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WO2025220005A1 - Composés et leurs utilisations en tant que modulateurs des récepteurs de la sérotonine - Google Patents

Composés et leurs utilisations en tant que modulateurs des récepteurs de la sérotonine

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Publication number
WO2025220005A1
WO2025220005A1 PCT/IL2025/050334 IL2025050334W WO2025220005A1 WO 2025220005 A1 WO2025220005 A1 WO 2025220005A1 IL 2025050334 W IL2025050334 W IL 2025050334W WO 2025220005 A1 WO2025220005 A1 WO 2025220005A1
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WO
WIPO (PCT)
Prior art keywords
formula
smc
disease
disorder
alkyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
PCT/IL2025/050334
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English (en)
Inventor
Bernard Lerer
Alan Kozikowski
Peretz GOLDING
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Hadasit Medical Research Services and Development Co
Original Assignee
Hadasit Medical Research Services and Development Co
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Publication of WO2025220005A1 publication Critical patent/WO2025220005A1/fr
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Anticipated expiration legal-status Critical

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia

Definitions

  • the present disclosure relates to compound and pharmaceutical uses thereof.
  • Serotonin also known as 5-hydroxytryptamine (5-HT)
  • 5-HT 5-hydroxytryptamine
  • Serotonin is a neurotransmitter that plays a central role in the functioning of the central nervous system (CNS) regulating various physiological and behavioral functions. Serotonin exerts its effects by binding to specific receptor proteins known as serotonin receptors.
  • a small molecule compound having a structure represented by the general Formula (la) or (lb): or a pharmaceutically acceptable salt, solvate, hydrate, any stereoisomer thereof, an isotopologue or physiologically functional derivative thereof, wherein each one of Xi, X2, X3, X4, is independently selected from N or C, each one of X5.
  • Xr, and X7 is independently selected from N, S, O or C, each of Ri, R2, R4, Re, and R7, if present, is independently hydrogen, deuterium, cyano, amino, amide, nitro, hydroxy, oxo, halo, C1-C12 alkyl, C1-C12 haloalkyl, C2-C12 alkenyl, C2-C12 haloalkenyl, C2-Ci2alkynyl, C2-C12 haloalkynyl, C1-C12 alkoxy, C1-C12 haloalkoxy, urea, sulfonylurea, sulfonamidyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, trifluoromethyl, -N(R n )(R 12 ), -C(O)R n , -CH2R 11 , -CO2R 11 , -C(
  • each R 11 and R 12 is independently H, hydroxyl, Ci- C12 alkyl, C1-C12 haloalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, R5 is -Z-Rs orL2- Z-Rs, Z is S, S(O), S(O 2 ), Rs is hydrogen, cyano, nitro, hydroxy, halo, CF3, C1-C12 haloalkyl, C1-C12 haloalkoxy, C1-C12 alkyl, C1-C12 alkoxy, aryl and N(R n )(R 12 ).
  • a composition comprising at least one SMC as defined herein.
  • a SMC or a composition as defined herein for use in modulating one or more serotonergic receptors is provided.
  • a SMC or a composition as defined herein for use in a method for treating, preventing, inhibiting, reducing, eliminating, protecting or delaying the onset of a disorder characterized by deregulated 5- HT1 A receptor function.
  • a SMC or composition as defined herein for use in a method for treating, preventing, inhibiting, reducing, eliminating, protecting or delaying a brain disease.
  • a method for modulating at least one serotonin receptor comprising contacting at least one serotonin receptor with at least one SMC or a composition as defined herein.
  • a method for treating, preventing, inhibiting, reducing, eliminating, protecting or delaying the onset of disorder characterized by deregulated 5- HT1A receptor function comprising administering to a subject in need thereof an effective amount of at least one SMC or a composition as defined herein to thereby treat the disorder.
  • a method for treating, preventing, inhibiting, reducing, eliminating, protecting or delaying the onset of brain disease comprising administering to a subject in need thereof an effective amount of at least one SMC or a composition as defined herein to thereby treat the brain disorder.
  • Figures 1A-1B are graphs showing HBL20017 binding affinity for various receptor and transporter targets using radioligand binding assays (Figure 1A) and HBL20017 affinity for various enzyme targets ( Figure IB).
  • FIGS 2A-2D shows head twitch response (HTR) results of Psilocybin (PSIL), and tested compounds, Figure 2 A HBL20016 and HBL20017 at various concentrations, Figures 2B-2D HBL20028 at various concentrations.
  • HTR head twitch response
  • PSIL Psilocybin
  • Figures 3A to 3F are graphs showing open field test (OFT), Figures 3A and 3B show the total distance induced by PSIL, HBL20016 and HBL20017, respectively, Figure 3C shows distance travelled 2 hours and 24 hours after HBL20017 6mg/kg, Figure 3D shows the distance covered by PSIL and HBL20028, Figure 3E shows the center duration by PSIL and HBL20028, Figure 3F shows the periphery duration by PSIL and HBL20028.
  • OFT open field test
  • Figures 4A to 4D are graphs showing marble burying (MB) experiments
  • Figure 4A shows results of MB induced by PSIL, HBL20016, HBL20017 at 30 minutes
  • Figure 4B shows the time course of MB of these compounds
  • Figure 4C shows results after 30 minutes for HBL20017
  • WAY 100635 (5-HT1A antagonist) and M100907
  • Figure 4D shows the time course of MB of these compounds.
  • Figure 5A-5D are graphs showing Self Grooming Duration
  • Figure 5A shows the effect of HBL20016 (6mg/kg), HBL20017 (6 mg/kg) and psilocybin (4.4 mg/kg) on total self-grooming duration of SAPAP3 KO mice up to 21 days following treatment administration versus control (vehicle) treatment.
  • Figure 5B shows the effect of the same treatments (without control) on total self-grooming duration of S APAP3 KO mice up to 42 days following treatment administration.
  • Figure 5C shows the effect of HBL20016 (6mg/kg), HBL20017 (6 mg/kg) and psilocybin (4.4 mg/kg) on head-body twitches of SAPAP3 KO mice up to 21 days following treatment administration versus control (vehicle) treatment.
  • Figure 5D shows the effect of the same treatments (without control) on head-body twitches of SAPAP3 KO mice up to 42 days following treatment administration.
  • Figures 6A to 6L are graphs showing obsessive-like Behavior in SAPAP3 Knockout Mice;
  • Figures 6A and 6B are graphs showing % Change from baseline to 21 days in total grooming bouts following treatment with HBL20016, HBL20017 at 6mg/kg IP or Vehicle,
  • Figure 6B includes treatment group that received psilocybin 4.4 mg/kg as a positive comparator;
  • Figures 6C and 6D are graphs showing % Change from baseline to 21 days in short self-grooming bouts following treatment with HBL20016, HBL20017 at 6mg/kg IP or Vehicle,
  • Figure 6D includes treatment group that received psilocybin 4.4 mg/kg as a positive comparator;
  • Figures 6E and 6F are graphs showing % Change from baseline to 21 days in long self-grooming bouts following treatment with HBL20016, HBL20017 at 6mg/kg IP or Vehicle,
  • Figure 6F includes treatment group that received psilocybin
  • Figures 8A and 8B are graphs showing Immobility Time and swimming Time.
  • SMC small molecule compounds
  • the small molecule compounds are characterized by maintaining function at specific serotonergic receptors, including 5-HT1 A and 5-HT2A receptor agonist activity.
  • the compounds described herein may act as 5-HT1A and 5-HT2A receptor agonist for treatment of disorders or diseases characterized by abnormal 5-HT1A and 5-HT2A receptor activity.
  • the small molecule compounds are characterized by minimized HT2B receptor activity.
  • a small molecule compound having a structure represented by general Formula (la): or a pharmaceutically acceptable salt, solvate, hydrate, any stereoisomer thereof, an isotopologue or physiologically functional derivative thereof, wherein a dashed line (— ) represent a single bond or a double bond, each one of Xi, X2, X3, X4, is independently selected from N or C, each one of X5.
  • SMC small molecule compound having a structure represented by general Formula (la): or a pharmaceutically acceptable salt, solvate, hydrate, any stereoisomer thereof, an isotopologue or physiologically functional derivative thereof, wherein a dashed line (— ) represent a single bond or a double bond, each one of Xi, X2, X3, X4, is independently selected from N or C, each one of X5.
  • Xr, and X7 is independently selected from N, S, O or C, each one of Ri, R2, R4, Re, and R7, if present, is independently selected from hydrogen, deuterium, cyano, amino, amide, nitro, hydroxy, oxo, halo, C1-C12 alkyl, C1-C12 haloalkyl, C2-C12 alkenyl, C2-C12 haloalkenyl, C2-Ci2alkynyl, C2-C12 haloalkynyl, C1-C12 alkoxy, Ci- C12 haloalkoxy, urea, sulfonylurea, sulfonamidyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, trifluoromethyl, -N(R n )(R 12 ), -C(O)R n , -CH2R 11 , -CO2R 11 ,
  • R 3 IS L2-R9, L 2 IS -(CH 2 ) m - ,-C(0)-, -o-, -NH-, -0-CH2-, -N-(CH 2 )m- -NH-C(O)- , each optionally substituted with Ci-Ci 2 alkyl, C1-C12 haloalkyl, or halo, m is selected from 0, 1, 2, 3, 4, 5 or 6,
  • R9 is hydrogen, cyano, amino, amide, nitro, hydroxy, oxo, halo, C1-C12 alkyl, C1-C12 haloalkyl, C2-C12 alkenyl, C2-C12 haloalkenyl, C 2 -Ci 2 alkynyl, C2-C12 haloalkynyl, C1-C12 alkoxy, C1-C12 haloalkoxy, urea, sulfonylurea, sulfonamidyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, trifluoromethyl, -N(R n )(R 12 ), -C(O)R n , -CH 2 R n , -CO 2 R n , -C(O)N(R n )(R 12 ), -SO 2 N(R n )(R 12 ), each R 11 and R 12 is
  • a SMC having a structure represented by the general Formula (lb): or a pharmaceutically acceptable salt, solvate, hydrate, any stereoisomer thereof, an isotopologue or physiologically functional derivative thereof, wherein each one of Xi, X 2 , X3, X4, is independently selected from N or C, each one of X5.
  • Xr, and X7 is independently selected from N, S, O or C, each of Ri, R 2 , R4, Re, and R7, if present, is independently hydrogen, deuterium, cyano, amino, amide, nitro, hydroxy, oxo, halo, C1-C12 alkyl, C1-C12 haloalkyl, C2-C12 alkenyl, C2-C12 haloalkenyl, C2-C12 alkynyl, C2-C12 haloalkynyl, C1-C12 alkoxy, C1-C12 haloalkoxy, urea, sulfonylurea, sulfonamidyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, trifluoromethyl, -N(R n )(R 12 ), -C(O)R n , -CH2R 11 , -CO2R 11 , -C
  • R 3 IS L2-R9, L 2 IS — (CH 2 )m- ,-C(O)-, -O-, -NH-, -O-CH2-, -N-(CH 2 ) m - -NH-C(O)- , each optionally substituted with C1-C12 alkyl, C1-C12 haloalkyl, or halo, m is selected from 0, 1, 2, 3, 4, 5 or 6,
  • R9 is hydrogen, cyano, amino, amide, nitro, hydroxy, oxo, halo, C1-C12 alkyl, C1-C12 haloalkyl, C2-C12 alkenyl, C2-C12 haloalkenyl, C2-Ci2alkynyl, C2-C12 haloalkynyl, C1-C12 alkoxy, C1-C12 haloalkoxy, urea, sulfonylurea, sulfonamidyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, trifluoromethyl, -N(R n )(R 12 ), -C(O)R n , -CH2R 11 , -CO2R 11 , -C(O)N(R n )(R 12 ), -SO2N(R n )(R 12 ), each R 11 and R 12 is independently H,
  • each one of Xi, X2, X3, and X4 is C.
  • X5 and Xe is C.
  • X 7 is N.
  • the present disclosure provides a SMC having a structure represented by the general Formula (la’): or a pharmaceutically acceptable salt, solvate, hydrate, any stereoisomer thereof, an isotopologue or physiologically functional derivative thereof, wherein each one of Xi, X2, X3, X4, X5.
  • Xrdon Ri, R2, R3, R4, R5, Re, and R7 are as defined above for SMC of Formula (la).
  • any one of Xi, X2, X3, X4, X5, Xe may be substituted with one or more of the corresponding substituents provided by R2, R3, R4, R5, Re, and R7.
  • the present disclosure provides a SMC having a structure represented by the general Formula (lb’): or a pharmaceutically acceptable salt, solvate, hydrate, any stereoisomer thereof, an isotopologue or physiologically functional derivative thereof, wherein each one of Xi, X2, X3, X4, R1, R2, R3, R4, R5, Re, and R7 are as defined above for SMC of Formula (lb).
  • the SMC having a structure represented by Formula (la), (lb), (la’), (lb’) at least one of Xi, X2, X3, and X4 is C.
  • in the SMC having a structure represented by Formula (la), (lb), (la’), (lb’) two of Xi, X2, X3, and X4 is C.
  • in the SMC having a structure represented by Formula (la), (lb), (la’), (lb’) three of Xi, X2, X3, and X4 is C.
  • each one of Xi, X2, X3, and X4 is C.
  • the SMC having a structure represented by the general Formula (Ic): or a pharmaceutically acceptable salt, solvate, hydrate, any stereoisomer thereof, isotopologueor physiologically functional derivative thereof, wherein each one of Ri, R2, R3, R4, R5.R6, and R7 are as defined above for SMC of Formula (lb).
  • R5 is -Z-Rs or L2-Z-R8, Z is S, S(O) or S(O 2 ) and Rs is hydrogen, cyano, nitro, hydroxy, halo, CF3, C1-C12 haloalkyl, Ci- C12 haloalkoxy, C1-C12 alkyl, C1-C12 alkoxy and aryl.
  • R5 is -Z-Rs
  • Z is S, S(O) or S(O 2)
  • R8 is hydrogen, CF3 or C1-C12 alkyl.
  • the SMC has a structure represented by the general Formula (II): or a pharmaceutically acceptable salt, solvate, hydrate, any stereoisomer thereof, an isotopologue or physiologically functional derivative thereof, each of Ri, R2, R4, Re, and R7, if present, is independently hydrogen, cyano, amino, amide, nitro, hydroxy, oxo, halo, C1-C12 alkyl, C1-C12 haloalkyl, C2-C12 alkenyl, C2-C12 haloalkenyl, Ci-Cnalkynyl, C2-C12 haloalkynyl, C1-C12 alkoxy, C1-C12 haloalkoxy, urea, sulfonylurea, sulfonamidyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, trifluoromethyl, -N(R): or a pharmaceutically acceptable salt, solvate
  • L 2 is -(CH 2 ) m -, -C(O)-, -O-, -NH-, -O-CH2-, -N- CH2-, and -NH-C(O)-, each optionally substituted with C1-C12 alkyl, C1-C12 haloalkyl, or halo
  • R9 is hydrogen, cyano, amino, amide, nitro, hydroxy, oxo, halo, C1-C12 alkyl, C1-C12 haloalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, or -N(R n )(R 12 ), each R 11 and R 12 is independently H, hydroxyl, C1-C12 alkyl and m is selected from 0, 1,
  • R 3 is L2-R9, L2 is -(CH2) m -, optionally substituted with C1-C12 alkyl, C1-C12 haloalkyl, or halo, R9 is hydrogen, heterocycloalkyl, or -N(R n )(R 12 ), each R 11 and R 12 is independently H, C1-C12 alkyl or R 11 and R 12 together with the nitrogen atom they are connected to form a ring system optionally include at least one of N, O and m is selected from 0, 1, 2, 3, 4, 5 or 6.
  • R3 is L2-R9
  • L2 is -(012)2- optionally substituted with C1-C12 alkyl, C1-C12 haloalkyl, or halo
  • R9 is hydrogen, heterocycloalkyl, or -N(R n )(R 12 )
  • each R 11 and R 12 is independently H, C1-C12 alkyl or R 11 and R 12 together with the nitrogen atom they are connected to form a ring system optionally include at least one of N, O.
  • R3 is L2-R9, L2 is -(CH2)2-, R9 is -N(R n )(R 12 ), each R 11 and R 12 is independently H, C1-C12 alkyl or R 11 and R 12 together with the nitrogen atom they are connected to form a ring system optionally include at least one of N, O.
  • the SMC has a structure represented by the general Formula (ma): or a pharmaceutically acceptable salt, solvate, hydrate, any stereoisomer thereof, an isotopologue or physiologically functional derivative thereof, wherein each one of Ri, R2, R4, Re, R7, Z, Rs R 11 and R 12 are as defined in Formula (II), each one of R13, R14, R15, Ri6 is independently from the other selected from the group consisting of hydrogen, halo, C1-C12 alkyl.
  • each one of R13, R14, R15, R16 is a hydrogen.
  • the SMC has a structure represented by the general Formula (mb): or a pharmaceutically acceptable salt, solvate, hydrate, any stereoisomer thereof, an isotopologue or physiologically functional derivative thereof, wherein each one of Ri, R2, R4, Re, R7, Z, Rs R 11 and R 12 are as defined in Formula (II).
  • each R 11 and R 12 is each Ci-Ce alkyl or R 11 and R 12 together with the nitrogen atom they are connected to form a ring system optionally include at least one of N, O.
  • the SMC has a structure represented by the general Formula of any one of Formula (IVa) or Formula (IVb): or a pharmaceutically acceptable salt, solvate, hydrate, any stereoisomer thereof, an isotopologue or physiologically functional derivative thereof, wherein each one of Ri, R2, R4, R6, R7, Z and Rs are as defined in Formula (II).
  • Z is S, S(O) or S(Ch). In some embodiments, Z is S.
  • Rs is hydrogen, cyano, nitro, hydroxy, halo, CF3, C1-C12 haloalkyl, C1-C12 haloalkoxy, C1-C12 alkyl, C1-C12 alkoxy, aryl and N(R n )(R 12 ).
  • Rs is hydrogen, cyano, nitro, hydroxy, halo, CF3, C1-C12 haloalkyl, C1-C12 haloalkoxy, C1-C12 alkyl, C1-C12 alkoxy and aryl.
  • Rs is hydrogen, CF3, C1-C12 alkyl.
  • R2 is hydrogen.
  • Z is S and Rs is hydrogen, CF3, C1-C12 alkyl. In some embodiments, Z is S(O) and Rs is C1-C12 alkyl. In some embodiments, Z is S(O2) and Rs is C1-C12 alkyl.
  • the SMC has a structure represented by the general Formula of any one of Formula (Va), Formula (Vb), Formula (Vc), Formula (Vd), Formula (Ve) or Formula (Vf): or a pharmaceutically acceptable salt, solvate, hydrate, any stereoisomer thereof, an isotopologue or physiologically functional derivative thereof, wherein Ri, R4, Re, R7, is as defined for Formula (II).
  • the SMC has a structure represented by the general Formula (Va).
  • the SMC has a structure represented by the general Formula (Vf).
  • each one of Ri, R2, R4, Re, and R7 is independently selected from hydrogen, cyano, amino, amide, nitro, hydroxy, halo, C1-C12 alkyl, C1-C12 haloalkyl, -CH2R 11 , wherein R 11 is selected from cycloalkyl, heterocycloalkyl, aryl, heteroaryl.
  • each one of Ri, R2, R4, Re, R7 is hydrogen, halo and C1-C12 alkyl, -CH2R 11 , wherein R 11 is cycloalkyl.
  • Ri is hydrogen or C1-C12 alkyl. In some embodiments, Ri is hydrogen or C1-C3 alkyl. In some embodiments, Ri is hydrogen. In some embodiments, Ri is C2 alkyl. In some embodiments, Ri is CH2R 11 , wherein R 11 is cycloalkyl. In some embodiments, Ri is CH2R 11 , wherein R 11 is cyclopropyl.
  • R2 is hydrogen
  • each one of R4, R6, R7 is independently from the other independently selected from the group consisting of hydrogen, halo, C1-C12 alkyl. In some embodiments, each one of R4, Re, R7, is independently from the other independently selected from the group consisting of hydrogen, halo, C1-C3 alkyl. In some embodiments, each one of R4, Re, R7, is independently from the other independently selected from the group consisting of hydrogen, fluorine, C1-C12 alkyl. In some embodiments, each one of R4, Re, R7, is independently from the other independently selected from the group consisting of hydrogen, fluorine, C1-C3 alkyl.
  • the SMC has a structure represented by a Formula of (Va) and Ri is hydrogen, at least one of R4, Re, R7 is not hydrogen.
  • the SMC has a structure represented by a Formula of (Va) and Ri is hydrogen, C1-C3 alkyl, or CH2R 11 , wherein R 11 is cyclopropyl, Ri is hydrogen, R4, Re, R7, is independently hydrogen, fluorine, C1-C3 alkyl.
  • in the SMC has a structure represented by a Formula of (Va) and Ri is CH2R 11 , wherein R 11 is cyclopropyl, R2 is hydrogen, R4, Re, R7, is independently hydrogen, fluorine, C1-C3 alkyl.
  • R2 is hydrogen, R4, Re, R7, is independently hydrogen, fluorine, C1-C3 alkyl.
  • in the SMC has a structure represented by a Formula of (Va) and Ri is C2 alkyl, R2 is hydrogen, R4, Re, R7, is independently hydrogen, fluorine, C1-C3 alkyl.
  • in the SMC has a structure represented by a Formula of (Vf) and Ri is hydrogen, C1-C3 alkyl, or CH2R 11 , wherein R 11 is cyclopropyl, R2 is hydrogen, R4, Re, R7, is independently hydrogen, fluorine, C1-C3 alkyl.
  • in the SMC has a structure represented by a Formula of (Vf) and Ri is CH2R 11 , wherein R 11 is cyclopropyl, R2 is hydrogen, R4, Re, R7, is independently hydrogen, fluorine, C1-C3 alkyl.
  • in the SMC has a structure represented by a Formula of (Vf) and Ri is hydrogen, R2 is hydrogen, R4, Re, R7, is independently hydrogen, fluorine, C1-C3 alkyl. In some embodiments, in the SMC has a structure represented by a Formula of (Vf) and Ri is C2 alkyl, R2 is hydrogen, R4, R6, R7, is independently hydrogen, fluorine, C1-C3 alkyl.
  • At least one SMC has a structure represented by at least one of the following:
  • HBL20010 N,N-dimethyl-2-(7-methyl-5-(methylthio)-lH-indol-3-yl)ethanamine
  • HBL20010 N,N-dimethyl-2-(7-methyl-5-(methylthio)-lH-indol-3-yl)ethanamine
  • HBL20010 pharmaceutically acceptable salt, solvate, hydrate, stereoisomer or physiologically functional derivative thereof
  • HBL001-7 2-(4-fhioro-5-(methylthio)-lH-indol-3-yl)-N,N-dimethylethanamine (denoted herein as HBL0017) or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer or physiologically functional derivative thereof,
  • HBL20024 4-fluoro-5-(methylthio)-3-(2-(pyrrolidin-l-yl)ethyl)-lH-indole (denoted herein as HBL20024) or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer or physiologically functional derivative thereof,
  • HBL0025 a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer or physiologically functional derivative thereof
  • HBL20026 or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer or physiologically functional derivative thereof, 2-(l-(cyclopropylmethyl)-4-fluoro-5-(methylthio)-lH-indol-3-yl)-N,N- dimethylethanamine (denoted herein as HBL20028), or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer or physiologically functional derivative thereof.
  • the SMC has a structure represented by one or more of Formula (XIII), Formula (XIV), Formula (XV), Formula (XXI) or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer or physiologically functional derivative thereof.
  • the SMC has a structure represented by Formula (XIII) (denoted herein HBL20015) or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer or physiologically functional derivative thereof.
  • the SMC has a structure represented by Formula (XIV) (denoted herein HBL20016) or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer or physiologically functional derivative thereof.
  • the SMC has a structure represented by Formula (XV) (denoted herein HBL20017) or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer or physiologically functional derivative thereof.
  • the SMC has a structure represented by Formula (XXI) (denoted herein HBL20028) or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer or physiologically functional derivative thereof.
  • a small molecule in the context of the present disclosure refers to a low molecular weight organic compound, having a molecular weight lower than 900 Daltons.
  • the SMC of the invention and/or used by the invention may be any SMC having a structure represented by Formula (la), Formula (la’), Formula (lb), Formula (lb’), Formula (Ic), Formula (II), Formula (Illa), Formula (mb), Formula (IVa), Formula (IVb), Formula (Va), Formula (Vb), Formula (Vc), Formula (Vd), Formula (Ve), or Formula (Vf), with the proviso that the compound is not any of the compounds detailed below:
  • the invention provides a SMCs of any one of the SMC having a structure represented by one or more of Formula (X), Formula (XI), Formula (XII), Formula (XHI), Formula (XIV), Formula (XV), Formula (XVI), Formula (XVII), Formula (XVIII), Formula (XIX), Formula (XX), or Formula (XXI) as described herein and any analogs or derivative thereof including any stereoisomer or salt thereof or any vehicle, matrix, nano- or micro-particle, or composition comprising the same.
  • the SMC is not represented by Formula (XIII). In some embodiments, the SMC is not represented by Formula (XIV). In some embodiments, the SMC is not represented by Formula (XV).
  • a further aspect of the present disclosure relates to a composition
  • a composition comprising as an active ingredient an effective amount of at least one SMC of the invention, the composition optionally further comprises at least one of pharmaceutically acceptable carrier/s, excipient/s, auxiliaries, and/or diluent/s.
  • the composition is a pharmaceutical composition comprising at least one SMC having a structure represented by any one of Formula (la), Formula (la’), Formula (lb), Formula (lb’), Formula (Ic), Formula (II), Formula (Illa), Formula (Illb), Formula (IVa), Formula (IVb), Formula (Va), Formula (Vb), Formula (Vc), Formula (Vd), Formula (Ve), or Formula (Vf).
  • the composition is a pharmaceutical composition comprising at least one SMC has a structure represented by one or more of Formula (X), Formula (XI), Formula (XII), Formula (XIII), Formula (XIV), Formula (XV), Formula (XVI), Formula (XVH), Formula (XVIII), Formula (XIX), Formula (XX), Formula (XXI), a combination thereof or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer or physiologically functional derivative thereof.
  • the composition is a pharmaceutical composition comprising at least one SMC having a structure represented by one or more of Formula (XV), Formula (XXI), a combination thereof or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer or physiologically functional derivative thereof.
  • the composition is a pharmaceutical composition comprising at least one SMC having the structure represented by Formula (XIII) or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer or physiologically functional derivative thereof.
  • the composition is a pharmaceutical composition comprising at least one SMC having the structure represented by Formula (XIV) or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer or physiologically functional derivative thereof.
  • the composition is a pharmaceutical composition comprising at least one SMC having the structure represented by Formula (XV) or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer or physiologically functional derivative thereof.
  • the composition is a pharmaceutical composition comprising at least one SMC having the structure represented by Formula (XXI) or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer or physiologically functional derivative thereof.
  • compositions of the invention may comprise an effective amount of at least one SMC of the invention.
  • compositions of the invention can be administered and dosed by the methods of the invention, in accordance with good medical practice, systemically, for example intravenously. It should be noted however that the invention may further encompass additional administration modes.
  • the pharmaceutical composition can be introduced to a site by any suitable route including oral, intranasal, or intraocular administration, intraperitoneal, subcutaneous, transcutaneous, topical, intramuscular, intraarticular, subconjunctival, or mucosal.
  • composition of the invention may optionally further comprise at least one of pharmaceutically acceptable carrier/s, excipient/s, additive/s diluent/s and adjuvant/s.
  • pharmaceutical compositions used to treat subjects in need thereof according to the invention may be prepared according to conventional techniques well known in the pharmaceutical industry. Such techniques include the step of bringing into association the active ingredients with the pharmaceutical carrier(s) or excipient(s). In general formulations are prepared by uniformly and intimately bringing into association the active ingredients, specifically, the compound of the invention with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product.
  • compositions may be formulated into any of many possible dosage forms such as, but not limited to, tablets, capsules, liquid syrups, soft gels, suppositories, and enemas.
  • the compositions of the present invention may also be formulated as suspensions in aqueous, non-aqueous or mixed media.
  • Aqueous suspensions may further contain substances which increase the viscosity of the suspension including, for example, sodium carboxymethylcellulose, sorbitol and/or dextran.
  • the suspension may also contain stabilizers.
  • the pharmaceutical compositions of the present invention also include, but are not limited to, emulsions and liposome-containing formulations. It should be understood that in addition to the ingredients particularly mentioned above, the formulations may also include other agents conventional in the art having regard to the type of formulation in question.
  • serotonergic receptors refers to a class of receptors found in the central nervous system (CNS) and other tissues throughout the body that respond to the neurotransmitter serotonin (5-hydroxytryptamine or 5-HT).
  • This class of receptors includes two main categories based on their signaling mechanisms: metabotropic (G-protein coupled) receptors and ionotropic (ligand-gated ion channel) receptors.
  • metabotropic receptors modulate intracellular signaling pathways through G-proteins, while the ionotropic receptors directly affect ion flow across the cell membrane.
  • 5-HT1 receptors include subtypes such as 5-HT1A, 5-HT1B, 5-HT1D, 5-HT1E, and 5-HT1F
  • 5-HT2 receptors include subtypes such as 5-HT2A, 5-HT2B, and 5-HT2C, 5-HT3 receptors, 5-HT4 receptors, 5-HT5 receptors, 5-HT6 receptors and 5-HT7 receptors.
  • HBL20010 showed strong efficacy at 5-HT2A and 5-HT2B, and less efficacy at 5-HT1 A.
  • HBL20011 and HBL20012 showed moderate efficacy at 5-HT2A and 5-HT2B, but no activity at all at 5-HT1A.
  • HBL20015, HBL20016 and HBL20017 showed agonistic activity both at 5-HT1 A, 5-HT2A and 5-HT1B, with HBL20017 showing the strongest efficacy at 5-HT1 A.
  • HBL20028 showed a reduction in functional activity at 5-HT2B while retaining the activity at both 5-HT1A and 5-HT2A.
  • the present disclosure provides at least one SMC or a composition comprising at least one SMC for use in modulating activity of one or more serotonergic receptors.
  • modulating or modulator includes at least one compound as describe herein that may alter function for example of one or more serotonergic receptors and encompasses receptor activators and/or receptor inhibitors.
  • Inhibitors are agents that inhibit, partially or totally block stimulation or activation, decrease, prevent, delay activation, inactivate, desensitize, or down regulate the receptor activity in accordance with the invention, e.g., antagonists, and include direct inhibitor/s and/or indirect inhibitor/s.
  • the antagonist may be a competitive antagonist. As appreciated, a competitive antagonist directly and physically blocks access of the agonist to the receptor.
  • the antagonist may be a negative allosteric modulator of one or more of the receptors described herein.
  • a negative allosteric modulator indirectly changes agonist binding by interacting at a secondary site on the receptor to diminish the ability of the agonist to bind to the primary site.
  • Activators are agents that induce, activate, stimulate, increase, facilitate, enhance activation, sensitize or up regulate the activation of receptor activity, e.g., agonists, and include indirect activator/s and/or indirect activator/s.
  • At least one SMC represented by any at least one of Formula (la), Formula (la’), Formula (lb), Formula (lb’), Formula (Ic), Formula (II), Formula (Illa), Formula (Illb), Formula (IVa), Formula (IVb), Formula (Va), Formula (Vb), Formula (Vc), Formula (Vd), Formula (Ve), or Formula (Vf) for use in modulating activity of one or more serotonergic receptors.
  • At least one SMC having a structure represented by at least one of Formula (X), Formula (XI), Formula (XII), Formula (XIII), Formula (XIV), Formula (XV), Formula (XVI), Formula (XVII), Formula (XVIII), Formula (XIX), Formula (XX), Formula (XXI), for use in modulating activity of one or more serotonergic receptors.
  • At least one SMC represented by any at least one of Formula (la), Formula (la’), Formula (lb), Formula (lb’), Formula (Ic), Formula (II), Formula (Illa), Formula (Illb), Formula (IVa), Formula (IVb), Formula (Va), Formula (Vb), Formula (Vc), Formula (Vd), Formula (Ve), or Formula (Vf), or having a structure represented by at least one of Formula (X), Formula (XI), Formula (XII), Formula (XIII), Formula (XIV), Formula (XV), Formula (XVI), Formula (XVII), Formula (XVIII), Formula (XIX), Formula (XX), Formula (XXI), for use in modulating activity of one or more of 5-HT1 A receptor and/or 5-HT2A receptor and/or 5-HT2B receptor and/or 5-HT2C receptor.
  • the compound represented by any one of Formula (la), Formula (la’), Formula (lb), Formula (lb’), Formula (Ic), Formula (II), Formula (Illa), Formula (Illb), Formula (IVa), Formula (IVb), Formula (Va), Formula (Vb), Formula (Vc), Formula (Vd), Formula (Ve), or Formula (Vf), or is one or more of compounds having the structure of one or more of Formula (X), Formula (XI), Formula (XII), Formula (XHI), Formula (XIV), Formula (XV), Formula (XVI), Formula (XVII), Formula (XVIII), Formula (XIX), Formula (XX), Formula (XXI) is for modulating 5-HT1A receptor.
  • 5-HT1A receptor refers to a subclass of a family of receptors for the neurotransmitter and peripheral signal mediator serotonin that may mediate a variety of central and peripheral physiologic functions of serotonin.
  • modulating 5-HT1A receptor refers to the ability of a SMC disclosed herein to alter the function of 5-HT1A receptor, for example, by increasing or decreasing the direct or indirect interaction between a 5-HT1 A receptor and a ligand, such as a natural binding ligand.
  • a 5-HT1 A receptor modulator may increase the activity or inhibit the activity of a 5- HT1 A receptor by acting as an agonist or antagonist of the 5-HT1A receptor.
  • At least one SMC is an activator of 5-HT1 A receptor. In some embodiments, at least one SMC is an agonist of 5-HT1 A receptor.
  • the SMC represented by any one of general Formula (la), Formula (la’), Formula (lb), Formula (lb’), Formula (Ic), Formula (II), Formula (Illa), Formula (Illb), Formula (IVa), Formula (IVb), Formula (Va), Formula (Vb), Formula (Vc), Formula (Vd), Formula (Ve), or Formula (Vf), is for use in activating 5-HT1 A receptor.
  • At least one SMC having the structure of any one of Formula (X), Formula (XI), Formula (XII), Formula (XIII), Formula (XIV), Formula (XV), Formula (XVI), Formula (XVII), Formula (XVIII), Formula (XIX), Formula (XX), Formula (XXI), is for use in activating 5-HT1A receptor.
  • At least one SMC having the structure of Formula (XIII), Formula (XIV), Formula (XV), Formula (XXI) or any combination thereof is for use in activating 5-HT1A receptor.
  • At least one SMC having the structure of (XIII) or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer or physiologically functional derivative thereof for use in activating 5-HT1 A receptor it is provided at least one SMC having the structure of (XIV) or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer or physiologically functional derivative thereof for use in activating 5-HT1 A receptor.
  • At least one SMC having the structure of (XV) or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer or physiologically functional derivative thereof for use in activating 5-HT1 A receptor In some embodiments that may be considered as aspects of the present disclosure, it is provided at least one SMC having the structure of (XXI) or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer or physiologically functional derivative thereof for use in activating 5-HT1 A receptor.
  • 5-HT2A receptor refers to a subclass of a family of receptors for the neurotransmitter and peripheral signal mediator serotonin that may mediate a plurality of central and peripheral physiologic functions of serotonin.
  • modulating 5-HT2A receptor refers to the ability of a compound disclosed herein to alter the function of 5-HT2A receptor, for example, by increasing or decreasing the direct or indirect interaction between a 5-HT2A receptor and a ligand, such as a natural binding ligand.
  • a 5-HT2A receptor modulator may increase the activity or inhibit the activity of a 5- HT2A receptor by acting as an agonist or antagonist of the 5-HT2A receptor.
  • At least one SMC is an activator of 5-HT2A receptor. In some embodiments, at least one SMC is an agonist of 5-HT2A receptor.
  • the SMC represented by any one of general Formula (la), Formula (la’), Formula (lb), Formula (lb’), Formula (Ic), Formula (II), Formula (Illa), Formula (Illb), Formula (IVa), Formula (IVb), Formula (Va), Formula (Vb), Formula (Vc), Formula (Vd), Formula (Ve), or Formula (Vf), is for use in activating 5-HT2A receptor.
  • At least one SMC having the structure of one or more of Formula (X), Formula (XI), Formula (XII), Formula (XIII), Formula (XIV), Formula (XV), Formula (XVI), Formula (XVII), Formula (XVIII), Formula (XIX), Formula (XX), Formula (XXI), is for use in activating 5-HT2A receptor.
  • At least one SMC having the structure of any one of Formula (XIII), Formula (XIV), Formula (XV), Formula (XXI) or any combination thereof is for use in activating 5-HT2A receptor.
  • At least one SMC having the structure of Formula (XIII) or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer or physiologically functional derivative thereof for use in activating 5-HT2A receptor In some embodiments that may be considered as aspects of the present disclosure, it is provided at least one SMC having the structure of Formula (XIV) or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer or physiologically functional derivative thereof for use in activating 5-HT2A receptor.
  • At least one SMC having the structure of Formula (XV) or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer or physiologically functional derivative thereof for use in activating 5-HT2A receptor it is provided at least one SMC having the structure of Formula (XXI) or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer or physiologically functional derivative thereof for use in activating 5-HT2A receptor.
  • At least one SMC is designed so as to minimize agonist activity at the 5-HT2B receptor.
  • the SMC represented by any one of general Formula (la), Formula (la’), Formula (lb), Formula (lb’), Formula (Ic), Formula (II), Formula (Illa), Formula (Illb), Formula (IVa), Formula (IVb), Formula (Va), Formula (Vb), Formula (Vc), Formula (Vd), Formula (Ve), or Formula (Vf), is for use in inhibiting 5-HT2B receptor.
  • 5-HT2B receptor refers to a subclass of a family of serotonin receptors which plays a role in mediating the effects of serotonin in the body and is involved in mood regulation, pain modulation, cognitive functions, motor control, addiction and reward pathways.
  • Example 6 providing results of Head Twitch Response (HTR) in mice - a behavior assay correlated with psychedelic trip in humans.
  • the HTR assay is a rapid side-to-side rotational head movement that occurs in mice after administration of serotonergic hallucinogens and other 5-HT2A agonists.
  • the absence of HTR indicates that the compound is not likely to induce the psychedelic trip in humans.
  • HBL20016 while the compound denoted as HBL20016 induces a strong HTR as compared with vehicle, the compound denoted as HBL20017 and as HBL20028 showed relatively low HTR as compared with vehicle.
  • the SMC described herein are characterized as being essentially free of a psychedelic effect.
  • 'essentially free of a psychedelic effect' refers to a level of psychedelic activity that is undetectable, negligible, or insufficient to produce a clinically relevant alteration in perception, cognition, mood, or behavior, as typically associated with classical psychedelics such as LSD, psilocybin, or mescaline. In some embodiments, this may correspond to lacking subjective psychedelic effects in human subjects, at therapeutic doses.
  • "essentially free” may correspond to ⁇ 10% activation of the 5-HT2A receptor relative to a reference psychedelic compound, such as psilocybin or LSD, at equimolar concentrations.
  • a reference psychedelic compound such as psilocybin or LSD
  • HBL20016 did not show a significant change in distance covered in the OFT over vehicle.
  • HBL20017 did show a significant decrease over vehicle at the higher dose administered when the test was done after one hour. However, after two and 24 hours, no significant effect was observed.
  • Example 8 providing results of Marble Burying (MB) experiments, a commonly used behavioral assay used to screen drugs for anti-obsessional properties, administration of HBL20016 of HBL0017 resulted in a decrease in MB as compared to vehicle, with the effect observed with administration of HLB20017 more pronounced than with HBL20016.
  • the MB results suggested that the significant reduction in MB observed with HBL0017 is mediated at least in part by the agonistic activity of HBL0017 at 5-HT1 A receptors.
  • Example 11 providing results of HBL20017 on MK-801 induced hyperactivity, MK-801 significantly increased activity compared to naive group and HBL20017 treatment showed decrease in MK-801 induced hyperactivity at 3, 6 and 10 mg/kg dose, compared to vehicle treatment.
  • Example 12 providing results of HBL20017 in Forced Swim Test (FST), vehicle treated group displayed signs of depression-like behavior, marked by increased immobility and decreased active behavior.
  • HBL20117 10 mg/kg recapitulated desipramine like effects by exhibiting significant reduction in immobility time, increased swimming behavior and significant rise in total active behavior when compared to vehicle treated group.
  • the compounds of the present disclosure may be suitable for treating disease or disorders mediated by one or more serotonergic receptors.
  • At least one SMC for use in treating a disease or disorder that is a serotonergic receptor mediated disorder.
  • the SMC may be suitable for treating disease or disorder that in which 5- HT1 A receptor function is dysregulated.
  • the term 5- HT1 A receptor mediated disorder as used herein refers to a condition or disease in which the function or activity of the 5-HT1A serotonergic receptor is dysregulated leading to physiological or behavioral abnormalities.
  • the 5- HT1A receptor mediated disorder may be at least partially ameliorated by modulating the activity of 5- HT1A receptors.
  • a 5-HT1A receptor-mediated disorder may be such that administration of a 5-HT1A receptor modulator would result in an effect on the disorder and would result in improvement in at least some of the subjects being treated with the modulator.
  • the 5-HT1A receptor-mediated disorder may be one or more of depression, anxiety, obsessive compulsive disorder, schizophrenia, autism spectrum disorders (ASD), PTSD, epilepsy, pain, sleep disorders, and obesity.
  • At least one SMC represented by any one of general Formula (la), Formula (la’), Formula (lb), Formula (lb’), Formula (Ic), Formula (II), Formula (Illa), Formula (Illb), Formula (IVa), Formula (IVb), Formula (Va), Formula (Vb), Formula (Vc), Formula (Vd), Formula (Ve), or Formula (Vf), or is one or more of compounds having the structure of one or more of Formula (X), Formula (XI), Formula (XII), Formula (XIII), Formula (XIV), Formula (XV), Formula (XVI), Formula (XVII), Formula (XVIII), Formula (XIX), Formula (XX), Formula (XXI), for use in a method of treating a 5- HT1 A receptor mediated disorder.
  • At least one SMC having the structure of any one of Formula (X), Formula (XI), Formula (XII), Formula (XHI), Formula (XIV), Formula (XV), Formula (XVI), Formula (XVII), Formula (XVIII), Formula (XIX), Formula (XX), Formula (XXI), or a combination thereof for use in a method of treating a 5- HT1A receptor mediated disorder.
  • a compound represented by structure (XIV) for use in a method of treating a 5- HT1 A receptor mediated disorder.
  • a compound represented by structure of Formula (XV) for use in a method of treating a 5- HT1 A receptor mediated disorder.
  • a compound represented by structure of Formula (XXI) for use in a method of treating a 5- HT1 A receptor mediated disorder.
  • the SMC may be suitable for treating disease or disorder that is a 5- HT2A receptor mediated disorder.
  • 5- HT2A receptor mediated disorder refers to a condition or disease in which the function or activity of the 5-HT2A serotonergic receptor is dysregulated or altered, leading to physiological or behavioral abnormalities.
  • the 5- HT2A receptor mediated disorder may be at least partially mediated by modulating 5-HT2A receptors.
  • a 5-HT2A receptor-mediated disorder is such that administration of a 5-HT2A receptor modulator would result in an effect on the disorder and would results in improvement in at least some of the subjects being treated with the modulator.
  • At least one SMC having the structure of any one of Formula (X), Formula (XI), Formula (XII), Formula (XHI), Formula (XIV), Formula (XV), Formula (XVI), Formula (XVII), Formula (XVIII), Formula (XIX), Formula (XX), Formula (XXI), or a combination thereof for use in a method of treating a 5- HT2A receptor mediated disorder.
  • a SMC represented by structure (XIV) for use in a method of treating a 5- HT2A receptor mediated disorder.
  • a SMC represented by structure (XV) for use in a method of treating a 5- HT2A receptor mediated disorder.
  • a SMC represented by structure (XXI) for use in a method of treating a 5- HT2A receptor mediated disorder.
  • the ability to modulate, e.g. activate at least one serotonergic receptor is highly valuable and may be applicable in methods for modulating serotonergic receptor activity and consequently treating various diseases.
  • the present disclosure provides a method for modulating activity of at least one serotonergic receptor.
  • the method comprises the step of contacting a cell comprising at least one serotonergic receptor with an effective amount of at least one SMC as described herein.
  • contacting means to bring, put, incubate or mix together. As such, a first item is contacted with a second item when the two items are brought or put together, e.g., by touching them to each other or combining them.
  • the term “contacting” includes all measures or steps which allow interaction between at least one compound and a cell, comprising in accordance with some embodiments at least one serotonergic receptor.
  • the methods of the invention comprise contacting a cell comprising the serotonergic receptor with an effective amount of at least one SMC of the invention in at least one of in vitro, in vivo, ex vivo methods.
  • the method is an in vitro method.
  • the method is an in in vivo method.
  • the method is an ex vivo method.
  • a method of modulating activity of at least one serotonergic receptor in a subject in need thereof is provided.
  • the present disclosure provides a method for treating, preventing, inhibiting, reducing, eliminating, protecting or delaying the onset of a 5- HT1 A receptor mediated disorder in a subject in need thereof.
  • the method comprises in some embodiments the step of administering to the subject a therapeutically effective amount of at least one SMC as defined by the present disclosure, or composition comprising the compound.
  • the present disclosure provides a method for treating, preventing, inhibiting, reducing, eliminating, protecting or delaying the onset of a 5- HT2A receptor mediated disorder in a subject in need thereof.
  • the method comprises in some embodiments the step of administering to the subject a therapeutically effective amount of at least one SMC as defined by the present disclosure, or composition comprising the compound.
  • At least one SMC modulator applicable by the methods of the present disclosure for treating, preventing, inhibiting, reducing, eliminating, protecting or delaying the onset of a 5- HT1A receptor mediated disorder and/or a 5- HT2A receptor mediated disorder in a subject in need thereof is represented by at least one of Formula (la), Formula (la’), Formula (lb), Formula (lb’), Formula (Ic), Formula (II), Formula (Illa), Formula (Illb), Formula (IVa), Formula (IVb), Formula (Va), Formula (Vb), Formula (Vc), Formula (Vd), Formula (Ve), or Formula (Vf),.
  • At least one SMC modulator applicable by the methods of the present disclosure for treating, preventing, inhibiting, reducing, eliminating, protecting or delaying the onset of a 5- HT1A receptor mediated disorder and/or a 5- HT2A receptor mediated disorder in a subject in need thereof is represented by one or more of Formula (X), Formula (XI), Formula (XII), Formula (XIII), Formula (XIV), Formula (XV), Formula (XVI), Formula (XVH), Formula (XVIII), Formula (XIX), Formula (XX), Formula (XXI), or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer or physiologically functional derivative thereof or any combinations thereof.
  • At least one SMC modulator applicable by the methods of the present disclosure for treating, preventing, inhibiting, reducing, eliminating, protecting or delaying the onset of a 5- HT1A receptor mediated disorder and/or a 5- HT2A receptor mediated disorder in a subject in need thereof is represented by at least one of Formula (XHI), (XIV), (XV), (XXI) or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer or physiologically functional derivative thereof or any combinations thereof.
  • At least one SMC modulator applicable by the methods of the present disclosure for treating, preventing, inhibiting, reducing, eliminating, protecting or delaying the onset of a 5- HT1 A receptor mediated disorder and/or a 5- HT2A receptor mediated disorder in a subject in need thereof is represented by Formula (XXI) or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer or physiologically functional derivative thereof or any combinations thereof.
  • the method is for treating, preventing, inhibiting, reducing, eliminating, protecting or delaying the onset of one or more disease mediated by 5- HT1 A receptor and/or 5- HT2A receptor including, inter alia, brain disorders.
  • the present disclosure provides a method for treating, preventing, inhibiting, reducing, eliminating, protecting or delaying the onset of at least one brain disorder in a subject in need thereof.
  • the method comprising administering to the subject a therapeutically effective amount of at least one SMC or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer or physiologically functional derivative thereof.
  • At least one SMC modulator applicable by the methods of the present disclosure for treating, preventing, inhibiting, reducing, eliminating, protecting or delaying the onset of a brain disorder in a subject in need thereof is represented by at least one of Formula (la), Formula (la’), Formula (lb), Formula (lb’), Formula (Ic), Formula (II), Formula (Illa), Formula (nib), Formula (IVa), Formula (IVb), Formula (Va), Formula (Vb), Formula (Vc), Formula (Vd), Formula (Ve), or Formula (Vf),.
  • At least one SMC modulator applicable by the methods of the present disclosure for treating, preventing, inhibiting, reducing, eliminating, protecting or delaying the onset of a brain disorder in a subject in need thereof is represented by one or more of Formula (X), Formula (XI), Formula (XII), Formula (XIII), Formula (XIV), Formula (XV), Formula (XVI), Formula (XVII), Formula (XVIII), Formula (XIX), Formula (XX), Formula (XXI), or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer or physiologically functional derivative thereof or any combinations thereof.
  • At least one SMC modulator applicable by the methods of the present disclosure for treating, preventing, inhibiting, reducing, eliminating, protecting or delaying the onset of a brain disorder in a subject in need thereof is represented by at least one of Formula (XIII), Formula (XIV), Formula (XV), Formula (XXI) or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer or physiologically functional derivative thereof or any combinations thereof.
  • At least one SMC modulator applicable by the methods of the present disclosure for treating, preventing, inhibiting, reducing, eliminating, protecting or delaying the onset of a brain disorder in a subject in need thereof is represented by Formula (XIII) or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer or physiologically functional derivative thereof or any combinations thereof.
  • At least one SMC modulator applicable by the methods of the present disclosure for treating, preventing, inhibiting, reducing, eliminating, protecting or delaying the onset of a brain disorder in a subject in need thereof is represented by Formula (XIV) or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer or physiologically functional derivative thereof or any combinations thereof.
  • At least one SMC modulator applicable by the methods of the present disclosure for treating, preventing, inhibiting, reducing, eliminating, protecting or delaying the onset of a brain disorder in a subject in need thereof is represented by Formula (XV) or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer or physiologically functional derivative thereof or any combinations thereof.
  • At least one SMC modulator applicable by the methods of the present disclosure for treating, preventing, inhibiting, reducing, eliminating, protecting or delaying the onset of a brain disorder in a subject in need thereof is represented by Formula (XXI) or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer or physiologically functional derivative thereof or any combinations thereof.
  • brain disorder also denoted as neurological disorder
  • brain disorder refers to conditions that affect the structure or function of the brain, leading to impairments in cognitive, sensory, motor, or behavioral abilities.
  • the brain disorder is a genetic disorder. In some embodiments, the brain disorder is a non-genetic disorder.
  • the brain disorder may be at least one of a neuropsychiatric disorder, a neurodegenerative disorder, a neuroinflammatory disorder, a neurodevel opmental disorder, a central nervous system (CNS)-mediated pain or pain- associated disorder, a seizure disorder.
  • the brain disorder involves dysfunction of the central nervous system
  • the brain disorder is at least one of a neuropsychiatric disease, a neurodegenerative disease, neuroinflammatory disease, pain and pain-associated disease.
  • the brain disorder is a neuropsychiatric disease.
  • neuropsychiatric disease refers to disease that involve both neurological and psychiatric components, often affecting mood, cognition, behavior, and emotion regulation.
  • the neuropsychiatric disease is one or more of major depressive disorder (depression), bipolar disorder, generalized anxiety disorder (GAD), obsessive-compulsive disorder (OCD), hoarding disorder, body dysmorphic disorder, post- traumatic stress disorder (PTSD), attention-deficit/hyperactivity disorder (ADHD), specific phobia, autism spectrum disorder, social phobia, panic disorder, social anxiety disorder, schizophrenia, schizoaffective disorder, psychotic depression, bipolar disorder with psychosis, Parkinson’s disease with psychosis, dementia with psychosis.
  • the neuropsychiatric disease is OCD.
  • the neuropsychiatric disease is one or more of depression, schizophrenia, OCD, PTSD, a bipolar disorder.
  • the neuropsychiatric disease is depression. In some embodiments, the neuropsychiatric disease is schizophrenia. In some embodiments, the neuropsychiatric disease is OCD. In some embodiments, the neuropsychiatric disease is PTSD. In some embodiments, the neuropsychiatric disease is a bipolar disorder. In some embodiments, the neuropsychiatric disease is one or more of GAD, panic disorder, social anxiety disorder, social phobia. In some embodiments the neuropsychiatric disease is a psychotic disorder. In some embodiments, the psychotic disorder is schizophrenia, schizoaffective disorder, psychotic depression, depression, bipolar disorder with psychosis, Parkinson’s disease with psychosis, dementia with psychosis. In some embodiments, the neuropsychiatric disease is a human grooming disorder or disease.
  • human grooming disorder may be classified as body-focused repetitive behaviors (BFRBs) and refers to one or more conditions in which individuals engage in repetitive self-grooming actions that may cause physical harm, disrupt daily life, or lead to emotional distress.
  • BFRBs body-focused repetitive behaviors
  • these disorders may be related to urges or compulsions to engage in behaviors such as skin picking, hair pulling, or nail biting, even when they result in negative consequences.
  • the human grooming disorder or disease is one or more of trichotillomania (compulsive hair pulling), dermatillomania (compulsive skin picking, also called excoriation disorder), and onychophagia (compulsive nail biting).
  • the neuropsychiatric disease is a tic disorder.
  • a tic disorder as used herein refers to a group of neurological conditions characterized by sudden, rapid, repetitive, and involuntary movements or sounds, known as tics.
  • the tic disorder is a provisional tic disorder or Tourette's syndrome.
  • the methods of the invention may be applicable for treating, inhibiting, arresting or delaying neuropsychiatric disease.
  • the methods of the invention for treating, inhibiting, arresting or delaying a neuropsychiatric disease comprises administering to the subject in need thereof a therapeutically effective amount of at least one SMC represented by at least one of Formula (la), Formula (la’), Formula (lb), Formula (lb’), Formula (Ic), Formula (II), Formula (Illa), Formula (Illb), Formula (IVa), Formula (IVb), Formula (Va), Formula (Vb), Formula (Vc), Formula (Vd), Formula (Ve), or Formula (Vf), or having a structure provided by one or more of Formula (X), Formula (XI), Formula (XII), Formula (XIII), Formula (XIV), Formula (XV), Formula (XVI), Formula (XVII), Formula (XVIII), Formula (XIX), Formula (XX), Formula (XXI), or a pharmaceutically acceptable salt, solv
  • the methods of the invention for treating, inhibiting, arresting or delaying neuropsychiatric disease comprises administering to the subject in need thereof a therapeutically effective amount of at least one SMC represented one or more of Formula (X), Formula (XI), Formula (XII), Formula (XIII), Formula (XIV), Formula (XV), Formula (XVI), Formula (XVH), Formula (XVIII), Formula (XIX), Formula (XX), Formula (XXI), or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer or physiologically functional derivative thereof or any combinations thereof.
  • the methods of the invention for treating, inhibiting, arresting or delaying neuropsychiatric disease comprises administering to the subject in need thereof a therapeutically effective amount of at least one SMC represented by at least one of Formula (XIV), (XV), (XXI) or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer or physiologically functional derivative thereof or any combinations thereof.
  • the methods of the invention for treating, inhibiting, arresting or delaying neuropsychiatric disease comprises administering to the subject in need thereof a therapeutically effective amount of at least one SMC represented by Formula (XXI) or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer or physiologically functional derivative thereof or any combinations thereof.
  • the methods of the invention for treating, inhibiting, arresting or delaying depression comprises administering to the subject in need thereof a therapeutically effective amount of at least one SMC represented by at least one of Formula (la), Formula (la’), Formula (lb), Formula (lb’), Formula (Ic), Formula (II), Formula (Illa), Formula (nib), Formula (IVa), Formula (IVb), Formula (Va), Formula (Vb), Formula (Vc), Formula (Vd), Formula (Ve), or Formula (Vf), or having a structure provided by one or more of Formula (X), Formula (XI), Formula (XII), Formula (XIII), Formula (XIV), Formula (XV), Formula (XVI), Formula (XVII), Formula (XVIII), Formula (XIX), Formula (XX), Formula (XXI), or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer or physiologically functional derivative thereof or any combinations thereof.
  • the methods of the invention for treating, inhibiting, arresting or delaying depression comprises administering to the subject in need thereof a therapeutically effective amount of at least one SMC represented by at least one of Formula (XIV), (XV), (XXI) or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer or physiologically functional derivative thereof or any combinations thereof.
  • the methods of the invention for treating, inhibiting, arresting or delaying depression comprises administering to the subject in need thereof a therapeutically effective amount of at least one SMC represented by Formula (XXI) or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer or physiologically functional derivative thereof or any combinations thereof.
  • the methods of the invention for treating, inhibiting, arresting or delaying schizophrenia comprises administering to the subject in need thereof a therapeutically effective amount of at least one SMC represented by at least one of Formula (la), Formula (la’), Formula (lb), Formula (lb’), Formula (Ic), Formula (II), Formula (Illa), Formula (nib), Formula (IVa), Formula (IVb), Formula (Va), Formula (Vb), Formula (Vc), Formula (Vd), Formula (Ve), or Formula (Vf), or having a structure provided by one or more of Formula (X), Formula (XI), Formula (XII), Formula (XIII), Formula (XIV), Formula (XV), Formula (XVI), Formula (XVII), Formula (XVIII), Formula (XIX), Formula (XX), Formula (XXI), or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer or physiologically functional derivative thereof or any combinations thereof.
  • the methods of the invention for treating, inhibiting, arresting or delaying Schizophrenia comprises administering to the subject in need thereof a therapeutically effective amount of at least one SMC represented by at least one of Formula (XIV), (XV), (XXI) or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer or physiologically functional derivative thereof or any combinations thereof.
  • the methods of the invention for treating, inhibiting, arresting or delaying Schizophrenia comprises administering to the subject in need thereof a therapeutically effective amount of at least one SMC represented by Formula (XXI) or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer or physiologically functional derivative thereof or any combinations thereof.
  • the methods of the invention for treating, inhibiting, arresting or delaying OCD comprises administering to the subject in need thereof a therapeutically effective amount of at least one SMC represented by at least one of Formula (la), Formula (la’), Formula (lb), Formula (lb’), Formula (Ic), Formula (II), Formula (Illa), Formula (Ob), Formula (IVa), Formula (IVb), Formula (Va), Formula (Vb), Formula (Vc), Formula (Vd), Formula (Ve), or Formula (Vf), or having a structure provided by one or more of Formula (X), Formula (XI), Formula (XII), Formula (XHI), Formula (XIV), Formula (XV), Formula (XVI), Formula (XVII), Formula (XVIII), Formula (XIX), Formula (XX), Formula (XXI), or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer or physiologically functional derivative thereof or any combinations thereof.
  • the methods of the invention for treating, inhibiting, arresting or delaying OCD comprises administering to the subject in need thereof a therapeutically effective amount of at least one SMC represented by at least one of Formula (XIV), Formula (XV), Formula (XXI) or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer or physiologically functional derivative thereof or any combinations thereof.
  • the methods of the invention for treating, inhibiting, arresting or delaying OCD comprises administering to the subject in need thereof a therapeutically effective amount of at least one SMC represented by Formula (XXI) or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer or physiologically functional derivative thereof or any combinations thereof.
  • the methods of the invention for treating, inhibiting, arresting or delaying PTSD comprises administering to the subject in need thereof a therapeutically effective amount of at least one SMC represented by at least one Formula (la), Formula (la’), Formula (lb), Formula (lb’), Formula (Ic), Formula (II), Formula (Illa), Formula (Ob), Formula (IVa), Formula (IVb), Formula (Va), Formula (Vb), Formula (Vc), Formula (Vd), Formula (Ve), or Formula (Vf), or having a structure provided by one or more of Formula (X), Formula (XI), Formula (XII), Formula (XHI), Formula (XIV), Formula (XV), Formula (XVI), Formula (XVII), Formula (XVIII), Formula (XIX), Formula (XX), Formula (XXI), or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer or physiologically functional derivative thereof or any combinations thereof.
  • the methods of the invention for treating, inhibiting, arresting or delaying PTSD comprises administering to the subject in need thereof a therapeutically effective amount of at least one SMC represented by at least one of Formula (XIV), Formula (XV), Formula (XXI) or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer or physiologically functional derivative thereof or any combinations thereof.
  • the methods of the invention for treating, inhibiting, arresting or delaying PTSD comprises administering to the subject in need thereof a therapeutically effective amount of at least one SMC represented Formula (XXI) or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer or physiologically functional derivative thereof or any combinations thereof.
  • the methods of the invention for treating, inhibiting, arresting or delaying bipolar disorder comprises administering to the subject in need thereof a therapeutically effective amount of at least one SMC represented by at least one of Formula
  • the methods of the invention for treating, inhibiting, arresting or delaying bipolar disorder comprises administering to the subject in need thereof a therapeutically effective amount of at least one SMC represented by at least one of Formula (XIV), Formula (XV), Formula (XXI) or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer or physiologically functional derivative thereof or any combinations thereof.
  • the methods of the invention for treating, inhibiting, arresting or delaying bipolar disorder comprises administering to the subject in need thereof a therapeutically effective amount of at least one SMC represented by Formula (XXI) or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer or physiologically functional derivative thereof or any combinations thereof.
  • the methods of the invention for treating, inhibiting, arresting or delaying one or more of GAD, panic disorder, social anxiety disorder, social phobia comprises administering to the subject in need thereof a therapeutically effective amount of at least one SMC represented by at least one of Formula (la), Formula (la’), Formula
  • the methods of the invention for treating, inhibiting, arresting or delaying one or more of GAD, panic disorder, social anxiety disorder, social phobia comprises administering to the subject in need thereof a therapeutically effective amount of at least one SMC represented by at least one of Formula (XIV), Formula (XV), Formula (XXI) or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer or physiologically functional derivative thereof or any combinations thereof.
  • the methods of the invention for treating, inhibiting, arresting or delaying one or more of GAD, panic disorder, social anxiety disorder, social phobia comprises administering to the subject in need thereof a therapeutically effective amount of at least one SMC represented by Formula (XXI) or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer or physiologically functional derivative thereof or any combinations thereof.
  • the methods of the invention for treating, inhibiting, arresting or delaying human grooming disorder comprises administering to the subject in need thereof a therapeutically effective amount of at least one SMC represented by at least one of Formula (la), Formula (la’), Formula (lb), Formula (lb’), Formula (Ic), Formula (II), Formula (Illa), Formula (Illb), Formula (IVa), Formula (IVb), Formula (Va), Formula (Vb), Formula (Vc), Formula (Vd), Formula (Ve), or Formula (Vf), or having a structure provided by one or more of Formula (X), Formula (XI), Formula (XII), Formula (XIII), Formula (XIV), Formula (XV), Formula (XVI), Formula (XVH), Formula (XVHI), Formula (XIX), Formula (XX), Formula (XXI), or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer or physiologically functional derivative thereof or any combinations thereof.
  • the methods of the invention for treating, inhibiting, arresting or delaying human grooming disorder comprises administering to the subject in need thereof a therapeutically effective amount of at least one SMC represented by at least one of Formula (XIV), Formula (XV), Formula (XXI) or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer or physiologically functional derivative thereof or any combinations thereof.
  • the methods of the invention for treating, inhibiting, arresting or delaying human grooming disorder comprises administering to the subject in need thereof a therapeutically effective amount of at least one SMC represented by Formula (XXI) or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer or physiologically functional derivative thereof or any combinations thereof.
  • the methods of the invention for treating, inhibiting, arresting or delaying tic disorder comprises administering to the subject in need thereof a therapeutically effective amount of at least one SMC represented by at least one of Formula (la), Formula (la’), Formula (lb), Formula (lb’), Formula (Ic), Formula (II), Formula (Illa), Formula (nib), Formula (IVa), Formula (IVb), Formula (Va), Formula (Vb), Formula (Vc), Formula (Vd), Formula (Ve), or Formula (Vf), or having a structure provided by one or more of one or more of Formula (X), Formula (XI), Formula (XII), Formula (XIII), Formula (XIV), Formula (XV), Formula (XVI), Formula (XVH), Formula (XVHI), Formula (XIX), Formula (XX), Formula (XXI), or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer or physiologically functional derivative thereof or any combinations thereof.
  • the methods of the invention for treating, inhibiting, arresting or delaying tic disorder comprises administering to the subject in need thereof a therapeutically effective amount of at least one SMC represented by at least one of Formula (XIV), Formula (XV), Formula (XXI) or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer or physiologically functional derivative thereof or any combinations thereof.
  • the methods of the invention for treating, inhibiting, arresting or delaying tic disorder comprises administering to the subject in need thereof a therapeutically effective amount of at least one SMC represented by Formula (XXI) or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer or physiologically functional derivative thereof or any combinations thereof.
  • the methods of the invention for treating, inhibiting, arresting or delaying Tourette's syndrome comprises administering to the subject in need thereof a therapeutically effective amount of at least one SMC represented by at least one of Formula (la), Formula (la’), Formula (lb), Formula (lb’), Formula (Ic), Formula (II), Formula (Illa), Formula (nib), Formula (IVa), Formula (IVb), Formula (Va), Formula (Vb), Formula (Vc), Formula (Vd), Formula (Ve), or Formula (Vf), or having a structure provided by one or more of Formula (X), Formula (XI), Formula (XII), Formula (XIII), Formula (XIV), Formula (XV), Formula (XVI), Formula (XVII), Formula (XVIII), Formula (XIX), Formula (XX), Formula (XXI), or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer or physiologically functional derivative thereof or any combinations thereof.
  • the methods of the invention for treating, inhibiting, arresting or delaying Tourete's syndrome comprises administering to the subject in need thereof a therapeutically effective amount of at least one SMC represented by at least one of Formula (XIV), Formula (XV), Formula (XXI) or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer or physiologically functional derivative thereof or any combinations thereof.
  • the methods of the invention for treating, inhibiting, arresting or delaying Tourete's syndrome comprises administering to the subject in need thereof a therapeutically effective amount of at least one SMC represented by Formula (XXI) or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer or physiologically functional derivative thereof or any combinations thereof.
  • the brain disorder is a neurodegenerative disease.
  • neurodegenerative disease refers to disease characterized by the gradual degeneration and loss of neurons in the brain, leading to cognitive decline, motor dysfunction, and other neurological symptoms.
  • the neurodegenerative disease is Alzheimer's disease, Parkinson's disease, Dementia, a disorder associated with protein misfolding, cognitive decline, Mild Cognitive Impairment (MCI), Parkinson's disease with MCI, Huntington's disease, Lewy body disease, Amyotrophic lateral sclerosis (ALS), Prion disease, Motor neuron disease (MND), Spinocerebellar ataxia (SCA), Spinal muscular atrophy (SMA), Friedreich's Ataxia, multiple sclerosis, Idiopathic Intracranial Hypertension, Cranial neuropathies, Trigeminal neuralgia, frontotemporal dementias (FTD), Senile Dementia (Dementia NOS), Motor Neuron Disease, or bipolar disorder.
  • MCI Mild Cognitive Impairment
  • ALS Amyotrophic lateral sclerosis
  • SCA Motor neuron disease
  • SCA Spinocerebellar ataxia
  • SMA Spinal muscular atrophy
  • Friedreich's Ataxia multiple sclerosis
  • the methods of the invention may be applicable for treating, inhibiting, arresting or delaying neurodegenerative disease.
  • the methods of the invention for treating, inhibiting, arresting or delaying a neurodegenerative disease comprises administering to the subject in need thereof a therapeutically effective amount of at least one SMC represented by at least one of Formula (la), Formula (la’), Formula (lb), Formula (lb’), Formula (Ic), Formula (II), Formula (Illa), Formula (Illb), Formula (IVa), Formula (IVb), Formula (Va), Formula (Vb), Formula (Vc), Formula (Vd), Formula (Ve), or Formula (Vf), or having a structure provided by one or more of Formula (X), Formula (XI), Formula (XII), Formula (XIII), Formula (XIV), Formula (XV), Formula (XVI), Formula (XVII), Formula (XVIII), Formula (XIX), Formula (XX), Formula (XXI), or a pharmaceutically acceptable salt, solvate, hydrate
  • the methods of the invention for treating, inhibiting, arresting or delaying neurodegenerative disease comprises administering to the subject in need thereof a therapeutically effective amount of at least one SMC represented one or more of Formula (X), Formula (XI), Formula (XII), Formula (XIII), Formula (XIV), Formula (XV), Formula (XVI), Formula (XVH), Formula (XVIII), Formula (XIX), Formula (XX), Formula (XXI), or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer or physiologically functional derivative thereof or any combinations thereof.
  • the methods of the invention for treating, inhibiting, arresting or delaying neurodegenerative disease comprises administering to the subject in need thereof a therapeutically effective amount of at least one SMC represented by at least one of Formula (XIV), Formula (XV), Formula (XXI) or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer or physiologically functional derivative thereof or any combinations thereof.
  • the methods of the invention for treating, inhibiting, arresting or delaying neurodegenerative disease comprises administering to the subject in need thereof a therapeutically effective amount of at least one SMC represented by Formula (XXI) or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer or physiologically functional derivative thereof or any combinations thereof
  • the neurodegenerative disease is Parkinson's disease, dementia or Alzheimer's disease.
  • the methods of the invention may be applicable for treating, inhibiting, arresting or delaying Parkinson's disease.
  • the methods of the invention for treating, inhibiting, arresting or delaying Parkinson's disease comprises administering to the subject in need thereof a therapeutically effective amount of at least one SMC represented by at least one of Formula (la), Formula (la’), Formula (lb), Formula (lb’), Formula (Ic), Formula (II), Formula (Illa), Formula (nib), Formula (IVa), Formula (IVb), Formula (Va), Formula (Vb), Formula (Vc), Formula (Vd), Formula (Ve), or Formula (Vf), or having a structure provided by one or more of Formula (X), Formula (XI), Formula (XII), Formula (XIII), Formula (XIV), Formula (XV), Formula (XVI), Formula (XVH), Formula (XVIII), Formula (XIX), Formula (XX), Formula (XXI), or a pharmaceutically acceptable salt, solvate, hydrate, stereo
  • the methods of the invention for treating, inhibiting, arresting or delaying Parkinson's disease comprises administering to the subject in need thereof a therapeutically effective amount of at least one SMC represented by at least one of Formula (XIV), Formula (XV), Formula (XXI) or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer or physiologically functional derivative thereof or any combinations thereof.
  • the methods of the invention for treating, inhibiting, arresting or delaying Parkinson's disease comprises administering to the subject in need thereof a therapeutically effective amount of at least one SMC represented by Formula (XXI) or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer or physiologically functional derivative thereof or any combinations thereof.
  • the methods of the invention may be applicable for treating, inhibiting, arresting or delaying Alzheimer's disease.
  • the methods of the invention for treating, inhibiting, arresting or delaying Parkinson's disease comprises administering to the subject in need thereof a therapeutically effective amount of at least one SMC represented by at least one of Formula (la), Formula (la’), Formula (lb), Formula (lb’), Formula (Ic), Formula (II), Formula (Illa), Formula (nib), Formula (IVa), Formula (IVb), Formula (Va), Formula (Vb), Formula (Vc), Formula (Vd), Formula (Ve), or Formula (Vf), or having a structure provided by one or more of Formula (X), Formula (XI), Formula (XII), Formula (XIII), Formula (XIV), Formula (XV), Formula (XVI), Formula (XVH), Formula (XVIII), Formula (XIX), Formula (XX), Formula (XXI), or a pharmaceutically acceptable salt, solvate, hydrate, stereo
  • the methods of the invention for treating, inhibiting, arresting or delaying Alzheimer's disease comprises administering to the subject in need thereof a therapeutically effective amount of at least one SMC represented by at least one of Formula (XIV), Formula (XV), Formula (XXI) or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer or physiologically functional derivative thereof or any combinations thereof.
  • the methods of the invention for treating, inhibiting, arresting or delaying Alzheimer's disease comprises administering to the subject in need thereof a therapeutically effective amount of at least one SMC represented by Formula (XXI) or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer or physiologically functional derivative thereof or any combinations thereof.
  • the methods of the invention may be applicable for treating, inhibiting, arresting or delaying dementia.
  • the methods of the invention for treating, inhibiting, arresting or delaying dementia comprises administering to the subject in need thereof a therapeutically effective amount of at least one SMC represented by at least one of Formula (la), Formula (la’), Formula (lb), Formula (lb’), Formula (Ic), Formula (II), Formula (Illa), Formula (nib), Formula (IVa), Formula (IVb), Formula (Va), Formula (Vb), Formula (Vc), Formula (Vd), Formula (Ve), or Formula (Vf), or having a structure provided by one or more of Formula (X), Formula (XI), Formula (XII), Formula (XIII), Formula (XIV), Formula (XV), Formula (XVI), Formula (XVII), Formula (XVIII), Formula (XIX), Formula (XX), Formula (XXI), or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer or physiologically
  • the methods of the invention for treating, inhibiting, arresting or delaying dementia comprises administering to the subject in need thereof a therapeutically effective amount of at least one SMC represented by at least one of Formula (XIV), Formula (XV), Formula (XXI) or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer or physiologically functional derivative thereof or any combinations thereof.
  • the methods of the invention for treating, inhibiting, arresting or delaying dementia comprises administering to the subject in need thereof a therapeutically effective amount of at least one SMC represented by Formula (XXI) or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer or physiologically functional derivative thereof or any combinations thereof.
  • the neurodegenerative disease may be characterized by neuroinflammatory processes.
  • the brain disorder is a neuroinflammatory disease.
  • neuroinflammatory disease refers to disease that involve inflammation of the central nervous system (CNS) and peripheral nervous system (PNS), which can lead to various neurological symptoms and damage to brain tissue.
  • CNS central nervous system
  • PNS peripheral nervous system
  • the neuroinflammatory disease is one or more of Multiple Sclerosis (MS), Guillain-Barre Syndrome (GBS), Acute Disseminated Encephalomyelitis (ADEM), Autoimmune Encephalitis, Neuromyelitis Optica (Devic's Disease), Meningitis, Traumatic Brain Injury (TBI), stroke, Multiple Sclerosis (MS), Chronic Inflammatory Demyelinating Polyneuropathy (CIDP), transverse myelitis, Neuromyelitis optica, acute disseminated encephalomyelitis, optic neuritis, meningitis, encephalitis, demyelinating diseases and inflammatory vascular changes in the central nervous system.
  • MS Multiple Sclerosis
  • GNS Guillain-Barre Syndrome
  • CIDP Chronic Inflammatory Demyelinating Polyneuropathy
  • transverse myelitis Neuromyelitis optica, acute disseminated encephalomyelitis, optic neuritis, meningitis,
  • the methods of the invention may be applicable for treating, inhibiting, arresting or delaying neuroinflammatory disease.
  • the methods of the invention for treating, inhibiting, arresting or delaying a neuroinflammatory disease comprises administering to the subject in need thereof a therapeutically effective amount of at least one SMC represented by at least one of Formula (la), Formula (la’), Formula (lb), Formula (lb’), Formula (Ic), Formula (II), Formula (Illa), Formula (Illb), Formula (IVa), Formula (IVb), Formula (Va), Formula (Vb), Formula (Vc), Formula (Vd), Formula (Ve), or Formula (Vf), or having a structure provided by one or more of Formula (X), Formula (XI), Formula (XII), Formula (XIII), Formula (XIV), Formula (XV), Formula (XVI), Formula (XVII), Formula (XVIII), Formula (XIX), Formula (XX), Formula (XXI), or a pharmaceutically acceptable salt, solvate, hydrate, stereo
  • the methods of the invention for treating, inhibiting, arresting or delaying neuroinflammatory disease comprises administering to the subject in need thereof a therapeutically effective amount of at least one SMC represented by at least one of Formula (XIV), Formula (XV), Formula (XXI) or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer or physiologically functional derivative thereof or any combinations thereof.
  • the methods of the invention for treating, inhibiting, arresting or delaying neuroinflammatory disease comprises administering to the subject in need thereof a therapeutically effective amount of at least one SMC represented by Formula (XXI) or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer or physiologically functional derivative thereof or any combinations thereof.
  • the brain disorder is pain and/or pain-associated disease.
  • pain and/or pain-associated disease as used herein refers to disease characterized by persistent pain.
  • pain is one or more of fibromyalgia, chronic back pain, neuropathic pain (e.g., caused by diabetic neuropathy or nerve injury), migraine headaches, Complex Regional Pain Syndrome (CRPS), chronic fatigue syndrome (CFS), pain from chemotherapy associated neuropathy, phantom limb pain.
  • neuropathic pain e.g., caused by diabetic neuropathy or nerve injury
  • migraine headaches e.g., Complex Regional Pain Syndrome (CRPS), chronic fatigue syndrome (CFS)
  • CFS chronic fatigue syndrome
  • pain associated disease may be pain associated with neuroinflammatory disease.
  • pain associated with neuroinflammatory disease comprises migraine, Trigeminal Neuralgia, Postherpetic Neuralgia, Arthritis.
  • the methods of the invention may be applicable for treating, inhibiting, arresting or delaying pain disease.
  • the methods of the invention for treating, inhibiting, arresting or delaying a pain and/or pain-associated disease comprises administering to the subject in need thereof a therapeutically effective amount of at least one SMC represented by at least one of Formula (la), Formula (la’), Formula (lb), Formula (lb’), Formula (Ic), Formula (II), Formula (Illa), Formula (mb), Formula (IVa), Formula (IVb), Formula (Va), Formula (Vb), Formula (Vc), Formula (Vd), Formula (Ve), or Formula (Vf), or having a structure provided by one or more of Formula (X), Formula (XI), Formula (XII), Formula (XIII), Formula (XIV), Formula (XV), Formula (XVI), Formula (XVII), Formula (XVIII), Formula (XIX), Formula (XX), Formula (XXI), or a pharmaceutically acceptable salt, solvate,
  • the methods of the invention for treating, inhibiting, arresting or delaying pain disease comprises administering to the subject in need thereof a therapeutically effective amount of at least one SMC represented by at least one of Formula (XIV), Formula (XV), Formula (XXI) or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer or physiologically functional derivative thereof or any combinations thereof.
  • the methods of the invention for treating, inhibiting, arresting or delaying pain disease comprises administering to the subject in need thereof a therapeutically effective amount of at least one SMC represented by Formula (XXI) or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer or physiologically functional derivative thereof or any combinations thereof.
  • the present disclosure provides use of at least one SMC in the preparation (manufacture) of a composition.
  • the composition is in some examples a pharmaceutical composition.
  • the invention provides methods for treating diseases or disorders specified above.
  • ''disease”, “disorder”, “condition” and the like as they relate to a subject's health, are used interchangeably and have meanings ascribed to each and all of such terms. It is understood that the interchangeably used terms "associated” and “related”, when referring to pathologies herein, mean diseases, disorders, conditions, or any pathologies which at least one of: share causalities, co-exist at a higher than coincidental frequency, or where at least one disease, disorder, condition or pathology causes a second disease, disorder, condition or pathology.
  • treatment refers to the administering of a therapeutic amount of the SMC or composition of the present invention which is effective to improve one or more undesired symptoms associated with a disease or condition as described herein.
  • the terms “treat”, “treating”, “treatment” or forms thereof, as used herein mean preventing, ameliorating or delaying the onset of one or more clinical indications of disease activity in a subject having a pathologic disorder.
  • Treatment refers to therapeutic treatment. Those in need of treatment are subjects suffering from a pathologic disorder. Specifically, providing a "preventive treatment” (to prevent) or a “prophylactic treatment” is acting in a protective manner, to defend against or prevent something, especially a condition or disease.
  • treatment or prevention refers to the complete range of therapeutically positive effects of administrating to a subject including inhibition, reduction of, alleviation of, and relief from, a condition and illness associated with one or more serotonergic receptors as described herein.
  • the present invention relates to the treatment of subjects or patients, in need thereof.
  • patient or “subject in need” it is meant any organism who may be affected by the above-mentioned conditions, and to whom the therapeutic and prophylactic methods herein described are desired, including humans, domestic and non-domestic mammals such as canine and feline subjects, bovine, simian, equine and rodents, specifically, murine subjects. More specifically, the methods of the invention are intended for mammals.
  • mammalian subject is meant any mammal for which the proposed therapy is desired, including human, livestock, equine, canine, and feline subjects, most specifically humans.
  • the term "effective amount” relates to the amount of an active agent being at least one SMC present in a composition, that is needed to provide a desired level of active agent in the bloodstream or at the site of action in an individual to be treated to give an anticipated physiological response when such composition is administered.
  • the precise amount will depend upon numerous factors, e.g., the active agent, the activity of the composition, the delivery device employed, the physical characteristics of the composition, intended patient use (i.e., the number of doses administered per day), patient considerations, and the like, and can readily be determined by one skilled in the art, based upon the information provided herein. It should be noted that the composition/s of the invention and any components thereof may be applied as a single daily dose or multiple daily doses, or every other day, once a week, once in 10 days, once in 2 weeks, etc.
  • the SMC is defined by any one of Formula (la), Formula (la’), Formula (lb), Formula (lb’), Formula (Ic), Formula (II), Formula (Illa), Formula (Illb), Formula (IVa), Formula (IVb), Formula (Va), Formula (Vb), Formula (Vc), Formula (Vd), Formula (Ve), or Formula (Vf), or having a structure provided by one or more of.
  • alkyl refers to a linear, branched saturated hydrocarbon having from 1 to 20 carbon atoms.
  • C1-C12 alkyl or C1-C12 alkylene refers to a linear (straight), branched saturated hydrocarbon having from 1 to 20 carbon atoms, preferably 1 to 12 carbon atoms, in some embodiments, contain from 2 to 8 carbons, in yet some embodiments from 2 to 5 carbons, in yet some further embodiments, from 1 to 3 carbon atoms. It should be noted that alkyl refers to an alkyl end chain and alkylene refers to a middle chain alkyl.
  • Representative C1-C12 alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, cyclopropyl, butyl, sec-butyl, iso-butyl, tert-butyl, cyclobutyl, pentyl, iso-pentyl, neo-pentyl, tert-pentyl, cyclopentyl, hexyl, cyclohexyl, heptyl, cycloheptyl, octyl, sec-octyl (1 -methylheptyl), and cyclooctyl.
  • the alkyl can be substituted or unsubstituted. When substituted, the substituent can be as described herein.
  • C1-C12 haloalkyF refers to a C1-C12 alkyl as defined above, with one or more hydrogens substituted by halogen atoms.
  • alkenyF refers to a linear (straight), branched unsaturated hydrocarbon having from 2 to 20 carbon atoms and at least one carbon-carbon double bond.
  • C2-C 12 alkenyF or C2-C 12 alkenylene refers to a linear, branched unsaturated hydrocarbon having from 2 to 12 carbon atoms and at least one carbon-carbon double bond, in some embodiments from 3 to 8 carbons, in yet some further embodiments, from 3 to 5 carbon atoms and at least one double bond.
  • alkenyl refers to an alkyl end chain and alkenylene refers to a middle chain alkyl.
  • C2-C/2 haloalkenyF refers to a CVCnalkenyl as defined above, with one or more hydrogens substituted by halogen atoms.
  • alkynyF refers to a linear, branched unsaturated hydrocarbon having from 2 to 20 carbon atoms and at least one carbon-carbon triple bond.
  • C2-C 12 alkynyF or "C2-Ci2alkynylene” as used herein refers to a linear, branched unsaturated hydrocarbon having from 2 to 12 carbon atoms in certain embodiments, from 3 to 8 carbons, and at least one triple bond (at least one carbon-carbon triple bond). It should be noted that alkynyl refers to an alkyl end chain and alkynylene refers to a middle chain alkyl.
  • C2-C/2 haloalkynyF refers to a C2-C12 alkynyl as defined above, with one or more hydrogens substituted by halogen atoms.
  • alkyl group refers to an alkyl group bonded to an oxygen atom.
  • C1-C12 alkoxyF refers to a C1-C12 alkyl group linked to an oxygen.
  • the alkyl group may include one to twelve carbon atoms, at times between one to eight carbon atoms, at times one to five carbon atoms and at times one to three carbon atoms. Representative examples are methoxy, ethoxy, n-propoxy, isopropoxy, butoxy, sec-butoxy, tert-butoxy, pentoxy, isopentoxy, hexoxy, isohexoxy and the like.
  • the alkoxy is ethoxy.
  • C1-C12 haloalkoxy refers to a C1-C12 alkoxy as defined above, with one or more hydrogens substituted by halogen atoms.
  • halogen refers to F, Cl, Br or I.
  • cyano describes a -ON group.
  • amino as used herein encompass primary, secondary, tertiary or quaternary amines where the point of attachment is through the nitrogen atom which is substituted.
  • nitro refers to -NO2.
  • hydroxy refers to an -OH group.
  • urea refers to -NR a -C(0)-NR a 2 or -NR a -C(0)NR a -, wherein R a is H or C1-C12 alkyl.
  • sulfonylurea refers to -S(0)2-NR a -C(0)-NR a - or -NR a -C(0)-NR a - SO2-, wherein R a is H or C1-C12 alkyl, e.g., an C1-C12 alkyl group as described herein.
  • sulfonamidyl refers to -S(0)2-NR a - or -NR a -S(0)2-, wherein R a is H or C1-C12 alkyl, e.g., an C1-C12 alkyl group as described herein.
  • a ring system refers to a mono- or multi- cyclic ring system having 5 to 12 atoms.
  • the ring system may be saturated, unsaturated or aromatic rings and the like including for example cycloalkyl, heterocycloalkyl, aryl, arylene, aromatic, heteroaromatic rings.
  • a ring system may contain two rings (bicyclic, etc.), for example aromatic rings and in such case the aromatic rings of the aryl group may be joined at a single point (e.g., biphenyl), or fused (e.g., naphthyl).
  • the heterocyclic ring may be optionally substituted, and may be saturated, unsaturated or aromatic.
  • saturated means that the compound does not contain double or triple bonds.
  • unsaturated means that the compound contains at least one double or triple bond.
  • aromatic as used herein means that the compound contains alternating double and single bonds.
  • cycloalkyl refers to a monocyclic or polycyclic radical that contains only carbon and hydrogen, and may be saturated, or partially unsaturated.
  • Cycloalkyl groups include groups having from 3 to 12 ring atoms (i.e. C3-C10 cycloalkyl). Examples of cycloalkyl groups include, but are not limited to, groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, norbornyl, and the like.
  • heterocycloalkyl can be a stable 3- to 12-membered non-aromatic ring radical that comprises three to twelve carbon atoms and from one to six heteroatoms selected from nitrogen, oxygen and sulfur.
  • heterocycloalkyl groups include, but are not limited to, groups such as dioxolanyl, thienyl[l,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrrolidine, pyrazo
  • aryl refers to a polyunsaturated, aromatic, hydrocarbon moiety which can be a single ring or multiple rings (e.g., 1 to 2 rings) which are fused together or linked covalently, having from six to twelve carbon atoms (i.e. C6-C12 aryl).
  • Non-limiting examples of aryl groups include phenyl, 1 -naphthyl, 2-naphthyl, and 4-biphenyl.
  • heteroaryF refers to aryls as defined above where one or more carbons are substituted by heteroatoms.
  • exemplary heteroatoms include, but not limited to, nitrogen, sulfur, and oxygen.
  • heteromatic refers to refers to a monocyclic or multi-cyclic (fused) aromatic ring system, where one or more of the atoms in the ring system is a heteroatom, that is, an element other than carbon, including but not limited to, nitrogen, oxygen or sulfur.
  • heteroaryl used interchangeably with the term “heteroaryl” denotes a heterocyclic aromatic ring systems containing 5 to 12 atoms, with at least one, preferably two carbon atoms and one or more heteroatoms selected from nitrogen, oxygen and sulfur.
  • Non-limiting examples include furan, thipohene, pyrrole, oxazole, oxadiazole, thiazole, imidazole, pyrazole, isoxazole, thiazolem benzofurna, indole, benzothiophene, benzoimidazole, indazole, benzoxazole, benzois oxazole, benzothiazole, isobenzfuran, isoidole, purine, pyridine, pyrazine, pyrimidine, pyrisazine, quinoline, quinozaline, quinazoline, isoquinoline, furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, isoxazolyl, isothiazolyl, 1,2,3-triazolyl, 1,2,4- triazolyl, pyranyl, pyridyl, pyridazinyl,
  • isotopologue refers to a compound that differs from a specific compound only in the isotopic composition of one or more of their atoms thereof.
  • an isotopologue of a compound have the same molecular structure, including the same sequence of bonded atoms, but differ in the isotopes of one or more of these atoms.
  • one or more of hydrogen atoms in a compound may be 2 H (deuterium).
  • substitutions described herein may be optionally substituted by one or more substituents.
  • the term “optionally substituted” refers to substitution with the named substituent or substituents, multiple degrees of substitution being allowed unless otherwise stated.
  • the carbon number refers to the carbon backbone and carbon branching, but does not include carbon atoms of the substituents, such as al
  • reference to SMC in accordance with the present disclosure encompass any one of a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer or physiologically functional derivative thereof or any combinations thereof.
  • salts refers to salts derived from organic and inorganic acids of a compound described herein.
  • Exemplary salts include, but are not limited to, sulfate, citrate, acetate, oxalate, chloride, hydrochloride, bromide, hydrobromide, iodide, nitrate, bisulfate, phosphate, acid phosphate, isonicotinate, lactate, salicylate, acid citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p- toluenesulfonate, camphorsulfonate, napthalenesulfonate, propionat
  • pharmaceutically acceptable salt also includes hydrates of a salt of a compound described herein.
  • small molecule or “compound” may include pharmaceutically acceptable forms of the recited compounds, including chelates, non-covalent complexes, and mixtures thereof.
  • solvate refers to an aggregate of a molecule with one or more solvent molecules, such as hydrate, alcoholate (aggregate or adduct with alcohol), and the like.
  • hydrate refers to a compound formed by the addition of water.
  • the hydrates may be obtained by any known method in the art by dissolving the compounds in water and recrystallizing them to incorporate water into the crystalline structure.
  • stereoisomer as used herein is meant to encompass an isomer that possess identical constitution as a corresponding stereoisomer, but which differs in the arrangement of its atoms in space from the corresponding stereoisomer.
  • the compounds of this invention include mixtures of enantiomers (possibly as a racemic mixture) as well as purified enantiomers or enantiomerically enriched mixtures.
  • the present invention also encompasses the individual enantiomer(s) (i.e. R or S) of the compounds being represented by the formulas above as racemic mixtures. Methods of preparing substantially isomerically pure compounds are known in the art.
  • a particular enantiomer of a compound of the present disclosure may be prepared by asymmetric synthesis, or by derivation with a chiral auxiliary, where the resulting diastereomeric mixture is separated and the auxiliary group cleaved to provide the pure desired enantiomers.
  • diastereomeric salts may be formed with an appropriate optically active acid or base, followed by resolution of the diastereomers thus formed by fractional crystallization or chromatographic means well known in the art, and subsequent recovery of the pure enantiomers.
  • enantiomerically enriched mixtures and pure enantiomeric compounds can be prepared by using synthetic intermediates that are enantiomerically pure in combination with reactions that either leave the stereochemistry at a chiral center unchanged or result in its complete inversion.
  • Techniques for inverting or leaving unchanged a particular stereocenter, and those for resolving mixtures of stereoisomers are well known in the art, and it is well within the ability of one of skill in the art to choose an appropriate method for a particular situation.
  • a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer or physiologically functional derivative thereof in the context of the present disclosure are considered to have similar biological or physiological activity as the small molecule to which they relate or any small molecule related thereof, for example, in modulating activity of at least one serotonergic receptor.
  • the present examples further encompass any enantiomers, prodrugs, and polymorphs of at least one SMC.
  • Crystal form or "polymorph,” as used herein include all crystalline and amorphous forms of a small molecule, including, for example, polymorphs, pseudopolymorphs, solvates, hydrates, unsolvated polymorphs (including anhydrates), conformational polymorphs, and amorphous forms, as well as mixtures thereof, unless a particular crystalline or amorphous form is referred to.
  • prodrug refers to a compound that may be converted under physiological conditions to the specified compound or to a pharmaceutically acceptable salt of such compound. Prodrugs may be useful for facilitating the administration of a parent drug. It should be noted that the SMCs described herein may be considered in some examples as a prodrug.
  • the terms “inhibition”, “moderation”, “reduction”, “decrease” or “attenuation” as referred to herein, relate to the retardation, restraining or reduction of a process by any one of about 1% to 99.9%, specifically, about 1% to about 5%, about 5% to 10%, about 10% to 15%, about 15% to 20%, about 20% to 25%, about 25% to 30%, about 30% to 35%, about 35% to 40%, about 40% to 45%, about 45% to 50%, about 50% to 55%, about 55% to 60%, about 60% to 65%, about 65% to 70%, about 75% to 80%, about 80% to 85% about 85% to 90%, about 90% to 95%, about 95% to 99%, or about 99% to 99.9%, 100% or more.
  • percentage values such as, for example, 10%, 50%, 120%, 500%, etc.
  • fold change values i.e., 0.1, 0.5, 1.2, 5, etc.
  • the term “about” as used herein indicates values that may deviate up to 1%, more specifically 5%, more specifically 10%, more specifically 15%, and in some cases up to 20% higher or lower than the value referred to, the deviation range including integer values, and, if applicable, non-integer values as well, constituting a continuous range. In some embodiments, the term “about” refers to ⁇ 10 %.
  • the phrase “at least one,” in reference to a list of one or more elements, should be understood to mean at least one element selected from any one or more of the elements in the list of elements, but not necessarily including at least one of each and every element specifically listed within the list of elements and not excluding any combinations of elements in the list of elements.
  • This definition also allows that elements may optionally be present other than the elements specifically identified within the list of elements to which the phrase “at least one” refers, whether related or unrelated to those elements specifically identified.
  • “at least one of A and B” can refer, in one embodiment, to at least one, optionally including more than one, A, with no B present (and optionally including elements other than B); in another embodiment, to at least one, optionally including more than one, B, with no A present (and optionally including elements other than A); in yet another embodiment, to at least one, optionally including more than one, A, and at least one, optionally including more than one, B (and optionally including other elements); etc.
  • range format is merely for convenience and brevity and should not be construed as an inflexible limitation on the scope of the invention. Accordingly, the description of a range should be considered to have specifically disclosed all the possible sub ranges as well as individual numerical values within that range. For example, description of a range such as from 1 to 6 should be considered to have specifically disclosed sub ranges such as from 1 to 3, from 1 to 4, from 1 to 5, from 2 to 4, from 2 to 6, from 3 to 6 etc., as well as individual numbers within that range, for example, 1, 2, 3, 4, 5, and 6. This applies regardless of the breadth of the range.
  • the residue was purified by prep-HPLC with the following conditions: Column: XSelect CSH Prep Fluoro-Phenyl OBD column, 19*250 mm, 5 pm; mobile phase A: water (0.05% HC1), mobile phase B: ACN; flow rate: 25 mL/min; gradient (B%): isocratic 12% to 26% B in 10 min; wavelength: 254/220 nm; RT: 9.7 min.
  • Example 2A Functional Receptor Assay in human embryonic kidney (HEK) cells
  • HEK human embryonic kidney
  • HEK cells expressing 5-HT receptors were trypsinised, counted and seeded in black, clear- bottomed 96 well plates at a density of 25,000 cells per well and incubated overnight in media containing 1% dialysed serum. Next day, media was removed from cell plates and replaced with 30 ⁇ l assay buffer (20 mM HEPES: HBSS, pH 7.4). Calcium 5 (Molecular Devices, R8186) dye solution (10 pl) was added to the wells and incubated at 37oC for 60 minutes. Dye solution was made up in 20 mM HEPES: HBSS, pH 7.4 + 2.5 mM probenecid.
  • Compound dilutions were performed in 100% DMSO then transferred to intermediate dilutions for a very limited amount of time ( ⁇ 10 minutes) just before adding to the cell plate.
  • agonist testing the plates were placed in the FLIPR (Fluorescent Imaging Plate Reader), after incubation with dye, and fluorescence monitored every 1 second in order to monitor baseline. After 20 seconds test compound or reference agonist (lOptl) was added to the wells and the fluorescence monitored for 5 minutes at ex/emm: 488nm/510-570nm.
  • the ECso of the test compounds and reference compounds was determined using GraphPad Prism software.
  • the EC50 values for the reference compounds were compared to historical assay and or literature data to ensure that it is within our acceptable ranges in order to validate each assay. Also % efficacy of test compounds measured against Emax of 5-HT was determined.
  • EC50 values were calculated for each compound in each cell line and provide an estimate for the potency of each tested compound for activating the specific receptor.
  • Table 1A shows the affinity (by EC50 values) of synthesized compounds to four different receptors.
  • the tested compounds exhibit varying degrees of activity across the tested receptors.
  • the compounds HBL20015, HBL20016 and HBL20017 showed relatively high efficacy at 5-HT1A receptor with HBL20017 showing the highest efficacy at 5-HT1A receptor, followed by HBL20015 and HBL20016.
  • HBL20010 showed low efficacy at 5-HT1 A receptor.
  • the compounds HBL20010, HBL20015, HBL20016 and HBL20017 showed high efficacy at 5-HT2A receptor and the compounds HBL20013, HBL20014 showed lower efficacy at 5-HT2A receptor.
  • the compounds HBL20010, HBL20015, HBL20016 and HBL20017 showed high efficacy towards 5-HT2B receptor whereas the compounds HBL20013, HBL20014 showed lower efficacy at 5-HT2B receptor.
  • the compound HBL20017 showed the highest efficacy at 5-HT2C receptor.
  • the compounds HBL20010 and HBL20016 also showed a higher efficacy at 5- HT2C receptor while the compounds HBL20013, HBL20015 and HBL20014 showed lower efficacy at 5-HT2C receptor.
  • HBL20017 is a potent agonist at 5-HT1B.
  • Table IB shows the affinity (by EC50 values) of HBL20028 to different receptors.
  • HBL20028 shows a reduction in functional activity at 5-HT2B as compared with the functional activity of HBL20017. HBL20028 retains significant functional activity at both 5-HT1A and 5-HT2A, associated with the downstream therapeutic effect.
  • Example 2A showed receptor activation at human 5-HT receptors. This example related to activation at mouse 5-HT receptors.
  • Cells were cultured in cell culture medium (F12 containing 10% dFBS, l x penicillinstreptomycin and 6 pg/ml puromycin) at 37°C, 5% (v/v) CO2. One day before the assays, cells were detached using TrypLETM Express and count cells using cell counter. Only cells with >85% viability are used for the assay. Cells were seeded at 12000 cells/well in 30 pl/well culture medium to a 384-well cell plate and incubate the cells overnight at 37oC, 5% (v/v) CO2.
  • F12 containing 10% dFBS, l x penicillinstreptomycin and 6 pg/ml puromycin
  • 2xdye solution was prepared following the manual of the FLIPR® Calcium 6 Assay Kit: Dye was diluted with assay buffer (20mM HEPES in lx HBSS, PH7.4); Probenecid was added to the final concentration of 5 and vortexed vigorously for 1-2 minutes. Medium was removed from cell plate by flicking the cell plate on towel papers. 10 ⁇ l of assay buffer and 10 ⁇ l of 2xdye solution were added to each well of the cell plate. The cell plate was placed on plate shaker, and agitated at 600rpm for 2 minutes. The plate was incubated at 37°C for 2 hours followed by additional 15-minute incubation at 25oC.
  • 3x compound in assay buffer was prepared: Reference compounds were diluted to required concentration with DMSO and added to a 384-well compound plate; Serial dilutions were prepared as follows: lOmM test compounds were added to the compound plate, and successive 3 -fold serial dilutions were prepared as follows. 90 pl/well of compounds were transferred from source plate to a 384-well compound plate by using an Echo. 30pl/well assay buffer were added to the compound plate. The plate was mixed on the plate shaker for 2 mins; The cell plate, compound plate and tips were put into FLIPR, and 1 O ⁇ l of 3x compound to the cell plate per well with FLIPR were transferred. The plate for 160 sec with 1 sec interval to obtain the data of agonist mode.
  • Table 2 shows the affinity (by EC50 values) of HBL20017 to 3 different receptors. Table 2 - ECso values for HBL20017
  • the EC50 of HBL20017 at mouse 5-HT2A is 6.37nM vs. EC50 in human 5-HT2A of 7.95nM.
  • the slightly higher EC50 in human receptor may indicate the necessity for a higher oral dose in humans to attain therapeutically relevant concentrations in the brain.
  • HBL20010 showed strong efficacy at 5-HT2A and 5-HT2B, and less efficacy at 5-HT1A.
  • HBL20011 and HBL20012 showed moderate efficacy at 5-HT2A and 5-HT2B, but no activity at all at 5- HT1A.
  • HBL20015, HBL20016 andHBL20017 showed agonistic activity both at 5-HT1A, 5-HT2A and 5-HT1B, with HBL20017 showing the strongest efficacy at 5-HT1A.
  • HBL20028 showed a reduction in functional activity at 5-HT2B while retaining the activity at both 5-HT1A and 5-HT2A.
  • the HepG2 cell culture medium consisting of Dulbecco’s Modified Eagle’s Medium (DMEM) supplemented with: 10% FBS, 1 xpenicillin-streptomycin mixture, lx non- essential amino acids (NEAA) and 1% Hepes was prepared.
  • DMEM Modified Eagle’s Medium
  • NEAA lx non- essential amino acids
  • Hepes was prepared.
  • the cultivated cells in T-75 flasks were rinsed with 5 mL PBS, aspirated off, added 3 mL trypsin/EDTA solution, and incubated at 37 °C for approximately 2 minutes or until the cells detached and floated. Trypsin/EDTA was inactived by adding cell culture medium containing FBS.
  • Test compound was 3-fold serial diluted for 8 doses and started from 30 mM of stock solution.
  • Control compound was 3-fold serial diluted for 8 doses and started from 30 mM of stock solution.
  • the plate was removed from the incubator and directly added 100 ⁇ L of the negative control and test article solutions, each in triplicate.
  • the plate(s) was returned to the incubator for 48 hours in a humidified, 37°C, 5% CO2 atmosphere.
  • % Vehicle control [(Read Compound- Read Blank)/(Read Vehicle - Read Blank)]* 100% ii.
  • the automated whole cell patch-clamp (Qube 384TM) technique is used to record outward potassium currents from a population of 10 cells.
  • ERG ether-a-go-go related gene potassium channel
  • cells are harvested using a cell detachment solution (e.g. AccutaseTM) and maintained in serum-free medium (CHO- S- SFM II) at room temperature for at least 120 min before recording.
  • serum-free medium CHO- S- SFM II
  • Stock solution is prepared in DMSO at 300x the final assay concentrations, and stored at -20°C until the day of assay.
  • a 500 ms pulse to -40 mV is delivered to measure the leaking current, which is subtracted from the tail current on-line. Then the cell is depolarized to +40 mV for 500ms and then to -80 mV over a 100ms ramp to elicit the hERG tail current. This is delivered once every 8s to monitor the current amplitude.
  • the assay is conducted at 27 ⁇ 1°C.
  • the Extracellular Solution (0.3% DMSO) is applied first and the cell is stabilized in the solution for 5 min. Then the test compound is applied from low to high concentrations sequentially on the same cell. The cells are incubated with either one or six test concentrations for 5 mins for each test concentration.
  • Table 3 summarizes results of cytotoxicity, hERG inhibition, and hepatocyte function for two tested compounds.
  • both HBL20016 and HBL20017 are not cytotoxic and show an acceptable level of hERG inhibition.
  • the study was designed to assess the safety and toxicity by measuring affinity for various cellular and enzymatic targets.
  • the panel was run at HBL20017 concentration of lOuM and targets that saw an affinity of greater than 50% as compared with the reference ligand were arbitrarily designated as “hits”.
  • Compound was tested at concentration 1.0E-05 to determine compound binding.
  • Compound binding was calculated as a % inhibition of the binding of a ligand specific for each target.
  • Compound enzyme inhibition effect was calculated as a % inhibition of control enzyme activity. Results showing an inhibition or stimulation higher than 50% are considered to represent significant effects of the test compounds. Only the calculable IC50 and EC50 are reported below. In each experiment and if applicable, the respective reference compound was tested concurrently with the test compounds.
  • Figure 1A shows HBL20017 binding affinity for various receptor and transporter targets using radioligand binding assays and Figure IB shows HBL20017 affinity for various enzyme targets.
  • Table 4 shows the inhibition (IC50) or stimulation (EC50) higher than 50% that were considered to represent a significant effect of the tested compound.
  • Table 4 Targets identified as hits at lOuM.
  • MAO-A - inhibition of MAO-A can result in slow metabolism of the drug and in extreme situations it may be associated with serotonin syndrome (particularly when combined with other serotonergic drugs)
  • 5-HT1A, 5-HT1B, 5-HT2A, 5-HT2B, and 5-HT3 - binding at these receptors is expected at high concentrations of tryptamine psychedelics.
  • Table 5 shows results of HBL20017 for different enzymes using enzyme and uptake assays.
  • Targets designated as “hits” in the Example 2 were analyzed in functional assays for those receptors to determine the clinical relevance of activation of inhibition at those receptors/enzymes. Activation and inhibition was presented here in terms of EC 50 and IC50, respectively.
  • the cells were cultured in a cell culture medium consisting of DMEM/F12, which contained 10% dialyzed FBS, l x penicillin-streptomycin, and 600 pg/mL hygromycin B, at 37°C in a 5% (v/v) CO2 environment.
  • DMEM/F12 which contained 10% dialyzed FBS, l x penicillin-streptomycin, and 600 pg/mL hygromycin B, at 37°C in a 5% (v/v) CO2 environment.
  • TrypLETM Express TrypLETM Express and counted with a cell counter, ensuring that only those with greater than 85% viability were used for the assay.
  • the medium was removed from the cell plate by flicking it onto towel paper. Then, 10 pL of assay buffer and 10 ⁇ L of the 2x dye solution were added to each well of the cell plate.
  • the cell plate was placed on a plate shaker, where it was agitated at 600 rpm for 2 minutes before being incubated at 37°C for 2 hours, followed by an additional 15-minute incubation at 25°C.
  • a 3 x compound solution was prepared in assay buffer.
  • Reference compounds were diluted to the required concentrations with DMSO and added to a 384- well compound plate, followed by serial dilutions.
  • Test compounds at a concentration of 10 mM were also added to the compound plate, with 3-fold serial dilutions performed.
  • 90pL per well of both the reference compounds and the test compounds was transferred from the source plate to the compound plate, and 30 ⁇ l of assay buffer was added to each well. The plate was then mixed on a plate shaker for 2 minutes.
  • the cell plate, compound plate, and tips were placed into the FLIPR, where10 ⁇ L of the 3x compound was transferred to each well of the cell plate.
  • the plate was read for 160 seconds at 1 -second intervals to collect data on the agonist mode. After this, the cell plate was kept in the dark at 25°C for 30 minutes. Data from the agonist reference compound were then used to calculate the EC80.
  • a 4* EC80 of the reference agonist was prepared in assay buffer, and 30 ⁇ l of this solution was added to a new 384- well compound plate. After the 30-minute incubation at 25 °C in the dark, the cell plate, the compound plate containing the 4* EC80, and the FLIPR tips were again placed into the FLIPR. Subsequently1, 0 ⁇ L of the 4* EC80 was transferred to each well of the cell plate.
  • the plate was read for 160 seconds with 1 -second intervals to obtain data on the antagonist mode.
  • the cells were cultured in a cell culture medium composed of DMEM/F12, which contained 10% FBS, l x penicillin-streptomycin, and 600 pg/mL hygromycin B, maintained at 37°C in a 5% (v/v) CO2 environment.
  • DMEM/F12 which contained 10% FBS, l x penicillin-streptomycin, and 600 pg/mL hygromycin B, maintained at 37°C in a 5% (v/v) CO2 environment.
  • TrypLETM Express TrypLETM Express and counted with a cell counter, ensuring that only those with over 85% viability were selected for the assay.
  • the medium was removed from the cell plate by flicking it onto towel paper. Subsequently, 10 ⁇ l of assay buffer and10 ⁇ L of the 2x dye solution were added to each well of the cell plate. The cell plate was then placed on a plate shaker, where it was agitated at 600 rpm for
  • a 3 x compound solution was prepared in assay buffer.
  • Reference compounds were diluted to the required concentrations with DMSO and added to a 384-well compound plate, where serial dilutions were performed.
  • Test compounds at a concentration of 10 mM were also added to the compound plate, along with further 3-fold serial dilutions.
  • 90 ⁇ l of the compounds was transferred from the source plate to the 384- well compound plate, and 30 ⁇ l of assay buffer was added to each well. The plate was then mixed on a plate shaker for 2 minutes.
  • the cell plate, compound plate, and tips were placed into the FLIPR, where10 ⁇ L of the 3x compound was transferred to each well of the cell plate.
  • the plate was read for 160 seconds at 1 -second intervals to gather data on the agonist mode. After this, the cell plate was stored in the dark at 25°C for 30 minutes.
  • Data obtained from the agonist reference compound were utilized to calculate the EC50 and EC80.
  • a 4x EC80 of the reference agonist was prepared in assay buffer, and 30 ⁇ l of this solution was added to a new 384- well compound plate. Following a 30-minute incubation at 25°C in the dark, the cell plate, the compound plate containing the 4x EC80, and the FLIPR tips were placed back into the FLIPR. Thereafter1, 0 ⁇ L of the 4* EC80 was transferred to each well of the cell plate.
  • the plate was read for 160 seconds at 1 -second intervals to collect data on the antagonist mode.
  • the cells were cultured in a cell culture medium comprising DMEM, which contained 10% FBS, l x penicillin-streptomycin, and 300 pg/mL G418, maintained at 37°C in a 5% (v/v) CO2 environment.
  • DMEM fetal bovine serum
  • the cells were detached using TrypLETM Express and counted with a cell counter, ensuring that only those with greater than 85% viability were selected for the assay.
  • the assay buffer was prepared using 1 x HBSS supplemented with 20 mM HEPES and 0.1% (w/v) BSA.
  • the lyophilized fluorescent dye/masking dye mixture was reconstituted by adding 10 mL of 1 x HBSS.
  • assay buffer After discarding the culture medium,10 ⁇ L of assay buffer was added to each well of the cell plate. Next, 6x serial diluted compounds were prepared in assay buffer. Reference compounds were diluted to the required concentrations with DMSO and added to a 384- well compound plate, where serial dilutions were performed. Test compounds at a concentration of 10 mM were also added to the compound plate, and 3-fold serial dilutions were conducted. Using an Echo, 120 ⁇ l of the compound was transferred from the source plate to the 384- well compound plate.
  • the cAMP assay buffer was prepared according to the specified formulation.
  • the reagents included 14 mL of 1 x HBSS with Ca 2 + and Mg 2 +, 75 ⁇ l of 1 M HEPES, 100 ⁇ L of 7.5% (w/v) BSA stabilizer (pH 7.4), and 14 ⁇ l of 500 mM IBMX.
  • the Eu-cAMP tracer working solution and Ulight-anti-cAMP working solution were prepared as follows: 20 ⁇ l of Eu-cAMP tracer stock was mixed with 2 mL of cAMP detection buffer, while10 ⁇ L of Ulight-anti-cAMP stock was combined with 2 mL of the same cAMP detection buffer.
  • Forskolin Forskolin was created starting from a 100 mM stock solution through 3-fold serial dilutions with 100% (v/v) DMSO.
  • ten doses of Dopamine were prepared starting from a 1 mM stock solution
  • ten doses of Spiperone were prepared from a 0.03 mM stock solution, both through 3-fold serial dilutions with 100% (v/v) DMSO.
  • ten doses of a test article were prepared starting from a 10 mM stock solution by the same method.
  • CHO-K1 cells stably expressing DRD2 receptors were harvested, and the cell count was obtained using a Countess cell counter. Only cells with greater than 85% viability were used for the assay. The cells were then diluted to UK) 5 cells/mL with the cAMP assay buffer and seeded at a density of 1,000 cells per well in a 384- well plate.
  • the plate was read using the Envision, and the ratio of Emission at 665 nm to Emission at 615 nm was plotted against the concentrations of compounds to create a curve and calculate the EC50 and EC90 of Dopamine.
  • the plate was read using the Envision, and the ratio of Emission at 665 nm to Emission at 615 nm was plotted against the concentrations of compounds to construct a curve and calculate the IC50.
  • the IX assay buffer was prepared. Using an Echo, lOO ⁇ l of diluted compounds was added to a 384-well plate, which was then centrifuged at 1,000 RPM for 1 minute. Following this, 5 ⁇ l of 2X MAO-A was added to the same plate, and it was centrifuged again at 1,000 RPM for 1 minute. Next, 5 ⁇ l of 2X substrate was added to the 384-well plate, which was centrifuged at 1,000 RPM for 1 minute and incubated at room temperature for 60 minutes.
  • the cells were cultured in cell culture medium consisting of DMEM/F12 with 10% FBS, l x penicillin-streptomycin, and 600 pg/mL hygromycin B at 37°C in a 5% (v/v) CO2 atmosphere.
  • the cells were detached using TrypLETM Express and counted with a cell counter. Only those cells with greater than 85% viability were used for the assay.
  • a total of 12,000 cells per well were seeded in 30 ⁇ l of culture medium into a 384-well cell plate, and the cells were incubated overnight at 37°C in a 5% (v/v) CO2 environment.
  • a 2x dye solution was prepared according to the manual of the FLIPR® Calcium 6 Assay Kit.
  • the dye was diluted with assay buffer (20 mM HEPES in 1 x HBSS, pH 7.4), probenecid was added to a final concentration of 5 mM, and the solution was vortexed vigorously for 1-2 minutes.
  • the medium was removed from the cell plate by flicking it onto towel paper.
  • 10 pL of assay buffer and10 ⁇ L of 2 dye solution were added to each well of the cell plate.
  • the plate was placed on a shaker and agitated at 600 RPM for 2 minutes. It was then incubated at 37°C for 2 hours, followed by an additional 15-minute incubation at 25°C.
  • the cell plate, compound plate, and tips were placed into the FLIPR, and 10 ⁇ L of the 3 x compound was transferred to each well of the cell plate using the FLIPR.
  • the plate was read for 160 seconds with 1 -second intervals to obtain data for the agonist mode, after which the cell plate was kept in the dark at 25 °C for 30 minutes.
  • Data from the agonist reference compound was used to calculate the EC80.
  • a 4x EC80 of the reference agonist was prepared in assay buffer, and 30 ⁇ l of this solution was added to a new 384-well compound plate. Following a 30-minute incubation at 25°C in the dark, the cell plate, compound plate containing the 4x EC80, and FLIPR tips were placed into the FLIPR. Ten ⁇ l of the 4x EC80 was transferred to each well of the cell plate using the FLIPR.
  • the plate was read for 160 seconds with 1 -second intervals to obtain data for the antagonist mode.
  • the cAMP assay buffer was prepared by combining the following reagents: 14 mL of 1 x HBSS with Ca 2+ and Mg 2+ , 75 ⁇ l of 1 M HEPES, 100 ⁇ L of a 7.5% (w/v) BSA stabilizer (pH 7.4), and 14 ⁇ l of 500 mM IBMX.
  • the Eu-cAMP tracer working solution consisted of 20 ⁇ l of Eu-cAMP tracer stock and 2 mL of cAMP detection buffer.
  • the Ulight-anti-cAMP working solution included 10 ⁇ L of Ulight-anti-cAMP stock and 2 mL of cAMP detection buffer.
  • ten doses of Dopamine were prepared starting from a 1 mM stock solution through 3-fold serial dilutions with 100% (v/v) DMSO. Additionally, ten doses of R(+)-SCH-23390 hydrochloride were prepared from a 0.1 mM stock solution using the same method. Similarly, ten doses of test compounds were prepared starting from a 10 mM stock solution by 3-fold serial dilutions with 100% (v/v) DMSO.
  • CHO-K1 cells stably expressing DRD1 receptors were harvested and counted with a Countess cell counter. Only cells with viability greater than 85% were utilized for the assay. The cells were diluted to a concentration of 1 * 10 5 cells/mL with the cAMP assay buffer and seeded at a density of 1,000 cells per well in a 384- well plate.
  • the plate was read using an EnVision microplate reader with excitation at 337 nm and emission at 615 nm and 665 nm.
  • the ratio of Emission 665 nm to Emission 615 nm was plotted against the concentrations of the compounds to build the curve and calculate the EC50 and EC90 of Dopamine.
  • the plate was read again using the EnVision microplate reader, and the ratio of Emission 665 nm to Emission 615 nm was plotted against the concentrations of the compounds to build the curve and calculate the IC50.
  • the cAMP assay buffer was prepared according to the following formulation: 14 ml of lx HBSS with Ca 2+ and Mg 2+ , 75 ⁇ l of 1 M HEPES, 100 ⁇ l of 7.5% (w/v) BSA stabilizer (pH 7.4), and 14 ⁇ l of 500 mM IBMX.
  • the Eu-cAMP tracer working solution and Ulight-anti-cAMP working solution were prepared as follows: for the Eu-cAMP tracer working solution, 20 ⁇ l of Eu-cAMP tracer stock was combined with 2 ml of cAMP detection buffer. For the Ulight-anti-cAMP working solution, 10 ⁇ l of Ulight-anti-cAMP stock was mixed with 2 ml of cAMP detection buffer.
  • a compound source plate was prepared.
  • Ten doses of Dopamine were prepared starting from a 1 mM stock solution using 3 -fold serial dilutions with 100% (v/v) DMSO.
  • ten doses of R(+)-SCH-23390 hydrochloride were prepared starting from a 0.1 mM stock solution by 3-fold serial dilutions with 100% (v/v) DMSO.
  • ten doses of test articles were prepared starting from a 10 mM stock solution using the same dilution method.
  • CHO-K1 cells stably expressing DRD2 receptors were harvested and counted using a Countess cell counter. Only cells with viability greater than 85% were utilized for the assay. The cells were diluted to a concentration of U l 0 5 cells/mL with the cAMP assay buffer and seeded at a density of 1000 cells/well in a 384- well plate.
  • the plate was read using an EnVision microplate reader with excitation at 337 nm and emission measured at 615 nm and 665 nm. The ratio of emission at 665 nm to 615 nm was plotted against the concentrations of compounds to generate a curve and calculate the EC50 and EC90 of Forskolin.
  • Forskolin was then transferred to each well of the assay plate to achieve its EC90 value using the Echo. Following this, lO ⁇ l of serially diluted Dopamine and test articles were added to each well of the assay plate with the DRD2 receptor-expressing cells. The cell plate was centrifuged, agitated, and incubated as described previously.
  • the cells were cultured in cell culture medium consisting of DMEM/F12 containing 10% FBS, 1 x penicillin-streptomycin, and 600 pg/ml hygromycin B at 37°C with 5% (v/v) CO2.
  • the cells were detached using TrypLETM Express and counted with a cell counter. Only cells with viability greater than 85% were used for the assay. A total of 12,000 cells per well were seeded in 30 ⁇ l of culture medium into a 384-well cell plate and incubated overnight under the same conditions.
  • a 2 - dye solution was prepared according to the FLIPR® Calcium 6 Assay Kit manual. This involved diluting the dye with assay buffer (20 mM HEPES in 1 x HBSS, pH 7.4), adding probenecid to a final concentration of 5 mM, and vortexing the solution vigorously for 1-2 minutes.
  • the medium was then removed from the cell plate by flicking it onto towel papers. Following this, 10 ⁇ L of assay buffer and of t1h0e ⁇ 2Lx dye solution was added to each well of the cell plate.
  • the cell plate was placed on a shaker and agitated at 600 RPM for 2 minutes, followed by an incubation at 37°C for 2 hours and an additional 15-minute incubation at 25°C.
  • a 3 x compound solution was prepared in assay buffer.
  • Reference compounds were diluted to the required concentration with DMSO and added to a 384-well compound plate, followed by performing serial dilutions.
  • Test compounds at a concentration of 10 mM were added to the compound plate, where they were subjected to 3-fold serial dilutions.
  • 90 ⁇ l of compounds were transferred from the source plate to the 384-well compound plate.
  • 30 ⁇ l of assay buffer was added to each well of the compound plate, which was then mixed on a plate shaker for 2 minutes.
  • the cell plate, compound plate, and tips were loaded into the FLIPR. A total of 10 ⁇ L of the 3 x compound was transferred to each well of the cell plate using the FLIPR. The plate was read for 160 seconds at 1 -second intervals to collect data for the agonist mode. After reading, the cell plate was kept at 25°C in the dark for 30 minutes.
  • Data obtained from the agonist reference compound in the cell plate were used to calculate the EC80.
  • a 4x EC80 solution of the reference agonist was prepared in assay buffer, and 30 ⁇ l of this solution was added to a new 384- well compound plate. Following a 30-minute incubation at 25°C in the dark, the cell plate, compound plate containing the 4* EC80, and FLIPR tips were placed into the FLIPR. A total of of th10e ⁇ 4L* EC80 was transferred to each well of the cell plate using the FLIPR. Finally, the plate was read for an additional 160 seconds at 1 -second intervals to obtain data for the antagonist mode.
  • Tables 6A-6M show functional or enzymatic assays.
  • Table 6C Functional Assay for Adrenergic Alpha 1A - agonist mode
  • Table 6D Functional Assay for Adrenergic Alpha 1A - antagonist mode
  • HBL20017 showed strong activity at Adrenergic Alpha 1 A receptor in both agonist and antagonist mode - with possible implications for vasoconstriction/dilation. Some inhibition was seen at Dopamine DI receptor, MAO-A, and norepinephrine transporter, but the concentrations at which the inhibition was observed are not likely to be clinically relevant.
  • the other targets did not show activity or inhibition across the range of concentrations studied.
  • the pharmacokinetic study was employed to determine the kinetics of the distribution of HBL20017 in serum and brain in mice to understand its bioavailability and exposure and to estimate a clinically-relevant human oral dose.
  • the formulation preparation was carried out as follows. For the intravenous (IV) dosing, a solution of 0.6 mg/mL of "30% PEG400/70% Saline" was prepared. Initially, 1.04 mg of HBL20017 was dissolved in 0.520 mL of PEG400, using vortexing and sonication to ensure complete dissolution. Subsequently, 1.213 mL of Saline was added, with further vortexing and sonication performed to achieve a homogenous solution.
  • IP intraperitoneal
  • All brain samples were homogenized by adding phosphate-buffered saline (PBS) at a volume ratio of 1 :3 (brain weight to PBS volume).
  • PBS phosphate-buffered saline
  • the actual concentration (ng/g) of the analyte was calculated by multiplying the detected value (ng/mL) by a factor of 4.
  • the stock solution of the analyte was diluted with a 50% acetonitrile in water solution.
  • a volume of 15 ⁇ l of each working solution (1, 2, 4, 10, 20, 100, 200, 1000, and 2000 ng/mL) was added to 30 ⁇ l of blank CD1 mouse brain homogenate, resulting in calibration standards ranging from 0.5 to 1000 ng/mL (0.5, 1, 2, 5, 10, 50, 100, 500, and 1000 ng/mL).
  • four quality control (QC) samples at concentrations of 1 ng/mL, 2 ng/mL, 5 ng/mL, 100 ng/mL, and 800 ng/mL were prepared independently from those used for the calibration curves. These QC samples were prepared on the day of analysis using the same method as the calibration standards.
  • a total of 45 ⁇ l of the calibration standards, QC samples, and unknown samples were combined with 200 ⁇ l of acetonitrile containing an internal standard mixture to precipitate proteins.
  • the samples were vortexed for 30 seconds and then centrifuged at 4°C at 4000 rpm for 15 minutes.
  • the supernatant was diluted threefold with water, and 1 ⁇ l of the diluted supernatant was injected into the LC/MS/MS system for quantitative analysis.
  • the High-Performance Liquid Chromatography (HPLC) system utilized in the analysis was a SHIMADZU setup comprising the following components: LC-40D X3 CN (Serial Nos. L22435901046 AE and L22435901060 AE), DGU-405 (Serial No. L22175904375 IX), CBM-40 CN (Serial No. L22115901836 CD), SIL-40C X3CN (Serial No. L22465901088 AE), and CTO-40C CN (Serial No. L22245903399 IK). Additionally, two plate changers were employed, with Serial Nos. L22225900352 CZ and L22225900399 CZ.
  • the analytical column used was an Agilent EC-C 18, 2.7 pm particle size, with dimensions of 3.0 x 30 mm.
  • the mass spectrometer coupled with the HPLC system was an AB API 5500+ LC/MS/MS (Serial No. EX231332109).
  • the mobile phase consisted of two solutions: Solution A, composed of 95% water and 5% acetonitrile, with 0.1% formic acid, and Solution B, composed of 95% acetonitrile and 5% water, also with 0.1% formic acid.
  • the gradient elution was performed at a flow rate of 0.8 mL/min, starting with 100% Solution A at 0.01 minutes and maintaining this composition until 0.50 minutes. At 2.40 minutes, the composition shifted to 50% Solution A and 50% Solution B, remaining at this ratio until 2.60 minutes. At 2.61 minutes, the system returned to 100% Solution A, which was maintained until 3.50 minutes.
  • the injection volumes were standardized at 5 ⁇ l for plasma samples and 1 ⁇ l for brain samples.
  • HBL20017 showed low hERG related risk.
  • the estimated human oral dose (required to achieve a brain concentration 9x that of the EC50 of HBL20017 at 5-HT2A) is 569mg, assuming that: the EC50 of HBL20017 in human 5-HT2A is equivalent to that of human 5-HT2A.
  • the fraction drug unbound (fu) in the brain is 4%.
  • the head-twitch response is a rapid side-to-side rotational head movement that occurs in mice after administration of serotonergic hallucinogens and other 5-HT2A agonists.
  • the absence of the HTR indicates that the compound is not likely to induce the psychedelic trip in humans.
  • Head twitch response was measured over 30 min by means of a magnetometer apparatus. Briefly, small neodymium magnets (N50, 3 mm diameter x 1 mm height, 50 mg), were attached to the outer ears of mice. After a 5-7-day recovery period, the ear-tagged animals were placed inside a magnetometer apparatus immediately after injection of vehicle, PSIL, or PME. The output was amplified (Pyle PP444 phono amplifier) and recorded at 1000 Hz using a NI USB-6001 (National Instruments, US) data acquisition system.
  • NI USB-6001 National Instruments, US
  • mice were injected with HBL20016, HBL20017 and HBL20028 as well as with psilocybin (a psychedelic compound - positive control), and vehicle (negative control). Results
  • Figure 2 and Table 8 show the total HTR response results (marker of serotonergic activity) for mice administered psylocibin, HBL20016 and HBL20017 at different concentrations; vehicle is shown as a negative control.
  • psylocibin As can be seen in Figure 2 administration of a vehicle has a marginal effect of HTR, whereas psylocibin (PSIL) induced an increase in HTR as measured in 30 minutes. As noted above, psylocibin is used as a positive control and showed an increase in HTR response.
  • HBL20016 increased HTR in a dose dependent manner with a large increase observed in a concentration of 6mg/kg, whereas HBL20017 showed a reduction in HTR as compared to vehicle at lower dose and a comparable effect to that of the vehicle at 6mg/kg.
  • HBL20016 induces a very strong HTR via its agnostic effect on 5-HT2A receptor, while HBL20017 has relatively low HTR.
  • Figures 2B-2D show the total HTR response results for mice administered psylocibin, and HBL20028 at different concentrations; vehicle is shown as a negative control.
  • administration of HBL20028 at doses of 6, 12, and 24 mg/kg did not result in a significant increase in HTR compared to vehicle.
  • administration of HBL20028 at doses of 6, 12, and 24 mg/kg did not result in a significant increase in peak HTR compared to vehicle.
  • Figure 2D administration of HBL20028 at doses of 6, 12, and 24 mg/kg did not result in a significant increase in HTR overtime.
  • HBL20028 has relatively low HTR.
  • mice activity and anxiety were done using the OFT.
  • the mouse was put into a box and its activity behavior was monitored. In case of hypoactivity, the mouse covers less distance in the box than the control mouse. In the case of hyperactivity, the mouse covers more distance in the box than the control mouse. When mice are anxious, more of their activity is confined to the periphery of the box. When mice are less anxious, more of their activity is in the center of the box.
  • HBL20028 was administered at 6 mg/kg, 12 mg/kg or 24 mg/kg or vehicle.
  • Figures 3A-3B shows the results of total distance in OFT for psilocybin, HBL20016 ( Figure 3A) and HBL20017 ( Figure 3B).
  • psilocybin resultsed in a reduction in total distance covered as compared to the vehicle such that the total distance was halved in psilocybin administered mice as compared to the vehicle administered mice.
  • psilocybin showed a reduced overall activity as indicated by the reduced total distance covered as compared to vehicle.
  • HBL20028 at a dose of 6 mg/kg did not affect locomotor activity compared to vehicle.
  • HBL20028 at 12 mg/kg and 24 mg/kg significantly reduced total distance covered suggesting a dose-dependent effect on motor behavior.
  • administration of HBL20028 at 12 mg/kg resulted in a statistically significant increase in time spent in the periphery.
  • Figure 4A shows the effect of Psilocybin (PSIL), HBL20016 and HBL20017 compounds on marble burying (MB) over 30 minutes.
  • PSIL Psilocybin
  • HBL20016 HBL20017 compounds
  • MB marble burying
  • HLB0017 significantly reduces MB even when its effect to reduce activity is taken into account in an analysis of covariance (upper panel).
  • the lower panel shows the effect when activity is not taken into account (analysis of variance without covariate).
  • Examples 9 and 10 Effect of HBL20016 and HBL20017 on obsessive self-grooming and head-body twitches in SAPAP3 KO mice.
  • mice The experiment is focused on the adult phenotype of SAPAP3 KO mice and is conducted as a clinical trial based on the individual phenotype of each mouse.
  • the homozygous mice are then randomly assigned to one of four treatment groups - Saline Vehicle (VEH), PSIL, HBL20016 and HBL20017.
  • PSIL is administered at a dose of 4.4 mg/kg i.p.
  • HBL20016 and HBL20017 were administered at a dose of 6mg/kg i.p..
  • the mice are video recorded for one hour at 48 hours, 12 days and 21 days after treatment and then 42 days after treatment and assessed by blinded observers for grooming frequency and grooming duration and number of head-body twitches.
  • Figure 5A shows the effect of HBL20016 (6mg/kg), HBL20017 (6 mg/kg) and psilocybin (4.4 mg/kg) on total self-grooming duration of SAPAP3 KO mice up to 21 days following treatment administration versus control (vehicle) treatment.
  • Figure 5B shows the effect of the same treatments (without control) on total self-grooming duration of SAPAP3 KO mice up to 42 days following treatment administration.
  • Figure 5C shows the effect of HBL20016 (6mg/kg), HBL20017 (6 mg/kg) and psilocybin (4.4 mg/kg) on headbody twitches of SAPAP3 KO mice up to 21 days following treatment administration versus control (vehicle) treatment.
  • Figure 5D shows the effect of the same treatments (without control) on head-body twitches of SAPAP3 KO mice up to 42 days following treatment administration.
  • Figures 6A to 6L are graphs showing obsessive-like Behavior in SAPAP3 Knockout Mice;
  • Figures 6A and 6B are graphs showing % Change from baseline to 21 days in total grooming bouts following treatment with HBL20016, HBL20017 at 6mg/kg IP or Vehicle.
  • Figure 6B includes treatment group that received psilocybin 4.4 mg/kg as a positive comparator;
  • Figures 6C and 6D are graphs showing % Change from baseline to 21 days in short self-grooming bouts following treatment with HBL20016, HBL20017 at 6mg/kg IP or Vehicle.
  • Figure 6F includes treatment group that received psilocybin 4.4 mg/kg as a positive comparator;
  • Figures 6E and 6F are graphs showing % Change from baseline to 21 days in long self-grooming bouts following treatment with HBL20016, HBL20017 at 6mg/kg IP or Vehicle.
  • Figure 6F includes treatment group that received psilocybin 4.4 mg/kg as a positive comparator.
  • Figures 6G and 6H are graphs showing % Change from baseline to 42 days in total grooming bouts following treatment with HBL20016, HBL20017 at 6mg/kg IP or Vehicle.
  • Figure 6H includes treatment group that received psilocybin 4.4 mg/kg as a positive comparator
  • Figures 61 and 6 J are graphs showing % Change from baseline to 42 days in short self-grooming bouts following treatment with HBL20016, HBL20017 at 6mg/kg IP or Vehicle.
  • Figure 6 J includes treatment group that received psilocybin 4.4 mg/kg as a positive comparator
  • Figures 6K 6L are graphs showing % Change from baseline to 42 days in long self-grooming bouts following treatment with HBL20016, HBL20017 at 6mg/kg IP or Vehicle.
  • Figure 6L includes treatment group that received psilocybin 4.4 mg/kg as a positive comparator.
  • Attenuation of MK-801 -induced hyperactivity in mice is commonly used test for prediction of antipsychotic activity.
  • the following data show the inhibition of MK-801 induced hyperactivity by HBL20017 at various doses as compared with vehicle (negative control) and olanzapine (positive control).
  • Figure 7 shows the results of the total distance.
  • Table 19 shows the results of this example.
  • MK-801 significantly increased activity compared to naive group.
  • HBL20017 treatment showed decrease in MK-801 induced hyperactivity at 3, 6 and 10 mg/kg dose, compared to vehicle treatment, (data not shown)
  • Olanzapine treatment showed significant decrease in total distance travelled compared to vehicle treatment.
  • the test is commonly used assess antidepressant potential of antidepressant compounds.
  • HBL20017 was shown at varying doses on parameters of the Forced Swim Test.
  • Figures 8A and 8B show results of immobility time and swimming time, respectively.
  • HBL20017, 1, 3 and 6 mg/kg, IP treatment group did not show any significant change in Immobility time or swimming behavior compared to vehicle treatment.
  • HBL20017, 10 mg/kg, IP treatment group exhibited significant increase in swimming behavior and decrease in mobility compared to vehicle treatment reflecting the antidepressant efficacy of HBL20017 at 10 mg/kg.
  • Desipramine HC1 20mg/kg, IP treated group exhibited significant decrease in immobility time and increased swimming behavior compared to vehicle treatment reflecting the antidepressant efficacy of Desipramine.
  • Figure 9 shows total active behavioral time.
  • HBL20017, 1, 3 and 6 mg/kg, IP treatment group did not show any significant change in total active behavior (Swimming +Climbing) compared to vehicle treatment.
  • HBL20017, 10 mg/kg, IP treatment group exhibited significant increase in active behavior (Swimming + Climbing) compared to vehicle treatment.
  • Desipramine HC1 20mg/kg, IP treatment group exhibited significant increase in active behavior (Swimming + Climbing) compared to vehicle treatment.
  • Table 12 The results are summarized in Table 12.
  • vehicle-treated group displayed signs of depression-like behavior, marked by increased immobility and decreased active behavior.
  • Desipramine alleviated the depression-like effects by exhibiting increased swimming time and decreased immobility time.
  • HBL20017 at 1, 3 and 6 mg/kg did not exhibit significant change in immobility time, swimming time compared to vehicle treated group.
  • HBL20117 10 mg/kg recapitulated desipramine like effects by exhibiting significant reduction in immobility time, increased swimming behavior and significant rise in total active behavior when compared to vehicle treated group.

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Abstract

La présente divulgation concerne un composé à petites molécules (SMC), une composition pharmaceutique le contenant et ses utilisations dans des méthodes de traitement d'une maladie cérébrale.
PCT/IL2025/050334 2024-04-15 2025-04-10 Composés et leurs utilisations en tant que modulateurs des récepteurs de la sérotonine Pending WO2025220005A1 (fr)

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