Small molecule allosteric modulators of the serotonin (5-HT) 5-HT2C and 5-HT2A receptors

Abstract

The present invention relates to novel 5HT receptor modulators, such as compounds of general formula (I) and general formula (II), or pharma- ceutically acceptable salts thereof.Methods of using the compounds include, for example, modulating 5-hydroxytryptamine (5-HT) receptor subtypes, including 5-hydroxytryptamine 2A receptors and / or 5-hydroxytryptamine 2C receptors, and treating conditions or diseases, which are associated with modulating 5-hydroxytryptamine 2A receptors and / or 5-hydroxytryptamine 2C receptors. [C38] TIFF2025511273000050.tif29156

Description

[Technical field]

[0001] [CROSS REFERENCE TO RELATED APPLICATIONS] This application claims priority to U.S. Patent Application No. 63 / 326,600, filed April 1, 2022, the contents of which are incorporated by reference in their entirety herein.

[0002] [STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT] This invention was made with Government support under Grant Nos. R21 MH093844, R01 DA038446, T32 DA007287, and F31 DA038922 awarded by the National Institutes of Health (NIH). The Government has certain rights in the invention. The field of the invention relates generally to novel small molecules that bind to and / or modulate serotonin receptor subtypes, and their preparation and uses. [Brief description of the drawings]

[0003] [Figure 1A] FIG. 1A shows chemical structures of certain olefinic compound embodiments in accordance with the present invention. [Figure 1B] FIG. 1B shows chemical structures of certain olefinic compound embodiments in accordance with the present invention. [Figure 1C] FIG. 1C shows chemical structures of certain olefinic compound embodiments in accordance with the present invention. [Diagram 2] FIG. 2 shows chemical structures of certain epoxy compound embodiments according to the present invention. [Diagram 3] FIG. 3 shows chemical structures of certain aziridine and cyclopropane compound embodiments in accordance with the present invention. [Figure 4] FIG. 4 shows chemical structures of certain fatty amide compound embodiments in accordance with the present invention. [Diagram 5] FIG. 5 shows chemical structures of certain arylalkylamide compound embodiments in accordance with the present invention. [Figure 6] FIG. 6 shows chemical structures of polar head ("PH") substituents included in certain arylalkylamide compound embodiments according to the present invention. [Figure 7-1] Sections A to F of FIG. 7 are graphs of concentration-response curves of Compounds 6 to 11 (1 nM) according to the present invention on 5-HT-induced Cai 2+ release in live h5-HT2CR-CHO cells. [Figure 7-2] Sections G to N of FIG. 7 are graphs of concentration-response curves of Compounds 12 to 19 (1 nM) according to the present invention on 5-HT-induced Cai 2+ release in live h5-HT2CR-CHO cells. [Figure 7-3] Sections O to V of FIG. 7 are graphs of concentration-response curves of Compounds 20 to 27 (1 nM) according to the present invention on 5-HT-induced Cai 2+ release in live h5-HT2CR-CHO cells. [Figure 7-4] Sections W to Y of FIG. 7 are graphs of concentration-response curves of Compounds 28 to 30 (1 nM) according to the present invention on 5-HT-induced Cai 2+ release in live h5-HT2CR-CHO cells. [Figure 8-1] Sections A-F of FIG. 8 are graphs of concentration-response curves of selected compounds according to the invention (1 nM) on 5-HT-induced Cai 2+ release in live h5-HT2AR-CHO cells. [Figure 8-2] Sections G-J of FIG. 8 are graphs of concentration-response curves of selected compounds according to the invention (1 nM) on 5-HT-induced Cai 2+ release in live h5-HT2AR-CHO cells. [Figure 9] Sections A-F of FIG. 9 are graphs of concentration-response curves of selected compounds according to the invention (1 nM) on 5-HT-induced Cai 2+ release in live h5-HT2BR-CHO cells. [Figure 10]Figures 10A and 10B are graphs of concentration-response curves of selected compounds according to the present invention (1 nM) on 5-HT-induced Cai 2+ release in live h5-HT2CR-CHO cells (Figure 10A) and h5-HT2AR-CHO cells (Figure 10B), respectively. [Figure 11] Figures 11A and 11B are graphs of concentration-response curves of selected compounds according to the invention (1 nM) on 5-HT-induced Cai 2+ release in live h5-HT2CR-CHO cells (Figure 11A) and h5-HT2AR-CHO cells (Figure 11B), respectively. [Figure 12] 12A and 12B are the 1H NMR spectrum and the 13C NMR spectrum of compound 13 (JPC0323) according to the present invention, respectively. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0004] All publications mentioned herein, to the extent they support the present invention, are incorporated by reference.

[0005] 1.0 Definition For the purposes of promoting an understanding of the principles of the invention, reference will now be made to certain specific embodiments and specific language will be used to describe them, but it will be understood that the scope of the invention is not intended to be limited by the embodiments, and that variations and modifications of the invention described, and further applications of the principles of the invention described therein, as would normally occur to one skilled in the art to which the invention pertains, are contemplated herein. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains.

[0006] For purposes of interpreting this specification, the following definitions shall apply, and where appropriate, terms used in the singular shall include the plural and vice versa. In the event that any definition set forth below conflicts with the usage of such word in any other document, including any document incorporated herein by reference, the definition set forth below shall always control for purposes of interpreting this specification and the accompanying claims, unless a contrary meaning is clearly intended (e.g., in the document in which the term is originally used). The use of "or" means "and / or" unless otherwise stated.

[0007] In this specification, the use of "a" means "one or more" unless specifically stated otherwise or unless the use of "one or more" is clearly inappropriate. The terms "comprise," "comprises," "comprising," "include," "includes," and "including" may be used interchangeably and are not intended to be limiting. Furthermore, when the term "comprising" is used in describing one or more embodiments, one of ordinary skill in the art will understand that in some specific instances, the embodiment(s) may alternatively be described using the terms "consisting essentially of" and / or "consisting of." As used herein, the term "about" refers to a ±10% variation from the set value. It is understood that such a variation is always included in any value provided herein, whether or not it is specifically referred to.

[0008] The term "pharmaceutical acceptable salt" refers to a salt of a compound of the present invention that is suitable for use in contact with the tissues of a patient without undue toxicity, within the scope of sound medical judgment. As used herein, the term "pharmaceutical acceptable salt" can include acetate, hydrobromide, hydrochloride, sulfate, bisulfate, nitrate, acetate, oxalate, valerate, oleate, palmitate, stearate, laurate, borate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthylate, mesylate, glucoheptonate, lactobionate, laurylsulfonate, and the like (see SM Barge et al., "Pharmaceutical Salts," J. Pharm. Sci., 66: 1-19 (1977), which is incorporated herein by reference in its entirety for further examples of pharmaceutical acceptable salts).

[0009] The term "HBTU" refers to 3-[bis(dimethylamino)methyliumyl]-3H-benzotriazole-1-oxide hexafluorophosphate (also known as 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate). The term "HOBt" refers to the following structure known as 1-hydroxybenzotriazole (including its hydrates and polymorphs):

[0010] [ka]

[0011] The term "DIEA" refers to N,N-diisopropylethylamine (also known as Hunig's base, DIPEA, and ethyldiisopropylamine). The term "DCM" refers to dichloromethane (also known as methylene chloride). The term "TFA" refers to trifluoroacetic acid. The term "rt" refers to room temperature.

[0012] The term "alkyl" as used herein alone or as part of another group refers to both straight and branched chain radicals, as well as cyclic alkyl groups. In one embodiment, the alkyl group has 1-12 carbons. In another embodiment, the alkyl group has 1-7 carbons. In another embodiment, the alkyl group has 1-6 carbons. In another embodiment, the alkyl group has 1-4 carbons. The term "alkyl" can include methyl, ethyl, propyl, isopropyl, butyl, t-butyl, isobutyl, pentyl, hexyl, isohexyl, heptyl, 4,4-dimethylpentyl, octyl, 2,2,4-trimethylpentyl, nonyl, decyl, undecyl, and dodecyl.

[0013] The term "heteroalkyl", alone or in combination with another term, unless otherwise stated, means a straight or branched chain having at least one carbon atom and at least one heteroatom selected from the group consisting of O, N, S, P, and Si. In certain embodiments, the heteroatom is selected from the group consisting of O and N. The heteroatom(s) can be located at any interior position of the heteroalkyl group or at the position where the alkyl group is attached to the remainder of the molecule. Up to two heteroatoms may be consecutive. As used herein, the term "alkylene" refers to straight and branched chain alkyl linking groups, i.e., an alkyl group that links one group to another within a molecule. In some embodiments, the term "alkylene" refers to -(CH) n -, in which case n is 2 to 8.

[0014] The term "aryl" refers to a polyunsaturated hydrocarbon substituent. Aryl groups can be monocyclic or polycyclic (e.g., fused or covalently linked 2 or 3 rings). Non-limiting examples of aryl and heteroaryl rings are phenyl, naphthyl, pyranyl, pyrrolyl, pyrazinyl, pyrimidinyl, pyrazolyl, pyridinyl, furanyl, thiophenyl, thiazolyl, imidazolyl, isoxazolyl, and the like. As used herein, the term "heteroaryl" refers to a group having 5 to 14 ring atoms, with 6, 10, or 14 7π electrons shared in a cyclic arrangement, containing carbon atoms and 1, 2, or 3 oxygen, nitrogen, or sulfur heteroatoms. Heteroaryl groups can be attached to the remainder of the molecule through a carbon or heteroatom. Particularly preferred heteroaryl groups include 1,2,3-triazole, 1,2,4-triazole, 5-amino 1,2,4-triazole, imidazole, oxazole, isoxazole, 1,2,3-oxadiazole, 1,2,4-oxadiazole, 3-amino-1,2,4-oxadiazole, 1,2,5-oxadiazole, 1,3,4-oxadiazole, pyridine, 2-aminopyridine, 4-aminopyridine, 2-aminoimidazoline, and 4-aminoimidazoline.

[0015] An "amino" group refers to an --NH2 group. An "amido" group refers to a -CONH group. An alkylamido group refers to a -CONHR group, where R is as defined above. A dialkylamido group refers to a -CONRR' group, where R and R' are as defined above. The terms "halogen" or "halo" as used herein alone or as part of another group refer to chlorine, bromine, fluorine, or iodine. The terms "hydroxy" or "hydroxyl" as used herein alone or as part of another group refer to an --OH group. An "alkoxy" group refers to an -O-alkyl group, where "alkyl" is defined above. In one embodiment, the alkyl group has 1-12 carbons. In another embodiment, the alkyl group has 1-7 carbons. In a further embodiment, the alkyl group has 1-6 carbons. In another embodiment, the alkyl group has 1-4 carbons. A "thio" group refers to a -SH group. An "alkylthio" group refers to a -SR group, where R is alkyl as defined above.

[0016] Unless otherwise noted, the term "heterocycle" or "heterocyclic ring" as used herein refers to a stable 5- to 7-membered monocyclic or stable 7- to 11-membered bicyclic heterocyclic ring system, any ring of which may be saturated or unsaturated and consists of carbon atoms and one to three heteroatoms selected from the group consisting of N, O, and S, the nitrogen and sulfur heteroatoms being optionally oxidized, and the nitrogen heteroatom being optionally quaternized, including any bicyclic group in which any of the heterocyclic rings defined above are fused to a benzene ring. The ring may contain one oxygen or sulfur, one to three nitrogen atoms, or a combination of one oxygen or sulfur and one or two nitrogen atoms. The heterocyclic ring may be attached at any heteroatom or carbon atom that results in the creation of a stable structure.

[0017] The term "alkylamino," as used herein alone or as part of another group, refers to an amino group substituted with one alkyl group having from 1 to 6 carbon atoms. The term "dialkylamino," as used herein alone or as part of another group, refers to an amino group substituted with two alkyl groups, each having from 1 to 6 carbon atoms. The term "arylamine" or "arylamino" as used herein alone or as part of another group refers to an amino group substituted with an aryl group, as defined above. As used herein, the term "arylalkyl" refers to an alkyl group substituted with an aryl group, such as Ph-CH2-.

[0018] Various groups are described herein as substituted or unsubstituted (i.e., optionally substituted). Optionally substituted groups can include one or more substituents independently selected from halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, oxo, carbamoyl, alkyl, heteroalkyl, alkoxy, alkylthio, alkylamino, (alkyl)2amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl. In certain embodiments, the optional substituents may be further substituted with one or more substituents independently selected from halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl (-C(O)NR2), unsubstituted alkyl, unsubstituted heteroalkyl, alkoxy, alkylthio, alkylamino, (alkyl)2amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, unsubstituted cycloalkyl, unsubstituted heterocyclyl, unsubstituted aryl, or unsubstituted heteroaryl. Exemplary optional substituents include -OH, oxo (=O), -Cl, -F, Br, C 1~4 Alkyl, phenyl, benzyl, -NH2, -NH(C 1~4 alkyl), -N(C 1~4 alkyl)2, -NO2, -S(C 1~4 Alkyl), -SO2(C 1~4 alkyl), -CO2(C 1~4 alkyl), and -O(C 1~4 alkyl), but are not limited to.

[0019] As used herein, the term "hydroxyalkyl" refers to an alkyl group (as defined above) substituted with a hydroxy substituent. In certain embodiments, the hydroxyalkyl group may be optionally further substituted with additional hydroxy substituents to provide dihydroxyalkyl and trihydroxyalkyl groups, including, for example, C1-C6 dihydroxyalkyl and C1-C6 trihydroxyalkyl groups. Exemplary hydroxyalkyl groups with additional hydroxy substituents can include, but are not limited to, -CH2CH(OH)CH2OH and -CH2CH(OH)CH(OH)CH3.

[0020] 2.0 Abbreviations Serotonin, 5-HT; 2A Receptor, 5-HT 2A R;5-HT 2B Receptor, 5-HT 2B R;5-HT 2C Receptor, 5-HT 2C R; serotonin 5-HT2 receptor, 5-HT2R; positive allosteric modulator, PAM; central nervous system, CNS; G protein-coupled receptor, GPCR; cocaine use disorder, CUD; d-lysergic acid diethylamide, LSD; major depressive disorder, MDD; lipophilic tail, LT; polar head, PH; extracellular loop 2, ECL2; structure-activity relationship, SAR; N,N,N',N'-tetramethyl-O-(1H-benzotriazol-1-yl)uronium hexafluorophosphate, HBTU; 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride, EDCI; N,N-diisopropylethylamine, DIPEA; trifluoroacetic acid, TFA; preparative thin layer chromatography, PTLC; phospholipase Cβ, PLCβ; intracellular calcium, Ca i 2+ ;Chinese hamster ovary, CHO;Maximum 5-HT-induced Ca i 2+ Emission, E max;negative allosteric regulator, NAM;National Institute of Mental Health, NIMH;psychoactive drug screening program, PDSP;multiparameter optimization, MPO;P-glycoprotein, P-gp;pharmacokinetics, PK;induced fit docking, IFD;ultra-precise, XP;standard precision, SP;extracellular loop, ECL;transmembrane helix, TM;human delayed rectifier potassium channel gene, hERG;half-life, T 1 / 2 .

[0021] 3.0 Compound Identifiers In some places herein, compound identifiers are included with numerical identifiers (e.g., 1, 2, 3...30), and in some other places herein, equivalent structures are referred to with alphanumeric identifiers. These compound identifiers are used interchangeably herein, according to the list of equivalent compound identifiers below.

[0022] [Table 1]

[0023] 4.0 Serotonin (e-HT) Receptors The structures of compounds 7-30 are shown in Figures 1A-1C using corresponding alphanumeric compound identifiers. Although the compounds in Figures 2-5 are shown with alphanumeric compound identifiers, these compounds are not necessarily referred to herein by their equivalent numerical identifiers. The substructures shown in Figure 6 are numbered according to compounds 7-30 and include substructures as substituents of the carboxamide nitrogen atom.

[0024] Fourteen serotonin (5-HT) receptors have been classified into one ionotropic receptor (5-HT3R) and one 5-HT 1~7Thirteen class A G protein-coupled receptors (GPCRs), designated 5-HT R, have been identified. The serotonin 5-HT2 receptor (5-HT2R) is a pharmacologically important member of the 5-HT receptor family, which is involved in the regulation of 5-HT 2A R, 5-HT 2B R, and 5-HT 2C R, which share approximately 80% sequence homology in their transmembrane (TM) ligand-binding domains. 2C R and 5-HT 2A 5-HT R has generated great interest among pharmacologists and medicinal chemists during the last decades. 2C R and 5-HT 2A R is widely distributed in the mammalian central nervous system (CNS) and mediates a variety of brain functions, including cognition, feeding, mood, learning, and memory.

[0025] These three 5-HT2R subtypes (5-HT 2A R, 5-HT 2B R, and 5-HT 2C 5-HT2R (5-HT2R) show similar molecular architectures and share highly conserved endogenous agonist (5-HT) binding sites, as well as intersecting signaling pathways and pharmacology. Conventional agonists target orthosteric ligand binding sites within the highly conserved seven-transmembrane bundle (7TM) of the receptor. Allosteric modulators that target distinct spatially and tissue distribution sites can provide a useful pharmacological paradigm for GPCR drug discovery. The design of allosteric modulators selectively targeting subtypes of 5-HT2R appears to be a feasible and realistic approach to avoid ligand binding to other 5-HT receptors and the serotonin reuptake transporter, and to selectively target 5-HT, which is believed to be associated with adverse effects in valvular heart disease and pulmonary hypertension. 2B This is particularly important in avoiding stimulation of R.

[0026] 5.1 Allosteric modulators of the 5-HT receptor Recent reports have identified 5-HT as an allosteric regulator of 5-HT2R, e.g.2C Certain compounds have been described, including positive allosteric modulators (PAMs) 1 to 5 of R. Compound 1 (PNU-69176E), a complex natural product derivative, was the first reported 5-HT 2C R PAMs and were characterized by conformation-dependent functional activity profiles.

[0027] Previous efforts to improve drug-like properties have included the preparation of analogs with changes in the α-D-galactopyranoside fragment, termed the polar head ("PH"), and an undecyl substituent at the 4-position of the piperidine, termed the lipophilic tail ("LT"). These efforts have resulted in the development of effective 5-HT 2C PAM2 (CYD-1-79) and 5-HT in R 2C These 5-HT 2C R PAMs have shown improved pharmacokinetic (PK) profiles in preclinical animal models and demonstrated in vivo activity. 2C As PAMs for R, N-benzyl-indole 4 (VA012) and piperazine-linked phenylcyclopropylmethanone 5 were prepared. Among them, compound 5 is a 5-HT 2B We also demonstrated the negative allosteric modulation (NAM) activity of R.

[0028] [ka]

[0029] Compound 6 [oleamide, (Z)-9-octadecenamide-], an endogenous fatty acid amide, has been identified in the cerebrospinal fluid of sleep-deprived cats and in human plasma. Compound 6 is involved in several biological and behavioral phenomena, such as sleep induction, conditioned place aversion, feeding regulation, and hypothermia. Oleamide 6 nonselectively inhibits 5-HT 1A R, 5-HT 2A R, 5-HT 2CIt has been noted that it acts as an agonist or allosteric modulator at 5-HT7R and as an inhibitor at 5-HT7R and other receptor systems.

[0030] Compound 7 is 5-HT 2C It shares the general features of a long LT and terminal PH with PAM2 (CYD-1-79) in R. The LT of 6 is longer than that of PAM2 (18-carbon tail vs. 15-carbon tail, respectively), but an energy-minimized overlay of 2 and 7 (an analog of 6 with a 1,2-diol PH fragment) suggests that the tail lengths may be similar in maximum length, depending on the conformation, due to the cis conformation of the double bond (17.98 Å vs. 17.78 Å).

[0031] compound In certain embodiments, the present invention provides a compound represented by formula I:

[0032] [ka]

[0033] or a pharma- ceutically acceptable salt thereof, During the ceremony, R 1 , R 2 , and R 3 is independently selected from H, substituted or unsubstituted aryl, heteroaryl, arylalkyl, heteroarylalkyl, carbonyl, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 alkoxy, C1-C6 hydroxyalkyl, C1-C6 ester, and heterocyclyl; R 4 is selected from H, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, arylalkyl, and heteroarylalkyl; X is -CH2CH2-, -CH=CH-,

[0034] [ka]

[0035] and is selected from the group consisting of R 5 is selected from H, C1-C6 alkyl, and arylalkyl; m is 0 to 20; n is 1 to 20.

[0036] In certain embodiments, the present invention provides a compound of formula (Ia): R 4 -(CH2) m -X-(CH2) n -C(=O)NH-(PH) Formula (Ia) or a pharma- ceutically acceptable salt thereof, During the ceremony, R 4 is selected from H, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, arylalkyl, and heteroarylalkyl; X is -CH2CH2-, -CH=CH-,

[0037] [ka]

[0038] is selected from the group consisting of R 5 is selected from H, C1-C6 alkyl, and arylalkyl; m is 0 to 20; n is 1 to 20; (PH) is any of the groups depicted in FIG.

[0039] In another aspect, the present invention provides a compound of formula (II):

[0040] [ka]

[0041] or a pharma- ceutically acceptable salt thereof, In the formula, R1 , R 2 , R 3 is independently selected from H, substituted or unsubstituted aryl, heteroaryl, arylalkyl, heteroarylalkyl, carbonyl, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 alkoxy, C1-C6 hydroxyalkyl, and C1-C6 ester; R 6 is selected from H, NO2, amino, CF3, halogen, alkyl, or alkoxy; R 7 is H or NR 8 R 9 and R 8 , R 9 is independently selected from H, alkyl, aryl, arylalkyl, cycloalkyl, alkoxy, and heteroalkyl; or R 8 , R 9 forms a five- or six-membered ring together with other atoms, X, Y, and Z are independently selected from CH and N; n is 1 to 7.

[0042] In some embodiments, the present invention provides a compound represented by formula (II-(R)) (also referred to herein as formula (IIa)) and formula (II-(S)) (also referred to herein as formula (IIb):

[0043] [ka]

[0044] or a pharma- ceutically acceptable salt thereof, The names of formula (II-(R)) and formula (II-(S)) are -NR 8 R 9 These refer to the R and S configurations at the chiral central carbon bonded to

[0045] How to use In some aspects, the present invention relates to a method of treating a disease or condition comprising administering to a patient a therapeutically effective amount of a compound of Formula (I), Formula (Ia), Formula (II), Formula (IIa), and Formula (IIb), or a combination thereof, or a pharma- ceutically acceptable salt thereof. In some embodiments, the treatment of the disease or condition involves modulation of the 5-hydroxytryptamine 2A receptor and / or the 5-hydroxytryptamine 2C receptor. In some embodiments, the above diseases or conditions can be treated by modulating the 5-hydroxytryptamine 2A receptor and / or the 5-hydroxytryptamine 2C receptor.

[0046] In some embodiments, the method includes using one or more compounds selected from any of Formula (I), Formula (Ia), Formula (II), Formula (IIa), and Formula (IIb), or a pharma- ceutically acceptable salt thereof, to modulate the 5-hydroxytryptamine 2A receptor and / or the 5-hydroxytryptamine 2C receptor. In some embodiments, the disease or condition is a substance use disorder, a psychiatric or neurological disorder, obesity, a mood disorder, or a seizure disorder.

[0047] It is understood that both of the foregoing descriptions are illustrative and therefore not limiting of the scope of the present invention. EXAMPLES

[0048] The following examples are provided only to illustrate the invention and are not intended to limit the scope of the invention described herein. The description of the preparation of certain compounds of the present invention is meant to exemplify certain embodiments of the present invention. The reagents and reactants used in the synthetic transformations outlined herein and below are merely exemplary. The present invention contemplates the use of the same or different reagents as those discussed herein to achieve the preparation of the compounds of the present invention.

[0049] Example 1 - Synthesis of Oleamide Analogues Certain compounds of formula I, such as oleamide analog 7 to oleamide analog 30, can be prepared according to Scheme 1. Effective and convenient one-step coupling of oleic acid, a long-chain unsaturated omega-9 fatty acid, with various amino alcohol analogs, amino acid residues, or monoamine-like fragments was performed by adapting the common condensing agents N,N,N',N'-tetramethyl-O-(1H-benzotriazol-1-yl)uronium hexafluorophosphate (HBTU) or 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI) in combination with 1-hydroxybenzotriazole and organic base N,N-diisopropylethylamine (DIPEA). Compounds 16 to 19 were subjected to saponification according to standard protocols to obtain the corresponding carbonyl acids Compounds 20 to 23. Compounds 7 to 30 achieved yields of 42% to 94%, which were then subjected to in vitro functional evaluation.

[0050] Scheme 1. Synthesis of oleamide analogue 7 to oleamide analogue 30

[0051] [ka]

[0052] The reagents and reactants used in the synthetic transformations outlined herein and below are merely exemplary, and the invention contemplates the use of reagents the same or different from those discussed herein to achieve the preparation of the compounds of the invention.

[0053] Summary. All commercially available reaction reagents and solvents were reagent grade and used directly. Preparative column chromatography was performed using silica gel 60, particle size 0.063 mm to 0.200 mm (70 mesh to 230 mesh, flash). Analytical TLC was performed using silica gel 60 F254 plates (Merck, Darmstadt). NMR spectra were obtained using a Bruker-600 ( 1 H, 600MHz; 13C, 150MHz) spectrometer or Bruker-300( 1 H, 300MHz; 13 C, 75 MHz). 1 H and 13 C NMR spectra were recorded using tetramethylsilane (TMS) as an internal standard. Chemical shifts are given in ppm and J values ​​in Hz. Melting points were obtained on a Thermo Scientific electrothermal digital melting point instrument. High-resolution mass spectra (HRMS) were performed on a Thermo Fisher LTQ Orbitrap Elite mass spectrometer. The parameters were as follows: nanoESI spray voltage was 1.8 kV, capillary temperature was 275 °C, resolution was 60000, and ionization was performed in positive mode. The purity of the final compounds was determined by a Shimadzu Corporation HPLC system (model CBM-20A LC-20AD SPD-20A UV / vis) under the following analytical conditions: Waters μBondapak C18 (300 mm × 3.9 mm); flow rate 0.5 mL / min; UV detection 254 nm and 210 nm; linear gradient from 30% aqueous acetonitrile (0.1% TFA) to 100% acetonitrile (0.1% TFA) over 20 min, followed by 30 min in the final solvent. All newly synthesized compounds were 1 H NMR, 13 Characterization was performed by C NMR, HRMS, and HPLC analyses. All biologically evaluated compounds were >95% pure.

[0054] General Procedure for the Synthesis of Compounds of the Invention As Exemplified by Oleamide Analog 7 through Oleamide Analog 30 To a solution of oleic acid (1.0 equiv.) in a solvent, such as dichloromethane (2 mL), HBTU (1.3 equiv.) or EDCI (1.5 equiv.) was added in combination with 1-hydroxybenzotriazole (1.5 equiv.) and stirred at room temperature, and then alcohol analogs, amino acid analogs, and monoamine-like fragments (1.1 equiv.) were added to the solution along with DIPEA (2.5 equiv.). The reaction mixture was stirred for another 8 hours, and the reaction was detected with potassium permanganate coloring agent using a TLC plate. After the reaction was completed, the solution was titrated with saturated aqueous ammonium chloride solution (10 mL) to quench the reaction, and then the mixture system was extracted with ethyl acetate (20 mL x 3), washed with water, brine, dried over anhydrous Na2SO4, and filtered. The organic solvent was concentrated under reduced pressure and purified on a silica gel column (DCM:MeOH = 99:1) to obtain the desired products 7 to 30.

[0055] N-(2,3-dihydroxypropyl)oleamide (7): Compound 7 (57 mg, 80%) was prepared as a white waxy material from oleic acid (0.20 mmol) following the general synthetic procedure for 7–30. 1 H NMR(300MHz,CDCl3) δ 6.13(s,1H), 5.36(h,J=4.0Hz,2H), 3.77(q,J=5.2Hz,1H), 3.57(t,J=4.1Hz,2H), 3.42(q,J=5.8Hz,2H), 2.23( t,J=7.6Hz,2H), 2.02(q,J=6.2Hz,4H), 1.64(t,J=7.4Hz,2H), 1.30(d,J=10.6Hz,20H), 0.89(t,J=6.4Hz,3H). 13 C NMR (75MHz, CDCl3) δ 175.3, 130.0, 129.7, 71.2, 63.6, 42.2, 36.6, 31.9, 29.8, 29.7, 29.5, 29.3, 29.2, 29.1, 27.22, 27.16, 25.7, 22.7, 14.1. C 21 H 41 NO3[M+H] + HRMS(ESI) calculated: 356.3159; measured: 356.3158.

[0056] N-(3-hydroxypropyl)oleamide (8): Compound 8 (25 mg, 52%) was prepared as a white solid from oleic acid (0.14 mmol) following the general synthetic procedure for 7–30. mp 63.0° C.–63.5° C.; 1 H NMR(300MHz,CDCl3) δ 5.91(s,1H), 5.43~5.30(m,2H), 3.64(t,J=5.6Hz,2H), 3.46~3.37(m,2H), 2.20(t,J=7.6Hz,2H) ), 2.02(q,J=6.2Hz,4H), 1.66(dt,J=14.6, 6.9Hz,4H), 1.42~1.18(m, 20H), 0.95~0.82(m, 3H). 13 C NMR(75MHz,CDCl3 / MeOD) δ 175.1, 129.9, 129.6, 59.1, 38.5, 36.5, 36.1, 36.0, 31.9, 31.8, 29.7, 29.6, 29.4, 29.23, 29.19, 29.1, 27.13, 27.10, 25.8, 22.6, 14.0. C 21 H 41 NO2[M+H] + HRMS(ESI) calculated: 340.3210; measured: 340.3352.

[0057] N-(2-hydroxyethyl)oleamide (9): Compound 9 (52 mg, 71%) was prepared as a white solid from oleic acid (0.27 mmol) following the general synthetic procedure for 7–30. mp 63.0° C.–63.5° C.; 1 H NMR(300MHz,CDCl3) δ 6.34(s,1H), 5.41~5.26(m, 2H), 3.70(t,J=4.9Hz,2H), 3.56(s,1H), 3.40(dd,J=10.2, 5.4Hz,2H), 2.2 4~2.15(m, 2H), 2.06~1.95(m, 4H), 1.73~1.51(m, 2H), 1.29(d,J=10.0Hz,20H), 0.88(t,J=6.7Hz,3H). 13C NMR (75MHz, CDCl3) δ 174.6, 130.0, 129.7, 62.1, 42.4, 36.6, 31.9, 29.8, 29.7, 29.5, 29.31, 29.28, 29.2, 27.21, 27.17, 25.7, 22.7, 14.1. C 20 H 40 NO2[M+H] + HRMS(ESI) calculated: 326.3054; measured: 326.3570.

[0058] (S)-N-(2,3-dihydroxypropyl)oleamide (10): Compound 10 (32 mg, 60%) was prepared as a white waxy material from oleic acid (0.15 mmol) following the general synthetic procedure for 7–30. 1 H NMR(300MHz,CDCl3) δ 6.44(t,J=6.1Hz,1H), 5.41~5.29(m,2H), 3.98(bs,1H), 3.85(s,1H), 3.76(t,J=5.2Hz,1H), 3.55(bs,2H), 3.40(tq,J=14. 1, 8.2, 6.8Hz, 2H), 2.22 (t, J=7.6Hz, 2H), 2.02 (q, J=6.4Hz, 4H), 1.77~1.54 (m, 2H), 1.40~1.19 (m, 20H), 0.93~0.84 (m, 3H). 13 C NMR (75MHz, CDCl3) δ 175.4, 130.0, 129.7, 71.1, 63.6, 42.1, 36.6, 31.9, 29.8, 29.7, 29.5, 29.32, 29.29, 29.2, 27.23, 27.18, 25.7, 22.7, 14.1. C 21 H 41 NO3[M+H] + HRMS(ESI) calculated: 356.3159; measured: 356.3154.

[0059] N-(1,3-dihydroxypropan-2-yl)oleamide (11): Compound 11 (58 mg, 60%) was prepared as a white wax from oleic acid (0.27 mmol) following the general synthetic procedure for 7–30. 1H NMR(300MHz,CDCl3) δ 6.69(d,J=7.9Hz,1H), 5.46~5.16(m,2H), 3.97~3.77(m,1H), 3.65(ddd,J=28.2, 11.3, 4.8Hz,4H), 2.86(s,2 H), 2.26~2.09(m, 2H), 2.07~1.85(m, 4H), 1.71~1.50(m, 2H), 1.26(d,J=9.6Hz,20H), 0.86(t,J=6.6Hz,3H). 13 C NMR (75MHz, CDCl3 / CD3OD) 13 C NMR(75MHz,CDCl3) δ 175.0, 130.0, 129.7, 61.7, 52.4, 52.3, 36.6, 36.5, 31.8, 29.71, 29.69, 29.5, 29.3, 29.2, 29.1, 27.2, 27.1, 25.7, 22.6, 14.0. C 21 H 41 NO3[M+H] + HRMS(ESI) calculated: 356.3159; observed: 356.3150.

[0060] N-((2S)-1,3-dihydroxy-1-phenylpropan-2-yl)oleamide (12): Compound 12 (61 mg, 94%) was prepared as an off-white waxy material from oleic acid (0.15 mmol) following the general synthetic procedure for 7–30. 1 H NMR(300MHz,CDCl3 / CD3OD) δ 7.41~7.14(m, 5H), 6.68~6.77(d,J=8.4Hz,1H), 5.39~5.25(m, 2H), 4.97(d,J=3.5Hz,1H), 4.08~3.99(m, 1H), 3.89(d,J=2.5Hz,2H), 3.63 (qd,J=11.1, 5.8Hz,2H), 2.08(t,J=7.3Hz,2H), 1.99(q,J=7.2Hz,4H), 1.44(p,J=7.4Hz,2H), 1.26(d,J=9.4Hz,20H), 0.92~0.78(m, 3H). 13C NMR(75MHz,CDCl3 / CD3OD) δ 175.0, 141.5, 129.9, 129.7, 128.1, 127.4, 125.7, 71.8, 62.2, 56.4, 56.3, 36.5, 3 6.4, 31.8, 29.69, 29.66, 29.4, 29.24, 29.19, 29.1, 29.0, 27.1, 25.7, 22.6, 14.0. C 27 H 45 NO3[M+H] + HRMS(ESI) calculated: 432.3472; observed: 432.3465.

[0061] N-(1,3-dihydroxy-2-(hydroxymethyl)propan-2-yl) (13): Compound 13 (73 mg, 94%) was prepared as a white wax from oleic acid (0.20 mmol) following the general synthetic procedure for 7–30. 1 H NMR(300MHz,CDCl3) δ 6.51(s,1H), 5.36(s,2H), 3.60(s,6H), 2.24(t,J=7.6Hz,2H), 2.02(d,J= 6.1Hz,4H), 1.62(s,2H), 1.30(d,J=11.4Hz,20H), 0.90(d,J=6.0Hz,3H). 13 C NMR (75MHz, CDCl3) δ 175.3, 130.0, 129.7, 61.8, 61.6, 37.0, 31.9, 29.7, 29.5, 29.3, 29.2, 29.1, 27.2, 25.8, 22.7, 14.1. C 22 H 44 NO4[M+H] + HRMS(ESI) calculated: 386.3265; measured: 386.3262.

[0062] N-(2,2-Diethoxyethyl)oleamide (14): Compound 14 (56 mg, 70%) was prepared as a colorless oil from oleic acid (0.20 mmol) following the general synthetic procedure for 7–30. 11H NMR (300 MHz, CDCl3) δ 5.78~5.65 (m, 1H), 5.41~5.25 (m, 2H), 4.50 (t, J = 5.2 Hz, 1H), 3.70 (dq, J = 9.6, 7.1 Hz, 2H), 3.53 (dq, J = 15.9, 6.8 Hz, 2H), 3.38 (t, J = 5.5 Hz, 2H), 2.17 (t, J = 7.6 Hz, 2H), 2.00 (q, J = 6.2 Hz, 4H), 1.62 (t, J = 7.4 Hz, 2H), 1.42~1.14 (m, 26H), 0.88 (t, J = 6.5 Hz, 3H). 13 13C NMR (75 MHz, CDCl3) δ 173.2, 130.0, 129.7, 100.8, 62.8, 41.9, 36.7, 31.9, 29.73, 29.68, 29.5, 29.3, 29.2, 29.1, 27.2, 27.1, 25.7, 22.6, 15.3, 14.1. C 24 H 47 NO3Na [M+Na] + The calculated value of HRMS (ESI) for [M+Na] is 420.3448; the measured value is 420.3446.

[0063] N-(2-(2-Hydroxyethoxy)ethyl)oleamide (15): Compound 15 (62 mg, 83%) was prepared as a colorless oil from oleic acid (0.20 mmol) according to the general synthetic procedure for 7~30. 1 1H NMR (300 MHz, CDCl3) δ 6.21~6.03 (m, 1H), 5.33 (q, J = 6.3 Hz, 2H), 3.82~3.69 (m, 2H), 3.57 (q, J = 4.4 Hz, 4H), 3.46 (q, J = 5.4 Hz, 2H), 2.59 (s, 1H), 2.18 (t, J = 7.6 Hz, 2H), 2.01 (q, J = 6.4 Hz, 4H), 1.63 (t, J = 7.4 Hz, 2H), 1.29 (d, J = 9.6 Hz, 20H), 0.88 (t, J = 6.3 Hz, 3H). 13 13C NMR (75 MHz, CDCl3) δ 173.5, 130.0, 129.7, 72.2, 70.0, 61.7, 39.2, 36.7, 31.9, 29.7, 29.5, 29.3, 29.1, 27.1, 25.7, 22.6, 14.1. C 22 H 44 NO3 [M+H] +HRMS(ESI) calculated: 370.3316; measured: 370.3314.

[0064] Methyl oleyl-L-allothreoninate (16): Compound 16 (113 mg, 68%) was prepared as a white solid from oleic acid (0.42 mmol) following the general synthetic procedure for 7–30. mp 63.0° C.–63.5° C. 1 H NMR(300MHz,CDCl3) δ 6.67~6.32(m, 1H), 5.47~5.10(m, 2H), 4.69~4.48(m, 1H), 4.33(s,1H), 3.74(s,3H), 3.26(s,1H), 2.27(t,J=7.6Hz) ,2H), 2.11~1.89(m, 4H), 1.79~1.51(m, 2H), 1.28(d,J=11.6Hz,20H), 1.19(d,J=6.4Hz,3H), 0.87(t,J=6.6Hz,3H). 13 C NMR(75MHz,CDCl3) δ 174.1, 171.7, 130.0, 129.7, 67.8, 57.3, 52.4, 38.6, 36.5, 31.9, 29.74, 29. 71, 29.5, 29.29, 29.27, 29.24, 29.15, 27.19, 27.16, 25.7, 22.6, 20.0, 14.1. C 23 H 43 NO4[M+H] + HRMS(ESI) calculated: 398.3265; measured: 398.3453.

[0065] Methyl oleyl-L-serinate (17): Compound 17 (100 mg, 62%) was prepared as a colorless oil from oleic acid (0.42 mmol) following the general synthetic procedure for 7–30. 1 H NMR(300MHz,CDCl3) δ 6.62(s,1H), 5.44~5.18(m, 2H), 4.77~4.54(m, 1H), 4.08~3.82(m, 2H), 3.78(s,3H), 3.36(s,1H), 2.3 3~2.15(m, 2H), 2.12~1.91(m, 4H), 1.78~1.51(m, 2H), 1.28(d,J=10.1Hz,20H), 0.88(t,J=6.6Hz,3H). 13C NMR(75MHz,CDCl3) δ 173.9, 171.1, 130.0, 129.7, 63.2, 54.6, 52.7, 36.4, 31.9, 29.8, 29.7, 29.5, 29.30, 29.26, 29.2, 29.1, 27.21, 27.17, 25.6, 22.7, 14.1. C 22 H 41 NO4[M+H] + HRMS(ESI) calculated: 384.3108; measured: 384.3457.

[0066] Methyl oleyl-L-tyrosinate (18): Compound 18 (143 mg, 74%) was prepared as a white solid from oleic acid (0.42 mmol) following the general synthetic procedure for 7–30. mp 71.5° C.–72.3° C.; 1 H NMR(300MHz,CDCl3) δ 7.16(s,1H), 6.95(d,J=8.5Hz,2H), 6.75(d,J=8.5Hz,2H), 6.05(d,J=8.0Hz,1H), 5.47~5.23(m,2H), 4.90(dt,J=8.0, 6.0Hz,1H), 3.75(s ,3H), 3.04(ddd,J=30.8, 14.0, 5.9Hz,2H), 2.29~2.11(m, 2H), 2.12~1.90(m, 4H), 1.71~1.48(m, 2H), 1.28(s,20H), 0.89(t,J=6.7Hz,3H). 13 C NMR(75MHz,CDCl3) δ 173.5, 172.5, 155.7, 130.2, 130.0, 129.8, 126.9, 115.6, 53.2, 52.4, 37.3, 36 .6, 31.9, 29.8, 29.7, 29.5, 29.3, 29.2, 29.1, 27.23, 27.19, 25.6, 22.7, 14.1. C 28 H 45 NO4[M+H] + HRMS(ESI) calculated: 460.3421; found: 460.3436.

[0067] Methyl oleyl-L-tryptophanate (19): Compound 19 (152 mg, 75%) was prepared as a yellow oil from oleic acid (0.42 mmol) following the general synthetic procedure for 7–30.1 H NMR(300MHz,CDCl3) δ 8.43(s,1H), 7.56(d,J=7.8Hz,1H), 7.37(d,J=8.0Hz,1H), 7.17(dtd,J=14.8, 7.1, 1.1Hz,2H), 6.98(d,J=2.4Hz,1H), 6.03(d,J=7.8Hz,1H), 5.49~5.24(m, 2H), 5.00(d t,J=7.9, 5.4Hz,1H), 3.71(s,3H), 3.34(dd,J=5.3, 1.4Hz,2H), 2.22~2.11(m, 2H), 2 .03(dd,J=7.8, 4.7Hz,4H), 1.69~1.50(m,2H), 1.30(s,20H), 0.91(t,J=6.7Hz,3H). 13 C NMR(75MHz,CDCl3) δ 172.9, 172.6, 136.2, 130.0, 129.8, 127.7, 122.7, 122.2, 119.6, 118.5, 111.3, 110.0, 52.9, 52 .3, 36.6, 31.9, 29.8, 29.7, 29.5, 29.34, 29.26, 29.2, 29.1, 27.7, 27.3, 27.2, 25.5, 22.7, 14.1. C 30 H 46 N2O3[M+H] + HRMS(ESI) calculated: 483.3581; observed: 483.3417.

[0068] Oleyl-L-allothreonine (20): Solid LiOH monohydrate (16.8 mg, 0.4 mmol) was added to a solution of 16 (40 mg, 0.10 mmol) in THF:HO; 3:1 (2 mL) at room temperature. The reaction mixture was stirred for 48 h and judged complete by TLC. The reaction mixture was neutralized with HCl and extracted with EtOAc (3×10 mL). The combined organic extracts were washed with brine (5 mL) and concentrated under reduced pressure to give 20 (25 mg, 66%) as a colorless gel. 1H NMR(600MHz,CDCl3) δ 6.99~6.71(bs,2H), 5.53~5.11(m, 2H), 4.52(d,J=6.9Hz,1H), 4.42(s,1H), 2.40~2.25(m, 2H), 2.1 0~1.89(m, 4H), 1.65(s,2H), 1.30(d,J=18.5Hz,20H), 1.22(d,J=5.2Hz,3H), 0.90(t,J=6.9Hz,3H). 13 C NMR(150MHz,CDCl3) δ 175.4, 174.3, 130.0, 129.6, 67.5, 57.7, 36.4, 31.9, 29.8, 29.6, 29.35, 29.32, 29.2, 27.24, 27.21, 25.8, 22.7, 19.4, 14.1. C 22 H 41 NO4[M+H] + HRMS(ESI) calculated: 384.3108; measured: 384.3166.

[0069] Oleyl-L-serine (21): Compound 21 (20 mg, 54%) was prepared as a white waxy material from 17 by a procedure similar to that used to prepare compound 20. 1 H NMR(300MHz,CDCl3) δ 5.31(td,J=4.7, 2.1Hz,2H), 4.52(t,J=3.8Hz,1H), 3.95(dd,J=11.6, 3.9Hz,1H), 3.80(dd,J=11.5, 3.7Hz,1H), 3.61( s, 3H), 2.25 (dt, J=10.4, 7.5Hz, 2H), 1.98 (q, J=6.3Hz, 4H), 1.71~1.50 (m, 2H), 1.38~1.18 (m, 20H), 0.94~0.78 (m, 3H). 13 C NMR(75MHz, CDCl3 / MeOD) δ 174.4, 172.7, 130.0, 129.7, 62.6, 36.3, 31.9, 29.71, 29.68, 29.5, 29.3, 29.24, 29.20, 29.1, 27.2, 25.5, 22.6, 14.0. C 21 H 39 NO4[M+H] + HRMS(ESI) calculated: 370.2952; observed: 370.2995.

[0070] Oleyl-L-tyrosine (22): Compound 22 (40 mg, 90%) was prepared as a white solid from 18 by a procedure similar to that used to prepare compound 20. mp 170.0°C - 170.5°C. 1 H NMR(600MHz,CDCl3) δ 6.90(d,J=8.0Hz,2H), 6.62(d,J=8.0Hz,2H), 5.41~5.11(m,2H), 4.38(s,1H), 3.94~3.59(bs,1H), 3.02~2.91( m, 1H), 2.90~2.74(m, 1H), 2.04~1.93(m, 6H), 1.44(d,J=6.2Hz,2H), 1.36~1.10(m, 20H), 0.85(t,J=7.0Hz,3H). 13 C NMR(150MHz,CDCl3 / MeOD) δ 177.9, 174.3, 155.3, 130.2, 129.9, 129.7, 128.3, 115.3, 56.1, 37.0, 36.4, 31.9, 29.7, 29.5, 29.30, 29.27, 29.2, 27.2, 25.7, 22.6, 14.0. C 27 H 43 NO4[M+H] + HRMS(ESI) calculated: 446.3265; observed: 446.3216.

[0071] Oleyl-L-tryptophan (23): Compound 23 (22 mg, 42%) was prepared as a white waxy material from 19 by a procedure similar to that used to prepare compound 20. 1 H NMR (300MHz, CDCl3) δ 8.42(s,1H), 7.57(d,J=7.8Hz,1H), 7.32(d,J=8.0Hz,1H), 7.19(t,J=7.2H z,1H), 7.11(t,J=7.2Hz,1H), 6.97(s,1H), 6.18(d,J=7.6Hz,1H), 5.46~5. 26(m, 2H), 4.92(dd,J=12.4, 5.4Hz,1H), 3.48~3.09(m, 2H), 2.12~1.93(m, 6H), 1.57~1.41 (m, 2H), 1.29 (s, 15H), 1.20 (s, 5H), 0.90 (t, J=6.7Hz, 3H). 13C NMR(75MHz,CDCl3) δ 175.5, 174.3, 136.1, 130.0, 129.8, 127.8, 123.3, 122.1, 119.7, 118.4, 111.5, 109.5, 53.6 , 36.4, 31.9, 29.8, 29.7, 29.6, 29.4, 29.3, 29.2, 29.1, 27.3, 27.2, 27.0, 25.4, 22.7, 14.1. C 29 H 44 N2O3[M+H] + HRMS(ESI) calculated value 469.3425; observed value 469.3500.

[0072] N-(4-hydroxybenzyl)oleamide (24): Compound 24 (40 mg, 69%) was prepared as a white solid from oleic acid (0.15 mmol) following the general synthetic procedure for 7–30. mp 71.5° C.–72.3° C. 1 H NMR(300MHz,CDCl3) δ 7.85~7.67(m, 1H), 7.14(d,J=8.5Hz,2H), 6.86(d,J=8.5Hz,2H), 6.03(t,J=5.5Hz,1H), 5.61~5.25(m, 2H), 4.39(d,J =5.6Hz,2H), 2.37~2.18(m,2H), 2.06(dd,J=7.9, 4.2Hz,4H), 1.79~1.61(m,2H), 1.34(s,20H), 0.95(t,J=6.7Hz,3H). 13 C NMR(75MHz,CDCl3) δ 173.8, 156.2, 130.0, 129.7, 129.20, 129.17, 115.8, 43.4, 36.8, 31.9, 29 .8, 29.7, 29.5, 29.32, 29.25, 29.2, 29.1, 27.23, 27.18, 25.8, 22.7, 14.1. C 25 H 41 NO2[M+H] + HRMS(ESI) calculated: 388.3210; observed: 388.3480.

[0073] N-(3,4-Dihydroxybenzyl)oleamide (25): Compound 25 (30 mg, 50%) was prepared as a colorless oil from oleic acid (0.15 mmol) following the general synthetic procedure for 7–30. 1 H NMR(300MHz,CDCl3) δ 6.93~6.79(m, 2H), 6.67(dd,J=8.1, 1.9Hz,1H), 6.17(t,J=5.7Hz,1H), 5.59~5.24(m, 2H), 4.34(d,J=5. 8Hz, 2H), 2.34~2.21(m, 2H), 2.15~1.95(m, 4H), 1.81~1.55(m, 2H), 1.34(s, 20H), 0.95(t,J=6.7Hz, 3H). 13 C NMR(75MHz,CDCl3) δ 174.4, 144.6, 144.3, 130.0, 129.8, 129.7, 119.7, 115.1, 114.9, 43.6, 36.8, 31 .9, 29.8, 29.7, 29.5, 29.3, 29.22, 29.19, 29.1, 27.23, 27.17, 25.8, 22.7, 14.1. C 25 H 41 NO3[M+H] + HRMS(ESI) calculated value 404.3159; measured value 404.3338.

[0074] N-(4-hydroxyphenethyl)oleamide (26): Compound 26 (24 mg, 42%) was prepared as a white waxy material from oleic acid (0.14 mmol) following the general synthetic procedure for 7–30. 1 H NMR(300MHz,CDCl3) δ 7.72(s,1H), 7.04(d,J=8.5Hz,2H), 6.94~6.74(m,2H), 5.83~5.68(m,1H), 5.49~5.25(m,2H), 3.52(q,J=6.9Hz,2H), 2.77(t,J=7.0Hz,2H), 2.25~2.14(m,2H), 2.13~1.97(m,4H), 1.77~1.53(m,2H), 1.32(s,20H), 0.93(t,J=6.7Hz,3H). 13C NMR(75MHz,CDCl3) δ 174.0, 155.4, 130.0, 129.7, 129.71, 129.66, 115.7, 41.0, 36.8, 34.8, 3 1.9, 29.8, 29.7, 29.5, 29.3, 29.2, 29.1, 27.23, 27.18, 25.8, 22.7, 14.1. C 26 H 43 NO2[M+H] + HRMS(ESI) calculated value 402.3367; measured value 402.3293.

[0075] N-(3,4-dihydroxyphenethyl)oleamide (27): Compound 27 (45 mg, 68%) was prepared as a white solid from oleic acid (0.14 mmol) following the general synthetic procedure for 7–30. mp 69.1° C.–71.0° C.; 1 H NMR(300MHz,CDCl3) δ 7.94(s,1H), 6.85(d,J=8.0Hz,1H), 6.79(d,J=2.0Hz,1H), 6.59(dd,J=8.0, 2.0Hz,1H), 5.86(t,J=5.1Hz,1H), 5.49~5.25(m,2H), 3.51(dd ,J=13.1,6.9Hz,2H), 2.72(t,J=7.1Hz,2H), 2.29~2.14(m,2H), 2.14~1.97(m,4H), 1.75~1.52(m,2H), 1.32(s,20H), 0.93(t,J=6.7Hz,3H). 13 C NMR(75MHz,CDCl3) δ 174.6, 144.5, 143.3, 130.4, 130.0, 129.7, 120.4, 115.5, 115.3, 41.0, 36.8, 34.9, 31. 9, 29.8, 29.7, 29.5, 29.33, 29.31, 29.21, 29.18, 29.1, 27.23, 27.18, 25.8, 22.7, 14.1. C 26 H 43 NO3[M+H] + HRMS(ESI) calculated: 418.3316; measured: 418.3624.

[0076] N-(2-morpholinoethyl)oleamide (28): Compound 28 (71 mg, 67%) was prepared as an off-white waxy material from oleic acid (0.27 mmol) following the general synthetic procedure for 7–30. 1 H NMR(300MHz,CDCl3) δ 5.99(s,1H), 5.44~55.26(m, 2H), 3.78~3.64(m, 4H), 3.37(q,J=6.0Hz,2H), 2.57~2.41(m, 6H), 2.19(t ,J=6.0Hz,2H), 2.08~1.94(m,4H), 1.73~1.54(m,2H), 1.30(d,J=11.9Hz,20H), 0.89(t,J=6.7Hz,3H). 13 C NMR(75MHz,CDCl3) δ 173.2, 130.0, 129.7, 66.9, 57.1, 53.3, 36.8, 35.5, 31.9, 29.8, 29.7, 29.5, 29.32, 29.29, 29.2, 27.22, 27.17, 25.8, 22.7, 14.1. C 24 H 46 N2O2[M+H] + HRMS(ESI) calculated: 395.3632; observed: 395.3628.

[0077] tert-Butyl (4-oleamidobutyl)carbamate (29): Compound 29 (73 mg, 81%) was prepared as a colorless oil from oleic acid (0.20 mmol) following the general synthetic procedure for 7–30. 1 H NMR(300MHz,CDCl3) δ 5.78(s,1H), 5.33(d,J=5.3Hz,2H), 4.66(s,1H), 3.26(q,J=6.2Hz,2H), 3.13(d,J=6.4Hz,2H), 2.16(t,J=7.6Hz,2H), 2 .08~1.94(m, 4H), 1.62(t,J=7.5Hz,2H), 1.51(d,J=4.5Hz,4H), 1.44(s,9H), 1.28(d,J=9.2Hz,20H), 0.93~0.83(m, 3H). 13C NMR(75MHz,CDCl3) δ 173.2, 156.1, 130.0, 129.7, 40.1, 39.0, 36.8, 31.9, 29.74, 29.70, 29.5 , 29.29, 29.25, 29.1, 28.4, 27.6, 27.20, 27.16, 26.7, 25.8, 22.7, 14.1. C 27 H 53 N2O3[M+H] + HRMS(ESI) calculated: 453.4051; measured: 453.4059.

[0078] tert-Butyl (4-oleamidomethyl)piperidine-1-carboxylate (30): Compound 30 (81 mg, 85%) was prepared as a colorless oil from oleic acid (0.20 mmol) following the general synthetic procedure for 7–30. 1 H NMR(300MHz,CDCl3) δ 5.59(t,J=6.1Hz,1H), 5.34(td,J=7.5, 4.7Hz,2H), 4.20~4.02(m, 2H), 3.15(s,2H), 2.68(t,J=12.8Hz,2H), 2.18(t,J=7.6Hz,2H), 2.02(q,J=6.7Hz,4H), 1.65(tt,J=8.3,4.3Hz,5H), 1.46(s,9H), 1.29(d,J=9.9Hz,20H), 1.19~1.09(m,2H), 0.89(t,J=6.5Hz,3H). 13 C NMR(75MHz,CDCl3) δ 173.3, 154.8, 130.0, 129.7, 79.4, 44.8, 43.6, 36.9, 36.4, 31.9, 29.8, 29.7, 2 9.5, 29.3, 29.24, 29.17, 29.13, 29.10, 28.4, 27.21, 27.16, 25.8, 22.7, 14.1. C 29 H 55 N2O3[M+H] + HRMS(ESI) calculated: 479.4207; observed: 479.4216.

[0079] Example 2: 5-HT-induced intracellular calcium (Ca i 2+ ) release Using a fluorescence-based assay to measure 5-HT-induced Cai 2+ The levels of the unedited (INI) human (h) isoform h5-HT were used as a measure of receptor activity. 2C Chinese hamster ovary (CHO) cells stably transfected with R (h5-HT 2C R-CHO cells), h5-HT 2A CHO cells stably transfected with R (h5-HT 2A R-CHO cells), or h5-HT 2B CHO cells stably transfected with R (h5-HT 2B R-CHO cells). i 2+ Ability to promote release (E max ) was confirmed and set as 100% response.

[0080] These assays were performed on unedited (INI) human h5-HT 2C Chinese hamster ovary (CHO) cells stably transfected with R (h5-HT 2C R-CHO cells) or human h5-HT 2A CHO cells stably transfected with R (h5-HT 2A R-CHO cells), or h5-HT 2B CHO cells stably transfected with R (h5-HT 2B The study was performed with h5-HT, h5-HT R-CHO cells, which were kindly provided by Drs. Kelly A. Berg and William P. C1arke (University of Texas Medical Science Center, San Antonio, TX). 2B R(CHO-Kl / 5-HT 2B R;h5-HT 2B h5-HT cells were purchased from GenScript (Piscataway, NJ). The cell growth environment was as follows: 37°C, 5% CO2, and 85% relative humidity. 2C R-CHO cells and h5-HT 2AR-CHO cells were cultured in GlutaMax-MEM medium (Invitrogen, Carlsbad, CA) containing 5% fetal bovine serum (Atlanta Biologicals, Atlanta, GA) and 100 μg / mL hygromycin (Mediatech, Manassas, VA). 2B R-CHO cells were cultured in Ham's F12 medium supplemented with 10% FBS and 200 μg / ml Zeocin (Thermo Fisher Scientific, Carlsbad, CA). All cells were passaged when they reached 80% confluency.

[0081] Ca i 2+ The release assay was carried out according to the following procedure. Specifically, cells (150 μL; passages 9 to 15) were cultured in optically clear, flat-bottom, black-walled 96-well culture plates at a density of 14,000 cells / well to 16,000 cells / well (FlexStation 3; Molecular Devices) or 30,000 cells / well (FLIPR) in serum-containing medium. TETRA After about 24 hours, the medium was replaced with serum-free (SF) GlutaMax-MEM medium (h5-HT 2C R-CHO cells and h5-HT 2A R-CHO cells) or serum-free Ham's F12 (h5-HT) supplemented with 20 nM to 100 μM putrescine (Sigma-Aldrich, St. Louis, MO), 20 nM to 100 μM progesterone (Sigma-Aldrich), and 1:100 ITS (1000 mg / L human recombinant insulin, 550 mg / L human recombinant transferrin, 0.67 mg / L selenium acid; Corning Inc., Corning, NY). 2B After a further 3 hours of incubation, the medium was replaced with h5-HT 2C R-CHO cells and h5-HT 2AThe SF+ medium for R-CHO cells was replaced with 40 μL of Hank's Balanced Salt Solution (HBSS; no CaCl2 or MgCl2, pH 7.4) and 40 μL of calcium 6 dye solution (FLIPR No-wash kit, Molecular Devices, Sunnyvale, CA) supplemented with 2.5 mM water-soluble probenecid (Sigma-Aldrich), and the plates were then incubated with the dye solution in the dark for 2 h at 37°C, followed by 15 min at room temperature. 2B For R-CHO cells, calcium 6 dye was incubated as above in the presence of serum-free Ham's F12 medium supplemented with progesterone, putrescine, and ITS. Drugs were diluted 5-fold in 1x HBSS, and controls included diluent at the same final concentration. Compound delivery (20 μL / well) was 15 min prior to addition of 5-HT (10 pM-100 μM; 25 μL / well), and a baseline was established for each well prior to addition of compound and 5-HT. Fluorescence measurements were then taken to measure 5-HT-induced Ca i 2+ To evaluate allosteric regulation of release, FlexStation 3 (Molecular Device) or FLIPR was used. TETRA Fluorescence was measured using a 240-second exposure time (gain 80-130, intensity 80%, exposure 0.3 seconds). For the FlexStation 3, compounds were added after establishing a 17-second baseline, and fluorescence was recorded every 1.7 seconds thereafter for 240 seconds. The maximum peak height for each well was determined by SoftMax software (Pro5.4.5). TETRA For 5-HT, compounds were added after establishing a 10 s baseline, and then fluorescence was recorded every 1 s for 120 s after compound and 360 s after 5-HT. The maximum peak height for each well was determined by ScreenWorks4.0 software. After the last measurement, cells were fixed overnight with 2% paraformaldehyde (Sigma). 5-HT-induced Ca in the presence of test compounds i 2+ Maximum Emission (E maxA four-parameter nonlinear regression analysis (GraphPad Prism7) was used to determine the E of 5-HT plus test compound, calculated from four to six biological replicates, each performed with three technical replicates. max E of 5-HT alone max Subsequently, a Welch unpaired t-test (GraphPad prism) was performed on E max were used for post-hoc comparisons of means. All statistical analyses were performed with an experimental error rate of α = 0.05. All treatment allocations were blinded to the investigators performing the in vitro assays and endpoint statistical analyses.

[0082] In previous studies, 5-HT 2C PAM2 in R inhibits 5-HT-induced Ca at a concentration of 1 nM. i 2+ Compounds 7 to 30 were therefore screened at 1 nM in the presence of increasing concentrations of 5-HT to demonstrate an increased upregulation of 5-HT-induced Ca release. i 2+ Release (E of 5-HT max At 1 nM, all test compounds inhibited h5-HT when applied 15 min prior to the addition of 5-HT. 2C R-CHO cells, h5-HT 2A R-CHO cells, or h5-HT 2B In R-CHO cells, Ca i 2+ The antibodies did not exhibit any intrinsic agonist activity to induce release (for details, see Figure 7, sections A-Y; Figure 8, sections A-J; Figure 9, sections A-F).

[0083] Without wishing to be limited to any particular theory, certain PH fragments may aid in the formation of interactions with ECL2 and certain TM helices of the receptor. Compounds 7 to 30, which have different PHs, were used to inhibit h5-HT in vitro. 2CThe results were screened in R-CHO cells (Table 1). Under these test conditions, oleamide (6) inhibited the 5-HT-induced Ca i 2+ 7, which has the same 1,2-diol pH as 2 and 3, showed a moderate increase in release (about 11%), but 2C R-induced Ca i 2+ (Table 1; Figure 7). Elimination of the central hydroxyl group of 7 yielded the less bulky oleylpropanolamide 8, which inhibited the 5-HT-induced Ca i 2+ Compound 9, which has an ethanolamide pH, promoted the release of 5-HT 2C The PAM activity of R was maintained (Table 1 ; Fig. 1A ).

[0084] Compound 2 is 5-HT 2C To demonstrate conformational preference for the PAM activity of R, compound 10 was next explored by introducing a 1,2-diol in the S configuration to the amide, but it was found to be not very active (Table 1). This suggests that the pH of the 1,2-diols in 2 and 3 is higher than that of 5-HT. 2C It was suggested that the oleamide derivatives that produce the PAM activity of R are less favorable. Compound 11, which has a 1,3-diol moiety for the PH of 1,2-diol, suppresses the 5-HT 2C R-induced Ca i 2+ Compound 12, which incorporates a phenyl group at the diol PH of 11, promoted an increase in 5-HT, as did compound 13, which has an additional hydroxymethyl group at 11 (Table 1; Figure 11A). 2C Compound 14, which contains an etherified hydroxyl group, did not elicit PAM activity (Table 1), possibly due to the lack of a terminal H-bond donor and the high bulk volume of PH. At the same time, elongation of the PH of 9 by etherification with another ethanol fragment was less favorable (15, Figure 3A). These findings suggest that 5-HT 2CWe suggest that the hydroxyl-containing moiety may be important for the allosteric enhancement of R and that an appropriately sized PH may be essential for the allosteric enhancement of 5-HT 2C It was suggested that this may be useful for the PAM activity of R.

[0085] As for some other novel compounds according to the present invention, chiral amino acids (16-23), terminal phenols (24 and 26), catechols (25 and 27), morpholinos (28), or amino (29 and 30) substituted alkylamines are capable of isolating 5-HT 2C The compounds showed mixed properties, including inactivity or allosteric enhancement of 5-HT at R (Table 1). 2C To enhance the PAM activity of R, hydroxyl- or terminal phenol-containing chiral amino acids were applied by condensation of the methyl esters of threonine, serine, and tyrosine to obtain compounds 16 to 18. Among them, compound 16 (Table 1; Figure 10A) was able to enhance the PAM activity of R by isolating 5-HT 2C Compound 19 (Table 1; Figure 11A), which introduced the indole-like tryptophan methyl ester of 5-HT to the terminal position of PH, showed 125.4% of the 5-HT-induced E max Saponification of this methyl ester afforded the free acids 20 to 23. However, these carbonyl acid derivatives 20 to 23 did not enhance the effect of 5-HT at 1 nM (Table 1). Furthermore, both the 4-aminoalkylphenol and catechol moieties were explored as possible PHs (24 to 27). The terminal phenolic compound 25, which has a PH of 4-aminomethylcatechol, enhanced the effect of 5-HT. 2C Although other terminal phenolic compounds with fewer phenolic hydroxyls or chains spaced with more carbons promoted the PAM activity of R (Table 1; Fig. 10A), 5-HT 2C The two-carbon-spaced morpholino compound (28) did not show any PAM effect for R (4-aminoalkylphenols 24, 26, and the two-carbon-spaced catechol 27, Table 1). When an aliphatic amine was used as the PH, the two-carbon-spaced morpholino compound (28) did not show any PAM effect for 5-HT 2CAlthough the PAM activity of R was demonstrated (Table 1; Figure 11A), the n-butylamine compound (29) with a bulky amine terminus did not show any activity against 5-HT 2C Surprisingly, when 4-(aminomethyl)piperidine was introduced into the terminal of oleamide, it did not induce the PAM effect of 5-HT 2C R-mediated Ca i 2+ A comparable decrease in release of approximately 10% was observed, indicating its potential to function as a negative allosteric regulator (NAM) relative to 30 (Table 1).

[0086] [Table 2]

[0087] [Table 3]

[0088] [Table 4]

[0089] [Table 5]

[0090] a Addition of synthetic compounds (1 nM) inhibited h5-HT 2C Increasing the concentration of 5-HT in R-CHO cells (vehicle, 10 -11 M~10 -6 M) Ca i 2+ The data were collected 15 min before the assessment of 5-HT-induced Ca release. i 2+ Emission (E max ) * p<0.05. maxComparisons of means were performed using unpaired t-tests with Welch's correction (GraphPad Prism). All statistical analyses were performed with an experiment-specific error rate of α = 0.05.

[0091] In Figures 10A and 10B, h5-HT 2C R-CHO cells (10A) or h5-HT 2A 5-HT-induced Ca in R-CHO cells (10B) i 2+ Concentration-response curves for Ca release are shown for Compound 8, Compound 12, Compound 15, Compound 16, and Compound 25. Representative curves show concentration-response curves for 5-HT in the absence (closed circles) and presence (closed triangles) of test compound; vehicle (open circles); and test compound evaluated alone (open triangles). Maximum 5-HT-induced Ca release in the absence of test compound i 2+ The release was set as 100% and the E max are shown in Tables 1 and 2.

[0092] Example 3: 5-HT-induced Ca i 2+ release 5-HT 2C A subset of 10 oleamide-like compounds characterized as PAMs of R (Table 1) were identified using h5-HT 2A In vitro Ca using R-CHO cells i 2+ This was further evaluated in an efflux assay (Table 2). 2A After screening these 10 analogs at 1 nM in R-CHO cells, compounds with two pharmacological profiles were identified. 2C Compounds 8, 12, 15, 16, and 25, which were identified as PAMs of R (Table 1; Fig. 10A), acted to inhibit 5-HT 2A R did not show any effect as an allosteric regulator (Table 2; Fig. 10B). 2C Compounds 9, 11, 13, 19, and 28, which were identified as PAMs of R (Table 1; FIG. 11A), acted on 5-HT 2AThe effect of 5-HT R as a PAM was shown (Table 2; Fig. 11B). 2C PAM (8, 12, 15, 16, and 25) and 5-HT 2C R / 5-HT 2A Dual PAMs of R (9, 11, 13, 19, and 28) were distinguished within the present series of oleamide-like compounds.

[0093] Compound 9, which has a hydroxyethyl PH, is a 5-HT 2A Compounds 11 and 13, which have a second and third hydroxymethyl group at the PH of 9, respectively, showed PAM activity against 5-HT 2A The allosteric effect of R was maintained (Table 2; Fig. 11B). This result indicates that the introduction of hydroxy moieties spaced two carbons apart enhances the allosteric effect of 5-HT 2A It was suggested that compound 19, which has methyltryptophan as the PH, and compound 28, which has a two-carbon linked morpholino PH, may be favorable for generating the PAM activity of 5-HT. 2A R acted as a PAM for 5-HT by extending the linker length of 9 by one more carbon (8), by etherification with another ethanol fragment (15), or by retaining the 1,3-diol moiety of 11 and adding a phenyl (12). 2A Compounds 16 and 25, which have longer pH values ​​as methylthreonine and 4-aminomethylcatechol, did not result in PAM activity of 5-HT 2A R did not result in PAM activity (Table 2). 2A The structure of the PAM in R is 5-HT 2C These results suggest that 5-HT may be more susceptible to changes in length and volume than PAM of R (Tables 1 and 2). 2C R PAMs 8, 12, 25, and 5-HT 2C R / 5-HT 2A R's dual PAM 9, 11, 13, h5-HT 2BThese compounds were evaluated in an in vitro functional assay in R-CHO cells (Table 3; Figure 9). 2B R-induced Ca i 2+ did not show any change in β-amyloides activity, either alone or in the presence of 5-HT (Table 3).

[0094] [Table 6]

[0095] [Table 7]

[0096] a Addition of synthetic compounds (1 nM) inhibited h5-HT 2A Increasing the concentration of 5-HT in R-CHO cells (vehicle, 10 -11 M~10 -6 M) Ca i 2+ The data were collected 15 min before the assessment of 5-HT-induced Ca release. i 2+ Emission (E max ) * p<0.05. max Comparisons of means were performed using unpaired t-tests with Welch's correction (GraphPad Prism). All statistical analyses were performed with an experiment-specific error rate of α = 0.05.

[0097] In Figures 11A and 11B, raw h5-HT 2C R-CHO cells (A) or h5-HT 2A 5-HT-induced Ca in R-CHO cells (B) i 2+Concentration-response curves for release are shown for Compound 9, Compound 11, Compound 13, Compound 19, and Compound 28. Representative curves show test compound versus concentration-response curves for 5-HT in the absence (closed circles) and presence (closed triangles); vehicle (open circles); and vehicle in the presence of test compound (open triangles). Maximum 5-HT-induced Ca release in the absence of test compound i 2+ The release was set as 100% and the E max are shown in Tables 1 and 2.

[0098] [Table 8]

[0099] a Addition of synthetic compounds (1 nM) inhibited h5-HT 2B Increasing the concentration of 5-HT in R-CHO cells (vehicle, 10 -11 M~10 -6 M) Ca i 2+ The data were collected 15 min before the assessment of 5-HT-induced Ca release. i 2+ Emission (E max ) * p<0.05. max Comparisons of means were performed using unpaired t-tests with Welch's correction (GraphPad Prism). All statistical analyses were performed with an experiment-specific error rate of α = 0.05.

[0100] Example 4: In vitro radioligand binding displacement studies. 5-HT 2C R and 5-HT 2AConsidering their in vitro dual activity in R, compounds 11 and 13 were selected for further pharmacological evaluation as representative tool compounds of active analogs. To explore the off-target profile of these two compounds, the National Institute of Mental Health (NIMH) Psychotropic Drug Screening Program (PDSP) was used for evaluation on a broad panel of GPCRs and monoamine transporters (Table 4). 11 inhibited 5-HT 2C R showed an average inhibition of 78.5% (K i In general, compounds 11 and 13 did not exhibit off-target effects at most of the receptors and monoamine transporters evaluated, with the exception of compound 13, which inhibited 5-HT 2A 5-HT against R 2C R does not have any obvious orthosteric substitutions, which is why 5-HT 2A / 2C These results suggest that this is an important feature for the selectivity of PAMs for the H3 receptor. Compounds 11 and 13 did not displace the binding to the human delayed rectifier potassium ion channel gene (hERG) potassium channel, suggesting a low risk of adverse cardiac events. Compound 13 binds to the H3 receptor (K i = 5.3 μM) and σ2 receptors (K i = 3.6 μM) was characterized for micromolar displacement.

[0101] Example 5: In vivo pharmacokinetics and brain penetrance analysis Male Sprague-Dawley rats (n=3 / treatment group; Beijing Vital River Laboratory, Animal Technology Co., Ltd., Beijing, China) weighing 200g-250g at the start of the experiment were housed three per cage in a sterile, temperature-controlled (20°C-26°C) and humidity-controlled (40%-70%) environment with a 12-h light-dark cycle and food and filtered water available ad libitum. Rats were randomly assigned to treatment groups. Vehicle [10% dimethyl sulfoxide (DMSO) and 90% 2-hydroxypropyl-β-cyclodextrin (HP-β-CD); Cyclodextrin Technologies Development, Inc., High Springs, FL, USA] or compound 13 dissolved in vehicle were administered to rats ip at 10mg / kg or po at 20mg / kg. Blood samples (300 μL) were collected from the jugular vein before administration and at 0.08, 0.25, 0.5, 1.0, 2.0, 4.0, 8.0, and 24 hours after administration for ip administration and at 0.25, 0.5, 1.0, 2.0, 4.0, 8.0, and 24 hours after administration for po administration. These blood samples were placed in heparinized tubes and centrifuged at 6000 rpm for 5 minutes at 4°C. Brain samples were collected at 0.25 and 1 hour after administration. All samples were stored at -20°C. The concentration of 13 in each sample was analyzed by Sandia MediTech Co., Ltd. The PK parameters of compound 13 were calculated by a non-compartmental model using WinNonlin 8.1 (Pharsight Corporation, ver 5.3, Mountain View, CA, USA). Maximum concentration (C max ) and time to reach maximum concentration (T max ) was obtained directly from the plasma concentration-time profile. The elimination rate constant (λ) was obtained by least-squares fitting the terminal log-linear part of the slope of the plasma concentration-time profile. The elimination half-life (t 1 / 2 ) was evaluated by 0.693 / λ. The area under the plasma concentration-time curve from time 0 to time t (AUC 0-t) is evaluated using the linear trapezoidal method and then further to infinity (AUC 0-inf ), formula: AUC 0-inf =AUC 0-t +Clast / λ. These PK parameters and brain concentrations are presented as mean ± SEM.

[0102] Example 6: CNS multi-parameter optimization A central nervous system (CNS) multi-parameter optimization (MPO) value was calculated for compound 13. CNS MPO was employed to increase the probability of pre-designing a CNS-targeted molecule that achieves CNS exposure. The calculated score for compound 13 is 3.3 out of a total score range of 0-6. Notably, for this set of molecules, the predictive properties are inherently limited by the small number of structurally comparable molecules included in the training data set. It is suggested that higher MPO values ​​are desirable for CNS drugs.

[0103] [Table 9]

[0104] a The binding displacement study was performed with 10 μM of compound 13. A result of more than 50% binding inhibition was considered as a reliable displacement of the target receptor radioligand by the test compound. b K i Values ​​were calculated by nonlinear regression analysis of the radioligand competition isotherms for >50% inhibition of ligand binding. NT = not analyzed, Avg. = average K from replicate experiments. i .

[0105] Example 7: Toxicity Profile of Compound 13 In silico toxicity predictions were performed to evaluate compound 13 across a variety of toxicity endpoints, including acute toxicity, hepatotoxicity, cytotoxicity, carcinogenicity, mutagenicity, immunotoxicity, adverse outcomes (Tox21) pathways, and toxicity targets (Table 5). These results suggest that compound 13 exhibits a profile consistent with low predictive value for adverse drug reactions or toxic effects, and is classified as a non-toxic class VI (LD 50 >5000 mg / kg). CYP450 inhibition studies were then performed in human liver microsomes to evaluate the inhibitory potential of compound 13 (10 μM) against CYP450 isoforms (Table 5). Compound 13 showed 20% or less inhibition of CYP3A4, CYP1A2, CYP2C8, CYP2C19, CYP2D6, and CYP2C9, and greater than 50% inhibition of CYP2B6.

[0106] [Table 10]

[0107] a For information on in silico toxicity prediction, see http: / / tox.charite.de / protox II / . Cytochrome P450 enzyme inhibition assays for compound 13 were performed at 10 μM and expressed as percent inhibition. b Toxicity classes are ranked from 1 to 6, with 1=high and 6=low. c ER-LBD = estrogen receptor ligand-binding domain; AR-LBD = androgen receptor ligand-binding domain; PPAR-gamma = peroxisome proliferator-activated receptor gamma; Nrf2 / ARE = ​​nuclear factor (erythroid-derived 2)-like 2 / antioxidant response element; HSE = heat shock factor response element; MMP = mitochondrial membrane potential; ATAD5 = ATPase family AAA domain-containing protein 5. d CYP3A4 (midazolam). e CYP3A4 (testosterone).

[0108] Example 8: Pharmacokinetics (PK) of Compound 13 In vitro membrane permeability evaluation of compound 13 was performed in hMDRI-MDCKII cells to investigate potential CNS permeability and drug efflux. As summarized, compound 13 exhibited moderate permeability and low efflux ratios of 0.6 and 0.4, respectively, in the absence or presence of P-glycoprotein (Pgp) inhibitors. Compound 13 showed a kinetic solubility of 48.55 μg / mL in PBS buffer. The disappearance rate of 13 after incubation with rat or human liver microsomes was observed to identify the intrinsic clearance in vitro. 13 is a novel 5-HT antagonist, which is a potent anti-inflammatory drug. 2C It showed a higher clearance rate than PAM R.

[0109] In vivo PK evaluation of compound 13 was performed in male Sprague-Dawley rats after a single dose of 10 mg / kg administered intraperitoneally (ip) or 20 mg / kg administered orally (po) to evaluate the drug-like properties of 13 and its potential as an in vivo probe. As summarized in Table 7, the t 1 / 2 = 2.41 ± 1.72 hours) or 13 (2.14 ± 0.18 hours) of 20 mg / kg administered po 2C Plasma exposure of PAM2 (AUC 0-inf Intravenous: 939 ± 108 ng·h·mL -1 ;po:737±56ng·hour·mL -1 ) and plasma exposure (AUC 0-inf ;ip:1885±232ng·hour·mL -1 ;po:615±94ng·hour·mL -1 ), but 5-HT 2C Slightly worse than PAM3 in R 42、44 Compound 13 showed brain / plasma (b / p) ratios of 0.589 (15 min) and 2.05 (1 h) after intraperitoneal administration, significantly higher than the reported cutoff of 0.3 for classifying CNS drugs.

[0110] [Table 11]

[0111] a T 1 / 2 , half-life; T max , time to reach maximum concentration; C max , highest concentration; AUC 0-inf , area under the plasma concentration time curve; time, time of brain harvest after dosing; brain concentration, average concentration of 13 in tissue samples. Experiments were tested in three biological replicates from male Sprague-Dawley rats, and data values ​​are presented as mean ± SEM (± standard error). Vehicle, 10% dimethylsulfoxide (DMSO):90% 2-hydroxypropyl-β-cyclodextrin (HP-β-CD). analog

[0112] 4.0 Illustrative Embodiments The present invention includes the following non-limiting exemplary embodiments: 1. In some embodiments, the present invention provides a compound represented by formula I:

[0113] [ka]

[0114] or a pharma- ceutically acceptable salt thereof, During the ceremony, R 1 , R 2 , and R 3 is independently selected from H, substituted or unsubstituted aryl, heteroaryl, arylalkyl, heteroarylalkyl, carbonyl, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 alkoxy, C1-C6 hydroxyalkyl, C1-C6 ester, and heterocyclyl; R 4 is selected from H, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, arylalkyl, and heteroarylalkyl; X is -CH2CH2-, -CH=CH-,

[0115] [ka]

[0116] is selected from the group consisting of R 5 is selected from H, C1-C6 alkyl, and arylalkyl; m is 0 to 20; n is 1 to 20. 2. In some embodiments, the present invention provides a method for the preparation of a compound comprising the steps of: 1 is H. 3. In some embodiments, the present invention provides a method for the preparation of a compound comprising the steps of: 1 and R 2 is H. 4. In some embodiments, the invention encompasses compounds of formula I where X is -CH=CH-. 5. In some embodiments, the invention encompasses compounds of formula I where X is -CH=CH-, and the -CH=CH- group is a cis isomer. 6. In some embodiments, the present invention relates to a compound according to the present invention, wherein X is -CH=CH-, the -CH=CH- group is a cis isomer, m is 8, n is 7, and R 4 is H. 7. In some embodiments, the present invention relates to a compound comprising:

[0117] [ka]

[0118] and the like. 8. In some embodiments, the present invention relates to a compound comprising:

[0119] [ka]

[0120] and the like. 9. In some embodiments, the present invention relates to a compound wherein X is:

[0121] [ka]

[0122] and the like. 10. In some embodiments, the invention encompasses compounds of formula I where X is -CH2CH2-. 11. In some embodiments, the present invention provides a method for the preparation of a compound comprising the steps of: 4 is selected from H, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, arylalkyl, and heteroarylalkyl. 12. In some embodiments, the present invention provides a method for the preparation of a compound comprising the steps of: 4 is H. 13. In some embodiments, the present invention encompasses a compound of formula I, or a pharma- ceutically acceptable salt thereof, the compound being

[0123] [ka]

[0124] and combinations thereof. 14. In some embodiments, the invention encompasses a compound of formula Ia, which is: CH3-(CH2)7-((cis)-CH=CH-)-(CH2)7-C(=O)NH-C(CH2OH)3Formula Ia or a pharma- ceutically acceptable salt thereof. 15. In some embodiments, the present invention encompasses a compound of formula I, or a pharma- ceutically acceptable salt thereof, the compound being

[0125] [ka]

[0126] The above formula is selected from the following formula: 16. In some embodiments, the present invention encompasses a compound of formula I, or a pharma- ceutically acceptable salt thereof, the compound being

[0127] [ka]

[0128] The above formula is selected from the following formula: 17. In some embodiments, the present invention encompasses a compound of formula I, or a pharma- ceutically acceptable salt thereof, the compound being

[0129] [ka]

[0130] The above formula is selected from the following formula: 18. In some embodiments, the invention encompasses a compound selected from any of the compounds depicted in Figure 10A, Figure 10B, Figure 11A, or Figure 11B, or a pharma- ceutically acceptable salt thereof. 19. In some embodiments, the present invention provides a compound of formula (Ia): R 4 -(CH2) m -X-(CH2) n -C(=O)NH-(PH) Formula (Ia) or a pharma- ceutically acceptable salt thereof, During the ceremony, R 4 is H, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, arylalkyl, or heteroarylalkyl; X is -CH2CH2-, -CH=CH-,

[0131] [ka]

[0132] and is selected from the group consisting of R 5 is selected from H, C1-C6 alkyl, and arylalkyl; m is 0 to 20; n is 1 to 20; (PH) is selected from any of the following groups numbered 7 to 30:

[0133] [ka]

[0134] 20. In some embodiments, the invention encompasses compounds of formula Ia, where (PH) is -C(CH2OH)3. 21. In some embodiments, the present invention relates to a compound according to the present invention, wherein X is (-CH=CH-), Includes compounds of formula Ia where (PH) is -C(CH2OH)3. 22. In some embodiments, the present invention relates to a compound according to the present invention, wherein X is (-CH=CH-), m is 8, n is 7, and R 4 is H, Includes compounds of formula Ia where (PH) is -C(CH2OH)3. 23. In some embodiments, the present invention provides a compound of formula 13: CH3-(CH2)7-((cis)-CH=CH-)-(CH2)7-C(=O)NH-C(CH2OH)3 Compound 13 or a pharma- ceutically acceptable salt thereof. 24. In some embodiments, the present invention encompasses a compound of formula I, or a pharma- ceutically acceptable salt thereof, the compound being

[0135] [ka]

[0136] The above formula is selected from the following formula: 25. In some embodiments, the present invention encompasses a compound of formula I, or a pharma- ceutically acceptable salt thereof, the compound being

[0137] [ka]

[0138] The above formula is selected from the following formula: 26. In some embodiments, the present invention encompasses a compound of formula I, or a pharma- ceutically acceptable salt thereof, the compound being

[0139] [ka]

[0140] The above formula is selected from the following formula: 27. In some embodiments, the present invention provides a compound of formula (II):

[0141] [ka]

[0142] Formula (II) or a pharma- ceutically acceptable salt thereof, In the formula, R 1 , R 2 , R 3 is independently selected from H, substituted or unsubstituted aryl, heteroaryl, arylalkyl, heteroarylalkyl, carbonyl, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 alkoxy, C1-C6 hydroxyalkyl, and C1-C6 ester; R 6 is selected from H, OH, NO2, amino, CF3, halogen, alkyl, or alkoxy; R 7 -H and -NR 8 R 9 is selected from R 8 , R 9 is independently selected from H, alkyl, aryl, arylalkyl, cycloalkyl, alkoxy, heteroalkyl, or R 8 , R 9 forms a five- or six-membered ring together with other atoms, X, Y, and Z are independently CH and N; n is 1 to 7. 28. In some embodiments, the present invention provides a method for the preparation of a compound comprising the steps of: 7 Ga-NR 8 R 9 or a pharma- ceutically acceptable salt thereof. 29. In some embodiments, the present invention provides a method for the preparation of a compound comprising the steps of: 7 Ga-NR 8 R 9 or a pharma- ceutically acceptable salt thereof, the structures of which are Formula (II)-(R) (also referred to as Formula (IIa)) and Formula (II)-(S) (also referred to as Formula (IIb)):

[0143] [ka]

[0144] Formula (II)-(R) and Formula (II)-(S) is selected from The nomenclature for formula II-(R) and formula II-(S) is -NR 8 R 9 These refer to the R and S configurations at the chiral central carbon bonded to 30. A method for treating a disease or condition, comprising administering to a patient a therapeutically effective amount of one or more compounds selected from any of Formula I, Formula Ia, Formula II, Formula IIa, and Formula IIb, and any combination thereof (or a pharma- ceutically acceptable salt thereof). 31. In some embodiments, the present invention encompasses a method of treating the above-mentioned disease or condition described in embodiment 30, wherein the treatment of the above-mentioned disease or condition involves modulation of the 5-hydroxytryptamine 2A receptor and / or the 5-hydroxytryptamine 2C receptor. 32. In some embodiments, the present invention encompasses a method of treating the above-mentioned disease or condition described in embodiment 30, wherein the above-mentioned disease or condition can be treated by modulating the 5-hydroxytryptamine 2A receptor and / or the 5-hydroxytryptamine 2C receptor. 33. In some embodiments, the present invention encompasses a method of treating the above-mentioned diseases or conditions described in embodiment 30, wherein the compounds described in the present invention modulate the 5-hydroxytryptamine 2A receptor and / or the 5-hydroxytryptamine 2C receptor. 34. In some embodiments, the invention encompasses a method of treating a disease or condition according to embodiment 30, wherein the disease or condition to which response is directed is a substance use disorder, a psychiatric or neurological disorder, obesity, a mood disorder, or a seizure disorder. 35. In some embodiments, the present invention encompasses a method of treating the above diseases or conditions described in embodiment 30, wherein the compound is administered intravenously. 36. In some embodiments, the invention encompasses a method of treating the above-mentioned diseases or conditions described in embodiment 30, wherein said patient has been diagnosed with a substance use disorder, obesity, a mood disorder, or a seizure disorder.

[0145] References Howell, LL; Cunningham, KA Serotonin 5-ht2 receptor interactions with dopamine function: Implications for therapeutics in cocaine use disorder. Pharmacol. Rev. 2015, 67, 176-197. Anastasio, NC; Liu, S.; Maili, L.; Swinford, SE; Lane, SD; Fox, RG; Hamon, SC; Nielsen, DA; Cunningham, KA; Moeller, FG Variation within the serotonin (5-ht) 5-ht2c receptor system aligns with vulnerability to cocaine cue reactivity. Transl. Psychiatry 2014, 4, e369. Anastasio, N. C.; Stutz, S. J.; Fink, L. H.; Swinford-Jackson, S. E.; Sears, R. M.; DiLeone, R. J.; Rice, K. C.; Moeller, F. G.; Cunningham, K. A. Serotonin (5-ht) 5-ht2a receptor (5-ht2ar):5-ht2cr imbalance in medial prefrontal cortex associates with motor impulsivity. ACS Chem. Neurosci. 2015, 6, 1248-1258. Anastasio, N. C.; Stutz, S. J.; Fox, R. G.; Sears, R. M.; Emeson, R. B.; DiLeone, R. J.; O'Neil, R. T.; Fink, L. H.; Li, D.; Green, T. A.; Moeller, F. G.; Cunningham, K. A. 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Claims

1. Formula I: 【Chemistry 25】 or a pharmaceutically acceptable salt thereof, During the ceremony, R １ , R ２ , and R ３ is independently selected from H, substituted or unsubstituted aryl, heteroaryl, arylalkyl, heteroarylalkyl, carbonyl, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 alkoxy, C1-C6 hydroxyalkyl, C1-C6 ester, heterocyclyl; R ４ is selected from H, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, arylalkyl, and heteroarylalkyl; +は、-CH ２ CH ２ -、-CH=CH-、 【Chemistry 26】 is selected from the group consisting of R ５ is selected from H, C1-C6 alkyl, and arylalkyl; m is 0 to 20; The compound or a pharmaceutically acceptable salt thereof, wherein n is 1 to 20.

2. 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein X is -CH=CH-.

3. 3. The compound of claim 2, or a pharmaceutically acceptable salt thereof, wherein the -CH=CH- group is a cis-isomer.

4. m is 8, n is 7, and R ４ is H, or a pharmaceutically acceptable salt thereof. 【Request Item 5】 【Chemistry 30】 2. The compound of claim 1, wherein the compound is selected from any one of the following: 【Request Item 6】 【Chemistry 31】 2. The compound of claim 1, wherein the compound is selected from any one of the following: 【Request Item 7】 【Chemistry 32】 2. The compound of claim 1, wherein the compound is selected from any one of the following: 【Request Item 8】 【Chemistry 33】 2. The compound of claim 1, wherein the compound is selected from any one of the following:

9. Formula (II): 【Transformation 34】 or a pharmaceutically acceptable salt thereof, In the formula, R １ , R ２ , R ３ is independently selected from H, substituted or unsubstituted aryl, heteroaryl, arylalkyl, heteroarylalkyl, carbonyl, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 alkoxy, C1-C6 hydroxyalkyl, and C1-C6 ester; R ６ H, OH, NO ２ , Amino, CF ３ , halogen, alkyl, and alkoxy; R ７ is H or NR ８ R ９ and R ８ , R ９ are independently selected from H, alkyl, aryl, arylalkyl, cycloalkyl, alkoxy, and heteroalkyl; or R ８ , R ９ forms a five- or six-membered ring together with other atoms, X, Y, and Z are independently selected from CH and N; The compound or a pharmaceutically acceptable salt thereof, wherein n is 1 to 7.

10. The structure of the compound is represented by Formula II-(R) and Formula II-(S): 【Chemistry 35】 is selected from The names of Formula II-(R) and Formula II-(S) are -NR ８ R ９ 10. The compound of claim 9, or a pharmaceutically acceptable salt thereof, wherein R and S configurations are respectively indicated at the chiral central carbon bonded to:

11. A method of treating a disease or condition comprising administering to a patient a therapeutically effective amount of a compound of formula I: 【Transformation 36】 or a pharmaceutically acceptable salt thereof, During the ceremony, R １ , R ２ , and R ３ is independently selected from H, substituted or unsubstituted aryl, heteroaryl, arylalkyl, heteroarylalkyl, carbonyl, C1-C6 alkyl, C1-C6 heteroalkyl, C1-C6 alkoxy, C1-C6 hydroxyalkyl, C1-C6 ester, heterocyclyl; R ４ is selected from H, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, arylalkyl, and heteroarylalkyl; +は、-CH ２ CH ２ -、-CH=CH-、 【Chemistry 37】 and is selected from the group consisting of R ５ is selected from H, C1-C6 alkyl; m is 0 to 20; The method, wherein n is 1 to 20.

12. 12. The method of claim 11, wherein the treatment of the disease or condition is associated with modulation of the 5-hydroxytryptamine 2A receptor and / or the 5-hydroxytryptamine 2C receptor.

13. 12. The method of claim 11, wherein the disease or condition can be treated by modulating the 5-hydroxytryptamine 2A receptor and / or the 5-hydroxytryptamine 2C receptor.

14. 12. The method of claim 11, wherein the compound according to Formula I modulates the 5-hydroxytryptamine 2A receptor and / or the 5-hydroxytryptamine 2C receptor.

15. 12. The method of claim 11, wherein the disease or condition to which response is directed is a substance use disorder, obesity, a mood disorder, or a seizure disorder.

16. A method of treating a disease or condition, comprising administering to a patient a therapeutically effective amount of a compound selected from any of Formula Ia, Formula II, Formula II-(R), and Formula II-(S), or a combination thereof, or a pharmaceutically acceptable salt thereof.

17. 17. The method of claim 16, wherein the treatment of the disease or condition is associated with modulation of the 5-hydroxytryptamine 2A receptor and / or the 5-hydroxytryptamine 2C receptor.

18. 17. The method of claim 16, wherein the disease or condition is treated by modulating the 5-hydroxytryptamine 2A receptor and / or the 5-hydroxytryptamine 2C receptor.

19. 17. The method of claim 16, wherein the compound(s), or a pharmaceutically acceptable salt thereof, modulates the 5-hydroxytryptamine 2A receptor and / or the 5-hydroxytryptamine 2C receptor.

20. 20. The method of claim 19, wherein the disease or condition to which response is directed is a substance use disorder, obesity, a mood disorder, or a seizure disorder.

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