CN117897376A

CN117897376A - Heterocyclic compounds and process for preparing same

Info

Publication number: CN117897376A
Application number: CN202280052820.8A
Authority: CN
Inventors: A·科齐克奥沃夫斯基; W·蒂克曼特尔; J·麦科维; U·拉班
Original assignee: Wisconsin Medical College Co; Guangming Intelligent Biological Science Co
Current assignee: Wisconsin Medical College Co; Guangming Intelligent Biological Science Co
Priority date: 2021-05-26
Filing date: 2022-05-25
Publication date: 2024-04-16

Abstract

The present disclosure relates to heterogenies of formula (I), formula (II) and formula (III)Ring compounds and their preparation and use. As contemplated herein, the heterocyclic compounds of formula (I), formula (II) and formula (III) may be used to treat neuropsychiatric and neurodegenerative, neuritic and pain disorders, including depression, as well as tobacco, opiate and cocaine addiction, alcoholism, post-traumatic stress disorder (PTSD), and neuropathic pain syndromes, including cluster headache and chemotherapy-induced peripheral neuropathy.

Description

Heterocyclic compounds and process for preparing same

Cross-reference:

the present application claims the benefit of U.S. patent application Ser. No. 63/193,062, filed on (i) 5 th month 26 of 2021, and U.S. patent application Ser. No. 63/309,735, filed on 2 nd month 14 of 2022.

Technical field:

the present disclosure relates to heterocyclic compounds and methods of making the same. The disclosure also relates to the use of the heterocyclic compounds as selective agents at serotonin receptors.

The background technology is as follows:

nupharicin is a naturally occurring magic compound that is produced by over 200 mushroom species collectively referred to as "nupharicin mushrooms". As a prodrug, nupharin is rapidly metabolized by the body to produce the bioactive compound nupharin (psilocin), which has a mental change effect that is not different from that produced by other hallucinogens such as lysergic acid diethylamide (LSD), mo Sika, and N, N-Dimethyltryptamine (DMT). These effects include, inter alia, euphoria, visual and mental hallucinations, changes in perception, distorted temporal sensations, and mental experiences, and may also include possible adverse effects such as nausea and panic attacks. For reference, the chemical structure of nudity is provided below.

As 5-HT _2A And 5-HT _2C Agonists of the receptor, galectin and nupharmic have been identified as having therapeutic potential. Due to 5-HT _2A Receptor activation appears to increase motor activity while 5-HT _2C Receptor activation appears to reduce motor activity and thus has varying degrees of 5-HT _2A And 5-HT _2C Active compounds will show different levels of pseudoactivity (Halberttadt AL, van der Heijden I, ruderman MA, risbrough VB, gingrich JA. Geyer MA, powell SB, neurophysichloropharmacology, 2009,34 (8): 1958-67). Although Hofmann and its co-workers have explored nuda in Sandoz along with other fantasy drugs (see, e.g., hofmann, a., troxler, f.us 3,075,992;US 3,078,214) more than 60 years ago, clinical studies on these drugs have significantly decreased by the beginning of the 70 th century-particularly after these drugs were placed in the us controlled substance act (Controlled Substance Act) schedule 1. However, while nupharicin and other fantasy drugs are listed as controlled substances in some jurisdictions, their research has never completely stopped, and recent clinical studies have led to renewed interest in the potential use of fantasy drugs, including nupharicin, in ever-evolving medical fields such as the treatment of Central Nervous System (CNS) diseases. CNS disorders include both refractory mental health disorders (Daniel J, haberman m. Clinical potential of psilocybin as a treatment for mental health conditions, vent. Health clin.2017,7 (1), 24-8), such as treatment-resistant or drug-resistant depression, and neurological disorders, such as cluster headaches.

Although galectin has been identified as having therapeutic potential for treating certain CNS diseases and disorders, it has also been identified as 5-HT _2B Receptor agonists and are therefore cardiotoxic. Thus, for maintenance of 5-HT _2A Receptor agonist activity but lack cardiotoxic 5-HT _2B Agonist active nupharicin and nupharicin safer drugsThere is an unmet need for analogues and analogues; in addition and at least in some cases, to maintain 5-HT _2A Receptor agonist activity but lack cardiotoxic 5-HT _2B There is an unmet need for safer drugs with agonist activity.

The invention comprises the following steps:

the present disclosure relates to indole compounds, such as 7-substituted indole compounds and 5-substituted indole compounds, which exhibit 5-HT _2A Receptor agonist activity while exhibiting low 5HT _2B Receptor agonist activity. In at least some cases, such compounds have also been shown to be relative to 5-HT _2C Receptors for 5-HT _2A Receptor selectivity. The compounds disclosed herein are useful in the treatment of depression including major depressive disorder, drug-resistant depression and psychotic depression, 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 and acute), eating disorders including anorexia, autism, cluster headache, migraine, dementia including Alzheimer's dementia, parkinson's dementia and dementia with lewy bodies, post-traumatic stress disorder, mood disorders associated with cancer, fragile X syndrome, autism spectrum disorders, bipolar disease, obsessive compulsive disorder, and Rattsyndrome (Rett syndrome) and other CNS disorders.

According to a part of the present disclosure, there is a chemical entity of formula I,

wherein R is ¹ 、R ² 、R ³ 、R ⁴ A, b, c, d, e, f and Z are as defined below, and wherein R ² Is substituted.

The chemical entity of formula I is a peptide having the formula I as compared to 5-HT _2B Subtype selective 5-HT _2A Receptor agonists. Chemical entities of formula I and pharmaceutical compositions thereofThe above-acceptable compositions are potentially useful for treating a variety of diseases and disorders associated with 5-HT2A receptor agonism. Such diseases and disorders include those described herein.

According to a part of the present disclosure, there is a chemical entity of formula II,

wherein R is ¹ 、R ² 、R ³ 、R ⁴ A, b, c, d, e, f and Z are as defined below.

The chemical entity of formula II is a peptide having the formula corresponding to 5-HT _2B Subtype selective 5-HT _2A Receptor agonists. The chemical entity of formula II and its pharmaceutically acceptable compositions are potentially useful for the treatment of a variety of conditions and 5-HT _2A Diseases and disorders associated with receptor agonism. Such diseases and disorders include those described herein.

According to a part of the present disclosure, there is a chemical entity of formula III,

wherein R is ³ 、R ⁴ A, b, c, d, e and f are defined below, and wherein R is ² Is O or S.

The chemical entity of formula III is of the formula relative to 5-HT _2B Subtype selective 5-HT _2A Receptor agonists. The chemical entities of formula III and pharmaceutically acceptable compositions thereof are potentially useful for treating a variety of conditions and 5-HT _2A Diseases and disorders associated with receptor agonism. Such diseases and disorders include those described herein.

This summary does not necessarily describe the full scope of all aspects of the disclosure. Other aspects, features and advantages will become apparent to those of ordinary skill in the art upon review of the following description of specific embodiments.

The specific embodiment is as follows:

directional terms such as "top", "bottom", "upward", "downward", "vertical" and "transverse" are used in the following description for the purpose of providing relative reference only, and are not intended to place any limitation on how any item is positioned during use, or mounted in an assembly or relative to the environment. When used herein in conjunction with the term "comprising," the use of the word "a" or "an" may refer to "one or more," 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 the plural. Any element expressed in a plurality also encompasses singular forms thereof. The term "plurality" as used herein refers to more than one, e.g., two or more, three or more, four or more, etc.

As used herein and unless otherwise specified, the term "about" when used to describe an recited value means within 10% of the recited value.

As used herein and unless otherwise specified, the term "alkenyl" refers to a substituted or unsubstituted, straight 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-pentadien-1-yl, 1, 4-pentadien-3-yl, and the like.

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).

As used herein and unless otherwise specified, 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 specified, alkyl Containing 1 to 7 carbon atoms (' C) ₁ -C ₇ Alkyl "). For example, in some embodiments, the alkyl group contains 1 to 6 carbon atoms ("C ₁ -C ₆ Alkyl "); in some embodiments, the alkyl group contains 1 to 5 carbon atoms ("C ₁ -C ₅ Alkyl "); 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 Alkyl "). Non-limiting examples of saturated alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, homologs and isomers of, for example, n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like. Examples of lower alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl and tert-butyl. A substituted alkyl group is an alkyl group having at least one but not more than five substituents, and the number of substituents does not exceed the number of hydrogen atoms in the unsubstituted group. In some embodiments, the substituent is a fluorine atom. Non-limiting examples of substituted alkyl groups include 2-hydroxyethyl, 2-methoxyethyl, CHF ₂ 、CF ₃ 、CH ₂ CF ₃ 、CF ₂ CF ₃ 4-fluorobutyl, etc.

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, 3-butyn-1-yl, and the like.

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 contain 6 or 10 ring members. Non-limiting examples of aryl groups include phenyl, naphthyl, and the like. The term "aryl" also refers to aryl groups that may be unsubstituted or substituted. For example, aryl groups may be unsubstituted, or may be independently selected from one, two or threeSubstitution of a 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 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.

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 appropriate), or in salt form, particularly in a pharmaceutically acceptable salt form, and furthermore, whether in solid form or otherwise. 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., polymorph, pseudohydrate, hydrate, or solvate). Similarly, the term encompasses compounds, whether provided in solid form or otherwise. Unless otherwise specified, all statements herein regarding "compounds" apply to the relevant chemical entities as defined.

As used herein and unless specified otherwise, the terms "comprising," "having," "including," "containing," and grammatical variants 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.

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, may be present, but that such additions do not materially affect the manner in which the recited composition, method, or use functions.

As used herein and unless otherwise specified, the term "consisting of" excludes the presence of additional elements and/or method steps when used herein in combination with a composition, use, or method.

As used herein and unless otherwise specified, the term "cycloalkyl" 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 unsaturated units, but is not aromatic; or (ii) bicyclo [ m.n.o ] ]Alkyl, wherein each of "m", "n", and "o" is independently an integer ranging from 0 to 5, and the sum of "m" + "n" + "o" ranges from 2 to 6. In some embodiments, cycloalkyl contains 3 to 8 ring carbon atoms ("C ₃ -C ₈ Cycloalkyl "). Non-limiting examples of cycloalkyl groups 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]And (3) amyl. Substituted cycloalkyl is a group having at least one but no 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, 4-difluorocyclohexyl, and the like.

As used herein and unless otherwise specified, the term "halogen" or "halo" used alone or as part of a larger moiety refers to fluorine, chlorine, bromine or iodine.

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 with nitrogen, oxygen, or sulfur.

As used herein and unless otherwise specified, the term "heteroaryl" alone or as part of a larger moiety (e.g., "(heteroaryl) alkyl) refers to a monovalent monocyclic or bicyclic group having 5 to 10 ring atoms, preferably 5, 6, 9, or 10 ring atoms, 6 or 10 pi electrons shared in a cyclic array, and having 1 to 4 ring heteroatoms in addition to ring carbon atoms. Examples of heteroaryl groups include thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, indolizinyl, benzofuranyl, benzothienyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, benzotriazole, quinolinyl, isoquinolinyl, purinyl, naphthyridinyl, pteridinyl, and the like. Heteroaryl groups may be unsubstituted or may be substituted with 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 -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.

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 saturated or partially unsaturated and has 1 to 4 heteroatoms in addition to ring carbon atoms. Non-limiting example package of heterocyclyl groupsIncluding tetrahydrofuranyl, pyrrolidinyl, tetrahydropyranyl, piperidinyl, morpholinyl, and the like. The heterocyclic group may be unsubstituted or may be substituted. For example, the heterocyclyl may be unsubstituted or may be substituted with 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 group, C ₁ -C ₆ Alkyl, substituted C ₁ -C ₆ Alkyl, and C ₃ -C ₆ Cycloalkyl groups.

As used herein and unless otherwise specified, the term "inactive" (and all terms related thereto, including "inactive") is used as in "EC ₅₀ (nM) "and" Eff% "(such terms as understood by those skilled in the art or equivalent) and when referring to a target for 5-HT _2B The active use of the receptor refers to a concentration of greater than 10,000nM (when in "EC ₅₀ (nM) "or 30% or less efficacy (when used in the context of" Eff% ").

As used herein and unless otherwise specified, 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 are either independent of the natural isotope composition or enriched or depleted in heavy isotopes ² H (D, deuterium) and ³ any isotopic composition of one or both of H (T, tritium) ranges from depleted to 0% to enriched to 100%.

As used herein and unless otherwise specified, the term "pharmaceutically acceptable salts" refers to those salts that are, 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 response and the like and are commensurate with a reasonable benefit/risk ratio. Pharmaceutically acceptable salts of the compounds provided in this disclosure include salts derived from suitable inorganic and organic acids and bases. Non-limiting examples of pharmaceutically acceptable salts include those 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 Salts of amino-containing compounds formed from acids, citric acid, succinic acid or malonic acid. Other non-limiting examples of pharmaceutically acceptable salts include adipates, alginates, ascorbates, aspartate, benzenesulfonates, benzoates, bisulphates, borates, butyrates, camphorates, camphorsulfonates, cyclopentane propionates, digluconates, dodecyl sulfate, ethanesulfonates, formates, fumarates, glucoheptanoates, glycerophosphate, gluconates, hemisulfates, heptanoates, caprates, hydroiodinates, 2-hydroxyethanesulfonates, lactonates, lactates, laurates, lauryl sulfates, malates, methanesulfonates, 2-naphthalenesulfonates, nicotinates, nitrates, oleates, palmates, pamonates, pectinates, persulfates, 3-phenylpropionates, pivalates, propionates, stearates, thiocyanates, p-toluenesulfonates, undecanoates, valerates, and the like. Other pharmaceutically acceptable salts include those derived from suitable bases such as alkali metals, alkaline earth metals, ammonium and N ⁺ (C _1-4 Alkyl group ₄ And (3) salt. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Other non-limiting examples of pharmaceutically acceptable salts include non-toxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate, and aryl sulfonate, as appropriate.

As used herein and unless otherwise specified, the term "subject" includes mammals (e.g., humans, and in some embodiments, prenatal human forms). In some embodiments, the subject has a related 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 the disease, disorder, or condition. In some embodiments, the subject is a mammal having one or more characteristics of susceptibility or risk for a disease, disorder, or condition. In some embodiments, the subject is a patient. In some embodiments, the subject is an individual who is administered and/or has been administered diagnosis and/or therapy. In some embodiments, the subject is a fetus, infant, child, adolescent, adult, or elderly person (i.e., the subject is older, such as greater than 50 years old). In some embodiments, a child refers to a human between the ages of 2 and 18 years. In some embodiments, adult refers to a human aged 18 years or older.

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

References to specific moieties, functional groups or substituents contemplate (where applicable) tautomers thereof.

Unless otherwise specified, structures depicted herein include all isomeric (e.g., enantiomer, diastereomer, and geometric (or conformational)) forms of the structure (e.g., R and S configuration, Z and E double bond isomers, and Z and E conformational isomers of each asymmetric center). Unless otherwise specified, compounds disclosed, taught or otherwise set forth in this disclosure contemplate all single stereochemical isomers, as well as enantiomers, diastereomers and geometric (or conformational) mixtures thereof. Unless otherwise specified, compounds disclosed, taught, or otherwise set forth in this disclosure contemplate all tautomeric forms thereof. In addition, unless specified otherwise, structures depicted herein include compounds in which only one or more isotopically enriched atoms are present. Such compounds are useful, for example, as analytical tools, probes in biological assays, or as therapeutic agents. In addition, heavier isotopes such as deuterium are incorporated ² H) Certain therapeutic advantages may be provided due to greater metabolic stability, e.g., increased in vivo half-life or reduced dosage requirements.

The chemical entities described herein are further illustrated by the classes, subclasses, and species disclosed herein. For the purposes of this disclosure, chemical elements are identified according to the periodic table of elements, CAS version Handbook of Chemistry and Physics, 75 th edition, inner cover, and specific functional groups are generally defined as described herein. In addition, the general principles of organic chemistry and specific functional moieties and reactivities are described in Thomas Sorrell, organic Chemistry, university Science Books, sausalato, 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 Carruther, some Modern Methods of Organic Synthesis, 3 rd edition, cambridge University Press, cambridge, 1987. In this disclosure, any atom that is not explicitly specified as a particular isotope is intended to represent any stable isotope of that atom.

Unless otherwise specified, structures depicted herein are also intended to include all stereoisomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structures; for example, the R and S configuration, Z and E double bond isomers, and Z and E conformational isomers for each asymmetric center. Thus, the compounds of the present invention contemplate all single stereochemical isomers as well as enantiomeric, diastereoisomeric and geometric (or conformational) mixtures thereof. Unless otherwise specified, the compounds of the present invention contemplate all tautomeric forms thereof. In addition, unless specified otherwise, structures depicted herein are also intended to include compounds in which only one or more isotopically enriched atoms are present. Such compounds are useful, for example, as analytical tools, probes in biological assays, or as therapeutic agents. In addition, heavier isotopes such as deuterium are incorporated ² H) Certain therapeutic advantages may be provided due to greater metabolic stability, e.g., increased in vivo half-life or reduced dosage requirements.

According to some embodiments of the chemical entities disclosed herein, there is a chemical entity of formula I:

wherein:

R ¹ : (i) selected from the group consisting of: H. c (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 group, 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 An alkyl group); or (ii) and R ² Together forming a chain of 2 to 4 carbon atoms to which are attached substituents independently selected from the group consisting of: H. c (C) ₁ -C ₆ Alkyl, aryl, heteroaryl, and any combination thereof;

R ² : (i) selected from the group consisting of: c (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 group, C ₃ -C ₆ Heterocyclyl, (C) ₃ -C ₆ Heterocyclyl) (C) ₁ -C ₆ Alkyl), aryl (C) ₁ -C ₆ Alkyl), 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); or (ii) and R ¹ Together forming a chain of 2 to 4 carbon atoms to which are attached substituents independently selected from the group consisting of: H. c (C) ₁ -C ₆ Alkyl, aryl, and heteroaryl; or (iii) forms a chain of 3 or 4 atoms with b, wherein one atom is selected from the group consisting of: C. n, O and S, while the remainder are carbon, said chain containing 0, 1 or 2 double bonds and having attached thereto substituents 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 、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, then selected from the group consisting of: H. c (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 group, C ₃ -C ₆ Heterocyclyl, (C) ₃ -C ₆ Heterocyclyl) (C) ₁ -C ₆ Alkyl), aryl (C) ₁ -C ₆ Alkyl), 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). In some embodiments, R ² Together with b, any one of the following is formed: CH (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＝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 S、NHCH 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. In some embodiments, R ² Together with b, any one of the following is formed: CH (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＝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 S、NHCH 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, wherein one or both hydrogen atoms, if present on the moiety, are replaced by substituents independently selected from the group consisting of And (3) substitution: 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 And cyano, or wherein two hydrogens, if attached to the same carbon atom, are replaced with oxo;

a: (i) selected from the group consisting of: H. halogen, lower alkyl, CHF ₂ 、CF ₃ 、OCH ₃ 、OCHF ₂ 、OCF ₃ 、SCHF ₂ 、SCH ₃ 、SCF ₃ And cyano; or (ii) forms with Z one of the following: (A) A saturated chain of one oxygen and one carbon atom (wherein the oxygen is attached to the 5-position of the indole ring of formula I), and (B) a chain of 2 or 3 carbon atoms to which 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 、CF ₃ 、OCHF ₂ 、OCF ₃ 、SCH ₃ 、SCHF ₂ 、SCF ₃ Cyano and oxo groups, and (C) a chain of 2 or 3 carbon atoms containing one double bond, 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 、CF ₃ 、OCHF ₂ 、OCF ₃ 、SCHF ₂ 、SCH ₃ 、SCF ₃ Cyano and oxo; or (iii) forms a chain of 3 or 4 atoms with b, wherein one atom is selected from the group consisting of: C. n, O and S, while the remainder are carbon, said chain containing 0, 1 or 2 double bonds and having attached thereto substituents 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 、CF ₃ 、OCHF ₂ 、OCF ₃ 、SCH ₃ 、SCHF ₂ 、SCF ₃ Cyano and oxo groupsThe method comprises the steps of carrying out a first treatment on the surface of the And is also provided with

b: (i) selected from the group consisting of: H. halogen, CH ₃ 、CHF ₂ 、CF ₃ 、OCH ₃ 、OCHF ₂ 、OCF ₃ 、SCH ₃ 、SCHF ₂ 、SCF ₃ And cyano; or (ii) forms a chain of 3 or 4 atoms with a, wherein one atom is selected from the group consisting of: C. n, O and S, while the remainder are carbon, said chain containing 0, 1 or 2 double bonds and having attached thereto substituents 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 、CF ₃ 、OCHF ₂ 、OCF ₃ 、SCH ₃ 、SCHF ₂ 、SCF ₃ Cyano and oxo; or (iii) and R ² Together forming a chain of 3 or 4 atoms, one of which is selected from the group consisting of: C. n, O and S, while the remainder are carbon, said chain containing 0, 1 or 2 double bonds and having attached thereto substituents 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 、CF ₃ 、OCHF ₂ 、OCF ₃ 、SCH ₃ 、SCHF ₂ 、SCF ₃ Cyano and oxo;

wherein:

R ³ : (i) selected from the group consisting of: H. c (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 An alkyl group); or (ii) and R ⁴ Together with the N atom to which they are attached form a 4-7 membered heterocyclyl ring; or (iii) with f and R ³ The attached N atoms together form an azetidine or pyrrolidine ring carrying a ring independently selected from the group consisting ofSubstituents: H. aryl, heteroaryl, C ₁ -C ₆ Alkyl and C ₃ -C ₆ Cycloalkyl; or (iv) with c and R ³ The attached N atoms together form an azetidine or pyrrolidine ring carrying substituents independently selected from the group consisting of: H. aryl, heteroaryl, halogen, C ₁ -C ₆ Alkyl and C ₃ -C ₆ Cycloalkyl;

R ⁴ : (i) selected from the group consisting of: H. c (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 An alkyl group); or (ii) and R ³ Together with the N atom to which they are attached form a 4-7 membered heterocyclyl ring;

wherein:

c. d, e and f are each H; or three of c, d, e and f are H and the remaining substituents are lower alkyl; or c and f are each H and d and e together are-CH ₂ -or-CH ₂ CH ₂ -thereby producing a cyclopropane or cyclobutane ring; or c, d and e are each H, and f, R ³ And R is ³ The attached N atoms together form an azetidine or pyrrolidine ring carrying substituents independently selected from the group consisting of: H. aryl, heteroaryl, C ₁ -C ₆ Alkyl and C ₃ -C ₆ Cycloalkyl; or d, e and f are each H, and c, R ³ And R is ³ The attached N atoms together form an azetidine or pyrrolidine ring carrying substituents independently selected from the group consisting of: H. aryl, heteroaryl, halogen, C ₁ -C ₆ Alkyl and C ₃ -C ₆ Cycloalkyl; or d, e and f are each H, and c and Z together contain 1 or 2 carbon atoms, thereby producing a pyran or oxaheptane ring bearing substituents independently selected from the group consisting of: H. halogen, C ₁ -C ₆ Alkyl and C ₃ -C ₆ Cycloalkyl; and is also provided with

Wherein:

z: (i) selected from the group consisting of: H. r is R ⁵ 、(R ⁶ )(R ⁷ )N-C(O)-、C ₁ -C ₆ alkyl-C (O), C ₃ -C ₆ cycloalkyl-C (O), aryl-C (O) and heteroaryl-C (O), wherein R ⁵ Selected from the group consisting of: c (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 wherein R is ⁶ And R is ⁷ Each independently selected from the group consisting of: H. c (C) ₁ -C ₄ Alkyl and C ₃ -C ₆ Cycloalkyl, or linked to form a 4-7 membered heterocyclyl; or (ii) is (R) ⁸ O)(R ⁹ O) P (O) -, wherein R ⁸ And R is ⁹ Each independently is a cationic counterion in the form of H or phosphate, such as sodium, potassium, half magnesium, half calcium, ammonium, or ammonium substituted with one or more alkyl or cycloalkyl groups; or (iii) forms together with c a linkage that results in a pyran or oxacycloheptane ring comprising substituents independently selected from the group consisting of: H. halogen, C ₁ -C ₆ Alkyl and C ₃ -C ₆ Cycloalkyl; or (iv) together with a forms one of the following: (A) A saturated chain of one oxygen and one carbon atom (wherein the oxygen is attached to the 5-position of the indole ring of formula I), and (B) a chain of 2 or 3 carbon atoms to which 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 、CF ₃ 、OCHF ₂ 、OCF ₃ 、SCH ₃ 、SCHF ₂ 、SCF ₃ Cyano and oxo, and (C) a chain of 2 or 3 carbon atoms containing one double bond and bearing substituents independently selected from the group consisting of: H. halogen (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.

According to other embodiments of the chemical entities disclosed herein, there is a chemical entity of formula II:

wherein:

R ¹ : (i) selected from the group consisting of: H. c (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 group, C ₃ -C ₆ Heterocyclyl, (C) ₃ -C ₆ Heterocyclyl) (C) ₁ -C ₆ Alkyl), aryl (C) ₁ -C ₆ Alkyl) or heteroaryl (C) ₁ -C ₆ An alkyl group); or (ii) and R ² Together forming a chain of 2 to 4 carbon atoms to which are attached substituents independently selected from the group consisting of: H. c (C) ₁ -C ₆ Alkyl, aryl, and heteroaryl;

R ² : (i) selected from the group consisting of: c (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 group, C ₃ -C ₆ Heterocyclyl, (C) ₃ -C ₆ Heterocyclyl) (C) ₁ -C ₆ Alkyl), aryl (C) ₁ -C ₆ Alkyl), heteroaryl (C) ₁ -C ₆ Alkyl), cyano, C (O) NH ₂ 、C(O)NH(C ₁ -C ₆ Alkyl group, C(＝NOH)(C ₁ -C ₆ Alkyl) and C (=noh) (C ₁ -C ₆ Substituted alkyl); or (ii) and R ² Together form C ₂ -C ₄ An alkyl linkage comprising substituents independently selected from the group consisting of: H. c (C) ₁ -C ₆ Alkyl, aryl, and heteroaryl; or (iii) forms a chain of 3 or 4 atoms with b, wherein one atom is selected from the group consisting of: C. n, O and S, while the remainder are carbon, said chain containing 0, 1 or 2 double bonds and having attached thereto substituents 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 、CF ₃ 、OCHF ₂ 、OCF ₃ 、SCH ₃ 、SCHF ₂ 、SCF ₃ Cyano and oxo; or (iv) if b is not H, then H. In some embodiments, R ² Together with b, any one of the following is formed: CH (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＝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 S、NHCH 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. In some embodiments, R ² Together with b, any one of the following is formed: CH (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＝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 S、NHCH ₂ CH ₂ CH ₂ 、CH ₂ NHCH ₂ CH ₂ 、CH ₂ CH ₂ NHCH ₂ 、CH ₂ CH ₂ CH ₂ NH, n=chch=ch, ch=nch=ch, ch=chn=ch, ch=chch=n, one or two hydrogen atoms, if present on a moiety, are replaced by substituents independently selected from the group consisting of: 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 And cyano, and wherein two hydrogens, if attached to the same carbon atom, are oxoA base substitution;

a: (i) selected from the group consisting of: H. halogen, CH ₃ 、CHF ₂ 、CF ₃ 、OCH ₃ 、OCHF ₂ 、OCF ₃ 、SCH ₃ 、SCF ₃ And cyano; or (ii) forms with Z one of the following: (A) A saturated chain of 2 or 3 carbon atoms, to which chain 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 、CF ₃ 、OCHF ₂ 、OCF ₃ 、SCH ₃ 、SCHF ₂ 、SCF ₃ Cyano and oxo groups, and (B) a chain of 2 or 3 carbon atoms containing one double bond, such chain bearing substituents 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 、CF ₃ 、OCHF ₂ 、OCF ₃ 、SCH ₃ 、SCF ₃ Cyano and oxo; or (iii) forms with b any of the following: saturated alkyl linkages, unsaturated alkyl linkages, saturated heteroalkyl linkages, and unsaturated heteroalkyl linkages comprising substituents 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 、CF ₃ 、OCHF ₂ 、OCF ₃ 、SCH ₃ 、SCF ₃ Cyano and oxo; or (iv) together with c forms one of the following: (A) A saturated chain of 1 or 2 carbon atoms and 1 oxygen atom, and (B) a saturated chain of 2 or 3 carbon atoms, to which chain substituents independently selected from the group consisting of: H. halogen, C ₁ -C ₆ Alkyl and C ₃ -C ₆ Cycloalkyl;

b: (i) selected from the group consisting of: H. halogen, CH ₃ 、CHF ₂ 、CF ₃ 、OCH ₃ 、OCHF ₂ 、OCF ₃ 、SCH ₃ 、SCHF ₂ 、SCF ₃ And cyano; or (ii) and R ² Together forming a chain of 3 or 4 atoms, one of which is selected from the group consisting of: C. n, O and S, while the remainder are carbon, said chain containing 0, 1 or 2 double bonds and having attached thereto substituents 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 、CF ₃ 、OCHF ₂ 、OCF ₃ 、SCH ₃ 、SCHF ₂ 、SCF ₃ Cyano and oxo; or (iii) forms with Z one of the following: (A) A saturated chain of one oxygen and one carbon atom (wherein the oxygen is attached to the 6-position of the indole ring of formula II), and (B) a chain of 2 or 3 carbon atoms to which 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 、CF ₃ 、OCHF ₂ 、OCF ₃ 、SCH ₃ 、SCHF ₂ 、SCF ₃ Oxo, and cyano, and (C) a chain of 2 or 3 carbon atoms containing one double bond and bearing substituents 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 、CF ₃ 、OCHF ₂ 、OCF ₃ 、SCH ₃ 、SCHF ₂ 、SCF ₃ Oxo, and cyano. In some embodiments, b and R ² Together forming any of the following: CH (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＝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 S、NHCH 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, and ch=chch=n. In some embodiments, b and R ² Together forming any of the following: CH (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＝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 S、NHCH 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, and ch=chch=n, wherein one or both hydrogen atoms, if present on the moiety, are replaced by substituents independently selected from the group consisting of: 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 And cyano, and wherein both hydrogens, if attached to the same carbon atom, are replaced with oxo;

wherein:

R ³ : (i) selected from the group consisting of: H. c (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 An alkyl group); or (ii) and R ⁴ Together with the N atom to which they are attached form a 4-7 membered heterocyclyl; or (iii) with f and R ³ The attached N atoms together form an azetidine or pyrrolidine ring, such ring comprising substituents independently selected from the group consisting of: H. aryl, heteroaryl, C ₁ -C ₆ Alkyl and C ₃ -C ₆ Cycloalkyl; or (iv) with c and R ³ The attached N atoms together form an azetidine or pyrrolidine ring carrying substituents independently selected from the group consisting of: H. aryl, heteroaryl, halogen, C ₁ -C ₆ Alkyl and C ₃ -C ₆ Cycloalkyl;

R ⁴ : (i) selected from the group consisting of: H. c (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 An alkyl group); or (ii) and R ³ Together with the N atom to which they are attached form a 4-7 membered heterocyclyl;

wherein:

c. d, e and f are each H; or three of c, d, e and f are each H, and the remaining substituents are lower alkyl; or c and f are H and d and e together are-CH ₂ -or-CH ₂ CH ₂ -thereby producing a cyclopropane or cyclobutane ring; or c, d and e are each H, and f, R ³ And R ³ The attached N atoms together form an azetidine or pyrrolidine ring carrying substituents independently selected from the group consisting of: H. aryl, heteroaryl, C ₁ -C ₆ Alkyl and C ₃ -C ₆ Cycloalkyl; or d, e and f are each H, and c, R ³ And R ³ The attached N atoms together form an azetidine or pyrrolidine ring carrying substituents independently selected from the group consisting of: H. aryl, heteroaryl, halogen, C ₁ -C ₆ Alkyl and C ₃ -C ₆ Cycloalkyl; or d, e and f are each H, and c and a together form a saturated chain of 1 or 2 carbon atoms and 1 oxygen atom, or a saturated chain of 2 or 3 carbon atoms, to which are attached substituents independently selected from the group consisting of: H. aryl, heteroaryl, halogen, C ₁ -C ₆ Alkyl and C ₃ -C ₆ Cycloalkyl;

z: (i) selected from the group consisting of: H. r is R ⁵ 、(R ⁶ )(R ⁷ )N-C(O)-、C ₁ -C ₆ alkyl-C (O), C ₃ -C ₆ cycloalkyl-C (O), aryl-C (O) or heteroaryl-C (O), wherein R ⁵ Selected from the group consisting of: c (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), heteroaryl and heteroaryl (C) ₁ -C ₆ Alkyl group),and wherein R is ⁶ And R is ⁷ Independently selected from the group consisting of: H. c (C) ₁ -C ₄ Alkyl, and C ₃ -C ₆ Cycloalkyl, or R ⁶ And R is ⁷ Can be linked to form a 4-7 membered heterocyclic group; or (ii) is (R) ⁸ O)(R ⁹ O) P (O) -, wherein R ⁸ And R is ⁹ Independently a cationic counterion in the form of H or phosphate, such as sodium, potassium, half magnesium, half calcium, ammonium, or ammonium substituted with one or more alkyl or cycloalkyl groups; or (iii) forms with a one of the following: (A) A saturated chain of 2 or 3 carbon atoms, to which chain 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 、CF ₃ 、OCHF ₂ 、OCF ₃ 、SCH ₃ 、SCHF ₂ 、SCF ₃ Cyano and oxo, and (B) a chain of 2 or 3 carbon atoms containing one double bond and bearing substituents 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 、CF ₃ 、OCHF ₂ 、OCF ₃ 、SCH ₃ 、SCHF ₂ 、SCF ₃ Cyano and oxo; or (iv) together with b forms one of the following: (A) A saturated chain of one oxygen and one carbon atom (wherein the oxygen is attached to the 6-position of the indole ring of formula II), and (B) a chain of 2 or 3 carbon atoms to which 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 、CF ₃ 、OCHF ₂ 、OCF ₃ 、SCH ₃ 、SCHF ₂ 、SCF ₃ Oxo, and cyano, and (C) a chain of 2 or 3 carbon atoms containing one double bond and bearing substituents 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 、CF ₃ 、OCHF ₂ 、OCF ₃ 、SCH ₃ 、SCHF ₂ 、SCF ₃ Oxo, and cyano; and is also provided with

Wherein: (i) If Z is methyl, R ² Not methyl; and (ii) if R ² Methyl, then Z is not methyl.

Of course, the chemical entity of formula II does not include 5-methoxy-7, n-trimethyltryptamine having a natural hydrogen isotopic composition, as this particular compound is disclosed in Glennon et al, j.med.chem.,1980,23 (11), 1222.

According to some embodiments of the chemical entities disclosed herein, there is a chemical entity of formula III:

wherein:

R ² is O or S;

x is a carbon chain which will R ² And indole ring structure and contains 2 to 4 carbon atoms, to which are attached substituents independently selected from the group consisting of: H. c (C) ₁ -C ₆ Alkyl, aryl, and heteroaryl;

a: (i) selected from the group consisting of: H. halogen, lower alkyl, CHF ₂ 、CF ₃ 、OCH ₃ 、OCHF ₂ 、OCF ₃ 、SCHF ₂ 、SCH ₃ 、SCF ₃ And cyano; or (ii) forms with Z one of the following: (A) A saturated chain of one oxygen and one carbon atom (wherein the oxygen is attached to the 5-position of the indole ring of formula I), and (B) a chain of 2 or 3 carbon atoms to which 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 、CF ₃ 、OCHF ₂ 、OCF ₃ 、SCH ₃ 、SCHF ₂ 、SCF ₃ Cyano and oxygenA substituent, and (C) a chain of 2 or 3 carbon atoms containing one double bond, 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 、CF ₃ 、OCHF ₂ 、OCF ₃ 、SCHF ₂ 、SCH ₃ 、SCF ₃ Cyano and oxo; or (iii) forms a chain of 3 or 4 atoms with b, wherein one atom is selected from the group consisting of: C. n, O and S, while the remainder are carbon, said chain containing 0, 1 or 2 double bonds and having attached thereto substituents 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 、CF ₃ 、OCHF ₂ 、OCF ₃ 、SCH ₃ 、SCHF ₂ 、SCF ₃ Cyano and oxo; and is also provided with

wherein:

R ³ : (i) selected from the group consisting of: H. c (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 An alkyl group); or (ii) and R ⁴ Together with the N atom to which they are attached form a 4-7 membered heterocyclyl ring; or (iii) with f and R ³ The attached N atoms together form an azetidine or pyrrolidine ring carrying substituents independently selected from the group consisting of: H. aryl, heteroaryl, C ₁ -C ₆ Alkyl and C ₃ -C ₆ Cycloalkyl; or (iv) with c and R ³ The attached N atoms together form an azetidine or pyrrolidine ring carrying substituents independently selected from the group consisting of: H. aryl, heteroaryl, halogen, C ₁ -C ₆ Alkyl and C ₃ -C ₆ Cycloalkyl;

R ⁴ : (i) selected from the group consisting of: H. c (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 An alkyl group); or (ii) and R ³ Together with the N atom to which they are attached form a 4-7 membered heterocyclyl ring; and is also provided with

Wherein:

c. d, e and f are each H; or three of c, d, e and f are H and the remaining substituents are lower alkyl; or c and f are each H,and d and e together are-CH ₂ -or-CH ₂ CH ₂ -thereby producing a cyclopropane or cyclobutane ring; or c, d and e are each H, and f, R ³ And R ³ The attached N atoms together form an azetidine or pyrrolidine ring carrying substituents independently selected from the group consisting of: H. aryl, heteroaryl, C ₁ -C ₆ Alkyl and C ₃ -C ₆ Cycloalkyl; or d, e and f are each H, and c, R ³ And R ³ The attached N atoms together form an azetidine or pyrrolidine ring carrying substituents independently selected from the group consisting of: H. aryl, heteroaryl, halogen, C ₁ -C ₆ Alkyl and C ₃ -C ₆ Cycloalkyl; or d, e, and f are each H, and c and Z together contain 1 or 2 carbon atoms, thereby producing a pyran or oxaheptane ring bearing substituents independently selected from the group consisting of: H. halogen, C ₁ -C ₆ Alkyl and C ₃ -C ₆ Cycloalkyl groups.

Examples of embodiments of chemical entities

Examples of chemical entities of formula I are shown in table 1 below.

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* Abbreviations used in the above tables have the following meanings: ac = acetyl; bn=benzyl; bu=butyl; clbn=m-chlorobenzyl; cypr = cyclopropyl; me=methyl; et=ethyl; FPh = p-fluorophenyl; mebn=m-methylbenzyl; 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 。

examples of chemical entities of formula II are shown in table 2 below.

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* Abbreviations used in the above tables have the following meanings: ac = acetyl; bn=benzyl; bu=butyl; clbn=m-chlorobenzyl; cypr = cyclopropyl; me=methyl; et=ethyl; FPh = p-fluorophenyl; mebn=m-methylbenzyl; ph=phenyl; piv = pivaloyl; pr=propyl; py = pyridinyl; z is 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 。

Examples of chemical entities of formula III are shown in table 3 below.

Pharmacology

₂ Serotonin receptor 5-HT function assay

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

To measure serotonin receptor function activation, selected compounds are subjected to Gq dissociation or Gq dependent calcium flux by Bioluminescence Resonance Energy Transfer (BRET). For measuring via, e.g. by BRETQuantitative Gq/gamma 1 dissociation to measure 5-HT ₂ Receptor-mediated Gq activation (McCorvy JD, wacker D, wang S, agegnehu B, liu J, lansu K, tribo AR, olsen RHJ, cheT, jin J, roth BL. Structural determinents of 5-HT2B receptor activation and biased agonism. Nat Struct Mol biol.2018;25 (9): 787-96), HEK293T cells were relay cultured in Dulbecco ' S modified eagle ' S medium (Dulbecco ' S Modified Eagle Medium) (DMEM) supplemented with 10% dialysis Fetal Bovine Serum (FBS) and human Gαq (Gαq-RLuc 8) fused with RLuc8, GFP fused to the C-terminus of human Gγ1 using TransiT-2020 ² (Gγ1-GFP ² ) Human Gβ1 and 5-HT ₂ The receptors were co-transfected at a ratio of 1:1:1:1. After at least 18-24 hours, transfected cells were plated in polylysine coated 96-well white clear bottom cell culture plates in DMEM containing 1% dialysis FBS at a density of 25,000-40,000 cells in 200 μl/well and incubated overnight. The next day, the medium was decanted and the cells were washed with 60 μl of drug buffer (1× HBSS,20mM HEPES,pH 7.4), then 60 μl of drug buffer was added per well. Cells were pre-incubated in a humidified atmosphere at 37 ℃ prior to receiving drug stimulation. Drug stimulation was performed using 30 μl of drug (3X) diluted in McCorvy buffer (1X HBSS,20mM HEPES,pH 7.4, supplemented with 0.3% fatty acid free BSA,0.03% ascorbic acid) and plates incubated for 1 hour at 37 ℃. Substrate addition was performed 15 minutes prior to reading and 10 μl RLuc substrate coelenterazine 400a was used for Gq dissociation of BRET ² (Prolume/Nanolight, 5. Mu.M final concentration). Light emission at 400nm and fluorescent GFP at 510nm of a plate were read using Mithras LB940 (multimode microplate reader (e.g., a multimode microplate reader supplied by Berthold)) ² And transmitting for 1 second per well. The BRET ratio of fluorescence/luminescence for each well was calculated using Graphpad Prism 8 (Graphpad Software inc., 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 to response relationship" to generate E _max And EC (EC) ₅₀ Parameter estimation values.

By methods known in the art (e.g.,investigation of the Structure-Activity Relationships of Psilocybin Analogues, ACS Phacol. Transl. Sci.2020, publication Date: december 14,2020, https:// doi. Org/10.1021/acsmptaci.0c00176) uses stably expressed 5-HT ₂ The Flp-In 293T-Rex tetracycline induction system measures calcium flux. The cell line was maintained in DMEM containing 10% FBS, 10. Mu.g/mL blasticidin and 100. Mu.g/mL hygromycin B. Receptor expression was induced with tetracycline (2 μg/mL) at least 20-24 hours prior to the assay, and cells were seeded at a density of 7,500 cells/well into 384-well poly-L-lysine coated black plates in DMEM containing 1% dialysis FBS. On the day of the assay, cells were incubated with Fluo-4 Direct dye (Invitrogen, 20. Mu.L/well) reconstituted in drug buffer (20 mM HEPES buffered HBSS, pH 7.4) containing 2.5mM probenecid for 1 hour at 37 ℃. Drug dilutions were prepared in McCorvy buffer (20 mM HEPES buffered HBSS,0.1% BSA,0.01% ascorbic acid, pH 7.4) at a final concentration of 5X. After loading the dye, cells were allowed to equilibrate to room temperature for 15 minutes and then placed in the FLIPR ^TETRA In a fluorescence imaging plate reader (Molecular Devices). FLIPR is performed ^TETRA Programmed to read baseline fluorescence for 10s (1 read/s) and then add 5 μl of drug/well and read fluorescence for a total of 5-10min (1 read/s). Fluorescence in each well was normalized to the average 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. The peak or AUC was plotted as a function of drug concentration and the data normalized to the percent 5-HT stimulation. Data were plotted and nonlinear regression was performed using "log (agonist to response relationship" in Graphpad Prism 8 to generate E _max And EC (EC) ₅₀ Parameter estimation values.

The functional activity of the various compounds disclosed herein for each of the 5-HT2A, 5-HT2B and 5-HT2C receptors is measured as compared and relative to the functional activity of 4-hydroxytryptamine for these receptors. The comparison of functional activities is provided in table 4 below. At least three replicates were performed for each compound:

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the compounds in Table 4 show that substitution at the 7-position on the indole ring results in a target for 5-HT _2B The functional activity of the receptor is correspondingly reduced.

Functional activity of compound 1 against these receptors was also measured compared to and relative to functional activity of nude oxacin against other receptor sites. The comparison of functional activities is provided in table 5 below.

Reportedly, against 5-HT _1F The functional activity of the receptor is associated with the treatment of migraine. Reportedly, against 5-HT ₆ The functional activity of the receptor is associated with the treatment of cognitive disorders (e.g., dementia, alzheimer's disease).

Chemical synthesis method

Non-limiting examples of procedures for preparing the compounds described herein are provided below.

The indole core numbers of the compounds of formula I are as follows:

similar numbering applies to compounds of formula II, as numbering is attached to the indole ring independent of its substituents. The synthesis of these compounds involves several steps, namely: (1) building a heterocyclic core (if not commercially available); (2) installing or modifying a 3-substituent; and (3) functional group conversion.

Indole compounds can be prepared in a variety of ways. Some indoles can be synthesized, for example, by the leimiguber-batch indole synthesis and modifications thereof, as shown by the following examples:

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the substituted 2-nitrobenzaldehydes are reacted with nitromethane to form substituted ortho-beta-dinitrostyrenes, which are then reduced to produce substituted indoles.

N-alkylation of N-alkylanilines with ethyl 4-bromoacetoacetate followed by ZnCl ₂ Cyclization represents another general indole synthesis method, as shown by the following examples:

Still other indoles can be prepared by Bartoli reaction, as shown by the following examples:

side chain mounting and/or modification methods may also be used. If no substituents are present at the 3-position, indoles (with or without 1-alkyl groups) can be usedOxalyl chloride acylation, ammonolysis of the remaining second acid halide functionality, and cleavage of the carbonyl group with LiAlH ₄ Or borane to methylene. Partial reduction products of hydroxyl groups leaving a benzyl position relative to indole ring protection may occur as byproducts and such products may be removed by chromatography by virtue of their higher polarity and may furthermore be purified by catalytic hydrogenolysis or (especially in the presence of additional hydrogenolyzable functional groups such as OBn) with Et ₃ SiH/CF ₃ COOH is converted to additional fully reduced material. The use of a reducing agent in deuterated form yields a compound having a tetradeuterated side chain as shown by the following example:

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in another method, the 3-position is formylated using the Vilsmeier-Haack scheme, the side chain is extended by one carbon atom with Wittig reagent (Wittig reagent), and the resulting indolylacetaldehyde is reductively aminated, as shown by the following example:

it is also possible to use (alkoxycarbonylmethylene) triphenylphosphane as wittig reagent. After saturation of the double bond, the additional carbon atom is replaced with nitrogen, for example by huffman degradation of the derivatized amide (Hofmann degradation) or by Ke Disi reaction (Curtius reaction) as shown. As an alternative to reductive alkylation with aldehydes, the amino groups may be acylated and then reacted with a hydride reagent such as LiAlH ₄ Or borane-THF for amide reduction. The use of deuterated reducing agents in this step provides another treatment for deuterating certain compounds disclosed herein. Acylated nitrogen may also be further alkylated by deprotonation and reaction with, for example, an alkyl halide or sulfonate. The reduction of the alkylated amide as described previously yields a compound carrying a dialkylated side chain N atom.

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In another synthetic sequence, indole-3-carbaldehyde is chain extended by nitroaldol reaction. Complete reduction of nitrovinyl groups to aminoethyl groups, e.g. by LiAlH ₄ Or by catalytic hydrogenation if the remaining functional groups present in the compound are allowed.

In this scheme, N-alkylation of amino groups is performed indirectly by acylation followed by reduction of the amide to an amine.

Certain synthetic methods for preparing indoles provide these indoles in the form of their 3-acetic acid or esters thereof. The acid may be esterified by various procedures and then the ester may be ammonolyzed by treatment with an amine in a polar solvent. Instead, the ester may be hydrolyzed to the acid and the acid converted to the amide by treatment with an activator, many of which are known in the art of peptide synthesis, and an appropriate amine. Then using reactive hydrides such as LiAlH ₄ Or borane-THF reduces the amide resulting from either procedure to an amine. This sequence is suitable for synthesis of a catalyst containing partially or fully deuterated ethylene (CH) by base-catalyzed H-D exchange adjacent to the amide carbonyl group and/or by using deuterated hydride reagent in the reduction step ₂ CH ₂ ) A portion of the compound.

The cyclopropane-containing side chain can be obtained by Kulinkovich amino cyclopropanation, as shown by the following examples:

cyclopropane is formed as a mixture of two diastereomers (cis and trans), each of which consists of equal amounts of its enantiomer. Diastereomers and the enantiomers of each diastereomer can be separated using standard techniques, such as crystallization, crystallization of diastereomeric salts with pure chiral acids, chromatography, or chromatography on chiral stationary phases.

To prepare compounds having a side chain containing a 2-substituted azetidine or pyrrolidine ring, the substituted indole is deprotonated with ethyl magnesium bromide. Both enantiomeric forms of N-Boc-azetidine-2-carboxylic acid and N-Boc-proline are commercially available; in the accompanying schemes, the S-isomer is shown. From these synthetic blocks, acid chlorides are formed in situ, and then reacted with deprotonated indoles to form 3-acylated indoles. After thorough reduction, N-methylazetidine or-pyrrolidine is obtained in which the methyl group is derived from reduction of the Boc group. On the other hand, removal of the Boc group prior to reduction results in a secondary amine lacking an N-methyl group.

To prepare compounds having a 3-substituted azetidine ring in the side chain, the deprotonated or 3-lithiated substituted indoles are alkylated with 1-azabicyclo [1.1.0] butane prepared in situ from 2, 3-dibromopropylamine hydrobromide.

To prepare compounds having 3-substituted pyrrolidine rings in the side chain, the substituted indoles are alkylated with N-substituted maleimides and then with LiAlH ₄ Reduction, as shown by the following examples:

additional and final functional group transformations may also be used herein. To achieve (cyclo) alkylation of the indole nitrogen, the indole is typically deprotonated and the alkyl group is introduced as a halide (or sulfonate or sulfate). Alternatively, a (cyclo) alkylboronic acid or a (cyclo) alkylboronic acid derivative may be used in the presence of air as an oxidant under copper catalysis (Chan-Lam reaction). This scheme is also applicable to (cyclo) alkyl groups where the corresponding halide or sulfonate is little or not electrophilic, such as cyclopropyl:

when a free hydroxyl group is desired on the indole ring, a widely used protected precursor is benzyl ether. O-benzyl is more prone to hydrogenolysis than benzyl on indole or side chain nitrogen; by appropriate selection of parameters such as hydrogen pressure, catalyst loading, reaction temperature, reaction time and solvent, undesired N-debenzylation may be limited or inhibited. If carbon-carbon double or triple bonds are present, these bonds are expected to undergo saturation, accompanied by O-debenzylation. If this is undesirable, the O-benzyl group may alternatively be removed by a variety of reagents including Lewis acids such as boron tribromide, 2-bromo-1, 3, 2-benzodioxaborolan and bromodimethylborane. On the other hand, a particular type of (cyclo) alkenyl electrophile, namely allylic electrophiles, is far more reactive than their saturated analogues and can be advantageously used for the yield improvement achievable with less reactive (cyclo) alkyl halides such as isobutyl iodide. Thus, methallyl bromide is used in its position and the additional double bond is removed simultaneously with the O-benzyl group; or one can maintain a functional group susceptible to hydrogenation or hydrogenolysis over a Pd catalyst by selecting alternative reaction conditions, while converting another functional group:

Similarly, 3-bromocyclopentene can be used as a precursor of N-cyclopentyl, and 3-bromocyclohexene can be used as a precursor of cyclohexyl. The leaving group on the 1-substituent can be used to form a ring with the hydroxyl group at position 7, as shown by the following example:

a common side reaction in the 1-alkylation of indoles in the appropriate position of the 3-side chain is the overalkylation to form quaternary ammonium salts. Excess N-alkyl, if it is the same as or more reactive than those already in place, can be removed by treatment with a strong, soft nucleophile such as a thiolate anion, as shown by the following example:

prolonged reaction periods or elevated temperatures may also result in partial or complete removal of the phenolic protecting groups.

In some cases, indoles lacking the 7-substituent are readily available, and the subsequent introduction of the 7-substituent is a viable synthetic method to obtain 7-substituted indoles. The literature (Hartung, c.g.; fecher, a.; chapell, b.; snieckus, v.org. lett.2003,5,1899) reports the implementation of this strategy using 1- (diethylcarbamoyl) indole as an example. The 2-position is the position of greatest reactivity for metallization and is blocked by silylation first; the second metallization occurs at the 7-position and the resulting organolithium intermediate can be directly alkylated as shown below:

Removal of both carbamoyl and silyl groups is accomplished by treatment with KOH. If the halogenating agent (e.g., I ₂ Or BrCH ₂ CH ₂ Br) is used as electrophile, the resulting aryl halide may be used as a reaction partner in a transition metal catalyzed coupling reaction, as already mentioned in the discussion of Bartoli indole synthesis. 4 obtainable by Bartoli synthesis,7-dibromoindole and 5, 7-dibromoindole exhibit different reactivities of two Br atoms to halogen-metal exchange after 1-protection with a large acyl group (Li, L.; martins, A. Tetrahedron Lett.2003,44, 5987-5990). 7-Br is selectively reacted and the resulting bromolithium indole can be captured by the addition of an appropriate electrophile. 4-Br or 5-Br may be retained or used for further halogen-metal exchange or coupling reactions. Phenols can be obtained from metallized indoles by reaction with borates followed by oxidation. The metallized indoles are reacted with t-butyl peroxybenzoate to form t-butoxyindoles, which represent embodiments of the present invention as well as protected precursors of the free phenols (by acid treatment), thereby providing alternatives to the benzyl protecting groups.

Cyclization of the oxacycle to the benzene moiety of the indole ring can be accomplished by the addition of the necessary additional carbon atoms via the claisen rearrangement (Claisen rearrangement). When available, allyl migration of oxygen from the 5-position occurs selectively at the 4-position. Two additional steps are required to cyclize the allylic phenol intermediate to form the dihydropyran ring. Since 7-substituted 5-oxindoles are not currently commercially available, in this case the introduction of the 7-substituent is achieved by the directional metallization process described above.

The corresponding propargyl ether directly forms the depicted pyran by spontaneous cyclization of the intermediate dienylphenol. In this case, the electron-withdrawing 3-formyl group is introduced and then used as a handle for side chain mounting, allowing for smoother rearrangement. The additional double bonds may be hydrogenated at a later stage.

For example, compounds having linked 3-and 4-substituents can be obtained by intramolecular Fu Lide-Krafft acylation (Friedel-Crafts acylation).

Deuterated forms of reagents and synthetic blocks may be used in a variety of ways to incorporate deuterium into the compounds described herein under the same or similar conditions as used for their counterparts having the natural hydrogen isotope composition. It has been mentioned to use commercially available LiAlD ₄ Or BD (BD) ₃ The THF complex reduces the 3-acyl group and the carboxamide on the indole nucleus. LiAlD ₄ Can be used in the same manner to reduce carbamate functional groups (such as Boc or Cbz derived amines) to N-CD ₃ . Methyl-d synthetic block ₃ Iodide, ethyl-d ₅ Iodide, allyl-d ₅ Bromide, formaldehyde-d ₂ Aqueous solution, paraformaldehyde-d ₂ And dimethylamine-d ₆ (free base and hydrochloride) are commercially available, the reducing agent NaBD commonly used in reductive amination/alkylation ₄ And NaBD ₃ CN is also commercially available. Deuterium can be used to catalyze deuteration and deuteration of the CC multiple bond and the C-heteroatom bond, respectively. Indole-d ₇ Are commercially available. Can be used in the presence of catalyst B (C) ₆ F ₅ ) ₃ In the presence of D ₂ O deuterates the electron-rich aromatic compound (indole is one example of this), particularly at those positions that are more susceptible to electrophilic attack than the unactivated aromatic ring (Li, w.; wang, m.; hu, y.; werner, t.org. lett.2017,19,5768).

It is also possible to react with an excess of D in the presence of a heterogeneous transition metal catalyst ₂ O reaction to deuterate aromatic and heteroaromatic compounds (Sawama, y.; park, k.; yamada, t.; sajiki, h.chem. Pharm. Bull.2018,66,21-28). Deuteration of a specific position in the indole ring can be achieved by: the compound carrying a halogen atom (typically Br or I) is subjected to a halogen-metal exchange reaction at the site to be deuterated, followed by a deuterating agent (such as D ₂ O or CH ₃ OD) quenching indolyl metal intermediates; or with Bu ₃ SnD and radical initiator (such as azobis (isobutyronitrile) or dibenzoyl peroxide) to the same precursorPerforming free radical deuteration dehalogenation on the body; or by reacting the same precursor with a deuteride source (such as Bu ₃ SnD or formic acid-d ₂ And a transition metal) catalyst.

The compounds disclosed herein having free phenolic hydroxyl groups are more susceptible to air or enzymatic oxidation than derivatized phenolic ethers and may be more polar than desired for optimal brain penetration. To alleviate these and other problems, the free phenolic hydroxyl groups may be protected with an electron withdrawing moiety such as an acyl, carbamoyl or phosphoryl derivative, which is cleaved by a hydrolase to restore the free phenol. Esterification of the phenolic hydroxyl groups can be accomplished with acid halides or anhydrides, typically in the presence of a base; or with a free carboxylic acid in the presence of a suitable activator, said carboxylic acid undergoing an initial reaction with said activator to form a more electrophilic derivative. The carbamates (carbamoyl derivatives) are obtained from phenols by reaction with isocyanates or N, N-dialkylcarbamoyl halides in the presence of bases or other catalysts. Phosphoric acid derivatives suitable for phosphorylation include POCl ₃ (Kargbo, R.B.et al ACS Omega 2020,5,16959-16966), di-and tetra-alkyl chlorophosphates, wherein "alkyl" represents hydrocarbon residues of various structures selected in a manner that is easy to remove. A commonly used "alkyl" for this purpose is benzyl. It has been observed that one benzyl group of the resulting aryl dibenzyl phosphate tends to quaternize the side chain amine functionality, resulting in the formation of a zwitterionic which is then subjected to hydrogenolysis cleavage of two different benzyl groups with hydrogen in the presence of a transition metal catalyst (Shirota, o.et al j. Nat. Prod.2003,66,885-887; sheaod, a.m. et al Synthesis 2020,52,688-694).

Example A of chemical Synthesis of Compound 1

Compound 1:3- [2- (dimethylamino) ethyl group]-7-methylindol-4-ol

Examples of synthesis of 3- [2- (dimethylamino) ethyl ] -7-methylindol-4-ol are provided below:

4- (benzyloxy) -1-methyl-2-nitrobenzene

Benzyl bromide (333 g,1.46mol,1.5 eq.) was added to a solution containing 4-methyl-3-nitrophenol (200 g,1.31 mol), K ₂ CO ₃ (5491 g,3.91mol,3.0 eq.) and acetone (2.0L). The resulting mixture was stirred at 20 ℃ to 25 ℃ for 16 hours, and then filtered. The filtrate was concentrated in vacuo. The residue was combined with residue from another batch (same scale) and the product was precipitated with hexane (100 mL) to give 4- (benzyloxy) -1-methyl-2-nitrobenzene (470 g, 74%) as a pale yellow solid. ¹ H NMR(300MHz,DMSO-d ₆ )δ7.61(d,J＝2.7Hz,1H),7.51-7.25(m,7H),5.19(s,2H),2.42(s,3H)。

4- (benzyloxy) -7-methylindole

at-30deg.C, at N ₂ Vinyl magnesium bromide (1.0M in THF, 1.64L,1.64mol,4.0 eq.) was added dropwise to a stirred solution of 4- (benzyloxy) -1-methyl-2-nitrobenzene (100 g,0.41 mol) in THF (2.0L) under an atmosphere. The resulting mixture was stirred at 0 ℃ for 2 hours, and then with NH ₄ The Cl solution was quenched. The organic layer was separated and concentrated under vacuum. The residue was combined with residue from three additional batches (same scale) and purified by flash chromatography on silica gel (0-20% EtOAc in petroleum ether) to give 4- (benzyloxy) -7-methylindole (134 g, 34%) as a yellow oil. MS (ESI, M/z): 238 (M+H) ⁺ 。

2- [4- (benzyloxy) -7-methylindol-3-yl ] -N, N-dimethylglyoxylamide

At 0℃under N ₂ Oxalyl chloride (64.3 g,0.51mol,3.0 eq.) was added dropwise to a stirred solution of 4- (benzyloxy) -7-methylindole (40.0 g,0.17 mol) in THF (800 mL) under an atmosphere. The resulting mixture was stirred at 0℃for 2h. A solution of dimethylamine in THF (2.0M, 0.51L,1.02mol,6.0 eq.) was added dropwise. The resulting mixture was stirred at 20 ℃ -25 ℃ for an additional 1 hour and then extracted three times with EtOAc. The combined organic layers were washed three times with brine, over Na ₂ SO ₄ Dried, and concentrated under vacuum. The residue was combined with the residue from the other two batches (same scale) and purified by flash chromatography on silica gel (0-100% EtOAc in petroleum ether containing 0.05% triethylamine) to give 2- [4- (benzyloxy) -7-methyl-1H-indol-3-yl as a brown solid]-N, N-dimethylglyoxylamide (90.0 g, 52%). MS (ESI, M/z): 337 (M+H) ⁺ 。

[2- [4- (benzyloxy) -7-methylindol-3-yl ] ethyl ] dimethylamine

At 0℃under N ₂ Lithium aluminum hydride (22.6 g,595mmol,10 eq.) was added in portions to 2- [4- (benzyloxy) -7-methylindol-3-yl under an atmosphere ]A stirred solution of N, N-dimethylglyoxylamide (20.0 g,59.5 mmol) in THF (400 mL). The mixture was stirred at 65 ℃ for 16 hours, and then Na was added in portions by adding at 0 ℃ ₂ SO ₄ ·10H ₂ O (230 g, 514 mmol,12 eq.) was quenched until foaming ceased and filtered. The filtrate was concentrated in vacuo. The residue was combined with the residue from the other three batches (same scale) and purified by flash chromatography on silica gel (on CH containing 0.05% triethylamine) ₂ Cl ₂ 0-20% methanol containing 0.05% triethylamine) to afford [2- [4- (benzyloxy) -7-methylindol-3-yl ] as a brown solid]Ethyl group]Dimethylamine (40.0 g, 54%). MS (ESI, M/z): 309 (M+H) ⁺ 。

3- [2- (dimethylamino) ethyl ] -7-methylindol-4-ol

10% Pd/C (wet, 750 mg) was added to [2- [4- (benzyloxy) -7-methylindol-3-yl ] at ambient temperature]Ethyl group]A stirred solution of dimethylamine (5.0 g,16.2 mmol) in methanol (50 mL) was used and the reaction mixture was placed in H ₂ Under an atmosphere. The mixture was stirred at 20 ℃ to 25 ℃ for 1.5 hours and then filtered. The filtrate was concentrated in vacuo. The residue combined with the residue from the other six batches (same scale) was purified by reverse phase flash chromatography at C ₁₈ Purification on silica gel (5% -20% acetonitrile in water) and further purification by supercritical fluid chromatography to yield 3- [2- (dimethylamino) ethyl group as a pale yellow solid]-7-methylindol-4-ol (5.56 g, 22%). ¹ H NMR(400MHz,DMSO-d ₆ )δ10.49(br s,1H),10.42(br s,1H),6.92(d,J＝2.4Hz,1H),6.58(d,J＝7.6Hz,1H),6.18(d,J＝7.6Hz,1H),2.89(t,J＝6.8Hz,2H),2.54(t,J＝6.8Hz,2H),2.29(s,3H),2.21(s,6H)。MS(ESI,m/z):219(M+H) ⁺ 。

Example B of chemical Synthesis of Compound 1

Another example of the synthesis of 3- [2- (dimethylamino) ethyl ] -7-methylindol-4-ol is provided below:

4-methoxy-7-methylindole

To 5-methoxy-2-methylaniline (50 g, 0.264 mol) in anhydrous CH under ice-cooling and moisture removal ₂ Cl ₂ BCl was added to the solution in (500 mL) ₃ Solution (in CH) ₂ Cl ₂ 1M,400mL,1.1 eq). Chloroacetonitrile (48 mL,0.73mol,2.0 eq.) was then added followed by AlCl ₃ (53.3 g,0.40mol,1.1 eq.). The resulting mixture was stirred at room temperature overnight.Adding NH ₄ Aqueous Cl solution, and the mixture was filtered. The filter cake is treated with CH ₂ Cl ₂ Washing, separating the phases of the filtrate, and further using CH ₂ Cl ₂ The aqueous phase was extracted. The combined organic phases were washed with brine, dried over Na ₂ SO ₄ Dried, and concentrated under reduced pressure. Dissolving the residue in dioxane and H ₂ O (10:1) and then NaBH is added ₄ (69g) A. The invention relates to a method for producing a fibre-reinforced plastic composite The mixture was stirred at room temperature overnight. Water was added and the mixture was filtered. The filtrate was treated with CH ₂ Cl ₂ And (5) extracting. The combined organic phases were washed with brine, dried over Na ₂ SO ₄ Dried, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: etOAc/petroleum ether 1:1) to afford indole (20 g, 34%) as an off-white solid. MS (ESI) for C ₁₀ H ₁₁ Calculated NO: 161; actual measurement value: 162 (M+H) ⁺ )。 ¹ H NMR(400MHz,CDCl ₃ )δ8.06(br s,1H),7.12(t,J＝2.8Hz,1H),6.89(d,J＝7.6Hz,1H),6.67(t,J＝2.8Hz,1H),6.45(d,J＝7.6Hz,1H),3.94(s,3H),2.43(s,3H)。

2- (4-methoxy-7-methylindol-3-yl) -N, N-dimethylglyoxylamides

Oxalyl chloride (15.6 g,124mmol,2 eq.) was added dropwise to a solution of 4-methoxy-7-methylindole (10.0 g,62.1 mmol) in dry diethyl ether (200 mL) with ice-salt cooling. The mixture was stirred in the cold bath for 3h after which time the indole was found to be consumed. The resulting slurry was added dropwise to Me with ice-salt cooling ₂ In a 40% aqueous solution of NH (56 mL). The resulting brown slurry was stirred at 0 ℃ for 1h, then warmed to room temperature and stirred overnight. The reaction mixture was filtered, and the filtrate was treated with NaHCO ₃ Aqueous treatment followed by CH ₂ Cl ₂ And (5) extracting. The combined organic phases were washed with water and brine, and dried over Na ₂ SO ₄ Dried, and concentrated under reduced pressure. Will be disabledThe residue was purified by column chromatography on silica gel (eluent: CH) ₂ Cl ₂ MeOH 60:1) to afford 2- (4-methoxy-7-methylindol-3-yl) -N, N-dimethylglyoxylamide (12.2 g, 75%) as a brown solid. MS (ESI) for C ₁₄ H ₁₆ N ₂ O ₃ Is calculated by the following steps: 260; actual measurement value: 261 (M+H) ⁺ )。 ¹ H NMR(400MHz,CDCl ₃ )δ9.86(br s,1H),7.63(d,J＝3.2Hz,1H),6.87(d,J＝8.0Hz,1H),6.52(d,J＝8.0Hz,1H),3.88(s,3H),3.13(s,3H),3.08(s,3H),2.32(s,3H)。

[2- (4-methoxy-7-methylindol-3-yl) ethyl ] dimethylamine

Under ice-salt cooling condition, under nitrogen atmosphere, liAlH is added ₄ (6.66 g,176 mmol) to a slurry of 2- (4-methoxy-7-methylindol-3-yl) -N, N-dimethylglyoxylamide (12.2 g,47 mmol) in dry THF (120 mL) was added. The mixture was heated to reflux overnight. Then a solution of 20vol% water in THF was added dropwise with ice cooling. The mixture was stirred for 0.5h, then filtered, and the filter cake was washed with THF. The phases of the filtrate were separated and the aqueous phase was further extracted with EtOAc. The combined organic phases were washed with brine, dried over NaSO ₄ Dried, and concentrated under reduced pressure. The residue is purified by column chromatography on silica gel (eluent: CH ₂ Cl ₂ 3.5M NH in MeOH ₃ 30:1) to afford the amine as a brown solid (8.2 g, 75%). MS (ESI) for C ₁₄ H ₂₀ N ₂ Calculated value of O: 232; actual measurement value: 233 (M+H) ⁺ )。 ¹ H NMR(400MHz,CDCl ₃ )δ7.87(br s,1H),6.90(s,1H),6.85(d,J＝8Hz,1H),6.40(d,J＝7.6Hz,1H),3.89(s,3H),3.07-3.03(m,2H),2.64-2.60(m,2H),2.38(s,3H),2.34(s,6H)。

3- [2- (dimethylamino) ethyl ] -7-methylindol-4-ol

To [2- (4-methoxy-7-methylindol-3-yl) ethyl ]]A mixture of dimethylamine (2.4 g,10.3 mmol) and pyridine hydrochloride (24.0 g,206mmol,20 eq.) was placed in a 100mL round bottom flask and heated at 150℃to 165℃for 4.5h. The reaction mixture was cooled to room temperature and dissolved in water with Na ₂ CO ₃ Basification and extraction with EtOAc. The organic phase was washed with brine, and dried over NaSO ₄ Dried, and concentrated under reduced pressure. The residue is purified by column chromatography on silica gel (eluent: CH ₂ Cl ₂ 3.5M NH in MeOH ₃ 40:1) to afford compound 1 (1.7 g, 75%) as an off-white solid. MS (ESI) for C ₁₃ H ₁₈ N ₂ Calculated value of O: 218; actual measurement value: 219 (M+H) ⁺ )。 ¹ H NMR(400MHz,CDCl ₃ )δ13.23(br s,1H),7.80(s,1H),6.86(s,1H),6.85(d,J＝8.4Hz,1H),6.50(d,J＝7.6Hz,1H),2.95-2.93(m,2H),2.70-2.68(m,2H),2.37(s,9H)。

Examples of chemical Synthesis of Compound 7

Compound 7:3- [2- (dimethylamino) ethyl ] -7- (2-hydroxyethyl) indol-4-ol

Examples of synthesis of 3- [2- (dimethylamino) ethyl ] -7- (2-hydroxyethyl) indol-4-ol are provided below:

4- (benzyloxy) -1-chloro-2-nitrobenzene

To a solution of 4-chloro-3-nitrophenol (22.0 g,126 mmol) in acetone (210 mL) and DMF (210 mL) under nitrogen was added K ₂ CO ₃ (27 g,196 mmol) and benzyl chloride (20 g,156 mmol). The mixture was stirred at 20℃to 25℃overnight. The water is added in the water-soluble polymer,and subjecting the resulting mixture to CH ₂ Cl ₂ And (5) extracting. The phases were separated and the organic phase was washed with water and brine, over Na ₂ SO ₄ Dried, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: etOAc/petroleum ether 1:20) to afford 4- (benzyloxy) -1-chloro-2-nitrobenzene (27.0 g, 81%) as a pale yellow oil.

2- [4- (benzyloxy) -2-nitrophenyl ] malonic acid diethyl ester

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To a suspension of NaH (10.6 g,267 mmol) in DMSO (345 mL) was added dropwise a solution of diethyl malonate (44.5 g,278 mmol) in DMSO (20 mL) followed by a solution of 4- (benzyloxy) -1-chloro-2-nitrobenzene (27.0 g,102 mmol) in DMSO (40 mL) under ice-cooling. The mixture was stirred at 110 ℃ overnight. The resulting dark brown suspension was quenched with acetic acid and with CH ₂ Cl ₂ And 0.5M aqueous HCl. The phases were separated and the mixture was further treated with CH ₂ Cl ₂ And (5) extracting. The combined organic phases were washed with water and brine, and dried over Na ₂ SO ₄ Dried, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: etOAc/petroleum ether 1:30) to afford 2- [4- (benzyloxy) -2-nitrophenyl as a yellow oil]Diethyl malonate (24.5 g, 62%). ¹ H NMR(400MHz,CDCl ₃ ) Delta 7.65 (d, j=2.4 hz, 1H), 7.44-7.36 (m, 6H), 7.23 (dd, j=2.8 and 8.8hz, 1H), 5.22 (s, 1H), 5.13 (s, 2H), 4.26-4.18 (m, 4H), 1.30-1.26 (m, 6H).

2- [4- (benzyloxy) -2-nitrophenyl ] acetic acid

To a solution of diethyl 2- (4- (benzyloxy) -2-nitrophenyl) malonate (20.0 g,51.6 mmol) in EtOH (450 mL) was added 10% aqueous NaOH (600 mL) at 20℃to 25 ℃ ). The resulting mixture was refluxed for 1.5h. EtOH was removed under reduced pressure and THF was added under ice cooling. Aqueous HCl (6M) was added dropwise to pH 1, and the solution was then refluxed for 1h. THF was removed and the residue was taken up with CH ₂ Cl ₂ And (5) extracting. Separating the phases, subjecting the organic phase to Na ₂ SO ₄ Dried and concentrated under reduced pressure. The residue is purified by column chromatography on silica gel (eluent: CH ₂ Cl ₂ MeOH 10:1) to afford 2- [4- (benzyloxy) -2-nitrophenyl ] as a yellow solid]Acetic acid (13.1 g, 88%).

2- [4- (benzyloxy) -2-nitrophenyl ] ethanol

To 2- [4- (benzyloxy) -2-nitrophenyl under ice-cooling conditions]To a solution of acetic acid (15.5 g,54 mmol) in THF (150 mL) was added drop wise BH ₃ THF solution (1M in THF; 135mL,2.5 eq.). The mixture was stirred at 20℃to 25℃for 5h. The mixture was treated with H ₂ O quenched and extracted with EtOAc. Separating the phases, subjecting the organic phase to Na ₂ SO ₄ Dried and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: etOAc/petroleum ether 1:5) to afford the title product as a brown solid (8.0 g, 54%). ¹ H NMR(400MHz,CDCl ₃ ) Delta 7.54 (d, j=2 hz, 1H), 7.44-7.33 (m, 5H), 7.31 (d, j=8.8 hz, 1H), 7.18 (dd, j=2.8 and 8.4hz, 1H), 5.11 (s, 2H), 3.91 (t, j=6.4 hz, 2H), 3.10 (t, j=6.4 hz, 2H).

4- (benzyloxy) -1- [2- (methoxymethoxy) ethyl ] -2-nitrobenzene

To 2- [4- (benzyloxy) -2-nitrophenyl under ice-cooling conditions]Ethanol (2.0 g,7.3 mmol) in CH ₂ Cl ₂ To a solution of (40 mL) was added ethyldiisopropylamine (2.84 g,21.9 mmol) and bromomethyl methyl ether (1.83 g,14.6 mmol). Will be mixedThe mixture was warmed to 20 ℃ to 25 ℃ and stirred at this temperature overnight. The reaction was quenched with MeOH and with CH under ice-cooled conditions ₂ Cl ₂ And (5) diluting. The solution was washed with brine. The organic phase was taken up in Na ₂ SO ₄ Dried and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: etOAc/petroleum ether 1:8) to afford 4- (benzyloxy) -1- [2- (methoxymethoxy) ethyl as a yellow oil]2-Nitrobenzene (2.0 g, 86%). ¹ H NMR(400MHz,CDCl ₃ ) Delta 7.53 (d, j=2.8 hz, 1H), 7.44-7.34 (m, 5H), 7.31 (d, j=8.8 hz, 1H), 7.14 (dd, j=2.8 and 8.4hz, 1H), 5.10 (s, 2H), 4.58 (s, 2H), 3.77 (t, j=6.4 hz, 2H), 3.27 (s, 3H), 3.14 (t, j=6.4 hz, 2H).

4- (benzyloxy) -7- [2- (methoxymethoxy) ethyl ] indole

At-40℃to 4- (benzyloxy) -1- (2- [ methoxymethoxy) ethyl]To a solution of 2-nitrobenzene (1.00 g,3.15 mmol) in THF (16 mL) was added dropwise a solution of vinylmagnesium bromide (1.0M in THF; 11.0 mL). The resulting mixture was stirred at-40℃for 4h. Saturated NH for reaction ₄ The aqueous Cl solution was quenched and extracted with EtOAc. Separating the phases, subjecting the organic phase to Na ₂ SO ₄ Dried and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: etOAc/petroleum ether 1:8) to afford 4- (benzyloxy) -7- [2- (methoxymethoxy) ethyl as a yellow oil]Indole (385 mg, 40%). ¹ H NMR(400MHz,CDCl ₃ )δ9.05(br s,1H),7.50(d,J＝7.6Hz,2H),7.39(t,J＝7.2Hz,2H),7.33-7.30(m,1H),7.14-7.13(m,1H),6.86(d,J＝8Hz,1H),6.71-6.70(m,1H),6.50(d,J＝8Hz,1H),5.22(s,2H),4.66(s,2H),3.86(t,J＝6Hz,2H),3.28(s,3H),3.08(t,J＝6Hz,2H)。

2- [4- (benzyloxy) -7- [2- (methoxymethoxy) ethyl ] indol-3-yl ] -N, N-dimethylglyoxylamide

To 4- (benzyloxy) -7- [2- (methoxymethoxy) ethyl under ice-cooling conditions]To a solution of indole (385 mg,1.24 mmol) in diethyl ether (7 mL) was added oxalyl chloride (314 mg,2.47 mmol) dropwise. The mixture was stirred for 3h and then added dropwise to 40% Me with ice/salt cooling ₂ Aqueous NH (5 mL). The mixture was warmed to 20-25 ℃ and stirred at this temperature overnight, then washed with water and brine. Separating the phases, subjecting the organic phase to Na ₂ SO ₄ Dried and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: etOAc/petroleum ether 1:1) to afford 2- [4- (benzyloxy) -7- [2- (methoxymethoxy) ethyl as a yellow oil]Indol-3-yl]-N, N-dimethylglyoxylamide (444 mg, 87%). ¹ H NMR(400MHz,CDCl ₃ )δ10.09(br s,1H),8.00(d,J＝3.2Hz,1H),7.55-7.52(m,2H),7.42-7.35(m,2H),7.32-7.29(m,1H),6.90(d,J＝8Hz,1H),6.58(d,J＝8Hz,1H),5.26(s,2H),4.67(s,2H),3.84(t,J＝6Hz,2H),3.29(s,3H),3.06(t,J＝5.2Hz,2H),3.00(s,3H),2.93(s,3H)。

[2- [4- (benzyloxy) -7- [2- (methoxymethoxy) ethyl ] indol-3-yl ] ethyl ] dimethylamine

To 2- [4- (benzyloxy) -7- [2- (methoxymethoxy) ethyl under ice-cooling conditions]Indol-3-yl]To a solution of N, N-dimethylglyoxylamide (440 mg,1.07 mmol) in toluene (6 mL) was added dropwise sodium bis (2-methoxyethoxy) aluminum dihydride (70% in toluene, 2.5g,8.5mmol,8 eq.). The mixture was warmed to 20-25 ℃ and stirred at this temperature overnight. The reaction was quenched with water and 15% aqueous NaOH was added. The mixture was extracted with EtOAc. The organic phase was washed with water and brine, dried over Na ₂ SO ₄ Dried, and concentrated under reduced pressure. The residue is purified by column chromatography on silica gel (eluent: CH ₂ Cl ₂ 3.5M NH in MeOH ₃ 50:1) to provide [2- [4- (benzyloxy) -7- [2- (methoxymethoxy) ethyl ] as a pale yellow solid]Indol-3-yl]Ethyl group]Dimethylamine (205 mg, 50%). MS (ESI, M/z): 383 (M+H) ⁺ 。 ¹ H NMR(400MHz,CDCl ₃ )δ8.79(br s,1H),7.49(d,J＝7.2Hz,2H),7.38(t,J＝7.2Hz,2H),7.32(d,J＝7.2Hz,1H),6.91(d,J＝2.4Hz,1H),6.83(d,J＝8Hz,1H),6.46(d,J＝8Hz,1H),5.17(s,2H),4.65(s,2H),3.84(t,J＝6Hz,2H),3.30(s,3H),3.07-3.03(m,4H),2.62-2.58(m,2H),2.14(s,6H)。

3- [2- (dimethylamino) ethyl ] -7- [2- (methoxymethoxy) ethyl ] indol-4-ol

To [2- [4- (benzyloxy) -7- [2- (methoxymethoxy) ethyl ]]Indol-3-yl]Ethyl group]To a solution of dimethylamine (175 mg,0.45 mmol) in MeOH (5 mL) was added 10% Pd/C (20 mg) and 20% Pd (OH) ₂ C (20 mg). The mixture was stirred under hydrogen atmosphere at 20-25 ℃ for 2h and then filtered. The filtrate was concentrated. The residue is purified by column chromatography on silica gel (eluent: CH ₂ Cl ₂ 3.5M NH in MeOH ₃ 50:1) to provide 3- [2- (dimethylamino) ethyl ] as a pale yellow solid]-7- [2- (methoxymethoxy) ethyl group]Indol-4-ol (109 mg, 82%).

3- [2- (dimethylamino) ethyl ] -7- [ 2-hydroxyethyl ] indol-4-ol

To 3- [2- (dimethylamino) ethyl group]-7- [2- (methoxymethoxy) ethyl group]To a solution of indol-4-ol (87 mg,0.3 mmol) in MeOH (3 mL) was added anhydrous HCl solution (4.0M in dioxane; 0.3mL,1.2mmol,4 eq.). The mixture was stirred at 50℃for 3h, cooled to 20℃to 25℃and treated with NaHCO ₃ The aqueous solution was basified and extracted with EtOAc. The organic phase was taken up in Na ₂ SO ₄ Dried and concentrated under reduced pressure. The residue was purified by column chromatographyPurification on silica gel (eluent: CH) ₂ Cl ₂ 3.5M NH in MeOH ₃ 50:1) to provide 3- [2- (dimethylamino) ethyl ] as a light brown solid]-7- [ 2-hydroxyethyl group]Indol-4-ol (46 mg, 64%). MS (ESI, M/z): 249 (M+H) ⁺ 。 ¹ H NMR(400MHz,CDCl ₃ )δ8.64(br s,1H),6.85(s,1H),6.84(d,J＝8Hz,1H),6.50(d,J＝8Hz,1H),3.95(t,J＝6Hz,2H),2.99(t,J＝6Hz,2H),2.96-2.93(m,2H),2.71-2.69(m,2H),2.38(s,6H)。

Examples of chemical Synthesis of Compound 8

Compound 8:3- [2- (dimethylamino) ethyl ] -7- (2-fluoroethyl) indol-4-ol

Examples of synthesis of 3- [2- (dimethylamino) ethyl ] -7- (2-fluoroethyl) indol-4-ol are provided below:

4- (benzyloxy) -1- (2-fluoroethyl) -2-nitrobenzene

To 2- [4- (benzyloxy) -2-nitrophenyl under ice-cooling conditions]Ethanol (6.4 g,22 mmol) in CH ₂ Cl ₂ To the solution in (100 mL) was added (diethylamino) sulfur trifluoride (DAST; 7.1g,44mmol,2 eq.). The mixture was warmed to 20 ℃ to 25 ℃ and stirred for 5h. Under ice conditions, the reaction was allowed to proceed with NaHCO ₃ Quenched with aqueous solution and quenched with CH ₂ Cl ₂ And (5) extracting. The organic phase was taken up in Na ₂ The SO4 was dried and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: etOAc/petroleum ether 1:20) to afford 4- (benzyloxy) -1- (2-fluoroethyl) -2-nitrobenzene (2.1 g, 32%) as a brown oil. ¹ H NMR(400MHz,CDCl ₃ ) Delta 7.59 (d, j=2.4 Hz, 1H), 7.44-7.34 (m, 5H), 7.32 (d, j=8 Hz, 1H), 7.17 (dd, j=2.4 Hz and 8Hz, 1H), 5.11 (s, 2H), 4.69 (dt, j=6 Hz (t) and 48Hz (d, 2H), 3.24 (dt, j=6 Hz (t) and 48Hz (d, 2H)24Hz(d),2H)。

4- (benzyloxy) -7- (2-fluoroethyl) indole

To a solution of 4- (benzyloxy) -1- (2-fluoroethyl) -2-nitrobenzene (2.1 g,7.6 mmol) in THF (26 mL) was added dropwise a solution of vinylmagnesium bromide (1.0 m in THF, 26mL,3.4 eq.) at-40 ℃. The mixture was stirred at-40℃for 4h. Saturated NH for reaction ₄ The aqueous Cl solution was quenched and extracted with EtOAc. The organic phase was taken up in Na ₂ SO ₄ Dried and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: etOAc/petroleum ether 1:20) to afford 4- (benzyloxy) -7- (2-fluoroethyl) indole (428 mg, 35%) as a brown solid. ¹ H NMR(400MHz,CDCl ₃ ) Delta 8.45 (br s, 1H), 7.50 (d, j=7.2 Hz, 2H), 7.39 (t, j=7.2 Hz, 2H), 7.32 (t, j=7.2 Hz, 1H), 7.15 (t, j=2.8 Hz, 1H), 6.88 (d, j=8 Hz, 1H), 6.74 (t, j=2.4 Hz, 1H), 6.53 (d, j=8 Hz, 1H), 5.22 (s, 2H), 4.75 (dt, j=6 Hz (t) and 48Hz (d), 2H), 3.18 (dt, j=6 Hz (t) and 28Hz (d), 2H).

2- [4- (benzyloxy) -7- (2-fluoroethyl) indol-3-yl ] -N, N-dimethylglyoxylamide

Oxalyl chloride (400 mg,3.98mmol,2 eq.) was added dropwise to a solution of 4- (benzyloxy) -7- (2-fluoroethyl) indole (425 mg,1.94 mmol) in diethyl ether (15 mL) with ice cooling. The mixture was stirred for 3h and then added dropwise to 40% Me with ice/salt cooling ₂ Aqueous NH (5 mL). The mixture was warmed to 20 ℃ to 25 ℃ and stirred overnight, then washed with water and brine. The organic phase was taken up in Na ₂ SO ₄ Dried and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: etOAc/petroleum ether 1:3) to afford 2- [4- (benzyloxy) -7- (2-fluoroethyl) indol-3-yl as a brown solid ]-N, N-dimethylGlyoxylamides (540 mg, 76%). ¹ H NMR(400MHz,CDCl ₃ ) δ9.81 (br s, 1H), 7.86 (d, j=3.2 Hz, 1H), 7.52 (d, j=7.2 Hz, 2H), 7.37 (t, j=7.2 Hz, 2H), 7.30 (d, j=7.2 Hz, 1H), 6.89 (d, j=8 Hz, 1H), 6.58 (d, j=8 Hz, 1H), 5.24 (s, 2H), 4.66 (dt, j=6 Hz (t) and 47.2Hz (d), 2H), 3.11 (dt, j=6 Hz (t) and 28.4Hz (d), 2H), 2.97 (s, 3H), 2.91 (s, 3H).

[2- [4- (benzyloxy) -7- (2-fluoroethyl) indol-3-yl ] ethyl ] dimethylamine

To 2- [4- (benzyloxy) -7- (2-fluoroethyl) indol-3-yl under ice-cooling conditions]To a solution of N, N-dimethylglyoxylamide (270 mg,0.73 mmol) in toluene (7 mL) was added dropwise sodium bis (2-methoxyethoxy) aluminum dihydride (70% in toluene, red aluminum (Red-Al), 1.06g,3.67mmol,5 eq.). The mixture was warmed to 20 ℃ to 25 ℃ and stirred overnight. The reaction was quenched with water and 15% aqueous NaOH was added. The mixture was extracted with EtOAc and the organic phase was washed with water and brine, over Na ₂ SO ₄ Dried, and concentrated under reduced pressure. The residue is purified by column chromatography on silica gel (eluent: CH ₂ Cl ₂ 3.5M NH in MeOH ₃ 30:1) to afford [2- [4- (benzyloxy) -7- (2-fluoroethyl) indol-3-yl ] as a brown solid]Ethyl group]Dimethylamine (165 mg, 67%). MS (ESI, M/z): 341 (M+H) ⁺ 。 ¹ H NMR(400MHz,CDCl ₃ ) Delta 8.25 (br s, 1H), 7.49 (d, j=7.2 Hz, 2H), 7.40-7.30 (m, 3H), 6.92 (d, j=1.6 Hz, 1H), 6.85 (d, j=8 Hz, 1H), 6.49 (d, j=8 Hz, 1H), 5.17 (s, 2H), 4.72 (dt, j=6 Hz (t) and 47.6Hz (d), 2H), 3.14 (dt, j=6 Hz (t) and 27.6Hz (d), 2H), 3.08-3.04 (m, 2H), 2.64-2.60 (m, 2H), 2.15 (s, 6H).

3- [2- (dimethylamino) ethyl ] -7- (2-fluoroethyl) indol-4-ol

To [2- [4- (benzyl)Oxy) -7- (2-fluoroethyl) indol-3-yl]Ethyl group]To a solution of dimethylamine (160 mg,0.48 mmol) in MeOH (8 mL) was added 10% Pd/C (20 mg) and 20% Pd (OH) ₂ C (20 mg). The mixture was stirred under hydrogen atmosphere at 20-25 ℃ for 2h, then filtered, and the filtrate was concentrated. The residue is purified by column chromatography on silica gel (eluent: CH ₂ Cl ₂ 3.5M NH in MeOH ₃ 50:1) to provide 3- [2- (dimethylamino) ethyl ] as a white solid]-7- (2-fluoroethyl) indol-4-ol (65 mg, 54%). MS (ESI, M/z): 251 (M+H) ⁺ 。 ¹ H NMR(400MHz,CDCl ₃ ) Delta 8.16 (br s, 1H), 6.86 (s, 1H), 6.85 (d, j=8 Hz, 1H), 6.51 (d, j=8 Hz, 1H), 4.73 (dt, j=6 Hz (t) and 47.2Hz (d), 2H), 3.13 (dt, j=6 Hz (t) and 28Hz (d), 2H), 2.96-2.94 (m, 2H), 2.72-2.70 (m, 2H), 2.38 (s, 6H).

Examples of chemical Synthesis of Compound 9

Compound 9:3- [2- (dimethylamino) ethyl ] -7-ethylindol-4-ol

Examples of synthesis of 3- [2- (dimethylamino) ethyl ] -7-ethylindol-4-ol are provided below:

[2- [4- (benzyloxy) -7-ethylindol-3-yl ] ethyl ] dimethylamine

To 2- [4- (benzyloxy) -7- (2-fluoroethyl) indol-3-yl under ice-cooling conditions]To a solution of N, N-dimethylglyoxylamide (220 mg,0.59 mmol) in toluene (5 mL) was added dropwise sodium bis (2-methoxyethoxy) aluminum dihydride (70% in toluene, red aluminum (Red-Al), 0.97g,4.8mmol,6 eq.). The mixture was heated to 80 ℃ and stirred at this temperature overnight. Will react with H ₂ O quench and add 15% NaOH aqueous solution. The mixture was extracted with EtOAc. The organic phase was washed with water and brine, dried over Na ₂ SO ₄ Dried, and concentrated under reduced pressure. The residue is purified by column chromatography on silica gel (eluent: CH ₂ Cl ₂ 3.5M NH in MeOH ₃ 30:1) to afford [2- [4- (benzyloxy) -7-ethylindol-3-yl ] as a brown solid]Ethyl group]Dimethylamine (76 mg, 39%). MS (ESI, M/z): 323 (M+H) ⁺ 。 ¹ H NMR(400MHz,CDCl ₃ )δ7.94(br s,1H),7.50(d,J＝7.2Hz,2H),7.38(t,J＝7.6Hz,2H),7.31-7.29(m,1H),6.90(d,J＝2.0Hz,1H),6.87(d,J＝7.6Hz,1H),6.50(d,J＝8Hz,1H),5.17(s,2H),3.06(t,J＝8Hz,2H),2.76(q,J＝7.6Hz,2H),2.63-2.59(m,2H),2.15(s,6H),1.32(t,J＝8Hz,3H)。

3- [2- (dimethylamino) ethyl ] -7-ethylindol-4-ol

To [2- [4- (benzyloxy) -7-ethylindol-3-yl ] under a hydrogen atmosphere]Ethyl group]To a solution of dimethylamine (70 mg,0.21 mmol) in MeOH (4 mL) was added Pd/C (20 mg) and Pd (OH) ₂ C (20 mg). The resulting mixture was stirred under hydrogen atmosphere at 20-25 ℃ for 2h, and then filtered. The filtrate was concentrated. The residue is purified by column chromatography on silica gel (eluent: CH ₂ Cl ₂ 3.5M NH in MeOH ₃ 50:1) to provide 3- [2- (dimethylamino) ethyl ] as a white solid]-7-ethylindol-4-ol (30 mg, 50%). MS (ESI, M/z): 233 (M+H) ⁺ 。 ¹ H NMR(400MHz,CDCl ₃ )δ7.84(br s,1H),6.88(d,J＝8.0Hz,1H),6.85(d,J＝2.0Hz,1H),6.53(d,J＝8Hz,1H),2.96-2.94(m,2H),2.75(q,J＝7.6Hz,2H),2.71-2.69(m,2H),2.37(s,6H),1.33(t,J＝8Hz,3H)。

Examples of chemical Synthesis of Compound 10

Compound 10:3- [2- (dimethylamino) ethyl ] -7-isopropylindol-4-ol

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Examples of synthesis of 3- [2- (dimethylamino) ethyl ] -7-isopropylindol-4-ol are provided below:

4- (benzyloxy) -1-bromo-2-nitrobenzene

4-bromo-3-nitrophenol (20.0 g,92.2 mmol), benzyl bromide (23.5 g,138mmol,1.5 eq.) K ₂ CO ₃ A mixture of (38.2 g,277mmol,3.0 eq.) and acetone (200 mL) was stirred at 20℃to 25℃for 16 hours and then filtered. The filtrate was concentrated in vacuo. The residue was purified by flash chromatography on silica gel (0-20% EtOAc in petroleum ether) to give 4- (benzyloxy) -1-bromo-2-nitrobenzene (26.8 g, 94%) as a yellow solid. ¹ H NMR(300MHz,DMSO-d ₆ )δ7.76(d,J＝9.0Hz,1H),7.72(d,J＝3.0Hz,1H),7.48-7.32(m,5H),7.26(dd,J＝9.0,3.0Hz,1H),5.18(s,2H)。

4- (benzyloxy) -7-bromoindole

At-5 ℃ under N ₂ Vinyl magnesium bromide (1.0M in THF, 261mL,4.0 eq.) was added dropwise to a stirred solution of 4- (benzyloxy) -1-bromo-2-nitrobenzene (20.0 g,32.5 mmol) in THF (400 mL) under an atmosphere. The resulting mixture was stirred at-5℃for 1 hour, then with NH ₄ The Cl solution was quenched and extracted three times with EtOAc. The combined organic layers were washed with water and brine, dried over Na ₂ SO ₄ Dried, and concentrated under vacuum. The residue was purified by flash chromatography on silica gel (0-20% EtOAc in petroleum ether) to give 4- (benzyloxy) -7-bromo-1H-indole (6.1 g, 31%) as a yellow oil. MS (ESI, M/z): 302,304 (M+H) ⁺ 。

2- [4- (benzyloxy) -7-bromoindol-3-yl) -N, N-dimethylglyoxylamide

Oxalyl chloride (3.8 g,30mmol,3.0 eq.) is added dropwise to a stirred solution of 4- (benzyloxy) -7-bromoindole (3.0 g,10.0 mmol) in THF (30 mL) at 0deg.C. The mixture was stirred at 20℃to 25℃for 16 hours. A solution of dimethylamine in THF (2.0M, 30mL,60mmol,6.0 eq.) was added dropwise at 0deg.C. The resulting mixture was stirred at 20-25 ℃ for an additional 1 hour, then diluted with water and extracted three times with EtOAc. The combined organic layers were washed with water and brine, dried over Na ₂ SO ₄ Dried, and concentrated under vacuum. The residue was purified by flash chromatography on silica gel (0-50% EtOAc in petroleum ether) to give 2- [4- (benzyloxy) -7-bromoindol-3-yl as a yellow solid]-N, N-dimethylglyoxylamide (2.0 g, 50%). MS (ESI, M/z): 401,403 (M+H) ⁺ 。

2- [4- (benzyloxy) -7- (2-propenyl) indol-3-yl ] -N, N-dimethyl-glyoxylamide

2- [4- (benzyloxy) -7-bromoindol-3-yl]-N, N-dimethylglyoxylamide (2.0 g,5.0 mmol), potassium trifluoroborate (1.5 g,10mmol,2.0 eq.) Pd (dppf) Cl ₂ ·CH ₂ Cl ₂ A mixture of (0.40 g,0.50mmol,0.10 eq), triethylamine (1.5 g,15mmol,3.0 eq.) and isopropanol (50 mL) at 80℃under N ₂ Stirred for 3 hours under atmosphere and then filtered. The filtrate was diluted with water and extracted three times with EtOAc. The combined organic layers were washed with water and brine, dried over Na ₂ SO ₄ Dried, and concentrated under vacuum. The residue was purified by flash chromatography on silica gel (0-80% EtOAc in petroleum ether) to give 2- [4- (benzyloxy) -7- (2-propenyl) indol-3-yl as a brown solid]-N, N-dimethylglyoxylamide (1.5 g, 82%). MS (ESI, M/z): 363 (M+H) ⁺ 。

[2- [4- (benzyloxy) -7- (2-propenyl) indol-3-yl ] ethyl ] dimethylamine

Lithium aluminum hydride (524 mg,13.8mmol,10 eq.) was added in portions to 2- [4- (benzyloxy) -7- (2-propenyl) indol-3-yl]A stirred solution of N, N-dimethylglyoxylamide (500 mg,1.38 mmol) in THF (10 mL). The resulting mixture was stirred at 60℃for 3 hours, then at 0℃with Na ₂ SO ₄ ·10H ₂ O quench and filter. The filter cake is treated with CH ₂ Cl ₂ Washing three times. The combined filtrate and washings were concentrated under vacuum. The residue was purified by reverse phase flash chromatography on C ₁₈ Purification on silica gel (on a silica gel containing 0.05% NH ₄ HCO ₃ 5% -50% acetonitrile in water) to yield [2- [4- (benzyloxy) -7- (2-propenyl) indol-3-yl ] as a brown oil]Ethyl group]Dimethylamine (270 mg, 58%). MS (ESI, M/z): 335 (M+H) ⁺ 。

3- [2- (dimethylamino) ethyl ] -7-isopropylindol-4-ol

[2- [4- (benzyloxy) -7- (2-propenyl) indol-3-yl ]]Ethyl group]A mixture of dimethylamine (250 mg,0.81 mmol), 10% Pd/C (dry, 25 mg), ammonium formate (153 mg,2.43mmol,3.0 eq.) and EtOH (8 mL) at 70℃under H ₂ Stirred for 3 hours under atmosphere and then filtered. The filtrate was concentrated in vacuo. The residue was purified by reverse phase flash chromatography on C ₁₈ Purification on silica gel (on a silica gel containing 0.05% NH ₄ HCO ₃ 5% -50% acetonitrile in water) to produce 3- [2- (dimethylamino) ethyl ] as a colorless solid]-7-isopropylindol-4-ol (63 mg, 34%). ¹ H NMR(300MHz,DMSO-d ₆ )δ10.49(br s,1H),10.34(br s,1H),6.90(d,J＝2.4Hz,1H),6.65(d,J＝7.8Hz,1H),6.22(d,J＝7.8Hz,1H),3.19(m,1H),2.87(t,J＝6.6Hz,2H),2.55-2.53(m,2H),2.21(s,6H),1.22(d,J＝6.6Hz,6H)。MS(ESI,m/z):247(M+H) ⁺ 。

Examples of chemical Synthesis of Compound 11

Compound 11:3- [2- (dimethylamino) ethyl ] -7-isopropyl-1-methylindol-4-ol

Examples of synthesis of 3- [2- (dimethylamino) ethyl ] -7-isopropyl-1-methylindol-4-ol are provided below:

[2- [4- (benzyloxy) -1-methyl-7- (2-propenyl) indol-3-yl ] ethyl ] dimethylamine

NaH (60% in mineral oil, 216mg,5.4mmol,2.0 eq.) is added in portions to [2- [4- (benzyloxy) -7- (2-propenyl) indol-3-yl ] at 0 ℃]Ethyl group]A stirred solution of dimethylamine (900 mg,2.69 mmol) in DMF (20 mL). The mixture was stirred at 0deg.C for 10 min, then methyl iodide (344 mg,2.43mmol,0.90 eq.) was added. The mixture is stirred for 1 hour at 20-25 ℃ and then NH is used ₄ The Cl solution was quenched and extracted three times with EtOAc. The combined organic layers were washed with water and brine, dried over Na ₂ SO ₄ Dried, and concentrated under vacuum. The residue was purified by flash chromatography on silica gel (on CH ₂ Cl ₂ 0-20% methanol) to give [2- [4- (benzyloxy) -1-methyl-7- (2-propenyl) indol-3-yl ] as a yellow oil]Ethyl group]Dimethylamine (560 mg, 59%). MS (ESI, M/z): 349 (M+H) ⁺ 。

3- [2- (dimethylamino) ethyl ] -7-isopropyl-1-methylindol-4-ol

[2- [4- (benzyloxy) -1-methyl-7- (2-propenyl) indol-3-yl ]]Ethyl group]Dimethylamine (280 mg,0.80mmol,1.0 eq.)) A mixture of 10% Pd-C (dry, 28 mg), ammonium formate (152 mg,2.41mmol,3.0 eq.) and ethanol (10 mL) in H ₂ Stirring was carried out at 70℃for 16 hours under an atmosphere, followed by filtration. The filtrate was concentrated in vacuo. The residue was purified by flash chromatography on silica gel (on CH ₂ Cl ₂ 0-30% methanol) in a solid phase) and the product was isolated by trituration with EtOAc to give 3- [2- (dimethylamino) ethyl ] as an off-white solid]-7-isopropyl-1-methylindol-4-ol (11.4 mg, 5%). ¹ H NMR(400MHz,DMSO-d ₆ )δ10.13(br s,1H),6.79(s,1H),6.75(d,J＝8.0Hz,1H),6.26(d,J＝7.6Hz,1H),3.87(s,3H),3.66(m,1H),2.85(t,J＝6.8Hz,2H),2.54-2.50(m,2H),2.20(s,6H),1.24(d,J＝6.8Hz,6H)。MS(ESI,m/z):261(M+H) ⁺ 。

Examples of chemical Synthesis of Compound 16

Compound 16:3- [2- [ isopropyl (methyl) amino ] ethyl ] -7-methylindol-4-ol

Examples of synthesis of 3- [2- [ isopropyl (methyl) amino ] ethyl ] -7-methylindol-4-ol are provided below:

2- [4- (benzyloxy) -7-methylindol-3-yl ] -N-isopropyl-N-methylacetaldehyde amide

To 4- (benzyloxy) -7-methylindole (500 mg,2.1 mmol) in dry Et under ice-cooling ₂ Oxalyl chloride (535 mg,4.2 mmol) was added dropwise to a solution in O (10 mL). The resulting brown to dark green slurry was stirred under ice cooling for 3h. After the indole was consumed, the slurry was added dropwise to N-methylisopropylamine (463mg, 6.3 mmol) and triethylamine (428 mg,6.3 mmol) in dry Et with ice cooling ₂ In solution in O. Adding CH ₂ Cl ₂ (2 mL). The mixture was stirred at 0deg.C for 2h, warmed to room temperature, and stirred Mix overnight and filter. The filtrate was treated with NaHCO ₃ Basification of the aqueous solution followed by CH ₂ Cl ₂ And (5) extracting. The organic phase is treated with H ₂ O and brine, washed with Na ₂ SO ₄ Dried, and concentrated under reduced pressure. The residue is purified by column chromatography on silica gel (eluent: CH ₂ Cl ₂ MeOH 60:1) to afford 2- [4- (benzyloxy) -7-methylindol-3-yl as a yellow solid]-N-isopropyl-N-methylacetaldehyde amide (637 mg, 85%). MS (ESI, M/z): 365 (M+H) ⁺ 。

N- [2- [4- (benzyloxy) -7-methylindol-3-yl ] ethyl ] -N-methylisopropylamine

To 2- [4- (benzyloxy) -7-methylindol-3-yl under ice-cooling conditions]To a solution of N-isopropyl-N-methylacetaldehyde (300 mg,0.82 mmol) in toluene (6 mL) was added dropwise 70% sodium bis (2-methoxyethoxy) aluminum hydride (red aluminum; 1.2g,4.12 mmol). The mixture was heated to 80 ℃ and stirred overnight. The reaction was quenched by dropwise addition of 15% aqueous NaOH under ice-cooling. The mixture was treated with CH ₂ Cl ₂ And (5) extracting. The organic phase is treated with H ₂ O and brine, washed with Na ₂ SO ₄ Dried, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (CH ₂ Cl ₂ 3.5M NH in MeOH ₃ 40:1) to provide N- [2- [4- (benzyloxy) -7-methylindol-3-yl ] as a brown solid ]Ethyl group]N-methylisopropylamine (251 mg, 90%). ¹ H NMR(400MHz,CDCl ₃ )δ7.86(br s,1H),7.48(d,J＝6.8Hz,2H),7.36(t,J＝7.2Hz,2H),7.30(t,J＝7.2Hz,1H),6.93(d,J＝2Hz,1H),6.83(d,J＝8Hz,1H),6.45(d,J＝8Hz,1H),5.17(s,2H),3.08-3.04(m,2H),2.81-2.75(m,1H),2.71-2.69(m,2H),2.38(s,3H),2.11(s,3H),0.93(d,J＝6.4Hz,6H)。

3- [2- [ isopropyl (methyl) amino ] ethyl ] -7-methylindol-4-ol

To N- [2- [4- (benzyloxy) -7-methylindol-3-yl]Ethyl group]-N-methyl isoTo a solution of propylamine (251 mg,0.75 mmol) in MeOH (10 mL) was added 10% Pd/C (25 mg) and 20% Pd (OH) ₂ C (25 mg). The reaction mixture was stirred under a hydrogen atmosphere for 3h, then filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (CH ₂ Cl ₂ 3.5M NH in MeOH ₃ 40:1) to provide 3- [2- [ isopropyl (methyl) amino ] as a brown solid]Ethyl group]-7-methylindol-4-ol (130 mg, 71%). MS (ESI, M/z): 247 (M+H) ⁺ 。 ¹ H NMR(400MHz,CDCl ₃ ) Delta 7.77 (br s, 1H), 6.85 (d, j=2.4 hz, 1H), 6.83 (d, j=7.6 hz, 1H), 6.48 (d, j=7.6 hz, 1H), 2.96-2.93 (m, 2H), 2.87 (quintuple peak, j=6.8 hz, 1H), 2.72-2.69 (m, 2H), 2.37 (s, 3H), 2.34 (s, 3H), 0.98 (d, j=6.8 hz, 6H).

Examples of chemical Synthesis of Compound 18

Compound 18: 3- [2- (dimethylamino) ethyl ] -7-methylindol-4-yl phosphate

Examples of synthesis of 3- [2- (dimethylamino) ethyl ] -7-methylindol-4-yl phosphate are provided below:

benzyl 3- [2- (Benzyldimethylammonium) ethyl ] -7-methylindol-4-yl phosphate

3- [2- (dimethylamino) ethyl group]7-methylindol-4-ol (9.51 g,43.6 mmol) was placed in a 1L 3-necked flask with stirring bar, ar balloon, septum and internal thermometer. Anhydrous THF (360 mL) was added to give an amber solution which was taken up in acetone/CO ₂ Cooling in the bath. After the internal temperature reached-70 ℃, a 2.5M solution of n-butyllithium in hexane (20.9 ml,52.3mmol,1.2 eq.) was added dropwise over 25min, maintaining the internal temperature at or below-70 ℃. The mixture was stirred in a cold bath for 10min and then briefly removed under countercurrent of ArSeptum, and tetrabenzyl pyrophosphate (25.8 g,47.9mmol,1.1 eq.) was added as a solid in one portion. The flask was again closed and the mixture was stirred at or below-70 ℃ for 2h. Subsequently, the temperature was raised to-30 ℃ over a period of 70min, and then maintained in the range of-30 ℃ to-20 ℃ for another 50min by occasional addition of dry ice to the cold bath. Ethyl acetate (400 mL) and amino-functionalized silica gel (Supelco No. 59791;26.5 g) were added and the viscous mixture was kept at 20℃to 25℃for 10min with occasional vortexing, then filtered on celite bed with suction into a 600mL sintered glass funnel (which is time consuming due to the silt nature of the solid). The residue was washed with EtOAc (4×100 ml). The combined filtrates were evaporated to give 23.4g of an amber oil (containing trace solids) which was taken up in CH ₂ Cl ₂ (80 mL). The solution was kept at its boiling point for 5min with a low intensity heat gun and then allowed to cool to 20-25 ℃ at which point a precipitate formed gradually. After standing overnight in a refrigerator at +5℃, the material was filtered on 60mL medium porosity frit and the fine precipitate was washed with cold CH ₂ Cl ₂ (3X 15 mL) washing. After drying in a membrane pump vacuum (nominally 6 torr), the light gray solid (designated fraction 1) was weighed to 10.5g. Analysis by reverse phase HPLC (column: restek Ultra AQ C) ₁₈ 250x 4.6mm,5 μm particle size. Solvent a: containing 0.05% (v/v) CF ₃ COOH water; solvent B: containing 0.05% (v/v) CF ₃ CH of COOH ₃ CN. Flow rate: 0.8mL/min. Gradient: 0-5min,50% B;5-17min,50-100% B;17-35min,100% B) showed the major product (t _R 13.9min;94.7 area%) and several uv absorbing impurities, the largest of which is t before the desired product _R Elution at 12.4min and integration was 4.0%. The mother liquor was concentrated to about 25mL and then stored at +5 ℃ to give an additional precipitate which was filtered off and taken up with CH ₂ Cl ₂ The washing is sufficient to remove a substantial portion of the violet color formed during the mother liquor treatment. Drying under vacuum gives a further 5.2g of a light grey powder (designated fraction 2) with a violet hue; the total crude product yield was 15.7g (75%). The HPLC purity of fraction 2 was 92.8% with polar UV absorbing impurities The amount reaches 5.3 percent.

Further purification of the above crude material may be effected in a number of ways. 2.46g of fraction 2 sample was dissolved in CH with warming ₂ Cl ₂ (5 mL) and filtered on a 0.45 μm syringe filter followed by rinsing with 0.5mL of rinse. This solution was injected onto a preparative HPLC column in 25 parts (about 0.3mL each) under the same conditions as the analytical run, but with a column diameter of 21.2mm and a flow rate of 17 mL/min. Each run was stopped after complete elution of the product peak to save time and solvent. Under these conditions, the product is at t _R Eluting at 12.4min and extending the tail for several minutes, while the main uv absorbing impurities form a distinct polar shoulder, which is excluded. The eluate containing the product was concentrated to about 1/4 of its volume (some CH still remained ₃ CN), at which point the product starts to oil (oil out), but then starts to crystallize, eventually forming nearly colorless needle-like star-shaped aggregates. The vortex gradually induces crystallization of the remaining amorphous material. Filtration, washing with water, and drying under vacuum gave 1.75g of slightly violet crystals, which were substantially pure as analyzed by HPLC (conditions above). However, this material ¹ H and ¹³ c NMR spectrum (in CD ₃ In OD) showed significant non-uv active aliphatic/cycloaliphatic impurities, temporarily identified as dicyclohexylurea (introduced by tetrabenzyl pyrophosphate, thus reagent ¹ Indicated by H NMR spectrum). 1.56g of this partially purified material was dissolved in boiling CH ₃ CN/water (19:1; 130 mL). Upon cooling to 20-25 ℃, crystallization started and was completed overnight at +5℃. Suction filtration with CH ₃ CN washing and drying under vacuum resulted in recovery of 1.32g of product in the form of colorless crystals of 100% purity by analytical HPLC (280 nm) and as by ¹ H NMR shows a lack of putative dicyclohexylurea impurities.

Alternatively, the first step of the purification sequence may be performed on silica gel by normal phase column chromatography. Thus, 1.70g of fraction 2 of the crude product was dissolved in MeOH and adsorbed on silica gel (10 g). The resulting solid was taken up in CHCl ₃ Silica gel column (26x 4.3 cm) prepared in MeOH/water/AcOH (66:29:4:1)Top and eluted with the same solvent mixture. The product specks were preceded by small amounts of impurities and followed by major ultraviolet absorbing byproducts. Analytical HPLC (280 nm) of the combined product-containing eluate indicated 98.8 area% purity. The eluate was evaporated under vacuum and the bath temperature was raised to 50 ℃ near the end point to indeed remove as much water and AcOH as possible, thus obtaining a reddish viscous glass (2.1 g). Dissolving the material in CH under warm condition ₃ CN/water (19:1; 80 mL). Complete dissolution occurred well below boiling point, but crystallization began rapidly and was completed overnight at +5℃. Isolation as described above yields 1.22g of tan crystals with 99.8% purity by analytical HPLC (280 nm) which lack the putative dicyclohexylurea impurity, as by ¹ H NMR.

Recrystallization under the above conditions without prior chromatography results in a material purity lower than that achieved by a combination of the two techniques. Thus, 0.42g of crude product (fraction 1) was isolated from CH ₃ CN/water (19:1; 35 mL) was recrystallized to recover 0.35g of pale gray crystals with 98.5% purity by analytical HPLC (280 nm) while retaining 1.3% of the main UV absorption by-product.

Benzyl 3- [2- (benzyldimethylammonium) ethyl]-7-methylindol-4-yl phosphate: ¹ H NMR(CD ₃ OD, TMS,500 MHz) delta 7.36-7.44 (m, 5H), 7.29-7.20 (m, 5H), 7.11 (s, 1H), 7.00,6.79 (ABq, 2H, j=7.8 Hz, high field part slightly widened), 4.96 (d, 2H, j _P-H =5.9 Hz), 4.53 (s, 2H), 3.61,3.45 (AA 'XX' multiplet, 4H, j _AX +J _AX' ＝16.9Hz),3.05(s,6H),2.40(s,3H)。 ¹³ C NMR(CD ₃ OD,TMS,125MHz)δ145.96(d,J _C-P ＝7.1Hz),139.44,139.37(d,J _C-P ＝8.5Hz),134.18(2C),131.75,130.23(2C),129.34(2C),129.03,128.76,128.66(2C),124.43,123.41,119.80(d,J _C-P ＝7.1Hz),117.58,110.25(d,J _C-P ＝2.4Hz),109.46,69.13,69.07(d,J _C-P ＝5.5Hz),67.54,50.29,21.49,16.39。

3- [2- (dimethylamino) ethyl ] -7-methylindol-4-yl phosphate

To 2.86g (5.98 mmol) of benzyl 3- [2- (benzyldimethylammonium) ethyl]To a solution of 7-methylindol-4-yl phosphate in MeOH (140 mL) was added 10% Pd/C (wet; oakwood No. 0232236; 283 mg). Atmosphere is H ₂ Alternatively, and the mixture is subjected to H at 20-25 DEG C ₂ Stirring for 2h under an atmosphere (balloon). The atmosphere was then replaced with Ar and the suspension was filtered over a 0.45 μm PTFE membrane. Analytical HPLC (column: restek Ultra AQ C) ₁₈ 250x 4.6mm,5 μm particle size. Solvent a: containing 0.05% (v/v) CF ₃ COOH water; solvent B: containing 0.05% (v/v) CF ₃ CH of COOH ₃ CN. Flow rate: 0.8mL/min. Gradient: 0-5min,10% B;5-25min,10% -100% of B;25-40min,100% B. UV detection at 280nm indicates a single major product (t _R 13.6min,99.6 area%). Evaporating the solution under vacuum at bath temperature up to 45 ℃ to obtain the brittle off-white foam of 3- [2- (dimethylamino) ethyl ] phosphate]-7-methylindol-4-yl ester (1.73 g, 97%). By passing through ¹ H NMR analysis, the material was pure except for a small amount of methanol (0.56 eq). ¹ H NMR(CD ₃ OD, TMS,500 MHz) delta 7.08 (s, 1H), 6.93,6.81 (ABq, 2H, j=7.8 Hz, low field part d, j=0.6 Hz), 3.40,3.29 (AA 'XX' multiplet, 4H, J) _AX +J _AX' ＝15.6Hz),2.88(s,6H),2.40(s,3H)。 ¹ H NMR (lower concentration of D ₂ The O, HDO signal is set to δ4.80,500 mhz) δ7.23 (s, 1H), 6.98,6.95 (ABq, 2H, j=8.0 Hz, high field portion d, j=1.1 Hz), 3.45,3.31 (AA 'XX' multiplet, 4H, J) _AX +J _AX' ＝14.9Hz),2.91(s,6H),2.44(s,3H)； ¹ H NMR (higher concentration of D ₂ The O, HDO signal is set to δ4.80,500 MHz) δ7.06 (s, 1H), 6.92,6.89 (ABq, 2H, J=8.1 Hz), 3.24,3.14 (AA 'XX' multiplet, 4H, J) _AX +J _AX' ＝15.2Hz),2.79(s,6H),2.36(s,3H)。 ¹³ C NMR(CD ₃ OD, TMS,125 MHz) δ 145.56,139.51,124.41,123.29,119.81,118.01,110.17 (supposedly 2C overlap), 60.44,43.43,23.26,16.38. ¹³ C NMR(D ₂ O, no standard, default calibration by software; 125 MHz) delta 143.64 (d, J _C-P ＝6.7Hz),137.64,123.89,122.27,117.81(d,J _C-P ＝6.7Hz),117.58,108.84(d,J _C-P ＝2.6Hz),108.35,58.75,21.46,15.23。

Examples of chemical Synthesis of Compound 20

Compound 20: acetic acid 3- [2- (dimethylamino) ethyl ] -7-methylindol-4-yl ester

An example of the synthesis of 3- [2- (dimethylamino) ethyl ] -7-methylindol-4-yl acetate is provided below:

compound 1 (0.23 mmol) and pyridine (0.30 mmol) were cooled on CH with an ice bath ₂ Cl ₂ (1 mL) of the solution. Acetic anhydride (255. Mu. Mol) was added. The mixture was stirred at room temperature for 2h or until the reaction was complete. Volatiles were removed under vacuum. The residue was purified by preparative HPLC and the eluate evaporated to give compound 20.

Examples of chemical Synthesis of Compound 26

Compound 26: [2- (4-methoxy-7-methylindol-3-yl) ethyl ] dimethylamine

Examples of synthesis of [2- (4-methoxy-7-methylindol-3-yl) ethyl ] dimethylamine are provided below:

4-methoxy-7-methylindole

at-30deg.C, at N ₂ Vinyl magnesium bromide (1.0M in THF, 120mL,120mmol,4.0 eq.) was added dropwise to a stirred solution of 4-methoxy-1-methyl-2-nitrobenzene (5.0 g,29.9 mmol) in THF (100 mL) under an atmosphere. The resulting mixture was stirred at 0deg.C for 2 hours Then using NH ₄ The Cl solution was quenched. The organic layer was separated and concentrated under vacuum. The residue was purified by flash chromatography on silica gel (0-30% EtOAc in petroleum ether) to give 4-methoxy-7-methylindole (1.2 g, 24%) as a pale yellow solid. MS (ESI, M/z): 162 (M+H) ⁺ 。

2- [4- (methoxy) -7-methylindol-3-yl ] -N, N-dimethylglyoxylamide

At 0℃under N ₂ Oxalyl chloride (2.0 g,9.3mmol,3.0 eq.) was added dropwise to a stirred solution of 4-methoxy-7-methylindole (500 mg,3.11 mmol) in THF (10 mL) under an atmosphere. The resulting mixture was stirred at 0 ℃ for 2 hours, and a solution of dimethylamine in THF (2.0 m,9.3ml,18.7mmol,6.0 eq.) was added dropwise. The mixture was stirred at 20-25 ℃ for another hour, then diluted with water and extracted three times with EtOAc. The combined organic layers were washed with brine, dried over Na ₂ SO ₄ Dried, and concentrated under vacuum. The residue was purified by flash chromatography on silica gel (0-90% EtOAc in petroleum ether containing 0.05% triethylamine) to give 2- (4-methoxy-7-methylindol-3-yl) -N, N-dimethylglyoxylamide (500 mg, 61%) as a yellow solid. MS (ESI, M/z): 261 (M+H) ⁺ 。

[2- (4-methoxy-7-methylindol-3-yl) ethyl ] dimethylamine

Lithium aluminum hydride (1.46 g,38.4mmol,20 eq.) was added in portions to a stirred solution of 2- (4-methoxy-7-methylindol-3-yl) -N, N-dimethylglyoxylamide (500 mg,1.92 mmol) in THF (20 mL) at 0deg.C. The resulting mixture was stirred at 65℃for 2 hours, then at 0℃with Na ₂ SO ₄ ·10H ₂ O quench and filter. Filtering the filtrateConcentrated under vacuum. The residue was purified by reverse phase flash chromatography on C ₁₈ Purification on silica gel (0-70% acetonitrile in water) to give [2- (4-methoxy-7-methylindol-3-yl) ethyl ] as a pale yellow solid]Dimethylamine (72 mg, 16%). ¹ H NMR(300MHz,DMSO-d ₆ )δ10.64(br s,1H),6.95(d,J＝2.4Hz,1H),6.72(d,J＝7.5Hz,1H),6.31(d,J＝7.8Hz,1H),3.78(s,3H),2.94-2.82(m,2H),2.47-2.39(m,2H),2.32(s,3H),2.19(s,6H)。MS(ESI,m/z):233(M+H) ⁺ 。

Examples of chemical Synthesis of Compound 33

Compound 33:3- [2- (dimethylamino) ethyl ] -6-fluoro-7-methylindol-4-ol

Examples of synthesis of 3- [2- (dimethylamino) ethyl ] -6-fluoro-7-methylindol-4-ol are provided below:

4-bromo-6-fluoro-7-methylindole

Vinylmagnesium bromide (1.0M in THF, 170mL,0.17mol,4.0 eq.) was added dropwise to a stirred mixture of 5-bromo-1-fluoro-2-methyl-3-nitrobenzene (10.0 g,42.7 mmol) in THF (100 mL) at 0deg.C. The mixture was stirred at 0deg.C for 1 hour, then with NH ₄ The Cl solution was quenched. The mixture was extracted three times with EtOAc. The organic layers were combined and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (0-25% etoac in petroleum ether) to give 4-bromo-6-fluoro-7-methylindole (2.6 g, 24%) as a brown oil. MS (ESI, M/z): 226,228 (M-H) ⁺ 。

2- (4-bromo-6-fluoro-7-methylindol-3-yl) -N, N-dimethylglyoxylamide

At 0℃under N ₂ Oxalyl chloride (4.3 g,34.2mmol,3.0 eq.) was added dropwise to a stirred solution of 4-bromo-6-fluoro-7-methyl-1H-indole (2.6 g,11.4 mmol) in THF (50 mL) under an atmosphere. The mixture was stirred at 0deg.C for 2h, and a solution of dimethylamine in THF (2.0M, 34mL,68mmol,6.0 eq.) was added dropwise. The mixture is stirred for a further hour at 20℃to 25℃and then treated with NH ₄ The Cl solution was quenched and extracted three times with EtOAc. The combined organic layers were washed with brine, dried over Na ₂ SO ₄ Dried, and concentrated under vacuum. The residue was purified by reverse phase flash chromatography on C ₁₈ Purification on silica gel (on a silica gel containing 0.5% NH ₄ HCO ₃ From 5% to 70% acetonitrile in water) to yield 2- (4-bromo-6-fluoro-7-methylindol-3-yl) -N, N-dimethylglyoxylamide (1.9 g, 46%) as a yellow solid. MS (ESI, M/z): 327,329 (M+H) ⁺ 。

2- (6-fluoro-4-hydroxy-7-methylindol-3-yl) -N, N-dimethylglyoxylamide

A mixture of 2- (4-bromo-6-fluoro-7-methylindol-3-yl) -N, N-dimethylglyoxylamide (4.0 g,12.2 mmol), KOH (3.4 g as 30% aqueous solution, 61mmol,5.0 eq.), cuI (0.70 g,3.7mmol,0.30 eq.) and DMF (50 mL) was taken at 120deg.C under N ₂ Stirred for 1 hour under an atmosphere, and then filtered. The filtrate was concentrated in vacuo. The residue was purified by reverse phase flash chromatography on C ₁₈ Purification on silica gel (5% -40% acetonitrile in water containing 0.5% trifluoroacetic acid) yielded 2- (6-fluoro-4-hydroxy-7-methylindol-3-yl) -N, N-dimethylglyoxylamide (0.80 g, 23%) as a yellow solid. MS (ESI, M/z): 265 (M+H) ⁺ 。

3- [2- (dimethylamino) ethyl ] -6-fluoro-7-methylindol-4-ol

2- (6-fluoro-4-hydroxy-7-methylindol-3-yl) -N, N-dimethylglyoxylamide (0.80 g,3.02 mmol) and LiAlH ₄ A mixture of (1.1 g,30mmol,10 eq.) in THF (30 mL) was stirred at 65deg.C for 16 hours. After cooling, the mixture was treated with CH ₂ Cl ₂ Diluting with Na ₂ SO ₄ ·10H ₂ O quench, and filter. The filtrate was concentrated in vacuo. The residue was purified by reverse phase flash chromatography on C ₁₈ Purification on silica gel (on a silica gel containing 0.5% NH ₄ HCO ₃ 5% -40% acetonitrile in water) to produce 3- [2- (dimethylamino) ethyl ] as a white solid]-6-fluoro-7-methylindol-4-ol (218 mg, 29%). ¹ H NMR(300MHz,DMSO-d ₆ ):δ11.40(br s,1H),10.65(br s,1H),6.93(s,1H),6.10(d,J _H-F =12.0 hz, 1H), 2.87-2.83 (m, 2H), 2.55-2.51 (m, 2H), 2.22 (s, 6H), 2.19-2.18 (narrow m, 3H). ¹⁹ F NMR(282MHz,DMSO-d ₆ ):δ-128.0。MS(ESI,m/z):237(M+H) ⁺ 。

Examples of chemical Synthesis of Compound 34

Compound 34: [2- (6-fluoro-4-methoxy-7-methylindol-3-yl) ethyl ] dimethylamine

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Examples of synthesis of [2- (6-fluoro-4-methoxy-7-methylindol-3-yl) ethyl ] dimethylamine are provided below:

2- (6-fluoro-4-methoxy-7-methylindol-3-yl) -N, N-dimethylglyoxylamide

A mixture of 2- (4-bromo-6-fluoro-7-methylindol-3-yl) -N, N-dimethylglyoxylamide (1.90 g,5.80 mmol), sodium methoxide (30% solution in methanol, 3.1g,17.4mmol,3.0 eq.), cuI (220 mg,1.16mmol,0.20 eq.) and DMF (20 mL) was taken at 120deg.C under N ₂ Stirred under atmosphere for 1h and then filtered. The filtrate was concentrated in vacuo. The residue was purified by flash chromatography on silica gel (on CH ₂ Cl ₂ To yield 2- (6-fluoro-4-methoxy-7-methylindol-3-yl) -N, N-dimethylglyoxylamide (0.80 g, 43%) as a yellow solid. MS (ESI, M/z): 279 (M+H) ⁺ 。

[2- (6-fluoro-4-methoxy-7-methylindol-3-yl) ethyl ] dimethylamine

2- (6-fluoro-4-methoxy-7-methylindol-3-yl) -N, N-dimethylglyoxylamide (0.80 g,2.87 mmol), liAlH ₄ A mixture of (1.1 g,29mmol,10 eq.) and THF (30 mL) was stirred at 65℃for 16 h. After cooling, the mixture was treated with CH ₂ Cl ₂ Diluting with Na ₂ SO ₄ ·10H ₂ O was quenched at 20 ℃ -25 ℃ and filtered. The filtrate was concentrated in vacuo. The residue was purified by reverse phase flash chromatography on C ₁₈ Purification on silica gel (containing 0.5% NH) ₄ HCO ₃ 5% -40% acetonitrile of the water) to produce [2- (6-fluoro-4-methoxy-7-methylindol-3-yl) ethyl ] as a colorless solid]Dimethylamine (55 mg, 7%). ¹ H NMR(400MHz,DMSO-d ₆ ):δ10.82(br s,1H),6.96(s,1H),6.33(d,J＝12.4Hz,1H),3.80(s,3H),2.87-2.83(m,2H),2.47-2.43(m,2H),2.24-2.23(m,3H),2.19(s,6H)。MS(ESI,m/z):251(M+H) ⁺ 。

Examples of chemical Synthesis of Compound 36

Compound 36:3- [2- (dimethylamino) ethyl ] -6-fluoroindol-4-ol

Examples of synthesis of 3- [2- (dimethylamino) ethyl ] -6-fluoroindol-4-ol are provided below:

2- (benzyloxy) -4-fluorobenzaldehyde

NaH (60% in mineral oil, 12.9g, 534 mmol,5 eq.) was added in portions to a stirred solution of 4-fluoro-2-hydroxybenzaldehyde (15.0 g,107 mmol) in DMF (150 mL) at 0deg.C. The mixture was stirred at 0℃for 10 min. Benzyl bromide (36.4 g,214mmol,2.0 eq.) was added to the mixture. The mixture is stirred for 16h at 20-25 ℃ and then NH is used ₄ The Cl solution was quenched and extracted three times with EtOAc. The combined organic layers were washed with water and brine, dried over Na ₂ SO ₄ Dried, and concentrated under vacuum. The residue was purified by flash chromatography on silica gel (0-75% EtOAc in petroleum ether) to afford 2- (benzyloxy) -4-fluorobenzaldehyde (22.0 g, 89%) as a yellow oil. MS (ESI, M/z): 231 (M+H) ⁺ 。

(2Z) -2-azido-2 '- (benzyloxy) -4' -fluoro cinnamic acid ethyl ester

at-10deg.C, at N ₂ Na metal (6.0 g,261mmol,4.0 eq.) was added in portions to absolute ethanol (300 mL) under stirring under an atmosphere. The mixture was stirred until the Na metal was completely dissolved. To this sodium ethoxide solution was added dropwise a solution of 2- (benzyloxy) -4-fluorobenzaldehyde (15.0 g,65.2 mmol) and ethyl 2-azidoacetate (33.7 g,261mmol,4.0 eq.) in ethanol (150 mL) over a period of 10 minutes at-10 ℃. The mixture was stirred for an additional 10 minutes, then ethyl trifluoroacetate (18.5 g,130mmol,2.0 eq.) was added. Stirring the obtained mixture at 20-25 ℃ for 16 hours, using NH ₄ The Cl solution was quenched and extracted three times with EtOAc. The combined organic layers were washed with brine, dried over Na ₂ SO ₄ Dried, and concentrated under vacuum. The residue was purified by flash chromatography on silica gel (0-70% EtOAc in petroleum ether) to afford (2Z) -2-azido-2 '- (benzyloxy) -4' -fluoro as a yellow solidEthyl cinnamate (11.0 g, 49%). MS (ESI, M/z): 341 (M+H) ⁺ 。

4- (benzyloxy) -6-fluoroindole-2-carboxylic acid ethyl ester

A solution of ethyl (2Z) -2-azido-2 '- (benzyloxy) -4' -fluoro cinnamate (11.0 g,32.3 mmol) in toluene (110 mL) was stirred at 110℃for 16 hours and then concentrated in vacuo. The residue was purified by flash chromatography on silica gel (0-85% EtOAc in petroleum ether) to give ethyl 4- (benzyloxy) -6-fluoroindole-2-carboxylate (7.0 g, 69%) as a yellow solid. MS (ESI, M/z): 314 (M+H) ⁺ 。

4- (benzyloxy) -6-fluoroindole-2-carboxylic acid

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A solution of sodium hydroxide (3.83 g,96mmol,5.0 eq.) in water (18 mL) was added to a stirred solution of ethyl 4- (benzyloxy) -6-fluoroindole-2-carboxylate (6.0 g,19.2 mmol) in THF (18 mL) and EtOH (18 mL) at 20℃to 25 ℃. The mixture was stirred at 20 ℃ to 25 ℃ for 3 hours, then acidified with HCl (1N) to pH 2-3 and extracted three times with EtOAc. The combined organic layers were washed with brine, dried over Na ₂ SO ₄ Dried and concentrated in vacuo to give crude 4- (benzyloxy) -6-fluoroindole-2-carboxylic acid (4.5 g) as a yellow solid, which was used in the next step without further purification. MS (ESI, M/z): 286 (M+H) ⁺ 。

4- (benzyloxy) -6-fluoroindole

A mixture of 4- (benzyloxy) -6-fluoroindole-2-carboxylic acid (4.5 g,15.8 mmol) and copper powder (0.30 g,4.7mmol,0.30 eq.) in quinoline (45 mL) was reacted at 220℃under N ₂ Stirring under atmosphereMix for 3 days and then filter. The filter cake was washed with EtOAc. The combined filtrates were washed with HCl (1N) and brine, and dried over Na ₂ SO ₄ Dried and then concentrated under vacuum. The residue was purified by flash chromatography on silica gel (on CH ₂ Cl ₂ 0-25% methanol) to give 4- (benzyloxy) -6-fluoroindole (500 mg, 13%) as a brown solid. MS (ESI, M/z): 242 (M+H) ⁺ 。

2- [4- (benzyloxy) -6-fluoroindol-3-yl ] -N, N-dimethylglyoxylamide

Oxalyl chloride (0.79 g,6.2mmol,3.0 eq.) is added dropwise to a stirred solution of 4- (benzyloxy) -6-fluoroindole (500 mg,2.07 mmol) in THF (5 mL) at 0deg.C. The resulting mixture was stirred at 20℃to 25℃for 4 hours. A solution of dimethylamine in THF (2.0M, 6.2mL,12.4mmol,6.0 eq.) was added. The mixture was stirred at 20-25 ℃ for 1 hour, then diluted with water and extracted three times with EtOAc. The combined organic layers were washed with water and brine, dried over Na ₂ SO ₄ Dried, and concentrated under vacuum. The residue was purified by flash chromatography on silica gel (on CH ₂ Cl ₂ 0-10% methanol) to provide 2- [4- (benzyloxy) -6-fluoroindol-3-yl as a yellow solid]-N, N-dimethylglyoxylamide (620 mg, 85%). MS (ESI, M/z): 341 (M+H) ⁺ 。

[2- [4- (benzyloxy) -6-fluoroindol-3-yl ] ethyl ] dimethylamine

Lithium aluminum hydride (1.1 g,29mmol,20 eq.) was added in portions to 2- [4- (benzyloxy) -6-fluoroindol-3-yl at 0deg.C]A stirred solution of N, N-dimethylglyoxylamide (500 mg,1.47 mmol) in 2-methyltetrahydrofuran (5 mL). The resulting solution was subjected to N at 80 ℃ ₂ Stirring for 16 hours under atmosphere, then using Na ₂ SO ₄ ·10H ₂ O quench and filter. The filter cake is treated with CH ₂ Cl ₂ Washing three times. The combined filtrate and washings were concentrated in vacuo to give [2- [4- (benzyloxy) -6-fluoroindol-3-yl ] as a brown oil]Ethyl group]Dimethylamine (500 mg crude) was used in the next step without further purification. MS (ESI, M/z): 313 (M+H) ⁺ 。

3- [2- (dimethylamino) ethyl ] -6-fluoroindol-4-ol

Will [2- [4- (benzyloxy) -6-fluoroindol-3-yl ]]Ethyl group]A mixture of dimethylamine (450 mg,1.44 mmol), 10% Pd/C (wet, 135 mg) and methanol (4.5 mL) was reacted at 20℃to 25℃under H ₂ Stirred for 3 hours under atmosphere and then filtered. The filtrate was concentrated in vacuo. The residue was purified by reverse phase flash chromatography on C ₁₈ Purification on silica gel (on a silica gel containing 0.05% NH ₄ HCO ₃ 5% -40% acetonitrile in water) to produce 3- [2- (dimethylamino) ethyl ] as a colorless solid]-6-fluoroindol-4-ol (36 mg, 11%). ¹ H NMR(400MHz,DMSO-d ₆ )δ10.66(br s,1H),6.90(d,J＝2.0Hz,1H),6.49(dd,J＝9.6,2.4Hz,1H),6.09(dd,J＝12.0,2.4Hz,1H),2.84(t,J＝6.4Hz,2H),2.55(t,J＝6.4Hz,2H),2.23(s,6H)。 ¹⁹ F NMR(376MHz,DMSO-d ₆ )δ-121.4。MS(ESI,m/z):223(M+H) ⁺ 。

Examples of chemical Synthesis of Compound 37

Compound 37:3- [2- (dimethylamino) ethyl ] -6-methylindol-4-ol

Examples of synthesis of 3- [2- (dimethylamino) ethyl ] -6-methylindol-4-ol are provided below:

2- (benzyloxy) -4-methylbenzaldehyde

NaH (60% in mineral oil, 3.5g,88mmol,1.2 eq.) was added in portions to a stirred solution of 2-hydroxy-4-methylbenzaldehyde (10.0 g,73.5 mmol) in DMF (100 mL) at 0deg.C. The mixture was stirred at 0deg.C for 10 min, then benzyl bromide (13.8 g,81mmol,1.1 eq.) was added. The mixture is stirred for 1 hour at 20-25 ℃ and then NH is used ₄ The Cl solution was quenched and extracted three times with EtOAc. The combined organic layers were washed with water and brine, dried over Na ₂ SO ₄ Dried, and concentrated under vacuum. The residue was purified by flash chromatography on silica gel (0-20% EtOAc in petroleum ether) to give 2- (benzyloxy) -4-methylbenzaldehyde (12.2 g, 73%) as a pale yellow solid. MS (ESI, M/z): 227 (M+H) ⁺ 。

(2Z) -2-azido-2 '- (benzyloxy) -4' -methyl cinnamic acid ethyl ester

at-10deg.C, at N ₂ Na metal (4.1 g,177mmol,4.0 eq.) was added in portions to absolute ethanol (200 mL) under stirring under an atmosphere. The mixture was stirred at-10℃for 4 hours. To this sodium ethoxide solution was added a mixture of 2- (benzyloxy) -4-methylbenzaldehyde (10.0 g,44.3 mmol), ethyl 2-azidoacetate (22.8 g,177mmol,4.0 eq.) and ethyl trifluoroacetate (12.5 g,88mmol,2.0 eq.). The reaction mixture was stirred at 20℃to 25℃for 2 days, then with NH ₄ The Cl solution was quenched and extracted three times with EtOAc. The combined organic layers were concentrated in vacuo. The residue was purified by flash chromatography on silica gel (0-20% EtOAc in petroleum ether) to give ethyl (2Z) -2-azido-2 '- (benzyloxy) -4' -methylcinnamate (5.7 g, 38%) as a yellow solid. MS (ESI, M/z): 338 (M+H) ⁺ 。

4- (benzyloxy) -6-methylindole-2-carboxylic acid ethyl ester

A solution of ethyl (2Z) -2-azido-2 '- (benzyloxy) -4' -methylcinnamate (5.7 g,16.9 mmol) in toluene (30 mL) was stirred at 100deg.C for 16 hours and then concentrated under vacuum. The residue was purified by flash chromatography on silica gel (0-80% EtOAc in petroleum ether) to give ethyl 4- (benzyloxy) -6-methylindole-2-carboxylate (5.0 g, 95%) as an off-white solid. MS (ESI, M/z): 310 (M+H) ⁺ 。

4- (benzyloxy) -6-methylindole-2-carboxylic acid

A solution of NaOH (1.3 g,32mmol,2.0 eq.) in water (10 mL) was added dropwise to a stirred solution of ethyl 4- (benzyloxy) -6-methylindole-2-carboxylate (5.0 g,16.2 mmol) in THF (10 mL) and EtOH (10 mL) at 20℃to 25 ℃. The resulting mixture was stirred at 20-25 ℃ for 16 hours and then diluted with water. The mixture was acidified to pH 1 with HCl (1M) and extracted three times with EtOAc. The combined organic layers were washed with water and brine, dried over Na ₂ SO ₄ Dried and concentrated in vacuo to give crude 4- (benzyloxy) -6-methylindole-2-carboxylic acid (4.5 g, 99%) as an off-white solid, which was used in the next step without further purification. MS (ESI, M/z): 282 (M+H) ⁺ 。

4- (benzyloxy) -6-methylindole

A mixture of 4- (benzyloxy) -6-methylindole-2-carboxylic acid (2.0 g,7.1 mmol), copper powder (0.1 g,2mmol,0.3 eq.) and quinoline (8 mL) was reacted at 220℃under N ₂ Stirring is carried out for 6 days under an atmosphere. The mixture was diluted with EtOAc and then filtered. The filtrate was washed with HCl (1M) and brine, then concentrated in vacuo. The residue was purified by reverse phase flash chromatography on C ₁₈ Purification on silica gel (on a silica gel containing 0.05% NH ₄ HCO ₃ From 5% to 50% acetonitrile in water) to yield 4- (benzyloxy) -6-methylindole (860 mg, 50%) as a yellow solid. MS (ESI, M/z): 238 (M+H) ⁺ 。

2- [4- (benzyloxy) -6-methylindol-3-yl ] -N, N-dimethylglyoxylamide

Oxalyl chloride (1.38 g,10.9mmol,3.0 eq.) is added dropwise to a stirred mixture of 4- (benzyloxy) -6-methylindole (860 mg,3.63 mmol), phthalimide (349 mg,2.36mmol,0.65 eq.) and diethyl ether (110 mL) at 0 ℃. Stirring the mixture at 20-25 ℃ for 1 hour; then, a solution of dimethylamine in THF (2.0 m,10.9ml,21.8mmol,6.0 eq.) was added dropwise at 0 ℃. The mixture was stirred at 20-25 ℃ for another hour, then diluted with water and extracted three times with EtOAc. The combined organic layers were washed with water and brine, dried over Na ₂ SO ₄ Dried, and concentrated under vacuum. The residue was purified by reverse phase flash chromatography on C ₁₈ Purification on silica gel (over a solution containing 0.05% NH ₄ HCO ₃ 5% -50% acetonitrile in water) to produce 2- [4- (benzyloxy) -6-methylindol-3-yl as a yellow solid]-N, N-dimethylglyoxylamide (300 mg, 26%). MS (ESI, M/z): 337 (M+H) ⁺ 。

[2- [4- (benzyloxy) -6-methylindol-3-yl ] ethyl ] dimethylamine

Lithium aluminum hydride (0.34 g,8.9mmol,10 eq.) was added to 2- [4- (benzyloxy) -6-methylindol-3-yl at 0deg.C]A stirred solution of N, N-dimethylglyoxylamide (300 mg,0.89 mmol) in 2-methyltetrahydrofuran (15 mL). The mixture was stirred at 80℃for 1 hour, at 0℃with Na ₂ SO ₄ ·10H ₂ Quenched and then filtered. The filtrate is put in trueConcentrating under the air. The residue was purified by reverse phase flash chromatography on C ₁₈ Purification on silica gel (in the presence of 0.05% NH ₄ HCO ₃ 5% -80% acetonitrile in water) to yield [2- [4- (benzyloxy) -6-methylindol-3-yl ] as a yellow oil]Ethyl group]Dimethylamine (160 mg, 58%). MS (ESI, M/z): 309 (M+H) ⁺ 。

3- [2- (dimethylamino) ethyl ] -6-methylindol-4-ol

Will [2- [4- (benzyloxy) -6-methylindol-3-yl ]]Ethyl group]A mixture of dimethylamine (160 mg,0.52 mmol), 10% Pd-C (dry, 24 mg) and MeOH (10 mL) at 20℃to 25℃under H ₂ Stirred for 3 hours under atmosphere and then filtered. The filtrate was concentrated in vacuo. The residue was purified by reverse phase flash chromatography on C ₁₈ Purification on silica gel (over a solution containing 0.05% NH ₄ HCO ₃ 5% -50% acetonitrile in water) to produce 3- [2- (dimethylamino) ethyl ] as a pale yellow solid]-6-methylindol-4-ol (23 mg, 20%). ¹ H NMR(300MHz,DMSO-d ₆ )δ10.42(br s,1H),6.82(s,1H),6.55(s,1H),6.12(s,1H),2.87-2.83(m,2H),2.52-2.50(m,2H),2.26-2.23(m,9H)。MS(ESI,m/z):219(M+H) ⁺ 。

Examples of chemical Synthesis of Compound 39

Compound 39: dimethyl [2- [ 7-methyl-4- [4- (trifluoromethyl) benzyloxy ] indol-3-yl ] ethyl ] amine

Examples of the synthesis of dimethyl [2- [ 7-methyl-4- [4- (trifluoromethyl) benzyloxy ] indol-3-yl ] ethyl ] amine are provided below:

2- (4-hydroxy-7-methylindol-3-yl) -N, N-dimethylglyoxylamides

At H ₂ 2- [4- (benzyloxy) -7-methylindol-3-yl ] under an atmosphere]A mixture of N, N-dimethylglyoxylamide (900 mg,2.68 mmol), 10% Pd/C (wet, 90 mg) and MeOH (9 mL) was stirred at 20℃to 25℃for 2 hours, then filtered. The filtrate was concentrated in vacuo to give crude 2- (4-hydroxy-7-methylindol-3-yl) -N, N-dimethylglyoxylamide (750 mg) as a yellow solid, which was used in the next step without further purification. MS (ESI, M/z): 247 (M+H) ⁺ 。

N, N-dimethyl-2- [ 7-methyl-4- [4- (trifluoromethyl) benzyloxy ] indol-3-yl ] glyoxylamide

2- (4-hydroxy-7-methylindol-3-yl) -N, N-dimethylglyoxylamide (750 mg,3.05 mmol), 1- (bromomethyl) -4- (trifluoromethyl) benzene (1.10 g,4.57mmol,1.5 eq.) K ₂ CO ₃ A mixture of (842 mg,6.10mmol,2.0 eq.) and acetone (4.0 mL) was stirred at 20℃to 25℃for 8 hours, then filtered. The filtrate was concentrated in vacuo. The residue was purified by flash chromatography on silica gel (0-50% EtOAc in petroleum ether) to give N, N-dimethyl-2- [ 7-methyl-4- [4- (trifluoromethyl) benzyloxy) as a yellow solid]Indol-3-yl]Glyoxylamides (560 mg, 37%). MS (ESI, M/z): 405 (M+H) ⁺ 。

Dimethyl [2- [ 7-methyl-4- [4- (trifluoromethyl) benzyloxy ] indol-3-yl ] ethyl ] amine

At 0 ℃, BH is added ₃ THF (1M in THF, 5.0mL,5.0mmol,5.0 eq.) was added dropwise to N, N-dimethyl-2- [ 7-methyl-4- [4- (trifluoromethyl) benzyloxy)]Indol-3-yl]Glyoxylamide (400 mg,0.99 mmol) in THF (8 mL) was stirred. The mixture was stirred at 20℃to 25℃for 16 hours, thenAfter quenching with MeOH at 0deg.C and with CH ₂ Cl ₂ Extraction is carried out three times. The combined organic layers were washed with brine, dried over Na ₂ SO ₄ Dried, and concentrated under vacuum. The residue was redissolved in THF (8 mL), and 1M aqueous HCl (4.0 mL) was added dropwise to this solution. The mixture was stirred at 50 ℃ for 2 days and then concentrated under vacuum. The residue was purified by preparative HPLC at C ₁₈ Purification on silica gel (on NH-containing ₄ HCO ₃ Gradient acetonitrile in water) to provide dimethyl [2- [ 7-methyl-4- [4- (trifluoromethyl) benzyloxy) as an off-white solid]Indol-3-yl]Ethyl group]Amine (29 mg, 7%). ¹ H NMR(400MHz,DMSO-d ₆ )δ10.23(br s,1H),7.66(d,J＝8.0Hz,2H),7.03-7.02(m,3H),6.51(d,J＝7.6Hz,1H),6.21(d,J＝7.6Hz,1H),5.60(s,2H),2.92(t,J＝7.2Hz,2H),2.56(t,J＝7.2Hz,2H),2.25(s,3H),2.22(s,6H)。MS(ESI,m/z):377(M+H) ⁺ 。

Examples of chemical Synthesis of Compound 64

Compound 64:3- [2- (dimethylamino) ethyl ] -4-oxindole-7-carbonitrile

Examples of synthesis of 3- [2- (dimethylamino) ethyl ] -4-oxindole-7-carbonitrile are provided below:

4- (benzyloxy) -7-bromoindole-3-carbaldehyde

POCl at 0deg.C ₃ (3.3 g,22mmol,2.2 eq.) was added to DMF (6.4 g,44mmol,4.4 eq.). The mixture was stirred at this temperature for 20 minutes. A solution of 4- (benzyloxy) -7-bromoindole (3.0 g,10.0 mmol) in DMF (30 mL) was then added to the foregoing mixture. The resulting mixture was stirred at 0 ℃ for 30 minutes; water (300 mL) was then added. The resulting mixture was stirred at 100deg.C for 1 hour and then quenched with aqueous NaOHKill and extract three times with EtOAc. The combined organic layers were washed with brine and concentrated in vacuo to give crude 4- (benzyloxy) -7-bromoindole-3-carbaldehyde (1.6 g, 48%) as a yellow solid which was used in the next step without further purification. MS (ESI, M/z): 330,332 (M+H) ⁺ 。

(E) -4- (benzyloxy) -7-bromo-3- (2-nitrovinyl) indole

At 20-25 ℃ under N ₂ NH is put under atmosphere ₄ OAc (0.19 g,2.4mmol,0.5 eq.) was added to a stirred solution of 4- (benzyloxy) -7-bromoindole-3-carbaldehyde (1.6 g,4.9 mmol) in nitromethane (16 mL). The mixture was stirred at 100 ℃ for 2 hours and then concentrated under vacuum. The residue was purified by flash chromatography on silica gel (0-50% EtOAc in petroleum ether) to give (E) -4- (benzyloxy) -7-bromo-3- (2-nitrovinyl) indole (1.7 g, 93%) as a yellow solid. MS (ESI, M/z): 373,375 (M+H) ⁺ 。

2- [4- (benzyloxy) -7-bromoindol-3-yl ] ethylamine

At 0℃under N ₂ Lithium aluminum hydride (0.36 g,9.4mmol,5.0 eq.) was added in portions to a stirred solution of (E) -4- (benzyloxy) -7-bromo-3- (2-nitrovinyl) indole (700 mg,1.88 mmol) in THF (7 mL) under an atmosphere. The resulting mixture was stirred at 20℃to 25℃for 1 hour, then at 0℃with Na ₂ SO ₄ ·10H ₂ O quench and filter. The filtrate was concentrated in vacuo to give crude 2- [4- (benzyloxy) -7-bromoindol-3-yl ] as a brown solid]Ethylamine (670 mg) was used in the next step without further purification. MS (ESI, M/z): 345,347 (M+H) ⁺ 。

[2- [4- (benzyloxy) -7-bromoindol-3-yl ] ] dimethylethylamine

30% aqueous formaldehyde (13.4 mL) was added to 2- [4- (benzyloxy) -7-bromoindol-3-yl at 0deg.C]Ethylamine (670 mg,1.95 mmol) in CH ₂ Cl ₂ (8.0 mL) and MeOH (2.0 mL). Stirring the mixture at 20-25 ℃ for 10 minutes; naBH (OAc) is then added ₃ (1.65 g,7.8mmol,4.0 eq.). The mixture was stirred at 20℃to 25℃for a further 1 hour, then NaHCO was used ₃ The solution was quenched and extracted three times with EtOAc. The combined organic layers were washed three times with brine, over Na ₂ SO ₄ Dried, and concentrated under vacuum. The residue was purified by reverse phase flash chromatography on C ₁₈ Purification on silica gel twice (0-20% acetonitrile in water) to give [2- [4- (benzyloxy) -7-bromoindol-3-yl ] as a brown solid]Ethyl group]Dimethylamine (360 mg, 49%). MS (ESI, M/z): 373,375 (M+H) ⁺ 。

4- (benzyloxy) -3- [2- (dimethylamino) ethyl ] indole-7-carbonitrile

At 20-25 ℃ under N ₂ Under an atmosphere, tBuXphos-Pd-G3 ([ (2-di-tert-butylphosphino-2 ',4',6 '-triisopropyl-1, 1' -biphenyl) (2 '-amino-1, 1' -biphenyl-2-yl)]Palladium (II) mesylate CAS accession number 1447963-75-8;79mg,0.10mmol,0.10 eq) of [2- [4- (benzyloxy) -7-bromoindol-3-yl ] are added]Ethyl group]Dimethylamine (360 mg,0.97 mmol) and Zn (CN) ₂ (225 mg,1.94mmol,2.0 eq.) in THF (2 mL) and water (10 mL). The resulting mixture was stirred at 80 ℃ for 16 hours, then diluted with water and extracted three times with EtOAc. The combined organic layers were washed three times with brine, over Na ₂ SO ₄ Dried, and concentrated under vacuum. The residue was purified by reverse phase flash chromatography on C ₁₈ Purification on silica gel (0-60% acetonitrile in water) to give 4- (benzyloxy) -3- [2- (dimethylamino) as a pale yellow solidRadical) ethyl radical]Indole-7-carbonitrile (170 mg, 55%). MS (ESI, M/z): 320 (M+H) ⁺ 。

3- [2- (dimethylamino) ethyl ] -4-oxindole-7-carbonitrile

4- (benzyloxy) -3- [2- (dimethylamino) ethyl]A mixture of indole-7-carbonitrile (170 mg,0.53 mmol) and 10% Pd/C (dry, 34 mg) in methanol (3.0 mL) at 20℃to 25℃under H ₂ Stirred for 16 hours under an atmosphere and then filtered. The filtrate was concentrated in vacuo. The residue was purified by preparative TLC on silica gel (on CH ₂ Cl ₂ 20% methanol) to produce 3- [2- (dimethylamino) ethyl ] as an off-white solid]-4-hydroxyindole-7-carbonitrile (48 mg, 39%). ¹ H NMR(400MHz,DMSO-d ₆ )δ11.37(br s,1H),7.32(d,J＝8.0Hz,1H),7.05(d,J＝2.4Hz,1H),6.35(d,J＝8.0Hz,1H),2.91(t,J＝6.0Hz,2H),2.65(t,J＝6.0Hz,2H),2.30(s,6H)。MS(ESI,m/z):230(M+H) ⁺ 。

Examples of chemical Synthesis of Compound 65

Compound 65:3- [2- (dimethylamino) ethyl ] -4-oxindole-7-carboxamide

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Examples of synthesis of 3- [2- (dimethylamino) ethyl ] -4-oxindole-7-carboxamide are provided below:

4- (benzyloxy) -3- [2- (dimethylamino) ethyl ] indole-7-carboxamide

4- (benzyloxy) -3- [2- (dimethylamino) ethyl]A mixture of indole-7-carbonitrile (250 mg,0.78 mmol), KOH (130 mg,2.34mmol,3.0 eq.) and EtOH (5 mL) was stirred at 80℃for 4 hoursAnd then filtered. The filtrate was concentrated in vacuo. The residue was purified by flash chromatography on silica gel (on CH ₂ Cl ₂ 0-15% MeOH) to provide 4- (benzyloxy) -3- [2- (dimethylamino) ethyl ] as a yellow solid]Indole-7-carboxamide (200 mg, 69%). MS (ESI, M/z): 338 (M+H) ⁺ 。

3- [2- (dimethylamino) ethyl ] -4-oxindole-7-carboxamide

4- (benzyloxy) -3- [2- (dimethylamino) ethyl]A mixture of indole-7-carboxamide (190 mg,0.56 mmol) and 10% Pd/C (wet, 57 mg) in MeOH (10 mL) at 20℃to 25℃under H ₂ Stirred for 1 hour under an atmosphere, and then filtered. The filtrate was concentrated in vacuo. The residue was purified by reverse phase flash chromatography on C ₁₈ Purification on silica gel (over a solution containing 0.5% NH ₄ HCO ₃ 5% -30% acetonitrile in water) to produce 3- [2- (dimethylamino) ethyl ] as a yellow solid]-4-hydroxyindole-7-carboxamide (68 mg, 48%). ¹ H NMR(300MHz,DMSO-d ₆ /D ₂ O):δ7.50(d,J＝8.1Hz,1H),6.99(s,1H),6.32(d,J＝8.1Hz,1H),2.93-2.88(m,2H),2.62-2.57(m,2H),2.26(s,6H)。MS(ESI,m/z):248(M+H) ⁺ 。

Examples of chemical Synthesis of Compound 77

Compound 77: 7-methyl-3- [ ((S) -1-methylazetidin-2-yl) methyl ] indol-4-ol

Examples of the synthesis of 7-methyl-3- [ ((S) -1-methylazetidin-2-yl) methyl ] indol-4-ol are provided below:

(R) -2- [4- (benzyloxy) -7-methylindole-3-carbonyl ] azetidine-1-carboxylic acid tert-butyl ester

To (R) -1- (tert-butoxycarbonyl) azetidine-2-carboxylic acid (916 mg,4.55mmol,0.9 eq.) in CH at 0deg.C ₂ Cl ₂ Oxalyl chloride (770 mg,6.07mmol,1.2 eq.) was added dropwise to the stirred solution in (10 mL). The mixture was stirred at 0deg.C for 10min, then DMF (0.1 mL) was added. The mixture was stirred for an additional 1h and then concentrated in vacuo to afford crude (R) -tert-butyl 2- (chlorocarbonyl) azetidine-1-carboxylate (1.1 g) as a yellow oil.

At N ₂ To 4- (benzyloxy) -7-methylindole (1.20 g,5.06mmol,1 eq.) in CH under an atmosphere at 0deg.C ₂ Cl ₂ EtMgBr (in Et) was added dropwise to the stirred solution in (12 mL) ₂ 2M in O, 3.0mL,6.0mmol,1.2 eq). The mixture was stirred at 0deg.C for 0.5h, then the above crude (R) -2- (chlorocarbonyl) azetidine-1-carboxylic acid tert-butyl ester (1.1 g) was added to the mixture at CH ₂ Cl ₂ (10 mL) of the solution. The mixture was stirred at 0deg.C for another 0.5h, then with NaHCO ₃ The solution was quenched and extracted three times with EtOAc. The combined organic layers were washed with water and brine, dried over Na ₂ SO ₄ Dried, and concentrated under vacuum. The residue was purified by flash chromatography on silica gel (0-80% EtOAc in petroleum ether) to afford (R) -2- [4- (benzyloxy) -7-methylindole-3-carbonyl as a yellow solid]Azetidine-1-carboxylic acid tert-butyl ester (490 mg, 23%). MS (ESI, M/z): 421 (M+H) ⁺ 。

4- (benzyloxy) -7-methyl-3- [ ((S) -1-methylazetidin-2-yl) methyl ] indole

At N ₂ Under an atmosphere, to (R) -2- [4- (benzyloxy) -7-methylindole-3-carbonyl at 60 ℃]A stirred solution of tert-butyl azetidine-1-carboxylate (490 mg,1.17 mmol) in THF (25 mL) was added lithium aluminum hydride (442 mg,11.7mmol,10.0 eq.) in portions. Stirring the mixture at 60deg.C for 16 hr, and cooling to 20deg.CAt-25 ℃ with Na ₂ SO ₄ ·10H ₂ O quench, and filter. The filtrate was concentrated in vacuo. The residue was purified by flash chromatography on silica gel (on CH ₂ Cl ₂ MeOH, both containing 0.05% triethylamine) to afford 4- (benzyloxy) -7-methyl-3- [ ((S) -1-methylazetidin-2-yl) methyl as a yellow oil]Indole (250 mg, 67%). MS (ESI, M/z): 321 (M+H) ⁺ 。

7-methyl-3- [ ((S) -1-methylazetidin-2-yl) methyl ] indol-4-ol

At H ₂ 4- (benzyloxy) -7-methyl-3- [ ((S) -1-methylazetidin-2-yl) methyl]A mixture of indole (250 mg,0.78 mmol) and 10% Pd/C (wet, 75 mg) in MeOH (25 mL) was stirred at 20℃to 25℃for 2h. The mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by reverse phase flash chromatography on C ₁₈ Purification on silica gel (5% -60% acetonitrile in water) to afford 7-methyl-3- [ ((S) -1-methylazetidin-2-yl) methyl as a gray solid]Indol-4-ol (21 mg, 12%). MS (ESI, M/z): 231 (M+H) ⁺ 。 ¹ H NMR(300MHz,DMSO-d ₆ )δ11.76(br s,1H),10.57(br s,1H),6.92(d,J＝2.4Hz,1H),6.60(dd,J＝7.5,0.9Hz,1H),6.19(d,J＝7.5Hz,1H),3.43-3.26(m,2H),3.04-2.78(m,3H),2.29(s,3H),2.09-2.00(m,4H),1.87-1.72(m,1H)。

Examples of chemical Synthesis of Compound 135

Compound 135: [2- (2, 3-dihydro- [1,4] oxazino [2,3,4-hi ] indol-6-yl) ethyl ] dimethylamine hydrochloride

Examples of synthesis of [2- (2, 3-dihydro- [1,4] oxazino [2,3,4-hi ] indol-6-yl) ethyl ] dimethylamine hydrochloride are provided below:

4-toluenesulfonic acid 2-hydroxyethyl ester

4-tosyl chloride (3.0 g,17.3 mmol) was added to ethylene glycol (40 mL) at 20℃to 25 ℃. After stirring for 30min, triethylamine (2.4 mL,17.3 mmol) was added. The mixture was stirred overnight at 20 ℃ -25 ℃ and then partitioned between EtOAc and water. The organic phase was washed with water and brine, dried over Na ₂ SO ₄ Dried, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: etOAc/petroleum ether 1:3) to afford 2-hydroxyethyl 4-toluenesulfonate (3.0 g, 84%) as a colorless liquid.

2- [7- (benzyloxy) indol-1-yl ] ethanol

To a solution of 7- (benzyloxy) indole (5.0 g,22.4 mmol) in DMF (40 mL) was added NaH (60% dispersion in oil; 1.8g,45 mmol) under ice-cooling and the resulting mixture was stirred for 30min. A solution of 2-hydroxymethyl 4-toluenesulfonate (9.7 g,44.8 mmol) in DMF (26 mL) was then added dropwise with ice-cooled carboxylic acid. The mixture was warmed to 20 ℃ to 25 ℃ and stirred overnight. The reaction was quenched with water, and the mixture was partitioned between water and EtOAc. The organic phase was washed with water and brine, dried over Na ₂ SO ₄ Dried, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: etOAc/petroleum ether 1:6) to afford 2- [7- (benzyloxy) indol-1-yl as a brown oil]Ethanol (4.3 g, 70%). ¹ H NMR(400MHz,CDCl ₃ )δ7.48-7.35(m,5H),7.24(d,J＝8.0Hz,1H),7.03(d,J＝2.8Hz,1H),7.00(t,J＝8.0Hz,1H),6.72(d,J＝7.6Hz,1H),6.45(d,J＝3.2Hz,1H),5.17(s,2H),4.46(t,J＝5.2Hz,2H),3.84(q,J＝6.8Hz,2H),1.44(t,J＝6.4Hz,1H)。

Methanesulfonic acid 2- [7- (benzyloxy) indol-1-yl ] ethyl ester

To 2- [7- (benzyloxy) indol-1-yl under ice-cooling conditions]Ethanol (3.9 g,14.6 mmol) and triethylamine (2.22 g,21.9 mmol) in CH ₂ Cl ₂ Methanesulfonyl chloride (2.17 g,19 mmol) was added to the solution in (75 mL). The resulting orange solution was stirred at 20-25 ℃ for 0.5h after which time period the starting material was found to have been consumed. Will react with H ₂ O quench and extract the product to CH ₂ Cl ₂ Is a kind of medium. The organic phase was dried and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: etOAc/petroleum ether 1:10) to afford 2- [7- (benzyloxy) indol-1-yl methanesulfonate as a yellow oil]Ethyl ester (3.4 g, 68%).

Methanesulfonic acid 2- (7-hydroxy indol-1-yl) ethyl ester

To methanesulfonic acid 2- [7- (benzyloxy) indol-1-yl under nitrogen atmosphere]To a solution of ethyl ester (1.6 g,4.6 mmol) in MeOH (45 mL) and EtOAc (10 mL) was added 10% Pd/C (250 mg) and 10% Pd (OH) ₂ C (250 mg). The reaction mixture was degassed with hydrogen and then stirred under a hydrogen atmosphere at 20 ℃ to 25 ℃ for 2h. The catalyst was filtered off and the filtrate was concentrated in vacuo. The residue was purified by column chromatography on silica gel (eluent: etOAc/petroleum ether 1:10) to afford 2- (7-hydroxyindol-1-yl) ethyl methanesulfonate (3.0 g, 99%) as an off-white solid. ¹ H NMR(400MHz,CDCl ₃ )δ7.19(d,J＝8.0Hz,1H),7.04(d,J＝2.8Hz,1H),6.91(t,J＝8.0Hz,1H),6.52(d,J＝7.6Hz,1H),6.44(d,J＝3.2Hz,1H),4.70(t,J＝4.2Hz,2H),4.59(t,J＝4.2Hz,2H),2.39(s,3H)。

2, 3-dihydro- [1,4] oxazino [2,3,4-hi ] indole

To a solution of 2- (7-hydroxyindol-1-yl) ethyl methanesulfonate (3.1 g,12.2 mmol) in DMF (61 mL) under ice-cooling conditions in an ice-water bath was added NaH (60% dispersion in oil; 0.97g,24.3 mmol) and the resulting mixture was stirred for 1h after which time the starting material was found to have been consumed. The reaction was quenched with water and the mixture was extracted with EtOAc. The organic phase was washed with water and brine, dried over Na ₂ SO ₄ Dried, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: etOAc/petroleum ether 1:10) to afford 2, 3-dihydro- [1,4] as a colorless oil]Oxazino [2,3,4-hi ]]Indole (1.7 g, 88%).

(2, 3-dihydro- [1,4] oxazino [2,3,4-hi ] indol-6-yl) -N, N-dimethyl-glyoxylamide

In ice-cooled condition to 2, 3-dihydro- [1,4]Oxazino [2,3,4-hi ]]Indole (1.70 g,10.7 mmol) in Et ₂ To a solution of O (50 mL) was added dropwise a solution of oxalyl chloride (2.7 g,21.4 mmol) in diethyl ether (10 mL). The resulting orange slurry was stirred for 3h under ice-cooling, then added dropwise to 40% Me under ice-cooling ₂ Aqueous NH (20 mL). The resulting yellow slurry was warmed to 20 ℃ to 25 ℃ and stirred overnight. The mixture was partitioned between 10% MeOH/CH ₂ Cl ₂ With NaHCO ₃ Between the aqueous solutions. The organic phase was washed with water and brine, dried over Na ₂ SO ₄ Dried, and concentrated under reduced pressure. The residue is purified by column chromatography on silica gel (eluent: CH ₂ Cl ₂ 3.5M NH in MeOH ₃ 100:1) to provide (2, 3-dihydro- [1, 4) as a white solid]Oxazino [2,3,4-hi ]]Indol-6-yl) -N, N-dimethylglyoxylamides (1.98 g, 72%). ¹ H NMR(400MHz,CDCl ₃ )δ7.87(s,1H),7.77(d,J＝8.0Hz,1H),7.20(t,J＝8.0Hz,1H),6.79(d,J＝7.6Hz,1H),4.50(t,J＝5.2Hz,2H),4.33(t,J＝5.2Hz,2H),3.11(s,3H),3.08(s,3H)。

[2- (2, 3-dihydro- [1,4] oxazino [2,3,4-hi ] indol-6-yl) ethyl ] dimethylamine

Under ice-cooling conditions to (2, 3-dihydro- [1, 4)]Oxazino [2,3,4-hi ]]Indol-6-yl) -N, N-dimethylglyoxylamide (200 mg,0.78 mmol) in dry THF (7 mL) was added drop-wise BH ₃ THF solution (1.0M in THF; 3.1mL,4 eq.). The mixture was heated to 50 ℃ and stirred overnight, then cooled to 20 ℃ -25 ℃. MeOH was added dropwise with ice cooling. The mixture was stirred under reflux for 2h. The solvent was evaporated under reduced pressure and the residue was purified by column chromatography on silica gel (eluent: CH ₂ Cl ₂ 3.5M NH in MeOH ₃ 100:1) to provide [2- (2, 3-dihydro- [1,4] as a yellow oil]Oxazino [2,3,4-hi ]]Indol-6-yl) ethyl]Dimethylamine (72 mg, 40%). MS (ESI, M/z): 231 (M+H) ⁺ 。 ¹ H NMR(400MHz,CDCl ₃ )δ7.17(d,J＝8.0Hz,1H),6.95(t,J＝8.0Hz,1H),6.90(s,1H),6.63(d,J＝7.6Hz,1H),4.50(t,J＝4.4Hz,2H),4.20(t,J＝4.4Hz,2H),2.96-2.90(m,2H),2.67-2.61(m,2H),2.33(s,6H)。

[2- (2, 3-dihydro- [1,4] oxazino [2,3,4-hi ] indol-6-yl) ethyl ] dimethylamine hydrochloride

To [2- (2, 3-dihydro- [1,4]]Oxazino [2,3,4-hi ]]Indol-6-yl) ethyl]Dimethylamine (68 mg,0.30 mmol) in CH ₂ Cl ₂ To the solution in (1 mL) was added a solution of anhydrous HCl in EtOH (1.0M; 0.45mL,1.5 eq.). The mixture was stirred at room temperature for 0.5h. The solvent was removed under reduced pressure and the residue was triturated with diethyl ether to provide [2- (2, 3-dihydro- [1,4] as a grey solid ]Oxazino [2,3,4-hi ]]Indol-6-yl) ethyl]Dimethylamine hydrochloride (7)3mg，93％)。MS(ESI,m/z):231(M+H) ⁺ 。 ¹ H NMR(400MHz,CD ₃ OD)δ7.20(s,1H),7.19(d,J＝8.0Hz,1H),6.96(t,J＝7.6Hz,1H),6.59(d,J＝7.6Hz,1H),4.49(t,J＝5.2Hz,2H),4.27(t,J＝5.2Hz,2H),3.48(t,J＝8.0Hz,2H),3.23(t,J＝8.0Hz,2H),2.96(s,6H)。

Application method

Based on several reported clinical trials using galectin itself, the indole compounds described herein are considered useful for the treatment of drug resistant depression.

US STAR D study reports that of all patients enrolled by primary care and psychosis clinics, more than half of the patients failed to achieve relief after first line antidepressant therapy and one third failed to relieve after four Acute treatment courses (Rush AJ, trivedi MH, wisniewski SR, nierenberg AA, stewart JW, warden D et al act and longer-term outcomes in depressed outpatients requiring one or several treatment steps: a STAR D report. Am. J. Psychiatry 2006; 163:1905-17).

In addition to the potential use of these analogs in the treatment of depression, other studies by the third party human volunteer community have revealed that galectins can be used in the treatment of tobacco and alcohol addiction. Furthermore, in a controlled clinical setting, nupharin was safely administered to subjects with OCD, and this drug treatment was found to result in a rapid relief of core OCD symptoms in several subjects (Moreno, f.a., wiegand, c.b., taitano, e.k., and elgado, p.l. "Safety, tolearability, and efficacy of psilocybin in patients with obsessive-compulsive disorder" j.clin.psychiatty 2006,67, 1735-1740).

Another potential use of these analogs is in the treatment of seizure disorders, including but not limited to, seizure disorders in infants, such as but not limited to, delavir syndrome (sourcbon, j.et al, "Serotonergic Modulation as Effective Treatment for Dravet Syndrome in a Zebrafish Mutant Model", ACS chem. Neurosci.2016,7,588-598).

The indole compounds described herein are considered safer than galectin because of the fact thatThey lack 5-HT _2B At least some undesirable characteristics of agonist-related activity.

Application method

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 indicated depends on the condition of the subject, and is further subject to a medical assessment (diagnosis) that considers the presence of signs, symptoms, and/or dysfunction; the risk of developing a particular sign, symptom and/or dysfunction, as well as other factors.

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, intracisternal or intrathecal by lumbar puncture, transurethral, nasal, transdermal, and parenteral administration (including intravenous, intramuscular, subcutaneous, intracoronary, intradermal, intramammary, intraperitoneal, intra-articular, intrathecal, retrobulbar, intrapulmonary injection, and/or surgical implantation at a specific site). Parenteral administration may be accomplished using needles and syringes or using high pressure techniques.

Pharmaceutical compositions include those in which an indole compound described herein is 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 the qualified practitioner based on the condition or disease diagnosed. The dosages and intervals can be individually adjusted to provide levels of indole compounds described herein sufficient to maintain the desired therapeutic effect. It is possible that the indole compounds described herein may require only infrequent administration (e.g., monthly, rather than daily) to achieve the desired therapeutic effect.

As contemplated herein, the therapeutically effective amount of the indole compounds described herein suitable for use in therapy will vary with the nature of the disorder being treated, the length of time of the desired activity, and the age and condition of the patient, and is ultimately determined by the attending physician. The dosages and intervals may be individually adjusted to provide a plasma level of indole compound sufficient to maintain the desired therapeutic effect. The desired dose may conveniently be administered in a single dose, or in multiple doses at appropriate intervals, for example 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 may be administered at the following frequency: four doses (q 4d x 4) are delivered four days apart at one dose per day; four doses (q 3d x 4) were delivered three days apart at one dose per day; one dose is delivered every five days (qd x 5); monday dose, for three weeks (qwk 3); five daily doses, two days of withdrawal, and five more daily doses (5/2/5); or any dosage regimen determined to be appropriate for the situation.

As contemplated herein, the indole compounds described herein may be administered in admixture with a pharmaceutical carrier selected according 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 conventional manner using one or more physiologically acceptable carriers comprising excipients and auxiliaries which facilitate processing of the compounds described herein.

When the indole compounds described herein are administered intravenously, water is a preferred carrier. Saline solutions and aqueous dextrose and glycerol solutions can also be employed 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, ethanol and the like. The compositions of the present invention may also contain minor amounts of wetting or emulsifying agents, or pH buffering agents, if desired.

These pharmaceutical compositions may be manufactured, for example, by conventional mixing, dissolving, granulating, dragee-making, emulsifying, encapsulating, entrapping or lyophilizing processes. Suitable formulations depend on the route of administration selected. When a therapeutically effective amount of an indole compound described herein is administered orally, the composition is typically in the form of a tablet, capsule, powder, solution or elixir. When administered in tablet form, the composition may additionally contain a solid carrier such as gelatin or an adjuvant. Tablets, capsules and powders contain from about 0.01% to about 95% and preferably from about 1% to about 50% of the indole compounds described herein. When applied in liquid form, a liquid carrier, such as water, petroleum, or oil of animal or vegetable origin, may be added. The liquid form of the composition may further comprise a physiological saline solution, a glucose or other saccharide solution, or a glycol. When applied in liquid form, the composition contains from about 0.1% to about 90% and preferably from about 1% to about 50% by weight of the compounds described herein.

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. The preparation of such parenterally acceptable solutions is within the skill of the art, taking into account pH, isotonicity, stability, and the like, as appropriate. Preferred compositions for intravenous, cutaneous or subcutaneous injection typically contain an isotonic vehicle. The indole compounds described herein may be infused with other liquids over a time span of 10-30 minutes or over several hours.

The indole compounds described herein can be readily combined with pharmaceutically acceptable carriers well known in the art. Such carriers 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.

Pharmaceutical formulations for oral use can be obtained by: the indole compounds described herein are added to solid excipients, with or without grinding the resulting mixture, and the mixture of granules is processed after adding suitable adjuvants (if desired) to obtain tablets or dragee cores. Suitable excipients include, for example, fillers and cellulose preparations. If desired, a disintegrant may be added.

The indole compounds described herein may be formulated for parenteral administration by injection (e.g., by bolus injection or continuous infusion). Formulations for injection may be presented in unit dosage form, for example, in ampoules or in multi-dose containers, with a preservative added. The composition may take the form of a suspension, solution or emulsion, such as in an oily or aqueous vehicle, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents.

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

In some embodiments, the suspension may also contain suitable stabilizers or agents that increase the solubility of the compounds and allow for the preparation of solutions of high concentration. Alternatively, the compositions of the invention may be in powder form prior to use for constitution with a suitable vehicle (e.g., sterile, pyrogen-free water).

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

The indole compounds described herein may 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 (ovule) with or without excipients, or in the form of elixirs or suspensions with flavouring or colouring agents. Such liquid formulations may be prepared with pharmaceutically acceptable additives such as suspending agents. The indole compounds described herein may also be injected parenterally, for example, intravenously, intramuscularly, subcutaneously or intracoronary. For parenteral administration, the indole compounds described herein may be best used in the form of a sterile aqueous solution which may contain other substances, for example 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 stropharia rugoso-annulata analogs.

Overview:

it is contemplated that any portion of any aspect or embodiment discussed in this specification may be implemented or combined with any portion of any other aspect or embodiment discussed in this specification. While specific embodiments have been described above, it should be understood that other embodiments are possible and are intended to be included herein. Modifications and adaptations to the foregoing embodiments, not shown, are possible for any person skilled in the art.

Unless defined otherwise, 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, citation of any reference herein shall not be construed as an admission that such reference is prior art to the present invention.

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 and any isotopologues and any pharmaceutically acceptable salts thereof:

wherein:

R ² : (i) selected from the group consisting of: c (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 group, C ₃ -C ₆ Heterocyclyl, (C) ₃ -C ₆ Heterocyclyl) (C) ₁ -C ₆ Alkyl), aryl (C) ₁ -C ₆ Alkyl), 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); or (ii) and R ¹ Together forming a chain of 2 to 4 carbon atoms to which are attached substituents independently selected from the group consisting of: H. c (C) ₁ -C ₆ Alkyl, aryl, and heteroaryl; or (iii) forms a chain of 3 or 4 atoms with b, wherein one atom is selected from the group consisting of: C. n, O and S, while the remainder are carbon, said chain containing 0, 1 or 2 double bonds and having attached thereto substituents 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 、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 group, then is selected fromThe group consisting of: H. c (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 group, C ₃ -C ₆ Heterocyclyl, (C) ₃ -C ₆ Heterocyclyl) (C) ₁ -C ₆ Alkyl), aryl (C) ₁ -C ₆ Alkyl), 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); in some embodiments, R ² Together with b, any one of the following is formed: CH (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＝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 S、NHCH 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; in some embodiments, R ² Together with b, any one of the following is formed: CH (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＝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 S、NHCH 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, wherein one or both hydrogen atoms, if present on the moiety, are replaced by substituents independently selected from the group consisting of: 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 And cyano, or wherein two hydrogens, if attached to the same carbon atom, are replaced with oxo;

a: (i) selected from the group consisting of: H. halogen, lower alkyl, CHF ₂ 、CF ₃ 、OCH ₃ 、OCHF ₂ 、OCF ₃ 、SCHF ₂ 、SCH ₃ 、SCF ₃ And cyano; or (ii) forms with Z one of the following: (A) A saturated chain of one oxygen and one carbon atom (wherein the oxygen is attached to the 5-position of the indole ring of formula I), and (B) a chain of 2 or 3 carbon atoms to which 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 、CF ₃ 、OCHF ₂ 、OCF ₃ 、SCH ₃ 、SCHF ₂ 、SCF ₃ Cyano and oxo groups, and (C) a chain of 2 or 3 carbon atoms containing one double bond, 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 、CF ₃ 、OCHF ₂ 、OCF ₃ 、SCHF ₂ 、SCH ₃ 、SCF ₃ Cyano and oxo; or (iii) forms a chain of 3 or 4 atoms with b, wherein one atom is selected from the group consisting of: C. n, O and S, while the remainder are carbon, said chain containing 0, 1 or 2 double bonds and having attached thereto substituents 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 、CF ₃ 、OCHF ₂ 、OCF ₃ 、SCH ₃ 、SCHF ₂ 、SCF ₃ Cyano and oxo; and is also provided with

b: (i) selected from the group consisting of: H. halogen, CH ₃ 、CHF ₂ 、CF ₃ 、OCH ₃ 、OCHF ₂ 、OCF ₃ 、SCH ₃ 、SCHF ₂ 、SCF ₃ And cyano; or (ii) forms a chain of 3 or 4 atoms with a, wherein one atom is selected from the group consisting of: C. n, O and S, while the remainder are carbon, the chain containing 0, 1 or 2 double bonds, and Attached to the chain is 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 、CF ₃ 、OCHF ₂ 、OCF ₃ 、SCH ₃ 、SCHF ₂ 、SCF ₃ Cyano and oxo; or (iii) and R ² Together forming a chain of 3 or 4 atoms, one of which is selected from the group consisting of: C. n, O and S, while the remainder are carbon, said chain containing 0, 1 or 2 double bonds and having attached thereto substituents 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 、CF ₃ 、OCHF ₂ 、OCF ₃ 、SCH ₃ 、SCHF ₂ 、SCF ₃ Cyano and oxo;

wherein:

R ⁴ : (i) Selected from the group consisting ofThe group consisting of: H. c (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 An alkyl group); or (ii) and R ³ Together with the N atom to which they are attached form a 4-7 membered heterocyclyl ring;

wherein:

c. d, e and f are each H; or three of c, d, e and f are H and the remaining substituents are lower alkyl; or c and f are each H and d and e together are-CH ₂ -or-CH ₂ CH ₂ -thereby producing a cyclopropane or cyclobutane ring; or c, d and e are each H, and f, R ³ And R ³ The attached N atoms together form an azetidine or pyrrolidine ring carrying substituents independently selected from the group consisting of: H. aryl, heteroaryl, C ₁ -C ₆ Alkyl and C ₃ -C ₆ Cycloalkyl; or d, e and f are each H, and c, R ³ And R ³ The attached N atoms together form an azetidine or pyrrolidine ring carrying substituents independently selected from the group consisting of: H. aryl, heteroaryl, halogen, C ₁ -C ₆ Alkyl and C ₃ -C ₆ Cycloalkyl; or d, e, and f are each H, and c and Z together contain 1 or 2 carbon atoms, thereby producing a pyran or oxaheptane ring bearing substituents independently selected from the group consisting of: H. halogen, C ₁ -C ₆ Alkyl and C ₃ -C ₆ Cycloalkyl; and is also provided with

Wherein:

z: (i) selected from the group consisting of: H. r is R ⁵ 、(R ⁶ )(R ⁷ )N-C(O)-、C ₁ -C ₆ alkyl-C (O), C ₃ -C ₆ cycloalkyl-C (O), aryl-C (O) and heteroaryl-C (O), wherein R ⁵ Selected from the group consisting of: c (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 wherein R is ⁶ And R is ⁷ Each independently selected from the group consisting of: H. c (C) ₁ -C ₄ Alkyl and C ₃ -C ₆ Cycloalkyl, or linked to form a 4-7 membered heterocyclyl; or (ii) is (R) ⁸ O)(R ⁹ O) P (O) -, wherein R ⁸ And R is ⁹ Each independently is a cationic counterion in the form of H or phosphate, such as sodium, potassium, half magnesium, half calcium, ammonium, or ammonium substituted with one or more alkyl or cycloalkyl groups; or (iii) forms together with c a linkage that results in a pyran or oxacycloheptane ring comprising substituents independently selected from the group consisting of: H. halogen, C ₁ -C ₆ Alkyl and C ₃ -C ₆ Cycloalkyl; or (iv) together with a forms one of the following: (A) A saturated chain of one oxygen and one carbon atom (wherein the oxygen is attached to the 5-position of the indole ring of formula I), and (B) a chain of 2 or 3 carbon atoms to which 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 、CF ₃ 、OCHF ₂ 、OCF ₃ 、SCH ₃ 、SCHF ₂ 、SCF ₃ Cyano and oxo, and (C) a chain of 2 or 3 carbon atoms containing one double bond and bearing substituents 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 、CF ₃ 、OCHF ₂ 、OCF ₃ 、SCH ₃ 、SCHF ₂ 、SCF ₃ Cyano and oxo.

2. The chemical compound of claim 1, wherein: (i) R is R ¹ Selected from the group consisting ofIs set of (3): h and C ₁ -C ₆ Alkyl, and (ii) R ² Is C ₁ -C ₆ Alkyl, C ₁ -C ₆ Substituted alkyl groups and CN.

3. The chemical compound of claim 2, wherein: (i) a is H; and (ii) b is selected from the group consisting of: h and halogen.

4. A chemical compound of claim 3, wherein each of c, d, e, and f is H.

5. The chemical compound of claim 4, wherein Z is selected from the group consisting of: H. c (C) ₁ -C ₆ Alkyl and (HO) (HO) P (O) -.

6. The chemical compound of claim 5, wherein R ³ And R is ⁴ Each of which is C ₁ -C ₆ An alkyl group.

7. The chemical compound of claim 6, wherein: (i) R is R ² Selected from the group consisting of: methyl and ethyl; and (ii) b is H.

8. The chemical compound of claim 7, wherein R ¹ Is H.

9. The chemical compound of claim 8, wherein R ³ And R is ⁴ Each of which is methyl.

10. The chemical compound of claim 6, wherein: (i) R is R ² Selected from the group consisting of: methyl and ethyl; and (ii) b is F.

11. The chemical compound of claim 6, wherein R ² Is C ₁ -C ₆ Substituted alkyl.

12. The chemical compound of claim 6, wherein the C ₁ -C ₆ The substituted alkyl group comprises a substituent selected from the group consisting of: OH, halogen, C ₁ -C ₂ Alkyl and alkoxy groups.

13. The chemical compound of claim 1, wherein: (i) R is R ¹ Is H; (ii) R is R ² 、R ³ And R is ⁴ Each of which is CH ₃ The method comprises the steps of carrying out a first treatment on the surface of the And (iii) each of a, b, c, d, e and f is H.

14. The chemical compound of claim 1, wherein: (i) R is R ¹ Is H; (ii) R is R ² 、R ³ And R is ⁴ Each of which is CH ₃ The method comprises the steps of carrying out a first treatment on the surface of the (iii) each of a, c, d, e and f is H; and (iv) b is F.

15. A method of treating a disorder comprising administering to a patient an effective amount of a compound of claim 1.

16. The method of claim 15, wherein the disorder is selected from the group consisting of: major depressive disorder, drug-resistant depression and psychotic depression, 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 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, mood disorder associated with cancer, fragile X syndrome, autism spectrum disorder, bipolar disorder, obsessive-compulsive disorder and Ratty syndrome.

17. A method of treating a disorder comprising administering to a patient an effective amount of a compound of claim 13.

18. The method of claim 17, wherein the disorder is selected from the group consisting of: major depressive disorder, drug-resistant depression and psychotic depression, 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 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, mood disorder associated with cancer, fragile X syndrome, autism spectrum disorder, bipolar disorder, obsessive-compulsive disorder and Ratty syndrome.

19. Use of a compound according to claim 13 for the treatment of a disorder selected from the group consisting of: major depressive disorder, drug-resistant depression and psychotic depression, 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 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, mood disorder associated with cancer, fragile X syndrome, autism spectrum disorder, bipolar disorder, obsessive-compulsive disorder and Ratty syndrome.

20. The use of claim 19, wherein the disorder is selected from the group consisting of: major depressive disorder, drug-resistant depressive disorder, and psychotic depression.