Phenethylamine and its preparation method

Abstract

This disclosure relates to 5-HT 2A It exhibits receptor agonist activity and inhibits 5-HT 2B Low receptor agonist activity or 5-HT 2B The present invention relates to compounds represented by formula I, which are considered to be inactive 5-HT receptor agonists. 2C 5-HT receptors 2A As contemplated herein, phenethylamines may be used for the treatment of neuropsychiatric, neurodegenerative, neuroinflammatory and pain disorders, including depression, drug (e.g., tobacco, opiate and cocaine) addiction, alcoholism, post-traumatic stress disorder (PTSD) and neuropathic pain syndromes, including cluster headache and chemotherapy-induced peripheral neuropathy. [Formula 1] TIFF2025503579000028.tif57161

Description

[Technical field]

[0001]

[0001] This disclosure relates to phenethylamines and methods for their preparation. This disclosure also relates to the use of phenethylamines as selective agents at serotonin receptors. [Background technology]

[0002]

[0002] Psilocybin is a naturally occurring hallucinogenic compound produced by over 200 species of mushrooms collectively known as "psilocybin mushrooms." As a prodrug, psilocybin is rapidly metabolized by the body to produce the bioactive compound psilocin, which has psychoactive effects distinct from those produced by other hallucinogens such as lysergic acid diethylamide (LSD), mescaline, and N,N-dimethyltryptamine (DMT). These effects include, among others, euphoria, visual and mental hallucinations, altered perception, distorted sense of time, and spiritual experiences, as well as possible adverse reactions such as nausea and panic attacks. For reference, the chemical structure of psilocin is provided in FIG. 1 herein.

[0003]

[0003] 5-HT 2A and 5-HT 2C As agonists of the 5-HT receptor, psilocybin and psilocin have been recognized for their therapeutic potential. 2A Activation of the receptor appears to enhance locomotor activity, but 5-HT 2C Activation of the 5-HT receptor appears to decrease locomotor activity, 2A and 5-HT 2CCompounds with varying degrees of activity exhibit varying levels of hallucinogenic activity (Non-Patent Document 1). Psilocybin, along with other hallucinogenic drugs, was explored by Hofmann and his co-workers over 60 years ago (see, for example, Patent Documents 1 and 2), but clinical trials of the drug by researchers by researchers substantially declined by the early 1970s, especially after the drug was placed in Schedule 1 of the Controlled Substances Act in the United States. However, despite their listing as controlled substances in certain jurisdictions, research on psilocybin and other hallucinogenic drugs has not completely stopped, and recent clinical studies have renewed interest in the potential application of hallucinogenic drugs (including psilocybin) in developing medical fields such as the treatment of central nervous system (CNS) disorders. CNS disorders can induce symptoms such as difficult-to-treat mental health disorders (Non-Patent Document 2), such as treatment-resistant or drug-resistant depression and neurological disorders such as cluster headaches.

[0004]

[0004] Psilocybin has been recognized for its therapeutic potential for treating certain CNS diseases and disorders, but 5-HT 2B It is also recognized as a receptor agonist, which means that psilocybin exhibits cardiotoxic activity. Therefore, it is believed to be at least cardiotoxic 5-HT 2B There is a need for safer drugs that lack agonist activity. Furthermore, at least in some instances, 2A Retains receptor agonist activity but inhibits cardiotoxic 5-HT 2B There is a need for safer drugs that lack agonist activity.

[0005]

[0005] In recent years, various 5-HT 2A Selective N-substituted phenethylamines have been identified. In particular, 25CN-NBOH and its closely related analogues inhibit the 5-HT 2C 5-HT receptors 2AThese compounds, however, are not without potential drawbacks. First, some compounds of this phenethylamine class can generate reactive benzoquinone metabolites, but removing one methoxy group from the compound results in the production of 5-HT 2A It has been found that, although selectivity is maintained, the production of such metabolites may be reduced. Second, certain compounds of this phenethylamine class have been shown to be highly toxic to humans, in particular causing cardiac arrest (Non-Patent Document 4). [Prior art documents] [Patent documents]

[0006] [Patent Document 1] U.S. Patent No. 3,075,992 [Patent Document 2] U.S. Patent No. 3,078,214 [Non-patent literature]

[0007] [Non-Patent Document 1] Halberstadt AL, van der Heijden I, Ruderman MA, Risbrough VB, Gingrich JA, Geyer MA, Powell SB, NeuropsychopHarmacology, 2009, 34(8):1958-67 [Non-Patent Document 2] Daniel J, Haberman M.Clinical potential of psilocybin as a treatment for mental health conditions.Ment.Health Clin.2017,7(1),24-8 [Non-Patent Document 3] Synthesis and structure-activity relationships of N-benzyl pHenethylamines as 5-HT2A / 2C agonists.Hansen M,PHonekeo K,Paine JS,Leth-Petersen S,Begtrup M,Braeuner-Osborne H,Kristensen JL.ACS Chem Neurosci.2014 Mar 19;5(3):243-9.doi: 10.1021 / cn400216u [Non-Patent Document 4] Zawilska JB, Kacela M, Adamowicz P, Front.Neurosci.2020;14:78 Summary of the Invention

[0008]

[0006] The present disclosure relates to 5-HT 2A It exhibits receptor agonist activity and inhibits 5-HT 2B Low receptor agonist activity or 5-HT 2B The present invention relates to compounds belonging to the phenethylamine class of molecules, which are considered to be inactive 5-HT receptor agonists. 2C 5-HT receptors 2A The compounds disclosed herein may be useful for treating depression, including major depressive disorder, drug-resistant depression and psychotic depression, addiction, including alcoholism, tobacco addiction, cocaine addiction and opioid addiction, pain symptoms, including neuropathic pain, chemotherapy-related neuropathy pain, phantom limb pain and fibromyalgia, inflammation, including chronic and acute, eating disorders, including anorexia, autism, cluster headache, migraine, dementia, including Alzheimer's dementia, Parkinson's disease dementia and Lewy body dementia, post-traumatic stress disorder, cancer-related mental distress, fragile X syndrome, autism spectrum disorder, bipolar disorder, obsessive-compulsive disorder, Rett syndrome, and other CNS disorders.

[0009] As part of this disclosure, the compound of formula I:

[0010] [ka] (In the formula, R 1 , R 2 , R 3 , R4, R5, R6, R7, R8, X, Y, Z, a, b and c are as defined herein. or an isotopic substitution or a pharma- ceutically acceptable salt thereof.

[0011] In another aspect of the present disclosure, a compound represented by formula 1:

[0012] [ka] or an isotope or a pharma- ceutically acceptable salt thereof, (a)R 1 is:(i)R 2 and R 3 are each independently selected from H, CH3, or halogen, then they are selected from the group consisting of H, C1-C4 alkyl, substituted C1-C4 alkyl, cyclopropyl, cyclobutyl, cyclopropylmethyl, 2-oxetanyl, 3-oxetanyl, OH, C1-C4 alkoxy, substituted C1-C4 alkoxy, C1-C4 alkylthio, substituted C1-C4 alkylthio, and halogen; or (ii) R 2 together with b to form an alkanediyl, alkenediyl, heteroalkanediyl, or heteroalkenediyl moiety; or (iii) together with b to form an alkanediyl, alkenediyl, or heteroalkanediyl moiety; (b)R 2 (i) R 1 and R 3are each independently selected from H, CH, or halogen, then they are selected from the group consisting of H, C1-C4 alkyl, substituted C1-C4 alkyl, cyclopropyl, cyclobutyl, cyclopropylmethyl, 2-oxetanyl, 3-oxetanyl, OH, C1-C4 alkoxy, substituted C1-C4 alkoxy, C1-C4 alkylthio, substituted C1-C4 alkylthio, and halogen; or (ii) R 1 together form an alkanediyl, alkenediyl, heteroalkanediyl, or heteroalkenediyl moiety; (c)R 3 (i) R 1 and R 2 are each independently selected from H, CH3 or halogen, then they are selected from the group consisting of H, C1-C4 alkyl, substituted C1-C4 alkyl, cyclopropyl, cyclobutyl, cyclopropylmethyl, 2-oxetanyl, 3-oxetanyl, OH, C1-C4 alkoxy, substituted C1-C4 alkoxy, C1-C4 alkylthio, substituted C1-C4 alkylthio and halogen; or (ii) together with Z form an alkanediyl, alkenediyl, heteroalkanediyl, or heteroalkenediyl moiety.

[0009] R 4 , R 5 , R 6 , R 7 and R 8 One of them is R 9 , OR 9 , S.R. 9 , S(O)R 9 , S(O)2R 9 , N(R 9 )C(O)R 9 , N(R 9 )C(O)OR 9 , N(R 9 )C(O)N(H)R 9 , N(R 9 )C(O)N(C1-C6 alkyl)R 9 , N(R 9 )S(O)2R 9 , CH2OR 9 , CH2SR 9 , CH2S(O)R 9, CH2S(O)2R 9 , CH2N(R 9 )C(O)R 9 , CH2N(R 9 )C(O)OR 9 , CH2N(R 9 )C(O)N(H)R 9 , CH2N(R 9 )C(O)N(C1-C6 alkyl)R 9 , CH2N(R 9 )S(O)2R 9 , CH=NOR 9 , C(C1-C6 alkyl)=NOR 9 , C(O)OR 9 , C(O)N(H)R 9 , C(O)N(C1-C6 alkyl)R 9 , CH2C(O)OR 9 , CH2C(O)N(H)R 9 , CH2C(O)N(C1-C6 alkyl)R 9 , CN, and halogen; R 4 , R 5 , R 6 , R 7 and R 8 the second one of R is H, C1-C4 alkyl, CHF2, CF3, OH, OCH3, OC2H5, OCHF2, OCF3, and halogen, and the remaining R 4 , R 5 , R 6 , R 7 and R 8 are each independently H, CH3, or halogen. If R 4 and R 5 When R 6 , R 7 and R 8 are each independently selected from the group consisting of H, CH3, and halogen. If R 4 When and b together form an alkanediyl, alkenediyl, or heteroalkanediyl moiety, R 6 , R 7and R 8 one of R is selected from the group consisting of H, C1-C4 alkyl, CHF2, CF3, OH, OCH3, OC2H5, OCHF2, OCF3 and halogen, and the remaining R 5 , R 6 , R 7 and R 8 are each independently selected from the group consisting of H, CH3, or halogen. If R 4 When R and c together form an alkanediyl, alkenediyl, or heteroalkanediyl moiety, 6 , R 7 and R 8 one of R is selected from the group consisting of H, C1-C4 alkyl, CHF2, CF3, OH, OCH3, OC2H5, OCHF2, OCF3 and halogen, and the remaining R 5 , R 6 , R 7 and R 8 are each independently selected from the group consisting of H, CH3, or halogen.

[0010] X is CN, C(O)NH2, C(O)N(H)R 9 , C(O)N(C1-C6 alkyl)R 9 , C(O)(C4-C6 heterocyclyl), CHF2, CF3, OH, O(C1-C6 alkyl), OCHF2, OCF3, S(C1-C6 alkyl), SCF3, SCHF2, F, Cl, aryl and heteroaryl. Y is H, CH3, C(O)R 9 , CH2OC(O)R 9 and C(O)OR 9 is selected from the group consisting of: Z is (i) H, C1-C 10 Alkyl, substituted C1-C 10 Alkyl, C1-C 10 Heteroalkyl, C2-C 10 Alkenyl, C2-C 10 Heteroalkenyl, C2-C 10Alkynyl, C3-C6 cycloalkyl, (C3-C6 cycloalkyl)(C1-C8 alkyl), (C3-C6 cycloalkyl)(C1-C8 heteroalkyl), C4-C6 heterocyclyl, (C4-C6 heterocyclyl)(C1-C8 alkyl), (C4-C6 heterocyclyl)(C1-C8 heteroalkyl), aryl(C1-C8 alkyl), aryl(C1-C8 heteroalkyl), heteroaryl(C1-C8 alkyl), heteroaryl(C1-C8 heteroalkyl), C(O)R 9 , C(O)OR 9 , CH2OC(O)R 9 , C(O)NH2, C(O)N(H)R 9 , C(O)N(C1-C6 alkyl)R 9 and C(O)(C4-C6 heterocyclyl); or (ii) R 3 together form an alkanediyl, alkenediyl, heteroalkanediyl, or heteroalkenediyl moiety. Two of a, b and c are each independently selected from the group consisting of H, CH3 and C2H5; the third of a, b and c is H, but c and R 4 When together form an alkanediyl, alkenediyl, or heteroalkanediyl moiety, a and b are each independently selected from H or CH3.

[0012] R 9 may each independently exist and are selected from the group consisting of H, C1-C6 alkyl, C1-C6 heteroalkyl, substituted C1-C6 alkyl, substituted C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 heteroalkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, (C3-C6 cycloalkyl)(C1-C6 alkyl)(C3-C6 cycloalkyl)(C1-C6 heteroalkyl), C3-C6 heterocyclyl, (C3-C6 heterocyclyl)(C1-C6 alkyl), (C3-C6 heterocyclyl)(C1-C6 heteroalkyl), aryl, aryl(C1-C6 alkyl), aryl(C1-C6 heteroalkyl), heteroaryl, heteroaryl(C1-C6 alkyl), and heteroaryl(C1-C6 heteroalkyl).

[0013] The chemical entities of formula I disclosed herein are 5-HT 2A The chemical entities of formula I, and their isotopologues and pharma- ceutically acceptable compositions, are 5-HT 2A It is believed to be useful in treating a variety of diseases and disorders associated with receptor agonism, including those described herein.

[0014] This summary does not necessarily describe the entire scope of all aspects of the present disclosure. Other aspects, features, and advantages will become apparent to those of ordinary skill in the art upon review of the following description of specific embodiments.

[0015] The accompanying drawings illustrate one or more embodiments. [Brief description of the drawings]

[0014] [Figure 1]

[0016] The chemical structure of psilocin is shown. [Diagram 2]

[0017] The chemical structure of Formula I is shown. [Diagram 3]

[0018] 1 is a graph showing HTR versus dose of Compound 109 (described herein) administered to mice. [Figure 4]

[0019] 1 is a graph showing HTR over time per dose (mg / kg) of Compound 109 (described herein) administered to mice. [Diagram 5]

[0020] 1 is a graph showing horizontal and vertical activity of rat subjects in a locomotor activity test in response to an intraperitoneal dose of Compound 109 (described herein). [Figure 6]

[0021] 1 shows a synthesis scheme for a compound having the chemical structure of Formula I. [Figure 7]

[0022] 1 shows a synthetic scheme for the benzyl portion of a compound having the chemical structure of Formula I. [Figure 8]

[0023] 1 shows a synthetic scheme for the phenethyl portion of a compound having the chemical structure of Formula I. [Figure 9]

[0024] FIG. 9a shows a synthetic scheme for compound 12 (described herein).

[0025] FIG. 9b shows another synthetic scheme for compound 12 (described herein). [Figure 10]

[0026] 1 shows a synthetic scheme for the phenethylamine component of compound 32 (described herein). [Figure 11]

[0027] 1 shows a synthetic scheme for the benzylamine component of compound 76 (described herein). [Figure 12]

[0028] FIG. 12a shows a portion of the chemical structure of Formula I, where a is a methyl group.

[0029] FIG. 12b shows a portion of the chemical structure of Formula I, where b is a methyl group.

[0030] FIG. 12c shows a portion of the chemical structure of Formula I, where c is a methyl group. [Figure 13]

[0031] FIG. 1 shows a scheme for the synthesis of one of the four stereoisomers of compound 86 (as described herein), where b and c are linked to form a ring. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0015]

[0032] Directional terms such as "top", "bottom", "upper", "lower", "vertical" and "lateral" are used in the following description to provide relative references only and are not intended to imply any limitations on how any article is positioned during use or attached within an assembly or to an environment. The use of the word "a" or "an" in conjunction with the term "comprising" herein can mean "one", but is also consistent with the meanings of "one or more", "at least one" and "one or more". Elements expressed in the plural also include the singular form thereof. The term "plurality" as used herein means two or more, e.g., two or more, three or more, four or more, etc.

[0033] As used herein, unless otherwise specified, the term "about," when used to describe a recited value, means within 10% of the recited value.

[0016]

[0034] Unless otherwise specified, the term "alkanediyl" as used herein alone or as part of a larger moiety refers to a substituted or unsubstituted straight-chain divalent hydrocarbon chain that may be attached through its terminal carbon atom and is fully saturated. Unless otherwise specified, alkanediyl groups contain 1 to 5 carbon atoms ("C1-C5 alkanediyl"). Non-limiting examples of alkanediyl groups include methylene, ethylene, trimethylene, tetramethylene, and pentamethylene. Substituted alkanediyl groups have at least one and no more than five substituents, up to the number of hydrogen atoms in the unsubstituted groups. Non-limiting examples of substituted alkanediyl groups include difluoromethylene, hydroxyethylene, methoxyethylene, CH2CH2C(O), CH2C(CH3)2CH2, CH2CH2CH(CF3)CH2, and the like.

[0017]

[0035] Unless otherwise specified, the term "alkenediyl" as used herein alone or as part of a larger moiety refers to a substituted or unsubstituted linear divalent hydrocarbon chain having at least two carbon atoms and at least one carbon-carbon double bond, which may be attached through its terminal carbon atom. Unless otherwise specified, alkenediyl groups include carbon atoms having 2 to 5 carbon atoms ("C2-C5 alkenediyl"). Non-limiting examples of alkenediyl groups include vinylene (CH=CH), propene-1,3-diyl (CH2CH=CH), 1-butene-1,4-diyl (CH2CH2CH=CH), 2-butene-1,4-diyl (CH2CH=CHCH2), and 1,3-butadiene-1,4-diyl (CH=CHCH=CH). For illustrative purposes, when a first end of a 1,3-butadiene-1,4-diyl group is bonded to a carbon-carbon (CC) double bond or a first carbon atom of an aromatic ring, and a second end of the 1,3-butadiene-1,4-diyl group is bonded to a CC double bond or a second carbon atom of an aromatic ring, and the second carbon atom is adjacent to the first carbon atom, the two adjacent carbon atoms and the 1,3-butadiene-1,4-diyl group together represent a benzene ring. For illustrative purposes, when a first end of a vinylene group is bonded to a CC double bond or a first carbon atom of an aromatic ring, and a second end of the vinylene group is bonded to a heteroatom (selected from the group consisting of N, O, and S) adjacent to the CC double bond or the second carbon atom of the aromatic ring, and the second carbon atom is adjacent to the first carbon atom, the vinylene group together with the two adjacent carbon atoms and the heteroatom bonded to the second carbon atom represent a pyrrole, furan, or thiophene ring.

[0036] As used herein, unless otherwise specified, the term "alkenyl" refers to a substituted or unsubstituted, straight or branched, monovalent hydrocarbon chain having at least two carbon atoms and at least one carbon-carbon double bond. Examples of alkenyl groups include allyl, vinyl, 2-propenyl, crotyl, 2-isopentenyl, 1,3-butadien-2-yl, 2,4-pentadien-1-yl, 1,4-pentadien-3-yl, and the like.

[0037] Unless otherwise specified, the term "alkoxy" as used herein alone or as part of a larger moiety refers to the groups -O-alkyl and -O-cycloalkyl. Unless otherwise specified, the term "substituted alkoxy" as used herein alone or as part of a larger moiety refers to the groups -O-(substituted alkyl) and -O-(substituted cycloalkyl).

[0018]

[0038] Unless otherwise specified, the term "alkyl" as used herein alone or as part of a larger moiety refers to a substituted or unsubstituted, straight or branched, monovalent hydrocarbon chain that is fully saturated. Unless otherwise specified, an alkyl group has from 1 to 7 carbon atoms ("C1-C7 alkyl"). For example, in some embodiments, an alkyl group contains from 1 to 6 carbon atoms ("C1-C6 alkyl"); in some embodiments, an alkyl group contains from 1 to 5 carbon atoms ("C1-C5 alkyl"); in some embodiments, an alkyl group contains from 1 to 4 carbon atoms ("C1-C4 alkyl" or "lower alkyl"); in some embodiments, an alkyl group contains from 3 to 7 carbon atoms ("C3-C7 alkyl"). Non-limiting examples of saturated alkyl groups include methyl, ethyl, n-propyl, i-propyl, n-butyl, t-butyl, i-butyl, s-butyl, homologs and isomers of, for example, n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like. Examples of lower alkyl groups include methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, i-butyl, and t-butyl. Substituted alkyl groups have at least one and no more than five substituents, equal to or less than the number of hydrogen atoms in the unsubstituted groups. In some embodiments, the substituent is a fluorine atom. Non-limiting examples of substituted alkyl groups include 2-hydroxyethyl, 2-methoxyethyl, CHF2, CF3, CH2CF3, CF2CF3, 4-fluorobutyl, and the like.

[0039] Unless otherwise specified, as used herein, the term "alkylthio" as used alone or as part of a larger moiety refers to the groups represented by -S-alkyl and -S-cycloalkyl. As used alone or as part of a larger moiety, "substituted alkylthio" as used alone or as part of a larger moiety refers to the groups represented by -S-(substituted alkyl) and -S-(substituted cycloalkyl).

[0040] As used herein, unless otherwise specified, the term "alkynyl" refers to a substituted or unsubstituted, straight or branched monovalent hydrocarbon chain having at least two carbon atoms and at least one carbon-carbon triple bond. Non-limiting examples of alkynyl groups include ethynyl, 1- and 3-propynyl, 3-butyn-1-yl, and the like.

[0019]

[0041] Unless otherwise specified, the term "aryl" as used herein alone or as part of a larger moiety (e.g., "(aryl)alkyl") refers to a monovalent monocyclic or bicyclic carbocyclic aromatic ring system. Unless otherwise specified, aryl groups contain 6 or 10 ring members. Non-limiting examples of aryl include phenyl, naphthyl, and the like. The term "aryl" also refers to aryl groups that may be unsubstituted or substituted. For example, an aryl group can be unsubstituted or substituted with one, two, or three groups independently selected from the group 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), C(O)(C1-C6 alkoxy), C(O)NH2, C(O)NH(C1-C6 alkyl), C(O)N(C1-C4 alkyl)(C1-C4 alkyl), C(O)-heterocyclyl, NHC(O)(C1-C6 alkyl), N(CH3)C(O)(C1-C6 alkyl) and cyano.

[0020]

[0042] Unless otherwise specified, the term "chemical entity" as used herein refers to a compound having the depicted structure, whether in its "free" form (e.g., "free compound" or "free base" or "free acid" form, as applicable) or in a salt form, particularly a pharma-ceutically acceptable salt form, and further in solid state form. In some embodiments, the solid state form is an amorphous (i.e., non-crystalline) form; in some embodiments, the solid state form is a crystalline form (e.g., a polymorph, pseudohydrate, hydrate, or solvate). Similarly, the term encompasses the compound, whether or not it is provided in solid form. Unless otherwise specified, all statements herein regarding "compound" apply to the relevant chemical entity as defined.

[0043] Unless otherwise specified, the terms "comprising," "having," "including," "containing," and grammatical variations thereof as used herein are inclusive or open-ended and do not exclude additional, unrecited elements and / or method steps. For example, "A includes 1, 2, and 3" means that A includes, but is not limited to, 1, 2, and 3.

[0044] Unless otherwise specified, the term "consisting essentially of" as used herein in connection with a composition, use, or method means that additional elements, method steps, or both additional elements and method steps may be present, but these additions do not materially affect the manner in which the recited composition, method, or use functions.

[0045] Unless otherwise specified, as used herein, the term "consisting of" in relation to a composition, use or method excludes the presence of additional elements and / or method steps.

[0046] As used herein, the term "cpd" is an abbreviation for the word "compound."

[0021]

[0047] Unless otherwise specified, the term "cycloalkyl," as used herein alone or as part of a larger moiety (e.g., "(cycloalkyl)alkyl"), means (i) a substituted or unsubstituted monovalent monocyclic hydrocarbon group that is fully saturated or contains one or more units of unsaturation, but is not aromatic; or (ii) a bicyclo[mno]alkyl, where "m," "n," and "o" are each independently integers ranging from 0 to 5, and the sum of "m" + "n" + "o" ranges from 2 to 6. In certain embodiments, a cycloalkyl group contains 3 to 8 ring carbon atoms ("C3-C8 cycloalkyl"). Non-limiting examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl, etc., as well as bicyclo[2.2.1]heptyl (also known as norbornyl) and bicyclo[1.1.1]pentyl. Substituted cycloalkyl groups have at least one and no more than five substituents. In certain embodiments, a substituent is a fluorine atom.Non-limiting examples of substituted cycloalkyl groups include 2-methylcyclopropyl, 4-hydroxycyclohexyl, 2-methoxycyclopentyl, 4,4-difluorocyclohexyl, and the like.

[0048] Unless otherwise stated, the terms "halogen" or "halo" as used herein alone or as part of a larger moiety refer to fluoro, chloro, bromo, or iodo.

[0049] Unless otherwise specified, the term "hERG risk" as used herein refers to human ether-a-go-go related gene (hERG) K + This refers to the risk of a compound potentially inhibiting the channel, thereby causing QT prolongation.

[0050] As used herein, unless otherwise specified, the term "heteroalkanediyl" refers to a substituted or unsubstituted alkanediyl group, as defined herein, in which one or more of the constituent carbon atoms is replaced by nitrogen, oxygen, or sulfur. Non-limiting examples of heteroalkanediyl groups include NH, O, S, CH2NH, CHO, CH2S, CH2CH2NH, CH2CHO, CH2CH2S, CH2NHCH2, CH2OCH2, CH2SCH2, OCH2O, OCH2S, SCH2S, CH2CH2CH2NH, CH2CH2NHCH2, CH2CH2CH2O, CH2CH2OCH2, CH2CH2CH2S, and CH2CH2SCH2. For illustrative purposes, if the points of attachment of a heteroalkanediyl group are non-equivalent (e.g., CH2CH2NHCH2) and the points are attached to non-equivalent positions of the chemical structure, then the attachment of the heteroalkanediyl group to the chemical structure can occur in either orientation (e.g., CH2CH2NHCH2 or CH2NHCH2CH2).

[0022]

[0051] Unless otherwise specified, the term "heteroalkenediyl" as used herein refers to a substituted or unsubstituted alkenediyl group, as defined herein, in which one or more of the constituent atoms are replaced with N, O, or S. Non-limiting examples of heteroalkenediyl groups include CH=N, CH=CHNH, CH=CHO, CH=CHS, CH=NCH2, N=N, CH=NNH, CH=NO, CH=NS, NHCH=N, OCH=N, SCH=N, HNN=N, CH=CHCH=N, CH=CHN=CH, CH=CHN=N, CH=NCH=N, N=CHCH=N, CH=NN=CH, CH=CHCH2NH, CH=CHCHO, and CH=CHCH2S. For illustrative purposes, when the attachment points of the heteroalkenediyl group are non-equivalent (e.g., CH=CHS) and the attachment points are attached to non-equivalent positions of the chemical structure, the attachment of the heteroalkenediyl group to the chemical structure can occur in either direction (e.g., CH=CHS or SCH=CH). For illustrative purposes, when the first attachment point of the heteroalkenediyl group is attached to a CC double bond or a first C atom of an aromatic ring, and the second attachment point of the heteroalkenediyl group is attached to a CC double bond or a second C atom of an aromatic ring, and the first C atom and the second C atom are adjacent to each other, the two adjacent C atoms and the heteroalkenediyl group together represent a heteroaromatic ring, and in particular, (i) when the heteroaromatic ring formed is a 5-membered ring, the single saturated atom of the heteroalkenediyl group is selected from the group consisting of N, O and S, and (ii) when the heteroaromatic ring formed is a 6-membered ring, the heteroalkenediyl group contains only C and N atoms as part of its backbone and contains two conjugated double bonds. For purposes of illustration, when a first point of attachment of a heteroalkenediyl group represented by the formula X=Y, where X and Y are independently selected from the group consisting of C and N, is attached to a C-C double bond or to a first atom of an aromatic ring, and a second point of attachment of the heteroalkenediyl group is attached to a heteroatom (selected from the group consisting of N, O and S) which is attached to a C-C double bond or to a second atom of an aromatic ring, wherein the second atom is adjacent to the first atom, then the moiety X=Y represents a 5-membered heteroaromatic ring together with said two adjacent atoms and said heteroatom attached to one of them.

[0052] As used herein, unless otherwise specified, the term "heteroalkenyl" refers to a substituted or unsubstituted alkenyl group, as defined herein, in which one or more of the constituent carbon atoms has been replaced by nitrogen, oxygen or sulfur.

[0053] As used herein, unless otherwise specified, the term "heteroalkyl" refers to a substituted or unsubstituted alkyl group, as defined herein, in which one or more of the constituent carbon atoms is replaced by nitrogen, oxygen, or sulfur.

[0023]

[0054] Unless otherwise specified, the term "heteroaryl" as used herein alone or as part of a larger moiety, e.g., as part of "(heteroaryl)alkyl", refers to a monovalent monocyclic or bicyclic group having 5 to 10 ring atoms, preferably 5, 6, 9 or 10, with 6 or 10 pi electrons shared in the cyclic arrangement, and from 1 to 4 ring heteroatoms in addition to the ring carbon atoms. Examples of heteroaryl groups include thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, indolizinyl, benzofuranyl, benzothiophenyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, benzotriazolyl, quinolyl, isoquinolyl, purinyl, naphthyridinyl, pteridinyl, and the like. Heteroaryl groups may be unsubstituted or substituted with one, two or three groups independently selected from halogen, OH, C1-C6 alkoxy, substituted C1-C6 alkoxy, C1-C6 alkylthio, substituted C1-C6 alkylthio, C1-C6 alkyl, substituted C1-C6 alkyl, C3-C6 cycloalkyl, substituted C3-C6 cycloalkyl, C(O)OH, C(O)(C1-C6 alkoxy), C(O)NH2, C(O)NH(C1-C6 alkyl), C(O)N(C1-C4 alkyl)(C1-C4 alkyl), C(O)-heterocyclyl, NHC(O)(C1-C6 alkyl), N(CH3)C(O)(C1-C6 alkyl) and cyano.

[0055] Unless otherwise specified, the term "heterocyclyl" as used herein alone or as part of a larger moiety (e.g., "(heterocyclyl)alkyl") refers to a monovalent, stable, 4- to 7-membered monocyclic or 7- to 10-membered bicyclic heterocyclic moiety that is either saturated or partially unsaturated and has from 1 to 4 heteroatoms in addition to the ring carbon atoms. Non-limiting examples of heterocyclyl groups include tetrahydrofuranyl, pyrrolidinyl, tetrahydropyranyl, piperidinyl, morpholinyl, and the like. Heterocyclyl groups can be unsubstituted or substituted. For example, heterocyclyl groups can be unsubstituted or substituted with one, two, or three groups independently selected from the group consisting of halogen, OH, O(C1-C6 alkyl), O(substituted C1-C6 alkyl), C1-C6 alkyl, substituted C1-C6 alkyl, and C3-C6 cycloalkyl.

[0024]

[0056] Unless otherwise specified, the term "HTR" as used herein refers to 5-HT 2A This refers to the head twitch response, which is a measure of activation.

[0057] Unless otherwise specified, the term "inactive" (and all related terms containing "inactive") as used herein means "EC 50 When used in the context of "5-HT (nM)" and "Eff%", as those terms are understood by those of ordinary skill in the art or an equivalent, 2B When used in reference to activity at a receptor, concentrations greater than 10,000 nM (EC 50 (nM)) or 30% or less efficacy (when used in the context of "Eff%").

[0058] Unless otherwise specified, the term "isotopologue" as used herein refers to a species that differs from a specified compound only in its isotopic composition. For example, all hydrogen atoms in a compound may be independently of either natural isotopic composition or heavy isotopes. 2 H (D, deuterium) and 3Any isotopic composition enriched or depleted in one or both of H (T, tritium), ranging from 0% depletion to 100% enrichment.

[0059] Unless otherwise specified, the term "low 2B activity" as used herein refers to a low EC 50 Compound 5-HT measured in terms of "(nm)" 2A Agonist activity (or 5-HT 2A receptor sensitivity) of the compound 2B Agonist activity (or 5-HT 2B The Eff% at each receptor was greater than the EC500 measured for each receptor. 50 For example, a compound may have the following properties: (i) 5-HT 2A The receptors are EC 50 is 1.0 nm and Eff% is 95%; and (ii) 5-HT 2B The receptors are EC 50 is 700 nm and the Eff% is 95%, the compound is considered to have "low 2B activity."

[0060] Unless otherwise specified, the term "mouse" as used herein refers to male C57BL / 6J mice (6-8 weeks old).

[0025]

[0061] Unless otherwise specified, the term "pharmaceutically acceptable salts" as used herein refers to salts that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, etc., and are commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts of the compounds provided in the present disclosure include salts derived from suitable inorganic and organic acids and bases. Non-limiting examples of pharmaceutically acceptable salts include salts of compounds containing an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid, or organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid. Other non-limiting examples of pharma- ceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, campHorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfonate, heptanoate, heptanesulfonate, and hexanoate. Examples of pharmaceutically acceptable salts include xanthate, hydriodide, 2-hydroxyethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, palmitate, pamoate, pectinate, persulfate, phenylpropionate, pivalate, propionate, stearate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, etc. Other pharmaceutically acceptable salts include alkali metal, alkaline earth metal, ammonium and N-type salts. + (C 1-4Representative alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further non-limiting examples of pharmaceutically acceptable salts include non-toxic ammonium, quaternary ammonium and amine cations formed, where appropriate, with counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkylsulfonates and arylsulfonates.

[0026]

[0062] Unless otherwise specified, the term "subject" as used herein includes mammals (e.g., humans, including in some embodiments, prenatal human forms). In some embodiments, the subject is afflicted with the relevant disease, disorder, or condition. In some embodiments, the subject is susceptible to the disease, disorder, or condition. In some embodiments, the subject exhibits one or more symptoms or characteristics of the disease, disorder, or condition. In some embodiments, the subject does not exhibit any symptoms or characteristics of the disease, disorder, or condition. In some embodiments, the subject is a mammal with one or more features characteristic of susceptibility to or risk for a disease, disorder, or condition. In some embodiments, the subject is a patient. In some embodiments, the subject is an individual to whom and / or to whom a diagnosis and / or treatment is being administered. In some embodiments, the subject is a fetus, an infant, a child, a teenager, an adult, or an elderly person (i.e., the subject is older, such as over 50 years of age). In some embodiments, the child is a human between 2 and 18 years of age. In some embodiments, the adult is a human aged 18 years or older.

[0063] Unless otherwise specified, the term "such as" as used herein is intended to be open ended. For example, "A can be a halogen, such as chlorine or bromine" means that "A" can be, but is not limited to, chlorine or bromine.

[0027]

[0064] Recitation to a particular moiety, functional group or substituent also contemplates its tautomers (where applicable).

[0065] Unless otherwise indicated, structures depicted herein include all isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structure (e.g., R and S configurations for each asymmetric center, Z and E double bond isomers, and Z and E conformational isomers). Unless otherwise indicated, compounds disclosed, taught, or suggested in this disclosure contemplate all single stereochemical isomers, as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures thereof. Unless otherwise indicated, compounds disclosed, taught, or suggested in this disclosure contemplate all tautomers thereof. Additionally, unless otherwise indicated, structures depicted herein include compounds that differ only in the presence of one or more isotopically enriched atoms. Such compounds may be useful, for example, as analytical tools, probes in biological assays, or as therapeutic agents. Additionally, deuterium ( 2 Incorporation of heavier isotopes such as H) may offer certain therapeutic advantages due to increased metabolic stability, such as increased in vivo half-life or reduced dosage requirements.

[0028]

[0066] The chemical compounds described herein are further exemplified by the classes, subclasses and species disclosed herein.For the purpose of this disclosure, chemical elements are identified according to the Periodic Table of the Elements, CAS Edition, Handbook of Chemistry and Physics, 75th Edition, inside cover, and specific functional groups are generally defined as described therein.Furthermore, the general principles of organic chemistry, as well as specific functional moieties and reactivities, are described in Thomas Sorrell, Organic Chemistry, University Science Books, Sausalito, 1999; Smith and March, March's Advanced Organic Chemistry, 5th Edition, John Wiley&Sons, Inc., New York, 2001; Larock, Comprehensive Organic Transformations, VCH Publishers, Inc., New York, 1989; and Carruthers, Some Modern Methods of Organic Synthesis, 3rd Edition, Cambridge University Press, Cambridge, 1987. In this disclosure, any atom not specifically designated as a particular isotope is meant to represent any stable isotope of that atom.

[0067] With reference to FIG. 2, in accordance with an embodiment of the chemical entity disclosed herein (including isotopologues or pharma- ceutically acceptable salts thereof), a compound having the following formula I:

[0029] [ka] (In the formula, R 1 (i) R 2 and R 3are each independently selected from H, CH3, or halogen, then they are selected from the group consisting of H, C1-C4 alkyl, substituted C1-C4 alkyl, cyclopropyl, cyclobutyl, cyclopropylmethyl, 2-oxetanyl, 3-oxetanyl, OH, C1-C4 alkoxy, substituted C1-C4 alkoxy, C1-C4 alkylthio, substituted C1-C4 alkylthio, and halogen; or (ii) R 2 together form an alkanediyl, alkenediyl, heteroalkanediyl, or heteroalkenediyl moiety, if the moiety contains at least one additional H atom, the moiety further comprises a first substituent selected from the group consisting of C1-C4 alkyl, substituted C1-C4 alkyl, cyclopropyl, cyclobutyl, cyclopropylmethyl, 2-oxetanyl, 3-oxetanyl, C1-C4 alkoxy, C1-C4 alkylthio, OCF3, OCHF2, SCF3, SCHF2, CN, and halogen, and R 3 When R is H, CH, or halogen, it may be substituted with a second substituent selected from the group consisting of C1-C4 alkyl, substituted C1-C4 alkyl, and halogen. For example, R 3 is H, CH3 or halogen, R 1 and R 2are both CH2CH2, CH2CH2CH2, CH2CH2CH2CH2, (CH2)5, CH=CHCH=CH, CH2CH2O, CH2OCH2, OCH2CH2, CH2CH2 CH2O, CH2CH2OCH2, CH2OCH2CH2, OCH2CH2CH2, OCH=CH, CH=CHO, OCH2O, OCH2CH2O, CH2CH2S, CH2SCH2 , SCH2CH2, CH2CH2CH2S, CH2CH2SCH2, CH2SCH2CH2, SCH2CH2CH2, SCH=CH, CH=CHS, ON=CH, CH=NO, OCH =N, N=CHO, SN=CH, CH=NS, SCH=N, N=CHS, NHCH=CH, CH=CHNH, -NHN=CH, CH=NNH, NHCH=N, N=CHNH, CH=CH or (iii) when together with b forms an alkanediyl, alkenediyl, or heteroalkanediyl moiety, said moiety may be substituted with a substituent selected from the group consisting of C1-C4 alkyl, substituted C1-C4 alkyl, cyclopropyl, cyclobutyl, cyclopropylmethyl, 2-oxetanyl, 3-oxetanyl, C1-C4 alkoxy, C1-C4 alkylthio, OCF3, OCHF2, SCF3, SCHF2, CN and halogen, and when said moiety contains at least one further H atom, a second substituent selected from the group consisting of C1-C4 alkyl, substituted C1-C4 alkyl and halogen, R 2 and R 3 is independently selected from H, CH, or halogen. For example, R 2 and R 3 are each independently selected from H, CH, or halogen, R 1 and b can form any one of the following non-limiting bonds: CH2, CH2CH2, CH2CH2CH2, CH=CH, CH2CH=CH, CH=CHCH2, OCH2, OCH2CH2, CH2OCH2, SCH2, SCH2CH2, and CH2SCH2; R 2 (i) R 1 and R 3are each independently selected from H, CH, or halogen, then they are selected from the group consisting of H, C1-C4 alkyl, substituted C1-C4 alkyl, cyclopropyl, cyclobutyl, cyclopropylmethyl, 2-oxetanyl, 3-oxetanyl, OH, C1-C4 alkoxy, substituted C1-C4 alkoxy, C1-C4 alkylthio, substituted C1-C4 alkylthio, and halogen; or (ii) R 1 together form an alkanediyl, alkenediyl, heteroalkanediyl, or heteroalkenediyl moiety, which may be substituted with substituents selected from the group consisting of C1-C4 alkyl, substituted C1-C4 alkyl, cyclopropyl, cyclobutyl, cyclopropylmethyl, 2-oxetanyl, 3-oxetanyl, C1-C4 alkoxy, C1-C4 alkylthio, OCF3, OCHF2, SCF3, SCHF2, CN, and halogen, and when the moiety contains at least one additional H atom, R 3 is H, CH3, or halogen, it may be substituted with a second substituent selected from the group consisting of C1-C4 alkyl, substituted C1-C4 alkyl, and halogen; R 3 (i) R 1 and R 2 are each independently selected from H, CH3 or halogen, then R is selected from the group consisting of H, C1-C4 alkyl, substituted C1-C4 alkyl, cyclopropyl, cyclobutyl, cyclopropylmethyl, 2-oxetanyl, 3-oxetanyl, OH, C1-C4 alkoxy, substituted C1-C4 alkoxy, C1-C4 alkylthio, substituted C1-C4 alkylthio and halogen; or (ii) when together with Z form an alkanediyl, alkenediyl, heteroalkanediyl, or heteroalkenediyl moiety, R 1 and R 2are each independently selected from H, CH, or halogen, the moiety may be substituted with a substituent selected from the group consisting of C1-C4 alkyl, substituted C1-C4 alkyl, cyclopropyl, cyclobutyl, cyclopropylmethyl, 2-oxetanyl, 3-oxetanyl, OH, C1-C4 alkoxy, C1-C4 alkylthio, OCF3, OCHF2, SCF3, SCHF2, CN, and halogen; R 4 , R 5 , R 6 , R 7 and R 8 One of them is R 9 , OR 9 , S.R. 9 , S(O)R 9 , S(O)2R 9 , N(R 9 )C(O)R 9 , N(R 9 )C(O)OR 9 , N(R 9 )C(O)N(H)R 9 , N(R 9 )C(O)N(C1-C6 alkyl)R 9 , N(R 9 )S(O)2R 9 , CH2OR 9 , CH2SR 9 , CH2S(O)R 9 , CH2S(O)2R 9 , CH2N(R 9 )C(O)R 9 , CH2N(R 9 )C(O)OR 9 , CH2N(R 9 )C(O)N(H)R 9 , CH2N(R 9 )C(O)N(C1-C6 alkyl)R 9 , CH2N(R 9 )S(O)2R 9 , CH=NOR 9 , C(C1-C6 alkyl)=NOR 9 , C(O)OR 9 , C(O)N(H)R 9 , C(O)N(C1-C6 alkyl)R 9 , CH2C(O)OR9 , CH2C(O)N(H)R 9 , CH2C(O)N(C1-C6 alkyl)R 9 , CN, and halogen; R 4 , R 5 , R 6 , R 7 and R 8 the second one of R is H, C1-C4 alkyl, CHF2, CF3, OH, OCH3, OC2H5, OCHF2, OCF3, and halogen, and the remaining R 4 , R 5 , R 6 , R 7 and R 8 are each independently H, CH3, or halogen; Or, R 4 and R 5 together form an alkanediyl, alkenediyl, heteroalkanediyl, or heteroalkenediyl moiety, the moiety may be substituted with a substituent selected from the group consisting of C1-C4 alkyl, substituted C1-C4 alkyl, cyclopropyl, cyclobutyl, cyclopropylmethyl, 2-oxetanyl, 3-oxetanyl, C1-C4 alkoxyOCF3, C1-C4 alkylthio, CN, and halogen, in which case R 6 , R 7 and R 8are each independently selected from the group consisting of H, CH3, and halogen. Non-limiting examples of alkanediyl moieties include CH2CH2, CH2CH2CH2, and CH2CH2CH2CH2. Non-limiting examples of alkenediyl moieties are CH=CHCH=CH. Non-limiting examples of heteroalkanediyl moieties include CH2CH2O, CH2OCH2, OCH2CH2, CH2CH2CH2O, CH2CH2OCH2, CH2OCH2CH2, OCH2CH2CH2, OCH2O, OCH2CH2O, CH2CH2S, CH2SCH2, SCH2CH2, CH2CH2CH2S, CH2CH2SCH2, CH2SCH2CH2, SCH2CH2CH2, NHCH2CH2, and NHCH2NH. Non-limiting examples of heteroalkenediyl moieties include OCH=CH, CH=CHO, SCH=CH, CH=CHS, ON=CH, CH=NO, OCH=N, N=CHO, SN=CH, CH=NS, SCH=N, N=CHS, NHCH=CH, CH=CHNH, NHN=CH, CH=NNH, NHCH=N, N=CHNH, CH=CHCH=N, CH=CHN=CH, CH=NCH=CH and N=CHCH=CH; Or, R 4 When R and b together form an alkanediyl, alkenediyl, or heteroalkanediyl moiety, (a) the moiety is optionally substituted with a first substituent selected from the group consisting of C1-C4 alkyl, substituted C1-C4 alkyl, cyclopropyl, cyclobutyl, cyclopropylmethyl, 2-oxetanyl, 3-oxetanyl, C1-C4 alkoxy, C1-C4 alkylthio, OCF3, OCHF2, SCF3, SCHF2, CN, and halogen, and (b) with a second substituent selected from the group consisting of C1-C4 alkyl, substituted C1-C4 alkyl, and halogen, where R 6 , R 7 and R 8 one of R is selected from the group consisting of H, C1-C4 alkyl, CHF2, CF3, OH, OCH3, OC2H5, OCHF2, OCF3 and halogen, and the remaining R 5 , R 6 , R 7 and R 8are each independently selected from the group consisting of H, CH3, or halogen. Non-limiting examples of alkanediyl moieties include CH2 and CH2CH2. Non-limiting examples of alkenediyl moieties are CH=CH. Non-limiting examples of heteroalkanediyl moieties include OCH2 and SCH2; Or, R 4 When R and c together form an alkanediyl, alkenediyl, or heteroalkanediyl moiety, 5 , R 6 , R 7 and R 8 one of R is selected from the group consisting of H, C1-C4 alkyl, CHF2, CF3, OH, OCH3, OC2H5, OCHF2, OCF3 and halogen, and the remaining R 5 , R 6 , R 7 and R 8 are each independently selected from the group consisting of H, CH, or halogen. Non-limiting examples of alkanediyl moieties include CH, CHCH, and CHCHCH. Non-limiting examples of alkenediyl moieties include CH=CH, CHCH=CH, and CH=CHCH. Non-limiting examples of heteroalkanediyl moieties include CHOCH, OCHCH, CHSCH, and SCHCH; X is CN, C(O)NH2, C(O)N(H)R 9 , C(O)N(C1-C6 alkyl)R 9 , C(O)(C4-C6 heterocyclyl), CHF2, CF3, OH, O(C1-C6 alkyl), OCHF2, OCF3, S(C1-C6 alkyl), SCF3, SCHF2, F, Cl, aryl and heteroaryl, but otherwise Z is alkyl and R 4 If is hydroxy, then CN, C(O)NH2, C(O)N(H)R 9 , C(O)N(C1-C6 alkyl)R 9, C(O)(C4-C6 heterocyclyl), CHF2, CF3, OH, O(C1-C6 alkyl), OCHF2, OCF3, S(C1-C6 alkyl), SCF3, SCHF2, aryl, and heteroaryl; Y is H, CH3, C(O)R 9 , CH2OC(O)R 9 and C(O)OR 9 selected from the group consisting of; Z is (i) H, C1-C 10 Alkyl, substituted C1-C 10 Alkyl, C1-C 10 Heteroalkyl, C2-C 10 Alkenyl, C2-C 10 Heteroalkenyl, C2-C 10 Alkynyl, C3-C6 cycloalkyl, (C3-C6 cycloalkyl)(C1-C8 alkyl), (C3-C6 cycloalkyl)(C1-C8 heteroalkyl), C4-C6 heterocyclyl, (C4-C6 heterocyclyl)(C1-C8 alkyl), (C4-C6 heterocyclyl)(C1-C8 heteroalkyl), aryl(C1-C8 alkyl), aryl(C1-C8 heteroalkyl), heteroaryl(C1-C8 alkyl), heteroaryl(C1-C8 heteroalkyl), C(O)R 9 , C(O)OR 9 , CH2OC(O)R 9 , C(O)NH2, C(O)N(H)R 9 , C(O)N(C1-C6 alkyl)R 9 and C(O)(C4-C6 heterocyclyl); or (ii) R 3together form an alkanediyl, alkenediyl, heteroalkanediyl, or heteroalkenediyl moiety, which may be substituted with one group selected from the group consisting of C1-C4 alkyl, substituted C1-C4 alkyl, cyclopropyl, cyclobutyl, cyclopropylmethyl, 2-oxetanyl, 3-oxetanyl, OH, C1-C4 alkoxy, C1-C4 alkylthio, OCF3, CN, and halogen. Examples of alkanediyl moieties include CH2CH2 and CH2CH2CH2; non-limiting examples of alkenediyl moieties include CH=CH; non-limiting examples of heteroalkanediyl moieties include CHO, CH2CH2O, CH2S, and CH2CH2S; non-limiting examples of heteroalkenediyl moieties include CH=N; where a, b and c are: (i) two of a, b and c are each independently selected from the group consisting of H, CH and CH, but the third of a, b and c is H; or (ii) b and c are both CH, CHCH, CHCHCH, or CHOCH, but a is H or CH; (iii) b and R 1together form an alkanediyl, alkenediyl or heteroalkanediyl moiety, which may be substituted with a first substituent selected from the group consisting of C1-C4 alkyl, substituted C1-C4 alkyl, cyclopropyl, cyclobutyl, cyclopropylmethyl, 2-oxetanyl, 3-oxetanyl, C1-C4 alkoxy, C1-C4 alkylthio, OCF3, OCHF2, SCF3, SCHF2, CN and halogen, and which contains at least one additional H atom, a second substituent selected from the group consisting of C1-C4 alkyl, substituted C1-C4 alkyl and halogen, one of a and c is H, CH3 or C2H5 and the other of a and c is H. Non-limiting examples of alkanediyl moieties include CH2, CH2CH2 and CH2CH2CH2. Non-limiting examples of alkenediyl moieties include CH=CH, CH2CH=CH and CH=CHCH2. Non-limiting examples of heteroalkanediyl moieties include CH2O, CH2CH2O, CH2OCH2, CH2S, CH2CH2S, and CH2SCH2; or (iv) b and R 4 When together form an alkanediyl, alkenediyl or heteroalkanediyl moiety, the moiety may be selected from the group consisting of C1-C4 alkyl, substituted C1-C4 alkyl, cyclopropyl, cyclobutyl, cyclopropylmethyl, 2-oxetanyl, 3-oxetanyl, C1-C4 alkoxy, C1-C4 alkylthio, OCF3, OCHF2, SCF3, SCHF2, CN and halogen, and when the moiety contains at least one additional H atom, a second substituent selected from the group consisting of C1-C4 alkyl, substituted C1-C4 alkyl and halogen, one of a and c is H, CH3 or C2H5 and the other of a and c is H. Non-limiting examples of alkanediyl moieties include CH2 and CH2CH2. Non-limiting examples of alkenediyl moieties include CH=CH. Non-limiting examples of heteroalkanediyl moieties include CH2O and CH2S; (v) c and R 4When together form an alkanediyl, alkenediyl, or heteroalkanediyl moiety, a and b are each independently selected from H or CH. Non-limiting examples of alkanediyl moieties include CH2, CH2CH2, and CH2CH2CH2CH2. Non-limiting examples of alkenediyl moieties include CH=CH and CH2CH=CH. Non-limiting examples of heteroalkyl moieties include CHO, CHOCH2, CH2CH2, CH2CH2O, CH2S, CH2SCH2, and CH2CH2S; and R 9 is, when present, independently selected from the group consisting of H, C1-C6 alkyl, C1-C6 heteroalkyl, substituted C1-C6 alkyl, substituted C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 heteroalkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, (C3-C6 cycloalkyl)(C1-C6 alkyl)(C3-C6 cycloalkyl)(C1-C6 heteroalkyl), C3-C6 heterocyclyl, (C3-C6 heterocyclyl)(C1-C6 alkyl), (C3-C6 heterocyclyl)(C1-C6 heteroalkyl), aryl, aryl(C1-C6 alkyl), aryl(C1-C6 heteroalkyl), heteroaryl, heteroaryl(C1-C6 alkyl), and heteroaryl(C1-C6 heteroalkyl).

[0068] Example Chemical Substances Examples of chemicals of Formula I are shown in Table 1. Table 1 Formula I * Examples of compounds

[0030] [Table 1] TIFF2025503579000006.tif230169TIFF2025503579000007.tif234169TIFF20255035790 00008.tif234169TIFF2025503579000009.tif249167TIFF2025503579000010.tif199169

[0069] The abbreviations used in the above table have the following meanings: Ac = acetyl; Bz = benzoyl; Bu = butyl; cpm = cyclopropylmethyl; d = C(O)N(CH3)2; e = S(O)2NH2; Et = ethyl; f = C(O)OMe; g = C(O)NHCH3; Me = methyl.

[0031]

[0070] Pharmacology Serotonin receptor 5-HT2 functional assay Below are described non-limiting examples of methods for measuring functional activation of serotonin receptors.

[0071] To measure functional activation of serotonin receptors, either Gq dissociation or Gq-dependent calcium flux by bioluminescence resonance energy transfer (BRET) was performed for selected compounds. To measure 5-HT2 receptor-mediated Gq activation via Gq / γ1 dissociation 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 2BTo study receptor activation and biased agonism. Nat Struct Mol Biol. 2018;25(9):787-96), HEK293T cells were subcultured in Dulbecco's modified Eagle's medium (DMEM) supplemented with 10% dialyzed fetal bovine serum (FBS) and co-transfected with RLuc8-fused human Gαq (GαqRLuc8), GFP2 fused to the C-terminus of human Gγ1 (Gγ1-GFP2), human Gβ1 and 5-HT2 receptors at a 1:1:1:1 ratio using TransiT-2020. After at least 18-24 h, the transfected cells were plated at a density of 25,000-40,000 cells per well in 200 μL onto polylysine-coated 96-well white clear-bottom cell culture plates in DMEM containing 1% dialyzed FBS and incubated overnight. The next day, the medium was decanted and the cells were washed with 60 μL of drug buffer (1×HBSS, 20 mM HEPES, pH 7.4) and then 60 μL of drug buffer was added per well. The cells were pre-incubated at 37° C. in a humidified atmosphere before being stimulated with drugs. Drug stimulation utilized the addition of 30 μL of drug (3×) diluted in McCorvy buffer (1×HBSS, 20 mM HEPES, pH 7.4 supplemented with 0.3% BSA fatty acid free, 0.03% ascorbic acid) and the plates were incubated for 1 hour at 37° C. Substrate addition was performed 15 minutes prior to reading and utilized 10 μL of the RLuc substrate coelenterazine 400a (Prolume / Nanolight, 5 μM final concentration) for Gq dissociation BRET2. Plates were read for emission at 400 nm and fluorescent GFP2 emission at 510 nm using a Mithras LB940 multimode microplate reader (e.g., provided by Berthold) for 1 second per well. BRET ratios of fluorescence / emission were calculated for each well and plotted as a function of drug concentration using GrapHpad Prism 8 (GrapHpad Software Inc., San Diego, CA). Data were normalized to % 5-HT stimulation and analyzed using nonlinear regression "log(agonist) vs. response" to determine Emax and EC 50 Parameter estimates were obtained.

[0072] Calcium flux was measured using a stable expression 5-HT2 Flp-In 293 T-Rex tetracycline-inducible system using methods known in the art (e.g., Investigation of the Structure-Activity Relationships of Psilocybin Analogues, ACS Pharmacol. Transl. Sci. 2020, Publication Date: December 14, 2020, https: / / doi.org / 10.1021 / acsptsci.0c00176). Cell lines were maintained in DMEM containing 10% FBS, 10 μg / mL blasticidin and 100 μg / mL hygromycin B. At least 20-24 hours prior to the assay, receptor expression was induced with tetracycline (2 μg / mL) and cells were seeded into 384-well poly-L-lysine-coated black plates at a density of 7,500 cells / well in DMEM containing 1% dialyzed FBS. On the day of the assay, cells were incubated for 1 h at 37 °C with Fluo-4 Direct dye (Invitrogen, 20 μL / well) reconstituted in 2.5 mM probenecid-containing drug buffer (20 mM HEPES-buffered HBSS, pH 7.4). Drug dilutions were prepared at 5x concentrations in McCorvy buffer (20 mM HEPES-buffered HBSS, 0.1% BSA, 0.01% ascorbic acid, pH 7.4). After dye loading, cells were allowed to equilibrate to room temperature for 15 min and then placed in a FLIPRTETRA fluorescent imaging plate reader (Molecular Devices). The FLIPRTETRA was programmed to read baseline fluorescence for 10 s (1 read / sec), after which 5 μL of drug was added per well and fluorescence was read for a total of 5–10 min (1 read / sec). Fluorescence for each well was normalized to the average of the first 10 readings of baseline fluorescence, then either the maximum fold peak increase above baseline or the area under the curve (AUC) was calculated. Either the peak or AUC was plotted as a function of drug concentration, and the data was normalized to percent of 5-HT stimulation. Data was plotted and nonlinear regression was performed in GrapHpad Prism 8 using "log(agonist) vs. response" to calculate Emax and EC50 Parameter estimates were obtained.

[0032]

[0073] 5-HT 2A , 5-HT 2B and 5-HT 2C The functional activity of the various compounds disclosed herein at each receptor was measured relative to and against the functional activity of 4-hydroxytryptamine at that receptor. A comparison of the functional activities is provided in Table 2 below. At least three replicates were performed for each compound.

[0033] [Table 2] TIFF2025503579000012.tif246169TIFF2025503579000013.tif249166TIFF2025503579000014.tif249163 TIFF2025503579000015.tif239169TIFF2025503579000016.tif249163TIFF2025503579000017.tif242169

[0074] Many of the compounds disclosed in this disclosure are 5-HT 2A It is active at receptors up to 400 nm, but not at 5-HT 2B It is "inactive" at the receptor and 5-HT 2C 5-HT receptors 2A Many of the compounds disclosed in this disclosure are more active at the 5-HT 2A Selectively activates the receptor and inhibits 5-HT 2B For example, the compounds disclosed herein may be 5-HT-α in the range of about 1 nm to about 400 nm, about 1 nm to about 300 nm, about 1 nm to about 200 nm, about 1 nm to about 100 nm, about 1 nm to about 90 nm, about 1 nm to about 80 nm, about 1 nm to about 60 nm, about 1 nm to about 50 nm, about 5 nm to about 95 nm, about 5 nm to about 80 nm, about 5 nm to about 65 nm, about 5 nm to about 50 nm, about 10 nm to about 90 nm, about 10 nm to about 80 nm, about 10 nm to less than about 70 nm, or any specific ratio therebetween. 2AFor example, the compounds disclosed herein may exhibit activity at the 5-HT receptor in the following ranges: about 1 to about 100 fold, about 10 to about 100 fold, about 10 to about 90 fold, about 10 to about 80 fold, about 10 to about 70 fold, about 10 to about 60 fold, about 10 to about 50 fold, about 20 to about 100 fold, about 20 to about 80 fold, about 20 to about 60 fold, about 30 to about 90 fold, about 30 to about 60 fold, or any specific range therebetween. 2C 5-HT receptors 2A In one embodiment, the compounds disclosed herein may exhibit selectivity for the 5-HT 2C 5-HT receptors 2A It exhibits 10- to 100-fold selectivity for the receptor.

[0034]

[0075] Table 3 below summarizes the 5-HT receptor activity of psilocin, compound 109 and compound 93.

[0035] [Table 3]

[0076] Phenethylamines of formula 1 are generally known to be potential "hERG risk". As a result, many of the compounds disclosed in Tables 1 and 2 were screened for possible "hERG risk" using pharmacological assays (e.g., the Eurofins™ hERG Cove APC assay). 5-HT 2A Compounds that showed strong efficacy at the receptor were compared for exposure / IC 50 We further evaluated "hERG risk" based on a hERG IC 30-fold greater than the therapeutic free plasma concentration. 50 The value is the threshold for considering a compound to be low "hERG risk".

[0077] An important factor for hERG risk assessment in the early drug discovery stage is the hERG IC 50 / In vitro 5-HT 2A ratio; compounds exhibiting a ratio of greater than 200 have a hERG IC to estimated therapeutic plasma Cmax of greater than 30. 50compounds exhibiting ratios between 150 and 200 generally indicate moderate hERG risk potential; compounds exhibiting IC of 150 or less generally indicate low hERG risk potential at clinically relevant dose levels. 50 (hERG) / EC 50 (5-HT 2A Compounds exhibiting a ) ratio generally exhibit a high hERG risk potential. The assessed "hERG risk" of the various compounds in Tables 1 and 2 is summarized in Table 4.

[0036] [Table 4]

[0078] Various compounds disclosed herein are subjected to in vitro SafeScreen44™ panel to identify off-target activity.The compounds of interest identified in the panel are then tested in follow-up functional assays to identify whether the compounds have significant off-target risk.As summarized in Table 5 below, compound 109 has no significant off-target activity.Other compounds have similar characteristics to compound 109 and are predicted to have no off-target activity.

[0037] [Table 5]

[0079] Further experiments were performed on Compound 109. Table 6 summarizes, among other things, the expected liver clearance of Compound 109 in various species, as determined by calculating the in vitro hepatocyte clearance over time and scaling the rate with the hepatocyte number in such species and the expected hepatic blood flow in such species.

[0038] [Table 6]

[0080] Tables 7a and b summarize, inter alia, the observed plasma and brain PK profiles in animals and predicted plasma and brain PK profiles in humans for (a) Compound 109 and (b) Compound 93.

[0039] [Table 7]

[0081] HTR was assessed using a head-mounted neodymium magnet and magnetometer detection coil as described in Halberstadt et al., PsychopHarmacology (Berl.), 2013, 227(4):727-739. Table 8 below shows the ED of head twitches in mice for various compounds disclosed herein compared to psilocybin. 50 FIG. 3 shows the HTR versus dose for compound 109.

[0040] [Table 8]

[0082] The experimental data summarized in Tables 6-8 demonstrate that compound 109 exhibits high brain penetration but lower central hallucinogenic (or hallucinogenic) effects than conventional hallucinogenic compounds such as psilocybin.

[0083] Referring to Figure 4, the short-lasting (less than 30 minutes) hallucinogenic effect of compound 109 is further shown. Figure 4 shows the HTR over time for different doses (measured in mg / kg) of compound 109. Similar short-lasting (less than 30 minutes) hallucinogenic effect (as suggested by HTR data) is observed in other compounds disclosed in the present disclosure. Compound 109 and other similar compounds also show long-lasting antidepressant effect (neuroplasticity modulation). In contrast, the hallucinogenic effect of many hallucinogenic compounds known in the art, such as psilocybin, is long-lasting (more than 30 minutes), but such long-lasting hallucinogenic effect is undesirable from the viewpoint of medical treatment.

[0084] Further experiments were also carried out with Compound 109. That is, intraperitoneal doses of up to 30 mg / kg of Compound 109 and various reference compounds were delivered to healthy rat subjects and to surgically induced abnormal rat subjects (olfactory bulbectomized rats). With respect to Compound 109, there is no indication that intraperitoneal doses of up to 30 mg / kg of such compounds affect normal motor activity in healthy rat subjects. However, single administration of such intraperitoneal doses results in a short plasma t of less than 1 hour in healthy rat subjects. 1 / 2 In contrast to the above, the results showed significant and long-lasting inhibition of abnormal behavioral activity in the surgery-induced abnormal rat subjects. Without being bound by theory, these observations are believed to be the result of the long-lasting neuroplasticity effect of Compound 109 on the surgery-induced abnormal rat subjects. Figure 5 summarizes the results of this experiment. The results of the test using psilocybin as a comparative hallucinogen support the idea that Compound 109 provides a sustainable acute antidepressant effect. Please note that in Figure 5, "VEH" refers to vehicle and "PSIL" refers to psilocybin.

[0085] Compound 93 also demonstrated high clearance in in vitro studies. The results of this experiment are summarized in Table 9.

[0041] [Table 9]

[0086] Chemical synthesis method: Non-limiting examples of procedures for preparing the compounds described herein are provided below.

[0087] N-benzylphenethylamines can be prepared by N-benzylation of phenethylamines or N-phenethylation of benzylamines. These reactions can be carried out in a manner that directly leads to the product of the oxidized state of the amine, for example using halides or sulfonates as alkylating agents. The amine nitrogen can be present in free form or there can be a protecting group that is removed at a later stage of the synthesis to avoid the common side reactions of dialkylation and quaternization. The reaction can also be carried out with electrophiles at higher oxidation states to give products such as imines or carboxamides, which need to be reduced in situ or in a subsequent step to reach the desired amine. For example, a commonly used protocol to carry out the reductive alkylation of primary amines consists of treating the amine with an aldehyde in the presence of a mild reducing agent (e.g. sodium borohydride, sodium cyanoborohydride or sodium triacetoxyborohydride). Dialkylation and direct reduction of the aldehyde prior to imine formation represent frequently observed side reactions. Amines also react easily with acylating agents such as acyl halides, carboxylic anhydrides or free carboxylic acids in the presence of condensing agents, many representatives of which are known from research in the field of peptide synthesis, to form carboxamides. Unlike imines, which are often sensitive to hydrolysis, carboxamides are stable compounds that are isolated and reduced to amines in a subsequent step. This reaction process usually requires strong reducing agents such as lithium aluminum hydride, sodium bis(2-methoxyethoxy)aluminum hydride (Red-Al®) or borane, which are not compatible with the nitrile functionality present in many target compounds, or the carboxamides need to be activated by treatment with strong electrophiles to form mixed imidic anhydrides.With triflic anhydride in its role, carboxamides can be reduced to amines by sodium borohydride without affecting nitriles and various other reducible functional groups (Huang, P.-Q.; Geng, H. Org. Chem. Front. 2015, 2, 150) or prepared by Hantzsch esters, which are mild hydride donors (Pelletier, G.; Bechara, WS; Charette, ABJ Am. Chem. Soc. 2010, 132, 12817). The general synthesis scheme of the target compounds of the present invention of formula I, where a=b=c=H, is shown in Figure 6.

[0088] The benzyl moiety components of the phenethylamines may be prepared by standard functional group transformations (not detailed in the scheme) as shown in FIG. 7, among other possible approaches; in such a diagram, Ar represents the substituent R 4 , R 5 , R 6 , R 7 and R 8 is a phenyl group.

[0042]

[0089] Similar and further functional group transformations can be carried out to afford the substituent R 1 , R 2 , R 3 , R 4 , R 5 , R6, R 7 and R 8 Commercially unavailable patterns of F can be obtained. Halogen substituents containing F can be accessed by halodecarboxylation of carboxylic acids (Varenikov, A.; Shapiro, E.; Gandelman, M. Chem. Rev. 2021, 121, 412). Aromatic fluorides can also be obtained from a number of other aromatic starting materials (Campbell, MG; Ritter, T. Chem. Rev. 2015, 115, 612), for example from aromatic amines via the Baltz-Schiemann reaction or from other halides by halogen exchange. Transition metal-mediated halogen exchange can be applied to various combinations of leaving and incoming halogens (Evano, G.; Nitelet, A.; Thilmany, P.; Dewez, DF Front. Chem. 2018, 6, article No. 114) Aryl triflates, which are readily available derivatives of phenols, also participate in this type of reaction (Sather, AC; Lee, HG; De La Rosa, VY; Yang, Y.; Mueuller, P.; Buchwald, SLJ Am. Chem. Soc. 2015, 137, 13433). Trifluoromethylated aromatic compounds can be prepared, for example, from carboxylic acids and SF4; from the Sandmeyer reaction of amines with sodium trifluoromethanesulfonate (Hong, J.; Wang, G.; Huo, L.; Zheng, C. Chin. J. Chem. 2017, 35, 761) or Togni's reagent II (1-trifluoromethyl-1,2-benziodoxol-3(1H)-one; Hong, J.; Huo, L.; Yang, Y.; Wang, G.; Zheng, C. Chem. Select 2017, 2, 3716); or from aryl halides by transition metal catalyzed nucleophilic trifluoromethylation (Roy, S.; Gregg, B. T.; Gribble, GW; Le, V.-D.; Roy, S. Tetrahedron 2011, 67, 2161). Difluoromethyl substituents are often generated from aldehydes by deoxofluorination. The group of reagents capable of this transformation has recently been expanded by the combination of Selectfluor® with diphenyl sulfide (He, G.; Xiao, X.; Jin, H.-Z.; Lin, J.-H.; Zhong, T.; Zheng, X.; Xiao, JC Tetrahedron 2021, 83, Article No. 131963). (Trifluoromethoxy)arenes can be prepared from phenols to their derived xanthates using the commercially available fluorinating agent, XtalFluor-E® (diethylaminodifluorosulfinium tetrafluoroborate (Yoritate, M.; Londregan, AT; Lian, Y.; Hartwig, JFJ Org. Chem. 2019, 84, 15767). Aromatic amines are converted to (trifluoromethoxy)arenes via the action of AgOCF3 on their derived diazonium salts (Org. Lett. 2019, 21, 8003). Trifluoromethylthio groups can be introduced into aromatics by substitution of other heteroatoms with SCF3 moieties or by electrophilic substitution of hydrogens in electron-rich aromatics (Barata-Vallejo, S.; Bonesi, S.; Postigo, A. Org. Biomol. Chem. 2016, 14, 7150). (Trifluoromethylthio)arenes can also be obtained from aryl thiols by reaction with electrophilic or free radical trifluoromethylating agents such as S-(trifluoromethyl)sulfonium salts or CF3 halides (reviewed with other methods in: Xu, X.-H.; Matsuzaki, K.; Shibata, N. Chem. Rev. 2015, 115, 731). (Difluoromethoxy)- and (difluoromethylthio)arenes can be obtained from phenols and arenethiols, respectively, and various sources of difluorocarbenes, a recent example being S-(difluoromethyl)diarylsulfonium salts (Liu, G.-K.; Qin, W.-B.; Li, X.; Lin, L.-T.; Wong, HNCJ Org. Chem. 2019, 84, 15948).

[0090] The building blocks of the phenethyl moiety can be prepared by standard functional group transformations as generally illustrated in the scheme shown in FIG. 8, among other possible approaches, where Ar is a substituent R 1 , R 2 and R 3 is a phenyl group.

[0091] As examples of the synthetic methodology in the previous paragraph, two syntheses of compound 12 are shown in Figures 9a and 9b.

[0092] A variety of heterocycles annulated to either benzene ring may be encountered in certain compounds of the present disclosure, R 1 and R 2 Between R 3 Between and Z and / or R 4 and R 5 As an example, compound 32 (R 1 and R 2 The phenethylamine component of compound 76 (R 4 and R 5 The synthesis of the benzylamine building blocks of

[0093] 12a, 12b and 12c show the synthesis of building blocks where a, b or c is a methyl group, respectively.

[0094] FIG. 13 shows a scheme for the synthesis of one of the four stereoisomers of compound 86, where b and c are linked to form a ring with the absolute and relative stereochemistry shown.

[0095] Deuterium can be incorporated into the compounds in a variety of ways, using deuteration of reagents and building blocks under the same or similar conditions as those used for their counterparts with natural hydrogen isotopic composition. Reduction of carboxamides with commercially available LiAlD4 or BD3-THF complexes leads to amines deuterated on the methylene group derived from the carbonyl group of the amide. Similarly, reductive amination / alkylation can be carried out with NaBD4 and NaBD3CN. Aromatic and heteroaromatic compounds can also introduce deuterium by reaction with excess DO in the presence of heterogeneous metal catalysts (Sawama, Y.; Park, K.; Yamada, T.; Sajiki, H. Chem. Pharm. Bull. 2018, 66, 21-28). Deuterium substitution at specific positions of aromatic or heteroaromatic rings can be achieved by halogen-metal exchange reactions on compounds bearing a halogen atom (typically Br or I) at the position to be deuterium-substituted, followed by quenching of the (hetero-)arylmetal intermediate with a deuterium-substituting agent such as DO or CHOD; or by free radical deuterodehalogenation of the same precursor with BuSnD and a radical initiator such as azobis(isobutyronitrile) or dibenzoyl peroxide; or by reaction of the same precursor with a deuterium source and a transition metal catalyst, such as BuSnD or formate-d2.

[0043]

[0096] How to use The compounds described herein are believed to be useful in treating depression (including major depressive disorder), drug-resistant depression, psychotic depression, and PTSD, and also function as stimulants, appetite suppressants, decongestants, bronchodilators, and hallucinogens.Furthermore, the compounds disclosed herein are also believed to be useful in treating addictions, including alcoholism, tobacco addiction, cocaine addiction, and opioid addiction; pain conditions, including neuropathic pain, chemotherapy-related neuropathy pain, phantom limb pain, and fibromyalgia; inflammation, including chronic and acute; eating disorders, including anorexia, autism, cluster headache, and migraine; dementia, including Alzheimer's dementia, Parkinson's dementia, and Lewy body dementia; mental distress associated with cancer; fragile X syndrome, autism spectrum disorder, bipolar disorder, obsessive-compulsive disorder, Rett syndrome, and other CNS disorders.

[0097] Substituted phenethylamines constitute a group of phenethylamine derivatives that contain phenethylamine as the "backbone"; in other words, this chemical class includes derivatives formed by replacing one or more hydrogen atoms in the phenethylamine backbone with other substituents. The class of substituted phenethylamines includes all of the substituted amphetamines and substituted methylenedioxyphenethylamines (e.g., MDMA), including many drugs that act as emotional stimulants, stimulants, hallucinogens, appetite suppressants, bronchodilators, decongestants, and / or antidepressants, among others.

[0098] Another potential use of these analogs is in the treatment of seizure disorders, including, but not limited to, infantile seizure disorders such as Dravet syndrome (Sourbon, J. et al. "Serotonergic Modulation as Effective “Treatment for Dravet Syndrome in a Zebrafish Mutant Model”, ACS Chem. Neurosci. 2016, 7, 588-598).

[0099] Another potential use of these analogs is in the treatment of obsessive-compulsive disorders, anxiety disorders, phobia disorders and aggression in animals, non-limiting examples of which include dogs, cats, pigs, mice and rats.Another potential use of these analogs is in inducing ureteral contractions in animals, non-limiting examples of which include dogs, cats, pigs, mice and rats.

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

[0044]

[0101] Method of administration As contemplated herein, a therapeutically effective amount of the compounds described herein is administered to a subject in need thereof. Whether such treatment is indicated depends on the subject's case and is further subject to a medical evaluation (diagnosis) that takes into account the signs, symptoms and / or dysfunctions present, the risk of developing a particular sign, symptom and / or dysfunction, and other factors.

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

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

[0104] As contemplated herein, the therapeutically effective amount of the compounds described herein adapted for use in therapy varies according to the nature of the condition to be treated, the length of time for which activity is desired, and the age and condition of the patient, and is ultimately determined by the attending physician. The dosage and administration interval can be individually adjusted to provide a plasma level of the compound sufficient to maintain the desired therapeutic effect. The desired dosage can be conveniently administered in a single dose or as multiple doses administered at appropriate intervals, for example, as one, two, three, four or more partial doses per day. Multiple administration is often desirable or required.

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

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

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

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

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

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

[0111] The compounds described herein may be formulated for parenteral administration by injection, for example, by bolus injection or continuous infusion.The preparations for injection may be provided in unit dosage form, for example, in ampoules or multi-dose containers, with the addition of preservatives.The compositions may take the form of suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulating agents such as suspending agents, stabilizing agents and / or dispersing agents.

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

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

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

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

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

[0117] Terms Used in This Specification Unless otherwise specified, all technical and scientific terms used in this specification have the same meaning as commonly understood by one of ordinary skill in the art to which the content of this disclosure belongs, unless otherwise defined. In addition, the citation of any reference herein should not be construed or deemed as an admission that such reference is prior art relevant to the content of this disclosure.

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

Claims

1. Formula 1: 【Chemistry 1】 (In the formula, R １ (i) R ２ and R ３ are each independently H, CH ３ or halogen, H, C １ ~C ４ Alkyl, substituted C １ ~C ４ Alkyl, cyclopropyl, cyclobutyl, cyclopropylmethyl, 2-oxetanyl, 3-oxetanyl, OH, C １ ~C ４ Alkoxy, substituted C １ ~C ４ Alkoxy, C １ ~C ４ Alkylthio, substituted C １ ~C ４ or (ii) R ２ together with b to form an alkanediyl, alkenediyl, heteroalkanediyl, or heteroalkenediyl moiety; or (iii) together with b to form an alkanediyl, alkenediyl, or heteroalkanediyl moiety; R ２ (i) R １ and R ３ are each independently H, CH ３ or halogen, H, C １ ~C ４ Alkyl, substituted C １ ~C ４ Alkyl, cyclopropyl, cyclobutyl, cyclopropylmethyl, 2-oxetanyl, 3-oxetanyl, OH, C １ ~C ４ Alkoxy, substituted C １ ~C ４ Alkoxy, C １ ~C ４ Alkylthio, substituted C １ ~C ４ or (ii) R １ together form an alkanediyl, alkenediyl, heteroalkanediyl, or heteroalkenediyl moiety; R ３ (i) R １ and R ２ are each independently H, CH ３ or halogen, H, C １ ~C ４ Alkyl, substituted C １ ~C ４ Alkyl, cyclopropyl, cyclobutyl, cyclopropylmethyl, 2-oxetanyl, 3-oxetanyl, OH, C １ ~C ４ Alkoxy, substituted C １ ~C ４ Alkoxy, C １ ~C ４ Alkylthio, substituted C １ ~C ４ or (ii) together with Z, forms an alkanediyl, alkenediyl, heteroalkanediyl, or heteroalkenediyl moiety; R ４ , R ５ , R ６ , R ７ and R ８ One of them is R ９ , OR ９ , S.R. ９ , S(O)R ９ , S(O) ２ R ９ , N(R ９ ) C(O)R ９ , N(R ９ ) C(O)OR ９ , N(R ９ )C(O)N(H)R ９ , N(R ９ )C(O)N(C １ ~C ６ Alkyl)R ９ , N(R ９ ) S (O) ２ R ９ , C.H. ２ OR ９ , C.H. ２ S.R. ９ , C.H. ２ S(O)R ９ , C.H. ２ S (O) ２ R ９ , C.H. ２ N (R ９ ) C(O)R ９ , C.H. ２ N (R ９ ) C(O)OR ９ , C.H. ２ N (R ９ )C(O)N(H)R ９ , C.H. ２ N (R ９ )C(O)N(C １ ~C ６ Alkyl)R ９ , C.H. ２ N (R ９ ) S (O) ２ R ９ , CH=NOR ９ , C(C １ ~C ６ alkyl) = NOR ９ , C(O)OR ９ ,C(O)N(H)R ９ , C(O)N(C １ ~C ６ Alkyl)R ９ , C.H. ２ C(O)OR ９ , C.H. ２ C(O)N(H)R ９ , C.H. ２ C(O)N(C １ ~C ６ Alkyl)R ９ , CN, and halogen; R ４ , R ５ , R ６ , R ７ and R ８ The second one of them is H, C １ ~C ４ Alkyl, CHF ２ , C.F. ３ , O.H., O.C.H. ３ , O.C. ２ H ５ , O.C.H.F. ２ , O.C.F. ３ and halogen, and the remaining R ４ , R ５ , R ６ , R ７ and R ８ are each independently H, CH ３ or halogen; Or, R ４ and R ５ When together form an alkanediyl, alkenediyl, heteroalkanediyl, or heteroalkenediyl moiety, R ６ , R ７ and R ８ are each independently H, CH ３ and halogen; Or, R ４ When R and b together form an alkanediyl, alkenediyl, or heteroalkanediyl moiety, ６ , R ７ and R ８ One of them is H, C １ ~C ４ Alkyl, CHF ２ , C.F. ３ , O.H., O.C.H. ３ , O.C. ２ H ５ , O.C.H.F. ２ , O.C.F. ３ and halogen, and the remaining R ５ , R ６ , R ７ and R ８ are each independently H, CH ３ or halogen; Or, R ４ When R and c together form an alkanediyl, alkenediyl, or heteroalkanediyl moiety, R ５ , R ６ , R ７ and R ８ One of them is H, C １ ~C ４ Alkyl, CHF ２ , C.F. ３ , O.H., O.C.H. ３ , O.C. ２ H ５ , O.C.H.F. ２ , O.C.F. ３ and halogen, and the remaining R ５ , R ６ , R ７ and R ８ are each independently H, CH ３ or halogen; X is CN, C(O)NH ２ ,C(O)N(H)R ９ , C(O)N(C １ ~C ６ Alkyl)R ９ , C(O)(C ４ ~C ６ Heterocyclyl), CHF ２ , C.F. ３ , OH, O(C １ ~C ６ alkyl), OCHF ２ , O.C.F. ３ , S(C １ ~C ６ alkyl), SCF ３ , S.C.H.F. ２ , F, Cl, aryl and heteroaryl; Y is H, CH ３ , C(O)R ９ , C.H. ２ O.C.(O)R ９ and C(O)OR ９ selected from the group consisting of Z is (i) H, C １ ~C １０ Alkyl, substituted C １ ~C １０ Alkyl, C １ ~C １０ Heteroalkyl, C ２ ~C １０ Alkenyl, C ２ ~C １０ Heteroalkenyl, C ２ ~C １０ Alkynyl, C ３ ~C ６ Cycloalkyl, (C ３ ~C ６ Cycloalkyl) (C １ ~C ８ Alkyl), (C ３ ~C ６ Cycloalkyl) (C １ ~C ８ Heteroalkyl), C ４ ~C ６ Heterocyclyl, (C ４ ~C ６ Heterocyclyl) (C １ ~C ８ Alkyl), (C ４ ~C ６ Heterocyclyl) (C １ ~C ８ Heteroalkyl), aryl (C １ ~C ８ Alkyl), aryl (C １ ~C ８ Heteroalkyl), Heteroaryl (C １ ~C ８ Alkyl), heteroaryl (C １ ~C ８ Heteroalkyl), C(O)R ９ , C(O)OR ９ , C.H. ２ O.C.(O)R ９ , C(O)NH ２ ,C(O)N(H)R ９ , C(O)N(C １ ~C ６ Alkyl)R ９ and C(O)(C ４ ~C ６ heterocyclyl); or (ii) R ３ together form an alkanediyl, alkenediyl, heteroalkanediyl, or heteroalkenediyl moiety; wherein two of a, b, and c are each independently H, CH ３ and C ２ H ５ the third of a, b and c is H, but c and R ４ When together form an alkanediyl, alkenediyl, or heteroalkanediyl moiety, a and b are each independently H or CH ３ and Here, R ９ each independently exists; H, C １ ~C ６ Alkyl, C １ ~C ６ Heteroalkyl, substituted C １ ~C ６ Alkyl, substituted C １ ~C ６ Heteroalkyl, C ２ ~C ６ Alkenyl, C ２ ~C ６ Heteroalkenyl, C ２ ~C ６ Alkynyl, C ３ ~C ６ Cycloalkyl, (C ３ ~C ６ Cycloalkyl) (C １ ~C ６ Alkyl) (C ３ ~C ６ Cycloalkyl) (C １ ~C ６ Heteroalkyl), C ３ ~C ６ Heterocyclyl, (C ３ ~C ６ Heterocyclyl) (C １ ~C ６ Alkyl), (C ３ ~C ６ Heterocyclyl) (C １ ~C ６ Heteroalkyl), aryl, aryl (C １ ~C ６ Alkyl), aryl (C １ ~C ６ Heteroalkyl), heteroaryl, heteroaryl (C １ ~C ６ Alkyl), heteroaryl (C １ ~C ６ heteroalkyl) or an isotope or a pharma- ceutically acceptable salt thereof.

2. (i) X is CN, OH, O(C １ ~C ６ alkyl), OCHF ２ , O.C.F. ３ , S(C １ ~C ６ alkyl), SCF ３ , S.C.H.F. ２ , F, Cl, aryl and heteroaryl; and (ii) Z is H and C １ ~C １０ 2. The compound of claim 1, wherein the compound is selected from the group consisting of alkyl, isotopically or pharma- ceutically acceptable salts thereof.

3. X is CN, OH, OCH ３ , F, Cl, CF ３ , S.C.H. ３ 3. The compound according to claim 2, wherein the compound is selected from the group consisting of oxazole, pyrimidine and isoxazole, or an isotope or a pharma- ceutically acceptable salt thereof.

4. R ４ is H, F, Cl, OH, OR ９ and S.C.H. ３ 4. The compound according to claim 2 or 3, selected from the group consisting of:

5. (i) X is CN; (ii) Z is H or CH ３ and (iii) R ４ is SCH ３ 5. The compound of claim 4, wherein:

6. R １ , R ２ , R ３ , a, b, y, c, R ５ , R ６ , R ７ and R ８ The compound according to claim 5, wherein is H, or an isotope or a pharma- ceutically acceptable salt thereof.

7. The compound has the structure: 【Chemistry 2】 6. The compound of claim 5, wherein:

8. (i) X is CF ３ (ii) Z is CH ３ and (iii) R ８ The compound of claim 4, or an isotope or a pharma- ceutically acceptable salt thereof, wherein:

9. R １ , R ２ , R ３ , a, b, y, c, R ４ , R ５ , R ６ and R ７ The compound according to claim 8, wherein is H, or an isotope or a pharma- ceutically acceptable salt thereof.

10. The compound has the structure: 【Chemistry 3】 9. The compound of claim 8, wherein:

11. R ４ 4. The compound according to claim 2 or 3, wherein and c together form a heteroalkanediyl moiety, or an isotope or a pharma- ceutically acceptable salt thereof.

12. R ４ and R ５ The compound according to claim 2 or 3, wherein together form a heteroalkanediyl moiety, or an isotope or a pharma- ceutically acceptable salt thereof.

13. The heteroalkanediyl moiety is NHCH ２ CH ２ , N.H.H. ２ NH and SCH ２ CH ２ 13. The compound of claim 12, selected from the group consisting of: or an isotope or a pharma- ceutically acceptable salt thereof.

14. R ５ But, OR ９ 4. The compound according to claim 2 or 3, wherein the compound is selected from the group consisting of F and Cl, or an isotope or a pharma- ceutically acceptable salt thereof.

15. R ９ C １ ~C ６ 15. The compound of claim 14, or an isotope or a pharma- ceutically acceptable salt thereof, wherein:

16. R ５ and R ４ The compound according to claim 2 or 3, wherein together form a heteroalkanediyl moiety, or an isotope or a pharma- ceutically acceptable salt thereof.

17. The heteroalkanediyl moiety is OCH ２ CH ２ Or OCH ２ 17. The compound of claim 16, wherein R is O, or an isotope or a pharma- ceutically acceptable salt thereof.

18. R ６ is H, F, Cl and OR ９ 4. The compound according to claim 2 or 3, selected from the group consisting of:

19. R ８ is H, F, Cl, OH, OR ９ and S.C.H. ３ 4. The compound according to claim 2 or 3, selected from the group consisting of:

20. (i) X is CN; (ii) Z is H or CH ３ and (iii) R ８ is SCH ３ 20. The compound of claim 19, wherein:

21. (i) X is CF ３ (ii) Z is CH ３ and (iii) R ４ 20. The compound of claim 19, or an isotope or a pharma- ceutically acceptable salt thereof, wherein:

22. R ８ 4. The compound according to claim 2 or 3, wherein and c together form a heteroalkanediyl moiety, or an isotope or a pharma- ceutically acceptable salt thereof.

23. R ８ and R ７ The compound according to claim 2 or 3, wherein together form a heteroalkanediyl moiety, or an isotope or a pharma- ceutically acceptable salt thereof.

24. The heteroalkanediyl moiety is NHCH ２ CH ２ , N.H.H. ２ NH and SCH ２ CH ２ 24. The compound of claim 23, selected from the group consisting of: or an isotope or a pharma- ceutically acceptable salt thereof.

25. R ７ But, OR ９ 4. The compound according to claim 2 or 3, wherein the compound is selected from the group consisting of F and Cl, or an isotope or a pharma- ceutically acceptable salt thereof.

26. R ９ C １ ~C ６ 26. The compound of claim 25, or an isotope or a pharma- ceutically acceptable salt thereof, wherein:

27. R ７ and R ８ The compound according to claim 2 or 3, wherein together form a heteroalkanediyl moiety, or an isotope or a pharma- ceutically acceptable salt thereof.

28. The heteroalkanediyl moiety is OCH ２ CH ２ Or OCH ２ 28. The compound of claim 27, wherein R is O, or an isotope or a pharma- ceutically acceptable salt thereof.

29. Use of a compound according to any one of claims 1 to 28 or an isotope or a pharma- ceutically acceptable salt thereof for the treatment of neuropsychiatric, neurodegenerative, neuroinflammatory and pain disorders.

30. 29. Use of a compound according to any one of claims 1 to 28, or an isotope or a pharma- ceutically acceptable salt thereof, as a medicament in the treatment of neuropsychiatric, neurodegenerative, neuroinflammatory and pain disorders.

31. 30. Use of a compound according to any one of claims 1 to 28, or an isotope or a pharma- ceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a neuropsychiatric disorder, a neurodegenerative disorder, a neuroinflammatory disorder and a pain disorder.

32. 32. The use according to any one of claims 29 to 31, wherein the neuropsychiatric, neurodegenerative, neuroinflammatory and pain disorders include depression, drug (e.g. tobacco, opiate and cocaine) addiction, alcoholism, post-traumatic stress disorder (PTSD) and neuropathic pain syndromes including cluster headache and chemotherapy-induced peripheral neuropathy.

33. 30. Use of a compound according to any one of claims 1 to 28, or an isotope or a pharma- ceutically acceptable salt thereof, for the treatment of obsessive-compulsive disorder, anxiety disorder, phobic disorder and aggression in an animal.

34. 34. The use according to claim 33, wherein the animal is selected from the group consisting of dogs, cats, pigs, mice and rats.

35. 30. Use of a compound according to any one of claims 1 to 28, or an isotope or a pharma- ceutically acceptable salt thereof, for inducing ureteral contraction in an animal.

36. 36. The use according to claim 35, wherein the animal is selected from the group consisting of dogs, cats, pigs, mice and rats.

37. 29. A method for treating neuropsychiatric, neurodegenerative, neuroinflammatory and pain disorders in a patient comprising administering an effective amount of a compound according to any one of claims 1 to 28 or an isotope or a pharma-ceutically acceptable salt thereof.

38. 29. A method for treating hypertension, hypotension, cardiovascular disease, vascular disorders such as stroke and stroke recovery in a patient comprising administering an effective amount of a compound according to any one of claims 1 to 28, or an isotope or a pharma-ceutically acceptable salt thereof.

39. 29. A method for modulating inflammation mediated by circulating platelet cells in a patient comprising administering an effective amount of a compound according to any one of claims 1 to 28, or an isotope or a pharma-ceutically acceptable salt thereof.

40. 29. A method for regulating intestinal motility in a patient, comprising administering an effective amount of a compound according to any one of claims 1 to 28, or an isotope or a pharma- ceutically acceptable salt thereof.

41. 29. A method for inducing ureteral contraction in an animal, comprising administering an effective amount of a compound according to any one of claims 1 to 28, or an isotope or a pharma- ceutically acceptable salt thereof.

42. 29. A method for treating obsessive-compulsive disorder, anxiety disorder, phobia disorder and aggression in an animal comprising administering an effective amount of a compound according to any one of claims 1 to 28 or an isotope or a pharma-ceutically acceptable salt thereof.

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