Discovery of a selective 5-HT2c agonist and 5-HT2a partial agonist by generative machine learning

Abstract

Disclosed are compounds having selectivity towards a serotonin 2 receptor (5-HT2), including 5-HT2A, 5-HT2B, and / or 5-HT2C, including a compound which is formula (I); (N-(2-(lH-indol-2-yl)ethyl)-2-(lH-indol-3-yl)-N-methylethan-1 -amine), or a pharmaceutically acceptable salts of the compounds. Methods and uses of the compounds in treating conditions treatable by agonism of 5-HT2A and / or 5-HT2C, the methods and uses comprising administering a disclosed compound to a subject in need thereof, are also disclosed.

Description

[0001] Attorney Docket No. 3270 / 30 PCT

[0002] DESCRIPTION

[0003] DISCOVERY OF A SELECTIVE 5-HT2C AGONIST AND 5-HT2A PARTIAL

[0004] AGONIST BY GENERATIVE MACHINE LEARNING

[0005] CROSS-REFERENCE TO RELATED APPLICATIONS

[0006] This application claims priority to and benefit of U.S. Provisional Application Serial No. 63 / 708,160, filed on October 16, 2024, the disclosure of which is incorporated herein by reference in its entirety.

[0007] GOVERNMENT SUPPORT

[0008] This invention was made with government support under Grant Numbers R44GM122196, 2R44ES031038, and R43DA055419 awarded by the National Institutes of Health. The government has certain rights in the invention.

[0009] BACKGROUND

[0010] Overreliance on opioids for treating chronic pain has resulted in an opioid epidemic, where the ongoing addiction crisis has caused an alarming number of deaths from opioid overdose. The CDC reports that 73,838 of the 107,941 drug overdose deaths in 2022 were caused by synthetic opioids h Despite the overwhelming addiction crisis, few treatments for opioid use disorder (OUD) exist, with the two most common treatments being buprenorphine and naloxone. However, in a randomized clinical trial it was shown that 65% and 72% of buprenorphine and buprenorphine / naloxone recipients, respectively, did not test drug-free 24 weeks later2. It is estimated that the financial cost associated with treating OUD is around $504 billion which points to the need for additional treatments to be developed3.

[0011] Recently, there has been renewed interest in using psychedelics (psilocybin, lysergic acid diethylamide (LSD), ibogaine and 3, 4-methylenedi oxymethamphetamine (MDMA)) as potential treatments for addiction, including OUD4’5. It is suggested that these psychedelic compounds can reduce drug-dependence and have a better safety profile than most addictive drugs4'6. While research in using psychedelics to treat addiction is promising, their exact mechanisms of action are not well understood. Psychedelic molecules belong to class of compounds known as psychoplastogens, which promote structural and functional neural plasticity7, and the reduction in drug-dependence has been attributed to the generation of new neural connections in the brain. However, as psychedelic compounds produce profound Attorney Docket No. 3270 / 30 PCT subjective experiences, it is still unclear whether their therapeutic potential is purely tied to an increase in neural plasticity8’9. The psychoplastogen effects of psychedelics have been linked to activation of the serotonin 2A (5-HT2A) receptor, which plays a major role in cortical neuron health10. However, psychedelic molecules exhibit promiscuous pharmacology, with most psychedelics activating multiple serotonin receptors9. Several analogs of psychedelic molecules have been proposed which induce neuroplasticity while seemingly lacking the psychedelic experiencen'13, suggesting that an appropriately selective psychedelic analog could treat OUD without significant adverse effects. While 5- HT2A appears to be a key target for neuroplasticity, 5-HT2C agonists have been proposed as potential treatments for addiction14'20, and in contrast 5-HT2B agonists have been shown to cause cardiac valvopathy21. Thus, the identification of 5-HT2A agonists and 5-HT2C agonists with selectivity over 5-HT2B represents a need in the art. Thus, we initially aimed to identify small molecule agonists starting from known psychedelic molecules which are likely 5- HT2A agonists by utilizing generative machine learning to predict novel chemical structures.

[0012] SUMMARY

[0013] In some examples, the presently disclosed subject matter provides a 5-HT agonist (e.g., a 5-HT2 agonist). In some examples, the compound is a selective agonist of 5-HT2A and / or 5-HT2C. In some examples, the 5-HT agonist is a 5-HT2A partial agonist. In some examples, the 5-HT agonist is a 5-HT2C selective agonist. In some examples, the 5-HT agonist is a 5-HT2A partial agonist and a 5-HT2C selective agonist. In some examples, the compound is

[0014] (N-(2-(lH-indol-2-yl)ethyl)-2-(lH-indol-3-yl)-N-methylethan-l-amine, CPI-7168), or a pharmaceutically acceptable salt thereof.

[0015] In some examples, the presently disclosed subject matter provides a method of treating a condition treatable by agonism of 5-HT2A and / or 5-HT2C, the method comprising administering a compound of the presently disclosed subject matter a subject in need thereof. In some examples, the presently disclosed subject matter provides a use of a compound of the presently dsi closed subject matter in preparing a medicament for treating Attorney Docket No. 3270 / 30 PCT a condition treatable by agonism of a serotonin 2 receptor (5-HT2), including 5-HT2A, 5- HT2B, and / or 5-HT2C in a subject in need thereof.

[0016] In some examples, the condition is a mental health condition. In some examples, the mental health condition is a psychosis, optionally a mental health condition characterized by psychosis, including but not limited to schizophrenia, schizoaffective disorder, and / or a delusional disorder; a neurodegenerative disease, optionally Alzheimer’s disease and / or Parkinson’s disease; or depression and / or bipolar depression; and / or seizures.

[0017] In some examples, the condition is an inflammatory disease, optionally cardiovascular inflammation, gut inflammation, and / or TNF-alpha-induced inflammation; wherein the condition is pain in the subject; wherein the condition is an addiction disorder; wherein the condition is obesity; and / or the condition is developmental encephalopathy and / or epileptic encephalopathy, optionally Dravet Syndrome, Lennox-Gastaut syndrome, Juvenile CLN3 Batten disease, CLN2 Batten disease, tuberous sclerosis complex, CDKL5 deficiency disorder, and / or Sturge-Weber syndrome. In some examples, the addiction disorder is opioid use disorder (OUD) and / or other addictive pharmacological agent.

[0018] In some examples, the presently disclosed subject matter provides a method of treating an addiction disorder, depression, obesity, sexual dysfunction, a developmental and epileptic encephalopathy (DEE), seizures, and / or another condition treatable by agonism of 5-HT2C, the method comprising administering a compound of the presently disclosed subject matter to a subject in need thereof. In some examples, the addiction disorder is opioid use disorder (OUD).

[0019] In some examples, the presently disclosed subject matter provides a use of a compound a compound of the presently disclosed subject matter in preparing a medicament for treating an addiction disorder depression, obesity, sexual dysfunction, a developmental and epileptic encephalopathy (DEE), seizures, and / or another condition treatable by agonism of 5-HT2c, in a subject in need thereof. In some examples, the addiction disorder is opioid use disorder (OUD).

[0020] Accordingly, it is an object of the presently disclosed subject matter to provide a 5- HT2C agonist compound and / or 5-HT2A partial agonist compound, and methods of using the same. An object of the presently disclosed subject matter having been stated hereinabove, and which is achieved in whole or in part by the presently disclosed subject matter, other objects will become evident as the description proceeds hereinbelow. Attorney Docket No. 3270 / 30 PCT

[0021] BRIEF DESCRIPTION OF THE FIGURES

[0022] Figures 1A-1C: Validation summaries for ECso regression models and binary activation models with a binarization cutoff of ECso = 100 nM for 5-HT2a (Figure 1A) 5- HT2b (Figure IB), and 5-HT2c (Figure 1C). For binary models (left), histograms of probability-like scores generated during cross-validation are plotted for the inactive and active classes; truth tables (representing the number of true negatives, false positives, false negatives, and true positives) are superimposed on the plots and color-coded. For the regression models (right), predicted ECso computed during cross-validation is plotted against measured ECso, and the mean absolute error (MAE) and the number of samples in the training set are superimposed on the plots; in a perfect regression model, all points would fall on the dotted line.

[0023] Figure 2. 5-point dose-response curves for CPI-7168 agonism of 5-HT2A (left, ECso = 53 nM), 5-HT2B (center, ECso > 1 pM), and 5-HT2C (right, ECso = 12 nM).

[0024] Figure 3. 5-point dose-response curves for CPI-7168 antagonism of 5-HT2A (left, ECso > 1 pM), 5-HT2B (center, EC50 = 0.2 pM), and 5-HT2C (right, EC50 = 0.8 pM).

[0025] Figure 4. 5-point dose-response curves for 2-(lH-indol-3-yl)-N-[2-(lH-indol-3- yl)ethyl]-N-methylethanamine agonism of 5-HT2A (left, EC50 = 8.0 nM), 5-HT2B (center, ECso = 0.1 nM), and 5-HT2c (right, EC50 = 0.6 nM).

[0026] Figure 5. Class and Subclass analysis of CPI-7168. Light gray indicates the antipsychotic class and dark gray shows the atypical antipsychotic subclass. See also Figure 6 for complete Class and subclass legend for SmartCube® analysis.

[0027] Figure 6. Class and subclass appendix for SmartCube® analysis. Light gray indicates the antipsychotic class and dark gray shows the atypical antipsychotic subclass.

[0028] Figure 7. Similarity analysis of the active dose against a panel of antipsychotics and two 5HT2C agonists. NP3SO2: vehicle; LORC: lorcaserin; VABL vabicaserin; ralmitaront; ulotaront; AMIS: amisulpride; ARI: aripiprazole; ASEN: asenapine; BREXP: brexpiprazole; CARIP: cariprazine; CHLOR: chlorpromazine; CZP: clozapine; HAL: haloperidol; NQUE: norquetiapine; OLA: olanzapine; OLA: olanzapine; PIMA: pimavanserin; PPZN; perphenazine; PZD: pimozide; QUE: quetiapine; RIS: risperidone; TROS XANO: trospium + xanomeline; XANO: xanomeline; ZIPRA: ziprasidone.

[0029] Figure 8. t-SNE plot showing structural diversity of the tested analogs compared to the 5-HT2C training set.

[0030] Figure 9: HPLC trace for / V-[2-(5-fluoro-U / -indol-3-yl)ethyl]propan-l-amine (CPI- 7171; also referred to herein as TJ26 96). Attorney Docket No. 3270 / 30 PCT

[0031] Figure 10: HPLC trace for 3-[2-(2,2-dimethylhydrazinyl)ethyl]-5-fluoro-lJ / -indole (CPI-7172, also referred to herein as TJ26 108).

[0032] Figure 11 : HPLC trace for A1-[2-(5-fhioro-l.H-indol-3-yl)ethyl]-A3, ^-dimethylpropane- 1,3 -diamine (CPI-7173; also referred to herein as TJ26 109).

[0033] Figure 12: HPLC trace for 3-[2-(5-fluoro-U / -indol-3-yl)ethyl]aminopropane-nitrile (CPI-7174; also referred to herein as TJ26 110).

[0034] Figure 13: HPLC trace for / ' / -[2-(5-fluoro- IT / -indol-3-yl)ethyl]-2,2-dimethyl- propan-1 -amine (CPI-7175; also referred to herein as TJ26 113).

[0035] ABBREVIATIONS

[0036] 5-HT2 = serotonin 2 receptor

[0037] ADME = absorption, distribution, metabolism, excretion

[0038] OUD = opioid use disorder

[0039] PK = pharmacokinetic

[0040] DETAILED DESCRIPTION

[0041] The presently disclosed subject matter will now be described more fully. The presently disclosed subject matter can, however, be embodied in different forms and should not be construed as limited to the examples set forth herein below. Rather, these examples are provided so that this disclosure will be thorough and complete, and will fully convey the scope of the examples to those skilled in the art.

[0042] All references listed herein, including but not limited to all patents, patent applications and publications thereof, and scientific journal articles, are incorporated herein by reference in their entireties to the extent that they supplement, explain, provide a background for, or teach methodology, techniques, and / or compositions employed herein.

[0043] I. GENERAL CONSIDERATIONS

[0044] The overuse of opioid drugs for treating chronic pain has led to an opioid epidemic, where overdose deaths continue to rise despite a lack of effective treatments for opioid use disorder (OUD). Recently, psychedelic compounds (psilocybin, lysergic acid diethyl amide (LSD) and 3,4-methylenedioxymethamphetamine (MDMA)) have shown promise to treat OUD by decreasing drug-dependence. It is hypothesized that the decrease in drugdependency is due to activation of the serotonin 2A receptor (5-HT2A). However, many Attorney Docket No. 3270 / 30 PCT psychedelics exhibit polypharmacology, including activation of multiple serotonin receptors. 5-HT2chas also been targeted by molecules as potential treatments for addiction.

[0045] To our knowledge, there are few if any known 5-HT2A agonists with selectivity over 5-HT2B and 2c. Thus, we initially aimed to identify small molecule agonists starting from known psychedelic molecules which are likely 5-HT2A agonists by utilizing generative machine learning to predict novel chemical structures.

[0046] To identify 5-HT agonists, publicly available data was used to create machine learning models for 5-HT2A, 2B, and 2c that could be used in a generative machine learning approach. Compounds were computationally designed and scored followed by synthesis based on their selectivity profile, ultimately leading to the discovery of a new tryptamine derivative, CPI-7168 (also referred to herein as CPI-CG-8) (N-(2-(lH-indol-2-yl)ethyl)-2- (lH-indol-3-yl)-N-methylethan-l-amine, also referred to herein as CPI-7168), which exhibits agonism of 5-HT2C (ECso = 12 nM), is a partial agonist of 5-HT2A (53nM) and shows no significant activity at 5-HT2B (ECso > 1 pM)., which exhibits relatively selective agonism of 5-HT2C (ECso = 12 nM). Subsequent in vivo evaluation in mice saw significant levels of CPI-7168 in the brain, despite rapid clearance and low stability in liver microsomes in vitro. In vivo assessment of mice dosed with CPI-7168 demonstrated an atypical antipsychotic signature as well. CPI-7168 represents a promising lead molecule as a new 5- HT2C selective agonist for OUD and other potential therapeutic indications, such as, but not limited to, a psychosis, another addiction disorder, depression, obesity, sexual dysfunction, a developmental and epileptic encephalopathy (DEE), seizures, and / or another condition treatable by agonism of 5-HT2C (e.g., anxiety).

[0047] Generative models have become increasingly used to produce molecules de novo22'25and have several different architectures (e.g. Recurrent Neural Networks23, Variational Autoencoders26and Generative Adversarial Networks27). These have been used to generate valid, novel molecules with desirable physicochemical properties28-31using SMILES, SELFIES or other molecular representations32, 33. Several examples using generative approaches have led to the design and synthesis (or purchase) and or testing of molecules with in vitro activity against various targets34-42. A single generative design process likely will not work for all scenarios. We recently described a MegaSyn™43‘44generative model, which is a generative neural network with a long short-term memory (LSTM) architecture characterized by the number of layers and the size of the hidden state. MegaSyn™ generative model is designed to generate sequences of tokens which can be decoded as SMILES string representations of molecules, by drawing from a learned probability Attorney Docket No. 3270 / 30 PCT distribution over possible tokens. Here, we have trained several generative machine learning models to design likely 5-HT receptor agonists using psilocin (the active metabolite of psilocybin) as a starting point. Compounds were then selected and synthesized based on their predicted activity as agonists of all three 5-HT2 receptors and were evaluated in vitro for agonism of each receptor.

[0048] Accordingly, in some examples, the presently disclosed subject matter provides a 5- HT agonist (e.g., a 5-HT2 agonist). In some examples, the compound is a selective agonist of 5-HT2A, 5-HT2B, and / or 5-HT2c.

[0049] II. DEFINITIONS

[0050] While the following terms are believed to be well understood by one of ordinary skill in the art, the following definitions are set forth to facilitate explanation of the presently disclosed subject matter.

[0051] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood to one of ordinary skill in the art to which the presently disclosed subject matter belongs.

[0052] Following long-standing patent law convention, the terms “a”, “an”, and “the” refer to “one or more” when used in this application, including the claims.

[0053] The term “and / or” when used in describing two or more items or conditions, refers to situations where all named items or conditions are present or applicable, or to situations wherein only one (or less than all) of the items or conditions is present or applicable.

[0054] The use of the term “or” in the claims is used to mean “and / or” unless explicitly indicated to refer to alternatives only or the alternatives are mutually exclusive, although the disclosure supports a definition that refers to only alternatives and “and / or.” As used herein “another” can mean at least a second or more.

[0055] The term “comprising”, which is synonymous with “including,” “containing,” or “characterized by” is inclusive or open-ended and does not exclude additional, unrecited elements or method steps. “Comprising” is a term of art used in claim language which means that the named elements are essential, but other elements can be added and still form a construct within the scope of the claim.

[0056] As used herein, the phrase “consisting of’ excludes any element, step, or ingredient not specified in the claim. When the phrase “consists of’ appears in a clause of the body of a claim, rather than immediately following the preamble, it limits only the element set forth in that clause; other elements are not excluded from the claim as a whole. Attorney Docket No. 3270 / 30 PCT

[0057] As used herein, the phrase “consisting essentially of’ limits the scope of a claim to the specified materials or steps, plus those that do not materially affect the basic and novel character! stic(s) of the claimed subject matter.

[0058] With respect to the terms “comprising”, “consisting of’, and “consisting essentially of’, where one of these three terms is used herein, the presently disclosed and claimed subject matter can include the use of either of the other two terms.

[0059] Unless otherwise indicated, all numbers expressing quantities of time, concentration, dosage and so forth used in the specification and claims are to be understood as being modified in all instances by the term “about”. Accordingly, unless indicated to the contrary, the numerical parameters set forth in this specification and attached claims are approximations that can vary depending upon the desired properties sought to be obtained by the presently disclosed subject matter.

[0060] As used herein, the term “about”, when referring to a value is meant to encompass variations of in one example ±20% or ±10%, in another example ±5%, in another example ±1%, and in still another example ±0.1% from the specified amount, as such variations are appropriate to perform the disclosed methods.

[0061] Numerical ranges recited herein by endpoints include all numbers and fractions subsumed within that range (e.g. 1 to 5 includes, but is not limited to, 1, 1.5, 2, 2.75, 3, 3.90, 4, and 5).

[0062] A disease or disorder is “alleviated” if the severity of a symptom of the disease, condition, or disorder, or the frequency at which such a symptom is experienced by a subject, or both, are reduced.

[0063] The terms “additional therapeutic compound” and “additional therapeutic agent”, as used in the context of the presently disclosed subject matter, refers to the use or administration of a compound for an additional therapeutic use for a particular injury, disease, or disorder being treated. Such a compound, for example, could include one being used to treat an unrelated disease or disorder, or a disease or disorder which may not be responsive to the primary treatment for the injury, disease, or disorder being treated.

[0064] As use herein, the terms “administration of’ and / or “administering” a compound should be understood to refer to providing a compound of the presently disclosed subject matter to a subject in need of treatment.

[0065] As used herein, an “agonist” is a composition of matter which, when administered to a mammal such as a human, enhances or extends a biological activity attributable to the level or presence of a target compound or molecule of interest in the subject. Attorney Docket No. 3270 / 30 PCT

[0066] As used herein, an “analog” of a chemical compound is a compound that, by way of example, resembles another in structure but is not necessarily an isomer (e.g., 5 -fluorouracil is an analog of thymine).

[0067] An “antagonist” is a composition of matter which when administered to a mammal such as a human, inhibits a biological activity attributable to the level or presence of a compound or molecule of interest in the subject.

[0068] The term “aqueous solution” as used herein can include other ingredients commonly used, such as sodium bicarbonate described herein, and further includes any acid or base solution used to adjust the pH of the aqueous solution while solubilizing a peptide.

[0069] The term “binding” refers to the adherence of molecules to one another, such as, but not limited to, enzymes to substrates, ligands to receptors, antibodies to antigens, DNA binding domains of proteins to DNA, and DNA or RNA strands to complementary strands.

[0070] “Binding partner”, as used herein, refers to a molecule capable of binding to another molecule.

[0071] The term “biocompatible”, as used herein, refers to a material that does not elicit a substantial detrimental response in the host.

[0072] The term “biological sample”, as used herein, refers to samples obtained from a subject, including but not limited to skin, hair, tissue, blood, plasma, cells, sweat, and urine.

[0073] "Co-administer" can include simultaneous and / or sequential administration of two or more agents.

[0074] A "compound," as used herein, refers to any type of substance or agent that is can be considered a drug, or a candidate for use as a drug, as well as combinations and mixtures of the above.

[0075] As used herein, a "derivative" of a compound refers to a chemical compound that can be produced from another compound of similar structure in one or more steps, as in replacement of H by an alkyl, acyl, or amino group.

[0076] The use of the word "detect" and its grammatical variants refers to measurement of the species without quantification, whereas use of the word "determine" or "measure" with their grammatical variants are meant to refer to measurement of the species with quantification. The terms "detect" and "identify" are used interchangeably herein.

[0077] As used herein, the terms “condition”, “disease condition”, “disease”, “disease state”, and “disorder” refer to physiological states that can be treated with the compounds of the presently disclosed subject matter, including physiological states in which diseased cells or cells of interest can be targeted with the compounds of the presently disclosed subject matter. Attorney Docket No. 3270 / 30 PCT

[0078] As used herein, the term “diagnosis” refers to detecting a risk or propensity to a condition, disease, or disorder. In any method of diagnosis exist false positives and false negatives. Any one method of diagnosis does not provide 100% accuracy.

[0079] A “disease” is a state of health of an animal wherein the animal cannot maintain homeostasis, and wherein if the disease is not ameliorated then the animal’s health continues to deteriorate.

[0080] In contrast, a “disorder” in an animal is a state of health in which the animal is able to maintain homeostasis, but in which the animal’s state of health is less favorable than it would be in the absence of the disorder. Left untreated, a disorder does not necessarily cause a further decrease in the animal’s state of health.

[0081] As used herein, an “effective amount” or “therapeutically effective amount” refers to an amount of a compound or composition sufficient to produce a selected effect, such as but not limited to alleviating symptoms of a condition, disease, or disorder. In the context of administering compounds in the form of a combination, such as multiple compounds, the amount of each compound, when administered in combination with one or more other compounds, can be different from when that compound is administered alone. Thus, an effective amount of a combination of compounds refers collectively to the combination as a whole, although the actual amounts of each compound can vary. The term “more effective” means that the selected effect occurs to a greater extent by one treatment relative to the second treatment to which it is being compared.

[0082] As used herein “injecting”, “applying”, and “administering” include administration of a compound of the presently disclosed subject matter by any number of routes and modes including, but not limited to, topical, oral, buccal, intravenous, intramuscular, intra-arterial, intramedullary, intrathecal, intraventricular, transdermal, subcutaneous, intraperitoneal, intranasal, enteral, topical, sublingual, vaginal, ophthalmic, pulmonary, vaginal, and rectal approaches.

[0083] As used herein, a “ligand” is a compound that specifically binds to a target compound or molecule. A ligand “specifically binds to” or “is specifically reactive with” a compound when the ligand functions in a binding reaction which is determinative of the presence of the compound in a sample of heterogeneous compounds.

[0084] As used herein, the term “linkage” refers to a connection between two groups. The connection can be either covalent or non-covalent, including but not limited to ionic bonds, hydrogen bonding, and hydrophobic / hydrophilic interactions. Attorney Docket No. 3270 / 30 PCT

[0085] As used herein, the term “linker” refers to a molecule that joins two other molecules either covalently or noncovalently, such as but not limited to through ionic or hydrogen bonds or van der Waals interactions.

[0086] As used herein, the term “mammal” refers to any member of the class Mammalia, including, without limitation, humans and nonhuman primates such as chimpanzees and other apes and monkey species; farm animals such as cattle, sheep, pigs, goats and horses; domestic mammals such as dogs and cats; laboratory animals including rodents such as mice, rats and guinea pigs, and the like. The term does not denote a particular age or sex. Thus, adult and newborn subjects, as well as fetuses, whether male or female, are intended to be included within the scope of this term.

[0087] As used herein, “parenteral administration” of a pharmaceutical composition includes any route of administration characterized by physical breaching of a tissue of a subject and administration of the pharmaceutical composition through the breach in the tissue. Parenteral administration thus includes, but is not limited to, administration of a pharmaceutical composition by injection of the composition, by application of the composition through a surgical incision, by application of the composition through a tissue-penetrating non-surgical wound, and the like. In particular, parenteral administration is contemplated to include, but is not limited to, subcutaneous, intraperitoneal, intramuscular, intrastemal injection, and kidney dialytic infusion techniques.

[0088] The term “pharmaceutical composition” refers to a composition comprising at least one active ingredient, whereby the composition is amenable to investigation for a specified, efficacious outcome in an animal (for example, without limitation, a human or other mammal). Those of ordinary skill in the art will understand and appreciate the techniques appropriate for determining whether an active ingredient has a desired efficacious outcome based upon the needs of the artisan.

[0089] “Pharmaceutically acceptable” means physiologically tolerable, for either human or veterinary application. Similarly, “pharmaceutical compositions” include formulations for human and veterinary use.

[0090] “Plurality” means at least two.

[0091] The term “prevent”, as used herein, means to stop something from happening, or taking advance measures against something possible or probable from happening. In the context of medicine, “prevention” generally refers to action taken to decrease the chance of getting a disease or condition or a symptom thereof. It is noted that “prevention” need not be absolute, and thus can occur as a matter of degree. For example, prevention can involve preventing some, Attorney Docket No. 3270 / 30 PCT but not all, symptoms or undesirable biological effects associated with a particular disease or disorder.

[0092] In some examples, a “preventive” or “prophylactic” treatment is a treatment administered to a subject who does not exhibit signs, or exhibits only early signs, of a condition, disease, or disorder. Thus, a prophylactic or preventative treatment can be administered for the purpose of decreasing the risk of developing pathology associated with developing the condition, disease, or disorder.

[0093] The term “protein” typically refers to large polypeptides. Conventional notation is used herein to portray polypeptide sequences: the left-hand end of a polypeptide sequence is the amino-terminus; the right-hand end of a polypeptide sequence is the carboxyl-terminus.

[0094] The term “subject” as used herein refers to a member of species for which treatment and / or prevention of a disease or disorder using the compositions and methods of the presently disclosed subject matter might be desirable. Accordingly, the term “subject” is intended to encompass in some examples any member of the Kingdom Animalia including, but not limited to the phylum Chordata (e.g., members of Classes Osteichythyes (bony fish), Amphibia (amphibians), Reptilia (reptiles), Aves (birds), and Mammalia (mammals), and all Orders and Families encompassed therein.

[0095] The compositions and methods of the presently disclosed subject matter are particularly useful for warm-blooded vertebrates. Thus, in some examples the presently disclosed subject matter concerns mammals and birds. More particularly provided are compositions and methods derived from and / or for use in mammals such as humans and other primates, as well as those mammals of importance due to being endangered (such as Siberian tigers), of economic importance (animals raised on farms for consumption by humans) and / or social importance (animals kept as pets or in zoos) to humans, for instance, carnivores other than humans (such as cats and dogs), swine (pigs, hogs, and wild boars), ruminants (such as cattle, oxen, sheep, giraffes, deer, goats, bison, and camels), rodents (such as mice, rats, and rabbits), marsupials, and horses. Also provided is the use of the disclosed methods and compositions on birds, including those kinds of birds that are endangered, kept in zoos, as well as fowl, and more particularly domesticated fowl, e.g., poultry, such as turkeys, chickens, ducks, geese, guinea fowl, and the like, as they are also of economic importance to humans. Thus, also provided is the use of the disclosed methods and compositions on livestock, including but not limited to domesticated swine (pigs and hogs), ruminants, horses, poultry, and the like.

[0096] A “sample”, as used herein, refers in some examples to a biological sample from a subject, including, but not limited to, normal tissue samples, diseased tissue samples, biopsies, blood, saliva, feces, semen, tears, and urine. A sample can also be any other source of material Attorney Docket No. 3270 / 30 PCT obtained from a subject which contains cells, tissues, or fluid of interest. A sample can also be obtained from cell or tissue culture.

[0097] The term “standard”, as used herein, refers to something used for comparison. For example, it can be a known standard agent or compound which is administered and used for comparing results when administering a test compound, or it can be a standard parameter or function which is measured to obtain a control value when measuring an effect of an agent or compound on a parameter or function. Standard can also refer to an “internal standard”, such as an agent or compound which is added at known amounts to a sample and is useful in determining such things as purification or recovery rates when a sample is processed or subjected to purification or extraction procedures before a marker of interest is measured. Internal standards are often a purified marker of interest which has been labeled, such as with a radioactive isotope, allowing it to be distinguished from an endogenous marker.

[0098] As used herein, a “subj ect in need thereof’ is a patient, animal, mammal, or human, who will benefit from a compound or a method of the presently disclosed subject matter.

[0099] The term “symptom”, as used herein, refers to any morbid phenomenon or departure from the normal in structure, function, or sensation, experienced by the patient and indicative of disease. In contrast, a “sign” is objective evidence of disease. For example, a bloody nose is a sign. It is evident to the patient, doctor, nurse, and other observers.

[0100] A “therapeutic” treatment is a treatment administered to a subject who exhibits signs of pathology for the purpose of diminishing or eliminating those signs.

[0101] A “therapeutically effective amount” of a compound is that amount of compound which is sufficient to provide a beneficial effect to the subject to which the compound is administered.

[0102] As used herein, the phrase “therapeutic agent” refers to an agent that is used to, for example, treat, inhibit, prevent, mitigate the effects of, reduce the severity of, reduce the likelihood of developing, slow the progression of, and / or cure, a disease or disorder.

[0103] The terms “treatment” and “treating” as used herein refer to both therapeutic treatment and prophylactic or preventative measures, wherein the object is to prevent or slow down (lessen) the targeted pathologic condition, prevent the pathologic condition, pursue or obtain beneficial results, and / or lower the chances of the individual developing a condition, disease, or disorder, even if the treatment is ultimately unsuccessful. Those in need of treatment include those already with the condition as well as those prone to have or predisposed to having a condition, disease, or disorder, or those in whom the condition is to be prevented. The term "treating" refers any effect, e.g., lessening, reducing, modulating, ameliorating, reversing or eliminating, that results in the improvement of the condition, disease, disorder, and the like, or ameliorating a symptom thereof. Attorney Docket No. 3270 / 30 PCT

[0104] As used herein the term “alkyl” can refer to C1-20 inclusive, linear (i.e., "straight-chain"), branched, or cyclic, saturated or at least partially and in some cases fully unsaturated (i.e., alkenyl and alkynyl) hydrocarbon chains, including for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl, octyl, ethenyl, propenyl, butenyl, pentenyl, hexenyl, octenyl, butadienyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, and allenyl groups. "Branched" refers to an alkyl group in which a lower alkyl group, such as methyl, ethyl or propyl, is attached to a linear alkyl chain. "Lower alkyl" refers to an alkyl group having 1 to about 8 carbon atoms (i.e., a C1-8 alkyl), e.g., 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms. "Higher alkyl" refers to an alkyl group having about 10 to about 20 carbon atoms, e.g., 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 carbon atoms. In certain examples, "alkyl" refers, in particular, to C1-8 straight-chain alkyls. In other examples, “alkyl” refers, in particular, to C1-8 branched-chain alkyls.

[0105] Alkyl groups can optionally be substituted (a “substituted alkyl”) with one or more alkyl group substituents, which can be the same or different. The term "alkyl group substituent" includes but is not limited to alkyl, substituted alkyl, halo, arylamino, acyl, hydroxyl, aryloxyl, alkoxyl, alkylthio, arylthio, aralkyloxyl, aralkylthio, carboxyl, alkoxycarbonyl, oxo, and cycloalkyl. In some examples, there can be optionally inserted along the alkyl chain one or more oxygen, sulfur or substituted or unsubstituted nitrogen atoms, wherein the nitrogen substituent is hydrogen, lower alkyl (also referred to herein as “alkylaminoalkyl”), or aryl.

[0106] Thus, as used herein, the term "substituted alkyl" includes alkyl groups, as defined herein, in which one or more atoms or functional groups of the alkyl group are replaced with another atom or functional group, including for example, alkyl, substituted alkyl, halogen, aryl, substituted aryl, alkoxyl, hydroxyl, nitro, amino, alkylamino, dialkylamino, sulfate, and mercapto.

[0107] The term "aryl" is used herein to refer to an aromatic substituent that can be a single aromatic ring, or multiple aromatic rings that are fused together, linked covalently, or linked to a common group, such as, but not limited to, a methylene or ethylene moiety. The common linking group also can be a carbonyl, as in benzophenone, or oxygen, as in diphenylether, or nitrogen, as in diphenylamine. The term "aryl" specifically encompasses heterocyclic aromatic compounds. The aromatic ring(s) can comprise phenyl, naphthyl, biphenyl, diphenyl ether, diphenylamine and benzophenone, among others. In particular examples, the term “aryl” means a cyclic aromatic comprising about 5 to about 10 carbon atoms, e.g., 5, 6, 7, 8, 9, or 10 carbon atoms, and including 5- and 6-membered hydrocarbon and heterocyclic aromatic rings.

[0108] The aryl group can be optionally substituted (a “substituted aryl”) with one or more aryl group substituents, which can be the same or different, wherein “aryl group substituent” includes Attorney Docket No. 3270 / 30 PCT alkyl, substituted alkyl, aryl, substituted aryl, aralkyl, hydroxyl, alkoxyl, aryloxyl, aralkyloxyl, carboxyl, acyl, halo, nitro, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, acyloxyl, acylamino, aroylamino, carbamoyl, alkylcarbamoyl, dialkylcarbamoyl, arylthio, alkylthio, alkylene, and -NR'R", wherein R' and R" can each be independently hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, and aralkyl.

[0109] Thus, as used herein, the term "substituted aryl" includes aryl groups, as defined herein, in which one or more atoms or functional groups of the aryl group are replaced with another atom or functional group, including for example, alkyl, substituted alkyl, halogen, aryl, substituted aryl, alkoxyl, hydroxyl, nitro, amino, alkylamino, dialkylamino, sulfate, and mercapto.

[0110] Specific examples of aryl groups include, but are not limited to, cyclopentadienyl, phenyl, furan, thiophene, pyrrole, pyran, pyridine, imidazole, benzimidazole, isothiazole, isoxazole, pyrazole, pyrazine, triazine, pyrimidine, quinoline, isoquinoline, indole, carbazole, and the like.

[0111] “Heteroaryl” as used herein refers to an aryl group that contains one or more non-carbon atoms (e.g., O, N, S, Se, etc) in the backbone of a ring structure. Nitrogen-containing heteroaryl moieties include, but are not limited to, pyridine, imidazole, benzimidazole, pyrazole, pyrazine, triazine, pyrimidine, and the like.

[0112] “Cyclic” and "Cycloalkyl" refer to a non-aromatic mono- or multicyclic ring system of about 3 to about 10 carbon atoms. The cycloalkyl group can be optionally partially unsaturated. The cycloalkyl group can be also optionally substituted with an alkyl group substituent as defined herein, oxo and / or alkylene. There can be optionally inserted along the cyclic alkyl chain one or more oxygen, sulphur or substituted or unsubstituted nitrogen atoms, wherein the nitrogen substituent is hydrogen, lower alkyl, or aryl, thus providing a heterocyclic group. Representative monocyclic cycloalkyl rings include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. Exemplary multicyclic cycloalkyl rings include adamantyl, octahydronaphthyl, decalin, camphor, camphane, and noradamantyl.

[0113] The term “heterocyclic” refers to a non-aromatic or aromatic mono- or multicyclic ring system of about 3 to about 12 atoms that comprises at least one heteroatom, e.g., N, O, or S. The group can be saturated, partially unsaturated, or unsaturated. Exemplary heterocyclic groups include, but are not limited to, furanyl, pyrrolyl, pyridinyl, pyranyl, piperidinyl, morpholinyl, dioxanyl, pyrrolidinyl, oxanyl, thiolanyl, and thiophenyl. Heterocyclic groups can be unsubstituted or substituted with one or more alkyl group substituents or aryl group substituents. Attorney Docket No. 3270 / 30 PCT

[0114] “Aralkyl” refers to an -alkyl-aryl group, optionally wherein the alkyl and / or aryl moiety is substituted. An exemplary aralkyl group is benzyl, i.e., -CH2C6H5.

[0115] "Alkylene" refers to a straight or branched bivalent aliphatic hydrocarbon group having from 1 to about 20 carbon atoms, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 carbon atoms. The alkylene group can be straight, branched or cyclic. The alkylene group also can be optionally unsaturated and / or substituted with one or more "alkyl group substituents." There can be optionally inserted along the alkylene group one or more oxygen, sulfur or substituted or unsubstituted nitrogen atoms (also referred to herein as “alkylaminoalkyl”), wherein the nitrogen substituent is alkyl as previously described. Exemplary alkylene groups include methylene (-CH2-); ethylene (-CH2-CH2-); propylene (- (CH2)3-); cyclohexylene (-CeHio-); -CH=CH— CH=CH-; -CH=CH-CH2-; -(CH2)q-N(R)- (CH2)r- , wherein each of q and r is independently an integer from 0 to about 20, e.g., 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20, and R is hydrogen or lower alkyl; methylenedioxyl (-O-CH2-O-); and ethyl enedioxyl (-O-(CH2)2-O~). An alkylene group can have about 2 to about 3 carbon atoms and can further have 6-20 carbons.

[0116] The term “arylene” refers to a bivalent aromatic group, e.g., a bivalent phenyl or napthyl group. The arylene group can optionally be substituted with one or more aryl group substituents and / or include one or more heteroatoms.

[0117] The term “aralkylene” refers to a bivalent group that includes both aromatic and nonaromatic groups.

[0118] The term “amino” refers to the group -N(R)2 wherein each R is independently H, alkyl, substituted alkyl, aryl, substituted aryl, aralkyl, or substituted aralkyl. The terms “aminoalkyl” and “alkylamino” can refer to the group -N(R)2 wherein each R is H, alkyl or substituted alkyl, and wherein at least one R is alkyl or substituted alkyl. “Arylamino” and “aminoaryl” refer to the group -N(R)2 wherein each R is H, aryl, or substituted aryl, and wherein at least one R is aryl or substituted aryl, e.g., aniline (i.e., -NHCeHs).

[0119] The term “thioalkyl” can refer to the group -SR, wherein R is selected from H, alkyl, substituted alkyl, aralkyl, substituted aralkyl, aryl, and substituted aryl. Similarly, the terms “thioaralkyl” and “thioaryl” refer to -SR groups wherein R is aralkyl and aryl, respectively.

[0120] The terms "halo", "halide", or "halogen" as used herein refer to fluoro, chloro, bromo, and iodo groups.

[0121] The terms "hydroxyl" and “hydroxy” refer to the -OH group.

[0122] The terms “mercapto” or “thiol” refer to the -SH group. Attorney Docket No. 3270 / 30 PCT

[0123] The terms “carboxylate” and “carboxylic acid” can refer to the groups -C(=O)O’ and - C(=O)OH, respectively. The term “carboxyl” can also refer to the -C(=O)OH group. In some examples, “carboxylate” or “carboxyl” can refer to either the -C(=O)O’ or -C(=O)OH group.

[0124] The term “carbonyl” refers to the -C(=O)- group.

[0125] The term “carbamate refers to the group -O-C(=O)-NH- or -O-C(=O)-NR’-, wherein R’ is alkyl, substituted alkyl, aralkyl, substituted aralkyl, aryl, or substituted aryl.

[0126] By the term "protecting group" is meant a group which inhibits or suppresses undesirable chemical reactions, but which is designed to be sufficiently reactive that it can be cleaved from the functional group in question to obtain the desired product under mild enough conditions that do not modify the rest of the molecule. Protecting groups are well known to those skilled in the art and are described in 'Protective Groups in Organic Synthesis', Theorodora W. Greene and Peter G. M. Wuts, (Third Edition, John Wiley & Sons, 1999).

[0127] The term “hydrophilic” can refer to a compound or chemical species or functional group that dissolves or preferentially dissolves in water and / or aqueous solutions.

[0128] The term “hydrophobic” refers to compounds, chemical species or functional groups, that do not significantly dissolve in water and / or aqueous solutions and / or which preferentially dissolve in fats and / or non-aqueous solutions.

[0129] A dashed line representing a bond in a chemical formula indicates that the bond can be either present or absent.

[0130] The term “monovalent” as used herein refers to a chemical moiety that has one site available for chemical bonding to another chemical moiety. Thus, a “monovalent moiety” can be a part of whole molecule that is attached to the remainder of the whole molecule via an attachment at one site on the monovalent moiety.

[0131] The term “bivalent” as used herein refers to a chemical moiety that has two sites available for chemical bonding to another chemical moiety or moieties.

[0132] III. REPRESENTATIVE COMPOSITIONS OF THE PRESENTLY DISCLOSED SUBJECT MATTER

[0133] The overuse of opioid drugs for treating chronic pain has led to an opioid epidemic, where overdose deaths continue to rise despite a lack of effective treatments for opioid use disorder (OUD). Recently, psychedelic compounds (psilocibin, lysergic acid diethyl amide (LSD) and 3,4-methylenedioxymethamphetamine (MDMA)) have shown promise to treat OUD by decreasing drug-dependence. It is hypothesized that the decrease in drugdependency is due to activation of the serotonin 2A receptor (5-HT2A). However, many psychedelics exhibit polypharmacology, including activation of multiple serotonin Attorney Docket No. 3270 / 30 PCT receptors. 5-HT2chas also been targeted by molecules as potential treatments for addiction. To identify selective 5-HT agonists, publicly available data was used to create machine learning models for 5-HT2A, 2B, and 2c that could be used in a generative machine learning approach. Compounds were computationally designed and scored followed by synthesis based on their selectivity profile, ultimately leading to the discovery of a new tryptamine derivative, CPI-7168 (also referred to herein as CPI-CG-8), which exhibits relatively selective agonism of 5-HT2C (ECso = 12 nM). Subsequent in vivo evaluation in mice saw significant levels of CPI-7168 in the brain, despite rapid clearance and low stability in liver microsomes in vitro. CPI-7168 represents a promising lead molecule as a new 5-HT2C selective agonist for OUD and other potential therapeutic indications, such as, but not limited to, another addiction disorder, depression, obesity, sexual dysfunction, a developmental and epileptic encephalopathy (DEE), seizures, and / or another condition treatable by agonism of 5-HT2C (e.g., anxiety).

[0134] Accordingly, in some examples, the presently disclosed subject matter provides a 5- HT agonist (e.g., a 5-HT2 agonist). In some examples, the compound is a selective agonist of 5-HT2A, 5-HT2B, and / or 5-HT2C. In some examples, the 5-HT agonist is a 5-HT2A partial agonist. In some examples, the 5-HT agonist is a 5-HT2C selective agonist. In some examples, the 5-HT agonist is a 5-HT2A partial agonist and a 5-HT2C selective agonist. In some examples, the presently disclosed subject matter provides an indole derivative selected from one of the compounds described in Example 2, e.g., CPI-7161, CPI-7162, CPI-7163, CPI-7164, CPI-7165, CPI-7166, CPI-7167, CPI-7168, CPI-7169, CPI-7170 or a compound of the Formula:

[0135] (i.e., a 5 -fluorotryptamine), e.g., wherein R is alkyl or substituted alkyl. In some examples, the 5 -fluorotryptamine is CPI-7171, CPI-7172, CPI-7173, CPI-7174, or CPI-7175. In some examples, the compound from Example 2 is provided as a pharmaceutically acceptable salt. In some examples, the compound is N-(2-(lH-indol-2-yl)ethyl)-2-(lH-indol-3-yl)-N- methylethan-1 -amine, i.e., CPI-7168. In some examples, the presently disclosed subject matter provides the 5-HT agonist (e.g., the 5-HT2 agonist) and / or indole derivative for use in treating a mental health condition, an addiction disorder (e.g., in treating OUD), depression, obesity, sexual dysfunction, a developmental and epileptic encephalopathy Attorney Docket No. 3270 / 30 PCT

[0136] (DEE), seizures, and / or another condition treatable by agonism of 5-HT2A and / or 5-HT2C. Other exemplary conditions are described elsewhere herein.

[0137] As noted above, in some examples, a compound or compounds of the presently disclosed subject matter (i.e., the 5-HT agonists, such as N-(2-(lH-indol-2-yl)ethyl)-2-(lH- indol-3-yl)-N-methylethan-l-amine, i.e., CPI-7168) can be provided as pharmaceutically acceptable salts. Such salts include, but are not limited to, pharmaceutically acceptable acid addition salts, pharmaceutically acceptable base addition salts, pharmaceutically acceptable metal salts, ammonium and alkylated ammonium salts, and combinations thereof.

[0138] Acid addition salts include salts of inorganic acids as well as organic acids. Representative examples of suitable inorganic acids include hydrochloric, hydrobromic, hydroiodic, phosphoric, sulfuric, nitric acids and the like. Representative examples of suitable organic acids include formic, acetic, trichloroacetic, trifluoroacetic, propionic, benzoic, cinnamic, citric, fumaric, glycolic, lactic, maleic, malic, malonic, mandelic, oxalic, picric, pyruvic, salicylic, succinic, methanesulfonic, ethanesulfonic, tartaric, ascorbic, pamoic, bismethylene salicylic, ethanedisulfonic, gluconic, citraconic, aspartic, stearic, palmitic, EDTA, glycolic, p-aminobenzoic, glutamic, benzenesulfonic, p-toluenesulfonic acids, sulphates, nitrates, phosphates, perchlorates, borates, acetates, benzoates, hydroxynaphthoates, glycerophosphates, ketoglutarates and the like.

[0139] Base addition salts include but are not limited to, ethylenediamine, N-methyl- glucamine, lysine, arginine, ornithine, choline, N, N'- dibenzylethylenediamine, chloroprocaine, diethanolamine, procaine, N-benzylphenethylamine, diethylamine, piperazine, tris (hydroxymethyl)- aminomethane, tetramethylammonium hydroxide, triethylamine, dibenzylamine, ephenamine, dehydroabietylamine, N-ethylpiperidine, benzylamine, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, ethylamine, basic amino acids, e. g., lysine and arginine dicyclohexylamine and the like.

[0140] Examples of metal salts include lithium, sodium, potassium, magnesium salts and the like. Examples of ammonium and alkylated ammonium salts include ammonium, methylammonium, dimethylammonium, trimethylammonium, ethylammonium, hydroxyethylammonium, diethylammonium, butylammonium, tetramethylammonium salts and the like.

[0141] In some examples, the presently disclosed compounds can further be provided as a solvate. Attorney Docket No. 3270 / 30 PCT

[0142] IV. REPRESENTATIVE METHODS AND USES OF THE PRESENTLY

[0143] DISCLOSED SUBJECT MATTER

[0144] In some examples the presently disclosed subject matter provides a method of treating a condition treatable by agonism of a serotonin 2 receptor (5-HT2), including 5- HT2A, 5-HT2B, and / or 5-HT2C in a subject in need thereof. In some examples, the method comprises administering a compound of the presently disclosed subject matter to a subject in need thereof. In some examples, the presently disclosed subject matter provides the use of a compound of the presently disclosed subject matter in preparing a medicament for treating a condition treatable by agonism of a serotonin 2 receptor (5-HT2), including 5- HT2A, 5-HT2B, and / or 5-HT2C in a subject in need thereof. In some examples, the conditon is treatable by agonism of 5-HT2A and / or 5-HT2C. In some examples, the subject is suffering from one or more conditions as disclosed herein.

[0145] In some examples, the condition is a mental heatlh condition, including a psychosis, inlcuding mental health conditions characterized by psychosis, including but not limited to schizophrenia, schizoaffective disorder, and / or a delusional disorder. In some examples the mental health condition is a neurodegenerative disease, such as Alzheimer’s disease and / or Parkinson’s disease. In some examples, the mental health condition is depression and / or bipolar depression. In some examples, the mental health condition is seizures.

[0146] In some examples, the condition is an inflammatory disease in several tissues including cardiovascular inflammation, gut inflammation, and / or TNF-alpha-induced inflammation. In some examples, the condition is pain in the subject, and thus, the presently disclosed subject matter provides a method of treating pain. In some examples the conidition is developmental encephalopathy and / or epileptic encephalopathy, including a range of syndromes such as Dravet Syndrome, Lennox-Gastaut syndrome, Juvenile CLN3 Batten disease, CLN2 Batten disease, tuberous sclerosis complex, CDKL5 deficiency disorder, Sturge-Weber syndrome and / or other rare epileptic disorders. In some examples, the addiction disorder is opioid use disorder (OUD) and / or other addictive pharmacological agent.

[0147] In some examples, the presently disclosed subject matter provides a method of treating an addiction disorder, depression, obesity, sexual dysfunction, a developmental and epileptic encephalopathy (DEE), seizures, and / or another condition treatable by agonism of 5-HT2C. In some examples, the method comprises administering a compound of the presently dsi closed subject matter to a subject in need thereof. In some examples, the addiction disorder is opioid use disorder (OUD). Attorney Docket No. 3270 / 30 PCT

[0148] In some examples, the presently disclosed subject matter provides the use of a compound of the presently dsi closed subject matter in preparing a medicament for treating an addiction disorder depression, obesity, sexual dysfunction, a developmental and epileptic encephalopathy (DEE), seizures, and / or another condition treatable by agonism of 5-HT2c, in a subject in need thereof. In some examples, the addiction disorder is opioid use disorder (OUD).

[0149] In some examples, the presently disclosed subject matter provides a method of treating a mental heatlh condition, including a psychosis, inlcuding mental health conditions characterized by psychosis, including but not limited to schizophrenia, schizoaffective disorder, and / or a delusional disorder. In some examples, the mental health condition is a neurodegenerative disease, such as Alzheimer’s disease and / or Parkinson’s disease. In some examples, the mental health condition is depression and / or bipolar depression. In some examples, the method comprises administering a compound of the presently dsiclosed subject matter to a subject in need thereof. In some examples, the presently disclosed subject matter provides the use of a compound of the presently disclosed subject matter in preparing a medicament for treating a mental heatlh condition, including a psychosis, inlcuding mental health conditions characterized by psychosis, including but not limited to schizophrenia, schizoaffective disorder, and / or a delusional disorder. In some examples the mental health condition is a neurodegenerative disease, such as Alzheimer’s disease and / or Parkinson’s disease. In some examples, the mental health condition is depression and / or bipolar depression. In some examples, the mental health condition is seizures.

[0150] In some examples, the compound of the presently disclosed subject matter is a 5-HT agonist (e.g., a 5-HT2 agonist). In some examples, the compound is a selective agonist of 5-HT2A, 5-HT2B, and / or 5-HT2C. In some examples, the 5-HT agonist is a 5-HT2A partial agonist. In some examples, the 5-HT agonist is a 5-HT2C selective agonist. In some examples, the 5-HT agonist is a 5-HT2A partial agonist and a 5-HT2C selective agonist. In some examples, the presently disclosed subject matter provides an indole derivative selected from one of the compounds described in Example 2, e.g., CPI-7161, CPI-7162, CPI-7163, CPI-7164, CPI-7165, CPI-7166, CPI-7167, CPI-7168, CPI-7169, CPI-7170 or a compound of the Formula: Attorney Docket No. 3270 / 30 PCT

[0151] (i.e., a 5 -fluorotryptamine), e.g., wherein R is alkyl or substituted alkyl. In some examples, the 5 -fluorotryptamine is CPI-7171, CPI-7172, CPI-7173, CPI-7174, or CPI-7175. In some examples, the compound from Example 2 is provided as a pharmaceutically acceptable salt. In some examples, the compound is N-(2-(lH-indol-2-yl)ethyl)-2-(lH-indol-3-yl)-N- methylethan-1 -amine, i.e., CPI-7168. In some examples, the presently disclosed subject matter provides a 5-HT agonist (e.g., the 5-HT2 agonist) and / or indole derivative. In some examples, the compound is provided as a pharmaceutically acceptable salt.

[0152] A compound of the presently disclosed subject matter can be used on a sample either in vitro (for example, on isolated cells or tissues) or in vivo in a subject (i.e. living organism, such as a patient). In some examples, the subject or patient is a human subject, although it is to be understood that the principles of the presently disclosed subject matter indicate that the presently disclosed subject matter is effective with respect to all vertebrate species, including mammals, which are intended to be included in the terms “subject” and “patient”. Moreover, a mammal is understood to include any mammalian species for which employing the compositions and methods disclosed herein is desirable, particularly agricultural and domestic mammalian species.

[0153] As such, the methods of the presently disclosed subject matter are particularly useful in warm-blooded vertebrates. Thus, the presently disclosed subject matter concerns mammals and birds. More particularly provided are methods and compositions for mammals such as humans and non-human primates, as well as other mammals of importance due to being endangered (such as Siberian tigers), of economic importance (animals raised on farms for consumption by humans), and / or of social importance (animals kept as pets or in zoos) to humans, for instance, carnivores other than humans (such as cats and dogs), swine (pigs, hogs, and wild boars), ruminants (such as cattle, oxen, sheep, giraffes, deer, goats, bison, and camels), and horses. Also provided is the treatment of birds, including the treatment of those kinds of birds that are endangered, kept in zoos or as pets (e.g., parrots), as well as fowl, and more particularly domesticated fowl, for example, poultry, such as turkeys, chickens, ducks, geese, guinea fowl, and the like, as they are also of economic importance to humans. Thus, also provided is the treatment of livestock including, but not limited to domesticated swine (pigs and hogs), ruminants, horses, poultry, and the like.

[0154] In some examples, a compound of the presently disclosed subject matter can include more than one of the compounds described herein or can include one or more of the compounds and one or more additional therapeutic agents. Thus, in some examples, the compound or compounds can be administered along with one or more additional therapeutic agents known in the art for treating a disease, disorder or condition treatable by agonism of 5-HT, e.g., agonism Attorney Docket No. 3270 / 30 PCT of 5-HT2A and / or 5-HT2C. The compounds and the one or more additional therapeutic agents can be provided in a single formulation or co-administered in separate formulations at about the same time or at different times (e.g., different times within the same day, week, or month).

[0155] In some examples, a compound of the presently disclosed subject matter can be formulated as a pharmaceutical composition. A compound of the presently disclosed subject matter can be administered as a pharmaceutical composition where the compound can be admixed with one or more pharmaceutically acceptable carriers. The term "pharmaceutically acceptable carrier" means a non-toxic material that does not interfere with the effectiveness of the biological activity of the active ingredients. In some examples, the pharmaceutically acceptable composition can also contain salts, buffering agents, preservatives, compatible carriers, and optionally other therapeutic agents.

[0156] Suitable methods for administration of a compound of the presently disclosed subject matter or pharmaceutically acceptable composition thereof to a subject include, but are not limited to intravenous injection, oral administration, buccal, topical, subcutaneous administration, intraperitoneal injection, pulmonary, intanasal, intracranial injection, and rectal administration. The particular mode of administering a composition matter depends on various factors, including the distribution and abundance of cells to be treated and mechanisms for metabolism or removal of the composition from its site of administration.

[0157] An effective dose of a compound of the presently disclosed subject matter is administered to a subject. Actual dosage levels of constituents of the compound of the presently disclosed subject matter can be varied so as to administer an amount of the composition that is effective to achieve the desired effect for a particular subject and / or target. The selected dosage level can depend upon the activity of the composition and the route of administration. In some examples, a compound of the presently disclosed subject matter can be used in dosages from 0.001 - 1000 mg / kg body weight.

[0158] After review of the disclosure herein of a compound if the presently disclosed subject matter, one of ordinary skill in the art can tailor the dosages to an individual subject, taking into account the particular formulation, method of administration to be used with the composition, and nature of the target to be treated. Such adjustments or variations, as well as evaluation of when and how to make such adjustments or variations, are well known to those of ordinary skill in the art.

[0159] The therapeutically effective amount can be determined by testing the compounds in an in vitro or in vivo model and then extrapolating therefrom for dosages in subjects of interest, e.g., humans. The therapeutically effective amount should be enough to exert a therapeutically Attorney Docket No. 3270 / 30 PCT useful effect in the absence of undesirable side effects in the subject to be treated with the composition.

[0160] Pharmaceutically acceptable carriers are well known to those skilled in the art and include, but are not limited to, from about 0.01 to about 0.1M and preferably 0.05M phosphate buffer or 0.8% saline. Such pharmaceutically acceptable carriers can be aqueous or non-aqueous solutions, suspensions and emulsions. Examples of non-aqueous solvents suitable for use in the presently disclosed subject matter include, but are not limited to, propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate. Aqueous carriers suitable for use in the presently disclosed subject matter include, but are not limited to, water, ethanol, alcoholic / aqueous solutions, glycerol, emulsions or suspensions, including saline and buffered media. Oral carriers can be elixirs, syrups, capsules, tablets and the like.

[0161] Liquid carriers suitable for use in the presently disclosed subject matter can be used in preparing solutions, suspensions, emulsions, syrups, elixirs and pressurized compounds. The active ingredient can be dissolved or suspended in a pharmaceutically acceptable liquid carrier such as water, an organic solvent, a mixture of both or pharmaceutically acceptable oils or fats. The liquid carrier can contain other suitable pharmaceutical additives such as solubilizers, emulsifiers, buffers, preservatives, sweeteners, flavoring agents, suspending agents, thickening agents, colors, viscosity regulators, stabilizers or osmo-regulators.

[0162] Liquid carriers suitable for use in the presently disclosed subject matter include, but are not limited to, water (partially containing additives as above, e.g. cellulose derivatives, preferably sodium carboxymethyl cellulose solution), alcohols (including monohydric alcohols and polyhydric alcohols, e.g. glycols) and their derivatives, and oils (e.g. fractionated coconut oil and arachis oil). Lor parenteral administration, the carrier can also include an oily ester such as ethyl oleate and isopropyl myristate. Sterile liquid carriers are useful in sterile liquid form comprising compounds for parenteral administration. The liquid carrier for pressurized compounds disclosed herein can be halogenated hydrocarbon or other pharmaceutically acceptable propellent.

[0163] Solid carriers suitable for use in the presently disclosed subject matter include, but are not limited to, inert substances such as lactose, starch, glucose, methyl-cellulose, magnesium stearate, dicalcium phosphate, mannitol and the like. A solid carrier can further include one or more substances acting as flavoring agents, lubricants, solubilizers, suspending agents, fillers, glidants, compression aids, binders or tablet-disintegrating agents; it can also be an encapsulating material. In powders, the carrier can be a finely divided solid which is in admixture with the finely divided active compound. In tablets, the active compound is mixed Attorney Docket No. 3270 / 30 PCT with a carrier having the necessary compression properties in suitable proportions and compacted in the shape and size desired. The powders and tablets preferably contain up to 99% of the active compound. Suitable solid carriers include, for example, calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, polyvinylpyrrolidine, low melting waxes and ion exchange resins.

[0164] Parenteral carriers suitable for use in the presently disclosed subject matter include, but are not limited to, sodium chloride solution, Ringer's dextrose, dextrose and sodium chloride, lactated Ringer's and fixed oils. Intravenous carriers include fluid and nutrient replenishers, electrolyte replenishers such as those based on Ringer's dextrose and the like. Preservatives and other additives can also be present, such as, for example, antimicrobials, antioxidants, chelating agents, inert gases and the like.

[0165] Carriers suitable for use in the presently disclosed subject matter can be mixed as needed with disintegrants, diluents, granulating agents, lubricants, binders and the like using conventional techniques known in the art. The carriers can also be sterilized using methods that do not deleteriously react with the compounds, as is generally known in the art. The compounds disclosed herein can take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and can contain formulatory agents such as suspending, stabilizing and / or dispersing agents. The compounds disclosed herein can also be formulated as a preparation for implantation or injection. Thus, for example, the compounds can be formulated with suitable polymeric or hydrophobic materials (e.g., as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives (e.g., as a sparingly soluble salt). Alternatively, the active ingredient can be in powder form for constitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use. Suitable formulations for each of these methods of administration can be found, for example, in Remington: The Science and Practice of Pharmacy, A. Gennaro, ed., 20th edition, Lippincott, Williams & Wilkins, Philadelphia, Pa.

[0166] For example, formulations for parenteral administration can contain as common excipients sterile water or saline, polyalkylene glycols such as polyethylene glycol, oils of vegetable origin, hydrogenated naphthalenes and the like. In particular, biocompatible, biodegradable lactide polymer, lactide / glycolide copolymer, or polyoxyethylenepolyoxypropylene copolymers can be useful excipients to control the release of active compounds. Other potentially useful parenteral delivery systems include ethylene-vinyl acetate copolymer particles, osmotic pumps, implantable infusion systems, and liposomes. Formulations for inhalation administration contain as excipients, for example, lactose, or can be aqueous solutions containing, for example, polyoxyethylene-9-auryl ether, glycocholate and deoxycholate, or oily solutions for administration in the form of nasal drops, or as a gel to be Attorney Docket No. 3270 / 30 PCT applied intranasally. Formulations for parenteral administration can also include glycocholate for buccal administration, methoxysalicylate for rectal administration, or citric acid for vaginal administration.

[0167] Further, formulations for intravenous administration can comprise solutions in sterile isotonic aqueous buffer. Where necessary, the formulations can also include a solubilizing agent and a local anesthetic to ease pain at the site of the injection. Generally, the ingredients are supplied either separately or mixed together in unit dosage form, for example, as a dry lyophilized powder or water free concentrate in a hermetically sealed container such as an ampule or sachet indicating the quantity of active agent. Where the compound is to be administered by infusion, it can be dispensed in a formulation with an infusion bottle containing sterile pharmaceutical grade water, saline or dextrose / water. Where the compound is administered by injection, an ampule of sterile water for injection or saline can be provided so that the ingredients can be mixed prior to administration.

[0168] Suitable formulations further include aqueous and non-aqueous sterile injection solutions that can contain antioxidants, buffers, bacteriostats, bactericidal antibiotics and solutes that render the formulation isotonic with the bodily fluids of the intended recipient; and aqueous and non-aqueous sterile suspensions, which can include suspending agents and thickening agents.

[0169] The compounds can further be formulated for topical administration. Suitable topical formulations include one or more compounds in the form of a liquid, lotion, cream or gel. Topical administration can be accomplished by application directly on the treatment area. For example, such application can be accomplished by rubbing the formulation (such as a lotion or gel) onto the skin of the treatment area, or by spray application of a liquid formulation onto the treatment area.

[0170] In some formulations, bioimplant materials can be coated with the compounds so as to improve interaction between cells and the implant.

[0171] Formulations of the compounds can contain minor amounts of wetting or emulsifying agents, or pH buffering agents. The formulations comprising the compound can be a liquid solution, suspension, emulsion, tablet, pill, capsule, sustained release formulation, or powder. The compounds can be formulated as a suppository, with traditional binders and carriers such as triglycerides.

[0172] Oral formulations can include standard carriers such as pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, polyvinyl pyrollidone, sodium saccharine, cellulose, magnesium carbonate, etc. Attorney Docket No. 3270 / 30 PCT

[0173] In some examples, the pharmaceutical composition comprising a compound or compounds of the presently disclosed subject matter can include an agent which controls release of the compound, thereby providing a timed or sustained release compound.

[0174] V. EXAMPLES

[0175] The following Examples have been included to provide guidance to one of ordinary skill in the art for practicing representative examples of the presently disclosed subject matter. In light of the present disclosure and the general level of skill in the art, those of skill can appreciate that the following Examples are intended to be exemplary only and that numerous changes, modifications, and alterations can be employed without departing from the scope of the presently disclosed subject matter.

[0176] EXAMPLE 1

[0177] Generative Machine Learning

[0178] MEGASYN™ generative model was utilized for the generative design of molecules, as described in a recent publication43, 44. MEGASYN™ generative model is initially trained on a large dataset of druglike molecules curated from ChEMBL60. The pretrained model can be “primed” by training on specified molecules, then trained to optimize multiple target scores simultaneously by a hill-climb training routine (training on top-scoring generated compounds). MEGASYN™ generative model target scores can be defined by outputs from predictive models, similarity comparisons, or anything else that can produce a numerical score.

[0179] For the first round of compounds (CPI-7161 through 7170, also referred to as CPL CG-1 through 10), binary random forest classification models were built to predict target activity on 5-HT2A, 2B, and 2c using ECso data curated from ChEMBL with an activity threshold of 100 nM. We optimized hyperparameters and validated the models using nested 5-fold cross validation. See Figures 1A-1C. MEGASYN™ models were primed with the psilocin structure but did not enforce this structure during the subsequent hill-climb training phase. During hill-climb training, we ranked molecules based on a composite score that maximizes the model score for 5-HT2A while minimizing the model scores for 2B and 2c. We discarded molecules that scored below fixed thresholds for QED score and a synthetic accessibility score adapted from the literature, as a means of filtering out unreasonable structures61, 62. Finally, we generated thousands of molecules from the fully trained MEGASYN™ models, ranked them by 5-HT2A activity scores, and selected 10 compounds Attorney Docket No. 3270 / 30 PCT for synthesis and testing based on predicted 5-HT2 receptor activity scores and synthesizability.

[0180] For the second round of compounds (TJ26 XX, CPI-7171 through 7175), support vector regression models were built to predict ECso values for 5-HT2A, 2B, and 2c using the same datasets as the binary models. We optimized hyperparameters and validated the models using nested 5-fold cross validation. See Figures 1A-1C. MEGASYN™ models were primed with the tryptamine substructure, and discarded molecules during hill-climb training if they did not contain the tryptamine substructure; this ensures that the MEGASYN™ models are only trained on molecules with the tryptamine substructure. Hillclimb training proceeded as before, except that the composite score used to rank generated molecules was based on regression models instead of binary models (where regression values were mapped to a score between 0 and 1 using a sigmoid function). We generated thousands of samples and kept 200 molecules with the highest predicted 5-HT2A ECSO and another 200 with the highest composite score representing selectivity of 5-HT2A over 5- HT2C. From these compounds, five were selected for synthesis and testing based on predicted 5-HT2 ECso values and synthesizability62.

[0181] EXAMPLE 2

[0182] Compound Synthesis

[0183] The first round of compounds (CPI-7161 through CPI-7170, also referred to herein as CPLCG-1 through 10) were synthesized as follows:

[0184] 3-(6-methyl-lH-indol-3-yl)propan-l-ol (CPI-7161, also referred to herein as CP-CG-

[0185] 1)

[0186] To a solution of m-tolylhydrazine hydrochloride (0.5 g, 3.16 mmol) in 3 mL of 4% aqueous sulfuric acid solution and 5 mL of acetonitrile, was added 3,4-dihydropyran (0.318 g, 3.79 mmol) dropwise within a period of 2 minutes at 100°C. The reaction mixture was stirred for 2 hours at 100°C, then cooled to room temperature and carefully poured into 30 mL of saturated NaHCCh solution. Then the product was extracted with ethyl acetate (20 mL x 3). Combined organic layer was dried over anhydrous sodium sulfate and evaporated to give the crude compound which was columned to afford 0.521 g.JH NMR (500 MHz, METHANOL-d4) 6 ppm 1.85 - 2.02 (m, 2 H) 2.42 (s, 3 H), 2.79 (m, 2 H) 3.62 (m, 2 H) Attorney Docket No. 3270 / 30 PCT

[0187] 6.77 - 6.88 (m, 1 H), 6.93 (s, 1 H), 7.07 - 7.17 (m, 1 H), 7.34 - 7.46 (m, 1 H). LCMS expected: 189.2, found: (M+H) 190.0.

[0188] N,N-dimethyl-2-(5-phenoxy-lH-indol-3-yl)ethan-l-amine (CPI-7162, also referred to herein as CP-CG-2)

[0189] To a solution of 2-(5-bromo-lH-indol-3-yl)ethan-l-amine (0.858 g, 3.591 mmol) in anhydrous methanol (20 mL) was added potassium acetate (0.382 g, 0.389 mmol) followed by sodium cyanoborohydride (0.881 mg, 14.02mmol ) under Ar atmosphere at 0 °C. A solution of formalin (38%, 8.616 mmol) in anhydrous methanol (15 mL) was then added dropwise , and the resulting solution was stirred at room temperature for 16 h. Aqueous Na2CC>3 (2 N) was added to adjust pH to 8-9 and the methanol was removed under reduce pressure. The residue was partitioned between DCM and water. The organic layer was washed with water and brine, dried over Na2SO4, and concentrated in vacuo to afford 2-(5- bromo-lH-indol-3-yl)-N,N-dimethylethan-l-amine (0.5 g, 52% yield). The crude product was taken to the next step.

[0190] To a stirred solution of 2-(5-bromo-lH-indol-3-yl)-N,N-dimethylethan-l-amine (0.5 g, 1.87 mmol) in dioxane (5 mL), Cui (70 mg, 0.36 mmol) and L-proline (120 mg, 1.04 mmol) were added under argon atmosphere, then phenol (230 mg, 2.44 mmol) was added and resulting mixture was stirred at 90 °C overnight. The solution was added to water, extracted with EA, dried over Na2SO4, concentrated in vacuo to give crude product which was purified by HPLC over a XB ridge Cl 8 100x19mm, 5um to obtain CG-CP-2 in 20 mg. ‘HNMR (500 MHz, METHANOL-d4) 8 ppm 2.34 (s, 6 H) 2.60 - 2.69 (m, 2 H), 2.85 - 2.93 (m, 2 H), 6.81 - 6.86 (m, 2 H), 6.87 - 6.93 (m, 1 H), 6.96 - 7.02 (m, 1 H), 7.12 (s, 1 H), 7.16 - 7.20 (m, 1 H), 7.24 - 7.30 (m, 2 H), 7.32 - 7.37 (m, 1 H). LCMS expected: 280.4, found: (M+H) 281.0.

[0191] 3-((l-methyl-lH-pyrrol-2-yl)methyl)-lH-indol-4-ol (CPI-7163, also referred to herein as CP-CG-3) Attorney Docket No. 3270 / 30 PCT

[0192] To a solution of lH-indol-4-ol (0.5 g, 3.76 mmol) in DCM (10 mL) was added 1- methyl-lH-pyrrole-2-carbaldehyde (0.492 g, 4.51 mmol) and sodium borohydride (0.213 g, 5.63 mmol, 1.5 equiv) at rt. Acetic acid (1.128 g, 18.78 mmol, 1.0842 mL) was slowly added for 2 minutes. The resulting mixture was stirred at 40°C overnight. Upon completion of the reaction (monitored by LCMS), solvent was evaporated and EtOAc (10 mL) was added. The organic layer was washed with water (2 x 10 mL), aq. solution of NaHCCh (2x10 mL) and brine (2 x 5 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford the crude material which was purified by HPLC using a Water Sunfire C18 OBD; Prep Column; 100 A, 5 pm, 19mm x 100 mm to afford the desired compound (25.7 mg, 95% purity, 3.2% yield). 1H NMR (500 MHz, METHANOL-d4) 8 ppm 3.32 (s, 3 H) 4.25 (s, 2 H) 5.84 - 5.90 (m, 1 H) 5.92 - 5.98 (m, 1 H) 6.28 - 6.37 (m, 1 H) 6.41 - 6.47 (m, 1 H) 6.52 - 6.61 (m, 1 H) 6.75 - 6.91 (m, 2 H). LCMS expected: 226.3, found: (M+H) 227.1.

[0193] 2-benzyl-3-(dimethylamino)propan-l-ol (CPI-7164, also referred to herein as CP- CG-4)

[0194] To a solution of ethyl 2-benzyl-3-(dimethylamino)propanoate (1.0 g, 4.25 mmol) in THF cooled to 0 °C was added a 1 ,0M solution of lithium aluminum hydride in THF (12.75 mL). The contents were then warmed to room temperature after the addition. On completion of the reaction, a 2 N NaOH solution was added to quench the reaction. The solids were filtered and then washed with additional THF. After drying over magnesium sulfate, the contents were concentrated over vacuum and then purified using an Agilent Cl 8 column, 5 pm, 19mm x 150 mm to afford 0.53 g of the desired product. 'H NMR (500 MHz, METHANOL-d4) 6 ppm 2.01 - 2.11 (m, 1 H), 2.20 (s, 6 H), 2.23 - 2.30 (m, 1 H) 2.38 - 2.51 (m, 1 H), 2.58 (m, 2 H), 3.45 - 3.58 (m, 2 H), 7.13 - 7.24 (m, 3 H), 7.28 (m, 2 H). LCMS expected: 193.3, found: (M+H) 194.0.

[0195] 3-(2-(piperidin-l-yl)ethyl)-lH-indole (CPI-7165, also referred to herein as CP-CG-5)

[0196] To a solution of 2-(lH-indol-2-yl) ethyl methanesulfonate (0.5 g, 2.1 mmol) in ACN (5 mL) was added piperidine (0.62 ml, 6.3 mmol). The contents were heated for an hour Attorney Docket No. 3270 / 30 PCT and then concentrated. HPLC purification over an Agilent C18 column, 5 pm, 19 mm x 150 mm to afford 0.18 g of the desired product as the formate salt. 'H NMR (500 MHz, METHANOL-d4) 6 ppm 1.45 - 1.58 (m, 2 H) 1.63 - 1.73 (m, 4 H), 2.46 - 2.74 (m, 6 H), 2.91 - 3.05 (m, 2 H) 6.92 - 7.14 (m, 3 H) 7.27 - 7.39 (m, 1 H) 7.49 - 7.58 (m, 1 H). LCMS expected: 228.3, found: (M+H) 228.9.

[0197] PhB OH Pd d f CI

[0198] N,N-dimethyl-2-(5-phenyl-lH-indol-3-yl)ethan-l-amine (CPI-7166, also referred to herein as CP-CG-6)

[0199] To a solution of 2-(5-bromo-lH-indol-3-yl)-N,N-dimethylethan-l-amine (0.2 g, 0.75 mmol) in dioxane was added phenylboronic acid (119 mg, 0.98 mmole), potassium phosphate (0.391 g, 2.25 mmole) and Pd(dppf C12-CH2C12 (60 mg). After degassing with nitrogen the contents were heated at reflux under nitrogen for 16h. After cooling the reaction was filtered over celite and then concentrated. Column chromatography afforded the desired product 0.08 g. 'H NMR (500 MHz, METHANOL-d4) 8 ppm 2.38 (s, 6 H), 2.67 - 2.79 (m, 2 H) 2.93 - 3.08 (m, 2 H) 7.08 - 7.16 (m, 1 H) 7.22 - 7.32 (m, 1 H) 7.41 (m, 5 H) 7.60 - 7.71 (m, 2 H) 7.72 - 7.81 (m, 1 H). LCMS expected: 264.4, found: (M+H) 265.0.

[0200] 3-(2-(dimethylamino)ethyl)-N-phenyl-lH-indol-5-amine (CPI-7167, also referred to herein as CP-CG-7)

[0201] To a solution of 2-(5-bromo-lH-indol-3-yl)-N,N-dimethylethan-l-amine (300 mg, 1.12 mmol) in dioxane (3 mL), CS2CO3 (0.731 g, 2.24 mmol), Pd(dba)2 (50 mg, 0.054 mmol), Xantphos (60 mg, 0.103 mmol) were added under Ar atmosphere, then aniline (130 mg, 1.39 mmol) was added, followed by stirring at 95 °C overnight. The reaction solution was diluted with water, extracted with EtOAc, dried over Na2SC>4, concentrated in vacuo to give crude product which was purified by flash chromatography (CHCI3 -MeOH) to obtain the compound CG-CP-7 in 30 mg, 9.6% yield. 'H NMR (500 MHz, METHANOL-d4) 6 ppm 2.37 (s, 6 H) 2.62 - 2.73 (m, 2 H) 2.86 - 2.98 (m, 2 H) 6.64 - 6.74 (m, 1 H) 6.90 - 6.99 Attorney Docket No. 3270 / 30 PCT

[0202] (m, 3 H) 7.02 - 7.08 (m, 1 H) 7.09 - 7.18 (m, 2 H) 7.23 - 7.36 (m, 2 H). LCMS expected: 279.4, found: (M+H) 280.2.

[0203] N-(2-(lH-indol-2-yl)ethyl)-2-(lH-indol-3-yl)-N-methylethan-l-amine (CPI-7168, also referred to herein as CP-CG-8)

[0204] To a stirred solution of 2-(lH-indol-2-yl) ethan-l-ol (0.2 g, 1.242 mmol) and triethylamine (0.1632 g, 0.224 mL, 1.613 mmol) in DCM (2.5 mL), methanesulfonyl chloride (0.1705 g, 0.115 mL, 1.49 mmol) was added at 0 °C. The reaction mixture was stirred at 0 °C for 1 h, then the reaction mixture was warmed to rt, and diluted with water. The aqueous layer was extracted with DCM, and the combined organic extracts were washed with brine, dried over Na2SC>4, filtered and concentrated under reduced pressure to afford 2-(lH-indol-2-yl)ethyl methanesulfonate (0.27 g, 90% yield). To the crude material in DMF (3.0 mL) was added DIPEA (0.292 g, 2.26 mmol, 0.39 mL) and the reaction was heated to 80 °C overnight under argon atmosphere. Then the mixture was partitioned between EtOAc and H2O. The organic phase was washed with water and brine, dried over Na2SC>4 and concentrated under vacuo. The residue was purified by HPLC to afford N-(2- (lH-indol-2-yl) ethyl)-2-(lH-indol-3-yl)-N-methylethan-l-amine as the formate salt in 90 mg. 'H NMR (400 MHz, DMSO) 8 10.87 (s, 1H), 10.79 (s, 1H), 7.52 (d, J= 7.8 Hz, 1H), 7.39 (d, J= 7.8 Hz, 1H), 7.33 (d, J= 8.1 Hz, 1H), 7.25 (d, J= 8.0 Hz, 1H), 7.15 (d, J = 2.3 Hz, 1H), 7.06 (t, J= 7.5 Hz, 1H), 7.01 - 6.85 (m, 3H), 6.17 (d, J= 2.0 Hz, 1H), 2.96 - 2.72 (m, 8H), 2.40 (s, 3H).13C NMR (101 MHz, DMSO) 6 138.28, 136.24, 135.94, 128.32, 127.23, 124.95, 122.61, 120.88, 120.05, 119.09, 118.60, 118.29, 118.21, 111.40, 110.66, 98.73, 57.73, 56.56, 41.48, 25.45, 22.45. LCMS expected: 317.4, found: (M+H) 318.1.

[0205] 2-(3-(3-(dimethylamino)propyl)-lH-indol-5-yl)phenol (CPI-7169, also referred to herein as CP-CG-9) Attorney Docket No. 3270 / 30 PCT

[0206] A solution of 3-(5-bromo-lH-indol-3-yl)propan-l-ol (0.529 g, 2.08 mmol) and triethylamine (0.632 g, 6.23 mmol, 0.873 mL) in dichloromethane (5 mL) was cooled to - 20 °C. Then methanesulfonyl chloride (0.286 g, 2.50 mmol) was added dropwise. Afterwards, the solution was allowed to warm up to room temperature. The reaction mixture was poured into water (20 mL) and extracted with dichloromethane (15 mL x 3). The combined organic layers were washed with saturated NaHCCh solution, then dried over anhydrous sodium sulfate and evaporated to obtain the compound (0.582 g, 84% yield, 80% purity by LC / MS), which was used in the next step without further purification. To this crude product was added dimethylamine hydrochloride (0.571 g, 7.00 mmol) and triethylamine (0.979 mL, 0.711 g, 7.00 mmol) in dry acetonitrile (10 mL) was heated at 60°C overnight. Then the solution was poured into saturated NaHSCk solution (20 mL), washed with dichloromethane (10 mL), then the aqueous layer was adjusted to pH=12 with concentrated sodium hydroxide solution. Afterwards the product was extracted with dichloromethane (15 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate and evaporated to give crude compound 5 (0.493 g, 100% yield, LC / MS purity: 68%), which was used in the next step without further purification.

[0207] To a solution of 3-(5-bromo-lH-indol-3-yl)-N,N-dimethylpropan-l-amine (0.493 g, 1.75 mmol) and 2-hydroxyphenylboronic acid (0.424 g ,1.93 mmol) were mixed in dioxane (10 mL) under inert atmosphere (argon), then potassium orthophosphate (1.12 g, 5.28 mmol) was added followed by Pd(dppf)C12-CH2C12 (115 mg). The mixture was degassed and left stirring overnight at 100 °C. Upon completion of the reaction the obtained solution was poured into water (20 mL) and extracted with ethyl acetate (15 mLx3). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and evaporated to give crude compound which was purified by HPLC using a XBridge BEH C18 5um 130A), to obtain the product (119 mg, 23% yield) as the formate salt.JH NMR (400 MHz, METHANOL-d4) 8 ppm 1.85 - 2.01 (m, 2 H) 2.25 (s, 6 H) 2.38 - 2.49 (m, 2 H) 2.74 - 2.85 (m, 2 H) 6.82 - 6.93 (m, 2 H) 7.01 - 7.05 (m, 1 H) 7.07 - 7.15 (m, 1 H) 7.23 - 7.31 (m, 2 H) 7.32 - 7.39 (m, 1 H) 7.63 - 7.72 (m, 1 H). LCMS expected: 294.4, found: (M+H) 295.3.

[0208] 5-methyl-l,3,4,5-tetrahydropyrrolo[4,3,2-de]quinoline (CPI-7170, also referred to herein as CP-CG-10) Attorney Docket No. 3270 / 30 PCT

[0209] To a stirred solution of 3-formyl-4-nitroindole 1 (4 g, 21 mmol) in MeOH (80 mL) and formamide (80 mL), NaBH4 (1 g, 27.3 mmol) was added. The reaction mixture was stirred at room temperature for 1 hour, and NaCN (10.3 g, 210.3 mmol) was added. Then it was heated to 100°C for 5 hours with stirring. After cooling, the resulting solution was diluted with brine and extracted with MeOH-CHCh (5:95). The organic layer was washed with brine, dried over Na2SO4, and evaporated under reduced pressure to give crude residue which was purified by column chromatography (dichloromethane / acetonitrile) to obtain compound 2 (1 g, 24% yield). The crude compound (500 mg, 2.5 mmol) in ethyl acetate (20 mL), 10% Pd / C (100 mg) was added, then the obtained mixture was hydrogenated for 8 hours at 70 °C at 80 atm. The reaction mass was filtered and evaporated in vacuo. The residue was purified by HPLC using XBRIDGE BEH C18 100*19mm to obtain 1, 3,4,5- tetrahydropyrrolo[4,3,2-de]quinoline (149 mg).

[0210] To a stirred solution of the amine (100 mg, 0.63 mmol) in methanol (7 mL), acetic acid (38 mg, 0.63 mmol) and 37% aq. formalin (154 mg, 1.9 mmol) were added. The reaction mixture was stirred at room temperature for 5 minutes, sodium triacetoxyborohydride (0.4 g, 1.9 mmol) was added and stirring was continued overnight. The reaction mixture was analyzed by LCMS and purified by HPLC using CHROMATOREX Cl 8 100* 19mm) to obtain target compound (9.8 mg) as the formate salt. 'HNMR (400 MHz, ACETONITRILE-d3) 8 ppm 2.90 (s, 3 H) 3.01 - 3.06 (m, 2 H) 3.19 - 3.25 (m, 2 H) 6.15 - 6.20 (m, 1 H) 6.69 - 6.73 (m, 2 H) 6.88 - 6.95 (m, 1 H). LCMS expected: 172.2, found: (M+H) 173.0.

[0211] The second round of tryptamines were synthesized utilizing an indole synthesis / reductive amination sequence shown in Scheme 1, below:

[0212] Scheme 1. Synthesis of 5 -fluorotryptamines. Attorney Docket No. 3270 / 30 PCT

[0213] Synthesis of the 5-fluorotyptamines commenced with the Fisher indole synthesis between 4-fluorophenylhydrazine (1) and 2, 3 -dihydrofuran to give 5-fluorotrpytophol (2). Silyl protection of the alcohol and carbamate protection of the indole N-H yielded silyl ether 3. Removal of the silyl group with tetrabutylammonium fluoride and subsequent oxidation with 2-iodoxybenzoic acid yielded aldehyde 4. Lastly, reductive amination with a desired amine gave a secondary amine (5), followed by removal of the carbamate protecting group with trifluoroacetic acid to yield the desired tryptamine (6).

[0214] Additional details of the synthesis of the second round compounds are as follows:

[0215] 5-fluorotryptophol (2)

[0216] The title compound was synthesized according to a modified procedure38. To a solution of 4-fluorophenylhydrazine hydrochloride (1.0 equiv) in THF (1.0 M) at rt was added a suspension of Montmorillonite K10 (0.75x mass of hydrazine) in H2O (0.5 M) and the mixture was heated to 70 °C. After 10 minutes, a solution of 2, 3 -dihydrofuran (1.0 equiv) in a minimal amount of THF was added in a dropwise manner and the reaction was allowed to proceed at 70 °C for 4 hours. The reaction was cooled to rt and the solids were filtered off, washing with EtOAc. The reaction was transferred to a separatory funnel and the aqueous layer was extracted with EtOAc (3x). The combined organic layers were washed with brine (lx), dried over Na2SO4, and concentrated to yield the desired product as a viscous brown oil. Analytical data was in agreement with reported values.

[0217] 1HNMR (400 MHz, CDCh) 6 8.04 (brs, 1H), 7.32 - 7.21 (m, lH), 7.14 (s, 1H), 6.96 (td, J= 9.0, 2.5 Hz, 1H), 3.90 (t, J= 6.3 Hz, 2H), 3.07 - 2.94 (m, 2H).13C NMR (101 MHz, CDCh) 6 157.82 (d, J = 234.3 Hz), 133.06, 127.91 (d, J = 9.5 Hz), 124.45, 112.48 (d, J = 4.8 Hz), 111.95 (d, J = 9.7 Hz), 110.43 (d, J = 26.4 Hz), 103.70 (d, J = 23.4 Hz), 62.54, 28.69. tert-butyl 3-[2-(tert-butyldimethylsiloxy)ethyl]-5-fluoro-U / -indole-l-carboxylate (3)

[0218] To a solution of 2 in CH2CI2 (0.1 M) at rt was added EtsN (3.0 equiv) and TBSC1 (1.2 equiv) successively and the reaction was allowed to proceed at rt. Upon consumption of the SM by TLC, sat. aq. NH4Q and water were added and the aqueous layer was extracted Attorney Docket No. 3270 / 30 PCT with CH2CI2 (3x), and the combined organic layers were tried over Na2SC>4 and concentrated.

[0219] To a solution of the crude silyl ether in CH2CI2 (0.1 M) at rt was added EtiN (3.0 equiv), DMAP (0.1 equiv), and BOC2O (1.2 equiv) successively. The reaction was allowed to proceed at rt. Upon consumption of the SM by TLC, sat. aq. NH4CI and water were added, and the reaction was stirred vigorously for 30 minutes. The layers were separated and the aqueous layer was extracted with CH2CI2 (3x). The combined organic layers were washed with brine (lx), dried over Na2SC>4, and concentrated. The crude material was purified by flash chromatography (10% EtOAc in hexanes) to yield the title compound as a viscous brown oil.

[0220] 'H NMR (400 MHz, CDCh) 6 8.07 (brs, 1H), 7.46 (s, 1H), 7.18 (dd, J= 9.0, 2.5 Hz, 1H), 7.01 (td, J= 9.1, 2.6 Hz, 1H), 3.86 (t, J= 6.8 Hz, 2H), 2.85 (td, J= 6.7, 1.1 Hz, 2H), 1.65 (s, 9H), 0.89 (s, 10H), 0.02 (s, 6H).13C NMR (101 MHz, CDCh) 6 159.31 (d, J = 238.72 Hz), 149.70, 131.94, 132.06, 125.06, 117.95 (d, J = 4.08 Hz), 116.23 (d, J= 9.04 Hz), 111.98 (d, J= 24.99 Hz), 104.85 (d, J= 23.69 Hz), 83.65, 62.88, 28.63, 28.35, 26.08, 18.46, -5.22. tert-butyl 5-fluoro-3-(2-oxoethyl)-U / -indole-l-carboxylate (4)

[0221] To a solution of 3 in THF (0.5 M) at 0 °C was added a 1.0 M solution of TBAF in THF in a rapid dropwise manner and the reaction was allowed to proceed at 0 °C for 4 hours. Upon consumption of the SM by TLC, sat. aq. NaHCCh was added and the reaction was allowed to warm to rt. The aqueous layer was extracted with EtOAc (3x) and the combined organic layers were washed with brine (lx), dried over Na2SO4, and concentrated to yield the crude alcohol as a viscous brown oil.

[0222] To a solution of the crude alcohol in EtOAc (0. IM) at rt was added IBX (3.0 equiv) in one portion. The reaction was heated to reflux for 3 hours. The reaction was cooled to rt and diluted with hexanes, then cooled to 0 °C. The solids were filtered off (washing with hexanes) to yield the crude aldehyde which was purified by flash chromatography (10% EtOAc in hexanes) to yield the title compound as viscous yellow oil.

[0223] ‘HNMR (400 MHz, CDCh) 6 9.78 (t, J= 2.1 Hz, 1H), 8.10 (brs, 1H), 7.61 (s, 1H), 7.15 - 7.02 (m, 2H), 3.74 (dd, J = 2.1, 1.0 Hz, 2H), 1.67 (s, 9H).13C NMR (101 MHz, CDCh) 6 198.05, 159.41 (d, J= 240.0 Hz), 149.33, 137.46, 131.14 (d, J= 9.6 Hz), 126.39, Attorney Docket No. 3270 / 30 PCT

[0224] 116.52 (d, J= 9.1 Hz), 112.63 (d, J= 25.0 Hz), 110.83 (d, J= 4.1 Hz), 104.47 (d, J= 24.0 Hz), 84.26, 39.93, 28.22.

[0225] General procedure: To a solution of aldehyde 4 in methanol (0.1 M) at rt was added the desired amine (1.0 equiv) and NaBHiCN (2.0 equiv) successively. The reaction was treated with glacial AcOH dropwise (bubbling occurs) until the pH maintained below 3 (orange / red to pH paper) and the reaction was allowed to proceed at rt. Upon consumption of the SM by TLC, the reaction was quenched by the addition of NaHCCh and the bulk of the MeOH was removed under reduced pressure. The resulting aqueous solution was extracted with CH2CI2 (3x) and the combined organic layers were concentrated. The crude material was redissolved in Et2O and cooled to 0 °C.1-2 drops of cone, hydrochloric acid was added and the resulting precipitate was collected by vacuum filtration (washing with chilled Et2O) to yield the crude hydrochloride salt as a white powder.

[0226] The crude material was suspended in CH2CI2 (1.0 M) and cooled to 0 °C. TFA (half the volume of CH2CI2) was added in a rapid dropwise manner and the reaction was allowed to proceed at 0 C for 3 hours. The reaction was warmed to rt and concentrated under reduced pressure to yield the crude TFA salt which was purified by reverse phase preparative HPLC to yield the DP as the formate salt.

[0227] A-[2-(5-fluoro-U / -indol-3-yl)ethyl]propan-l-amine (CPI-7171, also referred to herein as TJ26 96)

[0228] The title compound was synthesized according to the general procedure using propylamine. LCMS expected: 220.3, found: (M+H) 221.3. HPLC trace is shown in Figure 9. 3-[2-(2,2-dimethylhydrazinyl)ethyl]-5-fluoro-U / -indole (CPI-7172, also referred to herein as TJ26 108) Attorney Docket No. 3270 / 30 PCT

[0229] The title compound was synthesized according to the general procedure using 1,1- dimethylhydrazine. LCMS expected: 221 :3 (M+H) 222.1. HPLC trace is shown in Figure 10.

[0230] A1-[2-(5-fluoro-U / -indol-3-yl)ethyl]-A3,A3-dimethylpropane-l,3-di amine (CPI-7173, also referred to herein as TJ26 109)

[0231] The title compound was synthesized according to the general procedure using N, N- dimethyl-l,3-propanediamine. LCMS expected: 263.4, found: (M+H) 264.1. The HPLC trace is shown in Figure 11. 3-[2-(5-fluoro-U / -indol-3-yl)ethyl]aminopropanenitrile (CPI-7174, also referred to herein as TJ26 110)

[0232] The title compound was synthesized according to the general procedure using 3- aminopropionitrile. LCMS expected: 231.3, found: (M+H) 231.8. The HPLC trace is shown in Figure 12.

[0233] A-[2-(5-fluoro-U / -indol-3-yl)ethyl]-2,2-dimethylpropan-l -amine (CPI-7175, also referred to herein as TJ26 113)

[0234] The title compound was synthesized according to the general procedure using neopentylamine. LCMS expected: 248.4, found: (M+H) 249.1. The HPLC trace is shown in Figure 13.

[0235] 2-(lH-indol-3-yl)-N-[2-(lH-indol-3-yl)ethyl]-N-methylethanamine (CPI-7176) Attorney Docket No. 3270 / 30 PCT

[0236] To 0.27 g (1.7 mmol) of the alcohol in THF (4 mL) at 0 °C was added NaH (64 mg) followed by the addition of MsCl (0.114 ml). After stirring for 2 h, a solution of 2-(lH- indol-3-yl)-N-methylethan-l -amine (0.29 g, 1.7 mmol) was added in THF (3 mL). The contents were warmed to rt and then heated to reflux for 6 h. The reaction was concentrated and purified by reverse phase chromatography (Cl 8 column, 200mm, 20 micron, 20mm ID) with water w / 0.01% FA and ACN afforded the desired product. (65 mg, 12% yield). 'H NMR (400 MHz, CDCh) 6 8.19 (s, 2H), 7.53 (d, J= 7.9 Hz, 2H), 7.39 (d, J= 8.1 Hz, 2H), 7.23 (t, J= 7.7 Hz, 2H), 7.14 (t, J= 7.5 Hz, 2H), 7.08 (s, 2H), 3.24 - 3.50 (m, 8H), 2.94 (s, 3H).13C NMR (101 MHz, CDCh) 6 136.44, 126.58, 122.94, 122.74, 120.12, 118.23, 111.73, 109.86, 56.64, 40.60, 20.61.

[0237] EXAMPLE 3

[0238] Single-Dose 5-HTi Assays

[0239] Agonist and antagonist activity was evaluated based on the effect of the substrate on IP1 production in transfected HEK-293 cells relative to the control (5-HT) using homogenous time-resolved fluorescence detection

[0240] The assays were performed as described in the literature63. Briefly, the cells are suspended in a buffer containing 10 mM Hepes / NaOH (pH 7.4), 4.2 mM KC1, 146 mM NaCl, 1 mM CaCh, 0.5 mM MgCh, 5.5 mM glucose and 50 mM LiCl, then distributed in microplates at a density of 2x104 cells / well and incubated for 30 min at 37°C in the presence of buffer (basal control), test compound or reference agonist. For stimulated control measurement, separate assay wells contain 1 pM 5-HT. Following incubation, the cells are lysed and the fluorescence acceptor (D2- labeled IP1) and fluorescence donor (anti -IP 1 antibody labeled with europium cryptate) are added. After 60 min at room temperature, the fluorescence transfer is measured at Xex=337 nm and Xem=620 and 665 nm using a microplate reader (Envision, Perkin Elmer). The IP1 concentration is determined by dividing the signal measured at 665 nm by that measured at 620 nm (ratio). The results are expressed as a percent of the control response to 1 pM 5-HT. The standard reference agonist is 5-HT, which is tested in each experiment at several concentrations to generate a concentration-response curve from which its ECso value is calculated.

[0241] As described in Example 1, random forest classification and SVR models for 5- HT2A, 2B and 2c (see Figures 1A-1C) were generated and used in the MEGASYN™ molecule design process enabling the design of molecules (Table 1) that were then synthesized and Attorney Docket No. 3270 / 30 PCT tested. 5-HT2 agonism assays were performed as described in the literature63. Results are shown in Table 1, below.

[0242] More particularly, a panel of 10 initially designed compounds (CPI-CG-1 through 10, also referred to herein as CPI-7161 through 7170) and 5 in-house compounds at 1 pM for agonism of 5-HT2A, 5-HT2B, and 5-HT2C. Agonist activity was evaluated based on the effect of the substrate on IP1 production and is reported as a percentage of serotonin control activity (EC50 = 14 nM (2A), 2.6 nM (2B), and 2.3 nM (2C)).

[0243] Table 1. Agonist activity of tested compounds at 5-HT2A, B, andc (at 1.0 pM). Attorney Docket No. 3270 / 30 PCT

[0244] Structure-Activity Relationship

[0245] Of the compounds tested, very few displayed agonism of 5-HT2A and those that did (CPI-7162, CPI-7171, CPI-7172) were not selective. Compounds lacking the tryptamine substructure or lacking a heteroatom at the indole 5-position did not display significant agonism of any of the three 5-HT2 receptors at 1 pM, the exception being CPI-7168. Most Attorney Docket No. 3270 / 30 PCT compounds were substantially more active at 5-HT2C, with CPI-7162, CPI-7168, CPI-7171, and CPI-7172 exhibiting potent agonism of 5-HT2C. While these were largely non-selective, CPI-7168 displayed the best selectivity profile for the receptors tested. In most cases, smaller alkyl substituents on the basic nitrogen displayed better activity than those with bulkier alkyl groups or additional heteroatoms.

[0246] While we were unable to identify a selective 5-HT2A agonist, we discovered CPI- 7168 as being the most promising 5-HT2C agonist and subsequent 5-dose in vitro assays revealed an ECso of 12 nM (Figure 2). The combination of potent agonism and selectivity, while being the only active compound without a heteroatom at the indole 5-position, makes CPI-7168 a drug lead for further optimization.

[0247] Although the generative models were initially not optimized for 5-HT2C agonism, it is surprising that several compounds displayed activity at 5-HT2C, despite selectivity between 2A and 2c being notably difficult to achieve.

[0248] 5HT2 Dose-Response and ECso Determination

[0249] Given that CPI-7168 showed higher activity at 5HT2C compared to 5HT2A and 5HT2B at 1 pM, we next obtained ECso values against all three targets to gauge selectivity (Table 2, Figures 2-3). We found that CPI-7168 was a full agonist at 5-HT2C (ECso = 12 nM), a partial agonist at 5-HT2A (ECSO = 53 nM, max response = 32.4%), and was not a significant agonist at 5-HT2B (ECso > 1 pM). Furthermore, antagonism assays at the three targets showed that CPI-7168 is a weak antagonist of 5-HT2B (ECSO = 0.2 pM) and 5-HT2C (ECso = 0.8 pM) and does not show significant activity at 5-HT2A (Figure 3).

[0250] Table 2. Summary EC50 determination for CPI-7168 at 5-HT2A, 5-HT2B, and 5-HT2C.

[0251] We also obtained EC50 values of the known bis-tryptamine, 2-(lH-indol-3-yl)-N-[2- (lH-indol-3-yl)ethyl]-N-methylethanamine,54which is a symmetrical regioisomer of CPI- 7168, against the three 5-HT2 receptors to directly compare the effect of the 2- and 3-indolyl moieties (Table 3, Figure 4). Attorney Docket No. 3270 / 30 PCT

[0252] Table 3. Comparison of ECso values for CPI-7168 and CPI-7176 at 5-HT2A, 5-HT2B, and 5- HT2C. While the symmetrical isomer was a more potent agonist at all three receptors, it was significantly less selective, being most active at 5-HT2B and least active at 5-HT2A. Interestingly, the minor structural change between the compounds results in a decreased affinity for 5-HT2B, highlighting the role of the 2-indolyl moiety for selectivity. EXAMPLE 4

[0253] In vitro ADME

[0254] With an acceptable in vitro selectivity and a 5-HT2C ECso of 12 nM, we then assessed the in vitro ADME properties of CPI-7168. See Tables 4-12, below. Table 4. Summary in vitro ADME data for CPI-7168 Attorney Docket No. 3270 / 30 PCT

[0255] Table 5. Human plasma protein binding assay results for CPI-CG-8.

[0256] Table 6. CD1 mouse plasma protein binding assay results for CPI-CG-8.

[0257] Table 7. In vitro human plasma stability results for CPI-CG-8.

[0258] Table 8. In vitro CD1 mouse plasma stability results for CPI-CG-8. Attorney Docket No. 3270 / 30 PCT

[0259] Table 9. In vitro metabolic stability results for CPI-CG-8 in human liver microsomes.

[0260] Table 10. In vitro metabolic stability results for CPI-CG-8 in MLM-CD1 liver microsomes.

[0261] Table 11. Kinetic solubility data for CPI-CG-8.

[0262] Table 12. Bidirectional permeability across Caco-2 cell monolayers for CPI-CG-8. Attorney Docket No. 3270 / 30 PCT

[0263] Plasma protein binding assays showed that CPI-7168 (also referred to as CPI-CG- 8) was highly stable and almost entirely protein bound, with a very small percent of free drug in both human and mouse plasma. However, CPI-7168 displays significant metabolic instability in both human and mouse liver microsomes, likely a result of the unfunctionalized 3- position of the indole ring. Lastly, we saw that CPI-7168 was highly soluble, had acceptable cell permeability and was unlikely to be a substrate for efflux transporters based on the Caco-2 data.

[0264] EXAMPLE 5 In vivo ADME

[0265] We then performed in vivo pharmacokinetics (PK) analysis for CPI-7168 (also referred to as CPI-CG-8) in CD-I mice at 10 mg / kg intraperitonially (IP) to ensure acceptable concentrations in the brain. See Tables 13-15, below. Blood / tissue samples were collected at 5 min, 15 min, 30 min, 1 h, 2 h, 4 h, and 8 h after dosing and analyzed by LC- MS / MS.

[0266] Table 13. PK parameters for CPI-CG-8 in CD-I mice at 10 mg / kg IP.

[0267] Table 14. PK parameters for CPI-CG-8 in CD1 mouse plasma at 10 mg / kg. Attorney Docket No. 3270 / 30 PCT

[0268] Table 15. PK parameters for CPI-CG-8 in CD1 mouse brain at 10 mg / kg.

[0269] When administered IP in CD-I mice at 10 mg / kg, CPI-7168 showed a higher plasma half-life (ti / 2 = 2.11 h) than in the brain (ti / 2 = 1.5 h), and a higher clearance rate in the brain (6.4 mL / min / kg) than in the plasma (236 mL / min / kg). CPI-7168 at 10 mg / kg therefore showed good exposure levels in the brain (Cmax = 12,688 ng / mL, 34.9 pM), despite rapid clearance (ti / 2 = 1.5 h).

[0270] EXAMPLE 6 SmartCube® Screening

[0271] To evaluate the CNS-like activity of our lead compound, CPI-7168, we have utilized the SmartCube® assay from PsychoGenics64. The class and subclass analyses for CPI-7168 are shown in Figure 5 and the full class and subclass legend is shown in Figure 6. Activity for each dose was calculated using the corresponding vehicle group, given that the doses were tested at different dates.

[0272] At 7.5 mg / kg, CPI-7168 was behaviorally inactive (< 40%). At 40 mg / kg, CPI-7168 was robustly active and showed an antipsychotic (class) and consistent atypical antipsychotic signature (subclass). These drug classes are consistent with interaction of neurotransmitter receptors such as serotonin receptors.

[0273] A similarity analysis was also performed, which first computes a pairwise similarity score between each dose of the compounds using a binary machine learning classifier. Therefore, the difference measured between two different compounds directly translates to how different those two compounds are, and, on the other hand, if they are behaviorally indistinguishable, they are regarded as similar. Figure 7 shows the similarity of every pair of reference and screening compound at different doses. Similarity analysis of CPI-7168 (CPICG8 in Figure 7) shows strong similarity to clozapine (CZP) and pimavanserin (PIMA), as well as less robust similarity to asenapine (ASEN) and several other antipsychotics. Attorney Docket No. 3270 / 30 PCT

[0274] The SmartCube® assay is an automated testing platform which guides mice through a series of challenges to extract behavioral and physiological information for a given test compound. It is designed to measure numerous spontaneous behaviors in the same testing environment. Male C5H B16 mice were administered IP CPI-7168 at 7.5 and 40 mg / kg and were then exposed to a sequence of challenges (see below for further information on animals and compound formulation). Three high-resolution video cameras provided a constant 3D view of the mouse in the SmartCube® apparatus throughout the 45 min testing period. Digital videos of the mice were processed through computer segmentation algorithms to fit geometrical models to each mouse frame image. The resulting fitted parameters were then analyzed using behavioral classifier algorithms to extract behavioral states, such as rearing, locomotion, and immobility. This data was used to define a drug signature for PsychoGenic’s known reference compounds and establish a therapeutic class signature against which a test sample can be compared.

[0275] For class and subclass analyses, a reference data set has been built from hundreds of drug doses in multiple drug classes plus a control group that was given different types of vehicles alone. Drug classes are divided into subclasses. Each reference drug was tested at multiple doses appropriate for that drug in mice. The best performing classifiers were chosen from evaluation tests and two separate types of classifiers were built that make independent predictions thus at drug class and subclass levels. The behavioral signatures of the test drugs were evaluated using these classifiers to predict potential therapeutic utility.

[0276] SmartCube® Testing Platform Methods

[0277] Animals

[0278] Male C57 / B16 mice from Taconic Laboratories (Germantown, NY) were used. Upon receipt, mice were group-housed in OPTIMice® ventilated cages with 4 mice per cage. Mice were acclimated to the colony room for at least one week prior to test, and subsequently tested at approximately 8-9 weeks of age. All animals were examined, handled, and weighed prior to initiation of the study to assure adequate health and suitability and to minimize nonspecific stress associated with manipulation. During the course of the study, 12 / 12 light / dark cycles were maintained. The room temperature was 20-23°C with a relative humidity maintained between 30-70%. Chow and water were provided ad libitum for the duration of the study.

[0279] Compound Formulation

[0280] CPI-7168 (7.5 mg / kg) was formulated in 5% Pharmasolve, 30% P3 (1 : 1 : 1 PEG200, PEG400, propylene glycol) and 65% saline. Compounds were injected intraperitoneally at Attorney Docket No. 3270 / 30 PCT a dose volume of 10 mL / kg, 15 minutes prior to test. The SmartCube® test session lasted for 45 minutes.

[0281] EXAMPLE 7 t-SNE Visualization with 5HTic t-SNE plot

[0282] We generated a t-SNE plot to show the structural diversity of our machine learning data sets compared to the reported analogs (Figure 8). While most of our compounds contain the tryptamine substructure, we still see considerable structural diversity compared to the compounds in our 5-HT2C model training set. t-SNE plots allow visualization of high-dimensional data by embedding data into lower-dimensional space76. We generated 1024 ECFP6 fingerprints for each structure in our machine learning training sets and our set of designed molecules, which were then embedded into a two-dimensional vector using t-SNE, a variation of Stochastic Neighbor Embedding.

[0283] EXAMPLE 8

[0284] Discussion of Examples 1-7

[0285] Besides 5-HT2A agonists, 5-HT2C agonists have also been studied for their role in treating OUD14'20. Serotonin is a major modulator of dopamine neuronal activity, and the 5-HT2C receptor is a principal mechanism by which 5-HT inhibits dopamine function. Pharmacological studies with selective 5-HT2A and 5-HT2C agonists and antagonists demonstrate that while 5-HT2A activation stimulates dopamine release, 5-HT2C activation inhibits it, thus regulating the dopamine system by functionally opposing each other. 5-HT2C agonists were shown to reduce the firing rate of mesocorticolimbic dopamine neurons, causing reduction in dopamine release19, 45, 46. Similarly, activation of 5-HT2C also suppresses behavioral sensitization and withdrawal in heroin-treated mice, providing compelling preclinical evidence in the favor of 5-HT2C agonists as potential therapeutics for drug abuse. 5-HT2C agonism therefore becomes a viable strategy to treat substance use disorders like OUD47

[0286] Other uses of 5-HT2C agonists could include treatment for obesity, as they reduce food intake and body weight gain via their action in the arcuate nucleus of the hypothalamus47Researchers have looked at the mechanisms of 5-HT2C agonists and GLP-1 agonists separately48with findings highlighting 5-HT as an endogenous modulator of the central GLP-1 system, indicating a central interaction between 5-HT and GLP-1 involved in the Attorney Docket No. 3270 / 30 PCT control of food intake in rats49. 5-HT2C receptors are also implicated in the treatment of seizures, as they are highly expressed in the brain regions involved in multiple types of seizures50. Developmental and epileptic encephalopathy (DEE) is a form of rare childhood epilepsy which occurs on a background of developmental delay and is seen in children with onset younger than 3 years51’52. DEEs include a range of syndromes including Dravet Syndrome (DS), Lennox-Gastaut syndrome (LGS), Juvenile CLN3 (Batten), CLN2 Batten, tuberous sclerosis complex (TSC), CDKL5 deficiency disorder (CDD), Sturge-Weber syndrome and other rare epileptic disorders53. 5-HT2C knockout (KO) mice display spontaneous seizures and decreased threshold for proconvulsant stimuli54In addition, 5- HT2C modulation of hippocampal pyramidal GABAergic neurons suppresses hyperexcitability55. Moreover, 5-HT2C antagonists may worsen the seizure phenotype and can counteract the anti-epileptiform activity of FA56‘57. Lorcaserin is a selective 5-HT2C agonist which has been shown to decrease seizure-like behavior and epileptiform electrical activity in a scnlLab- / - mutant zebrafish model of DS58. Lorcaserin has also demonstrated reduction in frequency of motor seizures in children and young adults with treatmentresistant epilepsies like DS. CPLCG-8 (CPI-7168) would appear to have similar 5-HT2C agonist activity to lorcaserin59and yet is structurally dissimilar.

[0287] In vitro assessment of CPLCG-8 (CPL7168) suggests that metabolic stability is a feature to address while in vivo mouse PK seemed acceptable and the drug reached the brain with a good Brain / plasma C max ratio.

[0288] In vivo assessment of CPLCG-8 (CPL7168) in mice also demonstrated that mouse behavior was most like animals treated with atypical antipsychotics such as clozapine and pimavanserin. Interestingly, these compounds display quite different pharmacology, acting as 5-HT2A inverse agonists, while CPL7168 is a partial agonist at 5-HT2A. Moreover pimavanserin is an antagonist at 5-HT2C and clozapine has no activity at 5-HT2C71 72, in stark contrast to CPL7168. Given that 5-HT2C is not commonly associated with atypical antipsychotics, these findings may warrant further assessment and optimization of this compound.

[0289] In summary, we report the generative design, synthesis, and biological evaluation of a panel of novel 5-HT2 agonists. Machine learning models were trained on publicly available data and were used to assist a generative model in designing new molecules as potential 5- HT2 agonists. We identified CPL7168 as a 5-HT2C agonist (EC50 = 12 nM) and partial 5- HT2A agonist (EC50 = 53 nM) which displays good exposure in the mouse brain, as well as high protein binding and plasma stability in vitro. Future work will focus on broader Attorney Docket No. 3270 / 30 PCT screening against CNS targets as well as assessing the therapeutic potential of CPI-7168 in animal models in order to understand the relationship between agonism of 5-HT2C and therapeutic effect. In parallel, we will continue optimizing CPI-7168 to improve its metabolic stability, while addressing efficacy for OUD, obesity and DEE applications. We will also improve upon our existing machine learning models in continued efforts to generatively design more selective 5-HT2A agonists that explore chemical space beyond tryptamine analogs.

[0290] REFERENCES

[0291] All references listed in the instant disclosure, including but not limited to all patents, patent applications and publications thereof, scientific journal articles, and database entries (including but not limited to UniProt, EMBL, and GENBANK® biosequence database entries and including all annotations available therein) are incorporated herein by reference in their entireties to the extent that they supplement, explain, provide a background for, and / or teach methodology, techniques, and / or compositions employed herein. The discussion of the references is intended merely to summarize the assertions made by their authors. No admission is made that any reference (or a portion of any reference) is relevant prior art. Applicant reserves the right to challenge the accuracy and pertinence of any cited reference.

[0292] (1) NIDA. Drug Overdose Death Rates. 2024. accessed online at nida.nih.gov / research- topics / trends-statistics / overdose-death-rates .

[0293] (2) Lofwall, M. R.; Walsh, S. L.; Nunes, E. V.; Bailey, G. L.; Sigmon, S. C.; Kampman, K. M.; Frost, M.; Tiberg, F.; Linden, M.; Sheldon, B.; et al. Weekly and Monthly Subcutaneous Buprenorphine Depot Formulations vs Daily Sublingual Buprenorphine With Naloxone for Treatment of Opioid Use Disorder: A Randomized Clinical Trial. JAMA Intern Med 2018, 178 (6), 764-773. DOI: 10.1001 / jamainternmed.2018.1052 From NLM.

[0294] (3) Ropero-Miller, J. D.; Speaker, P. J. The hidden costs of the opioid crisis and the implications for financial management in the public sector. Forensic Sci Int 2019, 7, 227- 238. DOI: 10.1016 / j.fsisyn.2019.09.003 From NLM.

[0295] (4) Gasser, P.; Holstein, D.; Michel, Y.; Doblin, R.; Yazar-Klosinski, B.; Passie, T.; Brenneisen, R. Safety and efficacy of lysergic acid diethylamide-assisted psychotherapy for Attorney Docket No. 3270 / 30 PCT anxiety associated with life-threatening diseases. J Nerv Merit Dis 2014, 202 (7), 513-520.

[0296] DOI: 10.1097 / nmd.0000000000000113 From NLM.

[0297] (5) Johnson, M.; Richards, W .; Griffiths, R. Human hallucinogen research: guidelines for safety. J Psychopharmacol 2008, 22 (6), 603-620. DOI: 10.1177 / 0269881108093587 From NLM.

[0298] (6) Winkelman, M. Psychedelics as Medicines for Substance Abuse Rehabilitation: Evaluating Treatments with LSD, Peyote, Ibogaine and Ayahuasca. Current Drug Abuse Reviews 2014, 7 (2), 101-116. DOI: 10.2174 / 1874473708666150107120011.

[0299] (7) Vargas, M. V.; Meyer, R.; Avanes, A. A.; Rus, M.; Olson, D. E. Psychedelics and Other Psychoplastogens for Treating Mental Illness. (1664-0640 (Print)). From 2021.

[0300] (8) Griffiths, R.; Richards, W.; Johnson, M.; McCann, U.; Jesse, R. Mystical -type experiences occasioned by psilocybin mediate the attribution of personal meaning and spiritual significance 14 months later. Journal of Psychopharmacology 2008, 22 (6), 621- 632. DOI: 10.1177 / 0269881108094300.

[0301] (9) Cameron, L. P.; Patel, S. D.; Vargas, M. V.; Barragan, E. V.; Saeger, H. N.; Warren, H. T.; Chow, W. L.; Gray, J. A.; Olson, D. E. 5-HT2ARs Mediate Therapeutic Behavioral Effects of Psychedelic Tryptamines. ACS Chemical Neuroscience 2023, 14 (3), 351-358. DOI: 10.1021 / acschemneuro.2c00718.

[0302] (10) Saeger, H. A.-O.; Olson, D. A.-O. Psychedelic-inspired approaches for treating neurodegenerative disorders. (1471-4159 (Electronic)). From 2022 Jul.

[0303] (11) Cameron, L. P.; Tombari, R. J.; Lu, J.; Pell, A. J.; Hurley, Z. Q.; Ehinger, Y.; Vargas, M. V.; McCarroll, M. N.; Taylor, J. C.; Myers-Turnbull, D.; et al. A non-hallucinogenic psychedelic analogue with therapeutic potential. Nature 2021, 589 (7842), 474-479. DOI: 10.1038 / s41586-020-3008-z.

[0304] (12) Dunlap, L. E.; Azinfar, A.; Ly, C.; Cameron, L. P.; Viswanathan, J.; Tombari, R. J.; Myers-Turnbull, D.; Taylor, J. C.; Grodzki, A. C.; Lein, P. J.; et al. Identification of Psychoplastogenic N,N-Dimethylaminoisotryptamine (isoDMT) Analogues through Structure-Activity Relationship Studies. J Med Chem 2020, 63 (3), 1142-1155. DOI: 10.1021 / acs.jmedchem.9b01404 From NLM Medline. Attorney Docket No. 3270 / 30 PCT

[0305] (13) Lewis, V.; Bonniwell, E. M.; Lanham, J. K.; Ghaffari, A.; Sheshbaradaran, H.; Cao, A. B.; Calkins, M. M.; Bautista-Carro, M. A.; Arsenault, E.; Telfer, A.; et al. A non- hallucinogenic LSD analog with therapeutic potential for mood disorders. (2211-1247 (Electronic)). From 2023 Mar 28.

[0306] (14) Peng, Y.; McCorvy, J. D.; Harpsoe, K.; Lansu, K.; Yuan, S.; Popov, P.; Qu, L.; Pu, M.; Che, T.; Nikolajsen, L. F.; et al. 5-HT(2C) Receptor Structures Reveal the Structural Basis of GPCR Polypharmacology. Cell 2018, 172 (4), 719-730 e714. DOI: 10.1016 / j . cell .2018.01.001 From NLM Medline .

[0307] (15) Ubhayarathna, M.; Langmead, C. J.; Diepenhorst, N. A.; Stewart, G. D. Molecular and structural insights into the 5-HT(2C) receptor as a therapeutic target for substance use disorders. Br JPharmacol 2023. DOI: 10.1111 / bph.16233 From NLM Publisher.

[0308] (16) Jastrzebska, J.; Frankowska, M.; Smaga, I.; Hubalewska-Mazgaj, M.; Suder, A.; Pieniazek, R.; Przegalinski, E.; Filip, M. Evaluation of the 5-HT(2C) receptor drugs RO 60- 0175, WAY 161503 and mirtazepine in a preclinical model of comorbidity of depression and cocaine addiction. Pharmacol Rep 2023, 75 (1), 99-118. DOI: 10.1007 / s43440-022- 00428-2 From NLM Medline.

[0309] (17) Zhang, G.; Wu, X.; Zhang, Y. M.; Liu, H.; Jiang, Q.; Pang, G.; Tao, X.; Dong, L.; Stackman, R. W ., Jr. Activation of serotonin 5-HT(2C) receptor suppresses behavioral sensitization and naloxone-precipitated withdrawal symptoms in morphine-dependent mice. Neuropharmacology 2016, 101, 246-254. DOI: 10.1016 / j.neuropharm.2015.09.031 From NLM Medline.

[0310] (18) Lanteri, C.; Salomon, L.; Torrens, Y.; Glowinski, J.; Tassin, J. P. Drugs of abuse specifically sensitize noradrenergic and serotonergic neurons via a non-dopaminergic mechanism. Neuropsychopharmacology 2008, 33 (7), 1724-1734. DOI:

[0311] 10.1038 / sj.npp.1301548 From NLM Medline.

[0312] (19) Willins, D. L.; Meltzer, H. Y. Serotonin 5-HT2C agonists selectively inhibit morphine- induced dopamine efflux in the nucleus accumbens. Brain Res 1998, 781 (1-2), 291-299. DOI: 10.1016 / s0006-8993(97)01267-5 From NLM Medline. Attorney Docket No. 3270 / 30 PCT

[0313] (20) Wu, X.; Pang, G.; Zhang, Y. M.; Li, G.; Xu, S.; Dong, L.; Stackman, R. W., Jr.; Zhang, G. Activation of serotonin 5-HT(2C) receptor suppresses behavioral sensitization and naloxone-precipitated withdrawal symptoms in heroin-treated mice. Neurosci Lett 2015, 607, 23-28. DOI: 10.1016 / j.neulet.2015.09.013 From NLM Medline.

[0314] (21) Rothman, R. B.; Baumann, M. H. Serotonergic drugs and valvular heart disease. Expert Opin Drug Sqf 2009, 8 (3), 317-329. DOI: 10.1517 / 14740330902931524 From NLM Medline.

[0315] (22) Olivecrona, M.; Blaschke, T.; Engkvist, O.; Chen, H. Molecular de-novo design through deep reinforcement learning. Journal of Cheminformatics 2017, 9 (1), 48. DOI: 10.1186 / sl3321-017-0235-x.

[0316] (23) Segler, M. H. S.; Kogej, T.; Tyrchan, C.; Waller, M. P. Generating Focused Molecule Libraries for Drug Discovery with Recurrent Neural Networks. ACS Cent Sci 2018, 4 (1), 120-131. DOI: 10.1021 / acscentsci.7b00512.

[0317] (24) Meyers, J.; Fabian, B.; Brown, N. De novo molecular design and generative models. Drug discovery today 2021, 26 (11), 2707-2715. DOI: 10.1016 / j.drudis.2021.05.019.

[0318] (25) Bhisetti, G.; Fang, C. Artificial Intelligence-Enabled De Novo DesignDe novo designof Novel Compounds that Are Synthesizable. In Artificial Intelligence in Drug Design, Heifetz, A. Ed.; Springer US, 2022; pp 409-419.

[0319] (26) Gomez-Bombarelli, R.; Wei, J. N.; Duvenaud, D.; Hernandez-Lobato, J. M.; Sanchez- Lengeling, B.; Sheberla, D.; Aguilera-Iparraguirre, J.; Hirzel, T. D.; Adams, R. P.; Aspuru- Guzik, A. Automatic Chemical Design Using a Data-Driven Continuous Representation of Molecules. ACS Central Science 2018, 4 (2), 268-276. DOI: 10.1021 / acscentsci.7b00572.

[0320] (27) Prykhodko, O.; Johansson, S. V.; Kotsias, P.-C.; Arus-Pous, J.; Bjerrum, E. J.; Engkvist, O.; Chen, H. A de novo molecular generation method using latent vector based generative adversarial network. Journal of Cheminformatics 2019, 11 (1), 74. DOI: 10.1186 / S13321-019-0397-9.

[0321] (28) Hochreiter, S.; Schmidhuber, J. Long Short-Term Memory. Neural Computation 1997, 9 (8), 1735-1780. DOI: 10.1162 / neco.1997.9.8.1735 (acccessed 8 / 30 / 2024). Attorney Docket No. 3270 / 30 PCT

[0322] (29) Blaschke, T.; Olivecrona, M.; Engkvist, O.; Bajorath, J.; Chen, H. Application of Generative Autoencoder in De Novo Molecular Design. Molecular Informatics 2018, 37(1- 2), 1700123. DOI: 10.1002 / minf.201700123.

[0323] (30) Sanchez, B.; Outeiral, C.; Guimaraes, G.; Aspuru-Guzik, A. Optimizing distributions over molecular space. An Objective-Reinforced Generative Adversarial Network for Inverse-design Chemistry (ORGANIC),' 2017. DOI: 10.26434 / chemrxiv.5309668.

[0324] (31) Winter, R.; Montanari, F.; Steffen, A.; Briem, H.; Noe, F.; Clevert, D. A. Efficient multi-objective molecular optimization in a continuous latent space. Chem Sci 2019, 10 (34), 8016-8024. DOI: 10.1039 / c9sc01928f.

[0325] (32) Krenn, M.; Hase, F.; Nigam, A.; Friederich, P.; Aspuru-Guzik, A. Self-Referencing Embedded Strings (SELFIES): A 100% robust molecular string representation. Machine Learning: Science and Technology 2020, 1. DOI: 10.1088 / 2632-2153 / aba947.

[0326] (33) Jin, W.; Barzilay, R.; Jaakkola, T. Junction Tree Variational Autoencoder for Molecular Graph Generation. In Artificial Intelligence in Drug Discovery, Brown, N. Ed.; The Royal Society of Chemistry, 2020; p 0.

[0327] (34) Ivanenkov, Y. A.; Polykovskiy, D.; Bezrukov, D.; Zagribelnyy, B.; Aladinskiy, V.; Kamya, P.; Aliper, A.; Ren, F.; Zhavoronkov, A. Chemistry42: An Al-Driven Platform for Molecular Design and Optimization. J Chem Inf Model 2023, 63 (3), 695-701. DOI: 10.1021 / acs.jcim.2c01191 From NLM Medline.

[0328] (35) Ren, F.; Ding, X.; Zheng, M.; Korzinkin, M.; Cai, X.; Zhu, W.; Mantsyzov, A.; Aliper, A.; Aladinskiy, V.; Cao, Z.; et al. AlphaFold accelerates artificial intelligence powered drug discovery: efficient discovery of a novel CDK20 small molecule inhibitor. Chem Sci 2023, 14 (6), 1443-1452. DOI: 10.1039 / d2sc05709c From NLM PubMed-not-MEDLINE.

[0329] (36) Ren, F.; Aliper, A.; Chen, J.; Zhao, H.; Rao, S.; Kuppe, C.; Ozerov, I. V.; Zhang, M.; Witte, K.; Kruse, C.; et al. A small-molecule TNIK inhibitor targets fibrosis in preclinical and clinical models. Nat Biotechnol 2024. DOI: 10.1038 / s41587-024-02143-0 From NLM Publisher.

[0330] (37) Ivanenkov, Y.; Zagribelnyy, B.; Malyshev, A.; Evteev, S.; Terentiev, V.; Kamya, P.; Bezrukov, D.; Aliper, A.; Ren, F.; Zhavoronkov, A. The Hitchhiker's Guide to Deep Attorney Docket No. 3270 / 30 PCT

[0331] Learning Driven Generative Chemistry. ACS Med Chem Lett 2023, 14 (7), 901-915. DOI: 10.1021 / acsmedchemlett.3c00041 From NLM PubMed-not-MEDLINE.

[0332] (38) Salas-Estrada, L.; Provasi, D.; Qiu, X.; Kaniskan, H. U.; Huang, X. P.; DiBerto, J. F.; Lamim Ribeiro, J. M.; Jin, J.; Roth, B. L.; Filizola, M. De Novo Design of kappa-Opioid Receptor Antagonists Using a Generative Deep-Learning Framework. J Chem Inf Model 2023, 63 (16), 5056-5065. DOI: 10.1021 / acs.jcim.3c00651 From NLM Medline.

[0333] (39) Moret, M.; Helmstadter, M.; Grisoni, F.; Schneider, G.; Merk, D. Beam Search for Automated Design and Scoring of Novel ROR Ligands with Machine Intelligence*. Angew Chem int Ed Engl 2021, 60 (35), 19477-19482. DOI: 10.1002 / anie.202104405 From NLM Medline.

[0334] (40) Grisoni, F.; Huisman, B. J. H.; Button, A. L.; Moret, M.; Atz, K.; Merk, D.; Schneider, G. Combining generative artificial intelligence and on-chip synthesis for de novo drug design. SciAdv 2021, 7 (24). DOI: 10.1126 / sciadv.abg3338 From NLM Medline.

[0335] (41) Moret, M.; Pachon Angona, I.; Cotos, L.; Yan, S.; Atz, K.; Brunner, C.; Baumgartner, M.; Grisoni, F.; Schneider, G. Leveraging molecular structure and bioactivity with chemical language models for de novo drug design. Nat Commun 2023, 14 (1), 114. DOI: 10.1038 / s41467-022-35692-6 From NLM Medline.

[0336] (42) Korshunova, M.; Huang, N.; Capuzzi, S.; Radchenko, D. S.; Savych, O.; Moroz, Y. S.; Wells, C. I.; Willson, T. M.; Tropsha, A.; Isayev, O. Generative and reinforcement learning approaches for the automated de novo design of bioactive compounds. Commun Chem 2022, 5 (1), 129. DOI: 10.1038 / s42004-022-00733-0 From NLM PubMed-not-MEDLINE.

[0337] (43) Urbina, F.; Lowden, C. T.; Culberson, J. C.; Ekins, S. MegaSyn: Integrating Generative Molecular Design, Automated Analog Designer, and Synthetic Viability Prediction. ACS Omega 2022, 7 (22), 18699-18713. DOI: 10.1021 / acsomega.2c01404.

[0338] (44) Urbina, F.; Lentzos, F.; Invernizzi, C.; Ekins, S. A teachable moment for dual-use. Nature Machine Intelligence 2022, 4 (7), 607-607. DOI: 10.1038 / s42256-022-00511-6.

[0339] (45) Di Matteo, V.; Di Giovanni, G.; Di Mascio, M.; Esposito, E. Biochemical and electrophysiological evidence that RO 60-0175 inhibits mesolimbic dopaminergic function Attorney Docket No. 3270 / 30 PCT through serotonin(2C) receptors. Brain Res 2000, 865 (1), 85-90. DOI: 10.1016 / s0006- 8993(00)02246-0 From NLM Medline.

[0340] (46) Gobert, A.; Rivet, J. M.; Lejeune, F.; Newman-Tancredi, A.; Adhumeau-Auclair, A.;

[0341] Nicolas, J. P.; Cistarelli, L.; Melon, C.; Millan, M. J. Serotonin(2C) receptors tonically suppress the activity of mesocortical dopaminergic and adrenergic, but not serotonergic, pathways: a combined dialysis and electrophysiological analysis in the rat. Synapse 2000, 36 (3), 205-221. DOI: 10.1002 / (SICI)1098-2396(20000601)36:3<205::AID-

[0342] SYN5>3.0.CO;2-D From NLM Medline.

[0343] (47) Higgins, G. A.; Sellers, E. M.; Fletcher, P. J. From obesity to substance abuse: therapeutic opportunities for 5-HT2C receptor agonists. Trends Pharmacol Sci 2013, 34 (10), 560-570. DOI: 10.1016 / j .tips.2013.08.001 From NLM Medline.

[0344] (48) Howell, E.; Baumgartner, H. M.; Zallar, L. J.; Selva, J. A.; Engel, L.; Currie, P. J. Glucagon-Like Peptide-1 (GLP-1) and 5-Hydroxytryptamine 2c (5-HT(2c)) Receptor Agonists in the Ventral Tegmental Area (VTA) Inhibit Ghrelin-Stimulated Appetitive Reward. Ini J Mol Sci 2019, 20 (4). DOI: 10.3390 / ijms20040889 From NLM Medline.

[0345] (49) Leon, R. M.; Borner, T.; Reiner, D. J.; Stein, L. M.; Lhamo, R.; De Jonghe, B. C.; Hayes, M. R. Hypophagia induced by hindbrain serotonin is mediated through central GLP- 1 signaling and involves 5-HT2C and 5-HT3 receptor activation. Neuropsychopharmacology 2019, 44 (10), 1742-1751. DOI: 10.1038 / s41386-019-0384-x From NLM Medline.

[0346] (50) Lindquist, B. E.; Timbie, C.; Voskobiynyk, Y.; Paz, J. T. Thalamocortical circuits in generalized epilepsy: Pathophysiologic mechanisms and therapeutic targets. Neurobiol Dis 2023, 181, 106094. DOI: 10.1016 / j .nbd.2023.106094 From NLM Medline.

[0347] (51) Poke, G.; Stanley, J.; Scheffer, I. E.; Sadleir, L. G. Epidemiology of Developmental and Epileptic Encephalopathy and of Intellectual Disability and Epilepsy in Children. Neurology 2023, 100 (13), el363-el375. DOI: 10.1212 / WNL.0000000000206758 From NLM Medline.

[0348] (52) Howell, K. B.; Freeman, J. L.; Mackay, M. T.; Fahey, M. C.; Archer, J.; Berkovic, S. F.; Chan, E.; Dabscheck, G.; Eggers, S.; Hayman, M.; et al. The severe epilepsy syndromes Attorney Docket No. 3270 / 30 PCT of infancy: A population-based study. Epilepsia 2021, 62 (2), 358-370. DOI: 10.1111 / epi.16810 From NLM Medline.

[0349] (53) Guerrini, R.; Conti, V.; Mantegazza, M.; Balestrini, S.; Galanopoulou, A. S.; Benfenati, F. Developmental and epileptic encephalopathies: from genetic heterogeneity to phenotypic continuum. Physiol Rev 2023, 103 (1), 433-513. DOI: 10.1152 / physrev.00063.2021 From NLM Medline.

[0350] (54) Applegate, C. D.; Tecott, L. H. Global increases in seizure susceptibility in mice lacking 5-HT2C receptors: a behavioral analysis. Exp Neurol 1998, 154 (2), 522-530. DOI: 10.1006 / exnr.1998.6901 From NLM Medline.

[0351] (55) Gharedaghi, M. H.; Seyedabadi, M.; Ghia, J. E.; Dehpour, A. R.; Rahimian, R. The role of different serotonin receptor subtypes in seizure susceptibility. Exp Brain Res 2014, 232 (2), 347-367. DOI: 10.1007 / s00221-013-3757-0 From NLM Medline.

[0352] (56) Ishiura, S. [Serotonin receptor knockout mice], Nihon Shinkei Seishin Yakurigaku Zasshi 1999, 19 (5), 257-260. From NLM Medline.

[0353] (57) Brennan, T. J.; Seeley, W. W .; Kilgard, M.; Schreiner, C. E.; Tecott, L. H. Sound- induced seizures in serotonin 5-HT2c receptor mutant mice. Nat Genet 1997, 16 (4), 387- 390. DOI: 10.1038 / ng0897-387 From NLM Medline.

[0354] (58) Bialer, M.; Perucca, E. Lorcaserin for Dravet Syndrome: A Potential Advance Over Fenfluramine? CNS Drugs 2022, 36 (2), 113-122. DOI: 10.1007 / s40263-022-00896-3 From NLM Medline.

[0355] (59) Thomsen, W. J.; Grottick, A. J.; Menzaghi, F.; Reyes-Saldana, H.; Espitia, S.; Yuskin, D.; Whelan, K.; Martin, M.; Morgan, M.; Chen, W.; et al. Lorcaserin, a Novel Selective Human 5-Hydroxytryptamine2C Agonist: in Vitro and in Vivo Pharmacological Characterization. Journal of Pharmacology and Experimental Therapeutics 2008, 325 (2), 577. DOI: 10.1124 / jpet.107.133348.

[0356] (60) Gaulton, A.; Hersey, A.; Nowotka, M.; Bento, A. P.; Chambers, J.; Mendez, D.; Mutowo, P.; Atkinson, F.; Bellis, L. J.; Cibrian-Uhalte, E.; et al. The ChEMBL database in 2017. Nucleic Acids Res 2017, 45 (DI), D945-D954. DOI: 10.1093 / nar / gkwl074. Attorney Docket No. 3270 / 30 PCT

[0357] (61) Bickerton, G. R.; Paolini, G. V.; Besnard, J.; Muresan, S.; Hopkins, A. L. Quantifying the chemical beauty of drugs. Nat Chem 2012, 4 (2), 90-98. DOI: 10.1038 / nchem.l243.

[0358] (62) Ertl, P.; Schuffenhauer, A. Estimation of synthetic accessibility score of drug-like molecules based on molecular complexity and fragment contributions. J Cheminform 2009, 1 (1), 8. DOI: 10.1186 / 1758-2946-1-8 From NLM PubMed-not-MEDLINE.

[0359] (63) Porter, R. H.; Benwell, K. R.; Lamb, H.; Malcolm, C. S.; Allen, N. H.; Revell, D. F.; Adams, D. R.; Sheardown, M. J. Functional characterization of agonists at recombinant human 5-HT2A, 5-HT2B and 5-HT2C receptors in CHO-K1 cells. Br J Pharmacol 1999, 128 (1), 13-20. DOI: 10.1038 / sj .bjp.0702751 From NLM Medline. (64) Inc., P. SmartCube® In Vivo Al Platform for Compound Screening. 2025. https: / / www.psychogenics.com / in-vivo-ai-platforms / smartcube / (accessed.

[0360] It will be understood that various details of the presently disclosed subject matter may be changed without departing from the scope of the presently disclosed subject matter. Furthermore, the foregoing description is for the purpose of illustration only, and not for the purpose of limitation.

Claims

Attorney Docket No. 3270 / 30 PCTCLAIMSWhat is claimed is:

1. A compound which is(N-(2-(lH-indol-2-yl)ethyl)-2-(lH-indol-3-yl)-N-methylethan-l-amine, CPI-7168), or a pharmaceutically acceptable salt thereof.

2. A method of treating a condition treatable by agonism of 5-HT2A and / or 5- HT2C, the method comprising administering a compound of claim 1 to a subject in need thereof.

3. The method of claim 2, wherein the condition is a mental heatlh condition.

4. The method of claim 3, wherein the mental health condition is a psychosis, optionally a mental health condition characterized by psychosis, including but not limited to schizophrenia, schizoaffective disorder, and / or a delusional disorder; a neurodegenerative disease, optionally Alzheimer’s disease and / or Parkinson’s disease; or depression and / or bipolar depression; and / or seizures.

5. The method of claim 2, wherein the condition is an inflammatory disease, optionally cardiovascular inflammation, gut inflammation, and / or TNF-alpha-induced inflammation; wherein the condition is pain in the subject; wherein the condition is an addiction disorder; wherein the condition is obesity; and / or the condition is developmental encephalopathy and / or epileptic encephalopathy, optionally Dravet Syndrome, Lennox- Gastaut syndrome, Juvenile CLN3 Batten disease, CLN2 Batten disease, tuberous sclerosis complex, CDKL5 deficiency disorder, and / or Sturge-Weber syndrome.

6. The method of claim 5, wherein the addiction disorder is opioid use disorder (OUD) and / or other addictive pharmacological agent.Attorney Docket No. 3270 / 30 PCT7. Use of a compound of claim 1 in preparing a medicament for treating a condition treatable by agonism of a serotonin 2 receptor (5-HT2), including 5-HT2A, 5- HT2B, and / or 5-HT2C in a subject in need thereof.

8. The use of claim 7, wherein the condition is a mental heatlh condition.

9. The use of claim 8, wherein the mental health condition is a psychosis, optionally a mental health condition characterized by psychosis, including but not limited to schizophrenia, schizoaffective disorder, and / or a delusional disorder; a neurodegenerative disease, optionally Alzheimer’s disease and / or Parkinson’s disease; or depression and / or bipolar depression; and / or seizures.

10. The use of claim 7, wherein the condition is an inflammatory disease, optionally cardiovascular inflammation, gut inflammation, and / or TNF-alpha-induced inflammation; wherein the condition is pain in the subject; wherein the condition is an addiction disorder; wherein the condition is obesity; and / or the condition is developmental encephalopathy and / or epileptic encephalopathy, optionally Dravet Syndrome, Lennox- Gastaut syndrome, Juvenile CLN3 Batten disease, CLN2 Batten disease, tuberous sclerosis complex, CDKL5 deficiency disorder, and / or Sturge-Weber syndrome.

11. The use of claim 10, wherein the addiction disorder is opioid use disorder (OUD) and / or other addictive pharmacological agent.

12. A method of treating an addiction disorder, depression, obesity, sexual dysfunction, a developmental and epileptic encephalopathy (DEE), seizures, and / or another condition treatable by agonism of 5-HT2C, the method comprising administering a compound of claim 1 to a subject in need thereof.

13. The method of claim 12, wherein the addiction disorder is opioid use disorder (OUD).

14. Use of a compound of claim 1 in preparing a medicament for treating an addiction disorder depression, obesity, sexual dysfunction, a developmental and epilepticAttorney Docket No. 3270 / 30 PCT encephalopathy (DEE), seizures, and / or another condition treatable by agonism of 5-HT2c, in a subject in need thereof.

15. The use of claim 14, wherein the addiction disorder is opioid use disorder (OUD).

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