Reselgolic acid derivatives and methods

Abstract

Methods for preparing reserpic acid and its derivatives. Methods of using reserpic acid and its derivatives, for example, methods for treating neurodegenerative disorders. Derivatives of reserpic acid and its pharmaceutically acceptable salts.

Description

Technical Field

[0001] Cross - reference to Related Applications This application claims priority to U.S. Provisional Patent Application No. 63 / 341,162, filed May 12, 2022, which is incorporated herein by reference.

[0002] The present disclosure relates to a method for preparing lysergic acid and its derivatives. The present disclosure further relates to novel derivatives of lysergic acid. The present disclosure also relates to methods of treatment.

Background Art

[0003] Since Hoffman discovered lysergic acid diethylamide (LSD) in 1938, the medical use of this natural product derivative has been of great interest and has been considered controversial. For example, Sandoz Laboratories announced in the 1940s that LSD was a "treatment for everything," but the U.S. Congress, reacting in part to the counter - culture of the 1960s, made its possession and use illegal in 1968.

[0004] However, despite this past, some ergoline derivatives such as pergolide and lisuride have been brought to clinics for the treatment of Parkinson's disease and migraine. These ergoline structures are ligands of 5 - HTGCPR, an important receptor responsible for many downstream neuropharmacological phenotypes, in addition to the psychiatry drugs dimethyltryptamine (DMT) and 2,5 - dimethoxy - 4 - iodoamphetamine. Due to the therapeutic potential of LSD, several X - ray crystal structures have recently been obtained that enable the design of novel neuropharmacologically viable 5 - HT2A ligands. 2A

[0005] There are many known methods for the asymmetric or racemic synthesis of lysergic acid. However, many of the techniques are non - reproducible and / or extensive with respect to the number of steps required. These drawbacks can, in addition to limiting the feasibility and efficiency of the method for the production of certain analogs, add additional waste generated by the implementation of the method.

[0006] A practical synthesis of lysergic acid and its derivatives, including diverse LSD derivatives, is still needed.

Summary of the Invention

[0007] Compounds comprising lysergic acid and lysergic acid derivatives, and methods of making compounds such as lysergic acid and its derivatives are described herein. The simplicity and adaptability of the syntheses of the embodiments of the methods described herein can enable the development of unnatural analogs that can assist in the discovery of novel compounds having potentially important therapeutic indices for treating various neurodegenerative diseases, psychological disorders, cognitive disorders, behavioral disorders, and / or mood disorders.

[0008] In one aspect, provided herein is a method for synthesizing lysergic acid or its derivatives from simple aromatic precursors, etc. Lysergic acid derivatives can include those having substitutions on the benzenoid ring of the indole nucleus of lysergic acid. In some embodiments, the method includes a coupling, dearomatization, and cyclization of a halopyridine and a 4 - haloindole derivative in six total synthesis steps from commercially available starting materials. In some embodiments, the method provides a compound of formula (A)-

Chemical Formula

[0009] In another aspect, a compound or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutical formulation comprising the compound or a pharmaceutically acceptable salt or solvate thereof are provided. In some embodiments, the compound or a pharmaceutically acceptable salt or solvate thereof comprises formula (I) or formula (I’), [Chemical formula] wherein R 1 ~R 6 are independently selected from hydrogen, hydroxy, methoxy, halogen, or C 1 -C 20 hydrocarbyl, and as defined herein, C 1 -C 20 hydrocarbyl is unsubstituted or substituted. In some embodiments, at least one of R 1 ~R 6 is not hydrogen.

[0010] In another aspect, a method of treating a neurodegenerative disease in a patient in need thereof is provided herein. In some embodiments, the method comprises administering to a patient suffering from a neurodegenerative disease an effective amount of a compound or composition described herein or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the compounds and compositions described herein can be used as intermediates and precursors for treating one or more neurodegenerative diseases and / or for the production of lysergic acid derivatives such as prodrugs for treating one or more neurodegenerative diseases.

[0011] Other objects, features, and advantages of the methods and compounds described herein will become apparent from the following detailed description and the appended claims. However, various modifications and variations within the spirit and scope of this disclosure will be apparent to those skilled in the art from this detailed description, so it should be understood that the detailed description and specific examples are given by way of illustration only and are not intended to limit the disclosure to the particular embodiments shown.

[0012] Incorporation by reference All publications, patents, and patent applications mentioned herein are hereby incorporated by reference into this specification to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference.

DETAILED DESCRIPTION OF THE INVENTION

[0013] In one embodiment, a method for synthesizing lysergic acid from a simple aromatic precursor is provided herein. In some embodiments, the method includes synthesizing a derivative of lysergic acid. In some embodiments, the compounds described herein can be used for the treatment of neurodegenerative diseases including, but not limited to, Alzheimer's disease, Parkinson's disease, Huntington's disease, multiple sclerosis, and amyotrophic lateral sclerosis. In some embodiments, the compounds described herein can be used for the treatment of psychological disorders, cognitive disorders, behavioral disorders, and / or mood disorders. In some embodiments, a method for treating a neurodegenerative disease in a patient in need of treatment for a neurodegenerative disease is provided herein.

[0014] In some embodiments, the compounds of the present disclosure or pharmaceutically acceptable salts or solvates thereof are administered in an amount greater than about 30 μg, greater than about 40 μg, greater than about 50 μg, greater than about 60 μg, greater than about 70 μg, greater than about 80 μg, greater than about 90 μg, or greater than about 100 μg. In some embodiments, the compounds of the present disclosure or pharmaceutically acceptable salts or solvates thereof are administered in an amount of 100 μg.

[0015] In some embodiments, the compounds of the present disclosure, or pharmaceutically acceptable salts or solvates thereof, are administered in an amount greater than about 0.01 mg, greater than about 0.05 mg, greater than about 0.1 mg, greater than about 0.5 mg, greater than about 1 mg, or greater than about 10 mg.

[0016] In some embodiments, the compounds of the present disclosure, or pharmaceutically acceptable salts or solvates thereof, are administered in an amount greater than about 20 mg, greater than about 60 mg, greater than about 100 mg, greater than about 200 mg, greater than about 400 mg, or greater than about 500 mg.

[0017] In some embodiments, the compounds of the present disclosure, or pharmaceutically acceptable salts or solvates thereof, are administered in an effective amount of about 10 μg to about 500 μg (mg per patient body weight kg (mpk)). In some embodiments, the compounds of the present disclosure, or pharmaceutically acceptable salts or solvates thereof, can be administered in a regimen. The regimen can be configured to provide a therapeutically effective amount of the compound over a predetermined period (e.g., administration time). The regimen can be configured to limit or prevent side effects or undesirable complications of the compounds disclosed herein. Regimens useful for treating neurodegenerative diseases, psychological disorders, cognitive disorders, behavioral disorders, and / or mood disorders can include any number of dosing days that can be repeated as needed. The dosing period can be interrupted by a rest period without administration. For example, the regimen can include a dosing period that includes 2, 3, 5, 7, 10, 15, 21, 28, or more days. These periods can be repeated. For example, the regimen can include the aforementioned set number of days repeated 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or more times.

[0018] In some embodiments, the compounds described herein are formulated into pharmaceutical compositions. In one embodiment, a pharmaceutical composition comprising a compound described herein is administered to a subject in various ways by a plurality of administration routes including, but not limited to, oral, parenteral (e.g., intravenous, subcutaneous, intramuscular, intramedullary injection, intrathecal, direct intraventricular, intraperitoneal, intralymphatic, intranasal injection), intranasal, buccal, topical or transdermal administration routes.

[0019] In some embodiments, the pharmaceutical composition comprises from about 30 μg to about 500 μg of a compound of the present disclosure or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the pharmaceutical composition comprises from about 50 μg to about 400 μg of a compound of the present disclosure or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the pharmaceutical composition comprises from about 70 μg to about 300 μg of a compound of the present disclosure or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the pharmaceutical composition comprises from about 70 μg to about 100 μg of a compound of the present disclosure or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the pharmaceutical composition comprises from about 80 μg to about 120 μg of a compound of the present disclosure or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the pharmaceutical composition comprises from about 50 μg to about 100 μg of a compound of the present disclosure or a pharmaceutically acceptable salt or solvate thereof.

[0020] In some embodiments, the pharmaceutical composition does not contain additional excipients. In some embodiments, the pharmaceutical composition further comprises one or more pharmaceutically acceptable excipients.

[0021] In some embodiments, provided herein are pharmaceutical combinations comprising a pharmaceutical composition comprising a compound of the present disclosure that further comprises a commercially available drug used for the treatment of neurodegenerative diseases, psychological disorders, cognitive disorders, behavioral disorders and / or mood disorders. In some embodiments, the pharmaceutical combination achieves a synergistic effect that may allow for the use of lower dosages of one or more of the components of the combination.

[0022] In one embodiment, the compounds described herein are formulated into a pharmaceutical composition capable of passing through the blood-brain barrier.

[0023] Compound In one embodiment, compounds are provided herein. In some embodiments, the compound is a compound of formula (I) or formula (I’), or a pharmaceutically acceptable salt or solvate thereof,

Chemical Structure

[0024] wherein R 1 ~R 6 are independently selected from hydrogen, hydroxy, methoxy, halogen, or C 1 -C 20 hydrocarbyl. C 1 -C 20 hydrocarbyl may be C 1 -C 15 hydrocarbyl, C 1 -C 10 hydrocarbyl, C 1 -C 5 hydrocarbyl, or C 1 -C 3 hydrocarbyl. As described herein, each "hydrocarbyl" may be unsubstituted or substituted as defined herein.

[0025] In some embodiments, at least one of R 1 , R 2 , R 5 or R 6 is not hydrogen. In some embodiments, at least two of R 1 , R 2 , R 5 or R 6 are not hydrogen. In some embodiments, at least three of R 1 , R 2 , R 5 or R 6 are not hydrogen. In some embodiments, R 1 , R2 and R 5 or R 6 each is not hydrogen.

[0026] In some embodiments, R 3 and R 4 are not hydrogen. In some embodiments, R 3 and R 4 are not hydrogen, and R 1 and R 2 and R 5 or R 6 is hydrogen.

[0027] In some embodiments, R 3 and R 4 are different. In some embodiments, R 3 and R 4 are (i) not hydrogen and (ii) different.

[0028] In some embodiments, R 3 is hydroxy. In some embodiments, R 1 and R 2 and R 4 and R 5 and R 6 are hydrogen, and R 3 is hydroxy. In some embodiments, R 3 is methoxy. In some embodiments, R 1 and R 2 and R 4 and R 5 and R 6 are hydrogen, and R 3 is methoxy.

[0029] In some embodiments, R 1 and R 3 and R 4 and R 5 and R 6 are hydrogen, and R 2 is methyl.

[0030] In some embodiments, R 4is a halo substituent (e.g., chloro-, bromo-, iodo-). In some embodiments, R 1 , R 2 , R 3 , R 5 and R 6 are hydrogen, and R 4 is a halo substituent (e.g., chloro-, bromo-, iodo-).

[0031] In some embodiments, the compounds of formula (I) and their stereoisomers can be used for the treatment of neurodegenerative diseases, or psychological disorders, cognitive disorders, behavioral disorders and / or mood disorders. In some embodiments, the compounds of formula (I) can be further derivatized to produce an ester or amide prodrug of the compound of formula (I) or another analog of the compound of formula (I). Such esters, amides or other analogs of the compounds of formula (I) can be used for the treatment of one or more neurodegenerative diseases, or psychological disorders, cognitive disorders, behavioral disorders and / or mood disorders.

[0032] Method In some embodiments, methods for producing lysergic acid and its derivatives are provided herein.

[0033] In some embodiments, the method comprises providing a compound of formula (a)-

Chemical formula

Chemical formula

[0034] 1 ~R 6 6 are as defined herein. Iodine is shown as a substituent of formula (a), but other halogens are also contemplated.

[0035] In some embodiments, the method includes contacting a compound of formula (a) or formula (c) with a metal-containing compound to form a Grignard reagent. In some embodiments, the Grignard reagent is formed by contacting (i) a compound of formula (a) or formula (c) with (ii) i-PrMgCl·LiCl.

[0036] After contacting a compound of formula (a) or formula (c) with a metal-containing compound to form a Grignard reagent, the method further includes contacting the Grignard reagent with a compound of formula (b) or formula (d) to form a compound of formula (B)-

Chemical formula

[0037] In some embodiments, the method includes providing a compound of formula (B); contacting the compound of formula (B) with a protecting group precursor to form a protected compound comprising a protected indole nitrogen; contacting the protected compound with a methylating agent to form a methylated compound comprising a methylated pyridine nitrogen; and contacting the methylated compound with a reducing agent and then a base to form a compound of formula (A). In some embodiments, the method includes contacting a compound of formula (B) with a methylating agent to form a methylated compound comprising a methylated pyridine nitrogen; contacting the methylated compound with a protecting group precursor to form a protected compound comprising a protected indole nitrogen; and contacting the protected compound with a base to form a compound of formula (A):

Chemical formula

[0038] In the method described in this specification, any reducing agent or base can be used. In some embodiments, the reducing agent is NaBH 4 and the base is LiTMP.

[0039] In some embodiments, the method comprises providing a compound of formula (A); contacting the compound of formula (A) with a cyclizing agent to produce a cyclic compound; and contacting the cyclic compound with an agent effective to remove a protecting group to form a compound of formula (I).

Chemical formula

[0040] In some embodiments, the cyclic compound and its stereoisomers can be used for the treatment of neurodegenerative diseases, or psychological disorders, cognitive disorders, behavioral disorders and / or mood disorders.

[0041] In some embodiments, the cyclizing agent is a Heck cyclizing agent. In some embodiments, the cyclizing agent comprises tris(dibenzylidene-acetone)dipalladium(0) or bis(tri-tert-butylphosphine)palladium(0).

[0042] Any known protecting group can be used. In some embodiments, the protecting group is a tert-butyloxycarbonyl protecting group.

[0043] The agent effective to remove the protecting group can be a base such as KOH. The protecting group can be removed by contacting the compound with an aqueous KOH solution at a temperature of about 65°C to about 75°C.

[0044] All combinations of the groups described above for the various variables are contemplated herein. Throughout this specification, the groups and their substituents are selected by those skilled in the art to provide stable moieties and compounds.

[0045] Pharmaceutical composition In some embodiments, the compounds described herein are formulated into pharmaceutical compositions. The pharmaceutical compositions are formulated in a conventional manner using one or more pharmaceutically acceptable inert ingredients that facilitate the processing of the active compounds disclosed herein into pharmaceutically useful preparations. The appropriate formulation depends on the route of administration selected. An overview of pharmaceutical compositions described herein can be found, for example, in Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington’s Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, H.A. and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, N.Y., 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkins 1999), the disclosures of which are hereby incorporated by reference herein for such purpose.

[0046] As used herein, a pharmaceutical composition refers to a mixture of a compound disclosed herein and other chemical components (i.e., pharmaceutically acceptable inert ingredients), such as carriers, excipients, binders, fillers, suspending agents, flavoring agents, sweetening agents, disintegrants, dispersing agents, surfactants, lubricants, coloring agents, diluents, solubilizing agents, wetting agents, plasticizers, stabilizers, penetration enhancers, wetting agents, defoaming agents, antioxidants, preservatives, or combinations of one or more thereof. The pharmaceutical composition facilitates the administration of the compound to a subject in need thereof.

[0047] The pharmaceutical formulations described herein can be administered to a subject in various ways by a plurality of administration routes including, but not limited to, oral, parenteral (e.g., intravenous, subcutaneous, intramuscular, intramedullary injection, intrathecal, direct intraventricular, intraperitoneal, intralymphatic, intranasal injection), intranasal, buccal, topical or transdermal administration routes.

[0048] Treatment method Methods for treating neurodegenerative diseases are described herein. In some embodiments, methods for treating a neurodegenerative disease or condition are described herein, which methods include administering to a subject in need thereof an effective amount of a compound or derivative thereof disclosed herein.

[0049] The dosage used for the treatment of adults is typically in the range of about 0.01 mg to about 5000 mg per day, or in the range of about 0.01 mg to about 1000 mg per day. In one embodiment, the desired dosage is conveniently provided as a single dose or divided doses.

[0050] Definitions When a compound or formula is shown herein without indicating stereochemistry, the compound or formula is intended to read and encompass all stereoisomers, and accordingly, the applicant retains the right to claim any one or more stereoisomers of the compounds or formulas shown or described herein.

[0051] As used herein and in the appended claims, the singular forms "a", "an" and "the" include plural referents unless the context clearly dictates otherwise. Also, note that the term "or" is generally used in the sense including "and / or" unless the context clearly dictates otherwise. Further, the headings provided herein are for convenience only and do not interpret the scope or meaning of the claimed invention.

[0052] As used herein with respect to the selection of substituents, the term "independently" indicates that (i) the substituents at a particular position may be the same or different for each molecule of the formula (for example, (i) a compound of formula (I) can contain two molecules of formula (I), and each molecule may have the same or different C 1 -C 1 -C 20 hydrocarbyl selected for R; and / or (ii) two different labeled substituents selected from the same pool of substituents may be the same or different (for example, R 1 and R 2 of the molecule may both be selected from "C 1 -C 20 hydrocarbyl", and the C 1 -C 2 hydrocarbyl selected for R 1 -C 20 may be the same or different).

[0053] The following terms used herein, unless otherwise indicated, have the following meanings.

[0054] "Oxo" refers to the =O substituent. "Alkyl" refers to a straight-chain or branched hydrocarbon chain radical having 1 to 20 carbon atoms and bonded to the rest of the molecule by a single bond. An alkyl containing up to 10 carbon atoms is referred to as C 1 -C 10 alkyl, and similarly, for example, an alkyl containing up to 6 carbon atoms is C 1 -C 6 alkyl. Alkyls containing other numbers of carbon atoms (and other moieties defined herein) are represented similarly. Examples of alkyl groups include, but are not limited to, C 1 -C 10 alkyl, C 1 -C 9 alkyl, C 1 -C 8 alkyl, C 1 -C 7 alkyl, C 1 -C 6 alkyl, C 1 -C 5Alkyl, C 1 -C 4 Alkyl, C 1 -C 3 Alkyl, C 1 -C 2 Alkyl, C 2 -C 8 Alkyl, C 3 -C 8 Alkyl and C 4 -C 8 Alkyl is exemplified. Representative alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, 1-methylethyl (i-propyl), n-butyl, i-butyl, s-butyl, n-pentyl, 1,1-dimethylethyl (t-butyl), 3-methylhexyl, 2-methylhexyl, 1-ethyl-propyl, and the like. In some embodiments, the alkyl is methyl or ethyl. Preferably, C 1 -C 10 Alkyl is any of methyl, ethyl, n-propyl, isopropyl, and tert-butyl. Unless specifically indicated otherwise herein, the alkyl group may be optionally substituted.

[0055] "Alkylene" refers to a straight-chain or branched divalent hydrocarbon chain that links the rest of the molecule to a radical group. In some embodiments, the alkylene is -CH 2 -, -CH 2 CH 2 -, or -CH 2 CH 2 CH 2 -. In some embodiments, the alkylene is -CH 2 -. In some embodiments, the alkylene is -CH 2 CH 2 -. In some embodiments, the alkylene is -CH 2 CH 2 CH 2 -.

[0056] "Alkoxy" refers to a radical of the formula -OR, where R is an alkyl radical as defined herein, and unless specifically indicated otherwise herein, an alkoxy group may be optionally substituted as described below. Representative alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, pentyloxy. In some embodiments, the alkoxy is methoxy. In some embodiments, the alkoxy is ethoxy. "C 1 -C 10 The term "alkoxy" alone or in combination means the group C 1 -C 10 alkyl-O-, and "C 1 -C 10 alkyl" has the meaning as defined above, and methoxy (-OCH 3 ), ethoxy (-OCH 2 CH 3 ), n-propoxy (-OCH 2 CH 2 CH 3 ), iso-propoxy (-OCH(CH 3 ) 2 ), n-butoxy (-OCH 2 CH 2 CH 2 CH 3 ), sec-butoxy (-OCH(CH 3 )CH 2 CH 3 ), iso-butoxy (-OCH 2 CH(CH 3 ) 2 ), tert-butoxy (-OC(CH 3 ) 3 ), etc., including but not limited to these.

[0057] "Heteroalkyl" refers to an alkyl radical in which one or more carbon atoms of the alkyl are replaced by O, N (i.e., NH, N-alkyl) or an S atom. "Heteroalkylene" refers to a straight-chain or branched divalent heteroalkyl chain that links the rest of the molecule to a radical group. Unless specifically indicated otherwise herein, a heteroalkyl or heteroalkylene group may be optionally substituted. Representative heteroalkyl groups include, but are not limited to, -OCH 2 OMe, -OCH 2 CH 2 OMe, or -OCH 2 CH 2 OCH 2 CH 2 NH 2 is included, but not limited thereto. Representative heteroalkylene groups include, but are not limited to, -OCH 2 CH 2 O-, -OCH 2 CH 2 OCH 2 CH 2 O-, or -OCH 2 CH 2 OCH 2 CH 2 OCH 2 CH 2 O- is included, but not limited thereto.

[0058] "Alkylamino" refers to a radical of the formula -NHR or -NRR, wherein each R is independently an alkyl radical as defined above. Unless specifically indicated otherwise herein, an alkylamino group may be optionally substituted.

[0059] The term "aromatic" refers to a planar ring having a delocalized π-electron system containing 4n + 2 π-electrons, where n is an integer. Aromatics may be optionally substituted. The term "aromatic" includes both aryl groups (e.g., phenyl, naphthalenyl) and heteroaryl groups (e.g., pyridinyl, quinolinyl).

[0060] "Aryl" refers to an aromatic ring in which each of the atoms forming the ring is a carbon atom. The aryl group may be optionally substituted. 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 can be a monoradical or a diradical (i.e., an arylene group). Unless specifically indicated otherwise herein, the term "aryl" or the prefix "ar" (such as in "aralkyl") means an optionally substituted aryl radical.

[0061] "Carboxy" refers to -CO 2 H. In some embodiments, the carboxy moiety can be replaced with a "carboxylic acid bioisostere", which refers to a functional group or moiety that exhibits physical and / or chemical properties similar to those of the carboxylic acid moiety. The carboxylic acid bioisostere has biological properties similar to those of the carboxylic acid group. A compound having a carboxylic acid moiety can have similar physical and / or biological properties by exchanging the carboxylic acid moiety with a carboxylic acid bioisostere when compared to a carboxylic acid-containing compound. For example, in some embodiments, the carboxylic acid bioisostere ionizes at physiological pH to approximately the same extent as the carboxylic acid group. Examples of carboxylic acid bioisosteres include the following:

Chemical formula

[0062] As used herein, "C" 1 -C 20Terms such as "hydrocarbyl" generally refer to aliphatic, aryl, or arylalkyl groups containing 1 to 20 carbon atoms. Examples of aliphatic groups include, in each instance, alkyl groups, cycloalkyl groups, alkenyl groups, cycloalkenyl groups, alkynyl groups, alkadienyl groups, cyclic groups, etc., but are not limited thereto, and include all substituted, unsubstituted, branched, and straight-chain analogs or derivatives, and in each instance, have 1 to about 20 carbon atoms. Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl, isobutyl, pentyl, hexyl, isohexyl, heptyl, 4,4-dimethylpentyl, octyl, 2,2,4-trimethylpentyl, nonyl, decyl, undecyl, and dodecyl, but are not limited to these. The cycloalkyl moiety can be monocyclic or polycyclic, and examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and adamantyl. Further examples of alkyl moieties have straight-chain, branched, and / or cyclic moieties (e.g., 1-ethyl-4-methyl-cyclohexyl). Representative alkenyl moieties include vinyl, allyl, 1-butenyl, 2-butenyl, isobutenylenyl, 1-pentenyl, 2-pentenyl, 3-methyl-1-butenyl, 2-methyl-2-butenyl, 2,3-dimethyl-2-butenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 1-heptenyl, 2-heptenyl, 3-heptenyl, 1-octenyl, 2-octenyl, 3-octenyl, 1-nonenyl, 2-nonenyl, 3-nonenyl, 1-decenyl, 2-decenyl, and 3-decenyl. Representative alkynyl moieties include ethynyl, propynyl, 1-butynyl, 2-butynyl, 1-pentynyl, 2-pentynyl, 3-methyl-1-butynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 5-hexynyl, 1-heptynyl, 2-heptynyl, 6-heptynyl, 1-octynyl, 2-octynyl, 7-octynyl, 1-nonynyl, 2-nonynyl, 8-nonynyl, 1-decynyl, 2-decynyl, and 9-decynyl.Examples of aryl or arylalkyl moieties include, but are not limited to, anthracenyl, azulenyl, biphenyl, fluorenyl, indane, indenyl, naphthyl, phenanthrenyl, phenyl, 1,2,3,4-tetrahydro-naphthalene, tolyl, xylyl, mesityl, benzyl, etc. (including any heteroatom-substituted derivatives thereof).

[0063] Unless otherwise indicated, when the term "substituted" is used to describe a chemical structure or moiety, (i) polyvalent non-carbon atoms (e.g., oxygen, nitrogen, sulfur, phosphorus, etc.) are bonded to one or more carbon atoms of the chemical structure or moiety (e.g., "substituted" C 4 Hydrocarbyl can include a diethyl ether moiety, a methyl propionate moiety, an N,N-dimethylacetamide moiety, a butoxy moiety, etc., and "substituted" aryl C 12 Hydrocarbyl can include, but is not limited to, an oxydibenzene moiety, a benzophenone moiety, etc.), or (ii) one or more of its hydrogen atoms (e.g., chlorobenzene is generally aryl C "substituted" with a chlorine atom 6 Characterizable as hydrocarbyl), but are alcohol, alkoxy, alkanoyloxy, alkoxycarbonyl, alkenyl, alkyl (e.g., methyl, ethyl, propyl, t-butyl), alkynyl, alkylcarbonyloxy (-OC(O)alkyl), amide (-C(O)NH-alkyl- or -alkylNHC(O)alkyl), tertiary amine (e.g., alkylamino, arylamino, arylalkylamino), aryl, aryloxy, azo, carbamoyl (-NHC(O)O-alkyl- or -OC(O)NH-alkyl), carbamyl (e.g., CONH 2 , as well as CONH-alkyl, CONH-aryl, and CONH-arylalkyl), carboxyl, carboxylic acid, cyano, ester, ether (e.g., methoxy, ethoxy), halo, haloalkyl (e.g., -CCl 3 , -CF 3 , -C(CF 3 ) 3) Heteroalkyl, isocyanate, isothiocyanate, nitrile, nitro, oxo, phosphodiester, sulfide, sulfonamide (e.g., SO 2 NH 2 ), sulfone, sulfonyl (including alkylsulfonyl, arylsulfonyl and arylalkylsulfonyl), sulfoxide, thiol (e.g., sulfhydryl, thioether) or urea (-NHCONH-alkyl-), etc., derivatives of its structure or moiety substituted with chemical moieties or functional groups.

[0064] As used herein, the terms "includes", "is", "containing", "having", and "comprises" are used in an open-ended fashion and should therefore be construed to mean "including, but not limited to". When a compound or method is claimed or described using the term "comprising" various steps or components, the device, system or method can also "consist essentially of" or "consist of" the various steps or components, unless otherwise specified. As used herein, the term "about" means ±10% of the numerical value of the number for which it is used.

[0065] As used herein, the terms "effective amount" or "therapeutically effective amount" refer to a sufficient amount of an agent or compound administered to alleviate to some extent one or more of the symptoms of a disease or condition being treated. The result can be a reduction and / or alleviation of the signs, symptoms, or causes of a disease, or any other desired change in a biological system. For example, an "effective amount" for therapeutic use is the amount of a composition comprising a compound disclosed herein required to provide a clinically significant decrease in disease symptoms. The appropriate "effective" amount in any individual case can be determined using techniques such as dose escalation studies. An "effective amount" is an amount sufficient for a compound to achieve the stated purpose as compared to the absence of the compound (e.g., to achieve the administered effect, treat a disease, reduce enzyme activity, increase enzyme activity, reduce a signaling pathway, or reduce one or more symptoms of a disease or condition). Examples of an "effective amount" are amounts sufficient to contribute to the treatment, prevention, or reduction of disease symptom(s), and may also be referred to as a "therapeutically effective amount". The exact amount will depend on the purpose of the treatment and will be ascertainable by one of ordinary skill in the art using known techniques (see, e.g., Lieberman, Pharmaceutical Dosage Forms (vols. 1-3, 1992); Lloyd, The Art, Science and Technology of Pharmaceutical Compounding (1999); and Pickar, Dosage Calculations (1999)).

[0066] The terms "subject" or "patient" include mammals. Examples of mammals include, but are not limited to, humans. In one embodiment, the mammal is a human.

[0067] As used herein, the terms "treat," "treating," or "treatment" include reducing, attenuating, or ameliorating at least one symptom of a disease or condition, preventing additional symptoms, inhibiting a disease or condition, e.g., arresting the development of a disease or condition, alleviating a disease or condition, causing regression of a disease or condition, alleviating symptoms caused by a disease or condition, or prophylactically and / or therapeutically arresting symptoms of a disease or condition.

[0068] Various numerical ranges are disclosed herein. When the applicant discloses or claims any type of range, the applicant's intention is, unless otherwise specified, to individually disclose or claim each possible number that such range can reasonably encompass, including the endpoints of the range, as well as any subranges and combinations of subranges subsumed therein. Further, all numerical endpoints of the ranges disclosed herein are approximate values. By way of representative example, the applicant discloses that in some embodiments, a compound can be contacted with KOH at a temperature of about 65°C to about 75°C. This range should be construed to include about 65°C and about 75°C, and further to include "about" each of 66°C, 67°C, 68°C, 69°C, 70°C, 71°C, 72°C, 73°C, or 74°C, and all ranges and subranges between any of these values.

[0069] In this specification, when a document, act, or item of knowledge is referred to or discussed, this reference or discussion does not admit that the document, act, or item of knowledge or any combination thereof was publicly available, known to the public, part of common general knowledge, or constituted prior art under other applicable legal provisions as of the priority date; nor that it is known to be relevant to any attempt to solve any problem with which this specification is concerned.

[0070] Embodiments The following is a non-limiting list of embodiments of the present disclosure.

[0071] Embodiment 1. A method for synthesizing reserpic acid or a derivative thereof, comprising a compound of formula (A)-

Chemical formula

[0072] Embodiment 2. The method according to Embodiment 1, further comprising contacting the cyclic compound with an agent effective to remove the protecting group.

[0073] Embodiment 3. The method according to any one of the preceding embodiments, wherein the cyclizing agent is a Heck cyclizing agent.

[0074] Embodiment 4. The method according to any one of the preceding embodiments, wherein the cyclizing agent comprises tris(dibenzylidene-acetone)dipalladium(0) or bis(tri-tert-butylphosphine)palladium(0).

[0075] Embodiment 5. The method according to any one of the preceding embodiments, wherein the protecting group is a tert-butyloxycarbonyl protecting group.

[0076] Embodiment 6. A compound of formula (B)-

Chemical formula

[0077] Embodiment 7. The method according to any of the preceding embodiments, wherein the reducing agent is NaBH 4 as described in any of the preceding embodiments.

[0078] Embodiment 8. The method according to any of the preceding embodiments, wherein the base is lithium tetramethylpiperidide (LiTMP).

[0079] Embodiment 9. A compound of formula (a)-

Chemical formula

Chemical formula

[0080] Embodiment 10. The method according to any of the preceding embodiments, wherein the metal-containing compound comprises i-PrMgCl*LiCl.

[0081] Embodiment 11. A compound of formula (c)-

Chemical formula

Chem.

[0082] Embodiment 12. Deacetylating to form a compound of formula (I):

Chem.

[0083] Embodiment 13. A compound or a salt thereof formed by the method according to any of the preceding embodiments.

[0084] Embodiment 14. A compound or a salt thereof disclosed herein, such as any compound or a salt thereof disclosed in Scheme 1, Scheme 2, Scheme 3, Scheme 4 or Scheme 5.

[0085] Embodiment 15. A compound of formula (I) or a pharmaceutically acceptable salt thereof, or a compound of formula (I') or a pharmaceutically acceptable salt thereof, wherein

Chem.

[0086] Embodiment 16. Each C 1 -C 20 hydrocarbyl is independently C 1 -C 15 hydrocarbyl, C 1 -C 10 hydrocarbyl, C 1 -C 5 hydrocarbyl or C 1 -C 3 hydrocarbyl, the compound according to any of the preceding embodiments.

[0087] Embodiment 17. R 1 , R 2 , R 5 or R 6 in which at least one of them is not hydrogen, the compound according to any of the preceding embodiments.

[0088] Embodiment 18. R 1 , R 2 , R 5 or R 6 in which at least two of them are not hydrogen, the compound according to any of the preceding embodiments.

[0089] Embodiment 19. R 1 , R 2 , R 5 or R 6 in which at least three of them are not hydrogen, the compound according to any of the preceding embodiments.

[0090] Embodiment 20. R 1 , R 2 , R 5 or R 6 each of which is not hydrogen, the compound according to any of the preceding embodiments.

[0091] Embodiment 21. R 3 and R 4A compound as described in any of the preceding embodiments that is not hydrogen.

[0092] Embodiment 22. R 3 and R 4 is not hydrogen, and R 1 , R 2 , R 5 or R 6 is hydrogen, a compound as described in any of the preceding embodiments.

[0093] Embodiment 23. R 3 and R 4 are different, a compound as described in any of the preceding embodiments.

[0094] Embodiment 24. R 3 and R 4 is (i) not hydrogen and (ii) different, a compound as described in any of the preceding embodiments.

[0095] Embodiment 25. R 3 is hydroxy, a compound as described in any of the preceding embodiments.

[0096] Embodiment 26. R 1 , R 2 , R 4 , R 5 and R 6 are hydrogen, and R 3 is hydroxy, a compound as described in any of the preceding embodiments.

[0097] Embodiment 27. R 3 is methoxy, a compound as described in any of the preceding embodiments.

[0098] Embodiment 28. R 1 , R 2 , R 4 , R 5 and R 6 are hydrogen, and R 3 is methoxy, a compound as described in any of the preceding embodiments.

[0099] Embodiment 29.R 2 The compound according to any of the preceding embodiments, wherein is methyl.

[0100] Embodiment 30.R 1 , R 3 , R 4 , R 5 and R 6 are hydrogen, and R 2 is methyl, the compound according to any of the preceding embodiments.

[0101] Embodiment 31.R 4 is halogen (e.g., chloro-, bromo-, iodo-), the compound according to any of the preceding embodiments.

[0102] Embodiment 32.R 1 , R 2 , R 3 , R 5 and R 6 are hydrogen, and R 4 is halogen (e.g., chloro-, bromo-, iodo-), the compound according to any of the preceding embodiments.

[0103] Embodiment 33.R 1 , R 2 , R 5 or R 6 at least one of which is not hydrogen, the compound according to any of the preceding embodiments.

[0104] Embodiment 34.R 3 and R 4 at least one of which is not hydrogen, the compound according to any of the preceding embodiments.

[0105] Embodiment 35.R 4 is Cl, the compound according to any of the preceding embodiments.

[0106] Embodiment 36.R5 The compound according to any of the preceding embodiments, wherein is hydroxy.

[0107] Embodiment 37.R 6 The compound according to any of the preceding embodiments, wherein is methyl.

[0108] Embodiment 38. (i) A compound formed by the method according to any of the preceding embodiments or a pharmaceutically acceptable salt thereof, and / or (ii) a pharmaceutical composition comprising a compound according to any of the preceding embodiments or a pharmaceutically acceptable salt thereof.

[0109] Embodiment 39. The pharmaceutical composition according to embodiment 38, wherein the pharmaceutical composition is configured for one or more administration routes including, but not limited to, oral, parenteral (e.g., intravenous, subcutaneous, intramuscular, intramedullary injection, intrathecal, direct intraventricular, intraperitoneal, intralymphatic, intranasal injection), intranasal, buccal, topical or transdermal administration routes.

[0110] Embodiment 40. The pharmaceutical composition according to any of the preceding embodiments, further comprising one or more other components, such as one or more carriers, excipients, binders, fillers, suspending agents, flavoring agents, sweetening agents, disintegrants, dispersants, surfactants, lubricants, coloring agents, diluents, solubilizers, wetting agents, plasticizers, stabilizers, penetration enhancers, wetting agents, defoaming agents, antioxidants, preservatives, or one or more combinations thereof.

[0111] Embodiment 41. A method for treating a neurodegenerative disease in a patient in need thereof, the method comprising administering to a patient suffering from a neurodegenerative disease an effective amount of a compound according to any of the preceding embodiments or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to any of the preceding embodiments or any pharmaceutical composition described herein.

[0112] Embodiment 42. The method according to embodiment 41, wherein the compound or a salt thereof or the pharmaceutical composition is administered in an amount greater than about 30 μg, greater than about 40 μg, greater than about 50 μg, greater than about 60 μg, greater than about 70 μg, greater than about 80 μg, greater than about 90 μg, or greater than about 100 μg.

[0113] Embodiment 43. The method according to any of the preceding embodiments, wherein the compound or a salt thereof or the pharmaceutical composition is administered in an amount greater than about 0.01 mg, greater than about 0.05 mg, greater than about 0.1 mg, greater than about 0.5 mg, greater than about 1 mg, greater than about 10 mg, greater than about 20 mg, greater than about 60 mg, greater than about 100 mg, greater than about 200 mg, greater than about 400 mg, or greater than about 500 mg.

[0114] Embodiment 44. The method according to any of the preceding embodiments, wherein the compound or a salt thereof or the pharmaceutical composition is administered in an effective amount of about 10 μg to about 500 μg (mg / kg of patient body weight (mpk)).

Examples

[0115] Example The present invention is further illustrated by the following examples, which should in no way be construed as limiting its scope. On the contrary, after reading the description herein, it should be clearly understood that one can rely on various other aspects, embodiments, modifications, and their equivalents that may suggest themselves to those skilled in the art without departing from the spirit of the present invention or the scope of the appended claims. Therefore, other aspects of the present invention will be apparent to those skilled in the art from the consideration of this specification and the practice of the invention disclosed herein.

[0116] Example 1 - Synthesis of Lysergide

[0117] Scheme 1 shows the efforts to implement Strategy 1 for the synthesis of 2.

Chemical formula

[0118] Starting from bromopyridine 9, methylation of the pyridine nitrogen with MeOTf generated the intermediate N - methylpyridinium, which was subsequently trapped with Grignard reagent 11 to produce dihydropyridine 15 as the major positional isomer with a C6 / C4 ratio of 2.6:1 and an overall yield of 82%. Due to the additive directing effects of both the ester substituent and the bromide substituent, addition at C6 was predicted to be favored.

[0119] Next, reduction of the vinyl carbamate in 15 with LiAlH 4 proceeded in 80% yield, delivering a 1:1 mixture of diastereomers of acetal 16. Since the alpha - center to the ester is ultimately thermally decomposable during the construction of the ergoline framework, this mixture was considered to be ultimately unimportant for the synthesis of 2.

[0120] Subsequently, acetal 16 was treated with phenylhydrazine (10) and 4% H 2 SO 4 / EtOH mixture at elevated temperature to afford indole 8 in 61% yield. Notably, this Fischer indole reaction was attempted with various other phenylhydrazine derivatives but gave no observable indole product. This observation precluded the ability to generate modified downstream intermediates in the route to 2.

[0121] On the other hand, in 8, a final C - H cyclization was required to close the last six - membered ring seen in lysergic acid (2). Initially, following previous precedents for this type of transformation, the observable product was only cyclization at the C2 position of the indole heterocycle. Attempts to sterically block this unwanted cyclization were hampered by the inability to appropriately functionalize or protect the indole nitrogen under basic conditions. This could be due to the base - sensitivity of the tetrahydropyridine ring seen in 8, and the attempted conditions to deprotonate the indole nitrogen led to non - productive decomposition pathways. Ni catalysis or radical propagation (e.g., PET, Bu3 Further efforts to achieve cyclization of vinyl bromide using SnH and AIBN also mainly resulted in only dehydrogenation of 8.

[0122] Furthermore, although a reductive coupling strategy might have been possible via an intermediate such as 18, the Fischer indolization reaction of 16 was only operative with phenylhydrazine (10), disrupting any ability to prepare the benzene-fused functionalized indole homologues of 8. Importantly, since the same cyclization cleavage is required to forge the important C-C bond at the C4 position of the indole, a judicious change in the placement of the halogen is likely to enable a more competent and reliable Pd-catalyzed cyclization.

[0123] Scheme 2 shows the forward implementation of a second retrosynthetic strategy towards the synthesis of 2.

Chemical formula

[0124] Starting from iodopyridine 13, a heterocyclic nucleophile was generated by magnesium-halogen exchange and trapped with the commercially available aldehyde 14 to afford the intermediate alcohol (not shown) in 85% yield. Exposure of this intermediate to Et 3 SiH and TFA cleaved the Boc protecting group along with subsequent reduction of the benzyl alcohol to give indole 19 in good yield on a gram scale.

[0125] The next step in the synthesis involved reductive dearomatization of the pyridine to tetrahydropyridine. In this case, Boc protection of 19 followed by in situ methylation of the pyridine nitrogen gave the intermediate pyridinium. This intermediate was not isolated; rather, NaBH 4Treatment gave smooth formation of dihydropyridine 20 in 60% yield in one pot. Isomerization of the enoate with LiTMP gave a 2:3 diastereomer mixture of 12a and 12b, the latter of which was prepared for the crucial Heck cyclization. Conveniently, 12a could be converted to 12b with the same diastereomeric outcome by re-exposure to the isomerization conditions. Treatment of 12b with a catalytic amount of Fu's Pd 0 complex (generated in situ) enabled facile formation of 21 in excellent yields of 5:1:1 ratio along with the two diastereomeric alkene isomers of 22a and 22b. Similar transformations have been reported, but low yields and / or stoichiometric amounts of Pd have been required to achieve this cyclization, attesting to its difficult implementation. Furthermore, the central alpha stereochemistry to the ester in 12b was important for the success of this reaction and enabled syn-beta-hydride elimination to proceed after migratory insertion of the putative arylpalladium(II) intermediate. Finally, saponification and isomerization of the mixture of 21, 22a, and 22b were carried out as previously reported to give lysergic acid (2) in 50% yield. See Oppolzer, W.; Francotte, E.; Battig, K. Total Synthesis of (±)-Lysergic Acid by an Intramolecular Imino-Diels-Alder Reaction. Preliminary Communication. Helv. Chim. Acta 1981, 64(2), 478-481. https: / / doi.org / https: / / doi.org / 10.1002 / hlca.19810640212.

[0126] In conclusion, the concise synthesis of lysergic acid (2) was achieved in six steps from commercially available materials with an overall yield of 14%. Furthermore, the conversion of the final product to methyl lysergate (see US Patent Application Publication No. 2023 / 0116703), followed by conversion to the hydrazide (see Bioorg. Med. Chem. Lett., 2008, 18, 979 - 982), allows for the separation of enantiomers (see, for example, US Patent No. 2,447,214). The core of the simplicity of this approach was the strategic and redox - economic utilization of a heteroaromatic starting material as a functionalized precursor to the ergoline core. Additionally, this strategic approach was initially hampered by tactical difficulties that could not be overcome, but the inversion of the polar synthon enabled the construction of the final tetracyclic core. This simple and potentially modular platform can enable the synthesis and investigation of bioactive psychoplastogenic LSD derivatives that could be beneficial in drug discovery and psychotherapy. The molecular space afforded by this synthetic blueprint holds great promise for new neuropharmacological treatments and the increased use of psychiatry and its derivatives as novel neuropharmacological agents.

[0127] Example 2 - Synthesis of (±)-12 - chlorolysergic acid

Chemical Structure

[0128] Starting from iodopyridine 13, magnesium-halogen exchange followed by addition to aldehyde 14b (i.e., 4-bromo-5-chloro-1H-indole-3-carbaldehyde) gave the intermediate benzyl alcohol, which was reduced to give biaryl 23 in moderate yield over two steps. After methylation and reduction of the intermediate, Boc protection of the indole was carried out and this was advanced in 81% yield (over two steps) to give 24. This intermediate was subjected to base-mediated isomerization to give a 1:2 ratio of 25a / 25b in 83% yield. A small amount of the unwanted isomer (25a) could be recycled again to give a larger amount of 25b, which was advanced in excellent yield by Heck cyclization to generate enoate 26 in 57% yield. Hydrolysis of this mixture gave 12-chlorolysergic acid (27) in good yield.

[0129] Example 3 - Synthesis of (±)-13-hydroxylysergic acid

[0130] This example discloses the route to 13-hydroxy-LSD shown below. The indolyl iodide is constructed in three steps from 3-bromo-5-methoxyaniline (B). This iodide is then subjected to magnesium-halogen exchange and then quenched with commercially available pyridyl aldehyde A. The resulting benzyl alcohol is reduced with TFA and triethylsilane to give the corresponding biarylmethylene. This intermediate is methylated, reduced, and Boc protected to give the corresponding dihydropyridine in 29% yield over two steps.

[0131] This obtained tetrahydropyridine is isomerized with LiTMP to give the protic isomer which is the substrate for intermolecular Heck cyclization to obtain the ergoline skeleton. This Heck product is treated with aqueous KOH to produce 13-OMe-lysergic acid, which is coupled with diethylamine and demethylated to give 13-OH-LSD. The optically pure isomer is obtained by the resolution described for the resolution of lysergic acid above.

Chemical Structure

[0132] Example 4 - Synthesis of (±)-14-Methyllysergic Acid

[0133] This example discloses the route to 14-Me-LSD shown below. The required indolyl iodide is constructed in two steps from 4-bromo-2-nitrotoluene (B). This iodide is subjected to magnesium halogen exchange and then quenched with commercially available pyridyl aldehyde A. The resulting benzyl alcohol is reduced with TFA and triethylsilane to obtain the corresponding biaryl methylene. This intermediate is methylated, reduced, Boc-protected to obtain the corresponding dihydropyridine, which is isomerized with LiTMP to obtain an alkene isomer that is the substrate for intermolecular Heck cyclization, thereby obtaining the ergoline skeleton. This Heck product is treated with aqueous KOH to obtain 14-Me-lysergic acid, which is coupled with diethylamine to obtain 13-Me-LSD. Optically pure isomers are obtained by the resolution described for the resolution of lysergic acid above. [Chemical Structure]

[0134] Example 5 - General Experimental / Procedure Information

[0135] Unless otherwise specified, all reactions were carried out using a flame-dried round-bottom flask or reaction vessel. Unless otherwise specified, the reactions were carried out using a dry solvent under an inert atmosphere of nitrogen. Dry benzene (PhH), dichloromethane (CH 2 Cl 2 ), diethyl ether (Et 2 O), dimethylformamide (DMF), 1,4-dioxane, methanol (MeOH), acetonitrile (MeCN), and tetrahydrofuran (THF) were obtained by passing the previously degassed solvent through an activated alumina column. Yields were determined by chromatography and spectroscopy, unless otherwise specified. 1refers to a material that is homogeneous by 1H NMR. The NMR yield was compared to an internal standard of either trimethoxybenzene or dimethyl sulfone. The reaction was monitored by thin layer chromatography performed on Merck silica gel plates (glass back, 60G, F-254) or Sigma-Aldrich aluminum oxide plates (glass back, F-254). Basic silica plates were prepared by treating commercially available silica gel plates with 50:1 hexane:triethylamine and subsequently evaporating under reduced pressure. TLC plates were visualized using ultraviolet light and appropriate developing agents. NMR spectra were recorded on a Bruker Avance III 400, 500, or 600 MHz NMR spectrometer and calibrated using residual solvent as an internal reference (benzene-d 6 : 1 1H NMR δ = 7.16, 13 13C NMR δ = 128.06; CDCl 3 : 1 1H NMR δ = 7.26, 13 13C NMR δ = 77.16; CD 2 Cl 2 : 1 1H δ = 5.32, 13 13C NMR δ = 53.84; DMSO-d 6 : 1 1H δ = 2.50; methanol-d 4 : 1 1H δ = 3.31). 19 19F NMR spectra were calibrated using 3-fluoropyridine as an internal reference ( 19 19F NMR δ = -125.7). The following abbreviations or combinations thereof were used to describe multiplicity: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, br = broad, and app = apparent. When analyzing dihydropyridine products, CDCl 3 was passed through a pad of K 2 CO 3 prior to use. The crude NMR spectra were analyzed to determine the ratio of dihydropyridine positional isomers. Unisolated positional isomers were present in the crude 1It was assigned based on selected peaks of ¹H NMR. Flash column chromatography was performed using VWR silica gel (irregular, 60 Å, 40 - 60 μm), prepared basic silica gel, or deactivated aluminum oxide (alumina, for chromatography, neutral, Brockman I, 50 - 200 μm, 60 Å). Basic silica gel was prepared by treating commercially available silica gel with hexane:triethylamine at 50:1 and subsequently evaporating under reduced pressure. Deactivation of alumina to Brockman grade III alumina was achieved by adding pure water (5% w / w) to solid aluminum oxide. The mixture was shaken and then allowed to equilibrate by standing overnight in a sealed container. Preparative TLC was performed using Merck silica gel plates (glass - backed, 60G, F - 254), basic silica plates, or Sigma - Aldrich aluminum oxide plates (glass - backed, F - 254). High - resolution mass spectra (HRMS) were recorded on an Agilent 6230 TOF - MS spectrometer (DART). Reagents were purchased and used without further purification unless otherwise specified. All reagents were purchased from the following suppliers. 2,2’ - Azobis(2 - methylpropionitrile) was recrystallized from methanol.

[0136] Acros Organics: Borane dimethyl sulfide complex

[0137] Amresco: Magnesium chloride (anhydrous)

[0138] Cambridge Isotope Laboratories: Chloroform - d 1 , Acetone - d 6 .

[0139] Fisher Scientific: Ammonia hydroxide (concentrated), Phenylhydrazine, Phosphorus oxychloride, Pyridine, Sodium chloride, Sodium nitrite, and Zinc metal.

[0140] Macron Fine Chemicals: Sodium hydroxide.

[0141] Oakwood Chemical: Allyltributylstannane, di-tert-butyldicarbonate, 4-(dimethylamino)pyridine, 4,4’-di-tert-butyl-2,2’-bipyridyl, lithium aluminum hydride, magnesium sulfate, methyl chloroformate, methyl triflate, sodium bicarbonate, and 2,2,6,6-tetramethylpiperidine.

[0142] Sigma Aldrich: n-Butyllithium (2.5 M in hexanes), copper(I) iodide, N,N-dicyclohexylmethylamine, N,N’-diethylenediamine, hydrogen peroxide, iodine, isopropylmagnesium chloride lithium chloride solution (1.3 M in THF), lithium chloride, pyridinium chlorochromate, sodium borohydride, sodium iodide, triethylsilane, trifluoroacetic acid, trifluoromethanesulfonic acid, tris(dibenzylideneacetone)dipalladium(0), tri-tert-butylphosphonium tetrafluoroborate.

[0143] Spectrum Chemicals: Celite.

[0144] Strem: Bis(cyclooctadiene)nickel(0).

[0145] Synquest Laboratories:

[0146] VWR: Ammonium chloride

[0147] Ward’s Science: Hydrochloric acid and sulfuric acid

[0148] Methyl 6-iodonicotinate 173157-33-0 AA block $140 / g

[0149] Methyl 6-bromonicotinate 26218-78-0 AA block $2.48 / g

[0150] 4-Bromo-3-formyl-1H-indole, N-BOC protected 303041-88-5 AA block $91 / g

[0151] 4-Bromoindole-3-carboxaldehyde 98600-34-1 AA block $12.88 / g

[0152] 4-Bromoindole 52488-36-5 AA block $4.67 / g

Chem.

[0153] In a 30 mL test tube, pyridine XX (1.00 mmol) was suspended in Et2O (1.0 mL), and the mixture was placed under an N 2 atmosphere. The reaction vessel was placed in a water bath at room temperature, and the mixture was gently stirred. MeOTf (1.0 equivalent) was added dropwise to the mixture, and the reactants were stirred for 1 hour. After the disappearance of the starting material determined by TLC, the thick white mixture was concentrated in vacuo, redissolved in THF (4.0 mL), and then cooled to -78 °C. The Grignard reagent (1.0 equivalent) was added dropwise to the reactants, and the resulting yellow mixture was continuously stirred for 2 hours. Then, saturated NaHCO3 solution (4 mL) was added to quench the reaction, and the mixture was warmed to room temperature. The product was extracted with EtOAc (3 × 10 mL). The combined organic layers were washed with brine (15 mL), dried over MgSO 4 4, and concentrated under reduced pressure. Purification of the crude mixture by flash column chromatography (gradient 4:1 → 7:3 → 3:2 → 1:1 hexane:EtOAc, silica) gave 203.9 mg (59% yield) of dihydropyridine XX.

[0154] 1H NMR (400 MHz, CD2Cl2) δ 7.26 (s, 1H), 6.71 (d, J = 1.1 Hz, 1H), 4.54 - 4.47 (m, 1H), 4.38 (t, J = 3.8 Hz, 1H), 4.05 - 4.00 (m, 2H), 3.75 - 3.67 (m, 2H), 3.60 (s, 3H), 2.96 (s, 3H), 2.02 - 1.94 (m, 1H), 1.85 - 1.65 (m, 3H), 1.65 - 1.55 (m, 1H), 1.29 (dtt, J = 13.4, 2.7, 1.4 Hz, 1H).

Chem.

[0155] To a stirred suspension of dihydropyridine XX (1.00 g, 2.89 mmol) in THF (15 mL) at 0 °C was added a suspension of LAH (84.4 mg, 2.22 mmol) in THF (15 mL) over 5 minutes at 0 °C. The reaction mixture was stirred at 0 °C for an additional 40 minutes. When complete by TLC, the mixture was cooled to -78 °C and then EtOAc (7 mL) was added all at once. The mixture was stirred at -78 °C for 5 minutes and then warmed to 0 °C and stirred for 5 minutes. The mixture was then cooled to -78 °C and then saturated Rochelle's solution (7 mL) was added. The mixture was stirred at -78 °C for 5 minutes and then warmed to 0 °C and stirred for 5 minutes. Water (20 mL) was added to the mixture and the product was extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with brine (20 mL) and dried over MgSO 4 and concentrated under reduced pressure. Purification of the crude mixture by flash column chromatography (1:1 hexane:EtOAc eluent, silica) gave tetrahydropyridine XX (654 mg, 65% yield) as a 1.2:1 mixture of diastereomers.

[0156] Physical state: Pale yellow oil.

[0157] R f= 0.43 (eluent: 1:1 hexane:EtOAc, silica).

[0158] 1 H NMR (500 MHz, CDCl 3 ): δ 6.31 (q, J = 1.5 Hz, 1H), 6.21 (dt, J = 3.2, 1.0 Hz, 1H), 4.56 - 4.52 (m, 1.84H), 4.11 - 4.05 (m, 3.68H), 3.77 - 3.71 (m, 3.68H), 3.70 (s, 2.52H), 3.69 (s, 3H), 3.42 - 3.36 (m, 1H), 3.19 - 3.09 (m, 2.84), 2.96 - 2.91 (m, 0.84H), 2.90 - 2.78 (, 2.84H), 2.44 (s, 3H), 2.37 (s, 2.52H), 2.12 - 1.99 (m, 1.84H), 1.99 - 1.84 (m, 1.84H), 1.82 - 1.72 (m, 1.84H), 1.71 - 1.53 (m, 3.68H), 1.35 - 1.78 (m, 1.84H).

[0159] 13 C NMR (126 MHz, CDCl 3 ): δ 172.4, 172.1, 128.0, 126.9, 126.1, 124.6, 102.4, 102.4, 67.0, 67.0, 66.4, 66.2, 52.3, 52.3, 50.1, 46.5, 43.1, 42.5, 42.3, 39.8, 32.0, 30.2, 26.0, 25.9, 25.9, 24.7.

[0160] HRMS (DART): C 14 H 23 BrNO 4 + [M + H] + calculated value for 348.0805; measured value 348.0804.

Chemical Structure

[0161] To a scintillation vial containing acetal XX (155 mg, 0.444 mmol) and phenylhydrazine (131 μL), a solution mixture of 22:1 MeOH / concentrated H 2 SO 4 (3.0 mL) was added. Initially, a white solid and a red solution were formed. N 2 was flushed through the vial and sealed with a Teflon cap. The suspension was heated and stirred at 100 °C. The solid dissolved and the reaction mixture turned dark red. The reaction mixture was heated and stirred at 100 °C for 3 h. After this time, the reaction mixture was cooled to room temperature and poured into a 1:1 mixture of saturated Na 2 CO 3 solution and ice (6 mL). The product was extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with brine (20 mL), dried over MgSO 4 and concentrated under reduced pressure. Purification of the crude mixture by flash column chromatography (13:7 hexane / EtOAc eluent, silica) gave indole XX (94.7 mg, 59% yield) as a 1.8:1 mixture of diastereomers.

[0162] Physical state: yellow oil.

[0163] R f = 0.39 (13:7 hexane:EtOAc eluent, silica).

[0164] 1 H NMR (600 MHz, CDCl 3): δ 8.14 (s, 0.38H), 8.10 (s, 1H), 7.70 (app. d, J = 7.7 Hz, 1.38H), 7.33 (app. d, J = 8.0 Hz, 1.38H), 7.18 (app. t, J = 7.5 Hz, 1.38H), 7.15 - 7.09 (m, 2.76H), 6.39 (s, 0.38H), 6.33 (s, 1H), 3.71 (s, 1.14H), 3.69 (s, 3H), 3.54 - 3.44 (m, 1.38H), 3.41 - 3.25 (m, 4.14H), 3.22 - 3.11 (m, 1H), 3.09 - 2.8 (m, 3.14H), 2.45 (s, 4.14H).

[0165] 13 C NMR (151 MHz, CDCl 3 ): δ 172.2, 136.2, 136.2, 127.7, 125.8, 125.0, 122.9, 122.0, 121.9, 119.4, 119.4, 119.2, 119.1, 111.3, 111.2, 67.3, 67.3, 52.5, 52.3, 48.7, 45.9, 43.3, 42.3, 41.7, 39.5, 27.5, 26.8.

[0166] HRMS(DART): C 17 H 18 BrN 2 O 2 + [M - H] + Calculated value for 361.0546; measured value 361.0515.

Chemical Structure

[0167] CHCl 3A solution of pyridyl iodide XX (1.32 g, 5.00 mmol) in THF (5.0 mL) cooled in a dry ice bath (-61 °C) was charged with a solution of i-PrMgCl·LiCl (5.00 mL, 1.00 M, 5.00 mmol) over 2 minutes. The mixture was stirred in the cooling bath for 1 hour. When XX was consumed as determined by TLC, a solution of XX (1.78, 5.50 mmol) in THF (3.0 mL) was added dropwise to the mixture over 2 minutes. Any residual XX was transferred using additional THF (0.05 mL), and this solution was added dropwise over 1 minute. The resulting solution was stirred in the cooling bath for 1 hour. After this time, the bath was removed and the reaction mixture was slowly warmed to room temperature. The reaction mixture turned dark green upon warming and then finally amber. After about 1 hour at room temperature. The mixture was quenched with NH 4 Cl saturated solution (10 mL), charged with water (10 mL), and extracted with EtOAc (3 × 30 mL). The combined organic layers were washed with brine (15 mL), dried over MgSO 4 , and concentrated under reduced pressure. Purification of the crude mixture by flash column chromatography (1:1:0.05 hexane:EtOAc:DCM eluent, silica) gave alcohol XX (1.95 g, 85% yield).

[0168] Physical state: Light beige solid.

[0169] R f = 0.31 (11:9 hexane:EtOAc eluent, silica).

[0170] 1 H NMR (400 MHz, CDCl 3 ) δ 9.20 (s, 1H), 8.28 - 8.18 (m, 2H), 7.46 (s, 1H), 7.42 (d, J = 7.8 Hz, 2H), 6.75 (s, 1H), 3.95 (s, 2H), 1.61 (s, 9H).

[0171] 1313C NMR (151 MHz, CDCl3) δ 165.56, 165.17, 149.61, 148.98, 138.03, 137.17, 127.61, 127.53, 126.50, 125.53, 125.05, 122.17, 121.37, 114.72, 113.48, 84.65, 67.85, 52.52, 28.10.

[0172] HRMS(DART): C 21 H 22 BrN 2 O 5 + [M + H] + Calculated value for 461.0707; measured value 461.0735. [Chemical formula]

[0173] To a stirred solution of carbamate XX (1.95 g, 4.23 mmol) in THF (4.2 mL) at 0 °C was charged TFA (13 mL) all at once, turning the mixture dark amber. The mixture was warmed to room temperature and after 30 minutes, Et 3 SiH (4.05 mL, 25.4 mmol) was charged and the mixture was stirred at 35 °C for 14 hours. A further charge of Et 3 SiH (2.03 mL, 12.7 mmol) was added to the mixture and the reaction was left stirring at 35 °C for 1 hour. 1 Once completed as determined by 1H NMR analysis, the reaction mixture was poured into saturated NaHCO 3 solution (100 mL) and this was extracted with EtOAc (3 × 30 mL). The combined organic layers were washed with brine (15 mL), dried over MgSO 4 and concentrated under reduced pressure. Purification of the crude mixture by flash column chromatography (1:1 hexane:EtOAc eluent, silica) gave indole XX (1.02 g, 70% yield).

[0174] Physical state: Beige solid.

[0175] R f= 0.35 (1:1 hexane:EtOAc eluent, silica).

[0176] 1 1H NMR (400 MHz, CDCl3) δ 9.17 (s, 1H), 8.62 (s, 1H), 8.15 (dd, J = 8.2, 2.2 Hz, 1H), 7.28 (d, J = 7.7 Hz, 1H), 7.23 (d, J = 7.8 Hz, 1H), 7.18 (d, J = 8.2 Hz, 1H), 7.04 - 6.96 (m, 2H), 4.65 (s, 2H), 3.93 (s, 3H).

[0177] 13 13C NMR (151 MHz, CDCl3) δ 166.74, 166.03, 150.26, 137.79, 137.60, 125.41, 125.31, 124.07, 123.54, 123.11, 122.67, 114.16, 113.12, 110.72, 52.29, 35.12.

[0178] HRMS(DART): C 16 H 14 BrN 2 O 2 + [M+H] + calculated value for 345.0233; measured value 345.0257.

Chemical Structure

[0179] CH 2 Cl 2 Indole XX (85.0 mg, 246 μmol) and Boc in (12 mL) 2DMAP (1.6 mg, 52.0 μmol) was charged into a stirred solution of O (57.1 mg, 262 μmol). After 1.5 h, the reaction was determined to be complete by TLC. The reaction mixture was cooled to 0 °C and MeOTf (28.7 μL, 262 μmol) was charged all at once. The mixture was stirred at 0 °C for 1.5 h. When determined to be complete by TLC, the mixture was cooled to -78 °C. A solution of NaBH 4 (56.5 mg, 1.49 mmol) in MeOH (1.2 mL) was added to the pyridinium reaction mixture over 1 min and the reaction mixture turned yellow. The combined mixture was stirred at -78 °C for 1 h and then quenched with a 1:1 mixture of saturated NaHCO 3 solution and acetone (2 mL). The mixture was extracted with EtOAc (3 × 15 mL). The combined organic layers were washed with brine (15 mL), dried over MgSO 4 and concentrated under reduced pressure. Purification of the crude residue by flash column chromatography (3:2 EtOAc:hexane eluent, silica) afforded enoate XX (63.3 mg, 56% yield).

[0180] Physical state: white foam.

[0181] R f = 0.40 (3:2 EtOAc:hexane eluent, silica).

[0182] 1 H NMR (400 MHz, CDCl 3 ): δ 8.14 (d, J = 8.3 Hz, 1H), 7.40 (s, 1H), 7.35 (d, J = 7.7 Hz, 1H), 7.09 (t, J = 8.1 Hz, 1H), 6.96 (s, 1H), 3.73 (s, 3H), 3.52 - 3.31 (m, 3H), 3.17 (q, J = 4.6 Hz, 1H), 2.69 (dd, J = 14.2, 10.0 Hz, 1H), 2.54 (s, 3H), 2.20 (s, 2H), 1.65 (s, 9H).

[0183] 1313C NMR (151 MHz, CDCl3) δ 166.36, 149.10, 137.22, 137.03, 128.42, 128.08, 127.29, 125.80, 125.08, 117.93, 114.54, 114.07, 84.26, 56.74, 51.58, 51.03, 40.81, 28.41, 28.18, 25.87.

[0184] HRMS(DART): C 22 H 28 BrN 2 O 4 + [M + H] + Calculated value for 463.1232; measured value 463.1234

Chem.

[0185] To a stirred solution of HTMP (93.7 μL, 0.55 mmol) in THF (1.0 mL) was charged n-BuLi (230 μL, 2.35 M, 0.54 mmol) at 0 °C. After the solution was stirred for 50 minutes, it was cooled to -78 °C, and then enoate XX was added dropwise in THF (1.0 mL). The mixture changed from pale yellow to amber upon addition. The reaction mixture was stirred at -78 °C for 1 hour, then warmed to 0 °C and stirred for an additional 20 minutes. The reaction was quenched with saturated NH 4 Cl solution (1.0 mL). Water (10 mL) was added to this mixture and it was extracted with EtOAc (3 × 15 mL). The combined organic layers were washed with brine (15 mL), dried over MgSO 4 and concentrated under reduced pressure. The crude residue was purified by flash column chromatography on neutral silica (4:1 hexane:EtOAc eluent, silica) to afford the minor isomer XX (16.6 mg, 33% yield) and the major isomer XX (27.2 mg, 54% yield) in a 3:2 ratio.

[0186] Physical state: yellow oil

[0187] R f= 0.17 (eluent: 1:1 hexane:EtOAc, silica gel).

[0188] 1 1H NMR (600 MHz, CDCl3) δ 7.53 (s, 1H), 7.37 (dd, J = 7.8, 0.9 Hz, 1H), 7.11 (t, J = 8.0 Hz, 1H), 5.89 (d, J = 10.3 Hz, 1H), 5.71 (d, J = 10.3 Hz, 1H), 3.70 (s, 3H), 3.59 (dd, J = 14.8, 4.6 Hz, 1H), 3.48 - 3.42 (m, 1H), 3.30 - 3.25 (m, 1H), 3.20 (dd, J = 11.7, 5.3 Hz, 1H), 2.86 (dd, J = 15.0, 9.6 Hz, 1H), 2.68 (t, J = 10.2 Hz, 1H), 2.56 (s, 3H), 1.66 (s, 9H). Iso B

[0189] 1H NMR (400 MHz, CDCl3) δ 8.17 (d, J = 8.6 Hz, 1H), 7.48 (s, 1H), 7.38 (d, J = 8.7 Hz, 1H), 7.11 (t, J = 8.0 Hz, 1H), 5.91 (d, J = 10.6 Hz, 1H), 5.75 (d, J = 10.3 Hz, 1H), 3.75 (s, 3H), 3.53 - 3.45 (m, 1H), 3.40 - 3.33 (m, 1H), 3.32 - 3.22 (m, 2H), 2.92 - 2.83 (m, 2H), 2.56 (s, 3H), 1.67 (s, 9H). Iso A

[0190] 1313C NMR (151 MHz, CDCl3) δ 172.99, 149.15, 136.92, 130.44, 128.69, 127.28, 126.27, 125.03, 123.06, 117.07, 114.50, 114.03, 84.17, 61.09, 53.99, 51.99, 43.02, 41.57, 29.27, 28.19. Iso B

[0191] 13 13C NMR (151 MHz, CDCl3) δ 173.49, 149.16, 137.04, 130.42, 128.57, 127.23, 126.24, 124.98, 122.54, 117.51, 114.51, 114.02, 84.14, 60.32, 52.08, 50.31, 42.66, 38.48, 29.44, 28.20. Iso A

[0192] HRMS(DART):C 22 H 28 BrN 2 O 4 + [M+H] + Calculated value for [M+H] 463.1232; Measured value 463.1229

Chemical formula

[0193] In a 9 mL reaction vial, Pd 2 (dba) 3 (5.0 mg, 5.4 μmol) and P(t-Bu) 3 HBF 4 (3.0 mg, 10.8 μmol) were charged with the major isomer XX (25.0 mg, 0.054 mmol) in degassed 1,4-dioxane (2.7 mL), then Cy 2 NMe (13.9 μL, 64.8 μmol). The mixture was heated at 100 °C for 12 h. When determined by TLC to be complete, the mixture was charged with water (15 mL) and extracted with EtOAc (3 × 15 mL). The combined organic layers were washed with brine (15 mL) and MgSO4 It was dried and concentrated under reduced pressure. Purification of the crude residue by flash column chromatography (1:2 hexane:EtOAc eluent, silica) gave a mixture of tetracyclic XX and an unimportant mixture of a 1:1 diastereomeric mixture of methyl lysergate and isolysergate.

[0194] Physical state: yellow oil

[0195] R f = 0.23 (1:1 hexane:EtOAc eluent, silica).

[0196] 1 1H NMR 1H NMR (400 MHz, CDCl3) XX δ 7.80 (s, 1H), 7.37 - 7.27 (m, 2H), 7.13 (d, J = 7.3 Hz, 1H), 7.04 (s, 1H), 4.07 (s, 1H), 3.71 (s, 3H), 3.55 - 3.47 (m, 1H), 3.41 - 3.32 (m, 2H), 2.95 (dd, J = 15.4, 4.6 Hz, 1H), 2.73 - 2.65 (m, 1H), 2.60 (s, 3H), 1.66 (s, 9H). Diastereomer A δ 7.80(s,1H),7.37-7.27(m,2H),7.13(d,J=7.3 Hz,1H),6.60(s,1H),3.78(s,3H),3.55-3.47(m,2H),3.41-3.32(m,2H),2.73-2.65(m,2H),2.58(s,3H),1.66(s,9H). Diastereomer B δ 7.80(s,1H),7.37-7.27(m,2H),7.13(d,J=7.3 Hz,1H),6.55(d,J=4.0 Hz,1H),3.73(s,3H),3.55-3.47(m,1H),3.41-3.32(m,3H),2.73-2.65(m,2H),2.55(s,3H),1.66(s,9H).

[0197] 1313C NMR (151 MHz, CDCl3) XX δ 165.97, 150.01, 140.44, 135.82, 131.51, 128.87, 126.92, 125.61, 119.99, 119.79, 115.36, 113.56, 83.41, 57.26, 51.68, 48.64, 42.22, 39.21, 36.67, 28.23.

[0198] HRMS(DART): C 22 H 27 N 2 O 4 + [M + H] + Calculated value for 383.1970; measured value 383.1951

[0199]

Chem.

[0200] A stirred solution of compound XX (29.8 mg, 0.078 mmol) in ethanol (1 mL) and 1N KOH (1 mL) was heated at 70 °C for 3 h. When completed as determined by TLC, the mixture was cooled to room temperature and acidified to pH 5.8 with 1N HCl. The resulting solution was concentrated, and the residue was washed with cold water (3 × 1 mL) and acetone (1 mL) and then extracted with pyridine (1 mL). Evaporation of the pyridine gave lysergic acid as a brown solid in 52% yield.

[0201] 1 1H NMR 1 1H NMR (600 MHz, Pyr) δ 11.73 (s, 1H), 7.45 (s, 1H), 7.43 (d, J = 8.7 Hz, 1H), 7.31 - 7.28 (m, 1H), 7.26 (s, 1H), 4.11 - 4.04 (m, 1H), 3.63 (dd, J = 14.4, 6.0 Hz, 1H), 3.58 - 3.53 (m, 1H), 3.31 - 3.26 (m, 1H), 2.92 (q, J = 12.6 Hz, 2H), 2.52 (s, 3H).

[0202] The examples and embodiments described in this specification are for illustrative purposes only, and in light of which various modifications or changes may be suggested to those skilled in the art, and it is understood that they should be included within the spirit and scope of this application and the appended claims. All publications, patents, and patent applications cited in this specification are hereby incorporated by reference in their entirety for all purposes.

Claims

1. A method for synthesizing lysergic acid or its derivatives, including the following: Compound of formula (A) - 【Chemistry 1】 To give However, in the above formula, ProtG is a protecting group, X is a halogen, R １ ~R ６ These are independently hydrogen, hydroxyl, methoxy, halogen, or C １ -C ２０ Selected from hydrocarbil, Said C １ ~C ２０ Hydrocarbyl is either unsubstituted or substituted; The production of a cyclic compound by contacting the compound of formula (A) with a cyclizing agent; and The cyclic compound is brought into contact with an agent effective in removing the protecting group.

2. The method according to claim 1, wherein the cyclizing agent comprises tris(dibenzylidene-acetone)dipalladium(0) or bis(tri-tert-butylphosphine)palladium(0).

3. The method according to claim 1, wherein the protecting group is a tert-butyloxycarbonyl protecting group.

4. The method according to claim 1, further comprising the following: Compound of formula (B) - 【Chemistry 2】 To give; For the compound of formula (B), do the following without specifying the order: (i) Contacting with a protecting group precursor to produce protected indole nitrogen, and (ii) Contacting with a methylating agent to produce methylated pyridine nitrogen; and then, The compound of formula (B) above is brought into contact with (a) a reducing agent and / or (b) a base, in any order, to produce the compound of formula (A).

5. The reducing agent is NaBH ４ The method according to claim 4, wherein the base is lithium tetramethylpiperidide (LiTMP).

6. The method according to claim 4, further comprising: Compound of formula (a) - 【Transformation 3】 To give; To produce a Grignard reagent by contacting the compound of formula (a) with a metal-containing compound; and then, The Grignard reagent is brought into contact with the compound of formula (b), and the compound of formula (B) is obtained. 【Chemistry 4】 To generate.

7. The method according to claim 6, wherein the metal-containing compound comprises i-PrMgCl*LiCl.

8. The method according to claim 4, further comprising: Compound of formula (c) - 【Transformation 5】 To give; To produce a Grignard reagent by contacting the compound of formula (c) with a metal-containing compound; and then, The Grignard reagent is brought into contact with the compound of formula (d), and the compound of formula (B) is obtained. 【Transformation 6】 To generate.

9. The method according to any one of claims 1 to 8, further comprising generating a compound of formula (I) by deacetylation. 【Transformation 7】 In the formula, R １ to R ６ are each independently hydrogen, hydroxy, methoxy, halogen, or C １ -C ２０ hydrocarbyl, and the C １ -C ２０ hydrocarbyl is unsubstituted or substituted.

10. Compounds of formula (I) or pharmaceutically acceptable salts thereof, or formula (I') or pharmaceutically acceptable salts thereof: 【Transformation 8】 In each of the above formulas, R １ ~R ６ These are independently hydrogen, hydroxyl, methoxy, halogen, or C １ -C ２０ Selected from hydrocarbil, Said C １ ~C ２０ Hydrocarbil is either unsubstituted or substituted. R １ ~R ６ At least one of them is not hydrogen.

11. R ２ , R ３ or R ４ At least one of them is halogen, hydroxy, methoxy, or C １ -C ６ The compound according to claim 10, which is hydrocarbyl.

12. R ４ The compound according to claim 10, wherein is Cl.

13. R ５ Is hydroxyl, or R ６ The compound according to claim 10, wherein is methyl.

14. A pharmaceutical composition comprising the compound or a pharmaceutically acceptable salt described in claim 10.

15. A pharmaceutical composition for the treatment of neurodegenerative diseases, comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a compound of formula (I') or a pharmaceutically acceptable salt thereof as an active ingredient, 【Chemistry 9】 In the formula, R １ ~R ６ These are independently hydrogen, hydroxyl, methoxy, halogen, or C １ -C ２０ Selected from hydrocarbyl, the C １ -C ２０ A pharmaceutical composition in which hydrocarbil is either unsubstituted or substituted.

16. R ２ , R ３ or R ４ At least one of them is halogen, hydroxy, methoxy, or C １ ~C ６ The pharmaceutical composition according to claim 15, wherein the active ingredient is hydrocarbil.

17. R ４ The pharmaceutical composition according to claim 16, wherein is Cl.

18. R ５ The pharmaceutical composition according to claim 15, wherein is hydroxyl.

19. R ６ The pharmaceutical composition according to claim 15, wherein is methyl.

20. (i) R １ , R ２ , R ４ , R ５ and R ６ is hydrogen, R ３ Is it hydroxyl or methoxyl, or (ii) R １ , R ３ , R ４ , R ５ and R ６ is hydrogen, R ２ is methyl, The pharmaceutical composition according to claim 15.

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