Azepino-indoles and other heterocyclic compounds for treating brain disorders

Abstract

The present invention provides azepino-indole and other heterocyclic compounds and methods of using the compounds to treat brain disorders.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Patent Application No. 62 / 811,208, filed February 27, 2019, which is incorporated herein by reference in its entirety for all purposes. STATEMENT REGARDING INVENTIONS MADE WITH U.S. GOVERNMENT RESEARCH AND DEVELOPMENT SUPPORT

[0002] This invention was made with government support under Grant No. R01GM128997 awarded by the National Institutes of Health. The government has certain rights in this invention. [Background technology]

[0003] Background of the Invention Ibogaine, a hallucinogenic alkaloid, has strong anti-addictive properties in outpatient clinics and animal models. It has the potential to treat patients addicted to a variety of substances, including opiates, psychostimulants, alcohol, and nicotine. Furthermore, its therapeutic effects are long-lasting, which is attributed to its ability to improve addiction-related neural circuits by activating neurotrophic factor signaling. Ibogaine reduces withdrawal symptoms, alleviates drug craving, and prevents relapse. In rodents, ibogaine reduces drug self-administration and prevents drug-induced dopamine release in several brain regions. However, several safety concerns, including its toxicity, hallucinogenic potential, and tendency to induce cardiac arrhythmias via hERG channel inhibition, have hindered its clinical development.

[0004] Ibogaine enhances glial cell line-derived neurotrophic factor (GDNF) expression in the ventral tegmental area (VTA), and intra-VTA infusion of ibogaine reduces alcohol-seeking behavior in rodents. Ibogaine affects brain-derived neurotrophic factor (BDNF) and GDNF signaling in multiple brain regions implicated in the pathophysiology of addiction. Noribogaine (the active metabolite of ibogaine) is a potent psychoplastogen that can enhance the complexity of central neuronal dendritic arborization. Other psychoplastogens, such as lysergic acid diethylamide (LSD) and psilocin (the active metabolite of psilocybin), have similar anti-addictive properties in outpatient clinics. The ability of psychoplastogens to promote structural and functional neuroplasticity in addiction-related circuits may explain their ability to reduce drug-seeking behavior for weeks to months after a single administration. Moreover, by modifying neural circuits rather than simply blocking specific addictive substance targets (e.g., opioid receptors, nicotine receptors, etc.), psychoplastogens such as ibogaine have the potential to be broadly applicable anti-addiction drugs.

[0005] What is needed are new therapeutic agents that lack the toxicity and hallucinogenic effects of ibogaine, yet maintain its therapeutic efficacy. Surprisingly, the present invention satisfies these needs. Summary of the Invention

[0006] In one embodiment, the present invention provides a compound of formula I: [ka] {where, R 1 is hydrogen or C 1-6 alkyl; R 3a and R 3b are each independently hydrogen, C 1-6 Alkyl, C 3-8 Cycloalkyl, or C 4-14 alkyl-cycloalkyl; R 3c is hydrogen or C 1-6 alkyl; or R2 and R 3b are combined with the atom to which they are attached and independently represent hydrogen, C 1-6 Alkyl, C 3-8 Cycloalkyl, C 3-14 Alkyl-cycloalkyl, C 4-10 Heterocycloalkyl, C 4-16 Alkyl-heterocycloalkyl, C 6-12 Aryl, C 7-18 Alkyl-aryl, C 5-10 Heteroaryl or C 4-16 one to three R's that are alkyl-heteroaryl 9 C substituted with a group 5-8 Two R attached to the same atom form a heterocycloalkyl 9 groups combined to form =O; or R 2 and R 3c are combined with the atom to which they are attached and independently represent hydrogen, C 1-6 Alkyl, C 3-8 Cycloalkyl, C 3-14 Alkyl-cycloalkyl, C 4-10 Heterocycloalkyl, C 4-16 Alkyl-heterocycloalkyl, C 6-12 Aryl, C 7-18 Alkyl-aryl, C 5-10 Heteroaryl or C 4-16 one to three R's that are alkyl-heteroaryl 10 C substituted with a group 5-8 Two R's attached to the same atom form a cycloalkyl or 10 The groups combine to form =O;R 4 , R 5 , R 6 and R 7 are each independently hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, C 1-6 Haloalkyl, C 1-6 Alkylamines, C 1-6 Alkoxy, C 1-6Haloalkoxy, -OR 8a , -NO2, -CN, -C(O)R 8b , -C(O)OR 8b , -OC(O)R 8b , -OC(O)OR 8b , -N(R 8b R 8c ), -N(R 8b )C(O)R 8c , -C(O)N(R 8b R 8c ), -N(R 8b )C(O)OR 8c , -OC(O)N(R 8b R 8c ), -N(R 8b )C(O)N(R 8c R 8d ), -C(O)C(O)N(R 8b R 8c ), -S(O2)R 8b , -S(O)2N(R 8b R 8c ), C 3-8 Cycloalkyl, C 3-14 Alkyl-cycloalkyl, C 4-10 Heterocycloalkyl, C 4-16 Alkyl-heterocycloalkyl, C 6-12 Aryl, C 7-18 Alkyl-aryl, C 5-10 Heteroaryl, or C 4-16 alkyl-heteroaryl, where R 4 , R 5 , R 6 and R 7 at least one of is not H; or R 4 and R 5 , R 5 and R 6 , or R 6 and R 7 are combined with the atoms to which they are attached, and 3-6 Cycloalkyl, C 3-6 Heterocycloalkyl, C 6-12 Aryl or C 5-10 Forming a heteroaryl; R 8a , R 8b , R 8cand R 8d are independently H, C 1-6 alkyl; where R 2 and R 3b are combined with the atom to which they are attached to form a C7 heterocycloalkyl, and R 3a is methyl, R 5 is not OMe, OH, or Cl; where R 2 and R 3b are combined with the atom to which they are attached to form a C7 heterocycloalkyl, and R 3a When is ethyl, R 6 is not OMe; where R 2 and R 3b are combined with the atom to which they are attached to form a C7 heterocycloalkyl, and R 6 is methyl Cl, F, or -OMe, R 4 , R 5 , and R 7 at least one of R is not hydrogen; 2 and R 3b are combined with the atom to which they are attached to form a C6 heterocycloalkyl, and R 6 But C 1-6 Alkyl, halogen, C 1-6 When R is alkyloxy, -C(O)H, or -NH2, 4 , R 5 , and R 7 at least one of R 2 and R 3b are combined with the atom to which they are attached to form a C6 heterocycloalkyl, and R 6 When is methyl, halogen, or -C(O)H, R 4 , R 5 , and R 7 wherein at least one of is not methyl or Cl}, or a pharmaceutically acceptable salt or isomer thereof.

[0007] In another embodiment, the present invention provides a compound or a pharmaceutically acceptable salt thereof, wherein the compound is: [ka] is.

[0008] In another embodiment, the present invention provides a pharmaceutical composition comprising a compound of the present invention, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0009] In another embodiment, the present invention provides a method for enhancing neuroplasticity, comprising administering to a neuronal cell a compound of Formula I: [ka] {where, R 1 is hydrogen or C 1-6 alkyl; R 3a and R 3b are each independently hydrogen, C 1-6 Alkyl, C 3-8 Cycloalkyl, or C 4-14 alkyl-cycloalkyl; R 3c is hydrogen or C 1-6 alkyl; or R 2 and R 3b are combined with the atom to which they are attached and independently represent hydrogen, C 1-6 Alkyl, C 3-8 Cycloalkyl, C 3-14 Alkyl-cycloalkyl, C 4-10 Heterocycloalkyl, C 4-16 Alkyl-heterocycloalkyl, C 6-12 Aryl, C 7-18 Alkyl-aryl, C 5-10 Heteroaryl or C 4-16 one to three R's that are alkyl-heteroaryl 9 C substituted with a group 5-8 Two R attached to the same atom form a heterocycloalkyl 9groups combined to form =O; or R 2 and R 3c are combined with the atom to which they are attached and independently represent hydrogen, C 1-6 Alkyl, C 3-8 Cycloalkyl, C 3-14 Alkyl-cycloalkyl, C 4-10 Heterocycloalkyl, C 4-16 Alkyl-heterocycloalkyl, C 6-12 Aryl, C 7-18 Alkyl-aryl, C 5-10 Heteroaryl or C 4-16 one to three R's that are alkyl-heteroaryl 10 C substituted with a group 5-8 Two R's attached to the same atom form a cycloalkyl or 10 The groups combine to form =O;R 4 , R 5 , R 6 and R 7 are each independently hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, C 1-6 Haloalkyl, C 1-6 Alkylamines, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -OR 8a , -NO2, -CN, -C(O)R 8b , -C(O)OR 8b , -OC(O)R 8b , -OC(O)OR 8b , -N(R 8b R 8c ), -N(R 8b )C(O)R 8c , -C(O)N(R 8b R 8c ), -N(R 8b )C(O)OR 8c , -OC(O)N(R 8b R 8c ), -N(R 8b )C(O)N(R 8c R 8d ), -C(O)C(O)N(R8b R 8c ), -S(O2)R 8b , -S(O)2N(R 8b R 8c ), C 3-8 Cycloalkyl, C 3-14 Alkyl-cycloalkyl, C 4-10 Heterocycloalkyl, C 4-16 Alkyl-heterocycloalkyl, C 6-12 Aryl, C 7-18 Alkyl-aryl, C 5-10 Heteroaryl, or C 4-16 alkyl-heteroaryl, where R 4 , R 5 , R 6 and R 7 at least one of is not H; or R 4 and R 5 , R 5 and R 6 , or R 6 and R 7 are combined with the atoms to which they are attached, and 3-6 Cycloalkyl, C 3-6 Heterocycloalkyl, C 6-12 Aryl or C 5-10 forming a heteroaryl; and R 8a , R 8b , R 8c and R 8d are independently H, C 1-6 or a pharmaceutically acceptable salt thereof,

[0010] In another embodiment, the present invention provides a method of treating a brain disorder, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula I: [ka] {where, R 1 is hydrogen or C 1-6 alkyl; R 3a and R 3b are each independently hydrogen, C 1-6 Alkyl, C3-8 Cycloalkyl, or C 4-14 alkyl-cycloalkyl; R 3c is hydrogen or C 1-6 alkyl; or R 2 and R 3b are combined with the atom to which they are attached and independently represent hydrogen, C 1-6 Alkyl, C 3-8 Cycloalkyl, C 3-14 Alkyl-cycloalkyl, C 4-10 Heterocycloalkyl, C 4-16 Alkyl-heterocycloalkyl, C 6-12 Aryl, C 7-18 Alkyl-aryl, C 5-10 Heteroaryl or C 4-16 one to three R's that are alkyl-heteroaryl 9 C substituted with a group 5-8 Two R attached to the same atom form a heterocycloalkyl 9 groups combined to form =O; or R 2 and R 3c are combined with the atom to which they are attached and independently represent hydrogen, C 1-6 Alkyl, C 3-8 Cycloalkyl, C 3-14 Alkyl-cycloalkyl, C 4-10 Heterocycloalkyl, C 4-16 Alkyl-heterocycloalkyl, C 6-12 Aryl, C 7-18 Alkyl-aryl, C 5-10 Heteroaryl or C 4-16 one to three R's that are alkyl-heteroaryl 10 C substituted with a group 5-8 Two R's attached to the same atom form a cycloalkyl or 10 The groups combine to form =O;R 4 , R 5 , R 6 and R 7 are each independently hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C2-6 Alkynyl, halogen, C 1-6 Haloalkyl, C 1-6 Alkylamines, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -OR 8a , -NO2, -CN, -C(O)R 8b , -C(O)OR 8b , -OC(O)R 8b , -OC(O)OR 8b , -N(R 8b R 8c ), -N(R 8b )C(O)R 8c , -C(O)N(R 8b R 8c ), -N(R 8b )C(O)OR 8c , -OC(O)N(R 8b R 8c ), -N(R 8b )C(O)N(R 8c R 8d ), -C(O)C(O)N(R 8b R 8c ), -S(O2)R 8b , -S(O)2N(R 8b R 8c ), C 3-8 Cycloalkyl, C 3-14 Alkyl-cycloalkyl, C 4-10 Heterocycloalkyl, C 4-16 Alkyl-heterocycloalkyl, C 6-12 Aryl, C 7-18 Alkyl-aryl, C 5-10 Heteroaryl, or C 4-16 alkyl-heteroaryl, where R 4 , R 5 , R 6 and R 7 at least one of is not H; or R 4 and R 5 , R 5 and R 6 , or R 6 and R 7 are combined with the atoms to which they are attached, and 3-6 Cycloalkyl, C 3-6Heterocycloalkyl, C 6-12 Aryl or C 5-10 forming a heteroaryl; and R 8a , R 8b , R 8c and R 8d are independently H, C 1-6 and administering a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein the compound is a hydroxybenzoate, a hydroxybenzoate, or a pharmaceutically acceptable salt thereof, thereby treating a brain disorder.

[0011] In another embodiment, the present invention provides a method of enhancing at least one of translation, transcription, or secretion of a neurotrophic factor, comprising administering to a neuronal cell a compound of formula I: [ka] {where, R 1 is hydrogen or C 1-6 alkyl; R 3a and R 3b are each independently hydrogen, C 1-6 Alkyl, C 3-8 Cycloalkyl, or C 4-14 alkyl-cycloalkyl; R 3c is hydrogen or C 1-6 alkyl; or R 2 and R 3b are combined with the atom to which they are attached and independently represent hydrogen, C 1-6 Alkyl, C 3-8 Cycloalkyl, C 3-14 Alkyl-cycloalkyl, C 4-10 Heterocycloalkyl, C 4-16 Alkyl-heterocycloalkyl, C 6-12 Aryl, C 7-18 Alkyl-aryl, C 5-10 Heteroaryl or C 4-16 one to three R's that are alkyl-heteroaryl 9 C substituted with a group 5-8 Two R attached to the same atom form a heterocycloalkyl 9groups combined to form =O; or R 2 and R 3c are combined with the atom to which they are attached and independently represent hydrogen, C 1-6 Alkyl, C 3-8 Cycloalkyl, C 3-14 Alkyl-cycloalkyl, C 4-10 Heterocycloalkyl, C 4-16 Alkyl-heterocycloalkyl, C 6-12 Aryl, C 7-18 Alkyl-aryl, C 5-10 Heteroaryl or C 4-16 one to three R's that are alkyl-heteroaryl 10 C substituted with a group 5-8 Two R's attached to the same atom form a cycloalkyl or 10 The groups combine to form =O;R 4 , R 5 , R 6 and R 7 are each independently hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, C 1-6 Haloalkyl, C 1-6 Alkylamines, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -OR 8a , -NO2, -CN, -C(O)R 8b , -C(O)OR 8b , -OC(O)R 8b , -OC(O)OR 8b , -N(R 8b R 8c ), -N(R 8b )C(O)R 8c , -C(O)N(R 8b R 8c ), -N(R 8b )C(O)OR 8c , -OC(O)N(R 8b R 8c ), -N(R 8b )C(O)N(R 8c R 8d ), -C(O)C(O)N(R8b R 8c ), -S(O2)R 8b , -S(O)2N(R 8b R 8c ), C 3-8 Cycloalkyl, C 3-14 Alkyl-cycloalkyl, C 4-10 Heterocycloalkyl, C 4-16 Alkyl-heterocycloalkyl, C 6-12 Aryl, C 7-18 Alkyl-aryl, C 5-10 Heteroaryl, or C 4-16 alkyl-heteroaryl, where R 4 , R 5 , R 6 and R 7 at least one of is not H; or R 4 and R 5 , R 5 and R 6 , or R 6 and R 7 are combined with the atoms to which they are attached, and 3-6 Cycloalkyl, C 3-6 Heterocycloalkyl, C 6-12 Aryl or C 5-10 forming a heteroaryl; and R 8a , R 8b , R 8c and R 8d are independently H, C 1-6 or a pharmaceutically acceptable salt thereof, [Brief explanation of the drawings]

[0012] [Figure 1] Figure 1A to Figure 1B show the function-directed synthesis of ibogalogs. Figure 1A shows the key structural features of ibogaine and related alkaloids. Deletion of either the isoquinuclidine or the tetrahydroazepine leads to simplified ibogaine analogs. Figure 1B shows the synthesis of tetrahydroazepine-containing ibogalogs.

[0013] [Figure 2] Figures 2A-2K demonstrate that tabernanthalogs (TBGs) are safer analogs of ibogaine alkaloids. Figure 2A shows the design of ibogainalogs (IBGs) and TBGs, which are simplified analogs of ibogaine and tabernanthine, respectively. Figure 2B shows a mouse HTR assay demonstrating that TBG is not hallucinogenic. The doses (mg / kg) of IBG and TBG are shown. +Ctrl = 5-MeO-DMT (10 mg / kg). Figure 2C shows the solubility of various drugs in 0.9% saline solution. Figure 2D shows the inhibition of hERG channels expressed in HEK293 cells. Figure 2E shows that, unlike ibogaine, IBG and TBG do not cause bradycardia in larval zebrafish. Figure 2F shows the ratio of atrial to ventricular beats per minute (BPM). Deviation from 1 indicates increased risk of arrhythmia. Sertindole (SI) was used as a positive control. Figure 2G shows the confusion matrix for classification of IBO, NOR, IBG, and TBG (200 μM), as well as VEH and lethality controls. Cells indicate the percentage of classifications between the actual label (Y-axis) and the predicted label (X-axis). Figure 2H shows representative images of zebrafish treated with compound (100 μM) for 2 dpf. Scale bar = 1 mm. Figure 2I shows the percentage of viable and nonviable (abnormal or dead) zebrafish after treatment with compound (100 μM). Figure 2J shows the effect of compound treatment on abnormalities and lethality over time. Figure 2K shows agonist and antagonist activity at 5-HT2A and 5-HT2B receptors, as measured by Gq-mediated calcium flux. Data represent percent 5-HT fold over baseline responses from at least three independent experiments performed in duplicate. IBO = ibogaine, NOR = noribogaine.

[0014] [Figure 3]Figures 3A-3I show that TBG promotes neuroplasticity. Figure 3A shows representative images of rat embryonic central neurons (DIV6) treated with TBG or VEH. Scale bar = 10 μm. Figure 3B shows Sholl analysis of TBG- and VEH-treated neurons. Light shading represents the 95% confidence interval. Figure 3C shows the maximum number of intersections (Nmax) in the Sholl plot in b, demonstrating that TBG increases the complexity of dendritic arborization. Figure 3D shows that the effect of TBG on dendritic growth is blocked by the 5-HT2A antagonist ketanserin (KETSN). Figure 3E shows representative images of secondary branches of rat embryonic central neurons (DIV20) after 24 h of treatment with ibogalog. Scale bar = 2 μm. Figure 3F shows that TBG increases dendritic spine density in rat embryonic central neurons (DIV20) after 24 h of treatment. KET = ketamine. Figure 3G shows a schematic illustration of the design of the in vivo spine dynamics experiment using transcranial two-photon imaging. Figure 3H shows representative images of the same dendritic segment of mouse primary sensory cortex before (day 0) and after (day 1) treatment with VEH, DOI, or TBG. Blue, red, and white arrows represent newly formed spines, eliminated spines, and filopodia, respectively. Scale bar = 2 μm. Figure 3I shows quantification of spine dynamics revealing that DOI and TBG increase spine formation but have no effect on spine elimination.

[0015] [Figure 4]Figures 4A-4E demonstrate that TBG has antidepressant and anti-addiction properties. Figure 4A shows a schematic illustration of the FST experimental design. Mice were pre-tested, administered compounds, and then re-tested 24 h and 7 days after drug administration. Figure 4B shows quantification of immobility, revealing that TBG has antidepressant-like effects. Figure 4C shows the schedule for the binge drinking experiment. Bottles of 20% EtOH (white droplets) and HO (blue droplets) were available for 24-h periods every 1-2 days for 7 weeks. Between drinking sessions, two bottles of HO were provided. Figure 4D shows that TBG reduces EtOH consumption and preference during binge drinking sessions without affecting HO intake. Figure 4E shows that TBG administration results in a sustained reduction in EtOH consumption.

[0016] [Figure 5] Figures 5A-5B show the effect of ibogalogs on dendrite formation. Figure 5A shows a representative image of compound-treated rat embryonic central neurons (DIV6). Scale bar = 10 μm. Figure 5B shows the maximum number of intersections (Nmax) in the Sholl plot, demonstrating that tetrahydroazepine-containing ibogalogs are more effective at enhancing dendritic arbor complexity than isoquinuclicine-containing ibogalogs.

[0017] [Figure 6] Figure 6 shows that several ibogalogs promote dendrite formation. Sholl analysis (circle radius = 1.34 µM increase) demonstrates that cultured cortical neurons treated with several ibogalogs have more complex dendritic arborization compared to solvent controls (n = 52–83 neurons per treatment). The shaded areas surrounding each line represent the 95% confidence interval. The control compounds, isoquinuclidine, and tetrahydroazepine are shown in blue, purple, and red, respectively.

[0018] [Figure 7]Figure 7 shows that ibogaine hydrochloride exhibits limited solubility in various saline-based vehicles. Solutions of saline (0.9%) containing various percentages of cosolvents / additives were added to finely ground ibogaine hydrochloride. All attempts to improve solubility by milling, sonication, and mild heating (<50°C) failed. Furthermore, the addition of cosolvents (ethanol, dimethyl sulfoxide, glycerol), surfactants (Kolliphor), or hydrotropes (ATP) to the vehicle did not substantially improve solubility. The purity and identity of the ibogaine hydrochloride used in these studies were confirmed by a combination of NMR, LC-MS, and X-ray crystallography experiments.

[0019] [Figure 8] Figure 8 shows a heat map representing aggregate larval zebrafish locomotor activity per well compared to vehicle controls (sham Z-scores). Red and blue indicate higher and lower activity, respectively, compared to the vehicle control mean, whereas white indicates activity within ±1 SD from the control. Stimuli applied over time are shown in the heat map. The colors represent bright LED lights of the respective colors, the black output represents the waveform of the sound stimulus, and the gray vertical line represents physical tapping as a second sound stimulus.

[0020] [Figure 9] Figure 9 shows increasing concentrations of IBG and TBG that do not produce a motor response in larval zebrafish, approaching the lethal concentration of eugenol (100 μM). Concentration-response curves to the compounds are subjected to the series of stimuli shown in Figure 8. Responses are inversely proportional to classification accuracy; 0-20% indicates no ability, and 100% indicates perfect classification. Lower percentages indicate treatments that are more often classified as vehicle (blue) or lethal (red). Solid lines indicate median values, and shading indicates 95th percentile confidence intervals calculated by bootstrap. N = 8 wells / condition (64 animals / condition).

[0021] [Figure 10] Figure 10 shows that TBG does not induce seizures in larval zebrafish. Transgenic larval zebrafish expressing GCaMP5G were immobilized in agarose, treated with compounds, and imaged over time. PTZ, a known seizure-inducing compound, was used as a positive control. All compounds were treated at 200 μM (n=2 per condition).

[0022] [Figure 11] Figures 11A and 11B show that TBG (66 μM) does not cause developmental toxicity in zebrafish. Figure 11A shows the proportion of viable and nonviable (congenital abnormalities + death) zebrafish after treatment with VEH and TBG (66 μM) for 5 dpf (Fisher's exact test: p=0.3864). Figure 11B shows representative images of zebrafish treated with VEH and TBG (66 μM) for 2 and 5 dpf. Scale bar = 2 mm.

[0023] [Figure 12] Figure 12 shows concentration-response curves demonstrating the ability of ibogalogs and related compounds to activate 5-HT and opioid receptors. All compounds were assayed in parallel using the same drug dilutions. The graph reflects a representative concentration-response curve plotting the mean and SEM of data points performed in duplicate or triplicate. Assay details are described in the Methods.

[0024] [Figure 13] Figure 13 shows the pharmacological properties of ibogalogs and related compounds. Tables showing EC50 and Emax are estimated from at least two independent concentration-response curves performed in duplicate or triplicate. Log (Emax / EC50) activity is included as an estimate of system agonist activity; inactive = inactive in agonist mode; ND = not determined; blue squares = indicating antagonist activity; dark gray squares = inactive in agonist mode but not tested in antagonist mode; orange squares indicate inverse agonists.

[0025] [Figure 14] Figure 14 shows that screening of DMT derivatives and ibogalog reveals differences in 5-HT receptorome profiles. Ibogalog is a more selective 5-HT2A agonist than 5-MeO-DMT.

[0026] [Figure 15] FIG. 15 shows the dose response profiles of hallucinogenic and non-hallucinogenic compounds compared to the 5HT2A sensor assay in agonist mode.

[0027] [Figure 16] FIG. 16 shows the response profiles of hallucinogenic and non-hallucinogenic compounds compared to the 5HT2A sensor assay in agonist mode.

[0028] [Figure 17] FIG. 17 shows the dose-response profiles of 5HT, 6-MeO-DMT (FIG. 17A), and lisuride (FIG. 17B) on the 5HT2A sensor assay in antagonist mode.

[0029] [Figure 18] FIG. 18 shows the response profiles of hallucinogenic and non-hallucinogenic compounds to the 5HT2A sensor assay in antagonist mode. DETAILED DESCRIPTION OF THE INVENTION

[0030] Detailed Description of the Invention I. General Ibogaine has attracted attention as a potential plasticity-promoting anti-addiction drug; single administration of this hallucinogenic compound has demonstrated sustained efficacy for treating addiction to alcohol, opiates, nicotine, and psychostimulants. An analogue of ibogaine has been developed that can enhance fibroblast growth factor 2 (FGF2)-induced GDNF release in C6 glioma cells; however, the effect of this compound on neuroplasticity is unknown.

[0031] Ibogaine is highly plasticity-promoting. However, the hallucinogenic effects of ibogaine present a barrier to regulatory approval and severely restrict its therapeutic efficacy. It is possible to separate the drug's hallucinogenic effects from its ability to promote neuroplasticity. The compounds described herein, which lack the isoquinuclidine of ibogaine and transpose the methoxy group from the 5th to the 6th position of the indole, are non-hallucinogenic ibogaine derivatives that promote, for example, neuronal proliferation.

[0032] Compounds that can modify neural circuits controlling motivation, anxiety, and drug-seeking behavior have the potential to treat depression, post-traumatic stress disorder (PTSD), and substance abuse disorders (SUD). In some cases, such psychogenic drugs can produce sustained therapeutic effects due to the drug's potential to treat underlying pathological changes in the circuitry. Hallucinogenic compounds have distinguished themselves in this regard, for example, by promoting structural and functional neuroplasticity in key circuits, inducing therapeutic responses in multiple neuropsychiatric disorders, and producing beneficial effects that persist for months after single administration.

[0033] Water-soluble, non-hallucinogenic ibogaine analogs are described herein. Despite lacking hallucinogenic properties, the compounds described herein promote structural neuroplasticity, reduce alcohol consumption, and produce antidepressant-like effects in mice.

[0034] In some cases, hallucinogenic 5-HT 2A 5-HT agonists (e.g., DMT, LSD, DOI, etc.) are useful for treating neurological disorders such as neuropsychiatric disorders (Ly et al., 2018). However, the hallucinogenic and dissociative potential of such compounds limits their use in outpatient clinics. 2A Antagonists include 5-HT antagonists such as DMT, LSD, and DOI. 2A Blocks the neuritogenic and spinogenic effects of hallucinogenic compounds with agonist activity and inhibits 5-HT 2Ademonstrated a correlation between activation and the promotion of neuroplasticity ( Ly et al., 2018 ; Dunlap et al., 2020 ).

[0035] In some embodiments, non-hallucinogenic psychoplastogens are provided herein. In some embodiments, the non-hallucinogenic ibogaine analogs described herein exhibit improved physiochemical properties, for example, as a result of a reduction in total polar surface area. In some embodiments, the hallucinogenic 5-HT 2A Described herein are non-hallucinogenic compounds that demonstrate similar therapeutic efficacy as agonists. In some embodiments, the non-hallucinogenic compounds described herein are used to treat hallucinogenic 5-HT agonists for neurological disorders. 2A It provides better therapeutic efficacy compared to modulators.

[0036] The present invention provides azepino-indoles and other heterocyclic non-hallucinogenic compounds that are useful for treating a variety of brain disorders and other conditions, as well as for enhancing neuroplasticity or enhancing at least one of the translation, transcription, or secretion of neurotrophic factors. II. Definition

[0037] Unless specifically indicated otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. In addition, any methods or materials similar or equivalent to those described herein can be used in the practice of the present invention. For purposes of the present invention, the following terms are defined:

[0038] The use of "a," "an," or "the" includes not only single-component embodiments but also plural-component embodiments. For example, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "a cell" includes a plurality of such cells, reference to "the agent" includes reference to one or more agents known to those of skill in the art, and so forth.

[0039] Abbreviations: VEH = vehicle; KET = ketamine; IBO = ibogaine; NOR = noribogaine; IBG = ibogainelog; TBG = tabernanthalogue; KETSN = ketanserin; SI = sertindole; DOI = 2,5-dimethoxy-4-iodoamphetamine; FST = forced swim test; EtOH = ethanol, DMSO = dimethyl sulfoxide, ATP = adenosine triphosphate.

[0040] "Alkyl" means a straight or branched, saturated, aliphatic group having the indicated number of carbon atoms. 1-2 , C 1-3 , C 1-4 , C 1-5 , C 1-6 , C 1-7 , C 1-8 , C 1-9 , C 1-10 , C 2-3 , C 2-4 , C 2-5 , C 2-6 , C 3-4 , C 3-5 , C 3-6 , C 4-5 , C 4-6 and C 5-6 It may contain any number of carbons, such as, for example, C 1-6 Alkyl includes, but is not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, hexyl, etc. Alkyl can also refer to alkyl groups having up to 20 carbon atoms, including, but not limited to, heptyl, octyl, nonyl, decyl, etc. Alkyl groups can be substituted or unsubstituted.

[0041] "Alkylene" means a straight-chain or branched, saturated, aliphatic, i.e., divalent hydrocarbon group having the specified number of carbon atoms and linking at least two other groups. The two moieties linked to the alkylene can be linked to the same atom or different atoms of the alkylene group. For example, a straight-chain alkylene is -(CH2) where n is 1, 2, 3, 4, 5, or 6.n -divalent radical. Representative alkylene groups include, but are not limited to, methylene, ethylene, propylene, isopropylene, butylene, isobutylene, sec-butylene, pentylene, and hexylene. Alkylene groups can be substituted or unsubstituted.

[0042] "Alkenyl" means a straight or branched chain hydrocarbon having at least two carbon atoms and at least one double bond. Alkenyl includes C, C 2-3 , C 2-4 , C 2-5 , C 2-6 , C 2-7 , C 2-8 , C 2-9 , C 2-10 , C3, C 3-4 , C 3-5 , C 3-6 , C4, C 4-5 , C 4-6 , C5, C 5-6 Alkenyl groups can contain any number of carbons, such as C, C, and C6. Alkenyl groups can have any suitable number of double bonds, including, but not limited to, 1, 2, 3, 4, 5, or more. Examples of alkenyl groups include, but are not limited to, vinyl (ethenyl), propenyl, isopropenyl, 1-butenyl, 2-butenyl, isobutenyl, butadienyl, 1-pentenyl, 2-pentenyl, isopentenyl, 1,3-pentadienyl, 1,4-pentadienyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 1,3-hexadienyl, 1,4-hexadienyl, 1,5-hexadienyl, 2,4-hexadienyl, or 1,3,5-hexatrienyl. Alkenyl groups can be substituted or unsubstituted.

[0043] "Alkynyl" means either a straight chain or branched hydrocarbon having at least two carbon atoms and at least one triple bond. Alkynyl includes C, C 2-3 , C 2-4 , C 2-5 , C 2-6 , C 2-7 , C 2-8 , C 2-9 , C2-10 , C3, C 3-4 , C 3-5 , C 3-6 , C4, C 4-5 , C 4-6 , C5, C 5-6 The alkynyl group may contain any number of carbons, such as C, ...

[0044] "Cycloalkyl" means a saturated or partially unsaturated, monocyclic, fused bicyclic or bridged polycyclic ring assembly containing 3 to 12 ring atoms, or the indicated number of atoms. 3-6 , C 4-6 , C 5-6 , C 3-8 , C 4-8 , C 5-8 , C 6-8 , C 3-9 , C 3-10 , C 3-11 , and C 3-12The cycloalkyl group may contain any number of carbons, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cyclooctyl. Bicyclic compounds include spirocyclic compounds, fused bicyclic compounds, and bridged bicyclic compounds. Saturated bicyclic and polycyclic cycloalkyl rings include, for example, norbornane, [2.2.2]bicyclooctane, decahydronaphthalene, and adamantane. Cycloalkyl groups may also be partially unsaturated, having one or more double or triple bonds within the ring. Representative partially unsaturated cycloalkyl groups include, but are not limited to, cyclobutene, cyclopentene, cyclohexene, cyclohexadiene (1,3- and 1,4-isomers), cycloheptene, cycloheptadiene, cyclooctene, cyclooctadiene (1,3-, 1,4-, and 1,5-isomers), norbornene, and norbornadiene. Cycloalkyl is saturated monocyclic C 3-8 When cycloalkyl, exemplary groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. 3-6 When it is cycloalkyl, exemplary groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Cycloalkyl groups can be substituted or unsubstituted.

[0045] "Alkyl-cycloalkyl" refers to a group having an alkyl component and a cycloalkyl component, where the alkyl component connects the cycloalkyl component to the point of attachment. The alkyl component is as defined above, except that it is at least divalent, i.e., alkylene, in order to connect the cycloalkyl component and the point of attachment. In some cases, the alkyl component may be absent. The alkyl component may be any of the following: C 1-6 , C 1-2 , C 1-3 , C 1-4 , C 1-5 , C 2-3 , C 2-4 , C 2-5 , C 2-6 , C3-4 , C 3-5 , C 3-6 , C 4-5 , C 4-6 and C 5-6 The cycloalkyl moiety is as defined herein. Exemplary alkyl-cycloalkyl groups include, but are not limited to, methyl-cyclopropyl, methyl-cyclobutyl, methyl-cyclopentyl, and methyl-cyclohexyl.

[0046] "Heterocycloalkyl" refers to a cycloalkyl, as defined above, having 3 to 12 ring members and 1 to 4 N, O, and S heteroatoms. Heterocycloalkyl includes bicyclic compounds containing heteroatoms. Bicyclic compounds include spirocyclic compounds, fused bicyclic compounds, and bridged bicyclic compounds. The heteroatoms may be oxidized, for example, but not limited to, -S(O)- and -S(O)2-. Heterocycloalkyl groups can contain any number of ring atoms, such as 3 to 6, 4 to 6, 5 to 6, 3 to 8, 4 to 8, 5 to 8, 6 to 8, 3 to 9, 3 to 10, 3 to 11, or 3 to 12 ring members. Any suitable number of heteroatoms can be included in a heterocycloalkyl group, such as 1, 2, 3, or 4, or 1 to 2, 1 to 3, 1 to 4, 2 to 3, 2 to 4, or 3 to 4. Heterocycloalkyl groups can include groups such as aziridine, azetidine, pyrrolidine, piperidine, azepane, azocane, quinuclidine, pyrazolidine, imidazolidine, piperazine (1,2-, 1,3-, and 1,4-isomers), oxirane, oxetane, tetrahydrofuran, oxane (tetrahydropyran), oxepane, thiirane, thietane, thiolane (tetrahydrothiophene), thiane (tetrahydrothiopyran), oxazolidine, isoxazolidine, thiazolidine, isothiazolidine, dioxolane, dithiolane, morpholine, thiomorpholine, dioxane, or dithiane. Heterocycloalkyl groups can be fused to aromatic or non-aromatic ring systems to form members, including, but not limited to, indoline. Heterocycloalkyl groups can be unsubstituted or substituted. For example, heterocycloalkyl groups can be C 1-6It may be substituted with alkyl or oxo (=O) or the like.

[0047] "Alkyl-heterocycloalkyl" refers to a group having an alkyl component and a heterocycloalkyl component, where the alkyl component connects the heterocycloalkyl component to the point of attachment. The alkyl component is as defined above, except that it is at least divalent, i.e., alkylene, in order to connect the heterocycloalkyl component and the point of attachment. The alkyl component is as defined above, except that it is at least divalent, i.e., alkylene, in order to connect the heterocycloalkyl component and the point of attachment. The alkyl component is C 0-6 , C 1-2 , C 1-3 , C 1-4 , C 1-5 , C 1-6 , C 2-3 , C 2-4 , C 2-5 , C 2-6 , C 3-4 , C 3-5 , C 3-6 , C 4-5 , C 4-6 and C 5-6 The heterocycloalkyl group may contain any number of carbons, such as , ...

[0048] "Halogen" refers to fluorine, chlorine, bromine, and iodine.

[0049] "Haloalkyl" refers to an alkyl as defined above in which some or all of the hydrogen atoms are replaced with halogen atoms. Like alkyl groups, haloalkyl groups can have any suitable number of carbon atoms, such as C1-6. For example, haloalkyl includes trifluoromethyl, fluoromethyl, etc. In some cases, the term "perfluoro" can be used to define a compound or radical in which all hydrogen atoms are replaced with fluorine. For example, perfluoromethyl refers to 1,1,1-trifluoromethyl. Alkylamine

[0050] "Alkoxy" refers to an alkyl group having an oxygen atom connecting the alkyl group to the point of attachment: alkyl-O-. Like alkyl groups, alkoxy groups can have any suitable number of carbon atoms, such as C. Alkoxy groups include, for example, methoxy, ethoxy, propoxy, iso-propoxy, butoxy, 2-butoxy, iso-butoxy, sec-butoxy, tert-butoxy, pentoxy, hexoxy, and the like. Alkoxy groups may be further substituted with a variety of substituents described herein. Alkoxy groups may be substituted or unsubstituted.

[0051] "Haloalkoxy" refers to an alkoxy group in which some or all of the hydrogen atoms are replaced with halogen atoms. Like alkyl groups, haloalkoxy groups can have any suitable number of carbon atoms, such as C. Alkoxy groups can be substituted with one, two, three, or more halogens. When all hydrogens are replaced with halogens, such as fluorine, the compound is per-substituted, for example, perfluorinated. Haloalkoxy includes, but is not limited to, trifluoromethoxy, 2,2,2-trifluoroethoxy, perfluoroethoxy, and the like.

[0052] "Amine" refers to an -N(R) group, where the R groups can be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, etc. The R groups can be the same or different. The amino group can be primary (each R is hydrogen), secondary (one R is hydrogen), or tertiary (each R is other than hydrogen).

[0053] "Alkylamine" refers to an alkyl group, as defined herein, bearing one or more amino groups. The amino groups may be primary, secondary, or tertiary. The alkylamine may be further substituted with a hydroxy group to form an amino-hydroxy group. Alkylamines useful in the present invention include, but are not limited to, ethylamine, propylamine, isopropylamine, ethylenediamine, and ethanolamine. The amino group may be at the omega position of the alkyl group, linking the alkylamine to the point of attachment to the remainder of the compound, or linking at least two carbon atoms of the alkyl group together. One of ordinary skill in the art will recognize that other alkylamines are also useful in the present invention.

[0054] "Aryl" refers to an aromatic ring system having any suitable number of ring atoms and any suitable number of rings. Aryl groups can contain any suitable number of ring atoms, such as 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16 ring atoms, and 6 to 10, 6 to 12, or 6 to 14 ring members. Aryl groups can be monocyclic or fused to form bicyclic or tricyclic groups, or joined by bonds to form biaryl groups. Representative aryl groups include phenyl, naphthyl, and biphenyl. Other aryl groups include benzyl, which has a methylene linking group. Some aryl groups, such as phenyl, naphthyl, or biphenyl, have 6 to 12 ring members. Other aryl groups, such as phenyl or naphthyl, have 6 to 10 ring members. Other aryl groups, such as phenyl, have 6 ring members. Aryl groups can be substituted or unsubstituted.

[0055] "Alkyl-aryl" refers to a group having an alkyl component and an aryl component, where the alkyl component connects the aryl component to the point of attachment. The alkyl component is as defined above, except that it is at least divalent, i.e., alkylene, in order to connect the aryl component to the point of attachment. The alkyl component is as defined above, except that it is at least divalent, i.e., alkylene, in order to connect the aryl component to the point of attachment. The alkyl component is C 0-6 , C 1-2 , C 1-3 , C 1-4 , C 1-5, C 1-6 , C 2-3 , C 2-4 , C 2-5 , C 2-6 , C 3-4 , C 3-5 , C 3-6 , C 4-5 , C 4-6 and C 5-6 The alkyl-aryl group may contain any number of carbon atoms, such as aryl, aryl, aryl- ...

[0056] "Heteroaryl" refers to a monocyclic or fused bicyclic or tricyclic aromatic ring assembly containing 5 to 16 ring atoms, where 1 to 5 of the ring atoms are heteroatoms such as N, O, or S. A heteroaryl group can contain any number of ring atoms, such as 5 to 6, 3 to 8, 4 to 8, 5 to 8, 6 to 8, 3 to 9, 3 to 10, 3 to 11, or 3 to 12 ring members. Any suitable number of heteroatoms can be included in a heteroaryl group, such as 1, 2, 3, 4, or 5, or 1 to 2, 1 to 3, 1 to 4, 1 to 5, 2 to 3, 2 to 4, 2 to 5, 3 to 4, or 3 to 5. A heteroaryl group can have 5 to 8 ring members and 1 to 4 heteroatoms, or 5 to 8 ring members and 1 to 3 heteroatoms, or 5 to 6 ring members and 1 to 4 heteroatoms, or 5 to 6 ring members and 1 to 3 heteroatoms. Heteroaryl groups may include groups such as pyrrole, pyridine, imidazole, pyrazole, triazole, tetrazole, pyrazine, pyrimidine, pyridazine, triazine (1,2,3-, 1,2,4-, and 1,3,5-isomers), thiophene, furan, thiazole, isothiazole, oxazole, and isoxazole. Heteroaryl groups may be fused to an aromatic ring system, such as a phenyl ring, to form members including, but not limited to, benzopyrroles, e.g., indole and isoindole, benzopyridines, e.g., quinoline and isoquinoline, benzopyrazine (quinoxaline), benzopyrimidine (quinazoline), benzopyridazines, e.g., phthalazine and cinnoline, benzothiophene, and benzofuran. Other heteroaryl groups include heteroaryl rings connected by bonds, such as bipyridine. Heteroaryl groups may be substituted or unsubstituted.

[0057] "Alkyl-heteroaryl" refers to a group having an alkyl component and a heteroaryl component, where the alkyl component connects the heteroaryl component to the point of attachment. The alkyl component is as defined above except that it is at least divalent, i.e., alkylene, in order to connect the heteroaryl component and the point of attachment. The alkyl component is as defined above except that it is at least divalent, i.e., alkylene, in order to connect the heteroaryl component and the point of attachment. The alkyl component is C 0-6 , C 1-2 , C 1-3 , C1-4 , C 1-5 , C 1-6 , C 2-3 , C 2-4 , C 2-5 , C 2-6 , C 3-4 , C 3-5 , C 3-6 , C 4-5 , C 4-6 and C 5-6 The alkyl group may contain any number of carbons, such as , ...

[0058] "Salt" refers to an acid salt or a base salt of the compound used in the method of the present invention. Illustrative examples of pharmaceutically acceptable salts are salts of mineral acids (such as hydrochloric acid, hydrobromic acid, phosphoric acid, etc.), salts of organic acids (such as fumaric acid, acetic acid, propionic acid, glutamic acid, citric acid, etc.), and salts of quaternary ammonium salts (such as methyl iodide, ethyl iodide, etc.). It is understood that pharmaceutically acceptable salts are non-toxic. Further information regarding suitable pharmaceutically acceptable salts can be found in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, which is incorporated herein by reference.

[0059] The neutral forms of the compounds may be regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner. The parent compound may differ from the various salt forms in certain physical properties, such as solubility in polar solvents, but the salts are otherwise equivalent to the parent compound for purposes of the present invention.

[0060] "Pharmaceutically acceptable salt" refers to a compound in a salt form, wherein the compound is suitable for administration to a subject. Exemplary pharmaceutically acceptable salts include salts of acetic acid, ascorbic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethanesulfonic acid, edisylic acid, fumaric acid, gentisic acid, gluconic acid, glucoronic acid, glutamic acid, hippuric acid, hydrobromic acid, hydrochloric acid, isethionic acid, lactic acid, lactobionic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, mucic acid, naphthalenesulfonic acid, naphthalene-1,5-disulfonic acid, naphthalene-2,6-disulfonic acid, nicotinic acid, nitric acid, orotic acid, pamoic acid, pantothenic acid, phosphoric acid, succinic acid, sulfuric acid, tartaric acid, p-toluenesulfonic acid, and xinafoic acid, and the like.

[0061] A "pharmaceutically acceptable excipient" refers to a substance that aids in the administration of an active agent to a subject and the absorption of the active agent by a subject. Pharmaceutical excipients useful in the present invention include, but are not limited to, binders, fillers, disintegrants, lubricants, coating agents, sweeteners, flavoring agents, and coloring agents. One of ordinary skill in the art will recognize that other pharmaceutical excipients are useful in the present invention.

[0062] "Composition" refers to a product containing the specified ingredients in the specified amounts, as well as any product that results directly or indirectly from combining the specified ingredients in the specified amounts. "Pharmaceutically acceptable" means the carrier, diluent or excipient must be compatible with the other ingredients of the formulation.

[0063] "Isomers" refer to compounds that have different connectivity between atoms in the molecule, leading to different chemical structures despite the same chemical formula. Isomers include structural isomers and stereoisomers. Examples of structural isomers include, but are not limited to, tautomers and positional isomers. Examples of stereoisomers include, but are not limited to, diastereomers and enantiomers.

[0064] "Administering" refers to oral administration, administration as a suppository, topical contact, parenteral, intravenous, intraperitoneal, intramuscular, intralesional, intranasal or subcutaneous administration, intrathecal administration, or implantation of a sustained release device, e.g., a mini-osmotic pump, to a subject.

[0065] "Subject" refers to animals such as mammals, including, but not limited to, primates (e.g., humans), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice, etc. In certain embodiments, the subject is a human.

[0066] A "therapeutically effective amount," "therapeutically sufficient amount," or "effective or sufficient amount" refers to a dose that produces the therapeutic effect for which it is administered. The exact dose depends on the purpose of the treatment and can be ascertained by one of ordinary skill in the art using known techniques (see, for example, Lieberman, Pharmaceutical Dosage Forms (vols. 1-3, 1992); Lloyd, The Art, Science and Technology of Pharmaceutical Compounding (1999); Pickar, Dosage Calculations (1999); and Remington: The Science and Practice of Pharmacy, 20th Edition, 2003, Gennaro, Ed., Lippincott, Williams & Wilkins). In sensitized cells, the therapeutically effective amount is often lower than the conventional therapeutically effective amount in non-sensitized cells.

[0067] "Neuroplasticity" refers to the ability of the brain to continually change its structure and / or function throughout a subject's life. Examples of changes to the brain include, but are not limited to, the ability to adapt or respond to internal and / or external stimuli, such as injury, and the ability to generate new neurites, dendritic spines, and synapses.

[0068] "Brain disorders" refers to neurological disorders that affect the structure and function of the brain, including, but not limited to, Alzheimer's disease, Parkinson's disease, psychiatric disorders, depression, treatment-resistant depression, addiction, anxiety, post-traumatic stress disorder, suicidal ideation, major depressive disorder, bipolar disorder, schizophrenia, stroke, traumatic brain injury, and substance use disorders.

[0069] "Combination therapy" refers to a method of treating a disease or disorder in which two or more different pharmaceutical agents are administered in an overlapping dosing regimen, such that the subject is exposed to both agents simultaneously. For example, the compounds of the present invention can be used in combination with other pharmaceutically active compounds. The compounds of the present invention can be administered simultaneously or sequentially (as a single preparation or separate preparations) with the other drug therapy. Generally, combination therapy contemplates the administration of two or more drugs during a single cycle or course of therapy.

[0070] "Neurotrophic factors" refers to a family of soluble peptides or proteins that support the survival, growth, and differentiation of developing and mature neurons.

[0071] "Modulate" or "modulating" or "modulation" refers to an increase or decrease in the amount, quality, or effect of a particular activity, function, or molecule. By way of example and not by way of limitation, the term "modulate" refers to an increase or decrease in the amount, quality, or effect of a particular activity, function, or molecule. 2A Agonists, partial agonists, antagonists, and allosteric modulators (eg, positive allosteric modulators) of the ) are modulators of the receptor.

[0072] "Agonism" refers to the activation of a receptor or enzyme by a modulator or agonist, resulting in a biological response.

[0073] "Agonist" refers to a modulator that binds to a receptor or enzyme and activates the receptor to produce a biological response. By way of example only, "5HT 2A The "agonist" is a 5HT antagonist with a potency of approximately 100 μM or less. 2A Regarding activity EC 50In some embodiments, "agonist" includes full agonists or partial agonists. A "full agonist" refers to a modulator that binds to and activates a receptor with the maximal response that an agonist produces at the receptor. A "partial agonist" refers to a modulator that binds to and activates a given receptor but with partial efficacy, i.e., a less than maximal response at the receptor relative to a full agonist.

[0074] A "positive allosteric modulator" refers to a modulator that binds to a site different from the orthosteric binding site and enhances or amplifies the effect of an agonist.

[0075] "Antagonism" refers to the inactivation of a receptor or enzyme by a modulator or antagonist. Receptor antagonism is, for example, when a molecule is unable to bind to the receptor and cause activity.

[0076] "Antagonist" or "neutralizing antagonist" refers to a modulator that binds to a receptor or enzyme and prevents a biological response. Antagonists have no activity in the absence of an agonist or inverse agonist, but can prevent the activity of either, resulting in no change in the biological response.

[0077] "I C 50 " refers to the concentration of a substance (e.g., a compound or drug) required for 50% inhibition of a biological process. For example, IC 50 refers to the half-maximum (50%) inhibitory concentration (IC) of a substance as measured in a suitable assay. 50 is determined in an in vitro assay system. In some embodiments, IC as used herein 50 receptors, e.g., 5HT 2A This refers to the concentration of a modulator (e.g., antagonist or inhibitor) required for 50% inhibition of a signal. III. Compound

[0078] The present invention provides azepino-indoles and other heterocyclic non-hallucinogenic compounds (e.g., Formula (I) or Formula (Ia)) that are useful for treating a variety of brain disorders and other conditions. In some embodiments, the azepino-indoles and other heterocyclic compounds provided herein inhibit 5-HT 2A It is a modulator and promotes neuroplasticity (e.g., plasticity of cortical structures).

[0079] In some embodiments, the present invention provides a compound of formula I: [ka] {where, R 1 is hydrogen or C 1-6 alkyl; R 3a and R 3b are each independently hydrogen, C 1-6 Alkyl, C 3-8 Cycloalkyl, or C 4-14 alkyl-cycloalkyl; R 3c is hydrogen or C 1-6 alkyl; or R 2 and R 3b are combined with the atom to which they are attached and independently represent hydrogen, C 1-6 Alkyl, C 3-8 Cycloalkyl, C 3-14 Alkyl-cycloalkyl, C 4-10 Heterocycloalkyl, C 4-16 Alkyl-heterocycloalkyl, C 6-12 Aryl, C 7-18 Alkyl-aryl, C 5-10 Heteroaryl or C 4-16 one to three R's that are alkyl-heteroaryl 9 C substituted with a group 5-8 Two R attached to the same atom form a heterocycloalkyl 9 groups combined to form =O; or R 2 and R 3c are combined with the atom to which they are attached and independently represent hydrogen, C 1-6 Alkyl, C3-8 Cycloalkyl, C 3-14 Alkyl-cycloalkyl, C 4-10 Heterocycloalkyl, C 4-16 Alkyl-heterocycloalkyl, C 6-12 Aryl, C 7-18 Alkyl-aryl, C 5-10 Heteroaryl or C 4-16 one to three R's that are alkyl-heteroaryl 10 C substituted with a group 5-8 Two R's attached to the same atom form a cycloalkyl or 10 The groups combine to form =O;R 4 , R 5 , R 6 and R 7 are each independently hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, C 1-6 Haloalkyl, C 1-6 Alkylamines, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -OR 8a , -NO2, -CN, -C(O)R 8b , -C(O)OR 8b , -OC(O)R 8b , -OC(O)OR 8b , -N(R 8b R 8c ), -N(R 8b )C(O)R 8c , -C(O)N(R 8b R 8c ), -N(R 8b )C(O)OR 8c , -OC(O)N(R 8b R 8c ), -N(R 8b )C(O)N(R 8c R 8d ), -C(O)C(O)N(R 8b R 8c ), -S(O2)R 8b , -S(O)2N(R 8b R 8c ), C 3-8 Cycloalkyl, C3-14 Alkyl-cycloalkyl, C 4-10 Heterocycloalkyl, C 4-16 Alkyl-heterocycloalkyl, C 6-12 Aryl, C 7-18 Alkyl-aryl, C 5-10 Heteroaryl, or C 4-16 alkyl-heteroaryl, where R 4 , R 5 , R 6 and R 7 at least one of is not H; or R 4 and R 5 , R 5 and R 6 , or R 6 and R 7 are combined with the atoms to which they are attached, and 3-6 Cycloalkyl, C 3-6 Heterocycloalkyl, C 6-12 Aryl or C 5-10 Forming a heteroaryl; R 8a , R 8b , R 8c and R 8d are independently H, C 1-6 alkyl; where R 2 and R 3b are combined with the atom to which they are attached to form a C7 heterocycloalkyl, and R 3a is methyl, R 5 is not OMe, OH, or Cl; where R 2 and R 3b are combined with the atom to which they are attached to form a C7 heterocycloalkyl, and R 3a When is ethyl, R 6 is not OMe; where R 2 and R 3b are combined with the atom to which they are attached to form a C7 heterocycloalkyl, and R 6 When F, R 4 , R 5 , and R 7 at least one of R is not hydrogen;2 and R 3b are combined with the atom to which they are attached to form a C7 heterocycloalkyl, and R 6 is F, Cl, -Me, or -OMe, R 3a is -Me; where R 2 and R 3b are combined with the atom to which they are attached to form a C6 heterocycloalkyl, and R 6 But C 1-6 Alkyl, halogen, C 1-6 When R is alkyloxy, -C(O)H, or -NH2, 4 , R 5 , and R 7 at least one of R 2 and R 3b are combined with the atom to which they are attached to form a C6 heterocycloalkyl, and R 6 When is methyl, halogen, or -C(O)H, R 4 , R 5 , and R 7 wherein at least one of is not methyl or Cl}, or a pharmaceutically acceptable salt or isomer thereof.

[0080] In some embodiments, the present invention provides a compound of formula I: [ka] {where, R 1 is hydrogen or C 1-6 alkyl; R 3a and R 3b are each independently hydrogen, C 1-6 Alkyl, C 3-8 Cycloalkyl, or C 4-14 alkyl-cycloalkyl; R 3c is hydrogen or C 1-6 alkyl; or R 2 and R 3b are combined with the atom to which they are attached and independently represent hydrogen, C 1-6Alkyl, C 3-8 Cycloalkyl, C 3-14 Alkyl-cycloalkyl, C 4-10 Heterocycloalkyl, C 4-16 Alkyl-heterocycloalkyl, C 6-12 Aryl, C 7-18 Alkyl-aryl, C 5-10 Heteroaryl or C 4-16 one to three R's that are alkyl-heteroaryl 9 C substituted with a group 5-8 Two R attached to the same atom form a heterocycloalkyl 9 groups combined to form =O; or R 2 and R 3b are combined with the atom to which they are attached and independently represent hydrogen, C 1-6 Alkyl, C 3-8 Cycloalkyl, C 3-14 Alkyl-cycloalkyl, C 4-10 Heterocycloalkyl, C 4-16 Alkyl-heterocycloalkyl, C 6-12 Aryl, C 7-18 Alkyl-aryl, C 5-10 Heteroaryl or C 4-16 one to three R's that are alkyl-heteroaryl 10 C substituted with a group 5-8 Two R's attached to the same atom form a cycloalkyl or 10 The groups combine to form =O;R 4 , R 5 , R 6 and R 7 are each independently hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, C 1-6 Haloalkyl, C 1-6 Alkylamines, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -OR 8a , -NO2, -CN, -C(O)R 8b , -C(O)OR 8b, -OC(O)R 8b , -OC(O)OR 8b , -N(R 8b R 8c ), -N(R 8b )C(O)R 8c , -C(O)N(R 8b R 8c ), -N(R 8b )C(O)OR 8c , -OC(O)N(R 8b R 8c ), -N(R 8b )C(O)N(R 8c R 8d ), -C(O)C(O)N(R 8b R 8c ), -S(O2)R 8b , -S(O)2N(R 8b R 8c ), C 3-8 Cycloalkyl, C 3-14 Alkyl-cycloalkyl, C 4-10 Heterocycloalkyl, C 4-16 Alkyl-heterocycloalkyl, C 6-12 Aryl, C 7-18 Alkyl-aryl, C 5-10 Heteroaryl, or C 4-16 alkyl-heteroaryl, where R 4 , R 5 , R 6 and R 7 At least one of the following is ;R instead of H. 8b , R 8c and R 8d are each independently H or C 1-6 or a pharmaceutically acceptable salt or isomer thereof.

[0081] In some embodiments, R 1 is hydrogen or C 1-6 In some embodiments, R 1 is hydrogen, methyl, ethyl, or propyl. In some embodiments, R 1 is hydrogen or methyl. In some embodiments, R 1is hydrogen. In some embodiments, R 1 In some embodiments, the present invention provides a compound of formula 1 is hydrogen or methyl} or a pharmaceutically acceptable salt thereof. In some embodiments, the present invention provides a compound {wherein R 1 is hydrogen} or a pharmaceutically acceptable salt thereof.

[0082] In some embodiments, R 3a is hydrogen, C 1-6 Alkyl, C 3-8 Cycloalkyl, or C 4-14 In some embodiments, R 3a is hydrogen or C 1-6 In some embodiments, R 3a is hydrogen, methyl, ethyl, or propyl. In some embodiments, R 3a is hydrogen or methyl. In some embodiments, R 3a is methyl. In some embodiments, R 3a In some embodiments, the present invention provides a compound of formula 3a is hydrogen or C 1-6 In some embodiments, the present invention provides a compound {wherein R is an alkyl group} or a pharmaceutically acceptable salt thereof. 3a is hydrogen or methyl} or a pharmaceutically acceptable salt thereof.

[0083] In some embodiments, R 4 , R 5 , R 6 and R 7 are each independently hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, C 1-6 Haloalkyl, C 1-6 Alkylamines, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -OR 8a, -NO2, -CN, -C(O)R 8b , -C(O)OR 8b , -OC(O)R 8b , -OC(O)OR 8b , -N(R 8b R 8c ), -N(R 8b )C(O)R 8c , -C(O)N(R 8b R 8c ), -N(R 8b )C(O)OR 8c , -OC(O)N(R 8b R 8c ), -N(R 8b )C(O)N(R 8c R 8d ), -C(O)C(O)N(R 8b R 8c ), -S(O2)R 8b , -S(O)2N(R 8b R 8c ), C 3-8 Cycloalkyl, C 3-14 Alkyl-cycloalkyl, C 4-10 Heterocycloalkyl, C 4-16 Alkyl-heterocycloalkyl, C 6-12 Aryl, C 7-18 Alkyl-aryl, C 5-10 Heteroaryl, or C 4-16 alkyl-heteroaryl, where R 4 , R 5 , R 6 and R 7 at least one of is not H; or R 4 and R 5 , R 5 and R 6 , or R 6 and R 7 are combined with the atoms to which they are attached, and 3-6 Cycloalkyl, C 3-6 Heterocycloalkyl, C 6-12 Aryl or C 5-10 forming a heteroaryl; and R 8a , R 8b , R 8c and R 8dare independently H, C 1-6 It is alkyl.

[0084] In some embodiments, the present invention provides a compound of formula 4 , R 5 , R 6 and R 7 are each independently hydrogen, C 1-6 Alkyl, halogen, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -OR 8a , -NO2, -CN, -N(R 8b R 8c ), -N(R 8b )C(O)R 8c , -C(O)N(R 8b R 8c ), C 3-8 Cycloalkyl, C 3-14 Alkyl-cycloalkyl, C 4-10 Heterocycloalkyl, or C 4-16 alkyl-heterocycloalkyl, where R 4 , R 5 , R 6 and R 7 at least one of is not H; or R 4 and R 5 , R 5 and R 6 , or R 6 and R 7 are combined with the atoms to which they are attached, and 3-6 form a heterocycloalkyl; and R 8a , R 8b or R 8c are independently H, C 1-6 Alkyl or C 3-6 cycloalkyl} or a pharmaceutically acceptable salt thereof.

[0085] In some embodiments, the present invention provides a compound of formula 6 is C 1-6 Alkyl, halogen, C 1-6 Haloalkyl, C 1-6Alkoxy, C 1-6 Haloalkoxy, -OR 8a , -NO2, -CN, -N(R 8b R 8c ), -N(R 8b )C(O)R 8c , -C(O)N(R 8b R 8c ), C 3-8 Cycloalkyl, C 3-14 Alkyl-cycloalkyl, C 4-10 Heterocycloalkyl, or C 4-16 alkyl-heterocycloalkyl; or R 5 and R 6 are combined with the atoms to which they are attached, and 3-6 form a heterocycloalkyl; and R 8a , R 8b and R 8c are independently H, C 1-6 Alkyl or C 3-6 cycloalkyl} or a pharmaceutically acceptable salt thereof.

[0086] In some embodiments, the present invention provides a compound of formula 4 , R 5 , R 6 and R 7 are each independently hydrogen, C 1-6 Alkyl, halogen, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -OR 8a , -N(R 8b R 8c ), -N(R 8b )C(O)R 8c , C 4-10 Heterocycloalkyl, or C 4-16 alkyl-heterocycloalkyl, where R 4 , R 5 , R 6 and R 7 at least one of is not H; or R 5 and R 6are combined with the atoms to which they are attached, and 3-6 form a heterocycloalkyl; and R 8a , R 8b and R 8c are independently H, C 1-6 Alkyl or C 3-6 cycloalkyl} or a pharmaceutically acceptable salt thereof.

[0087] In some embodiments, the present invention provides a compound of formula 6 is C 1-6 Alkyl, halogen, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -OR 8a , -N(R 8b R 8c ), -N(R 8b )C(O)R 8c , C 4-10 Heterocycloalkyl, or C 4-16 alkyl-heterocycloalkyl; or R 5 and R 6 are combined with the atoms to which they are attached, and 3-6 form a heterocycloalkyl; and R 8a , R 8b and R 8c are independently H, C 1-6 Alkyl or C 3-6 cycloalkyl} or a pharmaceutically acceptable salt thereof.

[0088] In some embodiments, the present invention provides a compound of formula 4 , R 5 , R 6 and R 7 are each independently hydrogen, C 1-6 Alkyl, halogen, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -OR 8a , -N(R 8b R 8c ), or -N(R8b )C(O)R 8c where R 4 , R 5 , R 6 and R 7 At least one of the following is not H; 8a is H; and R 8b and R 8c are each independently H or -Me; or R 5 and R 6 are combined with the atoms to which they are attached, and 3-6 forming a heterocycloalkyl} or a pharmaceutically acceptable salt thereof.

[0089] In some embodiments, the present invention provides a compound of formula 4 , R 5 , R 6 and R 7 are each independently hydrogen, C 1-6 Alkyl, halogen, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 haloalkoxy, or -OR 8a where R 4 , R 5 , R 6 and R 7 At least one of the following is not H; 8a is H; or R 5 and R 6 are combined with the atoms to which they are attached, and 3-6 forming a heterocycloalkyl}.

[0090] In some embodiments, the present invention provides a compound of formula 4 , R 5 , R 6 and R 7 are each independently H, F, Cl, Br, -OH, -OMe, -CF3, -OCF3, -Me, -NMe2, -NHC(O)Me, or -N(Me)C(O)Me, where R 4 , R 5 , R 6and R 7 at least one of is not H; or R 5 and R 6 are combined to form a 1,3-dioxole ring, or a 1,4-dioxane ring} or a pharmaceutically acceptable salt thereof.

[0091] In some embodiments, the present invention provides a compound of formula 4 is H, F, -Me, -CF3, -OCF3, or -OMe; R 5 is H, F, Cl, Br, -Me, -CF3, -OCF3, -OH or -OMe; R 6 is H, F, -OH, -OMe, -OiPr, -Me, -CF3, -OCF3, -NMe2, -NHC(O)Me, or -N(Me)C(O)Me; or R 5 and R 6 are combined to form a 1,3-dioxole ring or a 1,4-dioxane ring; and R 7 is H, where R 4 , R 5 and R 6 wherein at least one of is not H} or a pharmaceutically acceptable salt thereof.

[0092] In some embodiments, the present invention provides a compound of formula 4 , R 5 , R 6 and R 7 are each independently H, F, Cl, Br, —OH, —OMe, —CF3, or —OCF3, where R 4 , R 5 , R 6 and R 7 at least one of is not H; or R 5 and R 6 are combined to form a 1,3-dioxole ring}.

[0093] In some embodiments, the present invention provides a compound of formula 4 is H, F, or -OMe; R 5is H, F, Cl, Br, —OH or —OMe; R 6 is H, F, -OMe, -CF3 or OCF3; or R 5 and R 6 are combined to form a 1,3-dioxole ring; and R 7 is H, where R 4 , R 5 , R 6 and R 7 at least one of which is not H}.

[0094] In some embodiments, the present invention provides a compound of formula 6 is F, —OH, —OMe, —OiPr, —Me, —CF3, —OCF3, —NMe2, —NHC(O)Me, or —N(Me)C(O)Me; or R 5 and R 6 are combined to form a 1,3-dioxole ring or a 1,4-dioxane ring} or a pharmaceutically acceptable salt thereof.

[0095] In some embodiments, R 4 and R 5 , R 5 and R 6 , or R 6 and R 7 are combined with the atoms to which they are attached, and 3-6 Cycloalkyl, C 3-6 Heterocycloalkyl, C 6-12 Aryl or C 5-10 In some embodiments, R 4 and R 5 , R 5 and R 6 , or R 6 and R 7 are combined with the atoms to which they are attached, and 3-6 Cycloalkyl or C 3-6 In some embodiments, R 4 and R 5are combined with the atoms to which they are attached, and 3-6 In some embodiments, R 5 and R 6 are combined with the atoms to which they are attached, and 3-6 In some embodiments, R 6 and R 7 are combined with the atoms to which they are attached, and 3-6 In some embodiments, R 5 and R 6 are combined to form a 1,3-dioxole ring or a 1,4-dioxane ring.

[0096] In some embodiments, R 3a and R 3b are each independently hydrogen, C 1-6 Alkyl, C 3-8 Cycloalkyl, or C 4-14 alkyl-cycloalkyl; or R 2 and R 3b are combined with the atom to which they are attached and independently represent hydrogen, C 1-6 Alkyl, C 3-8 Cycloalkyl, C 3-14 Alkyl-cycloalkyl, C 4-10 Heterocycloalkyl, C 4-16 Alkyl-heterocycloalkyl, C 6-12 Aryl, C 7-18 Alkyl-aryl, C 5-10 Heteroaryl or C 4-16 one to three R's that are alkyl-heteroaryl 9 C substituted with a group 5-8 form a heterocycloalkyl; or two R attached to the same atom 9 groups combined to form =O; or R 2 and R 3c are combined with the atom to which they are attached and independently represent hydrogen, C 1-6Alkyl, C 3-8 Cycloalkyl, C 3-14 Alkyl-cycloalkyl, C 4-10 Heterocycloalkyl, C 4-16 Alkyl-heterocycloalkyl, C 6-12 Aryl, C 7-18 Alkyl-aryl, C 5-10 Heteroaryl or C 4-16 one to three R's that are alkyl-heteroaryl 10 C substituted with a group 5-8 Two R's attached to the same atom form a cycloalkyl or 10 The groups combine to form =O.

[0097] In some embodiments, the present invention provides a compound of the present invention, 2 and R 3b are combined with the atom to which they are attached and independently represent hydrogen, C 1-6 Alkyl, C 3-8 Cycloalkyl, C 3-14 Alkyl-cycloalkyl, C 4-10 Heterocycloalkyl, C 4-16 Alkyl-heterocycloalkyl, C 6-12 Aryl, C 7-18 Alkyl-aryl, C 5-10 Heteroaryl or C 4-16 one to three R's that are alkyl-heteroaryl 9 C substituted with a group 5-8 Two R attached to the same atom form a heterocycloalkyl 9 and R is a substituted or unsubstituted aryl group; 2 and R 3b are combined with the atom to which they are attached to form C 5-8 In some embodiments, the present invention provides a compound {wherein R 2 and R 3bare combined with the atom to which they are attached to form C 7-8 forming a heterocycloalkyl} or a pharmaceutically acceptable salt thereof.

[0098] In some embodiments, the present invention provides a compound or a pharmaceutically acceptable salt thereof, wherein the compound of Formula I has the following structure: [ka] {where, R 6 is C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, C 1-6 Haloalkyl, C 1-6 Alkylamines, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -OR 8a , -NO2, -CN, -C(O)R 8b , -C(O)OR 8b , -OC(O)R 8b , -OC(O)OR 8b , -N(R 8b R 8c ), -N(R 8b )C(O)R 8c , -C(O)N(R 8b R 8c ), -N(R 8b )C(O)OR 8c , -OC(O)N(R 8b R 8c ), -N(R 8b )C(O)N(R 8c R 8d ), -C(O)C(O)N(R 8b R 8c ), -S(O2)R 8b , -S(O)2N(R 8b R 8c ), C 3-8 Cycloalkyl, C 3-14 Alkyl-cycloalkyl, C 4-10 Heterocycloalkyl, C 4-16 Alkyl-heterocycloalkyl, C 6-12 Aryl, C 7-18Alkyl-aryl, C 5-10 Heteroaryl, or C 4-16 alkyl-heteroaryl; or R 4 and R 5 , R 5 and R 6 , or R 6 and R 7 are combined with the atoms to which they are attached, and 3-6 Cycloalkyl, C 3-6 Heterocycloalkyl, C 6-12 Aryl or C 5-10 Forming a heteroaryl; R 8a , R 8b , R 8c and R 8d are independently H, C 1-6 alkyl; and n is 1, 2, or 3; where n is 2 and R 6 When F, R 4 , R 5 , and R 7 where n is 2 and at least one of R 6 is F, Cl, methyl, or OMe, R 3a is methyl; where n is 1 and R 6 But C 1-6 Alkyl, halogen, C 1-6 When R is alkyloxy, -C(O)H, or -NH2, 4 , R 5 , and R 7 at least one of n is not hydrogen; and where n is 1 and R 6 is methyl, halogen, or —C(O)H, R 4 , R 5 , and R 7 At least one of the groups has a substituent that is not methyl or Cl.

[0099] In some embodiments, the present invention provides a compound of Formula (Ia), or a pharmaceutically acceptable salt or isomer thereof, wherein the compound has the following structure: [ka] {where, R 1 is hydrogen or C 1-6 alkyl; R 3a is hydrogen, C 1-6 Alkyl, C 3-8 Cycloalkyl, or C 4-14 alkyl-cycloalkyl; R 3c is hydrogen or C 1-6 alkyl; R 4 , R 5 , and R 7 are each independently hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, C 1-6 Haloalkyl, C 1-6 Alkylamines, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -OR 8a , -NO2, -CN, -C(O)R 8b , -C(O)OR 8b , -OC(O)R 8b , -OC(O)OR 8b , -N(R 8b R 8c ), -N(R 8b )C(O)R 8c , -C(O)N(R 8b R 8c ), -N(R 8b )C(O)OR 8c , -OC(O)N(R 8b R 8c ), -N(R 8b )C(O)N(R 8c R 8d ), -C(O)C(O)N(R 8b R 8c ), -S(O2)R 8b , -S(O)2N(R 8b R 8c ), C 3-8 Cycloalkyl, C 3-14 Alkyl-cycloalkyl, C 4-10 Heterocycloalkyl, C 4-16 Alkyl-heterocycloalkyl, C 6-12 Aryl, C7-18 Alkyl-aryl, C 5-10 Heteroaryl, or C 4-16 alkyl-heteroaryl; R 6 is C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, C 1-6 Haloalkyl, C 1-6 Alkylamines, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -OR 8a , -NO2, -CN, -C(O)R 8b , -C(O)OR 8b , -OC(O)R 8b , -OC(O)OR 8b , -N(R 8b R 8c ), -N(R 8b )C(O)R 8c , -C(O)N(R 8b R 8c ), -N(R 8b )C(O)OR 8c , -OC(O)N(R 8b R 8c ), -N(R 8b )C(O)N(R 8c R 8d ), -C(O)C(O)N(R 8b R 8c ), -S(O2)R 8b , -S(O)2N(R 8b R 8c ), C 3-8 Cycloalkyl, C 3-14 Alkyl-cycloalkyl, C 4-10 Heterocycloalkyl, C 4-16 Alkyl-heterocycloalkyl, C 6-12 Aryl, C 7-18 Alkyl-aryl, C 5-10 Heteroaryl, or C 4-16 alkyl-heteroaryl; or R 4 and R 5 , R 5 and R 6 , or R 6 and R 7are combined with the atoms to which they are attached, and 3-8 Cycloalkyl or C 3-6 Forming a heterocycloalkyl; R 8a , R 8b , R 8c , and R 8d are each independently hydrogen, C 1-6 Alkyl or C 3-6 cycloalkyl; n is 1, 2, or 3; or salts and isomers thereof; where n is 1 and R 6 But C 1-6 Alkyl, halo, C(O)H, NH2, or C 1-6 When R is alkoxy, 4 , R 5 , and R 7 where n is 1 and at least one of R 6 is methyl, halogen, or C(O)H, R 4 , R 5 , and R 7 at least one of R is not methyl or Cl; 6 is F, Cl, methyl, or OMe, R 3a is methyl; and where n is 2 and R 6 When F, R 4 , R 5 , and R 7 At least one of them is not hydrogen.

[0100] In some embodiments, the present invention provides a compound or a pharmaceutically acceptable salt thereof, wherein the compound of Formula I or Ia has the following structure: [ka] It has.

[0101] In some embodiments, R 3a is methyl, and R 2 and R 3bare combined with the atom to which they are attached and independently represent hydrogen, C 1-6 Alkyl, C 3-8 Cycloalkyl, C 3-14 Alkyl-cycloalkyl, C 4-10 Heterocycloalkyl, C 4-16 Alkyl-heterocycloalkyl, C 6-12 Aryl, C 7-18 Alkyl-aryl, C 5-10 Heteroaryl or C 4-16 one to three R's that are alkyl-heteroaryl 9 C substituted with a group 5-8 Two R attached to the same atom form a heterocycloalkyl 9 The groups combine to form =O. In some embodiments, R 3a is methyl, and R 2 and R 3b are combined with the atom to which they are attached to form C 6-7 Forms a heterocycloalkyl.

[0102] In some embodiments, the present invention provides a compound of formula 3a is methyl} or a pharmaceutically acceptable salt thereof. In some embodiments, the present invention provides a compound or a pharmaceutically acceptable salt thereof, wherein the compound of Formula I or Ia has the following structure: [ka] It has.

[0103] In some embodiments, the present invention provides a compound or a pharmaceutically acceptable salt thereof, wherein the compound of Formula I or Ia has the following structure: [ka] {where, R 5 and R 6are each independently H, F, Cl, Br, I, -OH, -OMe, -OiPr, -Me, -CF3, -OCF3, -NMe2, -NHC(O)Me, or -N(Me)C(O)Me, where R 5 and R 6 at least one of is not H; or R 5 and R 6 are combined to form a 1,3-dioxole ring or a 1,4-dioxane ring.

[0104] In some embodiments, the present invention provides a compound or a pharmaceutically acceptable salt thereof, wherein the compound of Formula I or Ia has the following structure: [ka] {where, R 5 and R 6 are each independently F, Cl, Br, I, —OH, —OMe, —OiPr, —Me, —CF3, —OCF3, —NMe2, —NHC(O)Me, or —N(Me)C(O)Me; or R 5 and R 6 are combined to form a 1,3-dioxole ring or a 1,4-dioxane ring.

[0105] In some embodiments, the present invention provides a compound, wherein the compound of Formula I or Ia has the structure: [ka] {where, R 5 is H, F, Cl, Br, —OH, or —OMe; and R 6 is H, F, -OMe, -CF3 or OCF3, where R 5 and R 6 at least one of which is not H}.

[0106] In some embodiments, the present invention provides a compound or a pharmaceutically acceptable salt thereof, wherein the compound of Formula I or Ia has the following structure: [ka] {where, R 4 and R 6 are each independently H, F, Cl, Br, I, -OH, -OMe, -OiPr, -Me, -CF3, -OCF3, -NMe2, -NHC(O)Me, or -N(Me)C(O)Me, where R 4 and R 6 at least one of which is not H}.

[0107] In some embodiments, the present invention provides a compound or a pharmaceutically acceptable salt thereof, wherein the compound of Formula I or Ia has the following structure: [ka] {where, R 4 and R 6 are each independently F, Cl, Br, I, —OH, —OMe, —OiPr, —Me, —CF3, —OCF3, —NMe2, —NHC(O)Me, or —N(Me)C(O)Me}.

[0108] In some embodiments, the present invention provides a compound, wherein the compound has the following structure: [ka] or a pharmaceutically acceptable salt thereof.

[0109] In some embodiments, the present invention provides a compound or a pharmaceutically acceptable salt thereof, wherein the compound has the following structure: [ka] is.

[0110] In some embodiments, the present invention provides a compound or a pharmaceutically acceptable salt thereof, wherein the compound has the following structure: [ka] is.

[0111] In some embodiments, the present invention provides a compound or a pharmaceutically acceptable salt thereof, wherein the compound has the following structure: [ka] is.

[0112] In some embodiments, the present invention provides a compound or a pharmaceutically acceptable salt thereof, wherein the compound has the following structure: [ka] is.

[0113] In some embodiments, the present invention provides a compound or a pharmaceutically acceptable salt thereof, wherein the compound has the following structure: [ka] is.

[0114] In some embodiments, R 3a is hydrogen and R 2 and R 3b are combined with the atom to which they are attached and independently represent hydrogen, C 1-6 Alkyl, C 3-8 Cycloalkyl, C 3-14 Alkyl-cycloalkyl, C 4-10 Heterocycloalkyl, C 4-16 Alkyl-heterocycloalkyl, C 6-12 Aryl, C 7-18 Alkyl-aryl, C 5-10 Heteroaryl or C 4-16 one to three R's that are alkyl-heteroaryl 9 C substituted with a group 5-8 Two R attached to the same atom form a heterocycloalkyl 9The groups combine to form =O. In some embodiments, R 3a is hydrogen and R 2 and R 3b are combined with the atom to which they are attached to form C 6-7 Forms a heterocycloalkyl.

[0115] In some embodiments, the present invention provides a compound or a pharmaceutically acceptable salt thereof, wherein the compound of Formula I or Ia has the following structure: [ka] It has.

[0116] In some embodiments, the present invention provides a compound or a pharmaceutically acceptable salt thereof, wherein the compound has the following structure: [ka] is.

[0117] In some embodiments, R 3c is hydrogen or C 1-6 In some embodiments, R 3c is hydrogen, methyl, ethyl, or propyl. In some embodiments, R 3c is hydrogen.

[0118] In some embodiments, R 1 is C 1-6 In some embodiments, R 1 is methyl, ethyl, or propyl. In some embodiments, the present invention provides a compound or a pharmaceutically acceptable salt thereof, wherein the compound of Formula I or Ia has the following structure: [ka] It has.

[0119] In some embodiments, the present invention provides a compound or a pharmaceutically acceptable salt thereof, wherein the compound has the following structure: [ka] is.

[0120] In some embodiments, the present invention provides a compound of formula 2 and R 3c are combined with the atom to which they are attached and independently represent hydrogen, C 1-6 Alkyl, C 3-8 Cycloalkyl, C 3-14 Alkyl-cycloalkyl, C 4-10 Heterocycloalkyl, C 4-16 Alkyl-heterocycloalkyl, C 6-12 Aryl, C 7-18 Alkyl-aryl, C 5-10 Heteroaryl or C 4-16 one to three R's that are alkyl-heteroaryl 10 C substituted with a group 5-8 Two R's attached to the same atom form a cycloalkyl or 10 The groups combine to form =O} or a pharmaceutically acceptable salt thereof.

[0121] In some embodiments, the present invention provides a compound of formula 2 and R 3c are combined with the atoms to which they are attached, and each has one or two R, which is hydrogen. 10 C substituted with a group 5-6 Two R's attached to the same atom form a cycloalkyl or 10 The groups combine to form =O} or a pharmaceutically acceptable salt thereof.

[0122] In some embodiments, the present invention provides a compound or a pharmaceutically acceptable salt thereof, wherein the compound has the following structure: [ka] is.

[0123] The compounds of the present invention may also exist in the form of salts, such as acid salts or base salts of the compounds of the present invention. Illustrative examples of pharmaceutically acceptable salts are salts of mineral acids (such as hydrochloric acid, hydrobromic acid, phosphoric acid, etc.), salts of organic acids (such as fumaric acid, acetic acid, propionic acid, glutamic acid, citric acid, etc.), and salts of quaternary ammonium (such as methyl iodide, ethyl iodide, etc.). It is understood that pharmaceutically acceptable salts are non-toxic. Further information about suitable pharmaceutically acceptable salts can be found in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, which is incorporated herein by reference.

[0124] The present invention also includes isotopically labeled compounds of the present invention, in which one or more atoms are replaced by one or more atoms having a specified atomic mass or mass number. Examples of isotopes that can be incorporated into compounds of the present invention include, but are not limited to, isotopes of hydrogen, carbon, nitrogen, oxygen, fluorine, sulfur, and chlorine (e.g., 2 H, 3 H, 13 C. 14 C. 15 N, 18 O. 17 O. 18 F, 35 S and 36 Isotopically labeled compounds of the present invention are useful in tissue distribution assays of the compounds, and their prodrugs and metabolites; preferred isotopes for such assays include 3 H and 14 C. In addition, in certain circumstances, heavier isotopes such as deuterium ( 2Substitution with methyl groups such as methyl groups (H) may provide increased metabolic stability, which may result in therapeutic advantages such as increased in vivo half-life or reduced dosage requirements. In general, isotopically labeled compounds of the present invention can be prepared according to methods known to those skilled in the art by substituting an isotopically labeled reagent for a non-isotopically labeled reagent. Compounds of the present invention may be isotopically labeled at basic amines on the aromatic ring and at positions adjacent to the methyl group of a methoxy substituent.

[0125] The present invention includes all tautomers and stereoisomers of the compounds of the present invention, in mixtures or in pure or substantially pure form. The compounds of the present invention have asymmetric centers at carbon atoms, and therefore, the compounds of the present invention may exist as diastereomers, enantiomers, or mixtures thereof. All conformational isomers (e.g., cis and trans isomers) and all optical isomers (e.g., enantiomers and diastereomers), racemates, diastereomers, and other mixtures of such isomers, as well as solvates, hydrates, isomorphs, polymorphs, and tautomers, are within the scope of the present invention. The compounds of the present invention may be prepared using diastereomers, enantiomers, or racemic mixtures as starting materials. Furthermore, diastereomeric and enantiomeric products may be separated by chromatography, fractional crystallization, or other methods known to those skilled in the art. IV. Pharmaceutical Compositions and Formulations

[0126] In some embodiments, the present invention provides a pharmaceutical composition comprising a compound of the present invention, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0127] The compositions of the present invention can be prepared in a wide variety of oral, parenteral, and topical dosage forms. Oral preparations include tablets, pills, powders, capsules, liquids, lozenges, wafers, gels, syrups, slurries, suspensions, and the like, suitable for oral ingestion by a patient. The compositions of the present invention can also be administered by injection, i.e., intravenously, intramuscularly, intradermally, subcutaneously, intraduodenally, or intraperitoneally. The compositions described herein can also be administered by inhalation, for example, intranasally. Additionally, the compositions of the present invention can be administered transdermally. The compositions of the present invention can also be administered by ocular, intravaginal, and rectal routes (including suppositories), insufflation, powders, and aerosol formulations (for examples of steroid inhalants, see Rohatagi, J. Clin. Pharmacol. 35:1187-1193, 1995; Tjwa, Ann. Allergy Asthma Immunol. 75:107-111, 1995). Accordingly, the present invention also provides pharmaceutical compositions comprising a pharmaceutically acceptable carrier or excipient and a compound of the present invention.

[0128] For preparing pharmaceutical compositions from the compounds of the present invention, pharmaceutically acceptable carriers can be solid or liquid.Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules.Solid carriers can be one or more substances that can act as diluents, flavoring agents, binders, preservatives, tablet disintegrating agents, or encapsulating materials.Details about procedures for formulation and administration are fully described in scientific and patent literature, see, for example, the latest edition of Remington's Pharmaceutical Sciences, Maack Publishing Co, Easton PA ("Remington's").

[0129] In powders, the carrier is a finely divided solid that is in a mixture with the finely divided active ingredient. In tablets, the active ingredient is mixed with a carrier having the necessary binding properties in suitable proportions and compressed into the desired shape and size. The powders and tablets preferably contain 5% to 70% or 10% to 70% of the compound of the present invention.

[0130] Suitable solid excipients include, but are not limited to, magnesium carbonate, magnesium stearate, talc, pectin, dextrin, starch, tragacanth, low melting point waxes, cocoa butter, carbohydrates, sugars (including, but not limited to, lactose, sucrose, mannitol, or sorbitol, starches derived from corn, wheat, rice, potato, or other plants), celluloses (e.g., methylcellulose, hydroxypropylmethyl-cellulose, or sodium carboxymethylcellulose), and gums (including acacia and tragacanth), and proteins (including, but not limited to, gelatin and collagen). If desired, disintegrating or solubilizing agents (e.g., cross-linked polyvinylpyrrolidone, agar, alginic acid, or a salt thereof (e.g., sodium alginate)) may be added.

[0131] For preparing suppositories, a low melting wax, such as a mixture of fatty acid glycerides or cocoa butter, is first melted and the compound of the present invention is dispersed homogeneously therein by stirring. The molten homogeneous mixture is then poured into convenient sized molds, allowed to cool, and thereby to solidify.

[0132] Liquid form preparations include solutions, suspensions, and emulsions, for example, water or water / propylene glycol solutions.For parenteral injection, liquid preparations can be formulated in solutions in aqueous polyethylene glycol solution.

[0133] Aqueous solutions suitable for oral use can be prepared by dissolving the compounds of the present invention in water and adding suitable colorants, flavorings, stabilizers, and thickeners, as desired. Aqueous suspensions suitable for oral use can be prepared by dissolving the finely divided active ingredient in a viscous material (e.g., natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth, and gum arabic) and a dispersing or wetting agent (e.g., naturally occurring phosphatides (e.g., lecithin), condensation products of alkylene oxides with fatty acids (e.g., polyoxyethylene stearate), condensation products of ethylene oxide with long-chain aliphatic alcohols (e.g., heptadecaethyleneoxycetanol), condensation products of ethylene oxide with fatty acids and heptadecaethyleneoxycetanol), condensation products of ethylene oxide with fatty acids and heptadecaethyleneoxycetanol, ... The aqueous suspension may be prepared by dispersing in water a condensation product of ethylene oxide with a partial ester derived from a hexitol anhydride (e.g., polyoxyethylene sorbitol mono-oleate) or a condensation product of ethylene oxide with a partial ester derived from a fatty acid and a hexitol anhydride (e.g., polyoxyethylene sorbitan mono-oleate). The aqueous suspension may also contain one or more preservatives (e.g., ethyl p-hydroxybenzoate or n-propyl p-hydroxybenzoate), one or more coloring agents, one or more flavoring agents, and one or more sweetening agents (e.g., sucrose, aspartame, or saccharin). The formulation may be adjusted for osmolality.

[0134] Also included are solid form preparations intended to be converted immediately before use into liquid form preparations for oral administration.Such liquid forms include solutions, suspensions and emulsions.These preparations may contain, in addition to the active ingredient, colorants, flavors, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizers, etc.

[0135] Oily suspensions can be formulated by suspending the compounds of the present invention in a vegetable oil (e.g., peanut oil, olive oil, sesame oil, or coconut oil) or a mineral oil (e.g., liquid paraffin); or a mixture thereof. The oily suspensions can contain a thickening agent (e.g., beeswax, hard paraffin, or cetyl alcohol). Sweetening agents (e.g., glycerol, sorbitol, or sucrose) can be added to provide a palatable oral preparation. These preparations can be preserved by adding an antioxidant such as ascorbic acid. For examples of injectable oily vehicles, see Minto, J. Pharmacol. Exp. Ther. 281:93-102, 1997. The pharmaceutical preparations of the present invention can also be in the form of an oil-in-water emulsion. The oily phase can be a vegetable oil or a mineral oil, as described above, or a mixture thereof. Suitable emulsifying agents include naturally occurring gums (e.g., gum arabic and gum tragacanth), naturally occurring phosphatides (e.g., soybean lecithin), esters or partial esters derived from fatty acids and hexitol anhydrides (e.g., sorbitan mono-oleate) and condensation products of these partial esters with ethylene oxide (e.g., polyoxyethylene sorbitan mono-oleate). Emulsions may also contain sweetening and flavoring agents, as in the formulation of syrups and elixirs. Such formulations may also contain a demulcent, preservative, or coloring agent.

[0136] The compositions of the present invention can also be delivered as microspheres for slow release in the body. For example, the microspheres can be formulated for administration via intradermal injection of drug-containing microspheres that slowly release subcutaneously (see Rao, J. Biomater Sci. Polym. Ed. 7:623-645, 1995); as biodegradable injectable gel formulations (see, e.g., Gao Pharm. Res. 12:857-863, 1995); or as microspheres for oral administration (see, e.g., Eyles, J. Pharm. Pharmacol. 49:669-674, 1997). Both the transdermal and intradermal routes provide constant delivery over a period of weeks or months.

[0137] In some embodiments, the pharmaceutical compositions of the present invention can be formulated for parenteral administration (e.g., intravenous (IV) administration or administration into a body cavity or lumen of an organ). Preparations for administration typically comprise a solution of the composition of the present invention dissolved in a pharmaceutically acceptable carrier. Acceptable vehicles and solvents that can be used include water and Ringer's solution, isotonic sodium chloride. Additionally, sterile, fixed oils are conventionally employed as solvents or suspending media. For this purpose, any bland fixed oil, including synthetic mono- or diglycerides, can be used. Additionally, fatty acids, such as oleic acid, can similarly be used in the preparation of injectables. These solutions are sterile and generally free of undesirable matter. These preparations can be sterilized by conventional, well-known sterilization procedures. These preparations may contain pharmaceutically acceptable auxiliary substances as needed to approximate physiological conditions (e.g., pH adjusting and buffering agents, toxicity adjusting agents, e.g., sodium acetate, sodium chloride, potassium chloride, calcium chloride, sodium lactate, etc.). The concentration of the composition of the present invention in these preparations can vary widely and can be selected primarily based on fluid volume, viscosity, body weight, etc., according to the particular mode of administration selected and the patient's needs. For IV administration, the preparation can be a sterile injectable preparation (e.g., a sterile injectable aqueous or oily suspension). This suspension can be formulated according to known techniques using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation can also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent (e.g., a solution in 1,3-butanediol).

[0138] In some embodiments, formulations of the compositions of the present invention can be delivered using liposomes, which fuse with the cell membrane or are endocytosed, i.e., by using a ligand attached to the liposome or a ligand attached directly to an oligonucleotide that binds to a cell's surface membrane protein receptor, resulting in endocytosis. Liposomes can be used to target the delivery of the compositions of the present invention to target cells in vivo, particularly when the liposome surface carries a ligand specific to the target cell or is otherwise preferentially directed to a particular organ (see, e.g., Al-Muhammed, J. Microencapsul. 13:293-306, 1996; Chonn, Curr. Opin. Biotechnol. 6:698-708, 1995; Ostro, Am. J. Hosp. Pharm. 46:1576-1587, 1989). V. Administration

[0139] The compositions of the present invention can be delivered by any suitable means, including oral, parenteral, and topical. For topical administration, the compositions can be formulated as applicator sticks, solutions, suspensions, emulsions, gels, creams, ointments, pastes, jellies, paints, powders, and aerosols.

[0140] The pharmaceutical preparation is preferably in unit dosage form.In such form, the preparation is subdivided into unit doses containing appropriate amounts of the compound of the present invention.The unit dosage form can be a packaged preparation, the package containing discrete amounts of the preparation (for example, packaged tablets, capsules, and powders in vials or ampoules).Also, the unit dosage form can be a capsule, tablet, cachet, or lozenge itself, or the appropriate number of any of these in packaged form.

[0141] The compounds of the present invention can be present in any suitable amount, which can depend on various factors, including, but not limited to, the weight and age of the subject, the state of the disease, etc. Suitable dosage ranges of the compounds of the present invention include about 0.1 mg to about 10,000 mg, about 1 mg to about 1000 mg, about 10 mg to about 750 mg, about 25 mg to about 500 mg, or about 50 mg to about 250 mg. Suitable dosage ranges of the compounds of the present invention include about 1 mg, 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 200, 300, 400, 500, 600, 700, 800, 900, or 1000 mg.

[0142] The compounds of the present invention can be administered at any suitable frequency, interval, and duration. For example, the compounds of the present invention can be administered hourly, twice hourly, three or more times, daily, twice daily, three or more times, or once every 2, 3, 4, 5, 6, or 7 days to provide a preferred dosage level. When the compounds of the present invention are administered multiple times per day, typical intervals include 5, 10, 15, 20, 30, 45, and 60 minutes, and 1, 2, 4, 6, 8, 10, 12, 16, 20, and 24 hours. The compounds of the present invention can be administered once, twice, or three or more times over the course of 1 hour, 1-6 hours, 1-12 hours, 1-24 hours, 6-12 hours, 12-24 hours, 1 day, 1-7 days, 1 week, 1-4 weeks, 1 month, 1-12 months, 1 year or more, or indefinitely.

[0143] The compositions may also include other compatible therapeutic agents. The compounds described herein may be used in combination with each other, with other active agents known to be useful in modulating glucocorticoid receptors, or with adjuvants that may not be effective alone but may contribute to the effectiveness of the active agent.

[0144] The compounds of the present invention can be co-administered with another active agent. Co-administration includes administration of the compounds of the present invention and the active agent within 0.5, 1, 2, 4, 6, 8, 10, 12, 16, 20, or 24 hours of each other. Co-administration also includes administration of the compounds of the present invention and the active agent simultaneously, nearly simultaneously (e.g., within about 1, 5, 10, 15, 20, or 30 minutes of each other), or sequentially in any order. Furthermore, the compounds of the present invention and the active agent can each be administered once daily, or two, three, or more times per day to provide a desired daily dosage level.

[0145] In some embodiments, simultaneous administration can be achieved by co-formulation, i.e., preparing a single pharmaceutical composition containing both the compound of the invention and the active agent, hi other embodiments, the compound of the invention and the active agent are formulated separately.

[0146] The compound of the invention and the active agent may be provided in any suitable weight ratio in the compositions of the invention, such as about 1:100 to about 100:1 (w / w), or about 1:50 to about 50:1, about 1:25 to about 25:1, about 1:10 to about 10:1, or about 1:5 to 5:1 (w / w). The compound of the invention and the other active agent may be provided in any suitable weight ratio, such as about 1:100 (w / w), 1:50, 1:25, 1:10, 1:5, 1:4, 1:3, 1:2, 1:1, 2:1, 3:1, 4:1, 5:1, 10:1, 25:1, 50:1, or 100:1 (w / w). Other dosage amounts and dose ratios of the compound of the invention and the active agent are suitable in the compositions and methods of the invention. VI. Treatment Methods

[0147] The compound of the present invention can be used to enhance neuroplasticity.The compound of the present invention can also be used to treat any brain disease.The compound of the present invention can also be used to enhance at least one of the translation, transcription or secretion of neurotrophic factor.

[0148] In some embodiments, the compounds of the present invention are used to treat neurological disorders. In some embodiments, the compounds have, for example, anti-addictive, antidepressant, anxiolytic properties, or a combination thereof. In some embodiments, the neurological disorder is a neuropsychiatric disorder. In some embodiments, the neuropsychiatric disorder is a mood or anxiety disorder. In some embodiments, the neurological disorder is migraine, headache (e.g., cluster headache), post-traumatic stress disorder (PTSD), anxiety, depression, neurodegenerative disorders, Alzheimer's disease, Parkinson's disease, psychotic disorders, treatment-resistant depression, suicidal ideation, major depressive disorder, bipolar disorder, schizophrenia, stroke, traumatic brain injury, and addiction (e.g., substance use disorder). In some embodiments, the neurological disorder is migraine or cluster headache. In some embodiments, the neurological disorder is a neurodegenerative disorder, Alzheimer's disease, or Parkinson's disease. In some embodiments, the neurological disorder is a psychiatric disorder, treatment-resistant depression, suicidal ideation, major depressive disorder, bipolar disorder, schizophrenia, post-traumatic stress disorder (PTSD), addiction (e.g., substance use disorder), depression, or anxiety. In some embodiments, the neuropsychiatric disorder is a psychiatric disorder, treatment-resistant depression, suicidal ideation, major depressive disorder, bipolar disorder, schizophrenia, post-traumatic stress disorder (PTSD), addiction (e.g., substance use disorder), depression, or anxiety. In some embodiments, the neuropsychiatric or neurological disorder is post-traumatic stress disorder (PTSD), addiction (e.g., substance use disorder), schizophrenia, depression, or anxiety. In some embodiments, the neuropsychiatric or neurological disorder is addiction (e.g., substance use disorder). In some embodiments, the neuropsychiatric or neurological disorder is depression. In some embodiments, the neuropsychiatric or neurological disorder is anxiety. In some embodiments, the neuropsychiatric or neurological disorder is post-traumatic stress disorder (PTSD). In some embodiments, the neurological disorder is stroke or traumatic brain injury, hi some embodiments, the neuropsychiatric or neurological disorder is schizophrenia.

[0149] In some embodiments, the compounds of the present invention are used to enhance neuroplasticity. In some embodiments, the compounds described herein are used to treat brain disorders. In some embodiments, the compounds described herein are used to enhance at least one of translation, transcription, or secretion of neurotrophic factors.

[0150] In some embodiments, the compounds of the present invention are 5-HT 2A In some embodiments, the compounds of the present invention have activity as 5-HT modulators. 2A In some embodiments, the compounds of the present invention have activity as 5-HT modulators. 2A Activate receptors (e.g., allosteric modulation or 5-HT 2A 5-HT induces a biological response by activating receptors (modulating biological targets). 2A 5-HT agonism was associated with the promotion of neuroplasticity (Ly et al., 2018). As shown in Figure 7, 5-HT 2A The antagonist is 5-HT 2A In some embodiments, the compounds of the present invention inhibit the neuritogenesis and spinogenesis effects of hallucinogenic compounds with agonist activity, such as DMT, LSD, and DOI. 2A In some embodiments, the compounds of the present invention are selective 5-HT modulators and promote neuroplasticity (e.g., plasticity of cortical structures). 2AThe compounds are modulators and promote neuroplasticity (e.g., cortical structural plasticity). In some embodiments, promotion of neuroplasticity includes, for example, enhanced dendritic spine growth, increased synthesis of synaptic proteins, enhanced synaptic response, enhanced dendritic spreading complexity, enhanced dendritic branching content, enhanced spine formation, enhanced neurite formation, or any combination thereof. In some embodiments, enhanced neuroplasticity includes, for example, enhanced cortical structural plasticity in the anterior part of the brain. Hallucinogens (e.g., LSD and 5-MeO-DMT) act as agonists to modulate 5HT 2A Furthermore, compounds that are hallucinogenic in animals (e.g., humans), such as 5-MeO-DMT, LSD, DMT, and DOI, activate the 5HT receptor in an agonist mode, whereas their non-hallucinogenic congeners (lisuride (LIS) and 6-MeO-DMT) do not (Figure 15). 2A Compounds such as 6-MeO-DMT, LIS, 6-F-DET, L-MDMA, R-MDMA, Ketanserin, and BOL148, which activate the sensor assay but are non-hallucinogenic in animals (e.g., humans), act as 5HT antagonists in an agonist mode. 2A In some embodiments, the hallucinogenic potential of compounds of the invention is determined in vitro. In some embodiments, the hallucinogenic potential of compounds of the invention is determined in vitro by measuring the activity of 5HT 2A In some embodiments, the 5HT 2A The sensor assay is in an agonist mode or an antagonist mode. 2A The sensor assay is in the agonist mode. In some embodiments, compounds of the invention that do not activate the sensor in the agonist mode are non-hallucinogenic. In some embodiments, compounds of the invention that do not activate the sensor in the agonist mode are non-hallucinogenic compounds.

[0151] Additionally, non-hallucinogenic compounds (e.g., lisuride and 6-MeO-DMT) inhibit the 5HT 2A When the sensor assay is run in antagonist mode, it competes with 5-HT (Figures 17A and 17B). Furthermore, compounds that are non-hallucinogenic in animals (e.g., humans), such as 6-F-DET, Ketanserin, and BOL148, compete with 5-HT in the antagonist mode sensor assay. 2A In some embodiments, compounds of the present invention compete with 5HT binding to 5HT (Figure 18, at 10 μM compound). 2A In some embodiments, 5HT is prevented from binding to 2A The sensor assay is in antagonist mode. 2A Compounds of the invention that interfere with the binding of 5-HT to 5-HT have the potential to be non-hallucinogenic. In some embodiments, compounds of the invention interfere with the binding of 5-HT to 5-HT. 2A In some embodiments, the compound acts as a 5-HT antagonist, preventing the binding of 5-HT to 5-HT receptors and is a non-hallucinogenic compound. 2A Compounds of the present invention that interfere with the binding of 5-HT to ATP may be non-hallucinogenic. In some embodiments, compounds of the present invention that interfere with the binding of 5-HT in antagonist mode are non-hallucinogenic compounds. In some embodiments, compounds of the present invention that inhibit the response of a sensor assay in antagonist mode may be non-hallucinogenic. In some embodiments, compounds of the present invention that inhibit the response of a sensor assay in antagonist mode are non-hallucinogenic compounds.

[0152] In some embodiments, the results of the agonist mode sensor assay demonstrate that the compounds of the present invention inhibit 5-HT 2A In some embodiments, the results of the antagonist mode sensor assay suggest that the compounds of the present invention are non-psychedelic ligands of the 5-HT receptor. 2A In some embodiments, the results of the sensor assays in the agonist and antagonist modes suggest that the compounds of the present invention are non-psychedelic ligands of the 5-HT receptor. 2ATogether these findings suggest that it is a non-hallucinogenic ligand for the receptor.

[0153] In some embodiments, the compounds described herein are selective 5-HT 2A In some embodiments, the compounds described herein are 5-HT modulators. 2A In some embodiments, the compounds described herein are selective 5-HT modulators and promote neuroplasticity (e.g., plasticity of cortical structures). 2A and modulators and promote neuroplasticity (e.g., cortical structural plasticity). In some embodiments, promotion of neuroplasticity includes, for example, enhanced dendritic spine growth, increased synthesis of synaptic proteins, enhanced synaptic responses, enhanced dendritic spreading complexity, enhanced dendritic branching content, enhanced spine formation, enhanced neurite formation, or any combination thereof. In some embodiments, enhanced neuroplasticity includes, for example, enhanced cortical structural plasticity in the anterior part of the brain.

[0154] In some embodiments, 5-HT 2A modulators (e.g., 5-HT 2A In some embodiments, the non-hallucinogenic 5-HT 2A modulators (e.g., 5-HT 2A agonists) are used to treat neurological disorders, and their modulators do not induce dissociative side effects. In some embodiments, the hallucinogenic potential of the compounds described herein is assessed in vitro. In some embodiments, the hallucinogenic potential of the compounds described herein, as assessed in vitro, is compared to the hallucinogenic potential of a hallucinogenic homolog, as assessed in vitro. In some embodiments, the compounds described herein induce lower hallucinogenic potential in vitro compared to the hallucinogenic homolog.

[0155] In some embodiments, non-hallucinogenic 5-HT2A modulators (e.g., 5-HT 2A agonists) are used to treat neurological disorders. In some embodiments, the neurological disorder is characterized by reduced neuroplasticity, reduced plasticity of cortical structures, 5-HT 2A This includes reduced receptor content, reduced dendritic spreading complexity, loss of dendritic spines, reduced dendritic branching content, reduced spine formation, reduced neurite formation, neurite retraction, or any combination thereof.

[0156] In some embodiments, non-hallucinogenic 5-HT 2A modulators (e.g., 5-HT 2A In some embodiments, non-hallucinogenic 5-HT agonists are used to enhance neuroplasticity. 2A modulators (e.g., 5-HT 2A In some embodiments, non-hallucinogenic 5-HT agonists are used to treat brain disorders. 2A modulators (e.g., 5-HT 2A Agonists are used to enhance at least one of the translation, transcription, or secretion of neurotrophic factors. A. Methods for Enhancing Neuroplasticity

[0157] Neuroplasticity refers to the brain's ability to change structure and / or function throughout a subject's life. New neurons can be produced throughout a subject's life and incorporated into the central nervous system. Enhanced neuroplasticity includes, but is not limited to, promoting neuronal proliferation, promoting neuritogenesis, promoting synaptogenesis, promoting dendritogenesis, increasing the complexity of dendritic arborization, increasing dendritic spine density, and enhancing excitatory synapses in the brain. In some embodiments, enhanced neuroplasticity includes promoting neuronal proliferation, promoting neuritogenesis, promoting synaptogenesis, promoting dendritogenesis, increasing the complexity of dendritic arborization, and increasing dendritic spine density.

[0158] In some embodiments, enhanced neuronal plasticity may treat a neurodegenerative disorder, Alzheimer's disease, Parkinson's disease, a psychiatric disorder, depression, addiction, anxiety, post-traumatic stress disorder, treatment-resistant depression, suicidal ideation, major depressive disorder, bipolar disorder, schizophrenia, stroke, traumatic brain injury, or a substance use disorder.

[0159] In some embodiments, the present invention provides methods for enhancing neuroplasticity, comprising contacting a neuronal cell with any of the compounds of the present invention. In some embodiments, the enhanced neuroplasticity ameliorates the brain disorders described herein.

[0160] In some embodiments, compounds of the invention are used to enhance neuroplasticity. In some embodiments, compounds used to enhance neuroplasticity have, for example, anti-addictive, antidepressant, anxiolytic properties, or a combination thereof. In some embodiments, reduced neuroplasticity is associated with a neuropsychiatric disorder. In some embodiments, the neuropsychiatric disorder is a mood or anxiety disorder. In some embodiments, neuropsychiatric disorders include, for example, migraine, cluster headache, post-traumatic stress disorder (PTSD), schizophrenia, anxiety, depression, and addiction (e.g., substance abuse disorder). In some embodiments, brain disorders include, for example, migraine, addiction (e.g., substance use disorder), depression, and anxiety.

[0161] In some embodiments, experiments or assays that measure enhanced neuronal plasticity of any of the compounds of the present invention include phenotypic assays, dendritogenesis assays, spine formation assays, synaptogenesis assays, Sholl analysis, concentration-response experiments, 5-HT 2A Agonist assay, 5-HT 2A Antagonist assay, 5-HT 2A Binding assay, or 5-HT 2A Blocking experiments (e.g., ketanserin blocking experiments). In some embodiments, the experiment or assay to measure the hallucinogenic potential of any compound of Formula I or Formula (Ia) is a mouse head twitch response (HTR) assay.

[0162] In some embodiments, the present invention provides a method for enhancing neuroplasticity, comprising administering to a neuronal cell a compound of Formula I: [ka] {where, R 1 is hydrogen or C 1-6 alkyl; R 3a and R 3b are each independently hydrogen, C 1-6 Alkyl, C 3-8 Cycloalkyl, or C 4-14 alkyl-cycloalkyl; R 3c is hydrogen or C 1-6 alkyl; or R 2 and R 3b are combined with the atom to which they are attached and independently represent hydrogen, C 1-6 Alkyl, C 3-8 Cycloalkyl, C 3-14 Alkyl-cycloalkyl, C 4-10 Heterocycloalkyl, C 4-16 Alkyl-heterocycloalkyl, C 6-12 Aryl, C 7-18 Alkyl-aryl, C 5-10 Heteroaryl or C 4-16 one to three R's that are alkyl-heteroaryl 9 C substituted with a group 5-8 Two R attached to the same atom form a heterocycloalkyl 9 groups combined to form =O; or R 2 and R 3c are combined with the atom to which they are attached and independently represent hydrogen, C 1-6 Alkyl, C 3-8 Cycloalkyl, C 3-14 Alkyl-cycloalkyl, C 4-10 Heterocycloalkyl, C 4-16 Alkyl-heterocycloalkyl, C 6-12 Aryl, C7-18 Alkyl-aryl, C 5-10 Heteroaryl or C 4-16 one to three R's that are alkyl-heteroaryl 10 C substituted with a group 5-8 Two R's attached to the same atom form a cycloalkyl or 10 The groups combine to form =O;R 4 , R 5 , R 6 and R 7 are each independently hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, C 1-6 Haloalkyl, C 1-6 Alkylamines, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -OR 8a , -NO2, -CN, -C(O)R 8b , -C(O)OR 8b , -OC(O)R 8b , -OC(O)OR 8b , -N(R 8b R 8c ), -N(R 8b )C(O)R 8c , -C(O)N(R 8b R 8c ), -N(R 8b )C(O)OR 8c , -OC(O)N(R 8b R 8c ), -N(R 8b )C(O)N(R 8c R 8d ), -C(O)C(O)N(R 8b R 8c ), -S(O2)R 8b , -S(O)2N(R 8b R 8c ), C 3-8 Cycloalkyl, C 3-14 Alkyl-cycloalkyl, C 4-10 Heterocycloalkyl, C 4-16 Alkyl-heterocycloalkyl, C 6-12 Aryl, C 7-18 Alkyl-aryl, C5-10 Heteroaryl, or C 4-16 alkyl-heteroaryl, where R 4 , R 5 , R 6 and R 7 at least one of is not H; or R 4 and R 5 , R 5 and R 6 , or R 6 and R 7 are combined with the atoms to which they are attached, and 3-6 Cycloalkyl, C 3-6 Heterocycloalkyl, C 6-12 Aryl or C 5-10 forming a heteroaryl; and R 8a , R 8b , R 8c and R 8d are independently H, C 1-6 or a pharmaceutically acceptable salt thereof,

[0163] In some embodiments, the present invention provides a method for enhancing neuroplasticity, comprising treating a neuronal cell with a compound of formula I, wherein R 1 is hydrogen or C 1-6 alkyl; R 3a and R 3b are each independently hydrogen, C 1-6 Alkyl, C 3-8 Cycloalkyl, or C 4-14 alkyl-cycloalkyl; R 3c is hydrogen or C 1-6 alkyl; or R 2 and R 3b are combined with the atom to which they are attached and independently represent hydrogen, C 1-6 Alkyl, C 3-8 Cycloalkyl, C 3-14 Alkyl-cycloalkyl, C 4-10 Heterocycloalkyl, C 4-16 Alkyl-heterocycloalkyl, C 6-12Aryl, C 7-18 Alkyl-aryl, C 5-10 Heteroaryl or C 4-16 one to three R's that are alkyl-heteroaryl 9 C substituted with a group 5-8 Two R attached to the same atom form a heterocycloalkyl 9 groups combined to form =O; or R 2 and R 3b are combined with the atom to which they are attached and independently represent hydrogen, C 1-6 Alkyl, C 3-8 Cycloalkyl, C 3-14 Alkyl-cycloalkyl, C 4-10 Heterocycloalkyl, C 4-16 Alkyl-heterocycloalkyl, C 6-12 Aryl, C 7-18 Alkyl-aryl, C 5-10 Heteroaryl or C 4-16 one to three R's that are alkyl-heteroaryl 10 C substituted with a group 5-8 Two R's attached to the same atom form a cycloalkyl or 10 The groups combine to form =O;R 4 , R 5 , R 6 and R 7 are each independently hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, C 1-6 Haloalkyl, C 1-6 Alkylamines, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -OR 8a , -NO2, -CN, -C(O)R 8b , -C(O)OR 8b , -OC(O)R 8b , -OC(O)OR 8b , -N(R 8b R 8c ), -N(R 8b )C(O)R 8c , -C(O)N(R8b R 8c ), -N(R 8b )C(O)OR 8c , -OC(O)N(R 8b R 8c ), -N(R 8b )C(O)N(R 8c R 8d ), -C(O)C(O)N(R 8b R 8c ), -S(O2)R 8b , -S(O)2N(R 8b R 8c ), C 3-8 Cycloalkyl, C 3-14 Alkyl-cycloalkyl, C 4-10 Heterocycloalkyl, C 4-16 Alkyl-heterocycloalkyl, C 6-12 Aryl, C 7-18 Alkyl-aryl, C 5-10 Heteroaryl, or C 4-16 alkyl-heteroaryl, where R 4 , R 5 , R 6 and R 7 At least one of the following is not H; 8b , R 8c and R 8d are each independently H or C 1-6 or a pharmaceutically acceptable salt or isomer thereof, wherein the compound is an alkyl group; B. Methods for Treating Brain Disorders

[0164] In some embodiments, the present invention provides a method of treating a disease comprising administering to a subject in need thereof a therapeutically effective amount of a compound of the present invention. In some embodiments, the present invention provides a method of treating a brain disorder comprising administering to a subject in need thereof a therapeutically effective amount of a compound of the present invention. In some embodiments, the present invention provides a method of treating a brain disorder with combination therapy comprising administering to a subject in need thereof a therapeutically effective amount of a compound of the present invention and at least one additional therapeutic agent.

[0165] In some embodiments, 5-HT 2A modulators (e.g., 5-HT 2A agonists) are used to treat brain disorders. In some embodiments, the brain disorder is characterized by reduced neuroplasticity, reduced plasticity of cortical structures, 5-HT 2A This includes reduced receptor content, reduced dendritic spreading complexity, loss of dendritic spines, reduced dendritic branching, reduced spine formation, reduced neurite formation, neurite retraction, or any combination thereof.

[0166] In some embodiments, the compounds of the present invention are used to treat brain disorders. In some embodiments, the compounds have, for example, anti-addictive, anti-depressant, anti-anxiety properties, or a combination thereof. In some embodiments, the brain disorder is a neuropsychiatric disorder. In some embodiments, the neuropsychiatric disorder is a mood or anxiety disorder. In some embodiments, the brain disorder includes, for example, migraine, cluster headache, post-traumatic stress disorder (PTSD), anxiety, depression, schizophrenia, and addiction (e.g., substance abuse disorder). In some embodiments, the brain disorder includes, for example, migraine, addiction (e.g., substance use disorder), depression, and anxiety.

[0167] In some embodiments, the present invention provides a method for treating a brain disorder, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula I: [ka] {where, R 1 is hydrogen or C 1-6 alkyl; R 3a and R 3b are each independently hydrogen, C 1-6 Alkyl, C 3-8 Cycloalkyl, or C 4-14 alkyl-cycloalkyl; R 3c is hydrogen or C 1-6 alkyl; or R 2 and R3b are combined with the atom to which they are attached and independently represent hydrogen, C 1-6 Alkyl, C 3-8 Cycloalkyl, C 3-14 Alkyl-cycloalkyl, C 4-10 Heterocycloalkyl, C 4-16 Alkyl-heterocycloalkyl, C 6-12 Aryl, C 7-18 Alkyl-aryl, C 5-10 Heteroaryl or C 4-16 one to three R's that are alkyl-heteroaryl 9 C substituted with a group 5-8 Two R attached to the same atom form a heterocycloalkyl 9 groups combined to form =O; or R 2 and R 3c are combined with the atom to which they are attached and independently represent hydrogen, C 1-6 Alkyl, C 3-8 Cycloalkyl, C 3-14 Alkyl-cycloalkyl, C 4-10 Heterocycloalkyl, C 4-16 Alkyl-heterocycloalkyl, C 6-12 Aryl, C 7-18 Alkyl-aryl, C 5-10 Heteroaryl or C 4-16 one to three R's that are alkyl-heteroaryl 10 C substituted with a group 5-8 Two R's attached to the same atom form a cycloalkyl or 10 The groups combine to form =O;R 4 , R 5 , R 6 and R 7 are each independently hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, C 1-6 Haloalkyl, C 1-6 Alkylamines, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -OR8a , -NO2, -CN, -C(O)R 8b , -C(O)OR 8b , -OC(O)R 8b , -OC(O)OR 8b , -N(R 8b R 8c ), -N(R 8b )C(O)R 8c , -C(O)N(R 8b R 8c ), -N(R 8b )C(O)OR 8c , -OC(O)N(R 8b R 8c ), -N(R 8b )C(O)N(R 8c R 8d ), -C(O)C(O)N(R 8b R 8c ), -S(O2)R 8b , -S(O)2N(R 8b R 8c ), C 3-8 Cycloalkyl, C 3-14 Alkyl-cycloalkyl, C 4-10 Heterocycloalkyl, C 4-16 Alkyl-heterocycloalkyl, C 6-12 Aryl, C 7-18 Alkyl-aryl, C 5-10 Heteroaryl, or C 4-16 alkyl-heteroaryl, where R 4 , R 5 , R 6 and R 7 at least one of is not H; or R 4 and R 5 , R 5 and R 6 , or R 6 and R 7 are combined with the atoms to which they are attached, and 3-6 Cycloalkyl, C 3-6 Heterocycloalkyl, C 6-12 Aryl or C 5-10 forming a heteroaryl; and R 8a , R 8b , R 8c and R8d are independently H, C 1-6 and administering a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein the compound is a hydroxybenzoate, a hydroxybenzoate, or a pharmaceutically acceptable salt thereof, thereby treating a brain disorder.

[0168] In some embodiments, the present invention provides a method for treating a brain disorder, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula I, wherein R 1 is hydrogen or C 1-6 alkyl; R 3a and R 3b are each independently hydrogen, C 1-6 Alkyl, C 3-8 Cycloalkyl, or C 4-14 alkyl-cycloalkyl; R 3c is hydrogen or C 1-6 alkyl; or R 2 and R 3b are combined with the atom to which they are attached and independently represent hydrogen, C 1-6 Alkyl, C 3-8 Cycloalkyl, C 3-14 Alkyl-cycloalkyl, C 4-10 Heterocycloalkyl, C 4-16 Alkyl-heterocycloalkyl, C 6-12 Aryl, C 7-18 Alkyl-aryl, C 5-10 Heteroaryl or C 4-16 one to three R's that are alkyl-heteroaryl 9 C substituted with a group 5-8 Two R attached to the same atom form a heterocycloalkyl 9 groups combined to form =O; or R 2 and R 3b are combined with the atom to which they are attached and independently represent hydrogen, C 1-6 Alkyl, C 3-8 Cycloalkyl, C 3-14 Alkyl-cycloalkyl, C 4-10 Heterocycloalkyl, C 4-16 Alkyl-heterocycloalkyl, C6-12 Aryl, C 7-18 Alkyl-aryl, C 5-10 Heteroaryl or C 4-16 one to three R's that are alkyl-heteroaryl 10 C substituted with a group 5-8 Two R's attached to the same atom form a cycloalkyl or 10 The groups combine to form =O;R 4 , R 5 , R 6 and R 7 are each independently hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, C 1-6 Haloalkyl, C 1-6 Alkylamines, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -OR 8a , -NO2, -CN, -C(O)R 8b , -C(O)OR 8b , -OC(O)R 8b , -OC(O)OR 8b , -N(R 8b R 8c ), -N(R 8b )C(O)R 8c , -C(O)N(R 8b R 8c ), -N(R 8b )C(O)OR 8c , -OC(O)N(R 8b R 8c ), -N(R 8b )C(O)N(R 8c R 8d ), -C(O)C(O)N(R 8b R 8c ), -S(O2)R 8b , -S(O)2N(R 8b R 8c ), C 3-8 Cycloalkyl, C 3-14 Alkyl-cycloalkyl, C 4-10 Heterocycloalkyl, C 4-16 Alkyl-heterocycloalkyl, C 6-12 Aryl, C 7-18Alkyl-aryl, C 5-10 Heteroaryl, or C 4-16 alkyl-heteroaryl, where R 4 , R 5 , R 6 and R 7 At least one of the following is not H; 8b , R 8c and R 8d are each independently H or C 1-6 or a pharmaceutically acceptable salt thereof, thereby treating a brain disorder.

[0169] In some embodiments, the brain disorder is a neurodegenerative disorder, Alzheimer's disease, Parkinson's disease, a psychiatric disorder, depression, addiction, anxiety, post-traumatic stress disorder, treatment-resistant depression, suicidal ideation, major depressive disorder, bipolar disorder, schizophrenia, stroke, traumatic brain injury, or a substance use disorder.

[0170] In some embodiments, the brain disorder is a neurodegenerative disorder, Alzheimer's disease, or Parkinson's disease. In some embodiments, the brain disorder is a psychiatric disorder, depression, addiction, anxiety, or post-traumatic stress disorder. In some embodiments, the brain disorder is depression. In some embodiments, the brain disorder is addiction. In some embodiments, the brain disorder is treatment-resistant depression, suicidal ideation, major depressive disorder, bipolar disorder, schizophrenia, stroke, traumatic brain injury, or substance use disorder. In some embodiments, the brain disorder is treatment-resistant depression, suicidal ideation, major depressive disorder, bipolar disorder, schizophrenia, or substance use disorder. In some embodiments, the brain disorder is treatment-resistant depression, suicidal ideation, major depressive disorder, bipolar disorder, schizophrenia, or substance use disorder. In some embodiments, the brain disorder is stroke or traumatic brain injury. In some embodiments, the brain disorder is schizophrenia. In some embodiments, the brain disorder is alcohol use disorder.

[0171] In some embodiments, the method includes the use of any of the following steroids: lithium, olanzapine (Zyprexa), quetiapine (Seroquel), risperidone (Risperdal), ariprazole (Abilify), ziprasidone (Geodon), clozapine (Clozaril), divalproex sodium (Depakote), lamotrigine (Lamictal), valproic acid (Depakene), carbamazepine (Equetro), topiramate (Topamax), levomilnacipran (Fetzima), duloxetine (Cymbalta, Yentreve), venlafaxine (Effexor), citalopram (Celexa), fluvoxamine (Luvox), escitalopram (Lexapro), fluoxetine (Prozac), Further comprising administering one or more additional therapeutic agents that are paroxetine (Paxil), sertraline (Zoloft), clomipramine (Anafranil), amitriptyline (Elavil), desipramine (Norpramin), imipramine (Tofranil), nortriptyline (Pamelor), phenelzine (Nardil), tranylcypromine (Parnate), diazepam (Valium), alprazolam (Xanax), or clonazepam (Klonopin).

[0172] In some embodiments, the compounds of the invention are used in combination with standard of care therapies for the neurological disorders described herein. Non-limiting examples of standard of care therapies may include, for example, lithium, olanzapine, quetiapine, risperidone, aliprazole, ziprasidone, clozapine, divalproex sodium, lamotrigine, valproic acid, carbamazepine, topiramate, levomilnacipran, duloxetine, venlafaxine, citalopram, fluvoxamine, escitalopram, fluoxetine, paroxetine, sertraline, clomipramine, amitriptyline, desipramine, imipramine, nortriptyline, phenelzine, tranylcypromine, diazepam, alprazolam, clonazepam, or any combination thereof. Non-limiting examples of standard care therapies for depression include sertraline, fluoxetine, escitalopram, venlafaxine, or aripiprazole. Non-limiting examples of standard care therapies for depression are citralopram, escitalopram, fluoxetine, paroxetine, diazepam, or sertraline. C. Methods for enhancing at least one of translation, transcription, or secretion of neurotrophic factors

[0173] Neurotrophic factors refer to a family of soluble peptides or proteins that support the survival, growth, and differentiation of developing and mature neurons. Enhancing at least one of the translation, transcription, or secretion of neurotrophic factors can be useful for, but not limited to, enhancing neuroplasticity, promoting neuronal proliferation, promoting neuritogenesis, promoting synaptogenesis, promoting dendritogenesis, increasing dendritic arborization complexity, increasing dendritic spine density, and enhancing brain excitatory synapses. In some embodiments, enhancing at least one of the translation, transcription, or secretion of neurotrophic factors can enhance neuroplasticity. In some embodiments, enhancing at least one of the translation, transcription, or secretion of neurotrophic factors can enhance neuronal proliferation, promoting neuritogenesis, promoting synaptogenesis, promoting dendritogenesis, increasing dendritic arborization complexity, and / or increasing dendritic spine density.

[0174] In some embodiments, 5-HT 2A modulators (e.g., 5-HT 2A In some embodiments, a compound of Formula I or Formula (Ia) described herein is used to increase at least one of the translation, transcription, or secretion of a neurotrophic factor. In some embodiments, enhancing at least one of the translation, transcription, or secretion of a neurotrophic factor treats migraine, headache (e.g., cluster headache), post-traumatic stress disorder (PTSD), anxiety, depression, neurodegenerative disorders, Alzheimer's disease, Parkinson's disease, psychiatric disorders, treatment-resistant depression, suicidal ideation, major depressive disorder, bipolar disorder, schizophrenia, stroke, traumatic brain injury, and addiction (e.g., substance use disorder).

[0175] In some embodiments, experiments or assays used to measure increased translation of neurotrophic factors include ELISA, Western blotting, immunofluorescence, proteomics, and mass spectrometry. In some embodiments, experiments or assays used to measure increased transcription of neurotrophic factors include gene expression assays, PCR, and microarrays. In some embodiments, experiments or assays used to measure increased secretion of neurotrophic factors include ELISA, Western blotting, immunofluorescence, proteomics, and mass spectrometry.

[0176] In some embodiments, the present invention provides a method of enhancing at least one of translation, transcription, or secretion of a neurotrophic factor, comprising administering to a neuronal cell a compound of Formula I: [ka] {where, R 1 is hydrogen or C 1-6 alkyl; R 3a and R 3b are each independently hydrogen, C 1-6 Alkyl, C 3-8 Cycloalkyl, or C 4-14 alkyl-cycloalkyl; R 3c is hydrogen or C 1-6 alkyl; or R 2 and R 3b are combined with the atom to which they are attached and independently represent hydrogen, C 1-6 Alkyl, C 3-8 Cycloalkyl, C 3-14 Alkyl-cycloalkyl, C 4-10 Heterocycloalkyl, C 4-16 Alkyl-heterocycloalkyl, C 6-12 Aryl, C 7-18 Alkyl-aryl, C 5-10 Heteroaryl or C 4-16 one to three R's that are alkyl-heteroaryl 9C substituted with a group 5-8 Two R attached to the same atom form a heterocycloalkyl 9 groups combined to form =O; or R 2 and R 3c are combined with the atom to which they are attached and independently represent hydrogen, C 1-6 Alkyl, C 3-8 Cycloalkyl, C 3-14 Alkyl-cycloalkyl, C 4-10 Heterocycloalkyl, C 4-16 Alkyl-heterocycloalkyl, C 6-12 Aryl, C 7-18 Alkyl-aryl, C 5-10 Heteroaryl or C 4-16 one to three R's that are alkyl-heteroaryl 10 C substituted with a group 5-8 Two R's attached to the same atom form a cycloalkyl or 10 The groups combine to form =O;R 4 , R 5 , R 6 and R 7 are each independently hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, C 1-6 Haloalkyl, C 1-6 Alkylamines, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -OR 8a , -NO2, -CN, -C(O)R 8b , -C(O)OR 8b , -OC(O)R 8b , -OC(O)OR 8b , -N(R 8b R 8c ), -N(R 8b )C(O)R 8c , -C(O)N(R 8b R 8c ), -N(R 8b )C(O)OR 8c , -OC(O)N(R 8b R 8c ), -N(R8b )C(O)N(R 8c R 8d ), -C(O)C(O)N(R 8b R 8c ), -S(O2)R 8b , -S(O)2N(R 8b R 8c ), C 3-8 Cycloalkyl, C 3-14 Alkyl-cycloalkyl, C 4-10 Heterocycloalkyl, C 4-16 Alkyl-heterocycloalkyl, C 6-12 Aryl, C 7-18 Alkyl-aryl, C 5-10 Heteroaryl, or C 4-16 alkyl-heteroaryl, where R 4 , R 5 , R 6 and R 7 at least one of is not H; or R 4 and R 5 , R 5 and R 6 , or R 6 and R 7 are combined with the atoms to which they are attached, and 3-6 Cycloalkyl, C 3-6 Heterocycloalkyl, C 6-12 Aryl or C 5-10 forming a heteroaryl; and R 8a , R 8b , R 8c and R 8d are independently H, C 1-6 or a pharmaceutically acceptable salt thereof,

[0177] In some embodiments, the present invention provides a method for enhancing at least one of translation, transcription, or secretion of a neurotrophic factor, comprising administering to a neuronal cell a compound of formula I, wherein R 1 is hydrogen or C 1-6 alkyl; R 3a and R 3bare each independently hydrogen, C 1-6 Alkyl, C 3-8 Cycloalkyl, or C 4-14 alkyl-cycloalkyl; R 3c is hydrogen or C 1-6 alkyl; or R 2 and R 3b are combined with the atom to which they are attached and independently represent hydrogen, C 1-6 Alkyl, C 3-8 Cycloalkyl, C 3-14 Alkyl-cycloalkyl, C 4-10 Heterocycloalkyl, C 4-16 Alkyl-heterocycloalkyl, C 6-12 Aryl, C 7-18 Alkyl-aryl, C 5-10 Heteroaryl or C 4-16 one to three R's that are alkyl-heteroaryl 9 C substituted with a group 5-8 Two R attached to the same atom form a heterocycloalkyl 9 groups combined to form =O; or R 2 and R 3b are combined with the atom to which they are attached and independently represent hydrogen, C 1-6 Alkyl, C 3-8 Cycloalkyl, C 3-14 Alkyl-cycloalkyl, C 4-10 Heterocycloalkyl, C 4-16 Alkyl-heterocycloalkyl, C 6-12 Aryl, C 7-18 Alkyl-aryl, C 5-10 Heteroaryl or C 4-16 one to three R's that are alkyl-heteroaryl 10 C substituted with a group 5-8 Two R's attached to the same atom form a cycloalkyl or 10 The groups combine to form =O;R 4 , R 5 , R 6 and R 7 are each independently hydrogen, C1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, C 1-6 Haloalkyl, C 1-6 Alkylamines, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -OR 8a , -NO2, -CN, -C(O)R 8b , -C(O)OR 8b , -OC(O)R 8b , -OC(O)OR 8b , -N(R 8b R 8c ), -N(R 8b )C(O)R 8c , -C(O)N(R 8b R 8c ), -N(R 8b )C(O)OR 8c , -OC(O)N(R 8b R 8c ), -N(R 8b )C(O)N(R 8c R 8d ), -C(O)C(O)N(R 8b R 8c ), -S(O2)R 8b , -S(O)2N(R 8b R 8c ), C 3-8 Cycloalkyl, C 3-14 Alkyl-cycloalkyl, C 4-10 Heterocycloalkyl, C 4-16 Alkyl-heterocycloalkyl, C 6-12 Aryl, C 7-18 Alkyl-aryl, C 5-10 Heteroaryl, or C 4-16 alkyl-heteroaryl, where R 4 , R 5 , R 6 and R 7 At least one of the following is not H; 8b , R 8c and R 8d are each independently H or C 1-6 alkyl} or a pharmaceutically acceptable salt or isomer thereof. [Example]

[0178] VII. Working Examples Chemistry (General Principles). All reagents were obtained commercially unless otherwise noted. Reactions were performed using oven-dried (120 °C) glassware unless otherwise noted. Air- and moisture-sensitive liquids and solutions were transferred via syringe or stainless steel cannula. Organic solutions were concentrated under reduced pressure (~5 Torr) by rotary evaporation. Solvents were purified by passage through activated alumina columns under 12 psi of N2. Chromatography was performed using Fisher Chemical™ silica gel sorbent (230-400 mesh, grade 60). Compounds purified by chromatography were typically applied to the sorbent bed using the solvent conditions indicated, with minimal additional dichloromethane as needed for solubility. Thin-layer chromatography (TLC) was performed on Merck silica gel 60 F254 plates (250 μm). Visualization of the developed chromatograms was achieved by fluorescence quenching or staining with butanolic ninhydrin, aqueous potassium permanganate, ethanolic vanillin, or aqueous cerium ammonium molybdate (CAM).

[0179] Nuclear magnetic resonance (NMR) spectra were obtained as follows: 1 H and 13 For C, signals were acquired on either a Bruker 400 operating at 400 and 100 MHz or a Varian 600 operating at 600 and 150 MHz and were internally referenced against the residual solvent signal. 1 H NMR data were recorded as follows: chemical shift (δ, ppm), multiplicity (s, singlet; br s, broad singlet; d, doublet; t, triplet; q, quartet; quint, quintet; sext, sextet; m, multiplet), integral, and coupling constant (Hz). 13C NMR data are reported in terms of chemical shift (δ, ppm). Infrared spectra were recorded using a Thermo Scientific Nicolet iS10 spectrometer equipped with a Smart iTX Accessory (Diamond ATR) and are reported in terms of absorption frequency. Low-resolution mass spectra were obtained using a Waters Acuity Arc LC-MS.

[0180] The specific procedures used to synthesize the compounds reported in this manuscript are detailed below along with characterization data. Spectral data for each compound tested in biological assays ( 1 H and 13 C NMR spectrum). Example 1. Synthesis and Biological Activity of Ibogalog

[0181] The pharmacophore of ibogaine is shown in Figure 1 A. A series of tetrahydroazepine-containing compounds (Figure 1 B) that lack the isoquinuclidine characteristics of ibogaine were synthesized.

[0182] Fetal rat central neurons were treated for a short period (1 hour) and subsequently measured for the psychoplastogenic effects of the compounds described herein until the appropriate developmental period (71 hours). Using this short period (Dunlap, et al., Identification of Psychoplastogenic N,N-Dimethylaminoisotryptamine (isoDMT) Analogs Through Structure-Activity Relationship Studies. J. Med. Chem., 2019), ibogaine demonstrates psychoplastogenic effects as measured by the Sholl analysis. Therefore, the effects of ibogalogs 8-17 on dendritic growth were evaluated.

[0183] With the exception of 11a, the ibogalogs (8–10 and 11b) containing isoquinuclidine but lacking the tetrahydroazepine ring were either weak psychoplastogens or failed to promote neuronal proliferation compared to vehicle (VEH) controls (Figures 5 and 6). Ibogalogs (13–16) lacking isoquinuclidine but possessing the tetrahydroazepine were effective (Figures 5 and 6). Indole substitution at C5 with fluorine or chlorine was tolerated, but the sterically more demanding bromine substituent was not. Despite having a radically simplified chemical structure, IBG (13) performed as well as ibogaine.

[0184] HTR assays using 5-MeO-DMT (10 mg / kg) as a positive control (Figure 2B) were used to evaluate the hallucinogenic potential of IBG and tabernantalogues (TBG). While 5-MeO-DMT produces robust HTRs, its conformationally restricted analog, IBG, exhibits significantly reduced hallucinogenic potential. The 6-methoxy substituent of TBG did not exhibit hallucinogenic potential as measured by the HTR assay. For these in vivo studies, the fumarate salts of IBG and TBG were utilized. Unlike ibogaine hydrochloride, they are readily soluble in 0.9% saline up to 40 mg / mL (Figure 2C). The lack of water solubility of ibogaine (Figure 7) poses a potential problem not only for clinical formulations but also for administration to animals during preclinical studies.

[0185] The lipid solubility of ibogaine not only poses practical problems with its administration, but it may also be a major factor influencing its toxicity and adverse cardiac effects. Ibogaine has an IC of approximately 1 μM. 50 In contrast, IBG and TBG are approximately 10- and 100-fold less potent than ibogaine (IC of IBG). 50 IC of TBG = 19.3 μM 50= 148 μM), indicating a lower potential for cardiotoxicity. Administration of ibogaine to immobilized larval zebrafish resulted in a visually significant decrease in heart rate (Figure 2E) and a high potential for arrhythmia induction as measured by the ratio of atrial to ventricular beats per minute (BPM) (Figure 2F). Neither IBG nor TBG caused these undesirable phenotypes.

[0186] To compare the acute behavioral effects of ibogaine, IBG, and TBG, larval zebrafish were treated for 1 hour and then their locomotor activity during the previously described series of light and sound stimuli was quantified (Figure 8). With increasing concentrations, ibogaine, noribogaine, the hERG inhibitors haloperidol, sertindole, and terfenadine became phenotypically more distinct from the vehicle control, while closely resembling the lethal control (eugenol, 100 μM) (Figure 9). At the highest concentration tested (200 μM), noribogaine and a toxic pesticide (endosulfan) were phenotypically consistent with the lethal control. In contrast, IBG and TBG did not produce this phenotype. A machine learning approach showed that at the highest concentrations, IBG and TBG evoked locomotor responses similar to the vehicle control compared to ibogaine, noribogaine, or the lethal control (Figure 2G). This suggests that the novel compounds have an excellent acute safety profile.

[0187] Because ibogaine is known to induce seizures at very high doses, we assessed seizure potential using larval zebrafish expressing GCaMP5. Neither ibogaine nor TBG produced excessive neuronal activity, even when observed after treatment with the known seizure-inducing compound pentylenetetrazole (PTZ) (Figure 10).

[0188] Finally, in a well-established zebrafish developmental toxicity assay, ibogaine (100 μM) significantly enhanced birth defects and mortality at 2 and 5 days postfertilization (dpf), respectively (Figures 2H and 2I). At both time points, the proportion of viable versus nonviable fish was significantly different from vehicle controls (Fisher's exact test, p<0.0001). Ibogaine-treated animals suffered from a large number of birth defects. Noribogaine treatment resulted in superior survival, but the majority of animals developed yolk sac and / or hydropericardium. In marked contrast, both IBG and TBG treatment (100 μM) resulted in significantly fewer nonviable fish compared to ibogaine or noribogaine treatment at both 2 and 5 dpf (Fisher's exact test, p<0.0001 for ibogaine vs. IBG and ibogaine vs. TBG at both 2 and 5 dpf; p<0.0001 for noribogaine vs. IBG at both 2 and 5 dpf and noribogaine vs. TBG at 2 dpf; p=0.0083 for NOR vs. TBG at 5 dpf). Moreover, the effects of compound-induced malformations and / or lethality were both time- (Figure 2J) and concentration-dependent (Figure 11). Importantly, reducing the TBG concentration from 100 to 66 μM resulted in a proportion of viable versus nonviable fish that was statistically indistinguishable from vehicle controls after 5 dpf (Fisher's exact test, p=0.3864).

[0189] To confirm the correct targets of IBG and TBG, we performed a panel of serotonin (5-HT) and opioid receptor functional assays assessing canonical GPCR signaling. Unlike noribogaine, IBG and TBG exhibited weak or no opioid agonist activity (Figures 12 and 13). However, IBG and TBG exhibited significant activity against human (Figure 2K) and mouse 5-HT 2A Many 5-HT receptors, such as 5-MeO-DMT, have demonstrated potent agonist activity at the receptor (Figure 12). 2AAgonists are also agonists of the 5-HT2B receptor, which leads to valvular heart disease. Fortunately, IBG and TBG act as antagonists at the 5-HT2B receptor (Figure 2K). When profiles across the 5-HT receptorome were obtained, both compounds showed distinct profiles compared to 5-MeO-DMT (Figures 12, 13, and 14), including weak 5-HT1A and 5-HT2C agonist activity. In fact, IBG and TBG exert 5-HT activity over similar 5-HT or opioid receptors. 2A It exhibits a more selective and potentially safer profile than the weaker, conformationally restricted 5-MeO-DMT, which has a strong preference for activating receptors. Example 2. Compounds 4a and 4b

[0190] To a solution of pyridine (10.0 g, 126.4 mmol, 1.0 equiv) and sodium borohydride (4.8 g, 126.4 mmol, 1.0 equiv) in MeOH (56 mL, 2.3 M) at −78 °C was added benzyl chloroformate (18.0 mL, 21.6 g, 126.4 mmol, 1.0 equiv) by slow dropwise addition. Gas evolution was observed. The mixture was stirred at −78 °C for 3 h, diluted with EtO (100 mL) and H2O (50 mL), and warmed to room temperature. The aqueous layer was extracted with Et2O (3 × 50 mL). The combined organic extracts were washed with brine (3 × 50 mL), dried over Na2SO4, and concentrated under reduced pressure to give a clear oil. The product was passed through a short plug of silica gel using hexane:EtOAc (95:5) as the eluent. The resulting filtrate was concentrated under reduced pressure. After purging with nitrogen, methyl vinyl ketone (10.5 mL, 126.4 mmol, 1.0 equiv) was added to the flask, and the resulting solution was heated to 80° C. for 24 h. After the mixture was cooled to room temperature, MeOH (250 mL) was added, followed by 25% w / w aqueous Na-OMe (2.4 mL, 8.9 mmol, 0.07 equiv). The resulting mixture was stirred for 15 min, quenched with HO (5 mL), and then concentrated under reduced pressure. The residue was dissolved in DCM (250 mL) and then washed with brine (50 mL), followed by HO (100 mL). The organic layer was dried over NaSO and concentrated under reduced pressure. The product was purified by chromatography on silica gel (3:1 hexanes:EtOAc) to give a clear oil containing a mixture of 4a and 4b (26.5 g, 73% over 3 steps, ~1:1 exo:endo as a mixture of rotamers). [ka]

[0191] 1H NMR (CDCl3, 400 MHz) δ 7.4-7.2 (m, 5H), 6.57-6.23 (m, 2H), 5.22-4.94 (m, 3H), 3.33 (t, 1H, J = 10.3 Hz), 3.18-2.58 (m, 3H), 2.35-2.05 (m, 3H), 1.91-1.66 (m, 1H), 1.64-1.23 (m, 1H) ppm;IR (Smart iTX Diamond) ν 3060, 2957, 2878, 1699, 1417, 1366, 1337, 1300, 1279, 1113, 764, 699cm -1 ;C 17 H 20 LC-MS (ES) for NO3 [M+H] + ) calculated value 286.14, actual value 286.22. Example 3. Compounds 5a and 5b

[0192] To a mixture of 4a and 4b (4.8 g, 17.0 mmol, 1.0 equiv) in anhydrous THF (13 mL, 1.3 M) was added p-toluenesulfonyl hydrazide (3.16 g, 17.0 mmol, 1 equiv). The mixture was refluxed for 15–20 h until the starting material was consumed as determined by TLC. The reaction mixture was concentrated under reduced pressure, diluted with EtO (20 mL), and sonicated for 15 min. The white precipitate was filtered and washed with EtO (4 × 5 mL) to give 5b. The filtrate was concentrated under reduced pressure and purified by silica gel chromatography (gradient elution: 5:1 → 1:1 hexanes:EtOAc) to give 5a (75%; exo = 5.88 g, endo = 7.33 g, mixture of exo and endo = 2.62 g). [ka]

[0193] Isolated as a white solid (5.88 g, mixture of rotamers); 1H NMR (CDCl3, 400 MHz) δ 7.80 (dd, 2H, J = 20.1, 8.3 Hz), 7.43-7.26 (m, 4H), 7.25-7.11 (m, 3H), 6.49-6.36 (m, 2H), 5.10 (dd, 1H, J = 36.0, 12.3 Hz), 4.80-4.57 (m, 2H), 3.02 (dd, 1H, J = 10.0, 2.1 Hz), 2.92-2.84 (m, 1H), 2.75-2.67(m, 1H), 2.48-2.13 (m, 5H), 1.89 (s, 2H), 1.59 (s, 1H), 1.47 (s, 1H), 1.39-1.27 (m, 1H) ppm;IR (Smart iTX Diamond) ν 3207, 2952, 2876, 1675, 1418, 1368, 1337, 1303, 1258, 1165, 1117, 1030, 917, 813, 763, 705, 667, 552cm -1 ;C 24 H 28 LC-MS for N2O4S [M+H] (ES + ) calculated value 454.18, actual value 454.33. [ka]

[0194] Isolated as a white solid (7.33 g, mixture of rotamers); 1H NMR (CDCl3, 400 MHz) δ 7.79 (t, 2H, J = 8.9 Hz), 7.42-7.27 (m, 6H), 7.09 (d, 1H, J = 8.0 Hz), 6.21 (t, 1H, J = 7.3 Hz), 6.08-6.00 (m, 1H), 5.23-5.05 (m, 2H), 4.93-4.82 (m, 1H), 3.33-3.23 (m, 1H), 3.06-2.96 (m, 1H), 2.96-2.86 (m, 1H), 2.81-2.71 (m, 1H), 2.41 (s, 3H), 1.93-1.46 (m, 6H) ppm;IR (Smart iTX Diamond) ν 3105, 2939, 2878, 1671, 1446, 1420, 1372, 1338, 1322, 1298, 1280, 1262, 1241, 1167, 976, 932, 818, 804, 766, 724, 670, 550 cm -1 ;C 24 H 28 LC-MS for N2O4S [M+H] (ES + ) calculated value 454.18, actual value 454.33. Example 4. Compounds 6a and 6b

[0195] To a solution of 5a or 5b (3.78 g, 8.35 mmol, 1.0 equiv) in THF (16.7 mL, 2 M) was added sodium cyanoborohydride (2.1 g, 33.4 mmol, 4 equiv) and p-toluenesulfonic acid (159 mg, 0.835 mmol, 0.1 equiv). The mixture was refluxed for 18 h, diluted with HO (30 mL), and extracted with cyclohexane (5 × 25 mL). The combined organic extracts were washed with HO (20 mL), saturated aqueous NaHCO (20 mL), and brine (20 mL), then dried over NaSO and concentrated under reduced pressure to give either 6a or 6b. [ka]

[0196] Isolated as a clear oil (2.01 g, 57%, mixture of rotamers); 1 H NMR (CDCl3, 400 MHz) δ 7.41-7.27 (m, 5H), 6.55-6.38 (m, 1H), 6.33 (q, 1H, J = 7.7 Hz), 5.22-5.02 (m, 2H), 4.58 (d, 1H, J = 6.1 Hz), 3.30-3.20 (m, 1H), 3.08-2.96 (m, 1H), 2.75-2.58 (m, 1H), 1.69-1.59 (m, 1H), 1.53-1.30 (m, 3H), 1.05-0.98 (m, 1H), 0.98-0.84 (m, 3H) ppm;IR (Smart iTX Diamond) ν 3052, 2957, 2873, 1699, 1417, 1335, 1295, 1106, 986, 764, 699 cm -1 ;C 17 H 21 LC-MS for NO2 [M+H] (ES + ) calculated value 272.17, actual value 272.29. [ka]

[0197] Isolated as a clear oil (2.66 g, 62%, mixture of rotamers); 1H NMR (CDCl3, 400 MHz) δ 7.39-7.26 (m, 5H), 6.42-6.22 (m, 2H), 5.18-5.08 (m, 2H), 4.73-4.55 (m, 1H), 3.32-3.20 (m, 1H), 3.04-2.95 IR (Smart iTX Diamond) ν 3052, 2958, 2931, 2874, 1699, 1416, 1333, 1301, 1276, 1111, 977, 766, 698 cm -1 .C 17 H 21 LC-MS for NO2 [M+H] (ES + ) calculated value 272.17, actual value 272.29. Example 5. Compounds 8a and 8b

[0198] A solution of either 6a or 6b (132 mg, 0.95 mmol, 1.0 equiv) in acetic acid (0.5 mL, 1.9 M) was heated to 55 °C, after which sodium borohydride (165 mg, 4.37 mmol, 4.6 equiv) was added. Gas evolution was observed. The mixture was stirred at 55 °C for 10 h, diluted with HO (2 mL), cooled to 0 °C, and basified with solid NaOH (to pH = 14). The aqueous layer was extracted with EtO (4 × 10 mL), dried over NaSO, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (100:1 DCM:MeOH with 0.5% NHOH) to give the product. [ka]

[0199] Isolated as a yellow oil (12 mg, 7%); 1H NMR (CDCl3, 400 MHz) δ 3.05-2.96 (m, 1H), 2.47 (q, 2H, J = 7.2 Hz), 2.37 (t, 1H, J = 2.4 Hz), 2.20 (dt, 1H, J = 9.3, 1.5 Hz), 2.00-1.89 (m, 1H), 1.73-1.64 (m, 1H), 1.64-1.58 (m, 1H), 1.56-1.36 (m, 5H), 1.32-1.23 (m, 1H), 1.19-1.11 (m, 1H), 1.00 (t, 3H, J = 7.2 Hz), 0.86 (t, 3H, J = 7.1 Hz) ppm; 13 C NMR (CDCl3, 100 MHz) δ 56.67, 51.92, 49.18, 40.36, 32.76, 27.15, 26.89, 25.34, 21.52, 13.64, 11.98 ppm;IR (Smart iTX Diamond) ν 2955, 2926, 2857, 2793, 1458, 1372, 1259, 1100, 1048, 799cm -1 ;C 11 H 21 LC-MS for N [M+H] (ES + ) calculated value 168.18, actual value 168.33. [ka]

[0200] Isolated as a yellow oil (71.5 mg, 47%); 1H NMR (CDCl3, 400 MHz) δ 2.76 (dt, 1H, J = 9.8, 2.7 Hz), 2.65-2.46 (m, 3H), 2.45-2.39 (m, 1H), 1.91-1.70 (m, 3H), 1.66-1.55 (m, 3H), 1.47-1.37 (m, 1H), 1.35-1.20 (m, 2H), 1.07 (d, 3H, J = 14.4 Hz), 0.99 (dt, 1H, J = 6.3, 2.2 Hz), 0.88 (t, 3H, J = 7.4 Hz) ppm; 13 C NMR (CDCl3, 100 MHz) δ 55.71, 52.90, 49.55, 35.32, 32.94, 27.67, 26.63, 25.30, 20.02, 13.47, 12.19 ppm;IR (Smart iTX Diamond) ν 2958, 2931, 2872, 2860, 2792, 1464, 1371, 1217, 1161, 1094, 819, 756 cm -1 ;C 11 H 21 LC-MS for N [M+H] (ES + ) calculated value 168.17, actual value 168.25. Example 6. Preparation of 5-substituted tryptophols

[0201] General procedure for the preparation of hydrazines. Most hydrazines were commercially available; however, 4-iodo- and 4-benzyloxyhydrazines were synthesized in-house according to the following procedure. A 0.5 M solution of 4-substituted aniline (3.99 mmol, 1 equiv) in concentrated aqueous HCl was cooled to 0 °C, and then 2.0 M aqueous NaNO (3.91 mmol, 0.98 equiv) was added. The solution was stirred at 0 °C for 20 min. Next, a solution of SnCl 2 HO (10.4 mmol, 2.6 equiv) dissolved in concentrated aqueous HCl (2.4 mL) was added. The mixture was stirred for 2 h, warmed to room temperature, filtered, and rinsed with HO and Et 2 O. The solid was dried under reduced pressure and used immediately without further purification.

[0202] All 5-substituted tryptophols were prepared from the corresponding 4-substituted hydrazines as outlined herein. General scheme: [ka]

[0203] A solution of phenylhydrazine (0.5 g, 3.46 mmol, 1 equiv) in 10 mL of a 1:1 mixture of DMA and 4% aqueous H2SO4 was heated to 100 °C. To this solution was added 1,2-dihydrofuran (0.29 mL, 266 mg, 3.8 mmol, 1.1 equiv) by dropwise addition. The resulting mixture was stirred at 100 °C until the starting material was consumed (~3 h) as determined by TLC. The reaction was then cooled to room temperature and diluted with EtOAc (10 mL). The aqueous layer was extracted with EtOAc (5 x 10 mL). The combined organic extracts were washed with 5% aqueous LiCl (15 mL), saturated aqueous NaHCO3 (15 mL), and HO (15 mL) and then dried over Na2SO4. The resulting product was purified by chromatography on silica gel (3:1 hexane:EtOAc) to give the desired tryptophol as a brown solid (258 mg, 92%); 1 H NMR (CDCl3, 400 MHz) δ 8.23 ​​(s, 1H), 7.70-7.59 (m, 1H), 7.36 (d, 1H, J = 8.1 Hz), 7.25-7.19 (m, 1H), 7.15 (td, 1H, J = 7.6, 7.1, 1.0 Hz), 7.09-7.00 (m, 1H), 3.91 (t, 2H, J = 6.4 Hz), 3.04 (t, 2H, J = 6.4 Hz), 1.86 (s, 1H) ppm; 13C NMR (CDCl3, 100 MHz) δ 136.47, 127.44, 122.54, 122.23, 119.49, 118.86, 112.27, 111.26, 62.64, 28.77 ppm;IR (Smart iTX Diamond) ν 3390, 3322, 3059, 2933, 2905, 2863, 1456, 1424, 1352, 1338, 1229, 1094, 1045, 1005, 738, 591 cm -1 ;C 10 H 11 LC-MS for NO [M+H] (ES + ) calculated value 162.09, actual value 162.21. [ka]

[0204] A solution of p-MeO-phenylhydrazine (2 g, 11.45 mmol, 1 equiv) in 32.6 mL of a 1:1 mixture of DMA and 4% aqueous H2SO4 was heated to 100 °C. To this solution was added 1,2-dihydrofuran (0.95 mL, 0.883 g, 12.6 mmol, 1.1 equiv) by dropwise addition. The resulting mixture was stirred at 100 °C until the starting material was consumed (~5 h) as determined by TLC. The reaction was then cooled to room temperature and diluted with EtOAc (20 mL). The aqueous layer was extracted with EtOAc (4 x 25 mL). The combined organic extracts were washed with 5% aqueous LiCl (20 mL), saturated aqueous NaHCO3 (20 mL), and HO (20 mL) and then dried over Na2SO4. The resulting product was purified by chromatography on silica gel (gradient elution: 3:1→1:1 hexanes:EtOAc) to give the desired product as a yellow oil (1.71 g, 78%); 11H NMR (CDCl3, 400 MHz) δ 8.01 (s, 1H), 7.25 (s, 1H), 7.06 (d, 2H, J = 2.5 Hz), 6.88 (dd, 1H, J = 8.8, 2.4 Hz), 3.90 (t, 2H, J = 6.4 Hz), 3.87 (s, 3H), 3.01 (t, 2H, J = 6.4 Hz), 1.70 (s, 1H) ppm; 13 13C NMR (CDCl3, 100 MHz) δ 154.09, 131.70, 127.91, 123.46, 112.45, 112.09, 111.97, 100.76, 62.67, 56.06, 28.82 ppm; IR (Smart iTX Diamond) ν 3409, 2938, 2831, 1624, 1584, 1486, 1456, 1440, 1214, 1067, 1043, 922, 798 cm -1 ; C 11 H 13 LC-MS (ES + ) calculated value for [M+H] of NO2 is 192.10, measured value is 192.27.

Chemical Structure

[0205] A solution of p-BnO-phenylhydrazine (398 mg, 1.59 mmol, 1 equiv) in a 1:1 mixture of 32.6 mL of DMA and 4% aqueous H2SO4 was heated to 100 °C. To this solution was added 1,2-dihydrofuran (0.13 mL, 123 mg, 1.75 mmol, 1.1 equiv) by dropwise addition. The resulting mixture was stirred at 100 °C until the starting material was consumed (~3 h) as determined by TLC. The reaction was then cooled to room temperature and diluted with EtOAc (10 mL). The aqueous layer was extracted with EtOAc (4 x 10 mL). The combined organic extracts were washed with 5% aqueous LiCl (10 mL), saturated aqueous NaHCO3 (10 mL), and HO (2 x 10 mL) and then dried over Na2SO4. The resulting product was purified by chromatography on silica gel (gradient elution: 3:1→1:1 hexanes:EtOAc) to give the desired product as a brown oil (160 mg, 38%); 1 H NMR (CDCl3, 400 MHz) δ 7.95 (s, 1H), 7.49 (d, 2H, J = 7.4 Hz), 7.43-7.30 (m, 3H), 7.26 (s, 1H), 7.15 (d, 1H, J = 2.3 Hz), 7.06 (d, 1H, J = 2.2 Hz), 6.96 (dd, 1H, J = 8.8, 2.4 Hz), 5.12 (s, 2H), 3.89 (t, 2H, J = 6.3 Hz), 3.00 (t, 2H, J = 6.3 Hz), 1.59 (s, 1H) ppm; 13C NMR (CDCl3, 100 MHz) δ 153.25, 137.61, 131.79, 128.53, 127.85, 127.82, 127.63, 123.34, 113.13, 112.07, 111.93, 102.44, 71.04, 62.59, 28.77 ppm;IR (Smart iTX Diamond) ν 3419, 3062, 3032, 2929, 2878, 1624, 1582, 1483, 1454, 1381, 1293, 1219, 1194, 1064, 1043, 1025, 797, 740, 698 cm -1 ;C 17 H 18 LC-MS for NO2 [M+H] (ES + ) calculated value 268.13, actual value 268.24. Example 7. Compounds 9a and 9b

[0206] First, the hydroxyl group of tryptophol, as shown above, was converted to iodine. To accomplish this transformation, a solution of iodine (251 mg, 0.99 mmol, 1.4 equiv) and triphenylphosphine (260 mg, 0.99 mmol, 1.4 equiv) in DCM (2.75 mL, 0.25 M) was cooled to 0 °C. Tryptophol (0.71 mmol, 1.0 equiv) was then added dropwise. The solution was stirred until the starting material was consumed (~5 h), as determined by TLC. The reaction mixture was concentrated under reduced pressure to afford the alkyl iodide, which was used immediately without further purification.

[0207] In separate flasks, a mixture of 6a or 6b (271 mg, 1.0 mmol, 1.0 equiv) and 10% Pd / C (85 mg, 0.08 mmol, 0.08 equiv) was stirred in MeOH (5 mL, 0.2 M) under an atmosphere of N. The flasks were then purged with H gas and vigorously stirred under an atmosphere of H until the starting material was consumed (∼3 h) as determined by TLC. The mixture was filtered through a pad of Celite, which was washed with 50 mL of MeOH containing 1% aqueous NH. The filtrate was then dried over Na.sub.2SO.sub.4 and concentrated under reduced pressure to give a clear oil. The oil was immediately dissolved in DMF (2.5 mL, 0.4 M) and added to a flask containing crude alkyl iodide (271 mg, 1.0 mmol, 1.0 equiv, prepared as described above) and solid NaHCO (168 mg, 2 mmol, 2 equiv). The mixture was heated at 80 °C for 20 h, then cooled to room temperature and diluted with 1 M aqueous NaCO (15 mL) and EtOAc (15 mL). The aqueous layer was extracted with EtOAc (3 × 10 mL). The combined organic extracts were washed with HO (10 mL), 5% aqueous LiCl (10 mL), and brine (10 mL), then dried over NaSO and concentrated under reduced pressure. The product was purified by silica gel chromatography (100:1 DCM:MeOH with 0.5% NHOH). [ka]

[0208] Isolated as a tan solid (30 mg, 24%, 2 steps); 1H NMR (CDCl3, 400 MHz) δ 7.95 (s, 1H), 7.64 (d, 1H, J = 7.8 Hz), 7.35 (d, 1H, J = 8.0 Hz),7.24-7.16 (m, 1H), 7.16-7.10 (m, 1H), 7.05 (d, 1H, J = 1.8 Hz), 3.19-3.12 (m, 1H), 2.96-2.72 (m, 4H), 2.49 (s, 1H), 2.36 (d, 1H, J = 9.2 Hz), 2.09-1.99 (m, 1H), 1.79-1.71 (m, 1H), 1.71- 1.65 (m, 1H), 1.63-1.42 (m, 5H), 1.40-1.31 (m, 1H), 1.24-1.16 (m, 1H), 0.90 (t, 3H, J = 7.1 Hz) ppm; 13 C NMR (CDCl3, 100 MHz) δ 136.29, 127.83, 121.84, 121.65, 119.13, 119.04, 115.21, 111.15, 56.89, 56.82, 53.30, 40.62, 32.87, 27.44, 26.95, 25.35, 24.40, 21.97, 12.04 ppm;IR (Smart iTX Diamond) ν 3418, 3170, 3055, 2930, 2860, 2798, 1456, 1357, 1228, 1147, 1092, 740cm -1 ;C 19 H 26 LC-MS for N2 [M+H] (ES + ) calculated value 283.22, actual value 283.35. [ka]

[0209] Isolated as a tan solid (66 mg, 23%, 2 steps); 1H NMR (CDCl3, 400 MHz) δ 8.07 (s, 1H), 7.65 (d, 1H, J = 7.8 Hz), 7.35 (d, 1H, J = 8.0 Hz), 7.19 (t, 1H, J = 7.4 Hz), 7.12 (t, 1H, J = 7.4 Hz), 7.07-7.03 (m, 1H), 3.01-2.91 (m, 3H), 2.91-2.83 (m, 2H), 2.77-2.70 (m, 1H), 2.55-2.50 (m, 1H), 1.97-1.78 (m, 3H), 1.73-1.56 (m, 3H), 1.52-1.41 (m, 1H), 1.36-1.26 (m, 2H), 1.08-1.00 (m, 1H), 0.89 (t, 3H, J = 7.4 Hz) ppm; 13 C NMR (CDCl3, 100 MHz) δ 136.37, 127.73, 122.03, 121.65, 119.30, 119.10, 114.97, 111.21, 57.30, 56.20, 53.91, 35.48, 32.92, 27.68, 26.67, 25.26, 24.39, 20.15, 12.19 ppm;IR (Smart iTX Diamond) ν 3416, 3139, 3055, 2926, 2858, 2823, 1456, 1354, 1231, 1112, 1088, 738cm -1 ;C 19 H 26 LC-MS for N2 [M+H] (ES + ) calculated value 283.22, actual value 283.35. Example 8. Compounds 10a and 10b [ka]

[0210] Isolated as an amorphous brown solid (71.2 mg, 44%, 2 steps); 1H NMR (CDCl3, 400 MHz) δ 8.05 (s, 1H), 7.23 (d, 1H, J = 8.7 Hz), 7.09 (d, 1H, J = 2.0 Hz), 7.04-6.98 (m, 1H), 6.86 (dd, 1H, J = 8.8, 2.3 Hz), 3.88 (s, 3H), 3.27-3.12 (m, 1H), 2.96-2.76 (m, 4H), 2.54 (s, 1H), 2.37 (d, 1H, J = 9.3 Hz), 2.11-1.98 (m, 1H), 1.81-1.72 (m, 1H), 1.72-1.65 (m, 1H), 1.65-1.43 (m, 5H), 1.42-1.33 (m, 1H), 1.28-1.16 (m, 1H), 0.91 (t, 3H, J = 7.1 Hz) ppm; 13 C NMR (CDCl3, 100 MHz) δ 153.91, 131.50, 128.16, 122.60, 114.58, 111.97, 111.87, 101.05, 56.85, 56.57, 56.13, 53.35, 40.43, 32.66, 27.38, 26.78, 25.15, 24.20, 21.90, 12.03 ppm;IR (Smart iTX Diamond) ν 3415, 3045, 2931, 2860, 2828, 1624, 1585, 1485, 1456, 1215, 1172, 1064, 1032, 796 cm -1 ;C 20 H 29 LC-MS for NO [M+H] (ES + ) calculated value 313.23, actual value 313.34. [ka]

[0211] Isolated as an amorphous brown solid (56 mg, 18%, 2 steps); 11H NMR (CDCl3, 400 MHz) δ 8.67 (s, 1H), 7.23 (d, 1H, J = 8.8 Hz), 7.08 (d, 1H, J = 2.3 Hz), 7.00 (d, 1H, J = 1.9 Hz), 6.86 (dd, 1H, J = 8.8, 2.4 Hz), 3.85 (s, 3H), 3.02 - 2.93 (m, 3H), 2.93 - 2.86 (m, 2H), 2.80 - 2.73 (m, 1H), 2.63 - 2.56 (m, 1H), 2.02 - 1.83 (m, 3H), 1.75 - 1.59 (m, 3H), 1.55 - 1.44 (m, 1H), 1.40 - 1.29 (m, 2H), 1.07 (m, 1H), 0.92 (t, 3H, J = 7.4 Hz) ppm; 13 13C NMR (CDCl3, 100 MHz) δ 153.77, 131.57, 127.99, 122.66, 114.24, 114.21, 111.94, 100.83, 57.10, 56.10, 55.99, 53.63, 35.34, 32.87, 27.58, 26.60, 25.23, 24.32, 20.10, 12.14 ppm; IR (Smart iTX Diamond) ν 3412, 3041, 2930, 2871, 2827, 1625, 1586, 1486, 1456, 1216, 1173, 1064, 1032, 795 cm -1 ; C 20 H 29 N2O [M + H] for LC - MS (ES + ) calculated value 313.23, measured value 313.34. Example 9. Compounds 11a and 11b

[0212] First, 5-benzyloxy-isoquinuclidine was synthesized as previously described. This starting material (100 mg, 0.26 mmol, 1.0 equiv) was then dissolved in MeOH (1.3 mL, 0.2 M) containing 10% Pd / C (22 mg, 0.02 mmol, 0.08 equiv) under a N atmosphere. The flask was then purged with H gas and vigorously stirred under a H atmosphere until the starting material was consumed (∼24 h), as determined by TLC. The mixture was filtered through a pad of Celite, which was washed with 50 mL of MeOH containing 1% aqueous NHOH. The filtrate was then dried over NaSO and concentrated under reduced pressure to give a brown oil. The product was purified by silica gel chromatography (30:1 DCM:MeOH with 1% NHOH). [ka]

[0213] Isolated as a tan foam (32 mg, 41%, 3 steps); 1 H NMR (CDCl3, 400 MHz) δ 7.96 (s, 1H), 7.14 (d, 1H, J = 8.6 Hz), 6.94 (s, 1H), 6.83 (d, 1H, J = 1.8 Hz), 6.80-6.72 (dd, 1H, J = 8.6, 1.8 Hz), 5.74 (bs, 1H), 3.13 (dt, 1H, J = 9.2, 2.9 Hz), 2.93-2.71 (m, 4H), 2.56-2.49 (m, 1H), 2.35 (d, 1H, J = 9.5 Hz), 2.08-1.95 (m, 1H), 1.80-1.71 (m, 1H), 1.70-1.64 (m, 1H), 1.63-1.40 (m, 5H), 1.39-1.17 (m, 2H), 0.88 (t, 3H, J = 7.1 Hz) ppm; 13C NMR (CDCl3, 100 MHz) δ 149.82, 131.40, 128.36, 122.85, 114.05, 112.26, 111.91, 103.71, 56.99, 56.59, 53.67, 40.64, 32.59, 27.43, 26.66, 25.01, 23.95, 22.08, 12.17 ppm;IR (Smart iTX Diamond) ν 3400, 3278, 2929, 2860, 1625, 1581, 1456, 1362, 1186, 1092, 936, 796, 754cm -1 ;C 19 H 27 LC-MS for NO [M+H] (ES + ) calculated value 299.21, actual value 299.34. [ka]

[0214] Isolated as a tan foam (20 mg, 15%, 3 steps); 1 H NMR (CDCl3, 600 MHz) δ 7.98 (s, 1H), 7.16 (d, 1H, J = 8.6 Hz), 6.94 (s, 1H), 6.88 (d, 1H, J = 2.0 Hz), 6.78 (dd, 1H, J = 8.6, 2.2 Hz), 3.03-2.92 (m, 4H), 2.76-2.71 (m, 1H), 2.62-2.57 (m, 1H), 2.01-1.82 (m, 3H), 1.69 (s, 1H), 1.67-1.57 (m, 2H), 1.48-1.41 (m, 1H), 1.35-1.19 (m, 3H), 1.05-0.99 (m, 1H), 0.83 (t, 3H, J = 7.4 Hz) ppm; 13C NMR (CDCl3, 150 MHz) δ 150.66, 131.34, 128.18, 122.68, 113.51, 113.03, 112.03, 103.77, 57.33, 55.57, 54.52, 34.85, 32.65, 27.52, 26.35, 24.90, 24.01, 19.49, 12.09 ppm;IR (Smart iTX Diamond) ν 3402, 3286, 2924, 2857, 1625, 1581, 1456, 1377, 1208, 1080, 936, 795, 751cm -1 ;C 19 H 27 LC-MS for NO [M+H] (ES + ) calculated value 299.21, actual value 299.34. Example 10. Compound 12

[0215] To a solution of 4-substituted phenylhydrazine hydrochloride (1.0 mmol) in EtOH (0.1 M) was added 1-methylazepan-4-one hydrochloride (164 mg, 1.0 mmol, 1.0 equiv), followed by concentrated aqueous HCl (0.5 mL, 6.0 mmol, 6.0 equiv). The mixture was refluxed for 24 h and then concentrated under reduced pressure. The oily residue was dissolved in DCM (~25 mL) and basified with 1 M aqueous NaOH (~20 mL). The aqueous layer was extracted with DCM (3 x 20 mL). The combined organic extracts were dried over NaSO and concentrated under reduced pressure to give an oil that was purified by silica gel chromatography (20:1 DCM:MeOH with 0.5% NHOH). General scheme: [ka]

[0216] Isolated as a brown solid (127 mg, 64%); 1H NMR (CDCl3, 400 MHz) δ 7.78 (s, 1H), 7.50-7.43 (m, 1H), 7.28 (d, 1H, J = 1.6 Hz), 7.15-7.05 (m, 2H), 3.01-2.92 (m, 4H), 2.92-2.82 (m, 4H), 2.53 (s, 3H) ppm; 13 C NMR (CDCl 3--,, , 100 MHz) δ 136.10, 134.68, 129.05, 121.12, 119.36, 117.74, 112.89, 110.44, 58.05, 56.30, 46.16, 28.59, 23.95 ppm;IR (Smart iTX Diamond) ν 3140, 3055, 3032, 2904, 2829, 2756, 1451, 1337, 739 cm -1 ;C 13 H 17 LC-MS for N2 [M+H] (ES + ) calculated value 201.14, actual value 201.33. Example 11. Compound 13 [ka]

[0217] Isolated as a light brown solid (146 mg, 63%); 1 H NMR (CDCl3, 400 MHz) δ 7.74 (s, 1H), 7.15 (d, 1H, J = 8.7 Hz), 6.92 (d, 1H, J = 2.4 Hz), 6.77 (dd, 1H, J = 8.7, 2.4 Hz), 3.85 (s, 3H), 2.98-2.82 (m, 8H), 2.53 (s, 3H) ppm; 13C NMR (100 MHz, CDCl3) δ 154.13, 137.12, 129.79, 129.40, 112.70, 111.15, 110.91, 100.13, 58.04, 56.29, 56.11, 46.15, 28.61, 24.00 ppm. IR (Smart iTX Diamond) ν 3136, 3035, 2924, 2882, 2822, 1594, 1451, 1215, 1107, 1035, 837, 791 cm -1 ;C 14 H 19 LC-MS for NO [M+H] (ES + ) calculated value 231.15, actual value 231.32. Example 12. Compound 14 [ka]

[0218] It was synthesized from p-benzyloxyhydrazine, followed by hydrogenolysis of the benzyl group. Following Fisher indole cyclization, the benzyloxyindole was added to a mixture of 10% Pd / C (0.08 equiv) in MeOH (4.6 mL) under a N atmosphere. The slurry was stirred at room temperature for 12 h, filtered through a small pad of Celite, and rinsed with 50 mL of methanol and 1% ammonium hydroxide. The filtrate was concentrated under reduced pressure to a brown oil. The desired product was purified by silica gel chromatography (30:1 DCM:MeOH with 0.5% NH4OH) to give a white crystalline solid (80 mg, 40%, 2 steps). 1 H NMR (DMSO-d6, 400 MHz) δ 10.32 (s, 1H), 8.46 (s, 1H), 6.99 (d, 1H, J = 8.5 Hz), 6.65 (d, 1H, J = 2.2 Hz), 6.47 (dd, 1H, J = 8.5, 2.2 Hz), 2.87-2.79 (m, 2H), 2.70-2.68 (m, 6H), 2.39 (s, 3H) ppm; 13C NMR (DMSO-d6, 100 MHz) δ 150.18, 137.63, 129.39, 129.05, 111.02, 110.58, 110.00, 101.62, 57.95, 56.14, 45.80, 27.76, 23.70 ppm;IR (Smart iTX Diamond) ν 3391, 3273, 3047, 2927, 1590, 1455, 1200, 1111, 928, 840, 797, 735 cm -1 .C 13 H 17 LC-MS for NO [M+H] (ES + ) calculated value 217.13, actual value 217.32. Example 13. Compound 15 [ka]

[0219] Isolated as a yellow solid (97 mg, 88%); 1 H NMR (CDCl3, 400 MHz) δ 7.79 (s, 1H), 7.16 (dd, 1H, J = 8.8, 4.4 Hz), 7.09 (dd, 1H, J = 9.77, 2.37 Hz), 6.84 (td, 1H, J = 9.0, 2.4 Hz), 3.01-2.92 (m, 2H), 2.91-2.80 (m, 6H), 2.52 (s, 3H) ppm. 13C NMR (CDCl3, 100 MHz) δ 158.01 (d, J = 233.9 Hz), 138.24, 131.12, 129.50 (d, J = 9.5 Hz), 113.23 (d, J = 4.6 Hz), 110.90 (d, J = 9.7 Hz), IR (Smart iTX Diamond) ν 3146, 3103, 3040, 2929, 2880, 2809, 2753, 1584, 1453, 1169, 1103, 932, 855, 794, 767, 749 cm -1 .C 13 H 16 LC-MS (ES) for FN2 [M+H] + ) calculated value 219.13, actual value 219.31. Example 14. Compound 16 [ka]

[0220] Isolated as a yellow solid (89 mg, 62%); 1 H NMR (CDCl3, 400 MHz) δ 7.99 (s, 1H), 7.41 (d, 1H, J = 1.7 Hz), 7.14 (d, 1H, J = 8.5 Hz), 7.04 (dd, 1H, J = 8.5, 1.9 Hz), 2.98-2.79 (m, 8H), 2.52 (s, 3H) ppm; 13C NMR (CDCl3, 100 MHz) δ 137.82, 133.01, 130.16, 125.00, 121.13, 117.33, 112.68, 111.37, 57.84, 56.08, 46.04, 28.55, 23.85 ppm;IR (Smart iTX Diamond) ν 3128, 3085, 3020, 2922, 2849, 2736, 2694, 1446, 1361, 1316, 1052, 917, 851, 783, 718, 601 cm -1 .C 13 H 16 LC-MS for ClN2 [M+H] (ES + ) calculated value 235.10, actual value 235.30. Example 15. Compound 17 [ka]

[0221] Isolated as a brown solid (161 mg, 65%); 1 H NMR (CDCl3, 400 MHz) δ 7.93 (s, 1H), 7.57 (d, 1H, J = 1.24 Hz), 7.17 (dd, 1H, J = 8.5, 1.5 Hz), 7.10 (d, 1H, J = 8.5 Hz), 2.99-2.77 (m, 8H), 2.52 (s, 3H) ppm; 13 C NMR (CDCl3, 100 MHz) δ 137.66, 133.27, 130.84, 123.71, 120.45, 112.66, 112.58, 111.82, 57.86, 56.11, 46.12, 28.62, 23.91 ppm;IR (Smart iTX Diamond) ν 3126, 3082, 3020, 2922, 2848, 2733, 1575, 1450, 1316, 1113, 1046, 914, 852, 781, 739, 594 cm -1 .C 13 H 16LC-MS (ES) for BrN2 [M+H] + ) calculated value 279.05, actual value 279.22. Example 16. Compound 18

[0222] Compound 18 (TBG) was prepared similarly to compounds 12-17 with minor modifications. General scheme: [ka]

[0223] To an ice-cooled solution of 6 M aqueous HCl (15 mL), 3-methoxyaniline (2.2 mL, 20.0 mmol, 1.0 equiv) was added dropwise. Next, NaNO (1.520 g, 22.0 mmol, 1.1 equiv) was dissolved in HO (15 mL) and slowly added to the solution. After stirring at 0 °C for 15 min, SnCl (11.4 g, 60.0 mmol, 3.0 equiv) dissolved in concentrated aqueous HCl (15 mL) was added dropwise to the solution. After stirring at 0 °C for 2.5 h, the reaction mixture was filtered, washed with hexane, and dried under reduced pressure to give the product as a pale yellow solid, which was used without further purification.

[0224] To a solution of 3-methoxyphenylhydrazine hydrochloride (1.566 g, 9.0 mmol, 3.0 equiv) in 0.1 M EtOH (30 mL) was added 1-methylazepan-4-one hydrochloride (489 mg, 3.0 mmol, 1.0 equiv), followed by concentrated aqueous HCl (1.0 mL, 12.0 mmol, 4.0 equiv). The mixture was refluxed for 12 h and then concentrated under reduced pressure. The oily residue was dissolved in DCM (~25 mL) and basified with 1 M aqueous NaOH (~20 mL). The aqueous layer was extracted with DCM (3 x 20 mL). The combined organic extracts were dried over Na2SO4 and concentrated under reduced pressure to give a mixture of 6- and 4-substituted indoles. The 6-substituted indole was purified by chromatography on silica gel (10:1 DCM:MeOH with 0.5% NH4OH). [ka]

[0225] Isolated as a pale yellow solid (379 mg, 55%); 1 H NMR (CDCl3, 400 MHz) δ 7.67 (br s, 1H), 7.32 (d, 1H, J = 8.5 Hz), 6.80 - 6.73 (m, 2H), 3.83 (s, 3H), 2.98 - 2.83 (m, 8H), 2.53 (s, 3H) ppm; 13 C NMR (CDCl3, 100 MHz) δ 155.93, 135.33, 134.68, 123.59, 118.29, 112.53, 108.80, 94.66, 57.98, 56.34, 55.95, 45.93, 28.36, 23.91 ppm;IR (Smart iTX Diamond) ν 3153, 3121, 3073, 2940, 2879, 1628, 1458, 1197, 1033, 910, 834, 799 cm -1 ;C 14 H 19 LC-MS for NO [M+H] (ES +) calculated value 231.15, actual value 231.36. Example 17. Procedure for preparing compound 13 1 / 2 fumarate

[0226] Fumaric acid (116 mg, 1.0 mmol, 0.8 equiv) was added to a sealed tube containing acetone (12 mL). The solution was carefully heated until all the fumaric acid was dissolved. After the solution was cooled to room temperature, a solution of compound 13 free base (288 mg, 1.25 mmol, 1.0 equiv) in acetone (1 mL) was added, and the mixture was chilled in a freezer overnight. The solid was filtered, washed with acetone, and dried under reduced pressure to give 13 fumarate as a 2:1 salt (220 mg, 61%). 1 H NMR (CD3OD, 400 MHz) δ 7.15 (d, 1H, J = 8.7 Hz), 6.92 (s, 1H), 6.72 (d, 1H, J = 8.7 Hz), 6.68 (s, 1H), 3.80 (s, 3H), 3.42-3.34 (m, 4H), 3.18 (t, 2H, J = 5.5 Hz), 3.10 (t, 2H, J = 5.5 Hz), 2.91 (s, 3H) ppm; 13 C NMR (CD3OD, 100 MHz) δ 171.76, 155.37, 136.32, 135.55, 131.75, 129.59, 112.49, 112.31, 110.58, 100.58, 58.77, 56.70, 56.27, 44.77, 25.09, 21.55 ppm. IR (Smart iTX Diamond) ν 3384, 2979, 2924, 2297, 2822, 1695, 1551, 1353 1167, 982, 912, 802 cm -1 ;C 14 H 19 LC-MS for NO [M+H] (ES + ) calculated value 231.15, actual value 231.36. Example 18. Procedure for preparing compound 18 fumarate

[0227] Fumaric acid (77 mg, 0.66 mmol, 0.8 equiv) was added to a sealed tube containing acetone (8 mL). The solution was carefully heated until all the fumaric acid was dissolved. After the solution was cooled to room temperature, a solution of compound 18 free base (193 mg, 0.84 mmol, 1.0 equiv) in acetone (1 mL) was added, and the mixture was chilled in a freezer overnight. The solid was filtered, washed with acetone, and dried under reduced pressure to give 18 fumarate as a 1:1 salt (187 mg, 64%). 1 H NMR (CD3OD, 400 MHz) δ 7.28 (d, 1H, J = 8.7 Hz), 6.82 (s, 1H), 6.71 (s, 2H), 6.68 (d, 1H, J = 8.7 Hz), 3.79 (s, 3H), 3.54-3.45 (m, 4H), 3.22 (t, 2H, J = 5.3 Hz), 3.13 (t, 2H, J = 5.3 Hz), 3.00 (s, 3H) ppm; 13 C NMR (CD3OD, 100 MHz) δ 170.71, 157.57, 137.23, 135.99, 133.23, 123.71, 118.86, 110.47, 110.10, 95.31, 58.62, 56.68, 55.99, 44.48, 24.77, 21.35 ppm;IR (Smart iTX Diamond) ν 3375, 3008, 2899, 2505, 1694, 1556, 1337, 1162, 1034, 967, 814, 775 cm -1 ;C 14 H 19 LC-MS for NO [M+H] (ES + ) calculated value 231.15, actual value 231.36. Example 19. Procedure for large scale preparation of compound 18 fumarate

[0228] To an ice-cooled solution of 6 M aqueous HCl (30 mL), 3-methoxyaniline (4.4 mL, 40.0 mmol, 1.0 equiv) was added dropwise. Next, NaNO (3.040 g, 44.0 mmol, 1.1 equiv) was dissolved in HO (30 mL) and slowly added to the solution. After stirring at 0 °C for 15 min, SnCl (22.8 g, 120.0 mmol, 3.0 equiv) dissolved in concentrated aqueous HCl (30 mL) was added dropwise to the solution. After stirring at 0 °C for 2.5 h, the reaction mixture was filtered, washed with hexane, and dried under reduced pressure to give 3-methoxyphenylhydrazine hydrochloride (5.4 g, 78%) as a pale yellow solid, which was used without further purification.

[0229] To a solution of 3-methoxyphenylhydrazine hydrochloride (4.802 g, 27.6 mmol, 3.0 equiv) in 0.1 M EtOH (60 mL) was added 1-methylazepan-4-one hydrochloride (1.5 g, 9.2 mmol, 1.0 equiv), followed by concentrated aqueous HCl (3.1 mL, 36.8 mmol, 4.0 equiv). The mixture was refluxed for 12 h and then concentrated under reduced pressure. The oily residue was dissolved in DCM (~50 mL) and basified with 1 M aqueous NaOH (~50 mL). The aqueous layer was extracted with DCM (3 x 30 mL). The combined organic extracts were dried over NaSO and concentrated under reduced pressure to give a mixture of 6- and 4-substituted indoles. Addition of EtOAc to the crude product mixture resulted in the precipitation of the 6-substituted isomer, which was isolated by filtration. The mother liquor was concentrated and this procedure was repeated six times until a total of 1.028 g of Tabernantalogo free base (49%) was recovered.

[0230] Next, fumaric acid (408 mg, 3.5 mmol, 0.8 equiv) was added to a sealed tube containing acetone (20 mL). The solution was carefully heated until all of the fumaric acid was dissolved. After the solution was cooled to room temperature, a solution of compound 18 free base (1.028 mg, 4.4 mmol, 1.0 equiv) in acetone (5 mL) was added dropwise, and the mixture was chilled in a freezer overnight. The solid was filtered, washed with acetone, and dried under reduced pressure to give 18 fumarate as a 1:1 salt (1.055 g, 69%). Example 20. General Procedure for Examples 21-24 General synthetic scheme: [ka] General steps:

[0231] To a solution of substituted phenylhydrazine hydrochloride (1.0 mmol) in EtOH (0.1 M) was added 1-methylazepan-4-one hydrochloride (1.0 equiv), followed by concentrated aqueous HCl (6.0 equiv). The mixture was refluxed for 24 hours, and the progress of the reaction was monitored by TLC.

[0232] Workup and purification procedure: After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The oily residue was dissolved in DCM (~25 mL) and basified with 1 M aqueous NaOH (~20 mL). The aqueous layer was extracted with DCM (3 x 20 mL). The combined organic extracts were dried over Na2SO4 and concentrated under reduced pressure to give an oil, which was purified by combi-flash using 0.5% NH4OH with varying percentages of MeOH in CH2Cl2. The TLC washed fractions were evaporated, and the resulting residue was then diluted with EtOAc and washed with water two or three times. The organic layer was separated, then evaporated and dried to give the pure product.

[0233] Some compounds were purified by preparative HPLC purification, and the respective target compounds were captured by the purification method. Example 21. Compound 19 [ka]

[0234] Yield: 150 mg (8%, off-white solid). LCMS: 99%, m / z=217.1 [M+H] + 1 H NMR (DMSO-d6, 400 MHz): δ 10.42 (s, 1H), 7.20 (d, J=8.56 Hz, 1H), 6.72 (d, J=2.20 Hz, 1H), 6.57 (dd, J=2.20, 8.56 Hz, 1H), 3.72 (s, 3H), 2.87-2.91 (m, 4H), 2.79-2.82 (m, 2H), 2.68-2.72 (m, 2H). Example 22. Compound 20 and Compound 21 [ka]

[0235] The crude was purified by preparative HPLC to give fraction-1 and fraction-2. 1 According to 1 H NMR, fraction-2 is the compound on the left, while fraction-1 is the compound on the right.

[0236] Preparative HPLC purification method: HPLC column for preparation: Viridis BEH-2EP OBD, (250*19mm, 5 μ) Mobile phase A: 0.1% DEA in n-hexane Mobile phase B:EtOH:MeOH (50:50) Flow rate: 16.0mL / min Isocratic Table: [Table 1] Solvent used for dilution: methanol / ethanol.

[0237] Compound 20: Yield: 12.8% (80 mg, light brown solid). LCMS: 99.2%, m / z=285.2 [M+H] + 1 H NMR (DMSO-d6, 400 MHz): δ 10.97 (s, 1H), 7.43 (d, J=8.56 Hz, 1H), 7.18 (d, J=0.86 Hz, 1H), 6.87-6.92 (m, 1H), 2.88-2.93 (m, 2H), 2.72-2.83 (m, 6H), 2.41 (s, 3H).

[0238] Compound 21: Yield: 1.6% (10 mg, off-white solid). LC-MS: 99.6%, m / z=285.2 [M+H] + 1 H NMR (DMSO-d6, 400 MHz): δ 11.20 (br s, 1H), 7.27 (d, J=8.07 Hz, 1H), 7.02 (t, J=7.95 Hz, 1H), 6.87 (br d, J=7.09 Hz, 1H), 2.97-3.00 (m, 2H), 2.91-2.94 (m, 2H), 2.69-2.73 (m, 4H), 2.40 (s, 3H). Example 23. Compound 22 [ka]

[0239] Preparative HPLC purification method: Preparative HPLC column: X Select CSH C18 (250*19mm), 5μm Mobile phase A: Acetonitrile Mobile phase B: 0.05% ammonia in HO Flow rate: 15.0mL / min Gradient table: [Table 2] Solvent used for dilution: acetonitrile / MeOH

[0240] Yield: 15.6% (30 mg, off-white solid). LCMS: 99.6%, m / z=261.1 [M+H] + 1 H NMR (DMSO-d6, 400 MHz): δ 10.32 (s, 1H), 6.87 (s, 1H), 6.76 (s, 1H), 3.73 (d, J=1.59 Hz, 6H), 2.81-2.85 (m, 2H), 2.68-2.74 (m, 6H), 2.39 (s, 3H). Example 24. Compound 23 [ka]

[0241] Yield: 220 mg (34%, light brown solid). LCMS: 100%, m / z=245.1 [M+H] + 1 H NMR (DMSO-d6, 400 MHz): δ 10.45 (br s, 1H), 6.84 (s, 1H), 6.75 (s, 1H), 5.86 (s, 2H), 2.79-2.82 (m, 2H), 2.68 (br s, 6H), 2.37 (s, 3H). Example 25. Compound 24 and Compound 25 [ka]

[0242] The crude was purified by preparative HPLC to give fraction-1 and fraction-2. 1 Fraction-1 is # (left side) while fraction-2 is # (right side) according to 1 H NMR.

[0243] Preparative HPLC purification method: HPLC column for preparation: Viridis BEH-2EP OBD, (250*19mm, 5 μ) Mobile phase A: 0.1% DEA in n-hexane Mobile phase B:EtOH:MeOH (50:50) Flow rate: 16.0mL / min Isocratic Table: [Table 3] Solvent used for dilution: methanol / ethanol

[0244] Compound 24: Yield: 9.1% (80 mg, off-white solid). LCMS: 98.7%, m / z=215.2 [M+H] + 1 H NMR (DMSO-d6, 400 MHz): δ 10.47 (s, 1H), 7.22 (d, J=7.95 Hz, 1H), 7.00 (s, 1H), 6.74 (dd, J=0.98, 7.95 Hz, 1H), 2.84-2.88 (m, 2H), 2.70-2.76 (m, 6H), 2.40 (s, 3H), 2.35 (s, 3H).

[0245] Compound 25: Yield: 3.4% (30 mg, off-white solid). LC-MS: 95.8%, m / z=215.2 [M+H] + 1 H NMR (DMSO-d6, 400 MHz): δ 10.68 (br s, 1H), 7.05 (d, J=7.95 Hz, 1H), 6.82 (t, J=7.52 Hz, 1H), 6.62 (d, J=7.09 Hz, 1H), 3.10-3.14 (m, 2H), 2.89-2.92 (m, 2H), 2.81 (br s, 4H), 2.56 (s, 3H), 2.46 (br s, 3H). Example 26. Compound 26 and Compound 27 [ka]

[0246] The crude was purified by preparative HPLC to give fraction-1 and fraction-2. 1Fraction-1 is # (right side) while fraction-2 is # (left side) according to 1 H NMR.

[0247] Preparative HPLC purification method: Preparative HPLC column: Chiralpak IC, (250*30mm, 5 μ) Mobile phase A: 0.1% DEA in n-hexane Mobile phase B:EtOH:MeOH (80:20) Flow rate: 35.0mL / min Isocratic Table: [Table 4] Solvent used for dilution: methanol / ethanol

[0248] Compound 26: Yield: 24.6% (160 mg, off-white solid). LCMS: 100%, m / z=245.1 [M+H] + 1 H NMR (DMSO-d6, 400 MHz): δ 10.33 (s, 1H), 7.07 (s, 1H), 6.71 (s, 1H), 3.75 (s, 3H), 2.81-2.85 (m, 2H), 2.69-2.73 (m, 6H), 2.39 (s, 3H), 2.18 (s, 3H).

[0249] Compound 27: Yield: 3.1% (20 mg, off-white solid). LC-MS: 100%, m / z=245.1 [M+H] + 1 H NMR (DMSO-d6, 400 MHz): δ 10.63 (s, 1H), 6.89 (d, J=8.07 Hz, 1H), 6.75 (d, J=8.07 Hz, 1H), 3.65 (s, 3H), 3.03-3.06 (m, 2H), 2.82-2.85 (m, 2H), 2.64-2.67 (m, 4H), 2.37 (s, 3H), 2.23 (s, 3H). Example 27. Compound 28 [ka]

[0250] Compound 28: Yield: 4.7% (30 mg, light brown solid). LC-MS: 96.2%, m / z=261.2 [M+H] + 1 H NMR (DMSO-d6, 400 MHz): δ 10.44 (s, 1H), 6.32 (d, J=1.96 Hz, 1H), 6.05 (d, J=1.96 Hz, 1H), 3.76 (s, 3H), 3.71 (s, 3H), 3.02-3.04 (m, 2H), 2.77-2.80 (m, 2H), 2.64 (br dd, J=3.24, 6.17 Hz, 4H), 2.35 (s, 3H). Plasticity effect

[0251] Treatment of rat embryonic cortical neurons with TBG enhanced the complexity of dendritic arborization at 6 days in vitro (DIV6), as measured by Sholl analysis (Figure 3A-C). 2A The effect of TBG on dendritic growth appears to be ketanserin-5-HT 2A Antagonist pretreatment completely abrogated the effect, which was further validated by in vitro receptor profiling (Figure 3D).

[0252] In addition to promoting dendritic growth, TBG also enhances dendritic spine density to a degree comparable to that of ibogaine in mature cortical cultures (DIV20) (Figures 3E and 3F). We assessed the effect of TBG on cortical dendritic spine dynamics in vivo using transcranial two-photon imaging (Figure 3G). First, spines were imaged at specific dendritic sites defined by their relationship to blood vessels and dendritic structures. Next, animals were treated with vehicle, TBG, or hallucinogenic 5-HT. 2AThe agonist 2,5-dimethoxy-4-iodoamphetamine (DOI) was administered systemically. 24 h later, the same dendritic segments were reimaged, and the increased or decreased number of spines was quantified. Neither TBG nor DOI affected spine elimination. Both compounds enhanced spine formation in mouse primary sensory cortex (Figures 3H and 3I).

[0253] Enhanced cortical structural plasticity in the anterior brain mediates the sustained (>24 hours) antidepressant-like effects of ketamine, and 5-HT 2A Because TBG plays a role in the therapeutic effects of agonists, we evaluated the effects of TBG on forced swim test (FST) behavior (Figures 4A and 4B). First, a pretest was used to induce a depressive phenotype. Drugs were administered 24 hours after the pretest, and the FST was performed 24 hours and 7 days after drug administration. Both ketamine and TBG significantly reduced immobility 24 hours after drug administration.

[0254] To evaluate the anti-addictive potential of TBG, we utilized an alcohol consumption paradigm modeling human binge drinking and binge drinking behavior. Using a two-bottle choice setup (20% ethanol (v / v), EtOH vs. water, HO), mice were subjected to repeated cycles of binge drinking and withdrawal over a 7-week course (Figure 4C). This schedule resulted in severe EtOH consumption (11.44 ± 0.76 g / kg / 24 h), binge drinking behavior (3.89 ± 0.33 g / kg / 4 h), and produced alcohol blood concentrations equivalent to those of human subjects suffering from alcohol use disorder (AUD). Next, TBG or vehicle was administered by intraperitoneal injection 3 h before the drinking session, and EtOH and HO consumption were monitored (Figure 4C). As shown in Figure 4D, TBG robustly reduced EtOH consumption and binge drinking during the first 4 h in all animals (19 total). Water intake was unaffected (Figure 4D). TBG administration reduced ethanol consumption without affecting water intake for at least 2 days (Figure 4E). Similar effects have been observed previously with ibogaine, suggesting that TBG may be a highly effective agent for the treatment of AUD. Biological Protocols

[0255] Data Analysis and Statistics. Treatments were randomized, and data were analyzed by an experimenter blinded to treatment condition. Statistical analyses were performed using GraphPad Prism (version 8.1.2) unless otherwise noted. All comparisons were planned before each experiment. Data are presented as mean ± SEM, with asterisks indicating *p<0.05, **p<0.01, ***p<0.001, and ****p<0.0001, unless otherwise noted. Boxplots display three quartiles of the distribution, with whiskers extending to points within 1.5 IQRs (interquartile range) between the lower and upper quartiles. Observations outside this range are displayed separately. For Figures 2B, 3C, 3D, 3F, 3I, 4B, and 5B, compound treatments were compared to VEH controls using one-way ANOVA with Dunnett's post-hoc test. For Figures 2E and 2F, a paired t-test was used to compare time 0 and time 1 (before and after drug administration, respectively). For Figures 2I and 11, a Fisher's exact test was used to compare compound treatments, and p-values ​​are indicated in the text. For Figure 4D, a paired t-test was used to analyze data. For Figure 4E, a two-tailed ANOVA with Sidak's post-hoc test was used to analyze data.

[0256] Drugs. Ibogaine hydrochloride (IBO) and noribogaine (NOR) were provided by the NIH Drug Supply Program. Other chemicals, such as ketamine hydrochloride (KET, Fagron), ketanserin (KETSN, ApexBio), eugenol (Tokyo Chemical Industries), and 5-hydroxytriptan (Sigma-Aldrich), were purchased from commercial suppliers. 5-Methoxy-N,N-dimethyltryptamine fumarate (2:1, 5-MeO-DMT:fumaric acid) was synthesized in-house as previously described and was determined to be analytically pure based on NMR and LC-MS data. For cell culture experiments, VEH = 0.1% (agonist studies) or 0.2% (antagonist studies) molecular biology-grade dimethyl sulfoxide (Sigma-Aldrich). For in vivo experiments, VEH = USP-grade saline (0.9%). For all cellular experiments, the free base was used, whereas for in vivo studies the fumarate salts of the ibogainalogs and tabernantalogs were used.

[0257] Animals. All experimental procedures involving animals were approved by the UCD, UCSF, or UCSC Institutional Animal Care and Use Committee (IACUC) and adhered to the principles described in the National Institutes of Health Guide for the Care and Use of Laboratory Animals. The University of California, Davis (UCD), University of California, San Francisco (UCSF), and University of California, Santa Cruz (UCSC) are accredited by the Association for Assessment and Accreditation of Laboratory Animal Care International (AAALAC).

[0258] Calculation of CNS MPO Score. The CNS MPO score was calculated using previously established methods. Predicted PKA values ​​were determined using Marvin Sketch (19.25.0). LogP and total polar surface area were predicted using Molinspiration. LogD was calculated using the following equation: LogD=LogP-LOG 10 (1+10 (pka-7.4) ) was calculated using

[0259] Dendritic formation experiments. For dendritogenesis experiments performed using cultured cortical neurons, timed-pregnant Sprague-Dawley rats were obtained from Charles River Laboratories (Wilmington, MA). Complete culture, staining, and analysis were performed as previously described (Dunlap, L. et al., 2019).

[0260] Head Twitch Response (HTR). Head twitch response assays were performed as previously described using both male and female C57BL / 6J mice (two per treatment). Mice were obtained from Jackson Laboratory (Sacramento, CA) and were approximately 8 weeks old at the time of the experiment. Compounds were administered by intraperitoneal injection (5 mL / kg) using 0.9% saline as the vehicle. 5-MeO-DMT fumarate (2:1 amine / acid) was used as a positive control and synthesized as previously described. Behavior was videotaped and subsequently scored by two blinded observers, and the results were averaged (Pearson correlation coefficient = 0.93).

[0261] hERG Inhibition Studies. All experiments were performed manually at room temperature using the patch clamp technique in whole-cell mode with an EPC-10 amplifier (HEKA, Lambrecht / Pfalz, Germany). HEK-293 cells stably expressing hKv11.1 (hERG) under G418 selection were generously provided by Craig January (University of Wisconsin, Madison). Cells were cultured in DMEM containing 10% fetal bovine serum, 2 mM glutamine, 1 mM sodium pyruvate, 100 U / mL penicillin, 100 μg / mL streptomycin, and 500 mg / mL G418. Before experiments, cells were cultured to 60–80% confluence, lifted using TrypLE, and plated on poly-L-lysine-coated coverslips. Patch pipettes were pulled from soda-lime glass (micro-hematocrit tubing) and had resistances of 2–4 MΩ. The external solution was typically sodium Ringer's (160 mM NaCl, 4.5 mM KCl, 2 mM CaCl, 1 mM MgCl, 10 mM HEPES, pH 7.4, and 290–310 mOsm). The internal solution used was potassium fluoride with ATP (160 mM KF, 2 mM MgCl, 10 mM EGTA, 10 mM HEPES, 4 mM NaATP, pH 7.2, and 300–320 mOsm). Two step pulses (applied 10 s apart) from −80 mV to 40 mV for 2 s, followed by −60 mV for 4 s, were used to elicit hERG currents. The percent reduction in tail current amplified by drugs was measured, and data are presented as mean + / - SD. For all experiments, drug solutions were freshly prepared from 10 mM stock solutions in DMSO. The final DMSO concentration never exceeded 1%.

[0262] Serotonin and Opioid Receptor Functional Assays. 5-HT and opioid receptor functional assay screens were performed in parallel using the same compound dilutions and a 384-well format high-throughput assay platform. The assays used mouse 5-HT 2AActivity was assessed for all human isoforms of receptors except where noted. Receptor constructs in pcDNA vectors were generated from the Presto-Tango GPCR library with minor modifications. All compounds were serially diluted in drug buffer (HBSS, 20 mM HEPES, pH 7.4, supplemented with 0.1% bovine serum albumin and 0.01% ascorbic acid) and analyzed by FLIPR. TETRA The wells were distributed into 384-well assay plates using a 5-HT (Molecular Devices) kit. All plates included positive controls, including 5-HT (for all 5-HT receptors), DADLE (DOR), salvinorin A (KOR), and DAMGO (MOR). 2A For measurements of Gq-mediated calcium flux function, HEK Flp-In 293 T-Rex stable cell lines (Invitrogen) were loaded with Fluo-4 dye, stimulated with compounds per hour, and then analyzed by FLIPR. TETRABaseline (0-10 s) and peak fold above baseline fluorescence (5 min) were read at 25°C by a meter. For 5-HT6 and 5-HT7a functional assays, Gs-mediated cAMP accumulation was detected using a split luciferase GloSensor assay in HEKT cells with a 15 min drug incubation at 25°C and luminescence measured by a Microbeta Trilux (Perkin Elmer). For 5-HT1A, 5-HT1B, 5-HT1F, MOR, KOR, and DOR functional assays, G i / o-mediated cAMP inhibition was measured using a split luciferase GloSensor assay in HEKT cells performed as described above, but in combination with either 0.3 μM isoproterenol (5-HT1A, 5-HT1B, 5-HT1F) or 1 μM forskolin (MOR, KOR, and DOR) to stimulate endogenous cAMP accumulation. For measurement of 5-HT1D, 5-HT1E, 5-HT4, and 5-HT5A functional assays, β-arrestin2 recruitment was measured by Tango assay using HTLA cells expressing TEV-fused β-arrestin2 as previously described with minor modifications. Data from all assays were plotted and nonlinear regression was performed using "log(agonist) vs. response" in Graphpad Prism to calculate Emax and EC 50 Parameter estimates were obtained.

[0263] 5HT 2A Sensor analysis: 5HT in HEK293T (ATCC) 2A A stable line of sensors (sLight1.3s) was generated via lentiviral transduction of HIV-EF1α-sLight1.3 and propagated from a single colony. Lentivirus was produced using the second gene lentiviral plasmid, pHIV-EF1α-sLight1.3, pHCMV-G, and pCMV-deltaR8.2.

[0264] For the screening of 41 compounds, sLight1.3s cells were plated in 96-well plates at a density of 40,000 cells / well 24 h prior to imaging. On the day of imaging, compounds solubilized in DMSO were diluted from a 100 mM stock solution to working concentrations of 1 mM, 100 μM, and 1 μM in 1% DMSO. Immediately prior to imaging, cells grown in DMEM (Gibco) were washed twice with HBSS (Gibco). After the final wash, 180 μL of HBSS for agonist mode or 160 μL of HBSS for antagonist mode was added to each well. For the agonist mode, images were taken before and after the addition of 20 μL of compound working solution to wells containing 180 μL of HBSS. This produced final compound concentrations of 100 μM, 10 μM, and 100 nM in 0.1% DMSO. For antagonist mode, images were taken before and after the addition of 20 μL of 900 nM 5-HT, and again after the addition of 20 μL of compound working solution to produce final concentrations of 100 μM, 10 μM, and 100 nM of compound with 100 nM of 5HT and 0.1% DMSO. Each compound was run in triplicate (3 wells) for each concentration (100 μM, 10 μM, and 100 nM). In addition, 100 nM 5HT and 0.1% DMSO controls were also imaged within each plate.

[0265] Imaging was performed using a Leica DMi8 inverted microscope equipped with a 40x objective using FITC pre-set at 460 nm excitation and 512-542 nm emission. 2A The sensor-targeted cell membrane was autofocused using an adaptive focus controller, and five images were taken from different areas within the well, each of which was processed for 2x2 binning.

[0266] For data processing, the membrane from each image was segmented and analyzed using a custom algorithm written in MATLAB® that generated a single raw fluorescence intensity value. For each well, the five raw fluorescence intensity values ​​generated from the five images were averaged, and the change in fluorescence intensity (dFF) was calculated as follows: dFF=(F sat -F apo ) / F apo

[0267] For both agonist and antagonist modes, only the fluorescence intensity values ​​before compound addition in HBSS were used as F apo The fluorescence intensity value after compound addition is used as the F value. sat was used as the value.

[0268] For the agonist mode, data are presented as percent activation relative to 5HT, where 0 is the mean of the DMSO wells and 100 is the mean of the 100 μM 5HT wells. For the antagonist mode, the inactivation score was calculated as follows: Inactivation score = (dFFF(compound + 5HT) - dFF(5HT)) / dFF(5HT)

[0269] Spine formation experiments were performed as previously described (Ly, C. et al., 2018), except that cells were treated on DIV19 and fixed 24 hours after treatment on DIV20. Images were taken with a Nikon HCA Confocal microscope equipped with a 100x / NA 1.45 oil objective. DMSO and ketamine (10 μM) were used as vehicle and positive controls, respectively.

[0270] In vivo spine dynamics. Male and female Thy1-GFP-M mice (n = 5 per condition) were purchased from the Jackson Laboratory (JAX #007788) and housed in the UCSC animal care facility according to IACUC-approved protocols. In vivo transcranial two-photon imaging and data analysis were performed as previously described. Briefly, mice were anesthetized with an intraperitoneal (ip) injection of a mixture of ketamine (87 mg / kg) and xylazine (8.7 mg / kg). A small area of ​​the exposed skull was manually thinned to 20–30 μm to allow light penetration. Spines on apical dendrites of mouse primary sensory cortex were imaged using a Bruker Ultima IV two-photon microscope equipped with an Olympus water-immersion objective (40x, NA = 0.8) and a Ti:sapphire laser (Spectra-Physics Mai-Tai, 920 nm excitation wavelength). Images were taken at a magnification of 4.0x (pixel size 0.143 x 0.143 μm) and a Z-step size of 0.7 μm. Immediately after recovery from anesthesia administered before the first imaging session, mice received an i.p. injection (injection volume = 5 mL / kg) of DOI (10 mg / kg) or TBG (50 mg / kg). 24 h after drug administration, the animals were re-imaged. Dendritic spine dynamics were analyzed using ImageJ. Spine formation and elimination were quantified as a percentage of the number of spines on day 0.

[0271] Forced Swim Test (FST). Male C57 / BL6J mice (9–10 weeks old at the time of experimentation, n = 10 per condition) were obtained from the Jackson Lab and housed 4–5 mice / cage in the UCD vivarium according to an IACUC-approved protocol. After 1 week in the vivarium, each mouse was manipulated for approximately 1 min by a male experimenter over three consecutive days, leading to the first FST. All experiments were performed by the same male experimenter who performed the manipulation. During the FST, mice underwent a 6-min swim session in a 40 cm high, 20 cm diameter clear Plexiglas cylinder filled with 30 cm of water at 24 ± 1°C. Fresh water was used for all mice. After handling and acclimation to the experimenter, drug-naive mice were first subjected to a preliminary swim test to more reliably induce a depressive phenotype in subsequent FST sessions. Immobility scores for all mice were determined after pre-testing, and mice were randomly assigned to treatment groups to create groups with similar mean immobility scores for use in the two subsequent FST sessions. The following day, animals received an intraperitoneal injection of TBG (50 mg / kg), a positive control (ketamine, 3 mg / kg), or vehicle (saline). The following day, animals were subjected to the FST and then returned to their home cages. One week later, the FST was administered again to assess the sustained effects of the drugs. All FSTs were conducted between 8:00 AM and 1:00 PM for several hours. Experiments were videotaped and manually scored offline. Immobility time—defined as passive floating or maintaining a still state with no activity other than that required to keep the mouse's head above water—was scored over the last 4 minutes of the 6-minute trial.

[0272] Alcohol consumption. Male C57 / BL6J mice (6–8 weeks old) were obtained from Jackson Laboratory (Bar Harbor, ME) and individually housed in a room with a reverse light / dark cycle (lights on 10 PM–10 AM). The temperature was maintained constant at 22 ± 2°C, and the relative humidity was maintained at 50 ± 5%. Mice had free access to food and tap water. One week after acclimation to the vivarium, a two-bottle choice alcohol drinking paradigm was performed as previously described. For 7 weeks, mice had intermittent access to alcohol in their home cages. On Mondays, Wednesdays, and Fridays, two bottles—one containing 20% ​​ethanol and the other containing only water—were available 24 h a day. On Tuesdays, Thursdays, Saturdays, and Sundays, animals had access only to water. After 7 weeks, mice were administered TBG (50 mg / kg) or vehicle (saline) via intraperitoneal injection 3 h before the start of the drinking session. Ethanol (g / kg) and water (ml / kg) intake was observed for the first 4 hours (first binge drinking), the first 24 hours, and the next 24 hours. Next, when observing ethanol and water consumption, animals were given only water for 48 hours before the start of another drinking session. The bottle placement (right or left) was changed in each session to suppress placement preference. An extra bottle was used in an unused cage nearby to monitor leakage. Alcohol preference was calculated as the ratio between alcohol / (water + alcohol). Mice were tested using a counterbalanced within control design with a 1-week drug-free alcohol drinking regimen between treatments. One mouse was excluded because its bottle was leaking.

[0273] Although the foregoing invention has been described in some detail by way of illustration and example for purposes of clarity of understanding, those skilled in the art will recognize that certain changes and modifications may be practiced within the scope of the appended claims. Furthermore, each reference provided herein is incorporated by reference in its entirety to the same extent as if each reference were individually incorporated by reference. In the event of a conflict between the present application and the references provided herein, the present application shall control. The present invention may include the following aspects. [Item 1] Formula I below:

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Claims

1. The following structure: 【Chemistry 1】 or 【Chemistry 2】 {During the ceremony, R ４ is hydrogen, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, halogen, C １－６ Haloalkyl, C １－６ Alkylamines, C １－６ Alkoxy, C １－６ haloalkoxy, -OR ８ａ , -NO ２ , -CN, -C(O)R ８ｂ , -C(O)OR ８ｂ , -OC(O)R ８ｂ , -OC(O)OR ８ｂ , -N(R ８ｂ R ８ｃ ), -N(R ８ｂ ) C(O)R ８ｃ , -C(O)N(R ８ｂ R ８ｃ ), -N(R ８ｂ )C(O)OR ８ｃ , -OC(O)N(R ８ｂ R ８ｃ ), -N(R ８ｂ )C(O)N(R ８ｃ R ８ｄ ), -C(O)C(O)N(R ８ｂ R ８ｃ ), -S(O ２ ) R ８ｂ , -S(O) ２ N (R ８ｂ R ８ｃ ), C ３－８ Cycloalkyl, C ３－１４ Alkyl-cycloalkyl, C ４－１０ Heterocycloalkyl, C ４－１６ Alkyl-heterocycloalkyl, C ７－１８ Alkyl-aryl, C ５－１０ Heteroaryl, or C ４－１６ alkyl-heteroaryl; R ５ and R ７ are each independently hydrogen, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, halogen, C １－６ Haloalkyl, C １－６ Alkylamines, C １－６ Alkoxy, C １－６ haloalkoxy, -OR ８ａ , -NO ２ , -CN, -C(O)R ８ｂ , -C(O)OR ８ｂ , -OC(O)R ８ｂ , -OC(O)OR ８ｂ , -N(R ８ｂ R ８ｃ ), -N(R ８ｂ ) C(O)R ８ｃ , -C(O)N(R ８ｂ R ８ｃ ), -N(R ８ｂ )C(O)OR ８ｃ , -OC(O)N(R ８ｂ R ８ｃ ), -N(R ８ｂ )C(O)N(R ８ｃ R ８ｄ ), -C(O)C(O)N(R ８ｂ R ８ｃ ), -S(O ２ ) R ８ｂ , -S(O) ２ N (R ８ｂ R ８ｃ ), C ３－８ Cycloalkyl, C ３－１４ Alkyl-cycloalkyl, C ４－１０ Heterocycloalkyl, C ４－１６ Alkyl-heterocycloalkyl, C ６－１２ Aryl, C ７－１８ Alkyl-aryl, C ５－１０ Heteroaryl, or C ４－１６ alkyl-heteroaryl; R ６ is F, -OH, -OMe, -OiPr, -Me, -CF ３ , -OCF ３ , -NMe ２ , —NHC(O)Me, or —N(Me)C(O)Me; Or, R ４ and R ５ , R ５ and R ６ , or R ６ and R ７ are combined with the atoms to which they are attached to form C ３－６ forming a heterocycloalkyl; R ８ａ , R ８ｂ , R ８ｃ and R ８ｄ are each independently H or C １－６ is alkyl; Here, R ６ When is F, R ４ , R ５ , and R ７ wherein at least one of is not hydrogen}, or a pharmaceutically acceptable salt thereof or an isotopically labeled compound thereof.

2. In the above formula, R ４ , R ５ , and R ７ are each independently H, F, Cl, Br, —OH, —OMe, or —CF ３ , -OCF ３ , -Me, -NMe ２ , —NHC(O)Me, or —N(Me)C(O)Me; Or, R ５ and R ６ are combined to form a 1,3-dioxole ring or a 1,4-dioxane ring; 2. The compound of claim 1 or a pharmaceutically acceptable salt thereof.

3. In the above formula, R ４ H, F, -Me, -CF ３ , -OCF ３ or -OMe; R ５ is H, F, Cl, Br, -Me, -CF ３ , -OCF ３ , —OH or —OMe; R ６ F, -OH, -OMe, -OiPr, -Me, -CF ３ , -OCF ３ , -NMe ２ , —NHC(O)Me, or —N(Me)C(O)Me; Or, R ５ and R ６ are combined to form a 1,3-dioxole ring or a 1,4-dioxane ring; and R ７ is H, 2. The compound of claim 1 or a pharmaceutically acceptable salt thereof.

4. In the above formula, R ５ and R ６ are combined to form a 1,3-dioxole ring or a 1,4-dioxane ring; 2. The compound of claim 1 or a pharmaceutically acceptable salt thereof.

5. R ４ and R ５ , R ５ and R ６ , or R ６ and R ７ are combined with the atoms to which they are attached to form C ３－６ forming a heterocycloalkyl, 2. The compound of claim 1 or a pharmaceutically acceptable salt thereof.

6. The compound has the following structure: 【Transformation 3】 having 2. The compound of claim 1 or a pharmaceutically acceptable salt thereof.

7. The compound has the following structure: 【Chemistry 4】 {During the ceremony, R ５ is H, F, Cl, Br, I, -OH, -OMe, -OiPr, -Me, -CF ３ , -OCF ３ , -NMe ２ , —NHC(O)Me, or —N(Me)C(O)Me; Or, R ５ and R ６ or a pharmaceutically acceptable salt thereof, according to claim 1, wherein:

8. The compound has the following structure: 【Transformation 5】 {During the ceremony, R ５ is F, Cl, Br, I, -OH, -OMe, -OiPr, -Me, -CF ３ , -OCF ３ , -NMe ２ , —NHC(O)Me, or —N(Me)C(O)Me; Or, R ５ and R ６ are combined to form a 1,3-dioxole ring or a 1,4-dioxane ring; 2. The compound of claim 1 or a pharmaceutically acceptable salt thereof.

9. The compound has the following structure: 【Transformation 6】 {During the ceremony, R ４ is H, F, Cl, Br, I, -OH, -OMe, -OiPr, -Me, -CF ３ , -OCF ３ , -NMe ２ , —NHC(O)Me, or —N(Me)C(O)Me}; 2. The compound of claim 1 or a pharmaceutically acceptable salt thereof.

10. The compound has the following structure: 【Transformation 7】 {During the ceremony, R ４ is F, Cl, Br, I, -OH, -OMe, -OiPr, -Me, -CF ３ , -OCF ３ , -NMe ２ , —NHC(O)Me, or —N(Me)C(O)Me}; 2. The compound of claim 1 or a pharmaceutically acceptable salt thereof.

11. The compound is selected from the group consisting of: 【Transformation 8】 2. The compound of claim 1, wherein:

12. The compound is selected from the group consisting of: 【Chemistry 9】 2. The compound of claim 1, wherein:

13. The compound is selected from the group consisting of: 【Chemistry 10】 2. The compound of claim 1, wherein:

14. The compound has the following structure: 【Chemistry 11】 having 2. The compound of claim 1 or a pharmaceutically acceptable salt thereof.

15. The compound is selected from the group consisting of: 【Chemistry 12】 That is, 15. The compound of claim 14, or a pharmaceutically acceptable salt thereof.

16. The compound is selected from the group consisting of: 【Chemistry 13】 That is, 2. The compound of claim 1 or a pharmaceutically acceptable salt thereof.

17. The compound is selected from the group consisting of: 【Chemistry 14】 That is, 2. The compound of claim 1 or a pharmaceutically acceptable salt thereof.

18. The compound is selected from the group consisting of: 【Chemistry 15】 That is, 2. The compound of claim 1 or a pharmaceutically acceptable salt thereof.

19. The compound is selected from the group consisting of: 【Chemistry 16】 That is, 2. The compound of claim 1 or a pharmaceutically acceptable salt thereof.

20. The compound is selected from the group consisting of: 【Chemistry 17】 That is, 2. The compound of claim 1 or a pharmaceutically acceptable salt thereof.

21. The compound is selected from the group consisting of: [Chemistry 18] That is, 2. The compound of claim 1 or a pharmaceutically acceptable salt thereof.

22. The compound is selected from the group consisting of: 【Chemistry 19】 That is, 2. The compound of claim 1 or a pharmaceutically acceptable salt thereof.

23. The compound is selected from the group consisting of: 【Chemistry 20】 That is, 2. The compound of claim 1 or a pharmaceutically acceptable salt thereof.

24. The compound is selected from the group consisting of: 【Chemistry 21】 That is, 2. The compound of claim 1 or a pharmaceutically acceptable salt thereof.

25. The compound is selected from the group consisting of: 【Chemistry 22】 That is, 2. The compound of claim 1 or a pharmaceutically acceptable salt thereof.

26. The compound is selected from the group consisting of: 【Chemistry 23】 2. The compound of claim 1, wherein:

27. The compound is selected from the group consisting of: 【Chemistry 24】 That is, 2. The compound of claim 1 or a pharmaceutically acceptable salt thereof.

28. 28. A pharmaceutical composition comprising a compound according to any one of claims 1 to 27, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

29. 28. A pharmaceutical composition for enhancing neuroplasticity, comprising a compound according to any one of claims 1 to 27 or a pharmaceutically acceptable salt thereof in an amount sufficient to enhance neuroplasticity of a neuronal cell.

30. 28. A pharmaceutical composition for treating a brain disorder, comprising a therapeutically effective amount of a compound according to any one of claims 1 to 27, or a pharmaceutically acceptable salt thereof.

31. 31. The pharmaceutical composition of claim 30, wherein the brain disorder is a neurodegenerative disorder, Alzheimer's disease, or Parkinson's disease.

32. 31. The pharmaceutical composition of claim 30, wherein the brain disorder is a psychiatric disorder, depression, addiction, anxiety, or post-traumatic stress disorder.

33. 33. The pharmaceutical composition of claim 32, wherein the brain disorder is depression.

34. 33. The pharmaceutical composition of claim 32, wherein the brain disorder is addiction.

35. 31. The pharmaceutical composition of claim 30, wherein the brain disorder is treatment-resistant depression, suicidal ideation, major depressive disorder, bipolar disorder, or substance use disorder.

36. 31. The pharmaceutical composition of claim 30, wherein the brain disorder is schizophrenia.

37. 31. The pharmaceutical composition of claim 30, wherein the brain disorder is alcohol use disorder.

38. 31. The pharmaceutical composition of claim 30, wherein the brain disorder is stroke or traumatic brain injury.

39. Lithium, olanzapine (Zyprexa), quetiapine (Seroquel), risperidone (Risperdal), ariprazole (Abilify), ziprasidone (Geodon), clozapine (Clozaril), divalproex sodium (Depakote), lamotrigine (Lamictal), valproic acid (Depakene), carbamazepine (Equetro), topiramate (Topamax), levomilnacipran (Fetzima), duloxetine (Cymbalta, Yentreve), venlafaxine (Effexor), citalopram (Celexa), fluvoxamine (Luv) 39. The pharmaceutical composition of any one of claims 30-38, in combination with one or more additional therapeutic agents that are fluoxetine (Prozac), escitalopram (Lexapro), fluoxetine (Prozac), paroxetine (Paxil), sertraline (Zoloft), clomipramine (Anafranil), amitriptyline (Elavil), desipramine (Norpramin), imipramine (Tofranil), nortriptyline (Pamelor), phenelzine (Nardil), tranylcypromine (Parnate), diazepam (Valium), alprazolam (Xanax), or clonazepam (Klonopin).

40. 28. A pharmaceutical composition for enhancing at least one of translation, transcription, or secretion of a neurotrophic factor, comprising a compound according to any one of claims 1 to 27, or a pharmaceutically acceptable salt thereof, in an amount sufficient to enhance neuroplasticity of a neuronal cell.

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