivalents, 929 μmol) and triethylamine (513 mg, 706 μL, 12 equivalents, 5.07 mmol) were added, and the resulting suspension was stirred overnight at room temperature. Most of the solvent was removed under vacuum. The crude substance was dissolved in DMSO (1.9 mL), filtered, and 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) on a Waters X-Select CSH C18 ODB preparative column (130 Å, 5 µm, 30 mm x 100 mm) at a flow rate of 40 mL / min. -1The solution was eluted with a 0.1% formic acid gradient in water-MeCN for 12.5 min using UV light across all wavelengths with a PDA, QDA, and ELS detector. Throughout the method, an in-column dilution pump provided 2 mL / min of dilution. -1 MeCN, which is included in the following MeCN percentages. Gradient information: 0.0–0.5 min, 5% MeCN; 0.5–10.5 min, gradient from 5% MeCN to 32.5% MeCN; 10.5–10.6 min, gradient from 32.5% MeCN to 100% MeCN; 10.6–12.5 min, maintained at 100% MeCN. The clean fraction was evaporated in Genevac to give the title compound (23.0 mg, 35 μmol, 6%) as a grayish-white solid.

[0188] m / z 284.0 (M+H) 2+ (ES+) 1 H NMR (500 MHz, DMSO- d 6 δ 11.13 (d, J = 9.0 Hz, 2H), 8.15 (s, 0.75H), 8.05 (s, 2H), 7.31 (dd, J = 8.2, 2.4 Hz, 2H), 7.20 (dd, J = 9.1, 2.3Hz, 2H), 7.16 - 7.10 (m, 2H), 7.05 (d, J = 7.6 Hz, 1H), 6.83 (d, J = 7.6 Hz, 1H), 2.81 - 2.73 (m, 4H), 2.59 (s, 6H), 2.46 (d, J = 7.4 Hz, 2H), 2.07 (s, 6H), 2.00 (s, 6H). The 4x H peak is masked by the solvent. No 2x interchangeable H was observed.

[0189] Example 4. Synthesis of compound 104: bis(3-(2-(dimethylamino)ethyl)-1H-indole-4-yl) ester of 2-methoxyisophthalic acid, 2-formic acid Oxaloyl chloride (58 mg, 40 μL, 4.2 equivalents, 456 μmol) and one drop of DMF were added to a stirred solution of 2-methoxyisophthalic acid (21 mg, 1 equivalent, 109 μmol) in anhydrous DCM (4 mL) at room temperature under a nitrogen atmosphere. The reaction mixture was stirred at room temperature for 2 h. Volatile substances were removed under vacuum. The residue was redissolved in DCM (2 mL) and added at 0 °C to a solution of dephosphorylated psilocybin (50.4 mg, 2 equivalents, 217 μmol) and triethylamine (77 mg, 106 μL, 7 equivalents, 760 μmol) in DCM (2 mL). The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was diluted with water (5 mL) and transferred to a separatory funnel. The aqueous layer was extracted with DCM (3 x 10 mL). The combined organic layers were washed with brine (20 mL), dried (Na2SO4), filtered, and concentrated under vacuum. The crude product was purified by chromatography on an RP FlashC18 (24 g filter cartridge, 5-20% (0.1% formic acid in MeCN) / (0.1% formic acid in water)) to give the title compound (3.0 mg, 3.6 μmol, 3%) as a dark brown gel.

[0190] m / z 567.9 (M+H) + (ES+) 1 H NMR (500 MHz, DMSO- d 6 δ 11.14 (s, 2H), 8.38 (d, J = 7.8 Hz, 2H), 8.19 (s, 2H), 7.59 - 7.53 (m, 1H), 7.31 (dd, J = 8.2, 0.8 Hz, 2H), 7.20 (d, J = 2.3 Hz, 2H), 7.16 - 7.09 (m, 2H), 6.87 (dd, J = 7.6, 0.8 Hz, 2H), 3.99 (s, 3H), 2.84 - 2.77 (m, 4H), 2.57 - 2.52 (m, 4H), 2.09 (s, 12H). No 2x commutative H was observed.

[0191] Example 5. Synthesis of compound 105: bis(3-(2-(dimethylamino)ethyl)-1H-indole-4-yl) ester of 3,3'-oxydipropionic acid, 2-formic acid Oxaloyl chloride (268 mg, 185 μL, 4.2 equivalents, 2.11 mmol) and one drop of DMF were added to a stirred solution of 3,3'-oxydipropionic acid (81 mg, 1 equivalent, 502 μmol) in anhydrous DCM (4 mL) at room temperature under a nitrogen atmosphere. The reaction mixture was stirred at room temperature for 2 h. Volatile substances were removed under vacuum. The residue was dissolved in DCM (2 mL) and added at 0 °C to a solution of dephosphorylated psilocybin (205.2 mg, 2 equivalents, 1.01 mmol) and triethylamine (356 mg, 490 μL, 7 equivalents, 3.52 mmol) in DCM (2 mL). The reaction mixture was stirred at room temperature for 17 h. The reaction mixture was diluted with water (5 mL) and transferred to a separatory funnel. The aqueous layer was extracted with DCM (3 x 10 mL). The combined organic layers were washed with brine (20 mL), dried (Na2SO4), filtered, and concentrated under vacuum. The crude product was purified by chromatography on an RP FlashC18 filter (24 g filter cartridge, 5-30% (0.1% formic acid in MeCN) / (0.1% formic acid in water)) to give a red oily substance, bis(3-(2-(dimethylamino)ethyl)-1H-indol-4-yl) ester of 3,3'-oxydipropionic acid, and 2-formic acid (55.7 mg, 80 μmol, 16%, purity 90%). The substance was dissolved in acetone (3 mL) and a solution of fumaric acid (19 mg, 0.3 equivalent, 160 μmol) was added to the acetone (3 mL). The volatiles were removed under vacuum and the substance was purified by chromatography on an RPFlash C18 (12 g filter cartridge, 5-25% (0.1% formic acid in MeCN) / (0.1% formic acid in water)) to give the title compound (12.2 mg, 17 μmol, 3%) as a dark green oil.

[0192] m / z 534.9 (M+H) + (ES+) 1 H NMR (500 MHz, DMSO- d 6δ 11.04 (s, 2H), 8.20 (s, 2H), 7.23 (d, J = 8.2 Hz, 2H), 7.15 (d, J = 2.4 Hz, 2H), 7.01 - 6.97 (m, 2H), 6.64 (d, J = 7.4Hz, 2H), 3.85 (t, J = 6.2 Hz, 4H), 2.95 (t, J = 6.2 Hz, 4H), 2.82 - 2.77 (m, 4H), 2.56 - 2.53 (m, 4H), 2.26 (s, 12H). No 2x exchangeable H was observed.

[0193] Example 6. Synthesis of compound 106: bis(3-(2-(dimethylamino)ethyl)-1H-indol-4-yl) ester of 3-methylglutaric acid, 2-butenedioic acid, acetone Oxaloyl chloride (245 mg, 169 μL, 4.2 equivalents, 1.93 mmol) and one drop of DMF were added to a stirred solution of 3-methylglutaric acid (67 mg, 1 equivalent, 459 μmol) in anhydrous DCM (4 mL) at room temperature under a nitrogen atmosphere. The reaction mixture was stirred at room temperature for 2 h. Volatile substances were removed under vacuum. The residue was redissolved in DCM (2 mL) and added at 0 °C to a solution of dephosphorylated psilocybin (213 mg, 2 equivalents, 918 μmol) and triethylamine (325 mg, 448 μL, 7 equivalents, 3.21 mmol) in DCM (2 mL). The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was diluted with water (5 mL) and transferred to a separatory funnel. The aqueous layer was extracted with DCM (3 x 10 mL). The combined organic layers were washed with brine (20 mL), dried (Na2SO4), filtered, and concentrated under vacuum. The crude product was purified by chromatography on an RP FlashC18 filter (24 g filter cartridge, 5–20% (0.1% formic acid in MeCN) / (0.1% formic acid in water)) and dried overnight in a vacuum desiccator at 50 °C to give a viscous brown gel-like substance of bis(3-(2-(dimethylamino)ethyl)-1H-indol-4-yl) ester of 3-methylglutaric acid, 2-formic acid (65.0 mg, 87 μmol, 19%). A portion of the purified substance was dissolved in acetone (2 mL), and a solution of fumaric acid (10 mg, 1 equivalent, 89.5 μmol) in acetone (2 mL) was added. The mixture was placed in a freezer for 2 days, then allowed to stand at room temperature for 2 days. The liquid was poured off and the solid was removed from the vial and dried under vacuum to give the title compound (14.0 mg, 16 μmol, 3%) as a light brown solid.

[0194] m / z 519.3 (M+H) + (ES+) 1 H NMR (500 MHz, DMSO- d 6δ 11.12 (d, J = 1.7 Hz, 2H), 7.25 (dd, J = 8.1, 0.8 Hz, 2H), 7.19 (d, J = 2.4 Hz, 2H), 7.08 - 7.01 (m, 2H), 6.69 (dd, J = 7.7, 0.8 Hz, 2H), 6.55 (s, 4H), 2.94 - 2.86 (m, 6H), 2.82 - 2.70 (m, 6H), 2.62 - 2.54 (m, 1H), 2.42 (s, 12H), 2.08 (s, 6H), 1.19 (d, J = 6.6 Hz, 3H). No 4x commutative H was observed.

[0195] Example 7. Synthesis of compound 118: cyclohexane-1,3,5-tricarboxylic acid tris(3-(2-(dimethylamino)ethyl)-1H-indol-4-yl) ester, 1,5-formic acid, 1,5-fumaric acid and cyclohexane-1,3,5-tricarboxylic acid tris(3-(2-(dimethylamino)ethyl)-1H-indol-4-yl) ester, 3-formic acid Oxaloyl chloride (181 mg, 125 μL, 4.4 equivalents, 1.42 mmol) and one drop of DMF were added to a stirred solution of cyclohexane-1,3,5-tricarboxylic acid (70 mg, 1 equivalent, 324 μmol) in anhydrous DCM (3 mL) at room temperature under a nitrogen atmosphere. The reaction mixture was stirred at room temperature for 2 h. Volatile substances were removed under vacuum. The residue was dissolved in DCM (2 mL) and added at 0 °C to a solution of dephosphorylated psilocybin (202.0 mg, 3 equivalents, 969 μmol) and triethylamine (295 mg, 406 μL, 9 equivalents, 2.91 mmol) in DCM (2 mL). The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was diluted with water (5 mL) and transferred to a separatory funnel. The aqueous layer was extracted with DCM (3 x 10 mL). The combined organic layers were washed with brine (20 mL), dried (Na2SO4), filtered, and concentrated under vacuum. The crude product was purified by chromatography on an RP FlashC18 (24 g filter cartridge, 5-50% (0.1% formic acid in MeCN) / (0.1% formic acid in water)) to give a beige oily cyclohexane-1,3,5-tricarboxylic acid tris(3-(2-(dimethylamino)ethyl)-1H-indol-4-yl) ester, 3-formic acid (91.2 mg, 95 μmol, 29%).

[0196] m / z775.5 (M+H) + (ES+) 1 H NMR (500 MHz, DMSO- d 6 ) δ 11.06 (s, 3H), 8.19 (s, 3H), 7.25 (dd, J =8.0, 4.7 Hz, 3H), 7.16 (d, J = 2.4 Hz, 3H), 7.09 - 7.01 (m, 3H), 6.69 (dd, J= 11.6, 7.6 Hz, 3H), 3.17 - 3.09 (m, 3H), 2.81 (q, J = 9.7 Hz, 6H), 2.71 (d,J = 12.5 Hz, 2H), 2.54 (d, J = 5.1 Hz, 7H), 2.23 (d, J = 9.3 Hz, 18H), 1.88(q, J = 12.7 Hz, 3H). No 3x interchangeable H was observed.

[0197] The substance was dissolved in acetone (3 mL) and a solution of fumaric acid (38 mg, 1.0 equivalent, 0.33 mmol) was added to acetone (4 mL). The resulting solid was filtered, washed with acetone (2 mL), and dried in a vacuum desiccator for 6 h to give a beige solid of cyclohexane-1,3,5-tricarboxylic acid tris(3-(2-(dimethylamino)ethyl)-1H-indol-4-yl) ester, 1,5-formic acid, and 1,5-fumaric acid (13.4 mg, 13 μmol, 4%).

[0198] m / z 775.5 (M+H) + (ES+) 1 H NMR (500 MHz, DMSO- d 6δ 11.11 (s, 3H), 8.20 (s, 2H), 7.28 - 7.22 (m, 3H), 7.18 (d, J = 2.5 Hz, 3H), 7.09 - 7.02 (m, 3H), 6.72 - 6.67 (m, 3H), 6.54 (s, 3H), 3.18 (t, J = 12.9 Hz, 3H), 2.94 - 2.82 (m, 7H), 2.72 (dd, J = 20.3, 11.5 Hz, 8H), 2.35 (d, J = 3.1 Hz, 18H), 2.08 (s, 5H, 1 acetone solvate), 1.86 (q, J = 12.7 Hz, 3H). No 6x interchangeable 0.5H was observed.

[0199] Example 8. Synthesis of compound 119: ((ethane-1,2-diylbis(oxy))bis(ethane-2,1-diyl))bis(carbonate)bis(3-(2-(dimethylamino)ethyl)-1H-indole-4-yl) ester, 2-trans-butenedioic acid 2,2'-(ethane-1,2-dimethylbis(oxy))bis(ethane-1-ol) (100 mg, 1 equivalent, 666 μmol) was added to a stirred solution of triphosgene (198 mg, 1 equivalent, 666 μmol) and pyridine (293 mg, 300 μL, 5.6 equivalent, 3.71 mmol) in anhydrous DCM (2 mL) at 0 °C, and the reaction mixture was stirred at 0 °C for 2 h. Dephosphorylated psilocybin (272 mg, 2 equivalent, 1.33 mmol) was added to DMF (2 mL), and the reaction mixture was stirred at 0 °C for 2 h, then at room temperature for 16 h. The mixture was diluted with DCM (5 mL) and water (2 mL) and passed through a phase-sep cartridge. The crude product was purified by chromatography on an RP Flash C18 filter (24 g filter cartridge, 0-40% (0.1% formic acid in MeCN) / (0.1% formic acid in water) (elution 15%) to obtain a partially purified ((ethane-1,2-diylbis(oxy))bis(ethane-2,1-diyl))bis(carbonate)bis(3-(2-(dimethylamino)ethyl)-1H-indol-4-yl) ester, 2-formic acid (24.0 mg, 20.0 μmol, 3%), as a thick brown oil. The substance was dissolved in acetone (2 mL) and a solution of fumaric acid (9 mg, 3.8 equivalents, 77.5 μmol) in acetone (2 mL) was added. The mixture was cooled at -20 °C for 48 h. The resulting solid was separated by filtration, washed with MeCN (2 x 2 mL), and dried under vacuum to give the title compound (10.0 mg, 12 μmol, 2%) as a gray solid.

[0200] m / z 611.3 (M+H) + (ES+) 1 H NMR (500 MHz, DMSO- d 6δ 11.13 (s, 2H), 7.27 (d, J = 8.1 Hz, 2H), 7.20 (d, J = 2.3 Hz, 2H), 7.05 (dd, J = 7.9, 7.9 Hz, 2H), 6.78 (d, J = 7.6Hz, 2H), 6.55 (s, 4H), 4.40 - 4.30 (m, 4H), 3.75 - 3.68 (m, 4H), 3.61 (s, 4H), 2.87 - 2.79 (m, 4H), 2.70 - 2.59 (m, 4H), 2.35 (s, 12H). No 4x exchangeable H was observed.

[0201] Example 9. Synthesis of compound 120: bis(carbonate)bis(3-(2-(dimethylamino)ethyl)-1H-indol-4-yl) octane-1,8-diyl ester, 1,5-fumaric acid, 0.5-HCl Pyridine (319 mg, 0.33 mL, 4 equivalents, 4.03 mmol) was added to a solution of dephosphorylated psilocybin (205.8 mg, 1 equivalent, 1.01 mmol) and N,N'-disuccinimidyl carbonate (336 mg, 1.3 equivalent, 1.31 mmol) in anhydrous DCM (7 mL) at room temperature under a nitrogen atmosphere. The reaction mixture was stirred at room temperature for 1 h. Octane-1,8-diol (74 mg, 0.5 equivalent, 504 μmol) and N,N-dimethylpyridin-4-amine (123 mg, 1 equivalent, 1.01 mmol) were added to the reaction mixture, and the mixture was stirred at room temperature for 1 h. The mixture was then heated at 38 °C overnight. The reaction mixture was diluted with DCM (10 mL) and water (15 mL) and transferred to a separatory funnel. The aqueous layer was extracted with DCM (3 x 15 mL). The combined organic layers were washed with brine (30 mL), dried (Na₂SO₄), filtered, and concentrated under vacuum. The crude product was purified by chromatography on an RP Flash C18 filter (24 g filter cartridge, 5–40% (0.1% formic acid in MeCN) / (0.1% formic acid in water)) to give a partially purified bis(carbonate)bis(3-(2-(dimethylamino)ethyl)-1H-indol-4-yl)-octane-1,8-diyl ester, formic acid (45 mg, 51 μmol, 5%) as a viscous brown oil. The substance was dissolved in acetone (2 mL) and a solution of fumaric acid (16 mg, 0.14 equivalents, 139 μmol) was added to acetone (3 mL). The resulting solid was filtered, washed with acetone (2 mL), and dried under vacuum for 24 h to give the title compound (18.9 mg, 23 μmol, 2%) as a gray solid.

[0202] m / z 607.4 (M+H) + (ES+) 1H NMR (500 MHz, DMSO) δ 11.16 (s, 2H), 7.27 (dd, J = 8.1, 0.8 Hz,2H), 7.20 (d, J = 2.3 Hz, 2H), 7.09 - 7.02 (m, 2H), 6.78 (dd, J = 7.7, 0.8Hz, 2H), 6.55 (s, 3H), 4.23 (t, J = 6.6 Hz, 4H), 2.87 (dd, J = 9.8, 6.1 Hz, 4H), 2.75 (dd, J = 9.6, 6.3 Hz, 4H), 2.40 (s, 12H), 1.68 (p, J = 6.7 Hz, 4H),1.42 - 1.23 (m, 8H). No 3x interchangeable H was observed.

[0203] Example 10. Synthesis of compound 122: bis(3-(2-(dimethylamino)ethyl)-1H-indol-4-yl) glutarate, 1.75% fumaric acid, 0.25% HCl Triethylamine (0.59 g, 0.8 mL, 6 equivalents, 5.9 mmol) was added to a suspension of dephosphorylated psilocybin (200 mg, 1 equivalent, 979 μmol) in DMF (4 mL). Glutaryl dichloride (86 mg, 65 μL, 0.52 equivalents, 509 μmol) was added dropwise, and the reaction was stirred at room temperature for 18 h. The mixture was poured into ice / water (40 mL) and extracted with EtOAc (2 x 20 mL). The combined organic matter was washed sequentially with water: saline (50 mL), saline (50 mL), then dried (Na₂SO₄) and concentrated under vacuum. The crude product was purified by chromatography on an RP Flash C18 filter (40 g filter cartridge, 5-40% (0.1% formic acid in MeCN) / (0.1% formic acid in water)) (elution ~10%) to give a light brown oily bis(3-(2-(dimethylamino)ethyl)-1H-indol-4-yl) glutarate, 2-formic acid (125 mg, 227 μmol, 46%). A solution of fumaric acid (48 mg, 2 equivalents, 414 μmol) in acetone (3 mL) was added to a solution of the product (123 mg, 1 equivalent, 206 μmol) in acetone (15 mL). Initially, a solid precipitated from the acetone, but it became a gel upon separation. The substance was subjected to sonication in MeCN (10 mL). The resulting solid was separated by filtration and dried under vacuum to give the title compound (82.1 mg, 115 μmol, 56%) as a white solid. Further precipitation yielded a white solid bis(3-(2-(dimethylamino)ethyl)-1H-indol-4-yl) glutarate, 2-trans-butenedioic acid (15.8 mg, 21 μmol, 12%).

[0204] m / z 505.3 (M+H) + (ES+) 1 H NMR (500 MHz, DMSO- d 6δ 11.09 (s, 2H), 7.24 (d, J = 8.1 Hz, 2H), 7.18 (d, J = 2.3 Hz, 2H), 7.05 (t, J = 7.9 Hz, 2H), 6.71 (d, J = 7.6 Hz, 2H), 6.55 (s, 3.5H), 2.91 - 2.82 (m, 8H), 2.71 (t, J = 7.9 Hz, 4H), 2.37 (s, 12H), 2.09 (p, J = 7.5 Hz, 2H). No 4x exchangeable H was observed.

[0205] 1 H NMR (500 MHz, DMSO- d 6 δ 11.09 (s, 2H), 7.24 (d, J = 8.1 Hz, 2H), 7.18 (d, J = 2.3 Hz, 2H), 7.05 (dd, J = 7.9, 7.9 Hz, 2H), 6.71 (d, J = 7.6Hz, 2H), 6.56 (s, 4H), 2.88 - 2.81 (m, 8H), 2.69 (t, J = 7.9 Hz, 4H), 2.36 (s, 12H), 2.12 - 2.05 (m, 2H). No 4x exchangeable H was observed.

[0206] Example 11. Synthesis of compound 123: bis(3-(2-(dimethylamino)ethyl)-1H-indol-4-yl) adipic acid, 1.75% fumaric acid, 0.25% formic acid Oxaloyl chloride (262 mg, 181 μL, 4.2 equivalents, 2.06 mmol) and one drop of DMF were added to a stirred solution of adipic acid (71.8 mg, 1 equivalent, 492 μmol) in anhydrous DCM (4 mL) at room temperature under a nitrogen atmosphere. The reaction mixture was stirred at room temperature for 2 h. Volatile substances were removed under vacuum. The residue was dissolved in DCM (2 mL) and added at 0 °C to a solution of dephosphorylated psilocybin (200.8 mg, 2 equivalents, 983 μmol) and triethylamine (348 mg, 480 μL, 7 equivalents, 3.44 mmol) in DCM (2 mL). The reaction mixture was stirred at room temperature for 17 h. The reaction mixture was diluted with water (5 mL) and transferred to a separatory funnel. The aqueous layer was extracted with DCM (3 x 10 mL). The combined organic layers were washed with brine (20 mL), dried (Na2SO4), filtered, and concentrated under vacuum. The crude product was purified by chromatography on an RP Flash C18 filter (24 g filter cartridge, 5–30% (0.1% formic acid in MeCN) / (0.1% formic acid in water)) to give a red oily substance of bis(3-(2-(dimethylamino)ethyl)-1H-indol-4-yl) adipic acid ester, 2-formic acid (58.6 mg, 91 μmol, 19%). The substance was dissolved in acetone (3 mL) and a solution of fumaric acid (22 mg, 2 equivalents, 192 μmol) was added to acetone (4 mL). The resulting solid was filtered, washed with acetone (2 x 5 mL), and dried in a vacuum desiccator for 24 h to give the title compound (42.8 mg, 57 μmol, 12%) as a red solid.

[0207] m / z 519.3 (M+H) + (ES+) 1 H NMR (500 MHz, DMSO- d 6 δ 11.09 (s, 2H), 8.18 (s, 0.25H), 7.24 (d, J = 8.1 Hz, 2H), 7.17 (d, J = 2.4 Hz, 2H), 7.07 - 7.01 (m, 2H), 6.68 (d, J = 7.6 Hz, 2H), 6.54 (s, 3.5H), 2.91 - 2.84 (m, 4H), 2.83 - 2.71 (m, 8H), 2.41 (s, 12H), 1.80 (s, 4H). No 2x exchangeable 0.5H was observed.

[0208] Example 12. Synthesis of compound 124: bis(3-(2-(dimethylamino)ethyl)-1H-indole-4-yl) ester of pimecrolic acid, 2-formic acid At 0 °C, pimecrolimus dephosphorylated chloroplastrin (200 mg, 1 equivalent, 979 μmol) and triethylamine (119 mg, 1.2 equivalent, 1.17 mmol) in DMF (5 mL) were added dropwise. The reaction mixture was stirred at room temperature for 16 h. The mixture was diluted with ethyl acetate (20 mL). Water / salt solution (1:1, 50 mL) was added and the phases were separated. The aqueous phase was extracted with EtOAc (20 mL). The combined organic matter was washed with water / salt solution (1:1, 50 mL) and brine (50 mL), dried (Na2SO4), and concentrated under vacuum. The crude product was loaded onto diatomaceous earth and purified by chromatography on an RP Flash C18 filter (24 g filter cartridge, 5-30% (0.1% formic acid in MeCN) / (0.1% formic acid in water)) to give the title compound (30.0 mg, 46 μmol, 5%) as a viscous yellow oil.

[0209] m / z 533.3 (M+H) + (ES+) 1 ¹H NMR (500 MHz, DMSO) δ 11.05 (m, 2H), 8.19 (s, 2H), 7.23 (d, J = 8.1 Hz, 2H), 7.16 (d, J = 2.3 Hz, 2H), 7.06 - 7.00 (m, 2H), 6.66 (d, J = 7.6 Hz, 2H), 2.83 - 2.76 (m, 4H), 2.72 (t, J = 7.4 Hz, 4H), 2.61 - 2.55 (m, 4H), 2.28 (s, 12H), 1.76 (app. p, J = 7.5 Hz, 4H), 1.57 - 1.48 (m, 2H). No 2x exchangeable H was observed.

[0210] Example 13. Synthesis of compound 167: 3-(3-((3-(2-(dimethylamino)ethyl)-1H-indol-4-yl)oxy)-3-oxopropoxy)propionic acid.

[0211] Step 1: Preparation of 1,5-dioxane-2,8-dione 3,3'-oxydipropionic acid (5.00 g, 30.8 mmol, 1.00 eq) was added to... N,N' - Dicyclohexylcarbodiimide (7.00 g, 33.9 mmol, 1.10 eq) was added to an ice-cold EtOAc (50 mL) solution and stirred under nitrogen for 18 h, then warmed to room temperature. The resulting white suspension was strained through a celite tube. ® The mixture was filtered through a pad to remove solid byproducts, and the filter cake was washed with EtOAc (20 mL). The filtrate was evaporated under vacuum to give crude title compound (4.949 g, 97%) as a colorless oil. ¹H NMR analysis showed that the product was a mixture of the expected cyclic anhydride and other impurities, possibly straight-chain anhydrides. The substance was used without purification.

[0212] Step 2: Preparation of compound 167: 3-(3-((3-(2-(dimethylamino)ethyl)-1H-indol-4-yl)oxy)-3-oxopropoxy)propionic acid A stirred solution of 1,5-dioxane-2,8-dione (8, 4.51 g, 31.3 mmol, 2.13 eq) and TEA (6.3 mL, 45.2 mmol, 3.07 eq) in anhydrous DCM (30 mL) was added at room temperature to a stirred suspension of dephosphorylated psilocybin (3.004 g, 14.7 mmol, 1.00 eq) in anhydrous dichloromethane (30 mL), and the resulting deep red solution was stirred for 4.5 h. The reaction mixture was concentrated under vacuum to give a deep red gel, which was dissolved in DMSO and the solution was purified by preparative reversed-phase chromatography using Puriflash. ® A PF-15C18HP-0330 column and a gradient acidic mobile phase of 3-40% MeCN (containing 0.1 v / v% formic acid) in water were used for UV detection at 218 nm. The purified product fractions were combined and freeze-dried to obtain a colorless, glassy product, which was then wet-milled with MeCN (5 mL) to give 3-(3-((3-(2-(dimethylamino)ethyl)-1H-indol-4-yl)oxy)-3-oxopropoxy)propionic acid (compound 167,888 mg, 17%).

[0213] 1H NMR (400 MHz, DMSO-d6) δ (ppm): 11.04 (1H, bs), 7.23 (1H, d, J=7.8Hz), 7.14 (1H, d, J=2 Hz), 7.03 (1H, t, J=7.9 Hz), 6.65 (1H, d, J=7.3 Hz), 3.76 (2H, t, J=6 Hz), 3.65 (2H, t, J=6 Hz), 2.90 (2H, t, J=6 Hz), 2.85- 2.79(2H, m), 2.65- 2.58 (2H, m), 2.38 (2H, t, J=6 Hz), 2.31 (6H, Since the acid protons were exchanged with water in the DMSO-d6 solvent, no acid protons were observed.

[0214] UPLC-MS (method in Appendix 1): Rt = 3.50 min, [MH]+ = 349.3 Example 14. Study on the release of dephosphated psilocybin The plasma stability of the compounds and the release of dephosphorylated psilocybin were assessed by monitoring the disappearance of the parent compound in plasma (human or rat) at 37°C for up to 2 hours. The study was performed in duplicate, using a positive control (propantheline), a negative control (pepstatin), and a solvent control (DMSO) to confirm the suitability of the assay. Dephosphorylated psilocybin was also run as a control to monitor its formation semi-quantitatively.

[0215] Samples were analyzed using a Sciex™ MS500 TripleQuad QTRAP UHPLC system with a HESI-II electrospray source on a Waters™ Acquity UPLC® HSS T3 column (1.8 µm, 2.1 mm X 50 mm). The mobile phase consisted of water + 0.1% formic acid and methanol + 0.1% formic acid.

[0216] The elimination rate constant and half-life (t) were determined using Ln(MS reaction) and time plots. 1 / 2 In addition, the presence (in percentage) of psilocybin from the test compounds was monitored and evaluated based on the control psilocybin peak (time 0) to provide a semi-quantitative measurement of psilocybin release. Psilocybin release data are included in Table 5.

[0217] Table 5. Dephosphorylated psilocybin release

[0218] [1] The dephosphorylated psilocybin release efficiency (%) is calculated using the following equation: [2] The dephosphorylated psilocybin release data for this compound were obtained from rat plasma experiments.

[0219] Example 15. Pharmacokinetics of dephosphorylated psilocybin of compound 122 The pharmacokinetics of psilocybin dephosphorylated compound 122 were studied in plasma from male Sprague-Dawley (SD) rats (n=3) at 0.083–4 hours after delivery of a subcutaneous (SC) dose of 0.72 mg / kg psilocybin dephosphorylated (assuming 100% prodrug conversion). Additionally, brain samples (n=3) were collected approximately 1 hour later to determine the concentration of psilocybin dephosphorylated in the brain. Psilocybin dephosphorylated was quantified by high-performance liquid chromatography combined with tandem mass spectrometry (HPLC-MS / MS) based on matrix-matched calibration curves.

[0220] Animals: Male Sprague-Dawley rats (300-325 g upon arrival) were housed in groups of 2 or 3 and kept on a normal 12-hour light-dark cycle. Relative humidity (RH) was typically maintained at 55 ± 15%, and prolonged exposure to RH below 40% or above 70% was avoided. Throughout the study, animals had free access to a standard maintenance diet and tap water.

[0221] Compound: Compound 122 was dissolved in physiological saline (1.3 mg / kg) and adjusted to pH 7.4, and administered SC at a dose volume of 5 mL / kg to the back of the neck. The final pH was confirmed prior to administration, and the result was pH 6.3. This dose was chosen because it delivers 0.72 mg / kg of dephosphorylated psilocybin (assuming 100% conversion of the prodrug). Additional aliquots of the formulation were collected and stored at -80°C until analysis by high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS / MS) to confirm the minimum conversion (<2.5%) of compound 122 prior to administration and dephosphorylated psilocybin.

[0222] Sample Collection and Bioanalysis: Blood samples from the caudal vein were collected in K3EDTA-coated tubes at 0.083, 0.11, 0.25, 0.5, 0.75, 1, 2, and 4 hours post-administration, and collected by rotation within 30 minutes of collection to collect plasma (samples were placed on ice before centrifugation). Plasma samples were aliquoted and supplemented with DTT (10:1, plasma:DTT) to determine the final concentration of 5 mM DTT in the plasma sample. Plasma samples were stored on dry ice and then transferred to -80°C for analysis.

[0223] For 1-hour brain samples, the brain was collected after confirmation of death, rinsed in PBS, blotted dry, and then rapidly frozen. Brain samples were initially stored on dry ice and then transferred to -80°C for analysis.

[0224] To identify any dephosphorylated psilocybin present in the dosage form, dephosphorylated psilocybin and compound 122 standards were prepared in water. Three aliquots from the dosage form were diluted to a nominal concentration of 5 µg / mL and injected triplicate into HPLC-MS / MS. The conversion rate of dephosphorylated psilocybin in the dosage form was assessed using the relative percentage of the dephosphorylated psilocybin peak in the dosage form relative to the peak of the dephosphorylated psilocybin standard at 5 µg / mL.

[0225] Use an internal standard (100 ng / mL dephosphorylated psilocybin d) 10 Plasma and brain samples were extracted using an acetonitrile protein crash method. Brain samples were homogenized beforehand in 6.7 mMDTT in PBS at a ratio of 1:3 g / v. Samples were then thawed and centrifuged, and the supernatant was transferred to new tubes and lyophilized. Samples were reconstituted in 0.1% formic acid before HPLC-MS / MS injection. Dephosphorylated psilocybin in plasma and brain was quantified according to matrix-matched calibration curves, with additional quality controls. Standards and quality controls were extracted in the same manner as the test samples.

[0226] Data analysis: Non-compartmental analysis in WinNon-Lin (Certara, Phoenix, version 8.3.5.340) was used to estimate pharmacokinetic parameters. Figure 1 The data includes pharmacokinetic (PK) data for compound 122, which shows that after a subcutaneous dose of 1.3 mg / kg, compound 122 acts as a prodrug of dephosphorylated psilocybin, delivering dephosphorylated psilocybin to the plasma and brain of rats, and T... max It takes about 1 hour.

[0227] Example 16. Synthesis of compound 222 and its fumarate.

[0228] Step 1: Synthesis of tetradeuterated dephosphorylated psilocybin The reaction flask (250 mL) was purged with nitrogen. 3-(2-(dimethylamino)-2-oxoacetyl)-1H-indole-4-yl acetate (7.40 g, 1 eq, 27.0 mmol) and 2-methyltetrahydrofuran (81.4 mL) were added to the reaction flask. The mixture was stirred at ambient temperature (Tp = 22 C, RPM = 500) to dissolve 3-(2-(dimethylamino)-2-oxoacetyl)-1H-indole-4-yl acetate.

[0229] Lithium aluminum deuteride (4.25 g, 3.75 eq, 101 mmol) was weighed into eight individual vials (via 1 = 0.25 g; vials 2-6 = 0.5 g; vials 7-8 = 0.75 g). The lithium aluminum deuteride from each vial was added to the reaction flask. The solid portion (used for adding lithium aluminum deuteride) was rinsed with 7.40 mL of 2-methyltetrahydrofuran, and the rinse solution was added to the reaction flask.

[0230] Heat the reaction mixture to reflux for at least four hours (NLT). After the reaction is complete, cool the reaction mixture in an ice bath. Quench the reaction by adding a water-THF mixture (1.82 mL water and 6.48 mL THF) dropwise to the reaction mixture. Remove the reaction flask from the ice bath and stir the mixture at ambient temperature for at least 30 minutes. Add silica gel (7.40 g, 1 eq, 27.0 mmol) and sodium sulfate (7.40 g, 1 eq, 27.0 mmol) to the reaction flask in one go, and allow stirring at ambient temperature for NLT 30 minutes.

[0231] Pour the liquid contents of the reaction flask into filter 1, which is equipped with a nitrogen cone. Wash the reaction flask with THF (74.0 mL) by adding THF to the flask and stirring for NLT 5 minutes. After stirring, pour the liquid contents of the reaction flask into filter 1. Wash the reaction flask four times with THF (74.0 mL x 4) and pour the resulting liquid into filter 1. Filter the combined liquid contents in filter 1 and collect the filtrate into receiver 1. Transfer the solids and residual washes from filter 1 back to the reaction flask, rinse with THF (7.5 mL, 1 volume) and allow stirring for NLT 10 minutes. Transfer the resulting mixture in the reaction flask into filter 2. Wash the reaction flask with 74.0 mL of THF and transfer the resulting contents in the flask into filter 2. Collect the filtrate from filter 2 into receiver 1. Filter the combined filtrate in receiver 1 through a sintered filter fitted with a 1 cm diatomaceous earth pad. The filtrate was collected in a 250 mL Erlenmeyer flask and stirred overnight under nitrogen. After stirring, the filtrate in the Erlenmeyer flask was concentrated to dryness under reduced pressure to produce the first batch of crude tetradeuterated dephosphorylated psilocybin. The residual solids in the sintered filter were washed with DCM:MeOH (10%, 74 mL x 3). The washings were filtered, and the filtrate was collected and concentrated to dryness under pressure to obtain the second batch of crude tetradeuterated dephosphorylated psilocybin.

[0232] The crude tetradeuterated dephosphorylated psilocylin was recrystallized in isopropyl acetate to produce purified tetradeuterated dephosphorylated psilocylin (2.350 g) with a chemical purity of 99.34 area% (HPLC), a purity of 96.32 w / w% determined by NMR, and a residual solvent content of 1.17 w / w% (qNMR).

[0233] Step 2: Synthesize compound 222 3-(2-(dimethylamino)ethyl-1,1,2,2-d4)-1H-indole-4-ol (2.30 g, 2 equivalents, 11.0 mmol) and ethyl acetate (9.57 mL) were added to a 100 mL round-bottom flask equipped with a magnetic stir bar and a T-connector for nitrogen flow. The resulting mixture in the flask was stirred at room temperature. The reaction flask was inert with nitrogen. Diethyl (2E,13E)-2,14-dicyano-5,11-dioxo-4,8,12-trioxa-3,13-diazapentadecyl-2,13-dienedioic acid (2.70 g, 84% Wt, 1 eq, 5.52 mmol) dissolved in 12.7 mL of ethyl acetate was added dropwise to the flask. The resulting mixture in the flask was stirred at room temperature for at least 2 hours. Triethylamine (2.28 g, 3.1 mL, 4.09 eq, 22.6 mmol) was added to a flask, and the resulting mixture was stirred for at least 30 minutes. Water (11.5 mL) and ethyl acetate (11.5 mL) were added to a reaction flask, and the resulting mixture was stirred for at least 15 minutes. The organic layer of the resulting solution was separated by extraction and washed with water (11.5 mL x 3). The resulting organic layer was concentrated to dryness under vacuum to give crude compound 222 (2.24 g) with a purity of 95.2 area% (HPLC) and 74.05 w / w% (qH-NMR).

[0234] Step 2: Synthesize the fumarate of compound 222 To a round-bottom flask (25 mL), add bis(3-(2-(dimethylamino)ethyl-1,1,2,2-d4)-1H-indole-4-yl) 3,3'-oxydipropionic acid (1.66 g, 1 eq, 3.06 mmol), isopropanol (IPA, 8.72 mL), water (2.17 mL), and fumaric acid (710 mg, 2 eq, 6.12 mmol). Stir the resulting mixture in the flask overnight at room temperature. After stirring, filter the mixture in the flask through a sintered body connected to a nitrogen cone. Rinse the flask twice with a 2:1 mixture of IPA and water (1.66 mL x 2), and filter the rinsings through a sintered body connected to a nitrogen cone.

[0235] The solid obtained from filtration, along with isopropanol (7.67 mL) and water (3.80 mL), was added to a second round-bottom flask (25 mL). The mixture in the second flask was heated to 80 °C and filtered at 80 °C, and the filtrate was collected in a third flask. The mixture in the third flask was cooled to room temperature and stirred at room temperature for at least 4 hours. Stirring was stopped, and the mixture in the third flask was filtered. The third flask was rinsed twice with a 2:1 mixture of IPA and water (2.3 mL x 2), and the rinsing solution was filtered. Filtration yielded the fumarate of compound 222 as a solid (1.59 g, 72% yield), with a purity of 98.69 area% (HPLC). 1 H NMR (500 MHz, DMSO) δ 11.12 (d, J = 1.4Hz, 2H), 7.22 (d, J = 8.2 Hz, 2H), 7.16 (d, J = 2.3 Hz, 2H), 6.99 (t, J = 7.9 Hz, 2H), 6.65 (d, J = 7.6 Hz, 2H), 6.51 (s, 3H), 3.83 (t, J = 6.3 Hz, 4H), 2.99 (t, J =6.3 Hz, 4H), 2.46 (s, 12H).

Claims

1. A compound of formula (I), ， Or its pharmaceutically acceptable salt or its deuterated form, in: R 2 and R 3 Independently alkyl; R 4 It is an H or C(=O)O alkyl group; p is 2 or 3; R D It is a divalent or trivalent group selected from the following: alkylene, alkenylene, alkylene-O-alkylene, -(CH2) n -(OCH2CH2) m -, cycloalkylene, or arylene, or Each of them is optionally substituted by 1 to 4 groups selected from the following: halogen, OH, O alkyl, alkyl, NH2, NH (alkyl), N (alkyl)2, C(=O)OH, C(=O)O alkyl, OC (=O) alkyl, or C(=O) alkyl; n is 1, 2, 3, 4, 5, 6, 7 or 8; m is 1, 2, 3, 4, 5, 6, 7 or 8; r is 1, 2, or 3; The condition is when R 2 and R 3 When each is a non-deuterated alkyl group, then R D Not CH2, (CH2)2, (CH2)3, (CH2)4, (CH2)5, (CH2)8 , , , or , And the condition is that when R 2 and R 3 When each is CD3, then R D It is not (CH2)3.

2. The compound of claim 1, wherein R D The following are divalent or trivalent groups: C 1-12 Alkylene, C 1-6 Alkylene-OC 1-6 Alkylene, -(CH2) n -(OCH2CH2) m -、C 3-8 Cycloalkylene, arylene or Each of them is optionally substituted by 1 to 4 groups selected from the following: C 1-3 Alkyl, OH, OCH3, NH2, COOH or C(=O) alkyl.

3. The compound of claim 1, wherein R D It is a divalent or trivalent group selected from the following: alkylene, -O-alkylene, -(CH2) n -(OCH2CH2) m -, cycloalkylene, heterocyclic, aryl, heteroaryl or Each of them may be optionally substituted with OH, OCH3, NH2, COOH, cycloalkyl or C(=O)alkyl.

4. The compound of claim 1 or 3, wherein R D The following are divalent or trivalent groups: C 1-6 Alkylene-OC 1-6 Alkylene, -(CH2) n -(OCH2CH2) m -、C 3-8 Cycloalkylene, 3-8 membered heterocyclic alkylene, arylene, heteroarylene or Each of them may be optionally substituted with OH, OCH3, NH2, COOH, cycloalkyl or C(=O)alkyl.

5. The compound of claim 1, wherein the compound is a compound of formula (Ia). (I), Or its pharmaceutically acceptable salt or deuterated form, in: Each R 2 and R 3 Independently alkyl; Each R 4 Independently, it is an H or C(=O)O alkyl group; R E The divalent group is selected from the following: alkylene, cycloalkylene, arylene, alkylene-O-alkylene, -(CH2) n -(OCH2CH2) m -or Each of these groups may optionally be substituted by one or more groups selected from the following: halogen, alkyl, Oalkyl, NH2, NHC 1-6 Alkyl, NC ( 1-6 Alkyl)2, COOH, cycloalkyl and C(=O)O alkyl; n is 1, 2, or 3; m is 1, 2, or 3; and r can be 1, 2, or 3.

6. The compound of claim 5, wherein R E The divalent group is selected from the following: C 1-12 Alkylene, C 3-8 Cycloalkylene, arylene, C 1-6 Alkylene-OC 1-6 Alkylene, -(CH2) n -(OCH2CH2) m -or Each of these groups is optionally substituted by one or more groups selected from the following: halogen, C 1-3 Alkyl, O-alkyl, NH2, NHC 1-6 Alkyl, NC ( 1-6 Alkyl)2, COOH, C 3-8 Cycloalkyl and C(=O)Oalkyl.

7. The compound according to any one of claims 5-6, wherein the alkylene group is straight-chain or branched.

8. The compound of any one of claims 6-7, wherein the alkylene group is branched.

9. The compound according to any one of claims 1-8, wherein R D Or R E for , , , , , -(CH2)2-(OCH2CH2)2-, -(CH2)2-(OCH2CH2)3-, , , , , or .

10. The compound of claim 1, wherein the compound is a compound of formula (Ib). (Ib), Or its pharmaceutically acceptable salt or deuterated form, in: Each R 2 and R 3 Independently alkyl; Each R 4 Independently, it is an H or C(=O)O alkyl group; and R F It is a trivalent cycloalkyl or alkylene group.

11. The compound of claim 10, wherein R F Trivalent C 3-8 Cycloalkylene.

12. The compound of claim 10 or 11, wherein R F for .

13. A compound of formula (IIa), (IIa), Or its pharmaceutically acceptable salt or deuterated form, in: Each R 2 and R 3 Independently alkyl; Each R 4 Independently, it is an H or C(=O)O alkyl group; R H For --(CH2) n -(OCH2CH2) m -or alkylene; n is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12, and m is 1, 2, or 3; The condition is when R 2 and R 3 When each is CH3, then R H It is neither --(CH2)2- nor --(CH2)3-.

14. The compound of claim 13, wherein, n is 1, 2, 3, 4, 5, 6, 7, 8, and m can be 1, 2, or 3.

15. The compound of claim 13 or 14, wherein R H It is -(CH2)5-, -(CH2)8- or -(CH2)2-(OCH2CH2)2.

16. A compound of formula (III) (III), Or its pharmaceutically acceptable salt or its deuterated form, in: R 2 and R 3 Independently alkyl; R 4 It is an H or C(=O)O alkyl group; R 1 The alkylene group is -C(=O)OH, wherein the alkylene group is optionally substituted with OH, C(=O)OH, -OC(=O)alkyl, or NH2, or alkenyl-C(=O)OH, wherein the alkenyl group is optionally substituted with C(=O)OH, or cycloalkyl-C(=O)OH, wherein the cycloalkyl group is optionally substituted with C(=O)OH, or aryl-C(=O)OH, wherein the aryl group is optionally substituted with alkyl, Oalkyl, or C(=O)OH, or -(CH2CH2O). m -(CH2CH2) n -C(=O)OH, alkylene-O-alkylene-C(=O)OH, arylene-O(C=O)-alkylene-C(=O)O-arylene-C(=O)OH, O-alkylene-OH, wherein the alkylene group is optionally replaced by OH or -(OCH2CH2). m -OH substitution; m is 1, 2, or 3; and n is 1, 2, or 3. The condition is when R 2 and R 3 When each is an alkyl group, then R 1 Not (CH2)2C(=O)OH, (CH2)3C(=O)OH, -CH=CHC(=O)OH or .

17. The compound of claim 16, wherein R 1 C 1-10 Alkylene -C(=O)OH, wherein the alkylene is optionally replaced by OH, C(=O)OH, -OC(=O)alkyl or NH2, C 1-6 Substitution of the imidene group with -C(=O)OH, wherein the imidene group is optionally replaced by C(=O)OH, C 3-6 The cycloalkyl group is substituted with -C(=O)OH, wherein the cycloalkyl group is optionally substituted with C(=O)OH or arylene-C(=O)OH, wherein the arylene group is optionally substituted with alkyl, O-alkyl, or C(=O)OH or -(CH2CH2O). m -(CH2CH2) n -C(=O)OH、C 1-6 Alkylene-OC 1-6 Alkylene-C(=O)OH, arylene-O(C=O)-C 1-6 Alkylene-C(=O)O-arylene-C(=O)OH, OC 1-10 Alkylene-OH substitution, wherein the alkylene is optionally replaced by OH or -(OCH2CH2). m -OH substitution.

18. The compound of claim 16 or 17, wherein R 1 for , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or .

19. The compound according to any one of claims 16-18, wherein R 1 -(CH2CH2O) m -(CH2CH2) n -C(=O)OH.

20. The compound according to any one of claims 15-19, wherein R 1 for , or .

21. The compound according to any one of claims 16-20, wherein R 1 for .

22. The compound according to any one of claims 1-21, wherein R 2 and R 3 Independently for C 1-6 alkyl.

23. The compound according to any one of claims 1-22, wherein R 2 and R 3 It is -CH3.

24. The compound according to any one of claims 1-23, wherein R 4 For H or C (=O)OC 1-6 alkyl.

25. The compound according to any one of claims 1-24, wherein R 4 It is H or C(=O)OCH3.

26. The compound according to any one of claims 1-25, wherein R 4 For H.

27. The compound according to any one of claims 1-26, wherein R 2 and R 3 Independently CH3, and R 4 For H.

28. A compound selected from Table 1, its pharmaceutically acceptable salt, or its deuterated form.

29. A pharmaceutical composition comprising the compound of claims 1-30 or a pharmaceutically acceptable salt thereof.

30. A method of treating a disease, the method comprising administering the pharmaceutical composition of claim 29.

31. A method of treating a disease, the method comprising subcutaneously administering the pharmaceutical composition of claim 29.

32. A method of treating a disease, the method comprising subcutaneously administering a pharmaceutical composition comprising a compound selected from Tables 1, 2, 3, and 4, a pharmaceutically acceptable salt thereof, or a deuterated form thereof.

33. A method of treating a disease, the method comprising subcutaneous administration of a pharmaceutical composition comprising a compound of formula (I), or formula (IIa), or formula (III), or a pharmaceutically acceptable salt thereof, or a deuterated form thereof. (I)， Or its pharmaceutically acceptable salt or deuterated form, in: R 2 and R 3 Independently alkyl; R 4 It is an H or C(=O)O alkyl group; p is 2 or 3; R D It is a divalent or trivalent group selected from the following: alkyl, alkenyl, alkylene, -O-alkylene, -(CH2) n -(OCH2CH2) m -, cycloalkyl, aryl or Each of these groups may optionally be substituted with one of the following groups: OH, O-alkyl, NH2, NH(alkyl), N(alkyl)2, COOH, C(=O)Oalkyl, COOH, cycloalkyl or C(=O)alkyl; n is 1, 2, 3, 4, 5, 6, 7 or 8; m is 1, 2 or 3; and r is 1, 2, or 3; or (IIa), Or its pharmaceutically acceptable salt or deuterated form, in: Each R 2 and R 3 Independently alkyl; Each R 4 Independently, it is an H or C(=O)O alkyl group; R H -(CH2) n -(OCH2CH2) m -or alkylene; n is 1, 2, or 3, and m is 1, 2, or 3; or (III) Or its pharmaceutically acceptable salt or its deuterated form, wherein: R 2 and R 3 Independently alkyl; R 4 It is an H or C(=O)O alkyl group; R 1 The alkylene group is -C(=O)OH, wherein the alkylene group is optionally substituted with OH, C(=O)OH, -OC(=O)alkyl, or NH2, or alkenyl-C(=O)OH, wherein the alkenyl group is optionally substituted with C(=O)OH, or cycloalkyl-C(=O)OH, wherein the cycloalkyl group is optionally substituted with C(=O)OH, or aryl-C(=O)OH, wherein the aryl group is optionally substituted with alkyl, Oalkyl, or C(=O)OH, or -(CH2CH2O). m -(CH2CH2) n -C(=O)OH, alkylene-O-alkylene-C(=O)OH, arylene-O(C=O)-alkylene-C(=O)O-arylene-C(=O)OH, O-alkylene-OH, wherein the alkylene group is optionally replaced by OH or -(OCH2CH2). m -OH substitution; m is 1, 2, or 3. n is 1, 2, or 3. The condition is when R 2 and R 3 When each is an alkyl group, then R 1 Not (CH2)2C(=O)OH, (CH2)3C(=O)OH, -CH=CHC(=O)OH or .

34. The method of any one of claims 30-33, wherein the disease is a 5-HT2A receptor-related disease or condition.

35. The method of claim 34, wherein the neuropsychiatric disorder is selected from anxiety disorders, attention deficit hyperactivity disorder (ADHD), depression (including treatment-resistant depression), cluster headaches, decreased motivation, fatigue, boredom, migraines, Parkinson's disease, schizophrenia, eating disorders (including anorexia nervosa), mental illnesses, schizophrenia, schizophrenia-like disorders, schizoaffective disorder, type I bipolar disorder, type II bipolar disorder, major depressive disorder, psychotic depression, paranoia, common mental disorders, common paranoia, transient psychotic disorders, paranoid personality disorder, schizoaffective personality disorder, schizotypal personality disorder, anxiety disorders, social anxiety disorder, substance-induced anxiety disorder, selective mutism, panic disorder, panic attacks, agoraphobia, attention deficit syndrome, post-traumatic stress disorder (PTSD), premenstrual dysphoric disorder (PMDD), and premenstrual syndrome (PMS).

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