Indoline derivatives as serotonergic agents for treatment of related disorders

Abstract

The present application relates to indoline derivatives of general formula (I), to processes for their preparation, to compositions comprising said compounds and to their use for activating serotonin receptors in cells, and to the treatment of diseases, disorders or conditions by activating serotonin receptors in cells. The diseases, disorders or conditions include, for example, psychosis, psychiatric disorders, and CNS disorders and / or related endophenotypes and / or symptom populations. Wherein Q is selected from (Q1), (Q2), (Q2 '), (Q4) and (Q5). # imgabs0 #

Description

[0001] Related Applications

[0002] This application claims priority to co-pending U.S. Provisional Patent Application No. 63 / 332,450, filed on April 19, 2022, the contents of which are incorporated herein by reference in their entirety. Technical Field

[0003] The present application relates to indoline compounds useful in the fields of psychiatry, neurobiology and pharmacotherapy for the treatment of different conditions, such as psychiatric and neurological diseases, which are treated by activating serotonin receptors. Background Art

[0004] The applicant has several co-pending applications disclosing novel indole derivatives as serotonergic hallucinogens for the treatment of various CNS disorders, including PCT patent application publications WO2021 / 155470, WO2021 / 155468, and WO2021 / 155467, PCT application PCT / CA2022 / -50295, U.S. Provisional Application No. 63 / 260,470, and U.S. Provisional Application No. 63 / 449,715. These applications describe various pharmaceutical applications of such agents, including in the treatment of psychiatric and neurological diseases, and in the fields of psychiatry, neurobiology, and pharmacotherapy.

[0005] Psychedelics show promise in treating conditions such as major depressive disorder, refractory depression, post-traumatic stress disorder (PTSD), and substance use disorders, as well as existential distress and other conditions at the end of life. To date, hundreds of millions of dollars have been invested in companies developing novel psychedelics (see, e.g., C&EN March 7, 2022). As a result, it is believed that psychedelics will enter the mainstream of modern medicine as a treatment for refractory psychiatric disorders.

[0006] The therapeutic effects of classic hallucinogens such as mescaline, N,N-dimethyltryptamine (DMT), psilocybin, and lysergic acid diethylamide (LSD) are largely thought to be mediated through activation of serotonin 2A (5-HT2A) receptors. These drugs are increasingly being evaluated and used to treat neuropsychiatric disorders.

[0007] Many psychedelics have side effects, such as hallucinogenic effects, which prevent their use outside of clinical settings.

[0008] Some potential non-psychedelic hallucinogen analogs have been reported (Cunningham MJ et al., ACS Chem. Neurosci. 2023, 14, 1, 119-135, Hofman, A. LSD, My Problem Child: Reflections on Sacred Drugs, Mysticism, and Science; MAPS, Multidisciplinary Association for Psychedelic Studies: Santa Cruz, CA, 2009, Weingartner, H. et al., J. Clin. Pharmacol. New Drugs 1971, 11, 103-111, Shulgin. AT2-Amino-1-(2,5-dimethoxyphenyl)butanes; U.S. Patent No. 4105695A, Shulgin, AT Soc. Pharmacol. 1987, 1, 279-290, Cameron, et al. Nature 2021, 589 (7842) 474-479, Lu J.et al., Molecular Psychiatry, 2021, 26, 6237-6252, Cao et al., Science 2022, 375, 403-411, Vargas et al., Science, 2023, 379, 700-706). Although these non-psychedelic 5-HT 2A Results are encouraging for agonist but non-psychedelic 5-HT 2A Therapeutic development of agonists is still in its infancy.

[0009] There is still a need to provide new hallucinogenic and non-hallucinogenic 5-HT 2A Agonist molecules, used to treat e.g. psychiatric disorders. Summary of the invention

[0010] The compounds of the present invention bind to serotonin receptor subtypes, especially 5-HT 2A Direct binding modulates the activity of these receptors.

[0011] Therefore, the present application includes compounds of Formula I or pharmaceutically acceptable salts, solvates and / or prodrugs thereof:

[0012]

[0013] in:

[0014] R 1 Selected from C(O)R7 、CO2R 7 、C(O)N(R 7 )(R 7’ )、S(O)R 7 、SO2R 7 , C 1-6 Alkylene R 7 and R 7 ;

[0015] Q is selected from Q1, Q2, Q2', Q4 and Q5:

[0016]

[0017] is a single bond or a double bond, provided that when When it is a double bond, R 9 and R 15 does not exist, and when Q2 When it is a double bond, R 17 and R 25 does not exist;

[0018] R 2 , R 2’ and R 2” are independently selected from H, halo, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylene N(R 2a )(R 2b ) and SC 1-6 alkyl;

[0019] R 2a and R 2b Independently selected from H and C 1-6 alkyl;

[0020] R 3 , R 4 , R 5 and R 6 are independently selected from H, halo, N(R 5’ )(R 6’ ), C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylene N(R 5’ )(R 6’ ) and SC 1-6 Alkyl, the last four groups are optionally replaced by one or two selected from OH and C 1-6 Substitution of the alkoxy group; or

[0021] R 3 , R 4 , R5 and R 6 Two adjacent groups in the bond together to form O-(CH2) 1-2 O, and R 3 , R 4 , R 5 and R 6 The remaining groups in are independently selected from H, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, N(R 5’ )(R 6’ ), C 1-6 Alkylene N(R 5’ )(R 6’ ) and SC 1-6 Alkyl, or

[0022] R 3 , R 4 , R 5 and R 6 One of A, OA and C 1-4 Alkylene A, and R 3 , R 4 , R 5 and R 6 The remaining groups in are independently H or halo;

[0023] R 5’ and R 6’ Independently selected from H and C 1-6 alkyl;

[0024] A is selected from phenyl, C 3-6 Cycloalkyl, containing 1 to 4 independently selected from O, S, S(O), SO2, N and NR 54 The heterocyclic alkyl group of the heterocyclic alkyl group is 3-6-membered and contains 1 to 4 independently selected from O, S, S(O), SO2, N and NR 54 phenyl, C 3-10 Cycloalkyl, 3-membered to 6-membered heterocycloalkyl and 5-membered to 6-membered heteroaryl are optionally substituted with one or more substituents independently selected from the group consisting of halo, C 1-4 Alkyl, OC 1-4 Alkyl, N(R 54a )(R 54b ), C 1-4 Alkylene N(R 54a )(R 54b ) and SC 1-4 alkyl;

[0025] R 7 Selected from H, C 1-6 Alkyl, C 2-6 Alkenyl, C2-6 Alkynyl, phenyl, C 3-6 Cycloalkyl, containing 1 to 4 independently selected from O, S, N and NR 7” The heterocyclic alkyl group of the heterocyclic alkyl group is 3-6-membered and contains 1 to 4 independently selected from O, S, N and NR 7” The 5- to 6-membered heteroaryl group of the ... 55 、N(R 55 )(R 56 ) and SR 55 Substituents substituted, and / or C 1-6 The alkyl group is optionally substituted by one to three independently selected from O, C(O), CO2 and NR 57 The miscellaneous parts are interrupted;

[0026] R 7’ Selected from H and C 1-6 alkyl;

[0027] R 7” Selected from H and C 1-6 alkyl;

[0028] R 8 , R 9 , R 10 , R 11 , R 13 , R 14 , R 15 , R 16 , R 16’ , R 17 , R 17’ , R 18 , R 19’ , R 19 , R 19’ , R 21 , R 22’ , R 22 , R 22’ , R 23 , R 23’ , R 24 , R 24’ , R 25 , R 25’ , R 32 , R 33 , R 34 , R 36 , R 37 , R 38 , R 39 , R 40 , R 41 , R 42 , R 43 , R 44 , R46 , R 47 , R 48 , R 49 , R 50 , R 51 , R 52 and R 53 are independently selected from H, halo and C 1-6 alkyl;

[0029] R 12 , R 20 , R 20’ , R 35 and R 45 Independently selected from H, C 1-6 Alkyl and C(O)C 1-6 alkyl;

[0030] R 54 , R 55 , R 56 and R 57 Independently selected from H and C 1-6 alkyl;

[0031] R 54a and R 54b Independently selected from H and C 1-6 Alkyl; and

[0032] All available hydrogen atoms are optionally and independently replaced with fluorine atoms or chlorine atoms, and all available atoms are optionally substituted with alternative isotopes thereof.

[0033] In some embodiments, the compound of Formula I or a pharmaceutically acceptable salt, solvate and / or prodrug thereof is defined as follows:

[0034]

[0035] in:

[0036] R 1 is H;

[0037] Q is selected from Q1, Q2, Q2', Q4 and Q5:

[0038]

[0039] is a single bond or a double bond, provided that when When it is a double bond, R 9 and R 15 does not exist, and when Q2 When it is a double bond, R 17 and R 25 does not exist, and when Q2' When it is a double bond, R 16’ and R 25’ does not exist;

[0040] On the key means that the bond is attached to the remainder of the compound;

[0041] R 2 , R 2’ and R 2” are independently selected from H, halo, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylene N(R 2a )(R 2b ) and SC 1-6 alkyl;

[0042] R 2a and R 2b Independently selected from H and C 1-6 alkyl;

[0043] R 3 , R 4 , R 5 and R 6 are independently selected from H, halo, N(R 5’ )(R 6’ ), C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylene N(R 5’ )(R 6’ ) and SC 1-6 Alkyl, the last four substituents are selected from OH and C 1-6 Alkoxy, or

[0044] R 3 , R 4 , R 5 and R 6 Two adjacent groups in the bond together to form O-(CH2) 1-2 O, and R 3 , R 4 , R 5 and R 6 The remaining groups in are independently selected from H, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, N(R 5’ )(R 6’ ), C 1-6 Alkylene N(R 5’ )(R 6’ ) and SC 1-6 alkyl;

[0045] R 5’and R 6’ Independently selected from H and C 1-6 alkyl;

[0046] R 8 , R 9 , R 10 , R 11 , R 13 , R 14 , R 15 , R 16 , R 16’ , R 17 , R 17’ , R 18 , R 19’ , R 19 , R 19’ , R 21 , R 22’ , R 22 , R 22’ , R 23 , R 23’ , R 24 , R 24’ , R 25 , R 25’ , R 32 , R 33 , R 34 , R 36 , R 37 , R 38 , R 39 , R 40 , R 41 , R 42 , R 43 , R 44 , R 46 , R 47 , R 48 , R 49 , R 50 , R 51 , R 52 and R 53 are independently selected from H, halo and C 1-6 alkyl;

[0047] R 12 , R 20 , R 20’ , R 35 and R 45 Independently selected from H, C 1-6 Alkyl and C(O)C 1-6 alkyl;

[0048] All available hydrogen atoms are optionally and independently replaced with fluorine atoms or chlorine atoms, and all available atoms are optionally substituted with alternative isotopes thereof.

[0049] In another embodiment, the compounds of the present application are used as medicines. Therefore, the present application also includes the compounds of the present application for use as medicines.

[0050] The present application also includes a method of treating a psychotic disorder or a psychotic symptom, the method comprising administering to a subject in need thereof a therapeutically effective amount of one or more compounds of the present application.

[0051] The present application also includes a method for treating a psychiatric disorder, comprising administering a therapeutically effective amount of one or more compounds of the present application to a subject in need thereof.

[0052] The present application also includes methods of treating central nervous system (CNS) diseases, disorders or conditions and / or neurological diseases, disorders or conditions.

[0053] The present application also includes methods of treating endophenotypes and / or symptom clusters associated with a disease, disorder, or condition that is treated by activating serotonin receptors.

[0054] The present application further provides methods for preparing the compounds of the present application. General and specific methods will be discussed in more detail below and illustrated in the following examples.

[0055] From the following specific embodiments, other features and advantages of the present application will become apparent. However, it should be understood that although the specific embodiments and specific examples indicate the embodiments of the present application, they are only given by way of illustration, and the scope of the claims should not be limited by these embodiments, but should be given the broadest interpretation consistent with the entirety of this specification. BRIEF DESCRIPTION OF THE DRAWINGS

[0056] The present application will be described in more detail with reference to the accompanying drawings, in which:

[0057] Figure 1 Shown are scores for exemplary compound II-54 in the mouse head twitch assay at doses up to 60 mg / kg. DETAILED DESCRIPTION

[0058] definition

[0059] Unless otherwise stated, the definitions and embodiments described in this section and elsewhere are intended to apply to all embodiments and aspects of the application described herein, as would be understood by one skilled in the art.

[0060] As used herein, the term "compound of the application" or "compound of the present application" and the like refers to a compound of Formula I, and includes pharmaceutically acceptable salts, solvates and / or prodrugs thereof and all stereoisomers and regioisomers.

[0061] As used herein, the term "composition of the application" or "composition of the present application" and the like refers to a composition, such as a pharmaceutical composition, comprising one or more compounds of the present application.

[0062] As used herein, the term "and / or" means that the listed items are present or used alone or in combination. In fact, this term means the use or presence of "at least one" or "one or more" of the listed items. The term "and / or" with respect to pharmaceutically acceptable salts and / or solvates thereof means that the compounds of the present application exist in the form of individual salts and solvates as well as combinations of salts or solvates of the compounds of the present application, for example.

[0063] As used herein, the singular forms "a", "an", and "the" include plural references unless the context clearly dictates otherwise. For example, an embodiment including "a compound" should be understood to represent certain aspects with one compound or two or more additional compounds.

[0064] As used in this application and in the claims, the words “comprising” (and any form of comprising, such as “comprise” and “comprises”), “having” (and any form of having, such as “have” and “has”), “including” (and any form of including, such as “include” and “includes”), or “containing” (and any form of containing, such as “contain” and “contains”), are inclusive or open-ended and do not exclude additional, unrecited elements or process steps.

[0065] As used herein, the term "consisting of" and its derivatives are closed terms that specify the presence of stated features, elements, components, groups, integers and / or steps, and also exclude the presence of other unstated features, elements, components, groups, integers and / or steps.

[0066] As used herein, the term "consisting essentially of" is intended to specify the presence of stated features, elements, components, groups, integers, and / or steps, as well as the presence of those that do not materially affect the basic and novel characteristics of such features, elements, components, groups, integers, and / or steps.

[0067] In embodiments comprising an "additional" or "second" component (e.g., an additional or second compound), the second component as used herein is chemically different from the other components or the first component. The "third" component is different from the other components, and the first component and the second component and other listed components or "additional" components are similarly different.

[0068] As used herein, the term "suitable" means that the selection of a particular compound or condition will depend on the particular synthetic operation to be performed, the identity of the molecule to be transformed, and / or the particular use of the compound, but the selection is well within the skill of those skilled in the art. All process / method steps described herein will be carried out under conditions sufficient to provide the products shown. It will be understood by those skilled in the art that all reaction conditions, including, for example, reaction solvents, reaction times, reaction temperatures, reaction pressures, reactant ratios, and whether the reaction should be carried out under anhydrous or inert atmospheres, can be varied to optimize the yield of the desired product, and that doing so is within the skill of those skilled in the art.

[0069] As used herein, the terms "about", "substantially" and "approximately" mean a reasonable amount of deviation of the modified term such that the end result is not significantly changed. In the case where this deviation does not negate the meaning of the word it modifies, or unless the context suggests otherwise to a person skilled in the art, these degree terms should be interpreted as including a deviation of at least ±5% of the modified term.

[0070] This specification refers to many chemical terms and abbreviations used by those skilled in the art. However, for the sake of clarity and consistency, definitions of selected terms are provided.

[0071] As used herein, the term "solvate" means a compound, or salt, or zwitterion and / or prodrug of a compound, wherein molecules of a suitable solvent are incorporated into the crystal lattice.

[0072] As used herein, the term "prodrug" means a compound or salt of a compound that is converted to an active drug after administration.

[0073] As used herein, the term "zwitterion" means a molecule containing equal amounts of positively charged functional groups and negatively charged functional groups. Zwitterions are also known as "inner salts" and "dipole ions".

[0074] As used herein, whether used alone or as part of another group, the term "alkyl" means a straight or branched chain saturated alkyl group. The possible number of carbon atoms in the alkyl group is indicated by the prefix "C n1-n2 ”. Thus, for example, the term “C 1-6 "Alkyl" (or "C1-C6 alkyl") means an alkyl group having 1, 2, 3, 4, or 5 carbon atoms.

[0075] As used herein, whether used alone or as part of another group, the term "alkenyl" means a straight or branched unsaturated alkyl group containing at least one double bond. The possible number of carbon atoms in the alkylene group is indicated by the prefix "C n1-n2 " means. For example, the term C 2-6 Alkenyl means an alkenyl group having 2, 3, 4, 5 or 6 carbon atoms and at least one double bond.

[0076] As used herein, whether used alone or as part of another group, the term "alkynyl" means a straight or branched unsaturated alkynyl group containing at least one triple bond. The possible number of carbon atoms in the alkyl group is indicated by the prefix "C n1-n2 " means. For example, the term C 2-6 Alkynyl means an alkynyl group having 2, 3, 4, 5 or 6 carbon atoms.

[0077] As used herein, the term "alkoxy," when used herein, alone or in combination, includes an alkyl group attached to an oxygen linking atom.

[0078] As used herein, the term "fluoroalkoxy" refers to an alkoxy group as defined above wherein one or more available hydrogen atoms are replaced by fluorine.

[0079] As used herein, the term "deuterated alkoxy" refers to an alkoxy group as defined above wherein one or more of the available hydrogen atoms are replaced by deuterium.

[0080] As used herein, whether used alone or as part of another group, the term "cycloalkyl" means a saturated carbocyclic group containing 3 to 6 carbon atoms and one or more rings. The possible number of carbon atoms in a reference to a cycloalkyl group is indicated by the numerical prefix "C n1-n2 " means. For example, the term C 3-10 The cycloalkyl group means a cycloalkyl group having 3, 4, 5 or 6 carbon atoms.

[0081] As used herein, whether used alone or as part of another group, the term "heterocycloalkyl" refers to a cyclic group containing at least one non-aromatic ring and containing 3 to 6 atoms, one or more of which is a hetero moiety selected from O, S, S(O), SO2 and N, and the remaining atoms are C. Heterocycloalkyl is saturated or unsaturated (i.e., contains one or more double bonds). When heterocycloalkyl contains the prefix C n1-n2 or "n1 to n2", this prefix indicates the number of carbon atoms in the corresponding carbocyclic group, wherein one or more, suitably 1 to 4 ring atoms are replaced by heteroatoms selected from O, S, S(O), SO2 and N, and the remaining atoms are C.

[0082] As used herein, whether used alone or as part of another group, the term "heteroaryl" refers to a cyclic group containing at least one heteroaromatic ring and containing 5-6 atoms, one or more of which are heteroatoms selected from O, S and N, and the remaining atoms are C. When the heteroaryl group contains the prefix C n1-n2 When , this prefix indicates the number of carbon atoms in the corresponding carbocyclic group, wherein one or more, suitably 1 to 4, ring atoms are replaced by heteroatoms as defined above.

[0083] The term "halogen" (or "halo"), whether used alone or as part of another group, refers to a halogen atom and includes fluorine, chlorine, bromine and iodine.

[0084] As used herein, the term "haloalkyl" refers to an alkyl group as defined above in which one or more available hydrogen atoms are replaced by a halogen. Thus, for example, "C 1-6 "Haloalkyl" refers to a C1 to C6 straight or branched chain alkyl group as defined above having one or more halogen substituents.

[0085] As used herein, the term "deuterated alkyl" refers to an alkyl group as defined above in which one or more available hydrogen atoms are replaced by deuterium. Thus, for example, "C 1-6 "Deuterated alkyl" refers to a C1 to C6 straight or branched chain alkyl group as defined above having one or more deuterium substituents.

[0086] In "available hydrogen atom" or "available atom", the term "available" refers to an atom known by those skilled in the art to be capable of being replaced by a substituent.

[0087] As used herein, the term "one or more" items includes a single item selected from the list as well as a mixture of two or more items selected from the list.

[0088] As used herein, the term "alternative isotopes thereof" refers to isotopes of an element other than the most abundant isotope in nature.

[0089] In the compounds of Formula I and their pharmaceutically acceptable salts and / or solvates, the atoms may exhibit their natural isotopic abundance, or one or more atoms may be artificially enriched with a particular isotope having the same atomic number but an atomic mass or mass number different from the atomic mass or mass number predominantly found in nature. The present disclosure is intended to include all suitable isotopic variants of the compounds of Formula I and their pharmaceutically acceptable salts and / or solvates. For example, different isotopic forms of hydrogen (H) include protium ( 1 H), deuterium ( 2 H) and tritium ( 3 H). Protium is the major isotope of hydrogen found in nature.

[0090] As used herein, the term "all available atoms are optionally replaced by alternative isotopes" means that available atoms are optionally replaced by isotopes of that atom having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number predominantly found in nature.

[0091] The term "compound" refers to the compound, and in certain embodiments, any hydrate or solvate thereof in terms of its degree of stability. A hydrate is a compound complexed with water, and a solvate is a compound complexed with a solvent, and the solvent may be an organic solvent or an inorganic solvent. A "stable" compound is a compound that can be prepared and separated, and its structure and properties are maintained or can be caused to remain substantially unchanged within a certain period of time sufficient to allow the use of the compound for purposes described herein (e.g., therapeutic administration to a subject). The compounds of the present application are limited to stable compounds covered by the general formula (I), or pharmaceutically acceptable salts and / or solvates thereof.

[0092] The term "pharmaceutically acceptable" means compatible with the treatment of the subject.

[0093] The term "pharmaceutically acceptable carrier" means a non-toxic solvent, dispersant, excipient, adjuvant or other substance that is mixed with the active ingredient to allow for formation of a pharmaceutical composition (ie, a dosage form that can be administered to a subject).

[0094] The term "pharmaceutically acceptable salt" means an acid addition salt or a base addition salt that is suitable for or compatible with the treatment of a subject.

[0095] Acid addition salts suitable for or compatible with treatment of a subject are any non-toxic organic or inorganic acid addition salt of any basic compound.

[0096] Base addition salts suitable for or compatible with the treatment of a subject are any non-toxic organic or inorganic base addition salt of any acidic compound.

[0097] As used herein, the term "protecting group" or "PG" and the like refers to a chemical portion that protects or masks a reactive portion of a molecule to prevent side reactions in those reactive portions of the molecule while manipulating different portions of the molecule or making them reactive. After the manipulation or reaction is complete, the protecting group is removed under conditions that do not degrade or decompose the remainder of the molecule. A person skilled in the art can select a suitable protecting group. Many conventional protecting groups are known in the art, for example, "Protective Groups in Organic Chemistry" McOmie, JFW Ed, Plenum Press, 1973; Greene, TW and Wuts, PGM, "Protective Groups in Organic Synthesis", John Wiley & Sons, 3 rd Edition, 1999; and Kocienski, P. Protecting Groups, 3 rd Edition, 2003, Georg Thieme Verlag (The Americas).

[0098] As used herein, the term "subject" includes all members of the animal kingdom, including mammals, and appropriately refers to humans. Thus, the methods of the present application are suitable for both human therapy and veterinary applications.

[0099] As used herein and as is well known in the art, the term "treating" or "treatment" means a method of obtaining beneficial or desired results, including clinical results. Beneficial or desired clinical results include, but are not limited to, alleviation or improvement of one or more symptoms or conditions, reduction in extent of disease, stabilization (i.e., not worsening) of the disease state, prevention of disease spread, delay or slowing of disease progression, palliation or alleviation of the disease state, reduction of disease recurrence, and remission (whether partial or total), whether detectable or undetectable. "Treatment" may also mean prolonging survival compared to expected survival if not receiving treatment. As used herein, "treatment" also includes prophylactic treatment. For example, a subject with early-stage cancer may be treated to prevent cancer progression, or a subject in remission may be treated with a compound or composition of the present application to prevent recurrence. The method of treatment comprises administering to the subject a therapeutically effective amount of one or more compounds of the present application, and optionally consists of a single administration, or alternatively comprises a series of administrations.

[0100] As used herein, the term "effective amount" or "therapeutically effective amount" means an amount of one or more compounds of the present application that is effective at the dosage and time required to achieve the desired result. For example, in the context of treating a disease, disorder or condition mediated or treated by agonizing or activating serotonergic receptors and downstream second messengers, an effective amount is, for example, an amount that increases the activation compared to the activation without the administration of one or more compounds.

[0101] By "alleviating" a disease, disorder or condition, it is meant that the extent and / or adverse clinical manifestations of the disease, disorder or condition are reduced and / or the time course of progression is slowed or prolonged, as compared to not treating the disorder.

[0102] As used herein, the term "administering" means administering a therapeutically effective amount of one or more compounds or compositions of the present application to a cell, tissue, organ or subject.

[0103] As used herein, the terms "prevention" or "prophylaxis" or synonyms thereof refer to reducing the risk or probability of a patient developing a disease, disorder or condition or exhibiting symptoms associated with a disease, disorder or condition.

[0104] As used herein, a "disease, disorder, or condition" refers to a condition that is caused by activation of serotonin receptors (e.g., 5-HT 2A ), particularly diseases, disorders or conditions that are treated or treatable using a serotonin receptor agonist (e.g., one or more of the compounds of the present application described herein).

[0105] As used herein, the term "treating a disease, disorder or condition by activating a serotonin receptor" means that the disease, disorder or condition to be treated is directly or indirectly affected by, regulated by and / or has some biological basis, including serotonergic activity, particularly an increase in serotonergic activity. When the serotonergic activity associated with the disease, disorder or condition is stimulated by one or more compounds or compositions of the present application, these diseases respond favorably.

[0106] As used herein, the term "activation" includes agonism, partial agonism, and positive allosteric modulation of serotonin receptors.

[0107] As used herein, the term "5-HT 1A ” and “5-HT 2A ” refers to the 5-HT2 serotonin receptor 2A and 5-HT 2A Receptor subtype.

[0108] As used herein, the term "therapeutic agent" refers to any drug or active agent that has a pharmacological effect when administered to a subject.

[0109] As used herein, the term "equivalent dose of psilocybin" means that the compound is administered or used in the same molar amount as the corresponding dose of psilocybin.

[0110] II.Compounds

[0111] The present application includes compounds of Formula I or pharmaceutically acceptable salts, solvates and / or prodrugs thereof:

[0112]

[0113] in:

[0114] R 1 Selected from C(O)R 7 、CO2R 7 、C(O)N(R 7 )(R 7’ )、S(O)R 7 、SO2R 7 , C 1-6 Alkylene R 7 and R 7 ;

[0115] Q is selected from Q1, Q2, Q2', Q4 and Q5:

[0116]

[0117] is a single bond or a double bond, provided that when When it is a double bond, R 9 and R 15 does not exist, and when Q2 When it is a double bond, R 17 and R 25 does not exist, and when Q2' When it is a double bond, R 16’ and R 25’ does not exist;

[0118] On the key means that the bond is attached to the remainder of the compound;

[0119] R 2 , R 2’ and R 2” are independently selected from H, halo, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylene N(R 2a )(R 2b ) and SC 1-6 alkyl;

[0120] R 2aand R 2b Independently selected from H and C 1-6 alkyl;

[0121] R 3 , R 4 , R 5 and R 6 are independently selected from H, halo, N(R 5’ )(R 6’ ), C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylene N(R 5’ )(R 6’ ) and SC 1-6 Alkyl, the last four groups are optionally replaced by one or two selected from OH and C 1-6 The alkoxy substituent is substituted with, or

[0122] R 3 , R 4 , R 5 and R 6 Two adjacent groups in the bond together to form O-(CH2) 1-2 O, and R 3 , R 4 , R 5 and R 6 The remaining groups in are independently selected from H, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, N(R 5’ )(R 6’ ), C 1-6 Alkylene N(R 5’ )(R 6’ ) and SC 1-6 Alkyl, or

[0123] R 3 , R 4 , R 5 and R 6 One of A, OA and C 1-4 Alkylene A, and R 3 , R 4 , R 5 and R 6 The remaining groups in are independently H or halo;

[0124] R 5’ and R 6’ Independently selected from H and C 1-6 alkyl;

[0125] A is selected from phenyl, C 3-6Cycloalkyl, containing 1 to 4 independently selected from O, S, S(O), SO2, N and NR 54 The heterocyclic alkyl group of the heterocyclic alkyl group is 3-6-membered and contains 1 to 4 independently selected from O, S, S(O), SO2, N and NR 54 The 5- to 6-membered heteroaryl group of the heteroaryl group of 3-10 Cycloalkyl, 3-membered to 6-membered heterocycloalkyl and 5-membered to 6-membered heteroaryl are optionally substituted with one or more substituents independently selected from the group consisting of halo, C 1-4 Alkyl, OC 1-4 Alkyl, N(R 54a )(R 54b ), C 1-4 Alkylene N(R 54a )(R 54b ) and SC 1-4 alkyl;

[0126] R 7 Selected from H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, phenyl, C 3-6 Cycloalkyl, containing 1 to 4 independently selected from O, S, N and NR 7” The heterocyclic alkyl group of the heterocyclic alkyl group is 3-6-membered and contains 1 to 4 independently selected from O, S, N and NR 7” The 5- to 6-membered heteroaryl group of the ... 55 、N(R 55 )(R 56 ) and SR 55 Substituents substituted, and / or C 1-6 The alkyl group is optionally substituted by one to three independently selected from O, C(O), CO2 and NR 57 The miscellaneous parts are interrupted;

[0127] R 7’ Selected from H and C 1-6 alkyl;

[0128] R 7” Selected from H and C 1-6 alkyl;

[0129] R 8 , R 9 , R 10 , R 11 , R 13 , R 14 , R 15 , R 16 , R 16’ , R 17 , R17’ , R 18 , R 19’ , R 19 , R 19’ , R 21 , R 22’ , R 22 , R 22’ , R 23 , R 23’ , R 24 , R 24’ , R 25 , R 25’ , R 32 , R 33 , R 34 , R 36 , R 37 , R 38 , R 39 , R 40 , R 41 , R 42 , R 43 , R 44 , R 46 , R 47 , R 48 , R 49 , R 50 , R 51 , R 52 and R 53 are independently selected from H, halo and C 1-6 alkyl;

[0130] R 12 , R 20 , R 20’ , R 35 and R 45 Independently selected from H, C 1-6 Alkyl and C(O)C 1-6 alkyl;

[0131] R 54 , R 55 , R 56 and R 57 Independently selected from H and C 1-6 alkyl;

[0132] R 54a and R 54b Independently selected from H and C 1-6 Alkyl; and

[0133] All available hydrogen atoms are optionally and independently replaced with fluorine atoms or chlorine atoms, and all available atoms are optionally substituted with alternative isotopes thereof.

[0134] The present application includes compounds of Formula I or pharmaceutically acceptable salts, solvates and / or prodrugs thereof:

[0135]

[0136] in:

[0137] R 1 Selected from H, C(O)R 7 、CO2R 7 、C(O)N(R 7 )(R 7’ )、S(O)R 7 and SO2R 7 ;

[0138] Q is selected from Q1, Q2, Q3, Q4 and Q5:

[0139]

[0140] is a single bond or a double bond, provided that when When it is a double bond, R 9 and R 15 does not exist, and when Q2 When it is a double bond, R 17 and R 25 does not exist;

[0141] R 2 , R 2’ , R 2” , R 3 and R 6 are independently selected from H, halo, C 1-6 Alkyl and C 1-6 Alkoxy;

[0142] R 4 and R 5 One or two of are independently selected from H, halogen, C 1-6 Alkyl and C 1-6 Alkoxy, or

[0143] R 4 and R 5 Linked together to form O-(CH2) 1-2 O, or

[0144] R 4 and R 5 One of A, OA and C 1-4 Alkylene A, and R 4 and R 5 The other one in is H;

[0145] A is selected from phenyl, C3-6 Cycloalkyl, containing 1 to 4 independently selected from O, S, S(O), SO2, N and NR 54 The heterocyclic alkyl group of the heterocyclic alkyl group is 3-6-membered and contains 1 to 4 independently selected from O, S, S(O), SO2, N and NR 54 The 5- to 6-membered heteroaryl group of the heteroaryl group of 3-10 Cycloalkyl, 3-membered to 6-membered heterocycloalkyl and 5-membered to 6-membered heteroaryl are optionally substituted by one or more independently selected from halo, C 1-4 Alkyl and OC 1-4 Substitution of alkyl groups;

[0146] R 7 Selected from H and C 1-6 Alkyl, wherein the C 1-6 The alkyl group is optionally substituted by one or more independently selected from halo, OR 55 、N(R 55 )(R 56 ) and SR 55 and / or optionally substituted by one to three independently selected from O, C(O), CO2 and NR 57 The miscellaneous parts are interrupted;

[0147] R 7’ Selected from H and C 1-6 alkyl;

[0148] R 8 , R 9 , R 10 , R 11 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 21 , R 22 , R 23 , R 24 , R 25 , R 26 , R 27 , R 28 , R 29 , R 32 , R 33 , R 34 , R 36 , R 37 , R 38 , R 39 , R 40 , R 41 , R 42 , R 43, R 44 , R 46 , R 47 , R 48 , R 49 , R 50 , R 51 , R 52 and R 53 are independently selected from H, halo and C 1-6 alkyl;

[0149] R 12 , R 20 , R 35 and R 45 Independently selected from H, C 1-6 Alkyl and C(O)C 1-6 alkyl;

[0150] R 30 and R 31 Independently selected from H, C 1-6 Alkyl and C(O)C 1-6 Alkyl, or

[0151] R 30 and R 31 Together with the N atom to which they are attached, they form a 3- to 6-membered heterocyclic ring, wherein the 3- to 6-membered heterocyclic ring optionally contains one or two independently selected from O, S, S(O), SO2, N and NR 58 Additional miscellaneous parts;

[0152] R 54 , R 55 , R 56 , R 57 and R 58 Independently selected from H and C 1-6 Alkyl; and

[0153] All available hydrogen atoms are optionally and independently replaced by fluorine atoms or chlorine atoms, and all available atoms are optionally replaced by alternative isotopes thereof,

[0154] The condition is that when Q is Q3, R 26 , R 27 , R 28 and R 29 All are H and R 30 and R 31 is H or CH3, and:

[0155] R 1 , R 2 , R 2’ , R 2” , R 3 , R 4 , R 5 and R6 All are H,

[0156] R 1 , R 2 , R 2’ , R 2” , R 3 , R 5 and R 6 All are H and R 4 for OCH3, or

[0157] R 1 , R 2 , R 2’ , R 2” , R 3 , R 4 , R 5 and R 6 All are H and R 5 For OCH3,

[0158] The compound of formula I is then either the (R)-enantiomer or the (S)-enantiomer of the carbon to which Q is attached.

[0159] In some embodiments, when all available hydrogen atoms in a group are optionally replaced by halogen atoms, the halogen atoms are F, Cl or Br. In some embodiments, when all available hydrogen atoms in a group are optionally replaced by halogen atoms, the halogen atoms are F or Br. In some embodiments, when all available hydrogen atoms in a group are optionally replaced by halogen atoms, the halogen atoms are F or Cl. In some embodiments, when all available hydrogen atoms in a group are optionally replaced by halogen atoms, the halogen atoms are F.

[0160] In some embodiments, Q is Q1 and is a single bond, and the compound of Formula I or a pharmaceutically acceptable salt and / or solvate thereof has the following structure:

[0161]

[0162] in:

[0163] R 1 , R 2 , R 2’ , R 2” , R 3 , R 4 , R 5 , R 6 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13, R 14 and R 15 As defined for Formula I, and

[0164] All available hydrogen atoms are optionally and independently replaced with fluorine atoms or chlorine atoms, and all available atoms are optionally substituted with alternative isotopes thereof.

[0165] In some embodiments, Q is Q1 and is a double bond, and the compound of Formula I or a pharmaceutically acceptable salt and / or solvate thereof has the following structure:

[0166]

[0167] in:

[0168] R 1 , R 2 , R 2’ , R 2” , R 3 , R 4 , R 5 , R 6 , R 8 , R 10 , R 11 , R 12 , R 13 and R 14 As defined for Formula I, and

[0169] All available hydrogen atoms are optionally and independently replaced with fluorine atoms or chlorine atoms, and all available atoms are optionally substituted with alternative isotopes thereof.

[0170] In some embodiments, Q is Q2 and is a single bond, and the compound of Formula I or a pharmaceutically acceptable salt and / or solvate thereof has the following structure:

[0171]

[0172] in:

[0173] R 1 , R 2 , R 2’ , R 2” , R 3 , R 4 , R 5 , R 6 , R 16 , R 17 , R 18 , R 19 , R 20 , R21 , R 22 , R 23 , R 24 and R 25 As defined for Formula I, and

[0174] All available hydrogen atoms are optionally and independently replaced with fluorine atoms or chlorine atoms, and all available atoms are optionally substituted with alternative isotopes thereof.

[0175] In some embodiments, Q is Q2 and is a double bond, and the compound of Formula I or a pharmaceutically acceptable salt and / or solvate thereof has the following structure:

[0176]

[0177] in:

[0178] R 1 , R 2 , R 2’ , R 2” , R 3 , R 4 , R 5 , R 6 , R 16 , R 18 , R 19 , R 20 , R 21 , R 22 , R 23 and R 24 As defined for Formula I, and

[0179] All available hydrogen atoms are optionally and independently replaced with fluorine atoms or chlorine atoms, and all available atoms are optionally substituted with alternative isotopes thereof.

[0180] In some embodiments, Q is Q2' and is a single bond, and the compound of Formula I or a pharmaceutically acceptable salt and / or solvate thereof has the following structure:

[0181]

[0182] in:

[0183] R 1 , R 2 , R 2’ , R 2” , R 3 , R 4 , R 5 , R 6 , R16’ , R 17’ , R 18 '、R 19’ , R 20’ , R 21 '、R 22’ , R 23’ , R 24’ and R 25’ As defined for Formula I, and

[0184] All available hydrogen atoms are optionally and independently replaced with fluorine atoms or chlorine atoms, and all available atoms are optionally substituted with alternative isotopes thereof.

[0185] In some embodiments, Q is Q2' and is a double bond, and the compound of Formula I or a pharmaceutically acceptable salt and / or solvate thereof has the following structure:

[0186]

[0187] in:

[0188] R 1 , R 2 , R 2’ , R 2” , R 3 , R 4 , R 5 , R 6 , R 17’ , R 18 '、R 19’ , R 20’ , R 21 '、R 22’ , R 23’ and R 24’ As defined for Formula I, and

[0189] All available hydrogen atoms are optionally and independently replaced with fluorine atoms or chlorine atoms, and all available atoms are optionally substituted with alternative isotopes thereof.

[0190] In some embodiments, Q is Q4 And the compound of formula I or its pharmaceutically acceptable salt and / or solvate has the following structure:

[0191]

[0192] in:

[0193] R 1 , R 2 , R 2’ , R 2” , R3 , R 4 , R 5 , R 6 , R 32 , R 33 , R 34 , R 35 , R 36 , R 37 , R 38 , R 39 , R 40 and R 41 As defined for Formula I, and

[0194] All available hydrogen atoms are optionally and independently replaced with fluorine atoms or chlorine atoms, and all available atoms are optionally substituted with alternative isotopes thereof.

[0195] In some embodiments, Q is Q5 And the compound of formula I or its pharmaceutically acceptable salt and / or solvate has the following structure:

[0196]

[0197] in:

[0198] R 1 , R 2 , R 2’ , R 2” , R 3 , R 4 , R 5 , R 6 , R 42 , R 43 , R 44 , R 45 , R 46 , R 47 , R 48 , R 49 , R 50 , R 51 , R 52 and R 53 As defined for Formula I, and

[0199] All available hydrogen atoms are optionally and independently replaced with fluorine atoms or chlorine atoms, and all available atoms are optionally substituted with alternative isotopes thereof.

[0200] In some embodiments, R 1 , R 2 , R 2’ , R 3 , R 5 and R 6All are H, and the compound of Formula I or a pharmaceutically acceptable salt and / or solvate thereof has the following structure:

[0201]

[0202] in:

[0203] R 4 and Q are as defined for Formula I, and

[0204] All available hydrogen atoms are optionally and independently replaced with fluorine atoms or chlorine atoms, and all available atoms are optionally substituted with alternative isotopes thereof.

[0205] In some embodiments, R 1 , R 2 , R 2’ , R 2” , R 3 , R 4 and R 6 All are H, and the compound of Formula I or a pharmaceutically acceptable salt and / or solvate thereof has the following structure:

[0206]

[0207] in:

[0208] R 5 and Q are as defined for Formula I, and

[0209] wherein all available hydrogen atoms are optionally and independently replaced by fluorine atoms or chlorine atoms, and all available atoms are optionally replaced by alternative isotopes thereof.

[0210] In some embodiments, R 1 , R 2 , R 2’ , R 2” , R 3 and R 6 All are H, and the compound of Formula I or a pharmaceutically acceptable salt and / or solvate thereof has the following structure:

[0211]

[0212] in:

[0213] R 4 , R 5 and Q are as defined for Formula I, and

[0214] All available hydrogen atoms are optionally and independently replaced with fluorine atoms or chlorine atoms, and all available atoms are optionally substituted with alternative isotopes thereof.

[0215] In some embodiments, R 1 , R 2 , R 2’ and R 2” All are H and R 3 , R 4 , R 5 and R 6 All are D, and the compound of Formula I or a pharmaceutically acceptable salt and / or solvate thereof has the following structure:

[0216]

[0217] in:

[0218] Q is as defined for Formula I, and

[0219] All available hydrogen atoms are optionally and independently replaced with fluorine atoms or chlorine atoms, and all available atoms are optionally substituted with alternative isotopes thereof.

[0220] In some embodiments, R 8 , R 9 , R 10 , R 11 , R 13 , R 14 , R 15 , R 16 , R 16’ , R 17 , R 17’ , R 18 , R 19’ , R 19 , R 19’ , R 21 , R 22’ , R 22 , R 22’ , R 23 , R 23’ , R 24 , R 24’ , R 25 , R 25’ , R 32 , R 33 , R 34 , R 36 , R 37 , R 38 , R 39 , R 40 , R 41 , R 42 , R 43 , R 44 , R 46 , R 47 , R 48 , R 49 , R50 , R 51 , R 52 and R 53 Independently selected from H, D, F, Cl, C 1-6 Alkyl, C 1-6 Fluoroalkyl and C 1-6 In some embodiments, R 8 , R 9 , R 10 , R 11 , R 13 , R 14 , R 15 , R 16 , R 16’ , R 17 , R 17’ , R 18 , R 19’ , R 19 , R 19’ , R 21 , R 22’ , R 22 , R 22’ , R 23 , R 23’ , R 24 , R 24’ , R 25 , R 25’ , R 32 , R 33 , R 34 , R 36 , R 37 , R 38 , R 39 , R 40 , R 41 , R 42 , R 43 , R 44 , R 46 , R 47 , R 48 , R 49 , R 50 , R 51 , R 52 and R 53 is independently selected from H, F, D, CH3, CD2H, CDH2, CD3, CF3, CHF2, CH2CH3, CH(CH3)2, CH2CH2D, CH2CD2H and CD2CD3. In some embodiments, R 8 , R 9 , R 10 , R 11 , R 13 , R 14 , R 15 , R16 , R 16’ , R 17 , R 17’ , R 18 , R 19’ , R 19 , R 19’ , R 21 , R 22’ , R 22 , R 22’ , R 23 , R 23’ , R 24 , R 24’ , R 25 , R 25’ , R 32 , R 33 , R 34 , R 36 , R 37 , R 38 , R 39 , R 40 , R 41 , R 42 , R 43 , R 44 , R 46 , R 47 , R 48 , R 49 , R 50 , R 51 , R 52 and R 53 is independently selected from H, F, D, CH3, CD2H, CDH2, CD3, CF3, CHF2, CH2CH3, CH2CH2D, CH2CD2H and CD2CD3. In some embodiments, R 8 , R 9 , R 10 , R 11 , R 13 , R 14 , R 15 , R 16 , R 16’ , R 17 , R 17’ , R 18 , R 19’ , R 19 , R 19’ , R 21 , R 22’ , R 22 , R 22’ , R 23 , R 23’ , R 24 , R 24’ , R 25, R 25’ , R 32 , R 33 , R 34 , R 36 , R 37 , R 38 , R 39 , R 40 , R 41 , R 42 , R 43 , R 44 , R 46 , R 47 , R 48 , R 49 , R 50 , R 51 , R 52 and R 53 Independently selected from H and D.

[0221] In some embodiments, R 8 , R 9 , R 10 , R 11 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 21 , R 22 , R 23 , R 24 , R 25 , R 32 , R 33 , R 34 , R 36 , R 37 , R 38 , R 39 , R 40 , R 41 , R 42 , R 43 , R 44 , R 46 , R 47 , R 48 , R 49 , R 50 , R 51 , R 52 and R 53 Independently selected from H, D, F, Cl, C 1-6 Alkyl, C 1-6 Fluoroalkyl and C 1-6 In some embodiments, R 8 , R9 , R 10 , R 11 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 21 , R 22 , R 23 , R 24 , R 25 , R 32 , R 33 , R 34 , R 36 , R 37 , R 38 , R 39 , R 40 , R 41 , R 42 , R 43 , R 44 , R 46 , R 47 , R 48 , R 49 , R 50 , R 51 , R 52 and R 53 is independently selected from H, F, D, CH3, CD2H, CDH2, CD3, CF3, CHF2, CH2CH3, CH2CH2D, CH2CD2H and CD2CD3. In some embodiments, R 8 , R 9 , R 10 , R 11 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 21 , R 22 , R 23 , R 24 , R 25 , R 32 , R 33 , R 34 , R 36 , R 37 , R 38 , R 39 , R 40 , R 41 , R 42 , R 43, R 44 , R 46 , R 47 , R 48 , R 49 , R 50 , R 51 , R 52 and R 53 Independently selected from H and D.

[0222] In some embodiments, when Q is Q1 And in Q1 When it is a single bond, R 15 The stereochemistry at the bonded carbon is R or S. Thus, in some embodiments, Q1 is

[0223] In some embodiments, when Q is Q2 And in Q2 When it is a single bond, R 25 The stereochemistry at the bonded carbon is R or S. Thus, in some embodiments, Q2 is

[0224] In some embodiments, when Q is Q2' And in Q2 When it is a single bond, R 25’ The stereochemistry at the bonded carbon is R or S. Thus, in some embodiments, Q2' is

[0225] In some embodiments, when Q is When R 34 or R 44 The stereochemistry at the bonded carbon is R or S. Thus, in some embodiments, Q4 is And Q5 is

[0226] In some embodiments, R 34 or R 35 The stereochemistry at the bonded carbon is R. In some embodiments, R 34 or R 35 The stereochemistry at the bonded carbon is S.

[0227] In some embodiments, Q is selected from one of the following groups:

[0228]

[0229] Where R12 , R 20 , R 20’ , R 35 and R 45 As defined in Formula I.

[0230] In some embodiments, R 12 , R 20 , R 20’ , R 35 and R 45 Independently selected from H, C 1-4 Alkyl and C(O)C 1-4 In some embodiments, R 12 , R 20 , R 20’ , R 35 and R 45 Independently selected from H, D, C 1-4 Alkyl, C 1-4 Fluoroalkyl, C 1-4 Deuterated alkyl, C(O)C 1-4 Alkyl, C(O)C 1-4 Fluoroalkyl and C(O)C 1-4 In some embodiments, R 12 , R 20 , R 20’ , R 35 and R 45 Independently selected from H, D, CH3, CD2H, CDH2, CD3, CF3, CHF2, CH2CH3, CH(CH3)2, CH2CH2D, CH2CD2H, CD2CD3, CH3C(O), CD2HC(O), CDH2C(O), CD3C(O), CF3C(O), CHF2C(O), CH3CH2C(O), CH(CH3)2C(O), CH2DCH2C(O), CD2HCH2C(O) and CD3CH2C(O).

[0231] In some embodiments, R 12 , R 20 , R 20’ , R 35 and R 45 is independently selected from H, D, CH3, CD2H, CDH2, CD3, CF3, CHF2, CH2CH3, CH(CH3)2, CH2CH2D, CH2CD2H and CD2CD3. In some embodiments, R 12 , R 20 , R 20’ , R 35 and R45 is independently selected from H, D, CH3, CD2H, CDH2, CD3, CF3, CHF2, CH2CH3 and CH(CH3)2. In some embodiments, R 12 , R 20 , R 20’ , R 35 and R 45 is independently selected from H, D, CH3, CD3, CF2H, CF3 and CH(CH3)2. In some embodiments, R 12 , R 20 , R 20’ , R 35 and R 45 is independently selected from H, D, CH3, CD3, CF2H and CF3. 12 , R 20 , R 20’ , R 35 and R 45 is independently selected from H, D, CH3 and CD3. 12 , R 20 , R 20’ , R 35 and R 45 is independently selected from H, CH3 and CD3. In some embodiments, R 12 , R 20 , R 20’ , R 35 and R 45 Independently selected from CH3 and CD3.

[0232] In some embodiments, R 12 , R 20 , R 20’ , R 35 and R 45 is independently selected from H, D, H, D, CH3, CD2H, CDH2, CD3, CF3, CHF2, CH3C(O), CD2HC(O), CDH2C(O), CD3C(O), CF3C(O), CHF2C(O), CH3CH2C(O), CH(CH3)2C(O), CH2DCH2C(O), CD2HCH2C(O), and CD3CH2C(O). In some embodiments, R 12 , R 20 , R 20’ , R 35 and R 45is independently selected from H, D, CH3C(O), CD2HC(O), CDH2C(O), CD3C(O), CF3C(O), CHF2C(O), CH3CH2C(O), CH(CH3)2C(O), CH2DCH2C(O), CD2HCH2C(O), and CD3CD2C(O). In some embodiments, R 12 , R 20 , R 20’ , R 35 and R 45 Independently selected from H, CH3C(O), CD3C(O), CF2HC(O) and CF3C(O).

[0233] In some embodiments, Q is selected from one of the following groups:

[0234]

[0235] Where R 12 , R 20 , R 3 0. R 3 1. R 35 and R 45 Independently selected from H, D, C 1-6 Alkyl, C 1-6 Fluoroalkyl and C 1-6 In some embodiments, R 12 , R 20 , R 3 0. R 3 1. R 35 and R 45 Independently selected from H, C 1-4 Alkyl, C 1-4 Fluoroalkyl and C 1-4 In some embodiments, R 12 , R 20 , R 30 , R 31 , R 35 and R 45 is independently selected from H, CH3, CD3, CF2H and CF3. In some embodiments, R 12 , R 20 , R 30 , R 31 , R 35 and R 45 Independently selected from CH3 and CD3.

[0236] In some embodiments, Q is selected from one of the following groups:

[0237]

[0238] Where R 35 Selected from H, D, C 1-6 Alkyl, C 1-6 Fluoroalkyl and C 1-6 In some embodiments, R 35 Selected from H, C 1-4 Alkyl, C 1-4 Fluoroalkyl and C 1-4 In some embodiments, R 35 is selected from H, CH3, CD3, CF2H and CF3. In some embodiments, R 35 Selected from CH3 and CD3.

[0239] In some embodiments, R 1 Selected from C(O)R 7 、CO2R 7 、C(O)N(R 7 )(R 7’ )、S(O)R 7 、SO2R 7 , C 1-4 Alkylene R 7 and R 7 , wherein all available hydrogen atoms are optionally and independently replaced by fluorine atoms or deuterium atoms.

[0240] In some embodiments, R 1 Selected from C(O)R 7 、CO2R 7 、C(O)N(R 7 )(R 7’ )、S(O)R 7 and SO2R 7 In some embodiments, R 1 Selected from C(O)R 7 、CO2R 7 and C(O)N(R 7 )(R 7’ ). In some embodiments, R 1 Selected from C(O)R 7 and CO2R 7 .

[0241] In some embodiments, R 7’ Selected from H and C 1-4 In some embodiments, R 7’ Selected from H, D, C 1-4 Alkyl, C 1-4 Fluoroalkyl and C 1-4 In some embodiments, R7’ is selected from the group consisting of H, D, CH3, CD2H, CDH2, CD3, CF3, CHF2, CH2CH3, CH(CH3)2, CH2CH2D, CH2CD2H, and CD2CD3. In some embodiments, R 7’ is selected from H, CH3, CD3, CF2H and CF3. In some embodiments, R 7’ Selected from H, CH3 and CD3.

[0242] In some embodiments, R 1 Selected from R 7 and C 1-4 Alkylene R 7 In some embodiments, R 1 Selected from R 7 and C 1-2 Alkylene R 7 In some embodiments, R 1 For R 7 In some embodiments, R 1 C 1-2 Alkylene R 7 In some embodiments, R 1 is C1 alkylene R 7 (CH2R 7 ).

[0243] In some embodiments, R 7 Selected from H, C 1-4 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, phenyl, C 3-6 Cycloalkyl, containing 1 to 4 independently selected from O, S, N and NR 7” The heterocyclic alkyl group of the heterocyclic alkyl group is 3-6-membered and contains 1 to 4 independently selected from O, S, N and NR 7” The 5- to 6-membered heteroaryl group of the ... 55 、N(R 55 )(R 56 ) and SR 55 Substituents substituted, and / or C 1-4 The alkyl group is optionally substituted by one to three independently selected from O, C(O), CO2 and NR 57 and wherein all available hydrogen atoms are optionally and independently replaced by fluorine atoms or deuterium atoms.

[0244] In some embodiments, R 7 Selected from phenyl, C 3-6Cycloalkyl, containing 1 to 3 independently selected from O, S, S(O), SO2, N and NR 7” The heterocyclic alkyl group of the heterocyclic alkyl group is 3-6-membered and contains 1 to 3 independently selected from O, S, S(O), SO2, N and NR 7” 5- to 6-membered heteroaryl groups of the hetero moiety, these groups are optionally substituted by one or more independently selected from halogen, OR 55 、N(R 55 )(R 56 ) and SR 55 In some embodiments, R 7 Selected from phenyl, C 3-6 Cycloalkyl, containing 1 to 2 independently selected from O, S, S(O), SO2, N and NR 7” The heterocyclic 5- to 6-membered alkyl group of the heterocyclic group and containing 1 to 3 independently selected from O, S, N and NR 7” 5- to 6-membered heteroaryl groups of the hetero moiety, these groups are optionally substituted by one or more independently selected from halogen, OR 55 、N(R 55 )(R 56 ) and SR 55 and wherein all available hydrogen atoms are optionally and independently substituted with fluorine atoms or deuterium atoms.

[0245] In some embodiments, R 7 is optionally substituted by one or more independently selected from halogen, OR 55 、N(R 55 )(R 56 ) and SR 55 In some embodiments, R 7 is phenyl, wherein all available hydrogen atoms are optionally and independently substituted with fluorine atoms or deuterium atoms.

[0246] In some embodiments, R 7 is optionally substituted by one or more independently selected from halogen, OR 55 、N(R 55 )(R 56 ) and SR 55 Substituents substituted with C 3-6 In some embodiments, R 7 C 3-6 In some embodiments, R7 C 3-6 Cycloalkyl is selected from cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. 7 C 3-6 Cycloalkyl is selected from cyclopropyl, cyclobutyl and cyclopentyl. 7 C 3-6 Cycloalkyl is cyclopropyl.

[0247] In some embodiments, R 7 is a compound containing 1 to 3 independently selected from O, S, S(O), SO2, N and NR 7” The 3- to 6-membered heterocycloalkyl of the hetero moiety is optionally substituted by one or more independently selected from halogen, OR 55 、N(R 55 )(R 56 ) and SR 55 In some embodiments, R 7 is a compound containing 1 to 3 independently selected from O, S, S(O), SO2, N and NR 7” In some embodiments, R 7 Contains 1 to 2 independently selected from O, S, S(O), SO2, N and NR 7” The 3- to 6-membered heterocycloalkyl of the hetero moiety is selected from aziridinyl, oxiranyl, azetidinyl, oxetanyl, pyrrolidinyl, imidazolidinyl, imidazolinyl, pyrazolinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, thianyl, thianyl oxide, and thianyl dioxide. In some embodiments, R 7 Contains 1 to 2 independently selected from O, S, S(O), SO2, N and NR 7” The 3- to 6-membered heterocycloalkyl of the hetero moiety is selected from azetidinyl, oxetanyl, pyrrolidinyl, imidazolidinyl, imidazolinyl, pyrazolinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, thienyl and dioxythienyl. In some embodiments, R 7 Contains 1 to 2 independently selected from O, S, S(O), SO2, N and NR 7” The 3- to 6-membered heterocycloalkyl group of the hetero moiety is selected from tetrahydropyranyl, thienyl and dioxythienyl.

[0248] In some embodiments, R 7is a compound comprising 1 to 3 independently selected from O, S, N and NR 7” The 5- to 6-membered heteroaryl group of the hetero moiety is optionally substituted by one or more independently selected from halogen, OR 55 、N(R 55 )(R 56 ) and SR 55 In some embodiments, R 7 is a compound comprising 1 to 3 independently selected from O, S, N and NR 7” In some embodiments, R 7 Contains 1 to 3 independently selected from O, S, N and NR 7” The 5- to 6-membered heteroaryl of the hetero moiety is selected from pyrrolyl, furanyl, imidazolyl, oxazolyl, isoxazolyl, isothiazolyl, thiazolyl, pyrazolyl, thiophenyl, pyrazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl and triazinyl. In some embodiments, R 7 Contains 1 to 3 independently selected from O, S, N and NR 7” The 5- to 6-membered heteroaryl of the hetero portion is selected from pyrrolyl, imidazolyl, oxazolyl, isoxazolyl, isothiazolyl, thiazolyl, pyrazolyl, phenylthio, pyrazolyl and pyridinyl.

[0249] In some embodiments, R 7 Selected from C 2-6 Alkenyl and C 2-6 Alkynyl, which are optionally substituted by one or more independently selected from halo, OR 55 、N(R 55 )(R 56 ) and SR 55 In some embodiments, R 7 Selected from C 2-4 Alkenyl and C 2-4 Alkynyl, which are optionally substituted by one or more independently selected from halo, OR 55 、N(R 55 )(R 56 ) and SR 55 wherein all available hydrogen atoms are optionally and independently replaced by fluorine atoms or deuterium atoms.

[0250] In some embodiments, R 7 C 2-4 alkenyl, which is optionally substituted by one or more independently selected from halo, OR55 、N(R 55 )(R 56 ) and SR 55 In some embodiments, R 7 C 2-4 Alkenyl groups wherein all available hydrogen atoms are optionally and independently substituted with fluorine atoms or deuterium atoms.

[0251] In some embodiments, R 7 C 2-4 Alkynyl, which is optionally substituted by one or more independently selected from halo, OR 55 、N(R 55 )(R 56 ) and SR 55 In some embodiments, R 7 C 2-4 In some embodiments, R 7 is selected from C≡CH, C≡CCH3, CH2C≡CH, C≡CCH2CH3, CH2C≡CCH3. In some embodiments, R 7 CH2C≡CH.

[0252] In some embodiments, R 7 Selected from H and C 1-4 Alkyl, where C 1-4 The alkyl group is optionally substituted by one or more independently selected from halo, OR 55 、N(R 55 )(R 56 ) and SR 55 Substituents substituted, and / or C 1-4 The alkyl group is optionally substituted by one to three independently selected from O, C(O), CO2 and NR 57 In some embodiments, R 7 Selected from H and C 1-4 Alkyl, where C 1-4 The alkyl group is optionally substituted by one to three independently selected from F, Cl, OR 55 、N(R 55 )(R 56 ) and SR 55 Substituents substituted, and / or C 1-4 The alkyl group is optionally substituted by one to three independently selected from O, C(O), CO2 and NR 57The hetero moiety is interrupted by , and wherein all available hydrogen atoms are optionally and independently replaced by fluorine atoms or deuterium atoms.

[0253] In some embodiments, R 7 Selected from H and C 1-4 Alkyl, where C 1-4 The alkyl group is optionally substituted by one to three independently selected from F, Cl, OR 55 、N(R 55 )(R 56 ) and SR 55 In some embodiments, R 7 Selected from H and C 1-4 Alkyl, where C 1-4 Alkyl is optionally substituted OR 55 , and wherein all available hydrogen atoms are optionally and independently replaced by fluorine atoms or deuterium atoms.

[0254] In some embodiments, R 7 Selected from H and C 1-4 Alkyl, where C 1-4 The alkyl group is optionally substituted by one to three independently selected from O, C(O), CO2 and NR 57 In some embodiments, R 7 Selected from H and C 1-4 Alkyl, where C 1-4 The alkyl group is optionally interrupted by O, and wherein all available hydrogen atoms are optionally and independently substituted by fluorine atoms or deuterium atoms.

[0255] In some embodiments, R 7 Selected from H and C 1-4 In some embodiments, R 7 Selected from H, D, C 1-4 Alkyl, C 1-4 Fluoroalkyl and C 1-4 In some embodiments, R 7 is selected from the group consisting of H, D, CH3, CD2H, CDH2, CD3, CF3, CHF2, CH2CH3, CH(CH3)2, CH2CH2D, CH2CD2H, CH(CD3)2, and CD2CD3. In some embodiments, R 7 is selected from the group consisting of H, CH3, CD3, CF2H, CF3 and CH(CH3)2. In some embodiments, R 7is selected from H, CH3, CD3, CF2H and CF3. In some embodiments, R 7 is selected from the group consisting of H, CH3, CD3 and CH(CH3)2. 7 is selected from H, CH3 and CD3. In some embodiments, R 7 For H.

[0256] In some embodiments, R 1 For R 7 Therefore, in some embodiments, R 1 Selected from H and C 1-4 In some embodiments, R 1 Selected from H, D, C 1-4 Alkyl, C 1-4 Fluoroalkyl and C 1-4 In some embodiments, R 1 is selected from the group consisting of H, D, CH3, CD2H, CDH2, CD3, CF3, CHF2, CH2CH3, CH(CH3)2, CH2CH2D, CH2CD2H, and CD2CD3. In some embodiments, R 7 is H, D, CH3, CD3, CF3, CH2CH3 and CH(CH3)2, and R 1 is selected from the group consisting of H, D, CH3, CD3, CF3, CH2CH3, CH(CD3)2 and CH(CH3)2. 1 is selected from the group consisting of H, CH3, CD3, CF2H, CF3 and CH(CH3)2. In some embodiments, R 1 is selected from H, CH3, CD3, CF2H and CF3. In some embodiments, R 1 is selected from the group consisting of H, CH3, CD3 and CH(CH3)2. 1 For R 7 , and R 7 is selected from the group consisting of H, CH3, CD3 and CH(CH3)2. 1 is selected from H, CH3 and CD3. In some embodiments, R 1 is selected from CH3 and CD3. In some embodiments, when R 1 For R 7 , and R 7 When H, R 1 is H. Therefore, in some embodiments, R 1 For H.

[0257] In some embodiments, R 7”Selected from H and C 1-4 In some embodiments, R 7” Selected from H, D, C 1-4 Alkyl, C 1-4 Fluoroalkyl and C 1-4 In some embodiments, R 7” is selected from the group consisting of H, D, CH3, CD2H, CDH2, CD3, CF3, CHF2, CH2CH3, CH(CH3)2, CH2CH2D, CH2CD2H, and CD2CD3. In some embodiments, R 7” is selected from H, CH3, CD3, CF2H and CF3. In some embodiments, R 7” Selected from H, CH3 and CD3.

[0258] In some embodiments, R 2 , R 2’ and R 2” are independently selected from H, halo, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-3 Alkylene N(R 2a )(R 2b ) and SC 1-4 In some embodiments, R 2 , R 2’ and R 2” Independently selected from H, D, F, Cl, C 1-4 Alkyl, C 1-4 Fluoroalkyl, C 1-4 Deuterated alkyl, C 1-4 Alkoxy, C 1-4 Fluoroalkoxy, C 1-4 Deuterated alkoxy, C 1-3 Alkylene N(R 2a )(R 2b ), C 1-3 Fluoroalkylene N(R 2a )(R 2b ), C 1-3 Deuterated alkylene N(R 2a )(R 2b ), SC 1-4 Alkyl, SC 1-4 Fluoroalkyl and SC 1-4 In some embodiments, R 2 , R 2’ and R 2” Independently selected from H, D, F, Cl, C 1-4 Alkyl, C1-4 Fluoroalkyl, C 1-4 Deuterated alkyl, C 1-4 Alkoxy, C 1-4 Fluoroalkoxy, C 1-4 Deuterated alkoxy, C 1-3 Alkylene N(R 2a )(R 2b ), SC 1-4 Alkyl, SC 1-4 Fluoroalkyl and SC 1-4 Deuterated alkyl.

[0259] In some embodiments, R 2 , R 2’ and R 2” independently selected from H, D, F, Cl, Br, CH3, CD2H, CDH2, CD3, CF3, CHF2, CH2CH3, CH(CH3)2, CH2CH2D, CH2CD2H, CD2CD3, CH3O, CD2HO, CDH2O, CD3O, CF3O, CHF2O, CH2CH3O, CH(CH3)2O, CHD2CH2O, CD2HCH2O and CD3CD2O, C1-2 alkylene N(R 2a )(R 2b ), C 1-2 Fluoroalkylene N(R 2a )(R 2b ), C 1-2 Deuterated alkylene N(R 2a )(R 2b ), CH3S, CD2HS, CDH2S, CD3S, CF3S, CHF2S, CH2CH3S, CH(CH3)2S, CHD2CH2S, CD2HCH2S and CD3CD2S. In some embodiments, R 2 , R 2’ and R 2” Independently selected from H, D, F, Cl, Br, CH3, CD2H, CDH2, CD3, CF3, CHF2, CH2CH3, CH(CH3)2, CH2CH2D, CH2CD2H, CD2C D3, CH3O, CD2HO, CDH2O, CD3O, CF3O, CHF2O, CH2CH3O, CH(CH3)2O, CHD2CH2O, CD2HCH2O and CD3CD2O, C 1-2 Alkylene N(R 2a )(R 2b), CH3S, CD2HS, CDH2S, CD3S, CF3S, CHF2S, CH2CH3S, CH(CH3)2S, CHD2CH2S, CD2HCH2S and CD3CD2S.

[0260] In some embodiments, R 2 , R 2’ and R 2” is independently selected from H, D, F, CH3, CD2H, CDH2, CD3, CF3, CHF2, CH2CH3, CH(CH3)2, CH2CH2D, CH2CD2H, CD2CD3, CH3O, CD2HO, CDH2O, CD3O, CF3O, CHF2O, CH2CH3O, CH(CH3)2O, CHD2CH2O, CD2HCH2O, CD3CD2O, CH3S, CD2HS, CDH2S, CD3S, CF3S, CHF2S, CH2CH3S, CH(CH3)2S, CHD2CH2S, CD2HCH2S, and CD3CD2S. In some embodiments, R 2 , R 2’ and R 2” Independently selected from H, D, CH3S, CD2HS, CDH2S, CD3S, CF3S, CHF2S, CH2CH3S, CH(CH3)2S, CHD2CH2S, CD2HCH2S and CD3CD2S.

[0261] In some embodiments, R 2 , R 2’ and R 2” Independently selected from H, D, F, C 1-2 Alkylene N(R 2a )(R 2b ), C 1-2 Fluoroalkylene N(R 2a )(R 2b ) and C 1-2 Deuterated alkylene N(R 2a )(R 2b ).

[0262] In some embodiments, R 2 , R 2’ and R 2” Independently selected from H, D, F, Cl, C 1-4 Alkyl, C 1-4 Fluoroalkyl, C 1-4 Deuterated alkyl, C 1-4 Alkoxy, C 1-4 Fluoroalkoxy and C 1-4 In some embodiments, R 2, R 2’ and R 2” Independently selected from H, D, F, Cl, C 1-4 Alkyl, C 1-4 Fluoroalkyl, C 1-4 Deuterated alkyl, C 1-4 Alkoxy, C 1-4 Fluoroalkoxy and C 1-4 In some embodiments, R 2 , R 2’ and R 2” Independently selected from H, D, F, CH3, CD2H, CDH2, CD3, CF3, CHF2, CH2CH3, CH(CH3)2, CH2CH2D, CH2CD2H, CD2CD3, CH3O, CD2HO, CDH2O, CD3O, CF3O, CHF2O, CH2CH3O, CH(CH3)2O, CHD2CH2O, CD2HCH2O and CD3CD2O.

[0263] In some embodiments, R 2 , R 2’ and R 2” is independently selected from H, F, D, CH3O, CD2HO, CDH2O, CD3O, CF3O, CHF2O, CH2CH3O, CH(CH3)2O, CH2DCH2O, CD2HCH2O, and CD3CD2O. In some embodiments, R 2 , R 2’ and R 2” Independently selected from H, D, F, CH3O, CD3O, CF2HO and CF3O.

[0264] In some embodiments, R 2 , R 2’ and R 2” is independently selected from H, D, F, CH3, CD2H, CDH2, CD3, CF3, CHF2, CH2CH3, CH(CH3)2, CH2CH2D, CH2CD2H and CD2CD3. In some embodiments, R 2 , R 2’ and R 2” is independently selected from H, D, F, CH3, CD2H, CDH2, CD3, CF3, CHF2, CH2CH3 and CH(CH3)2. In some embodiments, R 2 , R 2’ and R 2” is independently selected from H, F, D, CH3, CD3, CF2H and CF3. 2 , R 2’ and R2” Independently selected from H, F, D, CH3 and CD3.

[0265] In some embodiments, R 2” is selected from the group consisting of H, F, D, CH3, CD3, CF2H and CF3. 2” is selected from H, D or F. In some embodiments, R 2” is selected from H or F. In some embodiments, R 2” For H.

[0266] In some embodiments, R 2 and R 2’ is independently selected from H, F, D, CH3, CD3, CF2H and CF3. 2 and R 2’ are independently selected from H, D or F. In some embodiments, R 2 and R 2’ Both are H, or R 2 and R 2’ Both are D. In some embodiments, R 2 and R 2’ Both are H.

[0267] In some embodiments, R 2 , R 2’ and R 2” are independently H, D or F. In some embodiments, R 2 , R 2’ and R 2” All are H or all are D. In some embodiments, R 2 , R 2’ and R 2” All are H.

[0268] In some embodiments, R 2a and R 2b Independently selected from H and C 1-4 In some embodiments, R 2a and R 2b Independently selected from H, D, C 1-4 Alkyl, C 1-4 Fluoroalkyl and C 1-4 In some embodiments, R 2a and R 2bis independently selected from H, D, CH3, CD2H, CDH2, CD3, CF3, CHF2, CH2CH3, CH(CH3)2, CH2CH2D, CH2CD2H and CD2CD3. In some embodiments, R 2a and R 2b is independently selected from H, CH3, CD3, CF2H and CF3. In some embodiments, R 2a and R 2b Independently selected from H, CH3 and CD3.

[0269] In some embodiments, R 3 , R 4 , R 5 and R 6 are independently selected from H, halo, N(R 5’ )(R 6’ ), C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylene N(R 5’ )(R 6’ ) and SC 1-4 Alkyl, the last four groups are optionally replaced by one or two selected from OH and C 1-4 In some embodiments, R 3 , R 4 , R 5 and R 6 independently selected from H, D, F, Cl, Br, N(R 5’ )(R 6’ ), C 1-4 Alkyl, C 1-4 Fluoroalkyl, C 1-4 Deuterated alkyl, C 1-4 Alkoxy, C 1-4 Fluoroalkoxy, C 1-4 Deuterated alkoxy, C 1-4 Alkylene N(R 5’ )(R 6’ ), C 1-4 Deuterated alkylene N(R 5’ )(R 6’ ), C 1-4 Fluoroalkylene N(R 5’ )(R 6’ ), SC 1-4 Alkyl, SC 1-4 Fluoroalkyl and SC 1-4 Deuterated alkyl, the last twelve groups are optionally replaced by one or two selected from OH, C 1-4 Alkoxy, C 1-4Fluoroalkoxy and C 1-4 In some embodiments, R 3 , R 4 , R 5 and R 6 independently selected from H, D, F, Cl, Br, N(R 5’ )(R 6’ ), C 1-4 Alkyl, C 1-4 Fluoroalkyl, C 1-4 Deuterated alkyl, C 1-4 Alkoxy, C 1-4 Fluoroalkoxy, C 1-4 Deuterated alkoxy, C 1-4 Alkylene N(R 5’ )(R 6’ ), SC 1-4 Alkyl, SC 1-4 Fluoroalkyl and SC 1-4 Deuterated alkyl, the last ten groups are optionally replaced by one or two selected from OH, C 1-4 Alkoxy, C 1-4 Fluoroalkoxy and C 1-4 The substituents of the deuterated alkoxy group are substituted.

[0270] In some embodiments, R 3 , R 4 , R 5 and R 6 independently selected from H, D, F, Cl, Br, N(R 5’ )(R 6’ ), C 1-4 Alkyl, C 1-4 Fluoroalkyl, C 1-4 Deuterated alkyl, C 1-4 Alkylene N(R 5’ )(R 6’ ), SC 1-4 Alkyl, SC 1-4 Fluoroalkyl and SC 1-4 Deuterated alkyl, the last seven groups are optionally replaced by one or two selected from OH, C 1-4 Alkoxy, C 1-4 Fluoroalkoxy and C 1-4 In some embodiments, R 3 , R 4 , R 5 and R 6 Independently selected from H, D, N(R 5’ )(R 6’ ), C 1-4 Alkyl, C 1-4 Fluoroalkyl, C 1-4Deuterated alkyl, C 1-4 Alkylene N(R 5’ )(R 6’ ), SC 1-4 Alkyl, SC 1-4 Fluoroalkyl and SC 1-4 Deuterated alkyl.

[0271] In some embodiments, R 3 , R 4 , R 5 and R 6 independently selected from H, D, F, Cl, Br, N(R 5’ )(R 6’ ), C 1-4 Alkyl, C 1-4 Fluoroalkyl, C 1-4 Deuterated alkyl and C 1-4 Alkylene N(R 5’ )(R 6’ ), the latter four groups are optionally replaced by one or two selected from OH, C 1-4 Alkoxy, C 1-4 Fluoroalkoxy and C 1-4 In some embodiments, R 3 , R 4 , R 5 and R 6 independently selected from H, D, F, Cl, Br, N(R 5’ )(R 6’ ), C 1-4 Alkyl, C 1-4 Fluoroalkyl, C 1-4 Deuterated alkyl and C 1-2 Alkylene N(R 5’ )(R 6’ In some embodiments, R 3 , R 4 , R 5 and R 6 One to three of are independently selected from H, D, F, N (R 5’ )(R 6’ ), CH3, CD2H, CDH2, CD3, CF3, CHF2, CH2CH3, CH(CH3)2, CH2CH2D, CH2CD2H, CD2CD3 and C 1-2 Alkylene N(R 5’ )(R 6’ ), and R 3 , R 4 , R 5 and R 6 The remaining groups in are selected from H and D. In some embodiments, R 3, R 4 , R 5 and R 6 one to three of which are independently selected from H, D, F, N(R 5’ )(R 6’ ), CH3, CD2H, CDH2, CD3, CF3, CHF2, CH2CH3, CH(CH3)2, CH2CH2D, CH2CD2H, CD2CD3 and CH2-alkylene N(R 5’ )(R 6’ ), and the remaining groups of R 3 , R 4 , R 5 and R 6 are selected from H and D. In some embodiments, R 3 , R 4 , R 5 and R 6 are independently selected from H, D, N(R 5’ )(R 6’ ), C 1-4 -alkyl, C 1-4 -fluoroalkyl, C 1-4 -deuterated alkyl and C 1-2 -alkylene N(R 5’ )(R 6’ ). In some embodiments, one to three of R 3 , R 4 , R 5 and R 6 are independently selected from H, D, N(R 5’ )(R 6’ ), CH3, CD2H, CDH2, CD3, CF3, CHF2, CH2CH3, CH(CH3)2, CH2CH2D, CH2CD2H, CD2CD3 and C1-2 alkylene N(R 5’ )(R 6’ ), and the remaining groups of R 3 , R 4 , R 5 and R 6 are selected from H and D.

[0272] In some embodiments, R 3 , R 4 , R 5 and R 6 are independently selected from H, D, F, Cl, Br, C 1-4 -alkyl, C 1-4 -fluoroalkyl, C 1-4 -deuterated alkyl, SC 1-4 -alkyl, SC 1-4 -fluoroalkyl and SC1-4 Deuterated alkyl, the latter six groups are optionally replaced by one or two selected from OH, C 1-4 Alkoxy, C 1-4 Fluoroalkoxy and C 1-4 In some embodiments, R 3 , R 4 , R 5 and R 6 One to three of the following are independently selected from H, D, F, Cl, C 1-3 Alkyl, C 1-3 Fluoroalkyl, C 1-3 Deuterated alkyl, SC 1-3 Alkyl, SC 1-3 Fluoroalkyl and SC 1-3 deuterated alkyl, and R 3 , R 4 , R 5 and R 6 The remaining groups in are selected from H and D. In some embodiments, R 3 , R 4 , R 5 and R 6 One to three of are independently selected from H, D, F, CH3, CD2H, CDH2, CD3, CF3, CHF2, CH2CH3, CH(CH3)2, CH2CH2D, CH2CD2H, CD2CD3, CH3S, CD2HS, CDH2S, CD3S, CF3S, CHF2S, CH2CH3S, CH(CH3)2S, CHD2CH2S, CD2HCH2S and CD3CD2S, and R 3 , R 4 , R 5 and R 6 The remaining groups in are selected from H and D. In some embodiments, R 3 , R 4 , R 5 and R 6 One to three of the following are independently selected from H, D, C 1-3 Alkyl, C 1-3 Fluoroalkyl, C 1-3 Deuterated alkyl, SC 1-3 Alkyl, SC 1-3 Fluoroalkyl and SC 1-3 deuterated alkyl, and R 3 , R 4 , R 5 and R 6 The remaining groups in are selected from H and D. In some embodiments, R 3 , R 4 , R 5 and R6 One to three of are independently selected from H, D, CH3, CD2H, CDH2, CD3, CF3, CHF2, CH2CH3, CH(CH3)2, CH2CH2D, CH2CD2H, CD2CD3, CH3S, CD2HS, CDH2S, CD3S, CF3S, CHF2S, CH2CH3S, CH(CH3)2S, CHD2CH2S, CD2HCH2S and CD3CD2S, and R 3 , R 4 , R 5 and R 6 The remaining groups in are selected from H and D.

[0273] In some embodiments, R 3 , R 4 , R 5 and R 6 are independently selected from H, halo, C 1-4 Alkyl and C 1-4 Alkoxy, the latter two groups are optionally substituted by one or two selected from OH and C 1-4 In some embodiments, R 3 , R 4 , R 5 and R 6 Independently selected from H, D, F, Cl, Br, C 1-4 Alkyl, C 1-4 Fluoroalkyl, C 1-4 Deuterated alkyl, C 1-4 Alkoxy, C 1-4 Fluoroalkoxy and C 1-4 deuterated alkoxy, the latter six groups are optionally substituted by one or two selected from OH, C 1-4 Alkoxy, C 1-4 Fluoroalkoxy and C 1-4 The substituents of the deuterated alkoxy group are substituted.

[0274] In some embodiments, R 3 , R 4 , R 5 and R 6 Independently selected from H, D, F, Cl, Br, C 1-4 Alkoxy, C 1-4 Fluoroalkoxy and C 1-4 Deuterated alkoxy, the last three groups are replaced by one or two selected from OH, C 1-4 Alkoxy, C 1-4 Fluoroalkoxy and C 1-4 In some embodiments, R 3, R 4 , R 5 and R 6 One of the following is selected from C 1-4 Alkoxy, C 1-4 Fluoroalkoxy and C 1-4 Deuterated alkoxy groups, these groups are replaced by one or two selected from OH, C 1-4 Alkoxy, C 1-4 Fluoroalkoxy and C 1-4 The substituent of deuterated alkoxy is substituted, and R 3 , R 4 , R 5 and R 6 The remaining groups in are independently selected from H, D, F, Cl, Br, C 1-4 Alkoxy, C 1-4 Fluoroalkoxy and C 1-4 In some embodiments, R 3 , R 4 , R 5 and R 6 One of the following is selected from C 1-3 Alkoxy, C 1-3 Fluoroalkoxy and C 1-3 Deuterated alkoxy groups, these groups are replaced by one or two selected from OH, C 1-3 Alkoxy, C 1-3 Fluoroalkoxy and C 1-3 The substituent of deuterated alkoxy is substituted, and R 3 , R 4 , R 5 and R 6 The remaining groups in are independently selected from H, D, CH3O, CD3O and CF3O. In some embodiments, R 3 and R 4 One of the following is selected from C 1-3 Alkoxy, C 1-3 Fluoroalkoxy and C 1-3 Deuterated alkoxy groups, these groups are replaced by one or two selected from OH, C 1-3 Alkoxy, C 1-3 Fluoroalkoxy and C 1-3 The substituent of deuterated alkoxy is substituted, and R 3 , R 4 , R 5 and R 6 The remaining groups in are independently selected from H, D, CH3O, CD3O and CF3O. In some embodiments, R 3 and R 4 One of the following is selected from C 1-3 Alkoxy, the C 1-3 Alkoxy is C 1-3Alkoxy substituted, and R 3 , R 4 , R 5 and R 6 The remaining groups in are independently selected from H, D, CH3O, CD3O and CF3O. In some embodiments, R 3 and R 4 One of them is C 1-3 Alkoxy, the C 1-3 The alkoxy group is substituted with a substituent selected from CH3O, CD3O and CF3O, and R 3 , R 4 , R 5 and R 6 The remaining groups in are independently selected from H, D, CH3O, CD3O and CF3O. In some embodiments, R 4 C 1-3 Alkoxy, the C 1-3 The alkoxy group is substituted with a substituent selected from CH3O, CD3O and CF3O, and R 3 , R 5 and R 6 The remaining groups in are independently selected from H, D, CH3O, CD3O and CF3O.

[0275] In some embodiments, R 3 , R 4 , R 5 and R 6 Independently selected from H, D, F, Cl, Br, C 1-4 Alkyl, C 1-4 Fluoroalkyl, C 1-4 Deuterated alkyl, C 1-4 Alkoxy, C 1-4 Fluoroalkoxy and C 1-4 In some embodiments, R 3 , R 4 , R 5 and R 6 One to three of the following are independently selected from H, D, F, Cl, C 1-3 Alkyl, C 1-3 Fluoroalkyl, C 1-3 Deuterated alkyl, C 1-3 Alkoxy, C 1-4 Fluoroalkoxy and C 1-4 deuterated alkoxy, and R 3 , R 4 , R 5 and R 6 The remaining groups in are selected from H and D.

[0276] In some embodiments, R 3, R 4 , R 5 and R 6 One to three of are independently selected from H, D, F, Cl, Br, CH3, CD2H, CDH2, CD3, CF3, CHF2, CH2CH3, CH(CH3)2, CH2CH2D, CH2CD2H, CD2CD3, CH3O, CD2HO, CDH2O, CD3O, CF3O, CHF2O, CH3CH2O, CH(CH3)2O, CH2DCH2O, CD2HCH2O and CD3CD2O, and R 3 , R 4 , R 5 and R 6 The remaining groups in are selected from H and D.

[0277] In some embodiments, R 3 , R 4 , R 5 and R 6 One to three of are independently selected from H, D, F, CH3O, CD2HO, CDH2O, CD3O, CF3O, CHF2O, CH2CH3O, CH(CH3)2O, CH2DCH2O, CD2HCH2O and CD3CD2O, and R 3 , R 4 , R 5 and R 6 The remaining groups in are selected from H and D.

[0278] In some embodiments, R 3 , R 4 , R 5 and R 6 One to three of them are F, and R 3 , R 4 , R 5 and R 6 The remaining groups in are independently selected from H and D. In some embodiments, R 3 , R 4 , R 5 and R 6 One or both of them are F, and R 3 , R 4 , R 5 and R 6 The remaining groups in are independently selected from H and D. In some embodiments, R 3 and R 4 One of them is F, and R 3 , R 4 , R 5 and R 6The remaining groups in are independently selected from H and D.

[0279] In some embodiments, R 3 , R 4 , R 5 and R 6 One to three of are independently selected from CH3O, CD2HO, CDH2O, CD3O, CF3O, CHF2O, CH2CH3O, CH(CH3)2O, CH2DCH2O, CD2HCH2O and CD3CD2O, and R 3 , R 4 , R 5 and R 6 The remaining groups in are independently selected from H and D. In some embodiments, R 3 , R 4 , R 5 and R 6 One to three of are independently selected from CH3O, CD2HO, CDH2O, CD3O, CF3O and CHF2O, and R 3 , R 4 , R 5 and R 6 The remaining groups in are independently selected from H and D. In some embodiments, R 3 , R 4 , R 5 and R 6 One or two of are independently selected from CH3O, CD2HO, CDH2O, CD3O, CF3O and CHF2O, and R 3 , R 4 , R 5 and R 6 The remaining groups in are independently selected from H and D.

[0280] In some embodiments, R 4 and R 5 One or both R 4 R 5 is independently selected from H, F, CH3O, CD2HO, CDH2O, CD3O, CF3O, CHF2O, CH2CH3O, CH(CH3)2O, CH2DCH2O, CD2HCH2O and CD3CD2O, and R 3 , R 4 , R 5 and R 6 The remaining groups in are selected from H and D. In some embodiments, R 4 and R 5One or two of are independently selected from CH3O, CD2HO, CDH2O, CD3O, CF3O, CHF2O, CH2CH3O, CH(CH3)2O, CH2DCH2O, CD2HCH2O and CD3CD2O, and R 3 , R 4 , R 5 and R 6 The remaining groups in are selected from H and D. In some embodiments, R 4 and R 5 One or two of are independently selected from OCH3, OCD2H, OCDH2, OCD3, OCF3 and OCHF2, and R 3 , R 4 , R 5 and R 6 The remaining groups in are independently selected from H and D. In some embodiments, R 4 and R 5 Two of are independently selected from OCH3, OCD2H, OCDH2, OCD3, OCF3 and OCHF2, and R 3 and R 6 Independently selected from H and D.

[0281] In some embodiments, R 3 , R 4 , R 5 and R 6 is independently selected from H, D, F, CH3, CD2H, CDH2, CD3, CF3, CHF2, CH2CH3, CH(CH3)2, CH2CH2D, CH2CD2H and CD2CD3, and R 3 , R 4 , R 5 and R 6 The remaining groups in are independently selected from H and D. In some embodiments, R 3 , R 4 , R 5 and R 6 One or two of are independently selected from CH3, CD2H, CDH2, CD3, CF3, CHF2, CH2CH3, CH(CH3)2, CH2CH2D, CH2CD2H and CD2CD3, and R 3 , R 4 , R 5 and R 6 The remaining groups in are independently selected from H and D. In some embodiments, R 4 and R 5One or two of are independently selected from CH3, CD2H, CDH2, CD3, CF3, CHF2, CH2CH3, CH(CH3)2, CH2CH2D, CH2CD2H and CD2CD3, and R 3 , R 4 , R 5 and R 6 The remaining groups in are independently selected from H and D. In some embodiments, R 3 , R 4 , R 5 and R 6 is selected from H and D. In some embodiments, R 3 , R 4 , R 5 and R 6 All D or R 3 , R 4 , R 5 and R 6 All are H.

[0282] In some embodiments, R 3 and R 6 Independently selected from H, D, Cl, F, C 1-4 Alkyl, C 1-4 Fluoroalkyl and C 1-4 In some embodiments, R 3 and R 6 Independently selected from H, D, Cl, F, C 1-2 Alkyl, C 1-2 Fluoroalkyl and C 1-2 In some embodiments, R 3 and R 6 is independently selected from H, D, F, Cl, Br, CH3, CD2H, CDH2, CD3, CF3 and CHF2. In some embodiments, R 3 and R 6 is independently selected from H, D, F, CH3, CF3 and CD3. 3 and R 6 are independently selected from H and D. In some embodiments, R 3 and R 6 At least one of is D. In some embodiments, R 3 and R 6 Each of is D. In some embodiments, R 3 and R 6 Each of them is H.

[0283] In some embodiments, R 4 and R 5One or both R 4 R 5 Independently selected from H, D, F, Cl, C 1-6 Alkyl, C 1-6 Fluoroalkyl, C 1-6 Deuterated alkyl, C 1-6 Alkoxy, C 1-6 Fluoroalkoxy and C 1-6 In some embodiments, R 4 and R 5 One or two of are independently selected from H, D, F, Cl, CH3, CF3, CF2H, CD3, CH3O, CF3O, CHF2O and CD3O.

[0284] In some embodiments, R 4 and R 5 Two of them are independently selected from D, F, Cl, C 1-6 Alkyl, C 1-6 Fluoroalkyl, C 1-6 Deuterated alkyl, C 1-6 Alkoxy, C 1-6 Fluoroalkoxy and C 1-6 In some embodiments, R 4 and R 5 Two of the above are independently selected from D, F, Cl, CH3, CF3, CF2H, CD3, CH3O, CF3O, CHF2O and CD3O.

[0285] In some embodiments, R 4 is H or D, and R 5 Selected from H, D, F, Cl, C 1-6 Alkyl, C 1-6 Fluoroalkyl, C 1-6 Deuterated alkyl, C 1-6 Alkoxy, C 1-6 Fluoroalkoxy and C 1-6 In some embodiments, R 4 is H or D, and R 5 Selected from D, F, Cl, CH3, CF3, CF2H, CD3, CH3O, CF3O, CHF2O and CD3O.

[0286] In some embodiments, R 5 is H or D, and R 4 Selected from H, D, F, Cl, C 1-6 Alkyl, C 1-6 Fluoroalkyl, C 1-6 Deuterated alkyl, C 1-6 Alkoxy, C 1-6 Fluoroalkoxy and C1-6 In some embodiments, R 5 is H or D, and R 4 Selected from D, F, Cl, CH3, CF3, CF2H, CD3, CH3O, CF3O, CHF2O and CD3O.

[0287] In some embodiments, R 3 , R 4 , R 5 and R 6 Two adjacent groups in the bond together to form O-(CH2) 1-2 O, and R 3 , R 4 , R 5 and R 6 The remaining groups in are independently selected from H, halogen, C 1-4 Alkyl, C 1-4 Alkoxy, N(R 5’ )(R 6’ ), C 1-4 Alkylene N(R 5’ )(R 6’ ) and SC 1-4 In some embodiments, R 3 , R 4 , R 5 and R 6 Two adjacent groups in the bond together to form O-(CH2) 1-2 O, and R 3 , R 4 , R 5 and R 6 The remaining groups in are independently selected from H, F, Cl, Br, C 1-4 Alkyl, C 1-4 Fluoroalkyl, C 1-4 Deuterated alkyl, C 1-4 Alkoxy, C 1-4 Fluoroalkoxy, C 1-4 Deuterated alkoxy, N(R 5’ )(R 6’ ), C 1-4 Alkylene N(R 5’ )(R 6’ ), C 1-4 Deuterated alkylene N(R 5’ )(R 6’ ), C 1-4 Fluoroalkylene N(R 5’ )(R 6’ ), SC 1-4 Alkyl, SC 1-4Fluoroalkyl and SC 1-4 In some embodiments, R 3 , R 4 , R 5 and R 6 Two adjacent groups in the bond together to form O-(CH2) 1-2 O, and R 3 , R 4 , R 5 and R 6 The remaining groups in are independently selected from H, F, Cl, Br, C 1-4 Alkyl, C 1-4 Fluoroalkyl, C 1-4 Deuterated alkyl, C 1-4 Alkoxy, C 1-4 Fluoroalkoxy, C 1-4 Deuterated alkoxy, N(R 5’ )(R 6’ ), C 1-4 Alkylene N(R 5’ )(R 6’ ), SC 1-4 Alkyl, SC 1-4 Fluoroalkyl and SC 1-4 Deuterated alkyl.

[0288] In some embodiments, R 3 , R 4 , R 5 and R 6 Two adjacent groups in the bond together to form O-(CH2) 1-2 O, and R 3 , R 4 , R 5 and R 6 The remaining groups in are independently selected from H, D, F, Cl, Br, C 1-4 Alkyl, C 1-4 Fluoroalkyl, C 1-4 Deuterated alkyl, N(R 5’ )(R 6’ ) and C 1-4 Alkylene N(R 5’ )(R 6’ In some embodiments, R 3 , R 4 , R 5 and R 6 Two adjacent groups in the bond together to form O-(CH2) 1-2 O, and R 3 , R 4 , R 5 and R 6The remaining groups in are independently selected from H, D, F, Cl, Br, C 1-4 Alkyl, C 1-4 Fluoroalkyl, C 1-4 Deuterated alkyl, N(R 5’ )(R 6’ ) and C 1-2 Alkylene N(R 5’ )(R 6’ In some embodiments, R 3 , R 4 , R 5 and R 6 Two adjacent groups in the bond together to form O-(CH2) 1-2 O, and R 3 , R 4 , R 5 and R 6 The remaining groups in are independently selected from H, D, F, CH3, CD2H, CDH2, CD3, CF3, CHF2, CH2CH3, CH(CH3)2, CH2CH2D, CH2CD2H, CD2CD3, N(R 5’ )(R 6’ ) and CH2 alkylene N(R 5’ )(R 6’ In some embodiments, R 4 and R 5 connected together to form O-(CH2)O, and R 3 and R 6 independently selected from H, D, F, CH3, CD2H, CDH2, CD3, CF3, CHF2, CH2CH3, CH(CH3)2, CH2CH2D, CH2CD2H, CD2CD3, N(R 5’ )(R 6’ ) and CH2 alkylene N(R 5’ )(R 6’ ).

[0289] In some embodiments, R 3 , R 4 , R 5 and R 6 Two adjacent groups in the bond together to form O-(CH2) 1-2 O, and R 3 , R 4 , R 5 and R 6 The remaining groups in are independently selected from H, D, F, Cl, Br, C 1-4 Alkyl, C 1-4 Fluoroalkyl, C 1-4 Deuterated alkyl, SC1-4 Alkyl, SC 1-4 Fluoroalkyl and SC 1-4 In some embodiments, R 3 , R 4 , R 5 and R 6 Two adjacent groups in the bond together to form O-(CH2) 1-2 O, and R 3 , R 4 , R 5 and R 6 The remaining groups in are independently selected from H, D, F, Cl, C 1-3 Alkyl, C 1-3 Fluoroalkyl, C 1-3 Deuterated alkyl, SC 1-3 Alkyl, SC 1-3 Fluoroalkyl and SC 1-3 In some embodiments, R 3 , R 4 , R 5 and R 6 Two adjacent groups in the bond together to form O-(CH2) 1-2 O, and R 3 , R 4 , R 5 and R 6 The remaining groups in are independently selected from H, D, F, CH3, CD2H, CDH2, CD3, CF3, CHF2, CH2CH3, CH(CH3)2, CH2CH2D, CH2CD2H, CD2CD3, CH3S, CD2HS, CDH2S, CD3S, CF3S, CHF2S, CH2CH3S, CH(CH3)2S, CHD2CH2S, CD2HCH2S and CD3CD2S. In some embodiments, R 4 and R 5 connected together to form O-(CH2)O, and R 3 and R 6 Independently selected from H, D, F, CH3, CD2H, CDH2, CD3, CF3, CHF2, CH2CH3, CH(CH3)2, CH2CH2D, CH2CD2H, CD2CD3, CH3S, CD2HS, CDH2S, CD3S, CF3S, CHF2S, CH2CH3S, CH(CH3)2S, CHD2CH2S, CD2HCH2S and CD3CD2S.

[0290] In some embodiments, R 5’ and R 6’ Independently selected from H and C 1-4In some embodiments, R 5’ and R 6’ Independently selected from H, D, C 1-4 Alkyl, C 1-4 Fluoroalkyl and C 1-4 In some embodiments, R 5’ and R 6’ is independently selected from H, D, CH3, CD2H, CDH2, CD3, CF3, CHF2, CH2CH3, CH(CH3)2, CH2CH2D, CH2CD2H and CD2CD3. In some embodiments, R 5’ and R 6’ is independently selected from H, CH3, CD3, CF2H and CF3. 5’ and R 6’ Independently selected from H, CH3 and CD3.

[0291] In some embodiments, R 3 , R 4 , R 5 and R 6 Two adjacent groups in the bond together to form O-(CH2) 1-2 O, and R 3 , R 4 , R 5 and R 6 The remaining groups in are independently selected from H, halogen, C 1-6 Alkyl and C 1-6 Alkoxy, wherein all available hydrogen atoms are optionally and independently substituted by fluorine atoms or deuterium atoms. 3 , R 4 , R 5 and R 6 Two adjacent groups in the bond together to form O-(CH2) 1-2 O, and R 3 , R 4 , R 5 and R 6 The remaining groups in are independently selected from H, halogen, C 1-4 Alkyl and C 1-4 Alkoxy, wherein all available hydrogen atoms are optionally and independently substituted by fluorine atoms or deuterium atoms. 3 , R 4 , R 5 and R 6 Two adjacent groups in the bond together to form O-(CH2) 1-2 O, and R 3 , R4 , R 5 and R 6 The remaining groups in are independently selected from H, F, Cl, Br, C 1-4 Alkyl, C 1-4 Fluoroalkyl, C 1-4 Deuterated alkyl, C 1-4 Alkoxy, C 1-4 Fluoroalkoxy and C 1-4 In some embodiments, R 3 , R 4 , R 5 and R 6 The two adjacent groups in the 3 , R 4 , R 5 and R 6 The remaining groups in are independently selected from H, D, F, Cl, Br, CH3, CD2H, CDH2, CD3, CF3, CHF2, CH2CH3, CH(CH3)2, CH2CH2D, CH2CD2H, CD2CD3, CH3O, CD2HO, CDH2O, CD3O, CF3O, CHF2O, CH3CH2O, CH(CH3)2O, CH2DCH2O, CD2HCH2O and CD3CD2O.

[0292] In some embodiments, R 4 and R 5 connected together to form O-(CH2)O, and R 3 and R 6 Independently selected from H, F, Cl, Br, C 1-4 Alkyl, C 1-4 Fluoroalkyl, C 1-4 Deuterated alkyl, C 1-4 Alkoxy, C 1-4 Fluoroalkoxy and C 1-4 In some embodiments, R 4 and R 5 connected together to form O-(CH2)O, and R 3 and R 6 is independently selected from H, D, F, Cl, Br, CH3, CD2H, CDH2, CD3, CF3, CHF2, CH2CH3, CH(CH3)2, CH2CH2D, CH2CD2H, CD2CD3, CH3O, CD2HO, CDH2O, CD3O, CF3O, CHF2O, CH3CH2O, CH(CH3)2O, CH2DCH2O, CD2HCH2O, and CD3CD2O. In some embodiments, R 4 and R5 connected together to form O-(CH2)O, and R 3 and R 6 is independently selected from H, D, F, CH3O, CD2HO, CDH2O, CD3O, CF3O, and CHF2O. In some embodiments, R 4 and R 5 connected together to form O-(CH2)O, and R 3 and R 6 Both are H, or R 3 and R 6 Both are D. In some embodiments, R 4 and R 5 connected together to form O-(CH2)O, and R 3 and R 6 Both are H.

[0293] In some embodiments, R 4 and R 5 Connect together to form O-CH2O.

[0294] In some embodiments, R 3 , R 4 , R 5 and R 6 One of A, OA and C 1-2 Alkylene A, and R 3 , R 4 , R 5 and R 6 The remaining groups in are independently H or halo, wherein all available hydrogen atoms are optionally and independently substituted by fluorine atoms or deuterium atoms. 3 , R 4 , R 5 and R 6 One of A, OA and C 1-2 Alkylene A, and R 3 , R 4 , R 5 and R 6 The remaining groups in are independently H, F, Br or Cl, wherein all available hydrogen atoms are optionally and independently replaced by fluorine atoms or deuterium atoms. 3 , R 4 , R 5 and R 6 one of which is selected from A, OA, CH2A, CF2A and CD2A, and R 3 , R 4 , R 5 and R 6The remaining groups in are independently H, D or F. In some embodiments, R 3 , R 4 , R 5 and R 6 one of which is selected from A, OA, CH2A, CF2A and CD2A, and R 3 , R 4 , R 5 and R 6 The remaining groups in are independently selected from H and D.

[0295] In some embodiments, R 3 , R 4 and R 5 One of A, OA and C 1-2 Alkylene A, and R 3 , R 4 , R 5 and R 6 The remaining groups in are independently H or halo, wherein all available hydrogen atoms are optionally and independently substituted by fluorine atoms or deuterium atoms. 3 , R 4 and R 5 one of which is selected from A, OA, CH2A, CF2A and CD2A, and R 3 , R 4 , R 5 and R 6 The remaining groups in are independently selected from H, F, Cl, Br, D and F. In some embodiments, R 3 , R 4 and R 5 one of which is selected from A, OA, CH2A, CF2A and CD2A, and R 3 , R 4 , R 5 and R 6 The remaining groups in are independently selected from H, D and F.

[0296] In some embodiments, R 4 and R 5 One of A, OA and C 1-2 Alkylene A, and R 4 and R 5 The other of R is H or D, wherein all available hydrogen atoms are optionally and independently replaced by fluorine atoms or deuterium atoms. 4 and R 5 one of which is selected from A, OA, CH2A, CF2A and CD2A, and R 4 and R 5The other of is H or D. In some embodiments, R 4 Selected from A, OA and C 1-2 Alkylene A, and R 5 is H or D, wherein all available hydrogen atoms are optionally and independently substituted by fluorine atoms or deuterium atoms. 4 is selected from A, OA, CH2A, CF2A and CD2A, and R 5 is H or D. In some embodiments, R 5 Selected from A, OA and C 1-2 Alkylene A, and R 4 is H or D, wherein all available hydrogen atoms are optionally and independently substituted by fluorine atoms or deuterium atoms. 5 is selected from A, OA, CH2A, CF2A and CD2A, and R 4 It is H or D.

[0297] In some embodiments, A is selected from phenyl, C 3-6 Cycloalkyl, containing 1 to 3 independently selected from O, S, S(O), SO2, N and NR 54 The heterocyclic alkyl group of the heterocyclic alkyl group is 3-6-membered and contains 1 to 3 independently selected from O, S, S(O), SO2, N and NR 54 phenyl, C 3-10 Cycloalkyl, 3-membered to 6-membered heterocycloalkyl, and 5-membered to 6-membered heteroaryl are optionally substituted with one or two substituents independently selected from the group consisting of F, Cl, Br, C 1-4 Alkyl, C 1-4 Deuterated alkyl, C 1-4 Fluoroalkyl, OC 1-4 Alkyl, OC 1-4 Deuterated alkyl, OC 1-4 Fluoroalkyl, N(R 54a )(R 54b ), C 1-4 Alkylene N(R 54a )(R 54b ), C 1-4 Deuterated alkylene N(R 54a )(R 54b ), C 1-4 Fluoroalkylene N(R 54a )(R 54b ), SC 1-4 Alkyl, SC 1-4 Deuterated alkyl and SC 1-4 In some embodiments, A is selected from phenyl, C 3-6Cycloalkyl, containing 1 to 3 independently selected from O, S, S(O), SO2, N and NR 54 The heterocyclic alkyl group of the heterocyclic alkyl group is 3-6-membered and contains 1 to 3 independently selected from O, S, S(O), SO2, N and NR 54 phenyl, C 3-10 Cycloalkyl, 3-membered to 6-membered heterocycloalkyl, and 5-membered to 6-membered heteroaryl are optionally substituted with one or two substituents independently selected from the group consisting of F, Cl, Br, C 1-4 Alkyl, C 1-4 Deuterated alkyl, C 1-4 Fluoroalkyl, OC 1-4 Alkyl, OC 1-4 Deuterated alkyl, OC 1-4 Fluoroalkyl, N(R 54a )(R 54b ), C 1-4 Alkylene N(R 54a )(R 54b ), SC 1-4 Alkyl, SC 1-4 Deuterated alkyl and SC 1-4 In some embodiments, A is selected from phenyl, C 3-6 Cycloalkyl, containing 1 to 2 independently selected from O, S, S(O), SO2, N and NR 54 The heterocyclic 5- to 6-membered alkyl group of the heterocyclic group and containing 1 to 3 independently selected from O, S, S(O), SO2, N and NR 54 phenyl, C 3-10 Cycloalkyl, 3-membered to 6-membered heterocycloalkyl, and 5-membered to 6-membered heteroaryl are optionally substituted with one or two substituents independently selected from the group consisting of F, Cl, C 1-4 Alkyl, C 1-4 Deuterated alkyl, C 1-4 Fluoroalkyl, OC 1-4 Alkyl, OC 1-4 Deuterated alkyl, OC 1-4 Fluoroalkyl, N(R 54a )(R 54b ), C 1-4 Alkylene N(R 54a )(R 54b ), SC 1-4 Alkyl, SC 1-4 Deuterated alkyl and SC 1-4 Fluoroalkyl.

[0298] In some embodiments, A is phenyl optionally substituted with one or two substituents independently selected from the group consisting of F, Cl, C 1-4 Alkyl, C1-4 Deuterated alkyl, C 1-4 Fluoroalkyl, OC 1-4 Alkyl, OC 1-4 Deuterated alkyl, OC 1-4 Fluoroalkyl, N(R 54a )(R 54b ), C 1-4 Alkylene N(R 54a )(R 54b ), SC 1-4 Alkyl, SC 1-4 Deuterated alkyl and SC 1-4 In some embodiments, A is phenyl optionally substituted with one or two substituents independently selected from the group consisting of F, Cl, C 1-4 Alkyl, C 1-4 Deuterated alkyl, C 1-4 Fluoroalkyl, OC 1-4 Alkyl, OC 1-4 Deuterated alkyl and OC 1-4 Fluoroalkyl.

[0299] In some embodiments, A is C optionally substituted with one or two substituents independently selected from the following 3-6 Cycloalkyl: F, Cl, C 1-4 Alkyl, C 1-4 Deuterated alkyl, C 1-4 Fluoroalkyl, OC 1-4 Alkyl, OC 1-4 Deuterated alkyl, OC 1-4 Fluoroalkyl, N(R 54a )(R 54b ), C 1-4 Alkylene N(R 54a )(R 54b ), SC 1-4 Alkyl, SC 1-4 Deuterated alkyl and SC 1-4 In some embodiments, A is C optionally substituted with one or two substituents independently selected from the following 3-6 Cycloalkyl: F, Cl, C 1-4 Alkyl, C 1-4 Deuterated alkyl, C 1-4 Fluoroalkyl, OC 1-4 Alkyl, OC 1-4 Deuterated alkyl and OC 1-4 In some embodiments, C in A 3-6 Cycloalkyl is selected from cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. 3-6 Cycloalkyl is cyclopropyl.

[0300] In some embodiments, A is a compound comprising 1 to 2 independently selected from O, S, S(O), SO2, N and NR 54 substituted with one or two substituents independently selected from the group consisting of F, Cl, C 1-4 Alkyl, C 1-4 Deuterated alkyl, C 1-4 Fluoroalkyl, OC 1-4 Alkyl, OC 1-4 Deuterated alkyl, OC 1-4 Fluoroalkyl, N(R 54a )(R 54b ), C 1-4 Alkylene N(R 54a )(R 54b ), SC 1-4 Alkyl, SC 1-4 Deuterated alkyl and SC 1-4 In some embodiments, A is a fluoroalkyl radical comprising 1 to 2 radicals independently selected from O, S, S(O), SO2, N, and NR 54 substituted with one or two substituents independently selected from the group consisting of F, Cl, C 1-4 Alkyl, C 1-4 Deuterated alkyl, C 1-4 Fluoroalkyl, OC 1-4 Alkyl, OC 1-4 Deuterated alkyl and OC 1-4 In some embodiments, A comprises 1 to 2 independently selected from O, S, S(O), SO2, N and NR 54 The 3- to 6-membered heterocycloalkyl of the hetero moiety is selected from aziridinyl, oxiranyl, azetidinyl, oxetanyl, pyrrolidinyl, imidazolidinyl, imidazolinyl, pyrazolinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, thienyl, oxidized thienyl and oxidized thienyl. In some embodiments, A contains 1 to 2 independently selected from O, S, S(O), SO2, N and NR 54 The 5- to 6-membered heterocycloalkyl of the hetero moiety is selected from piperidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, thienyl and dioxythienyl. In some embodiments, A contains 1 to 2 independently selected from O, S, S(O), SO2, N and NR 54 The 5- to 6-membered heterocycloalkyl group of the hetero moiety is selected from tetrahydropyranyl, thienyl and dioxythienyl.

[0301] In some embodiments, A is a compound comprising 1 to 3 independently selected from O, S, N, and NR 54substituted with one or two substituents independently selected from the group consisting of F, Cl, C 1-4 Alkyl, C 1-4 Deuterated alkyl, C 1-4 Fluoroalkyl, OC 1-4 Alkyl, OC 1-4 Deuterated alkyl, OC 1-4 Fluoroalkyl, N(R 54a )(R 54b ), C 1-4 Alkylene N(R 54a )(R 54b ), SC 1-4 Alkyl, SC 1-4 Deuterated alkyl and SC 1-4 In some embodiments, A is a fluoroalkyl group comprising 1 to 3 independently selected from O, S, N and NR 54 substituted with one or two substituents independently selected from the group consisting of F, Cl, C 1-4 Alkyl, C 1-4 Deuterated alkyl, C 1-4 Fluoroalkyl, OC 1-4 Alkyl, OC 1-4 Deuterated alkyl and OC 1-4 In some embodiments, A comprises 1 to 3 independently selected from O, S, N and NR 54 The 5- to 6-membered heteroaryl of the hetero moiety is selected from pyrrolyl, furanyl, imidazolyl, oxazolyl, isoxazolyl, isothiazolyl, thiazolyl, pyrazolyl, phenylthio, pyrazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyrazinyl and triazinyl. In some embodiments, A contains 1 to 3 independently selected from O, S, N and NR 54 The 5- to 6-membered heteroaryl of the hetero moiety is selected from pyrrolyl, imidazolyl, oxazolyl, isoxazolyl, isothiazolyl, thiazolyl, pyrazolyl, phenylthio, pyrazolyl and pyridinyl. In some embodiments, the 5- to 6-membered heteroaryl is optionally substituted by one or two substituents independently selected from the following: F, OC 1-4 Alkyl, OC 1-4 Deuterated alkyl and OC 1-4 Fluoroalkyl.

[0302] In some embodiments, R 54a and R 54b Independently selected from H and C 1-4 In some embodiments, R 54a and R 54b Independently selected from H, D, C 1-4 Alkyl, C1-4 Fluoroalkyl and C 1-4 In some embodiments, R 54a and R 54b is independently selected from H, D, CH3, CD2H, CDH2, CD3, CF3, CHF2, CH2CH3, CH(CH3)2, CH2CH2D, CH2CD2H and CD2CD3. In some embodiments, R 54a and R 54b is independently selected from H, CH3, CD3, CF2H and CF3. 54a and R 54b Independently selected from H, CH3 and CD3.

[0303] In some embodiments, R 54 , R 55 , R 56 , R 57 and R 58 Independently selected from H, D, C 1-4 Alkyl, C 1-4 Fluoroalkyl and C 1-4 In some embodiments, R 54 , R 55 , R 56 , R 57 and R 58 is independently selected from H, D, CH3, CF3 and CD3. 54 , R 55 , R 56 , R 57 and R 58 Independently selected from CH3 and CD3.

[0304] In some embodiments, R 54 , R 55 , R 56 and R 57 Independently selected from H, D, C 1-4 Alkyl, C 1-4 Fluoroalkyl and C 1-4 In some embodiments, R 54 , R 55 , R 56 , R 57 and R 58 is independently selected from H, D, F, CH3, CD2H, CDH2, CD3, CF3 and CHF2. In some embodiments, R 54 , R 55 , R 56 and R 57is independently selected from H, D, CH3, CF3 and CD3. 54 , R 55 , R 56 and R 57 Independently selected from CH3 and CD3.

[0305] In some embodiments, the compound of Formula I or a pharmaceutically acceptable salt, solvate and / or prodrug thereof is defined as follows:

[0306]

[0307] in:

[0308] R 1 is H;

[0309] Q is selected from Q1, Q2, Q4 and Q5:

[0310]

[0311] is a single bond or a double bond, provided that when When it is a double bond, R 9 and R 15 does not exist, and when Q2 When it is a double bond, R 17 and R 25 does not exist;

[0312] R 2 , R 2’ , R 2” , R 3 and R 6 independently selected from H, D and F;

[0313] R 4 and R 5 One or two of them are selected from H, C 1-4 Alkoxy, C 1-4 Fluoroalkoxy and C 1-4 deuterated alkoxy, or

[0314] R 4 and R 5 Linked together to form O-(CH2) 1-2 O;

[0315] R 8 , R 9 , R 10 , R 11 , R 13 , R 14 , R 15 , R 16 , R 17, R 18 , R 19 , R 21 , R 22 , R 23 , R 24 , R 25 , R 32 , R 33 , R 34 , R 36 , R 37 , R 38 , R 39 , R 40 , R 41 , R 42 , R 43 , R 44 , R 46 , R 47 , R 48 , R 49 , R 50 , R 51 , R 52 , R 54 , R 55 , R 56 and R 57 are independently selected from H and D; and

[0316] R 12 , R 20 , R 35 and R 45 Independently selected from H, C 1-4 Alkyl, C 1-4 Fluoroalkyl and C 1-4 Deuterated alkyl.

[0317] In some embodiments, the compound of Formula I or a pharmaceutically acceptable salt, solvate and / or prodrug thereof is defined as follows:

[0318]

[0319] in:

[0320] R 1 is H;

[0321] Q is selected from Q1, Q2, Q3, Q4 and Q5:

[0322]

[0323] is a single bond or a double bond, provided that when When it is a double bond, R 9 and R 15 does not exist, and when Q2 When it is a double bond, R17 and R 25 does not exist;

[0324] R 2 , R 2’ , R 2” , R 3 and R 6 independently selected from H, D and F;

[0325] R 4 and R 5 One or two of them are selected from H, C 1-4 Alkoxy, C 1-4 Fluoroalkoxy and C 1-4 deuterated alkoxy, or

[0326] R 4 and R 5 Linked together to form O-(CH2) 1-2 O;

[0327] R 8 , R 9 , R 10 , R 11 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 21 , R 22 , R 23 , R 24 , R 25 , R 26 , R 27 , R 28 , R 29 , R 32 , R 33 , R 34 , R 36 , R 37 , R 38 , R 39 , R 40 , R 41 , R 42 , R 43 , R 44 , R 46 , R 47 , R 48 , R 49 , R 50 , R 51 , R 52 , R 54 , R 55 , R56 and R 57 are independently selected from H and D; and

[0328] R 12 , R 20 , R 3 0. R 3 1. R 35 and R 45 Independently selected from H, C 1-4 Alkyl, C 1-4 Fluoroalkyl and C 1-4 Deuterated alkyl;

[0329] The condition is that when Q is Q3, R 2 6. R 2 7. R 2 8 and R 2 9 are all H and R 30 and R 31 is H or CH3, and:

[0330] R 1 , R 2 , R 2’ , R 2” , R 3 , R 4 , R 5 and R 6 All are H,

[0331] R 1 , R 2 , R 2’ , R 2” , R 3 , R 5 and R 6 All are H and R 4 for OCH3, or

[0332] R 1 , R 2 , R 2’ , R 2” , R 3 , R 4 , R 5 and R 6 All are H and R 5 For OCH3,

[0333] The compound of formula I is then either the (R)-enantiomer or the (S)-enantiomer of the carbon to which Q is attached.

[0334] In some embodiments, the compound of Formula I or a pharmaceutically acceptable salt, solvate and / or prodrug thereof is defined as follows

[0335]

[0336] in:

[0337] R 1 H

[0338] Q is selected from Q1, Q2, Q2', Q4 and Q5:

[0339]

[0340] is a single bond or a double bond, provided that when When it is a double bond, R 9 and R 15 does not exist, and when Q2 When it is a double bond, R 17 and R 25 does not exist, and when Q2' When it is a double bond, R 16’ and R 25’ is non-existent;

[0341] On the key means that the bond is attached to the remainder of the compound;

[0342] R 2 , R 2’ and R 2” independently selected from H, D and F;

[0343] R 3 , R 4 , R 5 and R 6 Independently selected from H, C 1-4 Alkoxy, C 1-4 Fluoroalkoxy and C 1-4 deuterated alkoxy, or

[0344] R 3 , R 4 , R 5 and R 6 Two adjacent groups in the bond together to form O-(CH2) 1-2 O, and R 3 , R 4 , R 5 and R 6 The remaining groups in are independently selected from H, halogen, C 1-6 Alkyl and C 1-6 Alkoxy, or

[0345] R 8 , R 9 , R 10 , R11 , R 13 , R 14 , R 15 , R 16 , R 16’ , R 17 , R 17’ , R 18 , R 19’ , R 19 , R 19’ , R 21 , R 22’ , R 22 , R 22’ , R 23 , R 23’ , R 24 , R 24’ , R 25 , R 25’ , R 32 , R 33 , R 34 , R 36 , R 37 , R 38 , R 39 , R 40 , R 41 , R 42 , R 43 , R 44 , R 46 , R 47 , R 48 , R 49 , R 50 , R 51 , R 52 and R 53 are independently selected from H, halo and C 1-6 alkyl;

[0346] R 12 , R 20 , R 20’ , R 35 and R 45 Independently selected from H, C 1-6 Alkyl and C(O)C 1-6 alkyl;

[0347] R 54 , R 55 , R 56 and R 57 Independently selected from H and C 1-6 Alkyl; and

[0348] All available hydrogen atoms are optionally and independently replaced with fluorine atoms or chlorine atoms, and all available atoms are optionally substituted with alternative isotopes thereof.

[0349] In some embodiments, the compound of Formula I or a pharmaceutically acceptable salt, solvate and / or prodrug thereof is defined as follows:

[0350]

[0351] in:

[0352] R 1 Selected from H, C(O)R 7 、CO2R 7 、C(O)N(R 7 )(R 7’ )、S(O)R 7 、SO2R 7 , C 1-6 Alkylene R 7 and R 7 ;

[0353] Q is selected from Q1, Q2, Q2', Q4 and Q5:

[0354]

[0355] is a single bond or a double bond, provided that when When it is a double bond, R 9 and R 15 does not exist, and when Q2 When it is a double bond, R 17 and R 25 does not exist, and when Q2' When it is a double bond, R 16’ and R 25’ does not exist;

[0356] On the key means that the bond is attached to the remainder of the compound;

[0357] R 2 , R 2’ and R 2” are independently selected from H, halo, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylene N(R 2a )(R 2b ) and SC 1-6 alkyl;

[0358] R 2a and R 2b Independently selected from H and C 1-6 alkyl;

[0359] R 3 and R6 are independently selected from H, halo, N(R 5’ )(R 6’ ), C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylene N(R 5’ )(R 6’ ) and SC 1-6 Alkyl, the last four groups are optionally replaced by one or two selected from OH and C 1-6 Substitution of alkoxy groups;

[0360] R 4 and R 5 are independently selected from H, halo, N(R 5’ )(R 6’ ), C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylene N(R 5’ )(R 6’ ) and SC 1-6 Alkyl, the last four groups are optionally replaced by one or two selected from OH and C 1-6 Substitution of the alkoxy group; or

[0361] R 4 and R 5 Linked together to form O-(CH2) 1-2 O; or

[0362] R 4 and R 5 One of A, OA and C 1-4 Alkylene A, and R 4 and R 5 The other of is H or halogen;

[0363] R 5’ and R 6’ Independently selected from H and C 1-6 Alkyl; A is selected from phenyl, C 3-6 Cycloalkyl, containing 1 to 4 independently selected from O, S, S(O), SO2, N and NR 54 The heterocyclic alkyl group of the heterocyclic alkyl group is 3-6-membered and contains 1 to 4 independently selected from O, S, S(O), SO2, N and NR 54 phenyl, C 3-10 Cycloalkyl, 3-membered to 6-membered heterocycloalkyl and 5-membered to 6-membered heteroaryl are optionally substituted with one or more substituents independently selected from the group consisting of halo, C 1-4 Alkyl, OC 1-4 Alkyl, N(R 54a )(R54b ), C 1-4 Alkylene N(R 54a )(R 54b ) and SC 1-4 alkyl;

[0364] R 7 Selected from H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, phenyl, C 3-6 Cycloalkyl, containing 1 to 4 independently selected from O, S, N and NR 7” The heterocyclic alkyl group of the heterocyclic alkyl group is 3-6-membered and contains 1 to 4 independently selected from O, S, N and NR 7” The 5- to 6-membered heteroaryl group of the heteroaryl group of the present invention, wherein the latter 5 groups are optionally substituted by one or more independently selected from halogen, OR 55 、N(R 55 )(R 56 ) and SR 55 Substituents substituted, and / or C 1-6 The alkyl group is optionally substituted by one to three independently selected from O, C(O), CO2 and NR 57 The miscellaneous parts are interrupted;

[0365] R 7’ Selected from H and C 1-6 alkyl;

[0366] R 7” Selected from H and C 1-6 alkyl;

[0367] R 8 , R 9 , R 10 , R 11 , R 13 , R 14 , R 15 , R 16 , R 16’ , R 17 , R 17’ , R 18 , R 19’ , R 19 , R 19’ , R 21 , R 22’ , R 22 , R 22’ , R 23 , R 23’ , R 24 , R 24’ , R 25 , R 25’ , R 32 , R33 , R 34 , R 36 , R 37 , R 38 , R 39 , R 40 , R 41 , R 42 , R 43 , R 44 , R 46 , R 47 , R 48 , R 49 , R 50 , R 51 , R 52 and R 53 are independently selected from H, halo and C 1-6 alkyl;

[0368] R 12 , R 20 , R 20’ , R 35 and R 45 Independently selected from H, C 1-6 Alkyl and C(O)C 1-6 alkyl;

[0369] R 54 , R 55 , R 56 and R 57 Independently selected from H and C 1-6 alkyl;

[0370] R 54a and R 54b Independently selected from H and C 1-6 Alkyl; and

[0371] All available hydrogen atoms are optionally and independently replaced with fluorine atoms or chlorine atoms, and all available atoms are optionally substituted with alternative isotopes thereof.

[0372] In some embodiments, the compound of Formula I or a pharmaceutically acceptable salt, solvate and / or prodrug thereof is defined as follows:

[0373]

[0374] in:

[0375] R 1 is H;

[0376] Q is selected from Q1, Q2, Q2', Q4 and Q5:

[0377]

[0378] is a single bond or a double bond, provided that when When it is a double bond, R 9 and R 15 does not exist, and when Q2 When it is a double bond, R 17 and R 25 does not exist, and when Q2' When it is a double bond, R 16’ and R 25’ does not exist;

[0379] On the key means that the bond is attached to the remainder of the compound;

[0380] R 2 , R 2’ and R 2” are independently selected from H, halo, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylene N(R 2a )(R 2b ) and SC 1-6 alkyl;

[0381] R 2a and R 2b Independently selected from H and C 1-6 alkyl;

[0382] R 3 , R 4 , R 5 and R 6 are independently selected from H, halo, N(R 5’ )(R 6’ ), C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylene N(R 5’ )(R 6’ ) and SC 1-6 Alkyl, the last four substituents are selected from OH and C 1-6 Alkoxy, or

[0383] R 3 , R 4 , R 5 and R 6 Two adjacent groups in the bond together to form O-(CH2) 1-2 O, and R 3 , R 4 , R 5 and R 6 The remaining groups in are independently selected from H, halogen, C 1-6Alkyl, C 1-6 Alkoxy, N(R 5’ )(R 6’ ), C 1-6 Alkylene N(R 5’ )(R 6’ ) and SC 1-6 alkyl;

[0384] R 5’ and R 6’ Independently selected from H and C 1-6 Alkyl; R 8 , R 9 , R 10 , R 11 , R 13 , R 14 , R 15 , R 16 , R 16’ , R 17 , R 17’ , R 18 , R 19’ , R 19 , R 19’ , R 21 , R 22’ , R 22 , R 22’ , R 23 , R 23’ , R 24 , R 24’ , R 25 , R 25’ , R 32 , R 33 , R 34 , R 36 , R 37 , R 38 , R 39 , R 40 , R 41 , R 42 , R 43 , R 44 , R 46 , R 47 , R 48 , R 49 , R 50 , R 51 , R 52 and R 53 are independently selected from H, halo and C 1-6 alkyl;

[0385] R 12 , R 20 , R 20’ , R 35 and R45 Independently selected from H, C 1-6 Alkyl and C(O)C 1-6 alkyl;

[0386] All available hydrogen atoms are optionally and independently replaced with fluorine atoms or chlorine atoms, and all available atoms are optionally substituted with alternative isotopes thereof.

[0387] In some embodiments, the compound of Formula I or a pharmaceutically acceptable salt, solvate and / or prodrug thereof is defined as follows:

[0388]

[0389] in:

[0390] R 1 Selected from H, C(O)R 7 、CO2R 7 、C(O)N(R 7 )(R 7’ )、S(O)R 7 、SO2R 7 , C 1-6 Alkylene R 7 and R 7 ;

[0391] Q is selected from Q1, Q2, Q2', Q4 and Q5:

[0392]

[0393] is a single bond or a double bond, provided that when When it is a double bond, R 9 and R 15 does not exist, and when Q2 When it is a double bond, R 17 and R 25 does not exist, and when Q2' When it is a double bond, R 16’ and R 25’ does not exist;

[0394] On the key means that the bond is attached to the remainder of the compound;

[0395] R 2 , R 2’ and R 2” are independently selected from H, halo, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylene N(R 2a )(R 2b) and SC 1-6 alkyl;

[0396] R 2a and R 2b Independently selected from H and C 1-6 alkyl;

[0397] R 3 , R 4 , R 5 and R 6 One of A, OA and C 1-4 Alkylene A, and R 3 , R 4 , R 5 and R 6 The remaining groups in are independently H or halo;

[0398] A is selected from phenyl, C 3-6 Cycloalkyl, containing 1 to 4 independently selected from O, S, S(O), SO2, N and NR 54 The heterocyclic alkyl group of the heterocyclic alkyl group is 3-6-membered and contains 1 to 4 independently selected from O, S, S(O), SO2, N and NR 54 phenyl, C 3-10 Cycloalkyl, 3-membered to 6-membered heterocycloalkyl and 5-membered to 6-membered heteroaryl are optionally substituted by one or more independently selected from halo, C 1-4 Alkyl and OC 1-4 The substituent of the alkyl group is substituted. A is selected from phenyl, C 3-6 Cycloalkyl, containing 1 to 4 independently selected from O, S, S(O), SO2, N and NR 54 The heterocyclic alkyl group of the heterocyclic alkyl group is 3-6-membered and contains 1 to 4 independently selected from O, S, S(O), SO2, N and NR 54 phenyl, C 3-10 Cycloalkyl, 3-membered to 6-membered heterocycloalkyl and 5-membered to 6-membered heteroaryl are optionally substituted with one or more substituents independently selected from the group consisting of halo, C 1-4 Alkyl, OC 1-4 Alkyl, N(R 54a )(R 54b ), C 1-4 Alkylene N(R 54a )(R 54b ) and SC 1-4 alkyl;

[0399] R 7 Selected from H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, phenyl, C3-6 Cycloalkyl, containing 1 to 4 independently selected from O, S, N and NR 7” The heterocyclic alkyl group of the 3- to 6-membered heterocyclic alkyl group and 5 contains 1 to 4 independently selected from O, S, N and NR 7” The 5- to 6-membered heteroaryl group of the heteroaryl group of the present invention, wherein the last 6 groups are optionally substituted by one or more independently selected from halogen, OR 55 、N(R 55 )(R 56 ) and SR 55 Substituents substituted, and / or C 1-6 The alkyl group is optionally substituted by one to three independently selected from O, C(O), CO2 and NR 57 The miscellaneous parts are interrupted;

[0400] R 7’ Selected from H and C 1-6 alkyl;

[0401] R 7” Selected from H and C 1-6 alkyl;

[0402] R 8 , R 9 , R 10 , R 11 , R 13 , R 14 , R 15 , R 16 , R 16’ , R 17 , R 17’ , R 18 , R 19’ , R 19 , R 19’ , R 21 , R 22’ , R 22 , R 22’ , R 23 , R 23’ , R 24 , R 24’ , R 25 , R 25’ , R 32 , R 33 , R 34 , R 36 , R 37 , R 38 , R 39 , R 40 , R 41 , R 42 , R 43 , R 44 , R 46 , R47 , R 48 , R 49 , R 50 , R 51 , R 52 and R 53 are independently selected from H, halo and C 1-6 alkyl;

[0403] R 12 , R 20 , R 20’ , R 35 and R 45 Independently selected from H, C 1-6 Alkyl and C(O)C 1-6 alkyl;

[0404] R 54 , R 55 , R 56 and R 57 Independently selected from H and C 1-6 alkyl;

[0405] R 54a and R 54b Independently selected from H and C 1-6 Alkyl; and

[0406] All available hydrogen atoms are optionally and independently replaced with fluorine atoms or chlorine atoms, and all available atoms are optionally substituted with alternative isotopes thereof.

[0407] Those skilled in the art will appreciate that the carbon to which Q is bonded is chiral. Thus, in some embodiments, the carbon to which Q is bonded is racemic. In some embodiments, the stereochemistry at the carbon to which Q is bonded is R. In some embodiments, the stereochemistry at the carbon to which Q is bonded is S. Thus, in some embodiments, the compound of Formula I may have one of the following structures or a mixture thereof:

[0408]

[0409] Those skilled in the art will further understand that when R 2 and R 2’ At the same time, R 2 and R 2’ The bonded carbon is also chiral. Therefore, the present application also includes all stereoisomers at this carbon center and mixtures thereof.

[0410] In some embodiments, the compound of Formula I is selected from the compounds listed in the following table or pharmaceutically acceptable salts, solvates and / or prodrugs thereof:

[0411]

[0412]

[0413]

[0414]

[0415]

[0416]

[0417]

[0418]

[0419]

[0420]

[0421]

[0422]

[0423]

[0424]

[0425] In some embodiments, the compound of Formula I is selected from the compounds listed in the following table or pharmaceutically acceptable salts, solvates and / or prodrugs thereof:

[0426]

[0427]

[0428]

[0429]

[0430]

[0431]

[0432]

[0433] In some embodiments, pharmaceutically acceptable salts are acid addition salts or base addition salts. Suitable salts can be selected by those skilled in the art. Suitable salts include acid addition salts, which can be formed, for example, by mixing a solution of the compound with a solution of a pharmaceutically acceptable acid such as hydrochloric acid, sulfuric acid, acetic acid, trifluoroacetic acid or benzoic acid. In addition, acids generally considered suitable for forming pharmaceutically useful salts from basic drug compounds are discussed, for example, by P. Stahl et al, Camille G. (eds) and Handbook of Pharmaceutical Salts. Properties, Selection and Use. (2002) Zurich: Wiley VCH; S. Berge et al, Journal of Pharmaceutical Sciences 1977 66 (1) 1-19; P. Gould, International J. of Pharmaceutics (1986) 33 201-217; Anderson et al, The Practice of Medicinal Chemistry (1996), Academic Press, New York; and The Orange Book (Food & Drug Administration, Washington, DC Con their website).

[0434] Acid addition salts suitable for subject treatment or compatible with subject treatment are any nontoxic organic acid or inorganic acid addition salts of any basic compound. The basic compound forming the acid addition salt includes, for example, a compound comprising an amine group. Exemplary inorganic acids forming suitable salts include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid and phosphoric acid, and acidic metal salts (such as sodium monohydrogen phosphate and potassium hydrogen sulfate). Exemplary organic acids forming suitable salts include monocarboxylic acids, dicarboxylic acids and tricarboxylic acids. Examples of such organic acids are, for example, acetic acid, trifluoroacetic acid, propionic acid, glycolic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, glutaric acid, fumaric acid, malic acid, tartaric acid, citric acid, ascorbic acid, maleic acid, hydroxymaleic acid, benzoic acid, hydroxybenzoic acid, phenylacetic acid, cinnamic acid, mandelic acid, salicylic acid, 2-phenoxybenzoic acid, p-toluenesulfonic acid and other sulfonic acids (e.g., methanesulfonic acid, ethanesulfonic acid and 2-hydroxyethanesulfonic acid). In some embodiments, exemplary acid addition salts also include acetate, ascorbate, benzoate, benzenesulfonate, bisulfate, borate, butyrate, citrate, camphor salt, camphorsulfonate, fumarate, hydrochloride, hydrobromide, hydroiodide, lactate, maleate, methanesulfonate ("mesylate"), naphthylsulfonate, nitrate, oxalate, phosphate, propionate, salicylate, succinate, sulfate, tartrate, thiocyanate, toluenesulfonate (also known as toluenesulfonate (tosylate)) and the like. In some embodiments, monoacid or diacid salts are formed, and such salts exist in hydrated, solvated or substantially anhydrous forms. In general, acid addition salts are more soluble in water and various hydrophilic organic solvents, and typically exhibit higher melting points compared to their free base forms. The selection criteria for suitable salts are known to those skilled in the art. Other non-pharmaceutically acceptable salts, such as but not limited to oxalates, may be used, for example, to isolate the compounds of the present application for laboratory applications, or for subsequent conversion to a pharmaceutically acceptable acid addition salt.

[0435] Base addition salts suitable for subject treatment or compatible with subject treatment are any nontoxic organic or inorganic base addition salts of any acidic compound. The acidic compound forming the basic addition salt includes, for example, a compound comprising a carboxylic acid group. The exemplary inorganic bases forming suitable salts include hydroxides and ammonia of lithium, sodium, potassium, calcium, magnesium or barium. The exemplary organic bases forming suitable salts include aliphatic, alicyclic or aromatic organic amines, such as isopropylamine, methylamine, trimethylamine, picoline, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucosamine, theobromine, purine, piperazine, piperidine, N-ethylpiperidine, polyamine resins, etc. Exemplary organic bases are isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline and caffeine. It may be useful to select a suitable salt, for example, so that the ester functional group (if any) elsewhere in the compound is not hydrolyzed. The selection criteria for suitable salts are known to those skilled in the art. In some embodiments, exemplary basic salts also include ammonium salts, alkali metal salts (such as sodium salts, lithium salts and potassium salts), alkaline earth metal salts (such as calcium salts and magnesium salts), salts formed with organic bases (e.g., organic amines (such as dicyclohexylamine, ramie amine, choline)) and salts formed with amino acids (such as arginine, lysine, etc.). Basic nitrogen-containing groups can be quaternized with agents such as lower alkyl halides (e.g., methyl, ethyl and butyl chlorides, bromides and iodides), dialkyl sulfates (e.g., dimethyl, diethyl and dibutyl sulfates), long chain halides (e.g., decyl, lauryl and stearyl chlorides, bromides and iodides), aralkyl halides (e.g., benzyl and phenethyl bromides), etc. Compounds carrying acidic moieties can be mixed with suitable pharmaceutically acceptable salts to provide, for example, alkali metal salts (e.g., sodium or potassium salts), alkaline earth metal salts (e.g., calcium or magnesium salts), and salts formed with suitable organic ligands (e.g., quaternary ammonium salts). In addition, in the presence of an acid (-COOH) or alcohol group, pharmaceutically acceptable esters can be used to alter the solubility or hydrolysis characteristics of the compound.

[0436] All such acid salts and base salts are intended to be pharmaceutically acceptable salts within the scope of the present application, and all acid salts and base salts are considered to be equivalent to the free form of the corresponding compound for the purpose of the present application. In addition, when the compound of the present application contains both a basic part (such as but not limited to aliphatic primary amine, secondary amine, tertiary amine or cyclic amine, aromatic amine or heteroaryl amine, pyridine or imidazole) and an acidic part (such as but not limited to tetrazole or carboxylic acid), zwitterions ("inner salts") can be formed, and are included in the term "salt" as used herein. It should be understood that some compounds of the present application can exist in the form of zwitterions, with anionic centers and cationic centers and net neutral charge in the same compound. Such zwitterions are included in the present application.

[0437] Solvates of the compounds of the present application include, for example, solvates made with pharmaceutically acceptable solvents. Examples of such solvents include water (the resulting solvate is referred to as a hydrate) and ethanol, etc. Suitable solvents are physiologically tolerable at the administered dose.

[0438] Prodrugs of the compounds of the present application include, for example, conventional esters formed with available hydroxyl, thiol, amino or carboxyl groups. Some common esters that have been used as prodrugs are phenyl esters, aliphatic (C1-C 24 ) esters, acyloxymethyl esters, carbamates and amino acid esters.

[0439] It should be understood and appreciated that, in some embodiments, the compounds of the present application may have at least one chiral center, and therefore may exist as enantiomers and / or diastereomers. It should be understood that all such isomers and mixtures of any ratio thereof are included within the scope of the present application. It should also be understood that, although the stereochemistry of the compound may be shown in any given compound listed herein, such compounds may also include a certain amount (e.g., less than 20%, suitably less than 10%, more suitably less than 5%) of the compounds of the present application with alternative stereochemistry. It is contemplated that any optical isomer, such as separated, pure or partially purified optical isomers or their racemic mixtures are included within the scope of the present application.

[0440] In some embodiments, the compounds of the present application may also include tautomeric forms, such as keto-enol tautomers, etc. By appropriate substitution, tautomers may be in equilibrium or spatially locked into a form. Any tautomeric forms and mixtures thereof that are expected to form with the compound are included within the scope of the present application.

[0441] The compounds of the present application may also exist in various amorphous and polymorphic forms, and it is intended that any amorphous form, polymorphic form, or mixture thereof is included within the scope of the present application.

[0442] The compounds of the present application may be further radiolabeled, and thus all radiolabeled forms of the compounds of the present application are included within the scope of the present application. Therefore, the compounds of the present application also include those compounds that incorporate one or more radioactive atoms in their structure.

[0443] In some embodiments, the compounds of the present application may also exist in zwitterionic form. Therefore, all zwitterionic forms of the compounds of the present application are included within the scope of the present application.

[0444] III. Composition

[0445] The compounds of the present application are suitably formulated into compositions using one or more carriers in a conventional manner. Therefore, the present application also includes compositions comprising one or more compounds of the present application and carriers. The compounds of the present application are suitable for being formulated into pharmaceutical compositions and are administered to subjects in a biocompatible form suitable for in vivo administration. Therefore, the present application also includes pharmaceutical compositions comprising one or more compounds of the present application and a pharmaceutically acceptable carrier. In an embodiment of the present application, the pharmaceutical composition is used to treat any disease, disorder or condition described herein.

[0446] As will be appreciated by those skilled in the art, the compounds of the present application are administered to the subject in various forms, according to the selected route of administration. For example, the compounds of the present application are administered by oral, inhalation, parenteral, buccal, sublingual, insufflation, epidural, intranasal, rectal, vaginal, patch, pump, mini pump, topical or transdermal administration, and the pharmaceutical composition is formulated accordingly. In some embodiments, the pump is used for regular or continuous delivery for administration. Conventional procedures and ingredients for selecting and preparing suitable compositions are described in, for example, Remington's Pharmaceutical Sciences (2000-20th edition) and The United States Pharmacopeia: The National Formulary (USP24NF19) published in 1999.

[0447] Parenteral administration includes systemic routes of delivery other than the gastrointestinal (GI) tract, and includes, for example, intravenous, intraarterial, intraperitoneal, subcutaneous, intramuscular, transepithelial, intranasal, intrapulmonary (e.g., by use of an aerosol), intrathecal, rectal, and topical (including use of a patch or other transdermal delivery device) administration. Parenteral administration can be performed by continuous infusion over a selected period of time.

[0448] In some embodiments, the compounds of the present application are administered orally, for example, with an inert diluent or an assimilable edible carrier, or encapsulated in a hard or soft shell gelatin capsule, or compressed into tablets, or incorporated directly into the food of the diet. In some embodiments, the compound is mixed with an excipient and used in the form of ingestible tablets, buccal tablets, lozenges, capsules, caplets, pills, granules, lozenges, chewing gums, powders, syrups, elixirs, wafers, aqueous solutions and suspensions. In the case of tablets, the carriers used include lactose, corn starch, sodium citrate and phosphates. Pharmaceutically acceptable excipients include binders (e.g., pregelatinized corn starch, polyvinyl pyrrolidone, or hydroxypropyl methylcellulose); fillers (e.g., lactose, microcrystalline cellulose, or calcium phosphate); lubricants (e.g., magnesium stearate, talc, or silicon dioxide); disintegrants (e.g., potato starch or sodium starch glycolate); or wetting agents (e.g., sodium lauryl sulfate), or solvents (e.g., medium chain triglycerides, ethanol, water). In an embodiment, the tablets are coated by methods known in the art. For tablets, capsules, caplets, pills, or granules for oral administration, a pH-sensitive enteric coating, such as Eudragits designed to control the release of the active ingredient, may optionally be used. TM Oral dosage forms also include modified release formulations, such as immediate release and timed release formulations. Examples of modified release formulations include, for example, sustained release (SR), extended release (ER, XR or XL), timed release (time-release / timed-release), controlled release (CR) or sustained release (CR or Contin), for example, in the form of coated tablets, osmotic delivery devices, coated capsules, microencapsulated microspheres, agglomerated particles (e.g., molecular sieve-type particles) or fine hollow permeable fiber bundles or short-cut hollow permeable fibers, agglomerated or retained in fiber packages. Timed release compositions are formulated into, for example, liposomes or compositions in which the active compound is protected by different degradable coatings (e.g., by microencapsulation, multilayer coatings, etc.). Liposomal delivery systems include, for example, small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles. In some embodiments, liposomes are formed by a variety of phospholipids (e.g., cholesterol, stearylamine or phosphatidylcholine). For oral administration in capsule form, useful carriers, solvents or diluents include lactose, medium chain triglycerides, ethanol and dry corn starch.

[0449] In some embodiments, the liquid preparation for oral administration takes the form of, for example, solution, syrup or suspension, or they are suitable for being present as a dry product, for reconstitution with water or other suitable vehicles before use. When an aqueous suspension and / or emulsion is administered orally, the compound of the present application is appropriately suspended or dissolved in an oil phase combined with an emulsifier and / or suspending agent. If necessary, certain sweeteners and / or flavoring agents and / or coloring agents may be added. Such liquid preparations for oral administration are prepared by conventional methods with pharmaceutically acceptable additives, such as suspending agents (e.g., sorbitol syrup, methylcellulose or hydrogenated edible fats); emulsifiers (e.g., lecithin or gum arabic); non-aqueous vehicles (e.g., medium chain triglycerides, almond oil, oily esters or ethanol); and preservatives (e.g., methylparaben or propylparaben or sorbic acid). Useful diluents include lactose and high molecular weight polyethylene glycols.

[0450] The compounds of the present application can also be freeze-dried and the lyophilizates obtained can be used, for example, for the preparation of injectable products.

[0451] In some embodiments, the compound of the present application is parenterally administered. For example, the solution of the compound of the present application is prepared in water and appropriately mixed with a surfactant (such as hydroxypropyl cellulose). In some embodiments, the dispersion is prepared in glycerol, liquid polyethylene glycol, DMSO and a mixture thereof containing or not containing alcohol and in oil. Under normal storage and use conditions, these preparations contain preservatives to prevent microbial growth. Those skilled in the art know how to prepare suitable preparations. For parenteral administration, a sterile solution of the compound of the present application is usually prepared, and the pH of the solution is appropriately adjusted and buffered. For intravenous injection, the total concentration of the solute should be controlled to make the preparation isotonic. For ocular administration, for example, an ointment or a dropperable liquid is delivered by an ocular delivery system known in the art (such as an applicator or an eye dropper). In some embodiments, such compositions include a mucus mimetic (such as hyaluronic acid, chondroitin sulfate, hydroxypropyl methylcellulose or polyvinyl alcohol), a preservative (such as sorbic acid, EDTA or benzyl chromium chloride), and a conventional amount of a diluent or carrier. For pulmonary administration, the diluent or carrier will be selected to be suitable for forming an aerosol.

[0452] In some embodiments, the compound of the present application is formulated for parenteral administration by injection, including the use of conventional catheter insertion techniques or infusions. Injectable preparations are present, for example, in unit dosage forms, such as in ampoules or multidose containers, and are added with preservatives. In some embodiments, the composition takes the form of a sterile suspension, solution or emulsion in an oily or aqueous vehicle, and contains a preparaton (such as a suspending agent, a stabilizer and / or a dispersant). In all cases, the dosage form must be sterile and must be a fluid that is easy to inject. Alternatively, the compound of the present application is suitably in a sterile powder form for reconstitution with a suitable vehicle (e.g., sterile pyrogen-free water) before use.

[0453] In some embodiments, the composition for intranasal administration is conveniently formulated into aerosols, drops, gels and powders. For intranasal administration or inhalation administration, the compound of the present application is conveniently delivered in the form of a solution, dry powder preparation or suspension from a pump spray container squeezed or pumped by the patient, or delivered as an aerosol spray from a pressurized container or a sprayer. Aerosol preparations generally include a solution or a fine suspension of active substances in a physiologically acceptable aqueous or non-aqueous solvent, and are generally present in a sealed container in a single dose or multiple doses in a sterile form, the container for example adopts the form of a cartridge or a refill used with an atomizing device. Alternatively, the sealed container is an integral dispensing device (e.g., a single dose nasal inhaler or an aerosol dispenser equipped with a metering valve), which is expected to be discarded after use. When the dosage form includes an aerosol dispenser, it will include a propellant (e.g., compressed gas (such as compressed air)) or an organic propellant (such as fluorochlorocarbons). Suitable propellants include, but are not limited to, dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, heptafluoroalkane, carbon dioxide or another suitable gas. In the case of a pressurized aerosol, the dosage unit is appropriately determined by providing a valve that delivers a metered amount. In some embodiments, a pressurized container or spray contains a solution or suspension of the active compound. Capsules and cartridges (e.g., made of gelatin) for inhalers or insufflators are, for example, formulated into a powder mixture containing the compound of the present application and a suitable powder base (such as lactose or starch). Aerosol dosage forms can also take the form of a pump atomizer.

[0454] Compositions suitable for buccal or sublingual administration include tablets, lozenges and pastilles, in which the compounds of the present application are formulated with a carrier such as sugar, acacia, tragacanth or gelatin and glycerin. Compositions for rectal administration are conveniently in the form of suppositories containing conventional suppository bases such as cocoa butter.

[0455] The suppository form of the compound of the present application can be used for vaginal, urethral and rectal administration. Such suppositories are generally composed of a mixture of substances that are solid at room temperature but melt at body temperature. The materials commonly used to produce such vehicles include, but are not limited to, mixtures of polyethylene glycols of various molecular weights and polyethylene glycol fatty acid esters. See, for example: for further discussion of suppository dosage forms, Remington's Pharmaceutical Sciences, 16th Ed, Mack Publishing, Easton, PA, 1980, pp. 1530-1533.

[0456] In some embodiments, the compound of the present application is connected to a soluble polymer as a targeted drug carrier. Such polymers include, for example, polyvinyl pyrrolidone, pyran copolymers, polyhydroxypropyl methacrylamide-phenol, polyhydroxyethyl asparagine-phenol or polyethylene oxide-polylysine substituted with palmitoyl residues. In addition, in some embodiments, the compound of the present application is connected to a class of biodegradable polymers that can be used to achieve controlled release of drugs, such as crosslinking or amphiphilic block copolymers of polylactic acid, polyglycolic acid, polylactic acid and polyglycolic acid, poly-ε caprolactone, polyhydroxybutyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates and hydrogels.

[0457] The compounds of the present application are particularly suitable for administration with the air of a nanocarrier system, such as a liposome, a micelle, a nanoparticle, a nanoemulsion, a lipid nanosystem, etc. (see, for example, Bhat, M. et al. Chem. and Phys. of Lipids, 2021, 236, 105053). Therefore, the present application includes a composition comprising one or more compounds of the present application and one or more components of a nanocarrier system.

[0458] The compounds of the present application, including pharmaceutically acceptable salts, solvates and / or prodrugs thereof, are suitable for use alone, but are generally administered in the form of a pharmaceutical composition in which one or more compounds of the present application (active ingredients) are combined with a pharmaceutically acceptable carrier. Depending on the mode of administration, the pharmaceutical composition will contain about 0.05% by weight to about 99% by weight or about 0.10% by weight to about 70% by weight of the active ingredient and about 1% by weight to about 99.95% by weight or about 30% by weight to about 99.90% by weight of a pharmaceutically acceptable carrier, all percentages by weight being based on the total composition.

[0459] In some embodiments, the compounds of the present application, including pharmaceutically acceptable salts, solvates and / or prodrugs thereof, are administered in the form of a composition comprising an additional therapeutic agent. Therefore, the present application also includes a pharmaceutical composition comprising one or more compounds of the present application or pharmaceutically acceptable salts and / or solvates thereof and an additional therapeutic agent, and optionally one or more pharmaceutically acceptable excipients. In some embodiments, the additional therapeutic agent is another known agent that can be used to treat a disease, disorder or condition by activating serotonin receptors, such as those listed in the methods and uses section below. In some embodiments, the additional therapeutic agent is a psychoactive drug.

[0460] In the above, the term "compound" also includes embodiments referring to one or more compounds.

[0461] IV. Methods and Uses of the Present Application

[0462] The compounds of the present application can be used to treat diseases, disorders or conditions by activating serotonin receptors. Therefore, the compounds of the present application can be used as drugs. Therefore, the present application also includes compounds of the present application used as drugs.

[0463] The present application also includes methods of treating a disease, disorder or condition by activating a serotonin receptor, the method comprising administering to a subject in need thereof a therapeutically effective amount of one or more compounds of the present application.

[0464] The present application also includes the use of one or more compounds of the present application for treating diseases, disorders or conditions by activating serotonin receptors, and the use of one or more compounds of the present application for preparing a medicament for treating diseases, disorders or conditions by activating serotonin receptors. The present application also includes one or more compounds of the present application for treating diseases, disorders or conditions by activating serotonin receptors.

[0465] In some embodiments, the treatment of a disease, disorder, or condition treatable by activating serotonin receptors has no hallucinogenic effects in a subject, or has reduced hallucinogenic effects in a subject compared to the hallucinogenic effects of administering a hallucinogenic drug such as psilocybin, DMT, or 5-MeO-DMT. In some embodiments, the treatment of a disease, disorder, or condition treatable by activating serotonin receptors has no hallucinogenic effects in a subject, or has reduced hallucinogenic effects in a subject compared to the hallucinogenic effects of administering an equivalent amount of psilocybin.

[0466] The present application includes a method for activating serotonin receptors in biological samples or subject cells, which includes administering an effective amount of one or more compounds of the present application to the cells. The present application also includes the use of one or more compounds of the present application for activating serotonin receptors in cells, and the use of one or more compounds of the present application for preparing a drug for activating serotonin receptors in cells and / or on cells. The present application also includes one or more compounds of the present application for activating serotonin receptors in cells. In some embodiments, the method or use is used to activate serotonin receptors in cells and / or on cells in biological samples or patients.

[0467] In some embodiments, activation of serotonin receptors has no hallucinogenic effect in a subject, or has reduced hallucinogenic effect in a subject compared to the hallucinogenic effect of administering an equivalent amount of a hallucinogenic drug (such as psilocybin, DMT, or 5-MeO-DMT). In some embodiments, the hallucinogenic drug is psilocybin. In some embodiments, activation of serotonin receptors has no hallucinogenic effect in a subject, or has reduced hallucinogenic effect in a subject compared to the hallucinogenic effect of administering an equivalent amount of psilocybin.

[0468] In some embodiments, the serotonin receptor is 5-HT 2A Therefore, the present application includes a method for activating 5-HT in cells in a biological sample or a patient. 2A The method comprises administering an effective amount of one or more compounds of the present application to cells. The present application also includes one or more compounds of the present application for activating 5-HT in cells. 2A Use of, and one or more compounds of the present application for preparing a 5-HT 2A The present application also includes one or more compounds of the present application for activating 5-HT in cells. 2A In some embodiments, the method or use is used to activate 5-HT2 in cells and / or on cells in a biological sample or patient. The present application also includes activating 5-HT 2A A method for treating a disease, disorder or condition comprising administering a therapeutically effective amount of one or more compounds of the present application to a subject in need. The present application also includes one or more compounds of the present application for activating 5-HT 2A The invention relates to the use of one or more compounds of the present invention for treating diseases, disorders or conditions, and the use of one or more compounds of the present invention for preparing a drug that activates 5-HT 2A The present invention also includes one or more compounds of the present invention for use in treating diseases, disorders or conditions by activating 5-HT 2A To treat a disease, disorder or condition.

[0469] In some embodiments, the compounds of the present application can be used to prevent, treat and / or reduce the severity of the subject's mental illness disorder and / or condition. Therefore, in some embodiments, the disease, disorder or condition treated by activating serotonin receptors is a mental illness. Therefore, the present application also includes a method for treating a mental illness, which includes administering a therapeutically effective amount of one or more compounds of the present application to a subject in need. The present application also includes the use of one or more compounds of the present application for treating mental illness, and the use of one or more compounds of the present application for preparing a drug for treating mental illness. The present application also includes one or more compounds of the present application for treating mental illness.

[0470] In some embodiments, the treatment of a psychotic disorder has no hallucinogenic effect in a subject, or has reduced hallucinogenic effect in a subject compared to the hallucinogenic effect of administering an equivalent amount of a hallucinogenic drug, such as psilocybin, DMT, or 5-MeO-DMT. In some embodiments, the hallucinogenic drug is psilocybin. In some embodiments, the treatment of a psychotic disorder has no hallucinogenic effect in a subject, or has reduced hallucinogenic effect in a subject compared to the hallucinogenic effect of administering an equivalent amount of psilocybin.

[0471] In some embodiments, the psychiatric disorder is selected from anxiety disorders (e.g., generalized anxiety disorder, panic disorder, social anxiety disorder, and specific phobia); depression disorders (such as hopelessness, loss of pleasure, fatigue, and suicidal thoughts); mood disorders (e.g., depression, bipolar disorder, cancer-related depression, anxiety disorders, and cyclothymic disorder); psychotic disorders (such as hallucinations, delusions, schizophrenia); impulse control and addiction disorders (such as pyromania (fire setting), kleptomania (stealing), and compulsive gambling; alcohol addiction; drug addiction (such as opioid addiction)); personality disorders (such as antisocial personality disorder, obsessive-compulsive personality disorder, and paranoid personality disorder); obsessive-compulsive disorder (OCD); and disorder, OCD) (such as thoughts or fears that cause the subject to perform certain rituals or lifestyle habits); post-traumatic stress disorder (PTSD); stress response syndrome (formerly known as adjustment disorder); dissociative disorder (formerly known as multiple personality disorder, or "split personality", and depersonalization disorder); factitious disorder; sexual and gender disorders (such as sexual dysfunction, gender identity disorder, and paraphilia); somatic symptom disorder (formerly known as psychosomatic disorder or somatoform disorder); and combinations thereof. In some embodiments, the psychiatric disorder is postpartum depression.

[0472] In some embodiments, the diseases, disorders, or conditions treated by activating serotonin receptors include cognitive impairment; ischemia (including stroke); neurodegeneration; refractory substance use disorder; sleep disorders; pain (e.g., social pain, acute pain, cancer pain, chronic pain, breakthrough pain, bone pain, soft tissue pain, neuralgia, referred pain, phantom limb pain, neuropathic pain, cluster headache, and migraine); obesity and eating disorders; epilepsy and spastic disorders; neuronal cell death; excitotoxic cell death; or a combination thereof.

[0473] In some embodiments, the disease, disorder or condition treated by activating serotonin receptors is neurodegeneration. In some embodiments, the disease, disorder or condition treated by activating serotonin receptors is decreased brain-derived neurotrophic factor (BDNF), mammalian target of rapamycin (mTOR) activation and / or inflammation.

[0474] In some embodiments, the psychiatric disorder is selected from hallucinations and delusions, and combinations thereof.

[0475] In some embodiments, the hallucination is selected from the group consisting of visual hallucinations, auditory hallucinations, olfactory hallucinations, gustatory hallucinations, tactile hallucinations, proprioceptive hallucinations, balance-receptive hallucinations, nociceptive hallucinations, thermal-receptive hallucinations, and temporal-receptive hallucinations, and combinations thereof.

[0476] In some embodiments, the disease, disorder or condition treated by activating serotonin receptors is a psychotic disorder or a psychotic symptom. Therefore, the present application also includes a method for treating a psychotic disorder or a psychotic symptom, which comprises administering a therapeutically effective amount of one or more compounds of the present application to a subject in need thereof.

[0477] The present application also includes the use of one or more compounds of the present application for treating psychosis or psychotic symptoms, and the use of one or more compounds of the present application for preparing a medicament for treating psychosis or psychotic symptoms. The present application also includes one or more compounds of the present application for treating psychosis or psychotic symptoms.

[0478] In some embodiments, administering a therapeutically effective amount of a compound of the present application to a subject in need thereof does not result in a worsening of psychosis or psychotic symptoms, such as, but not limited to, hallucinations and delusions. In some embodiments, administering a therapeutically effective amount of a compound of the present application to a subject in need thereof results in an improvement in psychosis or psychotic symptoms, such as, but not limited to, hallucinations and delusions. In some embodiments, administering a therapeutically effective amount of a compound of the present application to a subject in need thereof results in an improvement in psychosis or psychotic symptoms.

[0479] In some embodiments, the compounds of the present application can be used to treat central nervous system (CNS) disorders in a subject in need of treatment, which comprises administering to the subject a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0480] Therefore, in some embodiments, the disease, disorder or condition treated by activating serotonin receptors is a central nervous system (CNS) disease, disorder or condition and / or a neurological disease, disorder or condition. Therefore, the present application also includes a method for treating a CNS disease, disorder or condition and / or a neurological disease, disorder or condition, comprising administering a therapeutically effective amount of one or more compounds of the present application to a subject in need. The present application also includes one or more compounds of the present application for the treatment of CNS diseases, disorders or conditions and / or neurological diseases, disorders or conditions, and one or more compounds of the present application for the preparation of drugs for the treatment of CNS diseases, disorders or conditions and / or neurological diseases, disorders or conditions. The present application also includes one or more compounds of the present application for the treatment of CNS diseases, disorders or conditions and / or neurological diseases, disorders or conditions. In some embodiments, the CNS disease, disorder or condition and / or the nervous system disease, disorder or condition is selected from a nervous system disease, including neurodevelopmental diseases and neurodegenerative diseases, such as Alzheimer's disease; precocious dementia; Alzheimer's disease; vascular dementia; dementia with Lewy bodies; cognitive impairment, Parkinson's disease and Parkinson's related disorders (e.g., Parkinson's disease, corticobasal degeneration and supranuclear palsy); epilepsy; CNS trauma; CNS infection; CNS inflammation; stroke; multiple sclerosis; Huntington's disease; mitochondrial disease; fragile X syndrome; Angelman syndrome; hereditary ataxias; neuro-otology and oculomotor disorders; retinal neurodegenerative diseases; amyotrophic lateral sclerosis; tardive dyskinesia; ADHD; attention deficit hyperactivity disorder and attention deficit disorder; restless legs syndrome; Tourette's syndrome syndrome; schizophrenia; autism spectrum disorder; tuberous sclerosis; Rett syndrome; cerebral palsy; reward system disorders (including eating disorders (such as anorexia nervosa ("AN") and bulimia nervosa ("BN")); and binge eating disorder ("BED")), trichotillomania, dermotillomania, nail biting; migraine; fibromyalgia; and peripheral neuropathy of any etiology, and combinations thereof.

[0481] In some embodiments, the compounds of the present application can be used to treat endophenotypes and / or symptom groups of various neuropsychiatric disorders and CNS disorders in a subject in need of treatment, comprising administering to the subject a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0482] Therefore, in some embodiments, the disease, disorder or condition treated by activating serotonin receptors is an endophenotype or symptom group associated with the disease, disorder or condition. Therefore, the present application also includes a method for treating an endophenotype or symptom group associated with a disease, disorder or condition treated by activating serotonin receptors, which includes administering a therapeutically effective amount of one or more compounds of the present application to a subject in need. The present application also includes the use of one or more compounds of the present application for treating an endophenotype and / or symptom group associated with a disease, disorder or condition treated by activating serotonin receptors, and the use of one or more compounds of the present application for preparing a drug for treating an endophenotype and / or symptom group associated with a disease, disorder or condition treated by activating serotonin receptors. The present application also includes one or more compounds of the present application for treating an endophenotype and / or symptom group associated with a disease, disorder or condition treated by activating serotonin receptors. In some embodiments, the endophenotype and / or symptom group is associated with a disease, disorder or condition selected from a neuropsychiatric disease, disorder or condition and / or a nervous system disease, disorder or condition. In some embodiments, the nervous system disease is a CNS disease, disorder or condition.

[0483] In some embodiments, endophenotypes and / or symptom clusters are associated with neurodevelopmental and neurodegenerative diseases (e.g., apathy, anhedonia, impaired attention, impaired memory, deviated negative emotions, hypomania, impaired executive function, impulsive behavior, depressed mood, decreased libido, sensory gating, impaired prepulse inhibition, aggressive behavior, suicidal ideation, obesity, increased arousal, decreased arousal, hypersexuality, decreased exploratory behavior, hyperactivity, hypoactivity, sleep disturbances, incontinence, impaired social perception, rumination, and combinations thereof).

[0484] In some embodiments, the endophenotype and / or symptom cluster is selected from apathy, anhedonia, impaired attention, impaired memory, deviated negative emotions, hypomania, impaired executive function, impulsive behavior, depressed mood, decreased libido, sensory gating, impaired prepulse inhibition, aggressive behavior, suicidal ideation, obesity, increased arousal, decreased arousal, hypersexuality, decreased exploratory behavior, hyperactivity, hypoactivity, sleep disturbance, incontinence, impaired social perception, and rumination.

[0485] In some embodiments, a "subject in need thereof" is a subject suffering from the disease, disorder, or condition to be treated.

[0486] In some embodiments, a "subject in need thereof" is a subject expressing the endophenotype and / or symptom cluster to be treated.

[0487] In some embodiments, the subject is a mammal. In another embodiment, the subject is a human. In some embodiments, the subject is a non-human animal. In some embodiments, the subject is a canine. In some embodiments, the subject is a feline. Therefore, the compounds, methods and uses of the present application are directed to human and veterinary diseases, disorders and conditions.

[0488] In some embodiments, the compounds of the present application are useful for treating behavioral problems in feline or canine subjects.

[0489] Therefore, in some embodiments, the disease, disorder or condition treated by activating serotonin receptors is a behavioral problem of a feline or canine subject. Therefore, the present application also includes a method for treating behavioral problems, which includes administering a therapeutically effective amount of one or more compounds of the present application to a non-human subject in need. The present application also includes the use of one or more compounds of the present application for treating behavioral problems of non-human subjects, and the use of one or more compounds of the present application for preparing a medicament for treating behavioral problems of non-human subjects. The present application also includes one or more compounds of the present application for treating behavioral problems of non-human subjects.

[0490] In some embodiments, the behavioral problem is selected from, but not limited to, anxiety, fear, stress, sleep disturbance, cognitive dysfunction, aggressive behavior, making excessive noise, scratching, biting, and combinations thereof.

[0491] In some embodiments, the non-human subject is a canine. In some embodiments, the non-human subject is a feline.

[0492] The present application also includes a method for treating a disease, disorder or condition by activating serotonin receptors, comprising administering to a subject in need thereof a therapeutically effective amount of one or more compounds of the present application in combination with another known agent for treating a disease, disorder or condition by activating serotonin receptors. The present application also includes the use of a combination of one or more compounds of the present application with another known agent for treating a disease, disorder or condition by activating serotonin receptors for treating a disease, disorder or condition by activating serotonin receptors, and the use of a combination of one or more compounds of the present application with another known agent for treating a disease, disorder or condition by activating serotonin receptors for preparing a medicament for treating a disease, disorder or condition by activating serotonin receptors. The present application also includes a combination of one or more compounds of the present application with another known agent for treating a disease, disorder or condition by activating serotonin receptors for treating a disease, disorder or condition by activating serotonin receptors.

[0493] In some embodiments, the disease, disorder or condition treated by activating serotonin receptors is a mental illness. In some embodiments, the mental illness is selected from hallucinations and delusions and combinations thereof. In some embodiments, the disease, disorder or condition treated by activating serotonin receptors is a central nervous system (CNS) disorder. In some embodiments, the disease, disorder or condition treated by activating serotonin receptors is a psychotic disorder or a psychotic symptom. In some embodiments, the disease, disorder or condition treated by activating serotonin receptors is a behavioral problem in a non-human subject.

[0494] In some embodiments, the disease, disorder or condition treated by activating serotonin receptors is a psychiatric disorder, and one or more compounds of the present application are administered in combination with one or more additional treatments for psychiatric disorders. In some embodiments, additional treatments for psychiatric disorders are selected from antipsychotics, including typical antipsychotics and atypical antipsychotics; antidepressants (including selective serotonin reuptake inhibitors (SSRI) and selective norepinephrine reuptake inhibitors (SNRI)), tricyclic antidepressants and monoamine oxidase inhibitors (MAOI) (e.g., bupropion); anti-anxiety drugs (including benzodiazepines (such as alprazolam)); mood stabilizers (such as lithium and anticonvulsants (such as carbamazepine, divalproex sodium (valproic acid), lamotrigine, gabapentin and topiramate)). In some embodiments, the anticonvulsant is levetiracetam (leviteracetam) or brivaracetam (brivaracetam).

[0495] In some embodiments, the disease, disorder or condition treated by activating serotonin receptors is selected from attention deficit hyperactivity disorder and attention deficit disorder and their combination. In some embodiments, the disease, disorder or condition treated by activating serotonin receptors is attention deficit hyperactivity disorder and / or attention deficit disorder and their combination, and one or more compounds of the present application are used in combination with one or more other treatments for attention deficit hyperactivity disorder and / or attention deficit disorder and their combination. In some embodiments, the other treatment for attention deficit hyperactivity disorder and / or attention deficit disorder and their combination is selected from methylphenidate, atomoxetine and amphetamine and their combination.

[0496] In some embodiments, the disease, disorder or condition treated by activating serotonin receptors is dementia or Alzheimer's disease, and one or more compounds of the present application are administered in combination with one or more additional treatments for dementia or Alzheimer's disease. In some embodiments, additional treatments for dementia and Alzheimer's disease are selected from acetylcholinesterase inhibitors, NMDA antagonists and muscarinic agonists and antagonists and nicotinic agonists.

[0497] In some embodiments, the acetylcholinesterase inhibitor is selected from donepezil, galantamine, rivastigmine, and phenylserine, and combinations thereof.

[0498] In some embodiments, the NMDA antagonist is selected from MK-801, ketamine, phencyclidine, and memantine, and combinations thereof.

[0499] In some embodiments, the nicotinic agonist is nicotine, nicotinic acid, a nicotinic alpha 7 agonist, or an alpha 2 beta 4 agonist, or a combination thereof.

[0500] In some embodiments, the muscarinic agonist is a muscarinic M1 agonist or a muscarinic M4 agonist, or a combination thereof.

[0501] In some embodiments, the muscarinic antagonist is a muscarinic M2 antagonist.

[0502] In some embodiments, the disease, disorder or condition treated by activating serotonin receptors is a psychotic disorder or a psychotic symptom, and one or more compounds of the present application are administered in combination with one or more additional treatments for the psychotic disorder or psychotic symptoms. In some embodiments, the additional treatment for the psychotic disorder or psychotic symptoms is selected from a typical antipsychotic and an atypical antipsychotic.

[0503] In some embodiments, the typical antipsychotic is selected from the group consisting of acepromazine, acetophenazine, benperidol, bromperidol, butaperazine, carfenazine, chlorproethazine, chlorpromazine, chlorprothixene, clopenthixol, cyamemazine, ne), dixyrazine, droperidol, fluanisone, flupentixol, fluphenazine, fluspirilene, haloperidol, levomepromazine, lenperone, loxapine, mesoridazine, metitepine, molindone, moperone, oxypertine, oxyprotepine, penfluridol, perazine, periciazine, perphenazine, pimozide, pipamperone, piperacetazine, pipotiazine, prochlorperazine, promazine, prothiopentyl

[0013] The invention relates to thiabendyl, spiperone, sulforidazine, thiopropazate, thioproperazine, thioridazine, thiothixene, timiperone, trifluoperazine, trifluperidol, triflupromazine and zuclopenthixol, and combinations thereof.

[0504] In some embodiments, the atypical antipsychotic is selected from amoxapine, amisulpride, aripiprazole, asenapine, blondanserin, brexpiprazole, cariprazine, carpipramine, clocapramine, clorotepine, clotiapine, clozapine, iloperidone, levosulpiride, lurasidone, melperone, mosapramine, nemonapride, olanzapine, paliperidone, perospirone, quetiapine, remoxipride, reserpine, risperidone, sertindole, sulpiride, sultopride, tiapride, veralipride, ziprasidone and zotepine, and combinations thereof.

[0505] In some embodiments, the disease, disorder or condition treated by activating serotonin receptors is a psychiatric disorder, and one or more compounds of the present application are administered in combination with one or more additional treatments for the psychiatric disorder. In some embodiments, the additional treatment for the psychiatric disorder is selected from a typical antipsychotic and an atypical antipsychotic.

[0506] In some embodiments, the effective amount varies depending on factors such as the disease state, age, sex and / or weight of the subject or species. In some embodiments, the amount of one or more given compounds that will correspond to an effective amount will vary depending on a variety of factors, such as the given drug or compound, the drug formulation, the route of administration, the condition, the type of disease or disorder, the identity of the subject to be treated, etc., but can still be routinely determined by those skilled in the art.

[0507] In some embodiments, the compound of the present application is applied once, twice, three times or four times per year. In some embodiments, the compound of the present application is applied at least once a week. However, in another embodiment, the compound is applied to the subject at a frequency of about once every two weeks, three weeks or a month. In another embodiment, the compound is applied once a week to once a day. In another embodiment, the compound is applied 1, 2, 3, 4, 5 or 6 times a day. The length of the treatment period depends on a variety of factors, such as the severity of the disease, disorder or condition, the age of the subject, the concentration and / or activity of the compound of the present application and / or their combination. It should also be understood that the effective dose of the compound for treatment can be increased or decreased during a specific treatment regimen. By standard diagnostic assays known in the art, changes in dosage may occur and become apparent. In some cases, long-term administration is required. For example, the compound is applied to the subject in an amount sufficient to treat the subject and duration.

[0508] In some embodiments, the compounds of the present application are administered at a dose that causes hallucination or psychotomimetic and are taken in combination with psychotherapy or therapy, and can be administered once, twice, three times, or four times a year. However, in some embodiments, the compounds are administered to subjects at a dose that causes non-hallucination or psychotomimetic once a day, once every two days, once every three days, once a week, once every two weeks, once a month, once every two months, or once every three months.

[0509] The compounds of the present application are used alone or in combination with another known agent (e.g., the compounds of the present application) that can be used to treat a disease, disorder, or condition by activating serotonin receptors. When used in combination with another known agent that can be used to treat a disease, disorder, or condition by activating serotonin receptors, one embodiment is to administer the compounds of the present application simultaneously with those agents. As used herein, "simultaneous administration" of two substances to a subject means providing each of the two substances so that they are active in the individual at the same time. The exact details of administration will depend on the pharmacokinetics of the two substances when they are present in each other, and may include administering the two substances within a few hours of each other, or even administering one substance within 24 hours of administering another substance if the pharmacokinetics are appropriate. The design of a suitable dosing regimen is routine for those skilled in the art. In a particular embodiment, the two substances will be administered substantially simultaneously, i.e., a few minutes apart from each other, or administered in a single composition containing the two substances. Another embodiment of the present application is to administer a combination of agents to a subject in a non-simultaneous manner. In some embodiments, the compounds of the present application are administered simultaneously or sequentially with another therapeutic agent in separate unit dosage forms, or administered together in a single unit dosage form. Thus, the present application provides a single unit dosage form comprising one or more compounds of the present application, an additional therapeutic agent, and a pharmaceutically acceptable carrier.

[0510] The dosage of the compound of the present application varies according to many factors (e.g., the pharmacodynamic properties of the compound, the mode of administration, the age, health and weight of the recipient, the nature and extent of the symptoms, the frequency of treatment and the type of concurrent treatment (if any), and the clearance rate of the compound in the subject to be treated). Those skilled in the art can determine the appropriate dosage based on the above factors. In some embodiments, one or more compounds of the present application are initially administered at a suitable dosage, which is adjusted as needed according to the clinical response. The dosage is usually selected to maintain the serum level of one or more compounds of the present application at about 0.01 μg / cc to about 1000 μg / cc or about 0.1 μg / cc to about 100 μg / cc. As a representative example, for adults, the oral dosage of one or more compounds of the present application will be from about 10 μg / day to about 1000 mg / day, suitably from about 10 μg / day to about 500 mg / day, and more suitably from about 10 μg / day to about 500 mg / day. For parenteral administration, the representative amount of administration is about 0.0001 mg / kg to about 10 mg / kg, about 0.001 mg / kg to about 100 mg / kg, about 0.1 mg / kg to about 1000 mg / kg, or about 1 mg / kg to about 10000 mg / kg. For oral administration, the representative amount is about 0.001 μg / kg to about 10 mg / kg, about 0.1 μg / kg to about 100 mg / kg, about 0.01 μg / kg to about 1000 mg / kg, or about 1 μg / kg to about 10000 mg / kg. For the administration of suppositories, the representative amount is about 0.1 mg / kg to about 10 mg / kg or about 0.1 mg / kg to about 100 mg / kg.

[0511] In some embodiments, the dose is generally selected to maintain the serum level of one or more compounds of the present application at about 0.01 μg / cc to about 1000 μg / cc or about 0.1 μg / cc to about 100 μg / cc. As a representative example, for adults, the oral dose of one or more compounds of the present application will be about 10 μg / day to about 1000 mg / day, suitably about 10 μg / day to about 500 mg / day, and more suitably about 10 μg / day to about 200 mg / day. For parenteral administration, the representative amount of administration is about 0.0001 mg / kg to about 10 mg / kg, about 0.0001 mg / kg to about 1 mg / kg, about 0.01 mg / kg to about 0.1 mg / kg, or about 0.0001 mg / kg to about 0.01 mg / kg. For oral administration, a representative amount is about 0.001 μg / kg to about 10 mg / kg, about 0.1 μg / kg to about 10 mg / kg, about 0.01 μg / kg to about 1 mg / kg, or about 0.1 μg / kg to about 1 mg / kg. For administration in the form of a suppository, a representative amount is about 0.1 mg / kg to about 10 mg / kg or about 0.1 mg / kg to about 1 mg / kg.

[0512] In some embodiments of the present application, the composition is formulated for oral administration, and one or more compounds are suitably in tablet form, each tablet containing 0.1 mg, 0.25 mg, 0.5 mg, 0.75 mg, 1.0 mg, 5.0 mg, 10.0 mg, 20.0 mg, 25.0 mg, 30.0 mg, 40.0 mg, 50.0 mg, 60.0 mg, 70.0 mg, 75.0 mg, 80.0 mg, 90.0 mg, 100.0 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg, 850 mg, 900 mg, 950 mg or 1000 mg of active ingredient (one or more compounds of the present application). In some embodiments of the present application, one or more compounds of the present application are administered in a dose once daily, weekly, or monthly, or the total daily dose is divided into two, three, or four daily doses.

[0513] In some embodiments, the compounds of the present application are used or administered in an effective amount, including administering a dose or dosage regimen that has no clinically significant hallucinogenic / psychotomimetic effects. In some embodiments, the compounds of the present application are used or administered in an effective amount, including administering a dose or dosage regimen that provides a clinical effect similar to a human plasma psilocybin Cmax of 4 ng / mL or less and / or a human 5-HT Cmax of 40% or less. 2AClinical efficacy demonstrated by human CNS receptor occupancy or human plasma psilocybin Cmax of 1 ng / mL or less and / or human 5-HT of 30% or less 2A In some embodiments, the compounds of the present application are used or administered in an effective amount, including administering a dose or administration regimen that provides a clinical effect similar to 4 ng / mL or greater human plasma psilocybin Cmax and / or 40% or greater human 5-HT 2A Clinical effects demonstrated by human CNS receptor occupancy or 10 ng / mL or greater human plasma psilocybin Cmax and / or 60% or greater human 5-HT 2A Clinical effects manifested by human CNS receptor occupancy. In some embodiments, the compounds of the present application are used or administered in an effective amount, including administering a dose or dosage regimen that provides a clinical effect similar to that manifested by a human plasma psilocybin Tmax of more than 60 minutes, more than 120 minutes, or more than 180 minutes.

[0514] For the sake of clarity, in the above, the term "compound" also includes embodiments that mention one or more compounds. Likewise, the term "compound of the present application" also includes embodiments that mention only one compound.

[0515] V. Preparation of Compounds

[0516] The compounds of the present application can be prepared by various synthetic methods. The selection of specific structural features and / or substituents may affect the selection of one method relative to another method. It is within the knowledge of those skilled in the art to select a specific method for preparing a given compound of the present application. Some starting materials for preparing the compounds of the present application can be obtained from commercial chemical sources, or can be extracted from cells, plants, animals or fungi. Other starting materials are easily prepared from available precursors using direct conversions well known in the art, such as described below. In the schemes of some embodiments of the preparation methods of the compounds of the present application shown below, all variables are as defined in Formula I, unless otherwise indicated.

[0517] In some embodiments, as shown in Scheme 1, the compound of Formula I is prepared by reducing the corresponding indole compound A, wherein R 2’ and R 2” is H or D, where R 1 , R 2 , R 3 , R 4 , R 5 and R 6 As defined in Formula I.

[0518]

[0519] In some embodiments, the reduction is carried out using a silane reducing agent (e.g., triethylsilane or a deuterated form thereof in an acid such as trifluoroacetic acid). In some embodiments, the reaction is made enantioselective or diastereoselective by using a chiral reducing agent or a chiral auxiliary. In some embodiments, the reduction is carried out using any suitable reducing conditions known in the art, such as those described in He, Yi et al: Tetrahedron Letters (2014), 55(29), 3938-3941 and Somei, Masanori et al: Heterocycles (1995), 40(1), 119-22.

[0520] In some embodiments, as shown in Scheme 2, a compound of Formula A can be obtained:

[0521]

[0522] Thus, in some embodiments, in the presence of a palladium catalyst, for example, using the conditions described in Fricke et al, Chem. Eur. J., 2019, 25(4): 897–903], an in situ iodoaniline compound of formula B (wherein R 1 and R 3 -R 6 As defined in formula I) and an alkyne of formula C (wherein R 2 and Q are defined in Formula I) to provide a compound of Formula A. Those skilled in the art will appreciate that by using a compound of Formula B (wherein R 1 is a suitable protecting group) and removing the protecting group to provide a compound of Formula A. The reaction shown in Scheme 2 can also be used to provide a compound of Formula A.

[0523] In some embodiments, when Q is And R 32 and R 33 When is H or D, the compound of formula A is prepared as shown in Scheme 3:

[0524]

[0525]

[0526] Thus, in some embodiments, a compound of formula D (wherein R 1 -R 6 As defined in formula I) and a compound of formula F (wherein R 34 and R 36 -R 41As defined in Formula I, R 35 As defined in Formula I or is a suitable protecting group, and LG is a suitable leaving group (such as chloro)) to provide a compound of Formula G. For example, the keto group in the compound of Formula G is reduced using an Al-based reducing agent (such as lithium borohydride, lithium aluminum hydride or lithium aluminum deuteride) to provide a compound of Formula A, wherein R 32 and R 33 is H or D. If R 35 is a protecting group, it is removed in a single step, or when the protecting group is removed in the presence of an Al-based reducing agent, R 35 is removed during the reduction of the compound of formula G.

[0527] Those skilled in the art will appreciate that a similar reaction sequence can be used to prepare compounds of formula A, wherein Q is

[0528] In some embodiments, when Q is is a single bond, R 15 and R 12 As defined in Formula I, R 8 and R 9 Both are H, and R 10 , R 11 , R 13 and R 14 When is H or D, the compound of formula A is prepared as shown in Scheme 4:

[0529]

[0530] Thus, in some embodiments, the compound of formula D (wherein R 1 -R 6 As defined in formula I) and a compound of formula H (wherein R 12 As defined in Formula I or is a suitable protecting group and R 15 As defined in Formula I) in a suitable solvent such as acetic acid to provide a compound of Formula J. Reduction of the keto group in the compound of Formula J, for example using an Al-based reducing agent such as lithium borohydride, lithium aluminum hydride or lithium aluminum deuteride, provides a compound of Formula A, wherein Q is (Q1), is a single bond, R 15 As defined in Formula I, R 8 and R 9 Both are H, and R 10 , R 11 , R 13 and R 14 is H or D. If R 12is a protecting group, it is removed in a single step, or when the protecting group is removed in the presence of an Al-based reducing agent, R 12 is removed during the reduction of the compound of formula J. Those skilled in the art will appreciate that a similar reaction sequence can be used to prepare compounds of formula A, wherein Q is and For a single key.

[0531] In some embodiments, when Q is is a single bond or a double bond, R 8 and R 15 is H (when is a single key) or does not exist (when When R 10 , R 11 , R 13 and R 14 All are H and R 12 As defined in Formula I, compounds of Formula A are prepared as shown in Scheme 5:

[0532]

[0533] Thus, in some embodiments, the compound of formula D (wherein R 1 -R 6 As defined in formula I) with a dihalide or N-halosuccinimide compound (wherein X is a halide (such as Br or I)) to provide an intermediate compound of formula K, which reacts with a borono maleimido compound of formula L (wherein R 12 As defined in formula I or a suitable protecting group) in the presence of a palladium catalyst to provide a compound of formula A, wherein Q is is a double bond, and R 8 and R 15 Does not exist, R 10 , R 11 , R 13 and R 14 All are H and R 12 The compound is then hydrogenated by methods known in the art, such as in the presence of palladium on carbon ("Pd / C"), as defined in Formula I, to provide a compound of Formula A, wherein Q is is a single bond, R 8 , R 9 , R 10 , R 11 , R 13 and R 14 All are H and R12 As defined in Formula I. Those skilled in the art will appreciate that a similar reaction sequence can be used to prepare compounds of Formula A, wherein Q is

[0534] In some embodiments, when Q is is a single bond or a double bond, R 8 and R 15 is H (when is a single key) or does not exist (when is a double bond), and R 9 , R 10 , R 11 , R 12 , R 13 and R 14 As defined in Formula I, compounds of Formula A are prepared as shown in Scheme 6:

[0535]

[0536] Thus, in some embodiments, the compound of formula D (wherein R 1 -R 6 As defined in formula I) and an oxo-pyrrolidine of formula N (wherein R 9 , R 10 , R 11 , R 12 , R 13 and R 14 As defined in formula I), for example in a suitable solvent such as ethanol (EtOH) at a suitable temperature such as the reflux temperature of the reaction mixture to provide a compound of formula A, wherein Q is is a double bond, R 8 and R 15 does not exist, and R 9 , R 10 , R 11 , R 12 , R 13 and R 14 The compound is then reduced by methods known in the art, such as in the presence of palladium on carbon ("Pd / C"), as defined in Formula I, to provide a compound of Formula A, wherein Q is is a single bond, R 8 and R 15 is H, and R 9 , R 10 , R 11 , R 12 , R 13 and R 14As defined in Formula I. Those skilled in the art will appreciate that a similar reaction sequence can be used to prepare compounds of Formula A, wherein Q is

[0537] In some embodiments, as shown in Scheme 7, a compound of Formula A can be obtained:

[0538]

[0539] Thus, in some embodiments, the compound of formula M (wherein R 1 -R 3 , R 5 , R 6 As defined in formula I, and X' is a halogen (such as Br)) and a boric acid ester of formula N (wherein R 4 As defined in Formula I) in the presence of a palladium catalyst (such as (triphenylphosphine) palladium (0) (Pd (PPH3) 4)) and a suitable base (such as potassium carbonate), in a suitable solvent (such as dioxane and water), under suitable conditions to provide a compound of Formula A. In some embodiments, suitable conditions are as described in CN114249681A and Russell, Michael GNet al: Journal of Medicinal Chemistry (2001), 44 (23), 3881-3895.

[0540] In some embodiments, as shown in Scheme 8, a compound of formula A can be obtained, wherein R 4 is alkoxy or OA:

[0541]

[0542] Thus, in some embodiments, the compound of formula O (wherein R 4 is OH, and R 1 -R 3 , R 5 , R 6 As defined in formula I) and a compound of formula P (wherein X" is a suitable leaving group such as I or Br, and R 4 ' is alkyl or A as defined in Formula I) under suitable conditions (such as in the presence of a base (such as potassium carbonate) and in a suitable solvent (such as acetone)) to provide a compound of Formula A. Alternatively, in some embodiments, a compound of Formula O (wherein R 4 is OH, and R 1 , R 2 , R 3 , R 5 , R 6As defined in Formula I) with a suitable alcohol under suitable Mitsunobu reaction conditions (e.g., in the presence of diethyl azodicarboxylate (DEAD) and triphenylphosphine). In some embodiments, suitable conditions are any suitable conditions known in the art, such as the coupling conditions described in WO2005009958A1 and US6133287.

[0543] In some embodiments, as shown in Scheme 9, a compound of formula A can be obtained, wherein R 4 is alkoxy or OA.

[0544]

[0545] Thus, in some embodiments, the compound of formula Q (wherein R 4 is OH, and R 1 -R 3 , R 5 and R 6 As defined in formula I) and a compound of formula P (wherein X" is a suitable leaving group such as I or Br, and R 4 ' is alkyl or A as defined in Formula I) under suitable conditions (such as in the presence of a base (such as potassium carbonate) and in a suitable solvent (such as acetone)) to provide a compound of Formula D. Alternatively, in some embodiments, a compound of Formula Q (wherein R 4 is OH, and R 1 , R 2 , R 3 , R 5 and R 6 As defined in Formula I) with a suitable alcohol under suitable Mitsunobu reaction conditions (e.g., in the presence of diethyl azodicarboxylate (DEAD) and triphenylphosphine). In some embodiments, suitable conditions are any suitable conditions known in the art, such as the coupling conditions described in WO2005009958A1 and US6133287. Using methods similar to those described in Schemes 3 to 6 above, compounds of D can be converted to compounds of Formula A.

[0546] Those skilled in the art will appreciate that similar methods as described in Scheme 7 or 8 can be used to provide compounds of Formula I, wherein R 3 , R 5 , R 5 and R 6 Any one of them is an alkoxy group.

[0547] Those skilled in the art will appreciate that racemic compounds of Formula I can be resolved into individual diastereomers or isomers using techniques known in the art including, for example, chromatography, such as chiral HPLC and silica gel chromatography.

[0548] A compound of formula D or A (wherein R 2 , R 3 -R 6 One or more of the is deuterium) can be obtained, for example, using a hydrogen-deuterium exchange reaction on a suitable starting substrate (wherein the exchange reaction is catalyzed by Pd / C in D2O as described in Esaki, H. et al. Tetrahedron, 2006, 62: 10954-10961) and modifications thereof known to those skilled in the art.

[0549] The compound of formula A (wherein R 4 OCD3) can be obtained, for example, using the method described in Xu, YZ and Chen, CJ Label Compd. Radiopharm. (2006) 49: 897-902 and modifications and adaptations thereof known to those skilled in the art.

[0550] Compounds of Formula B, C, D, F, H, L, M and N, as well as other reagents used in the above schemes, are available from commercial sources or can be readily prepared using methods known in the art.

[0551] Those skilled in the art will appreciate that the intermediates and final compounds in the above schemes may be subjected to further manipulation of substituents using known chemistry to provide alternative compounds of the present application.

[0552] Nucleophilic displacement reaction conditions include any known reaction methods for nucleophilic reagents to replace leaving groups to form bonds, which are compatible with the intermediates and products shown in the above schemes, or can be used to prepare compounds of the present application. In some embodiments, such conditions include combining reactants in a suitable solvent in the presence of a base.

[0553] The salts of the compounds of the present application can be formed by methods known to those of ordinary skill in the art, for example, by reacting the compounds of the present application with a certain amount of acid or base (e.g., an equal amount of acid or base) in a medium (e.g., a medium in which the salt is precipitated) or in an aqueous medium, and then lyophilizing.

[0554] The formation of solvates will vary according to the compound and the solvate. Typically, solvates are formed by dissolving the compound in a suitable solvent and separating the solvate by cooling or using an anti-solvent. Solvates are typically dried or azeotropic at ambient conditions. Those skilled in the art can select suitable conditions for forming a specific solvate. Examples of suitable solvents are ethanol, water, etc. When water is a solvent, the molecule is referred to as a "hydrate". The formation of solvates of the compounds of the present application will vary according to the compound and the solvate. Typically, solvates are formed by dissolving the compound in a suitable solvent and separating the solvate by cooling or using an anti-solvent. Solvates are typically dried or azeotropic at ambient conditions. Those skilled in the art can select suitable conditions for forming a specific solvate.

[0555] The prodrug of the compound of the present application can be, for example, a conventional ester formed with an available hydroxyl, thiol, amino or carboxyl group. For example, an available hydroxyl or amino group can be acylated in the presence of a base and optionally in an inert solvent (e.g., an acyl chloride in pyridine) using an activated acid.

[0556] The isotopically enriched compounds of the present application and pharmaceutically acceptable salts and / or solvates thereof can be prepared by conventional techniques well known to those skilled in the art or by methods analogous to those described in the schemes and examples herein, using appropriate isotopically enriched reagents and / or intermediates without undue experimentation.

[0557] In the whole process described herein, it should be understood that, where appropriate, suitable protecting groups will be added to various reactants and intermediates in a manner that is readily understood by those skilled in the art, and subsequently removed therefrom. The conventional procedures using such protecting groups and examples of suitable protecting groups are described in, for example, "Protective Groups in Organic Synthesis", TW Green, PGM Wuts, Wiley-Interscience, New York, (1999). It should also be understood that converting a group or substituent into another group or substituent by chemical manipulation can be performed on any intermediate or final product on the synthetic path toward the final product, wherein the possible types of conversion are only limited to the inherent incompatibility of other functional groups carried by the molecule at this stage with the conditions or reagents used in the conversion. Such inherent incompatibility and methods of overcoming them by performing appropriate conversions and synthesis steps in appropriate order are readily understood by those skilled in the art. Examples of conversions are given herein, and it should be understood that the described conversions are not limited to general groups or substituents as examples of conversions. References and descriptions of other suitable transformations are given in "Comprehensive Organic Transformations-A Guide to Functional Group Preparations" RC Larock, VHC Publishers, Inc. (1989). References and descriptions of other suitable reactions are described in organic chemistry textbooks, such as "Advanced Organic Chemistry", March, 4th ed. McGraw Hill (1992) or "Organic Synthesis", Smith, McGraw Hill, (1994). Techniques for purifying intermediates and final products include, for example, normal and reverse phase chromatography on columns or rotating plates, recrystallization, distillation, and liquid-liquid or solid-liquid extraction, which are readily understood by those skilled in the art.

[0558] It should also be understood that by chemical operation, a group or substituent is converted into another group or substituent and can be carried out on any intermediate or final product on the synthetic path towards the final product, wherein the possible conversion type is only limited to the inherent incompatibility of other functional groups carried by the molecule at this stage with the conditions or reagents used in the conversion. Such inherent incompatibility and the method of overcoming them by carrying out appropriate conversion and synthesis steps in appropriate order are easily understood by those skilled in the art. The example of conversion is given herein, and it should be understood that the described conversion is not limited to the general group or substituent as the conversion example. In " Comprehensive Organic Transformations-A Guide to Functional Group Preparations " RC Larock, VHC Publishers, Inc. (1989), other suitable conversion references and descriptions are given. The references and descriptions of other suitable reactions are described in organic chemistry textbooks, such as " Advanced Organic Chemistry ", March, 4th ed.McGraw Hill (1992) or " Organic Synthesis ", Smith, McGraw Hill, (1994).

[0559] Techniques for purification of intermediates and final products include, for example, normal and reverse phase chromatography on columns or spinning plates, recrystallization, distillation and liquid-liquid or solid-liquid extraction, as will be readily appreciated by those skilled in the art.

[0560] The products of the methods of the present application can be isolated according to known methods, for example, the compounds can be isolated by evaporation of the solvent, filtration, centrifugation, chromatography or other suitable methods.

[0561] Those skilled in the art will recognize that when a reaction step of the present application is carried out in a variety of solvents or solvent systems, the reaction step can also be carried out in a mixture of suitable solvents or solvent systems.

[0562] Example

[0563] A. Chemical synthesis

[0564] General approach

[0565] All starting materials used herein are either commercially available or described in the literature. 1 H and 13 C NMR spectra were recorded on a Bruker 300, Bruker DPX 400 or Varian + 400 spectrometer, which was used for 1H NMR was operated at 300 MHz, 400 MHz and 400 MHz, respectively, in deuterated chloroform as solvent, using TMS or residual solvent signal as internal reference unless otherwise stated. All reported chemical shifts are in ppm on the delta scale, and the fine splitting of the signals appearing in the recording is usually indicated, for example, as s: singlet, br s: broad singlet, d: doublet, t: triplet, q: quartet, m: multit. Unless otherwise stated, in the following tables, 1 H NMR data were obtained at 400 MHz using CDCl3 as solvent.

[0566] The product was purified using Chem Elut extraction cartridges (Varian, Cat. No. 1219-8002), Mega BE-SI (Bond Elut Silica) SPE cartridges (Varian, Cat. Nos. 12256018; 12256026; 12256034) or by flash chromatography in a silica-packed glass column.

[0567] Example 1: 5-methoxy-3-(((S)-1-methylpyrrolidin-2-yl)methyl)indoline ((S)I-54)

[0568]

[0569] (S)-2-(2-(5-methoxy-1H-indole-3-carbonyl)pyrrolidin-1-yl)-1-phenyl-2- 2 Synthesis of (S)-4-ethyl-1-one: (2-oxo-2-phenyl-1-one) at 0°C 2 A solution of 4-ethyl)-D-proline (17.4 g, 69.806 mmol) in anhydrous THF (100 mL) was treated with thionyl chloride (10.2 mL, 139.613 mmol). The reaction was warmed to room temperature and then refluxed for 2 h. The reaction was warmed to room temperature, the solvent was evaporated and the crude was dried under vacuum to obtain the corresponding acid chloride.

[0570] At 5-10 ℃, 5-methoxy-1H-indole (10.2g, 69.806mmol) is in anhydrous CH2Cl2 (100mL) solution in anhydrous CH2Cl2 (40mL) in above-mentioned crude acid chloride and ethylmagnesium bromide (46.5mL, 139.61mmol, 3M in THF) are simultaneously processed 15min. And stir another 15min at the same temperature.The reaction is quenched with concentrated HCl (10mL), quenched with water (150mL) subsequently, and the product is extracted into CH2Cl2 (2x 150mL).By CH2Cl2 layer saturated NaHCO3 solution (50mL), brine (25mL) washing and dry (Na2SO4). The solvent was evaporated and the crude was purified by flash column chromatography (CH2Cl2 to EtOAc:CH2Cl2, 1:4) on silica gel to obtain the title compound (S)-4 (18.9 g, 71.5%) as a yellow solid; ESI-MS (m / z, %): 401 (M+Na, 100), 379 (MH + ).

[0571] Synthesis of (S)-5-methoxy-3-((1-methylpyrrolidin-2-yl)methyl)-1H-indole ((S)-5): A suspension of lithium aluminum hydride (2.53 g, 66.723 mmol) in anhydrous THF (40 mL) was reacted with (R)-2-(2-(5-methoxy-1H-indole-3-carbonyl)pyrrolidin-1-yl)-1-phenyl-2-yl in anhydrous THF (60 mL) at 0°C. 2 -Ethyl-1-one (5.05g, 13.344mmol)) was treated for 10min. The reaction was warmed to room temperature and then refluxed for 16 hours. The reaction was cooled to 0 ° C and then quenched by continuous addition of water (2.53mL), 2N NaOH solution (2.53mL) and water (2.53mL) in a 15min time period. The reaction was warmed to room temperature and stirred for 30min. The solid was filtered out and washed with THF (2x 50mL). The combined THF layer was evaporated and the crude material was purified on silica gel by column chromatography (MeOH containing 2M NH3:CH2Cl2, 5:95), to obtain the title compound (S) -5 (2.5g, 76.7%) in a light brown jelly. 1H NMR(CDCl3): δ7.98(brs,1H),7.27(d,1H,J=6.0Hz), 7.09(d,1H,J=3.0Hz), 7.03(d,1H,J=1.5Hz), 6.89(dd,1H,J=3.0,6.0Hz), 3.90(s,3H),3.20-3.14(m,2H),2.65-2.59(m,1H),2.51(s,3H),2.27-2.22(m,1H),1.91-1.56(m,5H); ESI-MS(m / z,%):245(MH + ,100).

[0572] Synthesis of 5-methoxy-3-(((S)-1-methylpyrrolidin-2-yl)methyl)indoline ((S)-I-54): A solution of (S)-5-methoxy-3-((1-methylpyrrolidin-2-yl)methyl)-1H-indole (0.33 g, 1.175 mmol) in trifluoroacetic acid (25 mL) was treated with triethylsilane (0.37 mL, 2.350 mmol) and the resulting solution was stirred at 50 °C overnight (16 h). The reaction was warmed to room temperature and the solvent was evaporated. The crude was basified with 4N NaOH solution and the product was extracted into CH2Cl2 (3x50 mL). The combined CH2Cl2 layers were dried (Na2SO4) and the solvent was evaporated to obtain the crude as a brown liquid. The crude was purified by column chromatography on silica gel (2M NH 3 in MeOH:CH 2 Cl 2 , 5:95) to obtain the title compound (S)-I-54 (0.11 g, 38%) as a light brown oil. 1 H NMR(DMSO-d6): δ6.69(s,1H),6.53(dd,1H,J=3.0,6.0Hz),6.42(d,1H,J=6.0Hz),5.02(brs,1H),3.64(s,3H),3.54(t,1H,J =6.0Hz),3.12-2.92(m,3H),2.22(s,3H),2.20-1.93(m,4H),1.68-1.60(m,2H),1.47-1.30(m,2H); ESI-MS(m / z,%):247(MH) + ,100).

[0573] Example 2: 5,6-dimethoxy-3-(((R)-1-methylpyrrolidin-2-yl)methyl)indoline ((R)-I-81)

[0574]

[0575] (R)-2-(2-(5,6-dimethoxy-1H-indole-3-carbonyl)pyrrolidin-1-yl)-1-phenyl-2- 2 Synthesis of (R)-30: (2-oxo-2-phenyl-1l 2 A solution of 4-ethyl)-D-proline (6.0 g, 24.067 mmol) in anhydrous THF (100 mL) was treated with thionyl chloride (3.51 mL, 48.134 mmol). The reaction was warmed to room temperature and then refluxed for 2 h. The reaction was warmed to room temperature, the solvent was evaporated and the crude was dried under vacuum to obtain the corresponding acid chloride.

[0576] At 5-10 ° C, a solution of 5,6-dimethoxy-1H-indole (4.26 g, 24.067 mmol) in anhydrous CH2Cl2 (100 mL) was treated with the above crude acid chloride and ethylmagnesium bromide (16.0 mL, 48.134 mmol, 3M in THF) in anhydrous CH2Cl2 (50 mL) for 15 min at the same time. And stirred for another 15 min at the same temperature. The reaction was quenched with concentrated HCl (10 mL) and treated and purified as described for compound 4 to obtain the title compound (R)-30 (6.2 g, 66%) as a tan solid. 1 H NMR(DMSO-d6): δ11.75(s,1H),8.25(dd,1H,J=3.0,4.5Hz),7.71,7.67(2s,1H),7.40-7.32(m,2H ),7.16-7.00(m,4H),5.24-4.91(m,3H),3.81-3.49(m,8H),2.39-2.30(m,1H),1.91-1.83(m,3H).

[0577] Synthesis of (R)-5,6-dimethoxy-3-((1-methylpyrrolidin-2-yl)methyl)-1H-indole ((R)-31): A suspension of lithium aluminum hydride (0.97 g, 25.613 mmol) in anhydrous THF (25 mL) was reacted with (R)-2-(2-(5,6-dimethoxy-1H-indole-3-carbonyl)pyrrolidin-1-yl)-1-phenyl-21 in anhydrous THF (25 mL) at 0°C. 2 -Ethan-1-one (2.0 g, 5.123 mmol) was treated for 10 min. The reaction was warmed to room temperature and then refluxed for another 16 hours. The reaction was worked up and purified as described for compound 5 to afford the title compound (R)-31 (1.05 g, 75%) as a brown solid. 1H NMR(DMSO-d6): δ10.43(s,1H),6.96(s,1H),6.92(s,1H,J=3.0Hz),6.85(s,1H),3.75(s,6H),2.9 8-2.94(m,2H),2.45-2.29(m,5H),2.12-2.07(m,1H),1.74-1.40(m,4H).ESI-MS(m / z,%):275(MH + ,100).

[0578] Synthesis of 5,6-dimethoxy-3-(((R)-1-methylpyrrolidin-2-yl)methyl)indoline ((R)-I-81): A solution of (R)-5,6-dimethoxy-3-((1-methylpyrrolidin-2-yl)methyl)-1H-indole (1.0 g, 3.645 mmol) in trifluoroacetic acid (50 mL) was treated with triethylsilane (1.16 mL, 7.29 mmol) and the resulting solution was stirred at 50 °C overnight (16 h). The reaction was worked up and purified as described for (S)-I-54 to afford the title compound (R)-I-81 (0.43 g, 43%) as a light brown solid. 1 H NMR(DMSO-d6): δ6.72(s,1H),6.23(s,1H),5.04(s,1H),3.66(s,3H),3.63(s,3H),3.53(t,1H,J=6.0Hz),3.08-3.00(m ,2H),2.95-2.91(m,1H),2.21(s,3H),2.13-1.91(m,4H),1.65-1.59(m,2H),1.44-1.27(m,2H).ESI-MS(m / z,%):277(MH + ,100).

[0579] Example 3: 5-methoxy-3-(((S)-1-(methyl-D3)pyrrolidin-2-yl)methyl-D2)indoline ((S)-I-56)

[0580]

[0581] Synthesis of (S)-5-methoxy-3-((1-(methyl-D3)pyrrolidin-2-yl)methyl-D2)-1H-indole ((S)-33): A suspension of lithium aluminum deuteride (1.11 g, 26.425 mmol) in anhydrous THF (25 mL) was reacted with (S)-2-(2-(5-methoxy-1H-indole-3-carbonyl)pyrrolidin-1-yl)-1-phenyl-21 in anhydrous THF (25 mL) at 0°C. 2-Ethan-1-one (2.0 g, 5.285 mmol) was treated for 10 min. The reaction was warmed to room temperature and then refluxed for another 16 hours. The reaction was worked up and purified as described for compound 5 to afford the title compound (S)-33 (1.3 g, 98%) as a brown gum. 1 H NMR (DMSO-d6): δ10.61(s,1H),7.21(d,1H,J=6.0Hz),7.08(d,1H,J=3.0Hz),6.96(d,1H,J=3.0Hz),6.70(dd,1H,J=3.0,4 .5Hz),3.76(s,3H),2.99-2.94(m,1H),2.35-2.29(m,1H),2.13-2.07(m,1H),1.75-1.41(m,4H); ESI-MS(m / z,%):250(MH + ,100).

[0582] Synthesis of 5-methoxy-3-(((S)-1-(methyl-D3)pyrrolidin-2-yl)methyl-D2)indoline ((S)-I-56): A solution of (S)-5-methoxy-3-((1-(methyl-D3)pyrrolidin-2-yl)methyl-D2)-1H-indole (1.3 g, 5.213 mmol) in trifluoroacetic acid (50 mL) was treated with triethylsilane (1.66 mL, 10.427 mmol) and the resulting solution was stirred at 50 °C overnight (16 h). The reaction was worked up and purified as described for (S)-I-54 to afford the title compound (S)-I-56 (0.69 g, 52.6%) as a brown oil. 1 H NMR (DMSO-d6): δ6.68(d,1H,J=3.0Hz), 6.51(dd,1H,J=3.0,4.5Hz), 6.41(d,1H,J=3.0Hz), 5.00(s,1H),3.63(s,3H),3. 53(t,1H,J=6.0Hz),3.10-2.91(m,3H),2.15-1.90(m,3H),1.66-1.60(m,2H),1.45-1.38(m,1H); ESI-MS(m / z,%):252(MH + ,100).

[0583] Example 4: 4-methoxy-3-(((R)-1-methylpyrrolidin-2-yl)methyl)indoline ((R)-I-94)

[0584]

[0585] (R)-2-(2-(4-methoxy-1H-indole-3-carbonyl)pyrrolidin-1-yl)-1-phenyl-2- 2 Synthesis of (R)-36: (2-oxo-2-phenyl-1l 2 A solution of 4-ethyl)-D-proline (5.2 g, 20.858 mmol) in anhydrous THF (60 mL) was treated with thionyl chloride (3.04 mL, 41.716 mmol). The reaction was warmed to room temperature and then refluxed for 2 h. The reaction was warmed to room temperature, the solvent was evaporated and the crude was dried under vacuum to obtain the corresponding acid chloride.

[0586] A solution of 4-methoxy-1H-indole (3.06 g, 24.067 mmol) in anhydrous CH2Cl2 (100 mL) was treated simultaneously with the above crude acid chloride and ethylmagnesium bromide (14.0 mL, 41.716 mmol, 3M in THF) in anhydrous CH2Cl2 (50 mL) at 5-10 ° C. for 15 min. and stirred at the same temperature for another 15 min. The reaction was quenched with concentrated HCl (10 mL) and treated and purified as described for compound 4 to obtain the title compound (R)-36 (5.56 g, 70.5%) as a tan solid. ESI-MS (m / z, %): 401 (M+Na), 379 (MH + ).

[0587] Synthesis of (R)-4-methoxy-3-((1-methylpyrrolidin-2-yl)methyl)-1H-indole ((R)-37): A suspension of lithium aluminum hydride (1.0 g, 26.426 mmol) in anhydrous THF (25 mL) was reacted with (R)-2-(2-(4-methoxy-1H-indole-3-carbonyl)pyrrolidin-1-yl)-1-phenyl-2-yl in anhydrous THF (25 mL) at 0°C. 2 -Ethan-1-one (2.0 g, 5.285 mmol) was treated for 10 min. The reaction was warmed to room temperature and then refluxed for another 16 hours. The reaction was worked up and purified as described for compound 5 to afford the title compound (R)-37 (1.25 g, 97%) as an off-white solid. 1 H NMR(DMSO-d6): δ10.72(s,1H),6.96-6.89(m,3H),6.42(dd,1H,J=3.0,6.0Hz),3.82(s,3H),3.28-3.3.25( m,1H),2.99-2.95(m,1H),2.46-2.35(m,5H),2.11-2.07(m,1H),1.67-1.44(m,4H); ESI-MS(m / z,%):245(MH+ ,100).

[0588] Synthesis of 4-methoxy-3-(((R)-1-methylpyrrolidin-2-yl)methyl)indoline ((R)-94): A solution of (R)-4-methoxy-3-((1-methylpyrrolidin-2-yl)methyl)-1H-indole (1.25 g, 5.116 mmol) in trifluoroacetic acid (50 mL) was treated with triethylsilane (1.63 mL, 10.232 mmol) and the resulting solution was stirred at 50 °C overnight (16 h). The reaction was worked up and purified as described for (S)-I-54 to afford the title compound (R)-I-94 (0.65 g, 51.6%) as a light brown solid. 1 H NMR(DMSO-d6): δ6.86(t,1H,J=3.0Hz), 6.19(d,1H,J=6.0Hz), 6.13(d,1H,J =6.0Hz),5.36(s,1H),3.70(s,6H),3.52-3.48(m,1H),3.25-3.22(m,1H),3 .16-3.13(m,1H),2.92-2.88(m,1H),2.18(s,3H),2.18-1.98(m,3H),1.86- 1.82(m,1H),1.61-1.55(m,2H),1.38-1.32(m,2H); ESI-MS(m / z,%):247(MH + ,100).

[0589] Example 5: 7-methoxy-3-(((R)-1-methylpyrrolidin-2-yl)methyl)indoline ((R)-I-95)

[0590]

[0591] (R)-2-(2-(7-methoxy-1H-indole-3-carbonyl)pyrrolidin-1-yl)-1-phenyl-2- 2 Synthesis of (R)-40: (2-oxo-2-phenyl-1-one) at 0°C 2 A solution of 4-ethyl)-D-proline (4.1 g, 16.446 mmol) in anhydrous THF (50 mL) was treated with thionyl chloride (2.4 mL, 32.892 mmol). The reaction was warmed to room temperature and then refluxed for 2 h. The reaction was warmed to room temperature, the solvent was evaporated and the crude was dried under vacuum to obtain the corresponding acid chloride.

[0592] At 5-10 ° C, a solution of 7-methoxy-1H-indole (2.42 g, 16.446 mmol) in anhydrous CH2Cl2 (100 mL) was treated with the above crude acid chloride and ethylmagnesium bromide (11.0 mL, 32.892 mmol, 3M in THF) in anhydrous CH2Cl2 (50 mL) for 15 min simultaneously. And stirred for another 15 min at the same temperature. The reaction was quenched with concentrated HCl (10 mL), and the reaction was treated and purified as described for compound 4 to obtain the title compound (R)-40 (3.3 g, 53%) as a tan solid. 1 H NMR (DMSO-d6): δ12.20-12.17(m,1H),8.34(dd,1H,J=3.0Hz),7.77(dd,1H,J=3.0,6.0Hz),7.41-7.31(m,2H),7.16-7.02(m,4H),6.83-6 .80(m,1H),5.29-4.90(m,3H),3.95(s,3H),3.55-3.48(m,2H),2.42-2.31(m,1H),1.91-1.80(m,3H); ESI-MS(m / z,%):401(M+Na),379(MH) + ).

[0593] Synthesis of (R)-7-methoxy-3-((1-methylpyrrolidin-2-yl)methyl)-1H-indole ((R)-41): A suspension of lithium aluminum hydride (1.0 g, 26.426 mmol) in anhydrous THF (25 mL) was reacted with (R)-2-(2-(7-methoxy-1H-indole-3-carbonyl)pyrrolidin-1-yl)-1-phenyl-21 in anhydrous THF (25 mL) at 0°C. 2 -Ethan-1-one (2.0 g, 5.285 mmol) was treated for 10 min. The reaction was warmed to room temperature and then refluxed for another 16 hours. The reaction was worked up and purified as described for (S)-5 in Example 1 to afford the title compound (R)-41 (1.06 g, 82%) as a brown solid. 1 H NMR (DMSO-d6): δ10.86(s,1H),7.10(d,1H,J=6.0Hz),6.91(s,1H),6.89(t,1H,J=6.0Hz),6.62(d,1H,J=6.0Hz),3.90(s ,3H),3.03-2.94(m,2H),2.49-2.43(m,2H),2.34(s,3H),2.13-2.08(m,1H),1.69-1.42(m,4H); ESI-MS(m / z,%):245(MH) + ).

[0594] Synthesis of 7-methoxy-3-(((R)-1-methylpyrrolidin-2-yl)methyl)indoline ((R)-I-95): A solution of (R)-7-methoxy-3-((1-methylpyrrolidin-2-yl)methyl)-1H-indole (1.0 g, 4.093 mmol) in trifluoroacetic acid (50 mL) was treated with triethylsilane (1.30 mL, 8.186 mmol) and the resulting solution was stirred at 50 °C overnight (16 h). The reaction was worked up and purified as described for (S)-I-54 to afford the title compound (R)-I-95 (0.48 g, 48%) as a light brown oil. 1 H NMR (DMSO-d6): δ6.68 (d, 1H, J = 6.0Hz), 6.66 (d, 1H, J = 6.0Hz), 6.55 (t, 1H, J = 3.0, 6.0Hz), 4.94 (s, 1H), 3.72 (s, 3H), 3.59-3.55 (m, 1H), 3.17-3. 14(m,1H),3.08-3.04(m,1H),2.95-2.91(m,1H),2.19(s,3H),2.16-1.9 2(m,4H),1.65-1.60(m,2H),1.44-1.30(m,2H); ESI-MS(m / z,%):247(MH + ).

[0595] Example 6: 5,6-dimethoxy-3-(((R)-1-(methyl-D3)pyrrolidin-2-yl)methyl)indoline ((R)-I-82)

[0596]

[0597] (R)-2-(2-((5,6-dimethoxy-1H-indol-3-yl)methyl)pyrrolidin-1-yl)-1-phenyl-2- 2 Synthesis of -1-ethyl-1-one (45): (R)-2-(2-(5,6-dimethoxy-1H-indole-3-carbonyl)pyrrolidin-1-yl)-1-phenyl-2-one was reacted with 2A solution of -2-one (3.11 g, 7.965 mmol) in anhydrous THF (60 mL) was treated dropwise with lithium borohydride (16.0 mL, 31.862 mmol, 2M solution in THF) and the resulting mixture was refluxed for another 4 h. The reaction was warmed to room temperature, then cooled to 0 ° C and quenched with methanol (25 mL). The reaction was warmed to room temperature and stirred for another 1 h. The reaction was diluted with ethyl acetate (150 mL) and washed with saturated NaHCO3 solution (50 mL), followed by brine (50 mL). The ethyl acetate layer was dried (Na2SO4) and the solvent was evaporated to obtain a crude product. The crude product was purified on silica gel by flash column chromatography (MeOH:CH2Cl2, 2:98) to obtain the title compound 45 (2.2 g, 73.4%) as a light yellow jelly. ESI-MS (m / z,%): 261 (100).

[0598] Synthesis of (R)-5,6-dimethoxy-3-((1-(methyl-D3)pyrrolidin-2-yl)methyl)-1H-indole (46): (R)-2-(2-((5,6-dimethoxy-1H-indol-3-yl)methyl)pyrrolidin-1-yl)-1-phenyl-21 2 A solution of -ethan-1-one (2.2 g, 5.844 mmol) in anhydrous THF (50 mL) was treated with lithium aluminum deuteride (0.61 g, 14.610 mmol). The reaction was processed and purified as described for compound 5 to afford the title compound 46 (1.04 g, 64.2%) as a light brown oil. ESI-MS (m / z, %): 278 (MH + ). 1 H NMR(DMSO-d6): δ10.45(s,1H),6.97(s,1H),6.93(d,1H,J=3.0Hz),6.86(s,1H),3.76(s,6H),2.99-2.94(m, 2H), 2.46-2.41(m,1H), 2.36-2.28(m,2H), 2.13-2.06(m,1H), 1.76-1.40(m,4H); ESI-MS(m / z,%): 278(100).

[0599] Synthesis of 5,6-dimethoxy-3-(((R)-1-(methyl-D3)pyrrolidin-2-yl)methyl)indoline (47): A solution of (R)-5,6-dimethoxy-3-((1-(methyl-D3)pyrrolidin-2-yl)methyl)-1H-indole (1.0 g, 3.605 mmol) in TFA (50 mL) was treated with triethylsilane (1.15 mL, 7.210 mmol) and the resulting solution was stirred at 50 °C overnight (16 h). The reaction was worked up and purified as described for compound (S)-I-54 to afford the title compound (R)-I-82 (0.35 g, 35%) as a light brown solid. 1 H NMR(DMSO-d6): δ6.73(s,1H),6.24(s,1H),5.06(brs,1H),3.67(s,3H),3.64(s,3H),3.54(t,1H,J=6.0Hz),3.10- 3.00(m,2H),2.96-2.91(m,1H),2.16-1.92(m,4H),1.67-1.60(m,2H),1.44-1.24(m,2H); ESI-MS(m / z,%):280(MH + ,100).

[0600] Examples 7 and 8: (S)-5-fluoro-3-(((R)-1-methylpyrrolidin-2-yl)methyl)indoline and (R)-5-fluoro-3-(((R)-1-methylpyrrolidin-2-yl)methyl)indoline ((S)-(R)-I-47, (R)-(R)-I-47)

[0601]

[0602] (R)-2-(2-(5-fluoro-1H-indole-3-carbonyl)pyrrolidin-1-yl)-1-phenyl-2- 2 Synthesis of 1-ethyl-ketone (49): (2-oxo-2-phenyl-1-one) was reacted with 2 A solution of 4-ethyl)-D-proline (6.1 g, 24.468 mmol) in anhydrous THF (100 mL) was treated with thionyl chloride (3.56 mL, 48.937 mmol). The reaction was warmed to room temperature and then refluxed for 2 h. The reaction was warmed to room temperature, the solvent was evaporated and the crude was dried under vacuum to obtain the corresponding acid chloride.

[0603] At 5-10 ℃, a solution of 5-fluoro-1H-indole (3.3 g, 24.468 mmol) in anhydrous CH2Cl2 (50 mL) was treated with the above crude acid chloride and ethylmagnesium bromide (16.3 mL, 48.937 mmol, 3M in THF) in anhydrous CH2Cl2 (50 mL) simultaneously for 15 min. And stirred at the same temperature for another 15 min. The reaction was quenched with concentrated HCl (10 mL), and the reaction was treated and purified as described for compound 4 to obtain the title compound 49 (6.79 g, 75.7%) as a light yellow solid. 1 H NMR(DMSO-d6): δ12.15(d,1H,J=6.0Hz),8.55-8.50(m,1H),7.90-7.83(m,1H),7.53-7.49(m,1H),7.39-7.32(m,2H),7.14-7.00( m,4H),5.25-4.89(m,2H),3.56-3.49(m,2H),2.45-2.40(m,1H),1.93-1.83(m,3H); ESI-MS(m / z,%):405(M+K),389(M+Na),367(MH) + ).

[0604] Synthesis of (R)-5-fluoro-3-((1-methylpyrrolidin-2-yl)methyl)-1H-indole (50): (R)-2-(2-(5-fluoro-1H-indole-3-carbonyl)pyrrolidin-1-yl)-1-phenyl-2-yl was reacted with 2 A solution of -ethan-1-one (2.0 g, 5.459 mmol) in anhydrous THF (50 mL) was treated with lithium aluminum hydride (1.03 g, 27.293 mmol). The reaction was worked up and purified as described for compound 5 to afford the title compound 50 (1.02 g, 81%) as an off-white solid. 1 H NMR(DMSO-d6): δ10.90(s,1H),7.32(dd,1H,J=3.0,6.0Hz),7.25-7.22(m,2H),6.92-6.86(m,1H),3.01-2.94 (m,2H),2.50-2.44(m,3H),2.34-2.28(m,4H),2.13-2.06(m,1H),1.71-1.41(m,4H); ESI-MS(m / z,%):233(MH + ).

[0605] Synthesis of 5-fluoro-3-(((R)-1-methylpyrrolidin-2-yl)methyl)indoline ((S)-(R)-I-47 (nonpolar diastereomer) and (S)-(R)-I-47 (polar diastereomer)): A solution of (R)-5-fluoro-3-((1-methylpyrrolidin-2-yl)methyl)-1H-indole (0.5 g, 2.152 mmol) in trifluoroacetic acid (10 mL) was treated with sodium cyanoborohydride (0.4 g, 6.457 mmol) at 0° C. After 30 min, the reaction was warmed to room temperature and stirred for an additional 3 h. The reaction was worked up and purified as described for compound (S)-I-54 to afford the title compound ((S)-(R)-I-47, (R)-(R)-I-47) (0.15 g, 30%) as a light brown oil. 1 H NMR(DMSO-d6): δ6.90-6.87(m,1H),6.74-6.69(m,1H),6.46-6.42(m,1H),5.33(s,1H),3.58-3.53(m,1H),3.16-3.03(m ,2H),2.98-2.93(m,1H),2.19(s,3H),2.09-1.95(m,3H),1.78-1.62(m,4H),1.47-1.44(m,1H); ESI-MS(m / z,%):235(MH) + Compound 52 (0.15 g, 30%) was obtained as a light brown oil. 1 H NMR(DMSO-d6): δ6.91-6.88(m,1H),6.74-6.69(m,1H),6.46-6.42(m,1H),5.33(s,1H),3.61-3.56(m,1H),3.17-3.08(m ,2H),2.96-2.92(m,1H),2.21(s,3H),2.15-1.92(m,5H),1.66-1.60(m,2H),1.44-1.34(m,2H); ESI-MS(m / z,%):235(MH) + ).

[0606] Example 9: 5-methoxy-3-(((R)-pyrrolidin-2-yl)methyl)indoline (55) ((R)-I-165)

[0607]

[0608] (R)-2-(2-((5-methoxy-1H-indol-3-yl)methyl)pyrrolidin-1-yl)-1-phenyl-2- 2Synthesis of -1-ethyl-1-one (53): (R)-2-(2-(5-methoxy-1H-indole-3-carbonyl)pyrrolidin-1-yl)-1-phenyl-2-one was reacted with 2 A solution of -ethan-1-one (3.8 g, 10.041 mmol) in anhydrous THF (60 mL) was treated dropwise with lithium borohydride (20.0 mL, 40.165 mmol, 2M solution in THF) and the resulting mixture was refluxed for an additional 4 h. The reaction was worked up and purified as described for compound 45 to afford the title compound 53 (2.5 g, 68.5%) as a light yellow gum.

[0609] Synthesis of (R)-5-methoxy-3-(pyrrolidin-2-ylmethyl)-1H-indole (54): Under an inert atmosphere, (R)-2-(2-((5-methoxy-1H-indol-3-yl)methyl)pyrrolidin-1-yl)-1-phenyl-21 2 A solution of -2-ethyl-1-one (2.5 g, 6.86 mmol) in methanol (50 mL) was treated with palladium on carbon (2.5 g, 10% on dry basis). The reaction was stirred for another 15 h with a Parr apparatus at 40 PSI under a hydrogen atmosphere. The reaction was filtered through a celite pad and washed with methanol (2 x 25 mL). The combined methanol layer was evaporated and the crude material was purified on silica gel by column chromatography (MeOH:CH2Cl2 containing 2M NH3, 5:95) to obtain the title compound 54 (1.2 g, 76%) as an off-white solid.

[0610] Synthesis of 5-methoxy-3-(((R)-pyrrolidin-2-yl)methyl)indoline ((R)-I-165): A solution of (R)-5-methoxy-3-(pyrrolidin-2-ylmethyl)-1H-indole (0.5 g, 2.171 mmol) in TFA (10 mL) was treated with triethylsilane (0.69 mL, 4.342 mmol) and the resulting solution was stirred at 50 °C overnight (16 h). The reaction was worked up and purified as described for compound (S)-I-54 to afford the title compound (R)-I-165 (0.4 g, 80%) as a light brown gum. 1H NMR(DMSO-d6): δ6.69(dd,1H,J=1.5,6.0Hz),6.66-6.49(m,1H),6.42(dd,1H,J=3.0,6.0Hz),5.00(brs,1H),3.62(s,3H),3.56-3.51(m,1H) ,3.18-2.92(m,2H),2.88-2.83(m,2H),2.72-2.69(m,1H),1.86-1.79(m,2H),1.68-1.48(m,3H),1.21-1.19(m,1H); ESI-MS(m / z,%):233(MH) + ).

[0611] A. Biological Testing

[0612] Example B1: FLIPR Assay: Human 5-HT 2A

[0613] Exemplary compounds of Formula I were evaluated in agonist mode targeting human 5-HT 2A (h5-HT 2A )Receptor effects:

[0614] Compound preparation and assay controls

[0615] Ia Reagents and Materials:

[0616]

[0617]

[0618] Ib Instruments and consumables used:

[0619]

[0620]

[0621] Ic Experimental Methods and Procedures:

[0622] 1. The cells were cultured in cell culture medium (DMEM containing 10% FBS, 1× penicillin-streptomycin, 300 μg / ml G418 and 100 μg / ml hygromycin B) at 37° C. and 5% (v / v) CO 2 .

[0623] 2. One day before the assay, use TrypLE TM Express cells were detached and counted using a cell counter. Only cells with a viability > 85% were used for the assay.

[0624] 3. 20,000 cells / well were seeded into 384-well cell plates in 30 μl / well culture medium and the cells were incubated overnight at 37°C, 5% (v / v) CO2.

[0625] 4. On the day of measurement, follow Prepare 2x dye solution according to the instruction manual of the Calcium 6 Assay Kit: i. Dilute the dye with assay buffer (20 mM HEPES in 1x HBSS, pH 7.4); ii. Add probenecid to a final concentration of 5 mM; iii. Vortex vigorously for 1-2 minutes.

[0626] 5. Remove the culture medium from the cell plate by flicking the cell plate on a paper towel.

[0627] 6. Add 10 μl of assay buffer and 10 μl of 2x dye solution to each well of the cell plate.

[0628] 7. Place the cell plate on a plate shaker and agitate the plate at 600 rpm for 2 minutes. Incubate the plate at 37°C for 2 hours, followed by incubation at 25°C for 15 minutes.

[0629] 8. Prepare 3x compounds in assay buffer: a. Dilute reference compound with DMSO to desired concentration. Add compound to 384-well compound plate; b. Perform serial dilutions; c. Add 10 mM test compound to compound plate and perform 3x serial dilutions. d. Transfer 60 nl / well of compound from source plate to 384-well compound plate (Corning, 3657) by using Echo; e. Add 20 μl / well of assay buffer to compound plate; f. Mix plate on plate shaker for 2 minutes;

[0630] 9. Place the cell plate, compound plate and tip into the FLIPR and transfer 10 μl of 3x compound to each well of the cell plate using the FLIPR.

[0631] Data analysis

[0632] i. The normalized fluorescence reading (RFU) was calculated as follows, where Fmax and Fmin represent the maximum and minimum values ​​of the calcium signal within the defined time window: RFU = Fmax – Fmin.

[0633] ii. Calculate the activation percentage using the following equation:

[0634]

[0635] iii. Using XLfit, the EC was calculated by fitting the Hill equation to the logarithm of the % activation versus the compound concentration. 50 .

[0636] Results and discussion

[0637] The exemplary compounds of Formula I were functionally evaluated for their effects on h5-HT in agonist mode using the FLIPR assay. 2A Table 1 shows the EC of the exemplary compounds of the present application. 50 (nM) and RFU data.

[0638] Table 1

[0639]

[0640] ND: Not Detected

[0641] Results and discussion

[0642] The exemplary compounds of Formula I were functionally evaluated for their effects on h5-HT in agonist mode using the FLIPR assay. 2A The role of receptors. 50 The (nM) concentrations and their corresponding RFU at 10 μM are shown in Table 1. This assay demonstrates that the compounds of the present application are potent agonists of the target human 5-HT2A receptor.

[0643] II. Human 5-HT 2A : Radioligand Binding Assay:

[0644] II.1. Materials and Instruments:

[0645] II.2. Instruments and consumables used:

[0646] project supplier Part Number <![CDATA[Microbeta 2 Microplate Counter]]> PerkinElmer 2450-0060 UniFilter-96GF / B PerkinElmer 6005177 TopSeal Biotss SF-800 MicroBeta Filtermate-96 PerkinElmer D961962 Seven small pH meters Mettler-Toledo S220 Ultrapure water meter Sichuan Youpu UPH-III-20T Benchtop centrifuge Hunan Xiangyi L550 Microplate shaker OSIM MX100-4A 384-well polypropylene microplate Labcyte PP-0200 96 round well plate Corning 3799 96 round deep well plate Axygen P-DW-11-C Echo LABCYTE 550

[0647] II.3 Experimental Procedure:

[0648] Prepare assay buffer according to the table below;

[0649] ii. Starting from a 10 mM stock solution, 8 doses of reference compound and test compound were prepared by 5-fold serial dilutions of 100%;

[0650] iii. Prepare (v / v) DMSO: a. Add 50 μl / well of 0.5% (v / v) PEI to UniFilter-96 GF / B plate. Seal the plate and incubate at 4°C for 3 hours; b. After incubation, wash the plate 3 times with ice-cold wash buffer (50 mM Tris, pH 7.4);

[0651] iv. Preparation of assay plates: a. Dilute the cell membrane with assay buffer and add to a 96-round deep-well plate at 330 μl / well to a concentration of 20 μg / well; b. Prepare 8 concentrations of reference compounds or test compounds and add to 96 round deep-well plates at 110 μl / well; c. Dilute [3H]-ketanserin to 5 nM (5 times the final concentration) with assay buffer and add to a 96-round deep-well plate at 110 μl / well.

[0652] v. The plate was centrifuged at 1000 rpm for 30 seconds and then agitated at 600 rpm for 5 minutes at room temperature.

[0653] vi. Seal the plate and incubate at 27°C for 90 minutes.

[0654] vii. Stop the incubation by vacuum filtration onto GF / B filter plates, followed by 4 washes with ice-cold wash buffer (50 mM Tris, pH 7.4).

[0655] viii. Dry the plates at 37°C for 45 minutes.

[0656] ix. Seal the filter plate and add 40 μl / well of scintillation cocktail.

[0657] x. Read the plate by using a Microbeta2 microplate counter.

[0658] Data Analysis:

[0659] For reference and test compounds, the results were expressed as % inhibition using the normalization equation: N = 100-100 x (U-C2) / (C1-C2), where U is the unknown value, C1 is the high control mean, and C2 is the low control mean. IC50 was determined by fitting the percent inhibition as a function of compound concentration using the Hill equation using XLfit.

[0660] Example B2: Human, Rat and Mouse Liver Microsome Stability

[0661] Target

[0662] The goal of this study is to evaluate the in vitro metabolic stability of representative compounds of the present application in the combined human and male mouse liver microsomes. The concentration of the parent compound in the reaction system was evaluated by LC-MS / MS for the stability in the combined human and male mouse liver microsomes. The in vitro intrinsic clearance of the test compound was also determined.

[0663] plan

[0664] Prepare the stock solution in the "Incubation Plate" containing phosphate buffer, ultrapure H2O, MgCl2 solution and liver microsomes according to the table below. Preheat the mixture in a 37°C water bath for 5 minutes.

[0665] Preparation of mother solution

[0666]

[0667] Add 40 μL of 10 mM NADPH solution to each well. The final concentration of NADPH is 1 mM. Prepare a negative control sample by replacing NADPH with 40 μL of ultrapure H2O. Prepare samples in duplicate. Negative controls are prepared in single copies.

[0668] To start the reaction, 4 μL of 200 μM test or control compound was added to each stock solution to obtain a final concentration of 2 μM. This study was performed in duplicate.

[0669] Aliquots of 50 μL were taken from the reaction solution at 0, 15, 30, 45 and 60 minutes. The reaction solution was terminated by adding 4 volumes of cold methanol and IS (100 nM alprazolam, 200 nM imipramine, 200 nM labetalol and 2 μM ketoprofen). The samples were centrifuged at 3,220 g for 40 minutes. An aliquot of 90 μL of the supernatant was mixed with 90 μL ultrapure H2O and then used for LC-MS / MS analysis.

[0670] All samples in this study were subjected to LC / MS analysis using a Shimadzu liquid chromatography separation system equipped with a degasser DGU-20A 5R ; Solvent delivery device LC-30AD; System controller SIL-30AC; Column oven CTO-30A; CTC analysis HTC PAL system. Using Triple Quad TM Mass spectrometry analysis was performed using a 5500 instrument.

[0671] All calculations were performed using Microsoft Excel.The peak area ratios of the test compounds to the internal standards (listed in the table below) were determined from the extracted ion chromatograms.

[0672] All calculations were performed using Microsoft Excel. Peak areas were determined from the extracted ion chromatograms. The slope value, k, was determined by linear regression of the percent parent drug remaining versus the natural logarithm of the incubation time curve.

[0673] In vitro half-life (in vitro t 1 / 2 ) is determined by the slope value:

[0674] In vitro 1 / 2 =-(0.693 / k)

[0675] In vitro 1 / 2 (min) converted to in vitro intrinsic clearance (in vitro CL int, in μL / min / mg protein) was performed using the following equation (average of two determinations):

[0676]

[0677] For compounds that showed an initial rapid disappearance followed by a slow disappearance or for control compounds, only time points within the initial rate were included in the calculations.

[0678] Results and discussion

[0679] Human, rat and mouse liver microsomes contain multiple drug metabolizing enzymes and are generally used to support in vitro ADME (absorption, distribution, metabolism and excretion) studies. These microsomes are used to examine the potential first-pass metabolic byproducts of orally administered drugs. The stability of representative compounds of the present application in human, rat and mouse liver microsomes was evaluated. Tables 2 and 3 show the results of stability studies.

[0680] Table 2

[0681]

[0682] Notice:

[0683] 1. For compounds that showed an initial rapid disappearance followed by a slow disappearance, only time points within the range of the initial rate were included in the calculations.

[0684] 2. If the calculated CL int <0, then T 1 / 2 and CL int Will be reported as "∞" and "0.00" respectively.

[0685] Table 3

[0686]

[0687]

[0688]

[0689] The stability of the exemplary compounds of the present application in human, rat and mouse liver microsomes was evaluated. Tables 2 and 3 show the results of the stability studies. These results show that the compounds of the present application show a stability spectrum across different species, including humans, rats and mice.

[0690] Example B3: Hallucinogenic Effects of Compounds of Formula I

[0691] Representative compounds of Formula I at different doses were evaluated for their effects on the head twitch response (HTR) and other behavioral responses as a behaviorally based model of hallucinogenic activity.

[0692] plan

[0693] Mouse head twitching

[0694] The test article of appropriate dose is administered to male C57BL / 6J mice (body weight range 20-30g), and after 1 minute of pretreatment time, is placed in a separate observation chamber. Visual assessment of the incidence of continuous head twitching in animals in a 1 hour period. Head twitching is defined as a rapid twitch of the head that is not caused by external tactile stimulation (Corne and Pickering, Psychopharmacologia, 1967, 11 (1): 65-78). Each head twitch is counted separately by a well-trained observer, and the data are expressed as the mean value+SEM of 6-10 mice per group. Mice are used in only a single experiment.

[0695] Results and discussion

[0696] The head twitch response of the exemplary compound (R)-I-54 (1-60 mg / kg SC) was compared to that of 5-MeO DMT and psilocybin ( Figure 1 , Table 4).

[0697] Table 4

[0698]

[0699] The head twitch response of the exemplary compound (R)-I-54 (1-60 mg / kg SC) was compared with that of 5-MeO DMT and psilocybin, and the results were evaluated and are shown in Table 4 above. These results show that psilocybin (0.1-10 mg / kg SC) produced a dose-related increase in the incidence of head twitch responses in male C57BL / 6 mice, which peaked at the 1 mg / kg dose. At the 3 mg / kg SC and 10 mg / kg SC doses, the incidence of head twitches decreased following psilocybin, resulting in an inverted U-shaped dose response. At these higher doses, the decrease in head twitches was accompanied by a decrease in movement and a decrease in core body temperature.

[0700] 5-MeO DMT (1-30 mg / kg SC) produced a monotonic increase in head twitches, although at doses of 3-30 mg / kg, other behavioral signs associated with serotonin syndrome (forepaw stepping, Straub tail, body twitching, backward walking) appeared and increased in frequency with these doses. Thus, head twitches at 30 mg / kg became somewhat erratic due to response competition and in some test subjects showed clear signs of serotonin syndrome, affecting the performance of head twitches.

[0701] In contrast to psilocybin and 5-MeO DMT, the exemplary compound (R)-I-54 (1-60 mg / kg SC) elicited only modest head twitch responses, with a peak response of 1.8 twitches at 30 mg / kg, although lower doses were also associated with minimal incidence of head twitches. Thus, the low expression of head twitches across the dose range tested does not appear to be the result of alternative, competing behaviors.

[0702] Rat behavioral testing

[0703] Male Sprague-Dawley rats (weight range 250-400 g) were administered the appropriate dose of the test article and, after a 1-minute pretreatment period, were placed in a locomotor activity box (dimensions 17"W x 17"L x 12"H) and continuously monitored for a 1-hour period, with data collected in 10-minute time segments. The animals were visually assessed for overt behavioral signs, including 5-HT 2A Receptor activation (wet dog shakes, back muscle contractions), 5-HT 2A Receptor activation (yawning, penis grooming) and 5-HT 1A Behavioral characteristics of behavior (forepaw stepping, hind limb abduction) (Halberzettl et al, Behav Brain Res. 256: 328-345, 2013). Other behavioral and physical signs characteristic of 5-HT syndrome (such as tremor, salivation, flat posture, core body temperature changes) were also measured. At the same time, the spontaneous activity of rats was measured using an automatic tracking system (Med Associates, VT, USA). The collected activity data included total distance traveled, number of feedings, and number of walks. All data are expressed as the mean + SEM of 6-10 rats per group.

[0704] Drug discrimination in rats

[0705] Male Sprague-Dawley rats were initially food restricted (single cage) by providing 18-20 g of food at the end of the day. After 7 days of adaptation to the food restriction procedure, they were trained to lever squeeze food (45 mg Bioserve pellets) daily for 1 week in a standard Class 2 operant conditioning chamber controlled by Med-PC software (Med. Associates Ins., St. Albans, VT). The rats were trained to press the food lever to FR 10The value was 10 lever presses to obtain one food reward. Once a stable food response was obtained on both response levers, discrimination training was initiated. Over a period of 20-50 training sessions, rats were trained to associate one lever with a training dose of psilocybin of 1 mg / kg SC and the second lever with a neutral stimulus (saline, SC) (Winter et al, Pharmacol Biochem Behav. 87(4):472-480, 2007). Training sessions lasted 30 minutes or until 50 pellets were delivered and continued until the animal obtained an appropriate stimulus control (defined as six consecutive training sessions in which the animal did not exceed 16 lever presses before the first reward was delivered and had at least 95% of total responses on the appropriate lever). At the end of each day, the rats continued to receive their daily food ration in their home cages.

[0706] Once training is complete, an alternative test is performed. On the test day, both levers are designated as active, i.e., every 10 responses on either lever result in the delivery of a food pellet. The test period lasts until 50 pellets are obtained or 30 minutes have passed. During the test period, the response rate is also measured.

[0707] Although the present application has been described with reference to examples, it should be understood that the scope of the claims should not be limited by the embodiments set forth in the examples, but should be given the broadest interpretation consistent with the description as a whole.

[0708] All patents, patent applications, and publications cited herein are incorporated herein by reference in their entirety. The disclosures of these publications are incorporated into this application by reference in order to more fully describe the prior art known to those skilled in the art as of the filing date described and claimed herein.

Claims

1. A compound of formula I or a pharmaceutically acceptable salt, solvate and / or prodrug thereof: in: R 1 Selected from C(O)R 7 、CO2R 7 、C(O)N(R 7 )(R 7’ )、S(O)R 7 、SO2R 7 , C 1-6 Alkylene R 7 and R 7 ; Q is selected from Q1, Q2, Q2', Q4 and Q5: is a single bond or a double bond, provided that when When it is a double bond, R 9 and R 15 does not exist, and when Q2 When it is a double bond, R 17 and R 25 does not exist, and when Q2' When it is a double bond, R 16’ and R 25’ does not exist; On the key means that the bond is attached to the remainder of the compound; R 2 , R 2’ and R 2” are independently selected from H, halo, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylene N(R 2a )(R 2b ) and SC 1-6 alkyl; R 2a and R 2b Independently selected from H and C 1-6 alkyl; R 3 , R 4 , R 5 and R 6 are independently selected from H, halo, N(R 5’ )(R 6’ ), C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylene N(R 5’ )(R 6’ ) and SC 1-6 Alkyl, the last four groups are optionally replaced by one or two selected from OH and C 1-6 The alkoxy substituent is substituted with, or R 3 , R 4 , R 5 and R 6 Two adjacent groups in the bond together to form O-(CH2) 1-2 O, and R 3 , R 4 , R 5 and R 6 The remaining groups in are independently selected from H, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, N(R 5’ )(R 6’ ), C 1-6 Alkylene N(R 5’ )(R 6’ ) and SC 1-6 Alkyl, or R 3 , R 4 , R 5 and R 6 One of A, OA and C 1-4 Alkylene A, and R 3 , R 4 , R 5 and R 6 The remaining groups in are independently H or halo; R 5’ and R 6’ Independently selected from H and C 1-6 alkyl; A is selected from phenyl, C 3-6 Cycloalkyl, containing 1 to 4 independently selected from O, S, S(O), SO2, N and NR 54 The heterocyclic alkyl group of the heterocyclic alkyl group is 3-6-membered and contains 1 to 4 independently selected from O, S, S(O), SO2, N and NR 54 The 5- to 6-membered heteroaryl group of the heteroaryl group of 3-10 Cycloalkyl, 3-membered to 6-membered heterocycloalkyl and 5-membered to 6-membered heteroaryl are optionally substituted with one or more substituents independently selected from the group consisting of halo, C 1-4 Alkyl, OC 1-4 Alkyl, N(R 54a )(R 54b ), C 1-4 Alkylene N(R 54a )(R 54b ) and SC 1-4 alkyl; R 7 Selected from H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, phenyl, C 3-6 Cycloalkyl, containing 1 to 4 independently selected from O, S, N and NR 7” The heterocyclic alkyl group of the heterocyclic alkyl group is 3-6-membered and contains 1 to 4 independently selected from O, S, N and NR 7” The 5- to 6-membered heteroaryl group of the ... 55 、N(R 55 )(R 56 ) and SR 55 Substituents, and / or the C 1-6 The alkyl group is optionally substituted by one to three independently selected from O, C(O), CO2 and NR 57 The miscellaneous parts are interrupted; R 7’ Selected from H and C 1-6 alkyl; R 7” Selected from H and C 1-6 alkyl; R 8 , R 9 , R 10 , R 11 , R 13 , R 14 , R 15 , R 16 , R 16’ , R 17 , R 17’ , R 18 , R 19’ , R 19 , R 19’ , R 21 , R 22’ , R 22 , R 22’ , R 23 , R 23’ , R 24 , R 24’ , R 25 , R 25’ , R 32 , R 33 , R 34 , R 36 , R 37 , R 38 , R 39 , R 40 , R 41 , R 42 , R 43 , R 44 , R 46 , R 47 , R 48 , R 49 , R 50 , R 51 , R 52 and R 53 are independently selected from H, halo and C 1-6 alkyl; R 12 , R 20 , R 20’ , R 35 and R 45 Independently selected from H, C 1-6 Alkyl and C(O)C 1-6 alkyl; R 54 , R 55 , R 56 and R 57 Independently selected from H and C 1-6 alkyl; R 54a and R 54b Independently selected from H and C 1-6 Alkyl; and All available hydrogen atoms are optionally and independently replaced with fluorine atoms or chlorine atoms, and all available atoms are optionally substituted with alternative isotopes thereof.

2. The compound of claim 1, wherein R 8 , R 9 , R 10 , R 11 , R 13 , R 14 , R 15 , R 16 , R 16’ , R 17 , R 17’ , R 18 , R 19’ , R 19 , R 19’ , R 21 , R 22’ , R 22 , R 22’ , R 23 , R 23’ , R 24 , R 24’ , R 25 , R 25’ , R 32 , R 33 , R 34 , R 36 , R 37 , R 38 , R 39 , R 40 , R 41 , R 42 , R 43 , R 44 , R 46 , R 47 , R 48 , R 49 , R 50 , R 51 , R 52 and R 53 Independently selected from H and D.

3. The compound of claim 1, wherein Q is selected from one of the following groups: Where R 12 , R 20 , R 20’ , R 35 and R 45 As defined in claim 1.

4. The compound as claimed in claim 3, wherein R 12 , R 20 , R 20’ , R 35 and R 45 Independently selected from H, C 1-4 Alkyl and C(O)C 1-4 An alkyl group in which all available hydrogen atoms are optionally and independently substituted with fluorine atoms or deuterium atoms.

5. The compound as claimed in claim 4, wherein R 12 , R 20 , R 20’ , R 35 and R 45 Independently selected from H, D, C 1-4 Alkyl, C 1-4 Fluoroalkyl, C 1-4 Deuterated alkyl, C(O)C 1-4 Alkyl, C(O)C 1-4 Fluoroalkyl and C(O)C 1-4 Deuterated alkyl.

6. The compound as claimed in claim 5, wherein R 12 , R 20 , R 20’ , R 35 and R 45 Independently selected from H, CH3 and CD3.

7. The compound of claim 3, wherein Q is selected from Where R 35 Selected from H, D, C 1-6 Alkyl, C 1-6 Fluoroalkyl and C 1-6 Deuterated alkyl.

8. The compound of claim 7, wherein R 35 Selected from H, CH3, CD3, CF2H and CF3.

9. The compound of any one of claims 1 to 8, wherein R 1 Selected from C(O)R 7 、CO2R 7 、C(O)N(R 7 )(R 7’ )、S(O)R 7 、SO2R 7 , C 1-4 Alkylene R 7 and R 7 , wherein all available hydrogen atoms are optionally and independently replaced by fluorine atoms or deuterium atoms.

10. The compound of claim 9, wherein R 1 Selected from C(O)R 7 、CO2R 7 、C(O)N(R 7 )(R 7’ )、S(O)R 7 and SO2R 7 .

11. The compound of claim 9, wherein R 1 Selected from R 7 and C 1-4 Alkylene R 7 .

12. A compound as claimed in any one of claims 1 to 11, wherein R 7 Selected from H, C 1-4 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, phenyl, C 3-6 Cycloalkyl, containing 1 to 4 independently selected from O, S, N and NR 7” The heterocyclic alkyl group of the heterocyclic alkyl group is 3-6-membered and contains 1 to 4 independently selected from O, S, N and NR 7” The 5- to 6-membered heteroaryl group of the ... 55 、N(R 55 )(R 56 ) and SR 55 Substituents, and / or the C 1-4 The alkyl group is optionally substituted by one to three independently selected from O, C(O), CO2 and NR 57 and wherein all available hydrogen atoms are optionally and independently replaced by fluorine atoms or deuterium atoms.

13. The compound of claim 12, wherein R 7 C 3-6 Cycloalkyl wherein all available hydrogen atoms are optionally and independently replaced by fluorine atoms or deuterium atoms.

14. The compound of claim 12, wherein R 7 Selected from H and C 1-4 Alkyl, where C 1-4 The alkyl group is optionally substituted with one or more independently selected from F, Cl, OR 55 、N(R 55 )(R 56 ) and SR 55 Substituents, and / or the C 1-4 The alkyl group is optionally substituted by one to three independently selected from O, C(O), CO2 and NR 57 and wherein all available hydrogen atoms are optionally and independently replaced by fluorine atoms or deuterium atoms.

15. The compound of claim 12, wherein R 7 Selected from H and C 1-4 An alkyl group in which all available hydrogen atoms are optionally and independently substituted with fluorine atoms or deuterium atoms.

16. The compound of claim 15, wherein R 7 Selected from H, D, C 1-4 Alkyl, C 1-4 Fluoroalkyl and C 1-4 Deuterated alkyl.

17. A compound as described in any one of claims 1 to 8, wherein R 1 For R 7 , and R 7 Selected from H, CH3, CD3 and CH(CH3)2.

18. A compound as claimed in any one of claims 1 to 10, wherein R 7” Selected from H and C 1-4 An alkyl group in which all available hydrogen atoms are optionally and independently substituted with fluorine atoms or deuterium atoms.

19. A compound as claimed in any one of claims 1 to 18, wherein R 2 , R 2’ and R 2” are independently selected from H, halo, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-3 Alkylene N(R 2a )(R 2b ) and SC 1-4 An alkyl group in which all available hydrogen atoms are optionally and independently substituted with fluorine atoms or deuterium atoms.

20. The compound of claim 19, wherein R 2 , R 2’ and R 2” Independently selected from H, D, F, Cl, C 1-4 Alkyl, C 1-4 Fluoroalkyl, C 1-4 Deuterated alkyl, C 1-4 Alkoxy, C 1-4 Fluoroalkoxy, C 1-4 Deuterated alkoxy, C 1-3 Alkylene N(R 2a )(R 2b ), SC 1-4 Alkyl, SC 1-4 Fluoroalkyl and SC 1-4 Deuterated alkyl.

21. The compound of claim 20, wherein R 2 , R 2’ and R 2” are independently H, D or F.

22. The compound of claim 20, wherein R 2 , R 2’ and R 2” All H, or R 2 , R 2’ and R 2” All are D.

23. The compound of claim 20, wherein R 2a and R 2b Independently selected from H, D, C 1-4 Alkyl, C 1-4 Fluoroalkyl and C 1-4 Deuterated alkyl.

24. A compound as described in any one of claims 1 to 23, wherein R 3 , R 4 , R 5 and R 6 are independently selected from H, halo, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Alkylene N(R 5’ )(R 6’ ) and SC 1-4 Alkyl, the last four groups are optionally replaced by one or two selected from OH and C 1-4 The substituents of the alkoxy group are substituted wherein all available hydrogen atoms are optionally and independently replaced with fluorine atoms or deuterium atoms.

25. The compound of claim 24, wherein R 3 , R 4 , R 5 and R 6 independently selected from H, D, F, Cl, Br, N(R 5’ )(R 6’ ), C 1-4 Alkyl, C 1-4 Fluoroalkyl, C 1-4 Deuterated alkyl, C 1-4 Alkoxy, C 1-4 Fluoroalkoxy, C 1-4 Deuterated alkoxy, C 1-4 Alkylene N(R 5’ )(R 6’ ), SC 1-4 Alkyl, SC 1-4 Fluoroalkyl, SC 1-4 Deuterated alkyl, the last ten groups are optionally replaced by one or two selected from OH, C 1-4 Alkoxy, C 1-4 Fluoroalkoxy and C 1-4 The substituents of the deuterated alkoxy group are substituted.

26. The compound of claim 25, wherein R 3 , R 4 , R 5 and R 6 independently selected from H, D, F, Cl, Br, N(R 5’ )(R 6’ ), C 1-4 Alkyl, C 1-4 Fluoroalkyl, C 1-4 Deuterated alkyl and C 1-2 Alkylene N(R 5’ )(R 6’ ).

27. The compound of claim 25, wherein R 3 , R 4 , R 5 and R 6 Independently selected from H, D, F, Cl, Br, C 1-4 Alkyl, C 1-4 Fluoroalkyl, C 1-4 Deuterated alkyl, SC 1-4 Alkyl, SC 1-4 Fluoroalkyl, SC 1-4 Deuterated alkyl.

28. The compound of claim 25, wherein R 3 , R 4 , R 5 and R 6 One of the following is selected from C 1-3 Alkoxy, C 1-3 Fluoroalkoxy and C 1-3 Deuterated alkoxy groups, these groups are replaced by one or two selected from OH, C 1-3 Alkoxy, C 1-3 Fluoroalkoxy and C 1-3 The substituent of deuterated alkoxy is substituted, and R 3 , R 4 , R 5 and R 6 The remaining groups in are independently selected from H, D, CH3O, CD3O and CF3O.

29. The compound of claim 25, wherein R 3 , R 4 , R 5 and R 6 Independently selected from H, D, F, Cl, Br, C 1-4 Alkyl, C 1-4 Fluoroalkyl, C 1-4 Deuterated alkyl, C 1-4 Alkoxy, C 1-4 Fluoroalkoxy and C 1-4 Deuterated alkoxy.

30. The compound of claim 29, wherein R 3 , R 4 , R 5 and R 6 One to three of are independently selected from H, D, F, CH3, CD2H, CDH2, CD3, CF3, CHF2, CH2CH3, CH(CH3)2, CH2CH2D, CH2CD2H, CD2CD3, CH3O, CD2HO, CDH2O, CD3O, CF3O, CHF2O, CH3CH2O, CH(CH3)2O, CH2DCH2O, CD2HCH2O and CD3CD2O, and R 3 , R 4 , R 5 and R 6 The remaining groups in are selected from H and D.

31. The compound of claim 30, wherein R 3 , R 4 , R 5 and R 6 One to three of are independently selected from H, D, F, CH3O, CD2HO, CDH2O, CD3O, CF3O, CHF2O, CH2CH3O, CH(CH3)2O, CH2DCH2O, CD2HCH2O and CD3CD2O, and R 3 , R 4 , R 5 and R 6 The remaining groups in are selected from H and D.

32. The compound of claim 30, wherein R 3 , R 4 , R 5 and R 6 One to three of them are F, and R 3 , R 4 , R 5 and R 6 The remaining groups in are independently selected from H and D.

33. The compound of claim 30, wherein R 3 , R 4 , R 5 and R 6 One to three of are independently selected from CH3O, CD2HO, CDH2O, CD3O, CF3O, CHF2O, CH2CH3O, CH(CH3)2O, CH2DCH2O, CD2HCH2O and CD3CD2O, and R 3 , R 4 , R 5 and R 6 The remaining groups in are independently selected from H and D.

34. The compound of claim 30, wherein R 4 and R 5 One or two of are independently selected from H, F, CH3O, CD2HO, CDH2O, CD3O, CF3O, CHF2O, CH2CH3O, CH(CH3)2O, CH2DCH2O, CD2HCH2O and CD3CD2O, and R 3 , R 4 , R 5 and R 6 The remaining groups in are selected from H and D.

35. The compound of claim 30, wherein R 3 , R 4 , R 5 and R 6 is independently selected from H, D, F, CH3, CD2H, CDH2, CD3, CF3, CHF2, CH2CH3, CH(CH3)2, CH2CH2D, CH2CD2H and CD2CD3, and R 3 , R 4 , R 5 and R 6 The remaining groups in are independently selected from H and D.

36. The compound of claim 30, wherein R 3 , R 4 , R 5 and R 6 All D or R 3 , R 4 , R 5 and R 6 All are H.

37. A compound as described in any one of claims 1 to 23, wherein R 3 , R 4 , R 5 and R 6 Two adjacent groups in the bond together to form O-(CH2) 1-2 O, and R 3 , R 4 , R 5 and R 6 The remaining groups in are independently selected from H, halogen, C 1-4 Alkyl, C 1-4 Alkoxy, N(R 5’ )(R 6’ ), C 1-4 Alkylene N(R 5’ )(R 6’ ) and SC 1-4 An alkyl group in which all available hydrogen atoms are optionally and independently substituted with fluorine atoms or deuterium atoms.

38. The compound of claim 37, wherein R 3 , R 4 , R 5 and R 6 Two adjacent groups in the bond together to form O-(CH2) 1-2 O, and R 3 , R 4 , R 5 and R 6 The remaining groups in are independently selected from H, F, Cl, Br, C 1-4 Alkyl, C 1-4 Fluoroalkyl, C 1-4 Deuterated alkyl, C 1-4 Alkoxy, C 1-4 Fluoroalkoxy, C 1-4 Deuterated alkoxy, N(R 5’ )(R 6’ ), C 1-4 Alkylene N(R 5’ )(R 6’ ), SC 1-4 Alkyl, SC 1-4 Fluoroalkyl and SC 1-4 Deuterated alkyl.

39. The compound of claim 38, wherein R 3 , R 4 , R 5 and R 6 Two adjacent groups in the bond together to form O-(CH2) 1-2 O, and R 3 , R 4 , R 5 and R 6 The remaining groups in are independently selected from H, D, F, Cl, Br, C 1-4 Alkyl, C 1-4 Fluoroalkyl, C 1-4 Deuterated alkyl, N(R 5’ )(R 6’ ), and C 1-2 Alkylene N(R 5’ )(R 6’ ).

40. The compound of claim 38, wherein R 3 , R 4 , R 5 and R 6 Two adjacent groups in the bond together to form O-(CH2) 1-2 O, and R 3 , R 4 , R 5 and R 6 The remaining groups in are independently selected from H, D, F, Cl, Br, C 1-4 Alkyl, C 1-4 Fluoroalkyl, C 1-4 Deuterated alkyl, SC 1-4 Alkyl, SC 1-4 Fluoroalkyl and SC 1-4 Deuterated alkyl.

41. The compound of claim 40, wherein R 4 and R 5 connected together to form O-(CH2)O, and R 3 and R 6 Independently selected from H, D, F, CH3, CD2H, CDH2, CD3, CF3, CHF2, CH2CH3, CH(CH3)2, CH2CH2D, CH2CD2H, CD2CD3, CH3S, CD2HS, CDH2S, CD3S, CF3S, CHF2S, CH2CH3S, CH(CH3)2S, CHD2CH2S, CD2HCH2S and CD3CD2S.

42. The compound of claim 38, wherein R 4 and R 5 connected together to form O-(CH2)O, and R 3 and R 6 Independently selected from H, F, Cl, Br, C 1-4 Alkyl, C 1-4 Fluoroalkyl, C 1-4 Deuterated alkyl, C 1-4 Alkoxy, C 1-4 Fluoroalkoxy and C 1-4 Deuterated alkoxy.

43. The compound of claim 38, wherein R 4 and R 5 connected together to form O-(CH2)O, and R 3 and R 6 Independently selected from H, D, F, CH3O, CD2HO, CDH2O, CD3O, CF3O and CHF2O.

44. A compound as described in any one of claims 24 to 26 and 37 to 39, wherein R 5’ and R 6’ Independently selected from H and C 1-4 An alkyl group in which all available hydrogen atoms are optionally and independently substituted with fluorine atoms or deuterium atoms.

45. A compound as described in any one of claims 1 to 23, wherein R 3 , R 4 , R 5 and R 6 One of A, OA and C 1-2 Alkylene A, and R 3 , R 4 , R 5 and R 6 The remaining groups in are independently H, F or Cl, wherein all available hydrogen atoms are optionally and independently substituted by fluorine atoms or deuterium atoms, R 3 , R 4 , R 5 and R 6 one of which is selected from A, OA, CH2A, CF2A and CD2A, and R 3 , R 4 , R 5 and R 6 The remaining groups in are independently selected from H and D.

46. ​​A compound as described in any one of claims 1 to 23 and 45, wherein A is selected from phenyl, C 3-6 Cycloalkyl, containing 1 to 2 independently selected from O, S, S(O), SO2, N and NR 54 The heterocyclic 5- to 6-membered alkyl group of the heterocyclic group and containing 1 to 3 independently selected from O, S, S(O), SO2, N and NR 54 The 5- to 6-membered heteroaryl group of the heteroaryl group of 3-10 Cycloalkyl, 3-membered to 6-membered heterocycloalkyl, and 5-membered to 6-membered heteroaryl are optionally substituted with one or two substituents independently selected from the group consisting of F, C, C 1-4 Alkyl, C 1-4 Deuterated alkyl, C 1-4 Fluoroalkyl, OC 1-4 Alkyl, OC 1-4 Deuterated alkyl, OC 1-4 Fluoroalkyl, N(R 54a )(R 54b ), C 1-4 Alkylene N(R 54a )(R 54b ), SC 1-4 Alkyl, SC 1-4 Deuterated alkyl and SC 1-4 Fluoroalkyl.

47. The compound of claim 46, wherein A is C optionally substituted by one or two substituents independently selected from 3-6 Cycloalkyl: F, Cl, C 1-4 Alkyl, C 1-4 Deuterated alkyl, C 1-4 Fluoroalkyl, OC 1-4 Alkyl, OC 1-4 Deuterated alkyl and OC 1-4 Fluoroalkyl.

48. The compound of claim 46, wherein A is a compound comprising 1 to 2 independently selected from O, S, S(O), SO2, N and NR 54 5- to 6-membered heterocycloalkyl of the hetero moiety, which is optionally substituted by one or two independently selected from F, Cl, C 1-4 Alkyl, C 1-4 Deuterated alkyl, C 1-4 Fluoroalkyl, OC 1-4 Alkyl, OC 1-4 Deuterated alkyl and OC 1-4 The substituent of the fluoroalkyl group is substituted.

49. The compound of claim 48, wherein A comprises 1 to 2 independently selected from O, S, S(O), SO2, N and NR 54 The 5- to 6-membered heterocycloalkyl group of the hetero moiety is selected from piperidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, thienyl, oxidized thienyl and dioxide thienyl.

50. The compound of claim 46, wherein A is a molecule comprising 1 to 3 independently selected from O, S, N and NR 54 substituted with one or two substituents independently selected from the group consisting of F, Cl, C 1-4 Alkyl, C 1-4 Deuterated alkyl, C 1-4 Fluoroalkyl, OC 1-4 Alkyl, OC 1-4 Deuterated alkyl and OC 1-4 Fluoroalkyl.

51. The compound of claim 46 or claim 50, wherein A comprises 1 to 3 independently selected from O, S, N and NR 54 The 5- to 6-membered heteroaryl of the hetero portion is selected from pyrrolyl, imidazolyl, oxazolyl, isoxazolyl, isothiazolyl, thiazolyl, pyrazolyl, phenylthio, pyrazolyl and pyridinyl.

52. The compound of claim 48, wherein R 54 Selected from H, D, C 1-4 Alkyl, C 1-4 Fluoroalkyl and C 1-4 Deuterated alkyl.

53. The compound of claim 1, wherein the compound of Formula I or a pharmaceutically acceptable salt, solvate and / or prodrug thereof is defined as follows: in: R 1 H Q is selected from Q1, Q2, Q2', Q4 and Q5: is a single bond or a double bond, provided that when When it is a double bond, R 9 and R 15 does not exist, and when Q2 When it is a double bond, R 17 and R 25 does not exist, and when Q2' When it is a double bond, R 16’ and R 25’ does not exist; On the key means that the bond is attached to the remainder of the compound; R 2 , R 2’ and R 2” independently selected from H, D and F; R 3 , R 4 , R 5 and R 6 Independently selected from H, C 1-4 Alkoxy, C 1-4 Fluoroalkoxy and C 1-4 deuterated alkoxy, or R 3 , R 4 , R 5 and R 6 Two adjacent groups in the bond together to form O-(CH2) 1-2 O, and R 3 , R 4 , R 5 and R 6 The remaining groups in are independently selected from H, halogen, C 1-6 Alkyl and C 1-6 Alkoxy, or R 8 , R 9 , R 10 , R 11 , R 13 , R 14 , R 15 , R 16 , R 16’ , R 17 , R 17’ , R 18 , R 19’ , R 19 , R 19’ , R 21 , R 22’ , R 22 , R 22’ , R 23 , R 23’ , R 24 , R 24’ , R 25 , R 25’ , R 32 , R 33 , R 34 , R 36 , R 37 , R 38 , R 39 , R 40 , R 41 , R 42 , R 43 , R 44 , R 46 , R 47 , R 48 , R 49 , R 50 , R 51 , R 52 and R 53 are independently selected from H, halo and C 1-6 alkyl; R 12 , R 20 , R 20’ , R 35 and R 45 Independently selected from H, C 1-6 Alkyl and C(O)C 1-6 alkyl; R 54 , R 55 , R 56 and R 57 Independently selected from H and C 1-6 Alkyl; and All available hydrogen atoms are optionally and independently replaced with fluorine atoms or chlorine atoms, and all available atoms are optionally substituted with alternative isotopes thereof.

54. The compound of claim 1, wherein the compound of Formula I or a pharmaceutically acceptable salt, solvate and / or prodrug thereof is defined as follows: in: R 1 Selected from H, C(O)R 7 、CO2R 7 、C(O)N(R 7 )(R 7’ )、S(O)R 7 、SO2R 7 , C 1-6 Alkylene R 7 and R 7 ; Q is selected from Q1, Q2, Q2', Q4 and Q5: is a single bond or a double bond, provided that when When it is a double bond, R 9 and R 15 does not exist, and when Q2 When it is a double bond, R 17 and R 25 does not exist, and when Q2' When it is a double bond, R 16’ and R 25’ does not exist; On the key means that the bond is attached to the remainder of the compound; R 2 , R 2’ and R 2” are independently selected from H, halo, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylene N(R 2a )(R 2b ) and SC 1-6 alkyl; R 2a and R 2b Independently selected from H and C 1-6 alkyl; R 3 and R 6 are independently selected from H, halo, C 1-6 Alkyl, N(R 5’ )(R 6’ ), C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylene N(R 5’ )(R 6’ ) and SC 1-6 Alkyl, the last four groups are optionally replaced by one or two selected from OH and C 1-6 Substitution of alkoxy groups; R 4 and R 5 are independently selected from H, halo, N(R 5’ )(R 6’ ), C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylene N(R 5’ )(R 6’ ) and SC 1-6 Alkyl, the last four groups are optionally replaced by one or two selected from OH and C 1-6 Substitution of the alkoxy group; or R 4 and R 5 Linked together to form O-(CH2) 1-2 O; or R 4 and R 5 One of A, OA and C 1-4 Alkylene A, and R 4 and R 5 The other of is H or halogen; R 5’ and R 6’ Independently selected from H and C 1-6 Alkyl; A is selected from phenyl, C 3-6 Cycloalkyl, containing 1 to 4 independently selected from O, S, S(O), SO2, N and NR 54 The heterocyclic alkyl group of the heterocyclic alkyl group is 3-6-membered and contains 1 to 4 independently selected from O, S, S(O), SO2, N and NR 54 The 5- to 6-membered heteroaryl group of the heteroaryl group of 3-10 Cycloalkyl, 3-membered to 6-membered heterocycloalkyl and 5-membered to 6-membered heteroaryl are optionally substituted with one or more substituents independently selected from the group consisting of halo, C 1-4 Alkyl, OC 1-4 Alkyl, N(R 54a )(R 54b ), C 1-4 Alkylene N(R 54a )(R 54b ) and SC 1-4 alkyl; R 7 Selected from H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, phenyl, C 3-6 Cycloalkyl, containing 1 to 4 independently selected from O, S, N and NR 7” The heterocyclic alkyl group of the heterocyclic alkyl group is 3-6-membered and contains 1 to 4 independently selected from O, S, N and NR 7” The 5- to 6-membered heteroaryl group of the ... 55 、N(R 55 )(R 56 ) and SR 55 Substituents, and / or the C 1-6 The alkyl group is optionally substituted by one to three independently selected from O, C(O), CO2 and NR 57 The miscellaneous parts are interrupted; R 7’ Selected from H and C 1-6 alkyl; R 7” Selected from H and C 1-6 alkyl; R 8 , R 9 , R 10 , R 11 , R 13 , R 14 , R 15 , R 16 , R 16’ , R 17 , R 17’ , R 18 , R 19’ , R 19 , R 19’ , R 21 , R 22’ , R 22 , R 22’ , R 23 , R 23’ , R 24 , R 24’ , R 25 , R 25’ , R 32 , R 33 , R 34 , R 36 , R 37 , R 38 , R 39 , R 40 , R 41 , R 42 , R 43 , R 44 , R 46 , R 47 , R 48 , R 49 , R 50 , R 51 , R 52 and R 53 are independently selected from H, halo and C 1-6 alkyl; R 12 , R 20 , R 20’ , R 35 and R 45 Independently selected from H, C 1-6 Alkyl and C(O)C 1-6 alkyl; R 54 , R 55 , R 56 and R 57 Independently selected from H and C 1-6 alkyl; R 54a and R 54b Independently selected from H and C 1-6 Alkyl; and All available hydrogen atoms are optionally and independently replaced with fluorine atoms or chlorine atoms, and all available atoms are optionally substituted with alternative isotopes thereof.

55. The compound of claim 1, wherein the compound of Formula I or a pharmaceutically acceptable salt, solvate and / or prodrug thereof is defined as follows: in: R 1 is H; Q is selected from Q1, Q2, Q2', Q4 and Q5: is a single bond or a double bond, provided that when When it is a double bond, R 9 and R 15 does not exist, and when Q2 When it is a double bond, R 17 and R 25 does not exist, and when Q2' When it is a double bond, R 16’ and R 25’ does not exist; On the key means that the bond is attached to the remainder of the compound; R 2 , R 2’ and R 2” are independently selected from H, halo, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylene N(R 2a )(R 2b ) and SC 1-6 alkyl; R 2a and R 2b Independently selected from H and C 1-6 alkyl; R 3 , R 4 , R 5 and R 6 are independently selected from H, halo, N(R 5’ )(R 6’ ), C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylene N(R 5’ )(R 6’ ) and SC 1-6 Alkyl, the last four substituents are selected from OH and C 1-6 Alkoxy, or R 3 , R 4 , R 5 and R 6 Two adjacent groups in the bond together to form O-(CH2) 1-2 O, and R 3 , R 4 , R 5 and R 6 The remaining groups in are independently selected from H, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, N(R 5’ )(R 6’ ), C 1-6 Alkylene N(R 5’ )(R 6’ ) and SC 1-6 alkyl; R 5’ and R 6’ Independently selected from H and C 1-6 alkyl; R 8 , R 9 , R 10 , R 11 , R 13 , R 14 , R 15 , R 16 , R 16’ , R 17 , R 17’ , R 18 , R 19’ , R 19 , R 19’ , R 21 , R 22’ , R 22 , R 22’ , R 23 , R 23’ , R 24 , R 24’ , R 25 , R 25’ , R 32 , R 33 , R 34 , R 36 , R 37 , R 38 , R 39 , R 40 , R 41 , R 42 , R 43 , R 44 , R 46 , R 47 , R 48 , R 49 , R 50 , R 51 , R 52 and R 53 are independently selected from H, halo and C 1-6 alkyl; R 12 , R 20 , R 20’ , R 35 and R 45 Independently selected from H, C 1-6 Alkyl and C(O)C 1-6 alkyl; All available hydrogen atoms are optionally and independently replaced with fluorine atoms or chlorine atoms, and all available atoms are optionally substituted with alternative isotopes thereof.

56. The compound of claim 1, wherein the compound of Formula I or a pharmaceutically acceptable salt, solvate and / or prodrug thereof is defined as follows: in: R 1 Selected from H, C(O)R 7 、CO2R 7 、C(O)N(R 7 )(R 7’ )、S(O)R 7 、SO2R 7 , C 1-6 Alkylene R 7 and R 7 ; Q is selected from Q1, Q2, Q2', Q4 and Q5: is a single bond or a double bond, provided that when When it is a double bond, R 9 and R 15 does not exist, and when Q2 When it is a double bond, R 17 and R 25 does not exist, and when Q2' When it is a double bond, R 16’ and R 25’ does not exist; On the key means that the bond is attached to the remainder of the compound; R 2 , R 2’ and R 2” are independently selected from H, halo, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylene N(R 2a )(R 2b ) and SC 1-6 alkyl; R 2a and R 2b Independently selected from H and C 1-6 alkyl; R 3 , R 4 , R 5 and R 6 One of A, OA and C 1-4 Alkylene A, and R 3 , R 4 , R 5 and R 6 The remaining groups in are independently H or halo; A is selected from phenyl, C 3-6 Cycloalkyl, containing 1 to 4 independently selected from O, S, S(O), SO2, N and NR 54 The heterocyclic alkyl group of the heterocyclic alkyl group is 3-6-membered and contains 1 to 4 independently selected from O, S, S(O), SO2, N and NR 54 The 5- to 6-membered heteroaryl group of the heteroaryl group of 3-10 Cycloalkyl, 3-membered to 6-membered heterocycloalkyl and 5-membered to 6-membered heteroaryl are optionally substituted by one or more independently selected from halo, C 1-4 Alkyl and OC 1-4 The substituent of the alkyl group is substituted, and A is selected from phenyl, C 3-6 Cycloalkyl, containing 1 to 4 independently selected from O, S, S(O), SO2, N and NR 54 The heterocyclic alkyl group of the heterocyclic alkyl group is 3-6-membered and contains 1 to 4 independently selected from O, S, S(O), SO2, N and NR 54 The 5- to 6-membered heteroaryl group of the heteroaryl group of 3-10 Cycloalkyl, 3-membered to 6-membered heterocycloalkyl and 5-membered to 6-membered heteroaryl are optionally substituted with one or more substituents independently selected from the group consisting of halo, C 1-4 Alkyl, OC 1-4 Alkyl, N(R 54a )(R 54b ), C 1-4 Alkylene N(R 54a )(R 54b ) and SC 1-4 alkyl; R 7 Selected from H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, phenyl, C 3-6 Cycloalkyl, containing 1 to 4 independently selected from O, S, N and NR 7” The heterocyclic alkyl group of the heterocyclic alkyl group is 3-6-membered and contains 1 to 4 independently selected from O, S, N and NR 7” The 5- to 6-membered heteroaryl group of the ... 55 、N(R 55 )(R 56 ) and SR 55 Substituents, and / or the C 1-6 The alkyl group is optionally substituted by one to three independently selected from O, C(O), CO2 and NR 57 The miscellaneous parts are interrupted; R 7’ Selected from H and C 1-6 alkyl; R 7” Selected from H and C 1-6 alkyl; R 8 , R 9 , R 10 , R 11 , R 13 , R 14 , R 15 , R 16 , R 16’ , R 17 , R 17’ , R 18 , R 19’ , R 19 , R 19’ , R 21 , R 22’ , R 22 , R 22’ , R 23 , R 23’ , R 24 , R 24’ , R 25 , R 25’ , R 32 , R 33 , R 34 , R 36 , R 37 , R 38 , R 39 , R 40 , R 41 , R 42 , R 43 , R 44 , R 46 , R 47 , R 48 , R 49 , R 50 , R 51 , R 52 and R 53 are independently selected from H, halo and C 1-6 alkyl; R 12 , R 20 , R 20’ , R 35 and R 45 Independently selected from H, C 1-6 Alkyl and C(O)C 1-6 alkyl; R 54 , R 55 , R 56 and R 57 Independently selected from H and C 1-6 alkyl; R 54a and R 54b Independently selected from H and C 1-6 Alkyl; and All available hydrogen atoms are optionally and independently replaced with fluorine atoms or chlorine atoms, and all available atoms are optionally substituted with alternative isotopes thereof.

57. A compound as described in any one of claims 1 to 21, wherein the compound of formula I has one of the following structures or a mixture thereof:

58. A compound as described in any one of claims 1 to 21, wherein R 2 and R 2’ Different, and R 2 and R 2’ The bonded carbon is chiral.

59. The compound of claim 1, selected from the following compounds or pharmaceutically acceptable salts, solvates and / or prodrugs thereof:

60. A composition comprising one or more compounds as claimed in any one of claims 1 to 59 and a carrier.

61. A pharmaceutical composition comprising one or more compounds as described in any one of claims 1 to 59 and a pharmaceutically acceptable carrier.

62. A composition comprising one or more compounds as described in any one of claims 1 to 59 and one or more components of a nanocarrier system.

63. The composition of claim 62, wherein the nanocarrier system is selected from the group consisting of liposomes, micelles, nanoparticles, nanoemulsions, and lipid nanosystems.

64. A method of treating a disease, disorder or condition by activating a serotonin receptor, the method comprising administering to a subject in need thereof a therapeutically effective amount of one or more compounds of any one of claims 1 to 59.

65. The method of treatment of claim 64, wherein the disease, disorder or condition treatable by activating serotonin receptors has no hallucinogenic effect in the subject or has a reduced hallucinogenic effect in the subject compared to the hallucinogenic effect of administering an equivalent amount of a hallucinogenic drug.

66. A method of treating a psychotic disorder, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound as described in any one of claims 1 to 59.

67. The method of claim 66, wherein the psychiatric disorder is selected from the group consisting of hallucinations and delusions, and combinations thereof.

68. The method of claim 66, wherein the psychiatric disorder is selected from anxiety disorders; depression; mood disorders; psychotic disorders; impulse control and addiction disorders; drug addiction; obsessive compulsive disorder (OCD); post-traumatic stress disorder (PTSD); stress response syndrome; dissociative disorders; depersonalization disorder; factitious disorder; sexual and gender disorders; and somatic symptom disorder, and combinations thereof.

69. A method of treating a psychotic disorder or psychotic symptoms, the method comprising administering to a subject in need thereof a therapeutically effective amount of one or more compounds of any one of claims 1 to 59.

70. A method of treating a central nervous system (CNS) disease, disorder or condition and / or a nervous system disease, disorder or condition, the method comprising administering to a subject in need thereof a therapeutically effective amount of one or more compounds as described in any one of claims 1 to 59.

71. The method of claim 70, wherein the CNS disease, disorder or condition and / or nervous system disease, disorder or condition is selected from a nervous system disease, including neurodevelopmental and neurodegenerative diseases such as Alzheimer's disease; precocious dementia; Alzheimer's disease; vascular dementia; dementia with Lewy bodies; cognitive impairment, Parkinson's disease and Parkinson's related diseases such as Parkinson's dementia, corticobasal degeneration and supranuclear palsy; epilepsy; CNS trauma; CNS infection; CNS inflammation; stroke; multiple sclerosis; Huntington's disease; mitochondrial disease; fragile X syndrome; Angelman syndrome symptoms; hereditary ataxias; neuro-otological and oculomotor disorders; retinal neurodegenerative diseases; amyotrophic lateral sclerosis; tardive dyskinesia; ADHD; attention deficit hyperactivity disorder and attention deficit disorder; restless legs syndrome; Tourette syndrome; schizophrenia; autism spectrum disorders; tuberous sclerosis complex; Rett syndrome; cerebral palsy; reward system disorders, including eating disorders such as anorexia nervosa ("AN") and bulimia nervosa ("BN"); and binge eating disorder ("BED"), trichotillomania, dermatophytes, nail biting; migraine; fibromyalgia; and peripheral neuropathies of any etiology, and combinations thereof.

72. A method of treating a cluster of endophenotypes and / or symptoms associated with a disease, disorder or condition treatable by activation of a serotonin receptor, the method comprising administering to a subject in need thereof a therapeutically effective amount of one or more compounds of any one of claims 1 to 59.

73. The method of claim 72, wherein the endophenotypes and / or symptom clusters are associated with neurodevelopmental and neurodegenerative diseases, such as apathy, anhedonia, impaired attention, impaired memory, negative mood deviation, hypomania, impaired executive function, impulsive behavior, depressed mood, decreased libido, sensory gating, impaired prepulse inhibition, aggressive behavior, suicidal ideation, obesity, increased arousal, decreased arousal, hypersexuality, decreased exploratory behavior, hyperactivity, hypoactivity, sleep disorders, incontinence, impaired social perception, rumination, and combinations thereof.

74. A method of treating a behavioral problem comprising administering to a non-human subject in need thereof a therapeutically effective amount of one or more compounds of any one of claims 1 to 59.

75. The method of claim 74, wherein the non-human subject is a canine or feline suffering from a neurological disease, behavioral problems, trainability problems, and / or combinations thereof.

76. The method of claim 75, wherein the neurological disease, behavioral problem, trainability problem includes but is not limited to anxiety, fear and stress, sleep disorders, cognitive dysfunction, aggressive behavior and / or combinations thereof.

77. A method of treating a disease, disorder or condition by activating a serotonin receptor, the method comprising administering to a subject in need thereof a therapeutically effective amount of one or more compounds of any one of claims 1 to 59 in combination with another agent known to be useful for treating a disease, disorder or condition by activating a serotonin receptor.

78. A pharmaceutical composition comprising a compound as claimed in any one of claims 1 to 59 and an additional therapeutic agent.

79. The composition of claim 78, wherein the additional therapeutic agent is a psychoactive drug.

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