Nitrogen-heptatriene-indole and other heterocyclic compounds used to treat brain diseases

Abstract

The present invention provides azacyclohepta-indoles and other heterocycles and methods of using the compounds to treat brain diseases.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims priority to U.S. Provisional Application No. 62 / 811,208, filed on February 27, 2019, which is incorporated herein by reference in its entirety for all purposes.

[0003] STATEMENT AS TO RIGHTS TO INVENTS MADE UNDER FEDERALLY SPONSORED RESEARCH AND DEVELOPMENT

[0004] 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 Art

[0005] The psychedelic alkaloid ibogaine has potent anti-addiction properties in clinical and animal models. Ibogaine has the potential to treat patients addicted to a variety of substances, including, for example, opioids, psychostimulants, alcohol, and nicotine. In addition, its therapeutic effects are long-lasting, which is attributed to its ability to alter addiction-related neural circuits by activating neurotrophic factor signaling. Ibogaine reduces drug withdrawal symptoms, reduces drug cravings, and prevents relapse. In rodents, ibogaine reduces drug self-administration and prevents drug-induced dopamine release in multiple brain regions. However, several safety issues have hindered the clinical development of ibogaine, including, for example, its toxicity, hallucinogenic potential, and tendency to induce arrhythmias through hERG channel inhibition.

[0006] Ibogaine increases the expression of glial cell line-derived neurotrophic factor (GDNF) in the ventral tegmental area (VTA), and intra-VTA infusions of ibogaine reduce alcohol-seeking behavior in rodents. Ibogaine affects signaling of brain-derived neurotrophic factor (BDNF) and GDNF in multiple brain regions implicated in the pathophysiology of addiction. Noribogaine, the active metabolite of ibogaine, is a potent psychoplastogen that increases the complexity of dendritic spines of cortical neurons. Other psychoplastogens, such as lysergic acid diethylamide (LSD) and dimethyl-4-hydroxytryptamine (the active metabolite of psilocybin), have clinically similar anti-addictive properties to ibogaine. 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. In addition, by altering neural circuits rather than simply blocking the targets of specific addictive substances (such as opioid receptors, nicotinic receptors, etc.), psychoplastic agents such as ibogaine have the potential to become broadly applicable anti-addiction agents.

[0007] What is needed are new compounds that lack the toxic and hallucinogenic effects of ibogaine but still retain therapeutic efficacy. Surprisingly, the present invention meets this need and others. Summary of the invention

[0008] In one embodiment, the present invention provides a compound of formula I or a pharmaceutically acceptable salt and isomer thereof:

[0009]

[0010] Where: R 1 is hydrogen or C 1-6 Alkyl; R 3a and R 3b are 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 Combined with the atoms to which they are attached, they form a group consisting of 1 to 3 R 9 C 5-8 Heterocycloalkyl, the R 9 are independently 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 Alkyl-heteroaryl, or two R attached to the same atom 9 The groups combine to form =O; or, R 2 and R 3c Combine with the atoms they are attached to form C 5-8 Cycloalkyl, which is composed of 1 to 3 R 10 Group substitution, R 10 The groups are each independently 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 Alkyl-heteroaryl, or two R attached to the same atom 10The groups combine to form =O; R 4 , R 5 , R 6 and R 7 are independently hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, C 1-6 Haloalkyl, C 1-6 Alkylamine, 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 Combine with the atoms to which they are attached to form C 3-6Cycloalkyl, C 3-6 Heterocycloalkyl, C 6-12 Aryl or C 5-10 Heteroaryl; R 8a , R 8b , R 8c and R 8d Each independently is H, C 1-6 Alkyl; when R 2 and R 3b Combined with the atoms to which they are attached, they form a C7 heterocycloalkyl group and R 3a When it is methyl, R 5 is not OMe, OH or Cl; when R 2 and R 3b Combined with the atoms to which they are attached, they form a C7 heterocycloalkyl group and R 3a When it is ethyl, R 6 Not OMe; when R 2 and R 3b Combined with the atoms to which they are attached, they form a C7 heterocycloalkyl group and R 6 When it is methyl, Cl, F or -OMe, then R 4 , R 5 and R 7 At least one of is not hydrogen; wherein when R 2 and R 3b Combined with the atoms to which they are attached, they form a C6 heterocycloalkyl group and R 6 C 1-6 Alkyl, halogen, C 1-6 When alkoxy, -C(O)H, -NH2, R 4 , R 5 and R 7 At least one of is not hydrogen; and wherein when R 2 and R 3b Combined with the atoms to which they are attached, they form a C6 heterocycloalkyl group and R 6 When it is methyl, halogen or -C(O)H, then R 4 , R 5 and R 7 At least one of them is not methyl or Cl.

[0011] In another embodiment, the present invention provides a compound, or a pharmaceutically acceptable salt thereof, wherein the compound is

[0012]

[0013] 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.

[0014] In another embodiment, the present invention provides a method of increasing neuronal plasticity, comprising contacting a neuronal cell with a compound of formula I or a pharmaceutically acceptable salt thereof:

[0015]

[0016] In an amount sufficient to increase neuronal plasticity of a neuronal cell, wherein: R 1 is hydrogen or C 1-6 Alkyl; R 3a and R 3b are 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 Combined with the atoms to which they are attached, they form a group consisting of 1 to 3 R 9 C 5-8 Heterocycloalkyl, the R 9 are independently 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 Alkyl-heteroaryl, or two R attached to the same atom 9 The groups combine to form =O; or, R 2 and R 3c Combine with the atoms they are attached to form C 5-8 Cycloalkyl, which is composed of 1 to 3 R 10 Group substitution, R 10 The groups are each independently 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 Alkyl-heteroaryl, or two R attached to the same atom 10 The groups combine to form =O; R 4 , R 5 , R 6 and R7 are independently hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, C 1-6 Haloalkyl, C 1-6 Alkylamine, 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 Combine with the atoms to which they are attached to form C 3-6 Cycloalkyl, C 3-6 Heterocycloalkyl, C 6-12 Aryl or C 5-10heteroaryl; and R 8a , R 8b , R 8c and R 8d Each independently is H, C 1-6 alkyl.

[0017] In another embodiment, the present invention provides a method of treating a brain disease, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula I:

[0018]

[0019] or a pharmaceutically acceptable salt thereof, thereby treating a brain disease, wherein: R 1 is hydrogen or C 1-6 Alkyl; R 3a and R 3b are 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 Combined with the atoms to which they are attached, they form a group consisting of 1 to 3 R 9 C 5-8 Heterocycloalkyl, R 9 The groups are each independently 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 Alkyl-heteroaryl, or two R attached to the same atom 9 The groups combine to form =O; or, R 2 and R 3c Combine with the atoms they are attached to form C 5-8 Cycloalkyl, which is composed of 1 to 3 R 10 Group substitution, R 10 The groups are each independently 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 C4-16 Alkyl-heteroaryl, or two R attached to the same atom 10 The groups combine to form =O; R 4 , R 5 , R 6 and R 7 are independently hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, C 1-6 Haloalkyl, C 1-6 Alkylamine, 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 6and R 7 Combine with the atoms to which they are attached to form C 3-6 Cycloalkyl, C 3-6 Heterocycloalkyl, C 6-12 Aryl or C 5-10 heteroaryl; and R 8a , R 8b , R 8c and R 8d Each independently is H, C 1-6 alkyl.

[0020] In another embodiment, the present invention provides a method for increasing at least one of translation, transcription or secretion of a neurotrophic factor, comprising contacting a neuronal cell with a compound of formula I or a pharmaceutically acceptable salt thereof:

[0021]

[0022] In an amount sufficient to increase neuronal plasticity of a neuronal cell, wherein: R 1 is hydrogen or C 1-6 Alkyl; R 3a and R 3b are 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 Combined with the atoms to which they are attached, they form a group consisting of 1 to 3 R 9 C 5-8 Heterocycloalkyl, R 9 The groups are each independently 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 Alkyl-heteroaryl, or two R attached to the same atom 9 The groups combine to form =O; or, R 2 and R 3c Combine with the atoms they are attached to form C 5-8 Cycloalkyl, which is composed of 1 to 3 R 10 Group substitution, R 10 The groups are each independently hydrogen, C 1-6 Alkyl, 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, or two R attached to the same atom 10 The groups combine to form =O; R 4 , R 5 , R 6 and R 7 are independently hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, C 1-6 Haloalkyl, C 1-6 Alkylamine, 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 Combine with the atoms to which they are attached to form C 3-6 Cycloalkyl, C 3-6 Heterocycloalkyl, C 6-12 Aryl or C 5-10 heteroaryl; and R 8a , R 8b , R 8c and R 8d Each independently is H, C 1-6 alkyl.

[0023] BRIEF DESCRIPTION OF THE DRAWINGS

[0024] Figure 1 A to Figure 1 B shows the function-directed synthesis of iboga analogs. Figure 1 A shows the main structural features of ibogaine and related alkaloids. The deletion of isoquinuclidine or tetrahydroazacycloheptatriene results in simplified ibogaine analogs. Figure 1 B shows the synthesis of tetrahydroazacycloheptatriene-containing ibogabine analogs.

[0025] Figure 2 A to Figure 2 K shows that tabernanthalog (TBG) is a safer analog of iboga alkaloids. Figure 2 A shows the design of ibogainalog (IBG) and TBG, which are simplified analogs of ibogaine and terpenoids, respectively. Figure 2 B shows the mouse HTR assay indicating that TBG is not hallucinogenic. The doses of IBG and TBG are indicated (mg / kg). +Ctrl = 5-MeO-DMT (10 mg / kg). Figure 2 C shows the solubility of various drugs in 0.9% saline solution. Figure 2 D shows inhibition of hERG channels expressed in HEK293 cells. Figure 2 E shows that unlike ibogaine, IBG and TBG do not induce bradycardia in zebrafish larvae. Figure 2 F shows the ratio of atrial to ventricular beats per minute (BPM). Deviations from 1 indicate an increased risk of arrhythmia. Sertindole (SI) served as a positive control. Figure 2G shows the confusion matrix for the classification of IBO, NOR, IBG and TBG (200 μM), plus VEH and lethal control. The cells show the classification ratio between the true label (Y-axis) and the predicted label (X-axis). Figure 2 H shows representative images of 2 days post fertilization (2 dpf) zebrafish treated with compounds (100 μM). Scale bar = 1 mm. Figure 2 I shows the proportion of surviving and non-surviving (deformed or dead) zebrafish after treatment with compound (100 μM). Figure 2 J shows the effect of compound treatment on malformations and mortality over time. Figure 2 K shows agonist and antagonist activity at 5-HT2A and 5-HT2B receptors measured by Gq-mediated calcium flux. Data represent percent fold response of 5-HT over baseline from at least three independent duplicate experiments. IBO = ibogaine, NOR = noribogamine.

[0026] Figure 3 A to Figure 3 I shows that TBG promotes neuroplasticity. Figure 3 A shows representative images of rat embryonic cortical neurons (DIV6) treated with TBG or VEH. Scale bar = 10 μm. Figure 3 B shows Sholl analysis of TBG and VEH treated neurons. Light shading represents 95% confidence intervals. Figure 3 C shows the maximum number of crossings (N) of the Shor diagram in b. max ), indicating that TBG increases the complexity of dendritic spines. Figure 3 D shows that the effect of TBG on dendritic growth was blocked by the 5-HT2A antagonist ketanserin (KETSN). Figure 3 E shows representative images of secondary branches of rat embryonic cortical neurons (DIV20) 24 hours after treatment with iboga analogs. Scale bar = 2 μm. Figure 3 F shows that TBG increases dendritic spine density on rat embryonic cortical neurons (DIV20) after 24 hours of treatment. KET = ketamine. Figure 3 G shows a schematic illustration of the experimental design of in vivo spine dynamics using transcranial 2-photon imaging. Figure 3 H shows representative images of the same dendritic segments from 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 3 I shows quantification of spine dynamics, demonstrating that DOI and TBG increased spine formation but had no effect on spine elimination.

[0027] Figure 4 A to Figure 4 E shows that TBG has antidepressant and anti-addictive properties. Figure 4 A shows a schematic illustration of the FST experimental design. Mice were pre-tested, dosed with compound, and then tested again 24 hours and 7 days after dosing. Figure 4 B shows quantification of immobility behavior, indicating that TBG has antidepressant-like effects. Figure 4 C shows the timeline of the alcohol abuse experiment. Bottles of 20% EtOH (white drops) and H2O (blue drops) were provided for 24 hours every 1-2 days for 7 weeks. During the drinking period, two bottles of H2O were provided. Figure 4 D shows that TBG reduced EtOH consumption and preference without affecting H2O intake during the binge drinking period. Figure 4 E shows that TBG administration resulted in a long-term decrease in EtOH consumption.

[0028] Figure 5 A to Figure 5 B shows the effect of iboga analogs on dendrite formation. Figure 5 A shows representative images of rat embryonic cortical neurons (DIV6) treated with compounds. Scale bar = 10 μm. Figure 5 B shows the maximum number of intersections (N) of the Short diagram. max ), indicating that tetrahydroazacycloheptatriene-containing ibocinolone analogs are more effective than isoquinuclidine-containing ibocinolone analogs in increasing dendritic spine (arbor) complexity.

[0029] Figure 6 Several iboga analogs are shown to promote dendrite formation. Shor analysis (circle radius = 1.34 μm increments) shows that cultured cortical neurons treated with several iboga analogs have more complex dendritic spines compared to vehicle controls (n = 52-83 neurons per treatment). The shaded area around each line represents the 95% confidence interval. The control compound, isoquinuclidine, and tetrahydroazacycloheptatriene are represented in blue, purple, and red, respectively.

[0030] Figure 7It was shown that ibogaine hydrochloride exhibits limited solubility in various salt-based carriers. Saline (0.9%) solutions containing varying percentages of co-solvents / additives were added to finely divided ibogaine hydrochloride. All attempts to improve its solubility by pulverization, sonication, and mild heating (<50°C) were unsuccessful. Furthermore, the addition of co-solvents (ethanol, dimethyl sulfoxide, glycerol), surfactants (Poloxamers Kolliphor), or hydrotropes (ATP) to the carrier did not substantially improve its solubility. The purity and identity of the ibogaine hydrochloride used in these studies was confirmed by a combination of NMR, LC-MS, and X-ray crystallography experiments.

[0031] Figure 8 A heat map representing the motor activity of zebrafish larvae aggregated in each well compared to vehicle controls (pseudo Z scores) is shown. Red and blue indicate activity above and below the vehicle control mean, respectively, while white indicates activity within ±1SD of the control. The stimulus applied over time is shown below the heat map. The colors represent the bright LED lights of the respective colors, the black trace represents the waveform of the acoustic stimulus, and the gray vertical lines represent the physical tapping as a secondary sound stimulus.

[0032] Fig. 9 It was shown that increasing concentrations of IBG and TBG did not produce a motor response in zebrafish larvae similar to that of a lethal concentration (100 μM) of eugenol. Concentration-response curves for compounds subjected to a range of stimuli are shown in Figure 1. Figure 8 Response is inversely proportional to classification accuracy; 0-20% indicates no ability and 100% indicates perfect classification. Lower percentages indicate that the treatment was more often classified as vehicle (blue) or lethal (red). Solid lines represent medians and shading represents 95% confidence intervals calculated by bootstrap. N=8 wells / condition (64 animals / condition).

[0033] Fig.10 TBG is shown not to induce seizures in zebrafish larvae. Transgenic zebrafish larvae expressing GCaMP5G were fixed in agarose, treated with compounds, and imaged over time. PTZ, a known seizure-inducing compound, served as a positive control. All compounds were treated at 200 μM (n=2 per condition).

[0034] Fig.11 A and Fig.11 B shows that TBG (66 μM) does not cause developmental toxicity in zebrafish. Fig.11A shows the proportion of surviving and non-surviving (deformed + dead) zebrafish treated with VEH and TBG (66 μM) at 5 days post fertilization (dpf) (Fisher's exact test: p=0.3864). Fig.11 B shows representative images of zebrafish treated with VEH and TBG (66 μM) at 2 and 5 days post fertilization. Scale bar = 2 mm.

[0035] Fig.12 Concentration-response curves are shown to demonstrate the ability of iboga analogs and related compounds to activate 5-HT and opioid receptors. All compounds were assayed in parallel using the same drug dilutions. The figures reflect representative concentration-response curves, which plot the mean and standard error SEM of data points tested in duplicate or triplicate. Assay details are described in the methods.

[0036] Fig.13 Pharmacological analysis of iboga analogs and related compounds is shown. The table shows the EC of at least two independent concentration-response curves tested in duplicate or triplicate. 50 and Emax estimate. Log(Emax / EC 50 ) activity is included as an estimate of the system's agonist activity; Inactive = no activity in agonist mode; ND = uncertain; blue boxes = exhibit antagonist activity; dark grey boxes = inactive in agonist mode but not tested in antagonist mode; orange boxes indicate inverse agonists.

[0037] Fig.14 Screening of DMT derivatives and iboga analogs shows differences in 5-HT receptor analysis results. iboga analogs are more selective for 5-HT than 5-MeO-DMT 2A Agonist.

[0038] Fig.15 The effects of psychedelic and non-psychedelic compounds on 5HT in agonist mode are shown. 2A Dose response plots of sensor assays.

[0039] Fig.16 The effects of hallucinogenic and non-hallucinogenic compounds on 5HT in agonist mode are shown. 2A Response graph of the sensor measurement.

[0040] Fig.17 It shows that 5HT, 6-MeO-DMT ( Fig.17 A) and lisuride ( Fig.17 B) 5HT in antagonist mode 2A Dose response plots of sensor assays.

[0041] Fig.18 The effects of both hallucinogenic and non-hallucinogenic compounds on 5HT in antagonist mode are shown. 2A Response graph of the sensor measurement. DETAILED DESCRIPTION OF THE INVENTION

[0043] I. Overview

[0044] Ibogaine has attracted attention as a potential anti-addiction agent that promotes plasticity; a single dose of this psychedelic compound has shown sustained efficacy in treating addiction to alcohol, opioids, nicotine, and psychostimulants. An ibogaine analog has been developed that is able to enhance fibroblast growth factor 2 (FGF2)-induced GDNF release in C6 glioma cells; however, the effects of this compound on neuroplasticity are unclear.

[0045] Ibogaine is highly plasticity-promoting. However, the hallucinogenic effects of ibogaine have posed a barrier to regulatory approval and severely limited its therapeutic potential. The hallucinogenic effects of a drug can be separated from its ability to promote neuroplasticity. The compounds described herein, which lack the isoquinuclidine ring of ibogaine and transpose the methoxy group from the 5-position to the 6-position of the indole, are non-hallucinogenic ibogaine derivatives that, for example, promote neuronal growth.

[0046] Compounds that can alter neural circuits that control motivation, anxiety, and drug-seeking behavior have the potential to treat depression, post-traumatic stress disorder (PTSD), and substance use disorders (SUD). In some cases, such psychoplastic drugs produce sustained therapeutic effects because these drugs treat the underlying pathological changes in the circuits. Psychedelic compounds stand out in this regard because, for example, they promote structural and functional neuroplasticity in key circuits, elicit therapeutic responses in a variety of neuropsychiatric disorders, and produce beneficial effects that last for months after a single dose.

[0047] Described herein are water-soluble, non-psychedelic analogs of ibogaine. Despite lacking psychedelic properties, the compounds described herein promote structural neuroplasticity, reduce alcohol consumption, and produce antidepressant-like effects in mice.

[0048] In some cases, the hallucinogenic 5-HT 2A Agonists (e.g., DMT, LSD, DOI, etc.) can be used to treat neurological diseases, such as neuropsychiatric disorders (Ly et al., 2018). However, the hallucinogenicity and dissociative potential of such compounds limit the use of these compounds in clinical practice. 2A Antagonists eliminate the 5-HT 2AThe neuritogenic and dendritic spinogenesis effects of psychedelic compounds with agonist activity (e.g., DMT, LSD, and DOI) suggest that 5-HT 2A Correlation between agonism and promotion of neural plasticity (Ly et al., 2018; Dunlap et al., 2020).

[0049] In some embodiments, provided herein are non-hallucinogenic psychoplastic agents. In some embodiments, described herein are non-hallucinogenic ibogaine analogs having improved physicochemical properties, for example, because of a reduction in total polar surface area. In some embodiments, described herein are non-hallucinogenic ibogaine analogs having improved physicochemical properties, for example, because of a reduction in total polar surface area. 2A In some embodiments, the non-hallucinogenic compounds described herein provide therapeutic potential similar to that of 5-HT agonists. 2A Better therapeutic potential of modulators.

[0050] The present invention provides azepino-indole and other heterocyclic non-psychedelic compounds that can be used to treat a variety of brain diseases and other disorders, as well as to increase neuronal plasticity, or to increase at least one of the translation, transcription or secretion of neurotrophic factors.

[0051] II. Definitions

[0052] Unless otherwise specifically indicated, all technical and scientific terms used herein have the same meaning as those generally understood by those of ordinary skill in the art to which the invention belongs. In addition, any method or material similar or identical to the method or material described herein can be used in the practice of the present invention. For purposes of the present invention, the following terms are defined.

[0053] "A," "an," or "the" include not only aspects having one member, but also aspects having multiple members. 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 and reference to "the agent" includes reference to one or more agents known to those skilled in the art, and so forth.

[0054] Abbreviations. VEH = vehicle; KET = ketamine; IBO = ibogaine; NOR = noribogaine; IBG = ibogaine analog; TBG = terpenoid analog; KETSN = ketanserin; SI = sertindole; DOI = 2,5-dimethoxy-4-iodoamphetamine; FST = forced swim test; EtOH = ethanol, DMSO = dimethyl sulfoxide, ATP = adenosine triphosphate.

[0055] "Alkyl" refers to a straight or branched chain saturated aliphatic group having a specified number of carbon atoms. Alkyl groups may include any number of carbon atoms, such as C 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 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 may also refer to an alkyl group having up to 20 carbon atoms, such as, but not limited to, heptyl, octyl, nonyl, decyl, etc. Alkyl may be substituted or unsubstituted.

[0056] "Alkylene" refers to a straight or branched chain saturated aliphatic group having a specified number of carbon atoms and connecting at least two other groups, i.e., a divalent hydrocarbon group. The two groups connected to the alkylene group can be connected to the same or different atoms on the alkylene group. For example, a straight chain alkylene group can be -(CH2) n -divalent radical, wherein n is 1, 2, 3, 4, 5 or 6. Representative alkylene groups include, but are not limited to, methylene, ethylene, propylene, isopropylene, butylene, isobutylene, sec-butylene, pentylene and hexylene. The alkylene group may be substituted or unsubstituted.

[0057] "Alkenyl" refers to a straight or branched chain hydrocarbon having at least 2 carbon atoms and at least one double bond. Alkenyl groups may include any number of carbon atoms, such as C2, 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 5-6and C6. The alkenyl group may have any suitable number of double bonds, including but not limited to 1, 2, 3, 4, 5 or more. Examples of alkenyl include but are not limited to vinyl (vinyl), 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. The alkenyl group may be substituted or unsubstituted.

[0058] "Alkynyl" refers to a straight or branched chain hydrocarbon having at least 2 carbon atoms and at least one triple bond. Alkynyl groups may include any number of carbon atoms, such as C2, 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 Examples of propynyl groups include, but are not limited to, ethynyl, propynyl, 1-butynyl, 2-butynyl, butadiynyl, 1-pentynyl, 2-pentynyl, isopentenyl, 1,3-pentadiynyl, 1,4-pentadiynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 1,3-hexadiynyl, 1,4-hexadiynyl, 1,5-hexadiynyl, 2,4-hexadiynyl, or 1,3,5-hexatriynyl. Alkynyl groups may be substituted or unsubstituted.

[0059] "Cycloalkyl" refers to a saturated or partially unsaturated monocyclic, bicyclic, fused bicyclic or bridged polycyclic ring assembly containing 3 to 12 ring atoms or the number of atoms specified. Cycloalkyl may include any number of carbon atoms, such as C 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 3-12. Saturated monocyclic cycloalkyl rings include, for example, 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, decalin, and adamantane. Cycloalkyl groups may also be partially unsaturated, having one or more double or triple bonds in 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. When the cycloalkyl group is a saturated monocyclic C 3-8 When cycloalkyl is a saturated monocyclic C 3-6 When cycloalkyl, exemplary groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. The cycloalkyl group may be substituted or unsubstituted.

[0060] "Alkyl-cycloalkyl" refers to a group having an alkyl component and a cycloalkyl component, wherein the alkyl component connects the cycloalkyl component to the point of attachment. The alkyl component is as defined above, except that the alkyl component is at least a divalent, alkylene group, connected to the cycloalkyl component and to the point of attachment. In some cases, the alkyl component may not be present. The alkyl component may include any number of carbon atoms, such as 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 , C 3-4 , C 3-5 , C 3-6 , C 4-5 , C 4-6 and C 5-6 The cycloalkyl component is as defined herein. Exemplary alkyl-cycloalkyl groups include, but are not limited to, methyl-cyclopropyl, methyl-cyclobutyl, methyl-cyclopentyl, and methyl-cyclohexyl.

[0061] "Heterocycloalkyl" refers to a cycloalkyl as defined above having 3 to 12 ring members and 1 to 4 heteroatoms of N, O and S. Heterocycloalkyl includes bicyclic compounds containing heteroatoms. Bicyclic compounds include spirocyclic compounds, fused bicyclic compounds and bridged bicyclic compounds. The heteroatoms can also be oxidized, such as but not limited to -S(O)- and -S(O)2-. Heterocycloalkyl can include 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 the heterocycloalkyl, 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 can include groups such as aziridine, azetidine, pyrrolidine, piperidine, azepan, azocane, quinuclidine, pyrazolidine, imidazolidine, piperazine (1,2-, 1,3- and 1,4-isomers), oxirane, oxetane, tetrahydrofuran, oxane (tetrahydropyran), oxepane, thiirane, thietane, thiolane (tetrahydrothiophene), thiacyclohexane (tetrahydrothiopyran), oxazolidine, isoxazolidine, thiazolidine, isothiazolidine, dioxolane, dithiolane, morpholine, thiomorpholine, dioxane or dithiane. Heterocycloalkyl can also be fused with aromatic or non-aromatic ring systems to form members including but not limited to dihydroindole. Heterocycloalkyl can be unsubstituted or substituted. For example, heterocycloalkyl can be C 1-6 The group may be substituted with alkyl or oxo (=O).

[0062] "Alkyl-heterocycloalkyl" refers to a group having an alkyl component and a heterocycloalkyl component, wherein the alkyl component connects the heterocycloalkyl component to the point of attachment. The alkyl component is as defined above, except that the alkyl component is at least divalent, an alkylene group, connected to the heterocycloalkyl component and to the point of attachment. The alkyl component may include any number of carbon atoms, such as 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 In some cases, the alkyl component may be absent. The heterocycloalkyl component is as defined above. The alkyl-heterocycloalkyl group may be substituted or unsubstituted.

[0063] "Halogen" refers to fluorine, chlorine, bromine and iodine.

[0064] "Haloalkyl" refers to an alkyl group as defined above in which some or all of the hydrogen atoms are replaced by halogen atoms. As with alkyl, haloalkyl may have any suitable number of carbon atoms, for example C 1-6 For example, haloalkyl includes trifluoromethyl, fluoromethyl, etc. In some cases, the term "perfluoro" can be used to define a compound or group in which all hydrogens are replaced by fluorine. For example, perfluoromethyl refers to 1,1,1-trifluoromethyl.

[0065] "Alkoxy" refers to an alkyl group with an oxygen atom connecting the alkyl group to the point of attachment: alkyl-O-. As with the alkyl group, the alkoxy group can have any suitable number of carbon atoms, such as C 1-6 Alkoxy groups include, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, 2-butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, hexyloxy, and the like. Alkoxy groups may be further substituted with various substituents described herein. Alkoxy groups may be substituted or unsubstituted.

[0066] "Haloalkoxy" refers to an alkoxy group in which some or all of the hydrogen atoms are replaced by halogen atoms. As with alkyl, haloalkoxy can have any suitable number of carbon atoms, for example, C 1-6 The alkoxy group may be substituted with 1, 2, 3 or more halogens. When all hydrogens are substituted with halogens, such as fluorine, the compound is fully substituted, such as perfluorinated. Haloalkoxy groups include, but are not limited to, trifluoromethoxy, 2,2,2-trifluoroethoxy, perfluoroethoxy, and the like.

[0067] "Amine" refers to a -N(R)2 group, where the R groups can be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, etc. The R groups can be the same or different. The amino group can be a primary amino group (each R is hydrogen), a secondary amino group (one R is hydrogen), or a tertiary amino group (each R is not hydrogen).

[0068] "Alkylamine" refers to an alkyl group as defined herein having one or more amino groups. The amino group may be a primary amino group, a secondary amino group, or a tertiary amino group. The alkylamine may be further substituted with a hydroxyl group to form an amino-hydroxyl 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 ω position of the alkyl group to connect the alkylamine to the point of attachment of the rest of the compound, or to connect at least two carbon atoms of the alkyl group together. One skilled in the art will appreciate that other alkylamines may be useful in the present invention.

[0069] "Aryl" refers to an aromatic ring system having any suitable number of ring atoms and any suitable number of rings. Aryl can include 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 can be monocyclic, fused to form a bicyclic or tricyclic group, or connected by a bond to form a diaryl group. Representative aryl includes phenyl, naphthyl and biphenyl. Other aryl includes benzyl, with a methylene linker. Some aryl has 6 to 12 ring members, such as phenyl, naphthyl or biphenyl. Other aryl has 6 to 10 ring members, such as phenyl or naphthyl. Some other aryl has 6 ring members, such as phenyl. Aryl can be substituted or unsubstituted.

[0070] "Alkyl-aryl" refers to a group having an alkyl component and an aryl component, wherein the alkyl component connects the aryl component to the point of attachment. The alkyl component is as defined above, except that the alkyl component is at least divalent, an alkylene group, connected to the aryl component and to the point of attachment. The alkyl component may include any number of carbon atoms, such as 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 In some cases, the alkyl component may not be present. The aryl component is as defined above. Examples of alkyl-aryl groups include, but are not limited to, benzyl and ethyl-benzene. Alkyl-aryl groups may be substituted or unsubstituted.

[0071] "Heteroaryl" refers to a monocyclic or fused bicyclic or tricyclic aromatic ring assembly containing 5 to 16 ring atoms, of which 1 to 5 ring atoms are heteroatoms, such as N, O or S. Heteroaryl groups can include 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 the 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. Heteroaryl groups 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 can 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 can also be fused to an aromatic ring system, such as a benzene ring, to form members including but not limited to benzopyrroles such as indole and isoindole, benzopyridines such as quinoline and isoquinoline, benzopyrazines (quinoxalines), benzopyrimidines (quinazolines), benzopyridazines such as phthalazine and cinnoline, benzothiophene and benzofurans. Other heteroaryl groups include heteroaryl rings connected by bonds, such as bipyridine. Heteroaryl can be substituted or unsubstituted.

[0072] "Alkyl-heteroaryl" refers to a group having an alkyl component and a heteroaryl component, wherein the alkyl component connects the heteroaryl component to the point of attachment. The alkyl component is as defined above, except that the alkyl component is at least divalent, an alkylene group, connected to the heteroaryl component and to the point of attachment. The alkyl component may include any number of carbon atoms, such as 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 In some cases, the alkyl component may be absent. The heteroaryl component is as defined herein. The alkyl-heteroaryl group may be substituted or unsubstituted.

[0073] "Salt" refers to an acid or base salt of a compound used in the methods of the present invention. Illustrative examples of pharmaceutically acceptable salts are inorganic acid (hydrochloric acid, hydrobromic acid, phosphoric acid, etc.) salts, organic acid (fumaric acid, acetic acid, propionic acid, glutamic acid, citric acid, etc.) salts, quaternary ammonium (methyl iodide, ethyl iodide, etc.) salts. It should be understood that pharmaceutically acceptable salts are non-toxic. Additional information about suitable pharmaceutically acceptable salts can be found in Remington's Pharmaceutical Sciences, 17th edition, Mack Publishing Company, Easton, Pennsylvania, 1985, which is incorporated herein by reference.

[0074] The neutral forms of the compounds can be regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner. The parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents, but in other respects, these salts are equivalent to the parent form of the compound for the purposes of the present invention.

[0075] "Pharmaceutically acceptable salt" refers to a compound in the form of a salt, wherein the compound is suitable for administration to a subject. Representative pharmaceutically acceptable salts include acetate, ascorbate, benzenesulfonate, benzoate, camphorsulfonate, citrate, ethanesulfonate, edisylate, fumarate, gentisate, gluconate, glucuronate, glutamate, hippurate, hydrobromide, hydrochloride, isethionate, lactate, lactobionate, maleate, malate, mandelate, methanesulfonate, mucate, naphthenate, naphthalene-1,5-disulfonate, naphthalene-2,6-disulfonate, nicotinate, nitrate, orotate, pamoate, pantothenate, phosphate, succinate, sulfate, tartrate, p-toluenesulfonate, and xinafoic acid salts, etc.

[0076] "Pharmaceutically acceptable excipient" refers to a substance that helps the active ingredient to be administered to a subject and absorbed by the subject. Pharmaceutical excipients that can be used in the present invention include, but are not limited to, binders, fillers, disintegrants, lubricants, coatings, sweeteners, flavoring agents, and pigments. Those skilled in the art will recognize that other pharmaceutical excipients can be used in the present invention.

[0077] "Composition" refers to a product comprising the specified ingredients in the specified amounts, as well as any product that results, directly or indirectly, from combination of 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.

[0078] "Isomers" refer to compounds that have the same chemical formula but different ways of connecting the atoms in the molecule, resulting in different chemical structures. Isomers include structural isomers and stereoisomers. Examples of structural isomers include, but are not limited to, tautomers and regioisomers. Examples of stereoisomers include, but are not limited to, diastereomers and enantiomers.

[0079] "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, such as a mini-osmotic pump, to a subject.

[0080] "Subject" refers to an animal, such as a mammal, 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.

[0081] "Therapeutically effective amount" or "therapeutically sufficient amount" or "effective amount or sufficient amount" refers to the dosage administered that produces a therapeutic effect. The exact dosage will depend on the purpose of the treatment and will be determined by one skilled in the art using known techniques (see, e.g., Lieberman, Pharmaceutical Dosage Forms (Volumes 1-3, 1992); Lloyd, The Art, Science and Technology of Drug Synthesis (1999); Pica, Dose Calculation (1999); and Remington: The Science and Practice of Pharmacy, 20th ed., Gennaro, Lippincott, Williams & Wilkins Publishers). In sensitized cells, the therapeutically effective dose is generally lower than the conventional therapeutically effective dose for non-sensitized cells.

[0082] "Neuronal plasticity" refers to the ability of the brain to continually change its structure and / or function throughout a subject's life. Examples of brain changes include, but are not limited to, the ability to adapt or respond to internal and / or external stimuli (e.g., due to injury), and the ability to generate new neurites, dendritic spines, and synapses.

[0083] “Brain disease” refers to a neurological disorder that affects brain structure and function. Brain diseases may include, but are not limited to, Alzheimer’s disease, Parkinson’s disease, psychological disorders, depression, treatment-resistant depression, addiction, anxiety disorders, post-traumatic stress disorder, suicidal ideation, major depressive disorder, bipolar disorder, schizophrenia, stroke, traumatic brain injury, and substance use disorder.

[0084] "Combination therapy" refers to a method of treating a disease or condition in which two or more different agents are administered in an overlapping regimen so that the subject is exposed to both agents simultaneously. For example, the compounds of the invention can be used in combination with other pharmaceutically active compounds. The compounds of the invention can be administered simultaneously with other drug therapies (as a single formulation or separate formulations) or sequentially. In general, combination therapy envisions the administration of two or more drugs during a single treatment cycle or course of treatment.

[0085] "Neurotrophins" refers to a family of soluble peptides or proteins that support the survival, growth, and differentiation of developing and mature neurons.

[0086] "Regulate" or "modulate" or "regulate" refers to an increase or decrease in the quantity, quality or effect of a particular activity, function or molecule. By way of illustration and not limitation, G protein-coupled receptors (e.g., 5HT 2A ) are modulators of receptors.

[0087] "Agonism" refers to the activation of a receptor or enzyme by a modulator or agonist to produce a biological response.

[0088] "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 term "agonist" can be used to refer to an agent that is agonist relative to 5HT 2A Activity showed an EC of no more than about 100 μM 50 In some embodiments, "agonist" includes a full agonist or a partial agonist. "Full agonist" refers to a modulator that binds to and activates a receptor with the maximum response that an agonist can elicit on the receptor. "Partial agonist" refers to a modulator that binds to and activates a given receptor, but has a partial effect on the receptor relative to a full agonist, i.e., less than the maximum response.

[0089] A "positive allosteric modulator" refers to a modulator that binds to a site different from the orthosteric binding site and enhances or amplifies the effects of an agonist.

[0090] "Antagonism" refers to the inactivation of a receptor or enzyme by a modulator or antagonist. For example, antagonism of a receptor occurs when a molecule binds to the receptor and does not allow activity to occur.

[0091] "Antagonist" or "neutral antagonist" refers to a modulator that binds to a receptor or enzyme and blocks a biological response. Antagonists have no activity in the absence of an agonist or inverse agonist, but can block the activity of either without causing a change in the biological response.

[0092] “IC 50 ” refers to the concentration of a substance (e.g., a compound or drug) required to inhibit a biological process by 50%. For example, IC 50 Refers to the half-maximal (50%) inhibitory concentration (IC) of a substance as determined in an appropriate assay. In some cases, IC 50 In some embodiments as used herein, IC 50 refers to receptors such as 5HT 2A The concentration of a modulator (eg, antagonist or inhibitor) required to achieve 50% inhibition.

[0093] III. Compounds

[0094] The present invention provides azacyclohepta-indole and other heterocyclic non-hallucinogenic compounds (e.g., Formula (I) or Formula (Ia)) for use in treating a variety of brain diseases and other conditions. In some embodiments, the azacyclohepta-indole and other heterocyclic compounds provided herein are 5-HT 2A modulators and promotes neural plasticity (e.g., cortical structural plasticity).

[0095] In some embodiments, the present invention provides a compound of formula I or a pharmaceutically acceptable salt and isomer thereof:

[0096]

[0097] Where: R 1 is hydrogen or C 1-6 Alkyl; R 3a and R 3b are 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 Combined with the atoms to which they are attached, they form a group consisting of 1 to 3 R 9 C 5-8 Heterocycloalkyl, the R 9 are independently 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 Alkyl-heteroaryl, or two R attached to the same atom 9 The groups combine to form =O; or, R 2 and R 3c Combine with the atoms they are attached to form C 5-8 Cycloalkyl, which is composed of 1 to 3 R 10 Group substitution, R 10 The groups are each independently 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 5-10Heteroaryl or C 4-16 Alkyl-heteroaryl, or two R attached to the same atom 10 The groups combine to form =O; R 4 , R 5 , R 6 and R 7 are independently hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, C 1-6 Haloalkyl, C 1-6 Alkylamine, 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 R6 and R 7 Combine with the atoms to which they are attached to form C 3-6 Cycloalkyl, C 3-6 Heterocycloalkyl, C 6-12 Aryl or C 5-10 Heteroaryl; R 8a , R 8b , R 8c and R 8d Each independently is H, C 1-6 Alkyl; wherein, when R 2 and R 3b Combined with the atoms to which they are attached, they form a C7 heterocycloalkyl group, and R 3a When it is methyl, R 5 is not OMe, OH or Cl; wherein, when R 2 and R 3b Combined with the atoms to which they are attached, they form a C7 heterocycloalkyl group, and R 3a When it is ethyl, R 6 Not OMe; when R 2 and R 3b Combined with the atoms to which they are attached, they form a C7 heterocycloalkyl group, and R 6 When F, R 4 , R 5 and R 7 At least one of is not hydrogen; wherein, when R 2 and R 3b Combined with the atoms to which they are attached, they form a C7 heterocycloalkyl group, and R 6 When it is F, Cl, -Me or -OMe, then R 3a is -Me; among them, when R 2 and R 3b Combined with the atoms to which they are attached to form a C6 heterocycloalkyl group, R 6 C 1-6 Alkyl, halogen, C 1-6 When alkoxy, -C(O)H, -NH2, R 4 , R 5 and R 7 At least one of is not hydrogen; and wherein, when R 2 and R 3b Combined with the atoms to which they are attached, they form a C6 heterocycloalkyl group, and R 6 When it is methyl, halogen or -C(O)H, then R 4 , R 5 and R 7 At least one of them is not methyl or Cl.

[0098] In some embodiments, the present invention provides a compound of formula I or a pharmaceutically acceptable salt and isomer thereof:

[0099]

[0100] Where R 1 is hydrogen or C 1-6 Alkyl; R 3a and R 3b are 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 Combined with the atoms to which they are attached, they form a group consisting of 1 to 3 R 9 C 5-8 Heterocycloalkyl, the R 9 are independently 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 Alkyl-heteroaryl, or two R attached to the same atom 9 The groups combine to form =O; or, R 2 and R 3b Combine with the atoms they are attached to form C 5-8 Cycloalkyl, which is composed of 1 to 3 R 10 Group substitution, R 10 The groups are each independently 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 Alkyl-heteroaryl, or two R attached to the same atom 10 The groups combine to form =O; R 4 , R 5 , R 6 and R 7 are independently hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, C 1-6Haloalkyl, C 1-6 Alkylamine, 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 them is not H; R 8b , R 8c and R 8d Each independently is H, C 1-6 alkyl.

[0101] In some embodiments, R 1 is hydrogen or C 1-6 In some embodiments, R 1 is hydrogen, methyl, ethyl or propyl. 1 is hydrogen or methyl. 1 is hydrogen. In some embodiments, R 1In some embodiments, the present invention provides a compound or a pharmaceutically acceptable salt thereof, wherein R 1 In some embodiments, the present invention provides a compound or a pharmaceutically acceptable salt thereof, wherein R 1 It's hydrogen.

[0102] In some embodiments, R 3a It 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. 3a is hydrogen or methyl. 3a In some embodiments, R 3a In some embodiments, the present invention provides a compound or a pharmaceutically acceptable salt thereof, wherein R 3a is hydrogen or C 1-6 In some embodiments, the present invention provides a compound or a pharmaceutically acceptable salt thereof, wherein R 3a is hydrogen or methyl.

[0103] In some embodiments, R 4 , R 5 , R 6 and R 7 are independently hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, C 1-6 Haloalkyl, C 1-6 Alkylamine, 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 8bR 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 Combine with the atoms to which they are attached to form C 3-6 Cycloalkyl, C 3-6 Heterocycloalkyl, C 6-12 Aryl or C 5-10 heteroaryl; and R 8a , R 8b , R 8c and R 8d Each independently is H, C 1-6 alkyl.

[0104] In some embodiments, the present invention provides a compound or a pharmaceutically acceptable salt thereof, wherein: R 4 , R 5 , R 6 and R 7 are 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 ), C3-8 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 Combine with the atoms to which they are attached to form C 3-6 heterocycloalkyl; and R 8a , R 8b or R 8c Each independently is H, C 1-6 Alkyl, or C 3-6 Cycloalkyl.

[0105] In some embodiments, the present invention provides a compound or a pharmaceutically acceptable salt thereof, wherein R 6 It is 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; or, R 5 and R 6 Combine with the atoms to which they are attached to form C 3-6 heterocycloalkyl; and R 8a , R 8b and R 8c Each independently is H, C 1-6 Alkyl or C 3-6 Cycloalkyl.

[0106] In some embodiments, the present invention provides a compound or a pharmaceutically acceptable salt thereof, wherein R 4 , R 5 , R 6 and R 7are 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 6 Combine with the atoms to which they are attached to form C 3-6 heterocycloalkyl; and R 8a , R 8b and R 8c Each independently is H, C 1-6 Alkyl or C 3-6 Cycloalkyl.

[0107] In some embodiments, the present invention provides a compound or a pharmaceutically acceptable salt thereof, wherein: R 6 It 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 Combine with the atoms to which they are attached to form C 3-6 heterocycloalkyl; and R 8a , R 8b and R 8c Each independently is H, C 1-6 Alkyl or C 3-6 Cycloalkyl.

[0108] In some embodiments, the present invention provides a compound or a pharmaceutically acceptable salt thereof, wherein: R 4 , R 5 , R 6 and R 7 are independently hydrogen, C1-6 Alkyl, halogen, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, –OR 8a 、-N(R 8b R 8c ), or -N(R 8b )C(O)R 8c , where R 4 , R 5 , R 6 and R 7 At least one of them is not H; R 8a is H; and R 8b and R 8c are each independently H or -Me; or, R 5 and R 6 Combine with the atoms to which they are attached to form C 3-6 Heterocycloalkyl.

[0109] In some embodiments, the present invention provides a compound wherein R 4 , R 5 , R 6 and R 7 are 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 is not H; and R 8a is H; or, R 5 and R 6 Combine with the atoms to which they are attached to form C 3-6 Heterocycloalkyl.

[0110] In some embodiments, the present invention provides a compound or a pharmaceutically acceptable salt thereof, wherein: R 4 , R 5 , R 6 and R 7 Each independently represents H, F, Cl, Br, -OH, -OMe, -CF3, -OCF3, -Me, -NMe2, -NHC(O)Me or -N(Me)C(O)Me, wherein R 4 , R 5 , R 6 and R 7 At least one of is not H; or, R 5 and R6 Combine to form 1,3-dioxole ring or 1,4-dioxane ring.

[0111] In some embodiments, the present invention provides a compound or a pharmaceutically acceptable salt thereof, wherein: R 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 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 At least one of them is not H.

[0112] In some embodiments, the present invention provides a compound wherein R 4 , R 5 , R 6 and R 7 Each independently represents H, F, Cl, Br, -OH, -OMe, -CF3 or -OCF3, wherein R 4 , R 5 , R 6 and R 7 At least one of is not H; or, R 5 and R 6 Combine to form a 1,3-dioxole ring.

[0113] In some embodiments, the present invention provides a compound wherein R 4 is H, F or -OMe; R 5 is H, F, Cl, Br, -OH or -OMe; R 6 is H, F, -OMe, -CF3 or -OCF3; or, R 5 and R 6 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 them is not H.

[0114] In some embodiments, the present invention provides a compound or a pharmaceutically acceptable salt thereof, wherein R 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 Combine to form 1,3-dioxole ring or 1,4-dioxane ring.

[0115] In some embodiments, R 4 and R 5 , R 5 and R 6 , or R 6 and R 7 Combine with the atoms to which they are attached to form C 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 Combine with the atoms to which they are attached to form C 3-6 Cycloalkyl or C 3-6 In some embodiments, R 4 and R 5 Combine with the atoms to which they are attached to form C 3-6 In some embodiments, R 5 and R 6 Combine with the atoms to which they are attached to form C 3-6 In some embodiments, R 6 and R 7 Combine with the atoms to which they are attached to form C 3-6 In some embodiments, R 5 and R 6 Combine to form 1,3-dioxole ring or 1,4-dioxane ring.

[0116] In some embodiments, R 3a and R 3b are independently hydrogen, C 1-6 Alkyl, C 3-8 Cycloalkyl or C 4-14 Alkyl-cycloalkyl; or, R 2 and R 3b Combined with the atoms to which they are attached, they form a group consisting of 1 to 3 R 9 C5-8 Heterocycloalkyl, where R 9 are independently 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 Alkyl-heteroaryl, or two R attached to the same atom 9 The groups combine to form =O; or, R 2 and R 3c Combine with the atoms they are attached to form C 5-8 Cycloalkyl, which is composed of 1 to 3 R 10 Group substitution, R 10 The groups are each independently 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 Alkyl-heteroaryl, or two R attached to the same atom 10 The groups combine to form =0.

[0117] In some embodiments, the present invention provides a compound of the present invention or a pharmaceutically acceptable salt thereof, wherein R 2 and R 3b Combined with the atoms to which they are attached, they form a group consisting of 1 to 3 R 9 C 5-8 Heterocycloalkyl, where R 9 are independently 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 Alkyl-heteroaryl, or two R attached to the same atom 9 In some embodiments, the present invention provides a compound or a pharmaceutically acceptable salt thereof, wherein R 2 and R3b Combine with the atoms they are attached to form C 5-8 In some embodiments, the present invention provides a compound or a pharmaceutically acceptable salt thereof, wherein R 2 and R 3b Combine with the atoms they are attached to form C 7-8 Heterocycloalkyl.

[0118] 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:

[0119]

[0120] Where: R 6 C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, C 1-6 Haloalkyl, C 1-6 Alkylamine, 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 C4-16 alkyl-heteroaryl; or, R 4 and R 5 , R 5 and R 6 , or R 6 and R 7 Combine with the atoms to which they are attached to form C 3-6 Cycloalkyl, C 3-6 Heterocycloalkyl, C 6-12 Aryl or C 5-10 Heteroaryl; R 8a , R 8b , R 8c and R 8d Each independently is H, C 1-6 Alkyl; and n is 1, 2 or 3; wherein, when n is 2 and R 6 When F, R 4 , R 5 and R 7 At least one of is not hydrogen; wherein, when n is 2 and R 6 When it is F, Cl, methyl or OMe, then R 3a is methyl; wherein, when n is 1 and R 6 C 1-6 Alkyl, halogen, C 1-6 When alkoxy, -C(O)H, -NH2, R 4 , R 5 and R 7 At least one of is not hydrogen; and wherein, when n is 1 and R 6 When it is methyl, halogen or -C(O)H, then R 4 , R 5 and R 7 At least one of them is not methyl or Cl.

[0121] 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:

[0122]

[0123] Where: R 1 is hydrogen or C 1-6 Alkyl; R 3a are 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; R 4 , R 5 and R 7 are independently hydrogen, C1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, C 1-6 Haloalkyl, C 1-6 Alkylamine, 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; R 6 C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, C 1-6 Haloalkyl, C 1-6 Alkylamine, 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 R8c )、-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 7 can combine with their respective attached atoms to form C 3-8 Cycloalkyl or C 3-6 Heterocycloalkyl; R 8a , R 8b , R 8c and R 8d Each independently is H, C 1-6 Alkyl or C 3-6 Cycloalkyl; n is 1, 2 or 3; or its salts and isomers; and wherein, when n is 1 and R 6 C 1-6 Alkyl, halogen, C(O)H, NH2 or C 1-6 When alkoxy, R 4 , R 5 and R 7 At least one of is not hydrogen; wherein, when n is 1 and R 6 When it is methyl, halogen or C(O)H, then R 4 , R 5 and R 7 At least one of is not methyl or Cl; wherein, when n is 2 and R 6 When it is F, Cl, methyl or OMe, then R3a is methyl; and wherein, when n is 2 and R 6 When F, R 4 , R 5 and R 7 At least one of them is not hydrogen.

[0124] In some embodiments, the present invention provides a compound or a pharmaceutically acceptable salt thereof, wherein the compound of Formula I or Formula Ia has the following structure:

[0125]

[0126] In some embodiments, R 3a is methyl, R 2 and R 3b Combined with the atoms to which they are attached, they form a group consisting of 1 to 3 R 9 C 5-8 Heterocycloalkyl, where R 9 are independently 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 Alkyl-heteroaryl, or two R attached to the same atom 9 The groups combine to form =O. In some embodiments, R 3a is a methyl group, and R 2 and R 3b Combine with the atoms they are attached to form C 6-7 Heterocycloalkyl.

[0127] In some embodiments, the present invention provides a compound or a pharmaceutically acceptable salt thereof, wherein R 3a In some embodiments, the present invention provides a compound or a pharmaceutically acceptable salt thereof, wherein the compound of Formula I or Formula Ia has the following structure:

[0128]

[0129] In some embodiments, the present invention provides a compound or a pharmaceutically acceptable salt thereof, wherein the compound of Formula I or Formula Ia has the following structure:

[0130]

[0131] Where: R 5 and R6 Each independently represents H, F, Cl, Br, I, -OH, -OMe, -OiPr, -Me, -CF3, -OCF3, -NMe2, -NHC(O)Me or -N(Me)C(O)Me, wherein R 5 and R 6 At least one of is not H; or, R 5 and R 6 Combine to form 1,3-dioxole ring or 1,4-dioxane ring.

[0132] In some embodiments, the present invention provides a compound or a pharmaceutically acceptable salt thereof, wherein the compound of Formula I or Formula Ia has the following structure:

[0133]

[0134] Where: R 5 and R 6 Each independently represents 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 Combine to form 1,3-dioxole ring or 1,4-dioxane ring.

[0135] In some embodiments, the present invention provides a compound, wherein the compound of Formula I or Formula Ia has the following structure:

[0136]

[0137] Where R 5 is H, F, Cl, Br, -OH or -OMe; R 6 is H, F, -OMe, -CF3 or -OCF3, where R 5 and R 6 At least one of them is not H.

[0138] In some embodiments, the present invention provides a compound or a pharmaceutically acceptable salt thereof, wherein the compound of Formula I or Formula Ia has the following structure:

[0139]

[0140] Where: R 4 and R 6 Each independently represents H, F, Cl, Br, I, -OH, -OMe, -OiPr, -Me, -CF3, -OCF3, -NMe2, -NHC(O)Me or -N(Me)C(O)Me, wherein R 4 and R6 At least one of them is not H.

[0141] In some embodiments, the present invention provides a compound or a pharmaceutically acceptable salt thereof, wherein the compound of Formula I or Formula Ia has the following structure:

[0142]

[0143] Where: R 4 and R 6 Each is independently F, Cl, Br, I, -OH, -OMe, -OiPr, -Me, -CF3, -OCF3, -NMe2, -NHC(O)Me or -N(Me)C(O)Me.

[0144] In some embodiments, the present invention provides a compound or a pharmaceutically acceptable salt thereof, wherein the compound is:

[0145]

[0146] In some embodiments, the present invention provides a compound or a pharmaceutically acceptable salt thereof, wherein the compound is

[0147]

[0148] In some embodiments, the present invention provides a compound or a pharmaceutically acceptable salt thereof, wherein the compound is

[0149]

[0150] In some embodiments, the present invention provides a compound or a pharmaceutically acceptable salt thereof, wherein the compound is

[0151]

[0152]

[0153] In some embodiments, the present invention provides a compound or a pharmaceutically acceptable salt thereof, wherein the compound is

[0154]

[0155] In some embodiments, the present invention provides a compound or a pharmaceutically acceptable salt thereof, wherein the compound is

[0156]

[0157] In some embodiments, R 3a is hydrogen, R 2 and R3b Combined with the atoms to which they are attached, they form a group consisting of 1 to 3 R 9 C 5-8 Heterocycloalkyl, where R 9 are independently 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 Alkyl-heteroaryl, or two R attached to the same atom 9 The groups combine to form =O. In some embodiments, R 3a is hydrogen, and R 2 and R 3b Combine with the atoms they are attached to form C 6-7 Heterocycloalkyl.

[0158] In some embodiments, the present invention provides a compound, or a pharmaceutically acceptable salt thereof, wherein the compound of Formula I or Formula Ia has the following structure:

[0159]

[0160] In some embodiments, the present invention provides a compound, or a pharmaceutically acceptable salt thereof, wherein the compound is

[0161]

[0162] In some embodiments, R 3c is hydrogen or C 1-6 In some embodiments, R 3c is hydrogen, methyl, ethyl or propyl. 3c It's hydrogen.

[0163] In some embodiments, R 1 It 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 Formula Ia has the following structure:

[0164]

[0165] In some embodiments, the present invention provides a compound or a pharmaceutically acceptable salt thereof, wherein the compound is

[0166]

[0167] In some embodiments, the present invention provides a compound or a pharmaceutically acceptable salt thereof, wherein R 2 and R 3c Combine with the atoms they are attached to form C 5-8 Cycloalkyl, which is composed of 1 to 3 R 10 Group substitution, R 10 The groups are each independently 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 Alkyl-heteroaryl, or two R attached to the same atom 10 The groups combine to form =0.

[0168] In some embodiments, the present invention provides a compound or a pharmaceutically acceptable salt thereof, wherein R 2 and R 3c Combine with the atoms they are attached to form C 5-6 Cycloalkyl, which is substituted by 1 to 2 R 10 Group substitution, or two R attached to the same atom 10 The groups combine to form =0.

[0169] In some embodiments, the present invention provides a compound or a pharmaceutically acceptable salt thereof, wherein the compound is

[0170]

[0171] The compounds of the present invention may also be in the form of salts, such as acid or base salts of the compounds of the present invention. Illustrative examples of pharmaceutically acceptable salts are inorganic acid (hydrochloric acid, hydrobromic acid, phosphoric acid, etc.) salts, organic acid (fumaric acid, acetic acid, propionic acid, glutamic acid, citric acid, etc.) salts, quaternary ammonium (methyl iodide, ethyl iodide, etc.) salts. It should be understood that pharmaceutically acceptable salts are non-toxic. Additional information on suitable pharmaceutically acceptable salts can be found in Remington's Pharmaceutical Sciences, 17th edition, Mack Publishing Company, Easton, Pennsylvania, 1985, which is incorporated herein by reference.

[0172] The present invention also includes isotopically labeled compounds of the present invention, wherein one or more atoms are replaced by one or more atoms having a specific atomic mass or mass number. Examples of isotopes that may be incorporated into the 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 Cl). Isotopically labeled compounds of the invention are useful in analyzing the tissue distribution of the compounds and their prodrugs and metabolites; preferred isotopes for such assays include 3 H and 14 C. In addition, in some cases, heavier isotopes such as deuterium ( 2 H)) substitution can provide better metabolic stability, thereby providing therapeutic advantages, such as extending the half-life in vivo or reducing dosage requirements. Isotope-labeled compounds of the present invention can generally be prepared by replacing non-isotope-labeled reagents with isotope-labeled reagents according to methods known to those skilled in the art. The compounds of the present invention can be isotope-labeled at positions adjacent to basic amines, in aromatic rings, and in the methyl group of methoxy substituents.

[0173] The present invention includes all tautomers and stereoisomers of the compounds of this invention, which can be in a mixture or in a pure or substantially pure form. The compounds of the present invention can have an asymmetric center at the carbon atom, so the compounds of the present invention can exist in diastereomeric or enantiomeric form or in a mixture thereof. All conformational isomers (for example, cis and trans isomers) and all optical isomers (for example, enantiomers and diastereomers), racemates, diastereomers and other mixtures of such isomers, as well as solvates, hydrates, isomorphs, polymorphs and tautomers are all within the scope of the present invention. Compounds according to the present invention can be prepared using diastereomers, enantiomers or racemic mixtures as starting materials. In addition, diastereomers and enantiomeric products can be separated by chromatography, fractional crystallization or other methods known to those skilled in the art.

[0174] IV. Pharmaceutical Compositions and Formulations

[0175] 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.

[0176] The pharmaceutical compositions of the present invention can be prepared into various oral, parenteral and topical dosage forms. Oral preparations include tablets, pills, powders, capsules, liquids, lozenges, cachets, gels, syrups, slurries, suspensions, etc. suitable for patient ingestion. The compositions of the present invention can also be administered by injection, i.e., intravenous, intramuscular, intradermal, subcutaneous, intraduodenal or intraperitoneal injection. In addition, the compositions described herein can be administered by inhalation, such as intranasal administration. In addition, the compositions of the present invention can be administered transdermally. The compositions of the present invention can also be administered by intraocular, intravaginal and intrarectal routes, including suppositories, insufflations, powders and aerosol preparations (e.g., steroid inhalers, see Rohataj, Journal of Pharmacy Clinical, 35: 1187-1193, 1995; Taiga, Annals of Allergy, Asthma and Immunology, 75: 107-111, 1995). Therefore, the present invention also provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier or excipient and a compound of the present invention.

[0177] For preparing pharmaceutical compositions from the compounds of the invention, pharmaceutically acceptable carriers may be solid or liquid. Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules. A solid carrier may be one or more substances which may also serve as a diluent, flavoring agent, binder, preservative, tablet disintegrant, or encapsulating material. Formulation and administration techniques are described in detail in the scientific and patent literature, see, for example, the latest edition of Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, Pennsylvania ("Remington's").

[0178] In powders, the carrier is a finely divided solid which is mixed 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. Powders and tablets preferably contain 5% to 70% or 10% to 70% of the compound of the invention.

[0179] Suitable solid excipients include, but are not limited to, magnesium carbonate; magnesium stearate; talc; pectin; dextrin; starch; tragacanth; low melting wax; cocoa butter; carbohydrates; sugars including, but not limited to, lactose, sucrose, mannitol or sorbitol, starch from corn, wheat, rice, potato or other plants; celluloses such as methylcellulose, hydroxymethylcellulose or sodium carboxymethylcellulose; and gums including gum arabic and tragacanth; and proteins including, but not limited to, gelatin and collagen. If desired, disintegrating agents or solubilizing agents may be added, such as cross-linked polyvinyl pyrrolidone, agar, alginic acid or a salt thereof, such as sodium alginate.

[0180] To prepare suppositories, a low melting wax, such as a mixture of fatty acid glycerides or cocoa butter, is first melted and the compound of the invention is uniformly dispersed therein by stirring. The molten homogeneous mixture is then poured into convenient sized molds, allowed to cool, and thereby solidify.

[0181] Liquid form preparations include solutions, suspensions, and emulsions, for example, water or water / propylene glycol solutions. For parenteral injection, liquid preparations may be formulated in solution in aqueous polyethylene glycol.

[0182] Aqueous solutions suitable for oral use can be prepared by dissolving the compound of the present invention in water and adding suitable coloring agents, flavoring agents, stabilizers and thickeners as required. Aqueous suspensions for oral use can be prepared by finely dispersing active ingredients with viscous substances, such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, hydroxymethylcellulose, sodium alginate, polyvinylpyrrolidone, tragacanth and gum arabic, and dispersants or wetting agents, such as natural phosphatides (such as lecithin), condensation products of alkylene oxide and fatty acids (such as polyoxyethylene stearate), condensation products of ethylene oxide and long-chain fatty alcohols (such as heptadecaethylene oxide hexadecanoate), condensation products of ethylene oxide and partial esters derived from fatty acids and hexitol (such as polyoxyethylene sorbitol monooleate) or condensation products of ethylene oxide and partial esters derived from fatty acids and hexitol anhydrides (such as polyoxyethylene sorbitan monooleate) are dispersed in water together. The aqueous suspension may also contain one or more preservatives, for example ethyl or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents and one or more sweetening agents, for example sucrose, aspartame or saccharin. The formulation may be adjusted for osmotic pressure.

[0183] Also included are preparations in solid form, which are intended to be converted into preparations in liquid form for oral administration shortly before use. Such liquid forms include solutions, suspensions and emulsions. In addition to the active ingredient, these preparations may also include coloring agents, flavoring agents, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizing agents, etc.

[0184] Oily suspensions can be prepared by suspending the compound of the invention in a vegetable oil such as peanut oil, olive oil, sesame oil or coconut oil, or a mineral oil such as liquid paraffin; or a mixture of these. Oily suspensions may contain thickeners, such as beeswax, hard paraffin or cetyl alcohol. Sweeteners may be added to provide a palatable oral preparation, such as glycerol, sorbitol or sucrose. These preparations can be preserved by adding antioxidants such as ascorbic acid. As an example of an injectable oil carrier, see Minto, J.Pharmacol.Exp.Ther.281:93-102,1997. The pharmaceutical preparations of the present invention may also be in the form of an oil-in-water emulsion. The oil phase may be the above-mentioned vegetable oil or mineral oil or a mixture thereof. Suitable emulsifiers include natural gums (e.g., gum arabic and tragacanth), natural phospholipids (e.g., soy lecithin), esters or partial esters derived from fatty acids and hexitol anhydrides (e.g., sorbitan monooleate), and condensation products of these partial esters with ethylene oxide (e.g., polyoxyethylene sorbitan monooleate). The emulsion may also contain sweeteners and flavorings, such as in the preparation of syrups and elixirs. Such preparations may also include a demulcent, a preservative, or a coloring agent.

[0185] The compositions of the present invention can also be delivered as microspheres for slow release in vivo. For example, the microspheres can be formulated for administration by intradermal injection of drug-containing microspheres, which are slowly released subcutaneously (see Rao, J. Biomater Sci. Polym. Ed. 7: 623-645, 1995); as biodegradable and 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). Transdermal and intradermal routes can provide sustained delivery for weeks or months.

[0186] In some embodiments, the pharmaceutical composition of the present invention can be formulated for parenteral administration, such as intravenous (IV) administration or administration into a body cavity or organ cavity. The preparation for administration generally comprises a solution of the composition of the present invention dissolved in a pharmaceutically acceptable carrier. Acceptable carriers and solvents that can be used include water and Ringer's solution, isotonic sodium chloride. In addition, sterile fixed oils can generally be used as solvents or suspension media. For this purpose, any mild fixed oil can be used, including synthetic monoglycerides or diglycerides. In addition, fatty acids such as oleic acid can also be used to prepare injections. These solutions are sterile and generally do not contain unwanted substances. These preparations can be sterilized by conventional, well-known sterilization techniques. The preparation may contain pharmaceutically acceptable auxiliary substances required for close physiological conditions, such as pH regulators and buffers, toxicity regulators, such as 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 will be selected mainly based on fluid volume, viscosity, body weight, etc., according to the selected specific mode of administration and the needs of the patient. For IV administration, the preparation can be a sterile injectable preparation, such as a sterile injectable aqueous or oily suspension. Such suspensions can be prepared using those suitable dispersants or wetting agents and suspending agents according to known techniques. The sterile injectable preparation can also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent (e.g., 1,3-butanediol solution).

[0187] In some embodiments, the preparation of the composition of the present invention can be delivered by using liposomes that fuse with the cell membrane or are endocytosed, that is, by using a ligand connected to the liposome or directly connected to the oligonucleotide, which binds to the cell surface membrane protein receptor to cause endocytosis. By using liposomes, especially when the liposome surface carries a ligand specific to the target cell or otherwise preferentially targets a specific organ, the composition of the present invention can be delivered to the target cell in vivo. (See, for example, Muhammad, Microcapsule Journal, 13: 293-306, 1996; Zong, New Perspectives in Biotechnology, 6: 698-708, 1995; Ostron, American Journal of Hospital Pharmacy, 46: 1576-1587, 1989).

[0188] V. Application

[0189] Compositions of the present invention can be delivered by any suitable means, including oral, parenteral and topical methods. Transdermal administration methods by topical routes can be formulated into applicators, solutions, suspensions, emulsions, gels, creams, ointments, pastes, jellies, paints, powders and aerosols.

[0190] The pharmaceutical formulation is preferably in unit dosage form. In this form, the formulation is subdivided into unit doses containing appropriate quantities of the compound of the invention. The unit dosage form can be a packaged formulation, the package containing discrete quantities of the formulation, such as packaged tablets, capsules, and powders in vials or ampoules. In addition, the unit dosage form can be a capsule, tablet, cachet, or lozenge itself, or can be any of the appropriate number of packaged forms.

[0191] The compounds of the present invention may be present in any suitable amount and may depend on a variety of factors, including but not limited to the weight and age of the subject, disease state, etc. Suitable dosage ranges of the compounds of the present invention include about 0.1 mg to about 10,000 mg, or about 1 mg to about 1000 mg, or about 10 mg to about 750 mg, or about 25 mg to about 500 mg, or about 50 mg to about 250 mg. Suitable dosages 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.

[0192] The compounds of the present invention can be used with any suitable frequency, interval and duration. For example, the compounds of the present invention can be used once per hour, or twice, three times or more times per hour, once a day, or twice, three times or more times per day, 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 used more than once a day, representative 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 times or more, and administration continues for 1 hour, 1-6 hours, 1-12 hours, 1-24 hours, 6-12 hours, 12-24 hours, 1 day, 1-7 days, one week, 1 to 4 weeks, one month, 1-12 months, one year or longer, even indefinitely.

[0193] The compositions may also contain 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 the glucocorticoid receptor, or with adjunct agents that may not be effective alone but may aid in the efficacy of the active agent.

[0194] The compounds of the present invention can be co-administered with another activating agent. Co-administration includes administration of the compounds of the present invention and activating agent respectively within 0.5, 1, 2, 4, 6, 8, 10, 12, 16, 20 or 24 hours. Co-administration also includes simultaneous, approximately simultaneous (e.g., each other within about 1, 5, 10, 15, 20 or 30 minutes) or sequential administration of the compounds of the present invention and activating agent in any order. In addition, the compounds of the present invention and activating agent can be administered once a day, or twice, three times or more times a day to provide a preferred dosage level every day.

[0195] In some embodiments, co-administration can be accomplished by co-formulation, ie, preparing a single pharmaceutical composition containing the compound of the invention and the active agent. In other embodiments, the compound of the invention and the active agent can be formulated separately.

[0196] The compounds of the invention and the active agent can be present in the compositions of the invention in any suitable weight ratio, for example, from about 1:100 to about 100:1 (w / w), or from about 1:50 to about 50:1, or from about 1:25 to about 25:1, or from about 1:10 to about 10:1, or from about 1:5 to about 5:1 (w / w). The compounds of the invention and the other active agent can be present in any suitable weight ratio, for example, from 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 doses and dose ratios of the compounds of the invention and the active agent are suitable for the compositions and methods of the invention.

[0197] VI. Treatment Methods

[0198] The compounds of the present invention can be used to increase neuronal plasticity. The compounds of the present invention can also be used to treat any brain disease. The compounds of the present invention can also be used to increase at least one of the translation, transcription or secretion of neurotrophic factors.

[0199] In some embodiments, the compounds of the present invention are used to treat neurological diseases. In some embodiments, the compound has, for example, anti-addiction properties, anti-depressant properties, antianxiety properties, or a combination thereof. In some embodiments, the neurological disease is a neuropsychiatric disease. In some embodiments, the neuropsychiatric disease is a mood or anxiety disorder. In some embodiments, the neurological disease is a migraine, a headache (e.g., a cluster headache), post-traumatic stress disorder (PTSD), anxiety, depression, a neurodegenerative disease, Alzheimer's disease, Parkinson's disease, a psychological disorder, treatment-resistant depression, suicidal ideation, major depressive disorder, bipolar disorder, schizophrenia, stroke, traumatic brain injury, and addiction (e.g., a substance use disorder). In some embodiments, the neurological disease is a migraine or a cluster headache. In some embodiments, the neurological disease is a neurodegenerative disease, Alzheimer's disease, or Parkinson's disease. In some embodiments, the neurological disease is a psychological 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 disease is a psychological 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 disease or neurological disease is post-traumatic stress disorder (PTSD), addiction (e.g., substance use disorder), schizophrenia, depression, or anxiety. In some embodiments, the neuropsychiatric disease or neurological disease is addiction (e.g., substance use disorder). In some embodiments, the neuropsychiatric disease or neurological disease is depression. In some embodiments, the neuropsychiatric disease or neurological disease is anxiety. In some embodiments, the neuropsychiatric disease or neurological disease is post-traumatic stress disorder (PTSD). In some embodiments, the neurological disease is a stroke or traumatic brain injury. In some embodiments, the neuropsychiatric or neurological disease is schizophrenia.

[0200] In some embodiments, the compounds of the present invention are used to increase neuronal plasticity. In some embodiments, the compounds described herein are used to treat brain diseases. In some embodiments, the compounds described herein are used to increase at least one of the translation, transcription or secretion of neurotrophic factors.

[0201] In some embodiments, the compounds of the present invention have the ability to function as 5-HT 2A In some embodiments, the compounds of the present invention have the activity of 5-HT 2AIn some embodiments, the compounds of the invention activate 5-HT 2A receptors (such as 5-HT 2A Allosteric modulation or regulation of the biological target of the receptor) triggers a biological response. 2A Agonism is associated with the promotion of neural plasticity (Ly et al., 2018). Psychedelic drugs (such as LSD and 5-MeO-DMT) activate 5HT in an agonist mode. 2A Sensors, but their non-psychedelic congeners (lisuride (LIS) and 6-MeO-DMT) do not ( Fig.15 In addition, compounds that have hallucinogenic effects in animals (e.g., humans) (e.g., 5-MeO-DMT, LSD, DMT, DOI) activate 5HT in an agonist mode. 2A Sensor assays, while compounds that are non-psychedelic in animals (e.g., humans), such as 6-MeO-DMT, LIS, 6-F-DET, L-MDMA, R-MDMA, ketanserin, BOL148, do not activate 5HT in the agonist mode 2A Sensor detection ( Fig.16 , 10 μM compound). In some embodiments, the hallucinogenicity of the compounds of the invention is determined in vitro. In some embodiments, 5HT 2A Sensor assays are used to measure the hallucinogenicity of compounds of the invention. In some embodiments, the 5HT 2A The sensor is in agonist mode or antagonist mode. In some embodiments, the 5HT 2A The sensor is determined to be in agonist mode. In some embodiments, a compound of the invention that does not activate the sensor in agonist mode is non-psychedelic. In some embodiments, a compound of the invention that does not activate the sensor in agonist mode is a non-psychedelic compound.

[0202] In addition, when 5HT 2A When the sensor assay is run in antagonist mode, non-psychedelic compounds (e.g., lisuride and 6-MeO-DMT) compete for 5-HT ( Fig.17 A and Fig.17 B) In addition, compounds that are not hallucinogenic in animals (e.g. humans) such as 6-F-DET, ketanserin, BOL148, compete with 5HT for binding to 5HT in an antagonist mode sensor assay 2A ( Fig.18 , 10 μM compound). In some embodiments, the compounds of the invention block the binding of 5-HT to 5HT 2A In some embodiments, 5HT 2A The sensor is in antagonist mode. In some embodiments, the inhibition of 5-HT and 5HT 2AThe combined compounds of the present invention have non-hallucinogenic potential. In some embodiments, blocking the 5-HT and 5HT 2A The combined compounds of the present invention are non-hallucinogenic. In some embodiments, the antagonist mode blocks the binding of 5-HT to 5HT 2A The compounds of the invention that bind have non-hallucinogenic potential. In some embodiments, the compounds of the invention that prevent the binding of 5-HT in the antagonist mode are non-hallucinogenic compounds. In some embodiments, the compounds of the invention that inhibit the response of a sensor assay in the antagonist mode have non-hallucinogenic potential. In some embodiments, the compounds of the invention that inhibit the response of a sensor assay in the antagonist mode are non-hallucinogenic compounds.

[0203] In some embodiments, the results of the agonist mode sensor assay indicate that the compounds of the invention are 5-HT 2A In some embodiments, the results of the antagonist mode sensor assay indicate that the compounds of the invention are 5-HT 2A In some embodiments, the results of the agonist mode and antagonist mode sensor assays together indicate that the compounds of the invention are 5-HT 2A Non-psychedelic ligands of the receptor.

[0204] In some embodiments, the compounds described herein are selective for 5-HT 2A In some embodiments, the compounds described herein are 5-HT 2A In some embodiments, the compounds described herein are selective 5-HT 2A Regulators and promote neural plasticity (e.g., cortical structural plasticity). In some embodiments, the promotion of neural plasticity includes, for example, increasing dendritic spine growth, increasing synaptic protein synthesis, enhancing synaptic responses, increasing dendritic spine complexity, increasing dendritic branch content, increasing spine generation, increasing neurogenesis, or any combination thereof. In some embodiments, increasing neural plasticity includes, for example, increasing cortical structural plasticity in the front of the brain.

[0205] 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 2AAgonists) are used to treat nervous system diseases, wherein the modulator does not cause dissociative side effects. In some embodiments, the hallucinogenicity of the compounds described herein is evaluated in vitro. In some embodiments, the hallucinogenicity of the compounds described herein evaluated in vitro is compared with the hallucinogenicity of the hallucinogenic homologs evaluated in vitro. In some embodiments, the compounds described herein cause less hallucinogenic potential in vitro compared to the hallucinogenic homologs.

[0206] In some embodiments, non-hallucinogenic 5-HT 2A Modulators (e.g., 5-HT 2A In some embodiments, the neurological diseases include decreased neuroplasticity, decreased cortical structural plasticity, 5-HT 2A Decreased receptor content, decreased dendritic spine complexity, loss of dendritic spines, decreased dendritic branching content, decreased spine initiation, decreased neurite outgrowth, axon retraction, or any combination thereof.

[0207] In some embodiments, non-hallucinogenic 5-HT 2A Modulators (e.g., 5-HT 2A Agonists) are used to increase neuronal plasticity. In some embodiments, non-hallucinogenic 5-HT 2A Modulators (e.g., 5-HT 2A Agonists) are used to treat brain diseases. In some embodiments, non-hallucinogenic 5-HT 2A Modulators (e.g., 5-HT 2A Agonists) are used to increase at least one of the translation, transcription or secretion of neurotrophic factors.

[0208] A. Methods to increase neuronal plasticity

[0209] Neuronal plasticity refers to the ability of the brain to change structure and / or function during the life of the subject. During the life of the subject, new neurons can be generated and integrated into the central nervous system. Increasing neuronal plasticity includes but is not limited to promoting neuronal growth, promoting neurite generation, promoting synapsis, promoting dendrite generation, increasing dendritic spine complexity, increasing dendritic spine density and increasing excitatory synapses in the brain. In some embodiments, increasing neuronal plasticity includes promoting neuronal growth, promoting neurite generation, promoting synapsis, promoting dendrite generation, increasing dendritic spine complexity and increasing dendritic spine density.

[0210] In some embodiments, increasing neuronal plasticity can treat a neurodegenerative disease, Alzheimer's disease, Parkinson's disease, a psychological 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.

[0211] In some embodiments, the present invention provides a method of increasing neuronal plasticity comprising contacting a neuronal cell with any of the compounds of the present invention. In some embodiments, increasing neuronal plasticity ameliorates a brain disease described herein.

[0212] In some embodiments, the compounds of the present invention are used to increase neuronal plasticity. In some embodiments, the compound for increasing neuronal plasticity has, for example, anti-addiction properties, anti-depressant properties, antianxiety properties, or a combination thereof. In some embodiments, reduced neuronal plasticity is associated with a neuropsychiatric disorder. In some embodiments, the neuropsychiatric disorder is a mood or anxiety disorder. In some embodiments, the neuropsychiatric disorder includes, for example, migraine, cluster headache, post-traumatic stress disorder (PTSD), schizophrenia, anxiety, depression, and addiction (e.g., substance abuse disorder). In some embodiments, brain diseases include, for example, migraine, addiction (e.g., substance use disorder), depression, and anxiety.

[0213] In some embodiments, the experiment or assay to determine whether any of the compounds of the invention increase neuronal plasticity is a phenotypic assay, a dendrite formation assay, a spine formation assay, a synaptogenesis assay, a Sholl analysis, a concentration-response experiment, a 5-HT 2A Agonist assay, 5-HT 2A Antagonist assay, 5-HT 2A Binding assay or 5-HT2A blocking assay (eg, ketanserin blocking assay). In some embodiments, the assay or assay to determine the hallucinogenicity of any compound of Formula I or Formula (Ia) is a mouse head twitch response (HTR) assay.

[0214] In some embodiments, the present invention provides a method for increasing neuronal plasticity, comprising contacting a neuronal cell with a compound of formula I or a pharmaceutically acceptable salt thereof:

[0215]

[0216] In an amount sufficient to increase neuronal plasticity of a neuronal cell, wherein: R 1 is hydrogen or C 1-6 Alkyl; R 3a and R 3b are 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 3bCombined with the atoms to which they are attached, they form a group consisting of 1 to 3 R 9 C 5-8 Heterocycloalkyl, the R 9 are independently 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 Alkyl-heteroaryl, or two R attached to the same atom 9 The groups combine to form =O; or, R 2 and R 3c Combine with the atoms they are attached to form C 5-8 Cycloalkyl, which is composed of 1 to 3 R 10 Group substitution, R 10 The groups are each independently 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 Alkyl-heteroaryl, or two R attached to the same atom 10 The groups combine to form =O; R 4 , R 5 , R 6 and R 7 are independently hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, C 1-6 Haloalkyl, C 1-6 Alkylamine, 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 8bR 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 Combine with the atoms to which they are attached to form C 3-6 Cycloalkyl, C 3-6 Heterocycloalkyl, C 6-12 Aryl or C 5-10 heteroaryl; and R 8a , R 8b , R 8c and R 8d Each independently is H, C 1-6 alkyl.

[0217] In some embodiments, the present invention provides a method of increasing neuronal plasticity, comprising contacting a neuronal cell with a compound of formula I or a pharmaceutically acceptable salt thereof in an amount sufficient to increase the neuronal plasticity of the neuronal cell, wherein: R 1 is hydrogen or C 1-6 Alkyl; R 3a and R 3b are independently hydrogen, C 1-6 Alkyl, C 3-8 Cycloalkyl or C 4-14 Alkyl-cycloalkyl; R 3c is hydrogen or C 1-6Alkyl; or, R 2 and R 3b Combined with the atoms to which they are attached, they form a group consisting of 1 to 3 R 9 C 5-8 Heterocycloalkyl, where R 9 are independently 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 Alkyl-heteroaryl, or two R attached to the same atom 9 The groups combine to form =O; or, R 2 and R 3b Combine with the atoms they are attached to form C 5-8 Cycloalkyl, which is composed of 1 to 3 R 10 Group substitution, R 10 The groups are each independently 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 Alkyl-heteroaryl, or two R attached to the same atom 10 The groups combine to form =O; R 4 , R 5 , R 6 and R 7 are independently hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, C 1-6 Haloalkyl, C 1-6 Alkylamine, 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 them is not H; R 8b , R 8c and R 8d Each independently is H, C 1-6 alkyl.

[0218] B. Methods for treating brain diseases

[0219] 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 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 disease with a 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.

[0220] In some embodiments, 5-HT 2A Modulators (e.g., 5-HT 2A In some embodiments, the brain disease includes decreased neuroplasticity, decreased cortical structural plasticity, 5-HT 2ADecreased receptor content, decreased dendritic spine complexity, loss of dendritic spines, decreased dendritic branching content, decreased spine initiation, decreased neurite outgrowth, neurite retraction, or any combination thereof.

[0221] In some embodiments, the compounds of the present invention are used to treat brain diseases. In some embodiments, the compounds have, for example, anti-addiction properties, anti-depressant properties, antianxiety properties, or a combination thereof. In some embodiments, the brain disease is a neuropsychiatric disease. In some embodiments, the neuropsychiatric disease is a mood disorder or an anxiety disorder. In some embodiments, the brain disease includes, for example, migraine, cluster headache, post-traumatic stress disorder (PTSD), anxiety, depression, schizophrenia, and addiction (e.g., drug abuse disorder). In some embodiments, the brain disease includes, for example, migraine, addiction (e.g., substance use disorder), depression, and anxiety.

[0222] In some embodiments, the present invention provides a method of treating a brain disease, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula I:

[0223]

[0224] or a pharmaceutically acceptable salt thereof, thereby treating a brain disease, wherein: R 1 is hydrogen or C 1-6 Alkyl; R 3a and R 3b are 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 Combined with the atoms to which they are attached, they form a group consisting of 1 to 3 R 9 C 5-8 Heterocycloalkyl, where R 9 are independently 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 Alkyl-heteroaryl, or two R attached to the same atom 9 The groups combine to form =O; or, R 2 and R 3cCombine with the atoms they are attached to form C 5-8 Cycloalkyl, which is composed of 1 to 3 R 10 Group substitution, R 10 The groups are each independently 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 Alkyl-heteroaryl, or two R attached to the same atom 10 The groups combine to form =O; R 4 , R 5 , R 6 and R 7 are independently hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, C 1-6 Haloalkyl, C 1-6 Alkylamine, 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 4-16Alkyl-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 Combine with the atoms to which they are attached to form C 3-6 Cycloalkyl, C 3-6 Heterocycloalkyl, C 6-12 Aryl or C 5-10 heteroaryl; and R 8a , R 8b , R 8c and R 8d Each independently is H, C 1-6 alkyl.

[0225] In some embodiments, the present invention provides a method for treating a brain disease, comprising administering a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof to a subject in need thereof, thereby treating the brain disease, wherein: R 1 is hydrogen or C 1-6 Alkyl; R 3a and R 3b are 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 Combined with the atoms to which they are attached, they form a group consisting of 1 to 3 R 9 C 5-8 Heterocycloalkyl, where R 9 are independently 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 Alkyl-heteroaryl, or two R attached to the same atom 9The groups combine to form =O; or, R 2 and R 3b Combine with the atoms they are attached to form C 5-8 Cycloalkyl, which is composed of 1 to 3 R 10 Group substitution, R 10 The groups are each independently 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 Alkyl-heteroaryl, or two R attached to the same atom 10 The groups combine to form =O; R 4 , R 5 , R 6 and R 7 are independently hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, C 1-6 Haloalkyl, C 1-6 Alkylamine, 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 3-14Alkyl-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 them is not H; R 8b , R 8c and R 8d Each independently is H, C 1-6 alkyl.

[0226] In some embodiments, the brain disease is a neurodegenerative disease, Alzheimer's disease, Parkinson's disease, a psychological 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.

[0227] In some embodiments, the brain disease is a neurodegenerative disease, Alzheimer's disease, or Parkinson's disease. In some embodiments, the brain disease is a psychological disorder, depression, addiction, anxiety, or post-traumatic stress disorder. In some embodiments, the brain disease is depression. In some embodiments, the brain disease is addiction. In some embodiments, the brain disease 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 disease is treatment-resistant depression, suicidal ideation, major depressive disorder, bipolar disorder, schizophrenia, or substance use disorder. In some embodiments, the brain disease is treatment-resistant depression, suicidal ideation, major depressive disorder, bipolar disorder, or substance use disorder. In some embodiments, the brain disease is stroke or traumatic brain injury. In some embodiments, the brain disease is schizophrenia. In some embodiments, the brain disease is alcohol use disorder.

[0228] In some embodiments, the method further comprises administering one or more additional therapeutic agents, namely lithium, olanzapine (Zyprexa), quetiapine (Seroquel), risperidone (Risperdal), ariprazole (Abilify), ziprasidone (Geodon), clozapine (Clozari l Kezhilu), 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), paroxetine (Paxil), sertraline (Zoloft), clomipramine (Anafranil), franil), amitriptyline (Elavil), desipramine (Norpramin), imipramine (Tofranil), nortriptyline (Pamelor), phenelzine (Nardil), tranylcypromine (Parnate), diazepam (Valium), alprazolam (Xanax), or clonazepam (Klonopin).

[0229] In some embodiments, the compound of the present invention is used in combination with standard care therapy for neurological diseases described herein. Non-limiting examples of standard care therapy may include, for example, lithium, olanzapine, quetiapine, risperidone, aripiprazole, ziprasidone, clozapine, divalproex sodium, lamotrigine, valproic acid, carbamazepine, topiramate, levamisole, 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 therapy for depression are sertraline, fluoxetine, escitalopram, venlafaxine or aripiprazole. Non-limiting examples of standard of care therapies for depression are citalopram, escitalopram, fluoxetine, paroxetine, diazepam, or sertraline.

[0230] C. Methods for increasing at least one of translation, transcription or secretion of neurotrophic factors

[0231] Neurotrophic factors refer to a family of soluble peptides or proteins that support the survival, growth and differentiation of developing and mature neurons. Increasing at least one of the translation, transcription or secretion of neurotrophic factors can be used for, but not limited to, increasing neuronal plasticity, promoting neuronal growth, promoting neurite generation, promoting synaptogenesis, promoting dendrite generation, increasing dendritic spine complexity, increasing dendritic spine density, and increasing excitatory synapses in the brain. In some embodiments, increasing at least one of the translation, transcription or secretion of neurotrophic factors can increase neuronal plasticity. In some embodiments, increasing at least one of the translation, transcription or secretion of neurotrophic factors can promote neuronal growth, promote neurite generation, promote synaptogenesis, promote dendrite generation, increase dendritic spine complexity and / or increase dendritic spine density.

[0232] In some embodiments, 5-HT 2A Regulators (such as 5-HT 2A Agonists) are used to increase at least one of the translation, transcription or secretion of neurotrophic factors. In some embodiments, the compounds of Formula I or Formula (Ia) described herein are used to increase at least one of the translation, transcription or secretion of neurotrophic factors. In some embodiments, at least one of the increased translation, transcription or secretion of neurotrophic factors can treat migraine, headache (e.g., cluster headache), post-traumatic stress disorder (PTSD), anxiety, depression, neurodegenerative diseases, Alzheimer's disease, Parkinson's disease, psychological disorders, treatment-resistant depression, suicidal ideation, major depressive disorder, bipolar disorder, schizophrenia, stroke, traumatic brain injury, and addiction (e.g., substance use disorder).

[0233] In some embodiments, experiments or assays for determining increased translation of neurotrophic factors include ELISA, Western blot, immunofluorescence assay, proteomics experiments, and mass spectrometry. In some embodiments, experiments or assays for determining increased transcription of neurotrophic factors include gene expression assays, PCR, and microarrays. In some embodiments, experiments or assays for determining increased secretion of neurotrophic factors include ELISA, Western blot, immunofluorescence assay, proteomics experiments, and mass spectrometry.

[0234] In some embodiments, the present invention provides a method for increasing at least one of translation, transcription or secretion of a neurotrophic factor, comprising contacting a neuronal cell with a compound of formula I or a pharmaceutically acceptable salt thereof:

[0235]

[0236] In an amount sufficient to increase neuronal plasticity of a neuronal cell, wherein: R 1 is hydrogen or C 1-6 Alkyl; R 3a and R 3b are 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 Combined with the atoms to which they are attached, they form a group consisting of 1 to 3 R 9 C 5-8 Heterocycloalkyl, R 9 The groups are each independently 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 Alkyl-heteroaryl, or two R attached to the same atom 9 The groups combine to form =O; or, R 2 and R 3c Combine with the atoms they are attached to form C 5-8 Cycloalkyl, which is composed of 1 to 3 R 10 Group substitution, R 10 The groups are each independently hydrogen, C 1-6 Alkyl, C 3-8 Cycloalkyl, C 3-14Alkyl-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 two R attached to the same atom 10 The groups combine to form =O; R 4 , R 5 , R 6 and R 7 are independently hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, C 1-6 Haloalkyl, C 1-6 Alkylamine, 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 , R6 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 Combine with the atoms to which they are attached to form C 3-6 Cycloalkyl, C 3-6 Heterocycloalkyl, C 6-12 Aryl or C 5-10 heteroaryl; and R 8a , R 8b , R 8c and R 8d Each independently is H, C 1-6 alkyl.

[0237] In some embodiments, the present invention provides a method of increasing at least one of translation, transcription or secretion of a neurotrophic factor, comprising contacting a neuronal cell with a compound of formula I or a pharmaceutically acceptable salt or isomer thereof, in an amount sufficient to increase neuronal plasticity of the neuronal cell, wherein: R 1 is hydrogen or C 1-6 Alkyl; R 3a and R 3b are 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 Combined with the atoms to which they are attached, they form a group consisting of 1 to 3 R 9 C 5-8 Heterocycloalkyl, where R 9 are independently 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 Alkyl-heteroaryl, or two R attached to the same atom 9 The groups combine to form =O; or, R 2 and R 3b Combine with the atoms they are attached to form C 5-8 Cycloalkyl, which is composed of 1 to 3 R 10 Group substitution, R10 The groups are each independently 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 Alkyl-heteroaryl, or two R attached to the same atom 10 The groups combine to form =O; R 4 , R 5 , R 6 and R 7 are independently hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, C 1-6 Haloalkyl, C 1-6 Alkylamine, 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 5-10Heteroaryl or C 4-16 Alkyl-heteroaryl, where R 4 , R 5 , R 6 and R 7 At least one of them is not H; R 8b , R 8c and R 8d Each independently is H, C 1-6 alkyl.

[0238] VII. Examples

[0239] Chemistry (general). 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 by syringe or stainless steel cannula. Organic solutions were concentrated by rotary evaporation under reduced pressure (~5 torr). Solvents were purified by passing through an activated alumina column under 12 psi N2. Chromatography was performed using Fisher ChemicalTM silica gel adsorbent (230-400 mesh, grade 60). Chromatographically purified compounds were applied to the adsorption bed using the specified solvent and the minimum amount of dichloromethane added as required for solubility. Thin layer chromatography (TLC) was performed on Merck silica gel 60F254 plates (250 μm). Chromatographic chromatograms were visualized by fluorescence quenching or by staining with butanol ninhydrin, aqueous potassium permanganate, ethanolic vanillin, or aqueous ceric ammonium molybdate (CAM).

[0240] Nuclear Magnetic Resonance (NMR) 1 H and 13 C spectra were acquired on a Bruker 400 operating at 400 and 100 MHz or a Varian-600 operating at 600 and 150 MHz, respectively, and internally referenced to the residual solvent signal. 1 H NMR data were reported as follows: chemical shift (δ, ppm), multiplicity (s, singlet; brs, broad singlet; d, doublet; t, triplet; q, quartet; quint, quintet; sext, sextet; m, multiplet), integration, and coupling constant (Hz). 13 C NMR data are reported as chemical shift (δ, ppm). Infrared spectra were recorded on a ThermoScientific Nicolet iS10 spectrometer with a Smart iTX accessory (diamond ATR) and reported as absorption frequencies. Low-resolution mass spectra were obtained using a Waters Acuity Arc LC-MS.

[0241] 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 are included ( 1 H and 13 C NMR spectroscopy).

[0242] Example 1. Synthesis and Biological Activity of Ibogalogs

[0243] The pharmacophore of ibogaine is Figure 1 A. A series of tetrahydroazacycloheptatriene-containing compounds lacking the isoquinuclidine characteristic of ibogaine were synthesized ( Figure 1 B).

[0244] Embryonic rat cortical neurons were treated for a brief period (1 hour) followed by an appropriate growth period (71 hours) to measure the psychoplastic effects of the compounds described herein. Using this brief treatment regimen (Dunlap et al., Identification of psychoplastic N,N-dimethylaminoisochrometamine (isoDMT) analogs by structure-activity relationship studies, Journal of Medicinal Chemistry, 2019), ibogaine exhibited psychoplastic effects as measured by Shor assay. Therefore, the effects of ibogaine analogs 8-17 on dendritic growth were evaluated.

[0245] With the exception of 11a, the ibogamic acid analogs containing an isoquinuclidine ring but no tetrahydroazacycloheptine ring (8-10 and 11b) were weak psychoplastic agents or did not promote neuronal growth compared with vehicle (VEH) controls ( Figure 5 and Figure 6 Iboga analogs (13-16) without the isoquinuclidine but retaining the tetrahydroazacycloheptaline are effective ( Figure 5 and Figure 6 ). Substitution of the indole at C5 with fluorine or chlorine is tolerated, but the more sterically demanding bromine substituent is not. IBG (13) behaves comparable to ibogaine despite its greatly simplified chemical structure.

[0246] HTR assay using 5-MeO-DMT (10 mg / kg) as a positive control ( Figure 2 B) was used to evaluate the hallucinogenic potential of IBG and theophylline analog (TBG). While 5-MeO-DMT produces a potent HTR, its conformationally constrained analog IBG exhibits significantly reduced hallucinogenic potential. The 6-methoxy substituent of TBG exhibited no hallucinogenic potential as measured by the HTR assay. For these in vivo studies, the fumarate salts of IBG and TBG were used. Unlike ibogaine HCl, they are readily soluble in 0.9% saline to 40 mg / mL ( Figure 2 C). Ibogaine lacks water solubility ( Figure 7 ) is a potential problem not only for clinical formulations, but also for dosing animals during preclinical trials.

[0247] The lipophilicity of ibogaine not only poses a practical problem for its administration, but may also be a major factor leading to its toxicity and adverse cardiac effects. 50 Inhibit hERG channels ( Figure 2 D). In contrast, IBG and TBG are approximately 10-fold and 100-fold less potent than ibogaine, respectively (IBG IC 50 =19.3μM; TBG IC 50 =148 μM), indicating a low potential for cardiotoxicity. Administration of ibogaine to immobilized zebrafish larvae resulted in a visually significant decrease in heart rate ( Figure 2 E) and, as measured by the ratio of atrial to ventricular beats per minute (BPM), increased likelihood of arrhythmia induction ( Figure 2 F) Neither IBG nor TBG induced these unwanted phenotypes.

[0248] To compare the acute behavioral effects of ibogaine, IBG, and TBG, larval zebrafish were treated for 1 h and then their locomotor activity was quantified during a series of light and sound stimulations as described previously ( Figure 8 As concentrations increased, ibogaine, noribogamine, and the hERG inhibitors haloperidol, sertindole, and terfenadine became phenotypically more different from vehicle controls and more similar to lethal controls (eugenol, 100 μM) ( Fig. 9 At the highest concentration tested (200 μM), noribogaine and a toxic pesticide (endosulfan) phenotypically resembled the lethal control. In contrast, IBG and TBG did not produce this phenotype. The machine learning approach showed that at the highest concentration, IBG and TBG elicited locomotor responses more similar to the vehicle control than did ibogaine, noribogaine, or the lethal control ( Figure 2 G). This indicates that the new compound has excellent acute safety.

[0249] Ibogaine is known to induce seizures at very high doses, so the epileptogenic potential of zebrafish larvae expressing GCaMP5 was evaluated. No excessive neural activity was observed with ibogaine and TBG after treatment with known seizure-inducing compounds such as pentylenetetrazol (PTZ). Fig.10 ).

[0250] Finally, in a well-established zebrafish developmental toxicity assay, ibogaine (100 μM) significantly increased malformation and mortality at 2 and 5 days post fertilization (dpf), respectively ( Figure 2 H and Figure 2I). The ratio of surviving to nonsurviving fish was significantly different from vehicle controls at both time points (Fisher's exact test, p<0.0001). Ibogaine-treated animals had numerous malformations. Noribogaine treatment increased survival, but most animals exhibited yolk sac and / or pericardial edema. In sharp contrast, IBG and TBG treatment (100 μM) resulted in significantly fewer nonsurviving fish than ibogaine or noribogaine treatment at 2 and 5 days post fertilization (Fisher's exact test, p<0.0001 for ibogaine versus IBG and ibogaine versus TBG at 2 and 5 days post fertilization; p<0.0001 for noribogaine versus IBG at 2 and 5 days post fertilization and noribogaine versus TBG at 2 days post fertilization; p=0.0083 for NOR versus TBG at 5 days post fertilization). Furthermore, the effects of compound-induced malformations and / or mortality were time-dependent ( Figure 2 J) and concentration-dependent ( Fig.11 Importantly, reducing the concentration of TBG from 100 μM to 66 μM resulted in a proportion of surviving and non-surviving fish at 5 days post fertilization that was statistically indistinguishable from vehicle controls (Fisher's exact test, p=0.3864).

[0251] To validate the targets of IBG and TBG, a battery of serotonin (5-HT) and opioid receptor functional assays assessing classical GPCR signaling were performed. Unlike noribogaine, IBG and TBG exhibit weak or no opioid agonist activity ( Fig.12 and Fig.13 However, IBG and TBG are not significantly different in humans ( Figure 2 K) and mouse 5-HT2A receptor ( Fig.12 ) show potent agonist activity. Many 5-HT2A agonists, such as 5-MeO-DMT, are also agonists of the 5-HT2B receptor, which can lead to valvular heart disease. Fortunately, IBG and TBG are antagonists of the 5-HT2B receptor ( Figure 2 K). When analyzed across the 5-HT receptor panel, both compounds showed different analytical results compared to 5-MeO-DMT ( Fig.12 , Fig.13 and Fig.14 ), including weaker 5-HT1A and 5-HT2C agonist activity. In fact, IBG and TBG exhibit a more selective and potentially safer profile than the less conformationally restricted 5-MeO-DMT, as well as their preferential activation of 5-HT over similar 5-HT receptors or opioid receptors. 2A Receptor.

[0252] Example 2. Compounds 4a and 4b

[0253] Benzyl chloroformate (18.0 mL, 21.6 g, 126.4 mmol, 1.0 equiv) was slowly added dropwise 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. Gas evolution was observed. The mixture was stirred at -78 °C for 3 hours, diluted with Et2O (100 mL) and H2O (50 mL), and then 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 produce a clear oil. The product was passed through a short plug of silica gel using hexane:EtOAc (95:5) as 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 neat 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 NaOMe aqueous solution (2.4 mL, 8.9 mmol, 0.07 equiv). The resulting mixture was stirred for 15 min, quenched with H2O (5 mL), and then concentrated under reduced pressure. The residue was dissolved in DCM (250 mL) and then washed with H2O (100 mL) and then brine (50 mL). The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The product was purified by silica gel chromatography (hexane: EtOAc 3:1) to give a clear oil containing a mixture of 4a and 4b (26.5 g, 73% over 3 steps, ~1:1 mixture of exo:endo rotamers).

[0254]

[0255] 1 H NMR(CDCl3,400MHz)δ7.4–7.2(m,5H),6.57–6.23(m,2H),5.22–4.94(m,3H),3.33(t, 1 H, 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, 699 cm -1 ; LC-MS (ES + )C 17 H 20The calculated value of NO3[M+H] is 286.14, and the measured value is 286.22.

[0256] Example 3. Compounds 5a and 5b

[0257] To a mixture of 4a and 4b (4.8 g, 17.0 mmol, 1.0 eq.) in anhydrous THF (13 mL, 1.3 M) was added p-toluenesulfonyl hydrazide (3.16 g, 17.0 mmol, 1 eq.). 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 Et2O (20 mL), and sonicated for 15 min. The white precipitate was filtered and washed with Et2O (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, exo and endo=2.62 g).

[0258]

[0259] Isolated as a white solid (5.88 g, mixture of rotamers); 1 H NMR (CDCl3, 400MHz) δ7.80 (dd, 2H, J = 20.1, 8.3Hz), 7.43–7.26 (m, 4H), 7.25–7. 11(m,3H),6.49–6.36(m,2H),5.10(dd,1H,J=36.0,12.3Hz),4.80–4.57(m,2H), 3.02(dd,1H,J=10.0,2.1Hz),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)ν3207,2952,2876,1675,1418,1368,1337,1303,1258,1165,1117,1030,917,813,763,705,667,552cm -1 ; LC-MS(ES+)C 24 H 28 Calculated value of N2O4S[M+H] 454.18, found 454.33.

[0260]

[0261] Isolated as a white solid (7.33 g, mixture of rotamers); 1H NMR(CDCl3,400MHz)δ7.79(t,2H,J=8.9Hz),7.42–7.27(m,6H),7.09(d,1H,J=8.0Hz),6.21(t,1H,J=7.3Hz),6.08–6.00(m,1H),5.23–5.05(m,2 IR (Smart iTX diamond)ν3105,2939,2878,1671,1446,1420,1372,1338,1322,1298,1280,1262,1241,1167,976,932,818,804,766,724,670,550cm -1 ; LC-MS(ES+)C 24 H 28 Calculated value of N2O4S[M+H] 454.18, found 454.33.

[0262] Example 4. Compounds 6a and 6b

[0263] To a solution of 5a or 5b (3.78 g, 8.35 mmol, 1.0 eq) in THF (16.7 mL, 2 M) was added sodium cyanoborohydride (2.1 g, 33.4 mmol, 4 eq) and p-toluenesulfonic acid (159 mg, 0.835 mmol, 0.1 eq). The mixture was refluxed for 18 h, diluted with H2O (30 mL), and extracted with cyclohexane (5×25 mL). The combined organic extracts were washed with H2O (20 mL), saturated aqueous NaHCO3 (20 mL), and brine (20 mL), then dried over Na2SO4 and concentrated under reduced pressure to give 6a or 6b.

[0264]

[0265] Isolated as a clear oil (2.01 g, 57%, mixture of rotamers); 1H NMR(CDCl3,400MHz)δ7.41–7.27(m,5H),6.55–6.38(m,1H),6.33(q,1H,J=7.7Hz),5.22–5.02(m,2H),4.58(d,1H,J=6.1Hz),3.30–3.20 IR (Smart) iTX diamond)ν3052,2957,2873,1699,1417,1335,1295,1106,986,764,699cm -1 ; LC-MS(ES+)C 17 H 21 The calculated value of NO2[M+H] is 272.17, and the measured value is 272.29.

[0266]

[0267] Isolated as a clear oil (2.62 g, 62%, mixture of rotamers); 1 H NMR(CDCl3,400MHz)δ7.39–7.26(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(m,1H),2.77–2.62(m,1H),2.05–1.91(m,1H),1.87–1.77(m,1H),1.28–1.11(m,1H),1.05–0.82(m,5H)ppm; IR(Smart iTX diamond)ν3052,2958,2931,2874,1699,1416,1333,1301,1276,1111,977,766,698cm -1 .LC-MS(ES+)C 17 H 21 The calculated value of NO2[M+H] is 272.17, and the measured value is 272.29.

[0268] Example 5. Compounds 8a and 8b

[0269] A solution of 6a or 6b (132 mg, 0.95 mmol, 1.0 eq.) in acetic acid (0.5 mL, 1.9 M) was heated to 55 °C, and sodium borohydride (165 mg, 4.37 mmol, 4.6 eq.) was added. Gas evolution was observed. The mixture was stirred at 55 °C for 10 hours, diluted with H2O (2 mL), cooled to 0 °C and basified with solid NaOH (until pH = 14). The aqueous layer was extracted with Et2O (4×10 mL), dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (100:1 DCM:MeOH, containing 0.5% NH4OH) to give the product.

[0270]

[0271] Isolated as yellow oil (12 mg, 7%); 1 H NMR(CDCl3,400MHz)δ3.05–2.96(m,1H),2.47(q,2H,J=7.2Hz),2.37(t,1H,J=2.4Hz),2.20(dt,1H,J=9.3,1.5Hz),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=7.2Hz),0.86(t,3H,J=7.1Hz)ppm; 13 C NMR (CDCl3, 100MHz) δ56.67, 51.92, 49.18, 40.36, 32.76, 27.15, 26.89, 25.34, 21.52, 13.64, 11.98ppm; IR (Smart iTX diamond) ν2955, 2926, 2857, 2793, 1458, 1372, 1259, 1100, 1048, 799cm -1 ; LC-MS(ES+)C 11 H 21 The calculated value of N[M+H] is 168.18, and the measured value is 168.33.

[0272]

[0273] Isolated as yellow oil (71.5 mg, 47%); 1H NMR(CDCl3,400MHz)δ2.76(dt,1H,J=9.8,2.7Hz),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=14.4Hz),0.99(dt,1H,J=6.3,2.2Hz),0.88(t,3H,J=7.4Hz)ppm; 13 C NMR (CDCl3, 100MHz) δ55.71, 52.90, 49.55, 35.32, 32.94, 27.67, 26.63, 25.30, 20.02, 13.47, 12.19ppm; IR (Smart iTX diamond) ν2958, 2931, 2872, 2860, 2792, 1464, 1371, 1217, 1161, 1094, 819, 756cm -1 ; LC-MS(ES+)C 11 H 21 The calculated value of N[M+H] is 168.17, and the measured value is 168.25.

[0274] Example 6.5 - Preparation of substituted tryptols

[0275] General steps for preparing hydrazine. Most hydrazines are commercially available, but 4-iodo and 4-benzyloxy hydrazines are synthesized internally according to the following steps. A 0.5M solution of 4-substituted aniline (3.99mmol, 1 equivalent) in a concentrated HCl aqueous solution is cooled to 0°C, followed by addition of a 2.0M NaNO aqueous solution (3.91mmol, 0.98 equivalent). The solution is stirred at 0°C for 20 minutes. Then, a solution of SnCl2 2H2O (10.4mmol, 2.6 equivalent) in a concentrated hydrochloric acid aqueous solution (2.4mL) is added. The mixture is stirred for 2 hours, warmed to room temperature, filtered, and rinsed with H2O and Et2O. The solid is dried under reduced pressure and used immediately without further purification.

[0276] All 5-substituted tryptophanols were prepared from the corresponding 4-substituted hydrazines as outlined herein.

[0277] General solution:

[0278]

[0279] A solution of phenylhydrazine (0.5 g, 3.46 mmol, 1 eq) 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 eq) by dropwise addition. The resulting mixture was stirred at 100°C until the starting material was consumed as determined by TLC (~3 hours). The reaction was then cooled to room temperature and diluted with EtOAc (10 mL). The aqueous layer was extracted with EtOAc (5×10 mL). The combined organic extracts were washed with 5% aqueous LiCl (15 mL), saturated aqueous NaHCO3 (15 mL), and H2O (15 mL), then dried over Na2SO4. The resulting product was purified by silica gel chromatography (3:1 hexanes:EtOAc) to give the desired tryptone as a brown solid (258 mg, 92%); 1 HNMR(CDCl3,400MHz)δ8.23(s,1H),7.70–7.59(m,1H),7.36(d,1H,J=8.1Hz),7.25–7.19(m,1H),7.15(td ,1H,J=7.6,7.1,1.0Hz),7.09–7.00(m,1H),3.91(t,2H,J=6.4Hz),3.04(t,2H,J=6.4Hz),1.86(s,1H)ppm; 13 C NMR (CDCl3, 100MHz) δ136.47, 127.44, 122.54, 122.23, 119.49, 118.86, 112.27, 111.26, 62.64, 28.77ppm; IR (Smart iTX diamond) ν3390, 3322, 3059, 2933, 2905, 2863, 1456, 1424, 1352, 1338, 1229, 1094, 1045, 1005, 738, 591cm -1 ; LC-MS(ES+)C 10 H 11 Calculated value of NO[M+H]: 162.09, found: 162.21.

[0280]

[0281] A solution of p-MeO-phenylhydrazine (2 g, 11.45 mmol, 1 eq.) 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 eq.) by dropwise addition. The resulting mixture was stirred at 100°C until the starting material was consumed as determined by TLC (~5 hours). The reaction was then cooled to room temperature and diluted with EtOAc (20 mL). The aqueous layer was extracted with EtOAc (4×25 mL). The combined organic extracts were washed with 5% aqueous LiCl (20 mL), saturated aqueous NaHCO3 (20 mL), and H2O (20 mL), then dried over Na2SO4. The obtained product was purified by silica gel chromatography (gradient elution: 3:1→1:1 hexane:EtOAc) to give the desired product (1.71 g, 78%) as a yellow oil; H 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 C NMR (CDCl3, 100MHz) δ154.09, 131.70, 127.91, 123.46, 112.45, 112.09, 111.97, 100.76, 62.67, 56.06, 28.82ppm; IR (Smart iTX diamond) ν3409, 2938, 2831, 1624, 1584, 1486, 1456, 1440, 1214, 1067, 1043, 922, 798cm -1 ; LC-MS(ES+)C 11 H 13 The calculated value of NO2[M+H] is 192.10, and the measured value is 192.27.

[0282]

[0283] A solution of p-BnO-phenylhydrazine (398 mg, 1.59 mmol, 1 eq.) in 4.54 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 (0.13 mL, 123 mg, 1.75 mmol, 1.1 eq.) by dropwise addition. The resulting mixture was stirred at 100°C until the starting material was consumed as determined by TLC (~3 hours). The reaction was then cooled to room temperature and diluted with EtOAc (10 mL). The aqueous layer was extracted with EtOAc (4×10 mL). The combined organic extracts were washed with 5% aqueous LiCl (10 mL), saturated aqueous NaHCO3 (10 mL), and H2O (2×10 mL), then dried over Na2SO4. The resulting product was purified by silica gel chromatography (gradient elution: 3:1→1:1 hexanes:EtOAc) to give the desired product (160 mg, 38%) as a brown oil; 1 H NMR (CDCl3, 400MHz) δ7.95 (s, 1H), 7.49 (d, 2H, J = 7.4Hz), 7.43–7.30 (m, 3H), 7.26 (s, 1H), 7.15 (d, 1H, J = 2.3Hz), 7.06 (d ,1H,J=2.2Hz),6.96(dd,1H,J=8.8,2.4Hz),5.12(s,2H),3.89(t,2H,J=6.3Hz),3.00(t,2H,J=6.3Hz),1.59(s,1H)ppm; 13 C NMR (CDCl3, 100MHz) δ153.25, 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, 28.77ppm; IR (Smart iTX diamond) ν3419, 3062, 3032, 2929, 2878, 1624, 1582, 1483, 1454, 1381, 1293, 1219, 1194, 1064, 1043, 1025, 797, 740, 698cm -1 ; LC-MS(ES+)C 17 H 18 The calculated value of NO2[M+H] is 268.13, and the measured value is 268.24.

[0284] Example 7. Compounds 9a and 9b

[0285] First, the hydroxyl group of the above-mentioned tryptophan is converted into iodide. In order to complete this conversion, a solution of iodine (251 mg, 0.99 mmol, 1.4 equivalents) and triphenylphosphine (260 mg, 0.99 mmol, 1.4 equivalents) in DCM (2.75 mL, 0.25 M) is cooled to 0 ° C. Then, tryptophan (0.71 mmol, 1.0 equivalents) is added dropwise. The solution is stirred until TLC determines that the starting material has been consumed (~ 5 hours). The reaction mixture is concentrated under reduced pressure to obtain an alkyl iodide, which can be used immediately without further purification.

[0286] In a separate flask, 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 N2 atmosphere. The flask was then purged with H2 gas and stirred vigorously under H2 atmosphere until the starting material was consumed as determined by TLC (~3 hours). The mixture was filtered over a pad of celite and washed with 50 mL of MeOH containing 1% NH4OH aqueous solution. The filtrate was then dried over Na2SO4 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 mixture containing unpurified alkyl iodide (271 mg, 1.0 mmol, 1.0 equiv, produced as described above) and solid NaHCO3 (168 mg, 2 mmol, 2 equiv). The mixture was heated at 80 ° C for 20 hours, then cooled to room temperature and diluted with 1M Na2CO3 aqueous solution (15mL) and EtOAc (15mL). The aqueous layer was extracted with EtOAc (3×10mL). The combined organic extracts were washed with H2O (10mL), 5% LiCl aqueous solution (10mL) and brine (10mL), then dried over Na2SO4 and concentrated under reduced pressure. The product was purified by silica gel chromatography (100:1DCM:MeOH, containing 0.5% NH4OH).

[0287]

[0288] Isolated as a tan solid (30 mg, 24%, 2 steps); 1H NMR (CDCl3, 400MHz) δ7.95 (s, 1H), 7.64 (d, 1H, J = 7.8Hz), 7.35 (d, 1H, J = 8.0Hz), 7.24–7. 16(m,1H),7.16–7.10(m,1H),7.05(d,1H,J=1.8Hz),3.19–3.12(m,1H),2.96–2.72(m,4H) ,2.49(s,1H),2.36(d,1H,J=9.2Hz),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=7.1Hz)ppm; 13 C NMR (CDCl 3 ,100MHz)δ136.29,127.83,121.84,121.65,119.13,119.04,115.21,111.15,56.89,56.82,53.30,40.62,32.87,27.44,26.95,25.35,24.40,21.97,12.04ppm;IR(Smart iTX diamond)ν3418,3170,3055,2930,2860,2798,1456,1357,1228,1147,1092,740cm -1 ; LC-MS(ES+)C 19 H 26 Calculated value of N2[M+H]: 283.22, found: 283.35.

[0289] Example 8. Compounds 10a and 10b

[0290]

[0291] Isolated as an amorphous brown solid (71.2 mg, 44%, 2 steps); 1H NMR (CDCl3, 400MHz) δ8.05 (s, 1H), 7.23 (d, 1H, J = 8.7Hz), 7.09 (d, 1H, J = 2.0Hz), 7.04–6. 98(m,1H),6.86(dd,1H,J=8.8,2.3Hz),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=9.3Hz),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=7.1Hz)ppm; 13 C NMR (CDCl3, 100MHz) δ153.91, 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, 12.03ppm; IR (Smart iTX diamond) ν3415, 3045, 2931, 2860, 2828, 1624, 1585, 1485, 1456, 1215, 1172, 1064, 1032, 796cm -1 ; LC-MS (ES+) calculated value for C20H29N2O [M+H] 313.23, found 313.34.

[0292]

[0293] Isolated as an amorphous brown solid (56 mg, 18%, 2 steps); 1H NMR (CDCl3, 400MHz) δ8.05 (s, 1H), 7.23 (d, 1H, J = 8.7Hz), 7.09 (d, 1H, J = 2.0Hz), 7.04–6. 98(m,1H),6.86(dd,1H,J=8.8,2.3Hz),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=9.3Hz),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=7.1Hz)ppm; 13 C NMR (CDCl3, 100MHz) δ153.91, 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, 12.03ppm; IR (Smart iTX diamond) ν3415, 3045, 2931, 2860, 2828, 1624, 1585, 1485, 1456, 1215, 1172, 1064, 1032, 796cm -1 ; LC-MS(ES+)C 20 H 29 The calculated value of N2O[M+H] is 313.23, and the measured value is 313.34.

[0294] Example 9. Compounds 11a and 11b

[0295] First, 5-benzyloxy-isoquinuclidine is synthesized as described above. Next, under N2 atmosphere, the starting material (100mg, 0.26mmol, 1.0 equivalent) is dissolved in MeOH (1.3mL, 0.2M) containing 10% Pd / C (22mg, 0.02mmol, 0.08 equivalent). Then use H2 gas to purge the flask and stir vigorously under H2 atmosphere until the starting material as determined by TLC is consumed (~24 hours). The mixture is filtered on a diatomaceous earth pad and washed with 50mL of MeOH containing 1% NH4OH aqueous solution. Then use Na2SO4 to dry the filtrate and concentrate under reduced pressure to obtain a brown oil. The product is purified by silica gel chromatography (30:1DCM:MeOH, containing 1% NH4OH).

[0296]

[0297] Isolated as a tan foam (32 mg, 41%, 3 steps); 1 H NMR (CDCl3, 400MHz) δ7.96 (s, 1H), 7.14 (d, 1H, J = 8.6Hz), 6.94 (s, 1H), 6.83 (d, 1H, J = 1.8 Hz),6.80–6.72(dd,1H,J=8.6,1.8Hz),5.74(bs,1H),3.13(dt,1H,J=9.2,2.9Hz),2.93– 2.71(m,4H),2.56–2.49(m,1H),2.35(d,1H,J=9.5Hz),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=7.1Hz)ppm; 13 C NMR (CDCl3, 100MHz) δ149.82, 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, 12.17ppm; IR (Smart iTX diamond) ν3400, 3278, 2929, 2860, 1625, 1581, 1456, 1362, 1186, 1092, 936, 796, 754cm -1 ; LC-MS(ES+)C 19 H 27 The calculated value of N2O[M+H] is 299.21, and the measured value is 299.34.

[0298]

[0299] Isolated as a tan foam (20 mg, 15%, 3 steps); 1H NMR (CDCl3, 600MHz) δ7.98 (s, 1H), 7.16 (d, 1H, J = 8.6Hz), 6.94 (s, 1H), 6.88 (d ,1H,J=2.0Hz),6.78(dd,1H,J=8.6,2.2Hz),3.03–2.92(m,4H),2.76–2.71(m,1 H),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=7.4Hz)ppm; 13 C NMR (CDCl3, 150MHz)δ150.66,131.34,128.18,122.68,113.51,113.03,112.03,103.77,57.33,55.57,54.52,34.85,32.65,27.52,26.35,24.90,24.01,19.49,12.09ppm; IR (Smart iTX diamond)ν3402,3286,2924,2857,1625,1581,1456,1377,1208,1080,936,795,751cm -1 ; LC-MS(ES+)C 19 H 27 The calculated value of N2O[M+H] is 299.21, and the measured value is 299.34.

[0300] Example 10. Compound 12

[0301] To a solution of 4-substituted phenylhydrazine hydrochloride (1.0 mmol) in EtOH (0.1 M) was added 1-methylazacycloheptane-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 hours and then concentrated under reduced pressure. The oily residue was dissolved in DCM (~25 mL) and basified with 1 M NaOH aqueous solution (~20 mL). The aqueous layer was extracted with DCM (3×20 mL). The combined organic extracts were dried over Na2SO4 and concentrated under reduced pressure to produce an oil, which was purified by silica gel chromatography (20:1 DCM:MeOH, containing 0.5% NH4OH).

[0302] General solution:

[0303]

[0304] Isolated as a brown solid (127 mg, 64%); 1 H NMR (CDCl3, 400MHz) δ7.78 (s, 1H), 7.50–7.43 (m, 1H), 7.28 (d, 1H, J = 1.6Hz) ,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--,, ,100MHz)δ136.10,134.68,129.05,121.12,119.36,117.74,112.89,110.44,58.05,56.30,46.16,28.59,23.95ppm;IR(Smart iTX diamond)ν3140,3055,3032,2904,2829,2756,1451,1337,739cm -1 ; LC-MS (ES + )C 13 H 17 Calculated value of N2[M+H] 201.14, found 201.33.

[0305] Example 11. Compound 13

[0306]

[0307] Isolated as a light brown solid (146 mg, 63%; 1 H NMR (CDCl3, 400MHz) δ7.74 (s, 1H), 7.15 (d, 1H, J = 8.7Hz), 6.92 (d, 1H, J = 2.4Hz) ,6.77(dd,1H,J=8.7,2.4Hz),3.85(s,3H),2.98–2.82(m,8H),2.53(s,3H)ppm; 13 C 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 ; LC-MS (ES + )C 14 H 19The calculated value of N2O[M+H] is 231.15, and the measured value is 231.32.

[0308] Example 12 Compound 14

[0309]

[0310] Synthesized from p-benzyloxyhydrazine, then p-benzyl is hydrogenated. After Fisher indole cyclization, benzyloxyindole is added to a mixture of 10% Pd / C (0.08 equivalent) in MeOH (4.6mL) under N2 atmosphere. The slurry is stirred at room temperature for 12 hours, filtered through a small diatomaceous earth pad, and rinsed with 50mL methanol and 1% ammonium hydroxide. The filtrate is concentrated under reduced pressure to a brown oil. The desired product is purified by silica gel chromatography (30:1DCM:MeOH, containing 0.5%NH4OH) to obtain a white crystalline solid (80mg, 40%, two steps). 1 H NMR(DMSO-d6,400MHz)δ10.32(s,1H),8.46(s,1H),6.99(d,1H,J=8.5Hz),6.65(d,1H,J=2 .2Hz),6.47(dd,1H,J=8.5,2.2Hz),2.87–2.79(m,2H),2.70–2.68(m,6H),2.39(s,3H)ppm; 13 C 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 .LC-MS(ES + )C 13 H 17 The calculated value of N2O[M+H] is 217.13, and the measured value is 217.32.

[0311] Example 13. Compound 15

[0312]

[0313] Isolated as a yellow solid (97 mg, 88%); 1H NMR (CDCl3, 400MHz) δ7.79 (s, 1H), 7.16 (dd, 1H, J = 8.8, 4.4Hz), 7.09 (dd, 1H, J = 9.77, 2.3 7Hz),6.84(td,1H,J=9.0,2.4Hz),3.01–2.92(m,2H),2.91–2.80(m,6H),2.52(s,3H)ppm. 13 C 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), 109.11 (d, J = 26.3 Hz), 102.86 (d, J = 23.4 Hz), 57.95, 56.19, 46.21, 28.77, 24.09 ppm. IR (SmartiTX diamond) ν 3146, 3103, 3040, 2929, 2880, 2809, 2753, 1584, 1453, 1169, 1103, 932, 855, 794, 767, 749 cm -1 .LC-MS(ES + )C 13 H 16 The calculated value of FN2[M+H] is 219.13, and the found value is 219.31.

[0314] Example 14. Compound 16

[0315]

[0316] Isolated as a yellow solid (89 mg, 62%); 1 H NMR (CDCl3, 400MHz) δ7.99 (s, 1H), 7.41 (d, 1H, J = 1.7Hz), 7.14 (d, 1H, J = 8.5Hz), 7.04 (dd, 1H, J = 8.5, 1.9Hz), 2.98–2.79 (m, 8H), 2.52 (s, 3H) ppm; 13 C NMR (CDCl3, 100MHz) δ137.82, 133.01, 130.16, 125.00, 121.13, 117.33, 112.68, 111.37, 57.84, 56.08, 46.04, 28.55, 23.85ppm; IR (Smart iTX diamond) ν3128, 3085, 3020, 2922, 2849, 2736, 2694, 1446, 1361, 1316, 1052, 917, 851, 783, 718, 601cm-1 .LC-MS(ES + )C 13 H 16 Calculated value of ClN2[M+H] 235.10, found 235.30.

[0317] Example 15. Compound 17

[0318]

[0319] Isolated as a brown solid (161 mg, 65%); 1 H NMR (CDCl3, 400MHz) δ7.93 (s, 1H), 7.57 (d, 1H, J = 1.24Hz), 7.17 (dd, 1H, J = 8.5, 1.5Hz), 7.10 (d, 1H, J = 8.5Hz), 2.99–2.77 (m, 8H), 2.52 (s, 3H) ppm; 13 C NMR (CDCl3, 100MHz) δ137.66, 133.27, 130.84, 123.71, 120.45, 112.66, 112.58, 111.82, 57.86, 56.11, 46.12, 28.62, 23.91ppm; IR (Smart iTX diamond) ν3126, 3082, 3020, 2922, 2848, 2733, 1575, 1450, 1316, 1113, 1046, 914, 852, 781, 739, 594cm -1 .LC-MS(ES + )C 13 H 16 Calculated value of BrN2[M+H] 279.05, found 279.22.

[0320] Example 16. Compound 18

[0321] Compound 18 (TBG) was prepared similarly to compounds 12-17 with slight modifications.

[0322] General solution:

[0323]

[0324] 3-Methoxyaniline (2.2 ml, 20.0 mmol, 1.0 equiv) was added dropwise to an ice-cold 6M aqueous HCl solution (15 mL). Next, NaNO2 (1.520 g, 22.0 mmol, 1.1 equiv) was dissolved in H2O (15 mL) and slowly added to the solution. After stirring at 0°C for 15 minutes, SnCl2 (11.4 g, 60.0 mmol, 3.0 equiv) dissolved in concentrated aqueous HCl solution (15 mL) was added dropwise to the solution. After stirring at 0°C for 2.5 hours, the reaction mixture was filtered, washed with hexane, and dried under reduced pressure to give the product as a light yellow solid, which was used without further purification.

[0325] 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-methylazacycloheptane-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 hours 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 (3×20 mL). The combined organic extracts were dried over Na2SO4 and concentrated under reduced pressure to produce a mixture of 6- and 4-substituted indoles. The 6-substituted indoles were purified by silica gel chromatography (10:1 DCM:MeOH, containing 0.5% NH4OH).

[0326]

[0327] Isolated as a light yellow solid (379 mg, 55%); 1 H NMR (CDCl3, 400MHz) δ7.67 (br s, 1H), 7.32 (d, 1H, J = 8.5Hz), 6.80–6.73 (m, 2H), 3.83 (s, 3H), 2.98–2.83 (m, 8H), 2.53 (s, 3H) ppm; 13 CNMR (CDCl3, 100MHz) δ155.93, 135.33, 134.68, 123.59, 118.29, 112.53, 108.80, 94.66, 57.98, 56.34, 55.95, 45.93, 28.36, 23.91ppm; IR (Smart iTX diamond) ν3153, 3121, 3073, 2940, 2879, 1628, 1458, 1197, 1033, 910, 834, 799cm -1 ; LC-MS (ES + )C14 H 19 The calculated value of N2O[M+H] is 231.15, and the measured value is 231.36.

[0328] Example 17. Preparation of Compound 131 / 2 Fumarate

[0329] Fumaric acid (116 mg, 1.0 mmol, 0.8 eq) 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 13 free base (288 mg, 1.25 mmol, 1.0 eq) in acetone (1 mL) was added and the mixture was cooled in a refrigerator 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, 400MHz) δ7.15 (d, 1H, J = 8.7Hz), 6.92 (s, 1H), 6.72 (d, 1H, J = 8.7Hz), 6.68 (s, 1H), 3.80(s,3H),3.42–3.34(m,4H),3.18(t,2H,J=5.5Hz),3.10(t,2H,J=5.5Hz),2.91(s,3H)ppm; 13 C NMR (CD3OD, 100MHz) δ171.76, 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, 21.55ppm. IR (Smart iTX diamond) ν3384, 2979, 2924, 2297, 2822, 1695, 1551, 1353 1167, 982, 912, 802cm -1 ; LC-MS (ES + )C 14 H 19 The calculated value of N2O[M+H] is 231.15, and the measured value is 231.36.

[0330] Example 18. Preparation steps of compound 18 fumarate

[0331] 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 18 free base (193 mg, 0.84 mmol, 1.0 equiv) in acetone (1 mL) was added, and the mixture was cooled in a refrigerator overnight. The solid was filtered, washed with acetone, and dried under reduced pressure to obtain 18 fumarate, which was a 1:1 salt (187 mg, 64%).1 H NMR (CD3OD, 400MHz) δ7.28 (d, 1H, J = 8.7Hz), 6.82 (s, 1H), 6.71 (s, 2H), 6.68 (d, 1H, J = 8.7Hz), 3.79(s,3H),3.54–3.45(m,4H),3.22(t,2H,J=5.3Hz),3.13(t,2H,J=5.3Hz),3.00(s,3H)ppm; 13 C NMR (CD3OD, 100MHz) δ170.71, 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, 21.35ppm; IR (Smart iTX diamond) ν3375, 3008, 2899, 2505, 1694, 1556, 1337, 1162, 1034, 967, 814, 775cm -1 ; LC-MS (ES + )C 14 H 19 The calculated value of N2O[M+H] is 231.15, and the measured value is 231.36.

[0332] Example 19. Large-scale preparation steps of compound 18 fumarate salt

[0333] 3-Methoxyaniline (4.4 ml, 40.0 mmol, 1.0 equiv) was added dropwise to an ice-cold 6M aqueous HCl solution (30 mL). Next, NaNO2 (3.040 g, 44.0 mmol, 1.1 equiv) was dissolved in H2O (30 mL) and slowly added to the solution. After stirring at 0°C for 15 min, SnCl2 (22.8 g, 120.0 mmol, 3.0 equiv) dissolved in concentrated aqueous HCl solution (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 as a light yellow solid (5.4 g, 78%), which was used without further purification.

[0334] To a solution of 3-methoxyphenylhydrazine hydrochloride (4.802 g, 27.6 mmol, 3.0 equiv) in 0.15 M EtOH (60 mL) was added 1-methylazacycloheptane-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 hours 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 (3×30 mL). The combined organic extracts were dried over Na2SO4 and concentrated under reduced pressure to produce a mixture of 6- and 4-substituted indoles. EtOAc was added to the unpurified product mixture to precipitate the 6-substituted isomer, which was separated by filtration. The mother liquor was concentrated and the process was repeated six times until a total of 1.028 g of thecatheline analog free base was collected (49%).

[0335] Next, fumaric acid (408 mg, 3.5 mmol, 0.8 equivalent) was added to a sealed tube containing acetone (20 mL). The solution was carefully heated until all the fumaric acid was dissolved. After the solution was cooled to room temperature, a solution of 18 free alkali (1.028 mg, 4.4 mmol, 1.0 equivalent) in acetone (5 mL) was added dropwise, and the mixture was cooled in a refrigerator overnight. The solid was filtered, washed with acetone, and dried under reduced pressure to obtain 18 fumarate salts, which were 1:1 salts (1.055 g, 69%).

[0336] Example 20. Common steps of Examples 21 to 24

[0337] General synthetic scheme:

[0338]

[0339] General steps:

[0340] To a solution of substituted phenylhydrazine hydrochloride (1.0 mmol) in EtOH (0.1 M) was added 1-methylazepan-4-one hydrochloride (1.0 eq) followed by concentrated aqueous HCl (6.0 eq). The mixture was refluxed for 24 h and the progress of the reaction was monitored by TLC.

[0341] Post-treatment and purification procedures: After the reaction was completed, the reaction mixture was concentrated under reduced pressure. The oily residue was dissolved in DCM (~25mL) and alkalized with 1M NaOH aqueous solution (~20mL). The aqueous layer was extracted with DCM (3×20mL). The combined organic extracts were dried with Na2SO4 and concentrated under reduced pressure to obtain an oil, which was purified by combi-flash using 0.5% NH4OH and different percentages of MeOH in CH2Cl2. The cleaner fractions were evaporated by TLC, and the obtained residue was then diluted with EtOAc and washed with water several times. The organic layer was separated, then evaporated and dried to obtain the pure product.

[0342] Some compounds were purified by preparative HPLC purification as described above for the respective target compounds.

[0343] Example 21. Compound 19

[0344]

[0345] Yield: 150 mg (8%, off-white solid). LCMS: 99%, m / z=217.1 [M+H] +1 HNMR (DMSO-d6, 400MHz): δ10.42(s,1H),7.20(d,J=8.56Hz,1H),6.72(d,J=2.20Hz,1H),6.57( dd,J=2.20,8.56Hz,1H),3.72(s,3H),2.87-2.91(m,4H),2.79-2.82(m,2H),2.68-2.72(m,2H).

[0346] Example 22. Compound 20 and Compound 21

[0347]

[0348] The crude product was purified by preparative HPLC to give fraction 1 and fraction 2. 1 By HNMR, fraction 2 was the above-mentioned left-hand compound, and fraction 1 was the above-mentioned right-hand compound.

[0349] Preparative HPLC purification method:

[0350] Preparative HPLC column: Viridis BEH-2EP OBD (250*19mm, 5μ)

[0351] Mobile phase A: 0.1% DEA in n-hexane

[0352] Mobile phase B: EtOH:MeOH (50:50)

[0353] Flow rate: 16.0mL / min

[0354] Isotonix table:

[0355] time ％A ％B 0 90 10 25 90 10

[0356] Dilution solvent: methanol / ethanol

[0357] Compound 20: Yield: 12.8% (80 mg, light brown solid). LCMS: 99.2%, m / z=285.2 [M+H] +1 HNMR(DMSO-d6,400MHz): δ10.97(s,1H),7.43(d,J=8.56Hz,1H),7.18(d,J=0.8 6Hz,1H),6.87-6.92(m,1H),2.88-2.93(m,2H),2.72-2.83(m,6H),2.41(s,3H).

[0358] Compound 21: Yield: 1.6% (10 mg, off-white solid). LC-MS: 99.6%, m / z=285.2 [M+H] +1 HNMR (DMSO-d6, 400MHz): δ11.20 (br s, 1H), 7.27 (d, J = 8.07Hz, 1H), 7.02 (t, J = 7.95Hz, 1H), 6.87 (br d,J=7.09Hz,1H),2.97-3.00(m,2H),2.91-2.94(m,2H),2.69-2.73(m,4H),2.40(s,3H).

[0359] Example 23. Compound 22

[0360]

[0361] Preparative HPLC purification method:

[0362] Preparative HPLC column: X-select CSH C18 (250*19mm), 5um

[0363] Mobile phase A: Acetonitrile

[0364] Mobile phase B: 0.05% ammonia in water

[0365] Flow rate: 15.0mL / min

[0366] Isotonix table:

[0367] time ％A ％B 0.01 20 80 3.00 20 80 20.00 30 70 24.00 30 70 24.10 100 0 30.00 100 0 30.10 20 80 35.00 20 80

[0368] Dilution solvent: Acetonitrile / MeOH

[0369] Yield: 15.6% (30 mg, off-white solid). LCMS: 99.6%, m / z=261.1 [M+H] +1 HNMR (DMSO-d6, 400MHz): δ10.32(s,1H),6.87(s,1H),6.76(s,1H),3.73(d,J=1.59Hz,6H),2.81-2.85(m,2H),2.68-2.74(m,6H),2.39(s,3H).

[0370] Example 24. Compound 23

[0371]

[0372] Yield: 220 mg (34%, light brown solid). LCMS: 100%, m / z=245.1 [M+H] +1 HNMR(DMSO-d6,400MHz): δ10.45(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).

[0373] Example 25. Compound 24 and Compound 25

[0374]

[0375] The crude product was purified by preparative HPLC to give fraction 1 and fraction 2. 1 HNMR, fraction 1 is # (left), and fraction 2 is # (right).

[0376] Preparative HPLC purification method:

[0377] Preparative HPLC column: Viridis BEH-2EP OBD (250*19mm, 5μ)

[0378] Mobile phase A: 0.1% DEA in n-hexane

[0379] Mobile phase B: EtOH:MeOH (50:50)

[0380] Flow rate: 16.0mL / min

[0381] Isotonix table:

[0382] time ％A ％B 0 97.2 2.8 25 97.2 2.8

[0383] Dilution solvent: Methanol / Ethanol

[0384] Compound 24: Yield: 9.1% (80 mg, off-white solid). LCMS: 98.7%, m / z=215.2 [M+H] +1 HNMR(DMSO-d6,400MHz): δ10.47(s,1H),7.22(d,J=7.95Hz,1H),7.00(s,1H),6.74(dd ,J=0.98,7.95Hz,1H),2.84-2.88(m,2H),2.70-2.76(m,6H),2.40(s,3H),2.35(s,3H).

[0385] Compound 25: Yield: 3.4% (30 mg, off-white solid). LC-MS: 95.8%, m / z=215.2 [M+H]+ 1 HNMR(DMSO-d6,400MHz): δ10.68(br s,1H),7.05(d,J=7.95Hz,1H),6.82(t,J=7.52Hz,1H),6.62(d,J=7.09Hz,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).

[0386] Example 26. Compound 26 and Compound 27

[0387]

[0388] The crude product was purified by preparative HPLC to give fraction 1 and fraction 2. 1 HNMR, fraction 1 is # (right), and fraction 2 is # (left).

[0389] Preparative HPLC purification method:

[0390] Preparative HPLC column: Chiralpak IC (250*30mm, 5μ)

[0391] Mobile phase A: 0.1% DEA in n-hexane

[0392] Mobile phase B: EtOH:MeOH (80:20)

[0393] Flow rate: 35.0mL / min

[0394] Isotonix table:

[0395] time ％A ％B 0 90 10 20 90 10

[0396] Dilution solvent: Methanol / Ethanol

[0397] Compound 26: Yield: 24.6% (160 mg, off-white solid). LCMS: 100%, m / z=245.1 [M+H]+ 1 HNMR(DMSO-d6,400MHz): δ10.33(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).

[0398] Compound 27: Yield: 3.1% (20 mg, off-white solid). LC-MS: 100%, m / z=245.1 [M+H]+ 1 HNMR (DMSO-d6, 400MHz): δ10.63 (s, 1H), 6.89 (d, J = 8.07Hz, 1H), 6.75 (d, J = 8.07Hz, 1H), 3.6 5(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).

[0399] Example 27. Compound 28

[0400]

[0401] Compound 28: Yield: 4.7% (30 mg, light brown solid). LC-MS: 96.2%, m / z=261.2 [M+H] +1 HNMR(DMSO-d6,400MHz): δ10.44(s,1H),6.32(d,J=1.96Hz,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=3.24,6.17Hz,4H),2.35(s,3H).

[0402] Plasticity Effect

[0403] As shown by Shor's analysis ( Figure 3 Treatment of rat embryonic cortical neurons with TBG resulted in an increase in dendritic spine complexity at day 6 in vitro (DIV6), as measured by AC). The effect of TBG on dendritic growth appeared to be 5-HT2A-dependent, as pretreatment with ketanserin, a 5-HT2A antagonist, completely abolished its effect ( Figure 3 D), which further validates the in vitro receptor analysis.

[0404] In addition to promoting dendritic growth, TBG also increased dendritic spine density to an extent comparable to that of ibogaine in mature cortical cultures (DIV20) ( Figure 3 E and Figure 3 F). Using transcranial 2-photon imaging ( Figure 3 G) The effects of TBG on cortical dendritic spine dynamics in vivo were assessed. First, spines were imaged at specific dendritic sites defined by their relationship to vasculature and dendritic architecture. Next, animals were systemically administered vehicle, TBG, or the hallucinogenic 5-HT2A agonist 2,5-dimethoxy-4-iodoamphetamine (DOI). 24 hours later, the same dendritic segments were re-imaged and the number of spines gained or lost was quantified. Neither TBG nor DOI affected spine elimination. Both compounds increased spine formation in the primary sensory cortex of mice ( Figure 3 H and Figure 3 I).

[0405] Since increased plasticity of cortical structures in the anterior brain mediates the sustained (>24 h) antidepressant-like effects of ketamine and plays a role in the therapeutic effects of 5-HT2A agonists, the effects of TBG on forced swim test (FST) behavior were evaluated. Figure 4 A and Figure 4 B). First, a pre-test was used to induce a depressive phenotype. Drugs were administered 24 h after the pre-test, and FST was performed 24 h and 7 d after drug administration. At 24 h after drug administration, both ketamine and TBG significantly reduced immobility.

[0406] To evaluate the anti-addictive potential of TBG, a drinking paradigm that mimics heavy drinking and binge drinking behavior in humans was used. Using a 2-bottle choice setup (20% ethanol (v / v), EtOH versus water, H2O), mice underwent repeated cycles of binge drinking and abstinence over the course of 7 weeks ( Figure 4 C). This schedule resulted in substantial EtOH consumption (11.44 ± 0.76 g / kg / 24 h) and binge drinking behavior (3.89 ± 0.33 g / kg / 4 h) and produced blood alcohol levels comparable to those of human subjects with alcohol use disorder (AUD). Next, TBG or vehicle was administered by intraperitoneal injection 3 h before the drinking session, and EtOH and H2O consumption were monitored ( Figure 4 C) Figure 4 As shown in D, TBG significantly reduced alcohol consumption during the first 4 h, with every animal (19 total) reducing EtOH consumption. Water intake was not affected ( Figure 4 D). Ethanol consumption was lower for at least two days after TBG administration, with no effect on water intake ( Figure 4 E). Previously, similar effects were observed for ibogaine, suggesting that TBG may be a highly effective drug for the treatment of AUD.

[0407] Biological Protocols

[0408] Data analysis and statistics. Treatments were randomized and data were analyzed by an experimenter blinded to treatment conditions. Statistical analyses were performed using GraphPad Prism (version 8.1.2), unless otherwise stated. All contrasts were planned before conducting each experiment. Data are presented as mean ± SEM, and asterisks indicate *p<0.05, **p<0.01, ***p<0.001, and ****p<0.0001, unless otherwise stated. Box plots depict three quartile values ​​of the distribution, with whiskers extending to points within 1.5 IQR (interquartile range) of the lower and upper quartiles. Observations outside this range are displayed separately. For Figure 2 B, 3C, 3D, 3F, 3I, 4B, and 5B, one-way ANOVA with Dunnett's post hoc test was used to compare compound-treated groups to the VEH control group. Figure 2 E and F, time 0 hour and time 1 hour (before and after drug administration, respectively) were compared using paired t-test. Figure 2 1 and 11, compound treatment groups were compared using Fisher's exact test, p values ​​are shown in the text. Figure 4 D, Data were analyzed using paired t test. Figure 4 E, Data were analyzed using two-way ANOVA with Sidak's post hoc test.

[0409] Drugs. Ibogaine hydrochloride (IBO) and noribogamine (NOR) were provided by the NIH Drug Supply Program. Other chemicals were purchased from commercial sources, such as ketamine hydrochloride (KET, Fagron), ketanserin (KETSN, ApexBio), eugenol (Tokyo Chemical Industry Co., Ltd.), and 5-hydroxytryptamine (Sigma-Aldrich). The fumarate salt of 5-methoxy-N,N-dimethyltryptamine (2:1, 5-MeO-DMT:fumaric acid) was synthesized in-house as described previously and was judged 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%). The free base was used for all cell experiments, while the fumarate salts of ibogaine analogs and chamoline analogs were used for in vivo studies.

[0410] Animals. All experimental procedures involving animals were approved by the Institutional Animal Care and Use Committee (IACUC) of UCD, UCSF, or UCSC and adhered to the principles described in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. UC Davis (UCD), UC San Francisco (UCSF), and UC Santa Cruz (UCSC) are accredited by the Association for Assessment and Accreditation of Laboratory Animal Care International (AAALAC).

[0411] Calculation of CNS MPO score. CNS MPO score was calculated using previously published methods. Predicted PKA values ​​were determined using MarvinSketch (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) ).

[0412] Dendrite generation experiments. For dendrite generation experiments using cultured cortical neurons, timed-pregnancy Sprague Dawley rats were obtained from Charles River Laboratories (Wilmington, MA). Complete culture, staining, and analysis details were performed as previously described. (Dunlap, L. et al., 2019)

[0413] Head Twitch Response (HTR). The head twitch response assay was performed as previously described using male and female C57BL / 6J mice (2 mice per treatment). Mice were obtained from Jackson Laboratories (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 a vehicle. As a positive control, 5-MeO-DMT fumarate (2:1 amine / acid) was used, which was synthesized as previously described. Behavior was videotaped and subsequently scored by two blinded observers, and the results were averaged (Pearson correlation coefficient = 0.93).

[0414] hERG inhibition studies. All experiments were performed manually at room temperature in the whole-cell mode of the patch clamp technique using an EPC-10 amplifier (HEKA, Lambrecht / Falz, Germany). HEK-293 cells stably expressing hKv11.1 (hERG) under G418 selection were a generous gift from Craig Janueri (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. Prior to the experiments, cells were cultured to 60–80% confluence and digested with TrypLE and seeded onto poly-L-lysine-coated coverslips. Patch pipettes were pulled from soda-lime glass (microhematocrit tubes) with a resistance of 2–4 MΩ. For the external solution, normal Ringer's sodium (160mM NaCl, 4.5mM KCl, 2mM CaCl2, 1mM MgCl2, 10mM HEPES, pH7.4 and 290-310mOsm) was used. The internal solution used was potassium fluoride (160mM KF, 2mM MgCl2, 10mM EGTA, 10mM HEPES, 4mM NaATP, pH=7.2 and 300-320mOsm) containing ATP. A 2-step pulse (applied once every 10 seconds), first added to 40mV for 2 seconds from -80mV, then to -60mV for 4 seconds, was used to induce hERG current. The percentage reduction of the tail current amplitude caused by the drug was determined, and the data were shown as mean + / -SD. For all experiments, drug solutions were freshly prepared from 10mM stock solutions in DMSO. The final DMSO concentration never exceeded 1%.

[0415] Serotonin and Opioid Receptor Functional Assays. Functional assay screens for 5-HT and opioid receptors were performed in parallel using the same compound dilutions and a high-throughput assay platform in a 384-well format. The assays evaluated the activity of all human isoforms of the receptors, with the exception of the mouse 5-HT2A receptor where noted. Receptor constructs in pcDNA vectors were generated from a slightly modified Presto-Tango GPCR library. 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 assayed using the FLIPR TETRA(Molecular Instruments) were dispensed into 384-well assay plates. Each plate contained positive controls such as 5-HT (for all 5-HT receptors), DADLE (DOR), KOR, and DAMGO (MOR). For measuring 5-HT2A, 5-HT2B, and 5-HT2C Gq-mediated calcium flux functions, HEK Flp-In 293T-Rex stable cell lines (Invitrogen) were loaded with Fluo-4 dye for one hour, stimulated with compounds, and incubated at 25°C on a FLIPR TETRA Baseline (0-10 seconds) and peak fluorescence in multiples over baseline (5 minutes) were read on the ELISA. For measurements of 5-HT6 and 5-HT7a functional assays, drugs were incubated for 15 minutes at 25°C and Gs-mediated cAMP accumulation was detected in HEKT cells using a split-luciferase GloSensor assay measuring luminescence on a Microbeta Trilux (PerkinElmer). For 5-HT1A, 5-HT1B, 5-HT1F, MOR, KOR, and DOR functional assays, Gi / o-mediated cAMP inhibition was measured in HEKT cells using a split-luciferase GloSensor assay, and experiments were performed similarly to those described above, but in combination with 0.3 μM isoproterenol (5-HT1A, 5-HT1B, 5-HT1F) or 1 μM forskolin (MOR, KOR, and DOR) to stimulate endogenous cAMP accumulation.

[0416] For measurements of 5-HT1D, 5-HT1E, 5-HT4, and 5-HT5A functional assays, β-arrestin 2 recruitment was measured by the Tango assay using HTLA cells expressing TEV fusion-β-arrestin 2 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 derive Emax and EC 50 Parameter estimates.

[0417] 5HT 2A Sensor analysis. A HEK293T (ATCC) 5HT2A sensor stable line (sLight 1.3s) was generated by lentiviral transduction of HIV-EF1α-sLight1.3 and propagated from a single colony. Lentivirus was produced using the second generation lentiviral plasmids pHIV-EF1α-sLight1.3, pHCMV-G, and pCMV-δR8.2.

[0418] To screen 41 compounds, sLight1.3s cells were seeded in 96-well plates at a density of 40,000 24 hours before imaging. On the day of imaging, compounds dissolved in DMSO were diluted from a 100mM stock solution to working concentrations of 1mM, 100μM, and 1μM, with a DMSO concentration of 1%. Immediately before imaging, cells grown in DMEM (Gibco) were washed 2 times with HBSS (Gibco), and 180μL HBSS (agonist mode) or 160μL HBSS (antagonist mode) was added to each well after the last wash. For the agonist mode, images were taken before and after 20μL of compound working solution was added to a well containing 180μL HBSS. This produced final compound concentrations of 100μM, 10μM, and 100nM, with a DMSO concentration of 0.1%. For antagonist mode, images were taken before and after adding 20 μL of 900 nM 5-HT and again after adding 20 μL of compound working solution to produce a final concentration of 100 nM of 5HT and a final concentration of 100 μM, 10 μM, and 100 nM of compound, with a DMSO concentration of 0.1%. For each concentration (100 μM, 10 μM, and 100 nM), each compound was tested in triplicate (3 wells). In addition, within each plate, 100 nM 5HT and 0.1% DMSO controls were also imaged.

[0419] Imaging was performed using a Leica DMi8 inverted microscope with a 40x objective using FITC preset for 460 nm excitation and 512-542 nm emission. For each well, the cell membrane targeting the 5HT2A sensor was automatically focused using adaptive focus control and 5 images were taken from different areas within the well, each image processed with 2 × 2 binning.

[0420] For data processing, membranes from each image were segmented and analyzed using a custom algorithm written in MATLAB, generating a single raw fluorescence intensity value. For each well, the 5 raw fluorescence intensity values ​​generated from the 5 images were averaged and the change in fluorescence intensity (dFF) was calculated as follows:

[0421] dFF=(F sat –F apo ) / F apo

[0422] For both agonist and antagonist modes, the fluorescence intensity value in HBSS alone before adding the compound was used as the F apo The fluorescence intensity value after adding the compound is used as F sat value.

[0423] For agonist mode, data are percent activation relative to 5HT, where 0 is the mean of DMSO wells and 100 is the mean of 100 μM 5HT wells. For antagonist mode, the fractional inactivation was calculated as:

[0424] Fractional inactivation = (dFFF(compound + 5HT) – dFF(5HT)) / dFF(5HT)

[0425] Spining assay. Spining assay was performed as described previously, except that cells were treated at DIV19 and fixed 24 h after treatment at DIV20 (Ly, C. et al., 2018). The images were taken on a Nikon HCA confocal microscope with a 100× / NA 1.45 oil objective. DMSO and ketamine (10 μM) were used as vehicle and positive controls, respectively.

[0426] In vivo spine dynamics. Male and female Thy1-GFP-M mice (n=5 per condition) were purchased from Jackson Laboratory (JAX#007788) and maintained in the UCSC animal facility under IACUC approved protocols. In vivo transcranial two-photon imaging and data analysis were performed as described previously. Briefly, mice were anesthetized by 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 for light transmission. Spines on the apical dendrites of the primary sensory cortex of mice were imaged using a Bruker Ultima IV two-photon microscope equipped with an Olympus water immersion objective (40×, NA=0.8) and a titanium: sapphire laser (Spectrum Physics Mai-Tai, excitation wavelength 920 nm). Images were taken with a zoom of 4.0 (pixel size 0.143×0.143 μm) and a Z step size of 0.7 μm. Mice were injected ip (injection volume = 5 mL / kg) with DOI (10 mg / kg) or TBG (50 mg / kg) immediately after they recovered from anesthesia administered before the first imaging session. Animals were imaged again 24 hours after administration. Dendritic spine dynamics were analyzed using ImageJ. Spine formation and elimination were quantified as a percentage of the number of spines on day 0.

[0427] Forced swimming test (FST). Male C57 / BL6J mice (9-10 weeks old at the time of the experiment, n=10 for each condition) were obtained from Jackson Laboratory and 4-5 mice / cage were housed in UCD animal housing according to IACUC approved protocols. After 1 week in the animal housing, the male experimenter handled each mouse for about 1 minute for 3 consecutive days before the first FST. All experiments were performed by the same male experimenter who performed the treatment. During the FST, mice swam for 6 minutes in a transparent plexiglass cylinder that was 40 cm high, 20 cm in diameter, and filled with 30 cm of 24±1°C water. Fresh water was used for each mouse. After handling and acclimation to the experimenter, the drug-naive mice first performed a pretest swim to more reliably induce a depressive phenotype in the subsequent FST period. The immobility scores of all mice were determined after the pretest, and the mice were randomly assigned to the treatment group to generate groups with similar average immobility scores for the next two FST periods. The next day, animals received an intraperitoneal injection of TBG (50 mg / kg), a positive control (ketamine, 3 mg / kg), or a vehicle (saline). The following day, animals performed the FST and were then returned to their cages. One week later, the FST was performed again to assess the continued effect of the drug. All FSTs were performed between 8 a.m. and 1 p.m. The experiments were videotaped and manually scored offline. Immobility time (defined as passive floating or remaining still with no activity other than that required to keep the mouse's head above the water) was scored during the last 4 minutes of the 6-minute trial.

[0428] Alcohol consumption. Male C57 / BL6J mice (6–8 weeks old) were obtained from Jackson Laboratory (Bar Harbor, ME) and housed individually in a reverse light / dark cycle room (lights on from 10:00 pm to 10:00 am). The temperature was kept constant at 22 ± 2 °C and the relative humidity was maintained at 50 ± 5%. Mice had ad libitum access to food and tap water. After one week of acclimation to the animal housing room, a two-bottle choice drinking paradigm was performed as described previously. Mice had intermittent access to alcohol in their home cages for 7 weeks. On Mondays, Wednesdays, and Fridays, two bottles—one containing 20% ​​ethanol and the other containing only water—were available 24 h. On Tuesdays, Thursdays, Saturdays, and Sundays, animals had access to water only. After 7 weeks, mice were administered TBG (50 mg / kg) or vehicle (saline) by intraperitoneal injection 3 h before the start of alcohol drinking. Ethanol (g / kg) and water (ml / kg) intake were monitored during the first 4 h (initial alcohol binge), the first 24 h, and the second 24 h. Next, when monitoring ethanol and water consumption, animals were given water only for 48 hours before another drinking session began. The placement of the bottle (right or left) was changed during each session to control for orientation preference. Extra bottles in nearby unused cages were used to monitor spillage. Alcohol preference was calculated as the ratio between alcohol / (water+alcohol). Mice were tested using a counterbalanced within-subject design with a one-week drug-free drinking regimen between treatments. One mouse was excluded due to a leaky bottle.

[0429] Although the foregoing invention has been described in some detail by way of illustration and example for the purpose of clear understanding, it will be appreciated by those skilled in the art that certain changes and modifications may be implemented within the scope of the appended claims. In addition, 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 prevail.

Claims

1. A compound having the following structure or a pharmaceutically acceptable salt and isomer thereof: in: R 4 is H, -Me, -OMe or -OCF3; R 5 is H, F, Cl, Br, -Me, -OH or -OMe; R 6 is -Me, -OMe or -OCF3; Or, R 5 and R 6 Combine to form a 1,3-dioxole ring or a 1,4-dioxane ring; and R 7 For H.

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, characterized in that R 5 and R 6 Combine to form 1,3-dioxole ring or 1,4-dioxane ring.

3. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, characterized in that: The compound has the following structure:

4. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, characterized in that: The compound has the following structure: in: R 5 is F, Cl, Br, -OH, -OMe or -Me; Or, R 5 and R 6 Combine to form 1,3-dioxole ring or 1,4-dioxane ring.

5. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, characterized in that: The compound has the following structure: in: R 4 It is H, -OMe, -Me or -OCF3.

6. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, characterized in that: The compound has the following structure: in: R 4 It is -OMe, -Me or -OCF3.

7. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, characterized in that: The compound is:

8. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein The compound is 9. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein The compound is 10. A pharmaceutical composition, characterized in that The invention comprises the compound according to any one of claims 1 to 9 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

11. Use of the compound according to any one of claims 1 to 9 or a pharmaceutically acceptable salt thereof in the preparation of a medicament, wherein the medicament is used to increase neuronal plasticity, characterized in that: The neuronal cell is contacted with the compound or a pharmaceutically acceptable salt thereof in an amount sufficient to increase the neuronal plasticity of the neuronal cell.

12. Use of a compound according to any one of claims 1 to 9 or a pharmaceutically acceptable salt thereof in the preparation of a medicament, wherein the medicament is used to treat brain diseases, characterized in that: The drug comprises a therapeutically effective amount of the compound or a pharmaceutically acceptable salt thereof; The brain disease is a neurodegenerative disease, a psychological disorder, depression, addiction, anxiety, post-traumatic stress disorder, suicidal ideation, bipolar disorder, substance use disorder, schizophrenia, stroke or traumatic brain injury.

13. The use according to claim 12, characterized in that The neurodegenerative disease is Alzheimer's disease or Parkinson's disease.

14. The use according to claim 12, characterized in that The depression is treatment resistant depression.

15. The use according to claim 12, characterized in that The depression is major depressive disorder.

16. The use according to claim 12, characterized in that The substance use disorder is alcohol use disorder.

17. The use according to claim 12, characterized in that The drug comprises one or more other therapeutic agents which are lithium, olanzapine, quetiapine, risperidone, aripiprazole, 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 or clonazepam.

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