N-substituted indoles and other heterocyclic compounds for treating brain disorders

Abstract

To provide compounds and methods of using the compounds for treating brain disorders.SOLUTION: The present invention provides N-substituted indoles and other heterocyclic compound for treating brain disorders.SELECTED DRAWING: Figure 1

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Patent Application No. 62 / 811,206, filed February 27, 2019, and No. 62 / 958,220, filed January 7, 2020, each of which is incorporated by reference in its entirety for all purposes. [Background technology]

[0002] 2. Background of the Invention Ketamine, N,N-dimethyltryptamine (DMT), and other psychoplastogens have potential as neurotherapeutics due to their ability to promote neuronal proliferation. Several important features of psychoplastogenic pharmacophores are disclosed herein. Also disclosed herein are isoDMT psychoplastogens that are more easily synthesized, have improved physicochemical properties, and have reduced hallucinogenic potential compared to their DMT counterparts.

[0003] Major depressive disorder and associated neuropsychiatric illnesses are among the leading causes of disability worldwide. Recently, the Food and Drug Administration (FDA) approved the dissociative anesthetic ketamine for treatment-resistant depression, making it the first mechanistically distinct drug to be introduced into psychiatry in nearly 30 years. In some cases, ketamine can correct the deterioration of neuronal structure associated with depression. Such structural changes include, for example, loss of dendritic spines and synapses in the prefrontal cortex (PFC), as well as a reduction in the complexity of dendritic spread. However, ketamine is an imperfect drug due, for example, to its potential for abuse and its dissociative effects that require hospitalization of patients during treatment. Treatment without such side effects is needed in outpatient clinics.

[0004] Compounds known as psychoplastogens promote neuronal proliferation through mechanisms involving activation of AMPA receptors, tropomyosin receptor kinase B (TrkB), and mammalian target of rapamycin (mTOR). In addition to ketamine, the tropane alkaloids scopolamine and GLYX-13 (i.e., rapastinel) have demonstrated psychoplastogenic properties, making this group of compounds potentially useful for treating a variety of neuropsychiatric disorders. Because pyramidal neurons of the PFC exhibit top-down control over brain regions that control motivation, fear, and reward, these results provide an explanation for compounds with the antidepressant, anti-anxiety, and anti-addiction effects of hallucinogens in the outpatient clinic.

[0005] The common pharmacophore of hallucinogenic compounds appears to be N,N-dimethyltryptamine (DMT, 1) (Figure 1). Because DMT produces antidepressant and anxiolytic behavioral effects in rodents and because DMT-containing medicinal baths have demonstrated clinical efficacy for treatment-resistant depression, DMT was used as the starting point for identifying the novel psychoplastogenic compounds described herein.

[0006] Thus, there is a need for new therapeutic agents for the treatment of major depressive disorder and neuropsychiatric disorders. The present invention satisfies this and other needs. Summary of the Invention

[0007] In one embodiment, the present invention provides a compound of formula I: [ka] wherein X is CR 3 ;R 1a and R 1b are each independently hydrogen, C 1-6 Alkyl, C 3-8 Cycloalkyl, or C 4-14 alkyl-cycloalkyl; R 1c is C 1-6 Alkyl, C 3-8 Cycloalkyl, or C 4-14alkyl-cycloalkyl; or R 1a , R 1b , and R 1c Two of them combine with the atom to which they are attached to form C 3-12 R forms a heterocycloalkyl; 2 , R 3 , R 4 , R 5 , R 6 and R 7 are each independently hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, C 1-6 Haloalkyl, C 1-6 Alkylamines, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -OR 8a , -NO 2 , -CN, -C(O)R 8b , -C(O)OR 8b , -OC(O)R 8b , -OC(O)OR 8b , -N(R 8b R 8c ), -N(R 8b )C(O)R 8c , -C(O)N(R 8b R 8c ), -N(R 8b )C(O)OR 8c , -OC(O)N(R 8b R 8c ), -N(R 8b )C(O)N(R 8c R 8d ), -C(O)C(O)N(R 8b R 8c ), -S(O 2 )R 8b , -S(O) 2 N(R 8b R 8c ), C 3-8 Cycloalkyl, C 3-14 Alkyl-Cycloalkyl, C 4-10 Heterocycloalkyl, C 4-16 Alkyl-heterocycloalkyl, C 6-12 Aryl, C 7-18Alkyl-aryl, C 5-10 Heteroaryl, or C 4-16 alkyl-heteroaryl; R 8a is 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 8b , R 8c , and R 8d are each independently H or C 1-6 alkyl; or R 1a , R 1b , or R 1c One of them is R 2 Combined with C 5-12 form a heterocycloalkyl; or R 2 and R 3 are combined with the atom to which they are attached to form C 4-8 Cycloalkyl, C 4-10 Heterocycloalkyl, or C 6-12 form an aryl; or R 4 and R 5 , R 5 and R 6 , or R 6 and R 7 are combined with the atom to which they are attached to form C 4-6 Cycloalkyl, C 4-6 Heterocycloalkyl, C 6-12 Aryl or C 5-10 forming a heteroaryl; and L is C 1-6 or a pharma- ceutically acceptable salt or isomer thereof, wherein R 1a , R 1b , and R 1c are Me, L is methylene, and X is CR 3 And R 2 , R3 , R 4 , R 5 , R 6 and R 7 is hydrogen, the compound has the structure: [ka] and wherein the compound has the following structure: [ka] or a pharma- ceutically acceptable salt or isomer thereof, wherein

[0008] In another embodiment, the present invention provides a compound of formula II: [ka] wherein X is CR 3 ;R 1a and R 1b are each independently hydrogen, C 1-6 Alkyl, C 3-8 Cycloalkyl, or C 4-14 alkyl-cycloalkyl; or R 1a and R 1b are combined with the atom to which they are attached to form C 3-12 R forms a heterocycloalkyl; 2 , R 3 , R 4 , R 5 , R 6 and R 7 are each independently hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, C 1-6 Haloalkyl, C 1-6 Alkylamines, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -OR 8a , -NO 2 , -CN, -C(O)R 8b , -C(O)OR 8b , -OC(O)R 8b, -OC(O)OR 8b , -N(R 8b R 8c ), -N(R 8b )C(O)R 8c , -C(O)N(R 8b R 8c ), -N(R 8b )C(O)OR 8c , -OC(O)N(R 8b R 8c ), -N(R 8b )C(O)N(R 8c R 8d ), -C(O)C(O)N(R 8b R 8c ), -S(O 2 )R 8b , -S(O) 2 N(R 8b R 8c ), C 3-8 Cycloalkyl, C 3-14 Alkyl-Cycloalkyl, C 4-10 Heterocycloalkyl, C 4-16 Alkyl-heterocycloalkyl, C 6-12 Aryl, C 7-18 Alkyl-aryl, C 5-10 Heteroaryl, or C 4-16 alkyl-heteroaryl; R 8a is 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 8b , R 8c , and R 8d are each independently H or C 1-6 alkyl; or R 1a or R 1b One of them is R 2 Combined with C 5-12 form a heterocycloalkyl; or R 2 and R3 are combined with the atom to which they are attached to form C 4-8 Cycloalkyl, C 4-10 Heterocycloalkyl, or C 6-12 form an aryl; or R 4 and R 5 , R 5 and R 6 , or R 6 and R 7 are combined with the atom to which they are attached to form C 4-6 Cycloalkyl, C 4-6 Heterocycloalkyl, C 6-12 Aryl or C 5-10 forming a heteroaryl; and L is C 1-6 or a pharma- ceutically acceptable salt or isomer thereof, wherein R 1a and R 1b When both are Me and L is methylene, R 2 , R 3 , R 4 , R 5 , R 6 and R 7 is not hydrogen, and the compound has the following structure: [ka] where R 1a and R 1b is Me, L is ethylene, and X is CR 3 When R 2 , R 3 , R 4 , R 5 , R 6 and R 7 at least one of R 1c is hydrogen and R 5 Br, Cl, F, -NH 2 , -NO 2 , or C 1-3 When R is alkoxy, 2 , R 3 , R 4 , R6 , or R 7 at least one of R 1c is hydrogen and R 5 When F, R 2 , R 3 , R 4 , R 6 , or R 7 At least one of is not hydrogen, and R 6 is not F, or a pharma- ceutically acceptable salt or isomer thereof.

[0009] In another embodiment, the present invention provides a pharmaceutical composition comprising a compound of the present invention and a pharma- ceutically acceptable excipient.

[0010] In another embodiment, the present invention provides a method of enhancing neuroplasticity, comprising administering to a neuronal cell a compound of formula I: [ka] wherein X is N or CR 3 ;R 1a , R 1b , and R 1c are each independently hydrogen, C 1-6 Alkyl, C 3-8 Cycloalkyl, or C 4-14 alkyl-cycloalkyl; or R 1a , R 1b , and R 1c Two of them combine with the atom to which they are attached to form C 3-12 R forms a heterocycloalkyl; 2 , R 3 , R 4 , R 5 , R 6 and R 7 are each independently hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, C 1-6 Haloalkyl, C 1-6 Alkylamines, C1-6 Alkoxy, C 1-6 Haloalkoxy, -OR 8a , -NO 2 , -CN, -C(O)R 8b , -C(O)OR 8b , -OC(O)R 8b , -OC(O)OR 8b , -N(R 8b R 8c ), -N(R 8b )C(O)R 8c , -C(O)N(R 8b R 8c ), -N(R 8b )C(O)OR 8c , -OC(O)N(R 8b R 8c ), -N(R 8b )C(O)N(R 8c R 8d ), -C(O)C(O)N(R 8b R 8c ), -S(O 2 )R 8b , -S(O) 2 N(R 8b R 8c ), C 3-8 Cycloalkyl, C 3-14 Alkyl-Cycloalkyl, C 4-10 Heterocycloalkyl, C 4-16 Alkyl-heterocycloalkyl, C 6-12 Aryl, C 7-18 Alkyl-aryl, C 5-10 Heteroaryl, or C 4-16 alkyl-heteroaryl; R 8a is 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 8b , R 8c and R 8d are each independently H or C1-6 alkyl; or R 1a , R 1b , or R 1c One of them is R 2 Combined with C 5-12 form a heterocycloalkyl; or R 2 and R 3 are combined with the atom to which they are attached to form C 4-8 Cycloalkyl, C 4-10 Heterocycloalkyl, or C 6-12 form an aryl; or R 4 and R 5 , R 5 and R 6 , or R 6 and R 7 are combined with the atom to which they are attached to form C 3-6 Cycloalkyl, C 3-6 Heterocycloalkyl, C 6-12 Aryl or C 5-10 forming a heteroaryl; and L is C 1-6 or a pharma- ceutically acceptable salt thereof, wherein the compound is

[0011] In another embodiment, the present invention provides a method of treating a brain disorder, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula I: [ka] wherein X is N or CR 3 ;R 1a , R 1b , and R 1c are each independently hydrogen, C 1-6 Alkyl, C 3-8 Cycloalkyl, or C 4-14 alkyl-cycloalkyl; or R 1a , R 1b , and R 1c Two of them combine with the atom to which they are attached to form C 3-12 R forms a heterocycloalkyl;2 , R 3 , R 4 , R 5 , R 6 and R 7 are each independently hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, C 1-6 Haloalkyl, C 1-6 Alkylamines, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -OR 8a , -NO 2 , -CN, -C(O)R 8b , -C(O)OR 8b , -OC(O)R 8b , -OC(O)OR 8b , -N(R 8b R 8c ), -N(R 8b )C(O)R 8c , -C(O)N(R 8b R 8c ), -N(R 8b )C(O)OR 8c , -OC(O)N(R 8b R 8c ), -N(R 8b )C(O)N(R 8c R 8d ), -C(O)C(O)N(R 8b R 8c ), -S(O 2 )R 8b , -S(O) 2 N(R 8b R 8c ), C 3-8 Cycloalkyl, C 3-14 Alkyl-Cycloalkyl, C 4-10 Heterocycloalkyl, C 4-16 Alkyl-heterocycloalkyl, C 6-12 Aryl, C 7-18 Alkyl-aryl, C 5-10 Heteroaryl, or C 4-16 alkyl-heteroaryl; R 8a is C 3-8 Cycloalkyl, C 3-14 Alkyl-Cycloalkyl, C4-10 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 8b , R 8c and R 8d are each independently H or C 1-6 alkyl; or R 1a , R 1b , or R 1c One of them is R 2 Combined with C 5-12 form a heterocycloalkyl; or R 2 and R 3 are combined with the atom to which they are attached to form C 4-8 Cycloalkyl, C 4-10 Heterocycloalkyl, or C 6-12 form an aryl; or R 4 and R 5 , R 5 and R 6 , or R 6 and R 7 are combined with the atom to which they are attached to form C 3-6 Cycloalkyl, C 3-6 Heterocycloalkyl, C 6-12 Aryl or C 5-10 forming a heteroaryl; and L is C 1-6 wherein R is an alkylene; R is an aryl group; and R is an aryl group; R is an aryl group; R is an aryl group; R is an aryl group;

[0012] In another embodiment, the present invention provides a method of enhancing at least one of the translation, transcription, or secretion of a neurotrophic factor, comprising administering to a neuronal cell a compound of formula I: [ka] wherein X is N or CR 3 ;R 1a, R 1b , and R 1c are each independently hydrogen, C 1-6 Alkyl, C 3-8 Cycloalkyl, or C 4-14 alkyl-cycloalkyl; or R 1a , R 1b , and R 1c Two of them combine with the atom to which they are attached to form C 3-12 R forms a heterocycloalkyl; 2 , R 3 , R 4 , R 5 , R 6 and R 7 are each independently hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, C 1-6 Haloalkyl, C 1-6 Alkylamines, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -OR 8a , -NO 2 , -CN, -C(O)R 8b , -C(O)OR 8b , -OC(O)R 8b , -OC(O)OR 8b , -N(R 8b R 8c ), -N(R 8b )C(O)R 8c , -C(O)N(R 8b R 8c ), -N(R 8b )C(O)OR 8c , -OC(O)N(R 8b R 8c ), -N(R 8b )C(O)N(R 8c R 8d ), -C(O)C(O)N(R 8b R 8c ), -S(O 2 )R 8b , -S(O) 2 N(R 8b R 8c ), C 3-8 Cycloalkyl, C 3-14Alkyl-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; R 8a is 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 8b , R 8c and R 8d are each independently H or C 1-6 alkyl; or R 1a , R 1b , or R 1c One of them is R 2 Combined with C 5-12 form a heterocycloalkyl; or R 2 and R 3 are combined with the atom to which they are attached to form C 4-8 Cycloalkyl, C 4-10 Heterocycloalkyl, or C 6-12 form an aryl; or R 4 and R 5 , R 5 and R 6 , or R 6 and R 7 are combined with the atom to which they are attached to form C 3-6 Cycloalkyl, C 3-6 Heterocycloalkyl, C 6-12 Aryl or C 5-10 forming a heteroaryl; and L is C 1-6 and n is an integer from 1 to 3. The method of claim 1, further comprising contacting a compound of formula (I) with a compound of formula (I) [Brief description of the drawings]

[0013] [Figure 1] Figure 1A and Figure 1B show the structures of compounds with the DMT pharmacophore. Figure 1A shows the DMT structure (highlighted in black), which is the core scaffold of several known psychoplastogenic compounds. Figure 1B shows the only difference between the chemical structures of DMT (1) and isoDMT (2), i.e., the C1 and C3 atoms of the indole are rearranged. Predicted chemical properties and calculated MPO scores are shown. clogD = calculated logD; TPSA = total polar surface area; HBD = hydrogen bond donor; MPO = multiple parameter optimization score.

[0014] [Diagram 2] Figure 2A, 2B, and 2C show that the indole NH of tryptamine derivatives is not required to promote dendrite formation. Figure 2A shows representative images of central neurons (DIV6) treated with compounds. Figure 2B shows Sholl analysis demonstrating that 1-Me-DMT (27) and isoDMT (2) enhance the complexity of dendritic spread to an extent comparable to DMT (1) (n=46-79 neurons). Figure 2C shows the maximum number of intersections (Nmax) of the Sholl plot in B. Data are expressed as mean ± SEM. *p<0.05, **p<0.01, ***p<0.001, ****p<0.0001 when compared to solvent control after one-way ANOVA with Dunnett's post-hoc test (F=9.702; DFn=4; DFd=304; p-value<0.0001). VEH=vehicle, KET=ketamine. Scale bar=20 μm.

[0015] [Diagram 3]Figures 3A and 3B show that DMT and isoDMT analogs produce comparable effects on dendritic spread complexity. Figure 3A shows the chemical structure of isoDMT, which is similar to DMT derivatives. Figure 3B shows the maximum number of intersections (Nmax) of Sholl analysis of central neurons treated with compounds (n=82-95 neurons). Data are expressed as mean ± SEM. *p<0.05, **p<0.01, ***p<0.001, ****p<0.0001 when compared to solvent control after one-way ANOVA with Dunnett's post-hoc test (F=11.17; DFn=5; DFd=524; p-value<0.0001). VEH=vehicle, KET=ketamine.

[0016] [Figure 4] Figures 4A-C show the establishment of essential psychoplastogen pharmacophores. Figure 4A shows the chemical structures of non-basic analogues of isoDMT2, and Figures 4B and 4C show the maximum number of intersections (Nmax) of the Sholl plots of central neurons treated with the compounds (n=46-85 neurons). The effect of modifications on the nitrogen basicity and aromatic ring was evaluated in Figures 4B and 4C, respectively. Data are expressed as mean ± SEM. *p<0.05, **p<0.01, ***p<0.001, ****p<0.0001 when compared to the solvent control after one-way ANOVA with Dunnett's post-hoc test (for B: F=19.03; DFn=4, DFd=273; p-value<0.0001; for C: F=6.933; DFn=8, DFd=599; p-value<0.0001). VEH=vehicle, KET=ketamine.

[0017] [Diagram 5]Figure 5 shows the effect of indole substitution on the ability of isoDMT to promote neuronal proliferation. The maximum number of intersections (Nmax) of Sholl plots of central neurons treated with compounds is shown (n=39-93 neurons). Data are expressed as mean ± SEM. *p<0.05, **p<0.01, ***p<0.001, ****p<0.0001 when compared to solvent control after one-way ANOVA with Dunnett's post-hoc test (R=For OMe: F=13.85; DFn=5, DFd=493; p-value<0.0001. R=For OBn: F=15.44; DFn=5, DFd=372; p-value<0.0001. R=For F: F=13.24; DFn=5, DFd=506; p-value<0.0001). VEH=vehicle, KET=ketamine.

[0018] [Figure 6] Figure 6 shows that concentration-response experiments demonstrate that DMT and isoDMT have similar psychoplastogenic potency. Maximum number of intersections (Nmax) of Sholl plots of central neurons treated with compounds at concentrations ranging from 10 μM to 10 pM (n=66-123 neurons). Data are presented as mean ± SEM. *p<0.05, **p<0.01, ***p<0.001, ****p<0.0001 when compared to solvent control after one-way ANOVA with Dunnett's post-hoc test (F=15.40; DFn=24; DFd=2,276; p-value<0.0001). V=vehicle, K=ketamine.

[0019] [Figure 7]Figure 7 shows that the psychoplastogenic effect of isoDMT is blocked by 5-HT2A antagonists. Maximum number of intersections (Nmax) of Sholl plots of central neurons treated with compounds in the presence (+) or absence (-) of the 5-HT2A antagonist ketanserin (n=45-63 neurons). Data are presented as mean ± SEM. ****p<0.0001 when compared to solvent control after one-way ANOVA with Dunnett's post-hoc test (F=13.92; DFn=8; DFd=461; p-value<0.0001). V=vehicle, K=ketamine, KTSN=ketanserin.

[0020] [Figure 8] Figure 8 demonstrates that mouse HTR assay demonstrates that psychoplastogenic isoDMT exhibits reduced hallucinogenic potency. Male and female mice were administered drug by intraperitoneal injection and the number of head twitches was recorded over the following 20 min (n=3-8 mice per condition). Data are presented as mean ± SEM. *p<0.05, **p<0.01, ***p<0.001, ****p<0.0001 when compared to solvent control after one-way ANOVA with Dunnett's post-hoc test. V=vehicle.

[0021] [Figure 9] FIG. 9 shows the ability of compounds of the invention to reduce a head twitch behavioral response in a head twitch response assay.

[0022] [Figure 10] FIG. 10 shows the dose response profiles of hallucinogenic and non-hallucinogenic compounds compared to the 5HT2A sensor assay in agonist mode.

[0023] [Figure 11] FIG. 11 shows the response profiles of hallucinogenic and non-hallucinogenic compounds (at 10 μM) compared to the 5HT2A sensor assay in agonist mode.

[0024] [Figure 12]FIG. 12A shows the dose response profiles of 5HT, 6-MeO-DMT, and FIG. 12B shows the dose response of lisuride on the 5HT2A sensor assay in antagonist mode.

[0025] [Figure 13] FIG. 13 shows the response profiles of hallucinogenic and non-hallucinogenic compounds (at 10 μM) to the 5HT2A sensor assay in antagonist mode.

[0026] [Figure 14] Figures 14A and 14B show the antidepressant properties of compounds of the invention in the forced swim test assay with both pretest (Figure 14A) and acute (Figure 14B) compound administration. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0027] Detailed Description of the Invention I. General principles The present invention provides N-substituted indole and other heterocyclic non-hallucinogenic compounds useful for treating a variety of brain disorders and other conditions, as well as for enhancing neuroplasticity and enhancing at least one of the translation, transcription, or secretion of neurotrophic factors.

[0028] Compounds that can modify the neural circuits that control motivation, anxiety, and drug-seeking behavior have the potential to treat depression, post-traumatic stress disorder (PTSD), and substance abuse disorders (SUD). Moreover, such psychoplastogenic drugs may produce long-lasting therapeutic effects, for example, due to their potential to treat underlying pathological changes in the circuitry. Hallucinogenic compounds have distinguished themselves in this respect, for example, by promoting structural and functional neuroplasticity in key circuits, inducing therapeutic responses in multiple neuropsychiatric disorders, and producing beneficial effects that persist for many months after a single administration.

[0029] In some cases, hallucinogenic 5-HT 2A5-HT agonists (e.g., DMT, LSD, DOI, etc.) are potential treatments for neurological disorders, such as neuropsychiatric disorders (Ly et al., 2018). However, the hallucinogenic and dissociative potential of such compounds limits their use in outpatient clinics. 2A Antagonists include 5-HT antagonists such as DMT, LSD, and DOI. 2A Blocks the neuritogenic and spinogenesis effects of hallucinogenic compounds with agonist activity and inhibits 5-HT 2A demonstrated a correlation between activation and promoting neuroplasticity ( Ly et al., 2018 ; Dunlap et al., 2020 ).

[0030] Non-hallucinogenic psychoplastogens are provided herein. Additionally, some isoDMT compounds have a potent inhibitory effect on serotonin receptors (e.g., 5HT 2A In some embodiments, the isoDMT analogs described herein have improved physiochemical properties as a result of the loss of hydrogen bond donors, which reduces the total polar surface area, and improves the central nervous system multiparameter optimization (MPO) scores (FIG. 1). In some embodiments, the isoDMT analogs described herein have improved physiochemical properties as a result of the loss of hydrogen bond donors, which reduces the total polar surface area, and improve the central nervous system multiparameter optimization (MPO) scores (FIG. 1). 2A Described herein are non-hallucinogenic compounds that demonstrate similar therapeutic efficacy as agonists. In some embodiments, the non-hallucinogenic compounds described herein are used to treat hallucinogenic 5-HT agonists for neurological disorders. 2A It offers better therapeutic efficacy than agonists. II. Definition

[0031] Unless otherwise specifically indicated, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. In addition, any methods or materials similar or equivalent to those described herein may be used in the practice of the present invention. For purposes of the present invention, the following terms are defined:

[0032] "A," "an," or "the" not only include aspects with one component, but also aspects with multiple components. For example, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "a cell" includes a plurality of such cells, reference to "the agent" includes reference to one or more agents known to those of skill in the art, and so forth.

[0033] Abbreviations used: DMT, N,N-dimethyltryptamine; PFC, prefrontal cortex; 5-HT 2A , serotonin 2A; MPO, multiple parameter optimization; LSD, lysergic acid diethylamide; TPSA, total polar surface area; MAP2, microtubule-associated protein 2; N max , maximum number of crossings; 5-HT2B, serotonin 2B; DIV, days in vitro; VEH, vehicle; KET, ketamine; SEM, standard error of the mean; ANOVA, analysis of variance; DOM, 2,5-dimethoxy-4-methylamphetamine; OMe, methoxy; OBn, benzyloxy; F, fluoro; μM, micromolar; nM, nanomolar; pM, picomolar; V, vehicle; K, ketamine; ATR, attenuated total reflectance; FT-IR, Fourier transform red Infrared spectroscopy; UHPLC, ultra-performance liquid chromatography; LRMS, low-resolution mass spectrometry; IACUC, Animal Care Committee; AAALAC, International Association for Accreditation of Laboratory Animal Facilities; BSA, bovine serum albumin; DPBS, Dulbecco's phosphate-buffered saline; mTOR, mammalian target of rapamycin; AMPA, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid; TrkB, tropomyosin receptor kinase B; HTR, head twitch response.

[0034] "Alkyl" means a straight or branched, saturated, aliphatic group having the indicated number of carbon atoms. 1-2 , C 1-3 , C 1-4 , C 1-5 , C 1-6 , C 1-7 , C 1-8 , C 1-9, C 1-10 , C 2-3 , C 2-4 , C 2-5 , C 2-6 , C 3-4 , C 3-5 , C 3-6 , C 4-5 , C 4-6 and C 5-6 For example, C 1-6 Alkyl includes, but is not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, hexyl, etc. Alkyl can also refer to alkyl groups having up to 20 carbon atoms, including, but not limited to, heptyl, octyl, nonyl, decyl, etc. Alkyl groups can be substituted or unsubstituted.

[0035] "Alkylene" means a straight or branched, saturated, aliphatic, i.e., divalent hydrocarbon group having the indicated number of carbon atoms and linking at least two other groups. The two moieties linked to the alkylene can be linked to the same atom or different atoms of the alkylene group. For example, a straight chain alkylene is -(CH 2 ) n - divalent radical. Representative alkylene groups include, but are not limited to, methylene, ethylene, propylene, isopropylene, butylene, isobutylene, sec-butylene, pentylene, and hexylene. The alkylene groups may be substituted or unsubstituted.

[0036] "Alkenyl" means a straight or branched chain hydrocarbon having at least two carbon atoms and at least one double bond. Alkenyl is defined as any one of the following: 2 , C 2-3 , C 2-4 , C 2-5 , C 2-6 , C 2-7 , C 2-8 , C 2-9 , C 2-10 , C 3 , C 3-4 , C3-5 , C 3-6 , C 4 , C 4-5 , C 4-6 , C 5 , C 5-6 , and C 6 Alkenyl groups may contain any number of carbons, such as 1, 2, 3, 4, 5 or more. Alkenyl groups may have any suitable number of double bonds, including, but not limited to, 1, 2, 3, 4, 5 or more. Examples of alkenyl groups include, but are not limited to, vinyl (ethenyl), propenyl, isopropenyl, 1-butenyl, 2-butenyl, isobutenyl, butadienyl, 1-pentenyl, 2-pentenyl, isopentenyl, 1,3-pentadienyl, 1,4-pentadienyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 1,3-hexadienyl, 1,4-hexadienyl, 1,5-hexadienyl, 2,4-hexadienyl, or 1,3,5-hexatrienyl. Alkenyl groups may be substituted or unsubstituted.

[0037] "Alkynyl" means either a straight chain or branched hydrocarbon having at least two carbon atoms and at least one triple bond. Alkynyl is defined as any one of the following: 2 , C 2-3 , C 2-4 , C 2-5 , C 2-6 , C 2-7 , C 2-8 , C 2-9 , C 2-10 , C 3 , C 3-4 , C 3-5 , C 3-6 , C 4 , C 4-5 , C 4-6 , C 5 , C 5-6 , and C 6It may contain any number of carbons, such as aryl, ...

[0038] "Cycloalkyl" means a saturated or partially unsaturated, monocyclic, fused bicyclic or bridged polycyclic ring assembly containing 3 to 12 ring atoms, or the indicated number of atoms. Cycloalkyl is defined as any of the following: 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 Cycloalkyl groups may contain any number of carbons, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cyclooctyl. Bicyclic compounds include spirocyclic compounds, fused bicyclic compounds, and bridged bicyclic compounds. Saturated bicyclic and polycyclic cycloalkyl rings include, for example, norbornane, [2.2.2]bicyclooctane, decahydronaphthalene, and adamantane. Cycloalkyl groups may also be partially unsaturated, with one or more double or triple bonds in the ring. Representative cycloalkyl groups that are partially unsaturated include, but are not limited to, cyclobutene, cyclopentene, cyclohexene, cyclohexadiene (1,3- and 1,4-isomers), cycloheptene, cycloheptadiene, cyclooctene, cyclooctadiene (1,3-, 1,4-, and 1,5-isomers), norbornene, and norbornadiene. Cycloalkyl is a saturated monocyclic C 3-8When cycloalkyl, exemplary groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. 3-6 When it is cycloalkyl, exemplary groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Cycloalkyl groups can be substituted or unsubstituted.

[0039] "Alkyl-cycloalkyl" refers to a group having an alkyl component and a cycloalkyl component, where the alkyl component connects the cycloalkyl component to the point of attachment. The alkyl component is as defined above, except that it is at least divalent, i.e., alkylene, in order to connect the cycloalkyl component to the point of attachment. In some cases, the alkyl component may be absent. The alkyl component may be any of the following: 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 Cycloalkyl moieties may contain any number of carbons, such as cycloalkyl, cycloalkyl- ...

[0040] "Heterocycloalkyl" refers to a cycloalkyl, as defined above, having 3-12 ring members and 1-4 N, O, and S heteroatoms. Heterocycloalkyl includes bicyclic compounds containing heteroatoms. Bicyclic compounds include spirocyclic compounds, fused bicyclic compounds, and bridged bicyclic compounds. The heteroatoms may be oxidized, e.g., -S(O)- and -S(O)-. 2 Heterocycloalkyl groups can include any number of ring atoms, such as 3-6, 4-6, 5-6, 3-8, 4-8, 5-8, 6-8, 3-9, 3-10, 3-11, or 3-12 ring members. Any suitable number of heteroatoms can be included in the heterocycloalkyl group, such as 1, 2, 3, or 4, or 1-2, 1-3, 1-4, 2-3, 2-4, or 3-4. Heterocycloalkyl groups may include groups such as aziridine, azetidine, pyrrolidine, piperidine, azepane, azocane, quinuclidine, pyrazolidine, imidazolidine, piperazine (1,2-, 1,3- and 1,4-isomers), oxirane, oxetane, tetrahydrofuran, oxane (tetrahydropyran), oxepane, thiirane, thietane, thiolane (tetrahydrothiophene), thiane (tetrahydrothiopyran), oxazolidine, isoxazolidine, thiazolidine, isothiazolidine, dioxolane, dithiolane, morpholine, thiomorpholine, dioxane, or dithiane. Heterocycloalkyl groups may be fused to aromatic or non-aromatic ring systems to form members, including, but not limited to, indoline. Heterocycloalkyl groups may be unsubstituted or substituted. For example, heterocycloalkyl groups may be C 1-6 It may be substituted with alkyl or oxo (=O) or the like.

[0041] "Alkyl-heterocycloalkyl" refers to a group having an alkyl component and a heterocycloalkyl component, where the alkyl component links the heterocycloalkyl component to a point of attachment. The alkyl component is as defined above, except that it is at least divalent, i.e., alkylene, in order to link the heterocycloalkyl component to the ...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 Heterocycloalkyl groups may contain any number of carbons, such as 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62,

[0042] "Halogen" refers to fluorine, chlorine, bromine, and iodine.

[0043] "Haloalkyl" refers to an alkyl, as defined above, in which some or all of the hydrogen atoms have been replaced with halogen atoms. Similar to alkyl groups, haloalkyl groups include C 1 - 6 For example, haloalkyl includes trifluoromethyl, fluoromethyl, and the like. In some cases, the term "perfluoro" can be used to define a compound or radical in which all hydrogens have been replaced with fluorine. For example, perfluoromethyl refers to 1,1,1-trifluoromethyl. Alkylamines

[0044] "Alkoxy" refers to an alkyl group having an oxygen atom connecting the alkyl group to the point of attachment: alkyl-O-. Like alkyl groups, alkoxy groups can be C 1 - 6Alkoxy groups can have any suitable number of carbon atoms, such as, for example, methoxy, ethoxy, propoxy, iso-propoxy, butoxy, 2-butoxy, iso-butoxy, sec-butoxy, tert-butoxy, pentoxy, hexoxy, and the like. Alkoxy groups can be further substituted with a variety of substituents described herein. Alkoxy groups can be substituted or unsubstituted.

[0045] "Haloalkoxy" refers to an alkoxy group in which some or all of the hydrogen atoms are replaced with halogen atoms. Similar to alkyl groups, haloalkoxy groups can be C 1 - 6 Alkoxy groups can have any suitable number of carbon atoms, such as 1, 2, 3, or more halogens. When all hydrogens are replaced with halogens, such as fluorine, the compound is per-substituted, such as perfluorinated. Haloalkoxy includes, but is not limited to, trifluoromethoxy, 2,2,2,-trifluoroethoxy, perfluoroethoxy, and the like.

[0046] "Amine" refers to an -N(R) group, where R group can be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, etc. 2 R refers to a group. The R groups can be the same or different. The amino groups can be primary (each R is hydrogen), secondary (one R is hydrogen) or tertiary (each R is other than hydrogen).

[0047] By "alkylamine" is meant an alkyl group, as defined herein, having one or more amino groups. The amino groups may be primary, secondary, or tertiary. The alkylamine may be further substituted with a hydroxy group to form an amino-hydroxy group. Alkylamines useful in the present invention include, but are not limited to, ethylamine, propylamine, isopropylamine, ethylenediamine, and ethanolamine. The amino group may be at the omega position of the alkyl group, linking the alkylamine to the point of attachment to the remainder of the compound, or linking at least two carbon atoms of the alkyl group together. Those skilled in the art will appreciate that other alkylamines are also useful in the present invention.

[0048] "Aryl" refers to an aromatic ring system having any suitable number of ring atoms and any suitable number of rings. Aryl groups can contain any suitable number of ring atoms, such as 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16 ring atoms, and 6 to 10, 6 to 12, or 6 to 14 ring members. Aryl groups can be monocyclic or fused to form bicyclic or tricyclic groups, or joined by bonds to form biaryl groups. Representative aryl groups include phenyl, naphthyl, and biphenyl. Other aryl groups include benzyl, which has a methylene linking group. Some aryl groups, such as phenyl, naphthyl, or biphenyl, have 6 to 12 ring members. Other aryl groups, such as phenyl or naphthyl, have 6 to 10 ring members. Other aryl groups, such as phenyl, have 6 ring members. Aryl groups can be substituted or unsubstituted.

[0049] "Alkyl-aryl" refers to a group having an alkyl component and an aryl component, where the alkyl component links the aryl component to a point of attachment. The alkyl component is as defined above, except that it is at least divalent, i.e., alkylene, in order to link the aryl component to the ... 0-6 , C 1-2 , C 1-3 , C 1-4 , C 1-5, C 1-6 , C 2-3 , C 2-4 , C 2-5 , C 2-6 , C 3-4 , C 3-5 , C 3-6 , C 4-5 , C 4-6 and C 5-6 The alkyl-aryl group may contain any number of carbons, such as aryl, aryl, aryl- ...

[0050] "Heteroaryl" refers to a monocyclic or fused bicyclic or tricyclic aromatic ring assembly containing 5-16 ring atoms, with 1-5 of the ring atoms being heteroatoms such as N, O, or S. A heteroaryl group can contain any number of ring atoms, such as 5-6, 3-8, 4-8, 5-8, 6-8, 3-9, 3-10, 3-11, or 3-12 ring members. Any suitable number of heteroatoms can be included in a heteroaryl group, such as 1, 2, 3, 4, or 5, or 1-2, 1-3, 1-4, 1-5, 2-3, 2-4, 2-5, 3-4, or 3-5. A heteroaryl group can have 5-8 ring members and 1-4 heteroatoms, or 5-8 ring members and 1-3 heteroatoms, or 5-6 ring members and 1-4 heteroatoms, or 5-6 ring members and 1-3 heteroatoms. Heteroaryl groups may include groups such as pyrrole, pyridine, imidazole, pyrazole, triazole, tetrazole, pyrazine, pyrimidine, pyridazine, triazine (1,2,3-, 1,2,4- and 1,3,5-isomers), thiophene, furan, thiazole, isothiazole, oxazole, and isoxazole. Heteroaryl groups may be fused to aromatic ring systems such as phenyl rings 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, benzothiophenes, and benzofurans. Other heteroaryl groups include heteroaryl rings linked by bonds, such as bipyridines. Heteroaryl groups may be substituted or unsubstituted.

[0051] "Alkyl-heteroaryl" refers to a group having an alkyl component and a heteroaryl component, where the alkyl component links the heteroaryl component to a point of attachment. The alkyl component is as defined above, except that it is at least divalent, i.e., alkylene, in order to link the heteroaryl component to the ... 0-6 , C 1-2 , C 1-3 , C1-4 , C 1-5 , C 1-6 , C 2-3 , C 2-4 , C 2-5 , C 2-6 , C 3-4 , C 3-5 , C 3-6 , C 4-5 , C 4-6 and C 5-6 The heteroaryl group may contain any number of carbons, such as , ...

[0052] "Salt" refers to the acid salt or base salt of the compound used in the method of the present invention. Illustrative examples of pharmaceutically acceptable salts are salts of mineral acids (such as hydrochloric acid, hydrobromic acid, phosphoric acid, etc.), salts of organic acids (such as fumaric acid, acetic acid, propionic acid, glutamic acid, citric acid, etc.), and salts of quaternary ammonium (such as methyl iodide, ethyl iodide, etc.). It is understood that pharmaceutically acceptable salts are non-toxic. Further information regarding suitable pharmaceutically acceptable salts can be found in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, which is incorporated herein by reference.

[0053] The neutral forms of the compounds may be regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner. The parent compounds differ from the various salt forms in certain physical properties, such as solubility in polar solvents, but otherwise the salts are equivalent to the parent compounds for purposes of the invention.

[0054] "Pharmaceutically acceptable salt" refers to a compound in a salt form, where the compound is suitable for administration to a subject. Representative pharmaceutically acceptable salts include salts of acetic acid, ascorbic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethanesulfonic acid, edisylic acid, fumaric acid, gentisic acid, gluconic acid, glucoronic acid, glutamic acid, hippuric acid, hydrobromic acid, hydrochloric acid, isethionic acid, lactic acid, lactobionic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, mucic acid, naphthalenesulfonic acid, naphthalene-1,5-disulfonic acid, naphthalene-2,6-disulfonic acid, nicotinic acid, nitric acid, orotic acid, pamoic acid, pantothenic acid, phosphoric acid, succinic acid, sulfuric acid, tartaric acid, p-toluenesulfonic acid, and xinafoic acid.

[0055] "Pharmaceutically acceptable excipient" refers to a substance that aids in the administration of an active agent to a subject and in the absorption of the active agent by a subject. Pharmaceutical excipients useful in the present invention include, but are not limited to, binders, fillers, disintegrants, lubricants, coating agents, sweeteners, flavoring agents, and coloring agents. Those skilled in the art will recognize that other pharmaceutical excipients are useful in the present invention.

[0056] "Composition" refers to a product containing the specified components in the specified amounts, as well as products that result directly or indirectly from combining the specified components in the specified amounts. "Pharmaceutically acceptable" means that the carrier, diluent or excipient must be compatible with the other ingredients of the formulation.

[0057] "Isomers" refer to compounds that have different connectivity between atoms in the molecule leading to different chemical structures despite the same chemical formula. Isomers include structural isomers and stereoisomers. Examples of structural isomers include, but are not limited to, tautomers and positional isomers. Examples of stereoisomers include, but are not limited to, diastereomers and enantiomers.

[0058] "Administering" refers to oral administration, administration as a suppository, topical contact, parenteral, intravenous, intraperitoneal, intramuscular, intralesional, intranasal or subcutaneous administration, intrathecal administration, or implantation of a sustained release device, e.g., a mini-osmotic pump, to a subject.

[0059] "Subject" refers to animals such as mammals, including, but not limited to, primates (e.g., humans), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice, etc. In certain embodiments, the subject is a human.

[0060] A "therapeutically effective amount", "therapeutically sufficient amount" or "effective or sufficient amount" refers to a dose that produces the therapeutic effect for which it is administered. The exact dose depends on the purpose of the treatment and can be ascertained by one of skill in the art using known techniques (see, for example, Lieberman, Pharmaceutical Dosage Forms (vols. 1 3, 1992); Lloyd, The Art, Science and Technology of Pharmaceutical Compounding (1999); Pickar, Dosage Calculations (1999); and Remington: The Science and Practice of Pharmacy, 20th Edition, 2003, Gennaro, Ed., Lippincott, Williams & Wilkins). In sensitized cells, the therapeutically effective amount is often less than the conventional therapeutically effective amount in non-sensitized cells.

[0061] "Neuroplasticity" refers to the ability of the brain to continually change its structure and / or function throughout a subject's life. Examples of changes to the brain include, but are not limited to, the ability to adapt or respond to internal and / or external stimuli, such as injury, and the ability to generate new neurites, dendritic spines, and synapses.

[0062] "Brain disorder" refers to a neurological disorder that affects the structure and function of the brain, including, but not limited to, Alzheimer's disease, Parkinson's disease, psychiatric disorders, depression, treatment-resistant depression, addiction, anxiety, post-traumatic stress disorder, suicidal ideation, major depressive disorder, bipolar disorder, schizophrenia, stroke, traumatic brain injury, and substance use disorders.

[0063] "Combination therapy" refers to a method of treating a disease or disorder, in which two or more different pharmaceutical agents are administered in an overlapping dosing schedule, such that the subject is exposed to both agents simultaneously. For example, the compounds of the present invention can be used in combination with other pharmacologic active compounds. The compounds of the present invention can be administered simultaneously or sequentially (as a single preparation or separate preparation) with respect to the other drug therapy. In general, combination therapy envisions the administration of two or more drugs during a single cycle or course of therapy.

[0064] "Neurotrophic factors" refers to a family of soluble peptides or proteins that support the survival, growth, and differentiation of developing and mature neurons.

[0065] "Modulate" or "modulating" or "modulation" refers to an increase or decrease in the amount, quality, or effect of a particular activity, function, or molecule. By way of example and not by way of limitation, G protein-coupled receptors (e.g., 5HT 2A ) agonists, partial agonists, antagonists, and allosteric modulators (eg, positive allosteric modulators) are modulators of the receptor.

[0066] "Agonism" refers to the activation of a receptor or enzyme by a modulator or agonist, resulting in a biological response.

[0067] "Agonist" refers to a modulator that binds to a receptor or enzyme and activates the receptor to produce a biological response. By way of example only, "5HT 2A The "agonist" is a 5HT antagonist with a potency of approximately 100 μM or less. 2A Regarding activity EC 50In some embodiments, the term "agonist" includes full agonists or partial agonists. A "full agonist" refers to a modulator that binds to and activates a receptor with the maximal response that an agonist produces at the receptor. A "partial agonist" refers to a modulator that binds to and activates a given receptor but with partial efficacy, i.e., a less than maximal response at the receptor relative to a full agonist.

[0068] A "positive allosteric modulator" refers to a modulator that binds to a site other than the orthosteric binding site and enhances or amplifies the effect of an agonist.

[0069] "Antagonism" refers to the inactivation of a receptor or enzyme by a modulator or antagonist. Receptor antagonism, for example, is when a molecule is unable to bind to the receptor and cause activity.

[0070] "Antagonist" or "neutral antagonist" refers to a modulator that binds to a receptor or enzyme and prevents a biological response. Antagonists have no activity in the absence of an agonist or inverse agonist, but can prevent the activity of either, resulting in no change in the biological response. III. Compound

[0071] The present invention provides N-substituted indoles and other heterocyclic compounds useful for the treatment of various brain disorders and other conditions. In some embodiments, the N-substituted indoles and other heterocyclic compounds provided herein inhibit 5-HT 2A It is a modulator and promotes neuroplasticity (e.g., plasticity of cortical structures).

[0072] In some embodiments, the present invention provides a compound according to the present invention having the following formula I: [ka] wherein X is N or CR 3 ;R 1a , R1b , and R 1c are each independently hydrogen, C 1-6 Alkyl, C 3-8 Cycloalkyl, or C 4-14 alkyl-cycloalkyl; or R 1a , R 1b , and R 1c Two of them combine with the atom to which they are attached to form C 3-12 R forms a heterocycloalkyl; 2 , R 3 , R 4 , R 5 , R 6 and R 7 are each independently hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, C 1-6 Haloalkyl, C 1-6 Alkylamines, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -OR 8a , -NO 2 , -CN, -C(O)R 8b , -C(O)OR 8b , -OC(O)R 8b , -OC(O)OR 8b , -N(R 8b R 8c ), -N(R 8b )C(O)R 8c , -C(O)N(R 8b R 8c ), -N(R 8b )C(O)OR 8c , -OC(O)N(R 8b R 8c ), -N(R 8b )C(O)N(R 8c R 8d ), -C(O)C(O)N(R 8b R 8c ), -S(O 2 )R 8b , -S(O) 2 N(R 8b R 8c ), C 3-8 Cycloalkyl, C 3-14Alkyl-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; R 8a is 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 8b , R 8c and R 8d are each independently H or C 1-6 alkyl; or R 1a , R 1b and R 1c One of them is R 2 , R 3 , R 4 , R 5 , R 6 and R 7 Combined with one of the C 5-6 Cycloalkyl or C 5-6 form a heterocycloalkyl; or R 2 and R 3 are combined with the atom to which they are attached to form C 6-12 can form an aryl; or R 4 and R 5 , R 5 and R 6 , or R 6 and R 7 are combined with the atom to which they are attached to form C 3-6 Cycloalkyl or C 3-6 heterocycloalkyl; and L can be C 1-6 or a salt or isomer thereof.

[0073] In some embodiments, the present invention provides a compound according to the present invention having the following formula I: [ka] wherein X is N or CR 3 ;R 1a , R 1b , and R 1c are each independently hydrogen, C 1-6 Alkyl, C 3-8 Cycloalkyl, or C 4-14 alkyl-cycloalkyl; or R 1a , R 1b , and R 1c Two of them combine with the atom to which they are attached to form C 3-12 R forms a heterocycloalkyl; 2 , R 3 , R 4 , R 5 , R 6 and R 7 are each independently hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, C 1-6 Haloalkyl, C 1-6 Alkylamines, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -OR 8a , -NO 2 , -CN, -C(O)R 8b , -C(O)OR 8b , -OC(O)R 8b , -OC(O)OR 8b , -N(R 8b R 8c ), -N(R 8b )C(O)R 8c , -C(O)N(R 8b R 8c ), -N(R 8b )C(O)OR 8c , -OC(O)N(R 8b R 8c ), -N(R 8b )C(O)N(R 8c R8d ), -C(O)C(O)N(R 8b R 8c ), -S(O 2 )R 8b , -S(O) 2 N(R 8b R 8c ), C 3-8 Cycloalkyl, C 3-14 Alkyl-Cycloalkyl, C 4-10 Heterocycloalkyl, C 4-16 Alkyl-heterocycloalkyl, C 6-12 Aryl, C 7-18 Alkyl-aryl, C 5-10 Heteroaryl, or C 4-16 alkyl-heteroaryl; R 8a is 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 8b , R 8c , and R 8d are each independently H or C 1-6 alkyl; or R 1a , R 1b , or R 1c One of them is R 2 , R 3 , R 4 , R 5 , R 6 or R 7 Combined with one of the C 5-12 form a heterocycloalkyl; or R 2 and R 3 are combined with the atom to which they are attached to form C 4-8 Cycloalkyl, C 4-10 Heterocycloalkyl, or C 6-12 form an aryl; or R 4 and R 5 , R5 and R 6 , or R 6 and R 7 are combined with the atom to which they are attached to form C 3-6 Cycloalkyl, C 3-6 Heterocycloalkyl, C 6-12 Aryl or C 5-10 forming a heteroaryl; and L is C 1-6 or a pharma- ceutically acceptable salt or isomer thereof, wherein R 1a and R 1b Both are Me and R 1c is hydrogen and L is methylene, R 2 , R 3 , R 4 , R 5 , R 6 and R 7 is not hydrogen, and the compound has the following structure: [ka] where R 1a and R 1b is Me, L is ethylene, and X is CR 3 When R 2 , R 3 , R 4 , R 5 , R 6 and R 7 at least one of R 1c is hydrogen and R 5 Br, Cl, F, -NH 2 , -NO 2 , or C 1-3 When R is alkoxy, 2 , R 3 , R 4 , R 6 , or R 7 at least one of R 1c is hydrogen and R 5 When F, R 2 , R 3 , R 4, R 6 , or R 7 At least one of is not hydrogen, and R 6 is not F; and here, R 1a , R 1b and R 1c are Me, L is methylene, and X is CR 3 and R 2 , R 3 , R 4 , R 5 , R 6 and R 7 is hydrogen, the compound is [ka] or a pharma- ceutically acceptable salt or isomer thereof.

[0074] In some embodiments, the present invention provides a compound of formula I: [ka] wherein X is CR 3 ;R 1a and R 1b are each independently hydrogen, C 1-6 Alkyl, C 3-8 Cycloalkyl, or C 4-14 alkyl-cycloalkyl; R 1c is C 1-6 Alkyl, C 3-8 Cycloalkyl, or C 4-14 alkyl-cycloalkyl; or R 1a , R 1b , and R 1c Two of them combine with the atom to which they are attached to form C 3-12 R forms a heterocycloalkyl; 2 , R 3 , R 4 , R 5 , R 6 and R 7 are each independently hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C2-6 Alkynyl, halogen, C 1-6 Haloalkyl, C 1-6 Alkylamines, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -OR 8a , -NO 2 , -CN, -C(O)R 8b , -C(O)OR 8b , -OC(O)R 8b , -OC(O)OR 8b , -N(R 8b R 8c ), -N(R 8b )C(O)R 8c , -C(O)N(R 8b R 8c ), -N(R 8b )C(O)OR 8c , -OC(O)N(R 8b R 8c ), -N(R 8b )C(O)N(R 8c R 8d ), -C(O)C(O)N(R 8b R 8c ), -S(O 2 )R 8b , -S(O) 2 N(R 8b R 8c ), C 3-8 Cycloalkyl, C 3-14 Alkyl-Cycloalkyl, C 4-10 Heterocycloalkyl, C 4-16 Alkyl-heterocycloalkyl, C 6-12 Aryl, C 7-18 Alkyl-aryl, C 5-10 Heteroaryl, or C 4-16 alkyl-heteroaryl; R 8a is 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 4-16alkyl-heteroaryl; R 8b , R 8c , and R 8d are each independently H or C 1-6 alkyl; or R 1a , R 1b , or R 1c One of them is R 2 Combined with C 5-12 form a heterocycloalkyl; or R 2 and R 3 are combined with the atom to which they are attached to form C 4-8 Cycloalkyl, C 4-10 Heterocycloalkyl, or C 6-12 form an aryl; or R 4 and R 5 , R 5 and R 6 , or R 6 and R 7 are combined with the atom to which they are attached to form C 4-6 Cycloalkyl, C 4-6 Heterocycloalkyl, C 6-12 Aryl or C 5-10 forming a heteroaryl; and L is C 1-6 or a pharma- ceutically acceptable salt or isomer thereof, wherein R 1a , R 1b , and R 1c are Me, L is methylene, and X is CR 3 And R 2 , R 3 , R 4 , R 5 , R 6 and R 7 is hydrogen, the compound has the structure: [ka] and wherein the compound has the following structure: [ka] or a pharma- ceutically acceptable salt or isomer thereof, wherein

[0075] In some embodiments, the present invention provides a compound or a pharma- ceutically acceptable salt thereof, wherein X is N or CR 3 In some embodiments, the present invention provides a compound or a pharma- ceutically acceptable salt thereof, wherein X is CR 3 In some embodiments, the present invention provides a compound or a pharma- ceutically acceptable salt thereof, wherein X is N.

[0076] In some embodiments, the present invention provides a compound, 3 ;R 2 and R 3 are each independently hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, C 1-6 Haloalkyl, C 1-6 Alkylamines, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -OR 8a , -NO 2 , -CN, -C(O)R 8b , -C(O)OR 8b , -OC(O)R 8b , -OC(O)OR 8b , -N(R 8b R 8c ), -N(R 8b )C(O)R 8c , -C(O)N(R 8b R 8c ), -N(R 8b )C(O)OR 8c , -OC(O)N(R 8b R 8c ), -N(R 8b )C(O)N(R 8c R 8d ), -C(O)C(O)N(R 8b R 8c ), -S(O 2 )R 8b , -S(O) 2 N(R 8bR 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 8a is 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; and R 8b , R 8c , and R 8d are each independently H or C 1-6 or a pharma- ceutically acceptable salt thereof, wherein R 1a , R 1b and R 1c are Me, L is methylene, and R 2 , R 3 , R 4 , R 5 , R 6 and R 7 is hydrogen, the compound has the structure: [ka] It is.

[0077] In some embodiments, the present invention provides a compound or a pharma- ceutically acceptable salt thereof, wherein the compound of formula I has the following structure: [ka] has.

[0078] In some embodiments, the present invention provides a compound 1a , R 1b , or R 1c are each independently, C 1-6 Alkyl, C 3-8 Cycloalkyl, or C 4-14 alkyl-cycloalkyl; or R 1a , R 1b , and R 1c Two of them combine with the atom to which they are attached to form C 3-12 R forms a heterocycloalkyl; 2 , R 3 , R 4 , R 6 and R 7 are each independently hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, C 1-6 Haloalkyl, C 1-6 Alkylamines, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -OR 8a , -NO 2 , -CN, -C(O)R 8b , -C(O)OR 8b , -OC(O)R 8b , -OC(O)OR 8b , -N(R 8b R 8c ), -N(R 8b )C(O)R 8c , -C(O)N(R 8b R 8c ), -N(R 8b )C(O)OR 8c , -OC(O)N(R 8b R 8c ), -N(R 8b )C(O)N(R 8c R 8d ), -C(O)C(O)N(R 8b R 8c ), -S(O 2 )R 8b , -S(O) 2 N(R 8b R 8c ), C 3-8Cycloalkyl, 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 5 is C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, C 1-6 Haloalkyl, C 1-6 Alkylamines, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -OR 8a , -NO 2 , -CN, -C(O)R 8b , -C(O)OR 8b , -OC(O)R 8b , -OC(O)OR 8b , -N(R 8b R 8c ), -N(R 8b )C(O)R 8c , -C(O)N(R 8b R 8c ), -N(R 8b )C(O)OR 8c , -OC(O)N(R 8b R 8c ), -N(R 8b )C(O)N(R 8c R 8d ), -C(O)C(O)N(R 8b R 8c ), -S(O 2 )R 8b , -S(O) 2 N(R 8b R 8c ), C 3-8 Cycloalkyl, C 3-14 Alkyl-Cycloalkyl, C 4-10 Heterocycloalkyl, C 4-16 Alkyl-heterocycloalkyl, C 6-12 Aryl, C 7-18 Alkyl-aryl, C 5-10Heteroaryl, or C 4-16 alkyl-heteroaryl; R 8a is 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; and R 8b , R 8c , and R 8d are each independently H or C 1-6 alkyl; or R 4 and R 5 , R 5 and R 6 , or R 6 and R 7 are combined with the atom to which they are attached to form C 4-6 Cycloalkyl, C 4-6 Heterocycloalkyl, C 6-12 Aryl or C 5-10 forming a heteroaryl group} or a pharma- ceutically acceptable salt thereof.

[0079] In some embodiments, the present invention provides a compound 1a and R 1b are each independently hydrogen or C 1-6 R is alkyl; 1c is C 1-6 R is alkyl; 2 and R 3 are each independently hydrogen, C 1-6 Alkyl, C 1-6 Alkoxy, halogen, or -C(O)C(O)N(R 8b R 8c ) and R 4 , R 5 , R 6 and R 7 are each independently hydrogen, C 1-6 Alkyl, halogen, C 1-6 Haloalkyl, C1-6 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 C 7-18 alkyl-aryl; or R 5 and R 6 are combined with the atom to which they are attached to form C 4-6 forming a heterocycloalkyl} or a pharma- ceutically acceptable salt thereof.

[0080] In some embodiments, the present invention provides a compound, 3 ;R 1a , R 1b and R 1c are each independently hydrogen or C 1-6 R is alkyl; 2 and R 3 are each independently hydrogen, C 1-6 Alkyl, or -C(O)C(O)N(R 8b R 8c ) or R 2 and R 3 are combined with the atom to which they are attached to form C 6-12 Forming an aryl group; R 4 , R 5 , R 6 and R 7 are each independently hydrogen, C 1-6 Alkyl, halogen, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, or -OR 8a where R 4 , R 5 , R 6 and R 7 At least one of is not H; and R 8a is C 7-18 alkyl-aryl; or R 5 and R6 are combined with the atom to which they are attached to form C 3-6 forming a heterocycloalkyl.

[0081] In some embodiments, the present invention provides a compound 1a and R 1b are each independently hydrogen, C 1-6 Alkyl, C 3-8 Cycloalkyl, or C 4-14 alkyl-cycloalkyl; or R 1a , R 1b , and R 1c Two of them combine with the atom to which they are attached to form C 3-12 In some embodiments, R 1a and R 1b are each independently hydrogen or C 1-6 In some embodiments, R 1a and R 1b are each independently hydrogen, methyl, ethyl, or propyl. In some embodiments, R 1a and R 1b are each independently hydrogen or methyl.

[0082] In some embodiments, the present invention provides a compound 1a and R 1b are independently hydrogen or methyl, and R 1c is methyl; or R 1a , R 1b , and R 1c Two of them combine with the atom to which they are attached to form C 3-8 In some embodiments, the present invention provides a compound {wherein R 1a and R 1b are each independently hydrogen or methyl; and R 1c is methyl; or R 1a , R1b , and R 1c Two of them combine with the atom to which they are attached to form C 3-8 forming a heterocycloalkyl} or a pharma- ceutically acceptable salt thereof.

[0083] In some embodiments, the present invention provides a compound 1c is C 1-6 Alkyl, C 3-8 Cycloalkyl, or C 4-14 In some embodiments, the present invention provides a compound {wherein R 1c is C 1-6 In some embodiments, R is an alkyl group, or a pharma- ceutically acceptable salt thereof. 1c In some embodiments, the present invention provides a compound of formula 1c is methyl} or a pharma- ceutically acceptable salt thereof. In some embodiments, R 1c is methyl.

[0084] In some embodiments, the present invention provides a compound 1a , R 1b , and R 1c are each methyl; or R 1a , R 1b , and R 1c Two of them combine with the atom to which they are attached to form C 3-8 In some embodiments, the present invention provides a compound {wherein R 1a , R 1b , and R 1c are each Me; or R 1a , R 1b , and R 1c Two of them combine with the atom to which they are attached to form C 3-8 forming a heterocycloalkyl} or a pharma- ceutically acceptable salt thereof.

[0085] In some embodiments, the present invention provides a compound 1a , R 1b , or R 1c One of them is R 2 , R 3 , R 4 , R 5 , R 6 or R 7 Combined with one of the C 5-12 In some embodiments, the present invention provides a compound {wherein R 1a , R 1b , or R 1c One of them is R 2 or R 7 Combined with one of the C 5-8 In some embodiments, the present invention provides a compound {wherein R 1a , R 1b , or R 1c One of them is R 2 Combined with C 5-8 forming a heterocycloalkyl} or a pharma- ceutically acceptable salt thereof.

[0086] In some embodiments, the present invention provides a compound 2 , R 3 , R 4 , R 5 , R 6 and R 7 are each independently hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, C 1-6 Haloalkyl, C 1-6 Alkylamines, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -OR 8a , -NO 2 , -CN, -C(O)R 8b , -C(O)OR 8b , -OC(O)R8b , -OC(O)OR 8b , -N(R 8b R 8c ), -N(R 8b )C(O)R 8c , -C(O)N(R 8b R 8c ), -N(R 8b )C(O)OR 8c , -OC(O)N(R 8b R 8c ), -N(R 8b )C(O)N(R 8c R 8d ), -C(O)C(O)N(R 8b R 8c ), -S(O 2 )R 8b , -S(O) 2 N(R 8b R 8c ), C 3-8 Cycloalkyl, C 3-14 Alkyl-Cycloalkyl, C 4-10 Heterocycloalkyl, C 4-16 Alkyl-heterocycloalkyl, C 6-12 Aryl, C 7-18 Alkyl-aryl, C 5-10 Heteroaryl, or C 4-16 alkyl-heteroaryl} or a pharma- ceutically acceptable salt thereof. 8a is 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; and R 8b , R 8c and R 8d are each independently H or C 1-6 It is an alkyl.

[0087] In some embodiments, the present invention provides a compound2 and R 3 are each independently hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, C 1-6 Haloalkyl, C 1-6 Alkylamines, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -OR 8a , -NO 2 , -CN, -C(O)R 8b , -C(O)OR 8b , -OC(O)R 8b , -OC(O)OR 8b , -N(R 8b R 8c ), -N(R 8b )C(O)R 8c , -C(O)N(R 8b R 8c ), -N(R 8b )C(O)OR 8c , -OC(O)N(R 8b R 8c ), -N(R 8b )C(O)N(R 8c R 8d ), -C(O)C(O)N(R 8b R 8c ), -S(O 2 )R 8b , -S(O) 2 N(R 8b R 8c ), C 3-8 Cycloalkyl, C 3-14 Alkyl-Cycloalkyl, C 4-10 Heterocycloalkyl, C 4-16 Alkyl-heterocycloalkyl, C 6-12 Aryl, C 7-18 Alkyl-aryl, C 5-10 Heteroaryl, or C 4-16 alkyl-heteroaryl} or a pharma- ceutically acceptable salt thereof.

[0088] In some embodiments, the present invention provides a compound 2 is hydrogen, C 1-6Alkyl, halogen, or C 1-6 In some embodiments, the present invention provides a compound {wherein R 2 In some embodiments, the present invention provides a compound {wherein R is hydrogen, methyl, ethyl, propyl, F, Cl, Br, I, methoxy, or ethoxy} or a pharma- ceutically acceptable salt thereof. 2 is hydrogen, Me, F or OMe} or a pharma- ceutically acceptable salt thereof.

[0089] In some embodiments, the present invention provides a compound 3 is hydrogen, C 1-6 Alkyl, C 1-6 Alkoxy, halogen, or -C(O)C(O)N(R 8b R 8c ), and R 8b and R 8c are each independently H or C 1-6 In some embodiments, the present invention provides a compound {wherein R 3 is hydrogen, methyl, ethyl, propyl, F, Cl, Br, I, methoxy, ethoxy, or -C(O)C(O)N(R 8b R 8c ), and R 8b and R 8c are each independently methyl, ethyl, or propyl} or a pharma- ceutically acceptable salt thereof.

[0090] In some embodiments, the present invention provides a compound 3 is hydrogen, C 1-6 Alkyl, C 1-6 Alkoxy, halogen, or -C(O)C(O)N(R 8b R 8c ) and R 8b and R 8c are each independently H or C 1-6 In some embodiments, the present invention provides a compound {wherein R3 is hydrogen, Me, F, -OMe or -C(O)C(O)NMe 2 or a pharma- ceutically acceptable salt thereof.

[0091] In some embodiments, the present invention provides a compound or a pharma- ceutically acceptable salt thereof, wherein the compound of formula I has the following structure: [ka] has.

[0092] In some embodiments, the present invention provides a compound or a pharma- ceutically acceptable salt thereof, wherein the compound of formula I has the following structure: [ka] has.

[0093] In some embodiments, the present invention provides a compound 1a and R 1b are combined with the atom to which they are attached to form C 3-12 In some embodiments, the present invention provides a compound {wherein R 1a and R 1b are combined with the atom to which they are attached to form C 3-8 In some embodiments, the present invention provides a compound {wherein R 1a and R 1b are combined with the atom to which they are attached to form C 3-8 forming a heterocycloalkyl} or a pharma- ceutically acceptable salt thereof.

[0094] In some embodiments, the present invention provides a compound 1a and R 1c are combined with the atom to which they are attached to form C 5-12In some embodiments, the present invention provides a compound {wherein R 1a and R 1c are combined with the atom to which they are attached to form C 5-8 In some embodiments, the present invention provides a compound {wherein R 1a and R 1c are combined with the atom to which they are attached to form C 5-6 In some embodiments, the present invention provides a compound {wherein R 1a and R 1c are combined with the atom to which they are attached to form C 5-8 forming a heterocycloalkyl} or a pharma- ceutically acceptable salt thereof.

[0095] In some embodiments, the present invention provides a method for the preparation of a compound of formula (Ia): [ka] {where, R 1a and R 1b are each independently, C 1-6 Alkyl, C 3-8 Cycloalkyl, or C 4-14 alkyl-cycloalkyl; R 1c is hydrogen, C 1-6 Alkyl, C 3-8 Cycloalkyl, or C 4-14 alkyl-cycloalkyl; or R 1a , R 1b , and R 1c Two of them combine with the atom to which they are attached to form C 3-12 R forms a heterocycloalkyl; 2 , R 3 , R 4 , R 6 and R 7 are each independently hydrogen, C 1-6 Alkyl, C 2-6Alkenyl, C 2-6 Alkynyl, halogen, C 1-6 Haloalkyl, C 1-6 Alkylamines, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -OR 8a , -NO 2 , -CN, -C(O)R 8b , -C(O)OR 8b , -OC(O)R 8b , -OC(O)OR 8b , -N(R 8b R 8c ), -N(R 8b )C(O)R 8c , -C(O)N(R 8b R 8c ), -N(R 8b )C(O)OR 8c , -OC(O)N(R 8b R 8c ), -N(R 8b )C(O)N(R 8c R 8d ), -C(O)C(O)N(R 8b R 8c ), -S(O 2 )R 8b , -S(O) 2 N(R 8b R 8c ), C 3-8 Cycloalkyl, C 3-14 Alkyl-Cycloalkyl, C 4-10 Heterocycloalkyl, C 4-16 Alkyl-heterocycloalkyl, C 6-12 Aryl, C 7-18 Alkyl-aryl, C 5-10 Heteroaryl, or C 4-16 alkyl-heteroaryl; R 5 are F, Cl, Br, and C 1-6 Alkyl, C 1-6 Haloalkoxy, -OR 8a , -NO 2 , -CN,C 2-6 Alkenyl, C 2-6 Alkynyl, -C(O)R 8b , -N(R 8b R 8c ), -N(R8b )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 8c R 8c ), -S(O 2 )R 8b , -S(O 2 )N(R 8b R 8c ), C 3-8 Cycloalkyl, C 3-14 Alkyl-Cycloalkyl, C 4-10 Heterocycloalkyl, C 4-16 Alkyl-heterocycloalkyl, C 6-12 Aryl, C 7-18 Alkyl-aryl or C 4-16 alkyl-heteroaryl; R 8a is 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 8b , R 8c and R 8d are each independently H or C 1-6 alkyl; or R 1a , R 1b , and R 1c One of them is R 2 or R 7 Combined with one of the C 5-6 Cycloalkyl or C 5-6 forming a heterocycloalkyl; and / or R 2 and R 3are combined with the atom to which they are attached to form C 6-12 form an aryl; or R 4 and R 5 , R 5 and R 6 , or R 6 and R 7 are combined with the atom to which they are attached to form C 3-6 Cycloalkyl or C 3-6 heterocycloalkyl, where R 1c is H and R 5 Br, Cl, F, -NH 2 , -NO 2 , or C 1 -C 3 When R is alkoxy, 2 , R 3 , R 4 , R 6 , or R 7 is not H; and 5 When F, R 6 is not F}, or a salt or isomer thereof, or a pharma- ceutically acceptable salt or solvate thereof.

[0096] In some embodiments, the present invention provides a compound represented by formula (Ia), 1a and R 1b are each independently, C 1-6 Alkyl, C 3-8 Cycloalkyl, or C 4-14 alkyl-cycloalkyl; R 1c is C 1-6 Alkyl, C 3-8 Cycloalkyl, or C 4-14 alkyl-cycloalkyl; or R 1a , R 1b , and R 1c Two of them combine with the atom to which they are attached to form C 3-12 R forms a heterocycloalkyl; 2 , R 3 , R 4 , R 6 and R 7are each independently hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, C 1-6 Haloalkyl, C 1-6 Alkylamines, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -OR 8a , -NO 2 , -CN, -C(O)R 8b , -C(O)OR 8b , -OC(O)R 8b , -OC(O)OR 8b , -N(R 8b R 8c ), -N(R 8b )C(O)R 8c , -C(O)N(R 8b R 8c ), -N(R 8b )C(O)OR 8c , -OC(O)N(R 8b R 8c ), -N(R 8b )C(O)N(R 8c R 8d ), -C(O)C(O)N(R 8b R 8c ), -S(O 2 )R 8b , -S(O) 2 N(R 8b R 8c ), C 3-8 Cycloalkyl, C 3-14 Alkyl-Cycloalkyl, C 4-10 Heterocycloalkyl, C 4-16 Alkyl-heterocycloalkyl, C 6-12 Aryl, C 7-18 Alkyl-aryl, C 5-10 Heteroaryl, or C 4-16 alkyl-heteroaryl; R 5 is C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, C 1-6 Haloalkyl, C 1-6 Alkylamines, C 1-6 Alkoxy, C 1-6Haloalkoxy, -OR 8a , -NO 2 , -CN, -C(O)R 8b , -C(O)OR 8b , -OC(O)R 8b , -OC(O)OR 8b , -N(R 8b R 8c ), -N(R 8b )C(O)R 8c , -C(O)N(R 8b R 8c ), -N(R 8b )C(O)OR 8c , -OC(O)N(R 8b R 8c ), -N(R 8b )C(O)N(R 8c R 8d ), -C(O)C(O)N(R 8b R 8c ), -S(O 2 )R 8b , -S(O) 2 N(R 8b R 8c ), C 3-8 Cycloalkyl, C 3-14 Alkyl-Cycloalkyl, C 4-10 Heterocycloalkyl, C 4-16 Alkyl-heterocycloalkyl, C 6-12 Aryl, C 7-18 Alkyl-aryl, C 5-10 Heteroaryl, or C 4-16 alkyl-heteroaryl; R 8a is 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 8b , R 8c and R 8d are each independently H or C 1-6 alkyl; or R1a , R 1b , and R 1c One of them is R 2 or R 7 Combined with one of the C 5-6 Cycloalkyl or C 5-6 form a heterocycloalkyl; or R 2 and R 3 are combined with the atom to which they are attached to form C 6-12 form an aryl; or R 4 and R 5 , R 5 and R 6 , or R 6 and R 7 are combined with the atom to which they are attached to form C 3-6 Cycloalkyl or C 3-6 heterocycloalkyl-forming compounds, salts and isomers thereof, or pharma- ceutically acceptable salts or solvates thereof are provided.

[0097] In some embodiments, the present invention provides a compound or a pharma- ceutically acceptable salt thereof, wherein the compound of formula I has the following structure: [ka] has.

[0098] In some embodiments, the present invention provides a compound or a pharma- ceutically acceptable salt thereof, wherein the compound of formula I has the following structure: [ka] has.

[0099] In some embodiments, the present invention provides a compound or a pharma- ceutically acceptable salt thereof, wherein the compound of formula I has the following structure: [ka] has.

[0100] In some embodiments, R 2 and R 3 are combined with the atom to which they are attached to form C 4-8 Cycloalkyl, C 4-10 Heterocycloalkyl, or C 6-12 Forming an aryl.

[0101] In some embodiments, the present invention provides a compound 4 , R 5 , R 6 and R 7 are each independently hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, C 1-6 Haloalkyl, C 1-6 Alkylamines, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -OR 8a , -NO 2 , -CN, -C(O)R 8b , -C(O)OR 8b , -OC(O)R 8b , -OC(O)OR 8b , -N(R 8b R 8c ), -N(R 8b )C(O)R 8c , -C(O)N(R 8b R 8c ), -N(R 8b )C(O)OR 8c , -OC(O)N(R 8b R 8c ), -N(R 8b )C(O)N(R 8c R 8d ), -C(O)C(O)N(R 8b R 8c ), -S(O 2 )R 8b , -S(O) 2 N(R 8b R 8c ), C 3-8 Cycloalkyl, C 3-14 Alkyl-Cycloalkyl, C 4-10 Heterocycloalkyl, C4-16 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 are combined with the atom to which they are attached to form C 4-6 Cycloalkyl, C 4-6 Heterocycloalkyl, C 6-12 Aryl or C 5-10 In some embodiments, the present invention provides a compound or a pharma- ceutically acceptable salt thereof, wherein R 4 , R 5 , R 6 or R 7 are each independently hydrogen, C 1-6 Alkyl, halogen, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -OR 8a , -NO 2 , -CN,C 3-8 Cycloalkyl, or C 3-14 It is an alkyl-cycloalkyl.

[0102] In some embodiments, the present invention provides a compound 8a is 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; and R 8b , R 8c and R 8dare each independently H or C 1-6 In some embodiments, the present invention provides a compound {wherein R 8a is C 3-8 Cycloalkyl, C 3-14 Alkyl-Cycloalkyl, C 4-16 Alkyl-heterocycloalkyl, C 7-18 Alkyl-aryl or C 4-16 alkyl-heteroaryl} or a pharma- ceutically acceptable salt thereof.

[0103] In some embodiments, the present invention provides a compound 4 and R 5 , R 5 and R 6 , or R 6 and R 7 are combined with the atom to which they are attached to form C 4-6 Cycloalkyl, C 4-6 Heterocycloalkyl, C 6-12 Aryl or C 5-10 In some embodiments, the present invention provides a compound {wherein R 4 and R 5 are combined with the atom to which they are attached to form C 4-6 In some embodiments, the present invention provides a compound {wherein R 5 and R 6 are combined with the atom to which they are attached to form C 4-6 In some embodiments, the present invention provides a compound {wherein R 6 and R 7 are combined with the atom to which they are attached to form C 4-6 In some embodiments, the present invention provides a compound {wherein R 5 and R6 are combined with the atom to which they are attached to form C 5-6 In some embodiments, the present invention provides a compound {wherein R 5 and R 6 are combined with the atoms to which they are respectively attached to form a 1,3-dioxole ring or a 1,4-dioxane ring} or a pharma- ceutically acceptable salt thereof.

[0104] In some embodiments, the present invention provides a compound 4 , R 5 , R 6 or R 7 are each independently hydrogen, C 1-6 Alkyl, halogen, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -OR 8a , -NO 2 , -CN,C 3-8 Cycloalkyl, or C 3-14 alkyl-cycloalkyl; or R 4 and R 5 , R 5 and R 6 , or R 6 and R 7 are combined with the atom to which they are attached to form C 5-6 forming a heterocycloalkyl; and R 8a is C 3-8 Cycloalkyl, C 3-14 Alkyl-Cycloalkyl, C 4-16 Alkyl-heterocycloalkyl, C 7-18 Alkyl-aryl or C 4-16 In some embodiments, the present invention provides a compound {wherein R 4 , R 5 , R 6 or R 7 are each independently hydrogen, C 1-6 Alkyl, halogen, C 1-6Alkoxy, C 1-6 Haloalkoxy, -OR 8a , or -NO 2 or R 4 and R 5 , R 5 and R 6 , or R 6 and R 7 are combined with the atom to which they are attached to form C 5 forming a heterocycloalkyl; and R 8a is C 7-18 In some embodiments, the present invention provides a compound {wherein R 4 , R 6 or R 7 are each independently hydrogen, C 1-6 Alkyl, halogen, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -OR 8a , or -NO 2 ;R 5 is C 1-6 Alkyl, halogen, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -OR 8a , or -NO 2 or R 4 and R 5 , R 5 and R 6 , or R 6 and R 7 are combined with the atom to which they are attached to form C 5 forming a heterocycloalkyl; and R 8a is C 7-18 In some embodiments, the present invention provides a compound {wherein R 4 , R 5 , R 6 or R 7 are each independently hydrogen, Me, F, Cl, Br, -OMe, -OCF 3 , -O-CH 2 -phenyl or -NO 2 or R5 and R 6 are combined with the atoms to which they are respectively attached to form a 1,3-dioxole ring or a 1,4-dioxane ring} or a pharma- ceutically acceptable salt thereof.

[0105] In some embodiments, the present invention provides a compound 5 is C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, C 1-6 Haloalkyl, C 1-6 Alkylamines, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -OR 8a , -NO 2 , -CN, -C(O)R 8b , -C(O)OR 8b , -OC(O)R 8b , -OC(O)OR 8b , -N(R 8b R 8c ), -N(R 8b )C(O)R 8c , -C(O)N(R 8b R 8c ), -N(R 8b )C(O)OR 8c , -OC(O)N(R 8b R 8c ), -N(R 8b )C(O)N(R 8c R 8d ), -C(O)C(O)N(R 8b R 8c ), -S(O 2 )R 8b , -S(O) 2 N(R 8b R 8c ), C 3-8 Cycloalkyl, C 3-14 Alkyl-Cycloalkyl, C 4-10 Heterocycloalkyl, C 4-16 Alkyl-heterocycloalkyl, C 6-12 Aryl, C 7-18 Alkyl-aryl, C 5-10 Heteroaryl, or C 4-16In some embodiments, the present invention provides a compound {wherein R 5 is C 1-6 Alkyl, halogen, C 1-6 Alkoxy, C 1-6 Haloalkoxy or -NO 2 In some embodiments, the present invention provides a compound, 5 is methyl, ethyl, propyl, F, Cl, Br, I, methoxy, ethoxy, -OCF 3 , -O-benzyl, or -NO 2 In some embodiments, the present invention provides a compound, 5 is methyl, F, Cl, Br, methoxy, -OCF 3 , -O-benzyl, or -NO 2 or a pharma- ceutically acceptable salt thereof.

[0106] In some embodiments, the present invention provides a compound 4 , R 6 and R 7 are each hydrogen; and R 5 Me, F, Cl, Br, -OMe, -CF 3 , -OCF 3 , -O-benzyl or -NO 2 In some embodiments, the present invention provides a compound, 5 Me, F, Cl, Br, -OMe, -CF 3 , -OCF 3 , -O-benzyl or -NO 2 and R 6 and R 7 are each independently hydrogen, Me, F, Cl, Br, -OMe, -OCF 3 , -O-CH 2 -phenyl or -NO 2 where R 6 and R 7wherein at least one of is not hydrogen} or a pharma- ceutically acceptable salt thereof.

[0107] In some embodiments, the present invention provides a compound, 3 ;R 1a , R 1b and R 1c are each independently hydrogen or C 1-6 R is alkyl; 2 and R 3 are each independently hydrogen, C 1-6 Alkyl, or -C(O)C(O)N(R 8b R 8c ) or R 2 and R 3 are combined with the atom to which they are attached to form C 6-12 Forming an aryl group; R 4 , R 5 , R 6 and R 7 are each independently hydrogen, C 1-6 Alkyl, halogen, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, or -OR 8a where R 4 , R 5 , R 6 and R 7 at least one of is not H; and R 8a is C 7-18 alkyl-aryl; or R 5 and R 6 are combined with the atom to which they are attached to form C 3-6 forming a heterocycloalkyl.

[0108] In some embodiments, the present invention provides a compound, 3 ;R 1a and R 1b are Me and R 1c is hydrogen or Me; R 2 is H, Me or -C(O)-C(O)N(Me)2 or R 2 and R 3 are combined to form a phenyl ring; R 4 , R 5 , R 6 and R 7 are each independently H, F, Br, -NO 2 , -OMe, -CF 3 , -OCF 3 or -Obenzyl; or R 5 and R 6 are combined to form a 1,3-dioxole ring.

[0109] In some embodiments, the present invention provides a compound, 3 ;R 1a and R 1b are Me and R 1c is hydrogen or Me; R 2 is H or Me; R 3 is H or -C(O)-C(O)N(Me) 2 ;R 4 is H, F, -OMe or -O-benzyl; R 5 H, F, Br, -OMe, -CF 3 OCF 3 or -O-benzyl; R 6 H, -NO 2 , -OMe, -OCF 3 or -O-benzyl; or R 2 and R 3 are combined to form a phenyl ring; or R 5 and R 6 are combined to form a 1,3-dioxole ring; and R 7 is H, F, -OMe, or -O-benzyl.

[0110] In some embodiments, the present invention provides a compound, 3 ;R 1a and R 1b are Me and R 1cis Me, Et, or Pr; R 2 is H, Me, -OMe, -F, or -C(O)-C(O)N(Me) 2 ;R 3 is H, Me, -OMe, -F, or -C(O)-C(O)N(Me) 2 ;R 4 , R 5 , R 6 and R 7 are each independently H, Me, -F, -Cl, Br, or -NO 2 , -OMe, -CF 3 , -OCF 3 or -Obenzyl; or R 5 and R 6 are combined to form a 1,3-dioxole ring or a 1,4-dioxane ring} or a pharma- ceutically acceptable salt thereof. In some embodiments, the present invention provides a compound {wherein X is CR 3 ;R 1a and R 1b are Me and R 1c is Me, Et, or Pr; R 2 is H, Me-F, -OMe; R 3 is H, Me, -F, -OMe, or -C(O)-C(O)N(Me) 2 ;R 4 is H, Me, -F, -OMe or -O-benzyl; R 5 -H, -Me, -F, -Cl, -Br, -OMe, -CF 3 OCF 3 or -O-benzyl; R 6 -H, -Me, -F, -NO 2 , -OMe, -OCF 3 or -O-benzyl; or R 5 and R 6 are combined to form a 1,3-dioxole ring or a 1,4-dioxane ring; and R 7 is H, Me, -F, -OMe, or -O-benzyl} or a pharma- ceutically acceptable salt thereof.

[0111] In some embodiments, the present invention provides a compound 1-6 In some embodiments, the invention provides a compound {wherein L is methylene, ethylene, propylene, or butylene} or a pharma- ceutically acceptable salt thereof. In some embodiments, the invention provides a compound {wherein L is methylene or ethylene} or a pharma- ceutically acceptable salt thereof. In some embodiments, the invention provides a compound {wherein L is ethylene} or a pharma- ceutically acceptable salt thereof. In some embodiments, the invention provides a compound {wherein L is methylene} or a pharma- ceutically acceptable salt thereof.

[0112] In some embodiments, the present invention provides a compound, wherein the compound has the following structure: [ka] Or a pharma- ceutical acceptable salt thereof.

[0113] In some embodiments, the present invention provides a compound, wherein the compound has the following structure: [ka] Or a pharma- ceutical acceptable salt thereof.

[0114] In some embodiments, the present invention provides a compound, wherein the compound has the following structure: [ka] Or a pharma- ceutical acceptable salt thereof.

[0115] In some embodiments, the present invention provides a compound, wherein the compound has the following structure: [ka] Or a pharma- ceutical acceptable salt thereof.

[0116] In some embodiments, the present invention provides a compound according to the present invention having the following formula II: [ka] wherein X is CR 3 ;R 1a and R 1b are each independently hydrogen, C 1-6 Alkyl, C 3-8 Cycloalkyl, or C 4-14 alkyl-cycloalkyl; or R 1a and R 1b are combined with the atom to which they are attached to form C 3-12 R forms a heterocycloalkyl; 2 , R 3 , R 4 , R 5 , R 6 , and R 7 are each independently hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, C 1-6 Haloalkyl, C 1-6 Alkylamines, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -OR 8a , -NO 2 , -CN, -C(O)R 8b , -C(O)OR 8b , -OC(O)R 8b , -OC(O)OR 8b , -N(R 8b R 8c ), -N(R 8b )C(O)R 8c , -C(O)N(R 8b R 8c ), -N(R 8b )C(O)OR 8c , -OC(O)N(R 8b R 8c ), -N(R 8b )C(O)N(R 8c R 8d ), -C(O)C(O)N(R 8b R8c ), -S(O 2 )R 8b , -S(O) 2 N(R 8b R 8c ), C 3-8 Cycloalkyl, C 3-14 Alkyl-Cycloalkyl, C 4-10 Heterocycloalkyl, C 4-16 Alkyl-heterocycloalkyl, C 6-12 Aryl, C 7-18 Alkyl-aryl, C 5-10 Heteroaryl, or C 4-16 alkyl-heteroaryl; R 8a is 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 8b , R 8c , and R 8d are each independently H or C 1-6 alkyl; or R 1a or R 1b One of them is R 2 Combined with C 5-12 form a heterocycloalkyl; or R 2 and R 3 are combined with the atom to which they are attached to form C 4-8 Cycloalkyl, C 4-10 Heterocycloalkyl, or C 6-12 form an aryl; or R 4 and R 5 , R 5 and R 6 , or R 6 and R 7 are combined with the atom to which they are attached to form C 4-6 Cycloalkyl, C 4-6 Heterocycloalkyl, C6-12 Aryl or C 5-10 forming a heteroaryl; and L is C 1-6 or a pharma- ceutically acceptable salt or isomer thereof, wherein R 1a and R 1b When both are Me and L is methylene, R 2 , R 3 , R 4 , R 5 , R 6 , and R 7 is not hydrogen, and the compound has the following structure: [ka] where R 1a and R 1b is Me, L is ethylene, and X is CR 3 When R 2 , R 3 , R 4 , R 5 , R 6 , and R 7 at least one of R 1c is hydrogen and R 5 Br, Cl, F, -NH 2 , -NO 2 , or C 1-3 When R is alkoxy, 2 , R 3 , R 4 , R 6 , or R 7 at least one of R 1c is hydrogen and R 5 When F, R 2 , R 3 , R 4 , R 6 , or R 7 At least one of is not hydrogen, and R 6 is not F, or a pharma- ceutically acceptable salt or isomer thereof.

[0117] In some embodiments, the present invention provides a compound or a pharma- ceutically acceptable salt thereof, wherein the compound of formula II has the following structure: [ka] has.

[0118] In some embodiments, the present invention provides a compound or a pharma- ceutically acceptable salt thereof, wherein the compound of formula II has the following structure: [ka] has.

[0119] In some embodiments, the present invention provides a compound 2 , R 3 , R 4 , R 5 , R 6 and R 7 wherein at least one of is not H} or a pharma- ceutically acceptable salt thereof.

[0120] In some embodiments, the present invention provides a compound 4 , R 5 , R 6 or R 7 are each independently hydrogen, C 1-6 Alkyl, halogen, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -OR 8a , -NO 2 , -CN,C 3-8 Cycloalkyl, or C 3-14 alkyl-cycloalkyl; or R 4 and R 5 , R 5 and R 6 , or R 6 and R 7 are combined with the atom to which they are attached to form C 5-6 forming a heterocycloalkyl; and R 8a is C 3-8Cycloalkyl, C 3-14 Alkyl-Cycloalkyl, C 4-16 Alkyl-heterocycloalkyl, C 7-18 Alkyl-aryl or C 4-16 In some embodiments, the present invention provides a compound {wherein R 4 , R 5 , R 6 or R 7 are each independently hydrogen, C 1-6 Alkyl, halogen, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -OR 8a , or -NO 2 or R 4 and R 5 , R 5 and R 6 , or R 6 and R 7 are combined with the atom to which they are attached to form C 5 forming a heterocycloalkyl; and R 8a is C 7-18 alkyl-aryl} or a pharma- ceutically acceptable salt thereof.

[0121] In some embodiments, the present invention provides a compound 4 , R 5 , R 6 or R 7 are each independently hydrogen, F, Cl, -OMe, -OCF 3 or -O-benzyl; or R 5 and R 6 In some embodiments, the present invention provides a compound of formula {wherein R 5 F, Cl, -OMe, -OCF 3 or -O-benzyl; or R 5 and R 6are combined with the atoms to which they are respectively attached to form a 1,3-dioxole ring or a 1,4-dioxane ring} or a pharma- ceutically acceptable salt thereof.

[0122] In some embodiments, the present invention provides a compound 5 F, Cl, -OMe, -OCF 3 or -O-benzyl; R 6 and R 7 are each independently hydrogen, F, Cl, -OMe, -OCF 3 or -O-benzyl, where R 6 and R 7 at least one of R 5 and R 6 are combined with the atoms to which they are respectively attached to form a 1,3-dioxole ring or a 1,4-dioxane ring} or a pharma- ceutically acceptable salt thereof.

[0123] In some embodiments, the present invention provides a compound, wherein the compound has the following structure: [ka] Or a pharma- ceutical acceptable salt thereof.

[0124] In some embodiments, the present invention provides a compound, wherein the compound has the following structure: [ka] Or a pharma- ceutical acceptable salt thereof.

[0125] In some embodiments, the present invention provides a compound 1a and R 1b are combined with the atom to which they are attached to form C 3-8 forming a heterocycloalkyl} or a pharma- ceutically acceptable salt thereof.

[0126] In some embodiments, the present invention provides a compound, wherein the compound has the following structure: [ka] Or a pharma- ceutical acceptable salt thereof.

[0127] In some embodiments, the present invention provides a compound, wherein the compound has the following structure: [ka] Or a pharma- ceutical acceptable salt thereof.

[0128] The compounds of the present invention may also be in the form of salts, such as the acid salts or base salts of the compounds of the present invention. Illustrative examples of pharmaceutically acceptable salts are salts of mineral acids (such as hydrochloric acid, hydrobromic acid, phosphoric acid, etc.), salts of organic acids (such as fumaric acid, acetic acid, propionic acid, glutamic acid, citric acid, etc.), and salts of quaternary ammonium (such as methyl iodide, ethyl iodide, etc.). It is understood that pharmaceutically acceptable salts are non-toxic. Further information on suitable pharmaceutically acceptable salts can be found in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, which is incorporated herein by reference.

[0129] In some embodiments, the compound of the invention is a salt containing fumaric acid. In some embodiments, the invention provides a compound, wherein the compound is a salt or a pharma- ceutically acceptable salt containing fumaric acid.

[0130] The present invention also includes isotopically labeled compounds of the invention, in which one or more atoms are replaced by one or more atoms having a specified atomic mass or mass number. Examples of isotopes that can be incorporated into compounds of the invention include, but are not limited to, isotopes of hydrogen, carbon, nitrogen, oxygen, fluorine, sulfur, and chlorine (e.g., 2 H,3 H, 13 C. 14 C. 15 N, 18 O. 17 O. 18 F, 35 S and 36 Isotopically labeled compounds of the present invention are useful in tissue distribution assays of the compounds, and their prodrugs and metabolites; preferred isotopes for such assays include 3 H and 14 C. In addition, in certain circumstances, heavier isotopes such as deuterium ( 2 Substitution with, for example, 1,3-dihydro-1,4-triazol-2,4-diaminetetraacetate (H) may provide increased metabolic stability, which may result in therapeutic advantages such as increased in vivo half-life or reduced dose requirements. In general, isotopically labeled compounds of the present invention can be prepared according to methods known to those skilled in the art by substituting an isotopically labeled reagent for a non-isotopically labeled reagent. Compounds of the present invention may be isotopically labeled at basic amines of aromatic rings and at positions adjacent to the methyl group of methoxy substituents.

[0131] The present invention includes all tautomers and stereoisomers of the compounds of the present invention, in mixtures or in pure or substantially pure form. The compounds of the present invention have asymmetric centers at carbon atoms, and therefore the compounds of the present invention may exist as diastereomers, enantiomers or mixtures thereof. All conformational isomers (e.g., cis and trans isomers) and all optical isomers (e.g., enantiomers and diastereomers), racemates, diastereomers and other mixtures of such isomers, as well as solvates, hydrates, isomorphs, polymorphs and tautomers, are within the scope of the present invention. The compounds according to the present invention may be prepared using diastereomers, enantiomers or racemic mixtures as starting materials. Furthermore, diastereomeric and enantiomeric products may be separated by chromatography, fractional crystallization or other methods known to those skilled in the art. IV. Pharmaceutical Compositions and Formulations

[0132] In some embodiments, the present invention provides a pharmaceutical composition comprising a compound of the present invention and a pharma- ceutically acceptable excipient.

[0133] The compositions of the present invention may be prepared in a wide variety of oral, parenteral and topical dosage forms. Oral preparations include tablets, pills, powders, capsules, liquids, lozenges, cachets, gels, syrups, slurries, suspensions, and the like, suitable for oral ingestion by the patient. The compositions of the present invention may also be administered by injection, i.e., intravenously, intramuscularly, intradermally, subcutaneously, intraduodenally, or intraperitoneally. The compositions described herein may also be administered by inhalation, for example, intranasally. Additionally, the compositions of the present invention may be administered transdermally. The compositions of the present invention may also be administered by intraocular, intravaginal and intrarectal routes (including suppositories), insufflation, powders, and aerosol formulations (for examples of steroid inhalants, see Rohatagi, J. Clin. Pharmacol. 35:1187-1193, 1995; Tjwa, Ann. Allergy Asthma Immunol. 75:107-111, 1995). Thus, the present invention also provides a pharmaceutical composition comprising a pharma- ceutically acceptable carrier or excipient and a compound of the present invention.

[0134] For preparing pharmaceutical compositions from the compounds of the present invention, pharma- ceutical acceptable carriers can be solid or liquid.Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories and dispersible granules.Solid carriers can be one or more substances that can act as diluents, flavorings, binders, preservatives, tablet disintegrating agents or encapsulating materials.Details regarding procedures for formulation and administration are fully described in the scientific and patent literature, see, for example, the latest edition of Remington's Pharmaceutical Sciences, Maack Publishing Co, Easton PA ("Remington's").

[0135] In powders, the carrier is a finely divided solid that is in a mixture with the finely divided active ingredient. In tablets, the active ingredient is mixed with a carrier having the necessary binding properties in suitable proportions and compressed into the desired shape and size. The powders and tablets preferably contain 5% to 70% or 10% to 70% of the compound of the present invention.

[0136] Suitable solid excipients include, but are not limited to, magnesium carbonate, magnesium stearate, talc, pectin, dextrin, starch, tragacanth, low melting waxes, cocoa butter, carbohydrates, sugars (including but not limited to lactose, sucrose, mannitol or sorbitol, starches derived from corn, wheat, rice, potato or other plants), celluloses (e.g., methylcellulose, hydroxypropylmethyl-cellulose or sodium carboxymethylcellulose), and gums (including acacia and tragacanth), and proteins (including but not limited to gelatin and collagen). If desired, disintegrating or solubilizing agents may be added (e.g., cross-linked polyvinylpyrrolidone, agar, alginic acid or a salt thereof (e.g., sodium alginate)).

[0137] For preparing suppositories, a low melting wax, such as a mixture of fatty acid glycerides or cocoa butter is first melted and the compound of the present invention is dispersed homogeneously therein by stirring. The molten homogeneous mixture is then poured into convenient sized molds, allowed to cool and thereby solidify.

[0138] Liquid form preparations include solutions, suspensions and emulsions, for example, water or water / propylene glycol solutions.For parenteral injection, liquid preparations can be formulated in solutions in aqueous polyethylene glycol solution.

[0139] Aqueous solutions suitable for oral use can be prepared by dissolving the compounds of the invention in water and adding suitable colorants, flavorings, stabilizers and thickening agents, as desired. Aqueous suspensions suitable for oral use are prepared by mixing the finely divided active ingredient with a viscous material (e.g., natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum arabic) and a dispersing or wetting agent (e.g., naturally occurring phosphatides (e.g., lecithin), condensation products of alkylene oxides with fatty acids (e.g., polyoxyethylene stearate), condensation products of ethylene oxide with long chain aliphatic alcohols (e.g., heptadecaethyleneoxycetanol), condensation products of ethylene oxide with fatty acids and heptadecaethyleneoxycetanol). The aqueous suspension may be prepared by dispersing in water with a condensation product of ethylene oxide with a partial ester derived from a xylitol (e.g., polyoxyethylene sorbitol mono-oleate) or a condensation product of ethylene oxide with a partial ester derived from a fatty acid and a hexitol anhydride (e.g., polyoxyethylene sorbitan mono-oleate). The aqueous suspension may also contain one or more preservatives (e.g., ethyl p-hydroxybenzoate or n-propyl p-hydroxybenzoate), one or more coloring agents, one or more flavoring agents, and one or more sweetening agents (e.g., sucrose, aspartame, or saccharin). The formulation may be adjusted for osmolality.

[0140] Also included are solid form preparations that are intended to be converted immediately before use into liquid form preparations for oral administration.Such liquid forms include solutions, suspensions and emulsions.These preparations may contain, in addition to the active ingredient, colorants, flavors, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizers, etc.

[0141] Oily suspensions can be formulated by suspending the compounds of the present invention in a vegetable oil (e.g., peanut oil, olive oil, sesame oil or coconut oil) or a mineral oil (e.g., liquid paraffin); or a mixture thereof. The oily suspensions can contain a thickening agent (e.g., beeswax, hard paraffin or cetyl alcohol). Sweetening agents (e.g., glycerol, sorbitol or sucrose) can be added to provide a palatable oral preparation. These preparations can be preserved by adding an antioxidant such as ascorbic acid. For an example of an injectable oily vehicle, see Minto, J. Pharmacol. Exp. Ther. 281:93-102, 1997. The pharmaceutical preparations of the present invention can also be in the form of oil-in-water emulsions. The oily phase can be a vegetable oil or a mineral oil, as described above, or a mixture thereof. Suitable emulsifying agents include naturally occurring gums (e.g., gum arabic and gum tragacanth), naturally occurring phosphatides (e.g., soybean lecithin), esters or partial esters derived from fatty acids and hexitol anhydrides (e.g., sorbitan mono-oleate) and condensation products of these partial esters with ethylene oxide (e.g., polyoxyethylene sorbitan mono-oleate). Emulsions may also contain sweetening and flavoring agents, as in the formulation of syrups and elixirs. Such formulations may also contain a demulcent, preservative, or coloring agent.

[0142] The compositions of the present invention can also be delivered as microspheres for slow release in the body. For example, microspheres can be formulated for administration via intradermal injection of drug-containing microspheres that slowly release subcutaneously (see Rao, J. Biomater Sci. Polym. Ed. 7:623-645, 1995); as biodegradable injectable gel formulations (see, e.g., Gao Pharm. Res. 12:857-863, 1995); or as microspheres for oral administration (see, e.g., Eyles, J. Pharm. Pharmacol. 49:669-674, 1997). Both transdermal and intradermal routes provide constant delivery over weeks or months.

[0143] In some embodiments, the pharmaceutical compositions of the present invention may be formulated for parenteral administration (e.g., intravenous (IV) administration or administration into a body cavity or lumen of an organ). Preparations for administration usually include a solution of the composition of the present invention dissolved in a pharma- ceutically acceptable carrier. Acceptable vehicles and solvents that can be used are water and Ringer's solution, isotonic sodium chloride. In addition, sterile fixed oils can be conventionally used as a solvent or suspending medium. For this purpose, any bland fixed oil can be used, including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid can be used in the preparation of injectables as well. These solutions are sterile and usually free of undesirable substances. These preparations can be sterilized by conventional, well-known sterilization procedures. They may contain pharma-ceutically acceptable auxiliary substances as required to approximate physiological conditions (e.g., pH adjusting and buffering agents, toxicity adjusting agents, e.g., sodium acetate, sodium chloride, potassium chloride, calcium chloride, sodium lactate, etc.). The concentration of the composition of the present invention in these preparations can vary widely and can be selected mainly based on the volume of fluid, viscosity, body weight, etc., according to the specific mode of administration selected and the needs of the patient. For IV administration, the preparation can be a sterile injectable preparation (e.g., a sterile injectable aqueous or oily suspension). This suspension can be formulated according to known techniques using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation can also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent (e.g., a solution in 1,3-butanediol).

[0144] In some embodiments, the formulation of the composition of the present invention can be delivered by using liposomes, which fuse with the cell membrane or are endocytosed, i.e., by using ligands attached to the liposomes or directly attached to oligonucleotides that bind to cell surface membrane protein receptors, resulting in endocytosis.The composition of the present invention can be delivered to target cells in vivo by using liposomes, particularly when the liposome surface has a ligand specific to the target cell or is otherwise preferentially directed to a particular organ (see, for example, Al-Muhammed, J. Microencapsul. 13:293-306, 1996; Chonn, Curr. Opin. Biotechnol. 6:698-708, 1995; Ostro, Am. J. Hosp. Pharm. 46:1576-1587, 1989). V. Administration

[0145] The compositions of the present invention can be delivered by any suitable means, including oral, parenteral and topical. Topical routes of transdermal administration can be formulated as applicator sticks, solutions, suspensions, emulsions, gels, creams, ointments, pastes, jellies, paints, powders and aerosols.

[0146] The pharmaceutical preparation is preferably in unit dosage form. In such form, the preparation is subdivided into unit doses containing appropriate amounts of the compound of the present invention. The unit dosage form can be a packaged preparation, the package containing discrete quantities of the preparation (for example, packaged tablets, capsules, and powders in vials or ampoules). Also, the unit dosage form can be a capsule, tablet, cachet, or lozenge itself, or the appropriate number of any of these in packaged form.

[0147] The compounds of the present invention may be present in any suitable amount, which may depend on various 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.

[0148] The compounds of the invention may be administered at any suitable frequency, interval and duration. For example, the compounds of the invention may be administered hourly, twice hourly, three or more times, once a day, twice a day, three or more times, or once every 2, 3, 4, 5, 6, or 7 days to provide a preferred dosage level. When the compounds of the invention are administered multiple times 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 invention may be administered once, twice, or three or more times for 1 hour, 1-6 hours, 1-12 hours, 1-24 hours, 6-12 hours, 12-24 hours, 1 day, 1-7 days, 1 week, 1-4 weeks, 1 month, 1-12 months, 1 year or more, or indefinitely.

[0149] The compositions may also include other compatible therapeutic agents. The compounds described herein may be used in combination with each other, with other active agents known to be useful in modulating the glucocorticoid receptor, or with adjuvants that may not be effective alone but may contribute to the effectiveness of the active agent.

[0150] The compound of the present invention may be co-administered with another active agent. Co-administration includes administration of the compound of the present invention and the active agent within 0.5, 1, 2, 4, 6, 8, 10, 12, 16, 20 or 24 hours of each other. Co-administration also includes administration of the compound of the present invention and the active agent simultaneously, nearly simultaneously (e.g., within about 1, 5, 10, 15, 20 or 30 minutes of each other) or sequentially in any order. Furthermore, the compound of the present invention and the active agent may each be administered once a day, or two, three or more times a day to provide a preferred daily dosage level.

[0151] In some embodiments, simultaneous administration may be achieved by co-formulation, i.e., preparing a single pharmaceutical composition that contains both the compound of the invention and the active agent, hi other embodiments, the compound of the invention and the active agent are formulated separately.

[0152] The compounds of the invention and the active agents may be provided in the compositions of the invention in any suitable weight ratio, such as about 1:100 to about 100:1 (w / w), or about 1:50 to about 50:1, about 1:25 to about 25:1, about 1:10 to about 10:1, or about 1:5 to 5:1 (w / w). The compounds of the invention and the other active agents may be provided in any suitable weight ratio, such as about 1:100 (w / w), 1:50, 1:25, 1:10, 1:5, 1:4, 1:3, 1:2, 1:1, 2:1, 3:1, 4:1, 5:1, 10:1, 25:1, 50:1, or 100:1 (w / w). Other dosage amounts and dose ratios of the compounds of the invention and the active agents are suitable in the compositions and methods of the invention. VI. Treatment Methods

[0153] The compound of the present invention can be used to enhance neuroplasticity.The compound of the present invention can also be used to treat any brain disease.The compound of the present invention can also be used to enhance at least one of the translation, transcription or secretion of neurotrophic factor.

[0154] In some embodiments, the compounds of the present invention are used to treat neurological disorders. In some embodiments, the compounds have, for example, anti-addictive, anti-depressant, anxiolytic properties, or a combination thereof. In some embodiments, the neurological disorder is a neuropsychiatric disorder. In some embodiments, the neuropsychiatric disorder is a mood or anxiety disorder. In some embodiments, the neurological disorder is a migraine, a headache (e.g., cluster headache), post-traumatic stress disorder (PTSD), anxiety, depression, a neurodegenerative disorder, Alzheimer's disease, Parkinson's disease, psychiatric disorders, treatment-resistant depression, suicidal ideation, major depressive disorder, bipolar disorder, schizophrenia, stroke, traumatic brain injury, and addiction (e.g., substance use disorder). In some embodiments, the neurological disorder is a migraine or cluster headache. In some embodiments, the neurological disorder is a neurodegenerative disorder, Alzheimer's disease, or Parkinson's disease. In some embodiments, the neurological disorder is a psychiatric disorder, treatment-resistant depression, suicidal ideation, major depressive disorder, bipolar disorder, schizophrenia, post-traumatic stress disorder (PTSD), addiction (e.g., substance use disorder), depression, or anxiety. In some embodiments, the neuropsychiatric disorder is a psychiatric disorder, treatment-resistant depression, suicidal ideation, major depressive disorder, bipolar disorder, schizophrenia, post-traumatic stress disorder (PTSD), addiction (e.g., substance use disorder), depression, or anxiety. In some embodiments, the neuropsychiatric or neurological disorder is a post-traumatic stress disorder (PTSD), addiction (e.g., substance use disorder), schizophrenia, depression, or anxiety. In some embodiments, the neuropsychiatric or neurological disorder is an addiction (e.g., substance use disorder). In some embodiments, the neuropsychiatric or neurological disorder is depression. In some embodiments, the neuropsychiatric or neurological disorder is anxiety. In some embodiments, the neuropsychiatric or neurological disorder is post-traumatic stress disorder (PTSD). In some embodiments, the neurological disorder is stroke or traumatic brain injury, hi some embodiments, the neuropsychiatric or neurological disorder is schizophrenia.

[0155] In some embodiments, the compounds of the present invention are used to enhance neuroplasticity. In some embodiments, the compounds described herein are used to treat brain disorders. In some embodiments, the compounds described herein are used to enhance at least one of translation, transcription, or secretion of neurotrophic factors.

[0156] In some embodiments, the compounds of the present invention are 2A In some embodiments, the compounds of the present invention have activity as 5-HT 2A In some embodiments, the compounds of the present invention have activity as 5-HT 2A Activate the receptor (e.g., allosteric modulation or 5-HT 2A They induce biological responses by activating 5-HT receptors (modulating biological targets). 2A 5-HT agonism was associated with enhanced neuroplasticity (Ly et al., 2018). As shown in Figure 7, 5-HT 2A The antagonist is 5-HT 2A In some embodiments, the compounds of the present invention inhibit the neuritogenesis and spinogenesis effects of hallucinogenic compounds with agonist activity, such as DMT, LSD, and DOI. 2A In some embodiments, the compounds of the present invention are selective 5-HT 2A It is a modulator and promotes neuroplasticity (e.g., cortical structural plasticity). In some embodiments, promotion of neuroplasticity includes, for example, enhanced dendritic spine growth, increased synthesis of synaptic proteins, enhanced synaptic response, enhanced dendritic spreading complexity, enhanced dendritic branching content, enhanced spine formation, enhanced neurite formation, or any combination thereof. In some embodiments, enhanced neuroplasticity includes, for example, enhanced cortical structural plasticity in the anterior part of the brain.

[0157] In some embodiments, 5-HT 2A Modulators (e.g., 5-HT 2A In some embodiments, the non-hallucinogenic 5-HT 2A Modulators (e.g., 5-HT 2A agonists) are used to treat neurological disorders and the modulators do not induce dissociative side effects. In some embodiments, the hallucinogenic potential of the compounds described herein is assessed in vitro. In some embodiments, the hallucinogenic potential of the compounds described herein, as assessed in vitro, is compared to the hallucinogenic potential of a hallucinogenic homolog, as assessed in vitro. In some embodiments, the compounds described herein induce lower hallucinogenic potential in vitro compared to the hallucinogenic homolog.

[0158] In some embodiments, the non-hallucinogenic 5-HT 2A Modulators (e.g., 5-HT 2A agonists) are used to treat neurological disorders. In some embodiments, the neurological disorders are characterized by reduced neuroplasticity, reduced plasticity of cortical structures, 5-HT 2A This includes reduced receptor content, reduced dendritic spreading complexity, loss of dendritic spines, reduced dendritic branching content, reduced spine formation, reduced neurite formation, neurite retraction, or any combination thereof.

[0159] In some embodiments, the non-hallucinogenic 5-HT 2A Modulators (e.g., 5-HT 2A In some embodiments, non-hallucinogenic 5-HT agonists are used to enhance neuroplasticity. 2A Modulators (e.g., 5-HT 2A In some embodiments, non-hallucinogenic 5-HT agonists are used to treat brain disorders. 2A Modulators (e.g., 5-HT 2AAgonists are used to enhance at least one of the translation, transcription, or secretion of a neurotrophic factor. A. Methods for Enhancing Neuroplasticity

[0160] Neuroplasticity refers to the brain's ability to change structure and / or function throughout a subject's life. New neurons can be produced throughout a subject's life and integrated into the central nervous system. Enhanced neuroplasticity includes, but is not limited to, promoting neuronal proliferation, promoting neuritogenesis, promoting synaptogenesis, promoting dendrite formation, enhancing the complexity of dendritic spreading, enhancing dendritic spine density, and enhancing excitatory synapses in the brain. In some embodiments, enhanced neuroplasticity includes promoting neuronal proliferation, promoting neuritogenesis, promoting synaptogenesis, promoting dendrite formation, enhancing the complexity of dendritic spreading, and enhancing dendritic spine density.

[0161] In some embodiments, enhanced neuronal plasticity may treat a neurodegenerative disorder, Alzheimer's disease, Parkinson's disease, psychiatric disorder, depression, addiction, anxiety, post-traumatic stress disorder, treatment-resistant depression, suicidal ideation, major depressive disorder, bipolar disorder, schizophrenia, stroke, traumatic brain injury, or substance use disorder.

[0162] In some embodiments, the present invention provides a method for enhancing neuroplasticity comprising contacting a neuronal cell with any of the compounds of the present invention. In some embodiments, the enhanced neuroplasticity ameliorates the brain disorders described herein.

[0163] In some embodiments, the compounds of the invention are used to enhance neuroplasticity. In some embodiments, the compounds used to enhance neuroplasticity have, for example, anti-addictive, anti-depressant properties, anxiolytic properties, or a combination thereof. In some embodiments, the reduced neuroplasticity is associated with a neuropsychiatric condition. In some embodiments, the neuropsychiatric condition is a mood or anxiety disorder. In some embodiments, the neuropsychiatric condition includes, for example, migraine, cluster headache, post-traumatic stress disorder (PTSD), schizophrenia, anxiety, depression, and addiction (e.g., substance abuse disorder). In some embodiments, the brain disorder includes, for example, migraine, addiction (e.g., substance use disorder), depression, and anxiety.

[0164] In some embodiments, the experiment or assay measuring the enhanced neuronal plasticity of any of the compounds of the present invention includes phenotypic assays, dendrite formation assays, spine formation assays, synaptogenesis assays, Sholl analysis, concentration-response experiments, 5-HT 2A Agonist assay, 5-HT 2A Antagonist assay, 5-HT 2A Binding assay, or 5-HT 2A Blocking Experiments (eg, Ketanserin Blocking Experiments). In some embodiments, an experiment or assay to measure the hallucinogenic potential of any compound of the present invention is the mouse Head Twitch Response (HTR) assay.

[0165] In some embodiments, the present invention provides a method of enhancing neuroplasticity, comprising administering to a neuronal cell a compound of formula I: [ka] wherein X is N or CR 3 ;R 1a , R 1b , and R 1c are each independently hydrogen, C 1-6 Alkyl, C 3-8 Cycloalkyl, or C 4-14alkyl-cycloalkyl; or R 1a , R 1b , and R 1c Two of them combine with the atom to which they are attached to form C 3-12 R forms a heterocycloalkyl; 2 , R 3 , R 4 , R 5 , R 6 , and R 7 are each independently hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, C 1-6 Haloalkyl, C 1-6 Alkylamines, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -OR 8a , -NO 2 , -CN, -C(O)R 8b , -C(O)OR 8b , -OC(O)R 8b , -OC(O)OR 8b , -N(R 8b R 8c ), -N(R 8b )C(O)R 8c , -C(O)N(R 8b R 8c ), -N(R 8b )C(O)OR 8c , -OC(O)N(R 8b R 8c ), -N(R 8b )C(O)N(R 8c R 8d ), -C(O)C(O)N(R 8b R 8c ), -S(O 2 )R 8b , -S(O) 2 N(R 8b R 8c ), C 3-8 Cycloalkyl, C 3-14 Alkyl-Cycloalkyl, C 4-10 Heterocycloalkyl, C 4-16 Alkyl-heterocycloalkyl, C 6-12 Aryl, C 7-18Alkyl-aryl, C 5-10 Heteroaryl, or C 4-16 alkyl-heteroaryl; R 8a is 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 8b , R 8c and R 8d are each independently H or C 1-6 alkyl; or R 1a , R 1b , or R 1c One of them is R 2 Combined with C 5-12 form a heterocycloalkyl; or R 2 and R 3 are combined with the atom to which they are attached to form C 4-8 Cycloalkyl, C 4-10 Heterocycloalkyl, or C 6-12 form an aryl; or R 4 and R 5 , R 5 and R 6 , or R 6 and R 7 are combined with the atom to which they are attached to form C 3-6 Cycloalkyl, C 3-6 Heterocycloalkyl, C 6-12 Aryl or C 5-10 forming a heteroaryl; and L is C 1-6 or a pharma- ceutically acceptable salt thereof, wherein the compound is

[0166] In some embodiments, the present invention provides a method for enhancing neuroplasticity, comprising administering to a neuronal cell a sufficient amount of a compound of formula I, wherein X is N or CR 3 ;R 1a , R 1b , and R 1c are each independently hydrogen, C 1-6 Alkyl, C 3-8 Cycloalkyl, or C 4-14 alkyl-cycloalkyl; or R 1a , R 1b , and R 1c Two of them combine with the atom to which they are attached to form C 3-12 R forms a heterocycloalkyl; 2 , R 3 , R 4 , R 5 , R 6 , and R 7 are each independently hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, C 1-6 Haloalkyl, C 1-6 Alkylamines, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -OR 8a , -NO 2 , -CN, -C(O)R 8b , -C(O)OR 8b , -OC(O)R 8b , -OC(O)OR 8b , -N(R 8b R 8c ), -N(R 8b )C(O)R 8c , -C(O)N(R 8b R 8c ), -N(R 8b )C(O)OR 8c , -OC(O)N(R 8b R 8c ), -N(R 8b )C(O)N(R 8c R 8d ), -C(O)C(O)N(R 8b R 8c ), -S(O2 )R 8b , -S(O) 2 N(R 8b R 8c ), C 3-8 Cycloalkyl, C 3-14 Alkyl-Cycloalkyl, C 4-10 Heterocycloalkyl, C 4-16 Alkyl-heterocycloalkyl, C 6-12 Aryl, C 7-18 Alkyl-aryl, C 5-10 Heteroaryl, or C 4-16 alkyl-heteroaryl; R 8a is 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 8b , R 8c and R 8d are each independently H or C 1-6 alkyl; or R 1a , R 1b and R 1c One of them is R 2 , R 3 , R 4 , R 5 , R 6 and R 7 Combined with one of the C 5-6 Cycloalkyl or C 5-6 form a heterocycloalkyl; or R 2 and R 3 are combined with the atom to which they are attached to form C 6-12 can form an aryl; or R 4 and R 5 , R 5 and R 6 , or R 6 and R 7are combined with the atom to which they are attached to form C 3-6 Cycloalkyl, or C 3-6 and L can form a heterocycloalkyl; 1-6 The method includes contacting a compound of formula (I) with a compound of formula (I) or salts and isomers thereof, wherein B. Methods of Treating Brain Disorders

[0167] In some embodiments, the present invention provides a method for 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 for treating a brain disorder comprising administering to a subject in need thereof a therapeutically effective amount of a compound of the present invention. In some embodiments, the present invention provides a method for treating a brain disorder in 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.

[0168] In some embodiments, 5-HT 2A Modulators (e.g., 5-HT 2A agonists) are used to treat brain disorders. In some embodiments, the brain disorders include reduced neuroplasticity, reduced plasticity of cortical structures, 5-HT 2A This includes reduced receptor content, reduced dendritic spreading complexity, loss of dendritic spines, reduced dendritic branching, reduced spine formation, reduced neurite formation, neurite retraction, or any combination thereof.

[0169] In some embodiments, the compounds of the present invention are used to treat brain disorders. In some embodiments, the compounds have, for example, anti-addictive, anti-depressant properties, anti-anxiety properties, or a combination thereof. In some embodiments, the brain disorder is a neuropsychiatric disorder. In some embodiments, the neuropsychiatric disorder is a mood or anxiety disorder. In some embodiments, the brain disorder includes, for example, migraine, cluster headache, post-traumatic stress disorder (PTSD), anxiety, depression, schizophrenia, and addiction (e.g., substance abuse disorder). In some embodiments, the brain disorder includes, for example, migraine, addiction (e.g., substance use disorder), depression, and anxiety.

[0170] In some embodiments, the present invention provides a method of enhancing neuroplasticity, comprising administering to a neuronal cell a compound of formula I: [ka] wherein X is N or CR 3 ;R 1a , R 1b , and R 1c are each independently hydrogen, C 1-6 Alkyl, C 3-8 Cycloalkyl, or C 4-14 alkyl-cycloalkyl; or R 1a , R 1b , and R 1c Two of them combine with the atom to which they are attached to form C 3-12 R forms a heterocycloalkyl; 2 , R 3 , R 4 , R 5 , R 6 , and R 7 are each independently hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, C 1-6 Haloalkyl, C 1-6 Alkylamines, C 1-6 Alkoxy, C 1-6Haloalkoxy, -OR 8a , -NO 2 , -CN, -C(O)R 8b , -C(O)OR 8b , -OC(O)R 8b , -OC(O)OR 8b , -N(R 8b R 8c ), -N(R 8b )C(O)R 8c , -C(O)N(R 8b R 8c ), -N(R 8b )C(O)OR 8c , -OC(O)N(R 8b R 8c ), -N(R 8b )C(O)N(R 8c R 8d ), -C(O)C(O)N(R 8b R 8c ), -S(O 2 )R 8b , -S(O) 2 N(R 8b R 8c ), C 3-8 Cycloalkyl, C 3-14 Alkyl-Cycloalkyl, C 4-10 Heterocycloalkyl, C 4-16 Alkyl-heterocycloalkyl, C 6-12 Aryl, C 7-18 Alkyl-aryl, C 5-10 Heteroaryl, or C 4-16 alkyl-heteroaryl; R 8a is 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 8b , R 8c and R 8d are each independently H or C 1-6 alkyl; or R1a , R 1b , or R 1c One of them is R 2 Combined with C 5-12 form a heterocycloalkyl; or R 2 and R 3 are combined with the atom to which they are attached to form C 4-8 Cycloalkyl, C 4-10 Heterocycloalkyl, or C 6-12 form an aryl; or R 4 and R 5 , R 5 and R 6 , or R 6 and R 7 are combined with the atom to which they are attached to form C 3-6 Cycloalkyl, C 3-6 Heterocycloalkyl, C 6-12 Aryl or C 5-10 forming a heteroaryl; and L is C 1-6 or a pharma- ceutically acceptable salt thereof, where X is an alkylene;

[0171] In some embodiments, the present invention provides a method of treating a brain disorder, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula I, 3 ;R 1a , R 1b , and R 1c are each independently hydrogen, C 1-6 Alkyl, C 3-8 Cycloalkyl, or C 4-14 alkyl-cycloalkyl; or R 1a , R 1b , and R 1c Two of them combine with the atom to which they are attached to form C 3-12 R forms a heterocycloalkyl; 2 , R 3 , R 4 , R 5 , R 6 , and R 7are each independently hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, C 1-6 Haloalkyl, C 1-6 Alkylamines, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -OR 8a , -NO 2 , -CN, -C(O)R 8b , -C(O)OR 8b , -OC(O)R 8b , -OC(O)OR 8b , -N(R 8b R 8c ), -N(R 8b )C(O)R 8c , -C(O)N(R 8b R 8c ), -N(R 8b )C(O)OR 8c , -OC(O)N(R 8b R 8c ), -N(R 8b )C(O)N(R 8c R 8d ), -C(O)C(O)N(R 8b R 8c ), -S(O 2 )R 8b , -S(O) 2 N(R 8b R 8c ), C 3-8 Cycloalkyl, C 3-14 Alkyl-Cycloalkyl, C 4-10 Heterocycloalkyl, C 4-16 Alkyl-heterocycloalkyl, C 6-12 Aryl, C 7-18 Alkyl-aryl, C 5-10 Heteroaryl, or C 4-16 alkyl-heteroaryl; R 8a is C 3-8 Cycloalkyl, C 3-14 Alkyl-Cycloalkyl, C 4-10 Heterocycloalkyl, C 4-16 Alkyl-heterocycloalkyl, C 6-12 Aryl, C 7-18Alkyl-aryl, C 5-10 Heteroaryl, or C 4-16 alkyl-heteroaryl; R 8b , R 8c and R 8d are each independently H or C 1-6 alkyl; or R 1a , R 1b and R 1c One of them is R 2 , R 3 , R 4 , R 5 , R 6 and R 7 Combined with one of the C 5-6 Cycloalkyl or C 5-6 form a heterocycloalkyl; or R 2 and R 3 are combined with the atom to which they are attached to form C 6-12 can form an aryl; or R 4 and R 5 , R 5 and R 6 , or R 6 and R 7 are combined with the atom to which they are attached to form C 3-6 Cycloalkyl, or C 3-6 and L can form a heterocycloalkyl; 1-6 and n is an integer from 1 to 3, and n is an integer from 1 to 3, thereby treating the brain disorder.

[0172] In some embodiments, the brain disorder is a neurodegenerative disorder, Alzheimer's disease, Parkinson's disease, a psychiatric disorder, depression, addiction, anxiety, post-traumatic stress disorder, treatment-resistant depression, suicidal ideation, major depressive disorder, bipolar disorder, schizophrenia, stroke, traumatic brain injury, or a substance use disorder.

[0173] In some embodiments, the brain disorder is a neurodegenerative disorder, Alzheimer's disease, or Parkinson's disease. In some embodiments, the brain disorder is a psychiatric disorder, depression, addiction, anxiety, or post-traumatic stress disorder. In some embodiments, the brain disorder is depression. In some embodiments, the brain disorder is addiction. In some embodiments, the brain disorder is treatment-resistant depression, suicidal ideation, major depressive disorder, bipolar disorder, schizophrenia, stroke, traumatic brain injury, or substance use disorder. In some embodiments, the brain disorder is treatment-resistant depression, suicidal ideation, major depressive disorder, bipolar disorder, schizophrenia, or substance use disorder. In some embodiments, the brain disorder is stroke or traumatic brain injury. In some embodiments, the brain disorder is treatment-resistant depression, suicidal ideation, major depressive disorder, bipolar disorder, or substance use disorder. In some embodiments, the brain disorder is schizophrenia. In some embodiments, the brain disorder is alcohol use disorder.

[0174] In some embodiments, the method includes the administration of any of the following drugs: lithium, olanzapine (Zyprexa), quetiapine (Seroquel), risperidone (Risperdal), ariprazole (Abilify), ziprasidone (Geodon), clozapine (Clozaril), divalproex sodium (Depakote), lamotrigine (Lamictal), valproic acid (Depakene), carbamazepine (Equetro), topiramate (Topamax), levomilnacipran (Fetzima), duloxetine (Cymbalta, Yentreve), venlafaxine (Effexor), citalopram ( and administering one or more additional therapeutic agents that are: Celexa), fluvoxamine (Luvox), escitalopram (Lexapro), fluoxetine (Prozac), paroxetine (Paxil), sertraline (Zoloft), clomipramine (Anafranil), amitriptyline (Elavil), desipramine (Norpramin), imipramine (Tofranil), nortriptyline (Pamelor), phenelzine (Nardil), tranylcypromine (Parnate), diazepam (Valium), alprazolam (Xanax), or clonazepam (Klonopin).

[0175] In some embodiments, the compounds of the present invention are used in combination with standard care therapies for the neurological disorders described herein. Non-limiting examples of standard care therapies may include, for example, lithium, olanzapine, quetiapine, risperidone, ariprazole, ziprasidone, clozapine, divalproex sodium, lamotrigine, valproic acid, carbamazepine, topiramate, levomilnacipran, duloxetine, venlafaxine, citalopram, fluvoxamine, escitalopram, fluoxetine, paroxetine, sertraline, clomipramine, amitriptyline, desipramine, imipramine, nortriptyline, phenelzine, tranylcypromine, diazepam, alprazolam, clonazepam, or any combination thereof. Non-limiting examples of standard care therapies for depression include sertraline, fluoxetine, escitalopram, venlafaxine, or aripiprazole. Non-limiting examples of standard care therapies for depression include citralopram, escitalopram, fluoxetine, paroxetine, diazepam, or sertraline. C. Methods for enhancing at least one of translation, transcription, or secretion of a neurotrophic factor

[0176] Neurotrophic factors refer to a family of soluble peptides or proteins that support the survival, growth, and differentiation of developing and mature neurons. Enhancing at least one of the translation, transcription, or secretion of neurotrophic factors can be useful for, but not limited to, enhancing neuroplasticity, promoting neuronal proliferation, promoting neuritogenesis, promoting synaptogenesis, promoting dendrite formation, enhancing dendritic spread complexity, enhancing dendritic spine density, and enhancing excitatory synapses in the brain. In some embodiments, enhancing at least one of the translation, transcription, or secretion of neurotrophic factors can enhance neuroplasticity. In some embodiments, enhancing at least one of the translation, transcription, or secretion of neurotrophic factors can enhance neuronal proliferation, promoting neuritogenesis, promoting synaptogenesis, promoting dendrite formation, enhancing dendritic spread complexity, and / or enhancing dendritic spine density.

[0177] In some embodiments, 5-HT 2A Modulators (e.g., 5-HT 2A In some embodiments, the compounds of the present invention are used to increase at least one of the translation, transcription, or secretion of neurotrophic factors. In some embodiments, the compounds of the present invention are used to increase at least one of the translation, transcription, or secretion of neurotrophic factors. In some embodiments, enhancing at least one of the translation, transcription, or secretion of neurotrophic factors treats migraine, headache (e.g., cluster headache), post-traumatic stress disorder (PTSD), anxiety, depression, neurodegenerative disorders, Alzheimer's disease, Parkinson's disease, psychiatric disorders, treatment-resistant depression, suicidal ideation, major depressive disorder, bipolar disorder, schizophrenia, stroke, traumatic brain injury, and addiction (e.g., substance use disorder).

[0178] In some embodiments, the experiments or assays used to measure the increase in translation of neurotrophic factors include ELISA, Western blotting, immunofluorescence, proteomics experiments, and mass spectrometry. In some embodiments, the experiments or assays used to measure the increase in transcription of neurotrophic factors include gene expression assays, PCR, and microarrays. In some embodiments, the experiments or assays used to measure the increase in secretion of neurotrophic factors include ELISA, Western blotting, immunofluorescence, proteomics, and mass spectrometry.

[0179] In some embodiments, the present invention provides a method of enhancing at least one of the translation, transcription, or secretion of a neurotrophic factor, comprising administering to a neuronal cell a sufficient amount of a compound of formula I: [ka] wherein X is N or CR 3 ;R 1a , R 1b , and R 1c are each independently hydrogen, C 1-6 Alkyl, C 3-8 Cycloalkyl, or C 4-14 alkyl-cycloalkyl; or R 1a , R 1b , and R 1c Two of them combine with the atom to which they are attached to form C 3-12 R forms a heterocycloalkyl; 2 , R 3 , R 4 , R 5 , R 6 , and R 7 are each independently hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, C 1-6 Haloalkyl, C 1-6 Alkylamines, C 1-6 Alkoxy, C 1-6Haloalkoxy, -OR 8a , -NO 2 , -CN, -C(O)R 8b , -C(O)OR 8b , -OC(O)R 8b , -OC(O)OR 8b , -N(R 8b R 8c ), -N(R 8b )C(O)R 8c , -C(O)N(R 8b R 8c ), -N(R 8b )C(O)OR 8c , -OC(O)N(R 8b R 8c ), -N(R 8b )C(O)N(R 8c R 8d ), -C(O)C(O)N(R 8b R 8c ), -S(O 2 )R 8b , -S(O) 2 N(R 8b R 8c ), C 3-8 Cycloalkyl, C 3-14 Alkyl-Cycloalkyl, C 4-10 Heterocycloalkyl, C 4-16 Alkyl-heterocycloalkyl, C 6-12 Aryl, C 7-18 Alkyl-aryl, C 5-10 Heteroaryl, or C 4-16 alkyl-heteroaryl; R 8a is 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 8b , R 8c and R 8d are each independently H or C 1-6 alkyl; or R1a , R 1b , or R 1c One of them is R 2 Combined with C 5-12 form a heterocycloalkyl; or R 2 and R 3 are combined with the atom to which they are attached to form C 4-8 Cycloalkyl, C 4-10 Heterocycloalkyl, or C 6-12 form an aryl; or R 4 and R 5 , R 5 and R 6 , or R 6 and R 7 are combined with the atom to which they are attached to form C 3-6 Cycloalkyl, C 3-6 Heterocycloalkyl, C 6-12 Aryl or C 5-10 forming a heteroaryl; and L is C 1-6 or a pharma- ceutically acceptable salt thereof, wherein the compound is

[0180] In some embodiments, the present invention provides a method of enhancing at least one of translation, transcription, or secretion of a neurotrophic factor, comprising administering to a neuronal cell a sufficient amount of a compound of formula I, wherein X is N or CR 3 ;R 1a , R 1b , and R 1c are each independently hydrogen, C 1-6 Alkyl, C 3-8 Cycloalkyl, or C 4-14 alkyl-cycloalkyl; or R 1a , R 1b , and R 1c Two of them combine with the atom to which they are attached to form C 3-12 R forms a heterocycloalkyl; 2 , R 3 , R 4 , R 5 , R 6, and R 7 are each independently hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, C 1-6 Haloalkyl, C 1-6 Alkylamines, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -OR 8a , -NO 2 , -CN, -C(O)R 8b , -C(O)OR 8b , -OC(O)R 8b , -OC(O)OR 8b , -N(R 8b R 8c ), -N(R 8b )C(O)R 8c , -C(O)N(R 8b R 8c ), -N(R 8b )C(O)OR 8c , -OC(O)N(R 8b R 8c ), -N(R 8b )C(O)N(R 8c R 8d ), -C(O)C(O)N(R 8b R 8c ), -S(O 2 )R 8b , -S(O) 2 N(R 8b R 8c ), C 3-8 Cycloalkyl, C 3-14 Alkyl-Cycloalkyl, C 4-10 Heterocycloalkyl, C 4-16 Alkyl-heterocycloalkyl, C 6-12 Aryl, C 7-18 Alkyl-aryl, C 5-10 Heteroaryl, or C 4-16 alkyl-heteroaryl; R 8a is C 3-8 Cycloalkyl, C 3-14 Alkyl-Cycloalkyl, C 4-10 Heterocycloalkyl, C 4-16 Alkyl-heterocycloalkyl, C 6-12Aryl, C 7-18 Alkyl-aryl, C 5-10 Heteroaryl, or C 4-16 alkyl-heteroaryl; R 8b , R 8c and R 8d are each independently H or C 1-6 alkyl; or R 1a , R 1b and R 1c One of them is R 2 , R 3 , R 4 , R 5 , R 6 and R 7 Combined with one of the C 5-6 Cycloalkyl or C 5-6 form a heterocycloalkyl; or R 2 and R 3 are combined with the atom to which they are attached to form C 6-12 can form an aryl; or R 4 and R 5 , R 5 and R 6 , or R 6 and R 7 are combined with the atom to which they are attached to form C 3-6 Cycloalkyl, or C 3-6 and L can form a heterocycloalkyl; 1-6 The method includes contacting a compound of formula (I) with a compound of formula (I) or salts and isomers thereof, wherein EXAMPLES

[0181] VII. Working Examples General. All reagents were obtained commercially and used without purification unless otherwise noted. DMSO was purified by passing through an activated alumina column under 12 psi of N2. Reactions were carried out using flame-dried glassware under reduced pressure (~1 Torr). Compounds purified by chromatography were adsorbed onto silica gel prior to addition. Thin layer chromatography was performed using Millipore Silica Gel 60 F 254The runs were performed on Silica Gel plates. Visualization of the developed chromatograms was performed by fluorescence quenching or by staining with ninhydrin or aqueous ceric ammonium molybdate (CAM).

[0182] Nuclear magnetic resonance (NMR) spectra are 1 H and 13 For C, signals were acquired on either a Bruker 400 operating at 400 and 100 MHz, a Varian 600 operating at 600 and 150 MHz or a Bruker 800 operating at 800 and 200 MHz and were internally referenced to the residual solvent signal. 1 H NMR data were recorded as follows: chemical shift (δ, ppm), multiplicity (s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet), integral, and coupling constant (Hz). 13 C NMR data are reported in terms of chemical shifts (δ, ppm). Infrared spectra were recorded using a Thermo Nicolet iS10 FT-IR spectrometer equipped with a Smart iTX Accessory (Diamond ATR) and are reported in frequencies of absorption (ν, cm -1). Liquid chromatography-mass spectrometry (LC-MS) was performed using a Waters LC-MS equipped with an ACQUITY Arc QDa detector. Ketamine was purchased from Fagron. DMT (1) and 6-F-DMT (29) were synthesized using previously established methods (>99% purity as measured by UHPLC) (Cameron, LP; Benson, CJ; Dunlap, LE; Olson, DE Effects of N,N-Dimethyltryptamine (DMT) on Rodent Behaviors Relevant to Anxiety and Depression. ACS Chem. Neurosci. 2018, 97, 1582-1590; Tombari, RJ; Saunders, CM; Wu, CY; Dunlap, LE; Tantillo, DJ; Olson, DE Ex Vivo Analysis of Tryptophan Metabolism Using 19F NMR, ACS Chem. Biol., 2019, 14, 1866-1873). For cell plasticity assays (ie, dendrite formation), all compounds were dissolved in DMSO and stored as 10 mM solutions at -20°C in the dark.

[0183] All compounds tested in the cell assay were confirmed to be >95% pure based on UHPLC analysis (Waters ACQUITY Arc) measuring absorbance at 254 and 280 nm. Mobile phase A consisted of 0.01% formic acid in water, and mobile phase B consisted of 0.01% formic acid in acetonitrile. All samples were injected in a volume of 5 μL, and the column temperature was maintained at 40° C. One of three methods was used depending on the particular compound. Method A utilized a CORTECS C18, 2.7 μm, 4.6×50 mm column, a flow rate of 0.6 mL / min, and a gradient of 10% to 90% mobile phase B over 3 minutes (and held for an additional 2 minutes). Method B utilized an XBridge BEH C18 2.5 μm, 2.1×100 mm column, a flow rate of 0.6 mL / min, and a gradient of 10% to 90% mobile phase B over 0.5 minutes (which was then held for an additional 4.5 minutes). Method C utilized a CORTECS C18, 2.7 μm, 4.6×50 mm column, a flow rate of 0.2 mL / min, and a gradient of 10% to 90% mobile phase B over 4 minutes (which was then held for an additional 2 minutes). Most of the compounds reported in this study were isolated as the fumarate salt, so the peak in the UHPLC trace corresponding to fumaric acid was not included in the purity calculations. Synthesis of isoDMT

[0184] Chemical reactions. An operationally simple and robust method for the synthesis of various isoDMTs under mild reaction conditions is described herein. Compound 2 was obtained in good yield using KOH and KI as bases to enhance reactivity via an in situ Finkelstein reaction. Both higher and lower concentrations resulted in reduced yields, and keeping the reaction at 0.4M proved optimal. Step A

[0185] In some embodiments, intermediates used in the preparation of compounds described herein are prepared as outlined in Scheme 1. Scheme 1 [ka]

[0186] In Scheme 1, L, R 1a-1c , and R 2 -R 7 is as described herein. In some embodiments, X is halo or sulfone. In some embodiments, halo is iodo, bromo, or chloro. In some embodiments, halo is chloro. In some embodiments, sulfone is tosylate, nosylate, brosylate, or mesylate. In some embodiments, X is chloro.

[0187] In some embodiments, indole I-1 is reacted with I-2 under suitable condensation reaction conditions, optionally followed by suitable salt formation conditions to provide substituted IsoDMT I-3. In some embodiments, suitable condensation reaction conditions include a suitable base, a suitable additive, a suitable solvent, a suitable time, and a suitable temperature. In some embodiments, the suitable base is a hydroxide base, a carbonate base, or a bicarbonate base. In some embodiments, the suitable base is a hydroxide base or a hydride base. In some embodiments, the suitable hydroxide base is sodium hydroxide or potassium hydroxide. In some embodiments, the suitable hydroxide base is potassium hydroxide. In some embodiments, the suitable hydride base is sodium hydride. In some embodiments, the suitable additive is a salt. In some embodiments, the salt is potassium iodide, sodium iodide, or lithium iodide. In some embodiments, the suitable salt is potassium iodide. In some embodiments, the suitable solvent is a polar aprotic solvent. In some embodiments, the polar aprotic solvent is dichloromethane (DCM), tetrahydrofuran (THF), ethyl acetate (EtOAc), acetone, dimethylformamide (DMF), or acetonitrile (MeCN). In some embodiments, the polar aprotic solvent is DMSO, DMF, MeCN, or acetone. In some embodiments, the polar aprotic solvent is DMSO. In some embodiments, the suitable time and suitable temperature are overnight and about 25° C.

[0188] In some embodiments, suitable salt forming conditions include a suitable acid in a suitable solvent at a suitable temperature for a suitable time. In some embodiments, the suitable acid is a carboxylic acid. In some embodiments, the carboxylic acid is fumaric acid. In some embodiments, the suitable solvent is acetone. In some embodiments, the suitable time and temperature are 5 minutes to 1 hour and 55°C.

[0189] For example, to a solution of the respective indole or related heterocycle in DMSO (0.4 M) was added 2-chloro-N,N-dimethylethylamine hydrochloride (1.1 equiv), potassium iodide (1.1 equiv), and potassium hydroxide pellets (5.0 equiv). The reaction was stirred at room temperature for 24 hours and then diluted with 1.0 M NaOH. (aq) The aqueous phase was extracted three times with DCM. The organic extracts were combined and diluted with Na 2 SO 4 The crude oil was dissolved in a minimum amount of acetone and added dropwise to a boiling solution of fumaric acid (1.0 equiv) in acetone. In most cases, a precipitate formed immediately and was stored at -20°C overnight. The resulting crystals were filtered and washed with several portions of ice-cold acetone to give the desired product. In cases where the desired product did not readily crystallize as the fumarate salt, the oil was purified by column chromatography (9:1 CH 2 Cl 2 :MeOH:1%NH 4 OH(aq)). Example 1. N,N-Dimethyltryptamine (DMT)

[0190] The following DMT compounds were prepared by methods known in the art. [ka] Example 2. 2-(1H-indol-1-yl)-N,N-dimethylethan-1-amine fumarate (1:1) (2, isoDMT) [ka]

[0191] Indole (100 mg, 0.85 mmol), 2-chloro-N,N-dimethylethylamine hydrochloride (135 mg, 0.94 mmol, 1.1 equiv), potassium iodide (156 mg, 0.94 mmol, 1.1 equiv), and potassium hydroxide (140 mg, 4.2 mmol, 5.0 equiv) were stirred in DMSO (2.15 mL) until the 2-chloro-N,N-dimethylethylamine was completely consumed (17-24 h) as determined by TLC. The reaction mixture was diluted with 1.0 M NaOH. (aq) (100 mL). The aqueous phase was extracted three times with DCM (25 mL). The organic extracts were combined and diluted with Na 2 SO 4 The mixture was dried over ice, filtered, and concentrated under reduced pressure to give a colorless oil. The crude oil was dissolved in acetone (2 mL) and added dropwise to a boiling solution of fumaric acid (99 mg, .85 mmol, 1.0 equiv) in acetone (4 mL). The precipitate that immediately formed was then stored at -20°C overnight. The crystals were filtered, washed with several portions of ice-cold acetone, and the desired product was obtained. (1:1 isoDMT:fumaric acid) (175 mg, 67%). Purity >99%. TLC R f (free base) = 0.50 (9:1 CH 2 Cl 2 :MeOH:1% NH 4 OH (aq) ); 1 H NMR (600 MHz, DMSO-d 6 ) δ 7.54 (d, 1H, J = 7.6 Hz), 7.48 (d, 1H, J = 7.6 Hz), 7.38 (d, 1H, J = 3.1 Hz), 7.13 (ddd, 1H, J = 7.6, 1.0 Hz), 7.01 (dd, 1H, J = 7.6, 1.0 Hz), 6.61 (s, 2H), 6.42 (d, 1H J = 3.1Hz), 4.29 (t, 2H, J = 6.7 Hz), 2.70 (t, 2H, J = 6.7 Hz), 2.26 (s, 6H). 13 C NMR (150 MHz, DMSO-d 6) δ 166.32, 135.66, 134.20, 128.82, 128.06, 120.96, 120.38, 118.88, 109.68, 100.54, 58.09, 44.83, 43.11 ppm;IR (Diamond, ATR) ν 3100, 2923, 2393, 1705cm -1 ;C 12 H 16 N 2 LRMS (ES+) calculated for + 188.13, found 189.38 (MH+); MP = 147-149°C. Example 3. 2-(4-Methoxy-1H-indol-1-yl)-N,N-dimethylethan-1-amine fumarate (1:1) (3) [ka]

[0192] Synthesized according to procedure A. Reaction carried out with 4-methoxyindole (100 mg, 0.68 mmol) and purified by crystallization. Yield = 95 mg, 42%. Purity = 96%. TLC R f (free base) = 0.35 (9:1 CH 2 Cl 2 :MeOH:1% NH 4 OH (aq) ); 1 H NMR (600 MHz, DMSO-d 6 ) δ 7.26 (d, 1H, J = 3.1 Hz), 7.10 (d, 1H, J = 7.8 Hz), 6.90 (t, 1H, J = 7.8 Hz), 6.66 (d, 1H, J = 7.8 Hz), 6.60 (s, 2H), 6.35 (d, 1H, J = 3.1 Hz), 4.49 (t, 2H, J = 7.0 Hz), 3.89 (s, 3H), 2.76 (t, 2H, J = 7.0 Hz), 2.32 (s, 6H) ppm; 13 C NMR (150 MHz, DMSO-d 6) δ 166.30, 146.96, 134.17, 130.46, 129.79, 124.94, 119.64, 113.33, 102.42, 100.93, 59.61, 55.32, 45.63, 44.63 ppm;IR (Diamond, ATR) ν 2929, 2455, 1712, 1644 cm -1 C 13 H 18 N 2 LRMS (ES+) calculated for O+ 219.15, found 220.33 (MH+); MP = 140-145°C. Example 4. 2-(5-Methoxy-1H-indol-1-yl)-N,N-dimethylethan-1-amine fumarate (1:1) (4) [ka]

[0193] Synthesized according to procedure A. Reaction carried out with 5-methoxyindole (100 mg, 0.68 mmol) and purified by crystallization. Yield = 111 mg, 49%. Purity = 98%. TLC R f (free base) = 0.66 (9:1 CH 2 Cl 2 :MeOH:1% NH 4 OH (aq) ); 1 H NMR (600 MHz, DMSO-d 6 ) δ 7.38 (d, 1H, J = 8.9 Hz), 7.33 (d, 1H, J = 3.0 Hz), 7.04 (d, 1H, J = 2.4 Hz), 6.77 (dd, 1H, J = 8.9, 2.4 Hz), 6.6 (s, 2H), 6.33 (d, 1H, J = 3.0 Hz), 4.29 (t, 2H, J = 6.8 Hz), 3.74 (s, 3H), 2.79 (t, 2H, J = 6.8 Hz), 2.30 (s, 6H) ppm; 13 C NMR (150 MHz, DMSO-d 6) δ 166.58, 153.42, 134.32, 130.90, 129.20, 128.48, 111.12, 110.39, 102.13, 100.34, 57.68, 55.30, 44.44, 42.91 ppm;IR (Diamond, ATR) ν 3035, 2923, 2446, 1715 cm -1 C 13 H 18 N 2 LRMS (ES+) calculated for O+ 219.15, found 220.19 (MH+); MP = 140-142°C. Example 5. 2-(6-Methoxy-1H-indol-1-yl)-N,N-dimethylethan-1-amine (5) [ka]

[0194] Synthesized according to procedure A. Reaction was carried out with 6-methoxyindole (147 mg, 1.0 mmol) and purified by chromatography. Yield = 148 mg, 68%. Purity > 99%. TLC R f (free base) = 0.32 (9:1 CH 2 Cl 2 :MeOH:1% NH 4 OH (aq) ); 1 H NMR (600 MHz, CDCl3) δ 7.49 (d, 1H, J = 7.8 Hz), 7.02 (d, 1H, J = 8.2 Hz), 6.82 (s, 2H), 6.78 (dd, 1H, J = 7.5 Hz), 6.42 (d, 1H, J = 7.8 Hz), 4.17 (t, 2H, J = 7.0 Hz), 2.31 (s, 3H), 2.69 (t, 2H, J = 7.0 Hz), 2.31 (s, 6H) ppm; 13C NMR (150 MHz, CDCl3) δ 156.30, 136.77, 127.04, 123.00, 121.67, 109.22, 101.31, 93.14, 59.00, 55.91, 45.94, 44.91 ppm;IR (Diamond, ATR) ν 2940, 2859, 2769, 1602 cm -1 C 13 H 18 N 2 LRMS calculated for O+ (ES+) 219.15, found 220.33 (MH+). The free base was used in the dendrite formation assay. Example 5'. 2-(6-Methoxy-1H-indol-1-yl)-N,N-dimethylethan-1-amine oxalate (5')

[0195] Synthesized according to procedure A. Reaction carried out with 6-methoxyindole (250 mg, 1.7 mmol) and purified by crystallization. Yield = 221 mg, 42%. Purity = 98%. 1 H NMR (600 MHz, CD 3 OD) δ 7.42 (d, 1H, J = 8.5 Hz), 7.16 (d, 1H, J = 2.9 Hz), 7.02 (s, 2H), 6.74 (d, 1H, J = 8.5 Hz), 6.44 (d, 1H, J = 2.9 Hz), 4.58 (t, 2H, J = 6.8 Hz), 3.87 (s, 3H), 3.56 (t, 2H, J = 7.0 Hz), 2.86 (s, 6H) ppm; 13 C NMR (150 MHz, CD 3 OD) δ 166.72, 158.20, 138.02, 127.52, 124.45, 122.61, 111.06, 103.58, 93.83, 57.22, 56.19, 44.04, 42.17 ppm;IR (Diamond, ATR) ν 3129, 3014, 2641, 1727 cm -1 C 13 H 18 N 2LRMS (ES+) calculated for O+ 219.15, found 220.05 (MH+). MP = 165-167°C. The oxalate salt was used in the HTR assay. Example 6. 2-(7-Methoxy-1H-indol-1-yl)-N,N-dimethylethan-1-amine fumarate (1:1) (6) [ka]

[0196] Synthesized according to procedure A. Reaction carried out with 7-methoxyindole (100 mg, 0.68 mmol) and purified by crystallization. Yield = 162 mg, 72%. Purity > 99%. TLC R f (free base) = 0.44 (9:1 CH 2 Cl 2 :MeOH:1% NH 4 OH (aq) ); 1 H NMR (600 MHz, DMSO-d 6 ) δ 7.26 (d, 1H, J = 3.1 Hz), 7.09-7.03 (m, 2H), 6.60 (s, 2H), 6.52 (dd, 1H, J = 6.1, 1.3 Hz), 6.41 (dd, 1H, J = 3.0, 0.7 Hz), 4.29 (t, 2H, J = 6.8 Hz), 3.86 (s, 3H), 2.75 (t, 2H, J = 6.8 Hz), 2.29 (s, 6H) ppm: 13 C NMR (150 MHz, DMSO-d 6 ) δ 166.46, 152.80, 137.02, 134.24, 127.14, 121.98, 118.38, 103.09, 99.16, 97.88, 57.83, 54.89, 44.60, 43.15 ppm;IR (Diamond, ATR) ν 3435, 3034, 2653, 1705 cm -1 C 13 H 18 N 2 LRMS (ES+) calculated for O+ 219.15, found 220.40 (MH+); Mp 120-123°C. Example 7. Benzyloxyindole

[0197] 4-, 5-, 6-, and 7-OBn indoles were synthesized using previously established methods. Example 8. 2-(4-(benzyloxy)-1H-indol-1-yl)-N,N-dimethylethan-1-amine fumarate (1:1) (8) [ka]

[0198] Synthesized according to procedure A. Reaction carried out with 4-benzyloxyindole (200 mg, 0.89 mmol) and purified by crystallization. Yield = 120 mg, 46%. Purity > 99%. TLC R f (free base) = 0.42 (9:1 CH 2 Cl 2 :MeOH:1% NH 4 OH (aq) ); 1 H NMR (400 MHz, CD 3 OD) δ 7.49 (d, 2H, J = 7.5 Hz), 7.37 (t, 2H, J = 7.5 Hz), 7.31 (t, 1H, J = 7.5 Hz), 7.20 (d, 1H, J = 3.26 Hz), 7.12 (m, 2H), 6.72 (s, 1H), 6.66 (m, 1H), 5.22 (s, 2H), 4.57 (t, 2H, J = 6.7 Hz), 3.50 (t, 2H, J = 6.7 Hz), 2.81 (s, 6H) ppm; 13 C NMR (100 MHz, CD 3 OD) δ 169.90, 153.99, 139.05, 138.85, 135.75, 129.47, 128.78, 128.47, 127.21, 124.18, 121.16, 103.87, 102.67, 101.07, 70.95, 57.32, 43.90, 42.46 ppm;IR (Diamond, ATR) ν 2918, 2493, 1701, 1639 cm -1 C19 H 22 N 2 LRMS (ES+) calculated for O+ 294.17, found 295.24 (MH+); MP = 145-150°C. Example 9. 2-(5-(benzyloxy)-1H-indol-1-yl)-N,N-dimethylethan-1-amine fumarate (1:1) (9) [ka]

[0199] Synthesized according to procedure A. Reaction carried out with 5-benzyloxyindole (287 mg, 1.3 mmol) and purified by crystallization. Yield = 133 mg, 25%. Purity > 99%. TLC R f (free base) = 0.47 (9:1 CH 2 Cl 2 :MeOH:1% NH 4 OH (aq) ); 1 H NMR (400 MHz, CD 3 OD) δ 7.44 (d, 2H, J = 7.5 Hz), 7.36 (m, 3H), 7.29 (d, 2H, J = 7.5 Hz), 7.24 (d, 1H, J = 3.2Hz), 7.15 (d, 1H, J = 2.4 Hz), 6.95 (dd, 1H, J = 2.4, 8.9 Hz), 6.72 (s, 2H), 6.43 (d, 1H, J = 3.2 Hz), 5.07 (s, 2H), 4.54 (t, 2H, J = 6.8 Hz), 3.45 (t, 2H, J = 6.8 Hz), 2.78 (s, 6H) ppm; 13 C NMR (200 MHz, CD 3 OD) δ 171.06, 154.78, 139.26, 136.11, 132.77, 130.89, 130.81, 129.44, 128.73, 128.61, 113.97, 110.95, 105.71, 103.24, 71.86, 57.66, 44.16, 42.77 ppm;IR (Diamond, ATR) ν 2916, 2516, 1698, 1639 cm-1 C 19 H 22 N 2 LRMS (ES+) calculated for O+ 294.17, found 295.17 (MH+); MP = 133-135°C. Example 10. 2-(6-(benzyloxy)-1H-indol-1-yl)-N,N-dimethylethan-1-amine (10) [ka]

[0200] Synthesized according to procedure A. Reaction carried out with 6-benzyloxyindole (370 mg, 1.7 mmol) and purified by chromatography. Yield = 184 mg, 38%. Purity > 97%. TLC R f (free base) = 0.45 (9:1 CH 2 Cl 2 :MeOH:1% NH 4 OH (aq) ); 1 H NMR (600 MHz, CD 3 OD) δ 7.47 (d, 2H, J = 7.4 Hz), 7.40 (d, 2H, J = 8.6 Hz), 7.37 (t, 1H J = 7.4 Hz), 7.30 (t, 1H, J = 7.4 Hz), 7.08 (d, 1H, J = 3.8 Hz), 6.96 (s, 1H), 6.78 (d, 1H, J = 8.6 Hz), 6.35 (d, 1H, J = 3.8 Hz), 5.15 (s, 2H), 4.22 (t, 2H, J = 7.3 Hz), 2.66 (t, 2H, J = 7.3 Hz), 2.26 (s, 6H) ppm; 13 C NMR (150 MHz, CDCl3) δ 156.39, 137.60, 136.66, 128.69, 127.97, 127.67, 127.22, 123.24, 121.68, 109.95, 101.31, 94.71, 70.87, 58.92, 45.91, 44.90 ppm;IR (Diamond, ATR) ν 3030, 2952, 2768, 1621 cm-1 C 19 H 22 N 2 LRMS (ES+) calculated for O+: 294.17, found: 295.10 (MH+). Example 11. 2-(7-(benzyloxy)-1H-indol-1-yl)-N,N-dimethylethan-1-amine (11) [ka]

[0201] Synthesized according to procedure A. Reaction carried out with 7-benzyloxyindole (119 mg, 0.53 mmol) and purified by chromatography. Yield = 51 mg, 23%. Purity > 99%. TLC R f (free base) = 0.48 (9:1 CH 2 Cl 2 :MeOH:1% NH 4 OH (aq) ); 1 H NMR (600 MHz, CDCl3) δ 7.49 (d, 2H, J = 7.4 Hz), 7.40 (t, 2H, J = 7.4 Hz), 7.34 (t, 1H, J = 7.4 Hz), 7.22 (d, 1H, J = 7.9 Hz), 7.01 (d, 1H, J = 3.0 Hz), 6.97 (t, 1H, J = 7.8 Hz), 6.70 (d, 1H, J = 7.8 Hz), 5.19 (s, 2H), 4.45 (t, 2H, J = 7.4 Hz), 2.62 (t, 2H, J = 7.4 Hz), 2.09 (s, 6H) ppm; 13 C NMR (150 MHz, CDCl3) δ 150.59, 146.71, 137.11, 131.25, 129.45, 128.75, 128.24, 128.15, 119.82, 114.16, 103.35, 101.60, 70.55, 61.02, 47.54, 45.64 ppm;IR (Diamond, ATR) ν 2940, 2821, 1575, 1439 cm -1 C 19 H 22 N2 LRMS (ES+) calculated for O+: 294.17, found: 295.24 (MH+). Example 12. 2-(4-Fluoro-1H-indol-1-yl)-N,N-dimethylethan-1-amine fumarate (1:1) (12) [ka]

[0202] Synthesized according to procedure A. Reaction carried out with 4-fluoroindole (135 mg, 1.0 mmol) and purified by crystallization. Yield = 164 mg, 51%. Purity > 99%. TLC R f (free base) = 0.39 (9:1 CH 2 Cl 2 :MeOH:1% NH 4 OH (aq) ); 1 H NMR (400 MHz, DMSO-d 6 ) δ 7.44 (d, 1H, J = 2.3 Hz), 7.35 (d, 2H, J = 8.3 Hz), 7.10 (dd, 2H, J = 7.4, 7.25 Hz), 6.79 (t, 2H, J = 9.5 Hz), 6.60 (s, 2H), 6.49 (d, 2H, J = 2.3 Hz), 4.32 (t, 2H, J = 6.7 Hz), 2.74 (t, 2H, J = 6.8 Hz), 2.28 (s, 6H) ppm; 13 C NMR (150 MHz, DMSO-d 6 ) δ 166.37, 156.67, 154.34, 138.56, 138.44, 134.21, 129.35, 121.63, 121.55, 116.74, 116.51, 106.48, 106.45, 103.70, 103.51, 96.24, 57.90, 44.73, 43.40 ppm;IR (Diamond, ATR) ν 3123, 2389, 1702, 1660 cm -1 C 12 H 16 FN 2LRMS (ES+) calculated for + 207.13, found 208.32 (MH+); MP = 145-149°C. Example 13. 2-(5-fluoro-1H-indol-1-yl)-N,N-dimethylethan-1-amine fumarate (1:1) (13) [ka]

[0203] Synthesized according to procedure A. Reaction carried out with 5-fluoroindole (135 mg, 1.0 mmol) and purified by crystallization. Yield = 145 mg, 45%. Purity >99%. TLC R f (free base) = 0.35 (9:1 CH 2 Cl 2 :MeOH:1% NH 4 OH (aq) ); 1 H NMR (400 MHz, DMSO-d 6 ) δ 7.50 (dd, 1H, J = 4.5, 4.3 Hz), 7.46 (d, 1H, J = 2.1 Hz), 7.29 (d, 1H, J = 9.5 Hz), 6.97 (t, 1H, J = 9.5 Hz), 6.60 (s, 2H), 6.41 (d, 1H, J = 2.1 Hz), 4.32 (t, 2H, J = 6.7 Hz), 2.79 (t, 2H, J = 6.7 Hz), 2.31 (s, 6H) ppm; 13 C NMR (150 MHz, DMSO-d 6 ) δ 166.59, 159.61, 158.06, 135.77, 135.69, 134.33, 129.54, 129.51, 124.72, 121.39, 121.32, 107.48, 107.32, 100.97, 96.32, 96.15, 57.66, 44.58, 43.00 ppm;IR (Diamond, ATR) ν 3036, 2049, 1723, 1663 cm -1 C 12 H 16 FN 2LRMS calculated for + (ES+) 207.13, found 207.40 (MH+); MP = 145-148°C. Example 14. 2-(6-fluoro-1H-indol-1-yl)-N,N-dimethylethan-1-amine fumarate (1:1) (14) [ka]

[0204] Synthesized according to procedure A. Reaction carried out with 6-fluoroindole (100 mg, 0.739 mmol) and purified by crystallization. Yield = 145 mg, 61%. Purity = 97%. TLC R f (free base) = 0.45 (9:1 CH 2 Cl 2 :MeOH:1% NH 4 OH (aq) ); 1 H NMR (600 MHz, DMSO-d 6 ) δ 7.52 (dd, 1H, J = 7.0, 3.0 Hz), 7.39-7.37 (m, 2H), 6.88-6.85 (m, 1H), 6.59 (s, 2H), 6.44 (d, 1H, J = 3.1 Hz), 4.29 (t, 2H, J = 6.8 Hz), 2.77 (t, 2H, J = 6.8 Hz), 2.30 (s, 6H) ppm; 13 C NMR (150 MHz, DMSO-d 6 ) δ 166.59, 159.61, 158.06, 136.16, 134.75, 129.95, 125.14, 121.78, 107.91, 107.74, 101.39, 96.74, 96.57, 57.66, 44.58, 43.00 ppm;IR (Diamond, ATR) ν 3058, 2385, 1698, 1634 cm -1 C 12 H 16 FN 2 LRMS (ES+) calculated for + 207.13, found 208.39 (MH+); MP = 141-147°C. Example 15. 2-(7-Fluoro-1H-indol-1-yl)-N,N-dimethylethan-1-amine fumarate (1:1) (15) [ka]

[0205] Synthesized according to procedure A. Reaction carried out with 7-fluoroindole (135 mg, 1.0 mmol) and purified by crystallization. Yield = 172 mg, 53%. Purity = 98%. TLC R f (free base) = 0.45 (9:1 CH 2 Cl 2 :MeOH:1% NH 4 OH (aq) ); 1 H NMR (400 MHz, DMSO-d 6 ) δ 7.41 (s, 1H), 7.35 (d, 1H, J = 7.6 Hz), 6.98-6.88 (m, 2H), 6.61 (s, 2H), 6.48 (s, 1H,), 4.37 (t, 2H, J = 6.7 Hz), 2.69 (t, 2H, J = 6.7 Hz), 2.23 (s, 6H) ppm; 13 C NMR (100 MHz, CD 3 OD) δ 169.37, 134.60, 133.26, 129.51, 119.90, 119.46, 116.82, 116.79, 107.06, 106.88, 102.78, 57.61, 57.61, 43.71, 43.67, 42.90 ppm;IR (Diamond, ATR) ν 3040, 2429, 1718. 1661 cm -1 C 12 H 16 FN 2 LRMS calculated for + (ES+) 207.13, found 207.33 (MH+); MP = 168-170°C. Example 16. N,N-Dimethyl-2-(2-methyl-1H-indol-1-yl)ethan-1-amine fumarate (1:1) (16) [ka]

[0206] Synthesized according to procedure A. Reaction carried out with 2-methylindole (100 mg, 0.76 mmol) and purified by crystallization. Yield (172 mg, 71%). Purity >99%. TLC R f (free base) = 0.47 (9:1 CH 2 Cl 2 :MeOH:1% NH 4 OH (aq) ); 1 H NMR (400 MHz, DMSO-d 6 ) δ 7.41 (d, 1H, J = 7.8 Hz), 7.37 (d, 1H, J = 7.8 Hz), 7.06 (t, 1H, J = 7.8 Hz), 6.96 (t, 1H, J = 7.8 Hz), 6.61 (s, 2H), 6.20 (d, J = 1.3 Hz, 1H), 4.24 (t, 2H, J = 7.0 Hz), 2.65 (t, 2H, J = 7.0 Hz), 2.42 (s, 3H), 2.31 (s, 6H) ppm; 13 C NMR (150 MHz, DMSO-d 6 ) 167.03, 137.08, 136.72, 134.75, 128.09, 120.58, 119.65, 119.62, 119.40, 109.61, 100.14, 57.82, 45.18, 12.76 ppm;IR (Diamond, ATR) ν 3040, 2489, 1700, 1606 cm -1 C 13 H 18 N 2 LRMS (ES+) calculated for + 203.15, found 204.43 (MH+); MP = 131-133°C. Example 17. 2-(5,6-difluoro-1H-indol-1-yl)-N,N-dimethylethan-1-amine fumarate (1:1) (17) [ka]

[0207] Synthesized according to procedure A. Reaction carried out with 5,6-difluoroindole (153 mg, 1.0 mmol) and purified by crystallization. Yield = 147 mg, 43%. Purity = 98%. TLC R f (free base) = 0.35 (9:1 CH 2 Cl 2 :MeOH:1% NH 4 OH (aq) ); 1 H NMR (400 MHz, DMSO-d 6 ) δ 7.64 (dd, 1H, J = 7.0, 4.7 Hz), 7.51 (dd, 1H, J = 8.5, 2.1 Hz), 7.45 (d, 1H, J = 2.1 Hz), 6.60 (s, 2H), 6.43 (d, 1H, J = 2.1 Hz), 4.28 (t, 2H, J = 6.5 Hz), 2.73 (t, 2H, J = 6.5 Hz), 2.27 (s, 6H) ppm; 13 C NMR (150 MHz, DMSO-d 6 ) δ 166.37, 134.21, 131.09, 130.99, 134.70, 130.67, 123.21, 123.12, 106.86, 106.67, 100.98, 100.94, 98.30, 98.08, 57.86, 44.71, 43.36 ppm;IR (Diamond, ATR) ν 3051, 2392, 1712, 1658 cm -1 C 12 H 16 F 2 N 2 + LRMS (ES+) calculated 224.11, found 225.28 (MH+); MP = 162-165°C. Example 18. 2-(4,6-difluoro-1H-indol-1-yl)-N,N-dimethylethan-1-amine fumarate (1:1) (18) [ka]

[0208] Synthesized according to procedure A. Reaction carried out with 4,6-difluoroindole (153 mg, 1.0 mmol) and purified by crystallization. Yield = 265 mg, 78%. Purity = >99%. TLC R f (free base) = 0.35 (9:1 CH 2 Cl 2 :MeOH:1% NH 4 OH (aq) ); 1 H NMR (400 MHz, DMSO-d 6 ) δ 7.44 (d, 1H, J = 2.8 Hz), 7.32 (d, 1H, J = 10.1 Hz), 6.83 (t, 1H, J = 10.1 Hz), 6.60 (s, 2H), 6.49 (d, 1H, J = 2.8 Hz), 4.31 (t, 2H, J = 6.6 Hz), 2.78 (t, 2H, J = 6.6 Hz), 2.31 (s, 6H) ppm; 13 C NMR (150 MHz, DMSO-d 6 ) δ 166.55, 159.33, 159.21, 156.99, 156.87, 156.03, 155.88, 153.58, 153.43, 137.50, 137.36, 137.22, 134.29, 129.82, 129.79, 113.42, 113.20, 96.61, 94.53, 94.30, 94.24, 94.00, 93.32, 93.28, 93.06, 93.02, 57.49, 44.49, 43.23 ppm;IR (Diamond, ATR) ν 3026, 2398, 1706, 1640 cm -1 C 12 H 16 F 2 N 2 + LRMS (ES+) calculated 224.11, found 225.28 (MH+); MP = 141-145°C. Example 19. N,N-Dimethyl-2-(6-nitro-1H-indol-1-yl)ethan-1-amine fumarate (1:1) (19) [ka]

[0209] Synthesized according to procedure A. Reaction carried out with 6-nitroindole (43.6 mg, 0.269 mmol) and purified by crystallization. Yield = 52 mg, 55%. Purity > 96%. TLC R f (free base) = 0.48 (9:1 CH 2 Cl 2 :MeOH:1% NH 4 OH (aq) ); 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.54 (d, 1H, J = 2.0 Hz), 7.90 (dd, 1H, J = 8.8, 2.0 Hz), 7.82 (d, 1H, J = 3.0 Hz), 7.72 (d, 1H, J = 8.8 Hz), 7.74 (s, 1H), 6.65 (d, 1H, J = 3.0 Hz), 6.60 (s, 2H), 4.44 (t, 2H, J = 6.3 Hz), 2.68 (t, 2H, J = 6.3 Hz), 2.23 (s, 6H) ppm; 13 C NMR (600 MHz, DMSO-d 6 ) δ 166.66, 136.18, 134.76, 134.59, 133.41, 121.04, 114.52, 107.53, 102.25, 58.98, 45.50, 44.18 ppm;IR (Diamond, ATR) ν 3048, 2922, 1704, 1607cm -1 C 12 H 16 N 3 O 2 + LRMS (ES+) calculated 233.12, found 234.25 (MH+); MP = 159-164°C. Example 20. 2-(5-bromo-1H-indol-1-yl)-N,N-dimethylethan-1-amine fumarate (1:1) (20) [ka]

[0210] Synthesized according to procedure A. Reaction carried out with 5-bromoindole (56.1 mg, 0.281 mmol) and purified by crystallization. Yield = 60 mg, 55%. Purity >99%. TLC R f (free base) = 0.49 (9:1 CH 2 Cl 2 :MeOH:1% NH 4 OH (aq) ); 1 H NMR (600 MHz, DMSO-d 6 ) δ 7.72 (d, J = 1.9 Hz, 1H), 7.48 (d, 1H, J = 8.7 Hz), 7.44 (d, 1H, J = 3.1 Hz), 7.23 (dd, 1H, J = 8.7, 1.9 Hz), 6.60 (s, 3H), 6.41 (d, 1H, J = 3.1 Hz), 4.27 (t, 2H, J = 6.6 Hz), 2.67 (t, 2H, J = 6.6 Hz), 2.22 (s, 6H) ppm; 13 C NMR (600 MHz, DMSO-d 6 ) δ 166.24, 134.47, 134.15, 130.46, 129.89, 123.81, 122.54, 111.87, 111.56, 100.28, 58.09, 44.86, 43.32 ppm;IR (Diamond, ATR) ν 2959, 2443, 1705, 1661 cm -1 C 12 H 16 BrN 2 LRMS (ES+) calculated for + 266.04, found 267.26 (MH+); MP = 140-142°C. Example 21. 2-(1-(2-(dimethylamino)ethyl)-1H-indol-3-yl)-N,N-dimethyl-2-oxoacetamide (21) [ka]

[0211] The reaction was carried out using 2-(1H-indol-3-yl)-N,N-dimethyl-2-oxoacetamide (synthesized (200 mg, 0.92 mmol) using the method developed by Speeter et al. (Speeter, ME; Anthony, WC The Action of Oxalyl Chloride on Indoles: a New Approach to Tryptamines. J. Am. Chem. Soc. 1954, 76, 6208-6210) and purified by chromatography). Yield = 92 mg, 35%. Purity = 98%. TLC R f (free base) = 0.38 (9:1 CH 2 Cl 2 :MeOH:1% NH 4 OH (aq) ); 1 H NMR (600 MHz, CDCl3) δ 8.32 (s, 1H), 7.92 (s, 1H), 7.37-7.29 (m, 3H), 4.21 (t, 2H, J = 7.0 Hz), 3.08 (s, 3H), 3.04 (s, 3H), 2.71 (t, 2H, J = 7.0 Hz), 2.27 (s, 6H) ppm; 13 C NMR (150 MHz, CDCl3) δ 185.64, 167.70, 138.82, 137.01, 126.36, 124.00, 123.28, 122.48, 113.45, 110.06, 58.40, 45.68 45.42, 37.59, 34.51 ppm;IR (diamond, ATR) ν 2981, 1734 1631, 1525 cm -1 C 16 H 21 N 3 O 2 + LRMS (ES+) calculated 287.16, observed 288.25 (MH+). Example 22. 2-(1H-benzo[d]imidazol-1-yl)-N,N-dimethylethan-1-amine fumarate (1:1) (22) [ka]

[0212] Synthesized according to procedure A. Reaction carried out with benzimidazole (200 mg, 1.6 mmol) and purified by crystallization. Yield = 218 mg, 45%. Purity = 98%. TLC R f (free base) = 0.42 (9:1 CH 2 Cl 2 :MeOH:1% NH 4 OH (aq) ); 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.23 ​​(s, 1H), 7.71-7.56 (m, 2H), 7.34-7.10 (m, 2H), 6.61 (s, 2H), 4.41 (t, 2H, J = 6.5 Hz), 2.83 (dd, 2H, J = 7.0, 6.0 Hz), 2.32 (s, 6H) ppm; 13 C NMR (100 MHz, CD 3 OD) δ 170.14, 144.78, 143.90, 135.81, 134.62, 124.80, 124.04, 120.36, 111.29, 57.46, 44.39, 41.80 ppm;IR (Diamond, ATR) ν 3054, 2384, 1707, 1654 cm -1 C 11 H 15 N 3 LRMS (ES+) calculated for + 189.13, found 190.23 (MH+); MP = 171-178°C. Example 23. N,N-Dimethyl-2-(1H-pyrrol-1-yl)ethan-1-amine fumarate (1:1) (23)

[0213] Synthesized according to procedure A. Reaction carried out with pyrrole (0.103 ml, 1.5 mmol) and purified by crystallization. Yield = 126 mg, 33%. Purity > 99%. TLC R f (free base) = 0.45 (9:1 CH 2 Cl 2 :MeOH:1% NH 4 OH (aq) ); 1H NMR (600 MHz, CD 3 OD) δ 6.80 (t, 2H, J = 2.2, Hz), 6.72 (s, 2H), 6.14 (t, 2H. J = 2.2, Hz), 4.34 (t, 2H, J = 6.4 Hz), 3.50 (dd, 2H, J = 6.4 Hz), 2.78 (s, 6H) ppm; 13 C NMR (100 MHz, CD 3 OD) δ 170.26, 136.21, 122.18, 110.89, 59.35, 45.83, 44.45 ppm;IR (Diamond, ATR) ν 2998, 2532, 1662, 1421 cm -1 C 8 H 14 N 2 LRMS (ES+) calculated for + 138.12, found 139.29 (MH+); MP = 174-180°C. Example 24. 2-(9H-carbazol-9-yl)-N,N-dimethylethan-1-amine fumarate (1:1) (24) [ka]

[0214] Synthesized according to procedure A. Reaction carried out with carbazole (100 mg, 0.57 mmol) and purified by crystallization. Yield = 102 mg, 51%. Purity >99%. TLC R f (free base) = 0.42 (9:1 CH 2 Cl 2 :MeOH:1% NH 4 OH (aq) ); 1 H NMR (600 MHz, DMSO-d 6 ) δ 8.15 (d, 2H, J = 7.8 Hz), 7.61 (d, 2H, J = 8.2 Hz), 7.48-7.44 (m, 2H), 7.23-7.19 (m, 2H), 6.61 (s, 2H), 4.52 (t, 2H, J = 7.0 Hz), 2.73 (t, 2H, J = 7.0 Hz), 2.31 (s, 6H) ppm;13 C NMR (100 MHz, DMSO-d 6 ) δ 169.78, 139.86, 134.76, 125.83, 123.17, 119.99, 119.39, 108.34, 54.39, 42.61, 37.85 ppm;IR (Diamond, ATR) ν 3053, 2405, 1720, 1660cm -1 C 16 H 18 N 2 LRMS (ES+) calculated for + 238.15, found 239.34 (MH+); MP = 182-184°C. Example 25. 1-Isopentyl-1H-indole (25)

[0215] Synthesized according to procedure A. Reaction carried out with indole (100 mg, 0.85 mmol) and 1-chloro-3-methylbutane (0.11 mg, 0.94 mmol, 1.1 equiv) and purified by chromatography (4:1 hexane:EtOAc). Yield = 85 mg, 53%. Purity = 97%. TLC R f = 0.70 (7:3 hexanes: EtOAc); 1 H NMR (600 MHz, CDCl3) δ 7.65 (d, 1H, J = 8.0 Hz), 7.36 (d, 1H, J = 8.0 Hz), 7.22 (t, 1H, J = 6.9 Hz), 7.11 (m, 2H), 6.49 (d, 1H, J = 3.1 Hz), 4.15 (t, 2H, J = 7.5 Hz), 1.74 (dd, 2H, J = 6.7 Hz), 1.62 (quint, 2H, J = 6.7 Hz), 0.98 (d, 1H, J = 6.7 Hz) ppm; 13C NMR (150 MHz, CDCl3) δ 135.78, 128.46, 127.58, 121.20, 120.83, 119.05, 109.28, 100.78, 44.44, 40.72, 38.92, 25.61, 22.37 ppm;IR (diamond, ATR) ν 3054, 2955, 2927, 2869 cm -1 C 13 H 17 LRMS (ES+) calculated for N+: 187.14; observed: 188.39 (MH+). Example 26. 3-(1H-indol-1-yl)-N,N-dimethylpropan-1-amine fumarate (1:1) (26) [ka]

[0216] Synthesized according to procedure A. Reaction carried out with indole (100 mg, 0.85 mmol) and 3-chloro-N,N-dimethylpropan-1-amine (160 mg, 0.98 mmol, 1.1 equiv) and purified by crystallization. Yield = 107 mg, 48%. Purity = 98%. TLC R f (free base) = 0.38 (9:1 CH 2 Cl 2 :MeOH:1% NH 4 OH (aq) ); 1 H NMR (600 MHz, DMSO-d 6 ) δ 7.54 (d, 1H, J = 7.8 Hz), 7.48 (d, 1H, J = 7.8 Hz), 7.36 (d, 1H, J = 3.1 Hz), 7.13 (td, 1H, J = 7.4, 1.0 Hz), 7.01 (td, 1H, J = 7.4, 1.0 Hz), 6.55 (s, 2H), 6.43 (dd, 1H, J = 3.1, 1.0 Hz), 4.21 (t, 2H, J = 6.8 Hz), 2.56 (t, 2H, J = 7.4 Hz), 2.40 (s, 6H), 2.00 (tt, 2H, J = 7.4, 6.8 Hz) ppm; 13C NMR (150 MHz, DMSO-d 6 ) δ 167.19, 135.60, 134.62, 128.49, 128.07, 120.99, 120.41, 118.90, 109.67, 100.61, 54.88, 43.41, 43.07, 26.26 ppm;IR (Diamond, ATR) ν 3435, 3034, 2653, 1705 cm -1 C 13 H 18 N 2 LRMS (ES+) calculated for + 203.15, found 204.36 (MH+); MP = 129-131°C. Example 27. N,N-Dimethyl-2-(1-methyl-1H-indol-3-yl)ethan-1-amine fumarate (1:1) (1-Me-DMT 27)

[0217] To an ice-cold solution of N-methyl-2-(1-methyl-1H-indol-3-yl)ethan-1-amine (0.14 g, 0.70 mmol) and glacial acetic acid (0.22 mL, 11 mmol, 5.0 equiv) in MeOH (12 mL) was added sodium cyanoborohydride (0.10 g, 1.6 mmol, 2 equiv), followed by 37% formaldehyde. (aq) (0.16 mL, 1.9 mmol, 6 equiv) was added. The reaction was stirred at room temperature for 5 h and then concentrated under reduced pressure. The crude material was then dissolved in CH 2 Cl 2 (50mL) and 1M NaOH (aq) (100 mL). The phases were separated and the aqueous phase was diluted with CH 2 Cl 2 (2x50mL). The organic extracts were combined and extracted with Na 2 SO 4 The mixture was dried over ice, filtered and concentrated under reduced pressure. The crude material was dissolved in acetone (5 mL) and added to a boiling solution of fumaric acid (0.088 g, 1 mmol, 1 equiv) in acetone (20 mL). A precipitate immediately formed and the solution was cooled to room temperature and then filtered. The resulting white solid was dried under reduced pressure to give the pure compound as the fumarate salt (1:1). Yield=0.108 g, 65%. Purity>99%. TLC R f(free base) = 0.19 (9:1 CH 2 Cl 2 :MeOH:1% NH 4 OH (aq) ); 1 H NMR (600 MHz, CD 3 OD) δ 7.60 (d, 1H, J = 8.0 Hz), 7.37 (d, 1H, J = 8.0 Hz), 7.20 (t, 1H, J = 8.0 Hz), 7.14 (s, 1H), 7.09 (t, 1H, J = 8.0 Hz), 6.69 (s, 2H), 3.78 (s, 3H), 3.42 (t, 2H, J = 7.8 Hz), 3.20 (t, 2H, J = 7.8 Hz), 2.91 (s, 6H) ppm; 13 C NMR (150 MHz, CD 3 OD) δ 171.44, 138.80, 136.23, 128.67, 128.59, 122.95, 120.20, 119.27, 110.53, 109.11, 59.12, 43.41, 32.77, 21.72 ppm;IR (Diamond, ATR) ν 3435, 3034, 2653, 1705 cm -1 C 13 H 18 N 2 LRMS (ES+) m / z calculated for + 202.15, found 203.37 (MH+); MP = 167-170°C. Example 28. 2-(5-Methoxy-1H-indol-3-yl)-N,N-dimethylethan-1-amine fumarate (2:1) (DMT-5-MeO, 28)

[0218] To an ice-cold solution of 5-methoxytryptamine (0.50 g, 2.2 mmol) and glacial acetic acid (0.60 mL, 11 mmol, 5.0 equiv) in MeOH (44 mL) was added sodium cyanoborohydride (0.305 g, 4.8 mmol, 2.2 equiv), followed by 37% formaldehyde. (aq) (0.46 mL, 5.7 mmol, 2.6 equiv) was added. The reaction was stirred at room temperature for 5 h and then concentrated under reduced pressure. The residue was dissolved in CH 2 Cl 2(50mL) and 1M NaOH (aq) (100 mL). The phases were separated and the aqueous phase was diluted with CH 2 Cl 2 (2x50mL). The organic extracts were combined and extracted with Na 2 SO 4 The mixture was dried over ice, filtered and concentrated under reduced pressure. The crude material was dissolved in acetone (5 mL) and added to a boiling solution of fumaric acid (0.26 g, 2.2 mmol, 0.7 equiv) in acetone (35 mL). A precipitate immediately formed and the solution was cooled to room temperature and then filtered. The resulting white solid was dried under reduced pressure to give the pure compound as the fumarate salt (2:1) (1:1). Yield=0.49 g, 80%. Purity=98%. TLC R f (free base) = 0.20 (9:1 CH 2 Cl 2 :MeOH:1% NH 4 OH (aq) ); 1 H NMR (600 MHz, CD 3 OD) δ 7.24 (d, 1H, J = 8.8 Hz), 7.14 (s, 1H), 7.07 (s, 1H), 6.78 (d, 1H, J = 8.8 Hz), 6.70 (s, 1H), 3.83 (s, 3H), 3.29 (m, 2H), 3.13 (t, 2H, J = 7.9 Hz), 2.83 (s, 6H) ppm; 13 C NMR (150 MHz, CD 3 OD) δ 174.36, 155.27, 137.09, 133.44, 128.49, 124.79, 113.20, 112.96, 110.05, 101.05, 59.25, 56.37, 43.56, 22.12 ppm;IR (Diamond, ATR) ν 3436, 3034 2654, 1705 cm -1 C 13 H 18 N 2 LRMS (ES+) m / z calculated for O+ 218.14, found 219.34 (MH+); MP = 175-177°C. Example 29. 2-(6-Fluoro-1H-indol-3-yl)-N,N-dimethylethan-1-amine (DMT-6-F, 29)

[0219] The following Example 29 was prepared by methods known in the art. [ka] Example 30. 2-(6-Methoxy-1H-indol-3-yl)-N,N-dimethylethan-1-amine fumarate (2:1) (DMT-6-MeO, 30)

[0220] To an ice-cold solution of 6-methoxytryptamine (0.40 g, 2.1 mmol) and glacial acetic acid (0.60 mL, 10 mmol, 5.0 equiv) in MeOH (42 mL) was added sodium cyanoborohydride (0.29 g, 4.6 mmol, 2.2 equiv), followed by 37% formaldehyde. (aq) (0.44 mL, 5.5 mmol, 2.6 equiv) was added. The reaction was stirred at room temperature for 5 h and then concentrated under reduced pressure. The residue was dissolved in CH 2 Cl 2 (45mL) and 1M NaOH (aq) (100 mL). The phases were separated and the aqueous phase was diluted with CH 2 Cl 2 (2x45mL). The organic extracts were combined and extracted with Na 2 SO 4 The crude material was dissolved in acetone (5 mL) and added to a boiling solution of fumaric acid (0.26 g, 2.2 mmol, 0.7 equiv) in acetone (35 mL). A precipitate immediately formed and the solution was cooled to room temperature and then filtered. The resulting white solid was dried under reduced pressure to give the pure compound as the fumarate salt (2:1). Yield=0.320 g, 55%. Purity=95%. TLC R f (free base) = 0.31 (9:1 CH 2 Cl 2 :MeOH:1% NH 4 OH (aq) ); 1 H NMR (600MHz, CD 3OD) δ 7.44 (d, 1H, J = 8.6 Hz), 7.04 (s, 1H), 6.88 (s, 1H), 6.70 (m, 2H), 3.78 (s, 3H), 3.32 (t, 2H, J = 7.5 Hz), 3.12 (t, 2H, J = 7.5 Hz), 2.84 (s, 6H) ppm; 13 C NMR (150 MHz, CD 3 OD) δ 173.79, 157.87, 138.97, 136.93, 122.89, 122.53, 119.64, 110.40, 109.99, 95.62, 59.12, 55.94, 43.36, 21.96 ppm;IR (Diamond, ATR) ν 2915, 2836, 1691, 1559 cm -1 C 13 H 18 N 2 LRMS (ES+) m / z calculated for O+ 218.14, found 219.29 (MH+); MP = 173-176°C. Example 31. 2-(1H-indol-1-yl)-N,N-dimethylacetamide (31)

[0221] To a solution of indole (117 mg, 1.0 mmol) in DMSO (2.5 mL, 0.4 M) was added 2-chloro-N,N-dimethylacetamide (0.11 mL, 1.1 mmol, 1.1 equiv), potassium iodide (182 mg, 1.1 mmol, 1.1 equiv), and potassium hydroxide pellets (280 mg, 5 mmol, 5.0 equiv). The reaction was stirred at room temperature for 24 h and then diluted with 1.0 M NaOH. (aq) The aqueous phase was extracted three times with DCM. The organic extracts were combined and diluted with Na 2 SO 4 The extract was dried over hexane, filtered and concentrated under reduced pressure to give an oil which was purified by chromatography (3:2 hexane:EtOAc). Yield=175 mg, 57%. Purity=99%. TLC R f = 0.15 (3:2 hexanes: EtOAc); 1 H NMR (600 MHz, CD 3OD) δ 7.53 (d, 1H, J = 7.9 Hz), 7.27 (d, 1H, J = 7.9 Hz), 7.12 (m, 2H), 7.01 (t, 1H, J = 7.5, Hz), 6.46 (d, 1H, J = 2.9 Hz), 5.01 (s, 2H), 3.15 (s, 3H), 2.96 (s, 3H) ppm; 13 C NMR (150 MHz, CDCl3) δ 167.4, 136.7, 128.7, 128.5, 122.0, 121.2, 119.8, 109.1, 102.4, 48.2, 36.7, 36.1 ppm;IR (diamond, ATR) ν 3021, 2922, 2877, 1648cm -1 C 12 H 14 N 2 LRMS (ES+) calcd for O+ 202.11, found 203.17 (MH+); MP = 58-61°C. Example 32. (R)-1-(5-Methoxy-1H-indol-1-yl)-N,N-dimethylpropan-2-amine, fumarate salt [ka]

[0222] 5-Methoxy-indole (500 mg, 3.40 mmol), (R)-1-chloro-N,N-dimethylpropan-2-amine (1.074 g, 6.79 mmol, 2 equiv), potassium iodide (1.128 mg, 6.79 mmol, 2 equiv), and potassium hydroxide (0.953 g, 16.9 mmol, 5.0 equiv) were stirred in DMSO (8.49 mL) for 24 hours. The reaction mixture was diluted with 1.0 M NaOH. (aq) (800 mL). The aqueous phase was extracted three times with DCM (75 mL). The organic extracts were combined and diluted with Na 2 SO 4 The crude oil was washed with 1% ammonium hydroxide and concentrated under reduced pressure to give a colorless oil. (aq)The crude oil was purified by flash chromatography eluting with 9:1 DCM:MeOH with hexanes. The purified oil was dissolved in acetone (2 mL) and added dropwise to a boiling solution of fumaric acid (0.394 g, 3.39 mmol, 1.0 equiv) in acetone (15 mL). The precipitate that immediately formed was filtered and washed with several portions of ice-cold acetone to give the desired product. If no precipitate formed, the mixture was concentrated until crystallization was promoted to give the desired product (1:1 mixture:fumaric acid). 1 H NMR (400 MHz, DMSO-d 6 ) δ 7.37 (d, 1H, J = 8.8 Hz), 7.30 (s, 1H), 7.03 (s, 1H, J = 3.1 Hz), 6.76 (d, 1H, J = 8.8 Hz), 6.61 (s, 2H), 6.32 (s, 1H), 4.25 (dd, 1H J = 6.3, 7.8 Hz), 4.02 (dd, 1H, J = 6.3, 7.8 Hz), 3.74 (s, 3H,) 3.11 (q, 1H, J = 6.3, 6.6, Hz), 2.30 (s, 6H), 0.84 (d, 3H, J = 6.6 Hz). 13 C NMR (100 MHz, MeOD-d4) δ 171.0, 155.8, 136.1, 132.8, 130.9, 129.7, 113.3, 111.2, 103.8, 103.3, 61.6, 56.2, 47.5, 39.9, 11.7 ppm. Example 33. (R)-1-(5-fluoro-1H-indol-1-yl)-N,N-dimethylpropan-2-amine, fumarate salt [ka]

[0223] 5-Fluoro-indole (100 mg, 0.739 mmol), (R)-1-chloro-N,N-dimethylpropan-2-amine (128 mg, 0.814 mmol, 1.1 equiv), potassium iodide (135 mg, 0.814 mmol, 1.1 equiv), and potassium hydroxide (166 mg, 15.8 mmol, 5.0 equiv) were stirred in DMSO (1.85 mL) for 24 hours. The reaction mixture was diluted with 1.0 M NaOH. (aq) (100 mL). The aqueous phase was extracted three times with DCM (25 mL). The organic extracts were combined and diluted with Na 2 SO 4 The crude oil was washed with 1% ammonium hydroxide and concentrated under reduced pressure to give a colorless oil. (aq) The crude oil was purified by flash chromatography eluting with 9:1 DCM:MeOH with hexanes. The purified oil was dissolved in acetone (2 mL) and added dropwise to a boiling solution of fumaric acid (86.8 mg, 0.739 mmol, 1.0 equiv) in acetone (5 mL). The precipitate that immediately formed was filtered and washed with several portions of ice-cold acetone to give the desired product. If no precipitate formed, the mixture was concentrated until crystallization was promoted to give the desired product (1:1 mixture:fumaric acid) (111 mg, 68%). 1 H NMR (400 MHz, MeOD-d4) δ 7.50 (dd, 1H, J = 4.3, 4.6 Hz), 7.36 (d, 1H, J = 3.0 Hz), 7.28 (dd, 1H, J = 2.0, 9.2Hz), 7.01 (td, 1H, J = 2.0, 9.2 Hz), 6.74 (s, 1H), 6.55 (d, 1H, J = 3.0 Hz), 4.63 (dd, 1H J = 6.9, 8.5, 5.2 Hz), 4.38 (dd, 1H, J = 8.8, 5.7, 8.59 Hz), 3.92 (m, 1H,) 2.89 (s, 6H), 1.25 (d, 3H, J = 6.7 Hz). 13C NMR (100 MHz, MeOD-d4) δ 170.9, 136.0, 131.0, 111.4, 111.3, 111.1, 106.7, 106.5, 103.6, 103.5, 61.6, 47.7, 40.2, 11.8 ppm. Example 34. 1-(1H-indol-1-yl)-N,N-dimethylpropan-2-amine [ka]

[0224] Synthesized according to procedure A. 1 H NMR (600 MHz, CD 3 OD) δ 7.59 (d, 1H, J = 7.6 Hz), 7.50 (d, 1H, J = 7.6 Hz), 7.29 (d, 1H, J = 3.1 Hz), 7.23 (t, 1H, J = 7.6 Hz), 7.09 (t, 1H, J = 7.6 Hz), 6.56 (d, 1H, J = 3.1 Hz), 4.64 (dd, 1H, J = 8.5, 6.4 Hz), 4.40 (dd, 1H, J = 8.5, 6.8 Hz), 3.97 (m), 2.90 (s, 6H), 1.27 (d, 3H, J = 6.7 Hz). Example 35. (R)-1-(1H-indol-1-yl)-N,N-dimethylpropan-2-amine [ka]

[0225] Synthesized according to procedure A. 1H NMR (600 MHz, CDCl3) δ 7.62 (d, 1H, J = 8.0 Hz), 7.36 (d, 1H, J = 8.0 Hz), 7.21 (t, 1H, J = 8.0 Hz), 7.10 (m, 1H), 6.50 (d, 1H, J = 3.0 Hz), 6.56 (d, 1H, J = 3.1 Hz), 4.34 (dd, 1H, J = 9.0, 5.0Hz), 3.92(dd, 1H, J = 9.0, 5.0Hz), 3.07 (m, 1H), 2.36 (s, 6H), 0.91 (d, 3H, J = 6.7 Hz). Example 36. (R)-1-(6-fluoro-1H-indol-1-yl)-N,N-dimethylpropan-2-amine [ka]

[0226] Synthesized according to procedure A. 1 H NMR (600 MHz, CDCL3) δ 7.40 (dd, 1H, J = 5.5, 3.1 Hz), 6.98 (d, 1H, J = 3.1 Hz), 6.91 (d, 1H, J = 11.8 Hz), 6.74 (t, 1H, J = 9.0 Hz), 6.35 (d, 1H, J = 3.1 Hz) 4.10 (dd, 1H, J = 8.5, 5.6 Hz), 3.74 (dd, 1H, J = 8.5, 5.6 Hz), 2.91 (m, 1H), 2.20 (s, 6H), 0.79 (d, 3H, J = 6.6Hz). Example 37. (R)-1-(4-methoxy-1H-indol-1-yl)-N,N-dimethylpropan-2-amine [ka]

[0227] Synthesized according to procedure A. 1H NMR (600 MHz, CDCL3) δ 7.04(t, 1H, J = 7.9 Hz), 6.89 (t, 1H, J = 7.9 Hz), 6.50 (d, 1H, J = 10.5 Hz), 6.41 (d, 1H, J = 8.01 Hz), 4.16 (dd, 1H, J = 8.5, 5.5 Hz), 3.83 (s, 3H), 3.77(dd, 1H, J = 8.5, 5.5 Hz), 2.94 (m, 1H), 2.23 (s, 6H), 0.79 (d, 3H, J = 6.5 Hz). Example 38. (R)-1-(7-Methoxy-1H-indol-1-yl)-N,N-dimethylpropan-2-amine [ka]

[0228] Synthesized according to procedure A. 1 H NMR (600 MHz, CDCL3) δ 7.02 (d, 1H, J = 7.8 Hz), 6.81 (m, 2H), 6.46 (t, 1H, J = 6.2 Hz), 6.25 (d, 1H, J = 3.0Hz), 4.44 (dd, 1H, J = 8.2, 5.5 Hz), 3.96 (dd, 1H, J = 8.2, 5.5 Hz), 3.77 (s, 3H) 2.91 (m, 1H), 2.19 (s, 6H), 0.79 (d, 3H, J = 6.7 Hz). Example 39. (R)-1-(9H-carbazol-9-yl)-N,N-dimethylpropan-2-amine [ka]

[0229] Synthesized according to procedure A. 1H NMR (600 MHz, CDCL3) δ 8.00 (d, 2H, J = 7.7 Hz), 7.34 (m, 4H), 7.13 (d, 1H, J = 7.6 Hz), 4.35 (dd, 1H, J = 9.8, 4.5 Hz), 4.09 (dd, 1H, J = 9.8, 4.5 Hz), 3.12 (m, 1H), 2.33 (s, 6H), 0.82 (d, 3H, J = 6.6 Hz). Example 40. (R)-1-(1H-benzo[d]imidazol-1-yl)-N,N-dimethylpropan-2-amine [ka]

[0230] Synthesized according to procedure A. 1 H NMR (600 MHz, CDCL3) δ 7.72 (s, 1H), 7.16 (d, 1H, J = 7.6 Hz), 7.32 (d, 1H, J = 11.8 Hz), 6.91 (m, 3H), 4.05 (dd, 1H, J = 7.5, 6.7 Hz), 4.10 (dd, 1H, J = 7.5, 6.7 Hz), 3.79 (dd, 1H, J = 8.5, 5.6 Hz), 2.86 (m, 1H), 2.06 (s, 6H), 0.69 (d, 3H, J = 6.6 Hz). Example 41. N-methyl-2-(1-methyl-1H-indol-3-yl)ethan-1-amine [ka]

[0231] tert-Butyl (2-(1H-indol-3-yl)ethyl)carbamate. CH 2 Cl 2 To an ice-cold solution of tryptamine (0.50 g, 3.1 mmol) and triethylamine (0.68 mL, 9.4 mmol, 3 equiv) in 10 mL of Boc 2 O (0.77 g, 3.7 mmol, 1.2 equiv) was added. The reaction was allowed to warm to room temperature and stirred overnight, then H 2The organic phase was separated and the aqueous phase was washed with CH 2 Cl 2 (2x50mL). The organic extracts were combined and 2 SO 4 It was dried over ice, filtered, and concentrated under reduced pressure to give an oil which was purified by chromatography on silica gel (8:2 hexanes:EtOAc) as a white solid (0.69 g, 85%).

[0232] N-Methyl-2-(1-methyl-1H-indol-3-yl)ethan-1-amine. To an ice-cold solution of sodium hydride (0.23 g, 5.8 mmol, 2.2 equiv) in DMF (3 mL) was added tert-butyl (2-(1H-indol-3-yl)ethyl)carbamate (0.69 g, 2.6 mmol) in DMF (3 mL). The reaction mixture was stirred at room temperature and then cooled to 0° C. Methyl iodide (0.4 mL, 5.8 mmol, 2.2 equiv) was added dropwise. The reaction was stirred at room temperature for 20 hours. The reaction was then cooled to 0° C., quenched with TFA (2 mL), and stirred for 30 minutes. The mixture was diluted with 1.0 M NaOH. (aq) (600 mL) and dilute with CH 2 Cl 2 (3x75mL). The organic phases were combined and extracted with Na 2 SO 4 It was dried over ice, filtered and concentrated under reduced pressure to give an oil (0.45 g, 90%) which was used without further purification. Step B General synthesis scheme [ka]

[0233] General Procedure-1 (GP-B1): To a stirred solution of A (1.0 eq) in DMF (10 vol) was added NaH (60% in mineral oil, 1.2 eq) at 0° C. The reaction mixture was stirred at 0° C. for 20 min. To the resulting reaction mixture was added Reagent B (1.0 eq), followed by NaI(Cat). The reaction was allowed to warm slowly to room temperature and stirred for 16 h. The progress of the reaction was monitored by TLC.

[0234] General Procedure-2 (GP-B2): To a stirred solution of A (1.0 eq) in DMF (10 vol) was added NaH (60% in mineral oil, 1.2 eq) at 0°C. The reaction mixture was stirred at 0°C for 20 min. To the resulting reaction mixture was added Reagent B (1.0 eq) followed by NaI(Cat). The reaction mixture was allowed to warm slowly to room temperature and stirred at 60-65°C for 16 h. The progress of the reaction was monitored by TLC.

[0235] General Procedure-3 (GP-B3): To a stirred solution of A (1.0 eq) in DMF (10 vol), add K 2 CO 3 (3.0 eq) was added, followed by Reagent B (2.0 eq) and NaI (1.0 eq) at room temperature, and the contents were then heated at 70° C. for 16 hours. The progress of the reaction was monitored by TLC.

[0236] General work-up / purification procedure-B1: The reaction was diluted and quenched with ice-cold water. 2N aqueous HCl was added until the pH of the solution was 2. The resulting aqueous layer was washed with EtOAc until the unreacted starting material was completely removed (TLC). The aqueous layer was then washed with NaHCO 3 The mixture was basified with aqueous ethyl acetate and extracted with EtOAc. The combined organic layers were then washed with water, followed by brine, and then with anhydrous Na 2 SO 4 Drying over and concentration gave the expected product which was sufficiently pure (>95% LC-MS and HPLC purity).

[0237] General work-up / purification procedure for B2: The reaction mixture was quenched with ice-cold water and extracted with ethyl acetate. The combined organic layers were washed with ice-cold water followed by washing with brine. The organic layers were separated and concentrated with Na 2 SO 4 Dry the mixture over 500° C. and concentrate under reduced pressure to give EtOAc / heptane or CH based on the polarity of the compound. 2 Cl 2 The material was purified by Combi-Flash chromatography using either a hexanes / MeOH gradient. Pure fractions were evaporated and dried to give compounds with LC-MS and HPLC purity of >95%. Example 42. 2-(5-Methoxy-1H-indol-1-yl)-N,N-dimethylethan-1-amine [ka]

[0238] Synthesized according to procedure B. Followed GP-1 and workup / purification procedure-1. Yield: 44% (brown liquid). LC-MS: 97.8%, m / z=219.2 [M+H] + 1 H NMR (DMSO-d 6 , 400 MHz): δ 7.30-7.37 (m, 2H), 7.03 (d, J=2.4 Hz, 1H), 6.76 (dd, J=2.4, 8.8 Hz, 1H), 6.30 (dd, J=0.4, 2.8 Hz, 1H), 4.19 (t, J=6.8 Hz, 2H), 3.74 (s, 3H), 2.57 (t, J=6.8 Hz, 2H), 2.17 (s, 6H). Example 43. 2-(6-Methoxy-1H-indol-1-yl)-N,N-dimethylethan-1-amine [ka]

[0239] Synthesized according to procedure B. Followed GP-1 and workup / purification procedure-1. Yield: 44% (brown liquid). LC-MS: 95.4%, m / z=219.2 [M+H] +1 H NMR (DMSO-d 6 , 400 MHz): δ 7.38 (d, J = 8.56 Hz, 1H), 7.21 (d, J=3.06 Hz, 1H), 6.98 (d, J=2.20 Hz, 1H), 6.64-6.67 (m, 1H), 6.31 (dd, J=0.73, 3.18 Hz, 1H), 4.19 (t, J=6.66 Hz, 2H), 3.79 (s, 3H), 2.58 (t, J=6.66 Hz, 2H), 2.19 (s, 6H). Example 44. 5-Methoxy-1-(2-(pyrrolidin-1-yl)ethyl)-1H-indole [ka]

[0240] Synthesized according to procedure B. Followed GP-1 and workup / purification procedure-1. Yield: 16% (yellow semi-solid). LC-MS: 98.2%, m / z=245.2 [M+H] + 1 H NMR (DMSO-d 6 , 400 MHz): δ 7.30-7.36 (m, 2H), 7.03 (d, J = 2.45 Hz, 1H), 6.76 (dd, J = 2.38, 8.86 Hz, 1H),6.31 (d, J = 3.06 Hz, 1H), 4.21 (t, J = 6.79 Hz, 2H), 3.74 (s, 3H), 2.75 (t, J = 6.72 Hz, 2H), 2.43-2.47 (m, 4H), 1.65 (td, J=3.15, 6.66 Hz, 4H). Example 45. 5-Methoxy-1-(2-(piperidin-1-yl)ethyl)-1H-indole [ka]

[0241] Synthesized according to procedure B. Followed GP-1 and workup / purification procedure-1. Yield: 34% (brown solid). LC-MS: 99.5%, m / z=259.2 [M+H]+ 1 H NMR (DMSO-d 6 , 400 MHz): δ 7.30 - 7.36 (m, 2H), 7.02 (d, J = 2.32 Hz, 1H), 6.75 (dd, J = 2.45, 8.80 Hz, 1H), 6.29 - 6.31 (m, 1H), 4.20 (t, J = 6.79 Hz, 2H), 3.74 (s, 3H), 2.55 - 2.60 (m, 2H), 2.32 - 2.42 (m, 4H), 1.46 (quin, J = 5.41 Hz, 4H), 1.33 - 1.39 (m, 2H). Example 46. 4-(2-(5-methoxy-1H-indol-1-yl)ethyl)morpholine

Chem.

[0242] Synthesized according to Procedure B. Continued with GP-1 and Workup / Purification Procedure-1. Yield: 28% (brown solid). LC-MS: 99.5%, m / z = 261.2 [M + H] + 1 H NMR (DMSO-d 6 , 400 MHz): δ 7.31 - 7.37 (m, 2H), 7.02 (d, J = 2.45 Hz, 1H), 6.76 (dd, J = 2.45, 8.80 Hz, 1H), 6.31 (dd, J = 0.67, 3.00 Hz, 1H), 4.23 (t, J = 6.66 Hz, 2H), 3.74 (s, 3H), 3.51 - 3.55 (m, 4H), 2.62 (t, J = 6.66 Hz, 2H), 2.38 - 2.42 (m, 4H). Example 47. 5-Chloro-1-(2-(pyrrolidin-1-yl)ethyl)-1H-indole

Chem.

[0243] Synthesized according to procedure B. Followed GP-1 and workup / purification procedure-1. Yield: 28% (brown liquid). LC-MS: 97%, m / z=248.11 [M+H] + 1 H NMR (DMSO-d 6 , 400 MHz): δ 7.57 (d, J = 1.96 Hz, 1H), 7.50 (d, J = 8.80 Hz, 1H), 7.46 (d, J = 3.06 Hz, 1H), 7.11 (dd, J = 2.08, 8.80 Hz, 1H), 6.40 (dd, J = 0.61, 3.06 Hz, 1H), 4.27 (t, J = 6.60 Hz, 2H), 2.77 (t, J = 6.60 Hz, 2H), 2.45 (br s, 4H), 1.64 (td, J = 3.16, 6.76 Hz, 4H). Example 48. 5-Chloro-1-(2-(piperidin-1-yl)ethyl)-1H-indole [ka]

[0244] Synthesized according to procedure B. Followed GP-1 and workup / purification procedure-2. Yield: 20% (yellow semi-solid). LC-MS: 95.18%, m / z=263.2 [M+H] + 1 H NMR (DMSO-d 6 , 400 MHz): δ 7.57 (d, J = 1.96 Hz, 1H), 7.50 (d, J = 8.68 Hz, 1H), 7.45 (d, J = 3.06 Hz, 1H), 7.11(dd, J = 1.77, 8.74 Hz, 1H), 6.40 (d, J = 2.81 Hz, 1H), 4.26 (br s, 2H), 2.53-2.62 (m, 2H), 2.32-2.43 (m, 4H), 1.32-1.50 (m, 6H). Example 49. 4-(2-(5-chloro-1H-indol-1-yl)ethyl)morpholine [ka]

[0245] Synthesized according to procedure B. Followed GP-1 and workup / purification procedure-1. Yield: 28% (colorless liquid). LC-MS: 98.9%, m / z=265.2 [M+H] + 1 H NMR (DMSO-d 6 , 400 MHz): δ 7.57 (d, J = 1.83 Hz, 1H), 7.52 (d, J = 8.80 Hz, 1H), 7.47 (d, J = 3.18 Hz, 1H), 7.12 (dd, J = 1.83, 8.68 Hz, 1H), 6.41 (d, J = 2.81 Hz, 1H), 4.28 (br t, J = 5.75 Hz, 2H), 3.52 (br s, 4H), 2.60-2.67 (m, 2H), 2.40 (br s, 4H). Example 50. 1-(2-(pyrrolidin-1-yl)ethyl)-5-(trifluoromethoxy)-1H-indole [ka]

[0246] Synthesized according to procedure B. Followed GP-2 and workup / purification procedure-2. Yield: 22% (brown semi-solid). LC-MS: 99.8%, m / z=299.2 [M+H] + 1 H NMR (CD 3 OD, 400 MHz):δ 7.43-7.50 (m, 2H), 7.37 (d, J=3.18 Hz, 1H), 7.07 (dd, J=0.98, 8.93 Hz, 1H), 6.52 (d, J=3.18 Hz, 1H), 4.39 (t, J=7.09 Hz, 2H), 3.03 (t, J=7.03 Hz, 2H), 2.68 (br s, 4H), 1.83 (td, J=3.33, 6.79 Hz, 4H). Example 51. 1-(2-(piperidin-1-yl)ethyl)-5-(trifluoromethoxy)-1H-indole [ka]

[0247] Synthesized according to procedure B. Followed GP-1 and workup / purification procedure-2. Yield: 25% (brown liquid). LC-MS: 99.6%, m / z=313.2 [M+H] + 1 H NMR (DMSO-d 6 , 400 MHz): δ 7.54-7.59 (m, 1H), 7.51 (d, J=3.06 Hz, 2H), 7.08 (dd, J=1.34, 8.93 Hz, 1H), 6.48 (dd, J=0.61, 3.06 Hz, 1H), 4.28 (t, J=6.66 Hz, 2H), 2.60 (t, J=6.66 Hz, 2H), 2.37 (br d, J=4.40 Hz, 4H), 1.45 (quin, J=5.41 Hz, 4H), 1.32-1.40 (m, 2H). Example 52. 4-(2-(5-(trifluoromethoxy)-1H-indol-1-yl)ethyl)morpholine [ka]

[0248] Synthesized according to procedure B. Followed GP-2 and workup / purification procedure-2. Yield: 22% (brown liquid). LC-MS: 98.27%, m / z=315.2 [M+H] + 1 H NMR (DMSO-d 6 , 400 MHz): δ 7.59 (d, J=8.93 Hz, 1H), 7.50-7.54 (m, 2H), 7.09 (dd, J=1.16, 8.99 Hz, 1H), 6.49 (d, J=2.93 Hz, 1H), 4.31 (t, J=6.54 Hz, 2H), 3.50-3.57 (m, 4H), 2.65 (br t, J=6.54 Hz, 2H), 2.42 (br s, 4H). Example 53. 2-(4-Methoxy-1H-indol-1-yl)-N,N-dimethylethan-1-amine [ka]

[0249] Synthesized according to procedure B. Followed GP-1 and workup / purification procedure-1. Yield: 27% (brown liquid). LC-MS: 98.9%, m / z=219.2 [M+H] + 1 H NMR (DMSO-d 6 , 400 MHz): δ 7.25 (d, J=3.18 Hz, 1H), 7.02-7.07 (m, 2H), 6.49-6.52 (m, 1H), 6.38-6.40 (m, 1H), 4.20 (t, J=6.72 Hz, 2H), 3.85 (s, 3H), 2.55-2.60 (m, 2H), 2.17 (s, 6H). Example 54. 2-(7-Methoxy-1H-indol-1-yl)-N,N-dimethylethan-1-amine [ka]

[0250] Synthesized according to procedure B. Followed GP-1 and workup / purification procedure-1. Yield: 27% (brown liquid). LC-MS: 98.8%, m / z=219.2 [M+H] + 1 H NMR (DMSO-d 6 , 400 MHz): δ 7.24 (d, J=3.06 Hz, 1H), 7.07-7.11 (m, 1H), 6.89 (t, J=7.82 Hz, 1H), 6.64 (d, J=7.70 Hz, 1H), 6.33 (d, J=3.06 Hz, 1H), 4.42 (t, J=6.97 Hz, 2H), 3.88 (s, 3H), 2.56 (t, J=6.97 Hz, 2H), 2.18 (s, 6H). Example 55. 2-(5-Methoxy-1H-benzo[d]imidazol-1-yl)-N,N-dimethylethan-1-amine [ka] Example 56. 2-(6-Methoxy-1H-benzo[d]imidazol-1-yl)-N,N-dimethylethan-1-amine [ka]

[0251] Synthesized according to procedure B. The reaction was attempted using GP-2 with a slight modification (1 eq NaI was used) as in Example 55. Workup / purification procedure-2 gave a mixture of regiomers. The mixture was separated by normal phase chiral HPLC purification using the following method. Both structures were confirmed by NOE analysis. Column: Chiralpak IC (250m x 4.6mm, 5μm) Mobile phase: 0.1% DEA in n-HEXANE Mobile phase B:DCM:MEOH(80:20) Program:A:B:80:20 Flow rate: 1.0ml / min

[0252] Yield: 10% (light yellow solid). LCMS: 99.8%, m / z = 220.1 [M+H] + 1 H NMR (DMSO-d 6 , 400 MHz): δ 8.11 (s, 1H), 7.48 (d, J=8.80 Hz, 1H), 7.15 (d, J=2.32 Hz, 1H), 6.87 (dd, J=2.32, 8.80 Hz, 1H), 4.27 (t, J=6.30 Hz, 2H), 3.77 (s, 3H), 2.62 (t, J=6.24 Hz, 2H), 2.17 (s, 6H). Example 57. 2-(1H-benzo[d]imidazol-1-yl)-N,N-dimethylethan-1-amine [ka]

[0253] Synthesized according to procedure B. Followed GP-1 and workup / purification procedure-2. Yield: 4% (colorless liquid). LCMS: 99.7%, m / z = 190.2 [M+H] + 1 H NMR (DMSO-d 6, 400 MHz): δ 8.20 (s, 1H), 7.62 (dd, J=7.95, 12.47 Hz, 2H), 7.16-7.27 (m, 2H), 4.32 (t, J=6.36 Hz, 2H), 2.64 (t, J=6.30 Hz, 2H), 2.18 (s, 6H). Example 58. N,N-Dimethyl-2-(2-methyl-1H-benzo[d]imidazol-1-yl)ethan-1-amine [ka]

[0254] Synthesized according to procedure B. Followed GP-3 and workup / purification procedure-2. Yield: 15% (yellow liquid). LCMS: 98.3%, m / z = 204.2 [M+H] + 1 H NMR (DMSO-d 6 , 400 MHz): δ 7.44-7.51 (m, 2H), 7.09-7.19 (m, 2H), 4.24 (t, J=6.66 Hz, 2H), 2.53-2.57 (m, 5H), 2.19 (s, 6H). Step C General synthesis scheme: [ka] General synthesis procedure:

[0255] Step-C1: To a stirred solution of compound D (1.0 eq) in DMF (10 mL) was added NaH (60% in mineral oil, 1.2 eq) at 0° C. The reaction mixture was stirred for 20 min, then compound E (1.0 eq) was added. The reaction mixture was allowed to warm slowly to room temperature and then stirred at the same temperature for 16 h. The progress of the reaction was monitored by TLC.

[0256] Work-up and purification after step-C1: The reaction mixture was quenched with ice-cold water and extracted with ethyl acetate. The combined organic layers were washed with ice-cold water, followed by washing with aqueous NaCl. The organic layer was separated and concentrated to give Na2 SO 4 The crude product was purified by combi-flash purification using 10 to 20% EtOAc in hexanes, followed by evaporation of the wash fractions (by TLC) and drying under reduced pressure to give compound F.

[0257] Step-C2:CH 2 Cl 2 To a stirred solution of compound F (1 eq) in (10 vol) was added triethylamine (2.5 eq) and the resulting solution was cooled to 0° C. To this was added mesyl chloride (1.5 eq), warmed to room temperature and stirred for 1-2 hours. The progress of the reaction was monitored by TLC.

[0258] Work-up after Step-C2: The reaction mixture was quenched with ice-cold water and CH 2 Cl 2 The combined organic layers were washed with saturated aqueous bicarbonate, followed by water. The organic layer was separated and extracted with Na 2 SO 4 Drying over and concentration gave crude compound G which was used in the next step without further purification.

[0259] Step C3: Compound G (1 eq) was added to a sealed tube followed by DMF (2 vol) and 40% aqueous dimethylamine (10 vol) and heated at 65° C. for 1-2 days. The progress of the reaction was monitored by TLC.

[0260] Work-up and purification after step C3: The reaction was quenched with water and extracted with EtOAc. The organic layer was separated and washed with water followed by brine. The separated organic layer was washed with anhydrous Na 2 SO 4 The crude product was separated by drying over 1000 ml of CH 2 Cl 2 in 5 to 10% EtOAc / CH 2 Cl 2Purification by combi-flash purification using 5-10% MeOH in hexanes, then the wash fractions (by TLC) were evaporated under reduced pressure and dried to give the target compound. Example 59. (R)-1-(5-methoxy-1H-indol-1-yl)-N,N-dimethylpropan-2-amine [ka]

[0261] Step-C1: Yield: 71% (light brown liquid). 1 H NMR (DMSO-d 6 , 400 MHz): δ 7.35 (d, J=8.93 Hz, 1H), 7.27 (d, J=3.06 Hz, 1H), 7.02 (d, J=2.32 Hz, 1H), 6.74 (dd, J=2.45, 8.80 Hz, 1H), 6.29-6.32 (m, 1H), 4.85 (d, J=4.77 Hz, 1H), 3.99-4.07 (m, 2H), 3.90-3.98 (m, 1H), 3.74 (s, 3H), 1.01 (d, J=6.11 Hz, 3H).

[0262] Step-C2: Yellow solid. 1 H NMR (DMSO-d 6 , 400 MHz): δ 7.45 (d, J=8.93 Hz, 1H), 7.33 (d, J=3.06 Hz, 1H), 7.04 (d, J=2.32 Hz, 1H), 6.80 (dd, J=2.32, 8.93 Hz, 1H), 6.38 (d, J=2.93 Hz, 1H), 4.92-5.01 (m, 1H), 4.34-4.40 (m, 2H), 3.75 (s, 3H), 2.54 (s, 3H), 1.33 (d, J=6.24 Hz, 3H).

[0263] Step C3: Yield: 16% (over two steps, brown liquid). [α] D 20 = -14.6 (C 0.5, CH 2 Cl 2). LC-MS: 99.4%, m / z=233.2 [M+H] + 1 H NMR (DMSO-d 6 , 400 MHz): δ 7.27-7.36 (m, 2H), 7.02 (d, J=2.32 Hz, 1H), 6.75 (dd, J=2.38, 8.86 Hz, 1H), 6.28-6.32 (m, 1H), 4.18 (dd, J=6.72, 14.18 Hz, 1H), 3.92-3.99 (m, 1H), 3.74 (s, 3H), 2.92-3.02 (m, 1H), 2.19 (s, 6H), 0.79 (d, J=6.60 Hz, 3H). Example 60. (R)-1-(5-fluoro-1H-indol-1-yl)-N,N-dimethylpropan-2-amine [ka]

[0264] Step-C1: Yield: 50% (light brown liquid). 1 H NMR (DMSO-d 6 , 400 MHz): δ 7.50 (dd, J=4.52, 8.93 Hz, 1H), 7.41 (d, J=3.06 Hz, 1H), 7.26-7.31 (m, 1H), 6.92-6.99 (m, 1H), 6.39-6.42 (m, 1H), 3.93-4.03 (m, 2H), 3.12-3.21 (m, 1H), 0.92 (d, J=6.36 Hz, 3H).

[0265] Step-C2: The mesiate is prepared using the general procedure given above, which is then dissolved in NaN in DMF (10 vol) at 70 °C. 3 (1.5eq) for 2 hours. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed twice with cold water and evaporated to give the crude product. This was treated with 10% Pd / C (50% moisture) in MeOH under hydrogen atmosphere to give the crude amine. The crude product was purified by HCl, ... 2 Cl2 Purification by combi-flash using 1% MeOH in 10 ml of ethyl acetate and evaporation of the wash fractions gave the amine, which was treated with paraformaldehyde (10 eq) in MeOH / DCM (10 vol, 2:1) then AcOH(Cat) followed by NaBH 3 CN (6.0 eq) was added and stirred for 1 h. The progress of the reaction was monitored by TLC. After aqueous workup, the crude was purified by preparative HPLC followed by combi-flash purification to give the above compound in 30% isolated yield.

[0266] The preparative HPLC purification method is as follows: HPLC column for preparation: Ymc triat actus C18 (250*20mm), 5μm Mobile phase A: Acetonitrile Mobile phase B: 5 mM ammonium bicarbonate Flow rate: 15.0mL / min Gradient table: [Table 1]

[0267] Yield: 30% (brown liquid). [α] D 20 = -15.9 (C 0.5, CH 2 Cl 2 ). LC-MS: 99.5%, m / z=221.2 [M+H] + 1 H NMR (DMSO-d 6 , 400 MHz): δ 7.40-7.49 (m, 2H), 7.28 (dd, J=2.51, 9.96 Hz, 1H), 6.92-6.98 (m, 1H), 6.39 (dd, J=0.61, 3.06 Hz, 1H), 4.18-4.25 (m, 1H), 4.01 (dd, J=7.27, 14.24 Hz, 1H), 2.94-3.03 (m, 1H), 2.19 (s, 6H), 0.81 (d, J=6.60 Hz, 3H). 19F NMR (DMSO-d 6, 376 MHz): δ -127.18 (s, 1F). Example 61. (R)-1-(6-fluoro-5-methoxy-1H-indol-1-yl)-N,N-dimethylpropan-2-amine [ka]

[0268] Step-C1: Yield: 74% (brown liquid). 1 H NMR (DMSO-d 6 , 400 MHz): δ 7.39 (d, J=12.23 Hz, 1H), 7.27 (d, J=3.06 Hz, 1H), 7.18-7.22 (m, 1H), 6.34 (dd, J=0.61, 3.06 Hz, 1H), 4.84 (d, J=4.77 Hz, 1H), 3.88-4.06 (m, 3H), 3.81 (s, 3H), 1.02 (d, J=6.11 Hz, 3H).

[0269] Step-C2: Brown solid. 1 H NMR (DMSO-d 6 , 400 MHz): δ 7.52 (d, J=12.23 Hz, 1H), 7.33 (d, J=3.06 Hz, 1H), 7.22 (d, J=8.56 Hz, 1H), 6.41 (dd, J=0.67, 3.12 Hz, 1H), 4.91-5.00 (m, 1H), 4.30-4.39 (m, 2H), 3.82 (s, 3H), 2.56 (s, 3H), 1.32-1.35 (m, 3H).

[0270] Step C3: Yield: 14% (over two steps, brown liquid). [α] D 20 = -19.7 (C 0.5, CH 2 Cl 2 LC-MS: 98.5%, 251.2 [M+H] + 1 H NMR (DMSO-d 6, 400 MHz): δ 7.38-7.44 (m, 1H), 7.30 (d, J=3.18 Hz, 1H), 7.22 (d, J=8.56 Hz, 1H), 6.35 (d, J=2.57 Hz, 1H), 4.15 (dd, J=7.09, 14.18 Hz, 1H), 3.96 (dd, J=7.15, 14.24 Hz, 1H), 3.83 (s, 3H), 2.93-3.03 (m, 1H), 2.20 (s, 6H), 0.81 (d, J=6.60 Hz, 3H). 19F NMR (DMSO-d 6 , 376 MHz): δ -142.08 (s, 1F). Example 62. (R)-1-(5,6-dimethoxy-1H-indol-1-yl)-N,N-dimethylpropan-2-amine

change

[0271] Structural-C1: Yield: 50% (thin brown liquid). 1 H NMR (DMSO-d 6 , 400 MHz): δ 7.13 (d, J=3.06 Hz, 1H), 7.03 (d, J=7.21 Hz, 2H), 6.23-6.26 (m, 1H), 4.84 (d, J=4.65 Hz, 1H), 3.91-4.01 (m, 3H), 3.79 (s, 3H), 3.73 (s, 3H), 1.02 (d, J=5.99 Hz, 3H).

[0272] ステップ-C2: Thin brown semi-solid. 1 H NMR (DMSO-d 6 , 400 MHz): δ 7.18 (d, J=3.18 Hz, 1H), 7.14 (s, 1H), 7.04 (s, 1H), 6.32 (d, J=3.06 Hz, 1H), 4.93-5.02 (m, 1H), 4.30-4.42 (m, 2H), 3.81 (s, 3H), 3.74 (s, 3H), 2.56 (s, 3H), 1.34 (d, J=6.36 Hz, 3H).

[0273] Step C3: Yield: 18% (over two steps, brown liquid). LC-MS: 94.8%, 263.2 [M+H] + 1 H NMR (DMSO-d 6 , 400 MHz): δ 7.14 (d, J=3.06 Hz, 1H), 6.99-7.03 (m, 2H), 6.25 (dd, J=0.61, 3.06 Hz, 1H), 4.12-4.19 (m, 1H), 3.91-3.98 (m, 1H), 3.72-3.81 (m, 6H), 2.93-3.02 (m, 1H), 2.21 (s, 6H), 0.81 (d, J=6.60 Hz, 3H). Example 63. (R)-1-(5,7-dimethoxy-1H-indol-1-yl)-N,N-dimethylpropan-2-amine [ka]

[0274] Step-C1: Yield: 35% (colorless liquid). 1 H NMR (DMSO-d 6 , 400 MHz): δ 7.10-7.16 (m, 1H), 6.58-6.61 (m, 1H), 6.27-6.30 (m, 1H), 4.74 (d, J=5.14 Hz, 1H), 4.09-4.32 (m, 2H), 3.83-3.92 (m, 4H), 3.71-3.73 (m, 3H), 0.91-1.00 (m, 3H).

[0275] Step-C2: Light yellow semi-solid. 1 H NMR (DMSO-d 6, 400 MHz): δ 7.14-7.20 (m, 1H), 6.61 (d, J=2.08 Hz, 1H), 6.35 (d, J=2.08 Hz, 1H), 6.29-6.32 (m, 1H), 4.87-4.95 (m, 1H), 4.41-4.52 (m, 2H), 3.85-3.89 (m, 3H), 3.72-3.74 (m, 3H), 2.56 (s, 3H), 1.23-1.35 (m, 3H).

[0276] Suppressor C3: Yield: 25% (2 Suppressor, brown liquid). [α] D 20 = -22.94 (C 0.25, CH 2 Cl 2 ). LC-MS: 99.25%, 263.2 [M+H] + 1 H NMR (DMSO-d 6 , 400 MHz): δ 7.13 (d, J=2.93 Hz, 1H), 6.58 (d, J=2.08 Hz, 1H), 6.29 (d, J=1.96 Hz, 1H), 6.23 (d, J=2.93 Hz, 1H), 4.38 (dd, J=6.30, 13.63 Hz, 1H), 4.06 (dd, J=7.83, 13.57 Hz, 1H), 3.85 (s, 3H), 3.72 (s, 3H), 2.88-2.97 (m, 1H), 2.20 (s, 6H), 0.73 (d, J=6.72 Hz, 3H). Example 64. (R)-1-(5-methoxy-6-methyl-1H-indol-1-yl)-N,N-dimethylpropan-2-amine

change

[0277] Structural-C1: Yield: 83% (colorless liquid). 1 H NMR (DMSO-d 6, 400 MHz): δ 7.25 (s, 1H), 7.19 (br d, J=2.81 Hz, 1H), 7.00 (s, 1H), 6.29 (br d, J=2.45 Hz, 1H), 4.84 (br d, J=4.40 Hz, 1H), 3.92-4.03 (m, 3H), 3.79 (s, 3H), 2.26 (s, 3H), 1.03 (br d, J=5.87 Hz, 3H).

[0278] Structural-C2: Thin yellow semi-solid. 1 H NMR (DMSO-d 6 , 400 MHz): δ 7.34 (s, 1H), 7.23 (d, J=3.06 Hz, 1H), 7.00 (s, 1H), 6.34 (dd, J=0.73, 3.06 Hz, 1H), 4.91-4.98 (m, 1H), 4.31-4.35 (m, 2H), 3.77 (s, 3H), 3.35 (s, 3H), 2.25 (s, 3H), 1.34 (d, J=6.24 Hz, 3H).

[0279] Structural C3: Yield: 8% (2 ステップにわたる, thin brown liquid). [α] D 20 = -19.10 (C 0.125, CH 2 Cl 2 ). LC-MS: 99%, 247.2 [M+H] + 1 H NMR (DMSO-d 6 , 400 MHz): δ 7.17-7.22 (m, 2H), 6.98 (s, 1H), 6.26-6.27 (m, 1H), 4.14 (dd, J=6.66, 14.12 Hz, 1H), 3.93 (dd, J=7.58, 14.18 Hz, 1H), 3.77 (s, 3H), 2.93-3.02 (m, 1H), 2.25 (s, 3H), 2.20 (s, 6H), 0.79 (d, J=6.60 Hz, 3H). Example 65. (R)-1-(5-methoxy-7-methyl-1H-indol-1-yl)-N,N-dimethylpropan-2-amine [ka]

[0280] Step-C1: Yield: 75% (light brown liquid). 1 H NMR (DMSO-d 6 , 400 MHz): δ 7.18 (d, J=3.06 Hz, 1H), 6.84 (d, J=2.45 Hz, 1H), 6.49 (d, J=2.08 Hz, 1H), 6.27 (d, J=3.06 Hz, 1H), 4.87 (d, J=5.14 Hz, 1H), 4.16 (dd, J=2.14, 6.17 Hz, 2H), 3.81-3.89 (m, 1H), 3.71 (s, 3H), 2.60 (s, 3H), 1.02 (d, J=6.11 Hz, 3H).

[0281] Step-C2: Light yellow syrup. 1 H NMR (DMSO-d 6 , 400 MHz): δ 7.27 (d, J=3.06 Hz, 1H), 6.86 (d, J=2.45 Hz, 1H), 6.54-6.56 (m, 1H), 6.35-6.37 (m, 1H), 4.82-4.90 (m, 1H), 4.48-4.52 (m, 2H), 3.72 (s, 3H), 2.61 (s, 3H), 2.41 (s, 3H), 1.34 (d, J=6.36 Hz, 3H).

[0282] Step C3: Yield: 11% (over 2 steps, brown liquid). [α] D 20 = -6.34 (C 0.5, CH 2 Cl 2 ). LC-MS: 99.43%, 247.2 [M+H] + 1 H NMR (DMSO-d 6, 400 MHz): δ 7.17 (d, J=3.06 Hz, 1H), 6.84 (d, J=2.45 Hz, 1H), 6.50 (d, J=1.96 Hz, 1H), 6.26 (d, J=3.06 Hz, 1H), 4.35 (dd, J=6.05, 14.37 Hz, 1H), 4.05-4.12 (m, 1H), 3.71 (s, 3H), 2.81-2.90 (m, 1H), 2.60 (s, 3H), 2.19 (s, 6H), 0.74 (d, J=6.60 Hz, 3H). Example 66. (R)-1-(5-methoxy-3-methyl-1H-indol-1-yl)-N,N-dimethylpropan-2-amine [ka]

[0283] Step-C1: Yield: 70% (light brown liquid).

[0284] Step-C2: Light yellow semi-solid.

[0285] Step C3: Yield: 19% (over 2 steps). [α] D 20 = -1.82 (C 0.5, CH 2 Cl 2 ). LC-MS: 99.76%, 247.1 [M+H] + 1 H NMR (DMSO-d 6 , 400 MHz): δ 7.28 (d, J=8.80 Hz, 1H), 7.06 (s, 1H), 6.94 (d, J=2.45 Hz, 1H), 6.74 (dd, J=2.45, 8.80 Hz, 1H), 4.07-4.14 (m, 1H), 3.85-3.92 (m, 1H), 3.76 (s, 3H), 2.88-2.98 (m, 1H), 2.18-2.22 (m, 9H), 0.78 (d, J=6.60 Hz, 3H). Example 67. (R)-1-(4,5-difluoro-1H-indol-1-yl)-N,N-dimethylpropan-2-amine [ka]

[0286] Step-C1: Yield: 58% (light brown liquid). 1 H NMR (DMSO-d 6 , 400 MHz): δ 7.45 (d, J=3.18 Hz, 1H), 7.33 (dd, J=3.42, 9.05 Hz, 1H), 7.09-7.17 (m, 1H), 6.53 (dd, J=0.79, 3.12 Hz, 1H), 4.89 (d, J=4.77 Hz, 1H), 4.10-4.16 (m, 1H), 4.00-4.07 (m, 1H), 3.90-3.99 (m, 1H), 1.04 (d, J=6.24 Hz, 3H).

[0287] Step-C2: Brown liquid. 1 H NMR (DMSO-d 6 , 400 MHz): δ 7.51 (d, J=3.18 Hz, 1H), 7.40-7.44 (m, 1H), 7.16-7.24 (m, 1H), 6.61 (dd, J=0.86, 3.18 Hz, 1H), 4.96-5.04 (m, 1H), 4.43-4.47 (m, 2H), 2.65 (s, 3H), 1.34 (d, J=6.36 Hz, 3H).

[0288] Step C3: Yield: 30% (over two steps, brown liquid). [α] D 20 = -25.0 (C 0.5, CH 2 Cl 2 ). LC-MS: 99.08%, m / z=239.2 [M+H] + 1 H NMR (DMSO-d 6, 400 MHz): δ 7.48 (d, J=3.06 Hz, 1H), 7.30-7.34 (m, 1H), 7.13 (ddd, J=7.89, 8.80, 11.19 Hz, 1H), 6.52 (dd, J=0.73, 3.18 Hz, 1H), 4.19-4.25 (m, 1H), 4.01-4.07 (m, 1H), 2.95-3.04 (m, 1H), 2.18 (s, 6H), 0.82 (d, J=6.60 Hz, 3H). Example 68. (R)-1-(5,6-difluoro-1H-indol-1-yl)-N,N-dimethylpropan-2-amine

change

[0289] Structural-C1: Yield: 63% (thin brown liquid). 1 H NMR (DMSO-d 6 , 400 MHz): δ 7.57-7.63 (m, 1H), 7.50 (dd, J=8.07, 11.37 Hz, 1H), 7.39 (d, J=3.18 Hz, 1H), 6.41 (dd, J=0.73, 3.18 Hz, 1H), 4.86 (d, J=4.89 Hz, 1H), 4.06-4.12 (m, 1H), 3.89-4.02 (m, 2H), 1.04 (d, J=6.11 Hz, 3H).

[0290] Structural-C2: Thin yellow semi-solid. 1 H NMR (DMSO-d 6 , 400 MHz): δ 7.71 (dd, J=6.97, 11.62 Hz, 1H), 7.51-7.57 (m, 1H), 7.44-7.46 (m, 1H), 6.49 (dd, J=0.73, 3.18 Hz, 1H), 4.94-5.02 (m, 1H), 4.39-4.43 (m, 2H), 2.61 (s, 3H), 1.34 (d, J=6.36 Hz, 3H).

[0291] Step C3: Yield: 30% (over two steps, brown liquid). [α] D 20 = -21.12 (C 0.5, CH 2 Cl 2 ). LC-MS: 96.1%, m / z=239.2 [M+H] + 1 H NMR (DMSO-d 6 , 400 MHz): δ 7.58-7.63 (m, 1H), 7.47-7.52 (m, 1H), 7.40-7.42 (m, 1H), 6.41 (dd, J=0.73, 3.06 Hz, 1H), 4.17 (dd, J=7.52, 14.24 Hz, 1H), 3.96-4.03 (m, 1H), 2.94-3.04 (m, 1H), 2.18 (s, 6H), 0.81 (d, J=6.60 Hz, 3H). 19F NMR (DMSO-d 6 , 376 MHz): δ -146.8 (d, J = 22.5 Hz, 1F), -150.82 (d, J = 24.0 Hz, 1F). Example 69. (R)-1-(5,7-difluoro-1H-indol-1-yl)-N,N-dimethylpropan-2-amine [ka]

[0292] Step-C1: Yield: 57% (colorless liquid). 1 H NMR (CDCl3, 400 MHz): δ 7.15 (d, J=3.06 Hz, 1H), 7.05 (dd, J=2.20, 9.05 Hz, 1H), 6.67-6.73 (m, 1H), 6.45-6.47 (m, 1H), 4.34 (ddd, J=1.22, 3.30, 14.06 Hz, 1H), 4.14-4.19 (m, 1H), 4.03-4.10 (m, 1H), 1.65 (d, J=4.03 Hz, 1H), 1.24 (d, J=6.11 Hz, 3H).

[0293] Step-C2: Yellow semi-solid.

[0294] Step C3: Yield: 50% (over two steps, colorless liquid). [α] D 20 = -28.5 (C 0.5, CH 2 Cl 2 ). LC-MS: 99.2%, m / z=239.1 [M+H] + 1 H NMR (DMSO-d 6 , 400 MHz): δ 7.44 (d, J=3.06 Hz, 1H), 7.15-7.19 (m, 1H), 6.90-6.97 (m, 1H), 6.47 (t, J=2.69 Hz, 1H), 4.29-4.35 (m, 1H), 4.04-4.10 (m, 1H), 2.91-3.00 (m, 1H), 2.18 (s, 6H), 0.80 (d, J=6.60 Hz, 3H). 19F NMR (DMSO-d 6 , 376 MHz): δ -124.28 (s, 1F), -132.87 (s, 1F). Example 70. (R)-1-(5-fluoro-6-methoxy-1H-indol-1-yl)-N,N-dimethylpropan-2-amine [ka]

[0295] Step-C1: Yield: 46% (colorless liquid).

[0296] Step-C2: Yellow semi-solid.

[0297] Step C3: Yield: 32% (over 2 steps, colorless liquid). [α] D 20 = -8.05 (C 0.5, CH 2 Cl 2 ). LC-MS: 98.4%, m / z=235.1 [M+H] + 1 H NMR (DMSO-d 6, 400 MHz): δ 7.24-7.32 (m, 2H), 7.17 (d, J=7.34 Hz, 1H), 6.30 (d, J=2.93 Hz, 1H), 4.18 (dd, J=7.03, 14.24 Hz, 1H), 3.96-4.03 (m, 1H), 3.87 (s, 3H), 2.94-3.05 (m, 1H), 2.21 (s, 6H), 0.82 (d, J=6.60 Hz, 3H). 19F NMR (DMSO-d 6 , 376 MHz): δ -146.29 (s, 1F). Example 71. (R)-1-(5-fluoro-6-methyl-1H-indol-1-yl)-N,N-dimethylpropan-2-amine

change

[0298] Structural-C1: Yield: 69% (thin brown liquid). 1 H NMR (DMSO-d 6 , 400 MHz): δ 7.33-7.37 (m, 1H), 7.30 (d, J=3.06 Hz, 1H), 7.22 (d, J=10.64 Hz, 1H), 6.32-6.34 (m, 1H), 4.84-4.87 (m, 1H), 3.91-4.08 (m, 3H), 2.32 (d, J=1.83 Hz, 3H), 1.03 (d, J=5.99 Hz, 3H).

[0299] Structural-C2: Thin yellow solid. 1 H NMR (DMSO-d 6 , 400 MHz): δ 7.46 (d, J=6.48 Hz, 1H), 7.36 (d, J=3.06 Hz, 1H), 7.25 (d, J=10.64 Hz, 1H), 6.39-6.41 (m, 1H), 4.94-5.02 (m, 1H), 4.32-4.43 (m, 2H), 2.56 (s, 3H), 2.33 (d, J=1.83 Hz, 3H), 1.34 (d, J=6.36 Hz, 3H).

[0300] Structural C3: Yield: 24% (2 ステップにわたる, thin brown liquid). [α] D 20 = -20.50 (C 0.5, CH 2 Cl 2 ). LC-MS: 99.3%, m / z=235.1 [M+H] + 1 H NMR (DMSO-d 6 , 400 MHz): δ 7.30-7.35 (m, 2H), 7.22 (d, J=10.64 Hz, 1H), 6.32 (d, J=3.06 Hz, 1H), 4.17 (dd, J=6.97, 14.18 Hz, 1H), 3.97 (dd, J=7.34, 14.18 Hz, 1H), 2.95-3.04 (m, 1H), 2.33 (d, J=1.59 Hz, 3H), 2.19 (s, 6H), 0.80 (d, J=6.60 Hz, 3H). 19F NMR (DMSO-d 6 , 376 MHz): δ -130.78 (s, 1F). Example 72. (R)-1-(5-fluoro-7-methyl-1H-indol-1-yl)-N,N-dimethylpropan-2-amine

change

[0301] Structural-C1: Yield: 72%, thin brown liquid. 1 H NMR (DMSO-d 6 , 400 MHz): δ 7.30 (d, J=3.06 Hz, 1H), 7.09 (dd, J=2.51, 9.35 Hz, 1H), 6.72 (dd, J=2.20, 10.39 Hz, 1H), 6.36 (d, J=3.06 Hz, 1H), 4.89 (d, J=5.14 Hz, 1H), 4.16-4.25 (m, 2H), 3.81-3.91 (m, 1H), 2.65 (s, 3H), 1.04 (d, J=6.24 Hz, 3H).

[0302] ステップ-C2: Yellow semi-solid. 1H NMR (DMSO-d 6 , 400 MHz): δ 7.39 (d, J=3.06 Hz, 1H), 7.13 (dd, J=2.45, 9.29 Hz, 1H), 6.78 (dd, J=1.96, 10.27 Hz, 1H), 6.44-6.46 (m, 1H), 4.89 (sxt, J=6.24 Hz, 1H), 4.50-4.60 (m, 2H), 2.66 (s, 3H), 2.46 (s, 3H), 1.35 (d, J=6.24 Hz, 3H).

[0303] Step C3: Yield: 19% (over two steps, light brown liquid). [α] D 20 = -2.43 (C 0.5, CH 2 Cl 2 ). LC-MS: 99.8%, m / z=235.1 [M+H] + 1 H NMR (DMSO-d 6 , 400 MHz): δ 7.30 (d, J=3.06 Hz, 1H), 7.09 (dd, J=2.45, 9.29 Hz, 1H), 6.73 (dd, J=2.02, 10.33 Hz, 1H), 6.35 (d, J=3.06 Hz, 1H), 4.38 (dd, J=6.30, 14.49 Hz, 1H), 4.11-4.18 (m, 1H), 2.82-2.92 (m, 1H), 2.65 (s, 3H), 2.19 (s, 6H), 0.76 (d, J=6.60 Hz, 3H). 19F NMR (DMSO-d 6 , 376 MHz): δ -127.62 (s, 1F).

[0304] 5-Fluoro-7-methyl-1H-indole was prepared from 4-fluoro-2-methyl-1-nitrobenzene using the Bartoli Indole synthesis (4-fluoro-2-methyl-1-nitrobenzene in THF (10 vol) was treated with 4 eq of 1M vinylmagnesium bromide at −40° C. for 3 h. After completion of the reaction by TLC, the reaction mixture was diluted with saturated NH4 The mixture was quenched with Cl and extracted with EtOAc. The combined organic layers were washed with brine followed by water to give the crude product. The crude product was purified by combi-flash using 5% EtOAc in hexanes and the wash fractions were evaporated to give 5-fluoro-7-methyl-1H-indole in 27% isolated yield. Example 73. (R)-1-(5-fluoro-2-methyl-1H-indol-1-yl)-N,N-dimethylpropan-2-amine [ka]

[0305] Step-C1: Yield: 33% (colorless liquid). 1 H NMR (DMSO-d 6 , 400 MHz): δ 7.36 (dd, J=4.52, 8.93 Hz, 1H), 7.13-7.17 (m, 1H), 6.81-6.87 (m, 1H), 6.17 (s, 1H), 4.86 (d, J=4.77 Hz, 1H), 3.89-4.05 (m, 3H), 2.40 (d, J=0.73 Hz, 3H), 1.08 (d, J=5.99 Hz, 3H).

[0306] Step-C2: Light brown semi-solid.

[0307] Step C3: Yield: 10% (over two steps, colorless liquid). [α] D 20 = -36.86 (C 0.25, CH 2 Cl 2 ). LC-MS: 94.4%, m / z=235.2 [M+H] + 1 H NMR (DMSO-d 6, 400 MHz): δ 7.34 (dd, J=4.52, 8.80 Hz, 1H), 7.15 (dd, J=2.45, 9.90 Hz, 1H), 6.86 (dt, J=2.57, 9.23 Hz, 1H), 6.18 (s, 1H), 4.16 (dd, J=6.42, 14.73 Hz, 1H), 3.93 (dd, J=7.58, 14.67 Hz, 1H), 2.92 (sxt, J=6.80 Hz, 1H), 2.40 (s, 3H), 2.22 (s, 6H), 0.81 (d, J=6.60 Hz, 3H). 19F NMR (DMSO-d 6 , 376 MHz): δ -127.21 (s, 1F). Example 74. (R)-1-(5-fluoro-3-methyl-1H-indol-1-yl)-N,N-dimethylpropan-2-amine

change

[0308] Structural-C1: Yield: 35% (thin brown liquid). 1 H NMR (DMSO-d 6 , 400 MHz): δ 7.41 (dd, J=4.52, 8.93 Hz, 1H), 7.16-7.23 (m, 2H), 6.89-6.95 (m, 1H), 4.85 (d, J=4.65 Hz, 1H), 3.87-4.04 (m, 3H), 2.20 (d, J=0.98 Hz, 3H), 1.02 (d, J=6.11 Hz, 3H).

[0309] ステップ-C2: Brown semi-solid. 1 H NMR (DMSO-d 6 , 400 MHz): δ 7.49 (dd, J=4.46, 8.92 Hz, 1H), 7.20-7.26 (m, 2H), 6.95-7.01 (m, 1H), 4.91-4.99 (m, 1H), 4.34 (d, J=5.65 Hz, 2H), 2.63 (s, 3H), 2.21 (s, 3H), 1.31 (d, J=6.54 Hz, 3H).

[0310] Step C3: Yield: 44% (over two steps, brown liquid). [α] D 20 = -18.4 (C 0.5, CH 2 Cl 2 ). LC-MS: 95%, m / z=235.2 [M+H] + 1 H NMR (DMSO-d 6 , 400 MHz): δ 7.40 (dd, J=4.46, 8.86 Hz, 1H), 7.17-7.23 (m, 2H), 6.89-6.96 (m, 1H), 4.14 (dd, J=6.91, 14.24 Hz, 1H), 3.90-3.97 (m, 1H), 2.91-3.00 (m, 1H), 2.17-2.23 (m, 9H), 0.80 (d, J=6.60 Hz, 3H). 19F NMR (DMSO-d 6 , 376 MHz): δ -127.47 (s, 1F). Example 75. (R)-1-(5-methoxy-1H-indol-1-yl)-N,N-dimethylbutan-2-amine [ka]

[0311] Step-C1: The epoxide used in the reaction was (S)-2-ethyloxirane and the rest of the procedure was the same as mentioned in the general procedure. Yield: 44% (light brown solid). 1 H NMR (DMSO-d 6 , 400 MHz): δ 7.34 (d, J=8.93 Hz, 1H), 7.27 (d, J=3.06 Hz, 1H), 7.02 (d, J=2.32 Hz, 1H), 6.73-6.77 (m, 1H), 6.30 (dd, J=0.73, 3.06 Hz, 1H), 4.81 (d, J=5.50 Hz, 1H), 3.95-4.10 (m, 2H), 3.74 (s, 3H), 3.63-3.70 (m, 1H), 1.21-1.42 (m, 2H), 0.88 (t, J=7.40 Hz, 3H).

[0312] Structural-C2: Thin yellow solid. 1 H NMR (DMSO-d 6 , 400 MHz): δ 7.43 (d, J=8.93 Hz, 1H), 7.34 (d, J=3.06 Hz, 1H), 7.04 (d, J=2.32 Hz, 1H), 6.80 (dd, J=2.45, 8.93 Hz, 1H), 6.38 (dd, J=0.73, 3.06 Hz, 1H), 4.81-4.87 (m, 1H), 4.41 (d, J=5.75 Hz, 2H), 3.75 (s, 3H), 2.53 (s, 3H), 1.65-1.76 (m, 1H), 1.54-1.63 (m, 1H), 0.97 (t, J=7.40 Hz, 3H).

[0313] Structural C3: Yield: 26% (2 ステップにわたる, brown solid). [α] D 20 = -22.57 (C 0.5, CH 2 Cl 2 ). LC-MS: 96.7%, m / z=247.2 [M+H] + 1 H NMR (DMSO-d 6 , 400 MHz): δ 7.27-7.33 (m, 2H), 7.03 (d, J=2.32 Hz, 1H), 6.75-6.78 (m, 1H), 6.31 (dd, J=0.73, 3.06 Hz, 1H), 4.17-4.24 (m, 1H), 3.94-4.00 (m, 1H), 3.74 (s, 3H), 2.69-2.76 (m, 1H), 2.23 (s, 6H), 1.40-1.51 (m, 1H), 1.07-1.19 (m, 1H), 0.81 (t, J=7.40 Hz, 3H). Example 76. (S)-1-(5-methoxy-1H-indol-1-yl)-N,N-dimethylbutan-2-amine

change

[0314] Step-C1: The epoxide used in the reaction was (R)-2-ethyloxirane and the rest of the procedure was the same as mentioned in the general procedure. Yield: 34% (light brown liquid). 1 H NMR (DMSO-d 6 , 400 MHz): δ 7.34 (d, J=8.93 Hz, 1H), 7.27 (d, J=2.93 Hz, 1H), 7.02 (d, J=2.32 Hz, 1H), 6.75 (dd, J=2.45, 8.93 Hz, 1H), 6.30 (d, J=2.93 Hz, 1H), 4.82 (d, J=5.50 Hz, 1H), 3.95-4.10 (m, 2H), 3.74 (s, 3H), 3.62-3.70 (m, 1H), 1.21-1.42 (m, 2H), 0.88 (t, J=7.40 Hz, 3H).

[0315] Step-C2: Light brown solid. 1 H NMR (DMSO-d 6 , 400 MHz): δ 7.45 (d, J=8.93 Hz, 1H), 7.36 (d, J=3.06 Hz, 1H), 7.06 (d, J=2.45 Hz, 1H), 6.82 (dd, J=2.45, 8.93 Hz, 1H), 6.40 (dd, J=0.61, 3.06 Hz, 1H), 4.82-4.90 (m, 1H), 4.43 (d, J=5.75 Hz, 2H), 3.77 (s, 3H), 2.55 (s, 3H), 1.67-1.78 (m, 1H), 1.55-1.64 (m, 1H), 0.98 (t, J=7.46 Hz, 3H).

[0316] Step C3: Yield: 52% (over 2 steps, brown solid). [α] D 20 = + 24.8 (C 0.5, CH 2 Cl 2 ). LC-MS: 99.68%, m / z=247.2 [M+H] + 1 H NMR (DMSO-d 6, 400 MHz): δ 7.27-7.33 (m, 2H), 7.02 (d, J=2.38 Hz, 1H), 6.76 (dd, J=2.38, 8.80 Hz, 1H), 6.30-6.32 (m, 1H), 4.21 (dd, J=6.79, 14.31 Hz, 1H), 3.94-4.01 (m, 1H), 3.74 (s, 3H), 2.68-2.76 (m, 1H), 2.23 (s, 6H), 1.41-1.51 (m, 1H), 1.07-1.18 (m, 1H), 0.81 (t, J=7.43 Hz, 3H). Example 77. (R)-1-(4,5-dimethoxy-1H-indol-1-yl)-N,N-dimethylpropan-2-amine [ka]

[0317] Step-C1: Yield: 75% (light brown liquid). 1 H NMR (DMSO-d 6 , 400 MHz): δ 7.24 (d, J=3.18 Hz, 1H), 7.12 (dd, J=0.61, 8.80 Hz, 1H), 6.89-6.92 (m, 1H), 6.39 (dd, J=0.67, 3.12 Hz, 1H), 4.84 (d, J=4.65 Hz, 1H), 3.91-4.01 (m, 3H), 3.88 (s, 3H), 3.77 (s, 3H), 1.03 (d, J=5.99 Hz, 3H).

[0318] Step-C2: Light brown liquid.

[0319] Step C3: Yield: 18% (over two steps, brown liquid). [α] D 20 = -11.7 (C 0.25, CH 2 Cl 2 ). LC-MS: 99.83%, m / z=263.1 [M+H] + 1 H NMR (DMSO-d 6, 400 MHz): δ 7.28 (d, J=3.06 Hz, 1H), 7.11 (d, J=8.80 Hz, 1H), 6.93 (d, J=8.80 Hz, 1H), 6.41 (d, J=3.06 Hz, 1H), 4.17 (dd, J=6.85, 14.18 Hz, 1H), 3.96 (dd, J=7.40, 14.24 Hz, 1H), 3.90 (s, 3H), 3.79 (s, 3H), 2.97-3.03 (m, 1H), 2.19 (s, 6H), 0.83 (d, J=6.60 Hz, 3H). Example 78. (R)-1-(5-fluoro-3-methoxy-1H-indol-1-yl)-N,N-dimethylpropan-2-amine [ka]

[0320] Step-C1: Yield: 50% (brown liquid).

[0321] Step-C2: Light yellow solid.

[0322] Step C3: Yield: 3% (over two steps, light brown liquid). [α] D 20 = -17.6 (C 0.25, CH 2 Cl 2 ). LC-MS: 99.13%, m / z=251.1 [M+H] + 1 H NMR (DMSO-d 6 , 400 MHz): δ 7.41 (dd, J=4.28, 9.05 Hz, 1H), 7.15 (dd, J=2.51, 9.48 Hz, 1H), 7.06 (s, 1H), 6.95 (dt, J=2.57, 9.23 Hz, 1H), 4.11 (dd, J=6.60, 14.18 Hz, 1H), 3.91 (dd, J=7.64, 14.24 Hz, 1H), 3.78 (s, 3H), 2.98 (sxt, J=6.90 Hz, 1H), 2.20 (s, 6H), 0.79 (d, J=6.60 Hz, 3H). 19F NMR (DMSO-d6 , 376 MHz): δ -127.6 (s, 1F). Example 79. (R)-1-(5,6-dichloro-1H-indol-1-yl)-N,N-dimethylpropan-2-amine [ka] Step-C1: Yield: 45% (light brown solid). 1 H NMR (DMSO-d 6 , 400 MHz): δ 7.85 (s, 1H), 7.78 (s, 1H), 7.45 (d, J=3.18 Hz, 1H), 6.43 (dd, J=0.67, 3.12 Hz, 1H), 4.85 (d, J=4.89 Hz, 1H), 4.11-4.16 (m, 1H), 3.99-4.05 (m, 1H), 3.90-3.97 (m, 1H), 1.05 (d, J=6.24 Hz, 3H). Step-C2: Light yellow semi-solid. Step C3: Yield: 30% (over two steps, light brown liquid). [α] D 20 = -24.14 (C 0.25, CH 2 Cl 2 ). LC-MS: 96.9%, m / z=271.0 [M+H] + 1 H NMR (DMSO-d 6 , 400 MHz): δ 7.86 (s, 1H), 7.79 (s, 1H), 7.49 (d, J=3.06 Hz, 1H), 6.45 (d, J=3.06 Hz, 1H), 4.21 (dd, J=7.76, 14.37 Hz, 1H), 4.07 (dd, J=6.60, 14.31 Hz, 1H), 2.98-3.04 (m, 1H), 2.19 (s, 6H), 0.84 (d, J=6.60 Hz, 3H). Step D General synthesis scheme: [ka] General synthesis procedure:

[0323] Step-D1: CHCl 3 A stirred solution of compound J (1 eq) in (10 vol) was added to SOCl at 0 °C. 2 (5 eq) was added and the resulting solution was heated at reflux for 12 h. The progress of the reaction was monitored by TLC.

[0324] Work-up after step-D1: The reaction mixture was evaporated and then co-evaporated twice with toluene (10 vol). The crude obtained was then used directly in the next step.

[0325] Step D2: To a stirred solution of compound H (1.0 eq) in DMF (10 vol) was added NaH (60% in mineral oil, 1.5 eq) at 0° C. The reaction mixture was stirred for 30 min, then compound I (1.0 eq) was added, followed by NaI (cat.). The reaction mixture was allowed to warm slowly to room temperature, then to 65° C. and stirred for 16 h. The progress of the reaction was monitored by TLC.

[0326] Work-up and purification: The reaction mixture was cooled to RT, quenched with ice-cold water, and extracted with ethyl acetate. The combined organic layers were washed with ice-cold water, followed by washing with aqueous NaCl. The organic layer was separated and washed with Na 2 SO 4 The crude material was extracted with CH 2 Cl 2 Purification by combi-flash purification using 2 to 5% MeOH in hexanes, followed by evaporation of the wash fractions (by TLC) and drying under vacuum gave the desired product. Example 80. (S)-5-Methoxy-1-((1-methylpiperidin-2-yl)methyl)-1H-indole [ka]

[0327] Step-D1: (S)-(1-Methylpiperidin-2-yl)methanol was reacted with SOCl using the general procedure shown above.2 to give the respective chlorides.

[0328] Step D2: Yield: 13% (over two steps, light brown semi-solid). [α] D 20 = -85.8 (C 0.25, CH 2 Cl 2 ). LC-MS: 99%, m / z=259.1 [M+H] + 1 H NMR (DMSO-d 6 , 400 MHz): δ 7.28-7.35 (m, 2H), 7.03 (d, J=2.32 Hz, 1H), 6.76 (dd, J=2.45, 8.80 Hz, 1H), 6.32 (d, J=2.81 Hz, 1H), 4.44-4.50 (m, 1H), 3.89-3.96 (m, 1H), 3.74 (s, 3H), 2.75-2.82 (m, 1H), 2.36 (br s, 3H), 2.24-2.31 (m, 1H), 1.97-2.08 (m, 1H), 1.37-1.58 (m, 3H), 1.05 (br d, J=9.05 Hz, 3H). Example 81. (S)-5-Methoxy-1-((1-methylpyrrolidin-2-yl)methyl)-1H-indole [ka]

[0329] Step-D1: (S)-(1-methylpyrrolidin-2-yl)methanol was reacted with SOCl using the general procedure shown above. 2 to give the respective chlorides.

[0330] Step D2: Yield: 11% (over 2 steps, brown liquid). [α] D 20 = -62.7 (C 0.45, CH 2 Cl 2 ). LC-MS: 98.14%, m / z=245.2 [M+H] + . 1 H NMR (DMSO-d6 , 400 MHz): δ 7.29-7.38 (m, 2H), 7.02 (d, J=2.45 Hz, 1H), 6.76 (dd, J=2.38, 8.86 Hz, 1H), 6.31 (d, J=2.93 Hz, 1H), 4.19 (dd, J=5.07, 14.12 Hz, 1H), 3.98 (dd, J=6.72, 14.18 Hz, 1H), 3.74 (s, 3H), 2.94 (td, J=4.33, 9.08 Hz, 1H), 2.52-2.58 (m, 1H), 2.10-2.22 (m, 4H), 1.53-1.75 (m, 3H), 1.42-1.50 (m, 1H). Example 82. (R)-5-Methoxy-1-((1-methylpiperidin-2-yl)methyl)-1H-indole [ka]

[0331] Prepared according to procedure D. Yield: 6% (over two steps, brown solid). [α] D 20 = + 101.19 (C 0.5, CH 2 Cl 2 ). LC-MS: 97.4%, m / z=259.2 [M+H] + 1 H NMR (DMSO-d 6 , 400 MHz): δ 7.27-7.35 (m, 2H), 7.03 (d, J=2.45 Hz, 1H), 6.76 (dd, J=2.45, 8.93 Hz, 1H), 6.32 (d, J=2.93 Hz, 1H), 4.46 (dd, J=4.28, 14.06 Hz, 1H), 3.92 (dd, J=8.50, 14.12 Hz, 1H), 3.74 (s, 3H), 2.76-2.81 (m, 1H), 2.35 (s, 3H), 2.25-2.30 (m, 1H), 1.99-2.06 (m, 1H), 1.36-1.57 (m, 3H), 1.00-1.10 (m, 3H). Example 83. (R)-5-Methoxy-1-((1-methylpyrrolidin-2-yl)methyl)-1H-indole [ka]

[0332] Step-D1: (R)-(1-methylpyrrolidin-2-yl)methanol was reacted with SOCl using the general procedure shown above. 2 to give the respective chlorides.

[0333] Step D2: After combi-flash purification, 80% pure product was obtained, which was further purified by preparative HPLC purification to obtain the cleaned final compound.

[0334] Details of the preparative HPLC purification are given below: Preparative HPLC column: Chiralpak IG, (250*30mm, 5 μ) Mobile phase A: 0.1% DEA in n-Hexane Mobile phase B:EtOH:MeOH (50:50) Flow rate: 35.0mL / min Isocratic Table: [Table 2]

[0335] Yield: 11% (over two steps, colorless solid). D 20 = + 79.47 (C 0.5, CH 2 Cl 2 ). LC-MS: 99.9%, m / z=245.1 [M+H] + 1 H NMR (DMSO-d 6, 400 MHz): δ 7.29-7.38 (m, 2H), 7.02 (d, J=2.32 Hz, 1H), 6.76 (dd, J=2.38, 8.86 Hz, 1H), 6.31 (d, J=2.93 Hz, 1H), 4.16-4.22 (m, 1H), 3.95-4.01 (m, 1H), 3.74 (s, 3H), 2.94 (td, J=4.37, 9.11 Hz, 1H), 2.52-2.58 (m, 1H), 2.18 (s, 3H), 2.09-2.15 (m, 1H), 1.53-1.72 (m, 3H), 1.41-1.50 (m, 1H). Step E General synthesis scheme: [ka] General synthesis procedure:

[0336] Step E1: To a stirred solution of K (1.0 eq) in DMF (10 vol) at 0° C. was added NaH (60% in mineral oil, 1.2 eq) and the reaction mixture was stirred for 20 min. Reagent L (1.0 eq) was added to the reaction, which was then allowed to slowly warm to room temperature and stirred for 16 h. The progress of the reaction was monitored by TLC. TLC showed a non-polar spot for K.

[0337] Work-up after step E1: The reaction mixture was quenched with ice-cold water and extracted with ethyl acetate. The combined organic layers were washed with ice-cold water followed by washing with brine. The organic layer was separated and concentrated to give Na 2 SO 4 Drying over and concentrating under reduced pressure gave the crude material which was purified by combi-flash chromatography using EtOAc / heptane, followed by evaporation of the wash fractions to give M.

[0338] Step E2: A stirred solution of M (1.0 eq) in DMF (10 vol) was added to K at room temperature. 2 CO 3(3 eq) was added, followed by the addition of Reagent N (1.2 eq) and NaI (1 eq), and then the reaction mixture was heated at 70° C. for 16 h. The progress of the reaction was monitored by TLC, which showed a polar spot for M.

[0339] Work-up after step E2: The reaction mixture was quenched with ice-cold water and extracted with ethyl acetate. The combined organic layers were washed with ice-cold water followed by washing with brine. The organic layer was separated and concentrated to give Na 2 SO 4 The crude material was extracted with CH 2 Cl 2 Purification by combi-flash chromatography using a / MeOH base followed by evaporation of the wash fractions (by TLC) and drying afforded the target compound in >95% LC-MS and HPLC purity. Example 84. 6-(2-(5-methoxy-1H-indol-1-yl)ethyl)-2-oxa-6-azaspiro[3.3]heptane [ka]

[0340] Prepared according to procedure E. Yield: 38% (over two steps), colorless liquid. LC-MS: 99%, m / z=273.2.1 [M+H] + . 1 H NMR (DMSO-d 6 , 400 MHz): δ 7.32 (d, J=8.93 Hz, 1H), 7.26 (d, J=3.06 Hz, 1H), 7.02 (d, J=2.32 Hz, 1H), 6.75 (dd, J=2.38, 8.86 Hz, 1H), 6.30 (d, J=2.93 Hz, 1H), 4.52 (s, 4H), 4.04 (t, J=6.30 Hz, 2H), 3.74 (s, 3H), 3.17 (s, 4H), 2.63-2.67 (m, 2H). Example 85. 6-(2-(5-chloro-1H-indol-1-yl)ethyl)-2-oxa-6-azaspiro[3.3]heptane [ka]

[0341] Prepared according to procedure E. Yield: 25% (over 2 steps), brown liquid. LC-MS: 97.3%, m / z=277.0 [M+H] + . 1 H NMR (DMSO-d 6 , 400 MHz): δ 7.57 (d, J=1.96 Hz, 1H), 7.46-7.49 (m, 1H), 7.40 (d, J=3.06 Hz, 1H), 7.09-7.12 (m, 1H), 6.40 (d, J=3.06 Hz, 1H), 4.52 (s, 4H), 4.08-4.11 (m, 2H), 3.18 (s, 4H), 2.67 (t, J=6.11 Hz, 2H). Example 86. (R)-1-(5-methoxy-2-methyl-1H-indol-1-yl)-N,N-dimethylpropan-2-amine [ka]

[0342] Prepared according to procedure C. 1 H NMR (DMSO-d 6 , 400 MHz): δ 7.20 (d, J=8.8 Hz, 1H), 6.95 (d, J= 2.4 Hz, 1H), 6.73 (dd, J=8.8 Hz, J=2.4 Hz, 1H), 6.14 (s, 1H), 4.29 (dd, J=4.8, 14.4 Hz, 1H), 4.06-3.99 (m, 1H), 3.79 (s, 3H), 3.25-3.10 (m, 1H), 2.48 (s, 6H), 2.42 (d, J=0.4 Hz, 3H), 0.92 (d, J=6.4 Hz, 3H). LCMS: 247.1 [M+H] + . Results and Discussion

[0343] SAR studies were performed by comparing the effects of DMT (1) with those of 1-Me-DMT (27) and isoDMT (2). DMT has the potential to act as a hydrogen bond donor when binding to its target receptor, whereas 27 and 2 did not. Both 27 and 2 enhanced dendritic spreading complexity to a degree comparable to 1 despite lacking an indole N-H bond (Figure 2), therefore this potential hydrogen bond interaction may not be important for the compounds to induce plasticity.

[0344] We chose 5-MeO-DMT (28) and 6-F-DMT (29) as electron-rich and electron-deficient DMT analogs, respectively. Compound 28 promotes neuritogenesis in the dentate gyrus and alleviates symptoms of depression and anxiety in humans. Compound 29 was predicted to be non-hallucinogenic because fluorination of DMT analogs attenuates their hallucinogenic potential. isoDMT analogs Examples 5 and 13 were performed similarly to 28 and 29 (Figure 3), and SAR data related to neuronal proliferation obtained using derivatives of the isoDMT scaffold could be applied to derivatives of the DMT scaffold by similarities due to the isosteric nature of the two structures.

[0345] Various isoDMT analogs were used to demonstrate key features of the psychoplastogen pharmacophore (Figure 4). Removing the basic amine of isoDMT to generate 25 resulted in a molecule that did not promote dendrite formation. Furthermore, compound 31 - the N,N-dimethylamide analog of isoDMT - did not promote neuronal proliferation, confirming the hypothesis that the basic nitrogen is required to promote plasticity (Figures 4A and 4B). Increasing the distance between the aromatic ring and the amine by one carbon (26) resulted in the N max This resulted in only a slight decrease in values ​​(Figure 4B).

[0346] Modifications of the aromatic ring were generally well tolerated (Figure 4C). Converting the indole to a benzimidazole (22), pyrrole (23), or carbazole (24) had minimal effects on the ability of these molecules to promote neuronal proliferation. Moreover, substitutions at the 2- and 3-positions of the indole (16 and 21, respectively) were well tolerated. Taken together, the minimal psychoplastogen pharmacophore appears to involve a modifiable aromatic ring separated from the basic nitrogen by a short linker.

[0347] Substitutions at the benzene ring of both DMT and isoDMT affect hallucinogenic potential. For example, 5-MeO-DMT (28), but not 6-MeO-DMT, displaced the hallucinogen 2,5-dimethoxy-4-methylamphetamine (DOM) in rats trained to discriminate saline from DOM. Similarly, 6-MeO-isoDMT (5), but not 5-MeO-isoDMT (Example 5), displaced the hallucinogenic training drug. Therefore, three series of analogs (Figure 5) substituted with either methoxy (electron-donating; Examples 3-6), benzyloxy (electron-donating, but sterically demanding; 8-11), or fluoro (electron-withdrawing; 12-15) groups were synthesized and tested. Substitutions at the 5-, 6-, and 7-positions were well tolerated regardless of the substituent. Substitutions at the 4-position, however, resulted in compounds that failed to enhance dendritic spreading complexity. Even fluorine substituents with very small van der Waals radii (1.2 and 1.47 for H and F, respectively) were not tolerated.

[0348] Concentration-response experiments were performed to determine whether DMT and isoDMT derivatives exhibited differences in psychoplastogenic potency (Figure 6). The isoDMT analogs (2 and Example 5) produced comparable maximum potency and had similar potency as isosteric DMT (1 and 28). Moreover, they were able to enhance dendritic spreading complexity at concentrations as low as 1 nM. These compounds showed efficacy and potency comparable to ketamine, further highlighting their potential as antidepressants. Finally, compound Example 4 proved to be an exceptional psychoplastogen, which is highly significant due to its low hallucinogenic potential in both drug discrimination and head twitch response (HTR) assays (Figure 8).

[0349] DMT and other hallucinogenic compounds are 5-HT 2A -dependent processes promote enhanced dendritic spreading complexity, dendritic spine density, and synaptogenesis. 2A Pretreatment of cortical cultures with the antagonist blocked the ability of 5-MeO-DMT (28) to enhance dendritic growth (Figure 7). Importantly, the psychoplastogenic effects of isoDMT were also blocked under these conditions, implicating 5-HT in their mechanism of action. 2A The receptor was also involved (Figure 7).

[0350] Hallucinogenic Potential. The hallucinogenic compound 5-MeO-DMT (28) produces a more robust, dose-dependent HTR in female mice. However, the isosteric compound 6-MeO-isoDMT (Example 5) is notably less potent (Figure 8). As expected based on the drug discrimination data, 6-MeO-DMT (30) did not produce HTR. Finally, the potent plasticity-promoting compounds (Examples 4, 59, and 60) did not produce any HTR (Figures 8 and 9), demonstrating that hallucinogenic potential and psychoplastogenicity cannot be separated.

[0351] Hallucinogens (e.g., LSD and 5-MeO-DMT) act in an agonist manner to inhibit 5HT 2AIn addition, compounds that are hallucinogenic in animals (e.g., humans), such as 5-MeO-DMT, LSD, DMT, and DOI, activate the 5HT receptor agonist assay in an agonist mode, whereas their non-hallucinogenic congeners (lisuride (LIS) and 6-MeO-DMT) do not (Figure 10). 2A Compounds such as 6-MeO-DMT, LIS, 6-F-DET, L-MDMA, R-MDMA, Ketanserin, and BOL148, which activate the sensor assay but are non-hallucinogenic in animals (e.g., humans), inhibit 5HT in an agonist mode. 2A In some embodiments, the hallucinogenic potential of the compounds of the invention is determined in vitro. In some embodiments, the hallucinogenic potential of the compounds of the invention is determined in vitro by measuring the 5HT 2A In some embodiments, the 5HT 2A The sensor assay is in an agonist mode or an antagonist mode. 2A The sensor assay is in agonist mode. In some embodiments, compounds of the invention that do not activate the sensor in agonist mode are non-hallucinogenic. In some embodiments, compounds of the invention that do not activate the sensor in agonist mode are non-hallucinogenic compounds.

[0352] In some embodiments, the hallucinogenic potential of compounds evaluated in the agonist mode is shown in Table 1. Table 1 [Table 3-1] [Table 3-2]

[0353] In addition, non-hallucinogenic compounds (e.g., lisuride and 6-MeO-DMT) have been shown to inhibit 5HT 2AWhen the sensor assay is run in antagonist mode, it competes with 5-HT (FIGS. 12A and 12B). Furthermore, compounds that are non-hallucinogenic in animals (e.g., humans), such as 6-F-DET, Ketanserin, and BOL148, compete with 5-HT in antagonist mode sensor assays. 2A (Figure 13, at 10 μM compound). In some embodiments, compounds of the invention compete with 5HT binding to 2A In some embodiments, the 5-HT is prevented from binding to 2A The sensor assay is in antagonist mode. 2A Compounds of the invention that interfere with the binding of 5-HT to 5-HT have the potential to be non-hallucinogenic. In some embodiments, compounds of the invention interfere with the binding of 5HT to 5-HT. 2A In some embodiments, the compound acts in an antagonist mode to inhibit the binding of 5-HT to 5-HT and is a non-hallucinogenic compound. 2A Compounds of the present invention that inhibit the binding of 5-HT to 5-HT may be non-hallucinogenic. In some embodiments, compounds of the present invention that inhibit the binding of 5-HT in antagonist mode are non-hallucinogenic compounds. In some embodiments, compounds of the present invention that inhibit the response of a sensor assay in antagonist mode may be non-hallucinogenic. In some embodiments, compounds of the present invention that inhibit the response of a sensor assay in antagonist mode are non-hallucinogenic compounds.

[0354] In some embodiments, the results of the agonist mode sensor assay show that the compounds of the present invention inhibit 5-HT 2A In some embodiments, the results of the antagonist mode sensor assay indicate that the compounds of the present invention are non-psychedelic ligands of the 5-HT 2A In some embodiments, the results of the agonist and antagonist sensor assays suggest that the compounds of the present invention are non-psychedelic ligands of the 5-HT 2A Together these suggest that it is a non-hallucinogenic ligand for the receptor.

[0355] In some embodiments, the hallucinogenic potential of compounds evaluated in the antagonist mode is shown in Table 2. Table 2 [Table 4]

[0356] Calcium flux assay. Calcium second messenger pathway. Calcium No Wash PLUS The assay is a non-imaging assay format that measures the signaling of GPCRs (e.g., 5HT) via Gq second messenger signaling in live cells. 2A Activation of Gq-linked GPCRs (e.g., 5HT 2A Calcium mobilization in other cell lines stably expressing GPCRs (e.g., 5HT) was observed using calcium-sensitive dyes that were internalized within the cells. 2A ) activation results in the release of calcium from intracellular stores and an increase in dye fluorescence that is measured in real time. In some embodiments, 5-HT 2A The ability of the compounds of the present invention to modulate function is measured using a calcium flux assay. In some embodiments, the compounds of the present invention activate the calcium flux assay. In some embodiments, activation of the calcium flux assay indicates that the compounds of the present invention modulate 5-HT 2A It indicates that it regulates the function.

[0357] In some embodiments, the compounds of the present invention are 5-HT 2A The ability to modulate function was assessed from the results of a calcium flux assay (Table 3). Table 3 [Table 5]

[0358] Forced swimming test. Enhanced cortical structural plasticity in the anterior brain mediates the sustained (>24 h) antidepressant-like effects of ketamine and 5-HT 2AThe effects of IsoDMT analogs on forced swimming test (FST) behavior (FIGS. 14A and 14B) were evaluated, since they play a role in the therapeutic effects of agonists. First, a pretest was used to induce a depressive phenotype. Compounds were administered 24 hours after the pretest, and the FST was performed 24 hours and 7 days after drug administration. Both the positive control (ketamine) and Example 59 significantly reduced immobility 24 hours after drug administration (FIGS. 14A vs. 14B).

[0359] Neurite outgrowth assay. Alterations in the pattern of neurite outgrowth have been associated with neurodegenerative disorders as well as trauma. Discovery of new therapeutic agents that can positively affect neuritogenesis is important for developing new therapeutic agents for neurological diseases. Measurement of neurite outgrowth of rat cortical neurons using an automated image-based assay was used to measure the neuroplasticity effects of the compounds of the present invention. In some embodiments, the compounds of the present invention enhance the pattern of neurite outgrowth. In some embodiments, the compounds of the present invention increase the average neurite length compared to a control. In some embodiments, the compounds of the present invention increase neurite branch points compared to a control. In some embodiments, the compounds of the present invention increase the average neurite length and neurite branch points compared to a control.

[0360] In some embodiments, the plastogenic potential of the compounds is shown in Table 4. Table 4 [Table 6] Assay

[0361] Dendritic formation assay. Historically, phenotypic screening has served better than target-based approaches to identify drugs with novel mechanisms of action. Having established a simple and robust method to obtain isoDMT analogs, we next tested their ability to enhance the complexity of dendritic spread in cultures of central neurons using a phenotypic assay. Following treatment, neurons were fixed and visualized using an antibody against a cytoskeletal protein-MAP2-a localized to the somatodendritic compartment of neurons. Sholl analysis was then performed and intersections (N max ) was used as a quantitative measure of the complexity of the dendritic spread. For statistical comparisons between specific compounds, the raw N max Values ​​were compared. Percent efficacy was expressed as N with respect to vehicle (DMSO) and positive (ketamine) controls, which corresponded to 0% and 100%, respectively. max It was determined by setting the value.

[0362] Animals. For dendrite formation experiments, timed-pregnant Sprague Dawley rats were obtained from Charles River Laboratories (Wilmington, MA). For head twitch response assays, male and female C57BL / 6J mice were obtained from Jackson Laboratory (Sacramento, CA). Mice were housed in groups of 4–5 (same sex) in a temperature- and humidity-controlled room maintained on a 12-h light / dark cycle. Animals weighed 17–30 g at the time of experimentation. All experimental procedures involving rodents were approved by the UC Davis Institutional Animal Care and Use Committee (IACUC) and adhered to the principles described in the National Institutes of Health Guide for the Care and Use of Laboratory Animals. UC Davis and UC San Francisco are accredited by the Association for Assessment and Accreditation of Laboratory Animal Care International (AAALAC).

[0363] Dendritogenesis-Sholl analysis. Dendritogenesis experiments were performed according to previously established methods with minor modifications. Neurons were plated in 96-well format (200 μL medium per well) at a density of approximately 15,000 cells / well in Neurobasal (Life Technologies) containing 1% penicillin-streptomycin, 10% heat-inactivated fetal bovine serum, and 0.5 mM glutamine. After 24 hours, the medium was replaced with Neurobasal containing 1xB27 supplement (Life Technologies), 1% penicillin-streptomycin, 0.5 mM glutamine, and 12.5 μM glutamic acid. After 3 days in vitro (DIV3), cells were treated with compounds. Unless otherwise noted, all compounds tested in the dendritogenesis assay were treated at 10 μM. Stock solutions of compounds in DMSO were first diluted 100-fold in Neurobasal and then further diluted 10-fold in each well (total dilution = 1:1000, 0.1% DMSO concentration). Treatments were randomized. After 1 hour, the medium was removed and replaced with fresh Neurobasal medium containing 1xB27 supplement, 1% penicillin-streptomycin, 0.5 mM glutamine, and 12.5 μM glutamic acid. Cells were grown for an additional 71 hours. At that time, neurons were fixed by removing 80% of the medium and replacing it with a volume of 4% aqueous paraformaldehyde (Alfa Aesar) equivalent to 50% of the working area of ​​the well. Cells were then incubated for 20 minutes at room temperature, after which the fixative was aspirated and each well was washed twice with DPBS. Cells were permeabilized using 0.2% Triton X-100 (ThermoFisher) in DPBS for 20 min at room temperature without shaking. Plates were blocked with antibody dilution buffer (ADB) containing 2% bovine serum albumin (BSA) in DPBS for 1 h at room temperature. Plates were then incubated overnight at 4° C. with gentle shaking in ADB containing chicken anti-MAP2 antibody (1:10,000; EnCor, CPCA-MAP2).The next day, the plates were washed three times with DPBS and once with 2% ADB in DPBS. The plates were incubated with ADB containing anti-chicken IgG secondary antibody conjugated to Alexa Fluor 488 (Life Technologies, 1:500) for 1 h at room temperature and washed five times with DPBS. After the final wash, 100 μL of DPBS was added per well and imaged with an ImageXpress Micro XL High-Content Screening System (Molecular Devices, Sunnyvale, CA) equipped with a 20x objective. Images were analyzed using ImageJ Fiji (version 1.51W). Images corresponding to each treatment were first sorted into individual folders, which were then blinded for data analysis. Plate controls (both positive and negative) were used to ensure that the assay was working properly, as well as to visually determine appropriate values ​​for brightness / contrast and thresholds, which were then applied across the remaining randomized 0 images. The brightness / contrast settings were then applied, and approximately 1-2 individual pyramidal-like neurons per image (i.e., no bipolar neurons) were selected using the rectangular selection tool and saved as separate files. Neurons that did not significantly overlap other cells or extend far beyond the field of view were selected. Threshold settings were then applied to individual images. The paintbrush tool was used to erase artifacts and dendrites arising from neighboring neurons (clean-up phase).Next, the point tool was used to select the center of the neuron, and the image was saved and processed using the following Sholl analysis batch macro (Table 5): run(“Sholl Analysis...”, “starting=0 ending=NaN radius_step=2 #_samples=1 integration=Mean enclosing=1 #_primary=4 infer fit linear polynomial=[Best fitting degree] most semi-log normalizer=Area create background=228 save do”); Sholl analysis circle radius = 2 pixel increments = 0.67 μm. All images were taken and analyzed by an experimenter blinded to treatment condition. The number of crossings for each neuron at each different radius was averaged to generate an average Sholl plot for each treatment. max Values ​​were simply determined by identifying the maximum of each plot. For each treatment, neurons were selected from 6 wells distributed across at least 2 plates (9 sites / well x 3 wells / plate x 2 plates). Each plate was prepared using neurons obtained from an independent pregnant dam. Table 5. Sholl validity [Table 7-1] [Table 7-2]

[0364] Ketanserin blockade experiments. For ketanserin blockade experiments (Figure 7), a slightly modified method was utilized. At DIV3, neurons were first treated with ketanserin (10 μM) for 1 h, followed by incubation with drug (1 μM) and ketanserin (10 μM) (final concentration of DMSO = 0.2%) for 1 h. After 1 h, the medium was removed and replaced with fresh Neurobasal medium containing 1xB27 supplement, 1% penicillin-streptomycin, 0.5 mM glutamine, and 12.5 μM glutamic acid. Cells were grown for an additional 71 h and then fixed, stained, and imaged.

[0365] Neurite outgrowth assay. Rat cortical neurons (20,000 cells / well) were freshly isolated from embryonic day 18 rats and cultured in Neurobasal Medium (+ B27). Cultured cells were plated in 96-well plates (avoiding the outer wells). At DIV4, neurons were treated with compounds or control (10 μM) for 1 hour, followed by complete washout of compounds. At DIV7, neurons were analyzed. Experiments were performed in triplicate. Neurite outgrowth was measured by analyzing the following parameters: cell body number, total neurite length (pixels), root count, segments, tip count, and node points. Changes in the pattern of neurite outgrowth of neurons were analyzed by immunocytology against βIII tubulin. Photographs were acquired by CellInsight CX7 from Thermo Fisher and analyzed using their software. The results generated by the instrument were maximum neurite length, tip count, root count, dendrite branch points, and total neurite length. Results were compared to DMSO controls and expressed as fold change in neuronal outgrowth.

[0366] 5HT 2A Sensor analysis. 5HT in HEK293T (ATCC) 2AA stable line of sensors (sLight1.3s) was generated via lentiviral transduction of HIV-EF1α-sLight1.3 and propagated from a single colony. Lentivirus was produced using the second generation lentiviral plasmids pHIV-EF1α-sLight1.3, pHCMV-G, and pCMV-deltaR8.2.

[0367] For screening of 41 compounds, sLight1.3s cells were plated in 96-well plates at a density of 40000 24 hours prior to imaging. On the day of imaging, compounds solubilized in DMSO were diluted from a stock solution of 100 mM to working concentrations of 1 mM, 100 μM and 1 μM with a DMSO concentration of 1%. Just prior to imaging, cells grown in DMEM (Gibco) were washed twice with HBSS (Gibco) and after the final wash, 180 μL of HBSS in agonist mode or 160 μL of HBSS in antagonist mode was added to each well. For agonist mode, images were taken before and after the addition of 20 μL of compound working solution to wells containing 180 μL of HBSS. This produced final compound concentrations of 100 μM, 10 μM and 100 nM with a DMSO concentration of 0.1%. For antagonist mode, images were taken before and after the addition of 20 μL of 900 nM 5-HT and again after the addition of 20 μL of compound working solution to produce 100 nM of 5HT, and 100 μM, 10 μM, and 100 nM final concentrations of compound with 0.1% DMSO concentration. Each compound was run in triplicate (3 wells) for each concentration (100 μM, 10 μM, and 100 nM). In addition, within each plate, 100 nM 5HT and 0.1% DMSO controls were also imaged.

[0368] Imaging was performed using a Leica DMi8 inverted microscope equipped with a 40x objective using FITC pre-set at 460 nm excitation and 512-542 nm emission. 2A The sensor-targeted cell membrane was autofocused using an adaptive focus controller, and five images were taken from different areas within the well, with each image processed for 2 × 2 binning.

[0369] For data processing, the membrane from each image was segmented and analyzed using a custom algorithm written in MATLAB® that generated a single raw fluorescence intensity value. For each well, the five raw fluorescence intensity values ​​generated from the five images were averaged and the change in fluorescence intensity (dFF) was calculated as follows: dFF=(F sat -F apo ) / F apo

[0370] For both agonist and antagonist modes, only the fluorescence intensity values ​​before compound addition in HBSS were used as F apo The fluorescence intensity value after compound addition was used as F sat was used as the value.

[0371] For agonist mode, data are presented as 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, inactivation scores were calculated as follows: Inactivation score = (dFFF(compound + 5HT) - dFF(5HT)) / dFF(5HT)

[0372] Calcium second messenger pathway. Cell lines were expanded from freezer stocks according to standard procedures. Cells were seeded in a total volume of 20 μL into black-walled, clear-bottom, poly-D-lysine coated 384-well microplates and incubated at 37°C for the appropriate time prior to testing. Assays were performed in 1x dye loading buffer consisting of 1x dye, 1x additive A and 2.5 mM Probenicid in HBSS / 20 mM Hepes. Probenicid was freshly prepared. Cells were loaded with dye prior to testing. Media was aspirated from cells and replaced with 20 μL of dye loading buffer. Cells were incubated at 37°C for 30-60 min.

[0373] For agonist measurements, cells were incubated with samples to elicit a response. After dye addition, cells were removed from the incubator and 10 μL of HBSS / 20 mM Hepes was added. Agonist standard curves were performed to determine EC values ​​for subsequent antagonist assays. 80 When defining the β-catenin concentration, 3x vehicle was included in the buffer. Cells were incubated in the dark at room temperature for 30 minutes to equilibrate plate temperature. Intermediate dilutions of sample stocks were performed to prepare 4x samples in assay buffer. Agonist activity of compounds was measured on a FLIPR Tetra (MDS). Calcium mobilization was observed for 2 minutes and then 10μL of 4x sample in HBSS / 20mM Hepes was added to cells and assayed after 5 seconds.

[0374] Compound activity was analyzed using the CBIS data analysis suite (ChemInnovation, CA). For agonist mode assays, percent activity was calculated using the following formula: % Activity=100%×(mean RFU of test sample−mean RFU of vehicle control) / (mean MAX RFU of control ligand−mean RFU of vehicle control).

[0375] Head twitch response experiments. Mice (9-10 weeks old) were injected intraperitoneally with compounds (5 ml / kg injection volume), placed in an empty cage, and filmed for 20 min. Between experiments, cages were cleaned with 70% ethanol. Each video was scored for the number of head twitches by two trained observers blinded to treatment condition, and the results were averaged (Pearson correlation coefficient = 0.91 and 0.99 for men and women, respectively).

[0376] Forced swim test (FST). Male C57 / BL6J mice (9–10 weeks old at the time of experimentation) were obtained from Jackson Lab and housed 4–5 mice / cage in the UCD vivarium following an IACUC-approved protocol. After 1 week in the vivarium, each mouse was manipulated for approximately 1 min by a male experimenter on three consecutive days leading to the first FST. All experiments were performed by the same male experimenter who had performed the manipulations. During the FST, mice underwent a 6-min swim session in a 40 cm high, 20 cm diameter clear Plexiglas cylinder filled with 30 cm of 24 ± 1°C water. Fresh water was used for all mice. After manipulation and acclimation to the experimenter, drug-naive mice were first subjected to a pre-swim test to more reliably induce a depression phenotype in the subsequent FST sessions. Immobility scores for all mice were determined after pre-testing, and mice were randomly assigned to treatment groups to create groups with similar mean immobility scores for use in the two subsequent FST sessions. The next day, animals received an intraperitoneal injection of experimental compound (20 mg / kg), positive control (ketamine, 3 mg / kg), or vehicle (saline). Thirty minutes after injection, animals were subjected to the FST and then returned to their home cages. All FSTs were performed during a period of several hours between 8:00 AM and 1:00 PM. Experiments were videotaped and manually scored offline. Immobility time - defined as passive floating or maintaining a still state with no activity other than that required to keep the mouse's head above water - was scored over the last 4 minutes of a 6-minute trial.

[0377] Statistical Analysis. Treatments were randomized and data were analyzed by an experimenter blinded to treatment condition. Statistical analysis was performed using GraphPad Prism (version 8.1.2). The specific tests used, F-statistics, degrees of freedom, and p-values ​​for main effects are indicated in the figure legends, where appropriate. All comparisons were planned before each experiment was performed. For dendritogenesis experiments, one-way ANOVA with Dunnett's post hoc test was deemed most appropriate. Ketamine was included as a positive control to ensure that the assays were performed properly.

[0378] Although the foregoing invention has been described in some detail by way of illustrations and examples for purposes of clarity of understanding, those skilled in the art will recognize that certain changes and modifications may be practiced within the scope of the appended claims.Furthermore, each reference provided herein is incorporated by reference in its entirety to the same extent as if each reference was individually incorporated by reference.In the event of any conflict between this application and the references provided herein, this application shall control.

Claims

1. Formula I below: 【Chemistry 1】 {During the ceremony, X is CR ３ and R １ａ and R １ｂ are each independently hydrogen, C １－６ Alkyl, C ３－８ Cycloalkyl, or C ４－１４ alkyl-cycloalkyl; R １ｃ is C １－６ Alkyl, C ３－８ Cycloalkyl, or C ４－１４ is alkyl-cycloalkyl; Or, R １ａ , R １ｂ , and R １ｃ Two of them combine with the atom to which they are attached to form C ３－１２ forming a heterocycloalkyl; R ２ , R ３ , R ４ , R ５ , R ６ and R ７ are each independently hydrogen, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, halogen, C １－６ Haloalkyl, C １－６ Alkylamines, C １－６ Alkoxy, C １－６ Haloalkoxy, -OR ８ａ , -NO ２ , -CN, -C(O)R ８ｂ , -C(O)OR ８ｂ , -OC(O)R ８ｂ , -OC(O)OR ８ｂ , -N(R ８ｂ R ８ｃ ), -N(R ８ｂ ) C(O)R ８ｃ , -C(O)N(R ８ｂ R ８ｃ ), -N(R ８ｂ ) C(O)OR ８ｃ , -OC(O)N(R ８ｂ R ８ｃ ), -N(R ８ｂ ) C(O)N(R ８ｃ R ８ｄ ), -C(O)C(O)N(R ８ｂ R ８ｃ ), -S(O ２ ) R ８ｂ , -S(O) ２ N (R ８ｂ R ８ｃ ), C ３－８ Cycloalkyl, C ３－１４ Alkyl-cycloalkyl, C ４－１０ Heterocycloalkyl, C ４－１６ Alkyl-heterocycloalkyl, C ６－１２ Aryl, C ７－１８ Alkyl-Aryl, C ５－１０ Heteroaryl, or C ４－１６ alkyl-heteroaryl; R ８ａ is 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 ８ｂ , R ８ｃ , and R ８ｄ are each independently H or C １－６ Is it alkyl; Or, R １ａ , R １ｂ , or R １ｃ One of the two is R ２ Combined with C ５－１２ forming a heterocycloalkyl; Or, R ２ and R ３ are combined with the atom to which they are attached to form C ４－８ Cycloalkyl, C ４－１０ Heterocycloalkyl, or C ６－１２ Forming an aryl; Or, R ４ and R ５ , R ５ and R ６ , or R ６ and R ７ are combined with the atom to which they are attached to form C ４－６ Cycloalkyl, C ４－６ Heterocycloalkyl, C ６－１２ Aryl, or C ５－１０ forming a heteroaryl; and L is C １－６ or a pharma- ceutically acceptable salt or isomer thereof, Here, R １ａ , R １ｂ , and R １ｃ are Me, L is methylene, and X is CR ３ And R ２ , R ３ , R ４ , R ５ , R ６ and R ７ is hydrogen, the compound has the structure: 【Chemistry 2】 and wherein the compound has the following structure: 【Chemistry 3】 or a pharma- ceutically acceptable salt or isomer thereof,

2. Compound {wherein, X is CR ３ and R ２ and R ３ are each independently hydrogen, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, halogen, C １－６ Haloalkyl, C １－６ Alkylamines, C １－６ Alkoxy, C １－６ Haloalkoxy, -OR ８ａ , -NO ２ , -CN, -C(O)R ８ｂ , -C(O)OR ８ｂ , -OC(O)R ８ｂ , -OC(O)OR ８ｂ , -N(R ８ｂ R ８ｃ ), -N(R ８ｂ ) C(O)R ８ｃ , -C(O)N(R ８ｂ R ８ｃ ), -N(R ８ｂ ) C(O)OR ８ｃ , -OC(O)N(R ８ｂ R ８ｃ ), -N(R ８ｂ ) C(O)N(R ８ｃ R ８ｄ ), -C(O)C(O)N(R ８ｂ R ８ｃ ), -S(O ２ ) R ８ｂ , -S(O) ２ N (R ８ｂ R ８ｃ ), C ３－８ Cycloalkyl, C ３－１４ Alkyl-cycloalkyl, C ４－１０ Heterocycloalkyl, C ４－１６ Alkyl-heterocycloalkyl, C ６－１２ Aryl, C ７－１８ Alkyl-Aryl, C ５－１０ Heteroaryl, or C ４－１６ alkyl-heteroaryl; R ８ａ is 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; and R ８ｂ , R ８ｃ , and R ８ｄ are each independently H or C １－６ alkyl} or a pharma- ceutically acceptable salt thereof, Here, R １ａ , R １ｂ and R １ｃ are each Me, L is methylene, and R ２ , R ３ , R ４ , R ５ , R ６ and R ７ is hydrogen, the compound has the structure: 【Chemistry 4】 2. The compound of claim 1, wherein:

3. The compound of formula I has the following structure: 【Chemistry 5】 3. The compound of claim 1 or 2, having the formula:

4. In the above formula, R １ａ , R １ｂ , or R １ｃ are each independently １－６ Alkyl, C ３－８ Cycloalkyl, or C ４－１４ is alkyl-cycloalkyl; Or, R １ａ , R １ｂ , and R １ｃ Two of them combine with the atom to which they are attached to form C ３－１２ forming a heterocycloalkyl; R ２ , R ３ , R ４ , R ６ and R ７ are each independently hydrogen, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, halogen, C １－６ Haloalkyl, C １－６ Alkylamines, C １－６ Alkoxy, C １－６ Haloalkoxy, -OR ８ａ , -NO ２ , -CN, -C(O)R ８ｂ , -C(O)OR ８ｂ , -OC(O)R ８ｂ , -OC(O)OR ８ｂ , -N(R ８ｂ R ８ｃ ), -N(R ８ｂ ) C(O)R ８ｃ , -C(O)N(R ８ｂ R ８ｃ ), -N(R ８ｂ ) C(O)OR ８ｃ , -OC(O)N(R ８ｂ R ８ｃ ), -N(R ８ｂ ) C(O)N(R ８ｃ R ８ｄ ), -C(O)C(O)N(R ８ｂ R ８ｃ ), -S(O ２ ) R ８ｂ , -S(O) ２ N (R ８ｂ R ８ｃ ), C ３－８ Cycloalkyl, C ３－１４ Alkyl-cycloalkyl, C ４－１０ Heterocycloalkyl, C ４－１６ Alkyl-heterocycloalkyl, C ６－１２ Aryl, C ７－１８ Alkyl-Aryl, C ５－１０ Heteroaryl, or C ４－１６ alkyl-heteroaryl; R ５ is C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, halogen, C １－６ Haloalkyl, C １－６ Alkylamines, C １－６ Alkoxy, C １－６ Haloalkoxy, -OR ８ａ , -NO ２ , -CN, -C(O)R ８ｂ , -C(O)OR ８ｂ , -OC(O)R ８ｂ , -OC(O)OR ８ｂ , -N(R ８ｂ R ８ｃ ), -N(R ８ｂ ) C(O)R ８ｃ , -C(O)N(R ８ｂ R ８ｃ ), -N(R ８ｂ ) C(O)OR ８ｃ , -OC(O)N(R ８ｂ R ８ｃ ), -N(R ８ｂ ) C(O)N(R ８ｃ R ８ｄ ), -C(O)C(O)N(R ８ｂ R ８ｃ ), -S(O ２ ) R ８ｂ , -S(O) ２ N (R ８ｂ R ８ｃ ), C ３－８ Cycloalkyl, C ３－１４ Alkyl-cycloalkyl, C ４－１０ Heterocycloalkyl, C ４－１６ Alkyl-heterocycloalkyl, C ６－１２ Aryl, C ７－１８ Alkyl-Aryl, C ５－１０ Heteroaryl, or C ４－１６ alkyl-heteroaryl; R ８ａ is 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; and R ８ｂ , R ８ｃ , and R ８ｄ are each independently H or C １－６ Is it alkyl; Or, R ４ and R ５ , R ５ and R ６ , or R ６ and R ７ are combined with the atom to which they are attached to form C ４－６ Cycloalkyl, C ４－６ Heterocycloalkyl, C ６－１２ Aryl, or C ５－１０ forming a heteroaryl, A compound according to any one of claims 1 to 3, or a pharma- ceutical acceptable salt thereof.

5. In the above formula, R １ａ and R １ｂ are each independently hydrogen or C １－６ is alkyl; R １ｃ is C １－６ is alkyl; R ２ and R ３ are each independently hydrogen, C １－６ Alkyl, C １－６ Alkoxy, halogen, or -C(O)C(O)N(R ８ｂ R ８ｃ ) and R ４ , R ５ , R ６ and R ７ are each independently hydrogen, C １－６ Alkyl, halogen, C １－６ Haloalkyl, C １－６ Alkoxy, C １－６ Haloalkoxy, or -OR ８ａ where R ４ , R ５ , R ６ and R ７ at least one of is not H; and R ８ａ is C ７－１８ is alkyl-aryl; Or, R ５ and R ６ are combined with the atom to which they are attached to form C ４－６ forming a heterocycloalkyl; The compound according to any one of claims 1 to 3, or a pharma- ceutical acceptable salt thereof.

6. In the above formula, R １ａ and R １ｂ are each independently hydrogen or methyl, and R １ｃ is methyl; Or, R １ａ , R １ｂ , and R １ｃ Two of them combine with the atom to which they are attached to form C ３－８ forming a heterocycloalkyl; The compound according to any one of claims 1 to 3, or a pharma- ceutical acceptable salt thereof.

7. In the above formula, R １ａ , R １ｂ , and R １ｃ are each Me; Or, R １ａ , R １ｂ , and R １ｃ Two of them combine with the atom to which they are attached to form C ３－８ forming a heterocycloalkyl, 7. The compound according to any one of claims 1 to 6, or a pharma- ceutical acceptable salt thereof.

8. In the above formula, R ２ is hydrogen, C １－６ Alkyl, halogen, or C １－６ is an alkoxy; 8. The compound according to any one of claims 1 to 7, or a pharma- ceutical acceptable salt thereof.

9. In the above formula, R ２ is hydrogen, Me, F or -OMe; 9. The compound according to any one of claims 1 to 8, or a pharma- ceutical acceptable salt thereof.

10. In the above formula, R ３ is hydrogen, C １－６ Alkyl, C １－６ Alkoxy, halogen, or -C(O)C(O)N(R ８ｂ R ８ｃ ) and R ８ｂ and R ８ｃ are each independently H or C １－６ is alkyl, 10. The compound according to any one of claims 1 to 9, or a pharma- ceutical acceptable salt thereof.

11. In the above formula, R ３ is hydrogen, Me, F, -OMe or -C(O)C(O)NMe ２ That is, 11. The compound according to any one of claims 1 to 10, or a pharma- ceutical acceptable salt thereof.

12. The compound of formula I has the following structure: 【Chemistry 6】 12. The compound according to any one of claims 1 to 11, or a pharma- ceutically acceptable salt thereof, having the formula:

13. The compound of formula I has the following structure: 【Chemistry 7】 12. The compound according to any one of claims 1 to 11, or a pharma- ceutically acceptable salt thereof, having the formula:

14. The compound of formula I has the following structure: 【Chemistry 8】 12. The compound according to any one of claims 1 to 11, or a pharma- ceutically acceptable salt thereof, having the formula:

15. The compound of formula I has the following structure: 【Chemistry 9】 15. The compound of any one of claims 1 to 12 or 14, or a pharma- ceutically acceptable salt thereof, having the formula:

16. The compound of formula I has the following structure: 【Chemistry 10】 15. The compound of any one of claims 1 to 11, 13 or 14, or a pharma- ceutically acceptable salt thereof, having the formula:

17. In the above formula, R １ａ and R １ｂ are combined with the atom to which they are attached to form C ３－８ forming a heterocycloalkyl, 14. The compound according to any one of claims 1 to 13, or a pharma- ceutical acceptable salt thereof.

18. In the above formula, R １ａ and R １ｃ are combined with the atom to which they are attached to form C ５－８ forming a heterocycloalkyl; 14. The compound according to any one of claims 1 to 13, or a pharma- ceutical acceptable salt thereof.

19. In the above formula, R ４ , R ５ , R ６ Or R ７ are each independently hydrogen, C １－６ Alkyl, halogen, C １－６ Haloalkyl, C １－６ Alkoxy, C １－６ Haloalkoxy, -OR ８ａ , -NO ２ , -C.N., C. ３－８ Cycloalkyl, or C ３－１４ is alkyl-cycloalkyl; Or, R ４ and R ５ , R ５ and R ６ , or R ６ and R ７ are combined with the atom to which they are attached to form C ５－６ forming a heterocycloalkyl; and R ８ａ is C ３－８ Cycloalkyl, C ３－１４ Alkyl-cycloalkyl, C ４－１６ Alkyl-heterocycloalkyl, C ７－１８ Alkyl-aryl, or C ４－１６ alkyl-heteroaryl; 19. A compound according to any one of claims 1 to 18, or a pharma- ceutical acceptable salt thereof.

20. In the above formula, R ４ , R ５ , R ６ Or R ７ are each independently hydrogen, C １－６ Alkyl, halogen, C １－６ Alkoxy, C １－６ Haloalkoxy, -OR ８ａ , or -NO ２ Is it; Or, R ４ and R ５ , R ５ and R ６ , or R ６ and R ７ are combined with the atom to which they are attached to form C ５ forming a heterocycloalkyl; and R ８ａ is C ７－１８ alkyl-aryl; 20. The compound according to any one of claims 1 to 19, or a pharma- ceutical acceptable salt thereof.

21. In the above formula, R ４ , R ６ Or R ７ are each independently hydrogen, C １－６ Alkyl, halogen, C １－６ Alkoxy, C １－６ Haloalkoxy, -OR ８ａ , or -NO ２ and R ５ is C １－６ Alkyl, halogen, C １－６ Alkoxy, C １－６ Haloalkoxy, -OR ８ａ , or -NO ２ Is it; Or, R ４ and R ５ , R ５ and R ６ , or R ６ and R ７ are combined with the atom to which they are attached to form C ５ forming a heterocycloalkyl; and R ８ａ is C ７－１８ alkyl-aryl; 20. The compound according to any one of claims 1 to 19, or a pharma- ceutical acceptable salt thereof.

22. In the above formula, R ４ , R ５ , R ６ Or R ７ are each independently hydrogen, Me, F, Cl, Br, -OMe, or -OCF ３ , —O—CH ２ -phenyl or -NO ２ Is it; Or, R ５ and R ６ are combined with the atoms to which they are respectively attached to form a 1,3-dioxole ring or a 1,4-dioxane ring; 21. The compound according to any one of claims 1 to 20, or a pharma- ceutical acceptable salt thereof.

23. In the above formula, R ４ , R ６ and R ７ are each hydrogen; and R ５ is Me, F, Cl, Br, -OMe, -CF ３ , -OCF ３ , —O-benzyl or —NO ２ That is, 23. A compound according to any one of claims 1 to 22, or a pharma- ceutical acceptable salt thereof.

24. In the above formula, R ５ is Me, F, Cl, Br, -OMe, -CF ３ , -OCF ３ , —O-benzyl or —NO ２ and R ６ and R ７ are each independently hydrogen, Me, F, Cl, Br, -OMe, or -OCF ３ , —O—CH ２ -phenyl or -NO ２ where R ６ and R ７ At least one of is not hydrogen, 23. A compound according to any one of claims 1 to 22, or a pharma- ceutical acceptable salt thereof.

25. In the above formula, X is CR ３ and R １ａ and R １ｂ are Me, respectively; R １ｃ is Me, Et, or Pr; R ２ is H, Me, -OMe, -F, or -C(O)-C(O)N(Me) ２ and R ３ is H, Me, -OMe, -F, or -C(O)-C(O)N(Me) ２ and R ４ , R ５ , R ６ and R ７ are each independently H, Me, -F, -Cl, -Br, or -NO ２ , -OMe, -CF ３ , -OCF ３ or -Obenzyl; Or, R ５ and R ６ are combined to form a 1,3-dioxole ring or a 1,4-dioxane ring; 3. The compound according to any one of claims 1 to 2, or a pharma- ceutical acceptable salt thereof.

26. In the above formula, X is CR ３ and R １ａ and R １ｂ are Me, respectively; R １ｃ is Me, Et, or Pr; R ２ is H, Me, -F, -OMe; R ３ is H, Me, -F, -OMe, or -C(O)-C(O)N(Me) ２ and R ４ is H, Me, -F, -OMe or -O-benzyl; R ５ is H, Me, -F, -Cl, -Br, -OMe, -CF ３ － O.C.F. ３ or -O-benzyl; R ６ is H, Me, -F, -NO ２ , -OMe, -OCF ３ or -O-benzyl; Or, R ５ and R ６ are combined to form a 1,3-dioxole ring or a 1,4-dioxane ring; and R ７ is H, Me, -F, -OMe, or -O-benzyl; 26. A compound according to any one of claims 1 to 2 or 25, or a pharma- ceutically acceptable salt thereof.

27. The compound is selected from the group consisting of: 【Chemistry 11】 or a pharma- ceutically acceptable salt thereof.

28. The compound is selected from the group consisting of: 【Chemistry 12】 or a pharma- ceutically acceptable salt thereof.

29. The compound is selected from the group consisting of: 【Chemistry 13】 or a pharma- ceutically acceptable salt thereof.

30. 30. The compound according to any one of claims 1 to 29, wherein the compound is a fumaric acid containing salt or a pharma- ceutical acceptable salt.

31. Formula II below: 【Chemistry 14】 {During the ceremony, X is CR ３ and R １ａ and R １ｂ are each independently hydrogen, C １－６ Alkyl, C ３－８ Cycloalkyl, or C ４－１４ is alkyl-cycloalkyl; Or, R １ａ and R １ｂ are combined with the atom to which they are attached to form C ３－１２ forming a heterocycloalkyl; R ２ , R ３ , R ４ , R ５ , R ６ , and R ７ are each independently hydrogen, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, halogen, C １－６ Haloalkyl, C １－６ Alkylamines, C １－６ Alkoxy, C １－６ Haloalkoxy, -OR ８ａ , -NO ２ , -CN, -C(O)R ８ｂ , -C(O)OR ８ｂ , -OC(O)R ８ｂ , -OC(O)OR ８ｂ , -N(R ８ｂ R ８ｃ ), -N(R ８ｂ ) C(O)R ８ｃ , -C(O)N(R ８ｂ R ８ｃ ), -N(R ８ｂ ) C(O)OR ８ｃ , -OC(O)N(R ８ｂ R ８ｃ ), -N(R ８ｂ ) C(O)N(R ８ｃ R ８ｄ ), -C(O)C(O)N(R ８ｂ R ８ｃ ), -S(O ２ ) R ８ｂ , -S(O) ２ N (R ８ｂ R ８ｃ ), C ３－８ Cycloalkyl, C ３－１４ Alkyl-cycloalkyl, C ４－１０ Heterocycloalkyl, C ４－１６ Alkyl-heterocycloalkyl, C ６－１２ Aryl, C ７－１８ Alkyl-Aryl, C ５－１０ Heteroaryl, or C ４－１６ alkyl-heteroaryl; R ８ａ is 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 ８ｂ , R ８ｃ , and R ８ｄ are each independently H or C １－６ Is it alkyl? Or R １ａ Or R １ｂ One of the two is R ２ Combined with C ５－１２ forming a heterocycloalkyl; Or, R ２ and R ３ are combined with the atom to which they are attached to form C ４－８ Cycloalkyl, C ４－１０ Heterocycloalkyl, or C ６－１２ Forming an aryl; Or, R ４ and R ５ , R ５ and R ６ , or R ６ and R ７ are combined with the atom to which they are attached to form C ４－６ Cycloalkyl, C ４－６ Heterocycloalkyl, C ６－１２ Aryl, or C ５－１０ forming a heteroaryl; and L is C １－６ or a pharma- ceutically acceptable salt or isomer thereof, Here, R １ａ and R １ｂ When both are Me and L is methylene, R ２ , R ３ , R ４ , R ５ , R ６ , and R ７ is not hydrogen, and the compound has the following structure: 【Chemistry 15】 except for; Here, R １ａ and R １ｂ is Me, L is ethylene, and X is CR ３ When R ２ , R ３ , R ４ , R ５ , R ６ , and R ７ at least one of is not hydrogen; Here, R １ｃ is hydrogen and R ５ is Br, Cl, F, -NH ２ , -NO ２ , or C １－３ When R is alkoxy, ２ , R ３ , R ４ , R ６ , or R ７ at least one of is not hydrogen; and Here, R １ｃ is hydrogen, R ５ When is F, R ２ , R ３ , R ４ , R ６ , or R ７ At least one of R ６ is not F, or a pharma- ceutically acceptable salt or isomer thereof.

32. The compound of formula II has the following structure: 【Chemistry 16】 32. The compound of claim 31 having the formula:

33. The compound of formula II has the following structure: 【Chemistry 17】 33. The compound of claim 31 or 32, having the formula:

34. In the above formula, R ２ , R ３ , R ４ , R ５ , R ６ and R ７ or a pharma- ceutically acceptable salt thereof.

34. The compound of any one of claims 31 to 33, wherein at least one of:

35. In the above formula, R ４ , R ５ , R ６ Or R ７ are each independently hydrogen, C １－６ Alkyl, halogen, C １－６ Haloalkyl, C １－６ Alkoxy, C １－６ Haloalkoxy, -OR ８ａ , -NO ２ , -C.N., C. ３－８ Cycloalkyl, or C ３－１４ is alkyl-cycloalkyl; Or, R ４ and R ５ , R ５ and R ６ , or R ６ and R ７ are combined with the atom to which they are attached to form C ５－６ forming a heterocycloalkyl; and R ８ａ is C ３－８ Cycloalkyl, C ３－１４ Alkyl-cycloalkyl, C ４－１６ Alkyl-heterocycloalkyl, C ７－１８ Alkyl-aryl, or C ４－１６ alkyl-heteroaryl; 35. The compound according to any one of claims 31 to 34, or a pharma- ceutical acceptable salt thereof.

36. In the above formula, R ４ , R ５ , R ６ Or R ７ are each independently hydrogen, C １－６ Alkyl, halogen, C １－６ Alkoxy, C １－６ Haloalkoxy, -OR ８ａ , or -NO ２ Is it; Or, R ４ and R ５ , R ５ and R ６ , or R ６ and R ７ are combined with the atom to which they are attached to form C ５ forming a heterocycloalkyl; and R ８ａ is C ７－１８ alkyl-aryl; 36. The compound according to any one of claims 31 to 35, or a pharma- ceutical acceptable salt thereof.

37. In the above formula, R ４ , R ５ , R ６ Or R ７ are each independently hydrogen, F, Cl, -OMe, or -OCF ３ or -O-benzyl; Or, R ５ and R ６ are combined with the atoms to which they are respectively attached to form a 1,3-dioxole ring or a 1,4-dioxane ring; 37. The compound according to any one of claims 31 to 36, or a pharma- ceutical acceptable salt thereof.

38. In the above formula, R ５ is F, Cl, -OMe, -OCF ３ or -O-benzyl; Or, R ５ and R ６ are combined with the atoms to which they are respectively attached to form a 1,3-dioxole ring or a 1,4-dioxane ring; 38. A compound according to any one of claims 31 to 37, or a pharma- ceutical acceptable salt thereof.

39. In the above formula, R ５ is F, Cl, -OMe, -OCF ３ or -O-benzyl; R ６ and R ７ are each independently hydrogen, F, Cl, -OMe, or -OCF ３ or -O-benzyl, where R ６ and R ７ at least one of is not hydrogen; Or, R ５ and R ６ are combined with the atoms to which they are respectively attached to form a 1,3-dioxole ring or a 1,4-dioxane ring; 38. A compound according to any one of claims 31 to 37, or a pharma- ceutical acceptable salt thereof.

40. The compound is selected from the group consisting of: 【Chemistry 18】 or a pharma- ceutically acceptable salt thereof.

41. The compound is selected from the group consisting of: 【Chemistry 19】 or a pharma- ceutically acceptable salt thereof.

42. In the above formula, R １ａ and R １ｂ are combined with the atom to which they are attached to form C ３－８ A compound according to any one of claims 31 to 39 which forms a heterocycloalkyl.

43. The compound is selected from the group consisting of: 【Chemistry 20】 or a pharma- ceutically acceptable salt thereof.

44. The compound is selected from the group consisting of: 【Chemistry 21】 or a pharma- ceutically acceptable salt thereof.

45. The compound according to any one of claims 31 to 44, wherein the compound is a fumaric acid containing salt or a pharma- ceutical acceptable salt.

46. 46. ​​A pharmaceutical composition comprising a compound according to any one of claims 1 to 45, and a pharma- ceutically acceptable excipient.

47. A method for enhancing neuroplasticity, comprising administering to a neuronal cell a compound of formula I: 【Chemical 22】 {During the ceremony, X is N or CR ３ and R １ａ , R １ｂ , and R １ｃ are each independently hydrogen, C １－６ Alkyl, C ３－８ Cycloalkyl, or C ４－１４ is alkyl-cycloalkyl; Or, R １ａ , R １ｂ , and R １ｃ Two of them combine with the atom to which they are attached to form C ３－１２ forming a heterocycloalkyl; R ２ , R ３ , R ４ , R ５ , R ６ and R ７ are each independently hydrogen, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, halogen, C １－６ Haloalkyl, C １－６ Alkylamines, C １－６ Alkoxy, C １－６ Haloalkoxy, -OR ８ａ , -NO ２ , -CN, -C(O)R ８ｂ , -C(O)OR ８ｂ , -OC(O)R ８ｂ , -OC(O)OR ８ｂ , -N(R ８ｂ R ８ｃ ), -N(R ８ｂ ) C(O)R ８ｃ , -C(O)N(R ８ｂ R ８ｃ ), -N(R ８ｂ ) C(O)OR ８ｃ , -OC(O)N(R ８ｂ R ８ｃ ), -N(R ８ｂ ) C(O)N(R ８ｃ R ８ｄ ), -C(O)C(O)N(R ８ｂ R ８ｃ ), -S(O ２ ) R ８ｂ , -S(O) ２ N (R ８ｂ R ８ｃ ), C ３－８ Cycloalkyl, C ３－１４ Alkyl-cycloalkyl, C ４－１０ Heterocycloalkyl, C ４－１６ Alkyl-heterocycloalkyl, C ６－１２ Aryl, C ７－１８ Alkyl-Aryl, C ５－１０ Heteroaryl, or C ４－１６ alkyl-heteroaryl; R ８ａ is 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 ８ｂ , R ８ｃ and R ８ｄ are each independently H or C １－６ Is it alkyl? Or, R １ａ , R １ｂ , or R １ｃ One of them is R ２ Combined with C ５－１２ forming a heterocycloalkyl; Or, R ２ and R ３ are combined with the atom to which they are attached to form C ４－８ Cycloalkyl, C ４－１０ Heterocycloalkyl, or C ６－１２ Forming an aryl; Or, R ４ and R ５ , R ５ and R ６ , or R ６ and R ７ are combined with the atom to which they are attached to form C ３－６ Cycloalkyl, C ３－６ Heterocycloalkyl, C ６－１２ Aryl, or C ５－１０ forming a heteroaryl; and L is C １－６ or a pharma- ceutically acceptable salt thereof.

48. A method for treating a brain disorder comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula I: 【Chemistry 23】 {During the ceremony, X is N or CR ３ and R １ａ , R １ｂ , and R １ｃ are each independently hydrogen, C １－６ Alkyl, C ３－８ Cycloalkyl, or C ４－１４ is alkyl-cycloalkyl; Or, R １ａ , R １ｂ , and R １ｃ Two of them combine with the atom to which they are attached to form C ３－１２ forming a heterocycloalkyl; R ２ , R ３ , R ４ , R ５ , R ６ and R ７ are each independently hydrogen, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, halogen, C １－６ Haloalkyl, C １－６ Alkylamines, C １－６ Alkoxy, C １－６ Haloalkoxy, -OR ８ａ , -NO ２ , -CN, -C(O)R ８ｂ , -C(O)OR ８ｂ , -OC(O)R ８ｂ , -OC(O)OR ８ｂ , -N(R ８ｂ R ８ｃ ), -N(R ８ｂ ) C(O)R ８ｃ , -C(O)N(R ８ｂ R ８ｃ ), -N(R ８ｂ ) C(O)OR ８ｃ , -OC(O)N(R ８ｂ R ８ｃ ), -N(R ８ｂ ) C(O)N(R ８ｃ R ８ｄ ), -C(O)C(O)N(R ８ｂ R ８ｃ ), -S(O ２ ) R ８ｂ , -S(O) ２ N (R ８ｂ R ８ｃ ), C ３－８ Cycloalkyl, C ３－１４ Alkyl-cycloalkyl, C ４－１０ Heterocycloalkyl, C ４－１６ Alkyl-heterocycloalkyl, C ６－１２ Aryl, C ７－１８ Alkyl-Aryl, C ５－１０ Heteroaryl, or C ４－１６ alkyl-heteroaryl; R ８ａ is 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 ８ｂ , R ８ｃ and R ８ｄ are each independently H or C １－６ Is it alkyl? Or, R １ａ , R １ｂ , or R １ｃ One of them is R ２ Combined with C ５－１２ forming a heterocycloalkyl; Or, R ２ and R ３ are combined with the atom to which they are attached to form C ４－８ Cycloalkyl, C ４－１０ Heterocycloalkyl, or C ６－１２ Forming an aryl; Or, R ４ and R ５ , R ５ and R ６ , or R ６ and R ７ are combined with the atom to which they are attached to form C ３－６ Cycloalkyl, C ３－６ Heterocycloalkyl, C ６－１２ Aryl, or C ５－１０ forming a heteroaryl; and L is C １－６ wherein R is an alkylene group, and R is an aryl group, thereby treating a brain disorder.

49. 49. The method of claim 48, wherein the brain disorder is a neurodegenerative disorder, Alzheimer's disease, or Parkinson's disease.

50. 49. The method of claim 48, wherein the brain disorder is a psychiatric disorder, depression, addiction, anxiety, or post-traumatic stress disorder.

51. 51. The method of claim 50, wherein the brain disorder is depression.

52. 51. The method of claim 50, wherein the brain disorder is addiction.

53. 49. The method of claim 48, wherein the brain disorder is treatment-resistant depression, suicidal ideation, major depressive disorder, bipolar disorder, schizophrenia, or a substance use disorder.

54. 49. The method of claim 48, wherein the brain disorder is a stroke or a traumatic brain injury.

55. Lithium, olanzapine (Zyprexa), quetiapine (Seroquel), risperidone (Risperdal), ariprazole (Abilify), ziprasidone (Geodon), clozapine (Clozalil), divalproex sodium (Depakote), lamotrigine (Lamictal), valproic acid (Depakene), carbamazepine (Equetro), topiramate (Topamax), levomilnacipran (Fetzima), duloxetine (Cymbalta, Yentreve), venlafaxine (Effexor), citalopram (Celexa), fluvoxamine (Luv 55. The method of any one of claims 48-54, comprising administering one or more additional therapeutic agents which are: fluoxetine (Prozac), paroxetine (Paxil), sertraline (Zoloft), clomipramine (Anafranil), amitriptyline (Elavil), desipramine (Norpramin), imipramine (Tofranil), nortriptyline (Pamelor), phenelzine (Nardil), tranylcypromine (Parnate), diazepam (Valium), alprazolam (Xanax), or clonazepam (Klonopin).

56. A method of enhancing at least one of translation, transcription, or secretion of a neurotrophic factor, comprising administering to a neuronal cell a compound of formula I: 【Chemistry 24】 {During the ceremony, X is N or CR ３ and R １ａ , R １ｂ , and R １ｃ are each independently hydrogen, C １－６ Alkyl, C ３－８ Cycloalkyl, or C ４－１４ is alkyl-cycloalkyl; Or, R １ａ , R １ｂ , and R １ｃ Two of them combine with the atom to which they are attached to form C ３－１２ Forming a heterocycloalkyl; R ２ , R ３ , R ４ , R ５ , R ６ and R ７ are each independently hydrogen, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, halogen, C １－６ Haloalkyl, C １－６ Alkylamines, C １－６ Alkoxy, C １－６ Haloalkoxy, -OR ８ａ , -NO ２ , -CN, -C(O)R ８ｂ , -C(O)OR ８ｂ , -OC(O)R ８ｂ , -OC(O)OR ８ｂ , -N(R ８ｂ R ８ｃ ), -N(R ８ｂ ) C(O)R ８ｃ , -C(O)N(R ８ｂ R ８ｃ ), -N(R ８ｂ ) C(O)OR ８ｃ , -OC(O)N(R ８ｂ R ８ｃ ), -N(R ８ｂ ) C(O)N(R ８ｃ R ８ｄ ), -C(O)C(O)N(R ８ｂ R ８ｃ ), -S(O ２ ) R ８ｂ , -S(O) ２ N (R ８ｂ R ８ｃ ), C ３－８ Cycloalkyl, C ３－１４ Alkyl-cycloalkyl, C ４－１０ Heterocycloalkyl, C ４－１６ Alkyl-heterocycloalkyl, C ６－１２ Aryl, C ７－１８ Alkyl-Aryl, C ５－１０ Heteroaryl, or C ４－１６ alkyl-heteroaryl; R ８ａ is 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 ８ｂ , R ８ｃ and R ８ｄ are each independently H or C １－６ Is it alkyl; Or, R １ａ , R １ｂ , or R １ｃ One of them is R ２ Combined with C ５－１２ forming a heterocycloalkyl; Or, R ２ and R ３ are combined with the atom to which they are attached to form C ４－８ Cycloalkyl, C ４－１０ Heterocycloalkyl, or C ６－１２ Forming an aryl; Or, R ４ and R ５ , R ５ and R ６ , or R ６ and R ７ are combined with the atom to which they are attached to form C ３－６ Cycloalkyl, C ３－６ Heterocycloalkyl, C ６－１２ Aryl, or C ５－１０ forming a heteroaryl; and L is C １－６ The method comprises contacting a compound of formula (I) with a compound of formula (I) wherein the compound is an alkylene.

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