Compounds and uses thereof as modulators of serotonin receptors

Abstract

The present disclosure relates to small molecule compound (SMC), pharmaceutical composition comprising the same, uses thereof in methods for treating brain disease.

Description

[0001] COMPOUNDS AND USES THEREOF AS MODULATORS OF SEROTONIN RECEPTORS

[0002] TECHNOLOGICAL FIELD

[0003] The present disclosure relates to compound and pharmaceutical uses thereof.

[0004] BACKGROUND ART

[0005] References considered to be relevant as background to the presently disclosed subject matter are listed below:

[0006] [1] Laban, Uros, et al. "A novel fluorinated tryptamine with highly potent serotonin 5-HT1A receptor agonist properties." Bioorganic & medicinal chemistry letters 11.6 (2001), 793-795.

[0007] [2] Blair, Joseph B., et al. "Effect of ring fluorination on the pharmacology of hallucinogenic tryptamines." Journal of medicinal chemistry 43.24 (2000): 4701-4710.

[0008] [3] US patent application publication No. US2023 / 0140635.

[0009] [4] Alexander and Ann Shulgin, Tihkal.

[0010] Acknowledgement of the above references herein is not to be inferred as meaning that these are in any way relevant to the patentability of the presently disclosed subject matter.

[0011] BACKGROUND

[0012] Serotonin, also known as 5-hydroxytryptamine (5-HT), 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.

[0013] The unique pharmacological properties of serotonin receptors have led to the development of various agonists and antagonists aimed at modulating their activity for therapeutic purposes. Synthesis and / or biological evaluation of a tryptamine analogues are described for example in [l]-[4]. GENERAL DESCRIPTION

[0014] In accordance with some aspects, it is provided a small molecule compound (SMC) 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(Rn)(R12), -C(O)Rn, -CH2R11, -CO2R11, -C(O)N(Rn)(R12), -SO2N(Rn)(R12), -SOR11, R3IS L2-R9, L2is -(CH2)m- ,-C(O)-, -O- -NH-, -O-CH2-, -N-(CH2)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(Rn)(R12), -C(O)Rn, -CH2R11, -CO2R11,

[0015] -C(O)N(Rn)(R12), -SO2N(Rn)(R12), each R11and R12is 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(O2), Rs is hydrogen, cyano, nitro, hydroxy, halo, CF3, C1-C12 haloalkyl, C1-C12 haloalkoxy, C1-C12 alkyl, C1-C12 alkoxy, aryl and N(Rn)(R12). In accordance with some other aspects, it is provided a composition comprising at least one SMC as defined herein.

[0016] In accordance with some other aspects, it is provided a SMC or a composition as defined herein for use in modulating one or more serotonergic receptors.

[0017] In accordance with some other aspects, it 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.

[0018] In accordance with some other aspects, it is provided a SMC or composition as defined herein for use in a method for treating, preventing, inhibiting, reducing, eliminating, protecting or delaying a brain disease.

[0019] In accordance with some other aspects, it is provided a method for modulating at least one serotonin receptor, the method comprising contacting at least one serotonin receptor with at least one SMC or a composition as defined herein.

[0020] In accordance with some other aspects, it is provided a method for treating, preventing, inhibiting, reducing, eliminating, protecting or delaying the onset of disorder characterized by deregulated 5- HT1A receptor function, the method 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.

[0021] In accordance with some other aspects, it is provided a method for treating, preventing, inhibiting, reducing, eliminating, protecting or delaying the onset of brain disease, the method 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.

[0022] In accordance with some other aspects, it is provided use of at least one SMC as defined herein in the manufacture of a composition. BRIEF DESCRIPTION OF THE DRAWINGS

[0023] In order to better understand the subject matter that is disclosed herein and to exemplify how it may be carried out in practice, embodiments will now be described, by way of non-limiting example only, with reference to the accompanying drawings, in which:

[0024] 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).

[0025] Figures 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.

[0026] 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.

[0027] 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 (5-HT2A antagonist), Figure 4D shows the time course of MB of these compounds.

[0028] 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.

[0029] 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 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 6J 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 6J includes treatment group that received psilocybin 4.4 mg / kg as a positive comparator; Figures 6K and 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.

[0030] Figure 7 is a graph showing total distance traveled, data is represented as Mean ± SEM (n=12) *p < 0.05, ***p < 0.001, ****p < 0.0001, vs Vehicle; ANOVA followed by Dunnett’s multiple comparison test.

[0031] Figures 8A and 8B are graphs showing Immobility Time and Swimming Time.

[0032] Figure 9 is a graph showing total active behavior; data is represented as Mean ± SEM (n=ll-12), **p<0.005, ****p < 0.0001 vs Vehicle; ANOVA followed by Dunnett’s Multiple comparison test. Statistical analysis carried out by Graph Pad Prism Software Version 9.5. DETAILED DESCRIPTION OF EMBODIMENTS

[0033] The disclosure is based on the development of novel small molecule compounds (SMC) that are modulators of serotonergic receptors that can be used in methods of treating disease mediated by these receptors, including, inter alia, brain disease.

[0034] As shown in the Examples below, the small molecule compounds are characterized by maintaining function at specific serotonergic receptors, including 5-HT1 A and 5-HT2A receptor agonist activity. Hence, it was suggested that 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. Interestingly, the small molecule compounds are characterized by minimized HT2B receptor activity.

[0035] Hence, the present disclosure provides in accordance with some aspects, a small molecule compound (SMC) 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(Rn)(R12), -C(O)Rn, -CH2R11, -CO2R11,

[0036] -C(O)N(Rn)(R12), -SO2N(Rn)(R12), -SOR11, R3IS L2-R9, L2IS -(CH2)m- ,-C(0)-, -o-, -NH-, -0-CH2-, -N-(CH2)m- -NH-C(O)- , each optionally substituted with Ci-Ci2alkyl, C1-C12 haloalkyl, or halo, m is selected from 0, 1, 2, 3, 4, 5 or 6,

[0037] 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(Rn)(R12), -C(O)Rn, -CH2Rn, -CO2Rn, -C(O)N(Rn)(R12), -SO2N(Rn)(R12), each R11and R12is independently H, hydroxyl, Ci- Ci2alkyl, C1-C12 haloalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, R5 is -Z-Rs or L2-Z-Rs, Z is S, S(O), or S(O2), and Rs is hydrogen, cyano, nitro, hydroxy, halo, CF3, C1-C12 haloalkyl, C1-C12 haloalkoxy, C1-C12 alkyl, C1-C12 alkoxy, aryl, N(R1 X)(R12); provided that if Xi, X2, X3, X4, X5 andXe is each C and X7 is N, Ri is hydrogen, Z is S, Rs is C3 alkyl, L2is (CH2)2, R9 is -N(Rn)(R12), R11and R12is each C3 alkyl, at least one of R2, R4, Re, R7 is not hydrogen.

[0038] The present disclosure provides in accordance with some aspects, 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, 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-C12 alkynyl, C2-C12 haloalkynyl, C1-C12 alkoxy, C1-C12 haloalkoxy, urea, sulfonylurea, sulfonamidyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, trifluoromethyl, -N(Rn)(R12), -C(O)Rn, -CH2R11, -CO2R11, -C(O)N(Rn)(R12), -SO2N(Rn)(R12), -SOR11,

[0039] R3IS L2-R9, L2IS — (CH2)m- ,-C(O)-, -O-, -NH-, -O-CH2-, -N-(CH2)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,

[0040] 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(Rn)(R12), -C(O)Rn, -CH2R11, -CO2R11, -C(O)N(Rn)(R12), -SO2N(Rn)(R12), each R11and R12is independently H, hydroxyl, Ci- C12 alkyl, C1-C12 haloalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, R5 is -Z-Rs o rL2-Z-Rs, Z is S, S(O), S(C>2), Rs is hydrogen, cyano, nitro, hydroxy, halo, CF3, C1-C12 haloalkyl, C1-C12 haloalkoxy, C1-C12 alkyl, C1-C12 alkoxy, aryl and N(R1 X)(R12); provided that if Xi, X2, X3, X4, X5 andXe is each C and X7 is N, Ri is hydrogen, Z is S, Rs is C3 alkyl, L2 is (CH2)2, R9 is -N(Rn)(R12), R11and R12is each C3 alkyl, at least one of R2, R4, Re, R7 is not hydrogen.

[0041] In some embodiments, in the SMC having a structure represented by Formula (la) or Formula (lb) each one of Xi, X2, X3, and X4 is C. In some embodiments, in the SMC having a structure represented by Formula (la) or Formula (lb), X5 and Xe is C. In some embodiments, in the SMC having a structure represented by Formula (la) or Formula (lb) X7is N.

[0042] In the following text, when referring to at least one small molecule compound it is to be understood as also referring to the compositions, pharmaceutical compositions, methods and uses disclosed herein. Thus, whenever providing a feature with reference to at least one compound, it is to be understood as defining the same feature with respect to the compositions, pharmaceutical compositions, methods, and uses, mutatis mutandis.

[0043] In accordance with some other aspects, 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. Xr„ Ri, R2, R3, R4, R5, Re, and R7 are as defined above for SMC of Formula (la).

[0044] It should be noted that when considering the SMC having a structure represented by Formula (la) and (la’) in which the dashed line may be a single bond or a double bond, 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. In addition, it should be noted that in cases in which each one of Xi, X2, X3, X4, X5, Xe is substituted with two of the corresponding substituents provided by R2, R3, R4, R5 ,Re, and R7, these two substitutions provided by any one of R2, R3, R4, R5 ,Re, and R7 may be the same or may be different and selected from the definitions provided in accordance with these Formulas.

[0045] In accordance with some other aspects, 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).

[0046] In some embodiments, in the SMC having a structure represented by Formula (la), (lb), (la’), (lb’) at least one of Xi, X2, X3, and X4 is C. In some embodiments, in the SMC having a structure represented by Formula (la), (lb), (la’), (lb’) two of Xi, X2, X3, and X4 is C. In some embodiments, in the SMC having a structure represented by Formula (la), (lb), (la’), (lb’) three of Xi, X2, X3, and X4 is C. In some embodiments, in the SMC having a structure represented by Formula (la), (lb), (la’), (lb’) each one of Xi, X2, X3, and X4 is C.

[0047] In accordance with some embodiments, 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).

[0048] In some embodiments, in the SMC having a structure represented by Formula (la), Formula (lb), Formula (la’), Formula (lb’), Formula (Ic), R5 is -Z-Rs or L2-Z-R8, Z is S, S(O) or S(O2) and Rs is hydrogen, cyano, nitro, hydroxy, halo, CF3, C1-C12 haloalkyl, Ci- C12 haloalkoxy, C1-C12 alkyl, C1-C12 alkoxy and aryl.

[0049] In some embodiments, in the SMC having a structure represented by Formula (la), Formula (lb), Formula (la’), Formula (lb’), Formula (Ic), R5 is -Z-Rs, Z is S, S(O) or S(O 2), R8 is hydrogen, CF3 or C1-C12 alkyl.

[0050] In some embodiments that may be considered as aspects of the invention, 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(Rn)(R12), -C(O)Rn, -CH2R11, -CO2R11, -C(O)N(Rn)(R12), -SO2N(Rn)(R12), -SOR11, R3IS L2-R9, L2is - (CH2)m- ,-C(O)-, -O-, -NH-, -O-CH2-, -N-(CH2)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-C12alkynyl, C2-C12 haloalkynyl, C1-C12 alkoxy, C1-C12 haloalkoxy, urea, sulfonylurea, sulfonamidyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, trifluoromethyl, -N(Rn)(R12), -C(O)Rn, -CH2R11, -CO2R11, -C(O)N(Rn)(R12), -SO2N(Rn)(R12), each R11and R12is independently H, hydroxyl, Ci- C12 alkyl, C1-C12 haloalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, or R11and R12together with the nitrogen atom they are connected to form a ring system optionally include at least one of N, O, 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, N(Rn)(R12).

[0051] In some embodiments, in the SMC having a structure represented by Formula (la), (lb), (la’), (lb’), (Ic), (II), R3IS L2-R9, L2is -(CH2)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(Rn)(R12), each R11and R12is independently H, hydroxyl, C1-C12 alkyl and m is selected from 0, 1, 2, 3, 4, 5 or 6.

[0052] In some embodiments, in the SMC having a structure represented by Formula (la), (lb), (la’), (lb’), (Ic), (II), R3is L2-R9, L2 is -(CH2)m-, optionally substituted with C1-C12 alkyl, C1-C12 haloalkyl, or halo, R9 is hydrogen, heterocycloalkyl, or -N(Rn)(R12), each R11and R12is independently H, C1-C12 alkyl or R11and R12together 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. In some embodiments, in the SMC having a structure represented by Formula (la), (lb), (la’), (lb’), (Ic), (II), 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(Rn)(R12), each R11and R12is independently H, C1-C12 alkyl or R11and R12together with the nitrogen atom they are connected to form a ring system optionally include at least one of N, O.

[0053] In some embodiments, in the SMC having a structure represented by one or more of Formula (la), Formula (lb), Formula (la’), Formula (lb’), Formula (Ic), Formula (II), R3 is L2-R9, L2 is -(CH2)2-, R9 is -N(Rn)(R12), each R11and R12is independently H, C1-C12 alkyl or R11and R12together with the nitrogen atom they are connected to form a ring system optionally include at least one of N, O.

[0054] In some embodiments, 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 R11and R12are 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.

[0055] In some embodiments, in the SMC having a structure represented by Formula (Illa), each one of R13, R14, R15, R16 is a hydrogen.

[0056] In some embodiments, 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 R11and R12are as defined in Formula (II).

[0057] In some embodiments, each R11and R12is each Ci-Ce alkyl or R11and R12together with the nitrogen atom they are connected to form a ring system optionally include at least one of N, O.

[0058] In some embodiments, 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).

[0059] In some embodiments, Z is S, S(O) or S(Ch). In some embodiments, Z is S.

[0060] In some embodiments, Rs is hydrogen, cyano, nitro, hydroxy, halo, CF3, C1-C12 haloalkyl, C1-C12 haloalkoxy, C1-C12 alkyl, C1-C12 alkoxy, aryl and N(Rn)(R12). In some embodiments, Rs is hydrogen, cyano, nitro, hydroxy, halo, CF3, C1-C12 haloalkyl, C1-C12 haloalkoxy, C1-C12 alkyl, C1-C12 alkoxy and aryl. In some embodiments, Rs is hydrogen, CF3, C1-C12 alkyl. In some embodiments, R2 is hydrogen.

[0061] In some embodiments, 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.

[0062] In some embodiments, 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). In some embodiments, the SMC has a structure represented by the general Formula (Va). In some embodiments, the SMC has a structure represented by the general Formula (Vf).

[0063] In some embodiments, 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, -CH2R11, wherein R11is selected from cycloalkyl, heterocycloalkyl, aryl, heteroaryl.

[0064] In some embodiments, each one of Ri, R2, R4, Re, R7, is hydrogen, halo and C1-C12 alkyl, -CH2R11, wherein R11is cycloalkyl.

[0065] In some embodiments, 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 CH2R11, wherein R11is cycloalkyl. In some embodiments, Ri is CH2R11, wherein R11is cyclopropyl.

[0066] In some embodiments, R2 is hydrogen.

[0067] In some embodiments, 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.

[0068] In some embodiments, in 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.

[0069] In some embodiments, in the SMC has a structure represented by a Formula of (Va) and Ri is hydrogen, C1-C3 alkyl, or CH2R11, wherein R11is cyclopropyl, Ri is hydrogen, R4, Re, R7, is independently hydrogen, fluorine, C1-C3 alkyl.

[0070] In some embodiments, in the SMC has a structure represented by a Formula of (Va) and Ri is CH2R11, wherein R11is cyclopropyl, 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 (Va) 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 (Va) and Ri is C2 alkyl, 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 hydrogen, C1-C3 alkyl, or CH2R11, wherein R11is cyclopropyl, 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 CH2R11, wherein R11is cyclopropyl, 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 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.

[0071] In some embodiments, at least one SMC has a structure represented by at least one of the following:

[0072] (a)

[0073] N,N-dimethyl-2-(7-methyl-5-(methylthio)-lH-indol-3-yl)ethanamine (denoted herein as HBL20010) or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer or physiologically functional derivative thereof,

[0074] (b)

[0075]

[0076] 2-(7-fluoro-5-(methylsulfinyl)-lH-indol-3-yl)-N,N-dimethylethanamine (denoted herein as HBL20013) or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer or physiologically functional derivative thereof,

[0077] (c)

[0078] 2-(7-fhioro-5-(methylsulfonyl)-lH-indol-3-yl)-N,N-dimethylethanamine (denoted herein as HBL20014) or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer or physiologically functional derivative thereof,

[0079] (d) 2-(7-fluoro-5-(methylthio)-lH-indol-3-yl)-N,N-dimethylethanamine (denoted herein as HBL20015) or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer or physiologically functional derivative thereof,

[0080] (e)

[0081] 2-(6-fhioro-5-(methylthio)-lH-indol-3-yl)-N,N-dimethylethanamine (denoted herein as HBL20016) or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer or physiologically functional derivative thereof,

[0082] (f)

[0083] 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,

[0084] (g) 2-(4-fluoro-5-((trifluoromethyl)thio)-lH-indol-3-yl)-N,N-dimethylethanamine (denoted herein as HBL2022) or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer or physiologically functional derivative thereof,

[0085] (h)

[0086] 2-(4-fhioro-5-(isopropyhhio)-lH-indol-3-yl)-N,N-dimethylethanamine (denoted herein as HBL20023) or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer or physiologically functional derivative thereof,

[0087] (i)

[0088] 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,

[0089]

[0090] 2-(4-fluoro-7-methyl-5-(methylthio)-lH-indol-3-yl)-N,N-dimethylethanamine

[0091] (denoted herein as HBL0025) or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer or physiologically functional derivative thereof,

[0092] (k)

[0093] 2-(l-ethyl-4-fhioro-5-(methyhhio)-lH-indol-3-yl)-N,N-dimethylethanamine

[0094] (denoted herein as 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.

[0095] In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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.

[0096] 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.

[0097] In yet some embodiments, 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:

[0098]

[0099] N,N-dimethyl-2-(5-(methylthio)-lH-indol-3-yl)ethanamine.

[0100] It should be appreciated that in some aspects, 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.

[0101] In some embodiments, 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).

[0102] A further aspect of the present disclosure relates to 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.

[0103] In some embodiments, 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).

[0104] In some embodiments, 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. In some embodiments, 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.

[0105] In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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.

[0106] The compositions of the invention may comprise an effective amount of at least one SMC of the invention.

[0107] The pharmaceutical 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. In other examples, 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.

[0108] In yet some further embodiments, the 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. More specifically, pharmaceutical compositions used to treat subjects in need thereof according to the invention, which may conveniently be presented in unit dosage form, 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. The 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.

[0109] As shown in Example 2 below the compounds described herein activated various serotonergic receptors. The term serotonergic receptors as used herein 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. The metabotropic receptors modulate intracellular signaling pathways through G-proteins, while the ionotropic receptors directly affect ion flow across the cell membrane.

[0110] The main families of this class of receptor 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.

[0111] As shown in Example 2 below demonstrating in vitro EC50 measurements, the compounds described herein showed varying degrees of activity at various serotonergic receptors. Specifically, 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. In addition, HBL20028 showed a reduction in functional activity at 5-HT2B while retaining the activity at both 5-HT1A and 5-HT2A.

[0112] Hence, in accordance with some aspects, 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.

[0113] The term modulating or modulator as used herein 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.

[0114] 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. In general, antagonists mediate their effects by binding to the active (orthosteric = right place) site or to allosteric (= other place) sites on any cognate protein (or receptor, in case applicable), or they may interact at unique binding sites not normally involved in the biological regulation of the cognate protein. 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. As appreciated, 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.

[0115] 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.

[0116] In some embodiments that may be considered as aspects of the present disclosure, it is provided 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.

[0117] In some embodiments that may be considered as aspects of the present disclosure, it is provided 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.

[0118] In some embodiments that may be considered as aspects of the present disclosure, it is provided 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.

[0119] In some embodiments that may be considered as aspects of the present disclosure, 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, as used herein, 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.

[0120] The term modulating 5-HT1A receptor, as used herein, 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.

[0121] 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.

[0122] In some embodiments, 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.

[0123] In some embodiments that may be considered as aspects of the present disclosure, 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.

[0124] In some embodiments that may be considered as aspects of the present disclosure, 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.

[0125] In some embodiments that may be considered as aspects of the present disclosure, 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.

[0126] In some embodiments that may be considered as aspects of the present disclosure, it is provided 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. In some embodiments that may be considered as aspects of the present disclosure, 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. In some embodiments that may be considered as aspects of the present disclosure, it is provided 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.

[0127] In some embodiments that may be considered as aspects of the present disclosure, the compound 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 (XHI), Formula (XIV), Formula (XV), Formula (XVI), Formula (XVII), Formula (XVIII), Formula (XIX), Formula (XX), Formula (XXI), is for modulating 5-HT2A receptor.

[0128] 5-HT2A receptor, as used herein, 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.

[0129] The term modulating 5-HT2A receptor, as used herein, 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.

[0130] 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.

[0131] In some embodiments, 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.

[0132] In some embodiments that may be considered as aspects of the present disclosure, 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.

[0133] In some embodiments that may be considered as aspects of the present disclosure, 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.

[0134] In some embodiments that may be considered as aspects of the present disclosure, 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.

[0135] 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 (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. 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 (XV) 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 (XXI) or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer or physiologically functional derivative thereof for use in activating 5-HT2A receptor.

[0136] In some embodiments, at least one SMC is designed so as to minimize agonist activity at the 5-HT2B receptor.

[0137] In some embodiments that may be considered as aspects of the present disclosure, 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.

[0138] 5-HT2B receptor, as used herein, 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.

[0139] The ability of the SMC described herein to modulate and specifically to activate (act as agonists) at 5-HT1 A receptor and / or 5-HT2A receptor is highly valuable and was shown to correlate with various in vivo studies shown in the Examples below.

[0140] As shown in 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. As demonstrated in Example 6, 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. These results suggest that HBL20028 and HBL20017 are associated with reduced psychedelic trip.

[0141] In some embodiments, the SMC described herein are characterized as being essentially free of a psychedelic effect. As used herein, '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. In some embodiments, "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. As shown in Example 7 providing results of Open Field Test (OFT) experiments. The ORF assay is used to assay general locomotor activity levels, anxiety, and willingness. HBL20016 did not show a significant change in distance covered in the OFT over vehicle. However, 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. In addition, HBL20028 at 12 mg / kg and 24 mg / kg significantly reduced total distance covered, suggesting a dose-dependent effect on motor behavior. Furthermore, HBL20028 at 24 mg / kg showed a trend towards increased center duration and at 12 mg / kg resulted in a statistically significant increase in time spent in the periphery. The results suggest that HBL20028 may be considered as reducing anxiety.

[0142] As shown in 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.

[0143] As shown in Examples 9 and 10 providing results of obsessive self-grooming experiments in SAPAP3 KO mice, single doses of HBL20016 and HBL20017 (6 mg / kg) both block the increase in total duration of self-grooming observed in vehicle-treated SAPAP3-KP mice over 21 days. In addition, there is also a significant effect of both treatments on number of head-body twitches. As shown, the effect of the treatment on grooming parameters extends to 42 days post-treatment. Similarly, the effect of the treatment on head-body twitches also extends to 42 days.

[0144] As shown in 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.

[0145] As shown in 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. Intriguingly, 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.

[0146] Based on the results shown herein, it was suggested that the compounds of the present disclosure may be suitable for treating disease or disorders mediated by one or more serotonergic receptors.

[0147] Hence, in accordance with some aspects, it is provided at least one SMC for use in treating a disease or disorder that is a serotonergic receptor mediated disorder.

[0148] In some embodiments, 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 (nib), 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 (XVH), Formula (XVHI), Formula (XIX), Formula (XX), Formula (XXI), is for use in treating a serotonergic receptor mediated disorder.

[0149] In some embodiments, the SMC may be suitable for treating disease or disorder that in which 5- HT1 A receptor function is dysregulated.

[0150] 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. In other words, 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. In some examples, 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.

[0151] In some aspects, it is provided 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.

[0152] In some aspects, it is provided 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.

[0153] In some aspects, it is provided a compound represented by structure (XIV) for use in a method of treating a 5- HT1 A receptor mediated disorder. In some aspects, it is provided a compound represented by structure of Formula (XV) for use in a method of treating a 5- HT1 A receptor mediated disorder. In some aspects, it is provided a compound represented by structure of Formula (XXI) for use in a method of treating a 5- HT1 A receptor mediated disorder.

[0154] In some embodiments, the SMC may be suitable for treating disease or disorder that is a 5- HT2A receptor mediated disorder.

[0155] The term 5- HT2A receptor mediated disorder as used herein 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. In other words, 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.

[0156] In some aspects, it is provided a compounds 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- HT2A receptor mediated disorder.

[0157] In some aspects, it is provided 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.

[0158] In some aspects, it is provided a SMC represented by structure (XIV) for use in a method of treating a 5- HT2A receptor mediated disorder. In some aspects, it is provided a SMC represented by structure (XV) for use in a method of treating a 5- HT2A receptor mediated disorder. In some aspects, it is provided a SMC represented by structure (XXI) for use in a method of treating a 5- HT2A receptor mediated disorder.

[0159] As noted herein, 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.

[0160] Hence, in accordance with some other aspects, 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.

[0161] The term “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. In the context of the present invention, 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.

[0162] In some embodiments, 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. In some embodiments, the method is an in vitro method. In some other embodiments, the method is an in in vivo method. In some embodiments, the method is an ex vivo method.

[0163] According with some aspects of the present disclosure, it is provided a method of modulating activity of at least one serotonergic receptor in a subject in need thereof.

[0164] In yet a further aspect, 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.

[0165] In yet a further aspect, 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.

[0166] In some embodiments, which can be considered as aspects of the present disclosure, 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),.

[0167] In some embodiments, which can be considered as aspects of the present disclosure, 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.

[0168] In some embodiments, which can be considered as aspects of the present disclosure, 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. In some embodiments, which can be considered as aspects of the present disclosure, 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.

[0169] In some embodiments, 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.

[0170] Hence in a further aspect, 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.

[0171] In some embodiments, which can be considered as aspects of the present disclosure, 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),.

[0172] In some embodiments, which can be considered as aspects of the present disclosure, 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.

[0173] In some embodiments, which can be considered as aspects of the present disclosure, 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.

[0174] In some embodiments, which can be considered as aspects of the present disclosure, 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.

[0175] In some embodiments, which can be considered as aspects of the present disclosure, 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.

[0176] In some embodiments, which can be considered as aspects of the present disclosure, 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.

[0177] In some embodiments, which can be considered as aspects of the present disclosure, 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.

[0178] The term brain disorder (also denoted as neurological disorder), as used herein refers to conditions that affect the structure or function of the brain, leading to impairments in cognitive, sensory, motor, or behavioral abilities.

[0179] In some embodiments, the brain disorder is a genetic disorder. In some embodiments, the brain disorder is a non-genetic disorder.

[0180] In some embodiments, 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. In some embodiments, the brain disorder involves dysfunction of the central nervous system

[0181] In some embodiments, the brain disorder is at least one of a neuropsychiatric disease, a neurodegenerative disease, neuroinflammatory disease, pain and pain-associated disease.

[0182] In some embodiments, the brain disorder is a neuropsychiatric disease. The term neuropsychiatric disease as used herein refers to disease that involve both neurological and psychiatric components, often affecting mood, cognition, behavior, and emotion regulation.

[0183] In some embodiments, 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. In some embodiments, the neuropsychiatric disease is OCD.

[0184] In some embodiments, the neuropsychiatric disease is one or more of depression, schizophrenia, OCD, PTSD, a bipolar disorder.

[0185] In some embodiments, 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.

[0186] As used herein 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. In some cases, 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.

[0187] In some embodiments, 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).

[0188] In some embodiments, 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. In some examples, the tic disorder is a provisional tic disorder or Tourette's syndrome.

[0189] In some embodiments, the methods of the invention may be applicable for treating, inhibiting, arresting or delaying neuropsychiatric disease. In some embodiments, 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, solvate, hydrate, stereoisomer or physiologically functional derivative thereof or any combinations thereof. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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.

[0190] In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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.

[0191] In some embodiments, 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. In some embodiments, 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. In some embodiments, 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.

[0192] In some embodiments, 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. In some embodiments, 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. In some embodiments, 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.

[0193] In some embodiments, 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

[0194] (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. In some embodiments, 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. In some embodiments, 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.

[0195] In some embodiments, 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

[0196] (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, hydrate, stereoisomer or physiologically functional derivative thereof or any combinations thereof. In some embodiments, 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. In some embodiments, 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.

[0197] In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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.

[0198] In some embodiments, 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. In some embodiments, 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. In some embodiments, 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.

[0199] In some embodiments, the brain disorder is a neurodegenerative disease. The term neurodegenerative disease as used herein 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.

[0200] In some embodiments 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.

[0201] In some embodiments, the methods of the invention may be applicable for treating, inhibiting, arresting or delaying neurodegenerative disease. In some embodiments, 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, stereoisomer or physiologically functional derivative thereof or any combinations thereof. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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

[0202] In some embodiments, the neurodegenerative disease is Parkinson's disease, dementia or Alzheimer's disease.

[0203] In some embodiments, the methods of the invention may be applicable for treating, inhibiting, arresting or delaying Parkinson's disease. In some embodiments, 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, stereoisomer or physiologically functional derivative thereof or any combinations thereof. In some embodiments, 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. In some embodiments, 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.

[0204] In some embodiments, the methods of the invention may be applicable for treating, inhibiting, arresting or delaying Alzheimer's disease. In some embodiments, 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, stereoisomer or physiologically functional derivative thereof or any combinations thereof. In some embodiments, 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. In some embodiments, 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.

[0205] In some embodiments, the methods of the invention may be applicable for treating, inhibiting, arresting or delaying dementia. In some embodiments, 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 functional derivative thereof or any combinations thereof. In some embodiments, 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. In some embodiments, 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.

[0206] In some embodiments, the neurodegenerative disease may be characterized by neuroinflammatory processes.

[0207] In some embodiments, the brain disorder is a neuroinflammatory disease. The term neuroinflammatory disease as used herein 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.

[0208] In some embodiments, 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.

[0209] In some embodiments, the methods of the invention may be applicable for treating, inhibiting, arresting or delaying neuroinflammatory disease. In some embodiments, 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, stereoisomer or physiologically functional derivative thereof or any combinations thereof. In some embodiments, 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. In some embodiments, 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. In some embodiments, the brain disorder is pain and / or pain-associated disease. The term pain and / or pain-associated disease as used herein refers to disease characterized by persistent pain.

[0210] In some embodiments, 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.

[0211] In some embodiments, pain associated disease may be pain associated with neuroinflammatory disease. In some embodiments, pain associated with neuroinflammatory disease comprises migraine, Trigeminal Neuralgia, Postherpetic Neuralgia, Arthritis.

[0212] In some embodiments, the methods of the invention may be applicable for treating, inhibiting, arresting or delaying pain disease. In some embodiments, 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, hydrate, stereoisomer or physiologically functional derivative thereof or any combinations thereof. In some embodiments, 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. In some embodiments, 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.

[0213] In accordance with some aspects, 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.

[0214] As noted above, the invention provides methods for treating diseases or disorders specified above.

[0215] As used herein, ''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.

[0216] The term “treatment” as used herein 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. Further, 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. The term “treatment or prevention” as used herein, 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.

[0217] The present invention relates to the treatment of subjects or patients, in need thereof. By “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. By “mammalian subject” is meant any mammal for which the proposed therapy is desired, including human, livestock, equine, canine, and feline subjects, most specifically humans.

[0218] 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.

[0219] As described above, 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. To better understand these Formula, the following definitions are provided.

[0220] The term “alkyl” as used herein refers to a linear, branched saturated hydrocarbon having from 1 to 20 carbon atoms. The term “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.

[0221] The term “C1-C12 haloalkyF as used herein refers to a C1-C12 alkyl as defined above, with one or more hydrogens substituted by halogen atoms.

[0222] The term “alkenyF as used herein refers to a linear (straight), branched unsaturated hydrocarbon having from 2 to 20 carbon atoms and at least one carbon-carbon double bond. The term “C2-C 12 alkenyF or "C2-C 12 alkenylene" as used herein 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. It should be noted that alkenyl refers to an alkyl end chain and alkenylene refers to a middle chain alkyl.

[0223] The term “C2-C / 2 haloalkenyF as used herein refers to a CVCnalkenyl as defined above, with one or more hydrogens substituted by halogen atoms.

[0224] The term “alkynyF as used herein refers to a linear, branched unsaturated hydrocarbon having from 2 to 20 carbon atoms and at least one carbon-carbon triple bond. The term “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.

[0225] The term “C2-C / 2 haloalkynyF as used herein refers to a C2-C12 alkynyl as defined above, with one or more hydrogens substituted by halogen atoms.

[0226] As used herein ''alkoxy' refers to an alkyl group bonded to an oxygen atom. Similarly, the term “C1-C12 alkoxyF as used herein refers to a C1-C12 alkyl group linked to an oxygen. At times, 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. In certain embodiments, the alkoxy is ethoxy.

[0227] The term “C1-C12 haloalkoxy” as used herein refers to a C1-C12 alkoxy as defined above, with one or more hydrogens substituted by halogen atoms.

[0228] The term “halogen” (halo or halide) refers to F, Cl, Br or I.

[0229] The term "cyano" describes a -ON group.

[0230] The term "amino" as used herein encompass primary, secondary, tertiary or quaternary amines where the point of attachment is through the nitrogen atom which is substituted.

[0231] The term "amide" describes a -C(=O)-NR'R" group, where R' and R" are any substituent as defined herein (for example any one of “R” substitutions).

[0232] As used herein, “nitro” refers to -NO2.

[0233] The term “hydroxy”, as used herein, refers to an -OH group.

[0234] As used herein, “oxo” refers to =0.

[0235] As used herein, “urea” refers to -NRa-C(0)-NRa2 or -NRa-C(0)NRa-, wherein Rais H or C1-C12 alkyl.

[0236] As used herein, “sulfonylurea” refers to -S(0)2-NRa-C(0)-NRa- or -NRa-C(0)-NRa- SO2-, wherein Rais H or C1-C12 alkyl, e.g., an C1-C12 alkyl group as described herein.

[0237] As used herein, “sulfonamidyl” refers to -S(0)2-NRa- or -NRa-S(0)2-, wherein Rais H or C1-C12 alkyl, e.g., an C1-C12 alkyl group as described herein.

[0238] As used 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. The term “saturated” as used herein means that the compound does not contain double or triple bonds. The term “unsaturated” as used herein means that the compound contains at least one double or triple bond. The term “aromatic” as used herein means that the compound contains alternating double and single bonds.

[0239] As used herein, “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.

[0240] As used herein, “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. Examples of 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, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, tetrahydropyrrole, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1 -oxo-thiomorpholinyl, 1 , 1 -dioxo-thiomorpholinyl, and the like.

[0241] As used herein, “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.

[0242] As used herein, the term “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. As used herein, "heteroaromatic" 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. The term "heteroaromatic" 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, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl, 1,2,4- triazinyl, 1,3,5-triazinyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4- oxadiazolyl, 1,2, 3 -triazine, 1 ,2,4-triazine, 1,3, 5 -triazine, 1,2, 3 -thiadiazo lyl, 1,2,4- thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, tetrazolyl, thiadiazinyl, [l,3,4]thiadiazole, thiadiazole, indolyl, isoindolyl, benzofuryl, benzothienyl, indazolyl, benzimidazolyl, benzothiazolyl, benzoisothiazolyl, benzoxazolyl, benzisoxazolyl, purinyl, quinazolinyl, quinolizinyl, quinolinyl, isoquinolinyl, quinoxalinyl, naphthyridinyl, pteridinyl, carbazolyl, azepinyl, diazepinyl, acridinyl and the like.

[0243] As used herein the term isotopologue refers to a compound that differs from a specific compound only in the isotopic composition of one or more of their atoms thereof. In other words, 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. For example, one or more of hydrogen atoms in a compound may be2H (deuterium).

[0244] Each one of the 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 term substituted as used herein means that the compounds may contain one or more substituents, including, but not limited to, optionally substituted OH, CF3, halogen, C(=O), -COOH, -NH2, CN, alkyl, alkenyl, alkynyl, alkylene, straight alkenylene, alkynylene, haloalkyl, haloalkenyl, haloalkynyl, alkoxy, carboxyl, halogen, ring system including three to twelve atoms, aromatic or heteroaromatic ring, C(=O)- alkyl. It should be noted that the carbon number, as used herein, refers to the carbon backbone and carbon branching, but does not include carbon atoms of the substituents, such as alkoxy substitutions and the like.

[0245] As described herein, 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.

[0246] The term "pharmaceutically acceptable salt" 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, propionate, succinate, fumarate, maleate, malonate, mandelate, malate, phthalate, and pamoate. The term “pharmaceutically acceptable salt” as used herein also refers to a salt of a compound described herein having an acidic functional group, such as a carboxylic acid functional group, and a base. Exemplary bases include, but are not limited to, hydroxide of alkali metals including sodium, potassium, and lithium; hydroxides of alkaline earth metals such as calcium and magnesium; hydroxides of other metals, such as aluminum and zinc; ammonia, organic amines such as unsubstituted or hydroxyl-substituted mono-, di-, or trialkylamines, dicyclohexylamine; tributyl amine; pyridine; N-methyl, N-ethylamine; diethylamine; triethylamine; mono-, bis-, or tris-(2-OH-(Ci-C6)-alkylamine), such as N,N-dimethyl-N-(2-hydroxyethyl)amine or tri-(2-hydroxyethyl)amine; N-methyl-D- glucamine; morpholine; thiomorpholine; piperidine; pyrrolidine; and amino acids such as arginine, lysine, and the like. The term “pharmaceutically acceptable salt” also includes hydrates of a salt of a compound described herein. The term "small molecule" or “compound” may include pharmaceutically acceptable forms of the recited compounds, including chelates, non-covalent complexes, and mixtures thereof. The term “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.

[0247] The term “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.

[0248] The term "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.

[0249] In accordance with some embodiments, 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. If, for instance, a particular enantiomer of a compound of the present disclosure is desired, it 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. Alternatively, where the molecule contains a basic functional group, such as amino, or an acidic functional group, such as carboxyl, 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. Alternatively, 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.

[0250] It should be further noted that 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.

[0251] The present examples further encompass any enantiomers, prodrugs, and polymorphs of at least one SMC.

[0252] "Crystalline 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.

[0253] The term “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.

[0254] All definitions, as defined and used herein, should be understood to control over dictionary definitions, definitions in documents incorporated by reference, and / or ordinary meanings of the defined terms.

[0255] It should be appreciated that 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.

[0256] With regards to the above, it is to be understood that, where provided, percentage values such as, for example, 10%, 50%, 120%, 500%, etc., are interchangeable with "fold change" values, i.e., 0.1, 0.5, 1.2, 5, etc., respectively. 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 %.

[0257] The indefinite articles “a” and “an,” as used herein in the specification and in the claims, unless clearly indicated to the contrary, should be understood to mean “at least one.” It must be noted that, as used in this specification and the appended claims, the singular forms “a”, “an” and “the” include plural referents unless the content clearly dictates otherwise.

[0258] As used herein in the specification and in the claims, 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. Thus, as a nonlimiting example, “at least one of A and B” (or, equivalently, “at least one of A or B,” or, equivalently “at least one of A and / or 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.

[0259] It should also be understood that, unless clearly indicated to the contrary, in any methods claimed herein that include more than one step or act, the order of the steps or acts of the method is not necessarily limited to the order in which the steps or acts of the method are recited.

[0260] It should be noted that various embodiments of this invention may be presented in a range format. It should be understood that the description in 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. Whenever a numerical range is indicated herein, it is meant to include any cited numeral (fractional or integral) within the indicated range. The phrases "ranging / ranges between" a first indicate number and a second indicate number and "ranging / ranges from" a first indicate number "to" a second indicate number are used herein interchangeably and are meant to include the first and second indicated numbers and all the fractional and integral numerals there between.

[0261] It is appreciated that certain features of the invention, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention, which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable sub combination or as suitable in any other described embodiment of the invention. Certain features described in the context of various embodiments are not to be considered essential features of those embodiments, unless the embodiment is inoperative without those elements.

[0262] Various embodiments and aspects of the present invention as delineated herein above and as claimed in the claims section below find experimental support in the following examples.

[0263] Disclosed and described, it is to be understood that this invention is not limited to the particular examples, methods steps, and compositions disclosed herein as such methods steps and compositions may vary somewhat. It is also to be understood that the terminology used herein is used for the purpose of describing particular embodiments only and not intended to be limiting since the scope of the present invention will be limited only by the appended claims and equivalents thereof.

[0264] The following examples are representative of techniques employed by the inventors in carrying out aspects of the present invention. It should be appreciated that while these techniques are exemplary of preferred embodiments for the practice of the invention, those of skill in the art, in light of the present disclosure, will recognize that numerous modifications can be made without departing from the spirit and intended scope of the invention.

[0265] NON-LIMITING EXAMPLES

[0266] Example 1: Compound synthesis

[0267] Synthesis of HBL20010

[0268] Step 1. N,N-dimethyl-2-(7-methyl-5-(methylthio)-lH-indol-3-yl)-2-oxoacetamide

[0269] To a solution of 7-methyl-5-(methylthio)-lH-indole (3.2g, 18.07mmol, purchased from Chukai PharmaTech) in ether (100 ml) was added oxalyl chloride (4.6 g, 3.1 ml, 36.15 mmol) dropwise at 0°C under nitrogen atmosphere. The resulting mixture was stirred at 0°C for 4h, then added to a solution of dimethylamine (16 ml, 40% in H2O, 90.35 mmol) in ether (100 ml) at 0°C. The reaction mixture was stirred at room temperature for 17h, evaporated and diluted with DCM. The organic phase was washed by sat. NaHCO3, brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted by DCM / MeOH (containing 1 % ammonia), v / v = 50 / 1) to afford the title product as a brown solid (1.0 g, 20%). LCMS calculated for C14H16N2O2S: 276.09; found: 276.85 [M+l], 1H NMR (400 MHz, CDC13): δ 9.19 (brs,lH), 8.10 (s,lH), 7.85 (d, J=3.2 Hz, 1H), 7.07 (s, 1H), 3.10 (s, 3H), 3.06 (s, 3H), 2.55 (s, 3H), 2.46 (s, 3H).

[0270] Step 2. N,N-dimethyl-2-(7-methyl-5-(methylthio)-lH-indol-3-yl)ethan-l-amine

[0271] To a mixture of LAH (97 mg, 2.54 mmol) in THF (2ml) was added N,N-dimethyl-2-(7- methyl-5-(methylthio)-lH-indol-3-yl)-2-oxoacetamide (100 mg, 0.36 mmol) in THF (2ml) at 0°C under nitrogen atmosphere. The resulting mixture was stirred at 70°C for 6h. The reaction was then cooled to 0°C and quenched by aqueous tetrahydrofuran solution, filtered. The filtrate was concentrated under reduced pressure and the residue was purified by preparative silica gel plate (eluted by DCM / MeOH (containing 1% ammonia), v / v = 10 / 1) to afford the title product as a brown solid (53 mg, 59%). LCMS calculated for C14H20N2S: 248.13; found: 249.00 [M+l], lH NMR (400 MHz, CDC13) δ 7.92 (brs,lH), 7.47 (s, 1H), 7.04 (s, 1H), 7.03 (d, J= 2.0 Hz, 1H), 2.94-2.90 (m, 2H), 2.66-2.62 (m, 2H), 2.52 (s, 3H), 2.44 (s, 3H), 2.36 (s, 6H).

[0272] Synthesis of HBL20013

[0273] Synthesis of l,3-dimethyl-5-(methylsulfanyl)-2-nitrobenzene

[0274] To a stirred mixture of 5-fluoro-l,3-dimethyl-2-nitrobenzene (5 g, 29.559 mmol, 1 equiv) in DMF (40 mL) was added sodium methanethiolate (2.49 g, 35.531 mmol, 1.20 equiv) in portions at 0 °C. The resulting mixture was stirred for additional 2 h at room temperature. The reaction was quenched with water and extracted with EA three times. The combined organic layers were dried over anhydrous NaiSO-i. After filtration, the filtrate was concentrated under reduced pressure to afford the title compound (4 g, 68.61%) as a brown solid. The crude product was used in the next step directly without further purification. LCMS (ESI): [M+H]+= 198.0.

[0275] Synthesis of 7-methyl-5f methylsulfanyl)- IH-indole

[0276] To a stirred solution of l,3-dimethyl-5-(methylsulfanyl)-2-nitrobenzene (4 g, 20.279 mmol, 1 equiv) in DMF (50 mL) were added DMF -DMA (7.25 g, 60.837 mmol, 3 equiv) and pyrrolidine (4.33 g, 60.837 mmol, 3 equiv) drop wise at room temperature. The resulting mixture was stirred for additional 4 h at 120 °C. Water was added to the reaction solution and the mixture was extracted with EtOAc. The combined organic layers were washed with water and dried over anhydrous NaiSO-i. After filtration, the filtrate was concentrated under reduced pressure. The residue was dissolved in EA (50 mL) and 10% Pd / C (6 g) was added. The resulting mixture was stirred for additional 4 h at room temperature under hydrogen. The resulting mixture was filtered and the filter cake was washed with EtOAc. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (5: 1) to afford the title compound (1.9 g, 52.85%) as a brown oil. LCMS (ESI): [M+H]+= 178.0.

[0277] Synthesis ofN,N-dimethyl-2-[7-methyl-5-(methylsulfanyl)-lH-indol-3-yl]-2-oxoacetamide

[0278] 1) oxaly! chloride, ether, O°C~rt

[0279] 2) dimethylamine, ether, -78°C~rt

[0280] To a stirred solution of 7-methyl-5-(methylsulfanyl)-lH-indole (1.9 g, 10.718 mmol, 1 equiv) in diethyl ether (50 mL) was added oxalic dichloride (4.08 g, 32.154 mmol, 3 equiv) dropwise at 0 °C .The resulting mixture was stirred for additional 2 h at rt. The precipitated solids were collected by filtration and washed with EtiO. This intermediate was suspended in diethyl ether (50 mL) and cooled to -78° C. To the above mixture was added di ethylamine (2 M in THF) (10.5 mL) dropwise at -78 °C. After the addition was complete the reaction was stirred for additional 2 h at room temperature. The precipitated solids were collected by filtration and washed with EtiO to afford the title compound (1.9 g, 64.15%) as a grey solid. LCMS (ESI): [M+H]+=277.1.

[0281] Synthesis of dimethyl( {2f 7 -methyl-5f methylsulfanyl)- lH-indol-3-yl] ethyl} famine

[0282] To a stirred mixture of N,N-dimethyl-2-[7-methyl-5-(methylsulfanyl)-lH-indol-3-yl]-2- oxoacetamide (1.9 g, 6.875 mmol, 1 equiv) in THF (20 mL) and 1,4-di oxane (10 mL) was added LAH (1.57 g, 41.250 mmol, 6 equiv) in portions at 0 °C. The resulting mixture was stirred overnight at 100 °C. The reaction was quenched with 1.57 mL water, 1.57 mL 15% NaOH (aq.) and 4.71 mL water at 0 °C. The resulting mixture was filtered and the filter cake was washed with EtOAc. The filtrate was concentrated under reduced pressure to afford the title compound (1.2 g, 70.27%) as a brown solid. The crude product was used in the next step directly without further purification. LCMS (ESI): [M+H]+= 249.1.

[0283] Synthesis of [2-(5-methanesulfinyl-7-methyl-lH-indol-3-yl)ethyl]dimethylamine PH- HBLS-MC-2023-01-A-0

[0284] To a stirred mixture of dimethyl({2-[7-methyl-5-(methylsulfanyl)-lH-indol-3- yl] ethyl })amine (400 mg, 1.610 mmol, 1 equiv) in THF (5 mL) and H2O (1 mL) were added oxone (270 mg, 1.606 mmol, 1.00 equiv) in portions at 0 °C. The resulting mixture was stirred for additional 2 h at room temperature. The mixture was filtered and the filter cake was washed with ethyl acetate. The mixture was neutralized to pH 8 with saturated NaiCOi (aq.) and concentrated under vacuum. The residue was purified by reversed- phase flash chromatography with the following conditions: column, Cl 8 silica gel; mobile phase, MeCN in water (10 mmol / L NH4HCO3), 0% to 50% gradient in 30 min; detector, UV 254 nm to afford the title compound (130.0 mg, 29.40%) as a colorless oil. LCMS (ESI): [M+H]+= 265.1.

[0285] ’H NMR (300 MHz, Chloroform-d) δ 8.48 (s, 1H), 7.80 (s, 1H), 7.22 (s, 1H), 7.12 (s, 1H), 2.96 (t, J= 7.8 Hz, 2H), 2.76 (s, 3H), 2.65 (t, J= 8.0 Hz, 2H), 2.48 (s, 3H), 2.34 (s, 6H).

[0286] Synthesis of HBL20014

[0287] Synthesis of l,3-dimethyl-5-(methylsulfanyl)-2-nitrobenzene

[0288] To a stirred mixture of dimethyl({2-[7-methyl-5-(methylsulfanyl)-lH-indol-3- yl] ethyl })amine (400 mg, 1.610 mmol, 1 equiv) in THF (5 mL) and H2O (1 mL) was added oxone (540 mg, 3.211 mmol, 1.99 equiv) in portions at 0 °C. The resulting mixture was stirred for additional 2 h at room temperature. The resulting mixture was filtered and the filter cake was washed with MeOH. The residue was neutralized to pH 8 with saturated NaiSOi (aq.). The resulting mixture was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, Cl 8 silica gel; mobile phase, MeCN in water (10 mmol / L NH4HCO3), 0% to 50% gradient in 30 min; detector, UV 254 nm to afford the title compound (124.3 mg, 26.43%) as a white solid. LCMS (ESI): [M+H]+= 281.1.

[0289] 'H NMR (500 MHz, Chloroform-d) δ 8.35 (s, 1H), 8.13 (s, 1H), 7.55 (s, 1H), 7.24 (s, 1H), 3.11 (s, 3H), 3.03 (t, J= 7.8 Hz, 2H), 2.75 (t, J= 7.8 Hz, 2H), 2.55 (s, 3H), 2.42 (s, 6H).

[0290] Synthesis of HBL20015

[0291] Synthesis of 7-Fluoro-5-(methylsulfanyl)-lH-indole

[0292] Under nitrogen, a mixture of 5-bromo-7-fluoro-lH-indole (2.5 g, 11.68 mmol, 1 equiv), sodium thiomethoxide (1.23 g, 17.52 mmol, 1.5 equiv), Pd(OAc)2 (655.6 mg, 2.92 mmol, 0.25 equiv) and BINAP (2.18 g, 3.50 mmol, 0.3 equiv) in dioxane (100 mL) was stirred at 100 °C for 15 hours. The resulting mixture was filtered and the filter cake was washed by dichloromethane. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (75 / 25) to afford 7-fluoro-5-(methylsulfanyl)-lH-indole (1.6 g, 75.59%) as a yellow solid. LC-MS: (ESI, m / z)'. 179.90 [M-H]'.

[0293] Synthesis of 2-[7-Fluoro-5-(methylsulfanyl)-lH-indol-3-yl]-N,N-dimethyl-2- oxoacetamide

[0294] To a solution of 7-fluoro-5-(methylsulfanyl)-lH- indole (1.5 g, 8.28 mmol, 1 equiv) in diethyl ether (15 mL) was added oxalyl chloride (3.15 g, 24.83 mmol, 3 equiv) by dropwise at 0 °C. The resulting mixture was stirred for 2 hours at room temperature. The precipitated solids were collected by filtration and washed with diethyl ether. This intermediate was dissolved in diethyl ether (15 mL) and cooled to -78 °C. To the above mixture was added dimethylamine (2 M in THE, 16 mL) by dropwise at -78 °C. The resulting mixture was stirred for 2 hours at room temperature. The mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with DCM / EA (65 / 35) to afford 2-[7-fluoro-5-(methylsulfanyl)- lH-indol-3-yl]-N,N-dimethyl-2-oxoacetamide (780 mg, 33.62%) as a grey solid.

[0295] LC-MS: (ESI, m / z)-. 278.85 [M-H]'.

[0296] Synthesis of 2-[7-Fluoro-5-(methylsulfanyl)-lH-indol-3-yl]ethyldimethylamine

[0297] To a mixture of 2-[7-fhioro-5-(methylsulfanyl)-lH-indol-3-yl]-N,N-dimethyl-2- oxoacetamide (500 mg, 1.78 mmol, 1 equiv) in tetrahydrofuran (20 mL) was added Li AIH4 (400 mg, 10.54 mmol, 5.91 equiv) by portions at 0 °C. The resulting mixture was stirred for 2 hours at 65 °C. The reaction was quenched with 1 mL water, 1 mL 15% NaOH (aq.) and 4 mL water at 0 °C. The resulting mixture was filtered and the filter cake was washed with acetate. The filtrate was concentrated under reduced pressure. The residue was purified by a reversed-phase flash chromatography with the following conditions: Cl 8 column; mobile phase, A: 0.05% NH4HCO3 in water, B: ACN, B% (5% ~ 35% in 20 min); detector, UV 254 nm to afford 2-[7-fluoro-5-(methylsulfanyl)-lH-indol-3- yl] ethyldimethylamine (175.4 mg, 38.89%) as a white solid.

[0298] 1H NMR (300 MHz, DMSO-J6, ppm ) δ 11.31 (s, 1H), 7.27 (d, J= 1.4 Hz, 1H), 7.22 - 7.19 (m, 1H), 6.91 (dd, J= 11.7, 1.4 Hz, 1H), 2.79 - 2.74 (m, 2H), 2.50 - 2.48 (m, 2H), 2.47 (s, 3H), 2.19 (s, 6H). LC-MS (ESI, m / z): 253.10 [M+H]+.

[0299] Synthesis of HBL20016

[0300] Synthesis of 6-Fluoro-5-(methylsulfanyl)-lH-indole

[0301] CH3SNa PdOAc BINAP DIEA

[0302] Under nitrogen, a mixture of 5-bromo-6-fluoro-lH-indole (2.5 g, 11.68 mmol, 1 equiv), sodium thiomethoxide (1.23 g, 17.52 mmol, 1.5 equiv), Pd(OAc)2 (655.6 mg, 2.92 mmol, 0.25 equiv) and BINAP (2.18 g, 3.50 mmol, 0.3 equiv) in dioxane (100 mL) was stirred at 100 °C for 15 hours. The resulting mixture was filtered. The filter cake was washed by dichloromethane and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (75 / 25) to afford 6- fhioro-5-(methylsulfanyl)-lH-indole (1.66 g, 78.42%) as a yellow solid.

[0303] LC-MS: (ESI, m / z\. 179.90 [M-H]’.

[0304] Synthesis of 2-[ 6-Fluoro-5-(methylsulfanyl)-lH-indol-3-yl]-N,N-dimethyl-2- oxoacetamide

[0305] To a solution of 6-fluoro-5-(methylsulfanyl)-lH-indole (1.56 g, 8.61 mmol, 1 equiv) in diethyl ether (15 mL) was added oxalyl chloride (3.28 g, 25.82 mmol, 3 equiv) by dropwise at 0 °C. The resulting mixture was stirred for 2 hours at room temperature. The precipitated solids were collected by filtration and washed with diethyl ether. This intermediate was dissolved in diethyl ether (15 mL) and cooled to -78 °C. To the above mixture was added dimethylamine (2 M in THF, 18 mL) by dropwise at -78 °C. The resulting mixture was stirred for 2 hours at room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with DCM / EA (55 / 45) to afford 2-[6-fhioro-5-(methylsulfanyl)-lH-indol-3-yl]-N,N- dimethyl-2-oxoacetamide (1.06 g, 40.85%) as a light yellow solid.

[0306] LC-MS: (ESI, m / z\. 278.85 [M-H]’.

[0307] Synthesis of 2-[ 6-Fluoro-5 f methylsulfanyl)- IH-indol- 3-yl] 'ethyldimethylamine

[0308] To a mixture of 2-[6-fhioro-5-(methylsulfanyl)-lH-indol-3-yl]-N,N-dimethyl-2- oxoacetamide (500 mg, 1.78 mmol, 1 equiv) in tetrahydrofuran (20 mL) was added LiAlFL (400 mg, 10.54 mmol, 5.91 equiv) by portions at 0 °C. The resulting mixture was stirred for 2 hours at 65 °C. The reaction was quenched with 1 mL water, 1 mL 15% NaOH (aq.) and 4 mL water at 0 °C. The resulting mixture was filtered and the filter cake was washed with ethyl acetate. The filtrate was concentrated under reduced pressure. The residue was purified by a reversed-phase flash chromatography with the following conditions: Cl 8 column; mobile phase, A: 0.05% NH4HCO3 in water, B: ACN, B% (5% ~ 35% in 22 min); detector, UV 254 nm to afford 2-[6-fluoro-5-(methylsulfanyl)-lH-indol-3- yl] ethyldimethylamine (130.4 mg, 28.83%) as a off-white solid.

[0309] ’H NMR (300 MHz, DMSO-Jr,, ppm) δ 10.89 (s, 1H), 7.50 (d, J= 7.4 Hz, 1H), 7.22 - 7.07 (m, 2H), 2.80 - 2.75 (m, 2H), 2.51 - 2.49 (m, 1H), 2.48 - 2.47 (m, 1H), 2.46 (s, 3H), 2.20 (s, 6H). LC-MS (ESI, m / z): 253.15 [M+H]+.

[0310] Synthesis of HBL20017

[0311] Synthesis of 2-Fluoro-3-methyl-l-(methylsulfanyl)-4-nitrobenzene

[0312] To a solution of l,2-difluoro-3-methyl-4-nitrobenzene (6 g, 34.66 mmol, 1 equiv) in ACN (80 mL) was added sodium thiomethoxide (2.91 g, 41.59 mmol, 1.2 equiv) by portions at 0 °C. The resulting mixture was stirred for 2 hours at room temperature. The mixture was diluted with ethyl acetate (500 mL) and washed by brine. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (95 / 5) to afford 2-fluoro- 3 -methyl- l-(methylsulfanyl)-4-nitrobenzene (4.1 g, 58.79%) as a yellow oil.

[0313] 1H NMR (300 MHz, DMSO-Jr,, / ? / ?m) 87.85 (dd, J = 8.8, 1.5 Hz lH), 7.11 (dd, J = 8.8, 1.5 Hz 1H), 2.54 (s, 3H), 2.52 (d, J= 2.6 Hz, 3H).

[0314] Synthesis of 4-Fluoro-5-(methylsulfanyl)-lH-indole °

[0315] To a solution of 2-fhroro-3-methyl-l-(methylsulfanyl)-4-nitrobenzene (3 g, 14.91 mmol, 1 equiv) in DMF (40 mL) were added DMF-DMA (5.33 g, 44.73 mmol, 3 equiv) and pyridine (3.54 g, 44.73 mmol, 3 equiv) by dropwise at room temperature. The resulting mixture was stirred for 4 hours at 120 °C. The resulting mixture was diluted with ethyl acetate (300 mL) and washed by brine. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was dissolved in EtOH (50 mL) and H2O (30 mL), then Fe (5.00 g, 89.45 mmol, 6 equiv) and NH4CI (7.97 g, 149.09 mmol, 10 equiv) were added at 80 °C. The resulting mixture was stirred for 48 hours at 80 °C. The resulting mixture was filtered and the filter cake was washed with ethyl acetate. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (78 / 22) to afford 4-fluoro-5- (methylsulfanyl)-lH-indole (1.2 g, 44.41%) as a brown solid.

[0316] LC-MS: (ESI, m / z): 179.95 [M-H]’.

[0317] Synthesis of 2-[ 4-Fluoro-5-(methylsulfanyl)-lH-indol-3-yl]-N,N-dimethyl-2- oxoacetamide

[0318] To a mixture of 4-fluoro-5-(methylsulfanyl)-lH-indole (1.56 g, 8.61 mmol, 1.00 equiv) in diethyl ether (15 mL) was added oxalyl chloride (3.28 g, 25.82 mmol, 3 equiv) dropwise at 0 °C. The resulting mixture was stirred for 2 hours at room temperature. The precipitated solids were collected by filtration and washed with diethyl ether. This intermediate was dissolved in diethyl ether (15 mL) and cooled to -78 °C. To the above mixture was added dimethylamine (2 M in THF, 18 mL) by dropwise at -78 °C. The resulting mixture was stirred for 2 hours at room temperature. The mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with DCM / EA (95 / 5) to afford 2-[4-fhioro-5-(methylsulfanyl)-lH-indol-3-yl]-N,N-dimethyl-2- oxoacetamide (920 mg, 38.13%) as a grey solid.

[0319] LC-MS: (ESI, m / z): 278.85 [M-H]’.

[0320] Synthesis of 2-[ 4-Fluoro-5-(methylsulfanyl)-lH-indol-3-yl]ethyldimethylamine

[0321] To a mixture of 2-[4-fhioro-5-(methylsulfanyl)-lH-indol-3-yl]-N,N-dimethyl-2- oxoacetamide (500 mg, 1.78 mmol, 1 equiv) in tetrahydrofuran (20 mL) was added Li AIH4 (400 mg, 10.54 mmol, 5.91 equiv) by portions at 0 °C. The resulting mixture was stirred for 12 hours at 100 °C. The reaction was quenched with 1 mL water, 1 mL 15% NaOH (aq.) and 4 mL water at 0 °C. The resulting mixture was filtered and the filter cake was washed with ethyl acetate. The filtrate was concentrated under reduced pressure. The residue was purified by a reversed-phase flash chromatography with the following conditions: Cl 8 column; mobile phase, A: 0.05% NH4HCO3 in water, B: ACN, B% (5% ~ 32% in 20 min); detector, UV 254 nm to afford 2-[4-fhroro-5-(methylsulfanyl)-lH-indol- 3 -yl] ethyldimethylamine (152.1 mg, 33.52%) as a off-white soild.

[0322] 1H NMR (300 MHz, DMSO-Jr,, ppm) δ 11.11 (s, 1H), 7.43 - 6.87 (m, 3H), 2.93 - 2.76 (m, 2H), 2.49 - 2.48 (m, 1H), 2.48 - 2.47 (m, 1H), 2.39 (s, 3H), 2.18 (s, 6H). LC-MS (ESI, m / z)-. 253.15 [M+H]+.

[0323] Synthesis of HBL20028

[0324] Synthesis of 2-fhioro-3-methyl-l-(methylsulfanyl)-4-nitrobenzene

[0325] To a solution of l,2-difluoro-3-methyl-4-nitrobenzene (10 g, 57.764 mmol, 1 equiv) in MeCN (150 mL) was added sodium thiomethoxide (4.86 g, 69.317 mmol, 1.2 equiv) by portions at 0 °C. The resulting mixture was stirred for 2 hours at room temperature. The resulting mixture was diluted with ethyl acetate (I L) and washed by brine. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (90 / 10) to afford 2-fluoro-3 -methyl- l-(methylsulfanyl)-4-nitrobenzene (9.8 g, 84.31% yield, 95% purity) as a yellow oil.

[0326] Synthesis of 4-fhioro-5-(methylsulfanyl)-lH-indole °

[0327] To a solution of 2-fluoro-3 -methyl- l-(methylsulfanyl)-4-nitrobenzene (9.7 g, 48.206 mmol, 1 equiv) in DMF (160 mL) was added dimethoxymethyldimethylamine (17.23 g, 144.618 mmol, 3.00 equiv) and pyridine (11.48 g, 145.100 mmol, 3.01 equiv) dropwise at room temperature. The resulting mixture was stirred for 4 hours at 120 °C. The mixture was diluted with ethyl acetate (800 mL) and washed by brine. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was dissolved in EtOH (240 mL) and H2O (120 mL), then Fe (16.18 g, 289.718 mmol, 6.01 equiv) and ammonium chloride (25.79 g, 482.060 mmol, 10.00 equiv) was added at 80 °C. The mixture was stirred for 5 hours at 80 °C. The resulting mixture was filtered and the filter cake was washed with ethyl acetate. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / DCM (1 / 1) to afford 4-fluoro-5-(methylsulfanyl)-lH-indole (3.8 g, 43.50% yield, 88% purity) as a brown solid. LC-MS: (ESI, m / z\. 180.15 [M-H]+.

[0328] Synthesis of 2-[4-fluoro-5-(methylsulfanyl)-lH-indol-3-yl]-N,N-dimethyl-2- oxoacetamide

[0329] To a solution of 4-fluoro-5-(methylsulfanyl)-lH-indole (3.8 g, 20.968 mmol, 1 equiv) in MTBE (80 mL) was added (COC1)2 (8.04 g, 63.323 mmol, 3.02 equiv) by dropwise at 0 °C. The resulting solution was stirred for 10 hours at room temperature. The reaction system was added to dimethylamine (40% in water) (73 mL) dropwise at 0 °C and stirred at room temperature for 0.5 hours. The MTBE of the system was concentrated under reduced pressure. The resulting solution was extracted with dichloromethane and the organic layers were combined. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with DCM / EA (50 / 50) to afford 2-[4-fluoro-5-(methylsulfanyl)- lH-indol-3-yl]-N,N-dimethyl-2-oxoacetamide (2.8 g, 47.64% yield, 87% purity) as an off- white solid. LC-MS: (ESI, m / z): 279.10 [M-H]+.

[0330] Synthesis of 2-[4-fluoro-5-(methylsulfanyl)-lH-indol-3-yl]ethyldimethylamine

[0331] To a mixture of 2-[4-fluoro-5-(methylsulfanyl)-lH-indol-3-yl]-N,N-dimethyl-2- oxoacetamide (2.8 g, 9.989 mmol, 1 equiv) in THF (100 mL) was added lithium aluminum hydride (2.24 g, 59.035 mmol, 5.91 equiv) in portions at 0 °C. The resulting mixture was stirred for 6 hours at 65 °C. The reaction was quenched with 5 mL water, 5 mL 15% NaOH (aq.) and 20 mL water at 0 °C. The resulting mixture was filtered and the filter cake was washed with ethyl acetate. The filtrate was concentrated under reduced pressure. The residue was purified by a reversed-phase flash chromatography with the following conditions: column, Cl 8 silica gel; mobile phase, A: 0.05% NH4HCO3 in water, B: MeOH, B% (5% ~ 73% in 40 min); detector, UV 254 nm to afford {2-[4-fhioro-5-(methylsulfanyl)- lH-indol-3-yl] ethyl (dimethylamine (640 mg, 25.39%yield, 96% purity) as an off-white solid. LC-MS (ESI, m / z)'. 253.10 [M+H]+.

[0332] Synthesis of {2-[l-(cyclopropylmethyl)-4-fluoro-5-(methylsulfanyl)indol-3- yl] ethyl} dimethylamine

[0333]

[0334] PH -H B LS-MC -2024-04-0

[0335] To a solution of {2-[4-fluoro-5-(methylsulfanyl)-lH-indol-3-yl]ethyl}dimethylamine (300 mg, 1.189 mmol, 1 equiv) in DMF (10 mL) was added NaH (71.32 mg, 2.973 mmol, 2.5 equiv) by portions at 0 °C. The resulting solution was stirred for 1 hour at 0 °C. To the reaction system was added (bromomethyl)cyclopropane (192.60 mg, 1.427 mmol, 1.2 equiv) at 0 °C and stirred at 0 °C for 1 hour. The reaction was poured into saturated ammonium chloride at 0 °C. The resulting mixture was extracted with ethyl acetate (100 mL). The combined organic layers were washed with saturated sodium chloride (5 x 20 mL) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, Cl 8 silica gel; mobile phase, water in acetonitrile, 10% to 65% gradient in 25 min; detector, UV 254 nm. This resulted in {2-[l- (cyclopropylmethyl)-4-fluoro-5-(methylsulfanyl)indol-3-yl]ethyl} dimethylamine (158.6 mg, 43.54% yield, 98.1% purity) as a brown oil.

[0336] Synthesis of 2-( l -(cyclopropylmethyl)-4-fluoro-5-(methylthio)- I H-indol-3-yl)-A,A- dimethylethan-1 -amine hydrochloride

[0337] PH -HBLS-MC -2024-04-0 P H -H B LS-MC -2024-04-50

[0338] To a solution of 2-(l-(cyclopropylmethyl)-4-fluoro-5-(methylthio)-lH-indol-3-yl)-N,N- dimethylethan-1 -amine (180 mg, 0.589 mmol, 1 equiv) in ethyl acetate (5 mL) was added hydrochloric acid (1 mL, 4M in ethyl acetate). The resulting solution was stirred for 1 hour at 25 °C. After completion, the resulting mixture was concentrated under reduced pressure. 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. This resulted in 2-(l- (cyclopropylmethyl)-4-fluoro-5-(methylthio)-lH-indol-3-yl)-N,N-dimethylethan-l -amine hydrochloride (138.4 mg, 0.40 mmol, 68% yield, 98.1% purity) as an off-white solid.

[0339] NMR (300 MHz, DMSO-d6 , ppm) δ 12.63 (s, 1H), 7.27 - 7.24 (m, 1H), 7.22 (s, 1H), 7.09 (d, J = 8.4 Hz, 1H), 3.91 (d, J = 8.0 Hz, 2H), 3.47 - 3.41 (m, 2H), 3.32 - 3.27 (m, 2H), 2.87 (d, 7 = 4.8 Hz, 6H), 2.47 (s, 3H), 1.27 - 1.19 (m, 1H), 0.70 - 0.65 (m, 2H), 0.40 -0.36 (m, 2H). LCMS (ESI, m / z): 307.05 [M+H]+.

[0340] Example 2: In vitro assays

[0341] Example 2A: Functional Receptor Assay in human embryonic kidney (HEK) cells

[0342] Methods

[0343] Compounds were tested for functional activity to determine EC 50 by using calcium flux assay in human embryonic kidney (HEK) cells expressing serotonin receptors, 5- HT1A, 5-HT1B, 5-HT2A, 5-HT2B,5-HT2C and 5-HT7.

[0344] 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 μl 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.

[0345] Compound dilutions (including serial 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. For 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.

[0346] 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.

[0347] 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.

[0348] Results

[0349] Table 1A shows the affinity (by EC50 values) of synthesized compounds to four different receptors.

[0350] Table 1A - ECso values for tested compounds

[0351] * The data for psilocin was taken from Sard H, Kumaran G, Morency C, et al. SAR of psilocybin analogs: discovery of a selective 5-HT 2C agonist. Bioorg Med Chem Lett. 2005;15(20):4555-4559.

[0352] As shown in Table 1A, 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.

[0353] 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.

[0354] 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.

[0355] 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.

[0356] In addition, the results show that HBL20017 is a potent agonist at 5-HT1B.

[0357] Table IB shows the affinity (by EC50 values) of HBL20028 to different receptors.

[0358] Table IB ECso values for HBL20028

[0359] As can be seen in Table IB, 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.

[0360] These results suggest selective binding to distinct serotonergic receptors. Example 2B: Pharmacology of HBL20017 in Mouse 5-HT Receptors

[0361] The results in Example 2A showed receptor activation at human 5-HT receptors. This example related to activation at mouse 5-HT receptors.

[0362] Methods

[0363] 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 TrypLE™ 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. On the assay day, 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 μl of assay buffer and 10 μl 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 Oμl 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.

[0364] Results

[0365] Table 2 shows the affinity (by EC50 values) of HBL20017 to 3 different receptors. Table 2 - ECso values for HBL20017

[0366] The EC50 of HBL20017 at mouse 5-HT2A is 6.37nM vs. EC50 in human 5-HT2A of 7.95nM.

[0367] 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.

[0368] In conjunction with the mouse pharmacokinetic study described below, this may allow for a more accurate estimate of an effective oral dose in humans.

[0369] The in vitro EC50 measurements demonstrate that the compounds showed varying degrees of activity at various serotonergic receptors. Specifically, 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. In addition, HBL20028 showed a reduction in functional activity at 5-HT2B while retaining the activity at both 5-HT1A and 5-HT2A.

[0370] Example 2C: Safety and Toxicity Profiling Assays

[0371] Methods

[0372] Cytoxicity Assessment

[0373] 1. Cell seeding

[0374] 1) 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. 2) 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.

[0375] 3) The cell suspension was removed to a conical tube and pellet cells by centrifugation at 150 x g for 5 minutes. The supernatant was aspirated carefully and HepG2 cells were resuspended in cell culture medium at a density of 150,000cells / mL. 20 μl of above cell suspension was added to each well of 384- well plate.

[0376] 4) The plates were Incubated overnight for the toxicity assay, 37°C, 5% CO2 atmosphere.

[0377] 2. Compound preparation and treatment i. Serial dilute compounds

[0378] 1) 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.

[0379] 2) The plate was removed from the incubator and directly added 100 μL 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.

[0380] 3. Detection

[0381] 1) After the incubation, the plates were removed from incubator. Pre-mixed Cell Titer-Gio reagent (20 μl per well) was added directly into the 384- well plates.

[0382] 2) The plates were shaken for 5 min on a plate shaker.

[0383] 3) The plates were incubated at room temperature for 10 minutes.

[0384] 4) After 10 minutes, the luminescence was recorded on a plate reader.

[0385] 4. Data analysis i. % Vehicle Control of test compound can be calculated using the following equation:

[0386] % Vehicle control = [(Read Compound- Read Blank) / (Read Vehicle - Read Blank)]* 100% ii. Plot % Vehicle Control against the concentration of test compounds, and fit the data to a sigmoidal dose-response curve with a variable slope using GraphPad Prism 8.0.2 Calculate the TC50 of the compound from the curve as the following equation:

[0387] Y = Bottom + (Top - Bottom) / (1 + 10A((LogTC50 - X)*HillSlope)) hERG Assay

[0388] The automated whole cell patch-clamp (Qube 384™) technique is used to record outward potassium currents from a population of 10 cells. Cells Recombinant CHO-K1 cell line expressing the human ERG (ether-a-go-go related gene) potassium channel (accession number U04270). On the day of the experiment, cells are harvested using a cell detachment solution (e.g. Accutase™) and maintained in serum-free medium (CHO- S- SFM II) at room temperature for at least 120 min before recording. On the instrument the cells are pipetted into each well of a 384-well plate in external solution. Stock solution is prepared in DMSO at 300x the final assay concentrations, and stored at -20°C until the day of assay. Each compound is tested as one (1) concentration per well. On the day of the assay, an aliquot of the stock solution is thawed and diluted into external solution to make final test concentrations. A final concentration of 0.33% DMSO is maintained for each concentration for the assay compounds and vehicle controls. Recording conditions: Intracellular Solution (mM) - 120 KF, 20 KC1, 10 HEPES, 10 EGTA (pH 7.2 by KOH); Extracellular Solution (mM) - 145 NaCl, 4 KC1, 1 MgC12, 2 CaC12, 10 HEPES, 10 Glucose (pH 7.4 by NaOH). After whole cell configuration is achieved, the cell is held at -80 mV. 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. Reference compound Verapamil is tested concurrently at six (6) concentrations to obtain an IC50 value. Data analysis: The percent inhibition of hERG channel is calculated by comparing the tail current amplitude before and after application of the compound (the current difference is normalized to vehicle control values). Cytotoxicity assay:

[0389] Extrapolated concentration resulting in 50% cell death in HepG2 cells hERG inhibition assay - Hepatocyte stability (human and mice):

[0390] In-vitro half-life of the compound as extrapolated from the rate of degradation of the compound when incubated with human / mouse hepatocytes

[0391] Results

[0392] Table 3 summarizes results of cytotoxicity, hERG inhibition, and hepatocyte function for two tested compounds.

[0393] Table 3 - Compounds characteristics

[0394] As can be seen in Table 3, both HBL20016 and HBL20017 are not cytotoxic and show an acceptable level of hERG inhibition.

[0395] Example 2D: Safety Screen Panel for HBL20017

[0396] 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”.

[0397] Methods

[0398] 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.

[0399] Results

[0400] 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.

[0401] Table 4 shows the inhibition (IC50) or stimulation (EC50) higher than 50% that were considered to represent a significant effect of the tested compound.

[0402] Table 4: Targets identified as hits at lOuM.

[0403] Twelve (11 receptors and one enzyme) of the 44 targets screened showed affinity for

[0404] HBL20017:

[0405] Adrenergic alpha 1 A and 2A - associated with effects on vasoconstriction / dilation.

[0406] Dopamine D 1 and D2 - associated with memory, learning and addiction. D2 is also the primary target for several antipsychotic drugs.

[0407] Histamine Hl - plays a role in inflammatory processes. 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)

[0408] 5-HT1A, 5-HT1B, 5-HT2A, 5-HT2B, and 5-HT3 - binding at these receptors is expected at high concentrations of tryptamine psychedelics.

[0409] Table 5 shows results of HBL20017 for different enzymes using enzyme and uptake assays.

[0410] Table 5: Enzymes identified as binders

[0411] Example 3: Functional Assays for HBL20017 at Safety Screen “Hits”

[0412] 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. Methods

[0413] 5-HT2B

[0414] 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. One day before the assays, the cells were detached using TrypLE™ Express and counted with a cell counter, ensuring that only those with greater than 85% viability were used for the assay.

[0415] On the following day, 12,000 cells were seeded in 30 μl of culture medium per well of a 384- well cell plate, and the cells were incubated overnight under the same conditions. On the day of the assay, a 2x dye solution was prepared according to the instructions from the FLIPR® Calcium 6 Assay Kit. The dye was diluted with assay buffer (20 mM HEPES in l x HBSS, pH 7.4), probenecid was added to achieve a final concentration of 5 mM, and the mixture was vortexed vigorously for 1 to 2 minutes.

[0416] The medium was removed from the cell plate by flicking it onto towel paper. Then, 10 pL of assay buffer and 10μL 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.

[0417] Meanwhile, 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. Using an Echo, 90pL per well of both the reference compounds and the test compounds was transferred from the source plate to the compound plate, and 30 μl of assay buffer was added to each well. The plate was then mixed on a plate shaker for 2 minutes.

[0418] The cell plate, compound plate, and tips were placed into the FLIPR, where10μL 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 μl 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, 0μL of the 4* EC80 was transferred to each well of the cell plate.

[0419] Finally, the plate was read for 160 seconds with 1 -second intervals to obtain data on the antagonist mode.

[0420] Histamine Receptor Hl

[0421] 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. One day prior to the assays, the cells were detached using TrypLE™ Express and counted with a cell counter, ensuring that only those with over 85% viability were selected for the assay.

[0422] On the day of the assay, 12,000 cells were seeded in 30 μl of culture medium per well of a 384-well cell plate, and the cells were incubated overnight under the same conditions. On the assay day, a 2x dye solution was prepared according to the instructions provided in the FLIPR® Calcium 6 Assay Kit. The dye was diluted with assay buffer (20 mM HEPES in

[0423] 1 x HBSS, pH 7.4), probenecid was added to a final concentration of 5 mM, and the solution was vortexed vigorously for 1 to 2 minutes.

[0424] The medium was removed from the cell plate by flicking it onto towel paper. Subsequently, 10 μl of assay buffer and10μL 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

[0425] 2 minutes before being incubated at 37°C for 2 hours, followed by an additional 15-minute incubation at 25°C.

[0426] In parallel, 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. Using an Echo, 90μl of the compounds was transferred from the source plate to the 384- well compound plate, and 30 μl of assay buffer was added to each well. The plate was then mixed on a plate shaker for 2 minutes.

[0427] The cell plate, compound plate, and tips were placed into the FLIPR, where10μL 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.

[0428] 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 μl 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, 0μL of the 4* EC80 was transferred to each well of the cell plate.

[0429] Finally, the plate was read for 160 seconds at 1 -second intervals to collect data on the antagonist mode.

[0430] Norepinephrine Transporter

[0431] 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. One day before the assays, the cells were detached using TrypLE™ Express and counted with a cell counter, ensuring that only those with greater than 85% viability were selected for the assay.

[0432] The following day, 16,000 cells were seeded in 30 μl of culture medium per well of a 384- well cell plate and incubated overnight under the same conditions. On the day of 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.

[0433] After discarding the culture medium,10μL 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, 120μl of the compound was transferred from the source plate to the 384- well compound plate.

[0434] Following this, 20 μl of assay buffer was added to each well of the compound plate. The plate was then centrifuged at 1,000 rpm for 1 minute. Thorough mixing was achieved by orbital shaking the compound plate at 600 rpm for 2 minutes.

[0435] Subsequently, 5 μl of compounds were transferred from the compound plate to the cell plate, and the plate was incubated at 37°C for 30 minutes. Afterward, 15 μl of the dye mixture solution was added to each well of the cell plate, followed by a 60-minute incubation at 37°C.

[0436] Finally, the plate was read using the FLIPR Tetra.

[0437] Dopamine Receptor D2

[0438] The cAMP assay buffer was prepared according to the specified formulation. The reagents included 14 mL of 1 x HBSS with Ca2+ and Mg2+, 75 μl of 1 M HEPES, 100 μL of 7.5% (w / v) BSA stabilizer (pH 7.4), and 14 μl of 500 mM IBMX.

[0439] The Eu-cAMP tracer working solution and Ulight-anti-cAMP working solution were prepared as follows: 20 μl of Eu-cAMP tracer stock was mixed with 2 mL of cAMP detection buffer, while10μL of Ulight-anti-cAMP stock was combined with 2 mL of the same cAMP detection buffer.

[0440] For the preparation of the compound source plate, ten doses of Forskolin were created starting from a 100 mM stock solution through 3-fold serial dilutions with 100% (v / v) DMSO. Similarly, ten doses of Dopamine were prepared starting from a 1 mM stock solution, and ten doses of Spiperone were prepared from a 0.03 mM stock solution, both through 3-fold serial dilutions with 100% (v / v) DMSO. Additionally, ten doses of a test article were prepared starting from a 10 mM stock solution by the same method.

[0441] Prior to the assay, 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)5cells / mL with the cAMP assay buffer and seeded at a density of 1,000 cells per well in a 384- well plate.

[0442] Using an Echo, 10μL of serially diluted Forskolin was transferred to each well of the assay plate containing the DRD2 receptor-expressing cells. The cell plate was then centrifuged at 1,000 rpm for 1 minute, followed by agitation at 600 rpm for 2 minutes, and incubated at 25°C for 30 minutes.

[0443] Subsequently, 5 μl of the Eu-cAMP tracer working solution and 5 μl of the Ulight-anti- cAMP working solution were added to each well of the plate. The plate underwent another centrifugation at 1,000 rpm for 1 minute, followed by agitation at 600 rpm for 2 minutes, and was then incubated at room temperature for 60 minutes.

[0444] The plate was read using an Envision (Xex=337 nm, Xem=615 nm and 665 nm), and the ratio of Emission at 665 nm to Emission at 615 nm was plotted against the concentrations of compounds to build a curve and calculate the EC50 and EC90 of Forskolin.

[0445] Following this, an appropriate amount of Forskolin was transferred to the plate to achieve its EC90 value using an Echo. Next, 10μL of serially diluted Dopamine and the test article were transferred to each well of the assay plate with DRD2 receptor-expressing cells by an Echo. After centrifuging the cell plate at 1,000 rpm for 1 minute and agitating at 600 rpm for 2 minutes, the plate was incubated at 25°C for another 30 minutes.

[0446] Again, 5 μl of the Eu-cAMP tracer working solution and 5 μl of the Ulight-anti-cAMP working solution were added to each well of the plate. The plate was centrifuged at 1,000 rpm for 1 minute, agitated at 600 rpm for 2 minutes, and incubated at room temperature for 60 minutes.

[0447] 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.

[0448] An appropriate amount of Forskolin and Dopamine was then transferred to reach their EC90 values into the plate with DRD2 receptor-expressing cells using an Echo. Following this, 10μL of serially diluted Spiperone and the test compound were transferred to each well of the assay plate. After centrifugation of the cell plate at 1,000 rpm for 1 minute and agitation at 600 rpm for 2 minutes, the plate was incubated at 25°C for 30 minutes. The same procedure was followed: 5 μl of the Eu-cAMP tracer working solution and 5 μl of the Ulight-anti-cAMP working solution were added to each well, followed by centrifugation, agitation, and a 60- minute incubation at room temperature.

[0449] Finally, 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.

[0450] Monoamine oxidase A (MAO- A)

[0451] The IX assay buffer was prepared. Using an Echo, lOOμl of diluted compounds was added to a 384-well plate, which was then centrifuged at 1,000 RPM for 1 minute. Following this, 5 μl of 2X MAO-A was added to the same plate, and it was centrifuged again at 1,000 RPM for 1 minute. Next, 5 μl 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.

[0452] After the incubation1, 0μL of detection reagent was added to each well, and the plate was centrifuged at 1,000 RPM for 1 minute. It was then incubated for an additional 20 minutes at room temperature before the luminescence signal was read.

[0453] Adrenergic Alpha 1A

[0454] 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.

[0455] One day before the assay, the cells were detached using TrypLE™ Express and counted with a cell counter. Only those cells with greater than 85% viability were used for the assay.

[0456] A total of 12,000 cells per well were seeded in 30 μl 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.

[0457] On the day of the assay, 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. Then, 10 pL of assay buffer and10μL 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.

[0458] Next, 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 serial dilutions. Test compounds at a concentration of 10 mM were added to the compound plate, and 3-fold serial dilutions were performed. Using an Echo, 90μl of compounds was transferred from the source plate to the 384-well compound plate. An additional 30 μl of assay buffer was added to each well of the compound plate, which was mixed on a shaker for 2 minutes.

[0459] The cell plate, compound plate, and tips were placed into the FLIPR, and 10μL 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.

[0460] 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 μl 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 μl of the 4x EC80 was transferred to each well of the cell plate using the FLIPR.

[0461] Finally, the plate was read for 160 seconds with 1 -second intervals to obtain data for the antagonist mode.

[0462] Dopamine DI

[0463] The cAMP assay buffer was prepared by combining the following reagents: 14 mL of 1 x HBSS with Ca2+and Mg2+, 75 μl of 1 M HEPES, 100 μL of a 7.5% (w / v) BSA stabilizer (pH 7.4), and 14 μl of 500 mM IBMX.

[0464] Next, the Eu-cAMP tracer working solution and Ulight-anti-cAMP working solution were prepared. The Eu-cAMP tracer working solution consisted of 20 μl of Eu-cAMP tracer stock and 2 mL of cAMP detection buffer. The Ulight-anti-cAMP working solution included 10μL of Ulight-anti-cAMP stock and 2 mL of cAMP detection buffer.

[0465] For the preparation of the compound source plate, 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.

[0466] Before conducting the assay, 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 * 105cells / mL with the cAMP assay buffer and seeded at a density of 1,000 cells per well in a 384- well plate.

[0467] Using an Echo, 10μL of Dopamine and 10μL of test compounds were transferred to each well of the assay plate containing DRD1 receptor-expressing cells. The cell plate was then centrifuged at 1,000 RPM for 1 minute and agitated at 600 RPM for 2 minutes, followed by a 30-minute incubation at 25°C.

[0468] Five μL of the Eu-cAMP tracer working solution and 5 μl of the Ulight-anti-cAMP working solution were added to each well of the plate. The plate was centrifuged again at 1,000 RPM for 1 minute, agitated at 600 RPM for 2 minutes, and incubated at room temperature for 60 minutes.

[0469] 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.

[0470] An appropriate amount of Dopamine was transferred to each well of the assay plate to reach its EC90 value using an Echo. Subsequently, 10μL of R(+)-SCH-23390 hydrochloride and 10μL of test compounds were transferred to each well of the assay plate. The cell plate underwent another centrifugation at 1,000 RPM for 1 minute, was agitated at 600 RPM for 2 minutes, and incubated at 25°C for 30 minutes. Five μl of the Eu-cAMP tracer working solution and 5 μl of the Ulight-anti-cAMP working solution were added to each well, followed by centrifugation and agitation as before, with a final 60-minute incubation at room temperature.

[0471] 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.

[0472] Dopamine D2

[0473] The cAMP assay buffer was prepared according to the following formulation: 14 ml of lx HBSS with Ca2+and Mg2+, 75 μl of 1 M HEPES, 100 μl of 7.5% (w / v) BSA stabilizer (pH 7.4), and 14 μl of 500 mM IBMX.

[0474] The Eu-cAMP tracer working solution and Ulight-anti-cAMP working solution were prepared as follows: for the Eu-cAMP tracer working solution, 20 μl of Eu-cAMP tracer stock was combined with 2 ml of cAMP detection buffer. For the Ulight-anti-cAMP working solution, 10 μl of Ulight-anti-cAMP stock was mixed with 2 ml of cAMP detection buffer.

[0475] Next, 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. Similarly, 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. Additionally, ten doses of test articles were prepared starting from a 10 mM stock solution using the same dilution method.

[0476] Before the assay, 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 05cells / mL with the cAMP assay buffer and seeded at a density of 1000 cells / well in a 384- well plate.

[0477] Using an Echo, 10μL of serially diluted Forskolin was transferred to each well of the assay plate containing the DRD2 receptor-expressing cells. The cell plate was then centrifuged at 1000 RPM for 1 minute, agitated at 600 RPM for 2 minutes, and incubated at 25°C for 30 minutes.

[0478] Subsequently, 5 μl of the Eu-cAMP tracer working solution and 5 μl of the Ulight-anti- cAMP working solution were added to each well of the plate. The plate was centrifuged again at 1000 RPM for 1 minute, agitated at 600 RPM for 2 minutes, and then incubated at room temperature for 60 minutes.

[0479] 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.

[0480] The appropriate amount of Forskolin was then transferred to each well of the assay plate to achieve its EC90 value using the Echo. Following this, lOμl 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.

[0481] Afterwards, 5 μl of the Eu-cAMP tracer working solution and 5 μl of the Ulight-anti- cAMP working solution were added to each well. The plate underwent the same centrifugation, agitation, and incubation as before. The plate was read again using the EnVision reader, and the ratio of emission at 665 nm to 615 nm was plotted to determine the EC50 and EC90 values of Dopamine.

[0482] Finally, the appropriate amounts of Forskolin and Dopamine were transferred to reach their respective EC90 values in the assay plate. Subsequently, lOμl of serially diluted Spiperone and test compounds were added to the wells, followed by centrifugation, agitation, and incubation as previously described. After this, 5 μl of the Eu-cAMP tracer working solution and 5 μl of the Ulight-anti-cAMP working solution were added to each well, and the plate was processed as before. The plate was read using the EnVision reader, and the ratio of emission at 665 nm to 615 nm was plotted against the concentrations of compounds to calculate the IC50. Adrenergic Apha2A

[0483] 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.

[0484] One day before the assays, the cells were detached using TrypLE™ 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 μl of culture medium into a 384-well cell plate and incubated overnight under the same conditions.

[0485] On the assay day, 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.

[0486] The medium was then removed from the cell plate by flicking it onto towel papers. Following this, 10μL of assay buffer and of t1h0eμ 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.

[0487] 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. Using an Echo, 90μl of compounds were transferred from the source plate to the 384-well compound plate. Additionally, 30 μl of assay buffer was added to each well of the compound plate, which was then mixed on a plate shaker for 2 minutes.

[0488] The cell plate, compound plate, and tips were loaded into the FLIPR. A total of 10μL 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.

[0489] 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 μl 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 th10eμ 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.

[0490] Results

[0491] Tables 6A-6M show functional or enzymatic assays.

[0492] Table 6A: Functional Assay for 5-HT1A - agonist mode

[0493] Table 6B: Enzymatic Assay for MAO- A

[0494] Table 6C: Functional Assay for Adrenergic Alpha 1A - agonist mode Table 6D: Functional Assay for Adrenergic Alpha 1A - antagonist mode

[0495] Table 6E: Functional Assay for Adrenergic Alpha 2A - agonist mode

[0496] Table 6F: Functional Assay for Adrenergic Alpha 2A - antagonist mode

[0497] Table 6G Functional Assay for Dopamine Receptor DI - agonist mode

[0498] Table 6H Functional Assay for Dopamine Receptor DI- antagonist mode Table 61 Functional Assay for Dopamine Receptor D2- antagonist mode

[0499] Table 6J Functional Assay for Dopamine Receptor D2 - antagonist mode

[0500] Table 6K Functional Assay for Histamine Receptor Hl- agonist mode

[0501] Table 6L Functional Assay for Histamine Receptor Hl - antagonist mode

[0502] Table 6M Functional Assay for Norepinephrine Transporter D2 - antagonist mode

[0503] As can be seen, 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.

[0504] The other targets did not show activity or inhibition across the range of concentrations studied.

[0505] Example 4: 5-HT2B Functional Assay for HBL20017 in Agonist and Antagonist Mode

[0506] Subsequent to the results of the radioligand binding assay, the functional activity of HBL20017 at 5-HT2B was assessed to determine whether the high affinity of the compound to the receptor results in activation or inhibition of activity. Tables 7A-7B show functional assays.

[0507] Table 7A functional assay for 5-HT2B - agonist mode

[0508] Table 7B functional assay for 5-HT2B - antagonist mode

[0509] The results indicate that both partial agonism (at lower concentrations) and full antagonism (at higher concentrations) contribute to the high affinity of HBL20017 to the 5-HT2B receptor seen in the results of the radioligand binding.

[0510] While activation of the 5-HT2B receptor has been shown to be associated with valvular heart disease, the frill inhibition of the receptor by the drug at higher concentrations is likely to mitigate the associated risk, especially with infrequent administration. Example 5: Pharmacokinetic study

[0511] 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.

[0512] Methods

[0513] 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.

[0514] For the oral (PO) dosing, a similar approach was taken to prepare a 0.6 mg / mL solution of "30% PEG400 / 70% Saline." In this instance, 1.40 mg ofHBL20017 was dissolved in 0.700 mL of PEG400, again utilizing vortexing and sonication. After the complete dissolution, 1.633 mL of Saline was added, and vortexing and sonication were employed once more to obtain a uniform solution.

[0515] Lastly, for the intraperitoneal (IP) dosing, the preparation of a 0.6 mg / mL solution of "30% PEG400 / 70% Saline" was conducted. In this step, 1.65 mg of HBL20017 was dissolved in 0.825 mL ofPEG400 through vortexing and sonication. Following this, 1.925 mL of Saline was added, and vortexing and sonication were applied to finalize the preparation of the solution.

[0516] All brain samples were homogenized by adding phosphate-buffered saline (PBS) at a volume ratio of 1 :3 (brain weight to PBS volume). The actual concentration (ng / g) of the analyte was calculated by multiplying the detected value (ng / mL) by a factor of 4.

[0517] To achieve the desired serial concentrations of working solutions, the stock solution of the analyte was diluted with a 50% acetonitrile in water solution. A volume of 15 μl of each working solution (1, 2, 4, 10, 20, 100, 200, 1000, and 2000 ng / mL) was added to 30 μl 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). Additionally, 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.

[0518] A total of 45 μl of the calibration standards, QC samples, and unknown samples (comprised of 30 μl brain homogenate and 15 μl blank solution) were combined with 200 μl 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 μl of the diluted supernatant was injected into the LC / MS / MS system for quantitative analysis.

[0519] HPLC Instrumentation and Conditions

[0520] 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.

[0521] 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).

[0522] HPLC Conditions

[0523] 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.

[0524] 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 μl for plasma samples and 1 μl for brain samples.

[0525] Results

[0526] At present, 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%.

[0527] Example 6: Head Twitch Response (HTR)

[0528] The head-twitch response (HTR) 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.

[0529] Methods

[0530] Head twitch response (HTR) 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. Recordings were performed using a MATLAB driver (MathWorks, US, R2021a version, along with the NI myDAQ support package) with the corresponding National Instruments support package for further processing. A custom MATLAB script was used to record the processed signal, which was presented as graphs showing the change in current as peaks (mAh). A custom graphic user interface created in our laboratory was used to further process the recording into an Excel spreadsheet.

[0531] Mice were injected with HBL20016, HBL20017 and HBL20028 as well as with psilocybin (a psychedelic compound - positive control), and vehicle (negative control). Results

[0532] 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.

[0533] 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.

[0534] As further shown in Figure 2, 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. These results suggest that HBL20016 is associated with an agonistic effect at 5-HT2A receptor resulting in hallucinogenic or psychoactive potential whereas HBL20017 does not induce hallucinogenic or psychoactive effect.

[0535] The results are summarized in Table 8 shown below.

[0536] Table 8 Head Twitch Response (HTR)

[0537] Taken together, the results of the HTR experiment suggested that HBL20016 induces a very strong HTR via its agnostic effect on 5-HT2A receptor, while HBL20017 has relatively low HTR.

[0538] 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. As shown in Figure 2B, administration of HBL20028 at doses of 6, 12, and 24 mg / kg did not result in a significant increase in HTR compared to vehicle. In addition, as shown in Figure 2C, 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. As shown in Figure 2D, administration of HBL20028 at doses of 6, 12, and 24 mg / kg did not result in a significant increase in HTR overtime. As can be seen in Figures 2B-2D, HBL20028 has relatively low HTR. These results support the use of HBL20028 and HBL20017 as therapeutic compounds which do not induce the psychedelic trip, the human equivalent of the HTR. This places these new compounds at an advantage over compounds like psylocybin, in the treatment of psychiatric disorders.

[0539] Example 7: Open field test (OFT)

[0540] Methods

[0541] Behavioral tests to assess 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.

[0542] C57Bl / 6j mice, ~12 weeks Injection of: Psilocybin (4.4 mg / kg) HBL 20017 (1 mg / kg) HBL 20017 (6 mg / kg) Vehicle; i.p. immediately before HTR testing OFT done immediately after 30 min. HTR i.e. 30 min. after drug administration. One way ANOVA with post-hoc Dunnet’s Test. Significance: p<0.05 (two tailed) n= 4-5 per group. In addition, HBL20028 was administered at 6 mg / kg, 12 mg / kg or 24 mg / kg or vehicle.

[0543] Results

[0544] Figures 3A-3B shows the results of total distance in OFT for psilocybin, HBL20016 (Figure 3A) and HBL20017 (Figure 3B).

[0545] Administration of psilocybin resulted 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. As shown in Figures 3A and 3B, psilocybin showed a reduced overall activity as indicated by the reduced total distance covered as compared to vehicle.

[0546] Administration of HBL20016 (Figure 3A) resulted in a total distance that was slightly but not significantly higher at Img / kg as compared to vehicle and at 6mg / kg comparable to the vehicle. In both tested concentrations, the total distance induced by HLB0016 was higher than that of psilocybin.

[0547] Administration of HBL20017 (Figure 3B), resulted in total distance that was comparable to vehicle at Img / kg and significant decrease in the total distance at higher dose of 6 mg / kg as compared to vehicle. This result was observed at one hour following administration of HBL20017. However, two hours and 24 hours after administration of HBL20017 6 mg / kg there was no significant effect on distance covered (Figure 3C). The results are summarized in Table 9 below.

[0548] Table 9 Open field test (OFT)

[0549] As shown in Figure 3D, administration of HBL20028 at a dose of 6 mg / kg did not affect locomotor activity compared to vehicle. In contrast, HBL20028 at 12 mg / kg and 24 mg / kg significantly reduced total distance covered, suggesting a dose-dependent effect on motor behavior. As shown in Figure 3E, HBL20028 at 24 mg / kg showed a trend towards increased center duration. As shown in Figure 3F, administration of HBL20028 at 12 mg / kg resulted in a statistically significant increase in time spent in the periphery. These results mean that this compound is beneficial in reducing manifestations of anxiety, and may be used for its treatment. Example 8: Anti-obsessional and anxiolytic effects.

[0550] Methods

[0551] Marble Burying Test (MBT) was performed in transparent cages containing ~4.5 cm fine sawdust. Twenty glass marbles were placed equidistant from each other in a 5 x 4 pattern. The experiment was done under dim light in a quiet room to reduce the influence of anxiety on behavior. The mice were left in the cage with the marbles for a 30- min period, after which the test was terminated by removing the mice. A marble was considered buried when two-thirds or more of its size was covered with burying substrate, and the number of buried marbles was counted after 30 min. All mice underwent a pretest without any injection, and the number of marbles buried was counted. Only mice that buried at least 15 marbles were selected to perform the test after drug administration. Eighty percent of pretested mice fulfilled this criterion and were used in the definitive experiment, which took place at least a week following the pretest.

[0552] Results

[0553] Figure 4A shows the effect of Psilocybin (PSIL), HBL20016 and HBL20017 compounds on marble burying (MB) over 30 minutes.

[0554] As can be seen in this Figure, administration of HBL20016 or HBL0017 resulted in a significant decrease in MB as compared to vehicle but the effect observed with HLB0017 was more pronounced than HBL20016. Administration of psilocybin also resulted in a significant decrease in MB. The time course is shown in Figure 4B.

[0555] The significant reduction in MB observed with HBL0017 indicates the potential anti-obsessional properties of this compound. Reduction in marble burying is also indicative of potential anxiolytic effects.

[0556] Further, the effect on MB was tested after administration of HBL20017, WAY 100635 (5-HT1A antagonist) and M100907 (5-HT2A antagonist) and combinations thereof.

[0557] As can be seen in Figure 4C, administration of HBL20017 resulted in a marked reduction in MB behavior as compared to vehicle (as shown in Figure 4A above). Figure 4D shows time course. Concurrent administration of the 5-HT1A antagonist, WAY100635, and HBL20017 prevented the significant effect of HBL20017 to reduce MB thus suggesting that the effect of HBL20017 to reduce marble burying is mediated via the 5 -HT1 A receptor.

[0558] Combined administration of HBL20017 with Ml 00907 was shown to significantly reduce MB as compared to vehicle. The fact that a 5-HT2A receptor antagonist did not block the effect of HBL20017 on marble burying suggests that the effect of HBL20017 to reduce marble burying is not mediated via the 5-HT2A receptor.

[0559] Table 10: Reduction in marble burying is independent of hypolocomotion

[0560] Tests of between subjects effects, dependent variable: MB a. R Squared = .371 (Adjusted R Squared = .309)

[0561] Tests of between subjects effects, dependent variable: MB a. R Squared = .335 (Adjusted R Squared = .287)

[0562] Table 10 shows the statistical significance of the reduction in MB for mice administered in HBL20017 (p < 0.001 (highlighted in green)). However, because locomotion was also suppressed in these mice, we were concerned that reduction in MB could be partially or completely a result of the reduced locomotion and not the anxiolytic effect of the drug. On re-running the statistical analysis, this time adding the hypolocomotion as a covariant, and found that the reduction in marble burying is still statistically significant p=0.006 (highlighted yellow).

[0563] As can be seen in this example (Table 10), 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).

[0564] Examples 9 and 10: Effect of HBL20016 and HBL20017 on obsessive self-grooming and head-body twitches in SAPAP3 KO mice.

[0565] Methods

[0566] 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. Adult mice aged >6 months, homozygous for the null mutation, undergo a battery of behavioral tests before treatment (compulsive behavior, general activity, anxiety level and cognitive function) and documentation of self- grooming and head twitches over one hour by video with blind assessment by two observers. 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. and 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.

[0567] Results

[0568] Effect on Self Grooming Duration in SAPAP3 Homozygous Knockout Mice:

[0569] 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.

[0570] 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.

[0571] Example 11: Effect of HBL20017 on MK-801 induced Hyperactivity

[0572] 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).

[0573] Methods

[0574] One Way ANOVA followed by Dunnett’s Multiple Comparison Test compared with Vehicle control

[0575] Table 11 shows analysis information. | | | | | | | | | Results

[0576] Figure 7 shows the results of the total distance. Table 19 shows the results of this example.

[0577] As can be seen, 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.

[0578] Example 12: Effect of HBL20017 in the Forced Swim Test (FST)

[0579] The test is commonly used assess antidepressant potential of antidepressant compounds. Here the effect of HBL20017 was shown at varying doses on parameters of the Forced Swim Test.

[0580] Methods

[0581] Data was analyzed using One Way ANOVA followed by Dunnett’s Multiple Comparison Test compared with Vehicle control. 1 animal from Desipramine and 1 animal from HBL20017 1 mg / kg, were outlier as per Grubb’s outlier test, Data from these 2 animals were not considered for calculation.

[0582] Results

[0583] Figures 8A and 8B show results of immobility time and swimming time, respectively. As can be seen, 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.

[0584] Figure 9 shows total active behavioral time. As can be seen, 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. The results are summarized in Table 12.

[0585] Table 12 Results summary

[0586] In conclusion, vehicle-treated group displayed signs of depression-like behavior, marked by increased immobility and decreased active behavior. However, Desipramine alleviated the depression-like effects by exhibiting increased swimming time and decreased immobility time.

[0587] HBL20017 at 1, 3 and 6 mg / kg did not exhibit significant change in immobility time, swimming time compared to vehicle treated group.

[0588] Intriguingly, 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.

Claims

CLAIMS:

1. A small molecule compound (SMC) having the general Formula (la) or (lb):or a pharmaceutically acceptable salt, solvate, hydrate, any stereoisomer thereof, or physiologically functional derivative thereof, wherein each one of Xi, X2, X3, X4, is independently selected from N or C, each one of X5,X6and X7 is independently selected from N, S, O or C, 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, C2-Ci2alkynyl, C2-C12 haloalkynyl, C1-C12 alkoxy, C1-C12 haloalkoxy, urea, sulfonylurea, sulfonamidyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, trifluoromethyl, -N(Rn)(R12), -C(O)Rn, -CH2R11, -CO2R11, -C(O)N(Rn)(R12), -SO2N(Rn)(R12), -SOR11,R3IS L2-R9, L2IS -(CH2)m- ,-C(O)-, -O-, -NH-, -O-CH2-, -N-(CH2)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, Ci- C12 haloalkyl, C2-C12 alkenyl, C2-C12 haloalkenyl, C2-Ci2alkynyl, C2-C12 haloalkynyl, Ci- C12 alkoxy, C1-C12 haloalkoxy, urea, sulfonylurea, sulfonamidyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, trifluoromethyl, -N(Rn)(R12), -C(O)Rn, -CH2R11, -CO2R11, -C(O)N(Rn)(R12), -SO2N(Rn)(R12),each R11and R12is independently H, hydroxyl, C1-C12 alkyl, C1-C12 haloalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl,R5 is -Z-R8 orL2-Z-Rs, Z is S, S(O), S(O2), Rs is hydrogen, cyano, nitro, hydroxy, halo, CF3, C1-C12 haloalkyl, C1-C12 haloalkoxy, C1-C12 alkyl, C1-C12 alkoxy, aryl and N(Rn)(R12).

2. The SMC of claim 1 having the general Formula (la’) or (lb’):

3. The SMC of claim 1 or 2 having the general Formula (Ic):

4. The SMC of any one of claims 1 to 3, wherein R5 is -Z-R8 or L2-Z-R8, Z is S, S(O) or S(O2) and Rs is hydrogen, cyano, nitro, hydroxy, halo, CF3, C1-C12 haloalkyl, C1-C12 haloalkoxy, C1-C12 alkyl, C1-C12 alkoxy and aryl.

5. The SMC of any one of claims 1 to 4, wherein R5 is -Z-Rs, Z is S, S(O) or S(O2), Rs is hydrogen, CF3 or C1-C12 alkyl.

6. The SMC of any one of claims 1 to 5, having the general Formula (II):

7. The SMC of any one of claims 1 to 6, whereRi is L2-R9, L2 is -(CH2)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(R1 1)(R12), each R11and R12is independently H, hydroxyl, C1-C12 alkyl and m is selected from 0, 1, 2, 3, 4, 5 or 6.

8. The SMC of any one of claims 1 to 7, wherein R3 is L2-R9, L2 is -(CH2)m-, optionally substituted with C1-C12 alkyl, C1-C12 haloalkyl, or halo, R9 is hydrogen, heterocycloalkyl, or -N(Rn)(R12), each R11and R12is independently H, C1-C12 alkyl or R11and R12together 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.

9. The SMC of any one of claims 1 to 8, wherein R3 is L2-R9, L2 is -(CH2)2- optionally substituted with C1-C12 alkyl, C1-C12 haloalkyl, or halo, R9 is hydrogen, heterocycloalkyl, or -N(Rn)(R12), each R11and R12is independently H, C1-C12 alkyl or R11and R12together with the nitrogen atom they are connected to form a ring system optionally include at least one of N, O.

10. The SMC of any one of claims 1 to 9, wherein R3 is L2-R9, L2 is -(CH2)2-, R9 is -N(Rn)(R12), each R11and R12is independently H, C1-C12 alkyl or R11and R12together with the nitrogen atom they are connected to form a ring system optionally include at least one of N, O.

11. The SMC of any one of claims 1 to 10, having the general Formula (mb):R12together with the nitrogen atom they are connected to form a ring system optionally include at least one of N, O.

13. The SMC of any one of claims 1 to 12, having the general Formula (IVa), (IVb):

14. The SMC of any one of claims 6 to 13, wherein Z is S, S(0) or S(Ch) and Rs is hydrogen, cyano, nitro, hydroxy, halo, CF3, C1-C12 haloalkyl, C1-C12 haloalkoxy, C1-C12 alkyl, C1-C12 alkoxy and aryl.

15. The SMC of claim 14, wherein Rs is hydrogen, CF3, C1-C12 alkyl.

16. The SMC of claim 14 or 15, wherein (i) Z is S and Rs is hydrogen, CF3, C1-C12 alkyl, (ii) Z is S(O) and Rs is C1-C12 alkyl o r(iii) Z is S(Ch) and Rs is C1-C12 alkyl.

17. The SMC of any one of claims 1 to 16, having the general Formula (Va), (Vb), (Vc), (Vd), (Ve) or (Vf):

18. The SMC of any one of claims 1 to 17, wherein each one of Ri, R2, R4, Re, and R7, is independently selected from hydrogen, cyano, amino, amide, nitro, hydroxy, halo, Ci- C12 alkyl, C1-C12 haloalkyl, -CH2R11, optionally wherein each one of Ri, R2, R4, Re, R7, is hydrogen, halo, -CH2R11and C1-C12 alkyl, R11is cycloalkyl, heterocycloalkyl, aryl, heteroaryl.

19. The SMC of any one of claims 1 to 18, wherein Ri is hydrogen or C1-C12 alkyl, -CH2R11, optionally Ri is hydrogen or C1-C3 alkyl, -CH2R11, R11is cycloalkyl optionally Ri is C2 alkyl, CH2R11, R11is cyclopropyl.

20. The SMC of any one of claims 1 to 19, wherein each one of R4, Re, R7, is independently from the other independently selected from the group consisting of hydrogen, halo, C1-C12 alkyl, optionally wherein each one of R4, Re, R7, is independently from the other independently selected from the group consisting of hydrogen, halo, C1-C3 alkyl, optionally wherein each one of R4, Re, R7, is independently from the other independently selected from the group consisting of hydrogen, fluorine, C1-C12 alkyl, optionally wherein each one of R4, Re, R7, is independently from the other independently selected from the group consisting of hydrogen, fluorine, C1-C3 alkyl.

21. The SMC of any one of claims 1 to 20, being one or more of the following:(a)N,N-dimethyl-2-(7-methyl-5-(methylthio)-lH-indol-3-yl)ethanamine (denoted herein as HBL20010) or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer or physiologically functional derivative thereof,(b)2-(7-fluoro-5-(methylsulfinyl)-lH-indol-3-yl)-N,N-dimethylethanamine (denoted herein as HBL20013) or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer or physiologically functional derivative thereof,(c)2-(7-fluoro-5-(methylsulfonyl)-lH-indol-3-yl)-N,N-dimethylethanamine (denoted herein as HBL20014) or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer or physiologically functional derivative thereof,(d)2-(7-fluoro-5-(methylthio)-lH-indol-3-yl)-N,N-dimethylethanamine (denoted herein as HBL20015) or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer or physiologically functional derivative thereof,(e)2-(6-fluoro-5-(methylthio)-lH-indol-3-yl)-N,N-dimethylethanamine (denoted herein as HBL20016) or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer or physiologically functional derivative thereof,(f)2-(4-fluoro-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,(g)2-(4-fluoro-5-((trifluoromethyl)thio)-lH-indol-3-yl)-N,N-dimethylethanamine(denoted herein as HBL2022) or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer or physiologically functional derivative thereof,(h)2-(4-fluoro-5-(isopropylthio)-lH-indol-3-yl)-N,N-dimethylethanamine (denoted herein as HBL20023) or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer or physiologically functional derivative thereof,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,(j)2-(4-fluoro-7-methyl-5-(methylthio)-lH-indol-3-yl)-N,N-dimethylethanamine(denoted herein as HBL0025) or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer or physiologically functional derivative thereof,(k)2-(l-ethyl-4-fluoro-5-(methylthio)-lH-indol-3-yl)-N,N-dimethylethanamine(denoted herein as HBL20026), or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer or physiologically functional derivative thereof,(1)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.

22. The SMC of any one of claims 1 to 21, represented by Formula (XIV), (XV) or(XXI).

23. The SMC of any one of claims 1 to 21, represented by Formula (XXI).

24. A composition comprising at least one SMC as defined in any one of claims 1 to 23.

25. The SMC of any one of claims 1 to 23 or the composition of claim 24 for use in modulating one or more serotonergic receptors.

26. The SMC or the composition for use of claim 25, wherein said serotonergic receptor is at least one of 5-HT1A, 5-HT2A, 5-HT1B, 5-HT2B, 5-HT2C or a combination thereof.

27. The SMC of any one of claims 1 to 23 or the composition of claim 24 for use in a method for treating, preventing, inhibiting, reducing, eliminating, protecting or delaying the onset of a disorder characterized by deregulated 5- HT1A receptor function.

28. The SMC or the composition for use of claim 27, wherein said disease or condition is a brain disease.

29. The SMC of any one of claims 1 to 23 or the composition of claim 24 for use in a method for treating, preventing, inhibiting, reducing, eliminating, protecting or delaying a brain disease.

30. The SMC or the composition for use of any one of claims 27 to 29, wherein said disease or condition is one or more of a neuropsychiatric disease, a neurodegenerative disease, neuroinflammatory disease, pain and pain-associated disease.

31. The SMC or the composition for use of claim 30, wherein said 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, panic disorder, social anxiety disorder, autism spectrum disorder, social phobia, schizophrenia, schizoaffective disorder, psychotic depression, bipolar disorder with psychosis, Parkinson’s disease with psychosis, dementia with psychosis.

32. The SMC or the composition for use of claim 30, wherein said neuropsychiatric disease is one or more of depression, schizophrenia, OCD, PTSD, a bipolar disorder.

33. The SMC or the composition for use of claim 30, wherein said neuropsychiatric disease is one or more of GAD, panic disorder, social anxiety disorder, social phobia.

34. The SMC or the composition for use of claim 30, wherein said neuropsychiatric disease is one or more of schizophrenia, schizoaffective disorder, psychotic depression, bipolar disorder with psychosis, Parkinson’s disease with psychosis, dementia with psychosis.

35. The SMC or the composition for use of claim 30, wherein said neuropsychiatric disease is a human grooming disorder or disease.

36. The SMC or the composition for use of claim 35, wherein said human grooming disorder or disease is one or more of trichotillomania (compulsive hair pulling), dermatillomania (compulsive skin picking), and onychophagia (compulsive nail biting).

37. The SMC or the composition for use of claim 30, wherein said neuropsychiatric disease is a tic disorder.

38. The SMC or the composition for use of claim 37, wherein said tic disorder is Tourette's syndrome.

39. The SMC or the composition for use of claim 30, wherein said neurodegenerative disease is one or more of Alzheimer's disease, Parkinson's disease, Huntington's disease, Amyotrophic Lateral Sclerosis (ALS), frontotemporal dementia, Multiple Sclerosis (MS).

40. The SMC or the composition for use of claim 39, wherein said neurodegenerative disease is Parkinson's disease, dementia or Alzheimer's disease.

41. The SMC or the composition for use of claim 30, wherein said neuroinflammatory disease is one or more of Multiple Sclerosis (MS), Guillain-Barre Syndrome, Acute Disseminated Encephalomyelitis (ADEM), Autoimmune Encephalitis, Neuromyelitis Optica (Devic's Disease), Age Associated Macular Degeneration (AMD).

42. The SMC or the composition for use of claim 30, wherein said pain disease is one or more of fibromyalgia, chronic back pain, neuropathic pain, migraine headaches, chronic fatigue syndrome (CFS).

43. A method for modulating at least one serotonin receptor, the method comprising contacting at least one serotonin receptor with at least one SMC as defined in any one of claims 1 to 23 or a composition as defined in claim 24.

44. The method of claim 43, wherein the contacting is in vitro.

45. The method of claim 43, wherein the contacting is in vivo.

46. A method for treating, preventing, inhibiting, reducing, eliminating, protecting or delaying the onset of disorder characterized by deregulated 5- HT1 A receptor function, the method comprising administering to a subject in need thereof an effective amount of at least one SMC as defined in any one of claims 1 to 23 or a composition of claim 24 to thereby treat the disorder.

47. The method of claim 46, wherein said disease or condition is one or more of a neuropsychiatric disease, a neurodegenerative disease, neuroinflammatory disease, pain and pain-associated disease.

48. The method of claim 47, wherein said 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, panic disorder, social anxiety disorder, autism spectrum disorder, social phobia, schizophrenia, schizoaffective disorder, psychotic depression, bipolar disorder with psychosis, Parkinson’s disease with psychosis, dementia with psychosis.

49. The method of claim 48, wherein said neuropsychiatric disease is a human grooming disorder or disease.

50. The method of claim 47, wherein said neurodegenerative disease is one or more of Alzheimer's Disease, Parkinson's Disease, Huntington's Disease, Amyotrophic Lateral Sclerosis (ALS), Frontotemporal Dementia, Multiple Sclerosis (MS).

51. The method of claim 47, wherein said neuroinflammatory disease is one or more of Multiple Sclerosis (MS), Guillain-Barre Syndrome, Acute Disseminated Encephalomyelitis (ADEM), Autoimmune Encephalitis, Neuromyelitis Optica (Devic's Disease), Age Associated Macular Degeneration (AMD).

52. The method of claim 47, wherein said pain disease is one or more of fibromyalgia, chronic back pain, neuropathic pain (e.g., caused by diabetic neuropathy or nerve injury),migraine headaches, chronic fatigue syndrome (CFS).

53. Use of at least one SMC as defined in any one of claims 1 to 23 in the manufacture of a composition.

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