Modified indole alkaloids for therapeutic use

Abstract

This invention expands the modification of indole alkaloids by biological conversion, providing modified indole alkaloids with improved physicochemical properties (e.g., stability against oxidation). [Solution] This specification discloses enzymatic and modified host cell methods for preparing modified indole alkaloids. Modified indole alkaloids, as well as their therapeutic uses for treating diseases and disorders, are also disclosed. This specification provides novel methods for producing modified indole alkaloids with therapeutic properties. Modification of indole alkaloids by these methods may lead to enhanced therapeutic properties such as improved solubility, improved bioavailability, increased drug concentration to therapeutic targets in the body, and improved therapeutic pharmacokinetic profiles.

Description

[Technical Field]

[0001] cross reference This application claims the benefits of U.S. Provisional Application No. 63 / 127,852 filed on 18 December 2020 and U.S. Provisional Application No. 63 / 163,590 filed on 19 March 2021, which are incorporated herein by reference in their entirety.

[0002] Sequence List This application includes an electronically submitted sequence listing in ASCII format, which is incorporated herein by reference in its entirety. The above ASCII copy, created on December 16, 2021, is named 54033-703_601_SL.txt and has a size of 161,974 bytes. [Background technology]

[0003] Indole alkaloids are a type of alkaloid that contains the structural component of indole. Many indole alkaloids also contain an isoprene group and are therefore called terpene indole or secologanin tryptamine alkaloids. They are one of the largest classes of alkaloids, containing over 4,100 known different compounds. Many of them have important biological activities, and some are used in medicine. The amino acid tryptophan is a biochemical precursor of indole alkaloids.

[0004] Simple and widely used indole derivatives are the biogenic amines tryptamine and 5-hydroxytryptamine (serotonin). The tryptamine skeleton is part of most indole alkaloids. For example, N,N-dimethyltryptamine (DMT), psilocine, and its phosphorylated psilocybin are simple derivatives of tryptamine. Another class includes β-carboline alkaloids accessed from tryptamine. One route involves the intramolecular Mannich reaction. Simple (non-isoprenoid) β-carboline derivatives include harmine, harmanine, harmane, and the slightly more complex cantinone. Harmanine was first isolated by Goebel in 1838, and harmine was first isolated by Fritsche in 1848.

[0005] A more complex group of indole alkaloids includes ergot alkaloids. Ergot alkaloids are a type of hemiterpenoid indole alkaloid associated with lysergic acid, which is formed in a multi-step biosynthetic reaction involving tryptophan and DMAPP. Many ergot alkaloids are amides of lysergic acid. The simplest amide is ergin. A more complex group includes water-soluble amino alcohol derivatives such as ergometrine and its isomer ergometrinine. Complex water-insoluble groups include the ergotamine group (including ergotamine, ergosine and their isomers), the ergoxin group (including ergostine, ergoptin, ergonine and their isomers), and the ergotoxin group (including ergocristine, α-ergocriptine, β-ergocriptine, ergocornin and their isomers).

[0006] Mitragyna alkaloids are another indole-based alkaloid class, and are active alkaloids abundantly found in the Southeast Asian plant Mitragyna speciosa, commonly known as kratom. The total alkaloid concentration in dried leaves ranges from 0.5 to 1.5%. In Thai varieties, mitragynine is the most abundant component (up to 66% of total alkaloids), while 7-hydroxymitragynine is a smaller component (up to 2% of total alkaloid content).

[0007] Modifying indole alkaloids can significantly alter their chemical and biological properties. For example, indole and indole alkaloids alone are almost insoluble in water, but the addition of charged chemical functional groups such as phosphates or carbohydrates increases their water solubility. In biological systems, the addition of such modifying functional groups can significantly alter the resulting biological activity and tissue targeting. In the end uses of these compounds, modifications have a significant impact on downstream formulations, formulations, pharmacokinetics, pharmacodynamics, and the final end use. The modified indole alkaloids discussed herein have therapeutic applications including, but not limited to, the treatment of major depressive disorder, treatment-resistant depression, addiction, anxiety, post-traumatic stress disorder, mania, psychosis, insomnia, hypersomnia, pain, Alzheimer's disease, Parkinson's disease, cluster headache, bulimia nervosa, migraine, irritable bowel syndrome, and other neurological disorders. The modified indole alkaloids discussed herein may, in some cases, induce dendritic spine growth in neurons. In some cases, the therapeutic target of modified indole alkaloids is aminergic G-binding protein receptor (GPCR). In some cases, modified indole alkaloids are metabolized in the body, and the resulting metabolites target disease-related proteins or receptors. In some cases, the receptor is a GPCR. Disease-related GPCRs that are therapeutic targets of modified indole alkaloids or their respective metabolites include, but are not limited to, the 5-hydroxytryptamine receptor. Modified indole alkaloids and their resulting metabolites can be used for the therapeutic targeting of HTR2A. Modified indole alkaloids and their resulting metabolites can be used for the therapeutic targeting of serotonin receptors. Modified indole alkaloids and their resulting metabolites can be used for the therapeutic targeting of melatonin receptors, including, but not limited to, MT1, MT2, and MT3. Modified indole alkaloids and their resulting metabolites can be used for the therapeutic targeting of opioid receptors, including, but not limited to, delta, kappa, mu, zeta, and nociceptin receptors.

[0008] Furthermore, solutions of known unmodified indole alkaloids have been reported to become unstable due to oxidation when exposed to air and light. Novel modified indole alkaloids can overcome this lack of stability. Enzymatic modification of indole alkaloids is a strategy to alter the physicochemical properties of indole alkaloids and improve their stability and water solubility (see, e.g., Gotvaldova et al., Drug Test Anal., 2021, 13, 439-446; Anastos et al., Science & Justice, 2006, 46(2), 91-96). The synthesis of modified indole alkaloids, particularly the esterification of indole alkaloids, is difficult using conventional organic synthesis methods. For example, the organic synthesis of psilocybin, a phosphorylated ester of psilocine, involves a seven-step synthesis protocol with a highly reactive substrate and protection and deprotection steps. However, the conversion of psilocine to psilocybin by enzymatic or biotransformation can be performed in one step using aqueous and neutral reaction conditions. This is just one example of the many advantages offered by the enzymatic and biological production of esterified indole alkaloids. As the need for novel therapeutic indole alkaloids with diverse properties increases, there is a need in the art to extend the modification of indole alkaloids by biotransformation to obtain modified indole alkaloids with improved physicochemical properties (e.g., stability against oxidation). [Prior art documents] [Non-patent literature]

[0009] [Non-Patent Document 1] Gotvaldova et al.,Drug Test Anal.,2021,13,439-446 [Non-Patent Document 2] Anastos et al.,Science & Justice,2006,46(2),91-96 [Overview of the Initiative] [Means for solving the problem]

[0010] In one aspect, provided herein is a compound of formula (Ia)

Chemical formula

Chemical formula

[0011] In certain embodiments, the compound of formula (I) is provided herein: [ka] or a pharmaceutically acceptable salt thereof, in the formula, R 1 and R 10 These are independently selected from hydrogen, C1-C6 alkyl, C2-C6 alkenyl, and C2-C6 alkynyl, where alkyl, alkenyl, and alkynyl may optionally be independently substituted with one or more substituents selected from halo, -OMe, -CN, -NH2, and -NO2. R 8 is -CR'2-, where each R' is independently selected from hydrogen, halo, haloalkyl, alkoxy, haloalkoxy, and amine. n is selected from 2, 3, and 4. R 9 is selected from C2-C6 alkyl, C2-C6 alkenyl, and C2-C6 alkynyl, where alkyl, alkenyl, and alkynyl may optionally be substituted by one or more substituents independently selected from halo, -OMe, -CN, -NH2, -NO2, and 3- to 8-membered heterocycles, and the 3- to 8-membered heterocycle may optionally be substituted by one or more substituents independently selected from halo, -OMe, -CN, -NH2, and -NO2. R 2 These are selected from hydrogen, halogens, C1-C6 alkyl groups, and C1-C6 haloalkyl groups. R 4 , R 5 , R 6 , and R 7 Each of these is independently selected from hydrogen, C1-C6 alkyl, A, J, Q, and X. A is [ka] And, J is [ka] And, Q is [ka] And, X is selected from glucose, xylose, galactose, rhamnose, and rutinose. R 13 This is selected from C1-C6 alkyl groups, which may optionally be substituted with hydrogen and one or more substituents independently selected from halo, -OMe, -CN, -NH2, and -NO2. R 14 The C1-C6 alkyl and C2-C6 alkenyl atoms are selected from C1-C6 alkyl and C2-C6 alkenyl atoms, which may optionally be substituted with one or more substituents independently selected from halo, -OMe, -CN, -NH2, and -NO2. R 15 This is selected from C1-C6 alkylenes and C2-C6 alkenylenes, where the C1-C6 alkylenes and C2-C6 alkenylenes may optionally be substituted with one or more substituents independently selected from halo, -OMe, -CN, -NH2, and -NO2. Here, R 4 , R 5 , R 6 , and R 7 At least one of them is A or Q, or R 5 , R 6 , and R 7 At least one of them is J or X.

[0012] In some embodiments, R 1 R is selected from hydrogen and C1-C3 alkyl groups. In some embodiments, R 1 It is hydrogen.

[0013] In some embodiments, R 10 This is independently selected from hydrogen, C1-C3 alkyl, and C2-C3 alkenyl, where the alkyl and alkenyl may optionally be substituted by one or more substituents independently selected from halo, -OMe, and -CN.

[0014] In some embodiments, each R' is independently selected from hydrogen, halo, and haloalkyl. In some embodiments, each R' is hydrogen.

[0015] In some embodiments, n is selected from 2 and 3. In some embodiments, n is 2.

[0016] In some embodiments, R 9 The alkyl and alkenyl atoms are selected from C2-C3 alkyl and C2-C3 alkenyl atoms, where the alkyl and alkenyl atoms may optionally be substituted with one or more substituents independently selected from halo, -OMe, and -CN. In this embodiment, R 9 It is a C2-C3 alkyl group.

[0017] In some embodiments, R 2 R is selected from hydrogen, halogens, and C1-C6 alkyl groups. In some embodiments, R 2 It is hydrogen.

[0018] In some embodiments, R 4 , R 5 , R 6 , and R 7 Each of these is independently selected from hydrogen, A, J, Q, and X. In some embodiments, R 4 , R 5 , R 6 , and R 7 Each is independently selected from hydrogen, J, and Q. In some embodiments, R 4 , R 5 , R 6 , and R 7 At least one of them is A or Q. In some embodiments, R 5 , R 6 , and R 7 At least one of them is J or X.

[0019] In some embodiments, R 13R is selected from hydrogen and C1-C3 alkyl groups which may optionally be substituted with one or more substituents independently selected from halo, -OMe, and -CN. In some embodiments, R 13 is hydrogen. In some embodiments, R 13 These are C1-C3 alkyl groups.

[0020] In some embodiments, R 14 is a C1-C3 alkyl group which may optionally be substituted with one or more substituents independently selected from halo, -OMe, and -CN.

[0021] In some embodiments, R 15 is a C1-C3 alkylene which may optionally be substituted with one or more substituents independently selected from halo, -OMe, and -CN.

[0022] In some embodiments, X is selected from glucose, galactose, and rhamnose.

[0023] In another embodiment, the following is provided herein: Formula (Ia): [ka] A method for treating a disease or disorder in a subject requiring the administration of a compound or a pharmaceutically acceptable salt thereof, wherein, R 1 and R 10 These are independently selected from hydrogen, C1-C6 alkyl, C2-C6 alkenyl, and C2-C6 alkynyl, where alkyl, alkenyl, and alkynyl may optionally be independently substituted with one or more substituents selected from halo, -OMe, -CN, -NH2, and -NO2. R 8 is -CR'2-, where each R' is independently selected from hydrogen, halo, haloalkyl, alkoxy, haloalkoxy, and amine. n is selected from 2, 3, and 4. R9 is selected from C2-C6 alkyl, C2-C6 alkenyl, and C2-C6 alkynyl, where the alkyl, alkenyl, and alkynyl may optionally be substituted by one or more substituents independently selected from halo, -OMe, -CN, -NH2, -NO2, and 3- to 8-member heterocycles, and the 3- to 8-member heterocycle may optionally be substituted by one or more substituents independently selected from halo, -OMe, -CN, -NH2, and -NO2, R 2 is selected from hydrogen, halogen, C1-C6 alkyl, and C1-C6 haloalkyl, R 4 R 5 R 6 and R 7 are each independently selected from hydrogen, C1-C6 alkyl, A, J, Q, and X, A is

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0025] In some embodiments, R 1 is selected from hydrogen and C1-C3 alkyl. In some embodiments, R 1 is hydrogen.

[0026] In some embodiments, R 10 is independently selected from hydrogen, C1-C3 alkyl, and C2-C3 alkenyl, where alkyl and alkenyl may optionally be substituted by one or more substituents independently selected from halo, -OMe, and -CN.

[0027] In some embodiments, each R' is independently selected from hydrogen, halo, and haloalkyl. In some embodiments, each R' is hydrogen.

[0028] In some embodiments, n is selected from 2 and 3. In some embodiments, n is 2.

[0029] In some embodiments, R 9is selected from C2-C3 alkyl and C2-C3 alkenyl, where the alkyl and alkenyl may optionally be substituted by one or more substituents independently selected from halo, -OMe, and -CN. In some embodiments, R 9 is C2-C3 alkyl.

[0030] In some embodiments, R 2 is selected from hydrogen, halogen, and C1-C6 alkyl. In some embodiments, R 2 is hydrogen.

[0031] In some embodiments, R 4 , R 5 , R 6 and R 7 are each independently selected from hydrogen, A, J, Q, and X. In some embodiments, R 4 , R 5 , R 6 and R 7 are independently selected from hydrogen, J, and Q. In some embodiments, at least one of R 4 , R 5 , R<​​​​​​​​​​​​​​​​​​​​​​​​is a C1-C3 alkyl group which may optionally be substituted with one or more substituents independently selected from halo, -OMe, and -CN.

[0034] In some embodiments, R 15 is a C1-C3 alkylene which may optionally be substituted with one or more substituents independently selected from halo, -OMe, and -CN. .

[0035] In some embodiments, X is selected from glucose, galactose, and rhamnose.

[0036] In some embodiments, the disease or disorder is major depression, treatment-resistant depression, addiction, anxiety, post-traumatic stress disorder, long-term grief disorder, complicated grief disorder, mania, psychosis, insomnia, hypersomnia, pain, Alzheimer's disease, Parkinson's disease, burnout syndrome, cluster headache, bulimia nervosa, migraine, or irritable bowel syndrome.

[0037] In another embodiment, the Specified Invention provides a method for treating a disease or disorder in a subject requiring the administration of a modified indole alkaloid.

[0038] In some embodiments, the modified indole alkaloid is a modified tryptamine alkaloid, a modified ibogamine alkaloid, a modified ergoline alkaloid, a modified beta-carbolin alkaloid, or a modified mitraginine alkaloid.

[0039] In some embodiments, the modified indole alkaloid is an acetylated indole alkaloid, an acylated indole alkaloid, a methylated indole alkaloid, a phosphorylated indole alkaloid, a sulfonated indole alkaloid, or a glycosylated indole alkaloid.

[0040] In yet another embodiment, the following are provided herein: A method for enzymatically preparing an indole alkaloid, comprising the step of contacting a compound of formula (Ia') with an enzyme and a co-substrate, Here, the compound of formula (Ia') is [ka] or having a pharmaceutically acceptable salt structure thereof, During the ceremony, R 1 and R 10 These are independently selected from hydrogen, C1-C6 alkyl, C2-C6 alkenyl, and C2-C6 alkynyl, where alkyl, alkenyl, and alkynyl may be independently substituted with one or more substituents selected from halo, -OMe, -CN, -NH2, and -NO2. R 8 is -CR'2-, where each R' is independently selected from hydrogen, halo, haloalkyl, alkoxy, haloalkoxy, and amine. n is selected from 2, 3, and 4. R 9 The alkyl group is selected from C2-C6 alkyl groups, C2-C6 alkenyl groups, and C2-C6 alkynyl groups, where the alkyl group, alkenyl group, and alkynyl group are each independently selected from halo, -OMe, -CN, -NH2, -NO2, and 3-8 membered heterocycles. These may be substituted as needed, and the 3- to 8-membered heterocycle may be substituted as needed by one or more substituents independently selected from halo, -OMe, -CN, -NH2, and -NO2. R 2 These are selected from hydrogen, halogens, C1-C6 alkyl groups, and C1-C6 haloalkyl groups. R 4 , R 5 , R 6 , and R 7 Each of these is independently selected from hydrogen, -OH, and C1-C6 alkyl, and R 4 , R 5 , R 6 , and R7 At least one of them is -OH.

[0041] In some embodiments, R 4 It is -OH.

[0042] In some embodiments, R 5 It is -OH.

[0043] In some embodiments, R 6 It is -OH.

[0044] In some embodiments, R 7 It is -OH.

[0045] In some embodiments, the enzyme is 4-hydroxytryptamine kinase.

[0046] In some embodiments, the enzyme is acetylserotonin O-methyltransferase.

[0047] In some embodiments, the enzyme is tryptamine n-methyltransferase.

[0048] In some embodiments, the enzyme is sulfotransferase 1A1.

[0049] In some embodiments, the enzyme is sulfotransferase 1A3.

[0050] In some embodiments, the enzyme is alcohol O-acetyltransferase 1.

[0051] In some embodiments, the enzyme is chloramphenicol acetyltransferase.

[0052] In some embodiments, the enzyme is UDP-glucuronosyltransferase. In some embodiments, UDP-glucuronosyltransferase is UDP-glucuronosyltransferase 1-6. In some embodiments, UDP-glucuronosyltransferase is UDP-glucuronosyltransferase 1-9. In some embodiments, UDP-glucuronosyltransferase is UDP-glucuronosyltransferase 1-10.

[0053] In some embodiments, the enzyme is oleandomycin glycosyltransferase.

[0054] In some embodiments, the enzyme is a glycosyltransferase.

[0055] In some embodiments, the enzyme is 4-dimethylallyltryptophan synthase.

[0056] In some embodiments, the enzyme is 7-dimethylallyltryptophan synthase.

[0057] Built-in by reference All publications, patents, and patent applications referenced herein are incorporated herein by reference to the same extent as each individual publication, patent, or patent application is specifically and individually indicated as being incorporated by reference. In embodiments of the present invention, for example, the following items are provided. (Item 1) Compound of formula (Ia): [ka] or a pharmaceutically acceptable salt thereof, in the formula, R 1 and R 10These are independently selected from hydrogen, C1-C6 alkyl, C2-C6 alkenyl, and C2-C6 alkynyl, where the alkyl, alkenyl, and alkynyl may optionally be independently substituted with one or more substituents selected from halo, -OMe, -CN, -NH2, and -NO2. R 8 is -CR'2-, where each R' is independently selected from hydrogen, halo, haloalkyl, alkoxy, haloalkoxy, and amine. n is selected from 2, 3, and 4. R 9 These are selected from C2-C6 alkyl, C2-C6 alkenyl, and C2-C6 alkynyl compounds. Selected, where the alkyl, alkenyl, and alkynyl may optionally be substituted by one or more substituents independently selected from halo, -OMe, -CN, -NH2, -NO2, and 3- to 8-membered heterocycles, and the 3- to 8-membered heterocycle may optionally be substituted by one or more substituents independently selected from halo, -OMe, -CN, -NH2, and -NO2. R 2 These are selected from hydrogen, halogens, C1-C6 alkyl groups, and C1-C6 haloalkyl groups. R 4 , R 5 , R 6 , and R 7 Each of these is independently selected from hydrogen, C1-C6 alkyl, A, J, Q, and X. A is [ka] And, J is [ka] And, Q is [ka] And, X is selected from glucose, xylose, galactose, rhamnose, rutinose, and disaccharides. R 13 This is selected from C1-C6 alkyl groups, which may optionally be substituted with hydrogen and one or more substituents independently selected from C1-C6 alkyl, oxo, halo, -OMe, -CN, -NH2, and -NO2. R 14 The C1-C6 alkyl and C2-C6 alkenyl atoms are selected from C1-C6 alkyl and C2-C6 alkenyl atoms, and the C1-C6 alkyl and C2-C6 alkenyl atoms may be optionally substituted with one or more substituents independently selected from halo, -OMe, -CN, -NH2, and -NO2. Alternatively, R 13 and R 14 These, together with the atoms to which they are bonded, form substituted or unsubstituted C3-C8 cycloalkyl groups, or substituted or unsubstituted 3-8 membered heterocycloalkyl groups, each having one or two heteroatoms independently selected from N, O, and S. R 15 The C1-C6 alkylene and C2-C6 alkenylene are selected from C1-C6 alkylene and C2-C6 alkenylene, which may optionally be substituted with one or more substituents independently selected from C1-C6 alkyl, halo, -OMe, -CN, -NH2, and -NO2. Here, the R 4 , R 5 , R 6 , and at least one of R7 is A, J, Q, or X, the compound or a pharmaceutically acceptable salt thereof. (Item 2) The aforementioned R 1 A compound or salt of item 1, wherein the compound is selected from hydrogen and C1-C3 alkyl groups. (Item 3) The aforementioned R 1 However, the compound or salt described in item 1 or 2 is hydrogen. (Item 4) The aforementioned R 10A compound or salt according to any one of items 1 to 3, wherein the alkyl and alkenyl are independently selected from hydrogen, C1-C3 alkyl, and C2-C3 alkenyl, and the alkyl and alkenyl may optionally be substituted with one or more substituents independently selected from halo, -OMe, and -CN. (Item 5) The compounds or salts described in any of items 1 to 4, wherein each of the aforementioned R' is independently selected from hydrogen, halo, and haloalkyl. (Item 6) A compound or salt described in any of items 1 to 5, wherein each of the aforementioned R's is hydrogen. (Item 7) A compound or salt according to any of items 1 to 6, wherein n is selected from 2 and 3. (Item 8) A compound or salt according to any of items 1 to 7, wherein n is 2. (Item 9) The aforementioned R 9 A compound or salt according to any one of items 1 to 8, wherein the alkyl and alkenyl are selected from C2-C3 alkyl and C2-C3 alkenyl, and the alkyl and alkenyl may optionally be substituted with one or more substituents independently selected from halo, -OMe, and -CN. (Item 10) The aforementioned R 9 A compound or salt listed in any of items 1 to 9, wherein the parent is a C2-C3 alkyl group. (Item 11) The aforementioned R 2 However, a compound or salt described in any of items 1 to 10, selected from hydrogen, halogens, and C1-C6 alkyl groups. (Item 12) The aforementioned R 2 However, a compound or salt listed in any of items 1-11, which is hydrogen. (Item 13) The aforementioned R 4 , R 5 , R 6 , and R 7 However, each is independently selected from hydrogen, A, J, Q, and X, and is a compound or salt of any of the compounds listed in items 1 to 12. (Item 14) The aforementioned R 4 , R 5 , R 6 , and R 7 However, each is independently selected from hydrogen, J, and Q, and is a compound or salt of any of the compounds listed in items 1 to 13. (Item 15) The aforementioned R 4 , R 5 , R 6 , and R 7 A compound or salt listed in any of items 1-14, wherein at least one of them is A or Q. (Item 16) The aforementioned R 5 , R 6 , and R 7 A compound or salt listed in any of items 1-14, wherein at least one of them is J or X. (Item 17) The aforementioned R 13 A compound or salt of any of items 1 to 16, selected from C1 to C3 alkyl groups, which may optionally be substituted with hydrogen and one or more substituents independently selected from C1 to C6 alkyl, oxo, halo, -OMe, and -CN. (Item 18) The aforementioned R 13 However, a compound or salt listed in any of items 1-17, which is hydrogen. (Item 19) The aforementioned R 13 A compound or salt listed in any of items 1 to 17, wherein the parent is a C1-C3 alkyl group. (Item 20) The aforementioned R 14 The compounds or salts described in any of items 1 to 19, which are C1-C3 alkyl groups, but which may be optionally substituted by one or more substituents independently selected from halo, -OMe, and -CN. (Item 21) The aforementioned R 15A compound or salt according to any of items 1 to 20, which is a C1-C3 alkylene, which may optionally be substituted with one or more substituents independently selected from C1-C6 alkyl, oxo, halo, -OMe, and -CN. (Item 22) A compound or salt according to any of items 1 to 21, wherein X is selected from glucose, galactose, and rhamnose. (Item 23) Equation (Ia): [ka] A method for treating a disease or disorder in a subject requiring the administration of a compound or a pharmaceutically acceptable salt thereof, wherein the formula is: R 1 and R 10 These are independently selected from hydrogen, C1-C6 alkyl, C2-C6 alkenyl, and C2-C6 alkynyl, where the alkyl, alkenyl, and alkynyl may optionally be independently substituted with one or more substituents selected from halo, -OMe, -CN, -NH2, and -NO2. R 8 is -CR'2-, where each R' is independently selected from hydrogen, halo, haloalkyl, alkoxy, haloalkoxy, and amine. n is selected from 2, 3, and 4. R 9 The alkyl, alkenyl, and alkynyl groups are selected from C2-C6 alkyl groups, C2-C6 alkenyl groups, and C2-C6 alkynyl groups, where the alkyl, alkenyl, and alkynyl groups may optionally be substituted by one or more substituents independently selected from halo, -OMe, -CN, -NH2, -NO2, and 3- to 8-membered heterocycles, and the 3- to 8-membered heterocycles may optionally be substituted by one or more substituents independently selected from halo, -OMe, -CN, -NH2, and -NO2. R 2 These are selected from hydrogen, halogens, C1-C6 alkyl groups, and C1-C6 haloalkyl groups. R 4, R 5 , R 6 , and R 7 Each of these is independently selected from hydrogen, C1-C6 alkyl, A, J, Q, and X. A is [ka] And, J is [ka] And, Q is [ka] And, X is selected from glucose, xylose, galactose, rhamnose, rutinose, and disaccharides. R 13 This is selected from C1-C6 alkyl groups, which may optionally be substituted with hydrogen and one or more substituents independently selected from C1-C6 alkyl, oxo, halo, -OMe, -CN, -NH2, and -NO2. R 14 The C1-C6 alkyl and C2-C6 alkenyl atoms are selected from C1-C6 alkyl and C2-C6 alkenyl atoms, and the C1-C6 alkyl and C2-C6 alkenyl atoms may be optionally substituted with one or more substituents independently selected from halo, -OMe, -CN, -NH2, and -NO2. Alternatively, R 13 and R 14 These, together with the atoms to which they are bonded, form substituted or unsubstituted C3-C8 cycloalkyl groups, or substituted or unsubstituted 3-8 membered heterocycloalkyl groups, each having one or two heteroatoms independently selected from N, O, and S. R 15The C1-C6 alkylene and C2-C6 alkenylene are selected from C1-C6 alkylene and C2-C6 alkenylene, which may optionally be substituted with one or more substituents independently selected from C1-C6 alkyl, halo, -OMe, -CN, -NH2, and -NO2. Here, the R 4 , R 5 , R 6 The method wherein at least one of R7 is A, J, Q, or X. (Item 24) The aforementioned R 1 The method according to item 23, wherein is selected from hydrogen and C1-C3 alkyl. (Item 25) The aforementioned R 1 The method described in item 23 or 24, wherein the hydrogen is hydrogen. (Item 26) The aforementioned R 10 The method according to any one of items 23 to 25, wherein the alkyl and alkenyl are independently selected from hydrogen, C1-C3 alkyl, and C2-C3 alkenyl, and the alkyl and alkenyl may optionally be substituted with one or more substituents independently selected from halo, -OMe, and -CN. (Item 27) The method according to any one of items 23 to 26, wherein each of the R's is independently selected from hydrogen, halo, and haloalkyl. (Item 28) The method according to any one of items 23 to 27, wherein each of the R's is hydrogen. (Item 29) The method according to any of items 23 to 28, wherein n is selected from 2 and 3. (Item 30) The method according to any of items 23 to 29, wherein n is 2. (Item 31) The aforementioned R 9 The method according to any one of items 23 to 30, wherein the alkyl and alkenyl are selected from C2-C3 alkyl and C2-C3 alkenyl, and the alkyl and alkenyl may optionally be substituted with one or more substituents independently selected from halo, -OMe, and -CN. (Item 32) The aforementioned R 9 The method according to any of items 23 to 31, wherein the alkyl group is C2-C3 alkyl. (Item 33) The aforementioned R 2 However, the method according to any of items 23 to 32, selected from hydrogen, halogens, and C1-C6 alkyl groups. (Item 34) The aforementioned R 2 The method described in any of items 23-33, wherein the hydrogen is hydrogen. (Item 35) The aforementioned R 4 , R 5 , R 6 , and R 7 However, independently selected from hydrogen, A, J, Q, and X, the method according to any of items 23 to 34. (Item 36) The aforementioned R 4 , R 5 , R 6 , and R 7 However, independently selected from hydrogen, J, and Q, the method described in any of items 23 to 35. (Item 37) The aforementioned R 4 , R 5 , R 6 , and R 7 The method described in any of items 23-36, wherein at least one of them is A or Q. (Item 38) The aforementioned R 5 , R 6 , and R 7 The method described in any of items 23-36, wherein at least one of them is J or X. (Item 39) The aforementioned R 13 The method according to any one of items 23 to 38, wherein hydrogen and a C1 to C3 alkyl group may optionally be substituted with one or more substituents independently selected from C1 to C6 alkyl, oxo, halo, -OMe, and -CN. (Item 40) The aforementioned R 13The method described in any of items 23-39, wherein the hydrogen is hydrogen. (Item 41) The aforementioned R 13 The method according to any of items 23 to 39, wherein is a C1-C3 alkyl group. (Item 42) The aforementioned R 14 The method according to any one of items 23 to 41, wherein the C1-C3 alkyl is optionally substituted by one or more substituents independently selected from halo, -OMe, and -CN. (Item 43) The aforementioned R 15 The method according to any one of items 23 to 42, wherein the C1-C3 alkylene is optionally substituted with one or more substituents independently selected from C1-C6 alkyl, oxo, halo, -OMe, and -CN. (Item 44) The method according to any one of items 23 to 43, wherein X is selected from glucose, galactose, and rhamnose. (Item 45) The method according to any one of items 23-44, wherein the disease or disorder is major depressive disorder, treatment-resistant depression, addiction, anxiety, post-traumatic stress disorder, long-term grief disorder, complicated grief disorder, mania, psychosis, insomnia, hypersomnia, pain, Alzheimer's disease, Parkinson's disease, burnout syndrome, cluster headache, bulimia nervosa, migraine, or irritable bowel syndrome. (Item 46) The aforementioned disease or disorder is major depressive disorder, treatment-resistant depression, addiction, anxiety, post-traumatic stress disorder The condition is a grief disorder, long-term grief disorder, complicated grief disorder, or bulimia nervosa, as described in any of items 23-45. (Item 47) A method for treating a disease or disorder in a subject requiring the administration of a modified indole alkaloid. (Item 48) The method according to item 47, wherein the modified indole alkaloid is a modified tryptamine alkaloid, a modified ibogamine alkaloid, a modified ergoline alkaloid, a modified beta-carbolin alkaloid, or a modified mitraginine alkaloid. (Item 49) The method according to item 47 or 48, wherein the modified indole alkaloid is an acetylated indole alkaloid, an acylated indole alkaloid, a methylated indole alkaloid, a phosphorylated indole alkaloid, a sulfonylated indole alkaloid, or a glycosylated indole alkaloid. (Item 50) A method for enzymatically preparing an indole alkaloid, wherein the method includes the step of contacting a compound of formula (Ia') with an enzyme and a co-substrate, The compound of formula (Ia') is [ka] or having a pharmaceutically acceptable salt structure thereof, During the ceremony, R 1 and R 10 These are independently selected from hydrogen, C1-C6 alkyl, C2-C6 alkenyl, and C2-C6 alkynyl, where the alkyl, alkenyl, and alkynyl may optionally be independently substituted with one or more substituents selected from halo, -OMe, -CN, -NH2, and -NO2. R 8 is -CR'2-, where each R' is independently selected from hydrogen, halo, haloalkyl, alkoxy, haloalkoxy, and amine. n is selected from 2, 3, and 4. R 9The alkyl, alkenyl, and alkynyl groups are selected from C2-C6 alkyl groups, C2-C6 alkenyl groups, and C2-C6 alkynyl groups, where the alkyl, alkenyl, and alkynyl groups may optionally be substituted by one or more substituents independently selected from halo, -OMe, -CN, -NH2, -NO2, and 3- to 8-membered heterocycles, and the 3- to 8-membered heterocycles may optionally be substituted by one or more substituents independently selected from halo, -OMe, -CN, -NH2, and -NO2. R 2 These are selected from hydrogen, halogens, C1-C6 alkyl groups, and C1-C6 haloalkyl groups. R 4 , R 5 , R 6 , and R 7 Each of these is independently selected from hydrogen, -OH, and C1-C6 alkyl, and the R 4 , R 5 , R 6 , and R 7 The method wherein at least one of is -OH. (Item 51) The aforementioned R 4 The method described in item 50, wherein the OH group is -OH. (Item 52) The aforementioned R 5 The method described in item 50, wherein the OH group is -OH. (Item 53) The aforementioned R 6 The method described in item 50, wherein the OH group is -OH. (Item 54) The aforementioned R 7 The method described in item 50, wherein the OH group is -OH. (Item 55) The method according to any one of items 50 to 54, wherein the enzyme is 4-hydroxytryptamine kinase. (Item 56) The method according to any one of items 50 to 54, wherein the enzyme is acetylserotonin O-methyltransferase. (Item 57) The method according to any one of items 50 to 54, wherein the enzyme is tryptamine n-methyltransferase. (Item 58) The method according to any one of items 50 to 54, wherein the enzyme is sulfotransferase 1A1. (Item 59) The method according to any one of items 50 to 54, wherein the enzyme is sulfotransferase 1A3. (Item 60) The method according to any one of items 50 to 54, wherein the enzyme is alcohol O-acetyltransferase 1. (Item 61) The method according to any one of items 50 to 54, wherein the enzyme is chloramphenicol acetyltransferase. (Item 62) The method according to any one of items 50 to 54, wherein the enzyme is UDP-glucuronosyltransferase. (Item 63) The method according to any one of items 50 to 54, wherein the enzyme is oleandomycin glycosyltransferase. (Item 64) The method according to any one of items 50 to 54, wherein the enzyme is a glycosyltransferase. (Item 65) The method according to any one of items 50 to 54, wherein the enzyme is 4-dimethylallyltryptophan synthase. (Item 66) The method according to any one of items 50 to 54, wherein the enzyme is 7-dimethylallyltryptophan synthase.

[0058] Novel features of the present invention are described in particular in the appended claims. A better understanding of the features and advantages of the present invention can be obtained by referring to the following detailed description illustrating the illustrated embodiments, in which the principles of the invention are utilized, and which is accompanied by the following drawings. [Brief explanation of the drawing]

[0059] [Figure 1]This figure shows the SDS-PAGE analysis of purified transferase protein compared to a standard-sized marker (L). The bands of the purified protein product from each expression plasmid are indicated by arrows within each SDS-PAGE gel.

[0060] [Figure 2] This figure shows the analysis of enzymatically produced 3-((3-(2-(diisopropylamino)ethyl)-1H-indole-4-yl)oxy)-3-oxopropanoic acid. A shows the LC-MS traces of the negative control of uncharged CoA (reaction 1), the thermoinactivating enzyme (reaction 2), and the product (reaction 3). B shows the MS spectrum of the product from reaction 3. C shows the UV-vis absorption spectrum of the product from reaction 3.

[0061] [Figure 3] This figure shows the relative ion number of the 2-((3-(2-(diisopropylamino)ethyl)-1H-indole-4-yl)oxy)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol product in reactions 4-8, where 4-hydroxy-N,N-diisopropyltryptamine was enzymatically glycosylated using various glucosyltransferase enzymes.

[0062] [Figure 4] This figure shows the relative ion numbers of the 3-(2-(diisopropylamino)ethyl)-1H-indole-4-yl bisulfate product in reactions 9-11 after enzymatic sulfonation of 4-hydroxy-N,N-diisopropyltryptamine using various sulfotransferase enzymes.

[0063] [Figure 5]This figure shows the functional agonism of the 5HT2A receptor, as measured by the peak calcium flux response, of 4-3-(2-(dipropylamino)ethyl)-1H-indole-4-yl phosphate dihydrogen (triangle) and 4-3-(2-(diisopropylamino)ethyl)-1H-indole-4-yl phosphate dihydrogen (square), treated with calf alkaline phosphatase, compared to 5-hydroxytryptamine (round).

[0064] [Figure 6] This figure shows the LC-MS traces of the 2-((3-(2-(diisopropylamino)ethyl)-1H-indole-4-yl)oxy)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol (compound C) sample alone (traces A and C) and the sample treated with human saliva (traces B and D). A shows the extraction of traces A and B with m / z 423.24, corresponding to the glycosylation product from reaction 47. B shows the extraction of traces C and D with m / z 261.19, corresponding to the deglycosylation product 4-hydroxy-N,N-diisopropyltryptamine.

[0065] [Figure 7] This figure shows the LC-MS traces of the 3-((3-(2-(diisopropylamino)ethyl)-1H-indole-4-yl)oxy)-3-oxopropanoic acid (compound D) sample alone (traces A and C) and the sample treated with human saliva (traces B and D). A shows the extraction of traces A and B with m / z 347.19, corresponding to the malonylation product from reaction 3. B shows the extraction of traces C and D with m / z 261.19, corresponding to the hydrolysis product 4-hydroxy-N,N-diisopropyltryptamine.

[0066] [Figure 8]This figure shows the LC-MS traces of the 3-(2-(diisopropylamino)ethyl)-1H-indole-4-yl-3-oxobutanoate (compound E) sample alone (traces A and C) and the sample treated with human saliva (traces B and D). A shows the extraction of traces A and B with m / z 345.21, corresponding to the acetylation product from reaction 3. B shows the extraction of traces C and D with m / z 261.19, corresponding to the hydrolysis product 4-hydroxy-N,N-diisopropyltryptamine. [Modes for carrying out the invention]

[0067] This specification provides novel methods for producing modified indole alkaloids with therapeutic properties. Modification of indole alkaloids by these methods may lead to enhanced therapeutic properties, such as improved solubility, increased bioavailability, increased drug concentration to therapeutic targets in the body, and improved therapeutic pharmacokinetic profiles. The methods described herein can modify indole alkaloids of chemical classes including, but not limited to, tryptamine, ergoline, mitragina alkaloids, β-carborine, and ibogamine compound classes.

[0068] definition Unless otherwise defined, all technical and scientific terms used herein have the same meanings as those generally understood by those skilled in the art to which this disclosure pertains.

[0069] As used herein, the singular “one” (a, an) and “the” (the) include multiple references unless the context clearly indicates otherwise.

[0070] The term “C x~y " means that when used in combination with chemical parts such as alkyl, alkenyl, or alkynyl, the chain contains a group with x to y carbon atoms. For example, "C 1~6The term "alkyl" refers to substituted or unsubstituted saturated hydrocarbon groups, including straight-chain alkyl and branched-chain alkyl groups containing 1 to 6 carbon atoms. x~y The term "alkylene" refers to a substituted or unsubstituted alkylene chain having x to y carbon atoms in the alkylene chain. For example, C 1~6 The alkylene may be selected from methylene, ethylene, propylene, butylene, pentylene, and hexylene, and any one of these may be substituted as needed.

[0071] "Alkyl" refers to substituted or unsubstituted saturated hydrocarbon groups, including linear alkyl and branched alkyl groups. Alkyl groups consist of 1 to 12 carbon atoms (for example, C 1~12 Alkyl), for example, 1 to 8 carbon atoms (C 1~8 Alkyl) or 1 to 6 carbon atoms (C 1~6 Alkyl groups may include alkyl groups. Exemplary alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, septyl, octyl, nonyl, and decyl. Alkyl groups are bonded to the rest of the molecule by single bonds. Unless otherwise specified herein, alkyl groups may be optionally substituted with one or more substituents, such as substituents described herein.

[0072] "Alkylene" refers to a straight-chain or branched-chain divalent hydrocarbon chain. Unless otherwise specified herein, alkylene groups may be substituted as necessary with one or more substituents, such as substituents described herein.

[0073] A "haloalkyl" refers to an alkyl group substituted with one or more halogens. Examples of haloalkyl groups include trifluoromethyl, difluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, and 1,2-dibromoethyl.

[0074] "Alkenyl" refers to a substituted or unsubstituted hydrocarbon group that contains a linear or branched alkenyl group with at least one double bond. An alkenyl group can contain 2 to 12 carbon atoms (for example, C 2~12 Alkenyl). Exemplary alkenyl groups include ethenyl (i.e., vinyl), propa-1-enyl, buta-1-enyl, penta-1-enyl, penta-1,4-dienyl, and the like. Unless otherwise specified herein, alkenyl groups may be substituted as necessary with one or more substituents, such as substituents described herein.

[0075] "Alkenylene" refers to a straight or branched divalent hydrocarbon chain containing at least one double bond. Unless otherwise specified herein, alkenylene groups may be substituted as necessary with one or more substituents, such as substituents described herein.

[0076] "Alkynyl" refers to a substituted or unsubstituted hydrocarbon group containing a linear or branched alkynyl group with at least one triple bond. An alkynyl group can contain 2 to 12 carbon atoms (for example, C 2~12 Alkynyl groups. Examples of alkynyl groups include ethynyl, propynyl, butynyl, pentynyl, and hexynyl. Unless otherwise specified herein, alkynyl groups may be substituted as necessary with one or more substituents, such as those described herein.

[0077] "Alkynylene" refers to a straight or branched divalent hydrocarbon chain containing at least one triple bond. Unless otherwise specified herein, the alkynylene group may be substituted as necessary with one or more substituents, such as substituents described herein.

[0078] "Aryl" refers to an aromatic ring in which each atom forming the ring is a carbon atom. The aryl group may be substituted as needed. Examples of aryl groups include, but are not limited to, phenyl and naphthyl. In some embodiments, the aryl is phenyl. Depending on the structure, the aryl group may be a monoradical or a diradical (i.e., an arylene group). Unless otherwise specified herein, the term "aryl" or the prefix "ar-" (e.g., "aralkyl") means that it includes aryl radicals, which may be substituted as needed.

[0079] A "heteroaryl" refers to a 3- to 12-membered aromatic ring containing at least one heteroatom, each heteroatom independently selected from N, O, and S. As used herein, heteroaryl rings can be selected from monocyclic or bicyclic and fused or bridging ring systems, where at least one of the rings in the ring system is aromatic, i.e., containing a cyclic delocalized (4n+2)π-electron system according to Hückel's theory. The heteroatom(s) in the heteroaryl may be oxidized as necessary. If one or more nitrogen atoms are present, they may be quaternized as necessary. The heteroaryl may be bonded to the rest of the molecule via any atom of the heteroaryl, such as the carbon or nitrogen atom of the heteroaryl, as long as its valence allows. Examples of heteroaryls include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzindolyl, 1,3-benzodioxolyl, benzofuranil, benzoxazolyl, benzo[d]thiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepinyl, benzo[b][1,4]oxazinyl, 1,4-benzodioxanil, benzonaphthofuranil, benzoxazolyl, benzodioxolyl, benzodioxynil, benzopyranil, benzopyranonil, benzofuranil, benzothienyl (benzothiophenyl), benzothieno[3,2-d]pyrimidinil, benzotriazolyl, and benzo[4,6] Midazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl, cyclopenta[d]pyrimidinyl, 6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-d]pyrimidinyl, 5,6-dihydrobenzo[h]quinazolinyl, 5,6-dihydrobenzo[h]cinnolinyl, 6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridadinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furanonyl, furo[3,2-c]pyridinyl, 5,6,7,8,9,10-hexahydrocycloocta[d]pyrimidinyl, 5,6,7,8,9,10-hexahydrocycloocta[d]pyrimidinyl, 5,6,7,8,910-Hexahydrocycloocta[d]pyridinyl, isothiazolyl, imidazolyl, indazolyl, indazolyl, isoindolyl, indolinyl, isoindolyl, isoquinolyl, indolidinyl, isoxazolyl, 5,8-methano-5,6,7,8-tetrahydroquinazolinyl, naphthilidinyl, 1,6-naphthilidinol, oxadiazolyl, 2- Oxoazepinyl, oxazolyl, oxyranil, 5,6,6a,7,8,9,10,10a-octahydrobenzo[h]quinazolinyl, 1-phenyl-1H-pyrrolyl, phenadinyl, phenothiazinyl, phenoxadinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyrazolo[3,4-d]pyrimidinyl, pyridinyl, pyrido[3,2-d]pyrimidinyl Midinyl, Pyrido[3,4-d]pyrimidinyl, Pyrazinyl, Pyrimidinyl, Pyridazinyl, Pyrrolyl, Quinazolinyl, Quinoxalinyl, Quinolinyl, Isoquinolinyl, Tetrahydroquinolinyl, 5,6,7,8-Tetrahydroquinazolinyl, 5,6,7,8-Tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidinyl, 6,7,8,9-Tetrahydro-5H-Cyc Examples include lohepta[4,5]thieno[2,3-d]pyrimidinyl, 5,6,7,8-tetrahydropyrido[4,5-c]pyridazinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, thieno[2,3-d]pyrimidinyl, thieno[3,2-d]pyrimidinyl, thieno[2,3-c]pridinyl, and thiophenyl (i.e., thienyl). Unless otherwise specified herein, heteroaryls may be optionally substituted with one or more substituents, such as those described herein.

[0080] The term "cycloalkyl" refers to monocyclic or polycyclic non-aromatic radicals in which each of the ring-forming atoms (i.e., the skeletal atoms) is a carbon atom. In some embodiments, cycloalkyls are saturated or partially unsaturated. In some embodiments, cycloalkyls are spirocyclic or crosslinked compounds. In some embodiments, cycloalkyls are condensed with an aromatic ring (in which case the cycloalkyl is bonded via a non-aromatic ring carbon atom). Cycloalkyl groups include those having 3 to 10 ring atoms. Representative cycloalkyls include, but are not limited to, those having 3 to 10 carbon atoms, 3 to 8 carbon atoms, 3 to 6 carbon atoms, or 3 to 5 carbon atoms. Examples of monocyclic cycloalkyl radicals include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Examples of polycyclic radicals include adamantyl, 1,2-dihydronaphthalenyl, 1,4-dihydronaphthalenyl, tetranyl, dekalinyl, 3,4-dihydronaphthalenyl-1(2H)-one, spiro[2.2]pentyl, norbornyl, and bisicle[1.1.1]pentyl. Unless otherwise specified herein, cycloalkyl groups may be substituted as needed.

[0081] The term "heterocycloalkyl" refers to a cycloalkyl group comprising at least one heteroatom selected from nitrogen, oxygen, and sulfur. Unless otherwise specified herein, heterocycloalkyl radicals may be monocyclic or bicyclic ring systems, which may include condensed (when condensed with an aryl or heteroaryl ring, the heterocycloalkyl is bonded via a non-aromatic ring atom) or bridged ring systems. The nitrogen, carbon, or sulfur atom in the heterocycloalkyl radical may be oxidized as required. The nitrogen atom may be quaternized as required. Heterocycloalkyl radicals may be partially or completely saturated. Examples of heterocycloalkyl radicals include, but are not limited to, dioxolanil, thienyl[1,3]dithianil, tetrahydroquinolyl, tetrahydroisoquinolyl, decahydroquinolyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianil, tetrahydropyranil, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, and 1,1-dioxo-thiomorpholinyl. The term heterocycloalkyl includes all ring forms of carbohydrates, including but not limited to monosaccharides, disaccharides, and oligosaccharides. Unless otherwise specified, heterocycloalkyls have 2 to 12 carbon atoms in the ring. When referring to the number of carbon atoms in a heterocycloalkyl, it should be understood that the number of carbon atoms in a heterocycloalkyl is not the same as the total number of atoms (including heteroatoms) that make up the heterocycloalkyl (i.e., the skeletal atoms of the heterocycloalkyl ring). Unless otherwise specified herein, heterocycloalkyls may be substituted as needed.

[0082] "Alkoxy" refers to an "-O-alkyl" group, where alkyl is defined herein.

[0083] The term "halo" or "halogen" refers to fluoro, chloro, bromo, and iodine.

[0084] The term “substituted” refers to a portion of a structure having a substituent on one or more carbon or heteroatoms that replaces hydrogen. It will be understood that “substituted” or “substituted with” implies implicit conditions, such as that such substitution conforms to the acceptable valencies of the substituted atom and substituent, and that the substitution results in a stable compound, such as one that does not spontaneously undergo transformations such as rearrangement, cyclization, or elimination. As used herein, the term “substituted” is intended to include all acceptable substituents of an organic compound. In a broader sense, acceptable substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of an organic compound. There may be one or more acceptable substituents for a given organic compound, and they may be the same or different. For the purposes of this disclosure, heteroatoms such as nitrogen may have substituents of any acceptable organic compound described herein that satisfy the hydrogen substituent and / or the valency of the heteroatom. Substituents may include any substituents described herein, such as halogens, hydroxyls, carbonyls (carboxyls, alkoxycarbonyls, formyls, or acyls, etc.), thiocarbonyls (thioesters, thioacetates, or thioformates, etc.), alkoxyls, phosphoryls, phosphates, phosphonates, phosphinates, aminos, amides, amidines, imines, cyanos, nitros, azides, sulfhydryls, alkylthios, sulfates, sulfonates, sulfonates, sulfamoyls, sulfonamides, sulfonyls, heterocyclyls, aralkyls, carbocyclics, heterocyclics, cycloalkyls, heterocycloalkyls, aromatics, and heteroaromatic moieties.

[0085] Those skilled in the art will understand that substituents can be substituted themselves, where appropriate. Unless specifically stated as “unsubstituted,” references to chemical moieties herein are understood to include substituted variants. For example, references to “heteroaryl” groups or moieties implicitly include both substituted and unsubstituted variants.

[0086] When substituent groups are identified by their conventional chemical formulas written from left to right, they equally encompass chemically identical substituents that would be obtained by writing the structure from right to left; for example, -CH2O- is equivalent to OCH2-.

[0087] "Optional" or "as needed" means that the event or situation described below may or may not occur, and that the description includes both cases in which the event or situation occurs and cases in which it does not occur. For example, "aryl which may be substituted as needed" means that the aryl group may or may not be substituted, and the description includes both substituted and unsubstituted aryl groups.

[0088] The compounds of this disclosure also include crystalline and amorphous forms of those compounds, pharmaceutically acceptable salts, and active metabolites of those compounds having the same kind of activity, for example, polymorphs, pseudopolymorphs, solvates, hydrates, non-solvated polymorphs (including anhydrous forms), stereochemical polymorphs, and amorphous forms of the compounds, as well as mixtures thereof.

[0089] The compounds described herein may exhibit their natural isotopic abundances, or one or more atoms may be artificially enriched with specific isotopes of the same atomic number, but their atomic masses or mass numbers may differ from those predominantly found in nature. All isotopic variations of the compounds disclosed herein, whether radioactive or not, are included within the scope of this disclosure. For example, hydrogen has 1 H (light hydrogen), 2 H (deuterium), and3 There are three natural isotopes of hydrogen called H (tritium). Deuterium is the most abundant isotope of hydrogen in nature. Enrichment with deuterium may yield certain therapeutic benefits, such as increased in vivo half-life and / or exposure, or may provide compounds useful for investigating the in vivo pathways of drug elimination and metabolism. Isotope-enriched compounds can be prepared by conventional techniques well known to those skilled in the art.

[0090] An "isomer" is a different compound that has the same molecular formula. A "stereoisomer" is an isomer that differs only in the arrangement of its atoms in space. An "enantiomer" is a pair of stereoisomers that are mirror images of each other and cannot be superimposed. A 1:1 mixture of a pair of enantiomers is a "racemic" mixture. The term "(±)" is used to indicate a racemic mixture as needed. A "diastereoisomer" or "diastereomer" is a stereoisomer that has at least two chiral atoms but is not a mirror image of each other. Absolute stereochemistry is defined according to the Cahn-Ingold-Prelog RS system. If a compound is a pure enantiomer, the stereochemistry of each chiral carbon can be designated as either R or S. Divided compounds whose absolute configuration is unknown can be designated as (+) or (-) depending on the direction in which plane polarization is rotated at the wavelength of the sodium D line (dextrorotatory or levorotatory). Certain compounds described herein contain one or more chiral centers, thus giving rise to enantiomers, diastereomers, and other stereoisomers, the chiral centers of which may be defined as (R)- or (S)- from the perspective of absolute stereochemistry. These chemicals, pharmaceutical compositions, and methods encompass all such conceivable stereoisomers, including racemic mixtures, optically pure forms, mixtures of diastereomers, and intermediate mixtures. Optically active (R)- and (S)- isomers can be prepared using chiral synthons or chiral reagents, or they can be separated using conventional techniques. The optical activity of a compound can be analyzed by any suitable method, including but not limited to chiral chromatography and polarimetric analysis, to determine the dominance of one stereoisomer over the other.

[0091] Chemicals containing carbon-carbon double bonds or carbon-nitrogen double bonds may exist in Z- or E- forms (or cis- or trans- forms). Furthermore, some chemicals may exist in various tautomerized forms. Unless otherwise specified, the chemicals described herein are intended to include all Z-, E-, and tautomerized forms.

[0092] The isolation and purification of the chemical substances and intermediates described herein can be carried out by any suitable separation or purification procedure, as necessary, such as filtration, extraction, crystallization, column chromatography, thin-layer chromatography, or thick-layer chromatography, or a combination thereof. Specific examples of suitable separation and isolation procedures can be obtained by referring to the following examples herein. However, other equivalent separation or isolation procedures may also be used.

[0093] Where stereochemistry is not specified, the specific small molecules described herein include, but are not limited to, isomers such as enantiomers and diastereomers, mixtures of enantiomers including racemates, mixtures of diastereomers, and other mixtures thereof, to the extent that a person skilled in the art can prepare them by routine experimentation. In those situations, a single enantiomer or diastereomer, i.e., an optically active form, can be obtained by asymmetric synthesis or by the resolution of a racemate or mixture of diastereomers. Resolution of racemic compounds or mixtures of diastereomers can be achieved, if possible, by conventional methods such as crystallization in the presence of a resolving agent, or chromatography, for example, using a chiral high-performance liquid chromatography (HPLC) column. Furthermore, a mixture of two enantiomers enriched with one of the two enantiomers can be purified and recrystallized and / or pulverized to provide a further optically enriched form of the major enantiomer. Furthermore, such specific small molecules include Z- and E- forms (or cis- and trans- forms) of specific small molecules having carbon-carbon double bonds or carbon-nitrogen double bonds. If a particular small molecule described herein exists in various tautomerized forms, the term “particular small molecule” is intended to include all tautomerized forms of that particular small molecule.

[0094] The term "salt" or "pharmaceutically acceptable salt" refers to salts derived from various organic and inorganic counterions known in the art. Pharmaceutically acceptable acid addition salts can be formed using inorganic and organic acids. Examples of inorganic acids that can induce salt formation include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid. Examples of organic acids that can induce salt formation include acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, and salicylic acid. Pharmaceutically acceptable base addition salts can be formed using inorganic and organic bases. Examples of inorganic bases that can induce salt formation include sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, and aluminum. Examples of organic bases that can induce salt formation include primary, secondary, and tertiary amines, substituted amines including naturally substituted amines, cyclic amines, and basic ion exchange resins, with isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine being particularly noteworthy. In some embodiments, the pharmaceutically acceptable base addition salt is selected from salts of ammonium, potassium, sodium, calcium, and magnesium.

[0095] As used herein, the terms “pharmaceutically acceptable excipient” or “pharmaceutically acceptable carrier” mean a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid excipient, diluent, additive, solvent or encapsulating material. Each carrier must be “acceptable” in the sense that it is compatible with the other components of the formulation and is not harmful to the patient. Some examples of materials that can function as a pharmaceutically acceptable carrier include: (1) sugars, e.g., lactose, glucose and sucrose; (2) starches, e.g., corn starch and potato starch; (3) cellulose and its derivatives, e.g., sodium carboxymethylcellulose, ethylcellulose and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, e.g., cocoa butter and suppository wax; (9) oils, e.g., peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil. Examples include sorghum oil and soybean oil, (10) glycols, such as propylene glycol, (11) polyols, such as glycerin, sorbitol, mannitol, and polyethylene glycol, (12) esters, such as ethyl oleate and ethyl laurate, (13) agar, (14) buffers, such as magnesium hydroxide and aluminum hydroxide, (15) alginic acid, (16) pyrogen-free water, (17) isotonic saline, (18) Ringer's solution, (19) ethyl alcohol, (20) phosphate buffer; and (21) other non-toxic compatible substances used in pharmaceutical formulations.

[0096] The terms “effective dose” or “therapeutic effective dose” refer to the amount of a compound described herein sufficient to affect the intended use, including but not limited to the treatment of the disease as defined below. The therapeutic effective dose may vary depending on the intended therapeutic use (in vivo) or the subject and disease state being treated, e.g., the subject’s weight and age, the severity of the disease state, the method of administration, etc. This can be readily determined by those skilled in the art. The term also applies to doses that induce a specific response in target cells, e.g., a decrease in platelet adhesion and / or cell migration. The specific dose will vary depending on the particular compound selected, the administration plan to be followed, whether it is administered in combination with other compounds, the timing of administration, the tissue to which it is administered, and the physical delivery system that carries it.

[0097] As used herein, “treatment” or “treating” means an approach to obtain a beneficial or desired outcome (including, but not limited to, therapeutic and / or preventive benefits) with respect to a disease, disorder, or medical condition. Therapeutic benefits may include, for example, the eradication or improvement of an underlying disorder being treated. Alternatively, therapeutic benefits may include the eradication or improvement of one or more physiological symptoms associated with an underlying disorder, such that improvement is observed in the subject, even if the subject still suffers from the underlying disorder. In certain embodiments, in terms of preventive benefits, a composition may be administered to a subject at risk of developing a particular disease, or to a subject reporting one or more physiological symptoms of a certain disease, even if the disease has not been diagnosed.

[0098] Modified indole alkaloids Using enzymes and biological systems containing these enzymes, functional groups can be transferred from a donor molecule to a receptor indole alkaloid. Indole alkaloids have the basic structure of indole. In some cases, indole alkaloids contain substituted indoles with receptor functional groups for the transferred donor molecule, forming modified indole alkaloids. In some cases, indole alkaloids contain substituted tryptamines with receptor functional groups for the transferred donor molecule, forming modified tryptamines. In some cases, indole alkaloids contain substituted beta-carborines with receptor functional groups for the transferred donor molecule, forming modified beta-carborines. In some cases, indole alkaloids contain substituted ergorines with receptor functional groups for the transferred donor molecule, forming modified ergorines. In some cases, indole alkaloids contain milagina alkaloids with receptor functional groups for the transferred donor molecule, forming modified milagina alkaloids. In some cases, indole alkaloids contain ibogamine alkaloids that have receptor functional groups for the transferred donor molecule, forming modified ibogamine alkaloids.

[0099] The process of transferring functional groups may include glycosylation, in which a carbohydrate, i.e., a glycosyl donor, is attached to a hydroxyl or other functional group (glycosyl acceptor) of another molecule. This forms the glucoside form of the indole alkaloid. The process of transferring functional groups may also include phosphorylation, in which a kinase or phosphotransferase enzyme transfers a phosphoryl group to a hydroxyl or other functional group (phosphoryl acceptor). This forms the phosphorylated form of the indole alkaloid. The process of transferring functional groups may also include sulfonation, in which a sulfate group, i.e., a sulfate donor, is attached to a hydroxyl or other functional group (sulfate acceptor) of another molecule. This forms the sulfate form of the indole alkaloid. The process of transferring functional groups may also include methylation, in which a methyltransferase enzyme transfers a methyl group, i.e., a methyl donor, to a hydroxyl or other functional group (methyl acceptor). This forms the methylated form of the indole alkaloid. This process of transferring functional groups may involve acylation, where an acyl group, or acyl donor, is attached to a hydroxyl or other functional group (acyl acceptor) of another molecule. This results in the formation of the acyl form of indole alkaloids.

[0100] In one embodiment, the compound of formula (Ia) is provided herein. [ka] or a pharmaceutically acceptable salt thereof, in the formula, R 1 and R 10 These are independently selected from hydrogen, C1-C6 alkyl, C2-C6 alkenyl, and C2-C6 alkynyl, where alkyl, alkenyl, and alkynyl may optionally be independently substituted with one or more substituents selected from halo, -OMe, -CN, -NH2, and -NO2. R 8 is -CR'2-, where each R' is independently selected from hydrogen, halo, haloalkyl, alkoxy, haloalkoxy, and amine. n is selected from 2, 3, and 4. R 9 is selected from C2-C6 alkyl, C2-C6 alkenyl, and C2-C6 alkynyl, where alkyl, alkenyl, and alkynyl may optionally be substituted by one or more substituents independently selected from halo, -OMe, -CN, -NH2, -NO2, and 3- to 8-membered heterocycles, and the 3- to 8-membered heterocycle may optionally be substituted by one or more substituents independently selected from halo, -OMe, -CN, -NH2, and -NO2. R 2 These are selected from hydrogen, halogens, C1-C6 alkyl groups, and C1-C6 haloalkyl groups. R 4 , R 5 , R 6 , and R 7 Each of these is independently selected from hydrogen, C1-C6 alkyl, A, J, Q, and X. A is [ka] And, J is [ka] And, Q is [ka] And, X is selected from glucose, xylose, galactose, rhamnose, rutinose, and disaccharides. R 13 This is selected from C1-C6 alkyl groups, which may optionally be substituted with hydrogen and one or more substituents independently selected from C1-C6 alkyl, oxo, halo, -OMe, -CN, -NH2, and -NO2. R 14The C1-C6 alkyl and C2-C6 alkenyl atoms are selected from C1-C6 alkyl and C2-C6 alkenyl atoms, which may optionally be substituted with one or more substituents independently selected from halo, -OMe, -CN, -NH2, and -NO2. Alternatively, R 13 and R 14 These, together with the atoms to which they are bonded, form substituted or unsubstituted C3-C8 cycloalkyl groups, or substituted or unsubstituted 3-8 membered heterocycloalkyl groups, each having one or two heteroatoms independently selected from N, O, and S. R 15 This is selected from C1-C6 alkylenes and C2-C6 alkenylenes, where the C1-C6 alkylenes and C2-C6 alkenylenes may optionally be substituted with one or more substituents independently selected from C1-C6 alkyl, halo, -OMe, -CN, -NH2, and -NO2. Here, R 4 , R 5 , R 6 , and at least one of R7 is A, J, Q, or X.

[0101] In certain embodiments, the compound of formula (I) is provided herein: [ka] or a pharmaceutically acceptable salt thereof, in the formula, R 1 and R 10 These are independently selected from hydrogen, C1-C6 alkyl, C2-C6 alkenyl, and C2-C6 alkynyl, where alkyl, alkenyl, and alkynyl may optionally be independently substituted with one or more substituents selected from halo, -OMe, -CN, -NH2, and -NO2. R 8 is -CR'2-, where each R' is independently selected from hydrogen, halo, haloalkyl, alkoxy, haloalkoxy, and amine. n is selected from 2, 3, and 4. R9 is selected from C2-C6 alkyl, C2-C6 alkenyl, and C2-C6 alkynyl, where alkyl, alkenyl, and alkynyl may optionally be substituted by one or more substituents independently selected from halo, -OMe, -CN, -NH2, -NO2, and 3- to 8-membered heterocycles, and the 3- to 8-membered heterocycle may optionally be substituted by one or more substituents independently selected from halo, -OMe, -CN, -NH2, and -NO2. R 2 These are selected from hydrogen, halogens, C1-C6 alkyl groups, and C1-C6 haloalkyl groups. R 4 , R 5 , R 6 , and R 7 Each of these is independently selected from hydrogen, C1-C6 alkyl, A, J, Q, and X. A is [ka] And, J is [ka] And, Q is [ka] And, X is selected from glucose, xylose, galactose, rhamnose, and rutinose. R 13 This is selected from C1-C6 alkyl groups, which may optionally be substituted with hydrogen and one or more substituents independently selected from halo, -OMe, -CN, -NH2, and -NO2. R 14 The C1-C6 alkyl and C2-C6 alkenyl atoms are selected from C1-C6 alkyl and C2-C6 alkenyl atoms, which may optionally be substituted with one or more substituents independently selected from halo, -OMe, -CN, -NH2, and -NO2. R15 This is selected from C1-C6 alkylenes and C2-C6 alkenylenes, where the C1-C6 alkylenes and C2-C6 alkenylenes may optionally be substituted with one or more substituents independently selected from halo, -OMe, -CN, -NH2, and -NO2. Here, R 4 , R 5 , R 6 , and R 7 At least one of them is A or Q, or R 5 , R 6 , and R 7 At least one of them is J or X.

[0102] In some embodiments, R 1 R is selected from hydrogen, C1-C6 alkyl, C2-C6 alkenyl, and C2-C6 alkynyl, where alkyl, alkenyl, and alkynyl may be independently and optionally substituted with one or more substituents selected from halo, -OMe, -CN, -NH2, and -NO2. In some embodiments, R 1 R is selected from hydrogen, C1-C6 alkyl, and C2-C6 alkenyl, where alkyl and alkenyl may be independently and optionally substituted with one or more substituents selected from halo, -OMe, -CN, -NH2, and -NO2. In some embodiments, R 1 R is selected from hydrogen and C1-C6 alkyl groups, where the alkyl group may optionally be substituted with one or more substituents independently selected from halo, -OMe, and -CN. In some embodiments, R 1 R is selected from hydrogen and C1-C3 alkyl groups. In some embodiments, R 1 is hydrogen. In some embodiments, R 1 These are C1-C3 alkyl groups.

[0103] In some embodiments, R 10R is selected from hydrogen, C1-C6 alkyl, C2-C6 alkenyl, and C2-C6 alkynyl, where alkyl, alkenyl, and alkynyl may be independently and optionally substituted with one or more substituents selected from halo, -OMe, -CN, -NH2, and -NO2. In some embodiments, R 10 R is selected from hydrogen, C1-C6 alkyl, and C2-C6 alkenyl, where alkyl and alkenyl may be independently and optionally substituted with one or more substituents selected from halo, -OMe, -CN, -NH2, and -NO2. In some embodiments, R 10 R is selected from hydrogen, C1-C3 alkyl, and C2-C3 alkenyl, where the alkyl and alkenyl may optionally be substituted with one or more substituents independently selected from halo, -OMe, and -CN. In some embodiments, R 10 R is independently selected from hydrogen, C1-C3 alkyl, and C2-C3 alkenyl. In some embodiments, R 10 is hydrogen. In some embodiments, R 10 is a C1-C3 alkyl group. In some embodiments, R 10 These are C2-C3 alkenyls.

[0104] In some embodiments, each R' is independently selected from hydrogen, halo, haloalkyl, alkoxy, haloalkoxy, and amine. In some embodiments, each R' is independently selected from hydrogen, halo, and haloalkyl. In some embodiments, each R' is hydrogen. In some embodiments, each R' is halo. In some embodiments, each R' is haloalkyl. In some embodiments, each R' is alkoxy. In some embodiments, each R' is haloalkoxy. In some embodiments, each R' is amine.

[0105] In some embodiments, n is selected from 2, 3, and 4. In some embodiments, n is selected from 2 and 3. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4.

[0106] In some embodiments, R 9 R is selected from C2-C6 alkyl, C2-C6 alkenyl, and C2-C6 alkynyl, where alkyl, alkenyl, and alkynyl may optionally be substituted by one or more substituents independently selected from halo, -OMe, -CN, -NH2, -NO2, and 3- to 8-membered heterocycles, and the 3- to 8-membered heterocycle may optionally be substituted by one or more substituents independently selected from halo, -OMe, -CN, -NH2, and -NO2. In some embodiments, R 9 R is selected from C2-C6 alkyl, C2-C6 alkenyl, and C2-C6 alkynyl, where alkyl, alkenyl, and alkynyl may optionally be substituted with one or more substituents independently selected from halo, -OMe, -CN, -NH2, -NO2, and 3- to 8-membered heterocycles, and the 3- to 8-membered heterocycle may optionally be substituted with one or more substituents independently selected from halo, -OMe, and -CN. In some embodiments, R 9 R is selected from C2-C6 alkyl and C2-C6 alkenyl groups, where the alkyl and alkenyl groups may optionally be substituted with one or more substituents independently selected from halo, -OMe, -CN, and -NH2. In some embodiments, R 9 R is selected from C2-C3 alkyl and C2-C3 alkenyl, where the alkyl and alkenyl may optionally be substituted with one or more substituents independently selected from halo, -OMe, and -CN. In some embodiments, R 9 is a C2-C3 alkyl group. In some embodiments, R 9 These are C2-C3 alkenyls.

[0107] In some embodiments, R 2 R is selected from hydrogen, halogens, C1-C6 alkyls, and C1-C6 haloalkyls. In some embodiments, R 2 R is selected from hydrogen, halogens, and C1-C6 alkyl groups. In some embodiments, R 2 is hydrogen. In some embodiments, R 2 is a halogen. In some embodiments, R 2 is a C1-C6 alkyl group. In some embodiments, R 2 These are C1-C6 haloalkyl groups.

[0108] In some embodiments, R 4 , R 5 , R 6 , and R 7 Each of these is independently selected from hydrogen, A, J, Q, and X. In some embodiments, R 4 , R 5 , R 6 , and R 7 Each is independently selected from hydrogen, J, and Q. In some embodiments, R 4 , R 5 , R 6 , and R 7 At least one of them is A or Q. In some embodiments, R 5 , R 6 , and R 7 At least one of them is J or X. In some embodiments, R 4 , R 5 , R 6 , and R 7 At least one of them is A. In some embodiments, R 4 is A. In some embodiments, R 5 In some embodiments, R 6 In some embodiments, R 7 In some embodiments, R 4 , R 5 , R 6 , and R 7At least one of them is Q. In some embodiments, R 4 is Q. In some embodiments, R 5 is Q. In some embodiments, R 6 is Q. In some embodiments, R 7 is Q. In some embodiments, R 5 , R 6 , and R 7 At least one of them is J. In some embodiments, R 5 In some embodiments, R 6 In some embodiments, R 7 In some embodiments, R 5 , R 6 , and R 7 At least one of them is X. In some embodiments, R 5 is X. In some embodiments, R 6 is X. In some embodiments, R 7 X is X.

[0109] In some embodiments, R 4 , R 5 , R 6 , and R 7 At least one of them is A, J, Q, or X. In some embodiments, R 4 , R 5 , and R 6 At least one of them is A, J, Q, or X. In some embodiments, R 4 , R 5 , and R 7 At least one of them is A, J, Q, or X. In some embodiments, R 5 , R 6 , and R 7 At least one of them is A, J, Q, or X. In some embodiments, R 4 and R 7 At least one of them is A, J, Q, or X. In some embodiments, R 4 and R 5At least one of them is A, J, Q, or X. In some embodiments, R 4 and R 6 At least one of them is A, J, Q, or X.

[0110] In some embodiments, R 4 is A, J, Q, or X, and R 5 , R 6 , and R 7 is hydrogen or a C1-C6 alkyl group. In some embodiments, R 4 is A, J, Q, or X, and R 5 , R 6 , and R 7 is hydrogen. In some embodiments, R 5 is A, J, Q, or X, and R 4 , R 6 , and R 7 is hydrogen or a C1-C6 alkyl group. In some embodiments, R 5 is A, J, Q, or X, and R 4 , R 6 , and R 7 is hydrogen. In some embodiments, R 6 is A, J, Q, or X, and R 4 , R 5 , and R 7 is hydrogen or a C1-C6 alkyl group. In some embodiments, R 6 is A, J, Q, or X, and R 4 , R 5 , and R 7 is hydrogen. In some embodiments, R 7 is A, J, Q, or X, and R 4 , R 5 , and R 6 is hydrogen or a C1-C6 alkyl group. In some embodiments, R 7 is A, J, Q, or X, and R 4 , R 5 , and R 6 It is hydrogen.

[0111] In some embodiments, R13 R is selected from hydrogen and C1-C6 alkyl groups which may optionally be substituted with one or more substituents independently selected from C1-C6 alkyl, oxo, halo, -OMe, -CN, -NH2, and -NO2. In some embodiments, R 13 is a C1-C6 alkyl which may optionally be substituted with one or more substituents independently selected from C1-C6 alkyl, oxo, halo, -OMe, -CN, -NH2, and -NO2. In some embodiments, R 13 is a C1-C6 alkyl which may be optionally substituted with one or more C1-C6 alkyls or oxos. In some embodiments, R 13 is a C1-C6 alkyl which may be optionally substituted with one or more C1-C6 alkyls. In some embodiments, R 13 This is a C1-C6 alkyl group which may be substituted as needed with one or more oxos.

[0112] In some embodiments, R 13 R is selected from C1-C6 alkyl groups, which may optionally be substituted with hydrogen and one or more substituents independently selected from halo, -OMe, -CN, -NH2, and -NO2. In some embodiments, R 13 R is selected from C1-C6 alkyl groups, which may optionally be substituted with hydrogen and one or more substituents independently selected from halo, -OMe, -CN, and -NH2. In some embodiments, R 13 R is selected from hydrogen and C1-C3 alkyl groups which may optionally be substituted with one or more substituents independently selected from halo, -OMe, and -CN. In some embodiments, R 13 is hydrogen. In some embodiments, R 13 These are C1-C3 alkyl groups.

[0113] In some embodiments, R 14R is selected from C1-C6 alkyl and C2-C6 alkenyl groups, where the C1-C6 alkyl and C2-C6 alkenyl groups may optionally be substituted with one or more substituents independently selected from halo, -OMe, -CN, -NH2, and -NO2. In some embodiments, R 14 R is selected from C1-C6 alkyl and C2-C6 alkenyl groups, where the C1-C6 alkyl and C2-C6 alkenyl groups may optionally be substituted with one or more substituents independently selected from halo, -OMe, and -CN. In some embodiments, R 14 is a C1-C3 alkyl which may optionally be substituted with one or more substituents independently selected from halo, -OMe, and -CN. In some embodiments, R 14 is a C1-C3 alkyl group. In some embodiments, R 14 These are C2-C3 alkenyls.

[0114] In some embodiments, R 13 and R 14 These, together with the atoms to which they are bonded, form a substituted or unsubstituted C3-C8 cycloalkyl or a substituted or unsubstituted 3-8 membered heterocycloalkyl having one or two heteroatoms independently selected from N, O, and S, respectively. In some embodiments, R 13 and R 14 These, together with the atoms to which they are bonded, form substituted or unsubstituted C3-C8 cycloalkyl groups. In some embodiments, R 13 and R 14 These, together with the atoms to which they are bonded, form substituted or unsubstituted 3- to 8-membered heterocycloalkyls having one or two heteroatoms independently selected from N, O, and S, respectively.

[0115] In some embodiments, R 13 and R 14These, together with the atoms to which they are bonded, form cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclooctyl, spiro[2.2]pentyl, norbornyl, or bisicle[1.1.1]pentyl. In some embodiments, R 13 and R 14 These, together with the atoms to which they are bonded, form a cyclopropyl group. In some embodiments, R 13 and R 14 These, together with the atoms to which they are bonded, form cyclobutyl. In some embodiments, R 13 and R 14 These, together with the atoms to which they are bonded, form cyclopentyl. In some embodiments, R 13 and R 14 These atoms, along with the atoms to which they are bonded, form a cyclohexyl molecule.

[0116] In some embodiments, R 13 and R 14 Together with the atoms to which they are bonded, they form dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, and 1,1-dioxo-thiomorpholinyl.

[0117] In some embodiments, R 15 R is selected from hydrogen and C1-C6 alkyl groups which may optionally be substituted with one or more substituents independently selected from C1-C6 alkyl, oxo, halo, -OMe, -CN, -NH2, and -NO2. In some embodiments, R15 is a C1-C6 alkyl which may optionally be substituted with one or more substituents independently selected from C1-C6 alkyl, oxo, halo, -OMe, -CN, -NH2, and -NO2. In some embodiments, R 15 is a C1-C6 alkyl which may be optionally substituted with one or more C1-C6 alkyls or oxos. In some embodiments, R 15 is a C1-C6 alkyl which may be optionally substituted with one or more C1-C6 alkyls. In some embodiments, R 15 This is a C1-C6 alkyl group which may be substituted as needed with one or more oxos.

[0118] In some embodiments, R 15 R is selected from C1-C6 alkylenes and C2-C6 alkenylenes, where C1-C6 alkylenes and C2-C6 alkenylenes may be optionally substituted with one or more substituents independently selected from halo, -OMe, -CN, -NH2, and -NO2. In some embodiments, R 15 R is selected from C1-C6 alkylenes and C2-C6 alkenylenes, where C1-C6 alkylenes and C2-C6 alkenylenes may be optionally substituted with one or more substituents independently selected from halo, -OMe, and -CN. In some embodiments, R 15 R is selected from C1-C3 alkylenes and C2-C3 alkenylenes, where C1-C3 alkylenes and C2-C3 alkenylenes may be optionally substituted with one or more substituents independently selected from halo, -OMe, and -CN. In some embodiments, R 15 is a C1-C3 alkylene which may be optionally substituted with one or more substituents independently selected from halo, -OMe, and -CN. In some embodiments, R 15 R is a C1-C3 alkylene. In some embodiments, 15 These are C2-C3 alkenylenes.

[0119] In some embodiments, X is selected from glucose, xylose, galactose, rhamnose, rutinose, and disaccharides. In some embodiments, X is selected from glucose, galactose, rhamnose, rutinose, and disaccharides. In some embodiments, X is selected from glucose, xylose, rhamnose, rutinose, and disaccharides. In some embodiments, X is selected from glucose, xylose, galactose, rutinose, and disaccharides. In some embodiments, X is selected from glucose, xylose, galactose, rhamnose, and disaccharides.

[0120] In some embodiments, X is a disaccharide.

[0121] In some embodiments, X is a disaccharide selected from the group consisting of sucrose, lactose, maltose, trehalose, cellobiose, chitobiose, kojibiose, nigerose, isomaltose, β,β-trehalose, α,β-trehalose, sophorose, laminaribiose, genthiobiose, trehalulose, turanose, maltulose, leucrose, isomaltulose, genthiobiose, mannoviobiose, melibiose, melibiurose, rutinose, rutinulose, and xylobiose.

[0122] In some embodiments, X is a disaccharide selected from the group consisting of sucrose, lactose, maltose, trehalose, cellobiose, and chitobiose.

[0123] In some embodiments, X is selected from glucose, xylose, galactose, rhamnose, and rutinose. In some embodiments, X is selected from glucose, galactose, and rhamnose. In some embodiments, X is glucose. In some embodiments, X is xylose. In some embodiments, X is galactose. In some embodiments, X is rhamnose. In some embodiments, X is rutinose.

[0124] In a particular embodiment, the compound of formula (I) is the compound of formula (Ib), [ka] In the formula, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , and R 8 This is defined in this specification as described above.

[0125] In a particular embodiment, the compound of formula (I) is the compound of formula (Ib-1), [ka] In the formula, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , and R 7 This is defined in this specification as described above.

[0126] In a particular embodiment, the compound of formula (I) is the compound of formula (Ib-2), [ka] In the formula, R 1 , R 2 , R 4 , and R 5 This is defined in this specification as described above.

[0127] In a particular embodiment, the compound of formula (I) is the compound of formula (Ic), [ka] R 1 and R 10These are independently selected from hydrogen, C1-C6 alkyl, C2-C6 alkenyl, and C2-C6 alkynyl, where alkyl, alkenyl, and alkynyl may optionally be independently substituted with one or more substituents selected from halo, -OMe, -CN, -NH2, and -NO2. R 8 is -CR'2-, where each R' is independently selected from hydrogen, halo, haloalkyl, alkoxy, haloalkoxy, and amine. n is selected from 2, 3, and 4. R 9 is selected from C2-C6 alkyl, C2-C6 alkenyl, and C2-C6 alkynyl, where alkyl, alkenyl, and alkynyl may optionally be substituted by one or more substituents independently selected from halo, -OMe, -CN, -NH2, -NO2, and 3- to 8-membered heterocycles, and the 3- to 8-membered heterocycle may optionally be substituted by one or more substituents independently selected from halo, -OMe, -CN, -NH2, and -NO2. R 2 These are selected from hydrogen, halogens, C1-C6 alkyl groups, and C1-C6 haloalkyl groups. R 4 It is selected from A, J, Q, and X. A is [ka] And, J is [ka] And, Q is [ka] And, X is selected from glucose, xylose, galactose, rhamnose, rutinose, and disaccharides. R 13This is selected from C1-C6 alkyl groups, which may optionally be substituted with hydrogen and one or more substituents independently selected from C1-C6 alkyl, oxo, halo, -OMe, -CN, -NH2, and -NO2. R 14 The C1-C6 alkyl and C2-C6 alkenyl atoms are selected from C1-C6 alkyl and C2-C6 alkenyl atoms, which may optionally be substituted with one or more substituents independently selected from halo, -OMe, -CN, -NH2, and -NO2. R 15 The substituent is selected from C1-C6 alkylenes and C2-C6 alkenylenes, where the C1-C6 alkylenes and C2-C6 alkenylenes may optionally be substituted with one or more substituents independently selected from C1-C6 alkyl, halo, -OMe, -CN, -NH2, and -NO2.

[0128] In certain embodiments, the compound of formula (Ic) is the compound of formula (Ic-1). [ka]

[0129] In certain embodiments, the compound of formula (Ic) is the compound of formula (Ic-2). [ka]

[0130] In certain embodiments, the compound of formula (Ic) is the compound of formula (Ic-3). [ka]

[0131] In certain embodiments, the compound of formula (Ic) is the compound of formula (Ic-4). [ka]

[0132] In certain embodiments, the compound of formula (Ic) is the compound of formula (Ic-4a). [ka]

[0133] In a particular embodiment, the compound of formula (I) is the compound of formula (Id), [ka] R 1 and R 10 These are independently selected from hydrogen, C1-C6 alkyl, C2-C6 alkenyl, and C2-C6 alkynyl, where alkyl, alkenyl, and alkynyl may optionally be independently substituted with one or more substituents selected from halo, -OMe, -CN, -NH2, and -NO2. R 8 is -CR'2-, where each R' is independently selected from hydrogen, halo, haloalkyl, alkoxy, haloalkoxy, and amine. n is selected from 2, 3, and 4. R 9 is selected from C2-C6 alkyl, C2-C6 alkenyl, and C2-C6 alkynyl, where alkyl, alkenyl, and alkynyl may optionally be substituted by one or more substituents independently selected from halo, -OMe, -CN, -NH2, -NO2, and 3- to 8-membered heterocycles, and the 3- to 8-membered heterocycle may optionally be substituted by one or more substituents independently selected from halo, -OMe, -CN, -NH2, and -NO2. R 2 These are selected from hydrogen, halogens, C1-C6 alkyl groups, and C1-C6 haloalkyl groups. R 4 It is selected from A, J, Q, and X. A is [ka] And, J is [ka] And, Q is [ka] And, X is selected from glucose, xylose, galactose, rhamnose, rutinose, and disaccharides. R 13 This is selected from C1-C6 alkyl groups, which may optionally be substituted with hydrogen and one or more substituents independently selected from C1-C6 alkyl, oxo, halo, -OMe, -CN, -NH2, and -NO2. R 14 The C1-C6 alkyl and C2-C6 alkenyl atoms are selected from C1-C6 alkyl and C2-C6 alkenyl atoms, which may optionally be substituted with one or more substituents independently selected from halo, -OMe, -CN, -NH2, and -NO2. R 15 The substituent is selected from C1-C6 alkylenes and C2-C6 alkenylenes, where the C1-C6 alkylenes and C2-C6 alkenylenes may optionally be substituted with one or more substituents independently selected from C1-C6 alkyl, halo, -OMe, -CN, -NH2, and -NO2.

[0134] Furthermore, in other embodiments, indole alkaloids are also provided herein. In some embodiments, the indole alkaloids provided herein are compounds of formula (II): [ka] or a pharmaceutically acceptable salt thereof, where R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and R 7 These are, independently, halo, -OH, and C. 1~5Alkyl, C 1~5 Alkoxy, C 2~5 Alkenyl, -C(O)(C 1~8 C (alkyl), which may be substituted as needed. 6~10 Aryl, 5-10 member heteroaryl, C 3~10 The substituents are selected from cycloalkyl groups, 3- to 10-membered heterocycloalkyl groups, NO2, NH2, COOH, CN, -SH, SO3, SO4, and PO4. In some embodiments, substituents on the indole alkaloid function as acceptor functional groups for which the enzyme transfers donor functional groups.

[0135] In this specification, tryptamine alkaloids are provided in a different embodiment. In some embodiments, the tryptamine alkaloids provided herein are compounds of formula (III): [ka] or a pharmaceutically acceptable salt thereof, where R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , and R 11 These are, independently, halo, -OH, and C. 1~5 Alkyl, C 1~5 Alkoxy, C 2~5 Alkenyl, -C(O)(C 1~8 C (alkyl), which may be substituted as needed. 6~10 Aryl, 5-10 member heteroaryl, C 3~10 The substituents are selected from cycloalkyl groups, 3- to 10-membered heterocycloalkyl groups, NO2, NH2, COOH, CN, -SH, SO3, SO4, and PO4. In some embodiments, substituents on the tryptamine alkaloid function as acceptor functional groups for which the enzyme transfers donor functional groups.

[0136] In this specification, ergoline alkaloids are provided in a different embodiment. In some embodiments, the ergoline alkaloids provided herein are compounds of formula (IV): [ka] or a pharmaceutically acceptable salt thereof, in the formula, [ka] R is a single bond or a double bond, 1 , R 2 , and R 3 These are, independently, halo, -OH, and C. 1~5 Alkyl, C 1~5 Alkoxy, C 2~5 Alkenyl, -C(O)(C 1~8 C (alkyl), which may be substituted as needed. 6~10 Aryl, 5-10 member heteroaryl, C 3~10 The substituents are selected from cycloalkyl groups, 3- to 10-membered heterocycloalkyl groups, NO2, NH2, COOH, CN, -SH, SO3, SO4, and PO4. In some embodiments, substituents on the ergoline alkaloid function as acceptor functional groups for which the enzyme transfers donor functional groups.

[0137] In this specification, beta-carboline alkaloids are provided in a different embodiment. In some embodiments, the beta-carboline alkaloids provided herein are compounds of formula (V): [ka] or a pharmaceutically acceptable salt thereof, in the formula, [ka] R is a single bond or a double bond, 1 , R 2 , R 3 , and R 4 These are, independently, halo, -OH, and C. 1~5 Alkyl, C 1~5Alkoxy, C 2~5 Alkenyl, -C(O)(C 1~8 C (alkyl), which may be substituted as needed. 6~10 Aryl, 5-10 member heteroaryl, C 3~10 The substituents are selected from cycloalkyl groups, 3- to 10-membered heterocycloalkyl groups, NO2, NH2, COOH, CN, -SH, SO3, SO4, and PO4, where R5 is H or methyl. In some embodiments, substituents on the beta-carbolin alkaloid function as acceptor functional groups for which the enzyme transfers donor functional groups.

[0138] In this specification, ibogamine alkaloids are provided in a different embodiment. In some embodiments, the ibogamine alkaloids provided herein are compounds of formula (VI): [ka] or a pharmaceutically acceptable salt thereof, where R 1 , R 2 , R 3 , and R 4 These are, independently, halo, -OH, and C. 1~5 Alkyl, C 1~5 Alkoxy, C 2~5 Alkenyl, -C(O)(C 1~8 C (alkyl), which may be substituted as needed. 6~10 Aryl, 5-10 member heteroaryl, C 3~10 The substituents are selected from cycloalkyl groups, 3- to 10-membered heterocycloalkyl groups, NO2, NH2, COOH, CN, -SH, SO3, SO4, and PO4. In some embodiments, substituents on the ibogamine alkaloid function as acceptor functional groups for which the enzyme transfers donor functional groups.

[0139] In this specification, mitraginine alkaloids are provided in a different embodiment. In some embodiments, the mitraginine alkaloids provided herein are compounds of formula (VII): [ka] or a pharmaceutically acceptable salt thereof, where R 1 , R 2 , R 3 , R 4 , and R 5 These are, independently, halo, -OH, and C. 1~5 Alkyl, C 1~5 Alkoxy, C 2~5 Alkenyl, -C(O)(C 1~8 C (alkyl), which may be substituted as needed. 6~10 Aryl, 5-10 member heteroaryl, C 3~10 The substituents are selected from cycloalkyl groups, 3- to 10-membered heterocycloalkyl groups, NO2, NH2, COOH, CN, -SH, SO3, SO4, and PO4. In some embodiments, substituents on the mitraginine alkaloid function as acceptor functional groups for which the enzyme transfers donor functional groups.

[0140] In some embodiments, the compounds provided herein are 2-(4-methoxy-1H-indole-3-yl)-N,N-dimethylethane-1-amine, 3-(2-(dimethylamino)ethyl)-1H-indole-4-yl dihydrogen phosphate, 3-(2-(dimethylamino)ethyl)-1H-indole-4-yl acetate, 3-(2-(dimethylamino)ethyl)-1H-indole-4-yl propionic acid, 3-(2-(dimethylamino)ethyl)-1H-indole-4-yl butyrate, 3-(2-(dimethylamino)ethyl)-1H-indole-4-yl isobutyrate, and 3-((3-(2-(dimethylamino)ethyl)-1H-indole-4-yl)oxy)-3-oxopropane 4-((3-(2-(dimethylamino)ethyl)-1H-indole-4-yl)oxy)-4-oxobutanoic acid, 5-((3-(2-(dimethylamino)ethyl)-1H-indole-4-yl)oxy)-5-oxopentanoic acid, 6-((3-(2-(dimethylamino)ethyl)-1H-indole-4-yl)oxy)-6-oxohexanoic acid, 2-((3-(2-(dimethylamino)ethyl)-1H-indole-4-yl)oxy)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol, 2-((3-(2-(dimethylamino)ethyl)-1H-indole-4-yl)oxy)-6-methyltetrahydro-2H-pyran-3,4,5-triol, N-(2-(4-methoxy-1H-indole-3-yl)ethyl)-N-propylpropan-1-amine, 3-(2-(dipropylamino))ethyl)-1H-indole-4-yl dihydrogen phosphate, 3-(2-(dipropylamino)ethyl)-1H-indole-4-yl acetate, 3-(2-(dipropylamino)ethyl)-1H-indole-4-yl propionic acid, 3-(2-(dipropylamino)ethyl)-1H-indole-4-yl butyrate, 3-(2-(dipropylamino)ethyl)-1H-indole-4-yl isobutyrate, 3-((3-(2-(dipropylamino)ethyl)-1H-indole-4-yl)oxy)-3-oxopropanoic acid, 4-( (3-(2-(dipropylamino)ethyl)-1H-indole-4-yl)oxy)-4-oxobutanoic acid, 5-((3-(2-(dipropylamino)ethyl)-1H-indole-4-yl)oxy)-5-oxopentanoic acid, 6-((3-(2-(dipropylamino)ethyl)-1H-indole-4-yl)oxy)-6-oxohexanoic acid, 2-((3-(2-(dipropylamino)ethyl)-1H-indole-4-yl)oxy)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol, 2-((3-(2-(dipropylamino)ethyl)-1H-indole-4-yl)oxy)-6-methyltetrahydro-2H-pyran-3,4,5-triol, N-allyl-N-(2-(4-methoxy-1H-indole-3-yl)ethyl)propane-2-en-1-amine, 3-(2-(diallylamino)ethyl)-1H-indole-4-yl dihydrogen phosphate, 3-(2-(diallylamino)ethyl)-1H-indole-4-yl acetate, 3-(2-(diallylamino)ethyl)-1H-indole-4-yl propionic acid, 3-(2-(diallylamino)ethyl)-1H-indole-4-yl butyrate, 3-(2-(diallylamino)ethyl)-1H-indole-4-yl isobutyrate, 3-((3-(2-(diallylamino)ethyl)-1H-indole-4-yl)oxy)-3-oxopropanoic acid, 4-( (3-(2-(diallylamino)ethyl)-1H-indole-4-yl)oxy)-4-oxobutanoic acid, 5-((3-(2-(diallylamino)ethyl)-1H-indole-4-yl)oxy)-5-oxopentanoic acid, 6-((3-(2-(diallylamino)ethyl)-1H-indole-4-yl)oxy)-6-oxohexanoic acid, 2-((3-(2-(diallylamino)ethyl))-1H-indole-4-yl)oxy)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol, 2-((3-(2-(diallylamino)ethyl)-1H-indole-4-yl)oxy)-6-methyltetrahydro-2H-pyran-3,4,5-triol, N-(2-(4-methoxy-1H-indole-3-yl)ethyl)-N-methylpropan-2-amine, 3-(2-(isopropyl(methyl)amino)ethyl)-1H-indole-4-yl) dihydrogen phosphate, 3-(2-(isopropyl(methyl)amino)ethyl)-1H-indole-4-yl) acetate, 3-(2-(isopropyl(methyl)amino)ethyl)-1H-indole-4-yl) propionic acid, 3-(2-(isopropyl(methyl)amino)ethyl)-1H-indole-4-yl) isobutyrate, 3-((3-(2-(isopropyl(methyl)amino))ethyl)-1H-indole-4-yl)oxy)-3-oxopropanoic acid, 4-((3-(2-(isopropyl(methyl)amino)ethyl)-1H-indole-4-yl)oxy)-4-oxobutanoic acid, 5-((3-(2-(isopropyl(methyl)amino)ethyl)-1H-indole-4-yl)oxy)-5-oxopentanoic acid, 6-((3-(2-(isopropyl(methyl)amino)ethyl)-1H-indole-4-yl)oxy)-6-oxohexanoic acid, 2-((3-(2-(isopropyl(methyl)amino)ethyl)-1H-indole-4-yl)oxy)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol, 2-((3-(2-(isopropyl(methyl)amino)ethyl)-1H-indole-4-yl)oxy)-6-methyltetrahydro-2H-pyran-3,4,5-triol, N-ethyl-N-(2-(4-methoxy-1H-indole-3-yl)ethyl)propan-2-amine, 3-(2-(ethyl(isopropyl)amino)ethyl)-1H-indole-4-yl) dihydrogen phosphate, 3-(2-(ethyl(isopropyl)amino)ethyl)-1H-indole-4-yl) acetate, 3-(2-(ethyl(isopropyl)amino)ethyl)-1H-indole-4-yl) propionic acid, 3-(2-(ethyl(isopropyl)amino)ethyl)-1H-indole-4-yl) isobutyrate, 3-((3-(2-(ethyl(isopropyl)amino)ethyl)-1H-indole-4-yl)oxy)-3-oxopropanoic acid, 4 -((3-(2-(ethyl(isopropyl)amino)ethyl)-1H-indole-4-yl)oxy)-4-oxobutanoic acid, 4-((3-(2-(ethyl(isopropyl)amino)ethyl)-1H-indole-4-yl)oxy)-5-oxopentanoic acid, 4-((3-(2-(ethyl(isopropyl)amino)ethyl)-1H-indole-4-yl)oxy)-6-oxohexanoic acid, 2-((3-(2-(ethyl(isopropyl)amino)ethyl)-1H-indole-4-yl)oxy)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol, 2-((3-(2-(ethyl(isopropyl)amino)ethyl)-1H-indole-4-yl)oxy)-6-methyltetrahydro-2H-pyran-3,4,5-Triol, N-Isopropyl-N-(2-(4-Methoxy-1H-Indole-3-yl)ethyl)propan-2-amine, 3-(2-(diisopropylamino)ethyl)-1H-Indole-4-yl dihydrogen phosphate, 3-(2-(diisopropylamino)ethyl)-1H-Indole-4-yl acetate, 3-(2-(diisopropylamino)ethyl)-1H-Indole-4-yl propionic acid, 3-(2-(diisopropylamino)ethyl)-1H-Indole-4-yl butyrate, 3-((3-(2-(diisopropylamino)ethyl)-1H-Indole-4-yl)oxy)-3-oxopropanoic acid, 4-((3- (2-(diisopropylamino)ethyl)-1H-indole-4-yl)oxy)-4-oxobutanoic acid, 5-((3-(2-(diisopropylamino)ethyl)-1H-indole-4-yl)oxy)-5-oxopentanoic acid, 6-((3-(2-(diisopropylamino)ethyl)-1H-indole-4-yl)oxy)-6-oxohexanoic acid, 2-((3-(2-(diisopropylamino)ethyl)-1H-indole-4-yl)oxy)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol, 2-((3-(2-(diisopropylamino)ethyl)-1H-indole-4-yl)oxy)-6-methyltetrahydro-2H-pyran-3,4,5-triol, N,N-Diethyl-2-(4-methoxy-1H-indole)-3-yl)ethane-1-amine, 3-(2-(diethylamino)ethyl)-1H-indole-4-yl dihydrogen phosphate, 3-(2-(diethylamino)ethyl)-1H-indole-4-yl acetate, 3-(2-(diethylamino)ethyl)-1H-indole-4-yl propionic acid, 3-(2-(diethylamino)ethyl)-1H-indole-4-yl butyrate, 3-(2-(diethylamino)ethyl)-1H-indole-4-yl isobutyrate, 3-((3-(2-(diethylamino)ethyl)-1H-indole-4-yl)oxy)-3-oxopropanoic acid, 4-((3-(2-(di Ethylamino)ethyl)-1H-indole-4-yl)oxy)-4-oxobutanoic acid, 5-((3-(2-(diethylamino)ethyl)-1H-indole-4-yl)oxy)-5-oxopentanoic acid, 6-((3-(2-(diethylamino)ethyl)-1H-indole-4-yl)oxy)-6-oxohexanoic acid, 2-((3-(2-(diethylamino)ethyl)-1H-indole-4-yl)oxy)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol, 2-((3-(2-(diethylamino)ethyl)-1H-indole-4-yl)oxy)-6-methyltetrahydro-2H-pyran-3,4,5-triol, N-ethyl-N-(2-(4-methoxy-1H-indole-3-yl)ethyl)propan-1-amine, 3-(2-(ethyl(propyl)amino)ethyl)-1H-indole-4-yl dihydrogen phosphate, 3-(2-(ethyl(propyl)amino)ethyl)-1H-indole-4-yl acetate, 3-(2-(ethyl(propyl)amino)ethyl)-1H-indole-4-yl propionic acid, 3-(2-(ethyl(propyl)amino)ethyl)-1H-indole-4-yl butyrate, 3-(2-(ethyl(propyl)amino)ethyl)-1H-indole-4-yl isobutyrate, 3-((3-(2-(ethyl(propyl)amino)ethyl)-1H-indole-4-yl)oxy)-3-oxopropanoic acid, 4-((3-(2-(ethyl(propyl)amino)ethyl)-1H-indole- 4-yl)oxy)-4-oxobutanoic acid, 5-((3-(2-(ethyl(propyl)amino)ethyl)-1H-indole-4-yl)oxy)-5-oxopentanoic acid, 6-((3-(2-(ethyl(propyl)amino)ethyl)-1H-indole-4-yl)oxy)-6-oxohexanoic acid, 2-((3-(2-(ethyl(propyl))amino)ethyl)-1H-indole-4-yl) Xy)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol, 2-((3-(2-(ethyl(propyl)amino)ethyl)-1H-indole-4-yl)oxy)-6-methyltetrahydro-2H-pyran-3,4,5-triol, N-(2-(4-methoxy-1H-indole)-3-yl)ethyl)-N-methylcyclopropanamine, dihydrogen phosphate 3-(2-, (Cyclopropyl(methyl)amino)ethyl)-1H-indole-4-yl, 3-(2-(Cyclopropyl(methyl)amino)ethyl)-1H-indole-4-yl acetate, 3-(2-(Cyclopropyl(methyl)amino)ethyl)-1H-indole-4-yl propionic acid, 3-(2-(Cyclopropyl(methyl)amino)ethyl)-1H-indole-4-yl butyrate, 3-(2-(Cyclopropyl(methyl)amino)ethyl)-1H-indole-4-yl isobutyrate, 3-((3-(2-(Cyclopropyl(methyl)amino)ethyl)-1H-indole-4-yl)oxy)-3-oxopropanoic acid, 4-((3-(2-(Cyclopropyl(methyl)amino)ethyl)-1H- Indole-4-yl)oxy)-4-oxobutanoic acid, 5-((3-(2-(cyclopropyl(methyl)amino)ethyl)-1H-indole-4-yl)oxy)-5-oxopentanoic acid, 6-((3-(2-(cyclopropyl(methyl)amino)ethyl)-1H-indole-4-yl)oxy)-6-oxohexanoic acid, 2-((3-(2-(cyclopropyl(methyl)amino)ethyl)-1H-indole-4-yl)oxy)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol, 2-((3-(2-(cyclopropyl(methyl)amino)ethyl)-1H-indole-4-yl)oxy)-6-methyltetrahydro-2H-pyran-3,4,5-triol, N-ethyl-2-(4-methoxy-1H-indole-3-yl)-N-methylethane-1-amine, 3-(2-(ethyl(methyl)amino)ethyl)-1H-indole-4-yl dihydrogen phosphate, 3-(2-(ethyl(methyl)amino)ethyl)-1H-indole-4-yl acetate, 3-(2-(ethyl(methyl)amino)ethyl)-1H-indole-4-yl propionic acid, 3-(2-(ethyl(methyl)amino)ethyl)-1H-indole-4-yl butyrate, 3-(2-(ethyl(methyl))amino)ethyl)-1H-indole-4-yl isobutyrate, 3-((3-(2-(ethyl(methyl))amino)ethyl)-1H-indole-4-yl)oxy)-3-oxopropanoic acid, 4- ((3-(2-(ethyl(methyl)amino)ethyl)-1H-indole-4-yl)oxy)-4-oxobutanoic acid, 4-((3-(2-(ethyl(methyl)amino)ethyl)-1H-indole-4-yl)oxy)-4-oxobutanoic acid, 6-((3-(2-(ethyl(methyl)amino)ethyl)-1H-indole-4-yl)oxy)-6-oxohexanoic acid, 2-((3-(2-(ethyl(methyl)amino)ethyl)-1H-indole-4-yl)oxy)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol, 2-((3-(2-(ethyl(methyl)amino)ethyl)-1H-indole-4-yl)oxy)-6-methyltetrahydro-2H-pyran-3,4,5-triol, N-(2-(4-methoxy-1H-indole-3-yl)ethyl)-N-methylpropane-2-en-1-amine, 3-(2-(allyl(methyl)amino)ethyl)-1H-indole-4-yl dihydrogen phosphate, 3-(2-(allyl(methyl)amino)ethyl)-1H-indole-4-yl acetate, 3-(2-(allyl(methyl)amino)ethyl)-1H-indole-4-yl propionic acid, 3-(2-(allyl(methyl)amino)ethyl)-1H-indole-4-yl butyrate, 3-(2-(allyl(methyl)amino)ethyl)-1H-indole-4-yl isobutyrate, 3-((3-(2-(allyl(methyl)amino)ethyl)-1H-indole-4-yl)oxy)-3-oxopropanoic acid, 4-((3-(2-(allyl(methyl)amino)ethyl)-1H-indole-4-yl)oxy)-4-oxobutanoic acid, 5-((3-(2-(allyl(methyl)amino)ethyl)-1H-indole-4-yl)oxy)-5-oxopentanoic acid, 6-((3-(2-(allyl(methyl)amino)ethyl)-1H-indole-4-yl)oxy)-6-oxohexanoic acid, 2-((3-(2-(allyl(methyl)amino)ethyl)-1H-indole-4-yl)oxy)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol, 2-((3-(2-(allyl(methyl)amino)ethyl)-1H-indole-4-yl)oxy)-6-methyltetrahydro-2H-pyran-3,4,5-triol, N-ethyl-N-(2-(4-methoxy-1H-indole)-3-yl)ethyl)propane-2-en-1-amine, 3-(2-(allyl(ethyl)amino)ethyl)-1H-indole-4-yl) dihydrogen phosphate, 3-(2-(allyl(ethyl)amino)ethyl)-1H-indole-4-yl) acetate, 3-(2-(allyl(ethyl)amino)ethyl)-1H-indole-4-yl) propionic acid, 3-(2-(allyl(ethyl)amino)ethyl)-1H-indole-4-yl) isobutyrate, 3-((3-(2-(allyl(ethyl)amino)ethyl)-1H-indole-4-yl)oxy)-3-oxopropanoic acid, 4-((3-(2-(allyl(ethyl)amino)ethyl)-1H-indole-4-yl)oxy)-4-oxobutanoic acid, 5-((3-(2-(allyl(ethyl)amino)ethyl)-1H-indole-4-yl)oxy)-5-oxopentanoic acid, 6-((3-(2-(allyl(ethyl)amino)ethyl)-1H-indole-4-yl)oxy)-6-oxohexanoic acid, 2-((3-(2-(allyl(ethyl)amino)ethyl)-1H-indole-4-yl)oxy)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol, 2-((3-(2-(allyl(ethyl)amino)ethyl)-1H-indole-4-yl)oxy)-6-methyltetrahydro-2H-pyran-3,4,5-triol, 4-methoxy-3-(2-(pyrrolidine-1-yl)ethyl)-1H-indole, dihydrogen phosphate 3-(2-(pyrrolidine-1-yl)ethyl)-1H-indole-4-yl, acetate 3-(2-(pyrrolidine-1-yl)ethyl)-1H-indole-4-yl, propionic acid 3-(2-(pyrrolidine-1-yl)ethyl)-1H-indole-4-yl, butyrate 3-(2-(pyrrolidine-1-yl)ethyl)-1H-indole-4-yl, isobutyrate 3-oxo-3-((3-(2-(pyrrolidine-1-yl)ethyl)-1H-indole-4-yl)oxy)propanoic acid, 4-oxo-4- ((3-(2-(pyrrolidine-1-yl)ethyl)-1H-indole-4-yl)oxy)butanoic acid, 5-oxo-5-((3-(2-(pyrrolidine-1-yl)ethyl)-1H-indole-4-yl)oxy)pentanoic acid, 6-oxo-6-((3-(2-(pyrrolidine-1-yl)ethyl)-1H-indole-4-yl)oxy)hexanoic acid, 2-(hydroxymethyl)-6-((3-(2-(pyrrolidine-1-yl)ethyl)-1H-indole-4-yl)oxy)tetrahydro-2H-pyran-3,4,5-triol, 2-methyl-6-((3-(2-(pyrrolidine)-1-yl)ethyl)-1H-indole-4-yl)oxy)tetrahydro-2H-pyran-3,4,5-triol, N-(2-(4-methoxy-1H-indole-3-yl)ethyl)acetamide, 3-(2-acetamidoethyl)-1H-indole-4-yl dihydrogen phosphate, 3-(2-acetamidoethyl)-1H-indole-4-yl acetate, 3-(2-acetamidoethyl)-1H-indole-4-yl propionic acid, 3-(2-acetamidoethyl)-1H-indole-4-yl butyrate, 3-(2-acetamidoethyl)-1H-indole-4-yl isobutyrate, 3-((3-(2-acetamidoethyl)-1H-indole-4-yl)oxy)-3-oxopropanoic acid, 4-((3-(2-acetamidoethyl)-1H-indole-4-yl)oxy C)-4-oxobutanoic acid, 5-((3-(2-acetamidoethyl)-1H-indole-4-yl)oxy)-5-oxopentanoic acid, 6-((3-(2-acetamidoethyl)-1H-indole-4-yl)oxy)-6-oxohexanoic acid, N-(2-(4-((3,4,5-trihydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-1H-indole-3-yl)ethyl)acetamide, N-(2-(4-((3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)-1H-indole-3-yl)ethyl)acetamide, 2-(5-methoxy-1H-indole-3-yl)-N,N-dimethylethane-1-amine, 3-(2-(dimethylamino)ethyl)-1H-indole-5-yl dihydrogen phosphate, 3-(2-(dimethylamino)ethyl)-1H-indole-5-yl acetate, 3-(2-(dimethylamino)ethyl)-1H-indole-5-yl propionic acid, 3-(2-(dimethylamino)ethyl)-1H-indole-5-yl butyrate, 3-(2-(dimethylamino)ethyl)-1H-indole-5-yl isobutyrate, 3-((3-(2-(dimethylamino)ethyl)-1H-indole-5-yl)oxy)-3-oxopropanoic acid, 4-((3-(2-(dimethylamino)ethyl)-1 H-indole-5-yl)oxy)-4-oxobutanoic acid, 5-((3-(2-(dimethylamino)ethyl)-1H-indole-5-yl)oxy)-5-oxopentanoic acid, 6-((3-(2-(dimethylamino)ethyl)-1H-indole-5-yl)oxy)-6-oxohexanoic acid, 2-((3-(2-(dimethylamino)ethyl)-1H-indole-5-yl)oxy)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol, 2-((3-(2-(dimethylamino)ethyl)-1H-indole-5-yl)oxy)-6-methyltetrahydro-2H-pyran-3,4,5-triol, N-(2-(5-methoxy-1H-indole-3-yl)ethyl)-N-propylpropan-1-amine, 3-(2-(dipropylamino)ethyl)-1H-indole-5-yl dihydrogen phosphate, 3-(2-(dipropylamino)ethyl)-1H-indole-5-yl acetate, 3-(2-(dipropylamino)ethyl)-1H-indole-5-yl propionic acid, 3-(2-(dipropylamino)ethyl)-1H -Indole-5-yl, 3-(2-(dipropylamino)ethyl)-1H-indole-5-yl isobutyrate, 3-((3-(2-(dipropylamino)ethyl)-1H-indole-5-yl)oxy)-3-oxopropanoic acid, 4-((3-(2-(dipropylamino)ethyl)-1H-indole-5-yl)oxy)-4-oxobutanoic acid, 5-((3-(2-(dipropylamino)ethyl)-1H-indole-5-yl)oxy )-5-oxopentanoic acid, 6-((3-(2-(dipropylamino)ethyl)-1H-indole-5-yl)oxy)-6-oxohexanoic acid, 2-((3-(2-(dipropylamino)ethyl)-1H-indole-5-yl)oxy)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol, 2-((3-(2-(dipropylamino)ethyl)-1H-indole-5-yl)oxy)-6-methyltetra Lahydro-2H-pyran-3,4,5-triol, N-allyl-N-(2-(5-methoxy-1H-indole-3-yl)ethyl)propa-2-en-1-amine, dihydrogen phosphate 3-(2-(diallylamino)ethyl)-1H-indole-5-yl, acetate 3-(2-(diallylamino)ethyl)-1H-indole-5-yl, propionic acid 3-(2-(, (Diallylamino)ethyl)-1H-indole-5-yl, 3-(2-(diallylamino)ethyl)-1H-indole-5-yl isobutyrate, 3-((3-(2-(diallylamino)ethyl)-1H-indole-5-yl)oxy)-3-oxopropanoic acid, 4-((3-(2-(diallylamino)ethyl)-1H-indole-5-yl)oxy)-4-oxobutanoic acid, 5-((3-(2-(diallylamino)ethyl)-1H-indole-5-yl)oxy) -5-oxopentanoic acid, 6-((3-(2-(diallylamino)ethyl)-1H-indole-5-yl)oxy)-6-oxohexanoic acid, 2-((3-(2-(diallylamino)ethyl)-1H-indole-5-yl)oxy)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol, 2-((3-(2-(diallylamino)ethyl)-1H-indole-5-yl)oxy)-6-methyltetrahydro-2H-pyran-3,4,5-triol, N-(2-(5-methoxy-1H-indole-3-yl)ethyl)-N-methylpropan-2-amine, 3-(2-(isopropyl(methyl)amino)ethyl)-1H-indole-5-yl) dihydrogen phosphate, 3-(2-(isopropyl(methyl)amino)ethyl)-1H-indole-5-yl) acetate, 3-(2-(isopropyl(methyl)amino)ethyl)-1H-indole-5-yl) propionic acid, 3-(2-(isopropyl(methyl)amino)ethyl)-1H-indole-5-yl) isobutyrate, 3-((3-(2-(isopropyl(methyl)amino)ethyl)-1H-indole-5-yl)oxy)-3-oxopropanoic acid, 4 -((3-(2-(isopropyl(methyl)amino)ethyl)-1H-indole-5-yl)oxy)-4-oxobutanoic acid, 5-((3-(2-(isopropyl(methyl)amino)ethyl)-1H-indole-5-yl)oxy)-5-oxopentanoic acid, 6-((3-(2-(isopropyl(methyl)amino)ethyl)-1H-indole-5-yl)oxy)-6-oxohexanoic acid, 2-((3-(2-(isopropyl(methyl)amino)ethyl)-1H-indole-5-yl)oxy)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol, 2-((3-(2-(isopropyl(methyl)amino)ethyl)-1H-indole-5-yl)oxy)-6-methyltetrahydro-2H-pyran-3,4,5-triol, N-ethyl-N-(2-(5-methoxy-1H-indole-3-yl)ethyl)propan-2-amine, 3-(2-(ethyl(isopropyl)amino)ethyl)-1H-indole-5-yl) dihydrogen phosphate, 3-(2-(ethyl(isopropyl)amino)ethyl)-1H-indole-5-yl) acetate, 3-(2-(ethyl(isopropyl)amino)ethyl)-1H-indole-5-yl) propionic acid, 3-(2-(ethyl(isopropyl)amino)ethyl)-1H-indole-5-yl) isobutyrate, 3-((3-(2-(ethyl(isopropyl)amino)ethyl)-1H-indole-5-yl)oxy)-3-oxopropanoic acid, 4 -((3-(2-(ethyl(isopropyl)amino)ethyl)-1H-indole-5-yl)oxy)-4-oxobutanoic acid, 4-((3-(2-(ethyl(isopropyl)amino)ethyl)-1H-indole-5-yl)oxy)-5-oxopentanoic acid, 4-((3-(2-(ethyl(isopropyl)amino)ethyl)-1H-indole-5-yl)oxy)-6-oxohexanoic acid, 2-((3-(2-(ethyl(isopropyl)amino)ethyl)-1H-indole-5-yl)oxy)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol, 2-((3-(2-(ethyl(isopropyl)amino)ethyl)-1H-indole-5-yl)oxy)-6-methyltetrahydro-2H-pyran-3,4,5-triol, N-isopropyl-N-(2-(5-methoxy-1H-indole-3-yl)ethyl)propan-2-amine, 3-(2-(diisopropylamino)ethyl)-1H-indole-5-yl dihydrogen phosphate, 3-(2-(diisopropylamino)ethyl)-1H-indole-5-yl acetate, 3-(2-(diisopropylamino)ethyl)-1H-indole-5-yl propionic acid, 3-(2-(diisopropylamino)ethyl)-1H-indole-5-yl butyrate, 3-(2-(diisopropylamino)ethyl)-1H-indole-5-yl isobutyrate, 3-((3-(2-(diisopropylamino)ethyl)-1H-indole-5-yl)oxy)-3-oxopropanoic acid, 4-((3- (2-(diisopropylamino)ethyl)-1H-indole-5-yl)oxy)-4-oxobutanoic acid, 5-((3-(2-(diisopropylamino)ethyl)-1H-indole-5-yl)oxy)-5-oxopentanoic acid, 6-((3-(2-(diisopropylamino)ethyl)-1H-indole-5-yl)oxy)-6-oxohexanoic acid, 2-((3-(2-(diisopropylamino)ethyl)-1H-indole-5-yl)oxy)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol, 2-((3-(2-(diisopropylamino)ethyl)-1H-indole-5-yl)oxy)-6-methyltetrahydro-2H-pyran-3,4,5-triol, N,N-Diethyl-2-(5-Methoxy-1H-Indole-3-yl)ethane-1-amine, 3-(2-(diethylamino)ethyl)-1H-Indole-5-yl dihydrogen phosphate, 3-(2-(diethylamino)ethyl)-1H-Indole-5-yl acetate, 3-(2-(diethylamino)ethyl)-1H-Indole-5-yl propionic acid, 3-(2-(diethylamino)ethyl)-1H-Indole-5-yl butyrate, 3-(2-(diethylamino)ethyl)-1H-Indole-5-yl isobutyrate, 3-((3-(2-(diethylamino)ethyl)-1H-Indole-5-yl)oxy)-3-oxopropanoic acid, 4-((3-(2-(diethylamino)ethyl) (Diethylamino)ethyl)-1H-indole-5-yl)oxy)-4-oxobutanoic acid, 5-((3-(2-(diethylamino)ethyl)-1H-indole-5-yl)oxy)-5-oxopentanoic acid, 6-((3-(2-(diethylamino)ethyl)-1H-indole-5-yl)oxy)-6-oxohexanoic acid, 2-((3-(2-(diethylamino)ethyl)-1H-indole-5-yl)oxy)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol, 2-((3-(2-(diethylamino)ethyl)-1H-indole-5-yl)oxy)-6-methyltetrahydro-2H-pyran-3,4,5-triol, N-ethyl-N-(2-(5-methoxy-1H-indole-3-yl)ethyl)propan-1-amine, 3-(2-(ethyl(propyl)amino)ethyl)-1H-indole-5-yl) dihydrogen phosphate, 3-(2-(ethyl(propyl)amino)ethyl)-1H-indole-5-yl) acetate, 3-(2-(ethyl(propyl)amino)ethyl)-1H-indole-5-yl) propionic acid, 3-(2-(ethyl(propyl)amino)ethyl)-1H-indole-5-yl) isobutyrate, 3-((3-(2-(ethyl(propyl)amino)ethyl)-1H-indole-5-yl)oxy)-3-oxopropanoic acid, 4- ((3-(2-(ethyl(propyl)amino)ethyl)-1H-indole-5-yl)oxy)-4-oxobutanoic acid, 5-((3-(2-(ethyl(propyl)amino)ethyl)-1H-indole-5-yl)oxy)-5-oxopentanoic acid, 6-((3-(2-(ethyl(propyl)amino)ethyl)-1H-indole-5-yl)oxy)-6-oxohexanoic acid, 2-((3-(2-(ethyl(propyl)amino)ethyl)-1H-indole-5-yl)oxy)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol, 2-((3-(2-(ethyl(propyl)amino)ethyl)-1H-indole-5-yl)oxy)-6-methyltetrahydro-2H-pyran-3,4,5-triol, N-(2-(5-methoxy-1H-indole-3-yl)ethyl)-N-methylcyclopropanamine, 3-(2-(cyclopropyl(methyl)amino)ethyl)-1H-indole-5-yl) dihydrogen phosphate, 3-(2-(cyclopropyl(methyl)amino)ethyl)-1H-indole-5-yl) acetate, 3-(2-(cyclopropyl(methyl)amino)ethyl)-1H-indole-5-yl) propionic acid, 3-(2-(cyclopropyl(methyl)amino)ethyl)-1H-indole-5-yl) isobutyrate, 3-((3-(2-(cyclopropyl(methyl)amino)ethyl)-1H-indole-5-yl)oxy)-3-oxopropanoic acid, 4-((3-(2-(cyclopropyl(methyl)amino)ethyl)-1H-indole-5-yl)oxy)-4-oxobutanoic acid, 5-((3-(2-(cyclopropyl(methyl)amino)ethyl)-1H-indole-5-yl)oxy)-5-oxopentanoic acid, 6-((3-(2-(cyclopropyl(methyl)amino)ethyl)-1H-indole-5-yl)oxy)-6-oxohexanoic acid, 2-((3-(2-(cyclopropyl(methyl)amino)ethyl)-1H-indole-5-yl)oxy)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol, 2-((3-(2-(cyclopropyl(methyl)amino)ethyl)-1H-indole-5-yl)oxy)-6-methyltetrahydro-2H-pyran-3,4,5-triol, N-ethyl-2-(5-methoxy-1H-indole-3-yl)-N-methylethane-1-amine, 3-(2-(ethyl(methyl)amino)ethyl)-1H-indole-5-yl dihydrogen phosphate, 3-(2-(ethyl(methyl)amino)ethyl)-1H-indole-5-yl acetate, 3-(2-(ethyl(methyl)amino)ethyl)-1H-indole-5-yl propionic acid, 3-(2-(ethyl(methyl)amino) )ethyl)-1H-indole-5-yl, isobutyrate 3-(2-(ethyl(methyl)amino)ethyl)-1H-indole-5-yl, 3-((3-(2-(ethyl(methyl)amino)ethyl)-1H-indole-5-yl)oxy)-3-oxopropanoic acid, 4-((3-(2-(ethyl(methyl)amino)ethyl)-1H-indole-5-yl)oxy)-4-oxobutanoic acid, 4-((3-(2-(ethyl(methyl)amino)ethyl (L)-1H-indole-5-yl)oxy)-4-oxobutanoic acid, 6-((3-(2-(ethyl(methyl)amino)ethyl)-1H-indole-5-yl)oxy)-6-oxohexanoic acid, 2-((3-(2-(ethyl(methyl)amino)ethyl)-1H-indole-5-yl)oxy)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol, 2-((3-(2-(ethyl(methyl)amino)ethyl )-1H-indole-5-yl)oxy)-6-methyltetrahydro-2H-pyran-3,4,5-triol, N-(2-(5-methoxy-1H-indole-3-yl)ethyl)-N-methylpropane-2-en-1-amine, dihydrogen phosphate 3-(2-(allyl(methyl)amino)ethyl)-1H-indole-5-yl, acetate 3-(2-(allyl(methyl)amino)ethyl)-1H-indole-5-yl, propionic acid 3-(2-, (allyl(methyl)amino)ethyl)-1H-indole-5-yl, 3-(2-(allyl(methyl)amino)ethyl)-1H-indole-5-yl butyrate, 3-(2-(allyl(methyl)amino)ethyl)-1H-indole-5-yl isobutyrate, 3-((3-(2-(allyl(methyl)amino)ethyl)-1H-indole-5-yl)oxy)-3-oxopropanoic acid, 4-((3-(2-(allyl(methyl)amino)ethyl)-1H-indole-5-yl)oxy)-4-oxobutanoic acid, 5-((3-(2-(allyl(methyl)amino )ethyl)-1H-indole-5-yl)oxy)-5-oxopentanoic acid, 6-((3-(2-(allyl(methyl)amino)ethyl)-1H-indole-5-yl)oxy)-6-oxohexanoic acid, 2-((3-(2-(allyl(methyl)amino)ethyl)-1H-indole-5-yl)oxy)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol, 2-((3-(2-(allyl(methyl)amino)ethyl)-1H-indole-5-yl)oxy)-6-methyltetrahydro-2H-pyran-3,4,5-triol, N-ethyl-N-(2-(5-methoxy-1H-indole-3-yl)ethyl)propane-2-en-1-amine, 3-(2-(allyl(ethyl)amino)ethyl)-1H-indole-5-yl) dihydrogen phosphate, 3-(2-(allyl(ethyl)amino)ethyl)-1H-indole-5-yl) acetate, 3-(2-(allyl(ethyl)amino)ethyl)-1H-indole-5-yl) propionic acid, 3-(2-(allyl(ethyl)amino)ethyl)-1H-indole-5-yl) isobutyrate, 3-((3-(2-(allyl(ethyl)amino)ethyl)-1H-indole-5-yl)oxy)-3-oxopropanoic acid, 4-((3-(2-(allyl(ethyl)amino)ethyl)-1H-indole-5-yl)oxy)-4-oxobutanoic acid, 5-((3-(2-(allyl(ethyl)amino)ethyl)-1H-indole-5-yl)oxy)-5-oxopentanoic acid, 6-((3-(2-(allyl(ethyl)amino)ethyl)-1H-indole-5-yl)oxy)-6-oxohexanoic acid, 2-((3-(2-(allyl(ethyl)amino)ethyl)-1H-indole-5-yl)oxy)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol, 2-((3-(2-(allyl(ethyl)amino)ethyl)-1H-indole-5-yl)oxy)-6-methyltetrahydro-2H-pyran-3,4,5-triol, 4-methoxy-3-(2-(pyrrolidine-1-yl)ethyl)-1H-indole, 3-(2-(pyrrolidine-1-yl)ethyl)-1H-indole-5-yl dihydrogen phosphate, 3-(2-(pyrrolidine-1-yl)ethyl)-1H-indole-5-yl acetate, 3-(2-(pyrrolidine-1-yl)ethyl)-1H-indole-5-yl propionic acid, 3-(2-(pyrrolidine-1-yl)ethyl)-1H-indole-5-yl butyrate, 3-(2-(pyrrolidine-1-yl)ethyl)-1H-indole-5-yl isobutyrate, 3-oxo-3-((3-(2-(pyrrolidine-1-yl)ethyl)-1H-indole-5-yl)oxy)propanoic acid, 4-oxo-4- ((3-(2-(pyrrolidine-1-yl)ethyl)-1H-indole-5-yl)oxy)butanoic acid, 5-oxo-5-((3-(2-(pyrrolidine-1-yl)ethyl)-1H-indole-5-yl)oxy)pentanoic acid, 6-oxo-6-((3-(2-(pyrrolidine-1-yl)ethyl)-1H-indole-5-yl)oxy)hexanoic acid, 2-(hydroxymethyl)-6-((3-(2-(pyrrolidine-1-yl)ethyl)-1H-indole-5-yl)oxy)tetrahydro-2H-pyran-3,4,5-triol, 2-methyl-6-((3-(2-(pyrrolidine-1-yl)ethyl)-1H-indole-5-yl)oxy)tetrahydro-2H-pyran-3,4,5-triol, N-(2-(5-methoxy-1H-indole-3-yl)ethyl)acetamide, 3-(2-acetamidoethyl)-1H-indole-5-yl dihydrogen phosphate, 3-(2-acetamidoethyl)-1H-indole-5-yl acetate, 3-(2-acetamidoethyl)-1H-indole-5-yl propionic acid, 3-(2-acetamidoethyl)-1H-indole-5-yl butyrate, 3-(2-acetamidoethyl)-1H-indole-5-yl isobutyrate, 3-((3-(2-acetamidoethyl)-1H-indole-5-yl)oxy)-3-oxopropanoic acid, 4-((3-(2-acetamidoethyl)-1H-indole-5-yl)oxy C)-4-oxobutanoic acid, 5-((3-(2-acetamidoethyl)-1H-indole-5-yl)oxy)-5-oxopentanoic acid, 6-((3-(2-acetamidoethyl)-1H-indole-5-yl)oxy)-6-oxohexanoic acid, N-(2-(5-((3,4,5-trihydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-1H-indole-3-yl)ethyl)acetamide, N-(2-(5-((3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)-1H-indole-3-yl)ethyl)acetamide, 2-(6-methoxy-1H-indole-3-yl)-N,N-dimethylethane-1-amine, 3-(2-(dimethylamino)ethyl)-1H-indole-6-yl dihydrogen phosphate, 3-(2-(dimethylamino)ethyl)-1H-indole-6-yl acetate, 3-(2-(dimethylamino)ethyl)-1H-indole-6-yl propionic acid, 3-(2-(dimethylamino)ethyl)-1H-indole-6-yl butyrate, 3-(2-(dimethylamino)ethyl)-1H-indole-6-yl isobutyrate, 3-((3-(2-(dimethylamino)ethyl)-1H-indole-6-yl)oxy)-3-oxopropanoic acid, 4-((3-(2-(dimethylamino)ethyl)-1 H-indole-6-yl)oxy)-4-oxobutanoic acid, 5-((3-(2-(dimethylamino)ethyl)-1H-indole-6-yl)oxy)-5-oxopentanoic acid, 6-((3-(2-(dimethylamino)ethyl)-1H-indole-6-yl)oxy)-6-oxohexanoic acid, 2-((3-(2-(dimethylamino)ethyl)-1H-indole-6-yl)oxy)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol, 2-((3-(2-(dimethylamino)ethyl)-1H-indole-6-yl)oxy)-6-methyltetrahydro-2H-pyran-3,4,5-triol, N-(2-(6-methoxy-1H-indole-3-yl)ethyl)-N-propylpropan-1-amine, 3-(2-(dipropylamino)ethyl)-1H-indole-6-yl dihydrogen phosphate, 3-(2-(dipropylamino)ethyl)-1H-indole-6-yl acetate, 3-(2-(dipropylamino)ethyl)-1H-indole-6-yl propionic acid, 3-(2-(dipropylamino)ethyl)-1H-indole-6-yl butyrate, 3-(2-(dipropylamino)ethyl)-1H-indole-6-yl isobutyrate, 3-((3-(2-(dipropylamino)ethyl)-1H-indole-6-yl)oxy)-3-oxopropanoic acid, 4-( (3-(2-(dipropylamino)ethyl)-1H-indole-6-yl)oxy)-4-oxobutanoic acid, 5-((3-(2-(dipropylamino)ethyl)-1H-indole-6-yl)oxy)-5-oxopentanoic acid, 6-((3-(2-(dipropylamino)ethyl)-1H-indole-6-yl)oxy)-6-oxohexanoic acid, 2-((3-(2-(dipropylamino)ethyl)-1H-indole-6-yl)oxy)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol, 2-((3-(2-(dipropylamino)ethyl)-1H-indole-6-yl)oxy)-6-methyltetrahydro-2H-pyran-3,4,5-triol, N-allyl-N-(2-(6-methoxy-1H-indole-3-yl)ethyl)propane-2-en-1-amine, 3-(2-(diallylamino)ethyl)-1H-indole-6-yl dihydrogen phosphate, 3-(2-(diallylamino)ethyl)-1H-indole-6-yl acetate, 3-(2-(diallylamino)ethyl)-1H-indole-6-yl propionic acid, 3-(2-(diallylamino)ethyl)-1H-indole-6-yl butyrate, 3-(2-(diallylamino)ethyl)-1H-indole-6-yl isobutyrate, 3-((3-(2-(diallylamino)ethyl)-1H-indole-6-yl)oxy)-3-oxopropanoic acid, 4- ((3-(2-(diallylamino)ethyl)-1H-indole-6-yl)oxy)-4-oxobutanoic acid, 5-((3-(2-(diallylamino)ethyl)-1H-indole-6-yl)oxy)-5-oxopentanoic acid, 6-((3-(2-(diallylamino)ethyl)-1H-indole-6-yl)oxy)-6-oxohexanoic acid, 2-((3-(2-(diallylamino)ethyl)-1H-indole-6-yl)oxy)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol, 2-((3-(2-(diallylamino)ethyl)-1H-indole-6-yl)oxy)-6-methyltetrahydro-2H-pyran-3,4,5-triol, N-(2-(6-methoxy-1H-indole-3-yl)ethyl)-N-methylpropan-2-amine, 3-(2-(isopropyl(methyl)amino)ethyl)-1H-indole-6-yl) dihydrogen phosphate, 3-(2-(isopropyl(methyl)amino)ethyl)-1H-indole-6-yl) acetate, 3-(2-(isopropyl(methyl)amino)ethyl)-1H-indole-6-yl) propionic acid, 3-(2-(isopropyl(methyl)amino)ethyl)-1H-indole-6-yl) butyrate, 3-(2-(isopropyl (methyl)amino)ethyl)-1H-indole-6-yl, 3-((3-(2-(isopropyl(methyl)amino)ethyl)-1H-indole-6-yl)oxy)-3-oxopropanoic acid, 4-((3-(2-(isopropyl(methyl)amino)ethyl)-1H-indole-6-yl)oxy)-4-oxobutanoic acid, 5-((3-(2-(isopropyl(methyl)amino)ethyl)-1H-indole-6-yl)oxy)-5-oxopentanoic acid, 6-((3-(2-(isopropyl(methyl)amino)ethyl)-1H-indole-6- Iyl)oxy)-6-oxohexanoic acid, 2-((3-(2-(isopropyl(methyl)amino)ethyl)-1H-indole-6-yl)oxy)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol, 2-((3-(2-(isopropyl(methyl)amino)ethyl)-1H-indole-6-yl)oxy)-6-methyltetrahydro-2H-pyran-3,4,5-triol, N-ethyl-N-(2-(6-methoxy-1H-indole-3-yl)ethyl)propan-2-amine, dihydrogen phosphate 3-(2-(ethyl (Isopropyl)amino)ethyl)-1H-indole-6-yl, 3-(2-(ethyl(isopropyl)amino)ethyl)-1H-indole-6-yl acetate, 3-(2-(ethyl(isopropyl)amino)ethyl)-1H-indole-6-yl propionic acid, 3-(2-(ethyl(isopropyl)amino)ethyl)-1H-indole-6-yl butyrate, 3-(2-(ethyl(isopropyl)amino)ethyl)-1H-indole-6-yl isobutyrate, 3-((3-(2-(ethyl(isopropyl)amino)ethyl)-1H-indole-6-yl, (I)oxy)-3-oxopropanoic acid, 4-((3-(2-(ethyl(isopropyl)amino)ethyl)-1H-indole-6-yl)oxy)-4-oxobutanoic acid, 4-((3-(2-(ethyl(isopropyl)amino)ethyl)-1H-indole-6-yl)oxy)-5-oxopentanoic acid, 4-((3-(2-(ethyl(isopropyl)amino)ethyl)-1H-indole-6-yl)oxy)-6-oxohexanoic acid, 2-((3-(2-(ethyl(isopropyl)amino)ethyl)-1H-indole-6-yl)oxy)-6-( Hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol, 2-((3-(2-(ethyl(isopropyl)amino)ethyl)-1H-indole-6-yl)oxy)-6-methyltetrahydro-2H-pyran-3,4,5-triol, N-isopropyl-N-(2-(6-methoxy-1H-indole-3-yl)ethyl)propan-2-amine, dihydrogen phosphate 3-(2-(diisopropylamino)ethyl)-1H-indole-6-yl, acetate 3-(2-(diisopropylamino)ethyl)-1H-indole-6-yl, propio 3-(2-(diisopropylamino)ethyl)-1H-indole-6-yl isobutyrate, 3-(2-(diisopropylamino)ethyl)-1H-indole-6-yl isobutyrate, 3-((3-(2-(diisopropylamino)ethyl)-1H-indole-6-yl)oxy)-3-oxopropanoic acid, 4-((3-(2-(diisopropylamino)ethyl)-1H-indole-6-yl)oxy)-4-oxobutanoic acid, 5-((3-(2-(diisopropylamino)ethyl (L)-1H-indole-6-yl)oxy)-5-oxopentanoic acid, 6-((3-(2-(diisopropylamino)ethyl)-1H-indole-6-yl)oxy)-6-oxohexanoic acid, 2-((3-(2-(diisopropylamino)ethyl)-1H-indole-6-yl)oxy)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol, 2-((3-(2-(diisopropylamino)ethyl)-1H-indole-6-yl)oxy)-6-methyltetrahydro-2H-pyran-3,4,5-triol, N,N-Diethyl-2-(6-methoxy-1H-indole-3-yl)ethane-1-amine, 3-(2-(diethylamino)ethyl)-1H-indole-6-yl dihydrogen phosphate, 3-(2-(diethylamino)ethyl)-1H-indole-6-yl acetate, 3-(2-(diethylamino)ethyl)-1H-indole-6-yl propionic acid, 3-(2-(diethylamino)ethyl)-1H-indole-6-yl butyrate, 3-(2-(diethylamino)ethyl)-1H-indole-6-yl isobutyrate, 3-((3-(2-(diethylamino)ethyl)-1H-indole-6-yl)oxy)-3-oxopropanoic acid, 4-((3-(2-(diethylamino)ethyl) (Tylamino)ethyl)-1H-indole-6-yl)oxy)-4-oxobutanoic acid, 5-((3-(2-(diethylamino)ethyl)-1H-indole-6-yl)oxy)-5-oxopentanoic acid, 6-((3-(2-(diethylamino)ethyl)-1H-indole-6-yl)oxy)-6-oxohexanoic acid, 2-((3-(2-(diethylamino)ethyl)-1H-indole-6-yl)oxy)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol, 2-((3-(2-(diethylamino)ethyl)-1H-indole-6-yl)oxy)-6-methyltetrahydro-2H-pyran-3,4,5-triol, N-ethyl-N-(2-(6-methoxy-1H-indole-3-yl)ethyl)propan-1-amine, 3-(2-(ethyl(propyl)amino)ethyl)-1H-indole-6-yl) dihydrogen phosphate, 3-(2-(ethyl(propyl)amino)ethyl)-1H-indole-6-yl) acetate, 3-(2-(ethyl(propyl)amino)ethyl)-1H-indole-6-yl) propionic acid, 3-(2-(ethyl(propyl)amino)ethyl)-1H-indole-6-yl) isobutyrate, 3-((3-(2-(ethyl(propyl)amino)ethyl)-1H-indole-6-yl)oxy)-3-oxopropanoic acid, 4- ((3-(2-(ethyl(propyl)amino)ethyl)-1H-indole-6-yl)oxy)-4-oxobutanoic acid, 5-((3-(2-(ethyl(propyl)amino)ethyl)-1H-indole-6-yl)oxy)-5-oxopentanoic acid, 6-((3-(2-(ethyl(propyl)amino)ethyl)-1H-indole-6-yl)oxy)-6-oxohexanoic acid, 2-((3-(2-(ethyl(propyl)amino)ethyl)-1H-indole-6-yl)oxy)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol, 2-((3-(2-(ethyl(propyl)amino)ethyl)-1H-indole-6-yl)oxy)-6-methyltetrahydro-2H-pyran-3,4,5-triol, N-(2-(6-methoxy-1H-indole-3-yl)ethyl)-N-methylcyclopropanamine, 3-(2-(cyclopropyl(methyl)amino)ethyl)-1H-indole-6-yl) dihydrogen phosphate, 3-(2-(cyclopropyl(methyl)amino)ethyl)-1H-indole-6-yl) acetate, 3-(2-(cyclopropyl(methyl)amino)ethyl)-1H-indole-6-yl) propionic acid, 3-(2-(cyclopropyl(methyl)amino)ethyl)-1H-indole-6-yl) isobutyrate, 3-((3-(2-(cyclopropyl(methyl)amino)ethyl)-1H-indole-6-yl)oxy)-3-oxopropanoic acid, 4-((3-(2-(cyclopropyl(methyl)amino)ethyl)-1H-indole-6-yl)oxy)-4-oxobutanoic acid, 5-((3-(2-(cyclopropyl(methyl)amino)ethyl)-1H-indole-6-yl)oxy)-5-oxopentanoic acid, 6-((3-(2-(cyclopropyl(methyl)amino)ethyl)-1H-indole-6-yl)oxy)-6-oxohexanoic acid, 2-((3-(2-(cyclopropyl(methyl)amino)ethyl)-1H-indole-6-yl)oxy)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol, 2-((3-(2-(cyclopropyl(methyl)amino)ethyl)-1H-indole-6-yl)oxy)-6-methyltetrahydro-2H-pyran-3,4,5-triol, N-ethyl-2-(6-methoxy-1H-indole-3-yl)-N-methylethane-1-amine, 3-(2-(ethyl(methyl)amino)ethyl)-1H-indole-6-yl dihydrogen phosphate, 3-(2-(ethyl(methyl)amino)ethyl)-1H-indole-6-yl acetate, 3-(2-(ethyl(methyl)amino)ethyl)-1H-indole-6-yl propionic acid, 3-(2-(ethyl(methyl)amino)ethyl)-1H-indole-6-yl butyrate, 3-(2-(ethyl(methyl)amino)ethyl)-1H-indole-6-yl isobutyrate, 3-((3-(2-(ethyl(methyl)amino)ethyl)-1H-indole-6-yl)oxy)-3-oxopropanoic acid, 4-( (3-(2-(ethyl(methyl)amino)ethyl)-1H-indole-6-yl)oxy)-4-oxobutanoic acid, 4-((3-(2-(ethyl(methyl)amino)ethyl)-1H-indole-6-yl)oxy)-4-oxobutanoic acid, 6-((3-(2-(ethyl(methyl)amino)ethyl)-1H-indole-6-yl)oxy)-6-oxohexanoic acid, 2-((3-(2-(ethyl(methyl)amino)ethyl)-1H-indole-6-yl)oxy)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol, 2-((3-(2-(ethyl(methyl)amino)ethyl)-1H-indole-6-yl)oxy)-6-methyltetrahydro-2H-pyran-3,4,5-triol, N-(2-(6-methoxy-1H-indole-3-yl)ethyl)-N-methylpropane-2-en-1-amine, 3-(2-(allyl(methyl)amino)ethyl)-1H-indole-6-yl dihydrogen phosphate, 3-(2-(allyl(methyl)amino)ethyl)-1H-indole-6-yl acetate, 3-(2-(allyl(methyl)amino)ethyl)-1H-indole-6-yl propionic acid, 3-(2-(allyl(methyl)amino)ethyl)-1H-indole-6-yl butyrate, 3-(2-(allyl(methyl)amino)ethyl)-1H-indole-6-yl isobutyrate, 3-((3-(2-(allyl(methyl)amino)ethyl)-1H-indole-6-yl)oxy)-3-oxopropanoic acid, 4-((3-(2-(allyl(methyl)amino)ethyl)-1H-indole-6-yl)oxy)-4-oxobutanoic acid, 5-((3-(2-(allyl(methyl)amino)ethyl)-1H-indole-6-yl)oxy)-5-oxopentanoic acid, 6-((3-(2-(allyl(methyl)amino)ethyl)-1H-indole-6-yl)oxy)-6-oxohexanoic acid, 2-((3-(2-(allyl(methyl)amino)ethyl)-1H-indole-6-yl)oxy)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol, 2-((3-(2-(allyl(methyl)amino)ethyl)-1H-indole-6-yl)oxy)-6-methyltetrahydro-2H-pyran-3,4,5-triol, N-ethyl-N-(2-(6-methoxy-1H-indole-3-yl)ethyl)propa-2-en-1-amine, 3-(2-(allyl(ethyl)amino)ethyl)-1H-indole-6-yl) dihydrogen phosphate, 3-(2-(allyl(ethyl)amino)ethyl)-1H-indole-6-yl) acetate, 3-(2-(allyl(ethyl)amino)ethyl)-1H-indole-6-yl) propionic acid, 3-(2-(allyl(ethyl)amino)ethyl)-1H-indole-6-yl) butyrate, 3-(3-) isobutyrate (2-(allyl(ethyl)amino)ethyl)-1H-indole-6-yl, 3-((3-(2-(allyl(ethyl)amino)ethyl)-1H-indole-6-yl)oxy)-3-oxopropanoic acid, 4-((3-(2-(allyl(ethyl)amino)ethyl)-1H-indole-6-yl)oxy)-4-oxobutanoic acid, 5-((3-(2-(allyl(ethyl)amino)ethyl)-1H-indole-6-yl)oxy)-5-oxopentanoic acid, 6-((3-(2-(allyl(ethyl)amino)ethyl )-1H-indole-6-yl)oxy)-6-oxohexanoic acid, 2-((3-(2-(allyl(ethyl)amino)ethyl)-1H-indole-6-yl)oxy)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol, 2-((3-(2-(allyl(ethyl)amino)ethyl)-1H-indole-6-yl)oxy)-6-methyltetrahydro-2H-pyran-3,4,5-triol, 4-methoxy-3-(2-(pyrrolidine-1-yl)ethyl)-1H-indole , dihydrogen phosphate 3-(2-(pyrrolidine-1-yl)ethyl)-1H-indole-6-yl, acetate 3-(2-(pyrrolidine-1-yl)ethyl)-1H-indole-6-yl, propionic acid 3-(2-(pyrrolidine-1-yl)ethyl)-1H-indole-6-yl, butyrate 3-(2-(pyrrolidine-1-yl)ethyl)-1H-indole-6-yl, isobutyrate 3-(2-(pyrrolidine-1-yl)ethyl)-1H-indole-6-yl, oxo-3-((3-(2-(pyrrolidine-1-yl)e, (Tyl)-1H-indole-6-yl)oxy)propanoic acid, 4-oxo-4-((3-(2-(pyrrolidine-1-yl)ethyl)-1H-indole-6-yl)oxy)butanoic acid, 5-oxo-5-((3-(2-(pyrrolidine-1-yl)ethyl)-1H-indole-6-yl)oxy)pentanoic acid, 6-oxo-6-((3-(2-(pyrrolidine-1-yl)ethyl)-1H-indole-6-yl)oxy)hexanoic acid, 2-(hydroxymethyl)-6-((3-(2-(pyrrolidine-1-yl)ethyl)-1H- (Isopropyl alcohol)( Midoethyl)-1H-indole-6-yl, 3-(2-acetamidoethyl)-1H-indole-6-yl butyrate, 3-(2-acetamidoethyl)-1H-indole-6-yl isobutyrate, 3-((3-(2-acetamidoethyl)-1H-indole-6-yl)oxy)-3-oxopropanoic acid, 4-((3-(2-acetamidoethyl)-1H-indole-6-yl)oxy)-4-oxobutanoic acid, 5-((3-(2-acetamidoethyl)-1H-indole-6-yl)oxy)-5-oxopentanoic acid, 6- ((3-(2-acetamidoethyl)-1H-indole-6-yl)oxy)-6-oxohexanoic acid, N-(2-(6-((3,4,5-trihydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-1H-indole-3-yl)ethyl)acetamide, N-(2-(6-((3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)-1H-indole-3-yl)ethyl)acetamide, 2-(7-methoxy-1H-indole-3-yl)-N,N-dimethylethane-1-amine, 3-(2-(dimethylamino)ethyl)-1H-indole-7-yl dihydrogen phosphate, 3-(2-(dimethylamino)ethyl)-1H-indole-7-yl acetate, 3-(2-(dimethylamino)ethyl)-1H-indole-7-yl propionic acid, 3-(2-(dimethylamino)ethyl)-1H-indole-7-yl butyrate, 3-(2-(dimethylamino)ethyl)-1H-indole-7-yl isobutyrate, 3-((3-(2-(dimethylamino)ethyl)-1H-indole-7-yl)oxy)-3-oxopropanoic acid, 4-((3-(2-(dimethylamino)ethyl)-1 H-indole-7-yl)oxy)-4-oxobutanoic acid, 5-((3-(2-(dimethylamino)ethyl)-1H-indole-7-yl)oxy)-5-oxopentanoic acid, 6-((3-(2-(dimethylamino)ethyl)-1H-indole-7-yl)oxy)-6-oxohexanoic acid, 2-((3-(2-(dimethylamino)ethyl)-1H-indole-7-yl)oxy)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol, 2-((3-(2-(dimethylamino)ethyl)-1H-indole-7-yl)oxy)-6-methyltetrahydro-2H-pyran-3,4,5-triol, N-(2-(7-methoxy-1H-indole-3-yl)ethyl)-N-propylpropan-1-amine, 3-(2-(dipropylamino)ethyl)-1H-indole-7-yl dihydrogen phosphate, 3-(2-(dipropylamino)ethyl)-1H-indole-7-yl acetate, 3-(2-(dipropylamino)ethyl)-1H-indole-7-yl propionate, 3-(2-(dipropylamino)ethyl)-1H-indole-7-yl butyrate, 3-(2-(dipropylamino)ethyl)-1H-indole-7-yl isobutyrate, 3-((3-(2-(dipropylamino)ethyl)-1H-indole-7-yl)oxy)-3-oxopropanoic acid, 4-( (3-(2-(dipropylamino)ethyl)-1H-indole-7-yl)oxy)-4-oxobutanoic acid, 5-((3-(2-(dipropylamino)ethyl)-1H-indole-7-yl)oxy)-5-oxopentanoic acid, 6-((3-(2-(dipropylamino)ethyl)-1H-indole-7-yl)oxy)-6-oxohexanoic acid, 2-((3-(2-(dipropylamino)ethyl)-1H-indole-7-yl)oxy)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol, 2-((3-(2-(dipropylamino)ethyl)-1H-indole-7-yl)oxy)-6-methyltetrahydro-2H-pyran-3,4,5-triol, N-allyl-N-(2-(7-methoxy-1H-indole-3-yl)ethyl)propane-2-en-1-amine, 3-(2-(diallylamino)ethyl)-1H-indole-7-yl dihydrogen phosphate, 3-(2-(diallylamino)ethyl)-1H-indole-7-yl acetate, 3-(2-(diallylamino)ethyl)-1H-indole-7-yl propionate, 3-(2-(diallylamino)ethyl)-1H-indole-7-yl butyrate, 3-(2-(diallylamino)ethyl)-1H-indole-7-yl isobutyrate, 3-((3-(2-(diallylamino)ethyl)-1H-indole-7-yl)oxy)-3-oxopropanoic acid, 4- ((3-(2-(diallylamino)ethyl)-1H-indole-7-yl)oxy)-4-oxobutanoic acid, 5-((3-(2-(diallylamino)ethyl)-1H-indole-7-yl)oxy)-5-oxopentanoic acid, 6-((3-(2-(diallylamino)ethyl)-1H-indole-7-yl)oxy)-6-oxohexanoic acid, 2-((3-(2-(diallylamino)ethyl)-1H-indole-7-yl)oxy)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol, 2-((3-(2-(diallylamino)ethyl)-1H-indole-7-yl)oxy)-6-methyltetrahydro-2H-pyran-3,4,5-triol, N-(2-(7-methoxy-1H-indole-3-yl)ethyl)-N-methylpropan-2-amine, 3-(2-(isopropyl(methyl)amino)ethyl)-1H-indole-7-yl) dihydrogen phosphate, 3-(2-(isopropyl(methyl)amino)ethyl)-1H-indole-7-yl) acetate, 3-(2-(isopropyl(methyl)amino)ethyl)-1H-indole-7-yl) propionic acid, 3-(2-(isopropyl(methyl)amino)ethyl)-1H-indole-7-yl) isobutyrate, 3-((3-(2-(isopropyl(methyl)amino)ethyl)-1H-indole-7-yl)oxy)-3-oxopropanoic acid, 4 -((3-(2-(isopropyl(methyl)amino)ethyl)-1H-indole-7-yl)oxy)-4-oxobutanoic acid, 5-((3-(2-(isopropyl(methyl)amino)ethyl)-1H-indole-7-yl)oxy)-5-oxopentanoic acid, 6-((3-(2-(isopropyl(methyl)amino)ethyl)-1H-indole-7-yl)oxy)-6-oxohexanoic acid, 2-((3-(2-(isopropyl(methyl)amino)ethyl)-1H-indole-7-yl)oxy)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol, 2-((3-(2-(isopropyl(methyl)amino)ethyl)-1H-indole-7-yl)oxy)-6-methyltetrahydro-2H-pyran-3,4,5-triol, N-ethyl-N-(2-(7-methoxy-1H-indole-3-yl)ethyl)propan-2-amine, 3-(2-(ethyl(isopropyl)amino)ethyl)-1H-indole-7-yl) dihydrogen phosphate, 3-(2-(ethyl(isopropyl)amino)ethyl)-1H-indole-7-yl) acetate, 3-(2-(ethyl(isopropyl)amino)ethyl)-1H-indole-7-yl) propionic acid, 3-(2-(ethyl(isopropyl)amino)ethyl)-1H-indole-7-yl) isobutyrate, 3-((3-(2-(ethyl(isopropyl)amino)ethyl)-1H-indole-7-yl)oxy)-3-oxopropanoic acid, 4 -((3-(2-(ethyl(isopropyl)amino)ethyl)-1H-indole-7-yl)oxy)-4-oxobutanoic acid, 4-((3-(2-(ethyl(isopropyl)amino)ethyl)-1H-indole-7-yl)oxy)-5-oxopentanoic acid, 4-((3-(2-(ethyl(isopropyl)amino)ethyl)-1H-indole-7-yl)oxy)-6-oxohexanoic acid, 2-((3-(2-(ethyl(isopropyl)amino)ethyl)-1H-indole-7-yl)oxy)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol, 2-((3-(2-(ethyl(isopropyl)amino)ethyl)-1H-indole-7-yl)oxy)-6-methyltetrahydro-2H-pyran-3,4,5-Triol, N-Isopropyl-N-(2-(7-Methoxy-1H-Indole-3-yl)ethyl)propan-2-amine, 3-(2-(diisopropylamino)ethyl)-1H-Indole-7-yl dihydrogen phosphate, 3-(2-(diisopropylamino)ethyl)-1H-Indole-7-yl acetate, 3-(2-(diisopropylamino)ethyl)-1H-Indole-7-yl propionic acid, 3-(2-(diisopropylamino)ethyl)-1H-Indole-7-yl butyrate, 3-(2-(diisopropylamino)ethyl)-1H-Indole-7-yl isobutyrate, 3-((3-(2-(diisopropylamino)ethyl)-1H-Indole-7-yl)oxy)-3-oxopropanoic acid, 4-((3- (2-(diisopropylamino)ethyl)-1H-indole-7-yl)oxy)-4-oxobutanoic acid, 5-((3-(2-(diisopropylamino)ethyl)-1H-indole-7-yl)oxy)-5-oxopentanoic acid, 6-((3-(2-(diisopropylamino)ethyl)-1H-indole-7-yl)oxy)-6-oxohexanoic acid, 2-((3-(2-(diisopropylamino)ethyl)-1H-indole-7-yl)oxy)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol, 2-((3-(2-(diisopropylamino)ethyl)-1H-indole-7-yl)oxy)-6-methyltetrahydro-2H-pyran-3,4,5-triol, N,N-diethyl-2-(7-methoxy-1H-indole-3-yl)ethane-1-amine, 3-(2-(diethylamino)ethyl)-1H-indole-7-yl dihydrogen phosphate, 3-(2-(diethylamino)ethyl)-1H-indole-7-yl acetate, 3-(2-(diethylamino)ethyl)-1H-indole-7-yl propionic acid, 3-(2-(diethylamino)ethyl)-1H-indole-7-yl butyrate, 3-(2-(diethylamino)ethyl isobutyrate )ethyl)-1H-indole-7-yl, 3-((3-(2-(diethylamino)ethyl)-1H-indole-7-yl)oxy)-3-oxopropanoic acid, 4-((3-(2-(diethylamino)ethyl)-1H-indole-7-yl)oxy)-4-oxobutanoic acid, 5-((3-(2-(diethylamino)ethyl)-1H-indole-7-yl)oxy)-5-oxopentanoic acid, 6-((3-(2-(diethylamino)ethyl)-1H-yl, Indole-7-yl)oxy)-6-oxohexanoic acid, 2-((3-(2-(diethylamino)ethyl)-1H-indole-7-yl)oxy)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol, 2-((3-(2-(diethylamino)ethyl)-1H-indole-7-yl)oxy)-6-methyltetrahydro-2H-pyran-3,4,5-triol, N-ethyl-N-(2-(7-methoxy-1H-indole (3-yl)ethyl)propan-1-amine, 3-(2-(ethyl(propyl)amino)ethyl)-1H-indole-7-yl dihydrogen phosphate, 3-(2-(ethyl(propyl)amino)ethyl)-1H-indole-7-yl acetate, 3-(2-(ethyl(propyl)amino)ethyl)-1H-indole-7-yl propionic acid, 3-(2-(ethyl(propyl)amino)ethyl)-1H-indole-7-yl butyrate, 3-(2-(ethyl(propyl) Pyr(propyl)amino)ethyl)-1H-indole-7-yl, 3-((3-(2-(ethyl(propyl)amino)ethyl)-1H-indole-7-yl)oxy)-3-oxopropanoic acid, 4-((3-(2-(ethyl(propyl)amino)ethyl)-1H-indole-7-yl)oxy)-4-oxobutanoic acid, 5-((3-(2-(ethyl(propyl)amino)ethyl)-1H-indole-7-yl)oxy)-5-oxopentanoic acid, 6-((3-( 2-(ethyl(propyl)amino)ethyl)-1H-indole-7-yl)oxy)-6-oxohexanoic acid, 2-((3-(2-(ethyl(propyl)amino)ethyl)-1H-indole-7-yl)oxy)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol, 2-((3-(2-(ethyl(propyl)amino)ethyl)-1H-indole-7-yl)oxy)-6-methyltetrahydro-2H-pyran-3,4,5-triol, N-(2-(7-methoxy-1H-indole-3-yl)ethyl)-N-methylcyclopropanamine, 3-(2-(cyclopropyl(methyl)amino)ethyl)-1H-indole-7-yl) dihydrogen phosphate, 3-(2-(cyclopropyl(methyl)amino)ethyl)-1H-indole-7-yl) acetate, 3-(2-(cyclopropyl(methyl)amino)ethyl)-1H-indole-7-yl) propionic acid, 3-(2-(cyclopropyl(methyl)amino)ethyl)-1H-indole-7-yl) isobutyrate, 3-((3-(2-(cyclopropyl(methyl)amino)ethyl)-1H-indole-7-yl)oxy)-3-oxopropanoic acid, 4-((3-(2-(cyclopropyl(methyl)amino)ethyl)-1H-indole-7-yl)oxy)-4-oxobutanoic acid, 5-((3-(2-(cyclopropyl(methyl)amino)ethyl)-1H-indole-7-yl)oxy)-5-oxopentanoic acid, 6-((3-(2-(cyclopropyl(methyl)amino)ethyl)-1H-indole-7-yl)oxy)-6-oxohexanoic acid, 2-((3-(2-(cyclopropyl(methyl)amino)ethyl)-1H-indole-7-yl)oxy)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol, 2-((3-(2-(cyclopropyl(methyl)amino)ethyl)-1H-indole-7-yl)oxy)-6-methyltetrahydro-2H-pyran-3,4,5-triol, N-ethyl-2-(7-methoxy-1H-indole-3-yl)-N-methylethane-1-amine, 3-(2-(ethyl(methyl)amino)ethyl)-1H-indole-7-yl dihydrogen phosphate, 3-(2-(ethyl(methyl)amino)ethyl)-1H-indole-7-yl acetate, 3-(2-(ethyl(methyl)amino)ethyl)-1H-indole-7-yl propionic acid, 3-(2-(ethyl(methyl)amino)ethyl)-1H-indole-7-yl butyrate, 3-(2-(ethyl(methyl)amino)ethyl)-1H-indole-7-yl isobutyrate, 3-((3-(2-(ethyl(methyl)amino)ethyl)-1H-indole-7-yl)oxy)-3-oxopropanoic acid, 4-( (3-(2-(ethyl(methyl)amino)ethyl)-1H-indole-7-yl)oxy)-4-oxobutanoic acid, 4-((3-(2-(ethyl(methyl)amino)ethyl)-1H-indole-7-yl)oxy)-4-oxobutanoic acid, 6-((3-(2-(ethyl(methyl)amino)ethyl)-1H-indole-7-yl)oxy)-6-oxohexanoic acid, 2-((3-(2-(ethyl(methyl)amino)ethyl)-1H-indole-7-yl)oxy)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol, 2-((3-(2-(ethyl(methyl)amino)ethyl)-1H-indole-7-yl)oxy)-6-methyltetrahydro-2H-pyran-3,4,5-triol, N-(2-(7-methoxy-1H-indole-3-yl)ethyl)-N-methylpropane-2-en-1-amine, 3-(2-(allyl(methyl)amino)ethyl)-1H-indole-7-yl dihydrogen phosphate, 3-(2-(allyl(methyl)amino)ethyl)-1H-indole-7-yl acetate, 3-(2-(allyl(methyl)amino)ethyl)-1H-indole-7-yl propionic acid, 3-(2-(allyl(methyl)amino)ethyl)-1H-indole-7-yl butyrate, 3-(2-(allyl(methyl)amino)ethyl)-1H-indole-7-yl isobutyrate, 3-((3-(2-(allyl(methyl)amino)ethyl)-1H-indole-7-yl)oxy)-3-oxopropanoic acid, 4-((3-(2-(allyl(methyl)amino)ethyl)-1H-indole-7-yl)oxy)-4-oxobutanoic acid, 5-((3-(2-(allyl(methyl)amino)ethyl)-1H-indole-7-yl)oxy)-5-oxopentanoic acid, 6-((3-(2-(allyl(methyl)amino)ethyl)-1H-indole-7-yl)oxy)-6-oxohexanoic acid, 2-((3-(2-(allyl(methyl)amino)ethyl)-1H-indole-7-yl)oxy)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol, 2-((3-(2-(allyl(methyl)amino)ethyl)-1H-indole-7-yl)oxy)-6-methyltetrahydro-2H-pyran-3,4,5-triol, N-ethyl-N-(2-(7-methoxy-1H-indole-3-yl)ethyl)propane-2-en-1-amine, 3-(2-(allyl(ethyl)amino)ethyl)-1H-indole-7-yl) dihydrogen phosphate, 3-(2-(allyl(ethyl)amino)ethyl)-1H-indole-7-yl) acetate, 3-(2-(allyl(ethyl)amino)ethyl)-1H-indole-7-yl) propionic acid, 3-(2-(allyl(ethyl)amino)ethyl)-1H-indole-7-yl) isobutyrate, 3-((3-(2-(allyl(ethyl)amino)ethyl)-1H-indole-7-yl)oxy)-3-oxopropanoic acid, 4-((3-(2-(allyl(ethyl)amino)ethyl)-1H-indole-7-yl)oxy)-4-oxobutanoic acid, 5-((3-(2-(allyl(ethyl)amino)ethyl)-1H-indole-7-yl)oxy)-5-oxopentanoic acid, 6-((3-(2-(allyl(ethyl)amino)ethyl)-1H-indole-7-yl)oxy)-6-oxohexanoic acid, 2-((3-(2-(allyl(ethyl)amino)ethyl)-1H-indole-7-yl)oxy)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol, 2-((3-(2-(allyl(ethyl)amino)ethyl)-1H-indole-7-yl)oxy)-6-methyltetrahydro-2H-pyran-3,4,5-triol, 4-methoxy-3-(2-(pyrrolidine-1-yl)ethyl)-1H-indole, dihydrogen phosphate 3-(2-(pyrrolidine-1-yl)ethyl)-1H-indole-7-yl, acetate 3-(2-(pyrrolidine-1)-yl)ethyl)-1H-indole-7-yl, propionic acid 3-(2-(pyrrolidine-1-yl)ethyl)-1H-indole-7-yl, butyrate 3-(2-(pyrrolidine-1-yl)ethyl)-1H-indole-7-yl, isobutyrate 3-oxo-3-((3-(2-(pyrrolidine-1-yl)ethyl)-1H-indole-7-yl)oxy)propanoic acid, 4-oxo-4 -((3-(2-(pyrrolidine-1-yl)ethyl)-1H-indole-7-yl)oxy)butanoic acid, 5-oxo-5-((3-(2-(pyrrolidine-1-yl)ethyl)-1H-indole-7-yl)oxy)pentanoic acid, 6-oxo-6-((3-(2-(pyrrolidine-1-yl)ethyl)-1H-indole-7-yl)oxy)hexanoic acid, 2-(hydroxymethyl)-6-((3-(2-(pyrrolidine-1-yl)ethyl)-1H-indole-7-yl)oxy)tetrahydro-2H-pyran-3,4,5-triol, 2-methyl-6-((3-(2-(pyrrolidine-1-yl)ethyl)-1H-indole-7-yl)oxy)tetrahydro-2H-pyran-3,4,5-triol, N-(2-(7-methoxy-1H-indole-3-yl)ethyl)acetamide, 3-(2-acetamidoethyl)-1H-indole-7-yl dihydrogen phosphate, 3-(2-acetamidoethyl)-1H-indole-7-yl acetate, 3-(2-acetamidoethyl)-1H-indole-7-yl propionic acid, 3-(2-acetamidoethyl)-1H-indole-7-yl butyrate, 3-(2-acetamidoethyl)-1H-indole-7-yl isobutyrate, 3-((3-(2-acetamidoethyl)-1H-indole)-7-yl)oxy)-3-oxopropanoic acid, 4-((3-(2-acetamidoethyl)-1H-indole-7-yl)oxy Selected from xy)-4-oxobutanoic acid, 5-((3-(2-acetamidoethyl)-1H-indole-7-yl)oxy)-5-oxopentanoic acid, 6-((3-(2-acetamidoethyl)-1H-indole-7-yl)oxy)-6-oxohexanoic acid, N-(2-(7-((3,4,5-trihydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-1H-indole-3-yl)ethyl)acetamide, and N-(2-(7-((3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)-1H-indole-3-yl)ethyl)acetamide, or pharmaceutically acceptable salts thereof.

[0141] In some embodiments, the compounds provided herein are modified ibogamine alkaloids. Examples of modified ibogamine alkaloids include, but are not limited to, 3-(((6R,6aS,7S,9R,11S)-7-ethyl-6,6a,7,8,9,10,12,13-octahydro-5H-6,9-methanopyrido[1',2':1,2]azepino[4,5-b]indole-2-yl)oxy)-3-oxopropanoic acid, 2-(((6R,6aS,7S,9R,11S) -7-ethyl-6,6a,7,8,9,10,12,13-octahydro-5H-6,9-methanopyrido[1',2':1,2]azepino[4,5-b]indole-2-yl)oxy)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol,4-(((6R,6aS,7S,9R,11S)-7-ethyl-6,6a,7,8,9,10,12 ,13-Octahydro-5H-6,9-methanopyrido[1',2':1,2]azepino[4,5-b]indole-2-yl)oxy)-4-oxobutanoic acid, 2-(((6R,6aS,7S,9R,11S)-7-ethyl-6,6a,7,8,9,10,12,13-Octahydro-5H-6,9-methanopyrido[1',2':1,2]azepino[4,5-b]indole Examples include -2-yl)oxy)-6-methyltetrahydro-2H-pyran-3,4,5-triol and 5-(((6R,6aS,7S,9R,11S)-7-ethyl-6,6a,7,8,9,10,12,13-octahydro-5H-6,9-methanopyrido[1',2':1,2]azepino[4,5-b]indole-2-yl)oxy)-5-oxopentanoic acid.

[0142] In some embodiments, the compounds provided herein are modified mitraginine alkaloids. Examples of modified mitraginine alkaloids include, but are not limited to, methyl(E)-2-((2S,3S,7aS,12bS)-3-ethyl-8-methoxy-7a-(sulfoxy)-1,2,3,4,6,7,7a,12b-octahydroindoro[2,3-a]quinoridine-2-yl)-3-methoxyacrylate, methyl(E)-2-((2S,3S,7aS,12bS)-3-ethyl-8-methoxy-7a-(propionyloxy)-1,2,3,4,6,7,7a,12b-octahydroindoro[2,3-a] Quinolidine-2-yl)-3-methoxyacrylate, 4-(((2S,3S,7aS,12bS)-2-((E)-1,3-dimethoxy-3-oxopropane-1-en-2-yl)-3-ethyl-8-methoxy-1,3,4,6,7,12b-hexahydroindoro[2,3-a]quinolidine-7a(2H)-yl)oxy)-4-oxobutanoic acid, methyl(E)-2-((2S,3S,7aS,12bS)-7a-acetoxy-3-ethyl-8-methoxy-1,2,3,4,6,7,7a,12b-octahydroin (Dro[2,3-a]quinoridine-2-yl)-3-methoxyacrylate, methyl(E)-2-((2S,3S,7aS,12bS)-3-ethyl-7a-(isobutyryloxy)-8-methoxy-1,2,3,4,6,7,7a,12b-octahydroindoro[2,3-a]quinoridine-2-yl)-3-methoxyacrylate, 5-(((2S,3S,7aS,12bS)-2-((E)-1,3-dimethoxy-3-oxopropa-1-en-2-yl)-3-ethyl-8-methoxy-1,3,4,6,7,12b -Hexahydroindro[2,3-a]quinoridine-7a(2H)-yl)oxy)-5-oxopentanoic acid, 3-(((2S,3S,7aS,12bS)-2-((E)-1,3-dimethoxy-3-oxopropa-1-en-2-yl)-3-ethyl-8-methoxy-1,3,4,6,7,12b-Hexahydroindro[2,3-a]quinoridine-7a(2H)-yl)oxy)-3-oxopropanoic acid, methyl(E)-2-((2S,3S,7aS,12bS))-3-ethyl-8-methoxy-7a-((3,4,Examples include 5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)-1,2,3,4,6,7,7a,12b-octahydroindoro[2,3-a]quinoridine-2-yl)-3-methoxyacrylate and methyl(E)-2-((2S,3S,7aS,12bS)-3-ethyl-8-methoxy-7a-((3,4,5-trihydroxy-6-methyltetrahydro-2H-pyran-2-yl)oxy)-1,2,3,4,6,7,7a,12b-octahydroindoro[2,3-a]quinoridine-2-yl)-3-methoxyacrylate.

[0143] In a particular embodiment, the compounds provided herein are [ka] [ka] [ka] It is selected from the group consisting of the following.

[0144] In a particular embodiment, the compounds provided herein are [ka] [ka] It is a compound of formula (Ia) selected from the group consisting of the following:

[0145] In a particular embodiment, the compounds provided herein are [ka] [ka] It is a compound of formula (Ia) selected from the group consisting of the following:

[0146] In a particular embodiment, the compounds provided herein are [ka] It is a compound of formula (Ia) selected from the group consisting of the following:

[0147] In a particular embodiment, the compound of formula (Ia) is [ka] That is the case.

[0148] In a particular embodiment, the compound of formula (Ia) is [ka] It is selected from the group consisting of the following.

[0149] In a particular embodiment, the compound of formula (Ia) is [ka] It is selected from the group consisting of the following.

[0150] In a particular embodiment, the compound of formula (Ia) is [ka] That is the case.

[0151] In a particular embodiment, the compound of formula (Ia) is [ka] That is the case.

[0152] In a particular embodiment, the compound of formula (Ia) is [ka] It is selected from the group consisting of the following.

[0153] In a particular embodiment, the compound of formula (Ia) is [ka] It is selected from the group consisting of the following.

[0154] enzyme In another embodiment, novel enzyme mixtures for transferring functional groups to indole alkaloids are provided herein. In some cases, the enzyme mixture transfers a donor functional group to an acceptor functional group on an indole alkaloid. In some cases, the enzyme mixture may be a mixture of an enzyme, a buffer, and a reactant. In some cases, the reactant may contain a donor functional group and an indole alkaloid. In some cases, the enzyme mixture may be a cell-free solution. In some cases, the enzyme mixture may contain unmodified host cells containing a transferase enzyme. In some cases, the enzyme mixture may contain modified host cells containing a transferase enzyme. In some cases, the enzyme mixture may contain unmodified host cells producing an indole alkaloid. In some cases, the enzyme mixture may contain modified host cells producing an indole alkaloid. Compositions of modified indole can be used for therapeutic and consumer applications.

[0155] Enzymes and whole-cell biocatalysts are becoming increasingly attractive as renewable methods for the production of specialty chemicals and pharmaceuticals. These biocatalysts are called modified host cells. Using in vitro enzymatic reactions and intact microorganisms as catalysts offers several advantages over conventional synthesis, such as high enantioselectivity and regioselectivity. An advantage of whole-cell biocatalysts is the ability to achieve multipart synthesis, where multiple intermediates produced in parallel in the same vessel are bound to the final product. Another feature of whole-cell biocatalysts is that they can catalyze reactions at ambient temperature and in aqueous solutions. This advantage can also be realized in ester synthesis. The modifications described herein are achieved by utilizing novel enzyme mixtures. A common class of these modifications is shown in Table 1 below. [Table 1]

[0156] Kinases are enzymes capable of transferring phosphate groups from adenosine triphosphate (ATP) to indole alkaloids to form phosphorylated indole alkaloids. In some cases, the transferase in an enzyme mixture is a kinase. These kinase enzymes can be utilized using in vitro systems. Kinase enzymes can also be expressed in microbial host cells. In some cases, one or more enzymes contain kinases. In some cases, kinases contain amino acid sequences having at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or at least 95% sequence identity with SEQ ID NOs: 1 and 2.

[0157] Methyltransferases are enzymes capable of transferring methyl groups from the donor S-adenosylmethionine (SAM) to indole alkaloids, thereby forming methylated indole alkaloids. In some cases, the transferase in an enzyme mixture is a methyltransferase. These methyltransferase enzymes are available using in vitro systems. Methyltransferase enzymes can also be expressed in microbial host cells as components of an enzyme mixture. In some cases, one or more enzymes include a methyltransferase. In some cases, the methyltransferase contains an amino acid sequence having at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or at least 95% sequence identity to either SEQ ID NOs: 3 and 4.

[0158] Sulfotransferases are enzymes capable of transferring a sulfur group from the donor 3'-phosphoadenosine-5'-phosphosulfate (PAPS) to an indole alkaloid to form sulfated indole alkaloids. In some cases, the transferase in an enzyme mixture is a sulfotransferase. These sulfotransferase enzymes can be used in vitro systems. Sulfotransferase enzymes can also be expressed in microbial host cells as components of an enzyme mixture. In some cases, one or more enzymes include a sulfotransferase. In some cases, the sulfotransferase contains an amino acid sequence having at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or at least 95% sequence identity to SEQ ID NOs. 5 and 6.

[0159] Acetyl-CoA is the most abundant acyl-CoA unit in cells and can be added in vitro by enzymatic reactions. Acyl-CoA can be readily used in the production of a wide range of acyl esters catalyzed by acyltransferase enzymes. Other acyl-CoA donor units for donating acyl groups to indole alkaloids include, but are not limited to, isobutyryl-CoA, butyryl-CoA, succinyl-CoA, malonyl-CoA, coumarate-CoA, glutaryl-CoA, adipoyl-CoA, and enoyl-CoA. Other donor units may be isoprenoid precursors, including, but not limited to, farnesyl pyrophosphate, geranylgeranyl pyrophosphate, and / or dimethylallyl pyrophosphate. Acyltransferases are enzymes that can transfer an acyl from an acyl-CoA molecule to an indole alkaloid to form acylated indole alkaloids. In some cases, the transferase in an enzyme mixture is an acyltransferase. These acyltransferase enzymes are available using in vitro systems. Acyltransferase enzymes can also be expressed in microbial host cells as components of enzyme mixtures. In some cases, one or more enzymes include acyltransferases. In some cases, the acyltransferases contain amino acid sequences having at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or at least 95% sequence identity to either SEQ ID NOs. 7 and 8.

[0160] Glycosylation can modulate the physiological properties of small molecules and peptides by having specific effects such as improved metabolic stability, membrane permeability, biodistribution, and ligand-target interactions. Therefore, numerous glycosylated natural and synthetic glycopeptides are important biochemical probes and therapeutic agents. While there are many methods for glycosylation of organic compounds, these methods typically require the protection of both the glycosyl donor and the receptor. The most common exception involves the application of glycosyltransferases, usually in an enzymatic environment. However, the chemical synthesis of glycosides is by no means straightforward and requires inefficient multi-step pathways. In some cases, the glycosyl donor molecule may be a nucleotide diphosphate sugar. In some cases, the nucleotide component of the nucleotide sugar may be uracil diphosphate (also known as UDP). The sugar component may be, but is not limited to, glucose, glucuronic acid, galacturonic acid, xylose, galactose, rhamnose, and rutinose. The sugar components may be, but are not limited to, D-glucose, D-glucuronic acid, D-galacturonic acid, D-xylose, D-galactose, D-rhamnose, and D-rutinose. Nucleotide diphosphate sugars (NDP sugars) or sugar nucleotides are activated monosaccharide donors used by glycosyltransferases (GTs) for glycosylation of various receptors. NDP sugars originate from the primary metabolism of common precursors such as UDP-glucose and are converted to various NDP sugars by sugar nucleotide processing enzymes. UDP sugars can be selected from the group including, but are not limited to, UDP-glucose, UDP-glucuronic acid, UDP-galacturonic acid, UDP-xylose, UDP-galactose, UDP-rhamnose, and UDP-rutinose. In some cases, the transferase in the enzyme mixture is a glucosyltransferase. These glucosyltransferase enzymes are available using in vitro systems. Glucosyltransferase enzymes can also be expressed in microbial host cells as components of enzyme mixtures. In some cases, one or more enzymes include glucosyltransferases.In some cases, the glucosyltransferase contains an amino acid sequence having at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or at least 95% sequence identity with any one of SEQ ID NOs: 9-12.

[0161] Prenyltransferases are a type of enzyme that transfers an allyl prenyl group to an acceptor molecule. The term "prenyltransferase" generally refers to prenyl diphosphate synthase. Prenyltransferases are generally classified into two classes, cis (or Z) and trans (or E), depending on the stereochemistry of the resulting product. Examples of transprenyltransferases include dimethylallyltransferase and geranylgeranyl pyrophosphate synthase. Cis-prenyltransferases include dehydrodolicol diphosphate synthase (involved in the production of dolicol precursors). Prenyltransferases are enzymes capable of transferring a prenyl molecule from the donor prenyl diphosphate to an indole alkaloid, forming sulfated indole alkaloids. In some cases, the transferase in an enzyme mixture is a prenyltransferase. These prenyltransferase enzymes are available using in vitro systems. Prenyltransferase enzymes can also be expressed in microbial host cells as components of enzyme mixtures. In some cases, one or more enzymes include prenyltransferases. In some cases, sulfotransferases include amino acid sequences having at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or at least 95% sequence identity with SEQ ID NOs. 13-14.

[0162] In some embodiments, one or more enzymes are those disclosed in Table 2 below. [Table 2-1] [Table 2-2] [Table 2-3] [Table 2-4] [Table 2-5] [Table 2-6] [Table 2-7]

[0163] Therefore, the object of this disclosure is to provide novel compositions and methods for producing indole alkaloids. In some embodiments, an enzyme mixture capable of transferring donor functional groups to acceptor functional groups on indole alkaloids can be biosynthetically produced by intracellular metabolic pathways.

[0164] In some cases, the enzymes incorporated into the enzyme mixture are artificial enzymes. In some cases, the amino acid sequence of the enzymes incorporated into the enzyme mixture may have been altered.

[0165] Enzyme mixing conditions and product generation In some cases, the enzyme mixture is reacted under aerobic conditions. In other cases, the enzyme mixture is reacted under anaerobic conditions.

[0166] In some cases, the enzyme may be buffered with, for example, phosphate, HEPES, or Tris. In some cases, the enzyme mixture may be a minimal medium containing, but not limited to, M9, MOPS, YNB, or ammonia salts, or a complex medium containing, for example, yeast extract, casamino acids, peptone, or tryptone. In some cases, the enzyme mixture may contain a reducing agent such as, for example, L-ascorbic acid, dithiothreitol, or mercaptoethanol. In some cases, the enzyme mixture may be supplemented with additional amino acids such as L-methionine, histidine, arginine, alanine, isoleucine, cysteine, aspartic acid, leucine, glutamine, asparagine, lysine, glycine, glutamic acid, proline, serine, phenylalanine, tyrosine, selenocysteine, threonine, pyrrolicin, tryptophan, or valine. In some cases, additional vitamins and cofactors, such as L-ascorbic acid, thiamine, pyridoxal phosphate, niacin, pyridoxine, biotin, folic acid, tetrahydrofolate, riboflavin, pantothenic acid, copper salts, magnesium salts, manganese salts, molybdenum salts, iron salts, zinc salts, nickel salts, glutathione, heme, or D-aminolevulinic acid, may also be added.

[0167] In some cases, the substituted anthranilate can be supplied to the enzyme mixture by a single addition, batch supply, or constant dilution during culture. In some cases, the substituted indole can also be supplied to the enzyme mixture by a single addition, batch supply, or constant dilution during culture.

[0168] In some cases, downstream products may be generated. In some cases, downstream products may be purified, for example, by isolating and purifying them from the culture medium, cell lysates, or both. In some cases, downstream products may be at least, or about 25% by weight, 30% by weight, 40% by weight, 50% by weight, 60% by weight, 70% by weight, 75% by weight, 80% by weight, 90% by weight, 95% by weight, or 99% by weight pure. Purification can be carried out by any known method or combination of methods, such as column chromatography, phase separation, precipitation, crystallization, decantation, gas stripping, membrane-reinforced separation, fractionation, adsorption / desorption, osmotic evaporation, thermal or vacuum desorption from solid phase, and solvent extraction of products immobilized or absorbed on solid phase. Purity can be evaluated by any suitable method, such as column chromatography, high-performance liquid chromatography (HPLC) analysis, or gas chromatography-mass spectrometry (GC-MS).

[0169] In some cases, the enzyme mixture may be converted to approximately 0.0015%, 0.002%, 0.005%, 0.01%, 0.02%, 0.05%, 0.1%, 0.12%, 0.14%, 0.16%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1.0%, 1.2%, 1.4%, 1.6%, 1.8%, 2.0%, 2.5%, 3.0%, 3.5%, 4.0%, 5.0%, 6.0%, 7.0%, or 8.0% or more of the supplied precursor in the enzyme mixture into the desired product. In some cases, the enzyme mixture may produce a desired product in a liquid medium at a concentration of at least 2 g / L, at least 3 g / L, at least 4 g / L, at least 5 g / L, at least 7 g / L, at least 10 g / L, or more than 50 g / L.

[0170] In some cases, the enzyme mixture may be converted to the desired product at a concentration of approximately 0.0015%, 0.002%, 0.005%, 0.01%, 0.02%, 0.05%, 0.1%, 0.12%, 0.14%, 0.16%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1.0%, 1.2%, 1.4%, 1.6%, 1.8%, 2.0%, 2.5%, 3.0%, 3.5%, 4.0%, 5.0%, 6.0%, 7.0%, or 8.0% or more of the carbon in the enzyme mixture. In some cases, the enzyme mixture may produce a desired product in the enzyme mixture at a concentration of at least 2 g / L, at least 3 g / L, at least 4 g / L, at least 5 g / L, at least 7 g / L, at least 10 g / L, or more than 50 g / L.

[0171] host cell Suitable host cells include cells that can be cultured in an enzyme mixture, such as single-celled organisms. Suitable host cells include yeast cells, fungal cells, insect cells, mammalian cells, algal cells, and bacterial cells. Suitable host cells may further include filamentous fungal cells. Suitable filamentous fungal cells include, for example, Aspergillus and Neurospora crassa.

[0172] The host cell may be a prokaryotic cell. Suitable prokaryotic cells include, but are not limited to, any of the various laboratory strains of Escherichia coli, Corynebacterium glutamicum, Lactobacillus sp., Salmonella sp., Shigella sp., Citrobacter, Enterobacter, Clostridium, Klebsiella, and Aerobacter. See, for example, Carrier et al. (1992) J.Immunol. 148:1176-1181; U.S. Patent No. 6,447,784; and Sizemore et al. (1995) Science 270:299-302. Examples of Salmonella strains that can be used in this disclosure include, but are not limited to, Salmonella typhi and S. typhimurium. Suitable Shigella strains include, but are not limited to, Shigella flexneri, Shigella sonnei, and Shigella disenteriae. Typically, laboratory strains are non-pathogenic. Other suitable non-limiting examples of bacteria include Bacillus subtilis, Pseudomonas pudita, Pseudomonas aeruginosa, Pseudomonas mevalonii, Rhodobacter sphaeroides, and Rhodobacter. Examples include, but are not limited to, *Escherichia capsulatus*, *Rhodospirillum rubrum*, and *Rhodococcus sp.*. In some cases, the host cell is *Escherichia coli*.

[0173] Non-limiting examples of suitable yeast host cells are strains selected from the Candida, Kluyveromyces, Saccharomyces, Schizosaccharomyces, Pichia, Hansenula, and Yarrowia species. In some cases, the yeast host cells may be selected from the group consisting of Saccharomyces carlsbergensis, Saccharomyces cerevisiae, Saccharomyces diastaticus, Saccharomyces douglasii, Saccharomyces kluyveri, Saccharomyces norbensis, Saccharomyces oviformis, Schizosaccharomyces pombe, Saccharomyces uvarum, Pichia kluyveri, Yarrowia lipolytica, Candida utilis, Candida cacaoi, and Geotrichum fermentans. Other useful yeast host cells include Kluyveromyces lactis, Kluyveromyces fragilis, Hansenula polymorpha, Pichia pastoris, Yarrowia lipolytica, Schizosaccharomyces pombe, Ustilgo maylis, Candida maltose, Pichia guillermondii, and Pichia methanoliol. Suitable yeast host cells include, but are not limited to, Pichia pastoris, Pichia finlandica, Pichia trehalophila, Pichia koclamae, Pichia membranaefaciens, Pichia opuntiae, Pichia thermotolerans, Pichia salictaria, Pichia guercuum, Pichia pijperi, Pichia stiptis, Pichia methanolica, Pichia sp., Saccharomyces cerevisiae, Saccharomyces sp., and Hansenula polymorpha.In some cases, the yeast host cell may be Saccharomyces cerevisiae. For example, the genetically modified cells of this disclosure may be genetically modified Saccharomyces cerevisiae cells.

[0174] Filamentous fungi can be characterized by a mycelial wall composed of chitin, cellulose, glucan, chitosan, mannan, and other complex polysaccharides. Vegetative growth may be by hyphae elongation, and carbon catabolism may be obligate aerobic. Suitable filamentous fungal strains include, but are not limited to, strains of Acremonium, Agaricus, Aspergillus, Aureobasidium, Chrysosporium, Coprinus, Cryptococcus, Filibasidium, Fusarium, Humicola, Magnaporthe, Mucor, Myceliophthora, Neocallimastix, Neurospora, Paecilomyces, Penicillium, Piromyces, Phanerochaete, Pleurotus, Schizophyllum, Talaromyces, Thermoascus, Thielavia, Tolypocladium, and Trichoderma. Non-specific examples of suitable filamentous fungal cells include, for example, Aspergillus niger, Aspergillus awamori, Aspergillus foetidus, Aspergillus sojae, Aspergillus fumigatus, and Aspergillus oryzae. Another example of a suitable fungal cell is Neurospora crassa cells.

[0175] Expression of heterologous proteins in modified host cells In some cases, nucleotide sequences encoding heterologous polypeptides can be operably ligated to transcriptional regulatory elements.

[0176] Promoters suitable for expression in bacteria include, but are not limited to, pT7, ptac, pLac, pLacUV5, pTet, pBAD, and the constitutive BBa series promoters in the Anderson promoter library (Kelly et al, “Measuring the activity of BioBrick promoters using an in vivo reference standard” Journal of Biological Engineering 2009 3:4). Promoters suitable for expression in yeast include, but are not limited to, TDH3, CCW12, CYC1, HIS3, GAL1, GAL10, ADH1, PGK, PHO5, GAPDH, ADC1, TRP1, URA3, LEU2, ENO, and TP1; as well as AOX1 (for example, for use in Pichia).

[0177] The expression vector may also contain a ribosome binding site and a transcription terminator for translation initiation. Furthermore, the expression vector may also contain appropriate sequences for amplifying expression.

[0178] In some cases, the expression of amino acid sequences may be optimized or biased towards codons in order to increase protein expression in vivo. This can be achieved by several algorithms (Hanson and Coller, Nature). Reviews Molecular Cell Biology volume 19, pages 20-30 (2018) (Quax, et al. Molecular Cell Review volume 59, July 16, 2015). In some cases, natural amino acid sequences can be used to encode amino acid sequences in vivo.

[0179] Pharmaceutical composition The compounds described herein can be formulated as pharmaceutical compositions. The pharmaceutical compositions may comprise (i) modified indole alkaloids provided herein; and (ii) pharmaceutically acceptable carriers, diluents, or excipients. Pharmaceutical compositions comprising the modified indole alkaloids described herein can be formulated according to known methods for preparing pharmaceutically useful compositions, thereby combining the therapeutic molecules in a mixture with pharmaceutically acceptable carriers, diluents, or excipients.

[0180] Sterile phosphate-buffered saline is an example of a pharmaceutically acceptable carrier. Other suitable carriers, diluents, or excipients are well known to those skilled in the art (see, for example, Gennaro (ed.), Remington's Pharmaceutical Sciences (Mack Publishing Company, 19th ed. 1995)). The formulation may further contain one or more excipients, preservatives, solubilizers, buffers, or albumin to prevent protein loss on the vial surface, etc.

[0181] Pharmaceutical compositions comprising modified indole alkaloids as described herein may be formulated in dosage forms selected from the group consisting of oral, intravenous, intranasal, suppository, intradermal, intramuscular, intraperitoneal, subcutaneous, epidural, sublingual, liquid, lozenge, rapid disintegrating tablet, lyophilized preparation, film, spray (including nasal spray, oral spray, or topical spray), or mucosal adhesives. Oral dosage forms may be selected from the group consisting of tablets, pills, pellets, capsules, powders, lozenges, granules, solutions, suspensions, emulsions, syrups, elixirs, sustained-release preparations, aerosols, and sprays. In some embodiments, modified indole alkaloids are formulated as liquids, lozenges, rapid disintegrating tablets, lyophilized preparations, films, sprays, or mucosal adhesives.

[0182] Pharmaceutical compositions comprising modified indole alkaloids as described herein may also contain one or more additional components, but are not limited to, mucosal adhesive compounds, buffers, plasticizers, stabilizers, taste masking agents, flavoring agents, colorants, preservatives, inert fillers, and combinations thereof.

[0183] In some embodiments, the formulation includes one or more solubilizers that increase the solubility of the active compound in the formulation. Suitable solubilizers include, for example, complexing agents and surfactants. Suitable complexing agents include unsubstituted cyclodextrins (alpha-cyclodextrin, beta-cyclodextrin, etc.) and substituted cyclodextrins (hydroxypropyl beta-cyclodextrin, sulfobutyl ether-beta-cyclodextrin, etc.). Suitable surfactants include polyoxyethylene sorbitan monolaurate (e.g., Tween® 20), polyoxyethylene sorbitan molooleate (e.g., Tween® 80), polyethylene glycol (15)-hydroxystearate (e.g., Kolliphor® HS 15), PEG-35 castor oil (e.g., Kolliphor® EL), and PEG-60 hydrogenated castor oil (e.g., Cremophor® RH 60).

[0184] In some embodiments, the formulation includes one or more buffers that maintain the pH of the IV solution within a pharmaceutically acceptable range. In certain embodiments, the buffer maintains the pH of the IV solution between approximately 5 and 9. In certain embodiments, the buffer maintains the pH of the IV solution at approximately 7.4. Suitable buffers include, for example, citrates, lactates, acetates, maleates, phosphates, etc.

[0185] In some embodiments, the formulation includes one or more density modifiers used to control the density of the IV formulation. Suitable density modifiers include, for example, glucose.

[0186] In some embodiments, the formulation includes one or more isotonic modifiers that provide the formulation to be isotonic with the tissue to prevent pain and inflammation when the formulation is administered. Suitable isotonic modifiers include, for example, electrolytes, monosaccharides, and disaccharides. Examples of isotonic modifiers include glycerin, glucose, potassium chloride, and sodium chloride.

[0187] In some embodiments, the formulation includes one or more thickening agents. Suitable thickening agents include, for example, povidone, hydroxyethylcellulose, polyvinyl alcohol, and carbomers (such as acrylic acid homopolymers and acrylic acid copolymers).

[0188] In some embodiments, the formulation includes one or more preservatives that increase the stability of the active compound in the formulation and / or provide antimicrobial activity. Suitable preservatives include, for example, antimicrobial agents and antioxidants. Examples of antimicrobial agents (the range of effective antimicrobial amounts is expressed as the weight of the antimicrobial agent per unit volume of the IV formulation, i.e., %w / v) include benzyl alcohol (approximately 0.1-3.0%w / v), methylparaben (approximately 0.08-0.1%w / v), propylparaben (0.001-0.023%w / v), phenol (0.2-0.5%w / v), cresol (0.2-0.5%w / v), methylparaben (0.1%w / v), chlorbutanol (0.25-0.5%w / v), sodium metabisulfite (0.025-0.66%w / v), sodium bisulfite (0.13-0.2%w / v), benzethonium chloride (0.08-0.1%w / v), and benzalkonium chloride (0.08-0.1%w / v). Examples of antioxidants include sodium bisulfite and other sulfites, ascorbic acid, ethylenediaminetetraacetic acid salts (including sodium), alpha-tocopherol, butylated hydroxylhydroxytoluene, and butylated hydroxyanisole.

[0189] Route of administration According to the methods of this disclosure, the modified indole alkaloids described herein can be administered to subjects by various modes of administration, including, for example, intramuscular, subcutaneous, intravenous, intraatrial, intraarticular, parenteral, intranasal, intrapulmonary, transdermal, intrapleural, subarachnoid, and oral routes of administration. For prophylactic and therapeutic purposes, the modified indole alkaloids described herein can be administered to subjects by single bolus delivery, via long-term continuous delivery (e.g., continuous transdermal delivery), or by repeated dosing protocols (e.g., hourly, daily, weekly, or monthly).

[0190] Kit / Product A pharmaceutical composition comprising a modified indole alkaloid as described herein may be supplied as a kit comprising a container containing the pharmaceutical composition as described herein. The pharmaceutical composition may be provided, for example, in the form of a single or multiple dose injectable solution, or as a sterile powder that is reconstituted before injection. Alternatively, such a kit may include a dry powder disperser, a liquid aerosol generator, or a nebulizer for administering the pharmaceutical composition. Such a kit may further include written information relating to the indications and uses of the pharmaceutical composition.

[0191] Enzymatic preparation method for modified indole alkaloids In yet another embodiment, the following are provided herein: A method for enzymatically preparing an indole alkaloid, comprising the step of contacting a compound of formula (Ia') with an enzyme and a co-substrate, Here, the compound of formula (Ia') is [ka] or having a pharmaceutically acceptable salt structure thereof, During the ceremony, R 1 and R 10These are independently selected from hydrogen, C1-C6 alkyl, C2-C6 alkenyl, and C2-C6 alkynyl, where alkyl, alkenyl, and alkynyl may optionally be independently substituted with one or more substituents selected from halo, -OMe, -CN, -NH2, and -NO2. R 8 is -CR'2-, where each R' is independently selected from hydrogen, halo, haloalkyl, alkoxy, haloalkoxy, and amine. n is selected from 2, 3, and 4. R 9 is selected from C2-C6 alkyl, C2-C6 alkenyl, and C2-C6 alkynyl, where alkyl, alkenyl, and alkynyl may optionally be substituted by one or more substituents independently selected from halo, -OMe, -CN, -NH2, -NO2, and 3- to 8-membered heterocycles, and the 3- to 8-membered heterocycle may optionally be substituted by one or more substituents independently selected from halo, -OMe, -CN, -NH2, and -NO2. R 2 These are selected from hydrogen, halogens, C1-C6 alkyl groups, and C1-C6 haloalkyl groups. R 4 , R 5 , R 6 , and R 7 Each of these is independently selected from hydrogen, -OH, and C1-C6 alkyl, and R 4 , R 5 , R 6 , and R 7 At least one of them is -OH.

[0192] In some embodiments, R 4 It is -OH.

[0193] In some embodiments, R 5 It is -OH.

[0194] In some embodiments, R 6 It is -OH.

[0195] In some embodiments, R 7 It is -OH.

[0196] In some embodiments, the enzyme is 4-hydroxytryptamine kinase.

[0197] In some embodiments, the enzyme is acetylserotonin O-methyltransferase.

[0198] In some embodiments, the enzyme is tryptamine n-methyltransferase.

[0199] In some embodiments, the enzyme is sulfotransferase 1A1.

[0200] In some embodiments, the enzyme is sulfotransferase 1A3.

[0201] In some embodiments, the enzyme is alcohol O-acetyltransferase 1.

[0202] In some embodiments, the enzyme is chloramphenicol acetyltransferase.

[0203] In some embodiments, the enzyme is UDP-glucuronosyltransferase. In some embodiments, UDP-glucuronosyltransferase is UDP-glucuronosyltransferase 1-6. In some embodiments, UDP-glucuronosyltransferase is UDP-glucuronosyltransferase 1-9. In some embodiments, UDP-glucuronosyltransferase is UDP-glucuronosyltransferase 1-10.

[0204] In some embodiments, the enzyme is oleandomycin glycosyltransferase.

[0205] In some embodiments, the enzyme is a glycosyltransferase.

[0206] In some embodiments, the enzyme is 4-dimethylallyltryptophan synthase.

[0207] In some embodiments, the enzyme is 7-dimethylallyltryptophan synthase.

[0208] For example, R 4 When is -OH, various modified indole alkaloids of formula (Ia) can be prepared as shown in the general synthesis scheme 1 below. Scheme 1: General synthesis of modified indole alkaloids using enzymatic conversion [ka]

[0209] Treatment method The compositions described herein include modified indole alkaloids having therapeutic uses for mental disorders including, but not limited to, depression and anxiety disorders, alcoholism, terminal illness, depression and anxiety associated with terminal illness, prolonged grief disorder, complicated grief disorder, and post-traumatic stress disorder. The modified indole alkaloids provided herein have therapeutic uses including, but not limited to, major depressive disorder, treatment-resistant depression, anxiety, post-traumatic mania, psychosis, insomnia, hypersomnia, Alzheimer's disease, Parkinson's disease, burnout syndrome, cluster headache, migraine, and other neurological disorders.

[0210] In some embodiments, the present disclosure provides a method for treating mental disorders by administering a modified indole alkaloid or a salt thereof to a patient in need. In some embodiments, the method comprises administering a modified indole alkaloid or a salt thereof to a patient in need of treatment.

[0211] In some embodiments, the methods provided herein do not result in a simultaneous increase or onset of negative symptoms such as depression or anxiety. Other negative symptoms may include agitation, tremors, or anxiety; indigestion, diarrhea or constipation; loss of appetite and weight loss; dizziness; blurred vision; dry mouth; excessive sweating; sleep disturbance (insomnia) or drowsiness; and / or headache.

[0212] In another embodiment, the following is provided herein: Formula (Ia): [ka] A method for treating a disease or disorder in a subject requiring the administration of a compound or a pharmaceutically acceptable salt thereof, wherein, R 1 and R 10 These are independently selected from hydrogen, C1-C6 alkyl, C2-C6 alkenyl, and C2-C6 alkynyl, where alkyl, alkenyl, and alkynyl may optionally be independently substituted with one or more substituents selected from halo, -OMe, -CN, -NH2, and -NO2. R 8 is -CR'2-, where each R' is independently selected from hydrogen, halo, haloalkyl, alkoxy, haloalkoxy, and amine. n is selected from 2, 3, and 4. R 9 is selected from C2-C6 alkyl, C2-C6 alkenyl, and C2-C6 alkynyl, where alkyl, alkenyl, and alkynyl may optionally be substituted by one or more substituents independently selected from halo, -OMe, -CN, -NH2, -NO2, and 3- to 8-membered heterocycles, and the 3- to 8-membered heterocycle may optionally be substituted by one or more substituents independently selected from halo, -OMe, -CN, -NH2, and -NO2. R 2 These are selected from hydrogen, halogens, C1-C6 alkyl groups, and C1-C6 haloalkyl groups. R 4 , R 5 , R6 , and R 7 Each of these is independently selected from hydrogen, C1-C6 alkyl, A, J, Q, and X. A is [ka] And, J is [ka] And, Q is [ka] And, X is selected from glucose, xylose, galactose, rhamnose, rutinose, and disaccharides. R 13 This is selected from C1-C6 alkyl groups, which may optionally be substituted with hydrogen and one or more substituents independently selected from C1-C6 alkyl, oxo, halo, -OMe, -CN, -NH2, and -NO2. R 14 The C1-C6 alkyl and C2-C6 alkenyl atoms are selected from C1-C6 alkyl and C2-C6 alkenyl atoms, which may optionally be substituted with one or more substituents independently selected from halo, -OMe, -CN, -NH2, and -NO2. Alternatively, R 13 and R 14 These, together with the atoms to which they are bonded, form substituted or unsubstituted C3-C8 cycloalkyl groups, or substituted or unsubstituted 3-8 membered heterocycloalkyl groups, each having one or two heteroatoms independently selected from N, O, and S. R 15 This is selected from C1-C6 alkylenes and C2-C6 alkenylenes, where the C1-C6 alkylenes and C2-C6 alkenylenes may optionally be substituted with one or more substituents independently selected from C1-C6 alkyl, halo, -OMe, -CN, -NH2, and -NO2. Here, R4 , R 5 , R 6 , and R 7 At least one of them is A, J, Q, or X.

[0213] In some embodiments, the following is provided herein: Formula (I): [ka] A method for treating a disease or disorder in a subject requiring the administration of a compound or a pharmaceutically acceptable salt thereof, wherein, R 1 and R 10 These are independently selected from hydrogen, C1-C6 alkyl, C2-C6 alkenyl, and C2-C6 alkynyl, where alkyl, alkenyl, and alkynyl may optionally be independently substituted with one or more substituents selected from halo, -OMe, -CN, -NH2, and -NO2. R 8 is -CR'2-, where each R' is independently selected from hydrogen, halo, haloalkyl, alkoxy, haloalkoxy, and amine. n is selected from 2, 3, and 4. R 9 is selected from C2-C6 alkyl, C2-C6 alkenyl, and C2-C6 alkynyl, where alkyl, alkenyl, and alkynyl may optionally be substituted by one or more substituents independently selected from halo, -OMe, -CN, -NH2, -NO2, and 3- to 8-membered heterocycles, and the 3- to 8-membered heterocycle may optionally be substituted by one or more substituents independently selected from halo, -OMe, -CN, -NH2, and -NO2. R 2 These are selected from hydrogen, halogens, C1-C6 alkyl groups, and C1-C6 haloalkyl groups. R 4 , R 5 , R 6 , and R 7 Each of these is independently selected from hydrogen, C1-C6 alkyl, A, J, Q, and X. A is [ka] And, J is [ka] And, Q is [ka] And, X is selected from glucose, xylose, galactose, rhamnose, and rutinose. R 13 This is selected from C1-C6 alkyl groups, which may optionally be substituted with hydrogen and one or more substituents independently selected from halo, -OMe, -CN, -NH2, and -NO2. R 14 The C1-C6 alkyl and C2-C6 alkenyl atoms are selected from C1-C6 alkyl and C2-C6 alkenyl atoms, which may optionally be substituted with one or more substituents independently selected from halo, -OMe, -CN, -NH2, and -NO2. R 15 This is selected from C1-C6 alkylenes and C2-C6 alkenylenes, where the C1-C6 alkylenes and C2-C6 alkenylenes may optionally be substituted with one or more substituents independently selected from halo, -OMe, -CN, -NH2, and -NO2. Here, R 4 , R 5 , R 6 , and R 7 At least one of them is A or Q, or R 5 , R 6 , and R 7 At least one of them is J or X.

[0214] In some embodiments, R 1R is selected from hydrogen, C1-C6 alkyl, C2-C6 alkenyl, and C2-C6 alkynyl, where alkyl, alkenyl, and alkynyl may be independently and optionally substituted with one or more substituents selected from halo, -OMe, -CN, -NH2, and -NO2. In some embodiments, R 1 R is selected from hydrogen, C1-C6 alkyl, and C2-C6 alkenyl, where alkyl and alkenyl may be independently and optionally substituted with one or more substituents selected from halo, -OMe, -CN, -NH2, and -NO2. In some embodiments, R 1 R is selected from hydrogen and C1-C6 alkyl groups, where the alkyl group may optionally be substituted with one or more substituents independently selected from halo, -OMe, and -CN. In some embodiments, R 1 R is selected from hydrogen and C1-C3 alkyl groups. In some embodiments, R 1 is hydrogen. In some embodiments, R 1 These are C1-C3 alkyl groups.

[0215] In some embodiments, R 10 R is selected from hydrogen, C1-C6 alkyl, C2-C6 alkenyl, and C2-C6 alkynyl, where alkyl, alkenyl, and alkynyl may be independently and optionally substituted with one or more substituents selected from halo, -OMe, -CN, -NH2, and -NO2. In some embodiments, R 10 R is selected from hydrogen, C1-C6 alkyl, and C2-C6 alkenyl, where alkyl and alkenyl may be independently and optionally substituted with one or more substituents selected from halo, -OMe, -CN, -NH2, and -NO2. In some embodiments, R 10 R is independently selected from hydrogen, C1-C3 alkyl, and C2-C3 alkenyl, where the alkyl and alkenyl may optionally be substituted with one or more substituents independently selected from halo, -OMe, and -CN. In some embodiments, R 10R is independently selected from hydrogen, C1-C3 alkyl, and C2-C3 alkenyl. In some embodiments, R 10 is hydrogen. In some embodiments, R 10 is a C1-C3 alkyl group. In some embodiments, R 10 These are C2-C3 alkenyls.

[0216] In some embodiments, each R' is independently selected from hydrogen, halo, haloalkyl, alkoxy, haloalkoxy, and amine. In some embodiments, each R' is independently selected from hydrogen, halo, and haloalkyl. In some embodiments, each R' is hydrogen. In some embodiments, each R' is halo. In some embodiments, each R' is haloalkyl. In some embodiments, each R' is alkoxy. In some embodiments, each R' is haloalkoxy. In some embodiments, each R' is amine.

[0217] In some embodiments, n is selected from 2, 3, and 4. In some embodiments, n is selected from 2 and 3. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4.

[0218] In some embodiments, R 9 R is selected from C2-C6 alkyl, C2-C6 alkenyl, and C2-C6 alkynyl, where alkyl, alkenyl, and alkynyl may optionally be substituted by one or more substituents independently selected from halo, -OMe, -CN, -NH2, -NO2, and 3- to 8-membered heterocycles, and the 3- to 8-membered heterocycle may optionally be substituted by one or more substituents independently selected from halo, -OMe, -CN, -NH2, and -NO2. In some embodiments, R 9R is selected from C2-C6 alkyl, C2-C6 alkenyl, and C2-C6 alkynyl, where alkyl, alkenyl, and alkynyl may optionally be substituted with one or more substituents independently selected from halo, -OMe, -CN, -NH2, -NO2, and 3- to 8-membered heterocycles, and the 3- to 8-membered heterocycle may optionally be substituted with one or more substituents independently selected from halo, -OMe, and -CN. In some embodiments, R 9 R is selected from C2-C6 alkyl and C2-C6 alkenyl groups, where the alkyl and alkenyl groups may optionally be substituted with one or more substituents independently selected from halo, -OMe, -CN, and -NH2. In some embodiments, R 9 R is selected from C2-C3 alkyl and C2-C3 alkenyl, where the alkyl and alkenyl may optionally be substituted with one or more substituents independently selected from halo, -OMe, and -CN. In some embodiments, R 9 is a C2-C3 alkyl group. In some embodiments, R 9 These are C2-C3 alkenyls.

[0219] In some embodiments, R 2 R is selected from hydrogen, halogens, C1-C6 alkyls, and C1-C6 haloalkyls. In some embodiments, R 2 R is selected from hydrogen, halogens, and C1-C6 alkyl groups. In some embodiments, R 2 is hydrogen. In some embodiments, R 2 is a halogen. In some embodiments, R2 is a C1-C6 alkyl. In some embodiments, R 2 These are C1-C6 haloalkyl groups.

[0220] In some embodiments, R 4 , R 5 , R 6 , and R 7 Each of these is independently selected from hydrogen, A, J, Q, and X. In some embodiments, R4 , R 5 , R 6 , and R 7 Each is independently selected from hydrogen, J, and Q. In some embodiments, R 4 , R 5 , R 6 , and R 7 At least one of them is A, J, Q, or X. In some embodiments, R 4 , R 5 , R 6 , and R 7 At least one of them is A. In some embodiments, R 4 In some embodiments, R 5 In some embodiments, R 6 In some embodiments, R 7 is A. In some embodiments, R 4 , R 5 , R 6 , and R 7 At least one of them is J. In some embodiments, R 4 is J. In some embodiments, R 5 is J. In some embodiments, R 6 is J. In some embodiments, R 7 is J. In some embodiments, R 4 , R 5 , R 6 , and R 7 At least one of them is Q. In some embodiments, R 4 is Q. In some embodiments, R 5 is Q. In some embodiments, R 6 is Q. In some embodiments, R 7 is Q. In some embodiments, R 4 , R 5 , R 6 , and R 7 At least one of them is X. In some embodiments, R 4 is X. In some embodiments, R 5 is X. In some embodiments, R6 is X. In some embodiments, R 7 X is X.

[0221] In some embodiments, R 13 R is selected from C1-C6 alkyl groups, which may optionally be substituted with hydrogen and one or more substituents independently selected from halo, -OMe, -CN, -NH2, and -NO2. In some embodiments, R 13 R is selected from C1-C6 alkyl groups, which may optionally be substituted with hydrogen and one or more substituents independently selected from halo, -OMe, -CN, and -NH2. In some embodiments, R 13 R is selected from hydrogen and C1-C3 alkyl groups which may optionally be substituted with one or more substituents independently selected from halo, -OMe, and -CN. In some embodiments, R 13 is hydrogen. In some embodiments, R 13 These are C1-C3 alkyl groups.

[0222] In some embodiments, R 14 C1-C6 alkyl and C2- C6 Selected from alkenyls, where the C1-C6 alkyl and C2-C6 alkenyls may optionally be substituted with one or more substituents independently selected from halo, -OMe, -CN, -NH2, and -NO2. In some embodiments, R 14 R is selected from C1-C6 alkyl and C2-C6 alkenyl groups, where the C1-C6 alkyl and C2-C6 alkenyl groups may optionally be substituted with one or more substituents independently selected from halo, -OMe, and -CN. In some embodiments, R 14 is a C1-C3 alkyl which may optionally be substituted with one or more substituents independently selected from halo, -OMe, and -CN. In some embodiments, R 14 is a C1-C3 alkyl group. In some embodiments, R 14 These are C2-C3 alkenyls.

[0223] In some embodiments, R 15 R is selected from C1-C6 alkylenes and C2-C6 alkenylenes, where C1-C6 alkylenes and C2-C6 alkenylenes may be optionally substituted with one or more substituents independently selected from halo, -OMe, -CN, -NH2, and -NO2. In some embodiments, R 15 R is selected from C1-C6 alkylenes and C2-C6 alkenylenes, where C1-C6 alkylenes and C2-C6 alkenylenes may be optionally substituted with one or more substituents independently selected from halo, -OMe, and -CN. In some embodiments, R 15 R is selected from C1-C3 alkylenes and C2-C3 alkenylenes, where C1-C3 alkylenes and C2-C3 alkenylenes may be optionally substituted with one or more substituents independently selected from halo, -OMe, and -CN. In some embodiments, R 15 is a C1-C3 alkylene which may be optionally substituted with one or more substituents independently selected from halo, -OMe, and -CN. In some embodiments, R 15 R is a C1-C3 alkylene. In some embodiments, 15 These are C2-C3 alkenylenes.

[0224] In some embodiments, X is selected from glucose, xylose, galactose, rhamnose, rutinose, and disaccharides. In some embodiments, X is selected from glucose, galactose, rhamnose, rutinose, and disaccharides. In some embodiments, X is selected from glucose, xylose, rhamnose, rutinose, and disaccharides. In some embodiments, X is selected from glucose, xylose, galactose, rutinose, and disaccharides. In some embodiments, X is selected from glucose, xylose, galactose, rhamnose, and disaccharides.

[0225] In some embodiments, X is a disaccharide.

[0226] In some embodiments, X is a disaccharide selected from the group consisting of sucrose, lactose, maltose, trehalose, cellobiose, chitobiose, kojibiose, nigerose, isomaltose, β,β-trehalose, α,β-trehalose, sophorose, laminaribiose, genthiobiose, trehalose, turanose, maltulose, leucrose, isomaltulose, genthiobiulose, mannoviobiose, melibiose, melibiulose, rutinose, rutinulose, and xylobiose.

[0227] In some embodiments, X is a disaccharide selected from the group consisting of sucrose, lactose, maltose, trehalose, cellobiose, and chitobiose.

[0228] In some embodiments, X is selected from glucose, xylose, galactose, rhamnose, and rutinose. In some embodiments, X is selected from glucose, galactose, and rhamnose. In some embodiments, X is glucose. In some embodiments, X is xylose. In some embodiments, X is galactose. In some embodiments, X is rhamnose. In some embodiments, X is rutinose.

[0229] In some embodiments, the disorder or condition is major depression, treatment-resistant depression, addiction, anxiety, post-traumatic stress disorder, chronic grief disorder, complicated grief disorder, mania, psychosis, insomnia, hypersomnia, pain, Alzheimer's disease, Parkinson's disease, cluster headache, bulimia nervosa, migraine, or irritable bowel syndrome. In some embodiments, the disorder or condition is major depression, treatment-resistant depression, addiction, anxiety, post-traumatic stress disorder, chronic grief disorder, complicated grief disorder, or bulimia nervosa. In some embodiments, the disorder or condition is major depression. In some embodiments, the disorder or condition is treatment-resistant depression. In some embodiments, the disorder or condition is addiction. In some embodiments, the disorder or condition is anxiety. In some embodiments, the disorder or condition is post-traumatic stress disorder. In some embodiments, the disorder or condition is bulimia nervosa. In some embodiments, the disorder is chronic grief disorder. In some embodiments, the disorder is complicated grief disorder.

[0230] In another embodiment, the Specified Invention provides a method for treating a disease or disorder in a subject requiring the administration of a modified indole alkaloid.

[0231] In some embodiments, the modified indole alkaloid is a modified tryptamine alkaloid, a modified ibogamine alkaloid, a modified ergoline alkaloid, a modified beta-carborine alkaloid, or a modified mitraginine alkaloid. In some embodiments, the modified indole alkaloid is a modified tryptamine alkaloid. In some embodiments, the modified indole alkaloid is a modified ibogamine alkaloid. In some embodiments, the modified indole alkaloid is a modified ergoline alkaloid. In some embodiments, the modified indole alkaloid is a modified beta-carborine alkaloid. In some embodiments, the modified indole alkaloid is a modified mitraginine alkaloid.

[0232] In some embodiments, the modified indole alkaloid is an acetylated indole alkaloid, an acylated indole alkaloid, a methylated indole alkaloid, a phosphorylated indole alkaloid, a sulfonylated indole alkaloid, or a glycosylated indole alkaloid. In some embodiments, the modified indole alkaloid is an acetylated indole alkaloid. In some embodiments, the modified indole alkaloid is an acylated indole alkaloid. In some embodiments, the modified indole alkaloid is a methylated indole alkaloid. In some embodiments, the modified indole alkaloid is a phosphorylated indole alkaloid. In some embodiments, the modified indole alkaloid is a sulfonylated indole alkaloid. In some embodiments, the modified indole alkaloid is a glycosylated indole alkaloid.

[0233] Dosage The effective amount of the composition of this disclosure varies depending on many different factors, including the means of administration, the target site, the patient's physiological state, whether the patient is human or animal, other drugs administered, whether the treatment is prophylactic or therapeutic, and the specific activity of the composition itself and its ability to elicit a desirable response in the individual. In some embodiments, the patient is human. In some embodiments, the patient is a non-human mammal. Typically, the dose plan is adjusted to provide the best possible therapeutic response, i.e., to optimize safety and efficacy.

[0234] Determining the effective dose in this context is typically based on animal model studies that follow human clinical trials, and is guided by determining the effective dose and administration protocol that significantly reduces the incidence or severity of the target disorder in the model subjects. For example, the therapeutically effective dose of modified indole alkaloids depends on the condition being treated, the severity and course of the condition, whether the modified indole alkaloids are administered for prophylactic or therapeutic purposes, previous therapies, the patient's medical history and response to the modified indole alkaloids, and the discretion of the attending physician. The modified indole alkaloids described herein may be administered to the patient as a single treatment or over a series of treatments, and may be administered to the patient at any time from the time of diagnosis. The modified indole alkaloids described herein may be administered as a monotherapy or in combination with other drugs or therapies useful for treating the condition in question.

[0235] In some embodiments, the therapeutic effective dose of a modified indole alkaloid or its salt is at least 0.01 mg. In some embodiments, the therapeutic effective dose of a modified indole alkaloid or its salt is 0.01 mg to 500 mg. In some embodiments, the therapeutic effective dose of a modified indole alkaloid or its salt is 500 mg to 1000 mg. In some embodiments, the therapeutic effective dose of a modified indole alkaloid or its salt is 0.01 mg to 1 mg. Such disclosures in this specification are intended to disclose all intervals within this range. For example, the disclosure of 0.01 mg to 1 mg is a disclosure of 0.01 mg, 0.02 mg, 0.03 mg, 0.04 mg, 0.05 mg, 0.06 mg, 0.07 mg, 0.08 mg, 0.09 mg, 0.1 mg, 0.2 mg, 0.3 mg, 0.4 mg, 0.5 mg, 0.6 mg, 0.7 mg, 0.8 mg, 0.9 mg, and 1 mg.

[0236] In some embodiments, the therapeutically effective dose of the modified indole alkaloid or its salt is 1 mg to 10 mg. In some embodiments, the therapeutically effective dose of the modified indole alkaloid or its salt is 10 mg to 20 mg. In some embodiments, the therapeutically effective dose of the modified indole alkaloid or its salt is 20 mg to 30 mg. In some embodiments, the therapeutically effective dose of the modified indole alkaloid or its salt is 30 mg to 40 mg. In some embodiments, the therapeutically effective dose of the modified indole alkaloid or its salt is 40 mg to 50 mg.

[0237] In some embodiments, the therapeutically effective dose of modified indole alkaloid or its salt is 50 mg to 100 mg. In some embodiments, the therapeutically effective dose of modified indole alkaloid or its salt is 100 mg to 150 mg. In some embodiments, the therapeutically effective dose of modified indole alkaloid or its salt is 150 mg to 200 mg. In some embodiments, the therapeuticly effective dose of modified indole alkaloid or its salt is 200 mg to 250 mg. In some embodiments, the therapeuticly effective dose of modified indole alkaloid or its salt is 250 mg to 300 mg. In some embodiments, the therapeuticly effective dose of modified indole alkaloid or its salt is 300 mg to 350 mg. In some embodiments, the therapeuticly effective dose of modified indole alkaloid or its salt is 350 mg to 400 mg. In some embodiments, the therapeuticly effective dose of modified indole alkaloid or its salt is 450 mg to 500 mg.

[0238] In some embodiments, the therapeutically effective dose of modified indole alkaloid or its salt is 500 mg to 550 mg. In some embodiments, the therapeutically effective dose of modified indole alkaloid or its salt is 550 mg to 600 mg. In some embodiments, the therapeutically effective dose of modified indole alkaloid or its salt is 600 mg to 650 mg. In some embodiments, the therapeuticly effective dose of modified indole alkaloid or its salt is 650 mg to 700 mg. In some embodiments, the therapeuticly effective dose of modified indole alkaloid or its salt is 700 mg to 750 mg. In some embodiments, the therapeuticly effective dose of modified indole alkaloid or its salt is 750 mg to 800 mg. In some embodiments, the therapeuticly effective dose of modified indole alkaloid or its salt is 800 mg to 850 mg. In some embodiments, the therapeuticly effective dose of modified indole alkaloid or its salt is 850 mg to 900 mg. In some embodiments, the therapeuticly effective dose of modified indole alkaloid or its salt is 900 mg to 950 mg. In some embodiments, the therapeutically effective dose of the modified indole alkaloid or its salt is 950 mg to 1000 mg. [Examples]

[0239] Example 1: Preparation of modified indole alkaloids Reagents: All enzymes were purchased from New England Biolabs. All synthetic oligonucleotides were ordered from Integrated DNA Technologies. All chemicals for gas chromatography (GC) standards, except for ethanol (VWR) and tetradecyl acetate (Ark Pharm, Inc.), were ordered from Sigma. I bought it from Aldrich.

[0240] Plasmid construction, cloning, and transformation: Target gene(s) and vector fragments were amplified using primer pairs from the template. The resulting fragments were joined by sequencing and golden gate cloning. 2.5 μL of the solution was used for transformation of E. coli. Plasmids were validated by colony PCR, restriction enzyme digestion, and sequencing.

[0241] Preparation of Enzyme Mixtures: Overnight cultures were grown in 5 mL of Luria Broth (LB) (Fisher BioReagents) containing appropriate antibiotics. The antibiotic concentrations were as follows: Kanamycin (50 μg / ml) (IBI Scientific), Chloramphenicol (40 μg / ml) (Fisher BioReagents), Ampicillin 250 (μg / ml) (Fisher BioReagents), Tetracycline (20 μg / ml) (Fisher BioReagents). M9 medium (33.7 mM Na2HPO4, 22 mM KH2PO4, 8.55 mM NaCl, 9.35 mM NH4Cl, 1 mM MgSO4, 0.1 mM CaCl2) (BD The medium was prepared using Bacto, 5g l-1 yeast extract (BD Bacto), 50g l-1 or 10g l-1 glucose (Fisher BioReagents), and a 1,000-fold dilution of A5 trace metal mixture (2.86g H3BO3 (Fisher Chemical), 1.81g MnCl2·4H2O (MP Biomedicals), 0.222g ZnSO4·7H2O (Sigma-Aldrich), 0.39g Na2MoO4·2H2O (Alfa Aesar), 0.079g CuSO4·5H2O (Sigma-Aldrich), 49.4mg Co(NO3)2·6H2O (Sigma-Aldrich) per liter of water). This medium is referred to here as "M9P". C2~C 1050 g l-1 glucose was used for the acetate ester experiments, and 10 g l-1 glucose was used for the tetradecyl acetate, isobutyric acid, and butyrate ester experiments. Optical density (D) was measured at 600 nm using a Synergy H1 Hybrid Plate Reader (BioTek Instruments, Inc.).

[0242] Substrate Supply Experiment: The overnight culture was inoculated at 1% in 5 mL of M9P in a 15 mL screw-cap culture tube. The cells were grown in a rotary shaker (250 r.pm) at 37°C until the D600 nm was approximately 0.4, followed by the addition of 1 mM isopropyl-β-d-thio-galactoside (IPTG) (Promega). The culture was incubated at 30°C for 1 hour after induction. Next, the target substrate was added to the culture. Preparation was carried out in a rotary shaker (250 r.pm) at 30°C for 24 hours. 1.5 mL of culture was collected for analysis every 24 hours. The 1.5 mL culture was centrifuged at 17,000 g for 3 minutes, and then 1 mL of the supernatant was transferred to a 2 mL GC vial for GC analysis.

[0243] Preparation of modified indole alkaloids by enzymatic conversion: Purified enzymes or cell lysates containing purified enzymes were mixed with cofactors and indole alkaloid substrates in their respective buffers. The reactions were carried out at room temperature or at the optimal temperature for producing the modified indole alkaloids.

[0244] Analysis was performed by chromatography / mass spectrometry (LCMS) using a 1260 Infinity LC system connected to a 6120 quadrupole mass spectrometer (Agilent Technologies). Zorbax Eclipse Plus C18 guard column (4.6 cm x 12.5 cm, 5 pm packing, Agilent) A mobile phase was connected to an Agilent ZORBAX StableBond-C18, 1.8 μm, 2.1 x 50 mm column at 20°C at a flow rate of 0.3 mL / min. The mobile phase consisted of a mixture of 0.1% formic acid (v / v) in acetonitrile and 0.1% formic acid (v / v) in water, and was eluted under the following gradient conditions (shown in relation to acetonitrile content): 0 min - 10%, 6 min - 100%, 7 min - 10%, 14 min - 10%. The mobile phase was delivered at a flow rate of 0.3 mL / min, and the total analysis run time was 14 minutes. Absorbance was measured using a diode array detector for UV-Vis analysis. MS was performed under atmospheric pressure ionization-positive conditions.

[0245] Example 2: Cloning and purification of transferase protein for modification of indole alkaloids Materials and cloning conditions Cloning enzymes and buffers were purchased from New England Biolabs (Ipswich, MA). Plasmids were constructed using MoClo Golden Gate Assembly and amplified using E. coli strain TG1 (Lucigen). Strains for plasmid construction were amplified in Luria Broth (LB) selected with 34 mg / L chloramphenicol, 100 mg / L ampicillin, and / or 25 mg / L kanamycin. All synthetic oligonucleotides and double-stranded DNA were ordered from Integrated DNA Technologies.

[0246] Plasmid construction, cloning, and transformation The following circular parent vectors were used to form the N-terminal and C-terminal His x6 transferase fusion protein (disclosed as SEQ ID NO: 28, "His x6"): (1) pNAB096 (N-terminal His x6 expression vector (disclosed as SEQ ID NO: 28, "His x6")) (SEQ ID NO: 16) (2) pNAB097 (N-terminal His x6 expression vector (disclosed as SEQ ID NO: 28, "His x6")) (SEQ ID NO: 17) (3) pNAB0098 (C-terminal His x6 expression vector (disclosed as SEQ ID NO: 28, "His x6")) (SEQ ID NO: 18)

[0247] An N-terminal 6xHis expression vector (disclosed as SEQ ID NO: 28, "His x6") was prepared for the 4-hydroxytryptamine kinase protein sequence (SEQ ID NO: 2). SEQ ID NO: 2 was codon-optimized for E. coli using the IDTDNA codon optimization tool. BsaI type II restriction enzyme sequences were added to the 5' and 3' ends of the sequence and synthesized as a Gblock by IDTDNA (Coralville, IA). The resulting linear dsDNA was reacted with pNAB0096 using the NEB® Golden Gate Assembly Kit (BsaI-HF® v2) according to the manufacturer's instructions. The reaction was transformed into E. coli strain TG1 (Lucigen) and plated on LB agar containing ampicillin / chloramphenicol. Clones with the pNAB2002 sequence were obtained after sequence validation by colony PCR, miniprep, and plasmid DNA sequencing. The obtained circular plasmid sequences are listed below. (4) pNAB2002 (Sequence ID: 19)

[0248] The O-methyltransferase protein sequence (SEQ ID NO: 3) was codon-optimized for E. coli using the IDTDNA codon optimization tool. BsaI type II restriction enzyme sequences were added to the 5' and 3' ends of the sequence and synthesized as a Gblock using IDTDNA (Coralville, IA). The resulting linear dsDNA was reacted with pNAB0096 using the NEB® Golden Gate Assembly Kit (BsaI-HF® v2) according to the manufacturer's instructions. The reaction was transformed into E. coli strain TG1 (Lucigen) and plated on LB agar containing ampicillin / chloramphenicol. Clones containing the pNAB2003 sequence were obtained after sequence validation by colony PCR, miniprep, and plasmid DNA sequencing. The resulting circular plasmid sequences are listed below. (5) pNAB2003 (Sequence ID 20)

[0249] Sulfotransferase protein sequences (SEQ ID NOs. 5 and 6) were codon-optimized for E. coli using the IDTDNA codon optimization tool. BsaI type II restriction enzyme sequences were added to the 5' and 3' ends of each sequence and synthesized as Gblocks using IDTDNA (Coralville, IA). The resulting linear dsDNA was reacted with pNAB0098 using the NEB® Golden Gate Assembly Kit (BsaI-HF® v2) according to the manufacturer's instructions. The reaction was transformed into E. coli strain TG1 (Lucigen) and plated on LB agar containing ampicillin / chloramphenicol. Clones containing the sequences pNAB2005 and pNAB2006 were obtained after sequence validation by colony PCR, miniprep, and plasmid DNA sequencing. (6) pNAB2005 (Sequence ID 21) (7) pNAB2006 (Sequence ID 22)

[0250] The acyltransferase protein sequence (SEQ ID NO: 8) of chloramphenicol acetyltransferase (CAT) derived from the Pseudomonas aeruginosa enzyme was codon-optimized for E. coli using the IDTDNA codon optimization tool. BsaI type II restriction enzyme sequences were added to the 5' and 3' ends of each sequence and synthesized as Gblocks using IDTDNA (Coralville, IA). The resulting linear dsDNA was reacted with pNAB0098 using the NEB® Golden Gate Assembly Kit (BsaI-HF® v2) according to the manufacturer's instructions. The reaction product was transformed into E. coli strain TG1 (Lucigen) and plated on LB agar containing ampicillin / chloramphenicol. Clones with the pNAB2008 sequence were obtained after sequence validation by colony PCR, miniprep, and plasmid DNA sequencing. (8) pNAB2008 (Sequence ID 23)

[0251] Glucosyltransferase protein sequences (SEQ ID NOs. 9-12) were codon-optimized for E. coli using the IDTDNA codon optimization tool. BsaI type II restriction enzyme sequences were added to the 5' and 3' ends of each sequence and synthesized as Gblocks using IDTDNA (Coralville, IA). The resulting linear dsDNA was reacted with pNAB0098 (C-terminal His x6 fusion (disclosed as SEQ ID NO: 28 "His x6")) using the NEB® Golden Gate Assembly Kit (BsaI-HF® v2) according to the manufacturer's instructions. The reaction products were transformed into E. coli strain TG1 (Lucigen) and plated on LB agar containing ampicillin / chloramphenicol. Clones containing the sequences of pNAB2009 (SEQ ID NO: 24), pNAB2010 (SEQ ID NO: 25), pNAB2011 (SEQ ID NO: 26), and pNAB2012 (SEQ ID NO: 27), corresponding to SEQ ID NOs. 9, 10, 11, and 12, respectively, were obtained after sequence validation by colony PCR, miniprep, and plasmid DNA sequencing. (9) pNAB2009 (Sequence ID 24) (10) pNAB2010 (Sequence ID 25) (11) pNAB2011 (Sequence ID 26) (12) pNAB2012 (Sequence ID 27)

[0252] Those skilled in the art will understand that DNA sequences can be obtained through various cloning techniques and DNA synthesis methods. They will also understand that several DNA sequences can produce the same protein product.

[0253] Expression and purification of transferase proteins Rosetta (DE3) cells (Novagen) were independently transformed with plasmids pNAB2002, pNAB2003, pNAB2005, pNAB2006, pNAB2008, pNAB2009, pNAB2010, pNAB2011, and pNAB2012 and selected on LB agar plates containing chloramphenicol and ampicillin. Overnight cultures were diluted in 4 L Terrific Broth (Fisher) using ampicillin selection and grown at 37°C at 200 rpm in an Innova44 shaker (New Brunswick Scientific), and induced at approximately OD600 3 using 1 mM isopropyl β-D-1-thiogalactopyranoside (IPTG). Next, cultures were grown at 18°C ​​for 21 hours for protein expression, and cells were collected by centrifugation.

[0254] The cell pellet was resuspended in 50 mM HEPES pH 7.0, 300 mM NaCl, 25 mM imidazole pH 8.0, and 1 mM DTT. The cell suspension was lysed by freeze / thaw and sonication. The lysate was purified using Ni-NTA agarose beads (Qiagen), and the proteins were dialyzed against 25 mM HEPES pH 7.0, 50 mM NaCl, and 1 mM DTT.

[0255] The N-terminus and C-terminus 6×His tags (disclosed as "His x6" in Sequence ID No. 28) were cleaved using TEV, and the final purified protein was concentrated to 15 mg / mL using a 10,000 MWCO Amicon Ultra-15 Centrifugal Filter Unit (EMD Millipore). The protein molecular weight and purity of each expressed enzyme protein were confirmed by SDS-PAGE as shown in Figure 1, compared to the Invitrogen® BenchMark® Protein Ladder (catalog number: 10747012) as a standard. The proteins were either used immediately in the reaction or frozen at -80°C for long-term storage and thawed on ice before use in the reaction.

[0256] Example 3: Enzymatic malonylation of 4-hydroxy-N,N-diisopropyltryptamine 4-hydroxy-N,N-diisopropyltryptamine (Cayman Chemicals MI, USA) was prepared at a concentration of 0.5 mg / mL in a 1:1 mixture of DMSO:PBS at pH 7.5. Malonylcoenzyme A tetralithium salt, and all buffers and reagents were purchased from Sigma-Aldrich, Inc. unless otherwise noted.

[0257] Using the buffers, indole alkaloid substrates, co-substrates, enzymes, and reagents listed in Table 3 below, 100 μL of reaction solution was prepared for each of reactions 1-3. [Table 3]

[0258] The reaction was carried out at 37°C for 6 hours, followed by quenching with 100 μL of 100 mM NaOH. The reaction mixture was centrifuged at 30,000 rcf, and the supernatant was transferred to a new sample tube.

[0259] A 5-microliter sample was injected into a ZORBAX StableBond-C18, 1.8 μm, 2.1 x 50 mm column at 20°C and a flow rate of 0.3 mL / min. The major ion species were detected in positive mode using a 6520 Accurate-Mass Q-TOF LC-MS (Agilent). The mobile phase consisted of a mixture of 0.1% formic acid (v / v) in acetonitrile and 0.1% formic acid (v / v) in water, and eluted under the following gradient conditions (shown in relation to acetonitrile content): 0 min - 10%, 6 min - 100%, 7 min - 10%, 14 min - 10%. The mobile phase was delivered at a flow rate of 0.3 mL / min, and the total analysis run time was 14 minutes.

[0260] Using Agilent MassHunter software, the malonylation product was detected based on the predicted mass of the parent compound (346.18 g / mol) using the m / z value of 347.18 for the [M+H]+ adduct with the predicted parent compound.

[0261] As shown in Figure 2A, LC-MS traces of the products of reactions 1-3 showed that the desired product, 3-((3-(2-(diisopropylamino)ethyl)-1H-indole-4-yl)oxy)-3-oxopropanoic acid, was not detected in reactions 1 and 2, but was detected in reaction 3. The desired acylation of the 4-hydroxy-N,N-diisopropyltryptamine substrate depends on the presence of both malonylcoenzyme A and the active enzyme (SEQ ID NO: 8). Figures 2B and 2C show the mass peak at 347.1892 and the UV-Vis absorption spectrum of the product of reaction 3, respectively. The product of reaction 3 and its mass spectrometry are summarized in Table 4 below. [Table 4]

[0262] Example 4: Enzymatic glycosylation of 4-hydroxy-N,N-diisopropyltryptamine 4-Hydroxy-N,N-diisopropyltryptamine (Cayman Chemicals MI, USA) was prepared at a concentration of 0.5 mg / mL in a 1:1 mixture of DMSO:PBS at pH 7.5. Uridine 5'-diphosphoglucose disodium hydrate (UDP-glucose) was purchased from Sigma-Aldrich, Inc. MO, USA. All buffers and reagents were purchased from Sigma-Aldrich, Inc. unless otherwise noted.

[0263] Using the buffers, indole alkaloid substrates, co-substrates, enzymes, and reagents listed in Table 5 below, 100 μL of reaction solution was prepared for each of reactions 4-8. [Table 5]

[0264] The reaction was carried out at 37°C for 3 hours, followed by quenching with 100 μL of 100 mM NaOH. The reaction mixture was centrifuged at 30,000 rcf, and the supernatant was transferred to a new sample tube.

[0265] A 5-microliter sample was injected into a ZORBAX StableBond-C18, 1.8 μm, 2.1 x 50 mm column at 20°C and a flow rate of 0.3 mL / min. The major ion species were detected in positive mode using a 6520 Accurate-Mass Q-TOF LC-MS (Agilent). The mobile phase consisted of a mixture of 0.1% formic acid (v / v) in acetonitrile and 0.1% formic acid (v / v) in water, and eluted under the following gradient conditions (shown in relation to acetonitrile content): 0 min - 10%, 6 min - 100%, 7 min - 10%, 14 min - 10%. The mobile phase was delivered at a flow rate of 0.3 mL / min, and the total analysis run time was 14 minutes.

[0266] Using Agilent MassHunter software, the glucosylation product was detected based on the predicted mass of the parent compound (422.24 g / mol) using the m / z value of 423.24 for the [M+H] adduct with the predicted parent compound. No mass of the glucosylation product was observed in the thermally inactivated enzyme sample or in reaction 8. Figure 3 shows the relative ion abundance of the glucosylation product (2-((3-(2-(diisopropylamino)ethyl)-1H-indole-4-yl)oxy)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol) by the glucosyltransferase enzyme in reactions 4-8. The reaction product and its mass spectrometry results for reaction 3 are summarized in Table 6 below. [Table 6-1] [Table 6-2]

[0267] Example 5: Enzymatic sulfonation of 4-hydroxy-N,N-diisopropyltryptamine 4-hydroxy-N,N-diisopropyltryptamine (Cayman Chemicals MI, USA) was prepared at a concentration of 0.5 mg / mL in a 1:1 mixture of DMSO:PBS at pH 7.5. Adenosine 3'-phosphate 5'-lithium phosphosulfate hydrate (PAPS) was purchased from Sigma-Aldrich, Inc. MO, USA. All buffers and reagents were purchased from Sigma-Aldrich, Inc. unless otherwise noted.

[0268] Using the buffers, indole alkaloid substrates, co-substrates, enzymes, and reagents listed in Table 7 below, 100 μL of reaction solution was prepared for each of reactions 9-11. [Table 7]

[0269] The reaction was carried out at 37°C for 5 hours, followed by quenching with 100 μL of 100 mM NaOH. The reaction mixture was centrifuged at 30,000 rcf, and the supernatant was transferred to a new sample tube.

[0270] A 5-microliter sample was injected into a ZORBAX StableBond-C18, 1.8 μm, 2.1 x 50 mm column at 20°C and a flow rate of 0.3 mL / min. The major ion species were detected in positive mode using a 6520 Accurate-Mass Q-TOF LC-MS (Agilent). The mobile phase consisted of a mixture of 0.1% formic acid (v / v) in acetonitrile and 0.1% formic acid (v / v) in water, and eluted under the following gradient conditions (shown in relation to acetonitrile content): 0 min - 10%, 6 min - 100%, 7 min - 10%, 14 min - 10%. The mobile phase was delivered at a flow rate of 0.3 mL / min, and the total analysis run time was 14 minutes.

[0271] Using Agilent MassHunter software, the sulfonation product was detected based on the predicted mass of the parent compound (340.15 g / mol) using the m / z value of 341.15 for the [M+H] adduct with the parent compound. No mass of the sulfonation product was observed in the thermally inactivated enzyme sample from reaction 11. The relative ion abundance of the sulfonation product 3-(2-(diisopropylamino)ethyl)-1H-indole-4-yl bisulfate by the sulfotransferase enzyme in reactions 9-11 is shown in Figure 4. The reaction products of reactions 9 and 10 are summarized in Table 8 below. [Table 8]

[0272] Example 6: Enzymatic modification of indole alkaloids Indole alkaloids were prepared at a concentration of 0.5 mg / ml in a 1:1 mixture of DMSO:PBS at pH 7.5. All buffers and reagents were purchased from Sigma-Aldrich, Inc. unless otherwise noted. Noribogaine hydrochloride was purchased from Toronto Research Chemicals, Toronto, ON, Canada.

[0273] Indole alkaloid substrate In this example, the following indole alkaloid substrates were used. • 4-Hydroxy-N,N-diisopropyltryptamine hydrochloride (Cayman Chemicals MI, USA) • 4-Hydroxy-N,N-dipropyltryptamine (Cayman Chemicals MI, USA) • 7-Hydroxymitraginine (Cayman Chemicals MI, USA) • Noribogaine hydrochloride (Toronto Research Chemicals, Toronto, ON, Canada) • 4-Hydroxy-5-methyl-N,N-dimethyltryptamine (Chemspace) • 5-Hydroxy-N,N-diisopropyltryptamine (Chemspace)

[0274] Co-substrate In this example, the following co-substrates were used. • Propanoylcoenzyme A (sodium salt) (Avanti Polar Lipids, Inc. AL, USA) • Butanoylcoenzyme A (sodium salt) (Avanti Polar Lipids, Inc. AL, USA) Hexanoylcoenzyme A (ammonium salt) (Avanti Polar Lipids, Inc. AL, USA) Octanoylcoenzyme A (ammonium salt) (Avanti Polar Lipids, Inc. AL, USA) Decanoylcoenzyme A (ammonium salt) (Avanti Polar Lipids, Inc. AL, USA) (E)-Buto-2-enoylcoenzyme A (sodium salt) (Avanti Polar Lipids, Inc. AL, USA) • Acetyl coenzyme A (sodium salt) (Cayman Chemicals MI, USA) Isobutyryl-coenzyme A (sodium salt) (Cayman Chemicals) MI, USA) Acetoacetyl-coenzyme A (sodium salt hydrate) (Cayman Chemicals MI, USA) • Adipoyl-coenzyme A (sodium salt) (Cayman Chemicals MI, USA) • Cyclohexanoyl-coenzyme A (Cayman Chemicals MI, USA) • Ethylmalonylcoenzyme A (sodium salt) (Cayman Chemicals) MI, USA) • Methylmalonyl-coenzyme A (sodium salt) (Cayman Chemicals MI, USA) S-(5'-adenosyl)-L-methionine chloride (hydrochloride) (Cayman Chemicals MI, USA) • Coenzyme A sodium hydrate (Sigma-Aldrich, Inc. MO, USA) • Malonylcoenzyme A tetralithium salt (Sigma-Aldrich, Inc. MO, USA) • Succinyl coenzyme A sodium salt (Sigma-Aldrich, Inc. MO, USA) • Glutaryl-coenzyme A (Sigma-Aldrich, Inc. MO, USA) • n-heptanoylcoenzyme A (lithium salt) (Sigma-Aldrich, Inc. MO, USA) Adenosine 5'-triphosphate disodium hydrate (ATP) (Sigma-Aldrich, Inc. MO, USA) Uridine 5'-diphosphoglucose disodium salt hydrate (UDP-glucose) (Sigma-Aldrich, Inc. MO, USA) • Adenosine 3'-phosphate 5'-lithium phosphosulfate hydrate (PAPS) (Sigma-Aldrich, Inc. MO, USA)

[0275] Enzymatic modification of indole alkaloids The following enzymatic modifications were carried out using the buffer, indole alkaloid substrate, co-substrate, enzyme, and reagents listed below. Acylation (Reactions 12a-29, 31-33, 38 and 39) A 100 μL reaction mixture consisting of the following components was prepared. 50mM HEPES pH 7.5 • 50mM NaCl • 5 mM MgCl2 • 1mM DTT 5 mM Acylcoenzyme A • 1 mM indole alkaloid substrate • Purified enzyme of 50 μM SEQ ID NO: 8 Phosphorylation (reactions 35, 36, and 37) A 100 μL reaction mixture consisting of the following components was prepared. 50mM HEPES pH 7.5 • 50mM NaCl • 5 mM MgCl2 • 1mM DTT 10 mM ATP • 1 mM indole alkaloid • 10 μM purified enzyme of SEQ ID NO: 2 Glucosylation (reactions 30 and 34) A 100 μL reaction mixture consisting of the following components was prepared. 50mM HEPES pH 7.5 • 50mM NaCl • 1mM DTT 5 mM MgCl2 • 10mM UDP-glucose • 1 mM indole alkaloid • Purified enzyme of 25 μM SEQ ID NO: 10 Methylation (reaction 40) A 100 μL reaction mixture consisting of the following components was prepared. 50mM HEPES pH 7.5 • 50mM NaCl • 1mM DTT 5 mM MgCl2 • 10 mM S-(5'-adenosyl)-L-methionine chloride (hydrochloride) (SAM) • 1 mM indole alkaloids • Purified enzyme of 25 μM SEQ ID NO: 3

[0276] The reaction was carried out at 37°C for 6 hours, followed by quenching with 100 μL of 100 mM NaOH. The reaction mixture was centrifuged at 30,000 rcf, and the supernatant was transferred to a new sample tube.

[0277] A 5-microliter sample was injected into a ZORBAX StableBond-C18, 1.8 μm, 2.1 x 50 mm column at 20°C and a flow rate of 0.3 mL / min. The major ion species were detected in positive mode using a 6520 Accurate-Mass Q-TOF LC-MS (Agilent). The mobile phase consisted of a mixture of 0.1% formic acid (v / v) in acetonitrile and 0.1% formic acid (v / v) in water, and eluted under the following gradient conditions (shown in relation to acetonitrile content): 0 min - 10%, 6 min - 100%, 7 min - 10%, 14 min - 10%. The mobile phase was delivered at a flow rate of 0.3 mL / min, and the total analysis run time was 14 minutes. The mass of modified indole alkaloid products was not detected in the thermoinactivating enzyme sample, indole alkaloid sample, or cofactor sample alone.

[0278] The reaction products of reactions 12a to 40 are summarized in Table 9 below. [Table 9-1] [Table 9-2] [Table 9-3] [Table 9-4] [Table 9-5] [Table 9-6] [Table 9-7] [Table 9-8] [Table 9-9]

[0279] Example 7: 5HT2A agonist activity by enzymatically digested modified indole alkaloids 1 mM 4-3-(2-(dipropylamino)ethyl)-1H-indole-4-yl dihydrogen phosphate (compound A) was incubated with 100 units of calf alkaline phosphatase at pH 7.9 and 25°C for 2 hours in a buffer containing 50 mM potassium acetate, 20 mM Tris-acetic acid, 10 mM magnesium acetate, and 100 μg / ml BSA. 1 mM 4-3-(2-(diisopropylamino)ethyl)-1H-indole-4-yl dihydrogen phosphate (compound B) was incubated with 100 units of calf alkaline phosphatase at pH 7.9 and 25°C for 2 hours in a buffer containing 50 mM potassium acetate, 20 mM Tris-acetic acid, 10 mM magnesium acetate, and 100 μg / ml BSA. The resulting solution containing the dephosphorylated products was used in a 5-HT2A receptor function assay.

[0280] 5-HT2 function experiments (measurement of Gq-mediated calcium flux) were performed using Flp-In T-REx293 cells (Invitrogen, Carlsbad, CA) expressing human 5-HT2A (h5-HT2A) receptor cDNA under the influence of tetracycline repressor protein. The cells were plated at a density of approximately 10,000 cells per well in a black, 384-well clear-bottom tissue culture plate in 40 μL of DMEM containing 1% dialyzed fetal bovine serum (FBS), and receptor expression was induced with 2 μg / mL of tetracycline.

[0281] After approximately 20-24 hours, the culture medium was decanted and replaced with 20 μL / well of drug buffer containing Fluo-4 Direct dye (Invitrogen) (HBSS, 20 mM HEPES, pH 7.4), and incubated at 37°C for 1-2 hours. The test substances (e.g., compound A and compound B) were diluted with drug buffer (HBSS, 20 mM HEPES, 0.1% bovine serum albumin, 0.01% ascorbic acid, pH 7.4).

[0282] Before the experiment, plates were equilibrated to room temperature, and calcium flux was measured using the FLIPRTETRA cell screening system (Molecular Devices, Sunnyvale, CA). To establish a baseline, the fluorescence of the plates was first read for 10 seconds (one read per second), then stimulated with drug diluent or buffer, and read again for another 120 seconds. Peak fluorescence in each well was normalized to the maximum increase factor relative to baseline. Data were normalized to the maximum peak factor relative to the basal fluorescence (100%) and baseline fluorescence (0%) generated by 5-hydroxytryptamine (5-HT). Data were analyzed using the sigmoid dose-response function in Prism 5.0 or 8.0 (GraphPad Software, San Diego, CA). Relative activity (RA) was expressed as EC. 50 E for parameter estimates max The ratio was expressed as a logarithm. Figure 5 shows the obtained data demonstrating the 5HT2A agonism of compound A and compound B compared to 5-HT.

[0283] Example 8: Treatment of modified indole alkaloids with human saliva preparations In this example, additional modified indole alkaloids were synthesized using enzymatic glycosylation conditions and subsequently digested in a human saliva sample.

[0284] Synthesis of modified indole alkaloids The indole alkaloid substrate was prepared at a concentration of 0.5 mg / mL in a 1:1 mixture of DMSO:PBS at pH 7.5. All buffers and reagents were purchased from Sigma-Aldrich, Inc. unless otherwise noted.

[0285] In this example, the following indole alkaloid substrates were used. 4-Hydroxy-N-methyl-N-ethyltryptamine (Cayman Chemicals MI, USA) 4-Hydroxy-N-methyl-N-propyltryptamine (Cayman Chemicals MI, USA) 4-Hydroxy-N-methyl-N-isopropyltryptamine (Cayman Chemicals MI, USA) 4-Hydroxy-N-methyl-N-allyltryptamine (Cayman Chemicals MI, USA) • 4-Hydroxy-N,N-diethyltryptamine (Cayman Chemicals) MI, USA) 4-Hydroxy-N-ethyl-N-propyltryptamine hemifumarate (Cayman Chemicals MI, USA) • 4-Hydroxy-N,N-dipropyltryptamine (Cayman Chemicals MI, USA) • 4-Hydroxy-N,N-diisopropyltryptamine hydrochloride (Cayman Chemicals MI, USA) • 4-Hydroxy-N,N-methyl-N-cyclopropyltryptamine hydrochloride (Cayman Chemicals MI, USA)

[0286] In this example, uridine 5'-diphosphoglucose disodium salt hydrate, item number U4625 (UDP-glucose) (Sigma-Aldrich, Inc. MO, USA) was used as a co-substrate.

[0287] Using the buffer, indole alkaloid substrate, co-substrate, enzyme, and reagents listed below, 100 μL of reaction solution was prepared for each of reactions 41-49. 50mM HEPES pH 7.5 • 50mM NaCl 5 mM MgCl2 • 1mM DTT • 5 mM UDP-glucose (co-substrate) • 100 μM indole alkaloid substrate • 50 μM purified enzyme of SEQ ID NO: 10

[0288] The reaction was carried out at 37°C for 3 hours, followed by quenching with 100 μL of 100 mM NaOH. The reaction mixture was centrifuged at 30,000 rcf, and the supernatant was transferred to a new sample tube.

[0289] A 5-microliter sample was injected into a ZORBAX StableBond-C18, 1.8 μm, 2.1 x 50 mm column at 20°C and a flow rate of 0.3 mL / min. The major ion species were detected in positive mode using a 6520 Accurate-Mass Q-TOF LC-MS (Agilent). The mobile phase consisted of a mixture of 0.1% formic acid (v / v) in acetonitrile and 0.1% formic acid (v / v) in water, and eluted under the following gradient conditions (shown in relation to acetonitrile content): 0 min - 10%, 6 min - 100%, 7 min - 10%, 14 min - 10%. The mobile phase was delivered at a flow rate of 0.3 mL / min, and the total analysis run time was 14 minutes. The mass of modified indole alkaloid products was not detected in the thermoinactivating enzyme sample, indole alkaloid sample, or cofactor sample alone.

[0290] The reaction products of reactions 41-49 are summarized in Table 10 below. [Table 10-1] [Table 10-2] [Table 10-3]

[0291] Digestion of modified indole alkaloids in human saliva samples Human saliva samples were collected from clinically asymptomatic adult subjects after 8 hours of fasting, 25 minutes before food intake. Saliva was collected by passively dripping saliva into a sterile 10 mL centrifuge tube over 5 minutes. Immediately after collection, the saliva samples were centrifuged (500 g, 4°C for 10 minutes), and the supernatant was collected and either used immediately or stored at -80°C until further use.

[0292] Eleven 100 μL reaction mixtures consisting of the following were prepared. 50mM HEPES pH 7.5 • 50mM NaCl • 100 μM modified indole alkaloid products (from reactions 3, 24, and 39-47, respectively) • 50 μL human saliva sample 2 mM calcium chloride 5 mM magnesium chloride

[0293] The reaction mixture was digested at 37°C for 2 hours, then heated to 80°C for 5 minutes to stop the reaction. The reaction mixture was then centrifuged at 30,000 rcf, and the supernatant was transferred to a new sample tube.

[0294] A 1 microliter sample was injected into a ZORBAX StableBond-C18, 1.8 μm, 2.1 x 50 mm column at 20°C and a flow rate of 0.3 mL / min. The major ion species were detected in positive mode using a 6520 Accurate-Mass Q-TOF LC-MS (Agilent). The mobile phase consisted of a mixture of 0.1% formic acid (v / v) in acetonitrile and 0.1% formic acid (v / v) in water, and eluted under the following gradient conditions (shown in relation to acetonitrile content): 0 min - 10%, 6 min - 100%, 7 min - 10%, 14 min - 10%. The mobile phase was delivered at a flow rate of 0.3 mL / min, and the total analysis run time was 14 minutes.

[0295] As shown in Figures 6A-6B, the modified indole alkaloid 2-((3-(2-(diisopropylamino)ethyl)-1H-indole-4-yl)oxy)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol (compound C, product of enzymatic glycosylation reaction 47) was deglycosylated by treatment with human saliva. LC-MS traces of compound C alone (traces A and C) are shown in Figure 6A, and LC-MS traces of compound C samples treated with human saliva (traces B and D) are shown in Figure 6B. Traces A and B extracted m / z 423.24, corresponding to the glycosylated product compound C. Traces C and D extracted m / z 261.19, corresponding to the deglycosylated product of compound C, which is 4-hydroxy-N,N-diisopropyltryptamine. These results indicate that human saliva completely deglycosylated the glucosylated indole alkaloid.

[0296] As shown in Figures 7A-7B, the modified indole alkaloid 3-((3-(2-(diisopropylamino)ethyl)-1H-indole-4-yl)oxy)-3-oxopropanoic acid (compound D, the product of enzymatic malonylation reaction 3) was hydrolyzed by treatment with human saliva. LC-MS traces of compound D alone (traces A and C) are shown in Figure 7A, and LC-MS traces of compound D samples treated with human saliva (traces B and D) are shown in Figure 7B. Traces A and B extracted m / z 347.19, corresponding to compound D. Traces C and D extracted m / z 261.19, corresponding to the hydrolyzed product of compound D, which is 4-hydroxy-N,N-diisopropyltryptamine. These results indicate that human saliva completely hydrolyzed compound D, the malonylation product.

[0297] As shown in Figures 8A-8B, the modified indole alkaloid 3-(2-(diisopropylamino)ethyl)-1H-indole-4-yl 3-oxobutanoate (compound E; product from enzymatic acetylation reaction 24) was hydrolyzed by treatment with human saliva. LC-MS traces of compound E alone (traces A and C) are shown in Figure 8A, and LC-MS traces of compound E samples treated with human saliva (traces B and D) are shown in Figure 8B. Traces A and B extracted m / z 345.21, corresponding to compound E. Traces C and D extracted m / z 261.19, corresponding to the hydrolyzed product of compound E, which is 4-hydroxy-N,N-diisopropyltryptamine. These results indicate that human saliva completely hydrolyzed compound E, the acetylated product.

[0298] The retention times for compound C (from reaction 47), compound D (from reaction 3), compound E (from reaction 24), and 4-hydroxy-N,N-diisopropyltryptamine are summarized in Table 11 below. [Table 11]

[0299] Example 9: 5HT2 subtype agonist activity of modified indole alkaloids The modified indole alkaloids prepared in reactions 41-49 and treated with human saliva in Example 8 were used at a concentration of 10 μM in 5-HT2A and 5-HT2C receptor function assays.

[0300] 5-HT2 functional experiments (measurement of Gq-mediated calcium flux) were performed using Flp-In T-REx293 cells (Invitrogen, Carlsbad, CA) that independently expressed human 5-HT2A (h5-HT2A) receptor and human 5-HT2C (h5-HT2C) receptor cDNA under the influence of tetracycline repressor protein. The cells were plated at a density of approximately 10,000 cells per well in a black 384-well clear-bottom tissue culture plate in 40 μL of DMEM containing 1% dialyzed fetal bovine serum (FBS), and receptor expression was induced with 2 μg / mL of tetracycline.

[0301] After approximately 20-24 hours, the culture medium was decanted and replaced with 20 μL / well of drug buffer containing Fluo-4 Direct dye (Invitrogen) (HBSS, 20 mM HEPES, pH 7.4), and incubated at 37°C for 1-2 hours. The test material (modified indole alkaloid products from reactions 41-49 treated with human saliva) was diluted with drug buffer (HBSS, 20 mM HEPES, 0.1% bovine serum albumin, 0.01% ascorbic acid, pH 7.4).

[0302] Before the experiment, plates were equilibrated to room temperature, and calcium flux was measured using the FLIPRTETRA cell screening system (Molecular Devices, Sunnyvale, CA). To establish a baseline, the fluorescence of the plates was first read for 10 seconds (one read per second), then stimulated with drug diluent or buffer, and read again for another 120 seconds. Peak fluorescence in each well was normalized to the maximum increase factor relative to baseline. Data were normalized to the maximum peak factor relative to the basal fluorescence (100%) and baseline fluorescence (0%) generated by 5-hydroxytryptamine (5-HT). Data were analyzed using the sigmoid dose-response function in Prism 5.0 or 8.0 (GraphPad Software, San Diego, CA). Relative activity (RA) was expressed as EC. 50 E for parameter estimates max It was expressed as the logarithm of the ratio.

[0303] Compared to the endogenous ligand 5-hydroxytryptamine (5HT), hydrolyzed (treated with human saliva) indole alkaloids 2-((3-(2-(ethyl(methyl)amino)ethyl)-1H-indole-4-yl)oxy-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol (compound 1) and 2-(hydroxymethyl)-6-((3-(2-(methyl(propyl)amino)ethyl)-1H-indole-4-yl)oxy)tetrahydro-2H-pyran-pyran n-3,4,5-triol (compound 2), 2-(hydroxymethyl)-6-((3-(2-(isopropyl(methyl))amino)ethyl)-1H-indole-4-yl)oxy)tetrahydro-2H-pyran-3,4,5-triol (compound 3), 2-((3-(2-(diethylamino)ethyl)-1H-indole-4-yl)oxy)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol (compound 4), 2-((3-(2-(ethyl(propyl)amino) )ethyl)-1H-indole-4-yl)oxy)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol (compound 5), 2-((3-(2-(dipropylamino)ethyl)-1H-indole-4-yl)oxy)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol (compound 6), 2-((3-(2-(diisopropylamino)ethyl)-1H-indole-4-yl)oxy)-6-(hydroxymethyl)tetrahydro-2H- EC of the 5HT2A agonist activity of pyran-3,4,5-triol (compound 7), 2-((3-(2-(allyl(methyl)amino)ethyl)-1H-indole-4-yl)oxy)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol (compound 8), and 2-((3-(2-(cyclopropyl(methyl)amino)ethyl)-1H-indole-4-yl)oxy)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol (compound 9) 50 and E max The percentage values ​​were obtained and summarized in Table 12 below.

[0304] [Table 12]

[0305] The EC2 of the 5HT2C agonist activity of indole alkaloid compounds 1-9, which were hydrolyzed (treated with human saliva), was compared with that of the endogenous ligand 5-hydroxytryptamine (5HT). 50 and E max The percentage values ​​were obtained and summarized in Table 13 below.

[0306] [Table 13]

[0307] While preferred embodiments of the present invention have been shown and described herein, it will be obvious to those skilled in the art that such embodiments are provided only as examples. Herein, those skilled in the art will anticipate numerous variations, modifications, and substitutions without departing from the present invention. It should be understood that various alternatives to the embodiments of the present invention described herein may be employed in the practice of the present invention. The following claims define the scope of the present invention, and the methods and structures contained within these claims, as well as their equivalents, are intended to be encompassed thereby.

Claims

[Claim 1] The invention described in the present specification.

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