Heterocyclic compound and method for preparing the same

Abstract

This document describes the compound of structural formula I, or the pharmaceutically acceptable salt thereof, and the stereoisomer thereof: I, A pharmaceutical composition comprising a compound of Formula I, as well as a method and / or use of a compound of Formula I for treating disorders, particularly depressive disorders.

Description

Technology Field

[0001] Cross-reference regarding related applications

[0002] This application claims priority to U.S. Patent Application No. 63 / 610,614 filed December 15, 2023, the entire specification of said application incorporated herein by reference.

[0003] (a) field

[0004] The disclosed subject matter relates to heterocyclic compounds and methods for preparing the same. The disclosed subject matter also relates to the use of heterocyclic compounds as selective agents of serotonin receptors. Background Technology

[0005] (b) Related prior art

[0006] Pylosybin is a naturally occurring hallucinogenic compound produced by over 200 species of mushrooms known collectively as "psilosybin mushrooms."

[0007]

[0008] psilocybin

[0009] As a prodrug, psilocybin is rapidly metabolized in the body to produce psilocin, a bioactive compound, which has psychoaltering effects not unlike those produced by other hallucinogens such as lysergic acid diethylamide (LSD), mescaline, and N,N-dimethyltryptamine (DMT). These effects include, in particular, euphoria, visual and mental hallucinations, changes in perception, a distorted sense of time, and spiritual experiences, and may also include possible side effects such as nausea and panic attacks.

[0010] 5-HT 2A and 5-HT 2C As receptor agonists, the therapeutic potential of psilocybin and psilocin has been recognized. 5-HT 2A While receptor activation appears to increase motor activity, 5-HT 2CSince receptor activation appears to reduce motor activity, various degrees of 5-HT 2A and 5-HT 2C Compounds possessing activity will exhibit varying levels of hallucinogenic activity. Pillocybin, along with other hallucinogenic drugs, was explored by Hofmann and his colleagues at Sandoz more than 60 years ago (see, e.g., Hofmann, A., Troxler, F. US3075992; US3078214), but clinical research on these drugs decreased significantly until the early 1970s—particularly in the United States Controlled Substance Act This was the case after it was listed on Schedule 1. However, despite being listed as a controlled substance in certain jurisdictions, research on psilocybin and other hallucinogenic drugs has never been completely halted, and recent clinical studies have revived interest in the potential applications of hallucinogenic drugs (including psilocybin) in evolving medical fields, such as the treatment of central nervous system (CNS) diseases. CNS diseases are difficult-to-treat mental health disorders, such as treatment-resistant depression or drug-resistant depression (Daniel J, Haberman M. Clinical potential of psilocybin as a treatment for mental health conditions. Ment. Health Clinic 2017, It includes all neurological disorders such as 7(1), 24-8), and cluster headaches.

[0011] Pillocibin is recognized for its therapeutic potential to treat certain CNS diseases and disorders, but 5-HT 2B It is also recognized as a receptor agonist and therefore has cardiotoxicity. For this reason, 5-HT 2A 5-HT maintains receptor agonist activity but is cardiotoxic 2B There is an unmet need for safer drugs and analogs of psilocybin and psilocin that lack agonist activity; furthermore, in at least some cases, 5-HT 2A5-HT maintains receptor agonist activity but is cardiotoxic 2B There is an unmet need for safer drugs that lack agonist activity.

[0012] According to one embodiment, a compound of structural formula I, or a pharmaceutically acceptable salt thereof, and a stereoisomer thereof are provided:

[0013]

[0014] I

[0015] Here:

[0016] R 1 is OH, and R 1 In the case of this OH, R 2 is different from OH and (i) Selected from the group consisting of H, halogen, lower alkyl, CHF2, CF3, NC, OCH3, OCHF2, OCF3, SCHF2, SCH3, SCF3, and cyano; or (ii) a It forms a ring composed of three or four atoms together with, wherein one of the atoms is selected from the group consisting of C, N, O, and S and the remainder is carbon, the chain contains zero, one, or two double bonds, and the chain is bonded with a substituent independently selected from the group consisting of H, halogen, OH, C1-C6 alkoxy, C1-C6 alkyl, C3-C6 cycloalkyl, CHF2, CF3, OCHF2, OCF3, SCH3, SCHF2, SCF3, cyano, and oxo;

[0017] R 2 is OH, and R 2 If α is OH, R 1 It is different from OH. (i) Selected from the group consisting of H, halogen, lower alkyl, CHF2, CF3, OCH3, OCHF2, OCF3, SCHF2, SCH3, SCF3, and cyano; or (ii) b or cIt forms a ring composed of 6 to 8 atoms together with, wherein one of the atoms is selected from the group consisting of C, N, O, and S and the remainder is carbon, the chain contains one or two double bonds, and the chain is bonded with a substituent independently selected from the group consisting of H, halogen, OH, C1-C6 alkoxy, C1-C6 alkyl, C3-C6 cycloalkyl, CHF2, CF3, OCHF2, OCF3, SCH3, SCHF2, SCF3, cyano, and oxo;

[0018] R 3 silver ( i ) C1-C6 alkyl, C1-C6 substituted alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, (C3-C6 cycloalkyl)(C1-C6 alkyl), C3-C6 heterocyclyl, (C3-C6 heterocyclyl)(C1-C6 alkyl), aryl, aryl(C1-C6 alkyl), heteroaryl, heteroaryl(C1-C6 alkyl), CN, C(O)NH2, C(O)NH(C1-C6 alkyl), C(O)N(C1-C3 alkyl)(C1-C6 alkyl), C(=NOH)(C1-C6 alkyl), and C(=NOH)(C1-C6 substituted alkyl), C(O)NH(aryl), C(O)N(alkyl)(aryl), NC, S(O)2NH2, Selected from the group consisting of S(O)2NH(C1-C6 alkyl) and S(O)2NH(aryl); or ( ii ) R 4 Forming a chain composed of 2 to 4 carbon atoms together with, wherein a substituent independently selected from the group consisting of H, C1-C6 alkyl, aryl, and heteroaryl is bonded to the chain; or ( iii ) a...to form a ring composed of three or four atoms, wherein one of the atoms is selected from the group consisting of C, N, O, and S and the remainder is carbon, the chain contains zero, one, or two double bonds, and the chain is bonded to a substituent independently selected from the group consisting of H, halogen, OH, C1-C6 alkoxy, C1-C6 alkyl, C3-C6 cycloalkyl, CHF2, CF3, OCHF2, OCF3, SCH3, SCF3, cyano, and oxo; or ( iv ) b If valogen, CH3, CHF2, CF3, OCH3, OCHF2, OCF3, SCH3, SCHF2, SCF3 or cyano, H, C1-C6 alkyl, C1-C6 substituted alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, (C3-C6 cycloalkyl)(C1-C6 alkyl), C3-C6 heterocyclyl, (C3-C6 heterocyclyl)(C1-C6 alkyl), aryl, aryl(C1-C6 alkyl), heteroaryl, heteroaryl(C1-C6 alkyl), CN, C(O)NH2, C(O)NH(C1-C6 alkyl), C(O)N(C1-C3 alkyl)(C1-C6 alkyl), C(=NOH)(C1-C6 alkyl), and Selected from the group consisting of C(=NOH)(C1-C6 substituted alkyl), and

[0019] Optionally, R 3 silver awith CH2CH2, CH2CH2CH2, CH2CH2CH2CH2, CH=CHCH=CH, OCH2CH2, CH2OCH2, CH2CH2O, OCH=CH, CH=CHO, OCH2O, SCH2CH2, CH2SCH2, CH2CH2S, SCH=CH, CH=CHS, NHCH2CH2, CH2NHCH2, CH2CH2NH, NHCH=CH, CH=CHNH, ON=CH, CH=NO, OCH=N, N=CHO, SN=CH, CH=NS, SCH=N, N=CHS, NHN=CH, CH=NNH, NHCH=N, N=CHNH, NHN=N, N=NNH, OCH2CH2CH2, CH2OCH2CH2, CH2CH2OCH2, CH2CH2CH2O, SCH2CH2CH2, CH2SCH2CH2, Forming any one of CH2CH2SCH2, CH2CH2CH2S NHCH2CH2CH2CH2, CH2NHCH2CH2, CH2CH2NCH2, CH2CH2CH2NH, N=CHCH=CH, CH=NCH=CH, CH=CHN=CH, CH=CHCH=N; and optionally, when present on the moiety, one or two hydrogen atoms are substituted with a substituent independently selected from the group consisting of halogen, OH, C1-C6 alkoxy, C1-C6 alkyl, C3-C6 cycloalkyl, CHF2, CF3, OCHF2, OCF3, SCH3, SCF3, and cyano, or when bonded to the same carbon atom, two hydrogens are substituted with an oxo group;

[0020] R 4 Is (i) Selected from the group consisting of H, C1-C6 alkyl, C1-C6 substituted alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, (C3-C6 cycloalkyl)(C1-C6 alkyl), C3-C6 heterocyclyl, (C3-C6 heterocyclyl)(C1-C6 alkyl), aryl(C1-C6 alkyl), arylsulfonyl, heteroarylsulfonyl, aryl(C1-C6 alkyl)sulfonyl, (C1-C6)alkylsulfonyl, and heteroaryl(C1-C6 alkyl)sulfonyl; or (ii) R3 Together with, it forms a chain composed of 2 to 4 carbon atoms, wherein a substituent independently selected from the group consisting of H, C1-C6 alkyl, aryl, heteroaryl, and any combination thereof is bonded to the chain;

[0021] R 5 is an H, D, C1-C6 alkyl, C1-C6 substituted alkyl;

[0022] R 6 silver: (i) Selected from the group consisting of H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, (C3-C6 cycloalkyl)(C1-C6 alkyl), aryl (C1-C6 alkyl), acetyl and heteroaryl (C1-C6 alkyl); or (ii) R 7 and together with the N atoms to which they are bonded, form a 4 to 7-membered heterocyclil ring; or (iii) e and R 6 Forming an azetidine or pyrrolidine ring with the bonded N atom, said ring having a substituent independently selected from the group consisting of H, aryl, heteroaryl, C1-C6 alkyl, and C3-C6 cycloalkyl; or (iv) b and R 6 Forming an azetidine or pyrrolidine ring together with the bonded N atom, said ring has a substituent independently selected from the group consisting of H, aryl, heteroaryl, halogen, C1-C6 alkyl, and C3-C6 cycloalkyl;

[0023] R 7 silver: (i) Selected from the group consisting of H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, (C3-C6 cycloalkyl)(C1-C6 alkyl), aryl (C1-C6 alkyl), acetyl and heteroaryl (C1-C6 alkyl); or (ii) R 6and together with the N atoms to which they are bonded, form a 4 to 7-membered heterocyclil ring;

[0024] a Is: (i) Selected from the group consisting of H, halogen, CH3, CHF2, CF3, OCH3, OCHF2, OCF3, SCH3, SCHF2, SCF3, NC, and cyano; or (ii) A ring composed of three or four atoms is formed together with a, wherein one of the atoms is selected from the group consisting of C, N, O, and S and the remainder is carbon, the chain contains zero, one, or two double bonds, and the chain is bonded to a substituent independently selected from the group consisting of H, halogen, OH, C1-C6 alkoxy, C1-C6 alkyl, C3-C6 cycloalkyl, CHF2, CF3, OCHF2, OCF3, SCH3, SCHF2, SCF3, cyano, and oxo; or (iii) R 3 It forms a ring composed of three or four atoms together with, wherein one of the atoms is selected from the group consisting of C, N, O, and S and the remainder is carbon, the chain contains zero, one, or two double bonds, and the chain is bonded with a substituent independently selected from the group consisting of H, halogen, OH, C1-C6 alkoxy, C1-C6 alkyl, C3-C6 cycloalkyl, CHF2, CF3, OCHF2, OCF3, SCH3, SCHF2, SCF3, cyano, and oxo; and

[0025] b , c , d and e are each independently H or; or b , c , d and e Three of them are H and the remaining substituents are lower alkyl groups; or b and e are H respectively, and c andd is together -CH2- or -CH2CH2-, thereby forming a cyclopropane or cyclobutane ring; or b , c and d are H respectively, and e , R 6 and R 6 The bonded N atoms together form an azetidine or pyrrolidine ring, said ring having a substituent independently selected from the group consisting of H, aryl, heteroaryl, C1-C6 alkyl, and C3-C6 cycloalkyl; or c , d and e are H respectively, and b , R 6 and R 6 These bonded N atoms together form an azetidine or pyrrolidine ring, said ring having a substituent independently selected from the group consisting of H, aryl, heteroaryl, halogen, C1-C6 alkyl, and C3-C6 cycloalkyl.

[0026] The above a It may be a halogen. The above a can be F. The above a It could be CF3. The above a can be H.

[0027] The above R 1 It can be OH and the above R 2 can be H.

[0028] The above R 1 can be H and the above R 2 can be OH.

[0029] The above R 4 can be H.

[0030] The above R 5 can be H.

[0031] In the compound of the present invention b , c , d and eEach can be H.

[0032] Compounds of chemical formula I can be compounds of chemical formula II:

[0033]

[0034] II

[0035] Here, R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , a , b , c , d and e Each is as defined above.

[0036] Compounds of chemical formula I can be compounds of chemical formula III:

[0037]

[0038] III

[0039] Here, R 1 , R 3 , R 4 , R 5 , R 6 , R 7 , a , b , c , d and e Each is as defined in Paragraph 1.

[0040] In the compound of the present invention, R 6 and R 7 Each can be CH3.

[0041] The compound of chemical formula I may be the compound of structural formula VI, or a pharmaceutically acceptable salt thereof, and a stereoisomer thereof:

[0042]

[0043] VI

[0044] Here:

[0045] R 1is OH, and R 1 In the case of this OH, R 2 is different from OH and is selected from the group consisting of H, halogen, lower alkyl, CHF2, CF3, NC, OCH3, OCHF2, OCF3, SCHF2, SCH3, SCF3, and cyano;

[0046] R 2 is OH, and R 2 If α is OH, R 1 is different from OH and is selected from the group consisting of H, halogen, lower alkyl, CHF2, CF3, OCH3, OCHF2, OCF3, SCHF2, SCH3, SCF3, and cyano;

[0047] R 3 C1-C6 alkyl, C1-C6 substituted alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, (C3-C6 cycloalkyl)(C1-C6 alkyl), C3-C6 heterocyclyl, (C3-C6 heterocyclyl)(C1-C6 alkyl), aryl, aryl(C1-C6 alkyl), heteroaryl, heteroaryl(C1-C6 alkyl), CN, C(O)NH2, C(O)NH(C1-C6 alkyl), C(O)N(C1-C3 alkyl)(C1-C6 alkyl), C(=NOH)(C1-C6 alkyl), and C(=NOH)(C1-C6 substituted alkyl), C(O)NH(aryl), C(O)N(alkyl)(aryl), NC, S(O)2NH2, Selected from the group consisting of S(O)2NH(C1-C6 alkyl) and S(O)2NH(aryl);

[0048] R 4 is selected from the group consisting of H, C1-C6 alkyl, C1-C6 substituted alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, (C3-C6 cycloalkyl)(C1-C6 alkyl), C3-C6 heterocyclyl, (C3-C6 heterocyclyl)(C1-C6 alkyl), aryl(C1-C6 alkyl), arylsulfonyl, heteroarylsulfonyl, aryl(C1-C6 alkyl)sulfonyl, (C1-C6)alkylsulfonyl, and heteroaryl(C1-C6 alkyl)sulfonyl;

[0049] R5 is an H, D, C1-C6 alkyl, C1-C6 substituted alkyl;

[0050] R 6 Silver is selected from the group consisting of H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, (C3-C6 cycloalkyl)(C1-C6 alkyl), aryl (C1-C6 alkyl), acetyl, and heteroaryl (C1-C6 alkyl);

[0051] R 7 Silver is selected from the group consisting of H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, (C3-C6 cycloalkyl)(C1-C6 alkyl), aryl (C1-C6 alkyl), acetyl, and heteroaryl (C1-C6 alkyl);

[0052] a is: selected from the group consisting of H, halogen, CH3, CHF2, CF3, OCH3, OCHF2, OCF3, SCH3, SCHF2, SCF3, NC, and cyano; and

[0053] b , c , d and e are each independently H or; or b , c , d and e Three of them are H, and the remaining substituents are lower alkyl groups.

[0054] A compound of chemical formula I can be a compound of chemical formula IV:

[0055]

[0056] IV.

[0057] The compound of chemical formula IV is chemical formula IV- S It can be a compound of:

[0058]

[0059] IV- S .

[0060] The compound of chemical formula IV is chemical formula IV- R It can be a compound of:

[0061]

[0062] IV- R .

[0063] The compound of chemical formula IV is chemical formula IV- S Compounds of and chemical formula IV- R It can be a racemic mixture of the compound:

[0064] and

[0065] IV-S IV-R.

[0066] Compounds of chemical formula I can be compounds of chemical formula V:

[0067]

[0068] V.

[0069] Compounds of chemical formula V are chemical formula V- S It can be a compound of:

[0070]

[0071] V- S .

[0072] Compounds of chemical formula V are chemical formula V- R It can be a compound of:

[0073]

[0074] V- R .

[0075] Compounds of chemical formula V are chemical formula V- S Compounds of and chemical formula V- R It can be a racemic mixture of the compound:

[0076] and

[0077] VS VR.

[0078] According to another embodiment, a pharmaceutical composition comprising a compound of the present invention and a pharmaceutically acceptable carrier is provided.

[0079] According to another embodiment, a compound of the present invention or a pharmaceutical composition of the present invention is provided for use in the treatment of a disorder in a patient who requires it.

[0080] According to another embodiment, a method for treating a disorder is provided, comprising administering an effective amount of the compound of the present invention or the pharmaceutical composition of the present invention to a patient.

[0081] According to another embodiment, the use of a compound of the present invention or a pharmaceutical composition of the present invention is provided for the treatment of a disorder in a patient who requires it.

[0082] In the compound for use of the present invention, the method of the present invention, or the use of the present invention, the disorder is one or more of major depressive disorder, drug-resistant depression and psychotic depression, addiction including alcoholism, tobacco addiction, cocaine addiction and opioid addiction, pain indications including neuropathic pain, pain due to chemotherapy-related neuropathy, phantom limb pain and fibromyalgia, inflammation (including chronic and acute), eating disorders including anorexia, autism, cluster headache, migraine, dementia including Alzheimer's dementia, Parkinson's disease dementia and Lewy body dementia, mild cognitive impairment, post-traumatic stress disorder, emotional distress related to cancer, fragile X syndrome, autism spectrum disorder, bipolar disorder, obsessive-compulsive disorder and Rett syndrome.

[0083] In the compound for use of the present invention, the method of the present invention, or the use of the present invention, the disorder is one or more of major depressive disorder, drug-resistant depression, and psychotic depression.

[0084] According to another embodiment, a combination drug therapy comprising the following is provided:

[0085] A compound according to the present invention, or a pharmaceutical composition of the present invention; and

[0086] N -methyl- D - Aspartate (NMDA) receptor antagonist.

[0087] In the combination drug therapy of the present invention, the NMDA receptor antagonist is at least one of ketamine, nitrous oxide, memantine, amantadine, noribogain, dextromethorphan, dextromethadone, or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof.

[0088] In the combination drug therapy of the present invention, the NMDA receptor antagonist is dextromethorphan.

[0089] The combination drug therapy of the present invention for use in the treatment of a disability in patients requiring this.

[0090] According to another embodiment, a method for treating a disorder is provided, comprising administering an effective amount of the combination drug therapy of the present invention to a patient.

[0091] According to another embodiment, the use of the combination drug therapy of the present invention for the treatment of a disorder in a patient requiring this is provided.

[0092] In combination drug therapy for use of the present invention, the method of the present invention, or the use of the present invention, the disorder is one or more of major depressive disorder, drug-resistant depression and psychotic depression, addiction including alcoholism, tobacco addiction, cocaine addiction and opioid addiction, pain indications including neuropathic pain, pain due to chemotherapy-related neuropathy, phantom limb pain and fibromyalgia, inflammation (including chronic and acute), eating disorders including anorexia, autism, cluster headache, migraine, dementia including Alzheimer's dementia, Parkinson's disease dementia and Lewy body dementia, mild cognitive impairment, post-traumatic stress disorder, emotional distress related to cancer, fragile X syndrome, autism spectrum disorder, bipolar disorder, obsessive-compulsive disorder and Rett syndrome.

[0093] In the combination drug therapy for the use of the present invention, the method of the present invention, or the use of the present invention, the disorder is one or more of major depressive disorder, drug-resistant depression, and psychotic depression.

[0094] The following terms are defined as follows.

[0095] In this specification, the use of the words "a" or "an" in conjunction with the term "comprising" may mean "one," but is also consistent with the meanings of "one or more," "at least one," and "one or more than one." Any element expressed in the singular form encompasses its plural form. Any element expressed in the plural form encompasses its singular form. As used in this specification, the term "plurality" means more than one, e.g., two or more, three or more, four or more, etc.

[0096] Unless otherwise specified in this specification, when used to describe a stated value, the term “about” means within 10% of the stated value.

[0097] Unless otherwise specified in this specification, the term “substituted” refers to a compound in which one or more hydrogen atoms are replaced by other atoms or groups.

[0098] Unless otherwise specified herein, the term “alkenyl” refers to a substituted or unsubstituted linear or branched monovalent hydrocarbon chain having at least two carbon atoms and at least one carbon-carbon (CC) double bond. Examples of alkenyl groups include allyl, vinyl, 2-propenyl, crotyl, 2-isopentenyl, 1,3-butadiene-2-yl, 2,4-pentadiene-1-yl, 1,4-pentadiene-3-yl, etc.

[0099] Unless otherwise specified in this specification, the term “alkoxy” used alone or as part of a larger moiety refers to the -O-alkyl and -O-cycloalkyl groups. Unless otherwise specified in this specification, the term “substituted alkoxy” used alone or as part of a larger moiety refers to the -O-(substituted alkyl) and -O-(substituted cycloalkyl) groups.

[0100] Unless otherwise specified herein, the term “alkyl” used alone or as part of a larger moiety means a fully saturated, substituted or unsubstituted linear or branched monovalent hydrocarbon chain. Unless otherwise specified, the alkyl group contains 1 to 7 carbon atoms (“C1-C7alkyl”). For example, in some embodiments, the alkyl group contains 1 to 6 carbon atoms (“C1-C6alkyl”); in some embodiments, the alkyl group contains 1 to 5 carbon atoms (“C1-C5alkyl”); in some embodiments, the alkyl group contains 1 to 4 carbon atoms (“C1-C4alkyl”), alternatively “lower alkyl”); and in some embodiments, the alkyl group contains 3 to 7 carbon atoms (“C3-C7alkyl”). Non-limiting examples of saturated alkyl groups include homologues and isomers such as methyl, ethyl, n-propyl, i-propyl, n-butyl, t-butyl, i-butyl, s-butyl, e.g., n-pentyl, n-hexyl, n-heptyl, n-octyl, etc. Examples of lower alkyl groups include methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, i-butyl, and t-butyl. The substituted alkyl group has at least one substituent, but not more than the number of hydrogen atoms in the unsubstituted group. In some embodiments, the substituent is a fluorine atom. Non-limiting examples of substituted alkyl groups include 2-hydroxyethyl, 2-methoxyethyl, CHF2, CF3, CH2CF3, CF2CF3, 4-fluorobutyl, etc.

[0101] Unless otherwise specified herein, the term “alkynyl” refers to a substituted or unsubstituted linear or branched monovalent hydrocarbon chain having at least two carbon atoms and at least one carbon-carbon triple bond. Non-limiting examples of alkynyl groups include ethinyl, 1- and 3-propynyl, 3-butyne-1-yl, etc.

[0102] Unless otherwise specified herein, the term “aryl (e.g., “(aryl)alkyl”) used alone or as part of a larger moiety refers to a monovalent monocyclic or bicyclic carbocyclic aromatic ring system. Unless otherwise specified, the aryl group contains six or ten ring members. Non-limiting examples of aryls include phenyl, naphthyl, etc. The term “aryl” also refers to an aryl group that may be unsubstituted or substituted. For example, the aryl group is unsubstituted or one, two, or three independently selected from the group consisting of halogen, OH, C1-C6 alkoxy, substituted C1-C6 alkoxy, C1-C6 alkylthio, substituted C1-C6 alkylthio, C1-C6 alkyl, substituted C1-C6 alkyl, C3-C6 cycloalkyl, substituted C3-C6 cycloalkyl, C(O)OH, C(O)(C1-C6 alkyl), C(N-OH)(C1-C6 alkyl), C(O)(C1-C6 alkoxy), C(O)NH2, C(O)NH(C1-C6 alkyl), C(O)N(C1-C4 alkyl)(C1-C4 alkyl), C(O)-heterocyclyl, NHC(O)(C1-C6 alkyl), N(CH3)C(O)(C1-C6 alkyl), and cyano. It can be replaced by more than that.

[0103] Unless otherwise specified or evident from the context, the term “chemical entity” refers to a compound having the indicated structure, whether in a “free” form (e.g., where applicable, in the form of a “free compound,” “free base,” or “free acid”), in a salt form, particularly a pharmaceutically acceptable salt form, furthermore, in a solid state form or any other form. In some embodiments, the solid state form is amorphous (i.e., non-crystalline); and in some embodiments, the solid state form is crystalline (e.g., polymorph, pseudohydrate, hydrate, or solvate). Similarly, the term encompasses the compound, whether provided in a solid form or any other form. Unless otherwise specified, all descriptions made in this specification regarding “compound” apply to the relevant chemical entity as defined.

[0104] Unless otherwise specified herein, the terms “comprising,” “having,” “including,” “containing,” and grammatical variations thereof are inclusive or open-ended and do not exclude additional undisclosed elements and / or method steps. For example, “A includes 1, 2, and 3” means that A includes, but is not limited to, 1, 2, and 3.

[0105] Unless otherwise specified herein, the term “consisting essentially of” as used herein in relation to a composition, use, or method indicates that additional elements, method steps, or both additional elements and method steps may be present, but such additions do not substantially affect the manner in which the described composition, method, or use functions.

[0106] Unless otherwise specified herein, the term “consisting of” as used herein in relation to a composition, use, or method excludes the presence of additional elements and / or method steps.

[0107] Unless otherwise specified herein, the term “cycloalkyl” used alone or as part of a larger moiety, e.g., “(cycloalkyl)alkyl”, refers to the following: (i) a substituted or unsubstituted monocyclic hydrocarbon radical that is fully saturated or contains one or more unsaturated units but is not aromatic; or (ii) a bicyclo[mno]alkyl (wherein “m”, “n” and “o” are each independently integers from 0 to 5, and the sum “m”+”n”+“o” is in the range of 2 to 6). In some embodiments, the cycloalkyl group contains 3 to 8 cyclic carbon atoms (“C3-C8 cycloalkyl”). Non-limiting examples of cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl, etc., as well as bicyclo[2.2.1]heptyl (also called norbornyl) and bicyclo[1.1.1]pentyl. The substituted cycloalkyl group has at least one substituent. In some embodiments, the substituent is a fluorine atom. Non-limiting examples of the substituted cycloalkyl group include 2-methylcyclopropyl, 4-hydroxycyclohexyl, 2-methoxycyclopentyl, 4,4-difluorocyclohexyl, etc.

[0108] Unless otherwise specified, the terms “halogen” or “halo” used in this specification, either alone or as part of a larger moiety, refer to fluoro, chloro, bromo, or iodo.

[0109] Unless otherwise specified in this specification, the term “heteroalkyl” refers to a substituted or unsubstituted, saturated or unsaturated alkyl group as defined in this specification, wherein one or more of its constituent carbon atoms are replaced by nitrogen, oxygen, or sulfur.

[0110] Unless otherwise specified herein, the term “heteroaryl,” used alone or as part of a larger moiety, e.g., “(heteroaryl)alkyl,” refers to a monovalent monocyclic or bicyclic group having 5 to 10, preferably 5, 6, 9, or 10 ring atoms, having 6 or 10 π electrons shared in a cyclic arrangement, and having 1 to 4 ring heteroatoms in addition to the ring carbon atoms. Examples of heteroaryl groups include thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, indolizinyl, benzofuranyl, benzothiophenyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, benzotriazolyl, quinolyl, isoquinolyl, furinyl, naftiridinyl, ptendmyl, etc. The heteroaryl group may be unsubstituted or substituted with one, two, three, or more groups independently selected from halogen, OH, C1-C6 alkoxy, substituted C1-C6 alkoxy, C1-C6 alkylthio, substituted C1-C6 alkylthio, C1-C6 alkyl, substituted C1-C6 alkyl, C3-C6 cycloalkyl, substituted C3-C6 cycloalkyl, C(O)OH, C(O)(C1-C6 alkoxy), C(O)NH2, C(O)NH(C1-C6 alkyl), C(O)N(C1-C4 alkyl)(C1-C4 alkyl), C(O)-heterocyclil, NHC(O)(C1-C6 alkyl), N(CH3)C(O)(C1-C6 alkyl), and cyano.

[0111] Unless otherwise specified herein, the term “heterocyclile (e.g., “(heterocyclile)alkyl”) used alone or as part of a larger moiety refers to a saturated or partially unsaturated, stable monovalent quaternary to hyphalic monocyclic or sevenary to tenary bicyclic heterocyclic moiety having 1 to 4 heteroatoms in addition to the cyclic carbon atom. Non-limiting examples of heterocyclile groups include tetrahydrofuranyl, pyrrolidinyl, tetrahydropyranyl, piperidinyl, morpholinyl, etc. Heterocyclile groups may be unsubstituted or substituted. For example, the heterocyclyl group may be unsubstituted or substituted with one, two, three, or more groups independently selected from the group consisting of halogen, OH, O(C1-C6 alkyl), O(substituted C1-C6 alkyl), C1-C6 alkyl, substituted C1-C6 alkyl, and C3-C6 cycloalkyl.

[0112] Unless otherwise specified in this specification, the term "inactive" (and all related terms, including "inactiveness") is understood by a person skilled in the art or an equivalent person of ordinary skill as "EC 50 When used in the context of (nM)" and "Eff%", and 5-HT 2B When used in relation to activity at receptors, concentrations greater than 10,000 nM ("EC 50 It means (when used in the context of "nM") or efficacy of 30% or less (when used in the context of "Eff%").

[0113] Unless otherwise specified herein, the term “isotope” refers to a species that differs from a particular compound only in its isotopic composition. For example, all hydrogen atoms in a compound are independently of a natural isotopic composition or are heavy isotopes. 2 H(D, deuterium) and 3Any isotopic composition enriched or depleted in one or both of H(T, tritium), ranging from depletion to 0% to enrichment to 100%. Deuterium may be introduced into the compounds described herein in various ways using deuterated forms of reagents and building blocks under the same or similar conditions as those used for counterparts having natural hydrogen isotopic compositions. The reduction of 3-acyl groups on indole nuclei and carboxamides using commercially available LiAlD4 or BD3-THF complexes has already been mentioned. LiAlD4 may be used in the same way to reduce urethane functional groups, such as Boc- or Cbz-derived amines, to N-CD3. The building block methyl- d 3-iodide, ethyl- d 5-iodide, allyl- d 5-bromide, formaldehyde-D2 aqueous solution, paraformaldehyde- d 2 and dimethylamine- d 3 (free base and hydrochloride) is commercially available, as are NaBD4 and NaBD3CN, which are reducing agents commonly used in reductive amination / alkylation. Deuterium gas is available for the catalytic deuteriumation of CC multiple bonds and the deuterium splitting of C-heteroatom bonds, respectively. Indole- d 7 is commercially available. Electron-rich aromatic compounds, such as indole, can be ring deuterated to D2O in the presence of catalyst B(C6F5)3, specifically at a position more vulnerable to electrophilic attack than the deactivated aromatic ring (Li, W.; Wang, M.-M.; Hu, Y.; Werner, T. Org. Lett. 2017, 19, 5768). Aromatic and heteroaromatic compounds may also be deuterated by reaction with excess D2O in the presence of a heterogeneous transition metal catalyst (Sawama, Y.; Park, K.; Yamada, T.; Sajiki, H. Chem. Pharm. Bull. 2018,66, 21-28). Deuteration of specific positions within an indole ring is achieved by quenching an indolyle metal intermediate with a deuterizing agent such as D2O or CH3OD following a halogen-metal exchange reaction for a compound having a halogen atom (typically Br or I) at the position to be deuterated; or by free radical deuterization dehalogenation of the same precursor with radical initiators such as Bu3SnD and azobis(isobutyronitrile) or dibenzoyl peroxide; or by deuterizing the same precursor with Bu3SnD or formic acid- d This can be achieved by reacting with a deuteride source such as 2 and a transition metal catalyst. The indole ring can be reduced to indoline using a deuteride-containing reducing agent such as Et3SiD as needed.

[0114] The term "neurological disorder" is intended to mean a disorder affecting the nerves and spinal cord present throughout the human body as well as the brain, which can cause significant changes in thinking, emotions, and / or behavior, and distress and / or functional problems in social, occupational, or family activities.

[0115] The term "neurodegenerative disorder" is intended to mean disorders and diseases affecting the nerves and spinal cord throughout the human body as well as the brain, which can cause significant changes in thinking, emotion, and / or behavior, and distress and / or functional problems in social, occupational, or family activities.

[0116] The term "psychiatric disorder" is intended to mean a disorder involving significant changes in thought, emotion, and / or behavior, and causing distress and / or problems of functioning in social, occupational, or family activities.

[0117] The term "time sufficient for / to" is intended to mean any period suitable for achieving treatment by the method of the present invention.

[0118] The term "therapeutic effective dose" is intended to mean an amount effective for treatment, or an amount sufficient to provide a therapeutic effect. A therapeutically effective dose is an amount that produces biological activity and causes some degree of relief from one or more symptoms of the disorder being treated, or inhibits the progression of the condition or at least a partial reversal. This will vary particularly depending on the individual. Typical daily doses of the active substance(s) may vary and will depend on various factors such as the individual needs of the patient (e.g., age, weight, etc. of the subject to be treated), the mode of administration, and the disease or condition and its severity.

[0119] Unless otherwise specified herein, the term “pharmaceuticalally acceptable salt” refers to a salt that is suitable for use in contact with tissues of humans and lower animals without excessive toxicity, irritation, allergic reaction, etc., within the scope of sound medical judgment and corresponds to a reasonable benefit-risk ratio. Pharmaceutically acceptable salts of the compounds provided in this disclosure include salts derived from suitable inorganic and organic acids and bases. Non-limiting examples of pharmaceutically acceptable salts include salts formed by a compound containing an amino group with an inorganic acid such as hydrochloric acid, hydrobromide, phosphoric acid, sulfuric acid, and perchloric acid, or with an organic acid such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid. Other non-limiting examples of pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphosulfonate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydriodide, 2-hydroxyethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, maleate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, palmitate, pamoate, pectinate, persulfate, These include 3-phenylpropionate, pivalate, propionate, stearate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, etc. Other pharmaceutically acceptable salts include alkali metals, alkaline earth metals, ammonium, and N +This includes those derived from suitable bases, such as (C1-4 alkyl) tetrasalts. Representative alkali metal salts or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, etc. Additional non-limiting examples of pharmaceutically acceptable salts include, where appropriate, non-toxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates, and aryl sulfonates.

[0120] Unless otherwise specified herein, the term “subject” includes mammals (e.g., humans, and in some embodiments, prenatal human forms). In some embodiments, the subject suffers from a related disease, disorder, or condition. In some embodiments, the subject is susceptible to the disease, disorder, or condition. In some embodiments, the subject exhibits one or more symptoms or features of the disease, disorder, or condition. In some embodiments, the subject does not exhibit any symptoms or features of the disease, disorder, or condition. In some embodiments, the subject is a mammal having one or more features characterizing susceptibility or risk to the disease, disorder, or condition. In some embodiments, the subject is a patient. In some embodiments, the subject is an individual on whom or for whom a diagnosis and / or therapy is being performed. In some embodiments, the subject is a fetus, infant, child, adolescent, adult, or elderly (i.e., the subject is elderly, such as being over 50 years of age). In some embodiments, a child refers to a human being aged 2 to 18 years. In some embodiments, adult refers to a human being aged 18 or older.

[0121] Unless otherwise specified herein, the phrase “such as” is intended to be open-ended. For example, the phrase “A may be a halogen such as chlorine or bromine” means that “A” may be chlorine or bromine, but is not limited thereto.

[0122] References to specific moiety, functional group, or substituent consider their tautomers (where applicable).

[0123] Unless otherwise noted, structures described herein include all isomers (e.g., enantiomers, diastereomers, and geometric (or morphological) isomers) of said structures and forms (e.g., R and S arrangements for each asymmetric center, Z and E double bond isomers, and Z and E form isomers). Unless otherwise noted, compounds disclosed, taught, or otherwise suggested in this disclosure consider all single stereochemical isomers as well as their enantiomers, diastereomers, and geometric (or morphological) mixtures. Unless otherwise noted, compounds disclosed, taught, or suggested in this disclosure consider all tautomeric forms. Additionally, unless otherwise noted, structures described herein include compounds that differ only in the presence of one or more isotope-enriched atoms. Such compounds may be useful, for example, as analytical tools, as probes in biological assays, or as therapeutic agents. Additionally, deuterium ( 2 The introduction of heavier isotopes such as H) offers specific therapeutic benefits resulting from greater metabolic stability, for example in vivo It may provide increased or reduced dosage requirements for half-life.

[0124] The chemical entities described herein are further exemplified by the classes, subclasses, and species disclosed herein. For the purposes of this disclosure, chemical elements are the CAS plate periodic table, Handbook of Chemistry and Physics, It is identified according to the inside cover of the 75th edition, and specific functional groups are generally defined as described therein. Additionally, the general principles of organic chemistry, as well as specific functional moiety and reactivity, are Thomas Sorrell, Organic Chemistry,University Science Books, Sausalito, 1999; Smith and March, March's Advanced Organic Chemistry, 5th edition, John Wiley & Sons, Inc., New York, 2001; Larock, Comprehensive Organic Transformations, VCH Publishers, Inc., New York, 1989; and Carruthers; Some Modem Methods of Organic Synthesis, Described in the third edition, Cambridge University Press, Cambridge, 1987. In this disclosure, any atom not specifically designated as a particular isotope means any stable isotope of the atom.

[0125] Unless otherwise noted, the structures described herein also imply that they include all stereoisomer forms of the structure (e.g., enantiomers, diastereomers, and geometric (or morphological) isomers), e.g., R and S arrangements for each asymmetric center, Z and E double bond isomers, and Z and E form isomers. Thus, the compounds in this specification consider all single stereochemical isomers as well as their enantiomers, diastereomers, and geometric (or morphological) mixtures. Unless otherwise noted, the compounds in this specification consider all tautomeric forms. Additionally, unless otherwise noted, the structures described herein also imply that they include compounds that differ only in the presence of one or more isotope-enriched atoms. Such compounds may be useful, for example, as analytical tools, as probes in biological assays, or as therapeutic agents. Additionally, deuterium ( 2 The introduction of heavier isotopes such as H) offers specific therapeutic benefits resulting from greater metabolic stability, for example In vivo It may provide increased or reduced dosage requirements for half-life.

[0126] The features and advantages of the subject matter of the present invention will become more apparent in light of the following detailed description of selected embodiments as illustrated in the accompanying drawings. As is recognized, the disclosed and claimed subject matter is subject to modification in various aspects without departing from the scope of the claims. Accordingly, the drawings and description are to be considered illustrative in nature and not restrictive, and the full scope of the subject matter is set forth in the claims. Brief explanation of the drawing

[0127] Further features and advantages of the present disclosure will become apparent from the following detailed description in conjunction with the accompanying drawings, in which: FIG. 1 shows 5-HT for the compound of formula IV in the optically pure form (racemic mixture), and PURM100 and PURM200, which are enantiomers of compound IV. 1A , 5-HT 2A , 5-HT 2B , 5-HT 2C and m5-HT 2A EC regarding 50 I will provide a graph as an example. EC 50 The values ​​are summarized in Table 1. FIG. 2 shows 5-HT in agent mode for the compound of formula IV in the optically pure form (racemic mixture), and PURM100 and PURM200, which are enantiomers of compound IV. 2A Example of a concentration response curve for . Figure 3 illustrates the plasma concentrations after intravenous (IV) or oral (PO) administration of a racemic mixture of compounds PURM100 and PURM200. Figure 4 illustrates the plasma concentration of compound PURM100 after intravenous (IV), intraperitoneal (IPA or IPB) or oral (PO) administration. Figure 5 illustrates the plasma concentrations of compound PURM200 after intravenous (IV), intraperitoneal (IPA or IPB) or oral (PO) administration. Figure 6 illustrates the head twitch response (HTR) in mice administered a racemic mixture of compound IV at doses ranging from 0.1 mg / kg to 10 mg / kg. The HTR for compound IV is minimal compared to the control DOI. The positive control is a racemic mixture of 2,5-dimethoxy-4-iodoamphetamine (DOI), a hallucinogenic drug and substituted amphetamine. Figure 7 illustrates that there was no change in motor activity in mice administered a racemic mixture of compound IV at a dose of 0.1 mg / kg to 3 mg / kg. Figure 8 illustrates the results of a Sholl analysis revealing that neurons treated with compounds PURM100 and PURM200 (each representing one of the enantiomer forms of compound IV) show an increase in the number of dendritic crossovers compared to the vehicle. Figure 9 illustrates the results of a Sholl analysis revealing that neurons treated with compounds PURM100 or PURM200 in the presence of IPTG show an increase in the number of dendritic crossings compared to the vehicle. Figure 10 illustrates that neural stem cell cultures treated for 48 hours with compounds PURM100 and PURM200 (at 10 μM, each individually representing one of the enantiomer forms of compound IV) showed an increase in the number of dendritic branches compared to the control treatment. Fig. 11 shows compounds PURM100 and PURM200 (at 10 μM, which each individually represent one of the enantiomer forms of compound IV), HT 2A We exemplify neural stem cell cultures treated for 48 hours in the presence of IPTG to silence receptors. Statistical analysis reveals a significant effect of drug treatment on dendritogenesis induced solely by BDNF treatment, indicating that 5-HT contributes to the effects observed with these compounds. 2AIt suggests that receptors are involved. Figure 12 illustrates the results shown in Figures 10 and 11, normalized by a multiple of baseline for the corresponding vehicle (control group) for comparison. Statistical analysis was performed on two variables—drug treatment and 5-HT. 2A It indicates a significant effect of receptor expression—and the interaction between them. This suggests that the drug's effect on dendrite formation is 5-HT 2A It means that receptor expression is required. Figure 13 shows images of cells treated with water (control) and compound IV, where 48 hours of treatment with compound IV causes an increase in the number of dendritic branches compared to the control treatment. Figure 14 illustrates the expression of c-fos in neurons treated with the pure enantiomers of compound IV, namely PURM100 and PURM200, in the presence or absence of IPTG. C-fos is a functional marker of neuronal activity and protein transcription cascade initiation. Figure 15 illustrates an increase in erg-1 expression, which indicates that PURM100 and PURM200 are 5-HT 2A It suggests that neurons can be activated in the absence of signal transmission. Figure 16 illustrates an increase in erg-2 expression, which indicates that PURM100 and PURM200 are 5-HT 2A It suggests that neurons can be activated in the absence of signal transmission. Note that similar features throughout the attached drawings are indicated by similar reference numbers. Specific details for implementing the invention

[0128] details

[0129] In embodiments, a compound of structural formula I, or a pharmaceutically acceptable salt thereof, and a stereoisomer thereof are disclosed:

[0130]

[0131] I

[0132] Here:

[0133] R 1 is OH, and R 1 In the case of this OH, R 2 is different from OH and (i) Selected from the group consisting of H, halogen, lower alkyl, CHF2, CF3, NC, OCH3, OCHF2, OCF3, SCHF2, SCH3, SCF3, and cyano; or (ii) a It forms a ring composed of three or four atoms together with, wherein one of the atoms is selected from the group consisting of C, N, O, and S and the remainder is carbon, the chain contains zero, one, or two double bonds, and the chain is bonded with a substituent independently selected from the group consisting of H, halogen, OH, C1-C6 alkoxy, C1-C6 alkyl, C3-C6 cycloalkyl, CHF2, CF3, OCHF2, OCF3, SCH3, SCHF2, SCF3, cyano, and oxo;

[0134] R 2 is OH, and R 2 If α is OH, R 1 is different from OH and is selected from the group consisting of (i) H, halogen, lower alkyl, CHF2, CF3, OCH3, OCHF2, OCF3, SCHF2, SCH3, SCF3, and cyano; or (ii) b or cIt forms a ring composed of 6 to 8 atoms together with, wherein one of the atoms is selected from the group consisting of C, N, O, and S and the remainder is carbon, the chain contains one or two double bonds, and the chain is bonded with a substituent independently selected from the group consisting of H, halogen, OH, C1-C6 alkoxy, C1-C6 alkyl, C3-C6 cycloalkyl, CHF2, CF3, OCHF2, OCF3, SCH3, SCHF2, SCF3, cyano, and oxo;

[0135] R 3 silver ( i ) C1-C6 alkyl, C1-C6 substituted alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, (C3-C6 cycloalkyl)(C1-C6 alkyl), C3-C6 heterocyclyl, (C3-C6 heterocyclyl)(C1-C6 alkyl), aryl, aryl(C1-C6 alkyl), heteroaryl, heteroaryl(C1-C6 alkyl), CN, C(O)NH2, C(O)NH(C1-C6 alkyl), C(O)N(C1-C3 alkyl)(C1-C6 alkyl), C(=NOH)(C1-C6 alkyl), and C(=NOH)(C1-C6 substituted alkyl), C(O)NH(aryl), C(O)N(alkyl)(aryl), NC, S(O)2NH2, Selected from the group consisting of S(O)2NH(C1-C6 alkyl) and S(O)2NH(aryl); or ( ii ) R 4 Forming a chain composed of 2 to 4 carbon atoms together with, wherein a substituent independently selected from the group consisting of H, C1-C6 alkyl, aryl, and heteroaryl is bonded to the chain; or ( iii ) a...to form a ring composed of three or four atoms, wherein one of the atoms is selected from the group consisting of C, N, O, and S and the remainder is carbon, the chain contains zero, one, or two double bonds, and the chain is bonded to a substituent independently selected from the group consisting of H, halogen, OH, C1-C6 alkoxy, C1-C6 alkyl, C3-C6 cycloalkyl, CHF2, CF3, OCHF2, OCF3, SCH3, SCF3, cyano, and oxo; or ( iv ) b If valogen, CH3, CHF2, CF3, OCH3, OCHF2, OCF3, SCH3, SCHF2, SCF3 or cyano, H, C1-C6 alkyl, C1-C6 substituted alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, (C3-C6 cycloalkyl)(C1-C6 alkyl), C3-C6 heterocyclyl, (C3-C6 heterocyclyl)(C1-C6 alkyl), aryl, aryl(C1-C6 alkyl), heteroaryl, heteroaryl(C1-C6 alkyl), CN, C(O)NH2, C(O)NH(C1-C6 alkyl), C(O)N(C1-C3 alkyl)(C1-C6 alkyl), C(=NOH)(C1-C6 alkyl), and Selected from the group consisting of C(=NOH)(C1-C6 substituted alkyl), and

[0136] Optionally, R 3 silver awith CH2CH2, CH2CH2CH2, CH2CH2CH2CH2, CH=CHCH=CH, OCH2CH2, CH2OCH2, CH2CH2O, OCH=CH, CH=CHO, OCH2O, SCH2CH2, CH2SCH2, CH2CH2S, SCH=CH, CH=CHS, NHCH2CH2, CH2NHCH2, CH2CH2NH, NHCH=CH, CH=CHNH, ON=CH, CH=NO, OCH=N, N=CHO, SN=CH, CH=NS, SCH=N, N=CHS, NHN=CH, CH=NNH, NHCH=N, N=CHNH, NHN=N, N=NNH, OCH2CH2CH2, CH2OCH2CH2, CH2CH2OCH2, CH2CH2CH2O, SCH2CH2CH2, CH2SCH2CH2, Forming any one of CH2CH2SCH2, CH2CH2CH2S NHCH2CH2CH2CH2, CH2NHCH2CH2, CH2CH2NCH2, CH2CH2CH2NH, N=CHCH=CH, CH=NCH=CH, CH=CHN=CH, CH=CHCH=N; and optionally, when present on the moiety, one or two hydrogen atoms are substituted with a substituent independently selected from the group consisting of halogen, OH, C1-C6 alkoxy, C1-C6 alkyl, C3-C6 cycloalkyl, CHF2, CF3, OCHF2, OCF3, SCH3, SCF3, and cyano, or when bonded to the same carbon atom, two hydrogens are substituted with an oxo group;

[0137] R 4 Is (i) Selected from the group consisting of H, C1-C6 alkyl, C1-C6 substituted alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, (C3-C6 cycloalkyl)(C1-C6 alkyl), C3-C6 heterocyclyl, (C3-C6 heterocyclyl)(C1-C6 alkyl), aryl(C1-C6 alkyl), arylsulfonyl, heteroarylsulfonyl, aryl(C1-C6 alkyl)sulfonyl, (C1-C6)alkylsulfonyl, and heteroaryl(C1-C6 alkyl)sulfonyl; or (ii) R3 Together with, it forms a chain composed of 2 to 4 carbon atoms, wherein a substituent independently selected from the group consisting of H, C1-C6 alkyl, aryl, heteroaryl, and any combination thereof is bonded to the chain;

[0138] R 5 is an H, D, C1-C6 alkyl, C1-C6 substituted alkyl;

[0139] R 6 silver: (i) Selected from the group consisting of H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, (C3-C6 cycloalkyl)(C1-C6 alkyl), aryl (C1-C6 alkyl), acetyl and heteroaryl (C1-C6 alkyl); or (ii) R 7 and together with the N atoms to which they are bonded, form a 4 to 7-membered heterocyclil ring; or (iii) e and R 6 Forming an azetidine or pyrrolidine ring with the bonded N atom, said ring having a substituent independently selected from the group consisting of H, aryl, heteroaryl, C1-C6 alkyl, and C3-C6 cycloalkyl; or (iv) b and R 6 Forming an azetidine or pyrrolidine ring together with the bonded N atom, said ring has a substituent independently selected from the group consisting of H, aryl, heteroaryl, halogen, C1-C6 alkyl, and C3-C6 cycloalkyl;

[0140] R 7 silver: (i) Selected from the group consisting of H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, (C3-C6 cycloalkyl)(C1-C6 alkyl), aryl (C1-C6 alkyl), acetyl and heteroaryl (C1-C6 alkyl); or (ii) R 6and together with the N atoms to which they are bonded, form a 4 to 7-membered heterocyclil ring;

[0141] a Is: (i) Selected from the group consisting of H, halogen, CH3, CHF2, CF3, OCH3, OCHF2, OCF3, SCH3, SCHF2, SCF3, NC, and cyano; or (ii) A ring composed of three or four atoms is formed together with a, wherein one of the atoms is selected from the group consisting of C, N, O, and S and the remainder is carbon, the chain contains zero, one, or two double bonds, and the chain is bonded to a substituent independently selected from the group consisting of H, halogen, OH, C1-C6 alkoxy, C1-C6 alkyl, C3-C6 cycloalkyl, CHF2, CF3, OCHF2, OCF3, SCH3, SCHF2, SCF3, cyano, and oxo; or (iii) R 3 It forms a ring composed of three or four atoms together with, wherein one of the atoms is selected from the group consisting of C, N, O, and S and the remainder is carbon, the chain contains zero, one, or two double bonds, and the chain is bonded with a substituent independently selected from the group consisting of H, halogen, OH, C1-C6 alkoxy, C1-C6 alkyl, C3-C6 cycloalkyl, CHF2, CF3, OCHF2, OCF3, SCH3, SCHF2, SCF3, cyano, and oxo; and

[0142] b , c , d and e are each independently H or; or b , c , d and e Three of them are H and the remaining substituents are lower alkyl groups; or b and e are H respectively, and c andd is together -CH2- or -CH2CH2-, thereby forming a cyclopropane or cyclobutane ring; or b , c and d are H respectively, and e , R 6 and R 6 The bonded N atoms together form an azetidine or pyrrolidine ring, said ring having a substituent independently selected from the group consisting of H, aryl, heteroaryl, C1-C6 alkyl, and C3-C6 cycloalkyl; or c , d and e are H respectively, and b , R 6 and R 6 These bonded N atoms together form an azetidine or pyrrolidine ring, said ring having a substituent independently selected from the group consisting of H, aryl, heteroaryl, halogen, C1-C6 alkyl, and C3-C6 cycloalkyl.

[0143] According to embodiments of the compound of structural formula I, or a pharmaceutically acceptable salt thereof, and a stereoisomer thereof, the R 1 is OH and R 2 is H, or the above R 1 is H and R 2 is OH.

[0144] According to one embodiment of a compound of structural formula I, or a pharmaceutically acceptable salt thereof, and a stereoisomer thereof, said compound is a compound of formula IV:

[0145]

[0146] IV.

[0147] According to one embodiment of a compound of structural formula I, or a pharmaceutically acceptable salt thereof, and a stereoisomer thereof, said compound is of formula IV- S It is a compound of:

[0148]

[0149] IV- S .

[0150] According to one embodiment of a compound of structural formula I, or a pharmaceutically acceptable salt thereof, and a stereoisomer thereof, said compound is of formula IV- R It is a compound of:

[0151]

[0152] IV- R .

[0153] According to one embodiment of a compound of structural formula I, or a pharmaceutically acceptable salt thereof, and a stereoisomer thereof, said compound is of formula IV- S Compounds of and chemical formula IV- R It is a racemic mixture of the compound:

[0154] and

[0155] IV-S IV-R.

[0156] According to one embodiment of a compound of structural formula I, or a pharmaceutically acceptable salt thereof, and a stereoisomer thereof, said compound is a compound of formula V:

[0157]

[0158] V.

[0159] Compounds of chemical formula V are chemical formula V- S It can be a compound of:

[0160]

[0161] V- S .

[0162] Compounds of chemical formula V are chemical formula V- R It can be a compound of:

[0163]

[0164] V- R .

[0165] Compounds of chemical formula V are chemical formula V- S Compounds of and chemical formula V- R It can be a racemic mixture of the compound:

[0166] and

[0167] V- S V- R .

[0168] According to other embodiments, a compound of structural formula II, or a pharmaceutically acceptable salt thereof, and a stereoisomer thereof are disclosed:

[0169]

[0170] II

[0171] Here:

[0172] R 2 is different from OH and (i) Selected from the group consisting of H, halogen, lower alkyl, CHF2, CF3, OCH3, OCHF2, OCF3, SCHF2, SCH3, SCF3, and cyano; or (ii) a It forms a ring composed of three or four atoms together with, wherein one of the atoms is selected from the group consisting of C, N, O, and S and the remainder is carbon, the chain contains zero, one, or two double bonds, and the chain is bonded with a substituent independently selected from the group consisting of H, halogen, OH, C1-C6 alkoxy, C1-C6 alkyl, C3-C6 cycloalkyl, CHF2, CF3, OCHF2, OCF3, SCH3, SCHF2, SCF3, cyano, and oxo;

[0173] R 3 silver ( i) selected from the group consisting of C1-C6 alkyl, C1-C6 substituted alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, (C3-C6 cycloalkyl)(C1-C6 alkyl), C3-C6 heterocyclyl, (C3-C6 heterocyclyl)(C1-C6 alkyl), aryl, aryl(C1-C6 alkyl), heteroaryl, heteroaryl(C1-C6 alkyl), CN, C(O)NH2, C(O)NH(C1-C6 alkyl), C(O)N(C1-C3 alkyl)(C1-C6 alkyl), C(=NOH)(C1-C6 alkyl), and C(=NOH)(C1-C6 substituted alkyl); or ( ii ) R 4 Forming a chain composed of 2 to 4 carbon atoms together with, wherein a substituent independently selected from the group consisting of H, C1-C6 alkyl, aryl, and heteroaryl is bonded to the chain; or ( iii ) a ...to form a ring composed of three or four atoms, wherein one of the atoms is selected from the group consisting of C, N, O, and S and the remainder is carbon, the chain contains zero, one, or two double bonds, and the chain is bonded to a substituent independently selected from the group consisting of H, halogen, OH, C1-C6 alkoxy, C1-C6 alkyl, C3-C6 cycloalkyl, CHF2, CF3, OCHF2, OCF3, SCH3, SCF3, cyano, and oxo; or ( iv ) bIf valogen, CH3, CHF2, CF3, OCH3, OCHF2, OCF3, SCH3, SCHF2, SCF3 or cyano, H, C1-C6 alkyl, C1-C6 substituted alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, (C3-C6 cycloalkyl)(C1-C6 alkyl), C3-C6 heterocyclyl, (C3-C6 heterocyclyl)(C1-C6 alkyl), aryl, aryl(C1-C6 alkyl), heteroaryl, heteroaryl(C1-C6 alkyl), CN, C(O)NH2, C(O)NH(C1-C6 alkyl), C(O)N(C1-C3 alkyl)(C1-C6 alkyl), C(=NOH)(C1-C6 alkyl), and Selected from the group consisting of C(=NOH)(C1-C6 substituted alkyl), and

[0174] Optionally, R 3 silver awith CH2CH2, CH2CH2CH2, CH2CH2CH2CH2, CH=CHCH=CH, OCH2CH2, CH2OCH2, CH2CH2O, OCH=CH, CH=CHO, OCH2O, SCH2CH2, CH2SCH2, CH2CH2S, SCH=CH, CH=CHS, NHCH2CH2, CH2NHCH2, CH2CH2NH, NHCH=CH, CH=CHNH, ON=CH, CH=NO, OCH=N, N=CHO, SN=CH, CH=NS, SCH=N, N=CHS, NHN=CH, CH=NNH, NHCH=N, N=CHNH, NHN=N, N=NNH, OCH2CH2CH2, CH2OCH2CH2, CH2CH2OCH2, CH2CH2CH2O, SCH2CH2CH2, CH2SCH2CH2, Forming any one of CH2CH2SCH2, CH2CH2CH2S NHCH2CH2CH2CH2, CH2NHCH2CH2, CH2CH2NCH2, CH2CH2CH2NH, N=CHCH=CH, CH=NCH=CH, CH=CHN=CH, CH=CHCH=N; and optionally, when present on the moiety, one or two hydrogen atoms are substituted with a substituent independently selected from the group consisting of halogen, OH, C1-C6 alkoxy, C1-C6 alkyl, C3-C6 cycloalkyl, CHF2, CF3, OCHF2, OCF3, SCH3, SCF3, and cyano, or when bonded to the same carbon atom, two hydrogens are substituted with an oxo group;

[0175] R 4 Is (i) Selected from the group consisting of H, C1-C6 alkyl, C1-C6 substituted alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, (C3-C6 cycloalkyl)(C1-C6 alkyl), C3-C6 heterocyclyl, (C3-C6 heterocyclyl)(C1-C6 alkyl), aryl(C1-C6 alkyl), arylsulfonyl, heteroarylsulfonyl, aryl(C1-C6 alkyl)sulfonyl, (C1-C6)alkylsulfonyl, and heteroaryl(C1-C6 alkyl)sulfonyl; or (ii) R3 Together with, it forms a chain composed of 2 to 4 carbon atoms, wherein a substituent independently selected from the group consisting of H, C1-C6 alkyl, aryl, heteroaryl, and any combination thereof is bonded to the chain;

[0176] R 5 is an H, D, C1-C6 alkyl, C1-C6 substituted alkyl.

[0177] R 6 silver: (i) Selected from the group consisting of H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, (C3-C6 cycloalkyl)(C1-C6 alkyl), aryl (C1-C6 alkyl), acetyl and heteroaryl (C1-C6 alkyl); or (ii) R 7 and together with the N atoms to which they are bonded, form a 4 to 7-membered heterocyclil ring; or (iii) e and R 6 Forming an azetidine or pyrrolidine ring with the bonded N atom, said ring having a substituent independently selected from the group consisting of H, aryl, heteroaryl, C1-C6 alkyl, and C3-C6 cycloalkyl; or (iv) b and R 6 Forming an azetidine or pyrrolidine ring together with the bonded N atom, said ring has a substituent independently selected from the group consisting of H, aryl, heteroaryl, halogen, C1-C6 alkyl, and C3-C6 cycloalkyl;

[0178] R 7 silver: (i) Selected from the group consisting of H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, (C3-C6 cycloalkyl)(C1-C6 alkyl), aryl (C1-C6 alkyl), acetyl and heteroaryl (C1-C6 alkyl); or (ii) R 6and together with the N atoms to which they are bonded, form a 4 to 7-membered heterocyclil ring;

[0179] a Is: (i) Selected from the group consisting of H, halogen, CH3, CHF2, CF3, OCH3, OCHF2, OCF3, SCH3, SCHF2, SCF3, and cyano; or (ii) A ring composed of three or four atoms is formed together with a, wherein one of the atoms is selected from the group consisting of C, N, O, and S and the remainder is carbon, the chain contains zero, one, or two double bonds, and the chain is bonded to a substituent independently selected from the group consisting of H, halogen, OH, C1-C6 alkoxy, C1-C6 alkyl, C3-C6 cycloalkyl, CHF2, CF3, OCHF2, OCF3, SCH3, SCHF2, SCF3, cyano, and oxo; or (iii) R 3 It forms a ring composed of three or four atoms together with, wherein one of the atoms is selected from the group consisting of C, N, O, and S and the remainder is carbon, the chain contains zero, one, or two double bonds, and the chain is bonded with a substituent independently selected from the group consisting of H, halogen, OH, C1-C6 alkoxy, C1-C6 alkyl, C3-C6 cycloalkyl, CHF2, CF3, OCHF2, OCF3, SCH3, SCHF2, SCF3, cyano, and oxo; and

[0180] b , c , d and e are each independently H or; or b , c , d and e Three of them are H and the remaining substituents are lower alkyl groups; or b and e are H respectively, and c and dis together -CH2- or -CH2CH2-, thereby forming a cyclopropane or cyclobutane ring; or b , c and d are H respectively, and e , R 6 and R 6 The bonded N atoms together form an azetidine or pyrrolidine ring, said ring having a substituent independently selected from the group consisting of H, aryl, heteroaryl, C1-C6 alkyl, and C3-C6 cycloalkyl; or c , d and e are H respectively, and b , R 6 and R 6 These bonded N atoms together form an azetidine or pyrrolidine ring, said ring having a substituent independently selected from the group consisting of H, aryl, heteroaryl, halogen, C1-C6 alkyl, and C3-C6 cycloalkyl.

[0181] According to one embodiment of a compound of structural formula II, or a pharmaceutically acceptable salt thereof, and a stereoisomer thereof, said compound is a compound of chemical formula IV:

[0182]

[0183] IV.

[0184] According to one embodiment of a compound of structural formula II, or a pharmaceutically acceptable salt thereof, and a stereoisomer thereof, said compound is of formula IV- S It is a compound of:

[0185]

[0186] IV- S .

[0187] According to one embodiment of a compound of structural formula II, or a pharmaceutically acceptable salt thereof, and a stereoisomer thereof, said compound is of formula IV- R It is a compound of:

[0188]

[0189] IV- R .

[0190] According to one embodiment of a compound of structural formula II, or a pharmaceutically acceptable salt thereof, and a stereoisomer thereof, said compound is of formula IV- S Compounds of and chemical formula IV- R It is a racemic mixture of the compound:

[0191] and

[0192] IV-S IV-R.

[0193] According to other embodiments, a compound of structural formula III, or a pharmaceutically acceptable salt thereof, and a stereoisomer thereof are disclosed:

[0194]

[0195] III

[0196] Here:

[0197] R 1 It is different from OH. (i) Selected from the group consisting of H, halogen, lower alkyl, CHF2, CF3, OCH3, OCHF2, OCF3, SCHF2, SCH3, SCF3, and cyano; or (ii) b or c It forms a ring composed of 6 to 8 atoms together with, wherein one of the atoms is selected from the group consisting of C, N, O, and S and the remainder is carbon, the chain contains one or two double bonds, and the chain is bonded with a substituent independently selected from the group consisting of H, halogen, OH, C1-C6 alkoxy, C1-C6 alkyl, C3-C6 cycloalkyl, CHF2, CF3, OCHF2, OCF3, SCH3, SCHF2, SCF3, cyano, and oxo;

[0198] R 3silver ( i ) selected from the group consisting of C1-C6 alkyl, C1-C6 substituted alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, (C3-C6 cycloalkyl)(C1-C6 alkyl), C3-C6 heterocyclyl, (C3-C6 heterocyclyl)(C1-C6 alkyl), aryl, aryl(C1-C6 alkyl), heteroaryl, heteroaryl(C1-C6 alkyl), CN, C(O)NH2, C(O)NH(C1-C6 alkyl), C(O)N(C1-C3 alkyl)(C1-C6 alkyl), C(=NOH)(C1-C6 alkyl), and C(=NOH)(C1-C6 substituted alkyl); or ( ii ) R 4 Forming a chain composed of 2 to 4 carbon atoms together with, wherein a substituent independently selected from the group consisting of H, C1-C6 alkyl, aryl, and heteroaryl is bonded to the chain; or ( iii ) a ...to form a ring composed of three or four atoms, wherein one of the atoms is selected from the group consisting of C, N, O, and S and the remainder is carbon, the chain contains zero, one, or two double bonds, and the chain is bonded to a substituent independently selected from the group consisting of H, halogen, OH, C1-C6 alkoxy, C1-C6 alkyl, C3-C6 cycloalkyl, CHF2, CF3, OCHF2, OCF3, SCH3, SCF3, cyano, and oxo; or ( iv ) bIf valogen, CH3, CHF2, CF3, OCH3, OCHF2, OCF3, SCH3, SCHF2, SCF3 or cyano, H, C1-C6 alkyl, C1-C6 substituted alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, (C3-C6 cycloalkyl)(C1-C6 alkyl), C3-C6 heterocyclyl, (C3-C6 heterocyclyl)(C1-C6 alkyl), aryl, aryl(C1-C6 alkyl), heteroaryl, heteroaryl(C1-C6 alkyl), CN, C(O)NH2, C(O)NH(C1-C6 alkyl), C(O)N(C1-C3 alkyl)(C1-C6 alkyl), C(=NOH)(C1-C6 alkyl), and Selected from the group consisting of C(=NOH)(C1-C6 substituted alkyl), and

[0199] Optionally, R 3 silver awith CH2CH2, CH2CH2CH2, CH2CH2CH2CH2, CH=CHCH=CH, OCH2CH2, CH2OCH2, CH2CH2O, OCH=CH, CH=CHO, OCH2O, SCH2CH2, CH2SCH2, CH2CH2S, SCH=CH, CH=CHS, NHCH2CH2, CH2NHCH2, CH2CH2NH, NHCH=CH, CH=CHNH, ON=CH, CH=NO, OCH=N, N=CHO, SN=CH, CH=NS, SCH=N, N=CHS, NHN=CH, CH=NNH, NHCH=N, N=CHNH, NHN=N, N=NNH, OCH2CH2CH2, CH2OCH2CH2, CH2CH2OCH2, CH2CH2CH2O, SCH2CH2CH2, CH2SCH2CH2, Forming any one of CH2CH2SCH2, CH2CH2CH2S NHCH2CH2CH2CH2, CH2NHCH2CH2, CH2CH2NCH2, CH2CH2CH2NH, N=CHCH=CH, CH=NCH=CH, CH=CHN=CH, CH=CHCH=N; and optionally, when present on the moiety, one or two hydrogen atoms are substituted with a substituent independently selected from the group consisting of halogen, OH, C1-C6 alkoxy, C1-C6 alkyl, C3-C6 cycloalkyl, CHF2, CF3, OCHF2, OCF3, SCH3, SCF3, and cyano, or when bonded to the same carbon atom, two hydrogens are substituted with an oxo group;

[0200] R 4 Is (i) Selected from the group consisting of H, C1-C6 alkyl, C1-C6 substituted alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, (C3-C6 cycloalkyl)(C1-C6 alkyl), C3-C6 heterocyclyl, (C3-C6 heterocyclyl)(C1-C6 alkyl), aryl(C1-C6 alkyl), arylsulfonyl, heteroarylsulfonyl, aryl(C1-C6 alkyl)sulfonyl, (C1-C6)alkylsulfonyl, and heteroaryl(C1-C6 alkyl)sulfonyl; or (ii) R3 Together with, it forms a chain composed of 2 to 4 carbon atoms, wherein a substituent independently selected from the group consisting of H, C1-C6 alkyl, aryl, heteroaryl, and any combination thereof is bonded to the chain;

[0201] R 5 is an H, D, C1-C6 alkyl, C1-C6 substituted alkyl;

[0202] R 6 silver: (i) Selected from the group consisting of H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, (C3-C6 cycloalkyl)(C1-C6 alkyl), aryl (C1-C6 alkyl), acetyl and heteroaryl (C1-C6 alkyl); or (ii) R 7 and together with the N atoms to which they are bonded, form a 4 to 7-membered heterocyclil ring; or (iii) e and R 6 Forming an azetidine or pyrrolidine ring with the bonded N atom, said ring having a substituent independently selected from the group consisting of H, aryl, heteroaryl, C1-C6 alkyl, and C3-C6 cycloalkyl; or (iv) b and R 6 Forming an azetidine or pyrrolidine ring together with the bonded N atom, said ring has a substituent independently selected from the group consisting of H, aryl, heteroaryl, halogen, C1-C6 alkyl, and C3-C6 cycloalkyl;

[0203] R 7 silver: (i) Selected from the group consisting of H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, (C3-C6 cycloalkyl)(C1-C6 alkyl), aryl (C1-C6 alkyl), acetyl and heteroaryl (C1-C6 alkyl); or (ii) R 6and together with the N atoms to which they are bonded, form a 4 to 7-membered heterocyclil ring;

[0204] a Is: (i) Selected from the group consisting of H, halogen, CH3, CHF2, CF3, OCH3, OCHF2, OCF3, SCH3, SCHF2, SCF3, and cyano; or (ii) A ring composed of three or four atoms is formed together with a, wherein one of the atoms is selected from the group consisting of C, N, O, and S and the remainder is carbon, the chain contains zero, one, or two double bonds, and the chain is bonded to a substituent independently selected from the group consisting of H, halogen, OH, C1-C6 alkoxy, C1-C6 alkyl, C3-C6 cycloalkyl, CHF2, CF3, OCHF2, OCF3, SCH3, SCHF2, SCF3, cyano, and oxo; or (iii) R 3 It forms a ring composed of three or four atoms together with, wherein one of the atoms is selected from the group consisting of C, N, O, and S and the remainder is carbon, the chain contains zero, one, or two double bonds, and the chain is bonded with a substituent independently selected from the group consisting of H, halogen, OH, C1-C6 alkoxy, C1-C6 alkyl, C3-C6 cycloalkyl, CHF2, CF3, OCHF2, OCF3, SCH3, SCHF2, SCF3, cyano, and oxo; and

[0205] b , c , d and e are each independently H or; or b , c , d and e Three of them are H and the remaining substituents are lower alkyl groups; or b and e are H respectively, and c and dis together -CH2- or -CH2CH2-, thereby forming a cyclopropane or cyclobutane ring; or b , c and d are H respectively, and e , R 6 and R 6 The bonded N atoms together form an azetidine or pyrrolidine ring, said ring having a substituent independently selected from the group consisting of H, aryl, heteroaryl, C1-C6 alkyl, and C3-C6 cycloalkyl; or c , d and e are H respectively, and b , R 6 and R 6 These bonded N atoms together form an azetidine or pyrrolidine ring, said ring having a substituent independently selected from the group consisting of H, aryl, heteroaryl, halogen, C1-C6 alkyl, and C3-C6 cycloalkyl.

[0206] According to one embodiment of a compound of structural formula III, or a pharmaceutically acceptable salt thereof, and a stereoisomer thereof, said compound is a compound of formula V:

[0207]

[0208] V.

[0209] Compounds of chemical formula V are chemical formula V- S It can be a compound of:

[0210]

[0211] V- S .

[0212] Compounds of chemical formula V are chemical formula V- R It can be a compound of:

[0213]

[0214] V- R .

[0215] Compounds of chemical formula V are chemical formula V- S Compounds of and chemical formula V- R It can be a racemic mixture of the compound:

[0216] and

[0217] V- S V- R .

[0218] According to other embodiments, a compound of structural formula VI, or a pharmaceutically acceptable salt thereof, and a stereoisomer thereof are disclosed:

[0219]

[0220] VI

[0221] Here:

[0222] R 1 is OH, and R 1 In the case of this OH, R 2 is different from OH and is selected from the group consisting of H, halogen, lower alkyl, CHF2, CF3, NC, OCH3, OCHF2, OCF3, SCHF2, SCH3, SCF3, and cyano;

[0223] R 2 is OH, and R 2 If α is OH, R 1 is different from OH and is selected from the group consisting of H, halogen, lower alkyl, CHF2, CF3, OCH3, OCHF2, OCF3, SCHF2, SCH3, SCF3, and cyano;

[0224] R 3C1-C6 alkyl, C1-C6 substituted alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, (C3-C6 cycloalkyl)(C1-C6 alkyl), C3-C6 heterocyclyl, (C3-C6 heterocyclyl)(C1-C6 alkyl), aryl, aryl(C1-C6 alkyl), heteroaryl, heteroaryl(C1-C6 alkyl), CN, C(O)NH2, C(O)NH(C1-C6 alkyl), C(O)N(C1-C3 alkyl)(C1-C6 alkyl), C(=NOH)(C1-C6 alkyl), and C(=NOH)(C1-C6 substituted alkyl), C(O)NH(aryl), C(O)N(alkyl)(aryl), NC, S(O)2NH2, Selected from the group consisting of S(O)2NH(C1-C6 alkyl) and S(O)2NH(aryl);

[0225] R 4 is selected from the group consisting of H, C1-C6 alkyl, C1-C6 substituted alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, (C3-C6 cycloalkyl)(C1-C6 alkyl), C3-C6 heterocyclyl, (C3-C6 heterocyclyl)(C1-C6 alkyl), aryl(C1-C6 alkyl), arylsulfonyl, heteroarylsulfonyl, aryl(C1-C6 alkyl)sulfonyl, (C1-C6)alkylsulfonyl, and heteroaryl(C1-C6 alkyl)sulfonyl;

[0226] R 5 is an H, D, C1-C6 alkyl, C1-C6 substituted alkyl;

[0227] R 6 Silver is selected from the group consisting of H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, (C3-C6 cycloalkyl)(C1-C6 alkyl), aryl (C1-C6 alkyl), acetyl, and heteroaryl (C1-C6 alkyl);

[0228] R 7Silver is selected from the group consisting of H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, (C3-C6 cycloalkyl)(C1-C6 alkyl), aryl (C1-C6 alkyl), acetyl, and heteroaryl (C1-C6 alkyl);

[0229] a is: selected from the group consisting of H, halogen, CH3, CHF2, CF3, OCH3, OCHF2, OCF3, SCH3, SCHF2, SCF3, NC, and cyano; and

[0230] b , c , d and e are each independently H or; or b , c , d and e Three of them are H, and the remaining substituents are lower alkyl groups.

[0231] According to other embodiments, a compound of structural formula I, II, III or VI, or a pharmaceutically acceptable salt thereof, and a stereoisomer thereof are disclosed, wherein a is a halogen, preferably F. According to another embodiment, in a compound of formula I, II or III a is CF3. According to another embodiment, in a compound of chemical formula I, II, III or VI a is H.

[0232] According to other embodiments, a compound of structural formula I, II, III or VI, or a pharmaceutically acceptable salt thereof, and a stereoisomer thereof are disclosed, wherein R 4 is H.

[0233] According to other embodiments, a compound of structural formula I, II, III or VI, or a pharmaceutically acceptable salt thereof, and a stereoisomer thereof are disclosed, and R 5 is H.

[0234] According to other embodiments, a compound of structural formula I, II, III or VI, or a pharmaceutically acceptable salt thereof, and a stereoisomer thereof are disclosed, wherein b , c , d and e Each is H.

[0235] According to other embodiments, a compound of structural formula I, II, III or VI, or a pharmaceutically acceptable salt thereof, and a stereoisomer thereof are disclosed, wherein R 6 and R 7 Each is CH3.

[0236] Method of use

[0237] The indoline compounds described in this specification are considered useful for the treatment of drug-resistant depression based on several clinical trials reported using psilocybin itself.

[0238] The U.S. STAR*D study reported that more than half of all patients recruited through primary care and psychiatric clinics did not achieve remission after first-line antidepressant treatment, and one-third could not experience remission even after four cycles of acute treatment (Rush AJ, Trivedi MH, Wisniewski SR, Nierenberg AA, Stewart JW, Warden D, et al. Acute and longer-term outcomes in depressed outpatients requiring one or several treatment steps: a STAR*D report. Am. J. Psychiatry 2006; 163:1905-17).

[0239] In addition to the potential uses of the compounds of the present invention in the treatment of depression, major depressive disorder, drug-resistant depression, and psychotic depression, other studies on human volunteers by third-party groups have shown that psilocybin can be used to treat tobacco and alcohol addiction. Furthermore, in a controlled clinical setting, psilocybin was safely administered to subjects with obsessive-compulsive disorder (OCD), and this drug treatment was found to result in an acute reduction of core OCD symptoms in several subjects (Moreno, FA, Wiegand, CB, Taitano, EK, and Delgado, PL "Safety, tolerability, and efficacy of psilocybin in 9 patients with obsessive-compulsive disorder") J. Clin. Psychiatry 2006, 67, 1735-1740).

[0240] Another potential use of the compounds of the present invention is in the treatment of seizure disorders, which include but are not limited to infantile seizure disorders such as (but not limited to) Dravet syndrome (Sourbon, J. et al. "Serotonergic Modulation as Effective Treatment for Dravet Syndrome in a Zebrafish Mutant Model", ACS Chem. Neurosci. 2016, 7, 588-593).

[0241] The indoline compounds described in this specification are 5-HT 2B - Considering that it lacks at least some of the undesirable characteristics of agent-related activity, it is considered safer than psilocybin.

[0242] Other potential uses of the compounds of the present invention are one or more of major depressive disorder, drug-resistant depression and psychotic depression, addiction including alcoholism, tobacco addiction, cocaine addiction and opioid addiction, pain indications including neuropathic pain, pain due to chemotherapy-related neuropathy, phantom limb pain and fibromyalgia, inflammation (including chronic and acute), eating disorders including anorexia, autism, cluster headache, migraine, dementia including Alzheimer's dementia, Parkinson's disease dementia and Lewy body dementia, mild cognitive impairment, post-traumatic stress disorder, emotional distress associated with cancer, fragile X syndrome, autism spectrum disorder, bipolar disorder, obsessive-compulsive disorder, and Rett syndrome.

[0243] Another potential use of the compounds of the present invention is as a combination drug therapy comprising the following:

[0244] A compound of formula I, II, III or IV according to the present invention; and

[0245] N -methyl- D - Aspartate (NMDA) receptor antagonist.

[0246] The above NMDA receptor antagonist is at least one of ketamine, nitrous oxide, memantine, amantadine, noribogain, dextromethorphan, dextromethadone, or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof. Preferably, the NMDA receptor antagonist is dextromethorphan.

[0247] The above combination drug therapy may be useful for the treatment of one or more of major depressive disorder, drug-resistant depression and psychotic depression, addiction including alcoholism, tobacco addiction, cocaine addiction and opioid addiction, pain indications including neuropathic pain, pain due to chemotherapy-related neuropathy, phantom limb pain and fibromyalgia, inflammation (including chronic and acute), eating disorders including anorexia, autism, cluster headache, migraine, dementia including Alzheimer's dementia, Parkinson's disease dementia and Lewy body dementia, mild cognitive impairment, post-traumatic stress disorder, emotional distress related to cancer, fragile X syndrome, autism spectrum disorder, bipolar disorder, obsessive-compulsive disorder and Rett syndrome.

[0248] The above combination drug therapy may be useful for the treatment of one or more of major depressive disorder, drug-resistant depression, and psychotic depression.

[0249] Methods of Administration

[0250] As considered herein, the therapeutically effective amount of the indoline compound described herein is administered to a subject who requires it. Whether such treatment is indicated depends on the individual case and further depends on a medical evaluation (diagnosis) that considers the presence of signs, symptoms and / or dysfunction, the risk of specific signs, symptoms and / or dysfunction, and other factors.

[0251] As considered herein, the indoline compounds described herein may be administered by any suitable route known in the art. Such routes include, but are not limited to, oral, buccal, inhalation, topical, sublingual, rectal, vaginal, intrathecal or intramedullary via lumbar puncture, transurethral, ​​nasal, percutaneous, transdermal, and parenteral administration (including intravenous, intramuscular, subcutaneous, intracoronary, intradermal, intramammary, intraperitoneal, intra-articular, intrathecal, retroocular, intrapulmonary injection and / or surgical implantation at specific sites). Parenteral administration may be achieved using needles and syringes, or by using high-pressure technology.

[0252] The pharmaceutical composition comprises an amount sufficient to administer the indoline compound described herein as an effective amount to achieve its intended purpose. The precise formulation, route of administration, and dosage are determined by a qualified medical professional in light of the diagnosed condition or disease. The dosage and dosing interval may be individually adjusted to provide a level of the indoline compound described herein sufficient to maintain the desired therapeutic effect. The indoline compound described herein may be administered infrequently ( for example It may only require monthly rather than daily.

[0253] As considered herein, the therapeutically effective dose of the indoline compound described herein, adapted for use in therapy, depends on the nature of the condition being treated, the duration of activity required, and the age and condition of the patient, and is ultimately determined by the attending physician. The dosage and dosing interval may be individually adjusted to provide plasma levels of the indoline compound sufficient to maintain the desired therapeutic effect. For convenience, the desired dose may be administered as a single dose or as multiple doses administered at appropriate intervals, for example, once, twice, three times, four times, or more divided doses per day. Multiple doses may often be desired or required. For example, the indoline compound described herein may be administered at the following frequencies: four doses delivered as once-daily doses at four-day intervals (q4d x 4); four doses delivered as once-daily doses at three-day intervals (q3d x 4); Doses delivered once daily at 5-day intervals (qd x 5); weekly doses for 3 weeks (qwk3); 5 daily doses followed by a 2-day break and then 5 daily doses again (5 / 2 / 5); or any dosing regimen determined to be appropriate for the situation.

[0254] As considered herein, the indoline compounds described herein may be administered as a mixture with a pharmaceutical carrier selected in consideration of the intended route of administration and standard pharmaceutical practices. Pharmaceutical compositions for use according to the indoline compounds described herein are formulated in a conventional manner using one or more physiologically acceptable carriers comprising excipients and adjuvants that facilitate the processing of the compounds described herein.

[0255] Water is a preferred carrier when the indoline compounds described herein are administered intravenously. Saline solutions and aqueous dextrose and glycerol solutions may also be used as liquid carriers, particularly for injectable solutions. Suitable pharmaceutical carriers also include excipients such as starch, glucose, lactose, sucrose, gelatin, malt, rice, wheat flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene glycol, water, ethanol, etc. The composition may also contain small amounts of wetting agents or emulsifiers, or pH buffers, if desired.

[0256] These pharmaceutical compositions may be prepared, for example, by conventional mixing, dissolving, granulating, making coated tablets, emulsifying, encapsulating, capturing, or freeze-drying processes. The appropriate formulation depends on the selected route of administration. When a therapeutically effective amount of the indoline compound described herein is administered orally, the composition is typically in the form of a tablet, capsule, powder, solution, or elixir. When administered in tablet form, the composition may additionally contain a solid carrier such as gelatin or an adjuvant. The tablet, capsule, and powder contain the indoline compound described herein in an amount of about 0.01% to about 95%, preferably about 1% to about 50%. When administered in liquid form, a liquid carrier such as water, petroleum, or oil of animal or vegetable origin may be added. The liquid form of the composition may additionally contain a physiological saline solution, dextrose or other sugar solution, or glycol. When administered in liquid form, the composition contains the compound described herein in an amount of about 0.1% to about 90% by weight, preferably about 1% to about 50%.

[0257] When a therapeutically effective amount of the indoline compound described herein is administered by intravenous, intradermal, or subcutaneous injection, the composition is in the form of a pyrogen-free, parenterally acceptable aqueous solution. The preparation of such a parenterally acceptable solution, with appropriate consideration of pH, isotonicity, stability, etc., is within the scope of the art. A preferred composition for intravenous, intradermal, or subcutaneous injection typically contains an isotonic vehicle. The indoline compound described herein may be infused with other fluids over a period of 10 to 30 minutes or over several hours.

[0258] The indoline compounds described herein can be easily combined with pharmaceutically acceptable carriers well known in the art. Such carriers enable the active agent to be formulated into tablets, pills, coated tablets, capsules, liquids, gels, syrups, slurries, suspensions, etc., for oral intake by the patient to be treated.

[0259] Oral pharmaceutical formulations may be obtained by adding an indoline compound described herein to a solid excipient, grinding or not grinding the resulting mixture, adding a suitable adjuvant if desired, and then processing the granulated mixture to obtain a tablet or a coated tablet core. Suitable excipients include, for example, fillers and cellulose preparations. If desired, a disintegrant may be added.

[0260] The indoline compounds described in this specification are by injection, for example It can be formulated for parenteral administration by bolus injection or continuous infusion. The injectable formulation is a unit dose type, for example It may be provided in an ampoule or multi-dose container with a preservative added. The composition may take the form of a suspending agent, solution, or emulsion in an oily or aqueous vehicle, and may contain formulation agents such as a suspending agent, a stabilizer, and / or a dispersing agent.

[0261] Pharmaceutical compositions for parenteral administration include an aqueous solution of an active agent in a water-soluble form. Additionally, suspensions of indoline compounds described herein may be prepared as suitable oily injection suspensions. Suitable lipophilic solvents or vehicles include fatty oils or synthetic fatty acid esters. Aqueous injection suspensions may contain substances that increase the viscosity of the suspension.

[0262] In some embodiments, the suspension may also contain a suitable stabilizer or formulation that increases the solubility of the compound and enables the preparation of a highly concentrated solution. Alternatively, the composition may be in powder form to be composed of a suitable vehicle, e.g., sterile water free of pyrogens, before use.

[0263] The indoline compounds described herein may also be formulated into rectal compositions containing, for example, a conventional suppository base, such as suppositories or retention enemas. In addition to the formulations described above, the indoline compounds described herein may also be formulated into depot formulations. Such sustained-release formulations may be administered by implantation (e.g., subcutaneous or intramuscular) or by intramuscular injection. Thus, for example, the indoline compounds described herein may be formulated with a suitable polymeric or hydrophobic material (e.g., as an emulsion in an acceptable oil) or an ion exchange resin.

[0264] The indoline compounds described herein may be administered orally, buccally, or sublingually in the form of tablets containing excipients such as starch or lactose, or as capsules or ovules in a mixture with excipients or alone, or as elixirs or suspensions containing flavorings or colorings. Such liquid formulations may be prepared with pharmaceutically acceptable additives such as suspending agents. The indoline compounds described herein may also be administered parenterally, for example, intravenously, intramuscularly, subcutaneously, or into the coronary arteries. For parenteral administration, the indoline compounds described herein may be best used in the form of sterile aqueous solutions containing other substances, for example, salts or monosaccharides such as mannitol or glucose, to make the solution isotonic with blood. In at least some embodiments, the indoline compounds described herein are psilocybin analogs.

[0265] The present invention will be more easily understood by referring to the following examples, which are presented to illustrate the invention rather than to limit its scope.

[0266] Example 1

[0267] Serotonin receptor 5-HT 2 Functional analysis

[0268] Non-limiting examples of methods for measuring serotonin receptor functional activation are described as follows.

[0269] To measure the functional activation of serotonin receptors, either Gq dissociation by bioluminescent resonance energy transfer (BRET) or Gq-dependent calcium influx is performed for selected compounds. To measure 5-HT2 receptor-mediated Gq activation via Gq / γ dissociation measured by BRET (McCorvy JD, Wacker D, Wang S, Agegnehu B, Liu J, Lansu K, Tribo AR, Olsen RHJ, Che T, Jin J, Roth BL. Structural determinants of 5-HT 2B receptor activation and biased agonism. Nat Struct Mol Biol. 2013; 25(9):787-96), HEK293T cells were subcultured in Dulbecco Modified Eagle Medium (DMEM) supplemented with 10% dialyzed fetal bovine serum (FBS), and using TransiT-2020 R Luc3-Fusion Human Gαq(Gαq- RLucS), GFP2 fused to the C-terminus of human Gγ, and Gγ are co-transfected with human Gβ and 5-HT2 receptors in a 1:1:1:1 ratio. After at least 18–24 hours, transfected cells are seeded into poly-L-lysine-coated 96-well white clear-bottom cell culture plates at a density of 25,000–40,000 cells per well in DMEM containing 1% dialyzed FBS at a volume of 200 μL and incubated overnight. The next day, the medium is drained, cells are washed with 60 μL of drug buffer (1x HBSS, 20 mM HEPES, pH 7.4), and then 60 pL of drug buffer is added per well. Cells are pre-incubated in a humidified atmosphere at 37°C prior to drug stimulation. Drug stimulation is administered in McCorvy buffer (1x HBSS, 20 mM HEPES, pH 7.4, 0.3% BSA). Addition of 30 μL of the diluted drug (3X) in a fatty acid-free solution supplemented with 0.03% ascorbic acid was used, and the plate was incubated at 37°C for 1 hour. Substrate addition was performed 15 minutes prior to reading, and for Gq dissociation of BRET2 R 10 pL of Luc substrate coelenterazine 400a was used (Prolume / Nanolight, final concentration 5 μM). The plates were Mithras LB940 (multimode microplate reader) (for example Readouts for luminescence at 400 nm and fluorescence GFP2 emission at 510 nm are performed at 1 second per well using the Berthold instrument. The BRET ratio of fluorescence to luminescence is calculated per well and plotted as a function of drug concentration using Graphpad Prism 8 (Graphpad Software Inc., San Diego, CA). Data are normalized by % 5-HT stimulation and analyzed using non-linear regression "log(agonist) versus response" to E max and EC 50 Calculate parameter estimates.

[0270] Calcium influx is measured using a stable expression 5-HT2Flp-In 293 T-Rex tetracycline-inducible system by methods known in the art. (for example Investigation of the Structure-Activity Relationships of Psilocybin Analogues, ACS Pharmacol. Transl. Sci. 2020, Publication Date: December 14, 2020, https: / / doi.org / 10.1021 / acsptsci.0c00176). Cell lines are maintained in DMEM containing 10% FBS, 10 μg / mL blasticidin, and 100 μg / mL hygromycin B. At least 20 to 24 hours prior to analysis, receptor expression is induced with tetracycline (2 μg / mL), and cells are seeded in 384-well poly-L-lysine coated black plates at a density of 7,500 cells per well in DMEM containing 1% dialyzed FBS. On the day of analysis, cells are incubated at 37°C for 1 hour with Fluo-4 Direct dye (Invitrogen, 20 pL / well) reconstituted in drug buffer containing 2.5 mM probenecid (20 mM HEPES buffer HBSS, pH 7.4). The drug diluent is prepared at 5X the final concentration in McCorvy buffer (20 mM HEPES-buffered HBSS, 0.1% BSA, 0.01% ascorbic acid, pH 7.4). After dye loading, the cells are equilibrated at room temperature for 15 minutes, then FLIPR® TETRA Insert into the fluorescence imaging plate reader (Molecular Devices). FLIPR® TETRAIt is programmed to read baseline fluorescence for 10 seconds (1 read per second), then add 5 μL of drug per well, and read fluorescence for a total of 5–10 minutes (1 read per second). The fluorescence in each well is normalized by the mean of the first 10 reads of baseline fluorescence, and then either the peak increase or the area under the curve (AUC) relative to baseline is calculated. Plot the peak or AUC as a function of drug concentration and normalize the data by % 5-HT stimulation. Plot the data and perform nonlinear regression using "log(agonist) vs. response" in Graphpad Prism 8 to E max and EC 50 Calculate parameter estimates.

[0271] 5-HT of the various compounds disclosed herein 2A , 5-HT 2B and 5-HT 2C The functional activity at each receptor is measured against and relative to the functional activity of 4-hydroxytryptamine at the corresponding receptor.

[0272] Example 2

[0273] Chemical synthesis method of the compound of chemical formula IV

[0274] A non-limiting example of a procedure for preparing a compound of Formula IV as described in this specification is provided below.

[0275] The indoline cores of the compound of chemical formula I are numbered as follows:

[0276]

[0277] A similar numbering system is applied to compounds of chemical formulas II, III, and IV, as the numbers are assigned to the indole ring regardless of the substituents.

[0278] The synthesis of the compound of formula IV involves several steps, namely (1) construction of a heterocyclic core; (2) introduction or modification of a 3-substituent; and (3) functional group conversion.

[0279]

[0280]

[0281]

[0282]

[0283]

[0284]

[0285] Example 3

[0286] Chemical synthesis method of the compound of chemical formula V

[0287] A non-limiting example of a procedure for preparing a compound of formula V as described in this specification is provided below.

[0288] The synthesis of a compound of formula V involves several steps, namely (1) construction of a heterocyclic core; (2) introduction or modification of a 3-substituent; and (3) functional group conversion.

[0289]

[0290]

[0291]

[0292]

[0293]

[0294]

[0295] Pharmacology

[0296] Example 4

[0297] Serotonin Receptor 5-HT Function Analysis #1

[0298] Non-limiting examples of methods for measuring serotonin receptor functional activation are described as follows.

[0299] HEK293 cells expressing 5-HT receptors are trypsinized, counted, seeded into black clear-bottom 96-well plates at a density of 25,000 cells per well, and incubated overnight in medium containing 1% dialysis serum. The next day, the medium is removed from the cell plates and replaced with 30 μl of assay buffer (20 mM HEPES:HBSS, pH 7.4). Calcium 5 (Molecular Devices, R8186) dye solution (10 μl) is added to the wells and incubated at 37°C for 60 minutes. The dye solution is prepared in 20 mM HEPES:HBSS, pH 7.4 + 2.5 mM probenecid. Compound dilutions (including serial dilutions) are performed in 100% DMSO and then transferred to an intermediate dilution for a very limited time (< 10 minutes) immediately before addition to the cell plates. Selected 5-HT receptor analysis panel (5-HT 1A , 5-HT 2A , 5-HT 2B , 5-HT 2C and m5-HT 2A Three types of compounds (racemic mixture, compound PURM100, and compound PURM200) are tested in triplicate at seven concentrations for ). The compounds are tested as agents at 100 μM, 10 μM, 1 μM, 0.1 μM, 0.01 μM, 1 nM, and 0.1 nM.

[0300] For the agent test: After incubation with the dye, place the plate into the FLIPR Penta high-throughput cell screening system and monitor fluorescence every 1 second to monitor the baseline. After 20 seconds, add the test compound or control agent (10 μl) to the well and monitor fluorescence for 5 minutes at excitation / emission: 488 nm / 510-570 nm. EC for the test compound and control compound 50 The values ​​were determined using GraphPad Prism software. EC for the control compound 50Values ​​are compared with existing analyses and / or literature data to confirm that they are within an acceptable range to validate each analysis. E of 5-HT max Determine the % efficacy of the test compound measured for.

[0301] The 5-HT of the racemic mixture of Compound IV, Compound PURM100, and Compound PURM200 disclosed herein 1A , 5-HT 2A , 5-HT 2B and 5-HT 2C The functional activity at each receptor was measured. A comparison of the functional activities is provided in Table 1 and Figure 1 as follows.

[0302] EC 50 (nM) / E max % Compound IV racemic mixture PURM100 PURM200 5-HT 1A >10000 / 45.9% >10000 / 68.5% -- / 0.39% 5-HT 2A 58 / 60.1% 52.5 / 62.8% 54.5 / 62.9% 5-HT 2B --- / 8.2% --- / 6.26% --- / 5.3% 5-HT 2C 699 / 74.9% 699.2 / 81.7% 998.0 / 58.5%

[0303] Table 1 - 5-HT receptor binding profile

[0304] High potency: Compound PURM100 and - R 5-HT 2A It possesses a high titer (less than 60 nM) toward the receptor. High titers allow for therapeutic effects to be elicited using lower doses. Lower doses can lead to fewer adverse side effects and superior patient outcomes. High titers lead to enhanced target receptor binding in complex biological systems (e.g., competition with endogenous molecules). The compound is 5-HT compared to other 5-HT receptors 2A It has high selectivity for. For example, 5-HT 2C Boda 5-HT 2A It unexpectedly exhibits approximately 13 times higher potency, minimizing off-target 5-HT effects. Low risk of cardiotoxicity: 5-HT to the mitral and aortic valves. 2B Receptors are densely distributed, and their activation increases the risk of valvular heart disease. Compounds PURM100 and - R 5-HT 2B Activation is lacking.

[0305] Example 5

[0306] Serotonin Receptor 5-HT Function Analysis #2

[0307] LgBiT-tagged 5-HT 2A HEK cells expressing smBiT beta-arrestin were washed with PBS to remove serum-containing medium, recovered into 1% dialysis serum-containing medium, counted, and seeded into white 96-well plates at a density of 25,000 cells per well. The next day, 25 μl of NanoGlo live cell substrate (Promega N2012) was added to each well, and the cells were incubated for 25 minutes. The compound was prepared as described for the 5-HTR calcium assay procedure outlined in Example 4 above, and 20 μl of the 5X compound solution was added to the cells. The cells were incubated at 37°C for 90 minutes, and Hidex TM The plate is read for luminescence using a plate reader.

[0308] EC of test compound and control compound 50 EC was determined using GraphPad Prism software. EC for the control compound 50 Values ​​are compared with existing analyses and / or literature data to confirm that they are within our acceptable ranges to validate each analysis. The % efficacy of the test compound is the E of 5-HT max Measurements were taken for. The results were generated by the Excel formula (Compound RFU - Average Minimum RFU) / (Average Maximum RFU - Average Minimum RFU))*100. EC 50 Values ​​were generated using the log(agonist) versus response (4-parameter) equation by Prism software (GraphPad Inc.). The raw data for 5-HT EC was generated using Prism software. 50 Normalized to the upper and lower bounds of the value. EC 50The values ​​were generated using the log(agent) versus response (3 parameters) equation by Prism software (GraphPad Inc).

[0309] Racemace of Compound IV EC 50 (nM) E max (%) Bias coefficient Ca 2+ / Gq 17.6 59.4 0.63 Beta-Arrestin 48.2 58.8

[0310] Table 2 - Ca 2+ Activating the / Gq path

[0311] Compound PURM100 EC 50 (nM) E max (%) Bias coefficient Ca 2+ / Gq 10.0 63 5.80 Beta-Arrestin 212 52

[0312] Table 3 - Ca 2+ Activating the / Gq path

[0313] Compound PURM200 EC 50 (nM) E max (%) Bias coefficient Ca 2+ / Gq 9.90 65 11.4 Beta-Arrestin 326 43

[0314] Table 4 - Ca 2+ Activating the / Gq path

[0315] Now refer to Fig. 2 and the tables above. Biased Gq signaling can activate phospholipase C (PLC), which hydrolyzes phosphatidylinositol 4,5-bisphosphate (PIP2) into two secondary messengers: inositol triphosphate (IP3) and diacylglycerol (DAG). These have various functions in cellular processes, such as influencing cell proliferation and neurotransmitter release. The enantiomers of Compound IV are each more biased toward the calcium / Gq signaling pathway than the racemic form. Reduced bias toward β-arrestin 2 is associated with Compound PURM100 and - R 5-HT upon repeated administration 2A Suggests that receptor desensitization / downregulation is potentially less. Potency for the Gq pathway: Compound IB- R , > Compound PURM100 > Racemic mixture. Ca 2+ The results of the analysis measuring the activation of the / Gq pathway showed that compound IV was all 5-HT 2A It indicates that it has a high titer (less than 60 nM).

[0316] Example 6

[0317] Hepatocellular stability

[0318] Hepatocellular stability is a measure indicating how quickly a drug candidate is metabolized in the liver. Hepatocellular stability analysis uses hepatocytes to determine how a compound is eliminated. in vitro It is a test. Hepatocellular stability analysis can be used for various purposes, including drug efflux, absorption studies, metabolite identification, and CYP induction / inhibition studies.

[0319] The hepatocyte stability analysis protocol was performed according to the following protocol:

[0320] Preparation of working solution

[0321] 1) Prepare 10 mM stock solutions of the test compound and the positive control compound in a suitable solvent (DMSO).

[0322] 2) In a separate conical tube, combine 198 μL of 50% acetonitrile / 50% water with 2 μL of 10 mM stock to dilute the 10 mM test compound and positive control to 100 μM.

[0323] production of liver cells

[0324] 1) Place the incubation medium (Williams E medium supplemented with GlutaMAX) and hepatocyte thawing medium in a 37°C water bath and heat them for at least 15 minutes before use. Boiled hepatocytes were prepared in a 100°C water bath for at least 15 minutes.

[0325] 2) Transfer the cryopreserved hepatocyte vial from the storage area, ensuring that the vial remains at a cryogenic temperature until the thawing process begins. Place the vial in a 37°C water bath and gently shake for 2 minutes to thaw the cells. Once thawing is complete, spray 70% ethanol onto the vial and transfer it to a biosafety cabinet.

[0326] 3) Using a wide-bore pipette tip, transfer the hepatocytes to a 50 mL conical tube containing thawing medium. Place the 50 mL conical tube into a centrifuge and centrifuge at 100 g for 10 minutes. Once centrifugation is complete, aspirate and remove the thawing medium, and approximately 1.5 × 10⁶ 6 Resuspend liver cells in sufficient incubation medium to achieve a cell / mL ratio.

[0327] 4) Count cells using AO / PI staining and determine viable cell density. Dilute cells with incubation medium to 0.5 × 10⁶ 6 Make it a working cell density of viable cells / mL.

[0328] Stability determination procedure

[0329] 1) Pipette 198 μL of hepatocytes and boiled hepatocytes into each well of a 96-well uncoated plate. Place the plate in an incubator to allow the hepatocytes to warm up for 10 minutes.

[0330] 2) Initiate the reaction by pipetting 2 μL of 100 μM of the test compound or positive control into each well of a 96-well uncoated plate. Return the plate to the incubator for the designed time.

[0331] 3) At 0.5, 15, 30, 60, 90, and 120 minutes, the well contents were transferred to a 25 μL aliquot. Subsequently, the aliquot was mixed with 6 times the volume (150 μL) of acetonitrile containing the internal standard IS (100 nM alprazolam, 200 nM caffeine, and 100 nM tolbutamide) to terminate the reaction. Vortexing was performed for 5 minutes. The sample was centrifuged at 3,220 g for 45 minutes. 100 μL of the supernatant aliquot was diluted with 100 μL of ultrapure water, and the mixture was used for LC / MS / MS analysis. All incubations were performed in duplicate.

[0332] Data analysis

[0333] All calculations were performed using Microsoft Excel. Peak areas were determined from the extraction ion chromatogram. The in vitro half-life of the parent compound (t 1 / 2 ) is determined by regression analysis of the parent compound loss percentage versus time curve.

[0334] in vitro Half-life (t in test tube) 1 / 2 ) was determined from the slope value:

[0335] In vitro t 1 / 2 = -0.693 / k

[0336] In vitro t 1 / 2 (Unit: minutes) of In vitro intrinsic clearance arance )( In vitro CL int , Unit: μL / min / 1×10 6 Conversion to cells was performed using the following formula (average of 2 measurements):

[0337] In vitro CL int = -kV / N

[0338] V = incubation volume (0.2 mL);

[0339] N = Number of hepatocytes per well (0.1 × 10 6 cell).

[0340] Scale-up CL int (mL / min / kg), predicted CL H Calculations of (mL / min / kg) and liver extraction rate (ER) were performed using the following formula:

[0341] Scale-up CL int = (0.693 / T 1 / 2 ) × (1 / (hepatocyte concentration(0.5 × 10⁻⁶) 6 Cells / mL))) × Scaling Factor

[0342] CL between predictions H = (QH × Scale-up CL int× fub) / (QH + Scale-up CL int × fub),

[0343] ER = CL between predictions H / Q H

[0344] Here, QH is hepatic blood flow (mL / min / kg), and fub is the fraction of unbound drugs in plasma, assumed to be 1. Table 5 below provides the scaling factors and other values ​​used in these calculations.

[0345] bell liver cell content Liver weight Scaling factor Liver blood flow (10 6 (cells / g liver) (g / kg bw) (10 6 cells / kg) (ml / min / kg) human being 99 25.7 2544.3 21 monkey 99 30 2970 44 dog 169 32 5408 31 rat 117 40 4680 68 mouse 135 88 11880 90

[0346] a Scaling Factor = (Hepatocyte Content) × (Liver Weight)

[0347] Table 5 - Scaling Factors for Predicting Intrinsic Clearance in Human, Monkey, Dog, Rat, and Mouse Hepatocytes

[0348] Retention rate % Processing rules ≥80% in 120 minutes If a T-test with p<0.05 is obtained, the calculated CL int Reports the value. If a T-test with p<0.05 is not obtained, and all other data points fall within the 80%–120% range (one data point within the 70%–130% range is allowed), CL int Report a value of 0, otherwise repeat the experiment. <80% in 120 minutes Always remove all remaining points from the calculation where less than 10% of the 0.5-minute sample remains, but keep at least 2 points. If a T-test with p<0.05 is obtained, the calculated CL int Reports the value. If a T-test with p<0.05 is not obtained, the experiment must be repeated.

[0349] Table 6 - Data Processing Rules

[0350] Compound ID bell In vitro t 1 / 2 (min) In vitro Cl int (uL / min / 10 6 cell) Scale-up CL int (mL / min / Kg) CL between predictions H (mL / min / Kg) Liver extraction rate (ER) Verapamil human being 20.68 67.03 170.56 18.70 0.89 monkey 4.58 302.52 898.49 41.95 0.95 dog 20.18 68.76 371.86 28.61 0.92 rat 5.18 267.56 1252.19 64.50 0.95 mouse 4.65 298.88 3550.75 87.77 0.98 Compound IV human being ∞ 0.00 0.00 0.00 0.00 monkey 37.25 37.23 110.58 31.47 0.72 dog 245.59 5.72 30.93 15.43 0.50 rat 59.47 23.31 109.08 41.89 0.62 mouse >380.57 <3.64 <43.27 <29.22 <0.32

[0351] Table 7 - Liver Clearance Rate

[0352] Remaining percentage (%) 0.5 minutes 15 minutes 30 minutes 60 minutes 90 minutes 120 minutes Compound ID bell Verapamil human being 100.00 51.46 27.32 13.25 5.89 3.71 monkey 100.00 11.16 1.79 0.42 0.40 0.25 dog 100.00 45.45 25.26 12.23 6.00 3.01 rat 100.00 14.38 2.69 0.49 0.33 0.21 mouse 100.00 11.54 0.04 0.17 0.11 0.11 Compound IV human being 100.00 100.48 105.92 98.02 84.54 93.52 monkey 100.00 82.42 60.37 27.77 21.24 25.33 dog 100.00 99.30 92.90 85.79 76.35 73.16 rat 100.00 99.26 80.71 63.60 35.30 44.52 mouse 100.00 101.07 100.69 91.43 82.95 88.15

[0353] Table 8 - Liver Clearance Rate

[0354] The above results show that Compound IV of the present invention exhibits a slow liver clearance rate compared to the verapamil control group.

[0355] Example 7

[0356] Plasma and brain pharmacokinetics in mice

[0357] Pharmacokinetic parameters were measured after intravenous (IV), oral (PO), and intraperitoneal (IP) administration of any one of the racemic mixture, compound PURM100, or compound PURM200 to CD-1 male mice. For IV administration, the compound was administered at 2 mg / kg; for PO administration, at 15 mg / kg; and for IP administration, at 5 mg / kg in saline solution. The administration solution volume was 0.4 mg / mL for IV, 3 mg / mL for PO, and 1 mg / mL for IP. Blood samples were collected at 0.083, 0.25, 0.5, 1, 2, 4, and 8 hours per dose (IV), or at 0.25, 0.5, 1, 2, 4, and 8 hours per dose (PO), or at 0.25, 0.5, 1, 2, 4, and 8 hours per dose (IP). Brain samples were collected at 0.25, 1, 4, and 8 hours per dose.

[0358] tissue manufacturing

[0359] Brain samples were homogenized with PBS at a ratio of 1:3 (W / V, 1:3). The final brain concentration in the tissue was corrected by multiplying by 4.

[0360] Preparation of plasma samples

[0361] The desired serial concentrations of the working solution were achieved by diluting the stock solution of the analyte with a 50% aqueous acetonitrile solution. 5 μL of the working solution (1, 2, 4, 10, 20, 100, 200, 1000, 2000 ng / mL) was added to 10 μL of blank plasma to obtain calibration standards ranging from 0.5 to 1000 ng / mL (0.5, 1, 2, 5, 10, 50, 100, 500, 1000 ng / mL) in a total volume of 15 μL. Four quality control samples for plasma at 1 ng / mL, 2 ng / mL, 50 ng / mL, and 800 ng / mL were prepared independently of those used in the calibration curve. These QC samples were prepared on the day of analysis in the same manner as the calibration standards.

[0362] 15 μL of standard, 15 μL of QC sample, and 15 μL of unknown sample (10 μL of plasma and 5 μL of blank solution) were each added to 200 μL of acetonitrile containing an IS mixture for protein precipitation. The samples were then vortexed for 30 seconds. After centrifugation at 4°C and 4700 rpm for 15 minutes, the supernatant was diluted with ultrapure water at a ratio of 1:2 (V / V), and then 10 μL of the diluted supernatant was injected into an LC / MS / MS system for quantitative analysis.

[0363] Preparation of brain samples

[0364] The desired serial concentrations of the working solution were achieved by diluting the stock solution of the analyte with a 50% aqueous acetonitrile solution. 15 μL of the working solution (1, 2, 4, 10, 20, 100, 200, 1000, 2000 ng / mL) was added to 30 μL of blank brain homogenate to obtain calibration standards ranging from 0.5 to 1000 ng / mL (0.5, 1, 2, 5, 10, 50, 100, 500, 1000 ng / mL) in a total volume of 45 μL. Four quality control samples of 1 ng / mL, 2 ng / mL, 50 ng / mL, and 800 ng / mL for the brain homogenate were prepared independently of those used in the calibration curve. These QC samples were prepared on the day of analysis in the same manner as the calibration standards.

[0365] 45 μL of standard, 45 μL of QC sample, and 45 μL of unknown sample (30 μL of brain homogenate and 15 μL of blank solution) were each added to 200 μL of acetonitrile containing an IS mixture for protein precipitation. The samples were then vortexed for 30 seconds. After centrifugation at 4°C and 4700 rpm for 15 minutes, the supernatant was diluted with ultrapure water at a ratio of 1:2 (V / V), and then 1 μL of the diluted supernatant was injected into an LC / MS / MS system for quantitative analysis. In this study, the limit of quantification (LOQ) was 0.5 ng / mL for plasma and 1 ng / mL for brain; the upper limit of quantification (UOQ) was 1000 ng / mL for both plasma and brain.

[0366] IV 5 mg / kg parameters unit average SD CV(%) Observed clearance (Cl_obs) mL / min / kg 110 8 7.59 Half-life (T 1 / 2 ) h 0.86 0.23 27.0 Initial concentration (C0) ng / mL 1325 473 35.7 Area under the curve (final measurement point; AUC) last ) h*ng / mL 751 50 6.61 Area under a curve (extrapolated to infinity; AUC) inf ) h*ng / mL 759 58 7.68 Percentage of extrapolated AUC (AUC_ %Extrap_ obs) % 1.10 1.24 113 Average time of stay (extrapolated to infinity; MRT) Inf _obs) h 0.713 0.133 18.7 Capacity Normalized AUC (AUC) up to the final point in time last / D) h*mg / mL 150 10 6.61 Observed steady-state volume of distribution (Vss_obs) L / kg 4.68 0.68 14.6 Oral bioavailability (F) % 69.8 13.8 19.8

[0367] Table 9 - Plasma pharmacokinetics of racemic mixtures

[0368] Brain concentration (ng / g) animal 7 8 9 10 11 12 Average (ng / g) SD (ng / g) CV (%) 4 hr 113 142 56 104 44 42.1 8 hr 7.88 13.3 9.64 10.3 2.8 27

[0369] Table 10 - Brain concentrations for racemic mixtures

[0370] Brain / Plasma Ratio animal 7 8 9 10 11 12 average SD CV (%) 4 hr 2.02 2.85 1.74 2.20 0.58 26.3 8 hr 2.23 2.55 1.54 2.10 0.52 24.6

[0371] Table 11 - Brain / Plasma Ratio for Racemic Mixtures

[0372] IV 2 mg / kg parameters unit average SD CV(%) Observed clearance (Cl_obs) mL / min / kg 71.1 13.6 19.2 Half-life (T 1 / 2 ) h 0.486 0.025 5.15 Initial concentration (intravenous, 2 mg / kg; CO) ng / mL 1394 19 1.38 Area under the curve (AUC) up to the final measurement point last ) h*ng / mL 481 102 21.1 Area under the curve extrapolated to infinity (AUC inf ) h*ng / mL 482 102 21.1 Percentage of extrapolated AUC (AUC_ %Extrap _obs) % 0.159 0.024 14.9 Average time of stay (extrapolated to infinity; MRT) Inf _obs) h 0.421 0.078 18.5 Capacity Normalized AUC (AUC) up to the final point in time last / D) h*mg / mL 241 51 21.1 Observed steady-state volume of distribution (Vss_obs) L / kg 1.76 0.18 9.98 Observed volume of distribution (after extravascular administration; VZ_obs) L / kg 3.01 0.71 23.7 Oral bioavailability (F) PO % 16.7 1.2 7.34 Maximum concentration (oral, 15 mg / kg) ng / mL 655 160 24.4 Intraperitoneal bioavailability (F) IP % 33.0 5.4 16.3 Maximum concentration (intraperitoneal, 5 mg / kg) ng / mL 666 75 11.3

[0373] Table 12 - Plasma pharmacokinetics of compound PURM100

[0374] Brain concentration and Kp after administration of an IP dose of 10 mpk PK parameters unit average brain Brain Kp T 1 / 2 h 0.467 T max h 0.250 C max ng / g 2970 4.46 AUC last h*ng / g 2598 6.56 AUC Inf h*ng / g 2605 6.56

[0375] Table 13 - Brain concentrations and Kp after administration of an IP dose of 10 mpk for compound PURM100

[0376] IV 2 mg / kg parameters unit average SD CV(%) Observed clearance (Cl_obs) mL / min / kg 55.7 11.0 19.8 Half-life (T 1 / 2 ) h 0.96 0.24 25.6 Initial concentration (intravenous, 2 mg / kg; CO) ng / mL 907 39 4.29 Area under the curve (AUC) up to the final measurement point last ) h*ng / mL 610 118 19.3 Area under the curve extrapolated to infinity (AUC inf ) h*ng / mL 614 117 19.0 Percentage of extrapolated AUC (AUC_ %Extrap _obs) % 0.63 0.45 72.0 Average time of stay (extrapolated to infinity; MRT) Inf _obs) h 0.93 0.19 20.2 Capacity Normalized AUC (AUC) up to the final point in time last / D) h*mg / mL 305 59 19.3 Observed steady-state volume of distribution (Vss_obs) L / kg 3.04 0.09 3.10 Observed volume of distribution (after extravascular administration; VZ_obs) L / kg 79.7 12.2 12.7 Oral bioavailability (F) PO % 1950 397 15.3 Maximum concentration (oral, 15 mg / kg) ng / mL 71.2 4.5 20.4 Intraperitoneal bioavailability (F) IP % 924 37 6.34 Maximum concentration (intraperitoneal, 5 mg / kg) ng / mL 55.7 11.0 3.95

[0377] Table 14 - Plasma pharmacokinetics of compound PURM200

[0378] Brain concentration and Kp after administration of an IP dose of 10 mpk PK parameters unit average brain Brain Kp T 1 / 2 h 1.01 T max h 0.250 C max ng / g 6920 7.49 AUC last h*ng / g 7696 7.07 AUC Inf h*ng / g 7718 7.06 AUC_ %Extrap_obs % 0.284 MRT Inf_obs h 0.885

[0379] Table 15 - Brain concentrations and Kp after administration of an IP dose of 10 mpk for Compound - PURM200

[0380] Brain permeability: From the above results, based on peak concentration, compound PURM100 (Kp Cmax = 4.46) and compound PURM200(Kp Cmax = 7.49) It can be seen that all of these effectively enter the brain immediately after administration (compounds PURM100 and - R , T max = 15 minutes).

[0381] Oral bioavailability: In addition, compound PURM100 (F = 70%) and compound PURM200 (F = 80%) both effectively enter the bloodstream upon oral administration.

[0382] Drug Exposure: The IV racemic mixture of compounds is rapidly cleared from the body (IV Cl_obs = 110 mL / min / Kg) and plasma concentration decreases by 50% after 52 minutes of administration. Compound PURM100 exhibits a clearance rate similar to that of the racemic mixture (IV Cl_obs = 71 mL / min / Kg) and plasma concentration decreases by 50% after 30 minutes of administration. Compound PURM200 has the slowest clearance rate (IV Cl_obs = 56 mL / min / Kg) and plasma concentration decreases by 50% after 58 minutes of administration. in vitro Liver clearance rate vs. in vivo Clearance rates suggest that mechanisms other than the liver contribute to the metabolism of these compounds.

[0383] Example 8

[0384] Human ether-a-go-go-related gene (hERG) analysis of racemic mixtures

[0385] The human ether-a-go-go-related gene (hERG) is a potassium channel that plays a key role in the electrical activity of the heart. in vitrohERG analysis is a key part of evaluating the potential of drugs to induce TdP (torsade de pointes) ventricular arrhythmias. The potential inhibitory effect of the racemic mixture of Compound IV on hERG channels was evaluated using a manual patch clamp system according to the protocol.

[0386] Cell lines and cell cultures

[0387] The HEK 293 cell line (Cat. K1236) stably expressing the hERG channel is used by Invitrogen TM Cells were purchased from. Cells were cultured in medium containing 85% DMEM, 10% dialyzed FBS, 0.1 mM non-essential amino acids (NEAA), 25 mM HEPES, 100 U / mL penicillin-streptomycin, 5 μg / mL blasticidin, and 400 μg / mL geneticin, and cells were cultured at 25 cm² under conditions of 5% CO2 and 37°C. 2 Grows in cell culture bottles. Cells are tested approximately 3 times a week with TrypLE TM Dispense using Express and maintain a density of approximately 40% to 80%. Prior to analysis, cells were induced with 1 μg / mL doxycycline for 48 hours. On the day of the experiment, the induced cells were resuspended and, prior to use, contained approximately 5 × 10⁶ cells per 3.5 cm cell culture dish. 5 Inoculate the cells onto a coverslip and culture in a medium free of blasticidin and geneticin. Note: The passage count of the cell line used for safety evaluation analysis is less than 60.

[0388] Solution preparation

[0389] chemical Supplier & Catalog Number MW / stock concentration Concentration (mM) NaCl Sigma S6191 58.44 132 KCl Sigma P5405 74.55 4 CaCl2 Sigma 21115 1 M 3 MgCl2 Sigma 63069 1 M 0.5 D-(+) glucose sigma G7528 180.16 11.1 HEPES Gibco 15630080 1 M 10

[0390] pH: Adjusted to 7.35 with NaOH.

[0391] Osmolality range: 285~295.

[0392] The above solution is filtered using a filter system and stored at 4°C before use.

[0393] Table 16 - Extracellular fluid

[0394] chemical Supplier & Catalog Number MW / stock concentration Concentration (mM) EGTA Sigma E3889 0.1M 10 HEPES Solarbio H8090 238.3 10 KCl Sigma P5405 74.55 10 NaCl Sigma S6191 58.44 10 KF Acros 201352500 58.09 110

[0395] pH: Adjusted to 7.2 with KOH

[0396] Osmolality range: 285~295

[0397] Use stock solution: 100mM EGTA adjusted to pH 8.2 with KOH

[0398] Note: Filter the above solution using a filter system and store at 4°C before use.

[0399] Table 17 - Intracellular fluid

[0400] Preparation of working solution for test compound

[0401] 1) The test compound was initially prepared as a stock solution in DMSO at a final concentration of 10 mM.

[0402] 2) Subsequently, the stock solution of each compound was serially diluted with DMSO in a ratio of 1:3 to further prepare three intermediate solutions containing 3.33, 1.11, and 0.37 mM, respectively.

[0403] 3) Prior to the experiment, the working solution was prepared by finally diluting the aforementioned intermediate solution 1000-fold using extracellular fluid, and accordingly, the final concentrations of the working solution were 30, 10, 3.33, 1.11, and 0.37 μM, and the 30 μM working solution was prepared by diluting a 10 mM DMSO stock 333.333-fold. The final DMSO concentration in the working solution was maintained in the range of 0.1-0.3% (v / v).

[0404] 4) IC 50 For determination, hERG current was tested in the presence of five capacities consisting of 30, 10, 3.33, 1.11, and 0.37 μM.

[0405] 5) Dofetilide was initially prepared as a stock solution in DMSO at a final concentration of 75 mM.

[0406] 6) Subsequently, the stock solution of dofetilide was serially diluted with DMSO to prepare five additional intermediate solutions containing 150, 50, 16.67, 5.56, and 1.85 μM, respectively.

[0407] 7) Prior to the experiment, the working solution was prepared by finally diluting the aforementioned intermediate solution 1000-fold using extracellular fluid, and accordingly, the final concentrations of the working solution were 150, 50, 16.67, 5.56, and 1.85 nM. The final DMSO concentration in the working solution was maintained in the range of 0.1% (v / v).

[0408] 8) IC 50 For determination, hERG current was tested in the presence of five capacities consisting of 150, 50, 16.67, 5.56, and 1.85 μM.

[0409] Experimental Procedure

[0410] 1) Remove the coverslip from the cell culture dish and place it on the microscope stage inside the bath chamber, and fill the glass electrode tip with intracellular fluid; then, the temperature controller (Warner Instruments TM , Use TC-324B) to raise the bath temperature of the bath chamber to 34°C.

[0411] 2) Locate the target cell using a ×10 objective lens. Locate the tip of the electrode under the microscope using the ×10 objective lens, focusing on the upper plane of the cell. Once the tip is in focus, advance the electrode downward toward the cell using the coarse control of the micromanipulator while simultaneously moving the objective lens to maintain the focus on the tip.

[0412] 3) When positioned directly above the cell, switch to a 40× objective lens and use the fine control of the micromanipulator to approach the cell surface in small steps.

[0413] 4) Gently apply suction through the side port of the electrode holder to form a giga-ohm seal.

[0414] 5) C fast Remove the capacitive current corresponding to the voltage step using [the device]. Obtain a full cell array by applying repeated, short, and strong suction until the membrane patch ruptures.

[0415] 6) At this point, set the membrane potential to -60 mV so that the hERG channel is not open. Subsequently, any spikes in capacitive current must be canceled out using the amplifier's Cslow.

[0416] 7) Set the holding potential to -90 mV for 500 ms; record the current at 20 kHz and filter at 10 kHz. The leakage current was tested at -80 mV for 500 ms.

[0417] 8) The hERG current was induced by depolarizing at +30 mV for 4.8 seconds, and then the voltage was returned to -50 mV for 5.2 seconds to remove the depolarization and observe the deactivation tail current. The maximum value of the tail current magnitude was used to determine the hERG current amplitude.

[0418] 9) To evaluate current stability, the current was recorded for 120 seconds. Drug administration was applied only to stable cells where the recording parameters exceeded the threshold.

[0419] 10) First, a vehicle control was applied to the cells to establish a baseline. The compound was applied once it was confirmed that the hERG current had stabilized for 5 minutes. The hERG current in the presence of the test compound was recorded for approximately 5 minutes to reach a steady state, and then 5 sweeps were obtained. For the dose-response test, 5 doses of the compound were applied to the cells cumulatively from low to high concentrations. Dofetilide at a concentration of 450 nM, a positive control, was also applied to each cell after hERG current measurements at the highest concentration of the test compound as an internal low-concentration control for normalizing the percentage of inhibition. To ensure the quality of cultured cells and the operation, the same batch of cells used for the compound was also used for testing the positive control dofetilide at the 5 administered concentrations.

[0420] Data analysis

[0421] Data acceptance criteria

[0422] The following criteria were used to determine data acceptability.

[0423] 1) Initial actual resistance > 1 GΩ;

[0424] 2) Leakage current is less than 50% of the contrast peak tail current at any point;

[0425] 3) The current amplitude of the normal test pulse current waveform (e.g., hERG peak tail) is greater than the prepulse current amplitude and the peak tail amplitude is >250 pA;

[0426] 4) Film resistance Rm > 500 MΩ;

[0427] 5) Access resistance (Ra) < 15 MΩ;

[0428] 6) Apparent run-down of peak current < 2.5% per minute.

[0429] Data that met the above criteria for hERG current quality were further analyzed according to the following steps.

[0430] 1) The current suppression percentage was calculated using the following formula. PatchMaster software was used to extract peak currents from the raw data.

[0431]

[0432] 2) The dose-response curve of the test compound was plotted as % inhibition rate against the concentration of the test compound using Graphpad Prism 8.0, and the data were fitted to a sigmoid dose-response curve with a variable slope.

[0433] Based on the above, the results are shown in the table below:

[0434] test compound hERG IC 50 [μM], tested at 34°C note Dofetilide 0.013 - Compound IV racemic mixture >30 29.86% inhibition at 30 μM

[0435] Table 18 - hERG Analysis Results

[0436] IC of dofetilide, the positive control 50 It is consistent with literature reports and shows excellent consistency across different experimental batches, suggesting that the current study was conducted under appropriate conditions and the results are reliable. IC50 when the percentage of hERG inhibition exceeds 50% in the presence of this compound at a dose concentration of 0.37 μM. 50 It is reported as <0.37 μM. IC 50 If the fitting result is greater than 30 μM or the maximum inhibition rate at 30 μM is less than 50%, IC 50 It was reported as > 30 μM. The generally acceptable ranking system used to determine the potency of test compounds inhibiting hERG channels is as follows: a) Low: IC 50 > 10 μM; b) Intermediate: 1 μM < IC 50 < 10 μM, or c) High: IC 50 < 1 μM. These results show that compound IV of the present invention exhibits a low hERG cardiovascular safety risk.

[0437] Example 9

[0438] Solubility analysis

[0439] The solubility of the compound PURM100 of the present invention was evaluated in 0.9% saline solution.

[0440] Research Procedure

[0441] Preparation of stock solution

[0442] Stock solutions of the test compound and control compound (progesterone and diclofenac) were prepared at a concentration of 10 mM in DMSO.

[0443] Solubility determination procedure

[0444] 15 μL of the stock solution (10 mM) of each sample was sequentially added to a 96-well rack. 485 μL of buffer was added to each vial of the lidless solubility sample plate. The analysis was performed in duplicate. One stirring stick was added to each vial, and it was sealed using a molded PTFE / silicone plug. The solubility sample plate was then transferred to an Eppendorf® Thermomixer® Comfort plate shaker and shaken at 1100 rpm for 2 hours at 25°C. After 2 hours, the plug was removed, the stirring stick was removed using a large magnet, and the sample from the solubility sample plate was transferred to a filter plate. All samples were filtered using a vacuum manifold. 5 μL of the filtrate and 5 μL of DMSO were taken, and 490 μL of a 1:1 mixture of H2O and methyl alcohol containing an internal standard was added to prepare a 100-fold diluted sample. Next, 20 μL of the 100-fold diluted sample was further diluted to a 1000-fold diluted sample by adding 180 μL of a mixture (1:1) of H2O and methyl alcohol containing an internal standard. A mixture (1:1) of H2O and methyl alcohol containing an internal standard was used in a fixed ratio to dilute the solution according to the peak shape. The dilution factor was changed according to the solubility value and the LC-MS signal response.

[0445] Preparation of 300 μM Standard (STD)

[0446] 6 μL was transferred from a 10 mM DMSO STD plate to an empty plate, and then 194 μL of DMSO was added to the plate to achieve an STD concentration of 300 μM. 5 μL of the 300 μM STD and 5 μL of buffer were aliquoted, and then 490 μL of a mixture (1:1) of H2O and acetonitrile containing an internal standard was added to create a 100-fold diluted STD concentration of 3 μM. Subsequently, 20 μL of the 100-fold diluted STD sample was further diluted by adding 180 μL of a mixture (1:1) of H2O and methyl alcohol containing an internal standard to create a 1000-fold diluted STD, so that the final STD concentration was 0.3 μM. A mixture (1:1) of H2O and methyl alcohol containing an internal standard was used in a specific ratio to dilute the solution according to the peak shape. The concentration of the standard sample was changed according to the LC-MS signal response.

[0447] Sample Analysis Procedure

[0448] The plate was placed in a well plate autosampler. The sample was evaluated by LC-MS / MS analysis.

[0449] Data analysis

[0450] All calculations were performed using Microsoft® Excel®.

[0451] The filtrate was analyzed, and quantification was performed against standards of known concentrations using LC combined with mass spectrum peak identification and quantification. The solubility values ​​of the test compound and control compound were calculated as follows:

[0452]

[0453] DF stands for dilution factor. The experiment was repeated after excluding values ​​of compounds that were not within the specified limits.

[0454] The results are presented in Table 19.

[0455] compound Solubility in 0.9% w / w saline solution (μM) Progesterone 12.99 diclofenac 295.53 Compound PURM100 315.92

[0456] Table 19 - Solubility data of test compounds and control compounds in 0.9% saline solution

[0457] The upper limit of this analysis was set to 300 μM. Values ​​approaching or exceeding 300 μM indicate that the compound may have a solubility of 300 μM or higher.

[0458] Example 10

[0459] Measurement of protein binding of compounds in human and mouse plasma using equilibrium dialysis

[0460] Research Procedure

[0461] Preparation of compound working solution

[0462] Working solutions of test compounds PURM100 and PURM200 and control compounds were prepared in DMSO at a concentration of 1 mM.

[0463] Preparation of pH 7.4 buffer solution

[0464] The basic solution was prepared by dissolving 14.2 g / L Na2HPO4 and 8.77 g / L NaCl in deionized water, and this solution could be stored at 4°C for up to 7 days. The acidic solution was prepared by dissolving 12.0 g / L NaH2PO4 and 8.77 g / L NaCl in deionized water, and this solution could be stored at 4°C for up to 7 days. The basic solution was titrated with the acidic solution to a pH of 7.4 and stored at 4°C for up to 7 days. The pH was checked on the day of the experiment and adjusted if it deviated from the specification of 7.4 ± 0.1.

[0465] Production of plasma

[0466] Set the water bath temperature to 37°C. Immediately thaw frozen plasma (stored at -80°C) in a 37°C water bath. Plasma samples were obtained from mixed male and female human plasma samples and mixed male and female CD-1 mice.

[0467] Manufacturing of work plates

[0468] Immerse the dialysis membrane in ultrapure water for 60 minutes to separate the strips, then immerse it in 20% ethanol for 20 minutes, and finally in dialysis buffer for 20 minutes. Mount the prepared membrane onto the dialysis unit and reinstall the unit according to the manufacturer's instructions. Turn on the air bath and allow it to preheat to 37°C. If the dialysis membrane is not used immediately, it can be stored at 4°C for a period not exceeding 4 weeks.

[0469] Preparation of control sample at 0 hours

[0470] Add 597 μL of blank plasma solution to each vial in a new plastic plate or a separate plastic tube, add 3 μL of the working solution of the test compound, and vortex at 1000 rpm for 2 minutes. The final volume percentage of the organic solvent is 0.5%, and the final concentration of the test compound is 5 μM. Immediately transfer 50 μL of the spiked plasma solution suspension to a 96-well plate to serve as the T=0 control sample. This sample is treated in the same way as the sample after incubation. Place all remaining spiked plasma solution in the incubator for the duration of the study.

[0471] Determination of the stability of a test compound in plasma solution

[0472] At the same time, the remaining spiked plasma solution sample in a plastic plate or a separate plastic tube is incubated in a CO2 incubator at 37°C for 6 hours under 5% CO2 conditions.

[0473] At T=6 hours, 50 μL of the original spiked plasma solution suspension is transferred to a 96-well plate for analysis.

[0474] Equilibrium Dialysis Procedure

[0475] Assemble the dialysis unit according to the manufacturer's instructions. Load 120 μL of plasma sample into the cell and dialyze against an equal volume of dialysis buffer (PBS). Perform the analysis in duplicate. Cover the unit with a gas-permeable lid and incubate on an orbital shaker in a CO2 incubator under 5% CO2 conditions at 37°C and 100 rpm for 6 hours. At the end of incubation, remove the lid and pipette 50 μL of the post-dialysis sample from both the buffer chamber and the plasma solution chamber into separate 96-well plates for analysis.

[0476] Sample preparation procedure

[0477] Add 50 μL of plasma solution to the buffer sample, and add an equal volume of PBS to the collected plasma solution sample. Shake the plate at 1000 rpm for 2 minutes, and add 400 μL of acetonitrile containing an appropriate internal standard (IS) to precipitate proteins and liberate compounds. Vortex at 1000 rpm for 10 minutes. Centrifuge at 3,220 g for 30 minutes. Then, transfer 100 μL of the supernatant to a new 96-well plate for analysis. Add 100 μL of distilled water to each sample and mix for analysis by LC-MS / MS.

[0478] Data analysis

[0479] All calculations are performed using Microsoft Excel. Determine the concentrations of the test compound and control compound in the buffer chamber and the plasma solution chamber. Calculate the binding percentage of the test compound(s) and control compound as follows:

[0480] % Non-bonding = (Area ratio 완충액 챔버 / Area ratio 혈장 용액 챔버 ) × 100

[0481] % combined = 100 - % uncombined

[0482] % recovery rate = (area ratio 완충액 챔버 + Area ratio혈장 용액 챔버 ) / (area ratio 총 시료 ) × 100

[0483] % Residual Rate = Area Ratio 6hr / Area ratio 0hr × 100

[0484] The results are presented in Table 20 below:

[0485] Compound ID bell % combined % non-combined % recovery rate % survival rate at 6 hours Ketoconazole human being 99.19 0.81 90.48 103.98 mouse 99.40 0.60 100.00 105.58 Compound PURM100 human being 5.76 94.24 97.30 100.50 mouse 10.56 89.44 88.28 81.62 Compound PURM200 human being -1.62 101.62 95.65 97.24 mouse 7.81 92.19 83.90 71.17

[0486] Table 20 - Protein binding results of test compounds PURM100 and PURM200 and control compound ketoconazole in human and mouse plasma

[0487] The above results show that the free fraction of the drugs is excellent, and therefore both compounds can interact with target receptors.

[0488] Example 11

[0489] Measurement of protein binding of compounds in mouse brain homogenates using equilibrium dialysis

[0490] Research Procedure

[0491] Preparation of pH 7.4 buffer solution

[0492] The basic solution was prepared by dissolving 14.2 g / L Na2HPO4 and 8.77 g / L NaCl in deionized water, and this solution could be stored at 4°C for up to 7 days. The acidic solution was prepared by dissolving 12.0 g / L Na2HPO4 and 8.77 g / L NaCl in deionized water, and this solution could be stored at 4°C for up to 7 days. The basic solution was titrated with the acidic solution to a pH of 7.4 and stored at 4°C for up to 7 days. The pH was checked on the day of the experiment and adjusted if it deviated from the specification of 7.4 ± 0.1.

[0493] Preparation of blank brain homogenate

[0494] Frozen mouse brain tissue was immediately thawed at room temperature. It was then weighed and homogenized with buffer at a ratio of 1:4 of brain weight (g) to buffer volume (mL). The mouse brain tissue was derived from male CD1 mice.

[0495] Preparation of working solution

[0496] Working solutions of the test compound and control compound were prepared in DMSO at a concentration of 200 μM.

[0497] Manufacturing of working plates

[0498] Immerse the dialysis membrane in ultrapure water for 60 minutes to separate the strips, then immerse it in 20% ethanol for 20 minutes, and finally in dialysis buffer for 20 minutes. Mount the prepared membrane onto the dialysis unit and reinstall the unit according to the manufacturer's instructions. Turn on the air bath and allow it to preheat to 37°C. If the dialysis membrane is not used immediately, it can be stored at 4°C for a period not exceeding 4 weeks.

[0499] Preparation of control sample at 0 hours

[0500] Add 597 μL of blank brain homogenate to each vial in a new plastic plate or a separate plastic tube, add 3 μL of working solution from each cassette, and vortex at 1000 rpm for 5 minutes. The final volume percentage of the organic solvent is 0.5%, and the final concentration of the test compound is 1 μM. Immediately transfer 50 μL of the spiked brain homogenate suspension to a 96-well plate to serve as a T=0 control sample. This sample is treated in the same way as the sample after incubation. Place all remaining spiked brain homogenate in the incubator for the duration of the study.

[0501] Determination of the stability of a test compound in brain homogenate

[0502] At the same time, the remaining spiked brain homogenate sample in a plastic plate or a separate plastic tube is incubated in a CO2 incubator at 37°C for 6 hours under 5% CO2 conditions. At T=6 hours, 50 μL of the original spiked brain homogenate is transferred to a 96-well plate for analysis.

[0503] Equilibrium Dialysis Procedure

[0504] Assemble the dialysis device according to the manufacturer's instructions. Load 120 μL of the brain homogenate sample into the cell and dialyze against an equal volume of dialysis buffer (PBS). Perform the analysis in duplicate. Seal the dialysis plate and place it in an incubator at 37°C and approximately 100 rpm under 5% CO2 conditions for 6 hours. At the end of dialysis, remove the seal and pipette 50 μL of each post-dialysis sample from both the buffer chamber and the brain homogenate chamber into separate tubes within the plate.

[0505] Sample preparation procedure

[0506] Add 50 μL of mouse brain homogenate to the buffer sample, and add an equal volume of PBS to the collected brain homogenate sample. Shake the plate at 1000 rpm for 2 minutes, and add 400 μL of acetonitrile containing an appropriate internal standard (IS) to precipitate proteins and liberate compounds. Vortex at 1000 rpm for 10 minutes. Centrifuge at 3.220 g for 30 minutes. Transfer 250 μL of the supernatant to a new 96-well plate and centrifuge again (3.220 g, 30 minutes). Then, transfer 100 μL of the supernatant to a new 96-well plate for analysis. Add 100 μL of distilled water to each sample and mix for analysis by LC-MS / MS. All compounds are tested in duplicate at 1 μM in the mouse brain homogenate.

[0507] Data analysis

[0508] All calculations are performed using Microsoft Excel.

[0509] The non-binding percentage, binding percentage, and recovery rate of the test compound are calculated as follows:

[0510] % non-combined 균질액 = (Area ratio 완충액 챔버 / Area ratio 균질액 챔버 ) × 100

[0511] % non-combined 뇌 = 1 / 5 / ((1 / (% non-joining 균질액 / 100)-1)+1 / 5) × 100

[0512] % combined 뇌 = 100 - % non-joining 뇌

[0513] % recovery rate = (area ratio 완충액 챔버 + Area ratio 균질액 챔버 ) / (area ratio 총 시료 ) × 100

[0514] % Residual Rate = Area Ratio 6hr / Area ratio 0hr × 100

[0515] The results are presented in Table 21 below:

[0516] Compound ID bell % combined 뇌 % non-combined 뇌 % recovery rate % survival rate at 6 hours Telmisartan mouse 98.36 1.64 110.03 107.51 Compound PURM100 mouse 27.20 72.80 56.45 59.07 Compound PURM200 mouse 57.26 42.74 46.93 56.41

[0517] Table 21 - Protein binding results of test compounds PURM100 and PURM200 and control compound telmisartan in mouse brain homogenates

[0518] The above results show that the free fraction of the drugs is excellent, and therefore both compounds can interact with target receptors.

[0519] Example 12

[0520] Analysis of non-hallucinogenic neuroplasticity-inducing substances

[0521] This experiment was conducted by de la Fuente Revenga, M. et al. Nature (2019) 9:14247 It was performed according to the method presented in

[0522] animal

[0523] Unless otherwise specified, experiments were performed on adult (10–20 weeks old) male C57BL / 6 mice (Taconic). Animals were provided with food and water, except during behavioral tests. Freely (ad libitum) They were housed in cages with up to 5 littermates at 23°C with a 12-hour light / dark cycle while being fed.

[0524] 5-HT 2A R Knockout (5-HT 2A Experiments using -KO) mice were performed on adult (10–20 weeks old) male 129S6 / SvEv mice. In these experiments, 5-HT 2A -KO and the control group are each heterozygotes ( Htr2a + / -) born from breeding individuals Htr2a - / - and Htr2a+ / + Represents an object.

[0525] Surgical implantation of magnets was adapted from a previously reported protocol (Hanks, JB & Gonzalez-Maeso). Mice were anesthetized using ketamine and xylazine (120 mg / kg and 12 mg / kg, respectively). A circular incision was made to remove a portion of the scalp. The membranous tissue inside and around the site was repeatedly washed with H2O2 and dried until the bone surface was exposed. Dental cement was applied to the exposed site to attach small neodymium magnets (6.0, 6.0, 1.5 mm, 490 mg) with their south poles facing the bone surface. The implants were kept exposed with the dental cement bordering the skin. Mice were allowed to recover for one or two weeks. The animals were subjected to repeated treatment with a holiday period of at least one week between studies.

[0526] Isoflurane anesthesia was rapidly induced with an initial dose of 2% (vol / vol). Once the anesthetic effect became pronounced, the DOI (1 mg / kg, intraperitoneal) was rapidly administered to the animal, and it was placed on a heating pad inside the isoflurane chamber. The dose of isoflurane was maintained at 1.5% for the next 30 minutes. The animal was monitored regularly.

[0527] drugs

[0528] (±)-2,5-dimethoxy-4-iodoamphetamine hydrochloride (DOI), compound PURM100 and compound PURM200. All drugs were dissolved in saline (0.9% NaCl) at appropriate volumes (0.005–0.01 ml per g body weight) and concentrations for administration (intraperitoneal). Vehicle treatment conditions represent an injection of saline (intraperitoneal) of a volume equivalent to the administered drug.

[0529] ingredient

[0530] Data acquisition was performed on a non-overlapping enamel-coated wire (30 AWG) coil with approximately 500 turns supported within a closed plastic container (internal dimensions, diameter 11 cm × height 14 cm), and the two terminals of each coil were connected to a phono preamplifier (Pyle PP444). The amplified signal output was recorded at a sampling rate of 1000 Hz using the myDAQ (National Instruments) data acquisition system controlled via MATLAB (Mathworks, version R2018a, with the NI myDAQ support package). The analog input range for each channel was ±10 V, and the ADC (analog-to-digital converter) was 16 bits. The amplified signal amplitude rarely exceeded the ±2.5 V range, which eliminated the risk of signal clipping. In total, we were able to perform simultaneous recording of four coils per session using two data acquisition systems (two coils per myDAQ unit), but this number could be expanded by using additional data acquisition systems or systems with more analog input channels. Visual identification of HTRs was performed on clips recorded at 60 FPS and 1080p resolution as previously described. To visually identify HTRs as signals on the data recorded by the magnetometer, the raw data was processed in the MATLAB suite. The recordings were bandpassed through a digital Butterworth filter from 40 to 200 Hz as previously described in Halberstadt, AL & Geyer, MA, and the filtered data was plotted in parallel with a spectrogram heatmap. HTRs were identified in the following cases: i) when the amplitude of the voltage signal exceeded the background noise level, and ii) when the peak maximum in the 70–110 Hz range on the spectrogram heatmap corresponded in time to a value often accompanied by an equivalent or larger harmonic from 40–60 Hz.

[0531] Automatic detection of HTR events relied on a script based on individual event detection between 70 and 110 Hz. Recorded data was bandpassed through a digital Butterworth filter between 70 and 110 Hz and converted to absolute values. After dual local maximum processing, each original wavelet was converted into a unipolar peak, which is identified as an HTR event if (i) the peak prominence exceeds 0.075 V, (ii) it is separated from any other event by at least 200 ms, and (iii) it has a width of less than 90 ms at half the prominence maximum.

[0532] Experiments involving the recording of piezoelectric sensor outputs were conducted using a paper tube (height 46 cm) with an open top surrounding a coil to allow the animal to jump vertically without escaping the container. Simultaneous recording of the coil and piezoelectric sensor signals was performed by connecting the amplified output of the coil to one analog input channel of the data acquisition system (as described above) and directly connecting the output of the piezoelectric sensor (ceramic diaphragm, 27 mm brass disc), which was secured with tape to the bottom of the plastic container, to another available analog input channel. The recorded data from the piezoelectric sensor was converted to absolute values ​​before baseline correction and maximum analysis in the MATLAB environment. Timestamps for maximum values ​​exceeding an absolute voltage of 0.3 V were annotated using the peak selection function. The 0.3 V threshold value was determined experimentally as described above and corresponded to approximately 8 standard deviations of the piezoelectric sensor signal from mice injected with 1 mg / kg DOI.

[0533] The matching analysis between HTR detection and the annotated piezoelectric sensor maximum value timestamp was automated. If the timestamp of the HTR detection system fell within a range defined as ±0.1 seconds of the piezoelectric sensor maximum value timestamp, the two events were considered matched.

[0534] The analytical standards (±)-2,5-dimethoxy-4-iodoamphetamine and 2,5-dimethoxy-4-bromophenethylamine were purchased from Cerilliant Corporation (Round Rock, TX). Acetonitrile, ammonium acetate, ethyl acetate, formic acid, hexane, methanol, sodium hydroxide, and water were purchased from Fisher Scientific (Hanover Park, IL, USA). All reagents were ACS grade or higher.

[0535] Statistical analysis

[0536] Statistical analysis is GraphPad TM Prism TM The study was performed using software version 8. Animals were randomly assigned to different experimental groups. Experiments combining DOI, PURM100, and PURM200 were conducted by crossing over the groups with a one-week interval between trials. Statistical significance for experiments involving different treatment groups was evaluated using a one-way Bonferroni post-hoc test, while for experiments involving two or more variables and treatment groups, it was evaluated using a two-way ANOVA followed by a Bonferroni post-hoc test. Statistical significance for experiments involving two treatment groups was evaluated using Student's t-test. The significance level was selected as P<0.05. All data are presented as mean ± standard error of the mean (SEM). The correlation between visual identification of HTR versus automated detection, and the correlation between visual analysis of signals versus automated detection by HTR, were evaluated by linear regression. The correlation between DOI levels and HTR in whole blood and whole brain was evaluated using the Pearson correlation coefficient.

[0537] Now refer to Figures 6 and 7. The results show that when the racemic mixture is administered to mice at doses of 0.1 mg / kg to 10 mg / kg, it causes a minimal head-shaking response (a surrogate indicator of the hallucinogenic response) (Figure 6), and does not cause changes in motor activity in mice administered at doses of 0.1 mg / kg to 3 mg / kg (Figure 7).

[0538] Example 13

[0539] Compounds PURM100 and PURM200 induce positive structural changes in cultured neurons.

[0540] method

[0541] Previously generated adherent neural stem cell lines (NSCs) from mouse fetuses In vitro It was used as an experimental model. These cells are proliferative and readily differentiate into neurons and glial cells when grown under appropriate cell culture conditions. The original NSC line contains 5-HT within its genome. 2A The cells were genetically engineered to possess shRNA sequences for the gene encoding the receptor. The expression of this shRNA is regulated by a promoter controlled by the presence of IPTG in the cell culture medium. Experiments were performed under both conditions, that is, with cells treated with IPTG or untreated throughout the process.

[0542] Five days after differentiation, when the neurons had acquired their phenotype, the cells were subjected to drug treatment as follows:

[0543] - Vehicle: H2O or DMSO

[0544] - BDNF [50 ng / ml]

[0545] - Silocine 10 μM

[0546] - Compound PURM100 10 μM

[0547] - Compound PURM200 10 μM

[0548] BDNF, compound PURM100 and compound PURM200 were dissolved in H2O, and silocine was dissolved in DMSO.

[0549] Phase-contrast microscopy images were taken 48 hours after treatment using a 40x objective lens. Dendritic arborization of the neurons was evaluated via Image Sholl analysis. The Sholl analysis tool included in ImageJ software was used to estimate dendritic complexity. This analysis involves establishing concentric circles from the center of the neuron cell body and quantifying the number of intersections formed by these circles with various dendrites extending from the neuron soma. The obtained data can be graphed to represent the number of intersections versus the distance from the neuron center. The Area Under the Curve (AUC) obtained from this graph was considered to compare and average the results of different experiments. The experiment was performed independently three times, analyzing 20 individual neurons per experimental condition.

[0550] result

[0551] Figures 8 and 9 show representative graphs representing the Sholl analysis from one of three independent experiments performed on cells grown in the absence (Figure 8) or presence (Figure 9) of IPTG in the culture medium. The Sholl analysis revealed that neurons treated with these compounds showed an increase in the number of dendritic crossings compared to vehicle-treated neurons. PSI represents psilocyne.

[0552] Figures 10 and 11 are bar graphs showing the mean ± SEM of the AUC from three independent experiments (n = 3) corresponding to the condition without IPTG (Figure 10) or the condition with IPTG (Figure 11). Statistical analysis of the results in Figure 10 by one-way ANOVA yielded significant results, indicating an effect on neuronal dendritic branching dependent on drug treatment. Bonferroni post-hoc analysis to compare these data between different treatment groups revealed significant differences between all drugs and their corresponding vehicles. No difference was found between the effects of compound PURM100 and compound PURM200 and psilocin.

[0553] Fig. 11 is 5-HT 2A This shows the results of the same experiment performed under conditions containing IPTG in the cell culture medium, where receptor expression is silenced. Statistical analysis indicates a significant effect of drug treatment on dendritic formation generated solely by BDNF treatment, which corresponds to the effects observed with compounds PURM100 and PURM200, as well as 5-HT 2A It suggests that receptors are involved.

[0554] Figure 12 shows data from the results presented in Figures 10 and 11, normalized to a multiple relative to baseline for the corresponding vehicle (control group) for comparison. A two-way ANOVA was performed considering drug treatment and the presence of IPTG in the culture medium as variables. Statistical analysis was performed on two variables—drug treatment and 5-HT 2A It indicates a significant effect of receptor expression—and the interaction between them. This suggests that the drug's effect on dendrite formation is 5-HT 2A It means that receptor expression is required.

[0555] Figure 13 shows images of cells treated with a racemic mixture of water (control) and compound IV, where 48 hours of treatment with compound IV causes an increase in the number of dendritic branches compared to the control treatment.

[0556] conclusion

[0557] Treatment of neuronal and glial-differentiated neural progenitor cells with compounds PURM100 and PURM200 induces a significant increase in dendritic formation in neurons to a degree similar to that of concurrent psilocyne treatment. 5-HT 2A In an equivalent analysis performed on cells grown in the presence of IPTG to silence receptor expression, these drugs showed no effect on dendrite formation, in contrast to BDNF included in the experiment as a positive control. In conclusion, 48 hours of treatment with compounds PURM100 and PURM200 promotes neuroplasticity, assessed as an increase in dendritic branching, and this effect is attributed to 5-HT 2A It depends on receptor expression.

[0558] Example 14

[0559] Compounds PURM100 and PURM200 immediately increase early gene expression

[0560] method

[0561] The cell line was the same as that used in the neuroplasticity experiment of Example 11, and the treatment was performed in parallel with the same drugs at the same concentrations. In this case, 5 days after differentiation, cells were treated with different drugs and vehicles for 45 minutes at 37°C and 5% CO2 conditions. After incubation, the cells were scraped and collected in a 1.5 mL centrifuge tube.

[0562] RNA extraction was performed by centrifuging the sample at 800g for 5 minutes at 4°C. The supernatant was discarded, and the cells were resuspended in 400 μL of RNA-Solv reagent (Omega Bio-Tek®). The sample was incubated at room temperature for 5 minutes, and 80 μL of chloroform was added. The sample was electro-mixed and allowed to stand at room temperature for 5 minutes, followed by centrifugation at 12,000g for 15 minutes at 4°C. The aqueous phase of the supernatant was collected and transferred to a new centrifuge tube, to which an equal volume of isopropanol was added. The sample was electro-mixed once again and allowed to stand at room temperature for 10 minutes. The sample was centrifuged one more time at 12,000g for 10 minutes at 4°C, and this time the supernatant was discarded. The pellet was resuspended in 1000 μL of refrigerated 100% ethanol, and the sample was centrifuged at 7600g for 10 minutes at room temperature. The supernatant was discarded, and the pellet was allowed to dry for 10 minutes before being resuspended in 10 μL of DEPC water (diethyl pyrocarbonate in water 1:1000). After 20 minutes at room temperature, RNA concentration was measured using a Nanodrop.

[0563] cDNA synthesis is Takara®'s PrimeScript TM The procedure was performed using RT Master Mix. For each sample, 500 ng of RNA, enough water to reach a final volume of 8 μL, and Takara's PrimeScript TM 2 μL of RT Master Mix was added to a 1.5 mL centrifuge tube. The sample was incubated at 37°C for 15 minutes, and the reaction was stopped using a 5-second cycle at 85°C. cDNA was measured using a Nanodrop, and the sample was then diluted with water to a final concentration of 100 ng / μL.

[0564] qPCR is BIO-RAD®'s transparent 96-well Multiplate® PCR Plates TMThe procedure was performed in [location]. The expression of c-fos, egr-1, and egr-2 was tested for each biological repeat. The expression of each gene was measured using the median cq value of four descriptive repeats. Gene expression in each biological sample was normalized to the housekeeping gene GAPDH. Each qPCR plate was loaded with 16 wells of cDNA for each treatment, resulting in a total of 96 wells. Each condition was tested for our three genes of interest and the housekeeping gene (4 wells per gene). To each well, 4 μL of cDNA and 6 μL of master mix containing iTaq Universal SYBR® Green Supermix (5 μL per well), forward primers (0.5 μL per well), and reverse primers (0.5 μL per well) were added.

[0565] Now, refer to Figures 14 through 16. The results show an increase in c-fos expression in neurons treated with compounds PURM100 and PURM200 in the presence or absence of IPTG (Figure 14). C-fos is a functional marker of neuronal activity and the initiation of the protein transcription cascade. Cells treated with compounds PURM200 and IPTG show increased expression of erg-1 and erg-2, which indicates that compound PURM200 is 5-HT 2A This suggests that neurons can be activated in the absence of signal transmission (Figs. 15 and 16).

[0566] Although preferred embodiments have been described above and illustrated in the accompanying drawings, it will be apparent to those skilled in the art that modifications may be made without departing from the present disclosure. Such modifications are considered possible modifications included within the scope of the present disclosure.

[0567] References

[0568] 1: Roche et al. A Virtual Screening Method for Prediction of the hERG Potassium Channel Liability of Compound Libraries. (2002) ChemBioChem. 3, 455-459.

[0569] 2: Glenn E. Kirsch et al. Variability in the measurement of hERG potassium channel inhibition: effects of temperature and stimulus patter. (2004) Journal of Pharmacological and Toxicological Methods 50, 93-101.

[0570] 3: Roger Marrannes et al. Computer programs to facilitate the estimation of time-dependent drug effects on ion channels. (2004) Computer Methods and Programs in Biomedicine 74, 167-181.

[0571] 4: Hanks, J. B. & Gonzalez-Maeso, J. Animal models of serotonergic psychedelics. ACS Chem. Neurosci. 4 , 33-42 (2013).

[0572] 5: Halberstadt, A. L. & Geyer, M. A. Characterization of the head-twitch response induced by hallucinogens in mice. Psychopharmacology (Berl). 227 , 727-739 (2013).

Claims

Claim 1 Compound of structural formula I, or a pharmaceutically acceptable salt thereof, and a stereoisomer thereof: I Here: R 1 is OH, and R 1 In the case of this OH, R 2 is different from OH and (i) Selected from the group consisting of H, halogen, lower alkyl, CHF2, CF3, NC, OCH3, OCHF2, OCF3, SCHF2, SCH3, SCF3, and cyano; or (ii) a It forms a ring composed of three or four atoms together with, wherein one of the atoms is selected from the group consisting of C, N, O, and S and the remainder is carbon, the chain contains zero, one, or two double bonds, and the chain is bonded to a substituent independently selected from the group consisting of H, halogen, OH, C1-C6 alkoxy, C1-C6 alkyl, C3-C6 cycloalkyl, CHF2, CF3, OCHF2, OCF3, SCH3, SCHF2, SCF3, cyano, and oxo; R 2 is OH, and R 2 If α is OH, R 1 It is different from OH. (i) Selected from the group consisting of H, halogen, lower alkyl, CHF2, CF3, OCH3, OCHF2, OCF3, SCHF2, SCH3, SCF3, and cyano; or (ii) b or c It forms a ring composed of 6 to 8 atoms together with, wherein one of the atoms is selected from the group consisting of C, N, O, and S and the remainder is carbon, the chain contains one or two double bonds, and the chain is bonded to a substituent independently selected from the group consisting of H, halogen, OH, C1-C6 alkoxy, C1-C6 alkyl, C3-C6 cycloalkyl, CHF2, CF3, OCHF2, OCF3, SCH3, SCHF2, SCF3, cyano, and oxo; R 3 silver ( i ) C1-C6 alkyl, C1-C6 substituted alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, (C3-C6 cycloalkyl)(C1-C6 alkyl), C3-C6 heterocyclyl, (C3-C6 heterocyclyl)(C1-C6 alkyl), aryl, aryl(C1-C6 alkyl), heteroaryl, heteroaryl(C1-C6 alkyl), CN, C(O)NH2, C(O)NH(C1-C6 alkyl), C(O)N(C1-C3 alkyl)(C1-C6 alkyl), C(=NOH)(C1-C6 alkyl), and C(=NOH)(C1-C6 substituted alkyl), C(O)NH(aryl), C(O)N(alkyl)(aryl), NC, S(O)2NH2, Selected from the group consisting of S(O)2NH(C1-C6 alkyl) and S(O)2NH(aryl); or ( ii ) R 4 Forming a chain composed of 2 to 4 carbon atoms together with, wherein a substituent independently selected from the group consisting of H, C1-C6 alkyl, aryl, and heteroaryl is bonded to the chain; or ( iii ) a ...to form a ring composed of three or four atoms, wherein one of the atoms is selected from the group consisting of C, N, O, and S and the remainder is carbon, the chain contains zero, one, or two double bonds, and the chain is bonded to a substituent independently selected from the group consisting of H, halogen, OH, C1-C6 alkoxy, C1-C6 alkyl, C3-C6 cycloalkyl, CHF2, CF3, OCHF2, OCF3, SCH3, SCF3, cyano, and oxo; or ( iv ) b If valogen, CH3, CHF2, CF3, OCH3, OCHF2, OCF3, SCH3, SCHF2, SCF3 or cyano, H, C1-C6 alkyl, C1-C6 substituted alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, (C3-C6 cycloalkyl)(C1-C6 alkyl), C3-C6 heterocyclyl, (C3-C6 heterocyclyl)(C1-C6 alkyl), aryl, aryl(C1-C6 alkyl), heteroaryl, heteroaryl(C1-C6 alkyl), CN, C(O)NH2, C(O)NH(C1-C6 alkyl), C(O)N(C1-C3 alkyl)(C1-C6 alkyl), C(=NOH)(C1-C6 alkyl), and Selected from the group consisting of C(=NOH)(C1-C6 substituted alkyl), optionally, R 3 silver a with CH2CH2, CH2CH2CH2, CH2CH2CH2CH2, CH=CHCH=CH, OCH2CH2, CH2OCH2, CH2CH2O, OCH=CH, CH=CHO, OCH2O, SCH2CH2, CH2SCH2, CH2CH2S, SCH=CH, CH=CHS, NHCH2CH2, CH2NHCH2, CH2CH2NH, NHCH=CH, CH=CHNH, ON=CH, CH=NO, OCH=N, N=CHO, SN=CH, CH=NS, SCH=N, N=CHS, NHN=CH, CH=NNH, NHCH=N, N=CHNH, NHN=N, N=NNH, OCH2CH2CH2, CH2OCH2CH2, CH2CH2OCH2, CH2CH2CH2O, SCH2CH2CH2, CH2SCH2CH2, Forming any one of CH2CH2SCH2, CH2CH2CH2S, NHCH2CH2CH2, CH2NHCH2CH2, CH2CH2NCH2, CH2CH2CH2NH, N=CHCH=CH, CH=NCH=CH, CH=CHN=CH, CH=CHCH=N; and optionally, when present on the moiety, one or two hydrogen atoms are substituted with a substituent independently selected from the group consisting of halogen, OH, C1-C6 alkoxy, C1-C6 alkyl, C3-C6 cycloalkyl, CHF2, CF3, OCHF2, OCF3, SCH3, SCF3, and cyano, or when bonded to the same carbon atom, two hydrogens are substituted with an oxo group; R 4 Is (i) Selected from the group consisting of H, C1-C6 alkyl, C1-C6 substituted alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, (C3-C6 cycloalkyl)(C1-C6 alkyl), C3-C6 heterocyclyl, (C3-C6 heterocyclyl)(C1-C6 alkyl), aryl(C1-C6 alkyl), arylsulfonyl, heteroarylsulfonyl, aryl(C1-C6 alkyl)sulfonyl, (C1-C6)alkylsulfonyl, and heteroaryl(C1-C6 alkyl)sulfonyl; or (ii) R 3 A chain consisting of 2 to 4 carbon atoms is formed together with, wherein a substituent independently selected from the group consisting of H, C1-C6 alkyl, aryl, heteroaryl, and any combination thereof is bonded to the chain; R 5 is an H, D, C1-C6 alkyl, C1-C6 substituted alkyl; R 6 silver: (i) Selected from the group consisting of H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, (C3-C6 cycloalkyl)(C1-C6 alkyl), aryl (C1-C6 alkyl), acetyl and heteroaryl (C1-C6 alkyl); or (ii) R 7 and together with the N atoms to which they are bonded, form a 4 to 7-membered heterocyclil ring; or (iii) e and R 6 Forming an azetidine or pyrrolidine ring with the bonded N atom, said ring having a substituent independently selected from the group consisting of H, aryl, heteroaryl, C1-C6 alkyl, and C3-C6 cycloalkyl; or (iv) b and R 6 Forming an azetidine or pyrrolidine ring together with the bonded N atom, said ring has a substituent independently selected from the group consisting of H, aryl, heteroaryl, halogen, C1-C6 alkyl, and C3-C6 cycloalkyl; R 7 silver: (i) Selected from the group consisting of H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, (C3-C6 cycloalkyl)(C1-C6 alkyl), aryl (C1-C6 alkyl), acetyl and heteroaryl (C1-C6 alkyl); or (ii) R 6 and together with the N atoms to which they are bonded, form a 4 to 7-membered heterocyclil ring; a Is: (i) Selected from the group consisting of H, halogen, CH3, CHF2, CF3, OCH3, OCHF2, OCF3, SCH3, SCHF2, SCF3, NC, and cyano; or (ii) A ring composed of three or four atoms is formed together with a, wherein one of the atoms is selected from the group consisting of C, N, O, and S and the remainder is carbon, the chain contains zero, one, or two double bonds, and the chain is bonded to a substituent independently selected from the group consisting of H, halogen, OH, C1-C6 alkoxy, C1-C6 alkyl, C3-C6 cycloalkyl, CHF2, CF3, OCHF2, OCF3, SCH3, SCHF2, SCF3, cyano, and oxo; or (iii) R 3 It forms a ring composed of three or four atoms together with, wherein one of the atoms is selected from the group consisting of C, N, O, and S and the remainder is carbon, the chain contains zero, one, or two double bonds, and the chain is bonded with a substituent independently selected from the group consisting of H, halogen, OH, C1-C6 alkoxy, C1-C6 alkyl, C3-C6 cycloalkyl, CHF2, CF3, OCHF2, OCF3, SCH3, SCHF2, SCF3, cyano, and oxo; and b , c , d and e are each independently H or; or b , c , d and e Three of them are H and the remaining substituents are lower alkyl groups; or b and e are H respectively, and c and d is together -CH2- or -CH2CH2-, thereby forming a cyclopropane or cyclobutane ring; or b , c and d are H respectively, and e , R 6 and R 6 The bonded N atoms together form an azetidine or pyrrolidine ring, said ring having a substituent independently selected from the group consisting of H, aryl, heteroaryl, C1-C6 alkyl, and C3-C6 cycloalkyl; or c , d and e are H respectively, and b , R 6 and R 6 A compound in which the bonded N atoms together form an azetidine or pyrrolidine ring, said ring having a substituent independently selected from the group consisting of H, aryl, heteroaryl, halogen, C1-C6 alkyl, and C3-C6 cycloalkyl. Claim 2 In paragraph 1, a A compound that is a halogen. Claim 3 In paragraph 2, a A compound in which F is the genus. Claim 4 In paragraph 1, a A compound in which α is CF3. Claim 5 In paragraph 1, a A compound in which is H. Claim 6 In paragraph 1 or 5, the above R 1 This is OH and R 2 A compound in which is H. Claim 7 In paragraph 1 or 5, the above R 1 This is H and R 2 A compound in which OH is Claim 8 In any one of Paragraph 1 and Paragraphs 5 through 7, R 4 A compound in which is H. Claim 9 In any one of Paragraph 1 and Paragraphs 5 through 8, R 5 A compound in which is H. Claim 10 In any one of Paragraph 1 and Paragraphs 5 through 9, b , c , d and e Compounds, each being H. Claim 11 In claim 1, the compound is a compound of formula II: II Here R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , a , b , c , d and e Each is as defined in Paragraph 1. Claim 12 In claim 1, the compound is a compound of chemical formula III: III Here R 1 , R 3 , R 4 , R 5 , R 6 , R 7 , a , b , c , d and e Each is as defined in Paragraph 1. Claim 13 In claim 1, the compound is a compound of structural formula VI, or a pharmaceutically acceptable salt thereof, and a stereoisomer thereof: VI Here:R 1 is OH, and R 1 In the case of this OH, R 2 is different from OH and is selected from the group consisting of H, halogen, lower alkyl, CHF2, CF3, NC, OCH3, OCHF2, OCF3, SCHF2, SCH3, SCF3, and cyano; R 2 is OH, and R 2 If α is OH, R 1 is different from OH and is selected from the group consisting of H, halogen, lower alkyl, CHF2, CF3, OCH3, OCHF2, OCF3, SCHF2, SCH3, SCF3, and cyano; R 3 C1-C6 alkyl, C1-C6 substituted alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, (C3-C6 cycloalkyl)(C1-C6 alkyl), C3-C6 heterocyclyl, (C3-C6 heterocyclyl)(C1-C6 alkyl), aryl, aryl(C1-C6 alkyl), heteroaryl, heteroaryl(C1-C6 alkyl), CN, C(O)NH2, C(O)NH(C1-C6 alkyl), C(O)N(C1-C3 alkyl)(C1-C6 alkyl), C(=NOH)(C1-C6 alkyl), and C(=NOH)(C1-C6 substituted alkyl), C(O)NH(aryl), C(O)N(alkyl)(aryl), NC, S(O)2NH2, Selected from the group consisting of S(O)2NH(C1-C6 alkyl) and S(O)2NH(aryl); R 4 is selected from the group consisting of H, C1-C6 alkyl, C1-C6 substituted alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, (C3-C6 cycloalkyl)(C1-C6 alkyl), C3-C6 heterocyclyl, (C3-C6 heterocyclyl)(C1-C6 alkyl), aryl(C1-C6 alkyl), arylsulfonyl, heteroarylsulfonyl, aryl(C1-C6 alkyl)sulfonyl, (C1-C6)alkylsulfonyl, and heteroaryl(C1-C6 alkyl)sulfonyl; R 5 is an H, D, C1-C6 alkyl, C1-C6 substituted alkyl; R 6 Silver is selected from the group consisting of H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, (C3-C6 cycloalkyl)(C1-C6 alkyl), aryl (C1-C6 alkyl), acetyl, and heteroaryl (C1-C6 alkyl); R 7 Silver is selected from the group consisting of H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, (C3-C6 cycloalkyl)(C1-C6 alkyl), aryl (C1-C6 alkyl), acetyl, and heteroaryl (C1-C6 alkyl); a is: selected from the group consisting of H, halogen, CH3, CHF2, CF3, OCH3, OCHF2, OCF3, SCH3, SCHF2, SCF3, NC, and cyano; and b , c , d and e are each independently H or; or b , c , d and e A compound in which three of the groups are H and the remaining substituents are lower alkyl groups. Claim 14 In any one of paragraphs 1 through 13, R 6 and R 7 Compounds, each having CH3. Claim 15 In claim 1, the compound is a compound of formula IV: IV. Claim 16 In item 15, the compound of the above chemical formula IV is chemical formula IV- S Compound: IV-S. Claim 17 In item 15, the compound of the above chemical formula IV is chemical formula IV- R Compound: IV-R. Claim 18 In item 15, the compound of the above chemical formula IV is chemical formula IV- S Compounds of and chemical formula IV- R Compound: a racemic chain of the compound and IV-S IV-R. Claim 19 In claim 1, the compound is a compound of formula V: V. Claim 20 A pharmaceutical composition comprising a compound of any one of claims 1 to 19 and a pharmaceutically acceptable carrier. Claim 21 A compound of any one of claims 1 to 19 or a pharmaceutical composition of claim 20 for use in the treatment of a disorder in a patient requiring this. Claim 22 A method for treating a disorder comprising administering an effective amount of a compound of any one of claims 1 to 19 or a pharmaceutical composition of claim 20 to a patient. Claim 23 The use of a compound of any one of claims 1 to 19 or a pharmaceutical composition of claim 20 for the treatment of a disorder in a patient requiring this. Claim 24 A compound, method, or use according to claim 21, a method according to claim 22, or a use according to claim 23, wherein the disorder is one or more of major depressive disorder, drug-resistant depression and psychotic depression, addiction including alcoholism, tobacco addiction, cocaine addiction and opioid addiction, pain indications including neuropathic pain, pain due to chemotherapy-related neuropathy, phantom limb pain and fibromyalgia, inflammation (including chronic and acute), eating disorders including anorexia, autism, cluster headache, migraine, dementia including Alzheimer's dementia, Parkinson's disease dementia and Lewy body dementia, mild cognitive impairment, post-traumatic stress disorder, emotional distress related to cancer, fragile X syndrome, autism spectrum disorder, bipolar disorder, obsessive-compulsive disorder and Rett syndrome. Claim 25 A compound for use of claim 21, a method of claim 22, or a use of claim 23, wherein the disorder is one or more of major depressive disorder, drug-resistant depression, and psychotic depression. Claim 26 As a combination drug therapy, a compound according to any one of claims 1 to 19, or a pharmaceutical composition of claim 20; and N -methyl- D - Combination drug therapy including aspartate (NMDA) receptor antagonists. Claim 27 In claim 26, a combination drug therapy wherein the NMDA receptor antagonist is at least one of ketamine, nitrous oxide, memantine, amantadine, noribogain, dextromethorphan, dextrophorphan and dextromethadone, or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof. Claim 28 In paragraph 27, a combination drug therapy in which the NMDA receptor antagonist is dextromethorphan. Claim 29 A combination drug therapy according to any one of paragraphs 26 to 28 for use in the treatment of a disorder in patients requiring this. Claim 30 A method for treating a disorder comprising administering an effective amount of a combination drug therapy according to any one of claims 26 to 28 to a patient. Claim 31 Use of any one of paragraphs 26 to 28 of the combination drug therapy for the treatment of a disorder in patients requiring this. Claim 32 A combination drug therapy, method, or use for the use of claim 29, the method of claim 30, or the use of claim 31, wherein the disorder is one or more of major depressive disorder, drug-resistant depression and psychotic depression, addiction including alcoholism, tobacco addiction, cocaine addiction and opioid addiction, pain indications including neuropathic pain, pain due to chemotherapy-related neuropathy, phantom limb pain and fibromyalgia, inflammation (including chronic and acute), eating disorders including anorexia, autism, cluster headache, migraine, dementia including Alzheimer's dementia, Parkinson's disease dementia and Lewy body dementia, mild cognitive impairment, post-traumatic stress disorder, emotional distress related to cancer, fragile X syndrome, autism spectrum disorder, bipolar disorder, obsessive-compulsive disorder and Rett syndrome. Claim 33 A combination drug therapy for use of claim 29, a method of claim 30, or a use of claim 31, wherein the disorder is one or more of major depressive disorder, drug-resistant depression, and psychotic depression.

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