Azepinoindole and method for preparing same

Abstract

The present disclosure relates to heterocyclic compounds of formula I. As contemplated herein, the heterocyclic compounds of formula I can be used to treat depression, as well as neuropsychiatric and neurodegenerative neuroinflammatory and pain disorders, including tobacco addiction, opiate addiction, cocaine addiction, alcoholism, post-traumatic stress disorder (PTSD), and neuropathic pain syndromes, including cluster headache and chemotherapy-induced peripheral neuropathy. [Formula 1] TIFF2025515146000044.tif61170

Description

[Technical field]

[0001] The present disclosure relates to heterocyclic compounds and methods for their preparation. The present disclosure also relates to the use of azepinoindoles as selective agents at serotonin receptors. [Background technology]

[0002] Psilocybin is a naturally occurring psychedelic compound produced by over 200 species of mushrooms collectively known as "psilocybin mushrooms." As a prodrug, psilocybin is rapidly metabolized in the body to produce the bioactive compound psilocin, which has mind-altering effects not very different from those produced by other hallucinogens such as lysergic acid diethylamide (LSD), mescaline, and N,N-dimethyltryptamine (DMT). These effects include, among others, euphoria, visual and mental hallucinations, altered perception, a distorted sense of time, and spiritual experiences, as well as possible adverse reactions such as nausea and panic attacks. For reference, the chemical structure of psilocin is provided in FIG. 1 herein.

[0003] 5-HT 2A and 5-HT 2C As agonists of the 5-HT receptor, psilocybin and psilocin are recognized for their therapeutic potential. 2A Activation of the receptor appears to increase locomotor activity, and 5-HT 2C Varying degrees of 5-HT receptor activation appear to decrease locomotor activity. 2A and 5-HT 2CActive compounds will exhibit varying levels of psychedelic activity (Non-Patent Document 1). Although psilocybin, along with other psychedelic drugs, was investigated by Hofmann and co-workers at Sandoz over 60 years ago (see, for example, Patent Documents 1 and 2), clinical investigation of these drugs substantially waned by the early 1970s, especially after these drugs were placed in Schedule 1 of the Controlled Substances Act in the United States. However, despite their listing as controlled substances in certain jurisdictions, research on psilocybin and other psychedelic drugs has not completely stopped, and recent clinical investigations have revived interest in the potential application of psychedelic drugs (including psilocybin) in evolving medical fields such as the treatment of central nervous system (CNS) disorders. CNS disorders include difficult-to-treat mental health disorders such as treatment-resistant or drug-resistant depression (Non-Patent Document 2), as well as neurological disorders such as cluster headaches.

[0004] Although psilocybin has been recognized for its therapeutic potential for treating certain CNS diseases and disorders, 5-HT 2B It is also recognized as a 5-HT receptor agonist and is therefore cardiotoxic. 2A Receptor agonist activity but cardiotoxic 5-HT 2B There is an unmet need for safer drugs and analogs of psilocybin and psilocin that lack agonist activity. Furthermore, at least in some instances, 5-HT 2A Receptor agonist activity but cardiotoxic 5-HT 2B There is an unmet need for safer drugs that lack agonist activity. [Prior art documents] [Patent documents]

[0005] [Patent Document 1] US 3,075,992 [Patent Document 2] US 3,078,214 [Non-patent literature]

[0006] [Non-Patent Document 1] Halberstadt AL, van der Heijden I, Ruderman MA, Risbrough VB, Gingrich JA. Geyer MA, Powell SB, Neuropsychopharmacology, 2009, 34(8):1958-67 [Non-Patent Document 2] Daniel J, Haberman M. Clinical potential of psilocybin as a treatment for mental health conditions. Ment. Health Clin. 2017, 7(1), 24-8 Summary of the Invention [Problem to be solved by the invention]

[0007] The present disclosure relates to indole compounds, in particular 5-HT 2A Receptor agonist activity, but not 5-HT 2B The compounds are from the azepinoindole class of compounds that have low receptor agonist activity. In at least some instances, such compounds are 2C 5HT than receptors 2A The compounds disclosed herein can be useful for treating depression, including major depressive disorder, drug-resistant depression and psychotic depression, addiction, including alcoholism, tobacco addiction, cocaine addiction and opioid addiction, pain symptoms, including neuropathic pain, pain from chemotherapy-related neuropathy, phantom limb pain and fibromyalgia, inflammation (including chronic and acute), eating disorders, including anorexia, autism, cluster headache, migraine, dementia, including Alzheimer's dementia, Parkinson's disease dementia and Lewy body dementia, post-traumatic stress disorder, mental distress associated with cancer, fragile X syndrome, autism spectrum disorder, bipolar disorder, obsessive-compulsive disorder, Rett syndrome and other CNS disorders. [Means for solving the problem]

[0008] According to some aspects of the present disclosure, a compound of formula I,

[0009] [ka] There are chemicals of R 1 , R 2 , R 3 , a, b, c 1 , c 2 , d 1 , d 2 , e 1 , e 2 , f 1 , f 2 , and Z are defined below.

[0010] The chemical compound of formula I is 5-HT 2A Receptor agonist, 5-HT 2B The chemical entity of formula I and its pharma- ceutical acceptable compositions are potentially useful for treating various diseases and disorders associated with 5-HT2A receptor agonism. Such diseases and disorders include those described herein.

[0011] This summary does not necessarily describe the full scope of all aspects of the present disclosure. Other aspects, features, and advantages will become apparent to those of ordinary skill in the art after reading the following description of the specific embodiments. [Brief description of the drawings]

[0012] One or more embodiments are illustrated in the accompanying drawings. [Figure 1] FIG. 1 depicts the chemical structure of psilocin. [Diagram 2] FIG. 1 depicts the chemical structure of compounds of formula I. [Diagram 3]FIG. 1 shows a graph depicting the time course of HTR per dose (mg / kg) for Compound 1 (described herein) when administered to mice. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0013] Directional terms such as "top", "bottom", "upper", "lower", "vertical", and "lateral" are used in the following description merely to provide relative reference and are not intended to imply any limitations on how any article will be placed in use or attached within an assembly or to an environment. The use of the singular when used herein in conjunction with the term "comprising" can mean "one", but is also consistent with the meanings of "one or more", "at least one", and "one or more". Any element expressed in the singular also includes its plural. Any element expressed in the plural also includes its singular. The term "plurality" as used herein means more than one, such as two or more, three or more, four or more, etc.

[0014] As used herein, and unless otherwise specified, the term "about," when used to describe a stated value, means within 10% of the stated value.

[0015] As used herein, and unless otherwise specified, the term "alkenyl" refers to a substituted or unsubstituted, linear or branched, monovalent hydrocarbon chain having at least two carbon atoms and at least one carbon-carbon (CC) double bond. Examples of alkenyl groups include allyl, vinyl, 2-propenyl, crotyl, 2-isopentenyl, 1,3-butadien-2-yl, 2,4-pentadien-1-yl, 1,4-pentadien-3-yl, and the like.

[0016] As used herein, and unless otherwise specified, the term "alkoxy" used alone or as part of a larger moiety refers to the groups -O-alkyl and -O-cycloalkyl. As used herein, and unless otherwise specified, the term "substituted alkoxy" used alone or as part of a larger moiety refers to the groups -O-(substituted alkyl) and -O-(substituted cycloalkyl).

[0017] As used herein, and unless otherwise specified, the term "alkyl" used alone or as part of a larger moiety means a substituted or unsubstituted, straight or branched, monovalent hydrocarbon chain that is fully saturated. Unless otherwise specified, an alkyl group has 1 to 7 carbon atoms ("C1-C7 alkyl"). For example, in some embodiments, an alkyl group has 1 to 6 carbon atoms ("C1-C6 alkyl"); in some embodiments, an alkyl group has 1 to 5 carbon atoms ("C1-C5 alkyl"); in some embodiments, an alkyl group has 1 to 4 carbon atoms ("C1-C4 alkyl" or "lower alkyl"); and further, in some embodiments, an alkyl group has 3 to 7 carbon atoms ("C3-C7 alkyl"). Non-limiting examples of saturated alkyl groups include methyl, ethyl, n-propyl, i-propyl, n-butyl, t-butyl, i-butyl, s-butyl, homologs and isomers of, for example, n-pentyl, n-hexyl, n-heptyl, and n-octyl. Examples of lower alkyl groups include methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, i-butyl, and t-butyl. Substituted alkyl groups are those that have at least one but not more than five substituents, and the number of substituents is equal to or less than the number of hydrogen atoms in the unsubstituted groups. In some embodiments, the substituent is a fluorine atom. Non-limiting examples of substituted alkyl groups include 2-hydroxyethyl, 2-methoxyethyl, CHF2, CF3, CH2CF3, CF2CF3, and 4-fluorobutyl.

[0018] As used herein, and unless otherwise specified, the term "alkynyl" refers to a substituted or unsubstituted, straight or branched, monovalent hydrocarbon chain having at least two carbon atoms and at least one carbon-carbon triple bond. Non-limiting examples of alkynyl groups include ethynyl, 1- and 3-propynyl, and 3-butyn-1-yl, and the like.

[0019] As used herein, and unless otherwise specified, the term "aryl" used alone or as part of a larger moiety (e.g., "(aryl)alkyl") refers to a monovalent monocyclic or bicyclic carbocyclic aromatic ring system. Unless otherwise specified, aryl groups have 6 or 10 ring members. Non-limiting examples of aryl include phenyl and naphthyl. The term "aryl" also refers to an aryl group that may be unsubstituted or substituted. For example, an aryl group can be unsubstituted or substituted with one, two, or three groups independently selected from the group including halogen, OH, C1-C6 alkoxy, substituted C1-C6 alkoxy, C1-C6 alkylthio, substituted C1-C6 alkylthio, C1-C6 alkyl, substituted C1-C6 alkyl, C3-C6 cycloalkyl, substituted C3-C6 cycloalkyl, C(O)OH, C(O)(C1-C6 alkyl), C(N-OH)(C1-C6 alkyl), C(O)(C1-C6 alkoxy), C(O)NH2, C(O)NH(C1-C6 alkyl), C(O)N(C1-C4 alkyl)(C1-C4 alkyl), C(O)-heterocyclyl, NHC(O)(C1-C6 alkyl), N(CH3)C(O)(C1-C6 alkyl), and cyano.

[0020] As used herein, and unless otherwise specified, the term "azepinoindole" refers to compounds of formula I throughout this disclosure.

[0021] As used herein, and unless otherwise specified or clear from the context, the substituent "c" is an integer from 1 to 5. 1 " or "c 2 " It refers to one of the following:

[0022] As used herein, and unless otherwise specified or clear from the context, the term "chemical entity" refers to a compound having the indicated structure, whether in its "free" form (e.g., "free compound" or "free base" or "free acid" form, as applicable, etc.) or in a salt form, particularly a pharma-ceutically acceptable salt form, and whether in a solid-state form or not. In some embodiments, the solid-state form is an amorphous (i.e., non-crystalline) form; in some embodiments, the solid-state form is a crystalline form (e.g., a polymorph, pseudohydrate, hydrate, or solvate, etc.). Similarly, the term encompasses the compound, whether or not it is provided in a solid form. Unless otherwise specified, all statements herein regarding a "compound" apply to the relevant chemical entity as defined.

[0023] As used herein, and unless otherwise specified, the terms "comprising," "having," "including," "containing," and grammatical variations thereof are inclusive or open-ended and do not exclude additional, unrecited elements and / or method steps. For example, "A includes 1, 2, and 3" means that A includes, but is not limited to, 1, 2, and 3.

[0024] As used herein, and unless otherwise specified, the term "consisting essentially of" when used herein in connection with a composition, use, or method means that additional elements, method steps, or both additional elements and method steps may be present, but that these additions do not materially affect the manner in which the described composition, method, or use functions.

[0025] As used herein, and unless otherwise specified, the term "consisting of" when used herein in relation to a composition, use, or method, excludes the presence of additional elements and / or method steps.

[0026] As used herein, and unless otherwise specified, the term "cycloalkyl" used alone or as part of a larger moiety (e.g., "(cycloalkyl)alkyl") refers to: (i) a substituted or unsubstituted monovalent monocyclic hydrocarbon group that is fully saturated or contains one or more units of unsaturation, but is not aromatic; or (ii) a bicyclo[mno]alkyl, where "m", "n", and "o" are each independently integers ranging from zero to 5, and the sum of "m" + "n" + "o" ranges from 2 to 6. In some embodiments, a cycloalkyl group has from 3 to 8 ring carbon atoms ("C3-C8 cycloalkyl"). Non-limiting examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl, and cycloheptyl, etc., as well as bicyclo[2.2.1]heptyl (also known as norbornyl) and bicyclo[1.1.1]pentyl. Substituted cycloalkyl groups are those that have at least one but not more than five substituents. In some embodiments, the substituent is a fluorine atom. Non-limiting examples of substituted cycloalkyl groups include 2-methylcyclopropyl, 4-hydroxycyclohexyl, 2-methoxycyclopentyl, and 4,4-difluorocyclohexyl.

[0027] As used herein, and unless otherwise specified or clear from the context, the substituent "d" is an integer from 1 to 5. 1 " or "d 2 " It refers to one of the following:

[0028] As used herein, and unless otherwise specified or clear from the context, the substituent "e" is an integer from 1 to 5. 1 " or "e 2 " It refers to one of the following:

[0029] As used herein, and unless otherwise specified or clear from the context, the substituent "f" is an integer from 1 to 5. 1 " or "f 2 " It refers to one of the following:

[0030] As used herein, and unless otherwise stated, the terms "halogen" or "halo" used alone or as part of a larger moiety, refer to fluoro, chloro, bromo, or iodo.

[0031] As used herein, and unless otherwise specified, the term "heteroalkyl" refers to a substituted or unsubstituted, saturated or unsaturated alkyl group, as defined herein, in which one or more of the constituent carbon atoms is replaced by nitrogen, oxygen, or sulfur.

[0032] As used herein, and unless otherwise specified, the term "heteroaryl" used alone or as part of a larger moiety, such as "(heteroaryl)alkyl", refers to a monovalent monocyclic or bicyclic group having 5 to 10 ring atoms, preferably 5, 6, 9, or 10 ring atoms, having 6 or 10 pi electrons shared in the cyclic arrangement, and further having 1 to 4 ring heteroatoms in addition to the ring carbon atoms. Examples of heteroaryl groups include thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, indolizinyl, benzofuranyl, benzothiophenyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, benzotriazolyl, quinolyl, isoquinolyl, purinyl, naphthyridinyl, and pteridinyl. Heteroaryl groups may be unsubstituted or substituted with one, two, or three groups independently selected from halogen, OH, C1-C6 alkoxy, substituted C1-C6 alkoxy, C1-C6 alkylthio, substituted C1-C6 alkylthio, C1-C6 alkyl, substituted C1-C6 alkyl, C3-C6 cycloalkyl, substituted C3-C6 cycloalkyl, C(O)OH, C(O)(C1-C6 alkoxy), C(O)NH2, C(O)NH(C1-C6 alkyl), C(O)N(C1-C4 alkyl)(C1-C4 alkyl), C(O)-heterocyclyl, NHC(O)(C1-C6 alkyl), N(CH3)C(O)(C1-C6 alkyl), and cyano.

[0033] As used herein, and unless otherwise specified, the term "heterocyclyl" used alone or as part of a larger moiety (e.g., "(heterocyclyl)alkyl") refers to a monovalent stable 4- to 7-membered monocyclic or 7- to 10-membered bicyclic heterocyclic moiety that is either saturated or partially unsaturated and has from 1 to 4 heteroatoms in addition to the ring carbon atoms. Non-limiting examples of heterocyclyl groups include tetrahydrofuranyl, pyrrolidinyl, tetrahydropyranyl, piperidinyl, and morpholinyl. Heterocyclyl groups can be unsubstituted or substituted. For example, heterocyclyl groups can be unsubstituted or substituted with one, two, or three groups independently selected from the group including halogen, OH, O(C1-C6 alkyl), O(substituted C1-C6 alkyl), C1-C6 alkyl, substituted C1-C6 alkyl, and C3-C6 cycloalkyl.

[0034] As used herein, and unless otherwise specified, the term "inactive" (and all related terms containing "inactive") means "inactive" as defined by the EC 50 When used with respect to "Eff% (nM)" and "Eff%", such terms are understood by one of ordinary skill in the art or an equivalent, and the 5-HT 2B When used in reference to activity at a receptor, concentrations greater than 10,000 nM ("EC 50 (nM)") or 30% or less efficacy (when used in reference to "Eff%").

[0035] As used herein, and unless otherwise specified, the term "isotopologue" refers to a species that differs from a specified compound only in its isotopic composition. For example, all hydrogen atoms in a compound are independently of natural isotopic composition or of heavy isotope composition. 2 H (D, deuterium) and 3 H (T, tritium) is any isotopic composition enriched or depleted in one or both isotopes, ranging from zero percent depletion to 100% enrichment.

[0036] As used herein, and unless otherwise specified, the term "pharmaceutically acceptable salt" refers to a salt that is, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic reactions, and the like, commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts of the compounds provided in the present disclosure include salts derived from suitable inorganic and organic acids and bases. Non-limiting examples of pharmaceutically acceptable salts include salts of compounds containing an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid, or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid. Other non-limiting examples of pharma- ceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexaphosphate, and the like. Other pharma- ceutically acceptable salts include salts of alkali metals, alkaline earth metals, ammonium salts, and N-type salts. + (C 1~4Representative alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further non-limiting examples of pharma-ceutically acceptable salts include non-toxic ammonium, quaternary ammonium, and amine cations formed, where appropriate, using counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkylsulfonates, and arylsulfonates.

[0037] As used herein, and unless otherwise specified, the term "subject" includes mammals (e.g., humans, in some embodiments, including prenatal human forms). In some embodiments, the subject is suffering from the relevant disease, disorder, or condition. In some embodiments, the subject is susceptible to the disease, disorder, or condition. In some embodiments, the subject exhibits one or more symptoms or characteristics of the disease, disorder, or condition. In some embodiments, the subject does not exhibit any symptoms or characteristics of the disease, disorder, or condition. In some embodiments, the subject is a mammal having one or more characteristics characteristic of susceptibility to or risk for a disease, disorder, or condition. In some embodiments, the subject is a patient. In some embodiments, the subject is an individual to whom and / or to whom a diagnosis and / or treatment is administered. In some embodiments, the subject is a fetus, an infant, a child, a teenager, an adult, or a geriatric (i.e., the subject is older, such as over 50 years of age). In some embodiments, a child refers to a human between 2 and 18 years of age. In some embodiments, an adult refers to a human aged 18 years or older.

[0038] As used herein, and unless otherwise specified, the phrase "such as" is intended to be open ended. For example, the phrase "A can be a halogen, such as chlorine or bromine" means that "A" can be, but is not limited to, chlorine or bromine.

[0039] Reference to a particular moiety, functional group, or substituent also contemplates its tautomers (if applicable).

[0040] Unless otherwise specified, structures depicted herein include all isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structure (e.g., R and S configurations for each asymmetric center, Z and E double bond isomers, and Z and E conformational isomers). Unless otherwise specified, compounds disclosed, taught, or otherwise suggested in this disclosure contemplate all single stereochemical isomers, as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures thereof. Unless otherwise specified, compounds disclosed, taught, or suggested in this disclosure contemplate all tautomeric forms thereof. In addition, unless otherwise specified, structures depicted herein include compounds that differ only in the presence of one or more isotopically enriched atoms. Such compounds may be useful, for example, as analytical tools, probes in biological assays, or as therapeutic agents. In addition, deuterium ( 2 Incorporation of heavier isotopes such as H) can offer certain therapeutic advantages resulting from greater metabolic stability, e.g., a longer in vivo half-life or reduced dosage requirements.

[0041] The chemical compounds described herein are further exemplified by the classes, subclasses, and species disclosed herein.For the purposes of this disclosure, chemical elements are identified according to the Periodic Table of the Elements, inside cover of the 75th edition of the CAS edition of "Handbook of Chemistry and Physics," and specific functional groups are generally defined as described therein.In addition, general principles of organic chemistry, as well as specific functional moieties and reactivities, are described in detail in Thomas Sorrell, Organic Chemistry, University Science Books, Sausalito, 1999; Smith and March, March's Advanced Organic Chemistry, 5th Edition, pp. 1171-1175, 2002;th Edition, John Wiley&Sons, Inc., New York, 2001; Larock, Comprehensive Organic Transformations, VCH Publishers, Inc., New York, 1989; and Carruthers, Some Modern Methods of Organic Synthesis, 3 rd Edition, Cambridge University Press, Cambridge, 1987. In this disclosure, any atom not specifically designated as a particular isotope is meant to represent any stable isotope of that atom.

[0042] Unless otherwise specified, structures depicted herein are also meant to include all stereoisomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structure; for example, R and S configurations for each asymmetric center, Z and E double bond isomers, and Z and E conformational isomers. Thus, the compounds contemplate all single stereochemical isomers, as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures thereof. Unless otherwise specified, the compounds contemplate all tautomeric forms thereof. In addition, unless otherwise specified, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. Such compounds may be useful, for example, as analytical tools, probes in biological assays, or as therapeutic agents. In addition, deuterium ( 2 Incorporation of heavier isotopes such as H) can offer certain therapeutic advantages resulting from greater metabolic stability, e.g., a longer in vivo half-life or reduced dosage requirements.

[0043] With reference to FIG. 2, and in accordance with some embodiments of the chemical entities disclosed herein (including isotopologues or pharma- ceutically acceptable salts thereof), there is a chemical entity of formula I:

[0044] [ka] R 1 is selected from the group consisting of (i) H, C1-C6 alkyl, C1-C6 substituted alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, (C3-C6 cycloalkyl)(C1-C6 alkyl), C3-C6 heterocyclyl, (C3-C6 heterocyclyl)(C1-C6 alkyl), aryl(C1-C6 alkyl), and heteroaryl(C1-C6 alkyl); or (ii) e 1 Or e 2 together form a chain of 2 to 4 carbon atoms, to which is attached a substituent independently selected from the group including H, C1-C6 alkyl, aryl, heteroaryl, and any combination thereof.

[0045] R 2are (i) C1-C6 alkyl, C1-C6 substituted alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, (C3-C6 cycloalkyl)(C1-C6 alkyl), C3-C6 heterocyclyl, (C3-C6 heterocyclyl)(C1-C6 alkyl), aryl, aryl(C1-C6 alkyl), heteroaryl, heteroaryl(C1-C6 alkyl), CN, C(O)NH2, C(O)NH(C1-C6 alkyl), C(O)N(C1-C3 or (ii) together with b, form a chain of 2 or 3 atoms, one atom of which is selected from the group consisting of C, N, O, and S, and the rest are carbon, the chain having 0, 1 or 2 double bonds, the chain containing H, halogen, OH, C1-C6 alkoxy, C1-C6 alkyl, C3-C6 alkoxy, C1-C6 alkyl, C3-C6 substituted alkyl, C1-C6 ... or (iv) when b is halogen, CH3, CHF2, CF3, OCH3, OCHF2, OCF3, SCH3, SCHF2, SCF3, or cyano, H, C1-C6 alkyl, C1-C6 substituted alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, (C ... In some embodiments, R is selected from the group including C1-C6 alkyl, C3-C6 heterocyclyl, (C3-C6 heterocyclyl)(C1-C6 alkyl), aryl, aryl(C1-C6 alkyl), heteroaryl, heteroaryl(C1-C6 alkyl), CN, C(O)NH, C(O)NH(C1-C6 alkyl), C(O)N(C1-C3 alkyl)(C1-C6 alkyl), C(=NOH)(C1-C6 alkyl), and C(=NOH)(C1-C6 substituted alkyl). 2is, with b, CH2CH2, CH2CH2CH2, CH2CH2CH2CH2, CH=CHCH=CH, OCH2CH2, CH2OCH2, CH2CH2O, OCH=CH, CH=CHO, OCH2O, SCH2CH2, CH2SCH2, CH2C H2S, SCH=CH, CH=CHS, NHCH2CH2, CH2NHCH2, CH2CH2NH, NHCH=CH, CH=CHNH, ON=CH, CH=NO, OCH=N, N=CHO, SN=CH, CH=NS, SCH=N, N=CHS, NHN= CH, CH=NNH, NHCH=N, N=CHNH, NHN=N, N=NNH, OCHCHCH, CHOCHCH, CHCHOCH, CHCHCHOCH, CHCHCHO, SCHCHCH, CHSCHCH, CHCHCHSCH, CHCHCHCHS, CHCHCHCHS, NHCHCHCH, CHNHCHCH, CHCHNCH, CHCHCHNH, N=CHCH=CH, CH=NCH=CH, CH=CHN=CH, CH=CHCH=N. In some embodiments, R 2together with b, CH2CH2, CH2CH2CH2, CH2CH2CH2CH2, CH=CHCH=CH, OCH2CH2, CH2OCH2, CH2CH2O, OCH=CH, CH=CHO, OCH2O, SCH2CH2, CH2SCH2, CH2CH2S, SCH=CH, CH=CHS, NHCH2CH2, CH2NHCH2, CH2CH2NH, NHCH=CH, CH=CHNH, ON=CH, CH=NO, OCH=N, N=CHO, SN=CH, CH=NS, SCH=N, N=CHS, NHN=CH, CH=NNH, NHCH=N, N=CHNH, NHN=N, N=NNH, OCH2CH2CH2, CH2OCH2CH2, CH2CH2OCH2, CH2CH2CH2O, SCH2CH2CH 2, CH2SCH2CH2, CH2CH2SCH2, CH2CH2CH2S, NHCH2CH2CH2, CH2NHCH2CH2, CH2CH2NCH2, CH2CH2CH2NH, N=CHCH=CH, CH=NCH=CH, CH=CHN=CH, CH=CHCH=N, where one hydrogen atom or two hydrogen atoms, if present on the moiety, are replaced by a substituent independently selected from the group including halogen, OH, C1-C6 alkoxy, C1-C6 alkyl, C3-C6 cycloalkyl, CHF2, CF3, OCHF2, OCF3, SCH3, SCF3, and cyano, or two hydrogens, if bonded to the same carbon atom, are replaced by an oxo group.

[0046] a is selected from the group consisting of (i) H, halogen, lower alkyl, CHF2, CF3, OCH3, OCHF2, OCF3, SCHF2, SCH3, SCF3, amine, and cyano, or (ii) together with Z, (A) a saturated chain of one oxygen and one carbon atom (the oxygen being attached to the 5-position of the indole ring of formula I), and (B) a chain of two or three carbon atoms to which are attached substituents independently selected from the group consisting of H, halogen, OH, C1-C6 alkoxy, C1-C6 alkyl, C3-C6 cycloalkyl, CHF2, CF3, OCHF2, OCF3, SCH3, SCHF2, SCF3, cyano, and oxo, and (C) H, halogen, OH, C1-C6 alkoxy, C1-C6 alkyl, C3-C6 cycloalkyl, or (iii) together with b form a chain of 2 or 3 carbon atoms having one double bond to which is attached a substituent independently selected from the group including C, N, O, and S, the remainder being carbon, the chain having 0, 1, or 2 double bonds to which is attached a substituent independently selected from the group including H, halogen, OH, C1-C6 alkoxy, C1-C6 alkyl, C3-C6 cycloalkyl, CHF2, CF3, OCHF2, OCF3, SCH3, SCHF2, SCF3, cyano, and oxo.

[0047] b is (i) selected from the group consisting of H, halogen, CH3, CHF2, CF3, OCH3, OCHF2, OCF3, SCH3, SCHF2, SCF3, amine, and cyano, or (ii) together with a forms a chain of 3 or 4 atoms, one atom of which is selected from the group consisting of C, N, O, and S, and the rest are carbon, the chain having 0, 1, or 2 double bonds and having attached thereto substituents independently selected from the group consisting of H, halogen, OH, C1-C6 alkoxy, C1-C6 alkyl, C3-C6 cycloalkyl, CHF2, CF3, OCHF2, OCF3, SCH3, SCHF2, SCF3, cyano, and oxo, or (iii) R2 together form a chain of 3 or 4 atoms, one atom of which is selected from the group including C, N, O, and S, and the rest are carbon, the chain having 0, 1, or 2 double bonds, and the chain having attached thereto a substituent independently selected from the group including H, halogen, OH, C1-C6 alkoxy, C1-C6 alkyl, C3-C6 cycloalkyl, CHF2, CF3, OCHF2, OCF3, SCH3, SCHF2, SCF3, cyano, and oxo.

[0048] R 3 is selected from the group consisting of (i) H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, (C3-C6 cycloalkyl)(C1-C6 alkyl), aryl(C1-C6 alkyl), acetyl, and heteroaryl(C1-C6 alkyl); or (ii) R 3 together with the N atom to which it is attached and f form an azetidine or pyrrolidine ring, such ring having substituents independently selected from the group including H, aryl, heteroaryl, C1-C6 alkyl, and C3-C6 cycloalkyl; or (iii) R 3 together with the N atom to which it is attached and d form an azetidine or pyrrolidine ring, such ring having substituents independently selected from the group including H, aryl, heteroaryl, halogen, C1-C6 alkyl, and C3-C6 cycloalkyl.

[0049] Each of c, d, e, and f is H or a lower alkyl group, or 1 and c 2 together form part of a spiro-fused cyclopropane or cyclobutane ring, and each of d, e, and f is H or a lower alkyl group, or 1 and d 2 together form part of a spiro-fused cyclopropane or cyclobutane ring, c, e, and f each being H or a lower alkyl group, or e 1 and e 2together form part of a spiro-fused cyclopropane or cyclobutane ring, and each of c, d, and f is H or a lower alkyl group, or 1 and f 2 together form part of a spiro-fused cyclopropane or cyclobutane ring, each of c, d, and e is H or a lower alkyl group, or one of c and one of d together form -CH2- or -CH2CH2-, thereby resulting in a fused cyclopropane or cyclobutane ring, and each of the remaining of c, d, e, and f is H or a lower alkyl group, or one of e and one of f together form -CH2- or -CH2CH2-, thereby resulting in a fused cyclopropane or cyclobutane ring, and each of the remaining of c, d, e, and f is H or a lower alkyl group, or one of c and one of e together form -CH2- or -CH2CH2-, thereby forming a bridged bicyclic portion. a bridged bicyclic moiety, wherein the remainder of each of c, d, e, and f is H or a lower alkyl group, or one of c and one of f together form -CH2- or -CH2CH2-, thereby forming a bridged bicyclic moiety, wherein the remainder of each of c, d, e, and f is H or a lower alkyl group, or one of d and one of e together form -CH2- or -CH2CH2-, thereby forming a bridged bicyclic moiety, wherein the remainder of each of c, d, e, and f is H or a lower alkyl group, or one of f and one of e together form -CH2- or -CH2CH2-, thereby forming a fused bicyclic moiety, wherein the remainder of each of c, d, e, and f is H or a lower alkyl group, or e is R 1 and together form a chain of 2 to 4 carbon atoms, to which is attached a substituent independently selected from the group consisting of H, C1-C6 alkyl, aryl, heteroaryl, and any combination thereof, or one of c and R 3 together form -CH- or -CHCH-, thereby resulting in a bridged bicyclic moiety, and the remainder of each of c, d, e, and f is H or a lower alkyl group, or one of d and R 3together form -CH- or -CHCH-, thereby forming a fused bicyclic moiety, and the remainder of each of c, d, e, and f is H or a lower alkyl group, or one of e and R 3 together form -CH- or -CHCH-, thereby forming a fused bicyclic moiety, and the remainder of each of c, d, e, and f is H or a lower alkyl group, or one of f and R 3 together form -CH2- or -CH2CH2-, thereby resulting in a bridged bicyclic moiety, and the remainder of each of c, d, e, and f is H or a lower alkyl group.

[0050] Z is (i) H, R 5 , (R 6 )(R 7 )NC(O)—, C1-C6 alkyl-C(O), C3-C6 cycloalkyl-C(O), aryl-C(O), and heteroaryl-C(O), where R 5 is selected from the group including C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, (C3-C6 cycloalkyl)(C1-C6 alkyl), aryl(C1-C6 alkyl), and heteroaryl(C1-C6 alkyl); R 6 and R 7 are each independently selected from the group consisting of H, C1-C4 alkyl, and C3-C6 cycloalkyl, or are joined to form a 4- to 7-membered heterocyclyl group; or (ii) (R 8 O)(R 9 O)P(O)-, where R 8 and R 9are each independently H or a cationic counterion in the form of a phosphate such as sodium, potassium, 1 / 2 magnesium, 1 / 2 calcium, ammonium, or ammonium substituted with one or more alkyl or cycloalkyl groups, or (iii) together with c form a chain resulting in a pyran or oxepane ring containing substituents independently selected from the group consisting of H, halogen, C1-C6 alkyl, and C3-C6 cycloalkyl, or (iv) together with a form a chain resulting in a pyran or oxepane ring containing substituents independently selected from the group consisting of H, halogen, C1-C6 alkyl, and C3-C6 cycloalkyl, or (A) a saturated chain of one oxygen and one carbon atom (the oxygen being attached to the 5-position of the indole ring of formula I), and (B) H, halogen, OH, (C) a chain of two or three carbon atoms having a substituent independently selected from the group including C1-C6 alkoxy, C1-C6 alkyl, C3-C6 cycloalkyl, CHF2, CF3, OCHF2, OCF3, SCH3, SCHF2, SCF3, cyano, and oxo; and (C) a chain of two or three carbon atoms having one double bond and having a substituent independently selected from the group including H, halogen, OH, C1-C6 alkoxy, C1-C6 alkyl, C3-C6 cycloalkyl, CHF2, CF3, OCHF2, OCF3, SCH3, SCHF2, SCF3, cyano, and oxo.

[0051] Example Chemical Substances Examples of chemical entities of Formula I are shown in Table 1 below.

[0052] [Table 1] TIFF2025515146000005.tif220170TIFF2025515146000006.tif222170TIFF2025515146000007.tif107170*The abbreviations used in the above table have the following meanings: Bn=benzyl; Cypr=cyclopropyl; Et=ethyl; HOBn=o-hydroxybenzyl; MeOBn-o-methoxybenzyl; MeSBn=o-(methylthio)benzyl; Ph=phenyl; Piv=pivaloyl; Pr=propyl; Z 1 =C(O)N(H)-i-Pr;Z2 =C(O)NMe2;Z 3 =P(O)(OH)2;Z 4 =P(O)(ONa)2;Z 5 =P(O)(OH)(ONa).

[0053] chemical synthesis Compounds of formula I have been prepared by two variants of the Fischer indole synthesis, examples of which are shown below.

[0054] In the first approach, a mixture of regioisomeric azepinoindoles was separated by Fischer indole synthesis involving an N-protected 4-oxoazepane and a substituted phenylhydrazine. Substituted phenylhydrazines are available, for example, from anilines by diazotization followed by reduction, for example with sodium sulfite or tin(II) salts, or from aryl halides by transition metal catalyzed amination / amidation with hydrazine hydrate (Kurandina, DV et al. Tetrahedron 2014, 70, 4043-4048) or with tert-butyl carbazate (Wolter, M.; Klapars, A.; Buchwald, SL Org. Lett. 2001, 3, 3803-3805; Jiang, L.; Lu, X.; Zhang, H.; Jiang, Y.; Ma, DJ Org. Chem. 2009, 74, 4542-4546) followed by removal of the tert-butoxycarbonyl group with acid. Recently, a variant of the Fischer indole synthesis has been described in which the aryl hydrazine is replaced by a 1-aryl-2-methylhydrazine (see below), typically giving better yields of the indole under milder reaction conditions (Schmidt. MAJ Org. Chem. 2022, 87, 1941-1960).

[0055] [ka] In another variant of the Fischer indole synthesis, alpha-branched aliphatic aldehydes react with arylhydrazines in the presence of acid to give 3,3-disubstituted 3H-indoles (indolenines) (e.g., Alfano, AI et al. React. Chem. Eng. 2020, 5, 2091-2100, etc.). For this purpose, low yields were initially obtained utilizing arylhydrazines in acetic acid as the solvent, but substitution of this building block with the corresponding 1-aryl-2-methylhydrazines led to a more efficient reaction. 1,2-Disubstituted hydrazine starting materials were accessible from aryl bromides by Pd-catalyzed amination with tert-butyl 1-methylcarbazate via common literature procedures (Mauger, C., Mignani, G. Adv. Synth. Catal. 2005, 347, 773-782; Schmidt, MAJ Org. Chem. 2022, 87, 1941-60).

[0056] In a subsequent step, further acid treatment of the 3,3-disubstituted 3H-indole resulted in its transformation to the 2,3-disubstituted 1H-indole (e.g., Rodriguez, JG; Temprano, FJ Chem. Soc., Perkin Trans. 1 1988, 3243-3247; Rodriguez, JG; Benito, Y.; Temprano, FJ Heterocyclic Chem. 1985, 22, 1207-1210; Wang, TST Tetrahedron Lett. 1975, 1637-1638, etc.). In this study, the commercially available acid-washed clay mineral montmorillonite (Kumar, BS Catal. Sci. Technol. 2014, 4, 2378-2396) was utilized as an acid at the boiling temperature of a non-polar high-boiling solvent such as bromobenzene or m-xylene. In the final step, both the benzyl and benzyloxycarbonyl protecting groups were removed by hydrogenolysis.

[0057] [ka] The following two schemes are presented as examples for different substituent patterns on the carbocyclic aromatic ring.

[0058] [ka] Azepanone building blocks bearing substituents e and / or f can be synthesized by photochemical rearrangement of N-alkylated succinimides (Kanaoka, Y.; Hatanaka, YJ Org. Chem. 1976, 41, 400-401) followed by standard functional group modification.

[0059] [ka] Substituted compounds of formula I bearing substituent f can also be obtained by spirocyclization of N-sulfonylated tryptamines with tert-butyl propargyl carbonate, followed by rearrangement of the thus obtained 3,3-disubstituted 3H-indoles to 2,3-disubstituted 1H-indoles (Montgomery, TD et al. Org. Lett. 2014, 16, 3480-3483), catalytic hydrogenation, and desulfonylation.

[0060] [ka] If the 2,5-azepanedione resulting from the photochemical rearrangement of an N-alkylsuccinimide is introduced into the Fischer indole synthesis prior to lactam reduction, the resulting indole, after protection of both nitrogen atoms, possesses an acidic methylene group adjacent to the lactam carbonyl, which can be exploited to introduce one or two substituents c by deprotonation with a strong base followed by alkylation.

[0061] [ka] The fully protected intermediates described above can also be utilized to introduce d-substituents by reduction of the lactam functionality to the hemiaminal, which is then nucleophilically alkylated with a Grignard reagent (e.g., Ong, DY et al. Angew. Chem. Int. Ed. 2020, 59, 11903-11907, etc.).

[0062] [ka] An example for the synthesis of the azabicyclic building blocks required to obtain the compounds of formula I annulated with a small ring is as follows:

[0063] [ka] Ring size analogues with 4-membered rings can be obtained in the same manner from the anhydride of cyclobutane-1,2-dicarboxylic acid. In addition, carbonyl rearrangement applied to the above ketones (e.g., Nakai, T.; Mimura, T. Tetrahedron Lett. 1979, 531-534; review: Nakai, T.; Mimura, TJ Synth. Org. Chem. Jpn. 1977, 35, 964-978; recent work: Wu, Z. et al. Science 2021, 374, 734-740, etc.) provides ketone precursors to compounds of formula I with small rings at the positions with substituents c and d.

[0064] [ka] The synthesis of 3-benzyl-3-azabicyclo[3.2.1]octan-6-one and 3-benzyl-3-azabicyclo[3.2.2]nonan-6-one is disclosed in US2005020830 by Allen, MP et al. These azabicyclo building blocks are intermediates in the synthesis of compounds of structure I in which substituents c and e are linked to form a bridge spanning the seven-membered ring.

[0065] [ka] The synthesis of 6-benzyl-6-azabicyclo[3.2.1]octane-2,7-dione is disclosed in Diaba, F. et al. Org. Lett. 2015, 17, 3860-3863. This compound can be used to synthesize compounds of structure I as shown below.

[0066] [ka] The synthesis of 3-(4-methoxyphenyl)-7-picolyl-7-azabicyclo[4.1.1]octane is disclosed in Zhao, J. et al. Org. Lett. 2017, 19, 4880-4883. Further transformations shown below provide azabicyclic ketones that can be used in the synthesis of compounds of structure I.

[0067] [ka] EXAMPLES

[0068] 7-Methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-10-ol Step 1: 4-(benzyloxy)-2-bromo-1-methylbenzene

[0069] [ka] A 500 mL three-neck flask equipped with a stir bar, septum, dropping funnel with septum, Ar balloon, and ice bath was charged with a suspension of NaH (60% in oil; 3.53 g, 88.2 mmol, 1.1 equiv) in anhydrous DMF (20 mL). To this suspension, a solution of 3-bromo-4-methylphenol (15.0 g, 80.2 mmol) in anhydrous DMF (60 mL) was added dropwise with stirring and cooling for 15 min to give an amber phenoxide suspension. The mixture was stirred in an ice bath for 15 min and stirred without cooling for an additional 15 min. After the mixture was recooled in an ice bath, BnBr (neat; 10.5 mL, 88.2 mmol, 1.1 equiv) was added dropwise for 35 min. The mixture was stirred without temperature control for 2 h, and then water (1 mL) was carefully added. The solvent was distilled under oil pump vacuum with gentle warming into a receiver cooled with dry ice. The residue was taken up in heptane (30 mL) and suction filtered over Celite from inorganic salts. The filter residue was washed with more heptane (2×20 mL) and the filtrate was evaporated. The evaporation residue was filtered over silica gel (11×7 cm, eluted first with hexane, then with EtOAc / hexane 1:19). Impure late fractions were collected separately, evaporated and subjected again to column chromatography (silica gel, 16×5.5 cm, hexane, then with EtOAc / hexane 1:49). Again, a small amount of impure late fraction was discarded. Essentially pure fractions from both columns were pooled and evaporated to give 20.8 g (94%) of the benzyl ether as a nearly colorless oil. 1H NMR(CDCl3,TMS)δ7.43-7.36(m,4H), 7.35-7.30(m,1H), 7.19(d,1H,J=2.6Hz), 7. 12(dd,1H,J=8.4,0.2Hz), 6.84(dd,1H,J=8.4,2.6Hz), 5.02(s,2H), 2.32(s,3H).

[0070] Step 2: tert-Butyl 2-[5-(benzyloxy)-2-methylphenyl]-1-methylhydrazine-1-carboxylate

[0071] [ka] A 100 mL three-neck flask equipped with a stir bar, glass stopper, septum, reflux condenser with Ar balloon, and heating mantle was charged with a suspension of NaH (60% in oil; 0.54 g, 13.6 mmol, 1.4 equiv) in toluene (4 mL). The suspension was gently warmed and 3-methyl-3-pentanol (2.15 mL, 17.5 mmol, 1.8 equiv) was added in small portions over 20 min to induce hydrogen evolution. After an additional 10 min, a clear brownish solution was obtained, which was allowed to cool to approximately room temperature. tert-Butyl 1-methylhydrazine-1-carboxylate (neat; 1.44 mL, 9.7 mmol) and 4-(benzyloxy)-2-bromo-1-methylbenzene (neat plus 0.5 mL toluene rinse; 2.69 g, 9.71 mmol) were added.

[0072] Meanwhile, a solution of X-Phos (186 mg, 0.39 mmol, 40 mequiv) in toluene (4 mL) was deoxygenated in another three-neck flask by evacuating three times and then backfilling with argon each time. To this solution was added palladium acetate (44 mg, 195 μmol, 20 mequiv) through a temporarily opened side neck. The mixture was stirred at room temperature for 25 minutes to give a dark brownish red catalyst solution, which was added by syringe to the above reaction mixture as the last component. The resulting dark amber mixture was heated to reflux for 8 hours. A precipitate began to form rapidly. After cooling, a thin layer chromatogram showed a major spot (silica gel, EtOAc / hexane 1:9 and 1:4: Rf approx. 0.2 and 0.5, respectively) along with some weak non-polar spots and a colored baseline material. Ethyl acetate / hexane 1:1 (60 mL) and water (50 mL) were added, the phases were separated, and the aqueous phase was extracted with ethyl acetate / hexane 1:1 (20 mL). The combined organic phases were concentrated, and m-xylene (10 mL) was added to the residue. The mixture was evaporated again to entrain the tertiary alcohol, resulting in a brown oil. This material was adsorbed onto silica gel (12 g) and chromatographed on silica gel (16 x 5.5 cm, EtOAc / hexane 1:8). Evaporation of the appropriate fractions afforded the aminated product as a tan solid (2.33 g, 70%). 1H NMR(CDCl3,TMS)δ7.44-7.40(m,2H), 7.39-7.35(m,2H), 7.31(m,1H), 6.95(dd,1H,J=8.2,0.4Hz), 6.42(dd,1 H,J=8.2,2.5Hz), 6.35(d,1H,J=2.5Hz), 5.90(br,1H), 5.01(s,2H), 3.19(s,3H), 2.11(s,3H), 1.39(br,9H).

[0073] Step 3: 1-[5-(benzyloxy)-2-methylphenyl]-2-methylhydrazine hydrochloride

[0074] [ka] In a 150 mL round bottom flask equipped with a stir bar, septum, and Ar balloon (connected via needle; to exclude moisture), the starting material (2.33 g, 6.80 mmol) was dissolved in a mixture of MeOH and CH2Cl2 (5 mL each). Neat chlorotrimethylsilane (1.30 mL, 10.2 mmol, 1.5 equiv) was added in small portions over 40 min with ice cooling. After stirring for an additional 20 min in the ice bath, the mixture consisted of a brown solution with suspended light colored solids. Stirring was continued at room temperature and the precipitate initially dissolved but eventually reappeared. The reaction was followed by TLC on silica gel after aqueous workup (1 M aqueous NaHCO3 / tert-BuOMe) with a small aliquot. Using tert-BuOMe / hexane 1:2 as the mobile phase, the starting material had an R of approximately 0.55. f The reaction mixture was stirred for 5 hours at 4° C. for 1 hour, giving a product free base of about 0.15. After 5.2 hours, toluene (10 mL) was added and the more volatile solvents were removed by partial evaporation, leaving the product as a suspension in toluene. The product was suction filtered, washed with a small amount of toluene, and dried under vacuum to give 1.54 g (81%) of a slightly pinkish powder. 1 H NMR (DMSO-d6, TMS) δ11.11(br s,2H), 7.83(br s,1H), 7.47-7.43(m,2H), 7.42-7.37(m,2H), 7.33(m,1H), 7.04(d,1H,J=8.5Hz), 6.87 (d,2H,J=2.3Hz), 6.58(dd,1H,J=8.3,2.4Hz), 5.08(s,2H), 2.84(s,3H), 2.11(s,3H).

[0075] Step 4: Benzyl 4-(benzyloxy)-7-methylspiro[indole-3,4'-piperidine]-1'-carboxylate

[0076] [ka] In a 100 mL round bottom flask with a stir bar and Ar balloon, a mixture of 1-[5-(benzyloxy)-2-methylphenyl]-2-methylhydrazine hydrochloride (522 mg, 1.87 mmol), N-Cbz-piperidine-4-carboxaldehyde (463 mg, 1.87 mmol), acetic acid (5 mL), and anhydrous NaOAc (161 mg, 1.96 mmol, 1.05 equiv) was stirred in an oil bath at 60° C. for 4.2 h. After cooling, thin layer chromatograms after aqueous workup (2 M aqueous Na2CO3 / EtOAc) of a small aliquot showed, in addition to baseline material, a single mobile spot (SiO2, EtOAc / hexane 1:1 and 65:35:R, respectively). f The solvent was mostly distilled under vacuum and to the residue was added 1M aqueous NaHCO3 solution and EtOAc (30 mL each). The phases were separated and the aqueous phase was further extracted with EtOAc (15 mL). The combined organic phases were dried over Na2SO4 and evaporated. The residue was quickly filtered over a silica gel column (12 x 2.5 cm, EtOAc / Hexane 2:1). Evaporation of the appropriate fractions gave 507 mg (61%) of an amber glass. 1 H NMR(CDCl3,TMS)δ8.52(s,1H), 7.38-7.33(m,8H), 7.33-7.27(m,2H), 7.07(dd,1H,J=8.4,0.7Hz), 6.72(d,1H,J=8.4Hz), 5.18(br,1H), 5.12(br s,3H), 4.38(br,1H), 4.31(br,1H), 3.22(br,2H), 2.64(br,2H), 2.51(s,3H), 1.41(br,2H). 13 C NMR (CDCl3, TMS) δ 174.42, 155.42, 153.76, 152.85, 136.98, 136.71, 130.30, 128.79, 128.66 (2C), 128.51 (2C), 128.03, 127.92 (2C), 127.84, 126.83 (2C), 123.63, 110.41, 69.77, 67.24, 57.29, 42.77, 28.31 (broadened), 16.01; one aromatic C and one aliphatic C not observed.

[0077] Step 5: Benzyl 10-(benzyloxy)-7-methyl-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate

[0078] [ka] In a 50 mL round bottom flask with reflux condenser / Ar balloon, stir bar, and heating mantle, a mixture of benzyl 4-(benzyloxy)-7-methylspiro[indole-3,4'-piperidine]-1'-carboxylate (507 mg, 1.15 mmol), montmorillonite KSF clay (1.20 g), and bromobenzene (5 mL) was stirred at reflux for 26.5 min, resulting in a dark colored clay. After cooling, a thin layer chromatogram showed a single well-defined spot (silica gel, EtOAc / hexane 1:1, R f The yield was approximately 0.65). The mixture was suction filtered over Celite and the filter residue was washed with CHCl (3×20 mL). The solution was partially evaporated to remove CHCl and the residual bromobenzene solution was chromatographed on silica gel (22×3.5 cm, EtOAc / hexane, first 1:19 to remove bromobenzene, then 1:2). Evaporation of the appropriate eluted fractions gave 369 mg (73%) of a tan solid. 1H NMR (CDCl3, TMS; M = major, mi = minor urethane rotamer; ratio approx. 11:9) δ 7.68 (br, 1H, M), 7.62 (br, 1H, mi), 7.47-7.43 (m, 2H, M + mi), 7.41-7.28 (m, 8H, M + mi), 6.79 (d, 1H, J, mi too much overlap with below to read), 6.78 (d, 1H, J = 7.8 Hz, M), 6.46 ( d,1H,J=7.6Hz,mi), 6.45(d,1H,J=7.7Hz,M), 5.18(s,2H,M+mi), 5.14(s,2H,M), 5.13(s,2H,mi), 3.76(m,2 H,mi), 3.70(m,2H,M), 3.42(m,2H,mi), 3.37(m,2H,M), 3.03(m,2H,M), 2.97(m,2H,mi), 2.36(s,3H,M+mi).

[0079] Step 6: 7-Methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-10-ol

[0080] [ka] Pharmacology Serotonin receptor 5-HT2 functional assay Non-limiting examples of methods for measuring functional activation of serotonin receptors are described below.

[0081] To measure functional activation of serotonin receptors, either Gq dissociation or Gq-dependent calcium flux by bioluminescence resonance energy transfer (BRET) was performed for selected compounds. To measure 5-HT2 receptor-mediated Gq activation via Gq / γ1 dissociation measured by BRET (McCorvy JD, Wacker D, Wang S, Agegnehu B, Liu J, Lansu K, Tribo AR, Olsen RHJ, Che T, Jin J, Roth BL. Structural determinants of 5-HT2B receptor activation and biased agonism. Nat Struct Mol Biol. 2018; 25(9):787-96), HEK293T cells were subcultured in Dulbecco's modified Eagle's medium (DMEM) supplemented with 10% dialyzed fetal bovine serum (FBS) and further transfected with TransiT-2020 to express RLuc8-fused human Gαq (Gαq-RLuc8), a GFP-GFP-GFP fused to the C-terminus of human Gγ1. 2 (Gγ1-GFP 2 ), human Gβ1, and 5-HT2 receptors were co-transfected at a ratio of 1:1:1:1. After at least 18-24 hours, the transfected cells were plated in polylysine-coated 96-well white clear-bottom cell culture plates in DMEM containing 1% dialyzed FBS at a density of 25,000-40,000 cells in 200 μL per well and incubated overnight. The next day, the medium was decanted and the cells were washed with 60 μL of drug buffer (1×HBSS, 20 mM HEPES, pH 7.4), and then 60 μL of drug buffer was added per well. The cells were preincubated at 37°C in a humidified atmosphere before being subjected to drug stimulation. Drug stimulation utilized the addition of 30 μL of drug (3X) diluted in McCorvy buffer (1X HBSS, 20 mM HEPES, pH 7.4, 0.3% BSA fatty acid free, supplemented with 0.03% ascorbic acid) and plates were incubated for 1 hour at 37°C. Substrate addition was performed 15 minutes prior to reading to allow for Gq dissociation BRET. 210 μL of the RLuc substrate coelenterazine 400a was used for (Prolume / Nanolight, 5 μM final concentration). Using a Mithras LB940 (multimode microplate reader, such as those provided by Berthold), plates were read at 1 sec per well for emission at 400 nm and fluorescence GFP at 510 nm. 2 The wells were read for emission. BrEt ratios of fluorescence / luminescence were calculated per well and plotted as a function of drug concentration using Graphpad Prism 8 (Graphpad Software Inc., San Diego, CA). Data were normalized to % 5-HT stimulation and analyzed using nonlinear regression "log(agonist) vs response" and E max and E.C. 50 Parameter estimates were obtained.

[0082] Calcium flux was measured using a stable expression 5-HT2Flp-In 293 T-Rex tetracycline-inducible system by methods known in the art (e.g., Investigation of the Structure-Activity Relationships of Psilocybin Analogues, ACS Pharmacol. Transl. Sci. 2020, Publication Date: December 14, 2020, https: / / doi.org / 10.1021 / acsptsci.0c00176, etc.). Cell lines were maintained in DMEM containing 10% FBS, 10 μg / mL blasticidin, and 100 μg / mL hygromycin B. At least 20-24 hours prior to the assay, receptor expression was induced with tetracycline (2 μg / mL) and cells were seeded at a density of 7,500 cells / well in 1% dialyzed FBS-containing DMEM in 384-well poly-L-lysine-coated black plates. On the day of the assay, cells were incubated for 1 hour at 37° C. with Fluo-4 Direct dye (Invitrogen, 20 μL / well) reconstituted in drug buffer (20 mM HEPES-buffered HBSS, pH 7.4) containing 2.5 mM probenecid. Drug dilutions were prepared to 5× final concentration in McCorvy buffer (20 mM HEPES-buffered HBSS, 0.1% BSA, 0.01% ascorbic acid, pH 7.4). After dye loading, cells were allowed to equilibrate to room temperature for 15 minutes and then incubated for 1 hour at 37° C. for 1 hour at 37° C. for 1 hour at 37° C. Drug dilutions were prepared to 5× final concentration in McCorvy buffer (20 mM HEPES-buffered HBSS, 0.1% BSA, 0.01% ascorbic acid, pH 7.4). After dye loading, cells were allowed to equilibrate to room temperature for 15 minutes and then incubated for 1 hour at 37° C. for 1 hour at 37° C. TETRA The plates were then placed in a fluorescent imaging plate reader (Molecular Devices). TETRAThe ELISA kit was programmed to read baseline fluorescence for 10 seconds (1 reading / second), after which 5 μL of drug was added per well and fluorescence was read for a total of 5-10 minutes (1 reading / second). Fluorescence in each well was normalized to the average of the first 10 readings relative to baseline fluorescence, and then either the maximum fold peak increase above baseline or the area under the curve (AUC) was calculated. Either the peak or AUC was plotted as a function of drug concentration, and the data was normalized to percent 5-HT stimulation. Data was plotted and nonlinear regression was performed in Graphpad Prism 8 using "log(agonist) vs response" to determine E max and E.C. 50 Parameter estimates were obtained.

[0083] The functional activity of various compounds disclosed herein at each of the 5-HT2A, 5-HT2B, and 5-HT2C receptors was measured against and compared to the functional activity of 4-hydroxytryptamine at those receptors. A comparison of the functional activities is provided in Table 2 below.

[0084] [Table 2] TIFF2025515146000027.tif205170TIFF2025515146000028.tif248170Table 3 below summarizes the 5-HT receptor activity of psilocin and Compound #1 (also known as Pharm-136).

[0085] [Table 3] Compounds of formula 1 are generally known to have the potential for "hERG risk". As a result, many of the compounds disclosed in Tables 1 and 2 were screened for possible "hERG risk" using pharmacological assays (e.g., Eurofins™ hERG Qube APC Assay, etc.). 5-HT 2ACompounds that showed strong efficacy at the receptor were compared for exposure / IC 50 We further evaluated the “hERG risk” based on a hERG IC that was 30-fold greater than the therapeutic free plasma concentration. 50 The value is the threshold for considering a compound to be of low "hERG risk."

[0086] An important factor for hERG risk assessment in the early drug discovery stage is the hERG IC 50 / in vitro5-HT 2A ratio; compounds exhibiting a ratio of greater than 200 have an estimated therapeutic plasma C of greater than 30 max hERG IC for 50 (which generally indicate low hERG risk potential at clinically relevant dose levels); compounds exhibiting ratios between 150 and 200 generally indicate moderate hERG risk potential; compounds exhibiting IC 50 (hERG) / EC 50 (5-HT 2A ) ratio generally indicates high hERG risk potential.

[0087] The Ames fluctuation data for Compound 1 is reported in Table 4.

[0088] [Table 4] TIFF2025515146000031.tif129170 Various compounds disclosed herein were subjected to in vitro SafeScreen44™ panel to identify off-target activity. Compounds of interest identified in the panel are then tested in follow-up functional assays to identify whether such compounds have significant off-target risk. As summarized in Table 5 below, compound 1 has no significant off-target activity. Other compounds are expected to share similar characteristics with compound 1 and have no off-target activity.

[0089] [Table 5] Further experiments were performed on Compounds 1, W5, and A93. Tables 6a, 6b, and 6c, among others, further summarize the predicted hepatic clearance of Compounds 1, W5, and A93 in various species, respectively, as determined by calculating the in vitro hepatocyte clearance over time and scaling such rate by the hepatocyte number of such species and the predicted hepatic blood flow rate in such species, as specified in Tables 6a, 6b, and 6c.

[0090] [Table 6a]

[0091] [Table 6b]

[0092] [Table 6c] Tables 7a and 7b summarize, among other things, the plasma PK profiles observed in animals for Compound 1.

[0093] [Table 7a]

[0094] [Table 7b] Head Twitch Response (HTR) was assessed using a head-mounted neodymium magnet and magnetometer detection coil as described in Halberstadt et al., Psychopharmacology (Berl.), 2013, 227(4): 727-739. Table 8 below shows the ED100 / ED200 in mice head twitching as a result of Compound 1 compared to psilocybin. 50 (measured at 60-minute intervals) are summarized.

[0095] [Table 8] Figure 3 illustrates the HTR versus dose of Compound 1. Throughout Figure 3, the HTR over time per different doses of Compound 1 (measured in mg / kg) is shown.

[0096] How to use The indole compounds described herein are believed to be useful for the treatment of medication-resistant depression based on several clinical trials that have been reported using psilocybin itself.

[0097] The US STAR*D study reported that more than half of all patients recruited through primary care and psychiatric clinics failed to achieve remission after first-line antidepressant treatment, and one-third failed to experience remission after four courses of acute treatment (Rush AJ, Trivedi MH, Wisniewski SR, Nierenberg AA, Stewart JW, Warden D, et al. Acute and longer-term outcomes in depressed outpatients requiring one or several treatment steps: a STAR*D report. Am. J. Psychiatry 2006; 163:1905-17).

[0098] In addition to the possible use of these analogs in the treatment of depression, other studies with independent groups of human volunteers have demonstrated that psilocybin can be used to treat tobacco and alcohol dependence. Furthermore, in a controlled clinical setting, psilocybin has been safely administered to subjects with OCD, and this medication has been shown to lead to acute relief of core OCD symptoms in some subjects (Moreno, FA, Wiegand, CB, Taitano, EK, and Delgado, PL "Safety, tolerability, and efficacy of psilocybin in 9 patients with obsessive-compulsive disorder" J. Clin. Psychiatry 2006, 67, 1735-1740).

[0099] Another potential use of these analogs is in the treatment of seizure disorders, including but not limited to infantile seizure disorders such as Dravet Syndrome (Sourbon, J. et al. "Serotonergic Modulation as Effective Treatment for Dravet Syndrome in a Zebrafish Mutant Model", ACS Chem. Neurosci. 2016, 7, 588-598).

[0100] The indole compounds described herein inhibit 5-HT 2B Given that it lacks at least some of the undesirable characteristics of agonist-associated activity, it is considered safer than psilocybin.

[0101] Method of administration As contemplated herein, a therapeutically effective amount of the indole compound described herein is administered to the subject in need thereof.Whether or not such treatment is required depends on the subject's case, and is further subjected to medical evaluation (diagnosis), which takes into account the signs, symptoms, and / or dysfunctions present, the risk of developing certain signs, symptoms, and / or dysfunctions, and other factors.

[0102] As contemplated herein, the indole compounds described herein may be administered by any suitable route known in the art. Such routes include, but are not limited to, oral, buccal, inhalation, topical, sublingual, rectal, vaginal, intracapsular or intrathecal via lumbar puncture, urethral, ​​nasal, percutaneous, transdermal, and parenteral administration (including intravenous, intramuscular, subcutaneous, intracoronary, intradermal, intramammary, intraperitoneal, intraarticular, intrathecal, retrobulbar, intrapulmonary injection, and / or surgical implantation at a specific site). Parenteral administration may be achieved using a needle and syringe or using high pressure techniques.

[0103] Pharmaceutical compositions include those in which the indole compounds described herein are present in an amount sufficient to be administered in an effective amount to achieve its intended purpose. The exact formulation, route of administration, and dosage will be determined by a qualified medical practitioner in consideration of the diagnosed condition or disease. Dosage amount and interval can be individually adjusted to provide a level of the indole compounds described herein sufficient to maintain the desired therapeutic effect. It is possible that the indole compounds described herein may only require infrequent administration (e.g., monthly as opposed to daily) to achieve the desired therapeutic effect.

[0104] As contemplated herein, the therapeutically effective amount of the indole compound described herein adapted for use in treatment varies according to the nature of the condition being treated, the length of time activity is desired, and the age and condition of the patient, and is ultimately determined by the attending physician. The dosage and administration interval can be individually adjusted to provide a plasma level of the indole compound sufficient to maintain the desired therapeutic effect. The desired dosage can be conveniently administered in a single dose or as multiple doses administered at appropriate intervals, for example, as one, two, three, four or more partial doses per day. Multiple administration is often desirable or required. For example, the indole compounds described herein may be administered at the following frequencies: 4 doses delivered as a single daily dose 4 days apart (q4d×4); 4 doses delivered as a single daily dose 3 days apart (q3d×4); 1 dose delivered per day 5 days apart (qd×5); 1 dose per week for 3 weeks (qwk3); 5 doses per day with 2 days of rest and then another 5 doses per day (5 / 2 / 5); or any dosing regimen determined to be appropriate for the circumstances.

[0105] As contemplated herein, the indole compounds described herein may be administered in admixture with a pharmaceutical carrier selected with respect to the intended route of administration and standard pharmaceutical practice. Pharmaceutical compositions for use in accordance with the indole compounds described herein are formulated in a conventional manner using one or more physiologically acceptable carriers, including excipients and adjuvants that facilitate processing of the compounds described herein.

[0106] When the indole compound described herein is administered intravenously, water is the preferred carrier.Saline and aqueous dextrose and glycerol solutions may also be used as liquid carriers, particularly for injectable solutions.Suitable pharmaceutical carriers also include excipients such as starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene glycol, water and ethanol.The composition can also contain a small amount of wetting or emulsifying agent or pH buffering agent if desired.

[0107] These pharmaceutical compositions can be prepared, for example, by conventional mixing, dissolving, granulating, dragee-making, emulsifying, encapsulating, encapsulating, or lyophilizing processes. The appropriate formulation depends on the route of administration chosen. When a therapeutically effective amount of the indole compound described herein is administered orally, the composition is typically in the form of a tablet, capsule, powder, liquid, or elixir. When administered in tablet form, the composition can further contain a solid carrier such as gelatin or an adjuvant. The tablets, capsules, and powders contain about 0.01% to about 95%, preferably about 1% to about 50%, of the indole compound described herein. When administered in liquid form, a liquid carrier such as water, petroleum, or oil of animal or vegetable origin can be added. The liquid form composition can further contain saline, dextrose or other sugar solution, or glycol. When administered in liquid form, the composition contains about 0.1 to about 90% by weight, preferably about 1 to about 50% by weight of the compound described herein.

[0108] When a therapeutically effective amount of the indole compounds described herein is administered by intravenous, cutaneous, or subcutaneous injection, the composition is in the form of a pyrogen-free, parenterally acceptable aqueous solution. Preparation of such parenterally acceptable solutions, taking into due consideration pH, isotonicity, stability, and the like, is within the skill of the art. Preferred compositions for intravenous, cutaneous, or subcutaneous injection typically contain an isotonic vehicle. The indole compounds described herein may be infused with other fluids over a period of 10 to 30 minutes or over a period of several hours.

[0109] The indole compounds described herein may be readily combined with pharma- ceutically acceptable carriers well known in the art that enable the active agents to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions, and the like, for oral ingestion by a patient to be treated.

[0110] Pharmaceutical preparations for oral use can be obtained by adding the indole compounds described herein to solid excipients, milling or not milling the resulting mixture, and then processing the mixture of granules, if desired, after adding suitable auxiliary agents, to obtain tablets or dragee cores.Suitable excipients include, for example, fillers and cellulose preparations.Disintegrants can be added if desired.

[0111] The indole compounds described herein may be formulated for parenteral administration by injection, e.g., by bolus injection or continuous infusion. The formulations for injection may be provided in unit dosage form, e.g., in ampoules or multi-dose containers, with added preservatives. The compositions may take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles, and may contain formulatory agents, such as suspending, stabilizing, and / or dispersing agents.

[0112] Pharmaceutical compositions for parenteral administration include aqueous solutions of the active agent in water-soluble form.In addition, the suspension of the indole compound described herein can be prepared as a suitable oily injection suspension.Suitable lipophilic solvents or vehicles include fatty oils or synthetic fatty acid esters.Aqueous injection suspensions can contain substances that increase the viscosity of the suspension.

[0113] In some embodiments, the suspension may also contain suitable stabilizers or agents which increase the solubility of the compounds and allow for the preparation of highly concentrated solutions. Alternatively, the composition may be in powder form for constitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use.

[0114] The indole compounds described herein may also be formulated into rectal compositions, such as suppositories or retention enemas, for example, containing conventional suppository bases.In addition to the formulations described above, the indole compounds described herein may also be formulated as depot preparations.Such long-acting formulations can be administered by implantation (e.g., subcutaneous or intramuscular) or by intramuscular injection.Thus, for example, the indole compounds described herein may be formulated with suitable polymeric or hydrophobic materials (e.g., as an emulsion in an acceptable oil) or ion exchange resins.

[0115] The indole compounds described herein may be administered orally, bucally, or sublingually in the form of tablets containing excipients such as starch or lactose, or in capsules or ovules, either alone or in admixture with excipients, or in the form of elixirs or suspensions containing flavorings or colorings. Such liquid preparations can be prepared with pharma- ceutically acceptable additives, such as suspensions. The indole compounds described herein may also be injected parenterally, for example, intravenously, intramuscularly, subcutaneously, or intracoronarily. For parenteral administration, the indole compounds described herein are best used in the form of a sterile aqueous solution that may contain other substances, such as salts or monosaccharides, such as mannitol or glucose, to make the solution isotonic with blood. In at least some embodiments, the indole compounds described herein are psilocybin analogs.

[0116] General Notes: It is contemplated that any portion of any aspect or embodiment discussed herein may be implemented or combined with any portion of any other aspect or embodiment discussed herein. Although specific embodiments are described above, it should be understood that other embodiments are possible and are intended to be included herein. Although not shown, modifications and adjustments of the above-described embodiments are possible that will be apparent to those skilled in the art.

[0117] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. In addition, the citation of any reference herein should not be construed or considered as an admission that such reference is prior art to the present invention.

[0118] The scope of the claims should not be limited by the example embodiments described herein, but should be accorded the broadest interpretation consistent with the entire description.

Claims

1. A compound of formula I or any isotope or pharma- ceutically acceptable salt thereof, 【Chemistry 1】 In the formula, R １ (i) H, C １ ~C ６ Alkyl, C １ ~C ６ Substituted alkyl, C ２ ~C ６ Alkenyl, C ２ ~C ６ Alkynyl, C ３ ~C ６ Cycloalkyl, (C ３ ~C ６ Cycloalkyl) (C １ ~C ６ Alkyl), C ３ ~C ６ Heterocyclyl, (C ３ ~C ６ Heterocyclyl) (C １ ~C ６ Alkyl), aryl (C １ ~C ６ alkyl), and heteroaryl (C １ ~C ６ (ii) selected from the group including e １ Or e ２ and forming a chain of 2 to 4 carbon atoms, the chain of 2 to 4 carbon atoms including H, C １ ~C ６ attached to a substituent independently selected from the group consisting of alkyl, aryl, heteroaryl, and any combination thereof; R ２ (i) C １ ~C ６ Alkyl, C １ ~C ６ Substituted alkyl, C ２ ~C ６ Alkenyl, C ２ ~C ６ Alkynyl, C ３ ~C ６ Cycloalkyl, (C ３ ~C ６ Cycloalkyl) (C １ ~C ６ Alkyl), C ３ ~C ６ Heterocyclyl, (C ３ ~C ６ Heterocyclyl) (C １ ~C ６ Alkyl), aryl, aryl(C １ ~C ６ Alkyl), Heteroaryl, Heteroaryl (C １ ~C ６ alkyl), CN, C(O)NH ２ , C(O)NH(C １ ~C ６ alkyl), C(O)N(C １ ~C ３ Alkyl) (C １ ~C ６ alkyl), C(=NOH)(C １ ~C ６ alkyl) and C(=NOH)(C １ ~C ６ or (ii) together with b, form a chain of 2 or 3 atoms, one atom of which is selected from the group consisting of C, N, O, and S, and the rest are carbon, said chain having 0, 1 or 2 double bonds, and the chain does not include any of H, halogen, OH, C, H, N, O, S, N, O, H ... １ ~C ６ Alkoxy, C １ ~C ６ Alkyl, C ３ ~C ６ Cycloalkyl, CHF ２ , C.F. ３ , O.C.H.F. ２ , O.C.F. ３ , S.C.H. ３ , SCF ３ (iv) b is bonded to a substituent independently selected from the group consisting of halogen, CH ３ , C.H.F. ２ , C.F. ３ , O.C.H. ３ , O.C.H.F. ２ , O.C.F. ３ , S.C.H. ３ , S.C.H.F. ２ , SCF ３ or cyano, H, C １ ~C ６ Alkyl, C １ ~C ６ Substituted alkyl, C ２ -C ６ Alkenyl, C ２ ~C ６ Alkynyl, C ３ ~C ６ Cycloalkyl, (C ３ ~C ６ Cycloalkyl) (C １ ~C ６ Alkyl), C ３ ~C ６ Heterocyclyl, (C ３ ~C ６ Heterocyclyl) (C １ ~C ６ Alkyl), aryl, aryl(C １ ~C ６ Alkyl), Heteroaryl, Heteroaryl (C １ ~C ６ alkyl), CN, C(O)NH ２ , C(O)NH(C １ ~C ６ alkyl), C(O)N(C １ -C ３ Alkyl) (C １ ~C ６ alkyl), C(=NOH)(C １ ~C ６ alkyl), and C(=NOH)(C １ ~C ６ substituted alkyl), and in some embodiments, R ２ together with b, CH ２ CH ２ CH ２ CH ２ CH ２ CH ２ CH ２ CH ２ CH ２ 、CH=CHCH=CH、OCH ２ CH ２ CH ２ SO ２ CH ２ CH ２ O、OCH=CH、CH=CHO、OCH ２ O, SCH ２ CH ２ CH ２ P.S. ２ CH ２ CH ２ S、SCH=CH、CH=CHS、NHCH ２ CH ２ CH ２ P.O. ２ CH ２ CH ２ I'm sorry, I'm sorry, I'm sorry, I'm sorry, I'm sorry, I'm sorry, I'm sorry, I'm sorry, I'm sorry I'm sorry, I'm sorry, I'm sorry, I'm sorry, I'm sorry, I'm sorry, I'm sorry ２ CH ２ CH ２ CH ２ SO ２ CH ２ CH ２ CH ２ SO ２ CH ２ CH ２ CH ２ O, SCH ２ CH ２ CH ２ CH ２ P.S. ２ CH ２ CH ２ CH ２ P.S. ２ CH ２ CH ２ CH ２ B, B ２ CH ２ CH ２ 、 CH ２ NHCH ２ CH ２ 、 CH ２ CH ２ NCH ２ 、 CH ２ CH ２ CH ２ NH, N=CHCH=CH, CH=NCH=CH, CH=CHN=CH, CH=CHCH=N, and any one of them forms. In some embodiments, R ２ together with b is CH ２ CH ２ 、 CH ２ CH ２ CH ２ 、 CH ２ CH ２ CH ２ CH ２ 、 CH=CHCH=CH, OCH ２ CH ２ 、 CH ２ OCH ２ 、 CH ２ CH ２ O, OCH=CH, CH=CHO, OCH ２ O, SCH ２ CH ２ 、 CH ２ SCH ２ 、 CH ２ CH ２ S, SCH=CH, CH=CHS, NHCH ２ CH ２ 、 CH ２ NHCH ２ 、 CH ２ CH ２ NH, NHCH=CH, CH=CHNH, ON=CH, CH=NO, OCH=NH, N=CHO, SN=CH, CH=NS, SCH=NH, N=CHS, NHN=CH, CH=NNH, NHCH=NH, N=CHNH, NHN=NH, N=NNH, OCH ２ CH ２ CH ２ 、 CH ２ OCH ２ CH ２ 、 CH ２ CH ２ OCH ２ 、 CH ２ CH ２ CH ２ O., S.C.H. ２ CH ２ CH ２ , C.H. ２ SCH ２ CH ２ , C.H. ２ CH ２ SCH ２ , C.H. ２ CH ２ CH ２ S, N.H.C.H. ２ CH ２ CH ２ , C.H. ２ N.H.C.H. ２ CH ２ , C.H. ２ CH ２ NCH ２ , C.H. ２ CH ２ CH ２ NH, N=CHCH=CH, CH=NCH=CH, CH=CHN=CH, CH=CHCH=N, where one hydrogen atom or two hydrogen atoms are present on the moiety, halogen, OH, C １ ~C ６ Alkoxy, C １ ~C ６ Alkyl, C ３ ~C ６ Cycloalkyl, CHF ２ , C.F. ３ , O.C.H.F. ２ , O.C.F. ３ , S.C.H. ３ , SCF ３ and cyano, or, if two hydrogens are bonded to the same carbon atom, is replaced by an oxo group, or any isotopologue or pharma- ceutically acceptable salt thereof.

2. a is (i) H, halogen, lower alkyl, CHF ２ , C.F. ３ , O.C.H. ３ , O.C.H.F. ２ , O.C.F. ３ , S.C.H.F. ２ , S.C.H. ３ , SCF ３ , amine, and cyano, or (ii) together with Z, (A) a saturated chain of one oxygen and one carbon atom, the oxygen being attached to the 5-position of the indole ring of formula I, and (B) H, halogen, OH, C １ ~C ６ Alkoxy, C １ ~C ６ Alkyl, C ３ ~C ６ Cycloalkyl, CHF ２ , C.F. ３ , O.C.H.F. ２ , O.C.F. ３ , S.C.H. ３ , S.C.H.F. ２ , SCF ３ (C) a chain of 2 or 3 carbon atoms to which is attached a substituent independently selected from the group consisting of H, halogen, OH, C １ ~C ６ Alkoxy, C １ ~C ６ Alkyl, C ３ ~C ６ Cycloalkyl, CHF ２ , C.F. ３ , O.C.H.F. ２ , O.C.F. ３ , S.C.H.F. ２ , S.C.H. ３ , SCF ３ or (iii) together with b, form a chain of 2 or 3 carbon atoms having one double bond to which is bonded a substituent independently selected from the group consisting of C, N, O, and S, the remainder being carbon, said chain having 0, 1, or 2 double bonds, said chain including at least one of H, halogen, OH, C, C-C-D-O-R-O-P ... １ ~C ６ Alkoxy, C １ ~C ６ Alkyl, C ３ ~C ６ Cycloalkyl, CHF ２ , C.F. ３ , O.C.H.F. ２ , O.C.F. ３ , S.C.H. ３ , S.C.H.F. ２ , SCF ３ , cyano, and oxo; and b is (i) H, halogen, CH ３ , C.H.F. ２ , C.F. ３ , O.C.H. ３ , O.C.H.F. ２ , O.C.F. ３ , S.C.H. ３ , S.C.H.F. ２ , SCF ３ , amine, and cyano, or (ii) together with a, form a chain of 3 or 4 atoms, one atom of which is selected from the group consisting of C, N, O, and S, and the rest are carbon, said chain having 0, 1, or 2 double bonds, said chain containing no or more of H, halogen, OH, C １ ~C ６ Alkoxy, C １ ~C ６ Alkyl, C ３ ~C ６ Cycloalkyl, CHF ２ , C.F. ３ , O.C.H.F. ２ , O.C.F. ３ , S.C.H. ３ , S.C.H.F. ２ , SCF ３ (iii) R ２ and form a chain of 3 or 4 atoms, one atom of which is selected from the group including C, N, O, and S, and the rest are carbon, the chain having 0, 1, or 2 double bonds, and the chain also having H, halogen, OH, C １ ~C ６ Alkoxy, C １ ~C ６ Alkyl, C ３ ~C ６ Cycloalkyl, CHF ２ , C.F. ３ , O.C.H.F. ２ , O.C.F. ３ , S.C.H. ３ , S.C.H.F. ２ , SCF ３ 10. The compound of claim 1, or any isotopologue or pharma- ceutically acceptable salt thereof, wherein R is an integer from 1 to 6; and R is an integer from 1 to 6;

3. R ３ (i) H, C １ ~C ６ Alkyl, C ２ ~C ６ Alkenyl, C ２ ~C ６ Alkynyl, C ３ ~C ６ Cycloalkyl, (C ３ ~C ６ Cycloalkyl) (C １ ~C ６ Alkyl), aryl (C １ ~C ６ alkyl), acetyl, and heteroaryl (C １ ~C ６ alkyl), or (ii) R ３ together with the N atom to which it is attached and f, form an azetidine or pyrrolidine ring, such rings being free of H, aryl, heteroaryl, C １ ~C ６ Alkyl, and C ３ ~C ６ or (iii) R ３ together with the N atom to which it is attached and d form an azetidine or pyrrolidine ring, such rings being free of H, aryl, heteroaryl, halogen, C １ ~C ６ Alkyl, and C ３ ~C ６ 2. The compound of claim 1, or any isotope or pharma- ceutically acceptable salt thereof, having substituents independently selected from the group comprising cycloalkyl.

4. Each of c, d, e, and f is H or a lower alkyl group, or １ and c ２ together form part of a spiro-fused cyclopropane or cyclobutane ring, and each of d, e, and f is H or a lower alkyl group, or １ and d ２ together form part of a spiro-fused cyclopropane or cyclobutane ring, c, e, and f each being H or a lower alkyl group, or e １ and e ２ together form part of a spiro-fused cyclopropane or cyclobutane ring, and each of c, d, and f is H or a lower alkyl group, or １ and f ２ together form part of a spiro-fused cyclopropane or cyclobutane ring, and each of c, d, and e is H or a lower alkyl group, or one of c and one of d are both -CH ２ - or -CH ２ CH ２ -, thereby resulting in a fused cyclopropane or cyclobutane ring, and the remainder of each of c, d, e, and f is H or a lower alkyl group, or one of e and one of f together are -CH ２ - or -CH ２ CH ２ -, thereby resulting in a fused cyclopropane or cyclobutane ring, and the remainder of each of c, d, e, and f is H or a lower alkyl group, or one of c and one of e together are -CH ２ - or -CH ２ CH ２ -, thereby resulting in a bridged bicyclic moiety, and the remainder of each of c, d, e, and f is H or a lower alkyl group, or one of c and one of f together are -CH ２ - or -CH ２ CH ２ -, thereby resulting in a bridged bicyclic moiety, and the remainder of each of c, d, e, and f is H or a lower alkyl group, or one of d and one of e together are -CH ２ - or -CH ２ CH ２ -, thereby resulting in a bridged bicyclic moiety, and the remainder of each of c, d, e, and f is H or a lower alkyl group, or one of f and one of e together are -CH ２ - or -CH ２ CH ２ -, thereby resulting in a fused bicyclic moiety, and each remainder of c, d, e, and f is H or a lower alkyl group, or e is R １ and forming a chain of 2 to 4 carbon atoms, and the chain of 2 to 4 carbon atoms is １ ~C ６ or one of c and R ３ Both are -CH ２ - or -CH ２ CH ２ -, whereby a bridged bicyclic moiety results, and the remainder of each of c, d, e, and f is H or a lower alkyl group, or one of d and R ３ Both are -CH ２ - or -CH ２ CH ２ -, whereby a fused bicyclic moiety results, and the remainder of each of c, d, e, and f is H or a lower alkyl group, or one of e and R ３ Both are -CH ２ - or -CH ２ CH ２ -, whereby a fused bicyclic moiety results, and the remainder of each of c, d, e, and f is H or a lower alkyl group, or one of f and R ３ Both are -CH ２ - or -CH ２ CH ２ -, whereby a bridged bicyclic moiety results, and the remainder of each of c, d, e, and f is H or a lower alkyl group, or any isotopologue or pharma- ceutically acceptable salt thereof.

5. Z is (i) H, R ５ , (R ６ ) (R ７ )NC(O)-,C １ ~C ６ Alkyl-C(O),C ３ ~C ６ is selected from the group consisting of cycloalkyl-C(O), aryl-C(O), and heteroaryl-C(O), where R ５ is C １ ~C ６ Alkyl, C ２ -C ６ Alkenyl, C ２ ~C ６ Alkynyl, C ３ ~C ６ Cycloalkyl, (C ３ ~C ６ Cycloalkyl) (C １ ~C ６ Alkyl), aryl (C １ ~C ６ alkyl), and heteroaryl (C １ ~C ６ alkyl), R ６ and R ７ are H, C, １ -C ４ Alkyl, and C ３ ~C ６ cycloalkyl, or joined to form a 4- to 7-membered heterocyclyl group; or (ii) (R ８ O) (R ９ O) P(O)—, where R ８ and R ９ are each independently H or a cationic counterion in the form of a phosphate such as sodium, potassium, 1 / 2 magnesium, 1 / 2 calcium, ammonium, or ammonium substituted with one or more alkyl or cycloalkyl groups, or (iii) c together with H, halogen, C １ ~C ６ Alkyl, and C ３ ~C ６ or (iv) together with a, (A) a saturated chain of one oxygen and one carbon atom, the oxygen being attached to the 5-position of the indole ring of formula I, and (B) H, halogen, OH, C １ ~C ６ Alkoxy, C １ ~C ６ Alkyl, C ３ ~C ６ Cycloalkyl, CHF ２ , C.F. ３ , O.C.H.F. ２ , O.C.F. ３ , S.C.H. ３ , S.C.H.F. ２ , SCF ３ (C) a chain of 2 or 3 carbon atoms to which is attached a substituent independently selected from the group consisting of , cyano, and oxo, and (D) a chain of 2 or 3 carbon atoms having one double bond and no substituent selected from the group consisting of H, halogen, OH, C １ ~C ６ Alkoxy, C １ ~C ６ Alkyl, C ３ ~C ６ Cycloalkyl, CHF ２ , C.F. ３ , O.C.H.F. ２ , O.C.F. ３ , S.C.H. ３ , S.C.H.F. ２ , SCF ３ 10. The compound of claim 1, or any isotopologue or pharma- ceutically acceptable salt thereof, wherein the aryl group is aryl, cyano, or oxo, and the aryl group is aryl.

6. (i) R １ But, H, C １ ~C ６ Alkyl, and C １ ~C ６ (ii) R ２ But, C １ ~C ６ Alkyl and C １ ~C ６ (iii) each of a and b is selected from the group consisting of H, halogen, lower alkyl, CHF ２ , C.F. ３ , O.C.H. ３ , O.C.H.F. ２ , O.C.F. ３ , S.C.H.F. ２ , S.C.H. ３ , SCF ３ and cyano; (iv) each of c, d, e, and f is H or a lower alkyl group; (v) R ３ is H and C １ ~C ６ 2. The compound of claim 1, or any isotope or pharma- ceutically acceptable salt thereof, selected from the group comprising alkyl.

7. The compound has the formula: 【Chemistry 2】 2. The compound of claim 1 having the formula:

8. The compound is 【Chemistry 3】 or a conjugate base thereof, or any isotopologue or pharma- ceutically acceptable salt thereof.

9. The compound is 【Chemistry 4】 or a conjugate base thereof, or any isotopologue or pharma- ceutically acceptable salt thereof.

10. The compound is 【Chemistry 5】 or a conjugate base thereof, or any isotopologue or pharma- ceutically acceptable salt thereof.

11. 11. A compound according to any one of claims 1 to 10, or any isotopologue or pharma- ceutically acceptable salt thereof, for use in treating a disorder in a patient.

12. 12. The compound of claim 11, or any isotopologue or pharmaceutically acceptable salt thereof, wherein the disorder is selected from the group comprising major depressive disorder, medication-resistant depression and psychotic depression, addiction including alcoholism, tobacco addiction, cocaine addiction, and opioid addiction, pain symptoms including neuropathic pain, pain from chemotherapy-associated neuropathy, phantom limb pain, and fibromyalgia, inflammation (including chronic and acute), eating disorders including anorexia, autism, cluster headache, migraine, dementia including Alzheimer's dementia, Parkinson's disease dementia, and dementia with Lewy bodies, post-traumatic stress disorder, mental distress associated with cancer, fragile X syndrome, autism spectrum disorder, bipolar disorder, obsessive-compulsive disorder, and Rett's syndrome.

13. 11. A compound according to any one of claims 8 to 10, or any isotopologue or pharma- ceutically acceptable salt thereof, for use in treating a disorder in a patient.

14. 14. The compound of claim 13, or any isotopologue or pharmaceutically acceptable salt thereof, wherein the disorder is selected from the group comprising major depressive disorder, medication-resistant depression and psychotic depression, addiction including alcoholism, tobacco addiction, cocaine addiction, and opioid addiction, pain symptoms including neuropathic pain, pain from chemotherapy-associated neuropathy, phantom limb pain, and fibromyalgia, inflammation (including chronic and acute), eating disorders including anorexia, autism, cluster headache, migraine, dementia including Alzheimer's dementia, Parkinson's disease dementia, and dementia with Lewy bodies, post-traumatic stress disorder, mental distress associated with cancer, fragile X syndrome, autism spectrum disorder, bipolar disorder, obsessive-compulsive disorder, and Rett syndrome.

15. 13. The compound of claim 12, or any isotopologue or pharma- ceutically acceptable salt thereof, wherein the disorder is selected from the group comprising major depressive disorder, drug-resistant depression, and psychotic depression.

16. 15. The compound of claim 14, or any isotopologue or pharma- ceutically acceptable salt thereof, wherein the disorder is selected from the group comprising major depressive disorder, drug-resistant depression, and psychotic depression.

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