Azepino indole and preparation method thereof

Abstract

The present disclosure relates to heterocyclic compounds of formula (I). As contemplated herein, the heterocyclic compounds of formula (I) are useful for the treatment of neuropsychiatric and neurodegenerative diseases, neuroinflammatory diseases, and pain disorders, including depression, e.g., neurodegenerative diseases, neuroinflammatory diseases, and pain disorders. And tobacco, opioid and cocaine addiction, alcoholism, post traumatic stress disorder (PTSD) and neuropathic pain syndrome, including cluster headache and chemotherapy induced peripheral neuropathy. # imgabs0 #

Description

Technical Field

[0001] The present disclosure relates to heterocyclic compounds and preparation methods thereof. The present disclosure also relates to the use of azaindoles as serotonin receptor selectors. Background Art

[0002] Psilocybin is a naturally occurring hallucinogenic compound produced by more than 200 species of mushrooms collectively referred to as "psilocybin mushrooms." As a prodrug, psilocybin is rapidly metabolized by the body to produce the bioactive compound psilocin, which has mind-altering effects similar to those produced by other hallucinogens such as lysergic acid diethylamide (LSD), mescaline, and N,N-dimethyltryptamine (DMT). These effects specifically include euphoria, visual and mental hallucinations, changes in perception, distorted sense of time, and spiritual experiences; they may also include possible adverse reactions such as nausea and panic attacks. For reference, this article Figure 1 The chemical structure of psilocybin is provided.

[0003] As 5-HT 2A and 5-HT 2C Psilocybin and psilocybin, agonists of 5-HT receptors, have been suggested to have therapeutic potential. 2A Activation of 5-HT receptors appears to increase locomotor activity, whereas 2C Activation of 5-HT receptors appears to reduce locomotor activity and thus to varying degrees 2A and 5-HT 2CActive compounds will show varying levels of hallucinogenic activity (Halberstadt AL, van der Heijden I, Ruderman MA, Risbrough VB, Gingrich JA. Geyer MA, Powell SB, Neuropsychopharmacology, 2009, 34 (8): 1958-67). Although Hofmann and collaborators explored psilocybin and other psychedelic drugs more than 60 years ago (e.g., see Hofmann, A., Troxler, F. US 3,075,992; US 3,078,214), by the early 1970s, clinical research on these drugs had declined significantly, especially after they were included in Schedule 1 of the Controlled Substance Act of the United States. However, despite the fact that psilocybin and other psychedelic drugs are listed as controlled substances in some jurisdictions, research on them has never completely stopped, and recent clinical studies have rekindled interest in the potential application of psychedelic drugs (including psilocybin) in evolving medical fields such as the treatment of central nervous system (CNS) diseases. CNS diseases include difficult-to-treat mental health disorders (Daniel J, Haberman M. Clinical potential of psilocybin as a treatment for mental health conditions. Ment. Health Clin. 2017, 7(1), 24-8), such as treatment-resistant depression or drug-resistant depression, and neurological disorders such as cluster headache.

[0004] Although psilocybin is recognized for its therapeutic potential in treating certain CNS diseases and conditions, it has also been identified as a 5-HT 2B receptor agonists and are therefore cardiotoxic. 2A Receptor agonist activity but lack of cardiotoxicity 5-HT 2B There is an unmet need for safer drugs with agonist activity and analogs of psilocybin and psilocybin; in addition, at least in some cases, there is a need for drugs that maintain 5-HT 2A Receptor agonist activity but lack of cardiotoxicity 5-HT 2B There is an unmet need for safer drugs with agonist activity. Summary of the invention

[0005] The present disclosure relates to indole compounds, in particular to compounds belonging to the aza-indole class, which have 5-HT 2A receptor agonist activity, while exhibiting low 5-HT 2BAt least in some cases, these compounds have 5-HT receptor agonist activity. 2A Receptor selectivity over 5-HT 2C The compounds disclosed herein can be used to treat depression (including major depressive disorder, drug-resistant depression and depression with psychotic symptoms), addiction (including alcoholism, tobacco addiction, cocaine addiction and opioid addiction), pain indications (including neuropathic pain, pain caused by chemotherapy-related neuropathy, phantom limb pain and fibromyalgia), inflammation (including chronic inflammation and acute inflammation), eating disorders (including anorexia, autism, cluster headache, migraine), dementia (including Alzheimer's dementia, Parkinson's dementia and Lewy body dementia), post-traumatic stress disorder, emotional distress associated with cancer, fragile X syndrome, autism spectrum disorder, bipolar disorder, obsessive-compulsive disorder, Rett syndrome and other CNS disorders.

[0006] According to one aspect of the present disclosure, there is provided a chemical entity of Formula I:

[0007]

[0008] Where 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 as defined below.

[0009] The chemical entity of formula I is 2B 5-HT isoform selective 2A The chemical entity of formula I or its pharmaceutically acceptable composition may be used to treat a variety of 5-HT 2A Diseases and conditions associated with receptor agonism. Such diseases and conditions include those described herein.

[0010] The present invention does not necessarily describe the full scope of all aspects of the present disclosure. For those of ordinary skill in the art, other aspects, features and advantages will be apparent by reading the following description of specific embodiments. BRIEF DESCRIPTION OF THE DRAWINGS

[0011] In the accompanying drawings, which illustrate one or more embodiments:

[0012] Figure 1 The chemical structure of psilocybin is depicted;

[0013] Figure 2 The chemical structure of the compound of formula I is depicted;

[0014] Figure 3 is a graph depicting the change in HTR over time per dose (mg / kg) when Compound 1 (as described herein) is administered to mice. DETAILED DESCRIPTION

[0015] Directional terms such as "top", "bottom", "upward", "downward", "vertical" and "lateral" are used in the following description only for the purpose of providing relative reference and are not intended to impose any limitations on how any item is positioned during use or how it is installed in an assembly or relative to the environment. When used in conjunction with the term "comprising" in this article, the use of the words "a" or "an" can mean "one", but it is also consistent with the meaning of "one or more", "at least one" and "one or more than one". Any element expressed in the singular also encompasses its plural form. Any element expressed in the plural also encompasses its singular form. The term "plurality" as used herein refers to more than one, such as two or more, three or more, four or more, etc.

[0016] As used herein and unless otherwise indicated, the term "about" when used in describing a recited value means within 10% of the recited value.

[0017] As used herein and unless otherwise indicated, 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-butadiene-2-yl, 2,4-pentadiene-1-yl, 1,4-pentadiene-3-yl, and the like.

[0018] As used herein and unless otherwise indicated, 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 indicated, the term "substituted alkoxy", used alone or as part of a larger moiety, refers to the groups -O-(substituted alkyl) and -O-(substituted cycloalkyl).

[0019] As used herein and unless otherwise indicated, the term "alkyl" used alone or as part of a larger moiety refers to a fully saturated, substituted or unsubstituted, straight or branched monovalent hydrocarbon chain. Unless otherwise indicated, an alkyl group contains 1 to 7 carbon atoms ("C 1 -C 7 For example, in some embodiments, an alkyl group contains 1 to 6 carbon atoms (“C 1 -C 6In some embodiments, an alkyl group contains 1 to 5 carbon atoms (“C 1 -C 5 In some embodiments, the alkyl group contains 1 to 4 carbon atoms ("C 1 -C 4 alkyl”, alternatively “lower alkyl”); and in some embodiments, the alkyl group contains 3 to 7 carbon atoms (“C 3 -C 7 The term "alkyl" refers to a group consisting of a saturated alkyl group, ... 2 CF 3 , CH 2 CF 3 CF 2 CF 3 , 4-fluorobutyl, etc.

[0020] As used herein and unless otherwise indicated, the term "alkynyl" refers to a substituted or unsubstituted, linear or branched, monovalent hydrocarbon chain having at least two carbon atoms and at least one carbon-carbon triple bond. Non-limiting examples of alkynyl include ethynyl, 1- and 3-propynyl, 3-butyn-1-yl, and the like.

[0021] As used herein and unless otherwise indicated, 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 indicated, aryl contains 6 or 10 ring members. Non-limiting examples of aryl include phenyl, naphthyl, etc. The term "aryl" also refers to aryl groups that can be unsubstituted or substituted. For example, aryl can be unsubstituted or can be substituted by one, two or three groups independently selected from the group consisting of halogen, OH, C 1 -C 6 Alkoxy, substituted C 1 -C 6 Alkoxy, C 1 -C 6 Alkylthio, substituted C 1 -C 6 Alkylthio, C 1 -C 6 Alkyl, substituted C1 -C 6 Alkyl, C 3 -C 6 Cycloalkyl, substituted C 3 -C 6 Cycloalkyl, C(O)OH, C(O)(C 1 -C 6 alkyl), C(N-OH)(C 1 -C 6 alkyl), C(O)(C 1 -C 6 Alkoxy), C(O)NH 2 、C(O)NH(C 1 -C 6 alkyl), C(O)N(C 1 -C 4 Alkyl)(C 1 -C 4 alkyl), C(O)-heterocyclyl, NHC(O)(C 1 -C 6 alkyl), N(CH 3 )C(O)(C 1 -C 6 alkyl) and cyano.

[0022] As used herein and unless otherwise indicated, the term "azaindole" refers to a compound of Formula I of the present disclosure.

[0023] As used herein and unless otherwise indicated or clear from the context, a substituent "c" refers to a substituent "c 1 " or "c 2 "

[0024] As used herein and unless otherwise indicated, the term "chemical entity" refers to a compound having an indicated structure, whether in its "free" form (e.g., "free compound" or "free base" or "free acid" form, as applicable), or in salt form, particularly a pharmaceutically acceptable salt form, and further, whether in solid form or otherwise. In some embodiments, the solid form is an amorphous (e.g., amorphous) form; in some embodiments, the solid form is a crystalline form (e.g., a polymorph, a pseudohydrate, a hydrate, or a solvate). Similarly, the term encompasses compounds provided in solid form or otherwise. Unless otherwise indicated, all statements herein about "compounds" apply to the relevant chemical entity as defined.

[0025] As used herein and unless otherwise indicated, the terms "comprising", "having", "including", "containing" and their grammatical variations 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.

[0026] As used herein and unless otherwise indicated, 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 such additions do not materially affect the way in which the recited composition, method, or use functions.

[0027] As used herein and unless otherwise indicated, the term "consisting of" excludes the presence of additional elements and / or method steps when used in connection with a composition, use or method herein.

[0028] As used herein and unless otherwise indicated, 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 radical which is fully saturated or contains one or more units of unsaturation, but is not aromatic; or (ii) a bicyclic [mno]alkyl radical, wherein each of "m", "n", and "o" is independently an integer in the range of 0 to 5, and the sum of "m" + "n" + "o" is in the range of 2 to 6. In some embodiments, the cycloalkyl radical contains 3 to 8 ring carbon atoms ("C 3 -C 8 The term "cycloalkyl" refers to a group consisting of a cycloalkyl radical and a cyclohexyl radical. Non-limiting examples of cycloalkyl radicals include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl, and the like, as well as bicyclo[2.2.1]heptyl (also known as norbornyl) and bicyclo[1.1.1]pentyl. Substituted cycloalkyl radicals are radicals having at least one but not more than five substituents. In some embodiments, the substituents are fluorine atoms. Non-limiting examples of substituted cycloalkyl radicals include 2-methylcyclopropyl, 4-hydroxycyclohexyl, 2-methoxycyclopentyl, 4,4-difluorocyclohexyl, and the like.

[0029] As used herein and unless otherwise indicated or clear from the context, a substituent "d" refers to the substituent "d 1 " or "d 2 "

[0030] As used herein and unless otherwise indicated or clear from the context, a substituent "e" refers to the substituent "e 1 ” or “e 2 "

[0031] As used herein and unless otherwise indicated or clear from the context, a substituent "f" refers to the substituent "f 1 " or "f 2 "

[0032] As used herein and unless otherwise indicated, the term "halogen" or "halo", used alone or as part of a larger moiety, refers to fluoro, chloro, bromo or iodo.

[0033] As used herein and unless otherwise indicated, the term "heteroalkyl" refers to a substituted or unsubstituted saturated or unsaturated alkyl group as defined herein, wherein one or more of the constituent carbon atoms is replaced by nitrogen, oxygen or sulfur.

[0034] As used herein and unless otherwise indicated, the term "heteroaryl", used alone or as part of a larger moiety (e.g., "(heteroaryl)alkyl"), refers to a monovalent monocyclic or bicyclic radical having 5 to 10 ring atoms, preferably 5, 6, 9 or 10 ring atoms, 6 or 10 π electrons shared in the cyclic array, and 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, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, indolizinyl, benzofuranyl, benzothienyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, benzotriazolyl, quinolyl, isoquinolyl, purinyl, naphthyridinyl, pteridinyl, and the like. The heteroaryl group may be unsubstituted or substituted by one, two or three groups independently selected from the group consisting of halogen, OH, C 1 -C 6 Alkoxy, substituted C 1 -C 6 Alkoxy, C 1 -C 6 Alkylthio, substituted C 1 -C 6 Alkylthio, C 1 -C 6 Alkyl, substituted C 1 -C 6 Alkyl, C 3 -C 6 Cycloalkyl, substituted C 3 -C 6 Cycloalkyl, C(O)OH, C(O)(C 1 -C 6 Alkoxy), C(O)NH 2 、C(O)NH(C 1 -C6 alkyl), C(O)N(C 1 -C 4 Alkyl)(C 1 -C 4 alkyl), C(O)-heterocyclyl, NHC(O)(C 1 -C 6 alkyl), N(CH 3 )C(O)(C 1 -C 6 alkyl) and cyano.

[0035] As used herein and unless otherwise indicated, 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 saturated or partially unsaturated and has 1 to 4 heteroatoms in addition to the ring carbon atoms. Non-limiting examples of heterocyclyls include tetrahydrofuranyl, pyrrolidinyl, tetrahydropyranyl, piperidinyl, morpholinyl, and the like. Heterocyclyls may be unsubstituted or may be substituted. For example, heterocyclyls may be unsubstituted or may be substituted by one, two, or three groups independently selected from the group consisting of halogen, OH, O(C 1 -C 6 alkyl), O(substituted C 1 -C 6 Alkyl), C 1 -C 6 Alkyl, substituted C 1 -C 6 Alkyl and C 3 -C 6 Cycloalkyl.

[0036] As used herein and unless otherwise indicated, the term "inactive" (and all terms related thereto, including "inactive") when used in the context of "EC 50 When used in the context of "(nM)" and "Eff%" (such terms as those understood by those skilled in the art or equivalent) and when referring to 5-HT 2B Receptor activity is used when the concentration is greater than 10,000 nM (when the EC 50 (nM)”) or an efficacy of 30% or less (when used in the context of “Eff %”).

[0037] As used herein and unless otherwise indicated, the term "isotopologue" refers to a species that differs from a particular compound only in isotopic composition. For example, all hydrogen atoms in a compound may be enriched or depleted in heavy isotopes independently of their natural isotopic composition. 2 H (D, deuterium) and3 Any isotopic composition of one or both of H (T, tritium), ranging from 0% depleted to 100% enriched.

[0038] As used herein and unless otherwise indicated, the term "pharmaceutically acceptable salt" refers to those salts that are suitable for contact with the tissues of humans and lower animals without excessive toxicity, irritation, allergic reaction, etc. and commensurate with a reasonable benefit / risk ratio within the scope of reasonable medical judgment. 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 including amino groups 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 pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, gluconate heptanoate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxyethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, pivalate, propionate, stearate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, and the like. Other pharmaceutically acceptable salts include those derived from appropriate bases such as alkali metal, alkaline earth metal, ammonium and N + (C 1-4 alkyl) 4 Salts. Representative alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, etc. Other non-limiting examples of pharmaceutically acceptable salts include, where appropriate, non-toxic ammonium, quaternary ammonium and amine cations formed using counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates and aryl sulfonates.

[0039] As used herein and unless otherwise indicated, the term "subject" includes mammals (e.g., humans, and in some embodiments, prenatal human forms). In some embodiments, the subject suffers from a relevant disease, disorder, or condition. In some embodiments, the subject is susceptible to a disease, disorder, or condition. In some embodiments, the subject exhibits one or more symptoms or features of a disease, disorder, or condition. In some embodiments, the subject does not exhibit any symptoms or features of a disease, disorder, or condition. In some embodiments, the subject is a mammal with one or more features of susceptibility or risk to a disease, disorder, or condition. In some embodiments, the subject is a patient. In some embodiments, the subject is an individual to whom diagnosis and / or therapy is being administered and / or has been administered. In some embodiments, the subject is a fetus, infant, child, teenager, adult, or elderly (i.e., the subject is older, such as greater than 50 years old). In some embodiments, a child refers to a human being between the ages of 2 and 18 years old. In some embodiments, an adult refers to a human being 18 years old or older.

[0040] As used herein and unless otherwise indicated, the phrase "such as" is intended to be open ended. For example, the phrase "A may be a halogen, such as chlorine or bromine" means that "A" may be, but is not limited to, chlorine or bromine.

[0041] Reference to a particular moiety, functional group or substituent contemplates its tautomers "where applicable".

[0042] Unless otherwise specified, structures depicted herein include all isomeric (e.g., enantiomers, diastereomers, 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 proposed in the present disclosure contemplate all single stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures thereof. Unless otherwise specified, compounds disclosed, taught, or otherwise proposed in the present disclosure contemplate all tautomeric forms thereof. In addition, unless otherwise specified, structures depicted herein include compounds that exist only in the presence of one or more isotopically enriched atoms. Such compounds can be used, for example, as analytical tools, probes in biological assays, or therapeutic agents. In addition, incorporation of heavier isotopes such as deuterium ( 2 H) may offer certain therapeutic advantages due to greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements.

[0043] The chemical entities described herein are further described by the classes, subclasses, and species disclosed herein. For purposes of this disclosure, chemical elements are identified according to the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75th edition, inside cover, 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 Thomas Sorrell, Organic Chemistry, University Science Books, Sausalito, 1999; Smith and March, March's Advanced Organic Chemistry, 5 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 intended to represent any stable isotope of that atom.

[0044] Unless otherwise specified, the structures depicted herein include all stereoisomers (e.g., enantiomers, diastereomers, 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). Therefore, the present compounds contemplate all single stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures thereof. Unless otherwise specified, the present compounds contemplate all tautomeric forms thereof. In addition, unless otherwise specified, the structures depicted herein are also meant to include compounds that consist solely of the presence of one or more isotopically enriched atoms. Such compounds can be used, for example, as analytical tools, probes in biological assays, or therapeutic agents. In addition, incorporation of heavier isotopes such as deuterium ( 2 H) may offer certain therapeutic advantages due to greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements.

[0045] refer to Figure 2 According to the examples of chemical entities disclosed herein (including isotopic configurations or pharmaceutically acceptable salts thereof), a chemical entity of Formula I is provided:

[0046]

[0047] R 1 :(i) R 1 Choose from 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 Heterocyclic group, (C 3 -C 6 Heterocyclic group (C 1 -C 6 Alkyl), aryl (C 1 -C 6 Alkyl) and heteroaryl (C 1 -C 6 alkyl); or (ii) R 1 With e 1 or e 2 together to form a chain of 2 to 4 carbon atoms to which are attached substituents, the substituents being independently selected from the group consisting of H, C 1 -C 6 The group consisting of alkyl, aryl, heteroaryl and any combination thereof.

[0048] R 2 :(i) R 2 Choose from 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 Heterocyclic group, (C 3 -C 6Heterocyclic group (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), phenyl and halogen; or (ii) R 2 Together with b, it forms a chain of 2 or 3 atoms, one of which is selected from the group consisting of C, N, O and S, while the remaining atoms are carbon atoms, the chain contains 0, 1 or 2 double bonds, and the chain is connected to independently selected from H, halogen, OH, C 1 -C 6 Alkoxy, C 1 -C 6 Alkyl, C 3 -C 6 Cycloalkyl, CHF 2 CF 3 , OCHF 2 、OCF 3 , SCH 3 、SCF 3 , cyano and oxo; or (iv) if b is halogen, CH 3 , CHF 2 CF 3 、OCH 3 , OCHF 2 、OCF 3 , SCH 3 , SCHF 2 、SCF 3 or cyano, R 2 Choose from H, C 1 -C 6 Alkyl, C 1 -C 6 Substituted alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 3 -C6 Cycloalkyl, (C 3 -C 6 Cycloalkyl)(C 1 -C 6 Alkyl), C 3 -C 6 Heterocyclic group, (C 3 -C 6 Heterocyclic group (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 In some embodiments, R 2 Together with b, it forms 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 2NH, 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, 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, SCH 2 CH 2 CH 2 , CH 2 SCH 2 CH 2 , CH 2 CH 2 SCH 2 , CH 2 CH 2 CH 2 SNHCH 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, or any one of them. In some embodiments, R 2 together with b forms 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 2O, 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=N, N=CHO, SN=CH, CH=NS, SCH=N, N=CHS, NHN=CH, CH=NNH, NHCH=N, N=CHNH, NHN=N, 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. SCH 2 CH 2 CH 2 , CH 2 SCH 2 CH 2 , CH 2 CH 2 SCH 2 , CH 2 CH 2 CH 2 SNH 2 CH 2 CH 2 , CH 2 NHCH 2 CH 2 , CH 2 CH 2 NCH 2 , CH 2 CH 2 CH 2 Any of NH, N=CHCH=CH, CH=NCH=CH, CH=CHN=CH, CH=CHCH=N, if present in the moiety, one or both hydrogen atoms are independently selected from halogen, OH, C1 -C 6 Alkoxy, C 1 -C 6 Alkyl, C 3 -C 6 Cycloalkyl, CHF 2 CF 3 , OCHF 2 、OCF 3 , SCH 3 、SCF 3 , and cyano, or if attached to the same carbon atom, two hydrogen atoms therein are replaced by oxo groups.

[0049] a: (i) a is selected from H, halogen, lower alkyl, CHF 2 CF 3 、OCH 3 , OCHF 2 、OCF 3 , SCHF 2 , SCH 3 、SCF 3 , amine and cyano; or (ii) a and Z together form one of (A), (B) and (C), (A) a saturated chain of one oxygen and one carbon atom (the oxygen is attached to the 5-position of the indole ring of Formula I), (B) a chain of 2 or 3 carbon atoms, the chain being connected to a halogen independently selected from H, OH, C 1 -C 6 Alkoxy, C 1 -C 6 Alkyl, C 3 -C 6 Cycloalkyl, CHF 2 CF 3 , OCHF 2 、OCF 3 , SCH 3 , SCHF 2 、SCF 3 , cyano and oxo, (C) a chain of 2 or 3 carbon atoms containing a double bond, the chain being connected to a group independently selected from H, halogen, OH, C 1 -C 6 Alkoxy, C 1 -C 6 Alkyl, C 3 -C 6 Cycloalkyl, CHF 2 CF 3 , OCHF 2 、OCF 3 , SCHF 2 , SCH 3 、SCF3 , cyano and oxo; or (iii) a and b together form a chain of 3 or 4 atoms, one of which is selected from the group consisting of C, N, O and S, the remaining atoms are carbon atoms, the chain contains 0, 1 or 2 double bonds, and the chain is connected to independently selected from H, halogen, OH, C 1 -C 6 Alkoxy, C 1 -C 6 Alkyl, C 3 -C 6 Cycloalkyl, CHF 2 CF 3 , OCHF 2 、OCF 3 , SCH 3 , SCHF 2 、SCF 3 , cyano and oxo.

[0050] b: (i) b is selected from H, halogen, CH 3 , CHF 2 CF 3 、OCH 3 , OCHF 2 、OCF 3 , SCH 3 , SCHF 2 、SCF 3 or (ii) b and a together form a chain of 3 or 4 atoms, one of which is selected from the group consisting of C, N, O and S, and the remaining atoms are carbon atoms, the chain contains 0, 1 or 2 double bonds, and the chain is connected to a group independently selected from H, halogen, OH, C 1 -C 6 Alkoxy, C 1 -C 6 Alkyl, C 3 -C 6 Cycloalkyl, CHF 2 CF 3 , OCHF 2 、OCF 3 , SCH 3 , SCHF 2 、SCF 3 , cyano and oxo; or (iii) b and R 2 Together they form a chain of 3 or 4 atoms, one of which is selected from the group consisting of C, N, O and S, the remaining atoms being carbon atoms, the chain containing 0, 1 or 2 double bonds, and the chain being connected with radicals independently selected from the group consisting of H, halogen, OH, C 1 -C 6Alkoxy, C 1 -C 6 Alkyl, C 3 -C 6 Cycloalkyl, CHF 2 CF 3 , OCHF 2 、OCF 3 , SCH 3 , SCHF 2 、SCF 3 , cyano and oxo.

[0051] R 3 :(i) R 3 Choose from 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 With f and R 3 The N atoms are connected together to form an azetidine or pyrrolidine ring with a moiety independently selected from H, aryl, heteroaryl, C 1 -C 6 Alkyl and C 3 -C 6 or (iii) R 3 With d and R 3 The N atoms are connected together to form an azetidine or pyrrolidine ring with a moiety independently selected from H, aryl, heteroaryl, halogen, C 1 -C 6 Alkyl, and C 3 -C 6 The substituents are composed of a cycloalkyl group.

[0052] c, d, e and f are independently H or a lower alkyl group; or c 1 With c 2 Together they form part of a spirofused cyclopropane or cyclobutane ring, and d, e and f are each H or a lower alkyl group; or d 1 With d 2Together they form part of a spirofused cyclopropane or cyclobutane ring, and c, e and f are each H or a lower alkyl group; or e 1 With e 2 Together they form part of a spirofused cyclopropane or cyclobutane ring, and c, d and f are each H or a lower alkyl group; or f 1 With f 2 Together they form part of a spirofused cyclopropane or cyclobutane ring, and c, d and e are each H or a lower alkyl group; or one of c and one of d together form -CH 2 -or-CH 2 CH 2 -, thereby producing a fused cyclopropane or cyclobutane ring, and the remainder of c, d, e and f are each H or a lower alkyl group; or one of e and one of f together form -CH 2 -or-CH 2 CH 2 -, thereby producing a fused cyclopropane or cyclobutane ring, and the remainder of c, d, e and f are each H or a lower alkyl group; or one of c and one of e together form -CH 2 -or-CH 2 CH 2 -, thereby producing a bridged bicyclic substructure, and the remainder of c, d, e and f are each H or a lower alkyl group; or one of c and one of f together form -CH 2 -or-CH 2 CH 2 -, thereby producing a bridged bicyclic substructure, and the remainder of c, d, e and f are each H or a lower alkyl group; or one of d is taken together with one of e to form -CH 2 -or-CH 2 CH 2 -, thereby producing a bridged bicyclic substructure, and the remainder of c, d, e and f are each H or a lower alkyl group; or one of f is taken together with one of e to form -CH 2 -or-CH 2 CH 2 -, thereby producing a fused bicyclic substructure, and the remainder of c, d, e and f are each H or a lower alkyl group; or e and R 1 Together they form a chain of 2 to 4 carbon atoms to which are attached two or more carbon atoms independently selected from H, C 1 -C 6 A substituent group consisting of an alkyl group, an aryl group, a heteroaryl group, and any combination thereof; or one of c and R 3 Together they form -CH 2 -or-CH 2 CH 2-, thereby producing a bridged bicyclic substructure, and each of the remaining c, d, e and f is H or a lower alkyl group; or one of d and R 3 Together they form -CH 2 -or-CH 2 CH 2 -, thereby producing a fused bicyclic substructure, and each of the remainder of c, d, e and f is H or a lower alkyl group; or one of e and R 3 Together they form -CH 2 -or-CH 2 CH 2 -, thereby producing a fused bicyclic substructure, and each of the remainder of c, d, e and f is H or a lower alkyl group; or one of f and R 3 Together they form -CH 2 -or-CH 2 CH 2 -, thereby creating a bridged bicyclic substructure, and the remainder of c, d, e and f are each H or a lower alkyl group.

[0053] Z: (i) Z is selected from H, R 5 , (R 6 )(R 7 )NC(O)-、C 1 -C 6 Alkyl-C(O), C 3 -C 6 The group consisting of cycloalkyl-C(O), aryl-C(O) and heteroaryl-C(O), wherein R 5 Choose from 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), and its R 6 and R 7 Each independently selected from H, C 1 -C 4 Alkyl and C 3 -C 6 or (ii) Z is (R8 O)(R 9 O)P(O)-, where R 8 and R 9 each independently selected from H or a cation counterion in phosphate form, such as sodium, potassium, half of magnesium, half of calcium, ammonium, or ammonium substituted with one or more alkyl or cycloalkyl groups; or (iii) Z and C together form a bond to produce a pyran or oxepane ring comprising a halogen independently selected from H, C 1 -C 6 Alkyl and C 3 -C 6 or (iv) Z together with a forms one of (A), (B) and (C), (A) a saturated chain of one oxygen and one carbon atom (the oxygen is attached to the 5-position of the indole ring of Formula I), (B) a chain of 2 or 3 carbon atoms, the chain being connected to a saturated chain independently selected from H, halogen, OH, C 1 -C 6 Alkoxy, C 1 -C 6 Alkyl, C 3 -C 6 Cycloalkyl, CHF 2 CF 3 , OCHF 2 、OCF 3 , SCH 3 , SCHF 2 、SCF 3 , cyano and oxo, (C) a chain of 2 or 3 carbon atoms containing a double bond and having independently selected from H, halogen, OH, C 1 -C 6 Alkoxy, C 1 -C 6 Alkyl, C 3 -C 6 Cycloalkyl, CHF 2 CF 3 , OCHF 2 、OCF 3 , SCHF 2 , SCH 3 、SCF 3 , cyano and oxo.

[0054] Examples of embodiments of chemical entities

[0055] Examples of chemical entities of Formula I are shown in Table 1 below.

[0056]

[0057]

[0058]

[0059]

[0060] *The abbreviations used in the above table have the following meanings: Bn = benzyl; Cypr = cyclopropyl; Et = ethyl; HOBn = o-hydroxyphenyl; MeOBn-o-methoxybenzyl; MeSBn = o-(methylthio)benzyl; Ph = phenyl; Piv = pivaloyl; Pr = propyl; Z 1 =C(O)N(H)-i-Pr; Z 2 =C(O)NMe 2 ; Z 3 =P(O)(OH) 2 ; Z 4 =P(O)(ONa) 2 ; Z 5 =P(O)(OH)(ONa).

[0061] Chemical synthesis

[0062] Compounds of formula I were prepared by two variations of the Fischer indole synthesis, examples of which are shown below.

[0063] In the first approach, the Fischer indole synthesis involves an N-protected 4-oxoazepane and a substituted phenylhydrazine to produce a mixture of separated regioisomeric azepinoindoles. Substituted phenylhydrazines can be obtained, for example, from aniline by diazotization followed by reduction (e.g. 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 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. A variation of the Fischer indole synthesis has recently been disclosed in which the arylhydrazine is replaced by 1-aryl-2-methylhydrazine (see below) to typically obtain better indole yields under milder reaction conditions (Schmidt. MAJ Org. Chem. 2022, 87, 1941-1960).

[0064]

[0065] In another variant of the Fischer indole synthesis, an α-branched aliphatic aldehyde reacts with an aryl hydrazine in the presence of an acid to produce a 3,3-disubstituted 3H-indole (indoline) (e.g., Alfano, AI et al. React. Chem. Eng. 2020, 5, 2091-2100). Although for the purposes of the present invention, low yields were initially obtained using aryl hydrazines in acetic acid as solvents, replacing the building block with the corresponding 1-aryl-2-methylhydrazine resulted in a more efficient reaction. 1,2-disubstituted hydrazine starting materials can be obtained by amination of aryl bromides with tert-butyl 1-carbazate methyl esters by general literature methods (Mauger, C., Mignani, G. Adv. Synth. Catal. 2005, 347, 773-782; Schmidt, MAJ Org. Chem. 2022, 87, 1941-60).

[0066] In a subsequent step, further acid treatment of the 3,3-disubstituted 3H-indole leads to its rearrangement 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). In this study, commercially available acid-washed clay mineral montmorillonite (Kumar, BSC Catal. Sci. Technol. 2014, 4, 2378-2396) was used as the acid at the boiling temperature of a non-polar, high boiling point solvent such as bromobenzene or m-xylene. In the last step, the benzyl and benzyloxycarbonyl protecting groups are removed by hydrogenolysis.

[0067]

[0068] The following two schemes are given as examples of different substituent patterns in carbocyclic aromatic rings.

[0069]

[0070]

[0071] Azacycloheptanone building blocks contain substituents e and / or substituents f and can be synthesized by photochemical rearrangement of N-alkylated succinimide (Kanaoka, Y.; Hatanaka, YJ Org. Chem. 1976, 41, 400-401) followed by standard functional group modification.

[0072]

[0073] The substituted compounds of formula I contain substituents f and can also be obtained by spirocyclization of N-sulfonylated tryptamine with tert-butyl propargyl carbonate, followed by rearrangement of the 3,3-disubstituted 3H-indole obtained therefrom to 2,3-disubstituted 1H-indole (Montgomery, TD et al. Org. Lett. 2014, 16, 3480-3483), catalytic hydrogenation and desulfonylation.

[0074]

[0075] If the 2,5-azacycloheptanediones generated by the photochemical rearrangement of N-alkylsuccinimides enter the Fischer indole synthesis before lactam reduction, then after protection of both nitrogen atoms the resulting indole contains an acidic methylene group adjacent to the lactam carbonyl, which can be used to install one or two substituents by deprotonation with a strong base followed by alkylation.

[0076]

[0077] The above fully protected intermediates can also be used to install D substituents by reducing the lactam functionality to a hemiaminal, followed by nucleophilic alkylation with a Grignard reagent (e.g. Ong, DY et al. Angew. Chem. Int. Ed. 2020, 59, 11903-11907).

[0078]

[0079] An example of the synthesis of the azabicyclic building blocks required to obtain the small ring annulation compound of Formula I is as follows:

[0080]

[0081] Homologues of ring sizes containing four-membered rings are obtained in the same manner from the anhydride of cyclobutane-1,2-dicarboxylic acid. In addition, the carbonyl transposition applied to the above ketones (Nakai, T.; Mimura, T. Tetrahedron Lett. 1979, 531-534; Review: Nakai, T.; Mimura, TJ Synth. Org. Jpn. 1977, 35, 964-978; Recent studies: Wu, Z. et al. Science 2021, 374, 734-740) provides ketone precursors of compounds of formula I, which contain a small ring at the position with substituents c and d.

[0082]

[0083] Allen, MP et al. disclose the synthesis of 3-benzyl-3-azabicyclo[3.2.1]octan-6-one and 3-benzyl-3-azabicyclo[3.2.2]nonan-6-one in US2005020830. These azabicyclic building blocks are intermediates in the synthesis of compounds of structure I, where substituents c and e are connected to form a bridge across the seven-membered ring.

[0084]

[0085] The synthesis of 6-benzyl-6-azabicyclo[3.2.1]octan-2,7-dione is disclosed in Diaba, F. et al. Org. Lett. 2015, 17, 3860-3863. This compound can be used to synthesize the compound of structure I shown below.

[0086]

[0087] The synthesis of 3-(4-methoxyphenyl)-7-methylpyridine-7-azabicyclo[4.1.1]octane is disclosed in Zhao, J. et al. Org. Lett. 2017, 19, 4880-4883. Further transformations as shown below produce azabicycloketones that can be used to synthesize compounds of structure I.

[0088]

[0089] Example 1. 7-Methyl-1,2,3,4,5,6-hexahydroazepine [4,5-b] indol-10-ol

[0090] Step 1. 4-(Benzyloxy)-2-bromo-1-toluene

[0091]

[0092] A suspension of NaH (60% in oil; 3.53 g, 88.2 mmol, 1.1 eq) in anhydrous DMF (20 mL) was placed in a 500 mL three-necked flask with a stirring bar, a septum, a dropping funnel with a septum, an Ar balloon, and an ice bath. A solution of 3-bromo-4-methylphenol (15.0 g, 80.2 mmol) in anhydrous DMF (60 mL) was added dropwise to the suspension under stirring and cooling over 15 minutes to give an amber suspension of phenolate. The mixture was stirred in an ice bath for 15 minutes and then stirred for another 15 minutes without cooling. After the mixture was cooled again in an ice bath, BnBr (pure; 10.5 mL, 88.2 mmol, 1.1 eq) was added dropwise over 35 minutes. The mixture was stirred for 2 hours without temperature control and then water (1 mL) was carefully added. The solvent was distilled into a receiver cooled with dry ice with gentle heating under oil pump vacuum. The residue was dissolved in heptane (30 mL) and the inorganic salts were removed by suction through diatomaceous earth. The filter residue was washed with more heptane (2×20 mL) and the filtrate was evaporated. The evaporation residue was filtered through silica gel (11×7 cm, eluted first with hexane, then with ethyl acetate / hexane 1:19). The impure late fractions were collected separately, evaporated, and column chromatographed again (silica gel, 16×5.5 cm, hexane, then ethyl acetate / hexane 1:49). A small amount of impure late fractions was removed again. Essentially pure fractions were collected from both columns and evaporated to give 20.8 g (94%) of benzyl ether as an almost colorless oil. 1H NMR (CDCl 3 ,TMS)δ7.43-7.36(m,4H),7.35-7.30(m,1H),7.19(d,1H,J=2.6Hz),7.12(d d,1H,J=8.4,0.2Hz),6.84(dd,1H,J=8.4,2.6Hz),5.02(s,2H),2.32(s,3H).

[0093] Step 2. tert-Butyl 2-[5-(benzyloxy)-2-methylphenyl]-1-methylhydrazine-1-carboxylate

[0094]

[0095] In a 100 mL three-necked flask equipped with a stirring bar, glass stopper, septum, reflux condenser with Ar balloon and heating mantle, a suspension of NaH (60% in oil; 0.54 g, 13.6 mmol, 1.4 equiv) in toluene (4 mL) was placed. 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 minutes, resulting in the evolution of hydrogen. After another 10 minutes, a clear brown solution was obtained, which was cooled to near room temperature. tert-Butyl 1-methylhydrazine-1-carboxylate (neat; 1.44 mL, 9.7 mmol) and 4-(benzyloxy)-2-bromo-1-toluene (neat with 0.5 mL toluene wash; 2.69 g, 9.71 mmol) were added.

[0096] Meanwhile, a solution of X-Phos (186 mg, 0.39 mmol, 40 milliequivalents) in toluene (4 mL) was deoxygenated in a separate three-necked flask by evacuating three times, each time with argon. Palladium acetate (44 mg, 195 μmol, 20 milliequivalents) was added to the solution through a temporarily opened side neck. The mixture was stirred at room temperature for 25 minutes to give a dark brown-red catalyst solution, which was added to the above reaction mixture as the last component via a syringe. The resulting dark amber mixture was heated to reflux for 8 hours. A precipitate began to form rapidly. After cooling, thin layer chromatography showed major spots (silica gel, ethyl acetate / hexane 1:9 and 1:4: Rf values ​​were approximately 0.2 and 0.5, respectively), in addition to several weak non-polar spots and 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 remove the tertiary alcohol to give a brown oil. The material was adsorbed onto silica gel (12 g) and chromatographed on silica gel (16×5.5 cm, ethyl acetate / hexane 1:8). Evaporation of the appropriate fractions gave the aminated product (2.33 g, 70%) as a tan solid. 1H NMR (CDCl 3 ,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,1H,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).

[0097] Step 3. 1-[5-(Benzyloxy)-2-methylphenyl]-2-methylhydrazine hydrochloride

[0098]

[0099] In a 150 mL round-bottom flask equipped with a stirring bar, a septum, and an Ar balloon (connected by a needle; to exclude moisture), the starting material (2.33 g, 6.80 mmol) was dissolved in MeOH and CH 2 Cl 2 (5 mL each). Pure trimethylsilyl chloride (1.30 mL, 10.2 mmol, 1.5 equiv) was added in small portions over 40 minutes under ice cooling. After stirring in the ice bath for another 20 minutes, the mixture consisted of a brown solution and suspended light-colored solids. Stirring was continued at room temperature and the precipitate began to dissolve, but eventually reappeared. The reaction was followed by a small aliquot (1 M NaHCO 3 TLC on silica gel after water treatment of aqueous solution / methyl tert-butyl ether. With methyl tert-butyl ether / hexane 1:2 as mobile phase, the Rf value of the starting material is about 0.55, and the product free base is about 0.15. After 5.2 hours, toluene (10 mL) was added and the more volatile solvent was removed by partial evaporation, leaving a suspension of the product in toluene. The product was filtered off with suction, washed with several small portions of toluene, and dried in vacuo to obtain 1.54 g (81%) of light pink powder. 1 H NMR (DMSO-d 6 ,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).

[0100] Step 4. Benzyl 4-(benzyloxy)-7-methylspiro[indole-3,4'-piperidine]-1'-carboxylate

[0101]

[0102] In a 100 mL round bottom flask with a stirring bar and an Ar balloon, a mixture of 1-[5-(benzyloxy)-2-methylphenyl]-2-methylhydrazine hydrochloride (522 mg, 1.87 mmol), N-Cbz-piperidine-4-carbaldehyde (463 mg, 1.87 mmol), acetic acid (5 mL) and anhydrous NaOAc (161 mg, 1.96 mmol, 1.05 equiv) was stirred in a 60 °C oil bath for 4.2 hours. After cooling, a small aliquot (2 M Na 2 CO 3The thin layer chromatogram after aqueous solution treatment with water / EtOAc showed a single mobile spot (SiO 2 , EtOAc / hexane 1:1 and 65:35:R f The values ​​were approximately 0.25 and 0.45, respectively). Most of the solvent was removed by vacuum distillation, and 1 M NaHCO 3 The phases were separated and the aqueous phase was further extracted with EtOAc (15 mL). The combined organic phases were washed with Na 2 SO 4 Dry and evaporate. The residue was quickly filtered on 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 (CDCl 3 ,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).13C NMR(CDCl 3 ,TMS)δ174.42,155.42,153.76,152.85,136.98,136.71,130.30,128.79,128.66(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(expanded),16.01; one aromatic C and one aliphatic C were not observed.

[0103] Step 5. Benzyl 10-(benzyloxy)-7-methyl-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate

[0104]

[0105] In a 50 mL round bottom flask equipped with a reflux condenser / Ar balloon, a stirring bar and a 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 temperature for 26.5, resulting in a dark color of the clay. After cooling, thin layer chromatography showed a single defined spot (silica gel, EtOAc / hexane 1:1, R f The value is about 0.65). The mixture was filtered through diatomaceous earth, and the residue was filtered through CH 2 Cl 2 The solution was partially evaporated to remove CH 2 Cl 2 The residual bromobenzene solution was chromatographed on silica gel (22 x 3.5 cm, EtOAc / hexanes, initially 1:19 to remove bromobenzene, then 1:2). Evaporation of the appropriate fractions gave 369 mg (73%) of a tan solid. 1 H NMR (CDCl 3 ,TMS; M = major, mi = minor urethane rotamer; ratio approximately 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, too much overlap to read J, mi), 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,2H,m i),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).

[0106] Step 6. 7-Methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-10-ol

[0107]

[0108] Pharmacology

[0109] Serotonin receptor 5-HT 2 Functional assays

[0110] Non-limiting examples of methods for measuring activation of serotonin receptor function are described below.

[0111] To measure serotonin receptor functional activation, selected compounds were subjected to Gq dissociation or Gq-dependent calcium flux by bioluminescence resonance energy transfer (BRET). 5-HT was measured by measuring Gq / γ1 dissociation by BRET 2 Receptor-mediated Gq activation (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-HT 2B receptor activation and biased agonism. Nat Struct Mol Biol. 2018; 25(9): 787-96), HEK293T cells were subcultured in Dulbecco's Modified Eagle Medium (DMEM) supplemented with 10% dialyzed fetal bovine serum (FBS) and transfected with human Gαq fused to RLuc8 (Gαq-RLuc8), C-terminally fused to GFP using TransiT-2020. 2 Human Gγ1 (Gγ1-GFP 2 ), human Gβ1, and 5-HT 2Receptors were co-transfected at a ratio of 1:1:1:1. After at least 18-24 hours, the transfected cells were plated at a density of 25,000-40,000 cells in 200 μL / well in DMEM containing 1% dialyzed FBS in a 96-well white transparent bottom cell culture plate coated with polylysine and incubated overnight. The next day, the culture medium was decanted, and the cells were washed with 60 μL of drug buffer (1×HBSS, 20mM HEPES, pH 7.4), and then 60 μL of drug buffer was added to each well. Before receiving drug stimulation, the cells were pre-incubated in a humidified atmosphere at 37°C. Drug stimulation was performed using the addition of 30 μL of drugs diluted in McCorvy buffer (1×HBSS, 20mM HEPES, pH 7.4, supplemented with 0.3% fatty acid-free BSA, 0.03% ascorbic acid) (3×), and the plate was incubated at 37°C for 1 hour. Substrate addition was performed 15 minutes before reading, and 10 μL of the RLuc substrate coelenterazine 400a was used for Gq dissociation BRET2 (Prolume / Nanolight, 5 μM final concentration). The plates were read for luminescence at 400 nm and fluorescent GFP at 510 nm using a Mithras LB940 (multi-mode microplate reader (e.g., a multi-mode microplate reader provided by Berthold)). 2 Emission was measured for 1 s per well. The BRET ratio of fluorescence / luminescence was calculated for each well using Graphpad Prism 8 (Graphpad Software Inc., San Diego, CA) and plotted as a function of drug concentration. Data were normalized to % 5-HT stimulation and analyzed using nonlinear regression "log (agonist) vs. response" to generate E max and EC 50 Parameter estimates.

[0112] Calcium flow was measured 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) using a stably expressed 5-HT2 Flp-In 293T-Rex tetracycline induction system. The cell line was maintained in DMEM containing 10% FBS, 10 μg / mL blasticidin and 100 μg / mL hygromycin B. At least 20-24 hours before the assay, receptor expression was induced with tetracycline (2 μg / mL), and cells were seeded into 384-well poly-L-lysine-coated black plates in DMEM containing 1% dialyzed FBS at a density of 7500 cells / well. On the day of determination, cells were incubated at 37°C for 1 hour with Fluo-4 Direct dye (Invitrogen, 20 μL / well) reconstructed in the drug buffer (HBSS buffered by 20mM HEPES, pH 7.4) containing 2.5mM probenecid. Drug dilutions were prepared with 5X final concentration in McCorvy buffer (HBSS buffered by 20mM HEPES, 0.1% BSA, 0.01% ascorbic acid, pH 7.4). After loading dye, cells were allowed to balance to room temperature for 15 minutes, and then placed in FLIPRTETRA fluorescence imaging plate reader (Molecular Devices). FLIPRTETRA was programmed to read baseline fluorescence 10s (1 reading / s), and 5 μL drugs / well were added afterwards, and fluorescence was read for 5-10min (1 reading / s) in total. The fluorescence in each well was normalized to the mean of the first 10 readings of baseline fluorescence, and then the maximum fold peak increase or area under the curve (AUC) relative to baseline was calculated. Peak value or AUC was plotted as a function of drug concentration, and the data were normalized to the percentage of 5-HT stimulation. Data were plotted and nonlinear regression was performed using the "log (agonist) vs. response" in Graphpad Prism 8 to generate E max and EC 50 Parameter estimates.

[0113] Various compounds disclosed herein target 5-HT 2A , 5-HT 2B and 5-HT 2CThe functional activity of each of the receptors was compared and measured relative to the functional activity of 4-hydroxytryptamine at these receptors. A comparison of the functional activities is provided in Table 2 below.

[0114]

[0115]

[0116]

[0117]

[0118] Table 3 below summarizes the 5-HT receptor activity of psilocybin, Compound 1 (also known as Pharm-136).

[0119]

[0120] Compounds of Formula I are generally considered to have potential "hERG risk" and therefore, are analyzed using pharmacological assays (e.g. Eurofins TM Many of the compounds disclosed in Tables 1 and 2 were screened for potential "hERG risk" using the hERG Qube APC assay. 50 , further evaluated the effects of 5-HT 2A The hERG IC values ​​of compounds with potent hERG receptors are 30-fold higher than the therapeutic free plasma concentrations. 50 The value is the threshold at which a compound is considered to have a low "hERG risk".

[0121] An important factor in assessing hERG risk in the early drug discovery phase is hERG IC 50 / in vitro 5-HT 2A ratio; compounds with a ratio greater than 200 will exhibit hERG IC 50 With estimated therapeutic plasma C max Compounds with a ratio of greater than 30 (which generally indicates low hERG potential at clinically relevant dose levels); compounds with a ratio between 150 and 200 generally indicate moderate hERG potential; compounds that exhibit IC 50 (hERG) / EC 50 (5-HT 2A ) ratio less than or equal to 150 generally indicates a high hERG risk potential.

[0122] The Ames fluctuation data for compound 1 are reported in Table 4:

[0123]

[0124]

[0125] In vitro Safety Screen 44 was performed on various compounds disclosed herein TM Detection, to identify the activity of missing the target. Then, the target compound identified in the group was tested in subsequent functional assays to identify whether these compounds have significant risk of missing the target. As summarized in Table 5 below, compound 1 does not have significant activity of missing the target. It is predicted that other compounds have similar characteristics to compound 1, and do not have activity of missing the target either.

[0126]

[0127] Additional testing was performed on compounds 1, W5, and A93. In addition, Tables 6a, 6b, and 6c summarize the expected hepatic clearance of compounds 1, W5, and A93 in various species, as shown in Tables 6a, 6b, and 6c, and determined by calculating the in vitro hepatocyte clearance rate over time and converting the rate using the hepatocyte counts of these species and the expected hepatic blood flow rate in these species.

[0128] Table 6a - Compound #1

[0129]

[0130] Table 6b - Compound W5

[0131]

[0132] Table 6c - Compound A93

[0133]

[0134] In addition, Table 7a and Table 7b summarize the plasma PK properties of Compound 1 observed in animals:

[0135] Table 7a

[0136]

[0137] Table 7b

[0138]

[0139] Head twitch responses (HTR) were assessed using a head-mounted neodymium magnet and a magnetometer detection coil as described by Halberstadt et al., Psychopharmacology (Berl.), 2013, 227(4):727-739. Table 8 below summarizes the ED of Compound 1 compared to psilocybin in head twitches in mice. 50 (measured at 60 minute intervals).

[0140] Table 8

[0141] Compound# <![CDATA[ED in head twitching 50 > Psilocybin 0.38mg / kg Cpd#1(Pharm-136) 3.6mg / kg

[0142] Figure 3 HTR of Compound 1 relative to dose is shown. Figure 3 , shows the change in HTR over time for different doses of Compound 1 (measured in mg / kg).

[0143] How to use

[0144] Based on several reported clinical trials using psilocybin itself, the indole compounds described herein are believed to be useful in treating treatment-resistant depression.

[0145] A 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 achieve 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).

[0146] In addition to the potential use of these analogs in the treatment of depression, other studies conducted by third-party groups of human volunteers have revealed that psilocybin can be used to treat tobacco addiction and alcohol addiction. In addition, in a controlled clinical setting, psilocybin was safely administered to subjects with OCD, and it was found that this drug treatment resulted in an acute reduction in core OCD symptoms in several 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).

[0147] Another potential use of these analogs is the treatment of epilepsy, including but not limited to infantile epilepsy 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).

[0148] The indole compounds described herein are believed to be safer than psilocybin because they lack at least some of the undesirable features of 5-HT2B agonist-related activity.

[0149] Application method

[0150] As contemplated herein, a therapeutically effective amount of an indole compound described herein is administered to a subject in need thereof. Whether such treatment is necessary depends on the subject's condition and is further subject to medical evaluation (diagnosis) that takes into account the presence of signs, symptoms and / or dysfunction, the risk of developing specific signs, symptoms and / or dysfunction, and other factors.

[0151] As contemplated herein, the indole compounds described herein can be administered by any suitable route known in the art. Such routes include, but are not limited to, oral, buccal, inhaled, topical, sublingual, rectal, vaginal, intracisternal or intrathecal by lumbar puncture, transurethral, ​​nasal, transdermal, 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 can be accomplished using a needle and syringe or using high pressure technology.

[0152] 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 their intended purpose. The exact formulation, route of administration, and dosage are determined by qualified practitioners based on the diagnosed condition or disease. The dosage and interval can be adjusted individually 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, rather than daily) to achieve the desired therapeutic effect.

[0153] As contemplated herein, the therapeutically effective amount of the indole compounds described herein for use in therapy varies with the nature of the condition being treated, the desired length of time of activity, and the age and condition of the patient, and is ultimately determined by the attending physician. The dose and interval can be adjusted individually to provide a plasma level of the indole compounds described herein sufficient to maintain the desired therapeutic effect. The desired dose can be conveniently administered in a single dose, or in multiple doses at appropriate intervals, such as one, two, three, four or more divided doses per day. Multiple doses may often be desired or required. For example, the indole compounds described herein can be administered at the following frequencies: four doses per day, four days apart (q4d×4); four doses per day, three days apart (q3d×4); one dose per day, five days apart (qd×5); one dose per week for three weeks (qwk3); five doses per day, two days off, and five doses per day (5 / 2 / 5); or any dosage regimen determined to be suitable for the situation.

[0154] As contemplated herein, the indole compounds described herein can be administered in admixture with a pharmaceutical carrier selected with regard to the intended route of administration and standard pharmaceutical practice. Pharmaceutical compositions for use according to the indole compounds described herein are formulated in a conventional manner using one or more physiologically acceptable carriers including adjuvants and auxiliaries that facilitate processing of the compounds herein.

[0155] When the indole compounds described herein are administered by intravenous injection, water is a preferred carrier. Saline solutions and aqueous solutions of glucose and glycerol can also be used as liquid carriers, particularly for injection solutions. Suitable pharmaceutical carriers also include excipients such as starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glyceryl monostearate, talc, sodium chloride, skimmed milk powder, glycerol, propylene glycol, water, ethanol, etc. If necessary, the composition may also contain a small amount of a wetting agent or emulsifier, or a pH buffer.

[0156] These pharmaceutical compositions can be prepared by, for example, conventional mixing, dissolving, granulating, making dragees, emulsifying, encapsulating, embedding or lyophilizing processes. Suitable formulations can be selected according to the route of administration. When a pharmaceutically effective amount of the indole compound described herein is administered orally, the compound is typically in the form of a tablet, capsule, powder, solution, or elixir. When administered in tablet form, the composition may also contain a solid carrier, such as gelatin or an adjuvant. 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 oils of animal and plant origin may be added. The composition in liquid form may further contain physiological saline solution, glucose or other sugar solutions or ethylene glycol. When administered in liquid form, the composition contains about 0.1% by weight to about 90% by weight (preferably about 1% by weight to about 50% by weight) of the compound described herein.

[0157] When a pharmaceutically 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. It is within the skill of the art to prepare such parenterally acceptable solutions with due consideration of pH, isotonicity, stability, etc. Compositions preferably administered by intravenous, cutaneous, or subcutaneous injection typically contain an isotonic carrier. The indole compounds described herein can be infused with other fluids over 10-30 minutes or several hours.

[0158] The indole compounds described herein can be readily combined with pharmaceutically acceptable carriers well known in the art. These carriers enable the active agents to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions, etc., for oral ingestion by a patient to be treated.

[0159] Oral pharmaceutical preparations can be obtained by adding the indole compounds described herein to solid excipients, grinding or not grinding the resulting mixture, and processing the granular mixture after adding suitable auxiliary agents (if necessary) to obtain tablets or dragee cores. Suitable excipients include, for example, fillers and cellulose preparations. If necessary, a disintegrant can be added.

[0160] The indole compounds described herein can be formulated for parenteral administration by injection (e.g., by bolus injection or continuous infusion). Injectable formulations can be present in unit dosage form, such as ampoules or multi-dose containers, and preservatives can be added. The composition can take the form of a suspension, solution, or emulsion in an oily or aqueous vehicle, and can contain preparatants, such as suspending agents, stabilizers, and / or dispersants.

[0161] Pharmaceutical compositions for parenteral administration include aqueous solutions of active agents in water-soluble form. In addition, suspensions of the indole compounds described herein can be prepared into suitable oily injection suspensions. Suitable lipophilic solvents or carriers include fatty oils or synthetic fatty acid esters. The injection suspension aqueous solution may include a substance that increases the viscosity of the suspension.

[0162] In some embodiments, the suspension may also contain suitable stabilizers or agents that increase the solubility of the compound to allow for the preparation of highly concentrated solutions. Alternatively, the composition may be in powder form for constitution with a suitable vehicle (eg, sterile pyrogen-free water) prior to use.

[0163] The indole compounds described herein can 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 can also be formulated into implants or injectable sustained-release injections (depot preparations) for parenteral administration. Such long-acting preparations can be administered by implantation (e.g., subcutaneous implantation or intramuscular implantation) or intramuscular injection. Thus, for example, the indole compounds described herein can be formulated with suitable polymers or hydrophobic materials (e.g., emulsions in acceptable oils) or ion exchange resins.

[0164] The indole compounds described herein can be administered orally, buccally, or sublingually in the form of tablets containing excipients such as starch or lactose, or in the form of capsules or ovules alone or mixed with excipients, or in the form of elixirs or suspensions containing flavoring agents or coloring agents. Such liquid compositions can be prepared using pharmaceutically acceptable additives such as suspending agents. The indole compounds described herein can also be injected parenterally, such as intravenously, intramuscularly, subcutaneously, or intracoronarily. For parenteral administration, the indole compounds described herein are preferably used in the form of sterile aqueous solutions, which may contain other substances, such as salts or monosaccharides (such as mannitol or glucose), to make the solution isotonic with the blood. At least in some embodiments, the indole compounds described herein are psilocybin analogs.

[0165] generally:

[0166] It is contemplated that any aspect or any portion of the embodiments discussed in this specification may be implemented or combined with any portion of any other aspect or embodiment discussed in this specification. Although specific embodiments have been described above, it should be understood that other embodiments are also possible and are intended to be included herein. It is clear to any person skilled in the art that modifications and adjustments to the aforementioned embodiments not shown are possible.

[0167] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those generally understood by those of ordinary skill in the art to which the invention belongs. In addition, the citation of any reference herein should not be interpreted or considered as admitting that these references are prior art of the present invention.

[0168] The scope of the claims should not be limited by the exemplary embodiments set forth herein, but should be given the broadest interpretation consistent with the description as a whole.

Claims

1. A chemical compound of formula I, or any isotopic configuration or pharmaceutically acceptable salt thereof: in: R 1 :(i) R 1 (ii) R 1 With e 1 or e 2 together forming a chain of 2 to 4 carbon atoms to which are attached substituents independently selected from the group consisting of H, C1-C6 alkyl, aryl, heteroaryl, and any combination thereof; and R 2 :(i) R 2 (ii) R is selected from the group consisting of 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 alkyl)(C1-C6 alkyl), C(═NOH)(C1-C6 alkyl), and C(═NOH)(C1-C6 substituted alkyl), phenyl, and halogen; or (ii) R 2 together with b, forms a chain of 2 or 3 atoms, one of which is selected from the group consisting of C, N, O and S, while the remaining atoms are carbon atoms, said chain containing 0, 1 or 2 double bonds, and to which the chain is 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, SCF3, cyano and oxo; or (iv) if b is halogen, CH3, CHF2, CF3, OCH3, OCHF2, OCF3, SCH3, SCHF2, SCF3 or cyano, R 2 is selected from the group consisting of 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, aryl(C1-C6 alkyl), heteroaryl, heteroaryl(C1-C6 alkyl), CN, C(O)NH2, 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); in some embodiments, R 2 Together with b, it forms CH2CH2, CH2CH2CH2, CH2CH2CH2CH2, CH=CHCH=CH, OCH2CH2, CH2OCH2, CH2CH2O, OCH=CH, CH=CHO, OCH2O, SCH2CH2, CH2SCH2, CH2CH 2S, 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=C H, CH═NNH, NHCH═N, N═CHNH, NHN═N, N═NNH, OCH2CH2CH2, CH2OCH2CH2, CH2CH2OCH2, CH2CH2CH2O, SCH2CH2CH2, CH2SCH2CH2, CH2CH2SCH2, CH2CH2CH2SNHCH2CH2CH2, CH2NHCH2CH2, CH2CH2NCH2, CH2CH2CH2NH, N═CHCH═CH, CH═NCH═CH, CH═CHN═CH, CH═CHCH═N; in some embodiments, R 2 Together with b, it forms CH2CH2, CH2CH2CH2, CH2CH2CH2CH2, CH=CHCH=CH, OCH2CH2, CH2OCH2, CH2CH2O, OCH=CH, CH=CHO, OCH2O, SCH2CH2, CH2SCH2, CH2CH2S, SCH=CH, CH=CHS, NHCH2CH2, CH2NH CH2, 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, CH2CH any of 2OCH2, CH2CH2CH2O, SCH2CH2CH2, CH2SCH2CH2, CH2CH2SCH2, CH2CH2CH2SNHCH2CH2CH2, CH2NHCH2CH2, CH2CH2NCH2, CH2CH2CH2NH, N=CHCH=CH, CH=NCH=CH, CH=CHN=CH, CH=CHCH=N, if present on the moiety, one or both hydrogen atoms are substituted by a substituent independently selected from the group consisting of halogen, OH, C1-C6 alkoxy, C1-C6 alkyl, C3-C6 cycloalkyl, CHF2, CF3, OCHF2, OCF3, SCH3, SCF3, and cyano, or if attached to the same carbon atom, two hydrogen atoms are substituted by oxo groups.

2. The chemical compound according to claim 1, wherein: a:(i) a is selected from H, halogen, lower alkyl, CHF2, CF3, OCH3, OCHF2, OCF3, SCHF2, SCH3, SCF3, amine and cyano; or (ii) a together with Z forms one of (A), (B) and (C), (A) a saturated chain of one oxygen and one carbon atom (the oxygen is attached to the 5-position of the indole ring of Formula I), (B) a chain of 2 or 3 carbon atoms, which is connected with 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, (C) a chain of 2 or 3 carbon atoms containing a double bond, which is connected (iii) a and b together form a chain of 3 or 4 atoms, one of which is selected from the group consisting of C, N, O and S, and the remaining atoms are carbon atoms, the chain containing 0, 1 or 2 double bonds, and the chain is connected with 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 b: (i) b is selected from the group consisting of H, halogen, CH3, CHF2, CF3, OCH3, OCHF2, OCF3, SCH3, SCHF2, SCF3, amine and cyano; or (ii) b and a together form a chain of 3 or 4 atoms, one of which is selected from the group consisting of C, N, O and S, and the remaining atoms are carbon atoms, the chain contains 0, 1 or 2 double bonds, and the chain is connected with 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) b and R 2 Together they form a chain of 3 or 4 atoms, one of which is selected from the group consisting of C, N, O and S, the remaining atoms being carbon atoms, the chain containing 0, 1 or 2 double bonds, and the chain being attached with 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.

3. The chemical compound according to claim 1 or 2, wherein: R 3 :(i) R 3 (ii) R 3 With f and R 3 The N atoms connected together form an azetidine or pyrrolidine ring, such ring having substituents independently selected from the group consisting of H, aryl, heteroaryl, C1-C6 alkyl and C3-C6 cycloalkyl; or (iii) R 3 With d and R 3 The attached N atoms together form an azetidine or pyrrolidine ring, such ring bearing substituents independently selected from the group consisting of H, aryl, heteroaryl, halogen, C1-C6 alkyl, and C3-C6 cycloalkyl.

4. The chemical compound according to any one of claims 1 to 3, wherein: c, d, e and f are independently H or a lower alkyl group; or c 1 With c 2 Together they form part of a spirofused cyclopropane or cyclobutane ring, and d, e and f are each H or a lower alkyl group; or d 1 With d 2 Together they form part of a spirofused cyclopropane or cyclobutane ring, and c, e and f are each H or a lower alkyl group; or e 1 With e 2 Together they form part of a spirofused cyclopropane or cyclobutane ring, and c, d and f are each H or a lower alkyl group; or f 1 With f 2 or one of c and one of d form -CH2- or -CH2CH2-, thereby producing a fused cyclopropane or cyclobutane ring, and each of the remaining c, d, e and f is H or a lower alkyl group; or one of e and one of f form -CH2- or -CH2CH2-, thereby producing a fused cyclopropane or cyclobutane ring, and each of the remaining c, d, e and f is H or a lower alkyl group; or one of c and one of e form -CH2- or -CH2CH2-, thereby producing a fused cyclopropane or cyclobutane ring, and each of the remaining c, d, e and f is H or a lower alkyl group; or one of c and one of e form -CH2- or -CH2CH2-, thereby producing a bridged bicyclic substructure, and c, d , e and f are each H or a lower alkyl group; or one of c and one of f are taken together to form -CH2- or -CH2CH2-, thereby producing a bridged bicyclic substructure, and each of the remaining c, d, e and f is H or a lower alkyl group; or one of d and one of e are taken together to form -CH2- or -CH2CH2-, thereby producing a bridged bicyclic substructure, and each of the remaining c, d, e and f is H or a lower alkyl group; or one of f and one of e are taken together to form -CH2- or -CH2CH2-, thereby producing a fused bicyclic substructure, and each of the remaining c, d, e and f is H or a lower alkyl group; or e and R 1 Together, they form a chain of 2 to 4 carbon atoms to which are attached substituents 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 they form -CH2- or -CH2CH2-, thereby producing a bridged bicyclic substructure, and the remainder of c, d, e and f are each H or a lower alkyl group; or one of d and R 3 together to form -CH2- or -CH2CH2-, thereby producing a fused bicyclic substructure, and the remainder of c, d, e and f are each H or a lower alkyl group; or one of e and R 3 together to form -CH2- or -CH2CH2-, thereby producing a fused bicyclic substructure, and the remainder of c, d, e and f are each H or a lower alkyl group; or one of f and R 3 Together they form -CH2- or -CH2CH2-, thereby creating a bridged bicyclic substructure, and the remainder of c, d, e and f are each H or a lower alkyl group.

5. The chemical compound according to any one of claims 1 to 4, wherein: Z: (i) Z is selected from 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), wherein R 5 is selected from the group consisting of 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), and its R 6 and R 7 are each independently selected from the group consisting of H, C1-C4 alkyl and C3-C6 cycloalkyl, or are linked to form a 4-7 membered heterocyclyl group; or (ii) Z is (R 8 O)(R 9 O)P(O)-, where R 8 and R 9 Each is independently selected from H or a cation counterion in the form of a phosphate, such as sodium, potassium, half of magnesium, half of calcium, ammonium, or ammonium substituted by one or more alkyl or cycloalkyl groups; or (iii) Z and c together form a bond to produce a pyran ring or an oxepane ring, the ring comprising a substituent independently selected from the group consisting of H, halogen, C1-C6 alkyl and C3-C6 cycloalkyl; or (iv) Z and a together form one of (A) and (B) and (C), (A) a saturated chain of one oxygen and one carbon atom (the oxygen is attached to the 5-position of the indole ring of Formula I), (B) a chain of 2 or 3 carbon atoms, the chain being connected (C) a chain of 2 or 3 carbon atoms containing a double bond and having 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.

6. The chemical compound according to claim 1, wherein: (i)R 1 is selected from the group consisting of H, C1-C6 alkyl and C1-C6 substituted alkyl; (ii) R 2 (iii) a and b are each selected from the group consisting of H, halogen, lower alkyl, CHF2, CF3, OCH3, OCHF2, OCF3, SCHF2, SCH3, SCF3 and cyano; (iv) c, d, e and f are each H or a lower alkyl group; and (v) R 3 Selected from the group consisting of H and C1-C6 alkyl.

7. The chemical compound according to claim 1, wherein the compound has the following chemical formula:

8. The chemical compound according to claim 1, wherein the compound is or its conjugate base.

9. The chemical compound according to claim 1, wherein the compound is or its conjugate base.

10. The chemical compound according to claim 1, wherein the compound is or its conjugate base.

11. A method of treating a disorder, the method comprising administering to a patient an effective amount of a compound as claimed in any one of claims 1 to 10.

12. The method according to claim 11, wherein: The condition is selected from the group consisting of major depressive disorder, treatment-resistant depression and depression with psychotic symptoms, addiction, pain indications, inflammation, eating disorders, dementia, post-traumatic stress disorder, emotional distress related to cancer, fragile X syndrome, autism spectrum disorder, bipolar disorder, obsessive-compulsive disorder, and Rett syndrome; the addiction includes alcoholism, tobacco addiction, cocaine addiction, and opioid addiction; the pain indications include neuropathic pain, pain caused by chemotherapy-related neuropathy, phantom limb pain, and fibromyalgia; the inflammation includes chronic inflammation and acute inflammation; the eating disorders include anorexia, autism, cluster headache, and migraine; the dementia includes Alzheimer's dementia, Parkinson's dementia, and Lewy body dementia.

13. A method of treating a disorder comprising administering to a patient an effective amount of a compound as claimed in any one of claims 8 to 10.

14. The method according to claim 13, wherein: The condition is selected from the group consisting of major depressive disorder, treatment-resistant depression and depression with psychotic symptoms, addiction, pain indications, inflammation, eating disorders, dementia, post-traumatic stress disorder, emotional distress related to cancer, fragile X syndrome, autism spectrum disorder, bipolar disorder, obsessive-compulsive disorder, and Rett syndrome; the addiction includes alcoholism, tobacco addiction, cocaine addiction, and opioid addiction; the pain indications include neuropathic pain, pain caused by chemotherapy-related neuropathy, phantom limb pain, and fibromyalgia; the inflammation includes chronic inflammation and acute inflammation; the eating disorders include anorexia, autism, cluster headache, and migraine; the dementia includes Alzheimer's dementia, Parkinson's dementia, and Lewy body dementia.

15. Use of a compound according to any one of claims 8 to 10 in the treatment of a condition selected from the group consisting of major depressive disorder, drug-resistant depression and depression with psychotic symptoms, addiction, pain indications, inflammation, eating disorders, dementia, post-traumatic stress disorder, emotional distress associated with cancer, fragile X syndrome, autism spectrum disorder, bipolar disorder, obsessive-compulsive disorder, Rett syndrome; the addiction includes alcoholism, tobacco addiction, cocaine addiction and opioid addiction; the pain indications include neuropathic pain, pain caused by chemotherapy-related neuropathy, phantom limb pain and fibromyalgia; the inflammation includes chronic inflammation and acute inflammation; the eating disorders include anorexia, autism, cluster headache, migraine; the dementia includes Alzheimer's dementia, Parkinson's dementia and Lewy body dementia.

16. Use according to claim 15, wherein the condition is selected from the group consisting of major depressive disorder, treatment-resistant depression and depression with psychotic symptoms.

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