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

Abstract

This invention provides compounds for treating brain disorders and methods for using these compounds. [Solution] N-substituted indoles and other heterocyclic compounds treat brain disorders.

Description

[Technical Field]

[0001] Cross-reference of related applications This application claims priority to U.S. Provisional Patent Application No. 62 / 811,206, filed on 27 February 2019, and U.S. Provisional Patent Application No. 62 / 958,220, filed on 7 January 2020, both of which are incorporated herein by reference for all purposes. [Background technology]

[0002] Background of the present invention Ketamine, N,N-dimethyltryptamine (DMT), and other psychoplastogens have potential as neurotherapies due to their ability to promote neuronal proliferation. Several important features of psychoplastogenic pharmacohores are disclosed herein. isoDMT psychoplastogens, which are easier to synthesize, have improved physiological and chemical properties, and have reduced hallucinogenic potential compared to their DMT counterparts, are also disclosed herein.

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

[0004] Compounds known as psychoplastogens promote neuron growth through mechanisms involved in the activation of AMPA receptors, tropomyosin receptor kinase B (TrkB), and mammalian target of rapamycin (mTOR). In addition to ketamine, the tropane alkaloid scopolamine and GLYX-13 (i.e., rapastinel) have demonstrated psychoplastogenic properties, suggesting that this group of compounds may have potential for treating various neuropsychiatric disorders. Since pyramidal neurons in the PFC exhibit top-down control across brain regions that regulate motivation, fear, and reward, these results provide an explanation for the antidepressant, anxiolytic, and anti-addictive effects of hallucinogenic compounds in outpatient settings.

[0005] The general pharmacophore of hallucinogenic compounds is thought to be N,N-dimethyltryptamine (DMT, 1) (Figure 1). DMT has been shown to produce antidepressant and anxiolytic behavioral effects in rodents, and a DMT-containing herbal infusion has demonstrated clinical efficacy against treatment-resistant depression. Therefore, DMT was used as a starting point for identifying the novel psychoplastogenic compounds described herein.

[0006] Thus, there is a need for new therapeutic agents for treating major depressive disorder and neuropsychiatric disorders. The present invention satisfies this need and other needs. SUMMARY OF THE INVENTION

[0007] In one embodiment, the present invention provides a compound of Formula I:

Chemical formula

[0008] In other embodiments, the present invention relates to the following formula II: [ka] {In the formula, X is CR 3 And; R 1a and R 1b These are, independently, hydrogen and C 1-6 Alkyl, C 3-8 Cycloalkyl, or C 4-14 It is alkyl-cycloalkyl; or, R 1a and R 1b They are combined with the atoms to which they are attached and C 3-12 Forms heterocycloalkyl groups; R 2 , R 3 , R 4 , R 5 , R 6 and R 7 These are, independently, hydrogen and C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkynyl, halogen, C 1-6 Haloalkyl, C 1-6 Alkylamine, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -OR 8a -NO2, -CN, -C(O)R 8b , -C(O)OR 8b -OC(O)R 8b , -OC(O)OR 8b , -N(R 8b R8c ), -N(R 8b )C(O)R 8c ,-C(O)N(R 8b R 8c ), -N(R 8b )C(O)OR 8c ,-OC(O)N(R 8b R 8c ), -N(R 8b )C(O)N(R 8c R 8d ), -C(O)C(O)N(R 8b R 8c ), -S(O2)R 8b -S(O)2N(R 8b R 8c ), C 3-8 Cycloalkyl, C 3-14 Alkyl-cycloalkyl, C 4-10 Heterocycloalkyl, C 4-16 Alkyl-heterocycloalkyl, C 6-12 Ariel, C 7-18 Alkyl-aryl, C 5-10 Heteroaryl, or C 4-16 It is an alkyl-heteroaryl; R 8a C 3-8 Cycloalkyl, C 3-14 Alkyl-cycloalkyl, C 4-10 Heterocycloalkyl, C 4-16 Alkyl-heterocycloalkyl, C 6-12 Ariel, C 7-18 Alkyl-aryl, C 5-10 Heteroaryl, or C 4-16 It is an alkyl-heteroaryl; R 8b , R 8c , and R 8d Each of these is independently H or C 1-6 Is it alkyl; or, R 1a or R 1b One of them is R 2 Combined with C 5-12 Forms a heterocycloalkyl group; or, R 2 and R 3 These are combined with the atoms to which they are attached, resulting in C 4-8 Cycloalkyl, C4-10 Heterocycloalkyl, or C 6-12 To form an aryl group; or, R 4 and R 5 , R 5 and R 6 , or R 6 and R 7 These are combined with the atoms to which they are attached, resulting in C 4-6 Cycloalkyl, C 4-6 Heterocycloalkyl, C 6-12 Aryl, or C 5-10 Forms a heteroaryl group; and L is C 1-6 A compound of alkylene, or a pharmaceutically acceptable salt or isomer thereof, where 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 At least one of them is not hydrogen, and the compound is as follows: [ka] It is the result of excluding R; here, 1a and R 1b If 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 them is not hydrogen; here, R 1c is hydrogen, and R 5 is Br, Cl, F, -NH2, -NO2, or C 1-3 When it is an alkoxy, R 2 , R 3 , R 4 , R 6 , or R 7 At least one of them is not hydrogen; and here, R 1c is hydrogen, R 5When F, R 2 , R 3 , R 4 , R 6 , or R 7 At least one of them is not hydrogen, and R 6 The present invention provides compounds that are not F, or pharmaceutically acceptable salts or isomers thereof.

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

[0010] In another embodiment, the present invention provides a method for enhancing neuronal plasticity, wherein a nerve cell is subjected to a sufficient amount of the following formula I: [ka] {In the formula, X is N or CR} 3 And; R 1a , R 1b , and R 1c These are, independently, hydrogen and C. 1-6 Alkyl, C 3-8 Cycloalkyl, or C 4-14 It is alkyl-cycloalkyl; or, R 1a , R 1b , and R 1c Two of them are combined with the atom to which they are attached to C 3-12 Forms heterocycloalkyl groups; R 2 , R 3 , R 4 , R 5 , R 6 and R 7 These are, independently, hydrogen and C. 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkynyl, halogen, C 1-6 Haloalkyl, C 1-6 Alkylamine, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -OR 8a -NO2, -CN, -C(O)R 8b , -C(O)OR8b -OC(O)R 8b , -OC(O)OR 8b , -N(R 8b R 8c ), -N(R 8b )C(O)R 8c ,-C(O)N(R 8b R 8c ), -N(R 8b )C(O)OR 8c ,-OC(O)N(R 8b R 8c ), -N(R 8b )C(O)N(R 8c R 8d ), -C(O)C(O)N(R 8b R 8c ), -S(O2)R 8b -S(O)2N(R 8b R 8c ), C 3-8 Cycloalkyl, C 3-14 Alkyl-cycloalkyl, C 4-10 Heterocycloalkyl, C 4-16 Alkyl-heterocycloalkyl, C 6-12 Ariel, C 7-18 Alkyl-aryl, C 5-10 Heteroaryl, or C 4-16 It is an alkyl-heteroaryl; R 8a C 3-8 Cycloalkyl, C 3-14 Alkyl-cycloalkyl, C 4-10 Heterocycloalkyl, C 4-16 Alkyl-heterocycloalkyl, C 6-12 Ariel, C 7-18 Alkyl-aryl, C 5-10 Heteroaryl, or C 4-16 It is an alkyl-heteroaryl; R 8b , R 8c and R 8d Each of these is 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 5-12Forms a heterocycloalkyl group; or, R 2 and R 3 These are combined with the atoms to which they are attached, resulting in C 4-8 Cycloalkyl, C 4-10 Heterocycloalkyl, or C 6-12 To form an aryl group; or, R 4 and R 5 , R 5 and R 6 , or R 6 and R 7 These are combined with the atoms to which they are attached, resulting in C 3-6 Cycloalkyl, C 3-6 Heterocycloalkyl, C 6-12 Aryl, or C 5-10 Forms a heteroaryl group; and L is C 1-6 The present invention provides a method comprising contacting a compound or pharmaceutically acceptable salt thereof that is an alkylene.

[0011] In another embodiment, the present invention relates to a method for treating brain damage, wherein a therapeutically effective amount of the following formula I is given to a subject in need: [ka] {In the formula, X is N or CR} 3 And; R 1a , R 1b , and R 1c These are, independently, hydrogen and C. 1-6 Alkyl, C 3-8 Cycloalkyl, or C 4-14 It is alkyl-cycloalkyl; or, R 1a , R 1b , and R 1c Two of them are combined with the atom to which they are attached to C 3-12 Forms heterocycloalkyl groups; R 2 , R 3 , R 4 , R 5 , R 6 and R 7 These are, independently, hydrogen and C. 1-6 Alkyl, C2-6 Alkenil, C 2-6 Alkynyl, halogen, C 1-6 Haloalkyl, C 1-6 Alkylamine, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -OR 8a -NO2, -CN, -C(O)R 8b , -C(O)OR 8b -OC(O)R 8b , -OC(O)OR 8b , -N(R 8b R 8c ), -N(R 8b )C(O)R 8c ,-C(O)N(R 8b R 8c ), -N(R 8b )C(O)OR 8c ,-OC(O)N(R 8b R 8c ), -N(R 8b )C(O)N(R 8c R 8d ), -C(O)C(O)N(R 8b R 8c ), -S(O2)R 8b -S(O)2N(R 8b R 8c ), C 3-8 Cycloalkyl, C 3-14 Alkyl-cycloalkyl, C 4-10 Heterocycloalkyl, C 4-16 Alkyl-heterocycloalkyl, C 6-12 Ariel, C 7-18 Alkyl-aryl, C 5-10 Heteroaryl, or C 4-16 It is an alkyl-heteroaryl; R 8a C 3-8 Cycloalkyl, C 3-14 Alkyl-cycloalkyl, C 4-10 Heterocycloalkyl, C 4-16 Alkyl-heterocycloalkyl, C 6-12 Ariel, C 7-18 Alkyl-aryl, C 5-10 Heteroaryl, or C 4-16 It is an alkyl-heteroaryl; R8b , R 8c and R 8d Each of these is 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 Forms a heterocycloalkyl group; or, R 2 and R 3 These are combined with the atoms to which they are attached, resulting in C 4-8 Cycloalkyl, C 4-10 Heterocycloalkyl, or C 6-12 To form an aryl group; or, R 4 and R 5 , R 5 and R 6 , or R 6 and R 7 These are combined with the atoms to which they are attached, resulting in C 3-6 Cycloalkyl, C 3-6 Heterocycloalkyl, C 6-12 Aryl, or C 5-10 Forms a heteroaryl group; and L is C 1-6 The present invention provides a method for treating brain damage by administering a compound that is alkylene.

[0012] In another embodiment, the present invention relates to a method for enhancing at least one of the translation, transcription, or secretion of a neurotrophic factor, wherein a neuron is subjected to a sufficient amount of the following formula I: [ka] {In the formula, X is N or CR} 3 And; R 1a , R 1b , and R 1c These are, independently, hydrogen and C. 1-6 Alkyl, C 3-8 Cycloalkyl, or C 4-14 It is alkyl-cycloalkyl; or, R 1a , R 1b, and R 1c Two of them are combined with the atom to which they are attached to C 3-12 Forms heterocycloalkyl groups; R 2 , R 3 , R 4 , R 5 , R 6 and R 7 These are, independently, hydrogen and C. 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkynyl, halogen, C 1-6 Haloalkyl, C 1-6 Alkylamine, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -OR 8a -NO2, -CN, -C(O)R 8b , -C(O)OR 8b -OC(O)R 8b , -OC(O)OR 8b , -N(R 8b R 8c ), -N(R 8b )C(O)R 8c ,-C(O)N(R 8b R 8c ), -N(R 8b )C(O)OR 8c ,-OC(O)N(R 8b R 8c ), -N(R 8b )C(O)N(R 8c R 8d ), -C(O)C(O)N(R 8b R 8c ), -S(O2)R 8b -S(O)2N(R 8b R 8c ), C 3-8 Cycloalkyl, C 3-14 Alkyl-cycloalkyl, C 4-10 Heterocycloalkyl, C 4-16 Alkyl-heterocycloalkyl, C 6-12 Ariel, C 7-18 Alkyl-aryl, C 5-10 Heteroaryl, or C 4-16 It is an alkyl-heteroaryl; R 8a C3-8 Cycloalkyl, C 3-14 Alkyl-cycloalkyl, C 4-10 Heterocycloalkyl, C 4-16 Alkyl-heterocycloalkyl, C 6-12 Ariel, C 7-18 Alkyl-aryl, C 5-10 Heteroaryl, or C 4-16 It is an alkyl-heteroaryl; R 8b , R 8c and R 8d Each of these is 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 Forms a heterocycloalkyl group; or, R 2 and R 3 These are combined with the atoms to which they are attached, resulting in C 4-8 Cycloalkyl, C 4-10 Heterocycloalkyl, or C 6-12 To form an aryl group; or, R 4 and R 5 , R 5 and R 6 , or R 6 and R 7 These are combined with the atoms to which they are attached, resulting in C 3-6 Cycloalkyl, C 3-6 Heterocycloalkyl, C 6-12 Aryl, or C 5-10 Forms a heteroaryl group; and L is C 1-6 The present invention provides a method that involves contacting a compound that is an alkylene with another compound. [Brief explanation of the drawing]

[0013] [Figure 1]Figures 1A and 1B show the structures of compounds containing DMT pharmacophores. Figure 1A shows the DMT structures (highlighted in black) that serve as core scaffolds for several known psychoplastogenic compounds. Figure 1B shows the only structural difference between DMT(1) and isoDMT(2), namely the rearrangement of the C1 and C3 atoms of indole. 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] [Figure 2] Figures 2A, 2B, and 2C show that the tryptamine derivative indole NH is not required to promote dendritic formation. Figure 2A shows representative images of central neurons (DIV6) treated with the compound. Figure 2B shows a Sholl analysis demonstrating that 1-Me-DMT(27) and isoDMT(2) enhance the complexity of dendritic spread to a degree comparable to DMT(1) (n=46-79 neurons). Figure 2C shows the maximum number of intersections (Nmax) of the Sholl plots in B. Data are expressed as mean ± SEM. After one-way ANOVA with Dunnett's post-hoc test (F=9.702; DFn=4; DFd=304; p-value < 0.0001) compared to solvent control, *p<0.05, **p<0.01, ***p<0.001, ****p<0.0001. VEH = Vehicle, KET = Ketamine. Scale bar = 20 μm.

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

[0016] [Figure 4] Figures 4A to 4C show the establishment of essential psychoplastogen pharmacophores. Figure 4A shows the chemical structure of a non-basic analog of isoDMT2, and Figures 4B and 4C show the maximum number of intersections (Nmax) of the Scholl plot for central neurons treated with the compound (n=46 to 85 neurons). The effects of nitrogen basicity and modification of the aromatic ring were evaluated in Figures 4B and 4C, respectively. Data are expressed as mean ± SEM. When compared with solvent controls after one-way ANOVA with Dunnett's post-hoc test (for B: F=19.03; DFn=4, DFd=273; p<0.0001; for C: F=6.933; DFn=8, DFd=599; p<0.0001), *p<0.05, **p<0.01, ***p<0.001, ****p<0.0001. VEH = vehicle, KET = ketamine.

[0017] [Figure 5]Figure 5 shows the effect of indole substitution on the ability of isoDMT to promote neuronal proliferation. It shows the maximum number of intersections (Nmax) in the Sholl plot of central neurons treated with the compound (n=39-93 neurons). Data are expressed as mean ± SEM. When compared to the solvent control after one-way ANOVA with Dunnett's post-hoc test (R=OMe: F=13.85; DFn=5, DFd=493; p<0.0001; R=OBn: F=15.44; DFn=5, DFd=372; p<0.0001; R=F: F=13.24; DFn=5, DFd=506; p<0.0001), *p<0.05, **p<0.01, ***p<0.001, ****p<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. The maximum number of intersections (Nmax) of Scholl plots for central neurons treated with the compound at concentrations ranging from 10 μM to 10 pM (n=66 to 123 neurons). Data are expressed as mean ± SEM. After one-way ANOVA with Dunnett's post-hoc test (F=15.40; DFn=24; DFd=2,276; p-value < 0.0001), compared to the solvent control, the results were *p<0.05, **p<0.01, ***p<0.001, ****p<0.0001. V=vehicle, K=ketamine.

[0019] [Figure 7]Figure 7 shows that the psychoplastic effect of isoDMT is blocked by a 5-HT2A antagonist. The maximum number of crossovers (Nmax) in Scholl plots of central neurons treated with the compound in the presence (+) or absence (-) of the 5-HT2A antagonist ketanserine (n=45-63 neurons). Data are expressed as mean ± SEM. After comparing with a solvent control using a one-way ANOVA with Dunnett's post-hoc test (F=13.92; DFn=8; DFd=461; p<0.0001), p<0.0001 was observed. V=vehicle, K=ketamine, KTSN=ketanserine.

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

[0021] [Figure 9] Figure 9 shows the ability of the compound of the present invention to reduce the head spasm behavioral response in a head spasm response assay.

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

[0023] [Figure 11] Figure 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]Figure 12A shows the dose-response profiles for 5HT and 6-MeO-DMT, and Figure 12B shows the dose-response of lislide to the 5HT2A sensor assay in antagonist mode.

[0025] [Figure 13] Figure 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 illustrate the antidepressant properties of the compounds of the present invention in forced swimming assays under both preliminary (Figure 14A) and acute (Figure 14B) compound administration. [Modes for carrying out the invention]

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

[0028] Compounds that can modify neural circuits that control motivation, anxiety, and drug-seeking behavior have the potential to treat depression, post-traumatic stress disorder (PTSD), and substance abuse disorder (SUD). Furthermore, such psychoplastogens may produce sustained therapeutic effects, for example, due to their potential to treat potential pathological changes in the neural network. Hallucinogenic compounds were identified in this respect, for example, by promoting structural and functional neuroplasticity in major circuits, inducing therapeutic responses in multiple neuropsychiatric disorders, and producing beneficial effects that persist for months after monotherapy.

[0029] In some cases, hallucinogenic 5-HT 2AAgonists (e.g., DMT, LSD, DOI, etc.) are potential therapeutic agents 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 settings. 5-HT 2A Antagonists include, for example, 5-HT drugs such as DMT, LSD, and DOI. 2A It inhibits the neurite formation and spinogenesis effects of hallucinogenic compounds with agonist activity, and 5-HT 2A We demonstrated a correlation between function and the promotion of neural plasticity (Ly et al., 2018; Dunlap et al., 2020).

[0030] Non-hallucinogenic psychoplastogens are provided herein. Furthermore, some isoDMT compounds exhibit differences in serotonin receptor activity (e.g., 5HT) compared to their DMT counterparts. 2A ) has comparable affinity. In some embodiments, the isoDMT analogs described herein have improved physiological and chemical properties as a result of the loss of hydrogen bond donors that reduce the total polar surface area, and improve the central nervous system multiple parameter optimization (MPO) score (Figure 1). In some embodiments, hallucinogenic 5-HT 2A Non-hallucinogenic compounds that demonstrate similar therapeutic efficacy as agonists are described herein. In some embodiments, the non-hallucinogenic compounds described herein are hallucinogenic 5-HT for neurological disorders. 2A It offers better therapeutic efficacy compared to agonists. II. Definition

[0031] Unless otherwise specified, all technical and scientific terms used herein have the same meaning as those generally understood by those skilled in the art to which the present invention belongs. In addition, any method or material similar to or equivalent to those described herein may be used in carrying out the present invention. For the purposes of the present invention, the following terms are defined:

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

[0033] Abbreviations used: DMT, N,N-dimethyltryptamine; PFC, anterior frontal cortex; 5-HT 2A Serotonin 2A; MPO, Multiple Parameter Optimization; LSD, Lysergic Acid Diethylamide; TPSA, Total Polarity Surface Area; MAP2, Microtubule-Associated Protein 2; N max , maximum number of intersections; 5-HT2B, serotonin 2B; DIV, days in vitro; VEH, vehicle; KET, ketamine; SEM, standard error of mean; ANOVA, analysis of variance; DOM, 2,5-dimethoxy-4-methylamphetamine; OMe, methoxy; OBn, benzyloxy; F, fluoro; μM, micromoles; nM, nanomoles; pM, picomoles; V, vehicle; K, ketamine; ATR, attenuated total internal reflection; FT-IR, Fourier transform red External spectroscopy; UHPLC, ultra-high performance liquid chromatography; LRMS, low-resolution mass spectrometry; IACUC, Committee on Laboratory Animals; AAALAC, International Association of Accredited 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, cephalic spasm response.

[0034] "Alkyl" refers to a linear or branched, saturated, or aliphatic group having the indicated number of carbon atoms. 1-2 , C 1-3 , C 1-4 , C 1-5 , C 1-6 , C 1-7 , C 1-8 , C 1-9, C 1-10 , C 2-3 , C 2-4 , C 2-5 , C 2-6 , C 3-4 , C 3-5 , C 3-6 , C 4-5 , C 4-6 and C 5-6 It can contain any number of carbon atoms, such as C. 1-6 Alkyls include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, and hexyl. Alkyls also include, but are not limited to, heptyl, octyl, nonyl, and decyl, and can also refer to alkyl groups having up to 20 carbon atoms. Alkyls may be substituted or unsubstituted.

[0035] "Alkylene" refers to a linear or branched, saturated, aliphatic group, i.e., a divalent hydrocarbon group, having the indicated number of carbon atoms and linked to at least two other groups. The two parts linked to the alkylene can be linked to the same or different atoms of the alkylene group. For example, a linear alkylene is -(CH2) where n is 1, 2, 3, 4, 5, or 6. n It can be a divalent group. Typical alkylene groups include, but are not limited to, methylene, ethylene, propylene, isopropylene, butylene, isobutylene, sec-butylene, pentylene, and hexylene. The alkylene group may be substituted or unsubstituted.

[0036] "Alkenyl" refers to a straight-chain or branched hydrocarbon having at least two carbon atoms and at least one double bond. Alkenyl is C2, C 2-3 , C 2-4 , C 2-5 , C 2-6 , C 2-7 , C 2-8 , C 2-9 , C 2-10 , C3, C 3-4 , C 3-5 , C 3-6 , C4, C4-5 , C 4-6 , C5, C 5-6 Alkenyl groups may contain any number of carbon atoms, such as C6. 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-hexadienyl. 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 C2, C 2-3 , C 2-4 , C 2-5 , C 2-6 , C 2-7 , C 2-8 , C 2-9 , C 2-10 , C3, C 3-4 , C 3-5 , C 3-6 , C4, C 4-5 , C 4-6 , C5, C 5-6 , and C6, and may contain any number of carbon atoms. Examples of alkynyl groups include, but are not limited to, acetylenyl, propynyl, 1-butynyl, 2-butynyl, butadiinyl, 1-pentynyl, 2-pentynyl, isopentinyl, 1,3-pentadinyl, 1,4-pentadinyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 1,3-hexadinyl, 1,4-hexadinyl, 1,5-hexadinyl, 2,4-hexadinyl, or 1,3,5-hexatriinyl. The alkynyl group may be substituted or unsubstituted.

[0038] "Cycloalkyl" refers to a saturated or partially unsaturated, monocyclic, fused bicyclic, or bridging polycyclic ring assembly containing 3 to 12 ring atoms, or the number of atoms indicated. Cycloalkyl is C 3-6 , C 4-6 , C 5-6 , C 3-8 , C 4-8 , C 5-8 , C 6-8 , C 3-9 , C 3-10 , C 3-11 , and C 3-12 These can contain any number of carbon atoms. Saturated monocyclic cycloalkyl rings include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cyclooctyl. Bicyclic compounds include spirocyclic compounds, condensed bicyclic compounds, and cross-linked bicyclic compounds. Saturated bicyclic and polycyclic cycloalkyl rings include, for example, norbornane, [2.2.2]bicyclooctane, decahydronaphthalene, and adamantane. Cycloalkyl groups can also be partially unsaturated, having one or more double or triple bonds within the ring. Representative partially unsaturated cycloalkyl groups include, but are not limited to, cyclobutene, cyclopentene, cyclohexene, cyclohexadiene (1,3- and 1,4-isomers), cycloheptene, cycloheptadiene, cyclooctene, cyclooctadiene (1,3-, 1,4- and 1,5-isomers), norbornene, and norbornadiene. Cycloalkyl saturated monocyclic C 3-8 When the group is cycloalkyl, exemplary groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. 3-6 When referring to cycloalkyl groups, exemplary groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Cycloalkyl groups may be substituted or unsubstituted.

[0039] "Alkyl-cycloalkyl" refers to a group having an alkyl component and a cycloalkyl component, where the alkyl component links to the cycloalkyl component at its bonding site. The alkyl component is as defined above, except that it is at least divalent, i.e., alkylene, in order to link to the cycloalkyl component and the bonding site. In some cases, the alkyl component may be absent. The alkyl component is C 1-6 , C 1-2 , C 1-3 , C 1-4 , C 1-5 , C 2-3 , C 2-4 , C 2-5 , C 2-6 , C 3-4 , C 3-5 , C 3-6 , C 4-5 , C 4-6 and C 5-6 These may contain any number of carbon atoms. Cycloalkyl components are as defined herein. Exemplary alkyl-cycloalkyl groups include, but are not limited to, methyl-cyclopropyl, methyl-cyclobutyl, methyl-cyclopentyl, and methyl-cyclohexyl.

[0040] A "heterocycloalkyl" refers to a cycloalkyl group as defined above, having 3 to 12 ring members and 1 to 4 N, O, and S heteroatoms. Heterocycloalkyls include bicyclic compounds containing heteroatoms. Bicyclic compounds include spirocyclic compounds, condensed bicyclic compounds, and bridged bicyclic compounds. The heteroatoms may be oxidized, for example, -S(O)- and -S(O)2-, but are not limited to these. A heterocycloalkyl group may contain any number of ring members, such as 3 to 6, 4 to 6, 5 to 6, 3 to 8, 4 to 8, 5 to 8, 6 to 8, 3 to 9, 3 to 10, 3 to 11, or 3 to 12. Any suitable number of heteroatoms, such as 1, 2, 3, or 4, or 1 to 2, 1 to 3, 1 to 4, 2 to 3, 2 to 4, or 3 to 4, may be included in a heterocycloalkyl group. 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, thiran, thiethane, thiolane (tetrahydrothiophene), thian (tetrahydrothiopyran), oxazolidine, isoxazolidine, thiazolidine, isothiazolidine, dioxolane, dithiolane, morpholine, thiomorpholine, dioxane, or dithiane. Heterocycloalkyl groups may condense to aromatic or non-aromatic ring systems to form members containing, but not limited to, indoline. Heterocycloalkyl groups may be unsubstituted or substituted. For example, a heterocycloalkyl group may contain C 1-6 It may be substituted with alkyl or oxo (=O), etc.

[0041] "Alkyl-heterocycloalkyl" refers to a group having an alkyl component and a heterocycloalkyl component, where the alkyl component links to the heterocycloalkyl component at its bonding site. The alkyl component is as defined above, except that it is at least divalent, i.e., alkylene, in order to link to the heterocycloalkyl component and the bonding site. The alkyl component is C 0-6 , C1-2 , 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 It may contain any number of carbon atoms, such as those mentioned above. In some cases, it may lack an alkyl component. The heterocycloalkyl component is as defined above. The alkyl-heterocycloalkyl group may be substituted or unsubstituted.

[0042] "Halogens" refer to fluorine, chlorine, bromine, and iodine.

[0043] A "haloalkyl" refers to an alkyl group, as defined above, in which some or all of the hydrogen atoms are replaced by halogen atoms. Like alkyl groups, haloalkyl groups can have any preferred number of carbon atoms, such as C1-6. Examples of haloalkyl groups include trifluoromethyl and fluoromethyl. In some cases, the term "perfluoro" may be used to define a compound or radical in which all hydrogens are replaced by fluorine. For example, perfluoromethyl refers to 1,1,1-trifluoromethyl. Alkylamines

[0044] "Alkoxy" refers to an alkyl group having an oxygen atom linked to the alkyl group at the bonding site: alkyl-O-. Similar to alkyl groups, alkoxy groups may have any preferred number of carbon atoms, such as C1-6. Examples of alkoxy groups include methoxy, ethoxy, propoxy, iso-propoxy, butoxy, 2-butoxy, iso-butoxy, sec-butoxy, tert-butoxy, pentoxy, and hexoxy. Alkoxy groups may be further substituted with various substituents described herein. Alkoxy groups may be substituted or unsubstituted.

[0045] A "haloalkoxy" refers to an alkoxy group in which some or all of the hydrogen atoms are replaced by halogen atoms. Similar to alkyl groups, haloalkoxy groups can have any preferred number of carbon atoms, such as C1-C6. The alkoxy group can be substituted with one, two, three, or more halogens. When all hydrogens are replaced with halogens, such as fluorine, the compound is per-substituted, for example, perfluorinated. Examples of haloalkoxys include, but are not limited to, trifluoromethoxy, 2,2,2-trifluoroethoxy, and perfluoroethoxy.

[0046] "Amine" refers to a -N(R)2 group in which the R group can be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl. The R groups may be the same or different. The amino group can be primary (each R is hydrogen), secondary (one R is hydrogen), or tertiary (each R is not hydrogen).

[0047] "Alkylamine" means an alkyl group as defined herein, having one or more amino groups. The amino groups may be primary, secondary, or tertiary. Alkylamines may be further substituted with hydroxyl groups to form an amino-hydroxyl group. Useful alkylamines 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 to link the alkylamine to the bond site with the remainder of the compound, or to link at least two carbon atoms of the alkyl group together. Those skilled in the art will understand that other alkylamines may also be useful in the present invention.

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

[0049] "Alkyl-aryl" refers to a group having an alkyl component and an aryl component, where the alkyl component links to the aryl component at a bonding site. The alkyl component is as defined above, except that it is at least divalent, i.e., alkylene, in order to link to the aryl component and the bonding site. The alkyl component is C 0-6 , C 1-2 , C 1-3 , C 1-4 , C 1-5 , C 1-6 , C 2-3 , C 2-4 , C 2-5 , C 2-6 , C 3-4 , C 3-5 , C 3-6 , C 4-5 , C 4-6 and C 5-6 It may contain any number of carbon atoms, such as those mentioned above. The aryl component is as defined above. In some cases, the alkyl component may be absent. Examples of alkyl-aryl groups include, but are not limited to, benzyl and ethyl-benzene. The alkyl-aryl group may be substituted or unsubstituted.

[0050] A "heteroaryl" refers to a monocyclic, fused bicyclic, or tricyclic aromatic ring assembly containing 5 to 16 ring atoms, where 1 to 5 of the ring atoms are heteroatoms such as N, O, or S. A heteroaryl group may contain any number of ring atoms, such as 5 to 6, 3 to 8, 4 to 8, 5 to 8, 6 to 8, 3 to 9, 3 to 10, 3 to 11, or 3 to 12 ring members. Any appropriate number of heteroatoms, such as 1, 2, 3, 4, or 5, or 1 to 2, 1 to 3, 1 to 4, 1 to 5, 2 to 3, 2 to 4, 2 to 5, 3 to 4, or 3 to 5, may be contained in a heteroaryl group. A heteroaryl group may have 5 to 8 ring members and 1 to 4 heteroatoms, or 5 to 8 ring members and 1 to 3 heteroatoms, or 5 to 6 ring members and 1 to 4 heteroatoms, or 5 to 6 ring members and 1 to 3 heteroatoms. Heteroaryl groups may include 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 condense with aromatic ring systems such as phenyl rings to form members including, but not limited to, benzopyrrole, e.g., indole and isoindole, benzopyridine, e.g., quinoline and isoquinoline, benzopyrazine (quinoxaline), benzopyrimidine (quinazoline), benzopyridazine, e.g., phthalazine and cinnoline, benzothiophene, and benzofuran. Other heteroaryl groups include heteroaryl rings linked by bonds, such as bipyridine. 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 to the heteroaryl component at a bonding site. The alkyl component is as defined above, except that it is at least divalent, i.e., alkylene, in order to link to the heteroaryl component and the bonding site. The alkyl component is C 0-6 , C 1-2 , C 1-3 , C1-4 , C 1-5 , C 1-6 , C 2-3 , C 2-4 , C 2-5 , C 2-6 , C 3-4 , C 3-5 , C 3-6 , C 4-5 , C 4-6 and C 5-6 It may contain any number of carbon atoms, such as those mentioned above. In some cases, it may lack an alkyl component. The heteroaryl component is as defined herein. The alkyl-heteroaryl group may be substituted or unsubstituted.

[0052] "Salt" refers to the acidic or basic salt of a compound used in the method of the present invention. Exemplary examples of pharmaceutically acceptable salts include salts of mineral acids (such as hydrochloric acid, hydrobromic acid, and phosphoric acid), salts of organic acids (such as fumaric acid, acetic acid, propionic acid, glutamic acid, and citric acid), and salts of quaternary ammonium compounds (such as methyl iodide and ethyl iodide). Pharmaceutically acceptable salts are understood to be non-toxic. Further information on preferred 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 form of the compound may be regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner. The original compound may have certain physical properties, such as solubility in polar solvents, that differ from the various salt forms, but otherwise, its salt is equivalent to the original compound for the purposes of this invention.

[0054] "Medicinally acceptable salts" refer to compounds in salt form that are suitable for administration to a subject. Representative medicinally 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, glucuronic acid, glutamic acid, hippuric acid, hydrobromic acid, hydrochloric acid, isethionic acid, lactic acid, lactobionic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, mucoic 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] "Pharmacovigilant excipients" refer to substances that assist in the administration of an active substance to a target and in the absorption of the active substance by a control. Useful pharmaceutical excipients in the present invention include, but are not limited to, binders, bulking agents, disintegrants, lubricants, coating agents, sweeteners, flavoring agents, and colorants. Those skilled in the art will recognize that other pharmaceutical excipients are useful in the present invention.

[0056] "Composition" means a product containing a specified component in a specified amount, and any product directly or indirectly resulting from a combination of specified components in a specified amount. "Pharmacovigilant" means that the carrier, diluent, or excipient must be compatible with the other components of the composition.

[0057] An "isomer" refers to a compound that, despite having the same chemical formula, possesses different interatomic connections within the molecule, resulting in different chemical structures. Examples of isomers include structural isomers and stereoisomers. Examples of structural isomers, though not limited to these, include tautomers and positional isomers. Examples of stereoisomers, though not limited to these, include diastereomers and enantiomers.

[0058] "Administration" refers to oral administration, suppository administration, topical contact, parenteral administration, intravenous, intraperitoneal, intramuscular, intrafocal, intranasal or subcutaneous administration, subarachnoid administration, or implantation of a continuous release device, such as a mini-osmosis pump.

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

[0060] "Therapeutic effective dose," "therapeutic sufficient dose," or "effective or sufficient dose" refers to the amount that produces a therapeutic effect when administered. The appropriate dose depends on the purpose of the treatment and can be determined by those skilled 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 therapeutic effective dose is often lower than the conventional therapeutic effective dose for unsensitized cells.

[0061] "Neuroplasticity" refers to the brain's ability to continuously change its structure and / or function throughout its lifespan. Examples of brain changes, though not limited to these, include the ability to adapt to or respond to internal and / or external stimuli such as injury, as well as the ability to generate new neurites, dendritic spines, and synapses.

[0062] "Brain disorder" refers to neurological disorders that affect the structure and function of the brain. Brain disorders are not limited to these, but include Alzheimer's disease, Parkinson's disease, mental 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 plan such that the subject is simultaneously exposed to both agents. For example, the compounds of the present invention can be used in combination with other pharmaceutically active compounds. The compounds of the present invention may be administered simultaneously or sequentially (as single preparations or separate preparations) with other drug therapies. Generally, combination therapy envisions the administration of two or more drugs during a single cycle or course of treatment.

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

[0065] "To regulate" or "to regulate" or "regulation" refers to an increase or decrease in the amount, characteristics, or effect of a particular activity, function, or molecule. Not as an illustrative means or limitation, but as an example of a G protein-binding receptor (e.g., 5HT). 2A Agonists, partial agonists, antagonists, and allosteric modulators (e.g., positive allosteric modulators) of the receptor are modulators of the receptor.

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

[0067] An "agonist" refers to a modulator that binds to a receptor or enzyme and activates the receptor, thereby producing a biological response. For example, "5HT" is used. 2A The "agonist" is 5HT with a concentration of approximately 100 μM or less. 2A Regarding activity EC 50It can be used to refer to compounds exhibiting the following characteristics. In 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 in the maximum response induced by the agonist at the receptor. A “partial agonist” refers to a modulator that binds to and activates a given receptor, but has a partial efficacy at the receptor that is weaker than the maximum response induced by a full agonist.

[0068] A "positive allosteric modulator" refers to a modulator that binds to a site different from the orthosteric binding site, thereby enhancing or amplifying the effect of an agonist.

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

[0070] An "antagonist" or "neutralizing antagonist" refers to a modulator that binds to a receptor or enzyme and inhibits the biological response. An antagonist is completely inactive in the absence of an agonist or inverse agonist, but can inhibit the activity of either, thereby preventing an alteration of 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 are 5-HT 2A It acts as a modulator and promotes neural plasticity (e.g., plasticity of cortical structures).

[0072] In some embodiments, the present invention relates to the following formula I: [ka] {In the formula, X is N or CR} 3 And; R 1a , R1b , and R 1c These are, independently, hydrogen and C. 1-6 Alkyl, C 3-8 Cycloalkyl, or C 4-14 It is alkyl-cycloalkyl; or, R 1a , R 1b , and R 1c Two of them are combined with the atom to which they are attached to C 3-12 Forms heterocycloalkyl groups; R 2 , R 3 , R 4 , R 5 , R 6 and R 7 These are, independently, hydrogen and C. 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkynyl, halogen, C 1-6 Haloalkyl, C 1-6 Alkylamine, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -OR 8a -NO2, -CN, -C(O)R 8b , -C(O)OR 8b -OC(O)R 8b , -OC(O)OR 8b , -N(R 8b R 8c ), -N(R 8b )C(O)R 8c ,-C(O)N(R 8b R 8c ), -N(R 8b )C(O)OR 8c ,-OC(O)N(R 8b R 8c ), -N(R 8b )C(O)N(R 8c R 8d ), -C(O)C(O)N(R 8b R 8c ), -S(O2)R 8b -S(O)2N(R 8b R 8c ), C 3-8 Cycloalkyl, C 3-14 Alkyl-cycloalkyl, C 4-10 Heterocycloalkyl, C4-16 Alkyl-heterocycloalkyl, C 6-12 Ariel, C 7-18 Alkyl-aryl, C 5-10 Heteroaryl, or C 4-16 It is an alkyl-heteroaryl; R 8a C 3-8 Cycloalkyl, C 3-14 Alkyl-cycloalkyl, C 4-10 Heterocycloalkyl, C 4-16 Alkyl-heterocycloalkyl, C 6-12 Ariel, C 7-18 Alkyl-aryl, C 5-10 Heteroaryl, or C 4-16 It is an alkyl-heteroaryl; R 8b , R 8c and R 8d Each of these is independently H or C 1-6 Is it 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 Forms a heterocycloalkyl group; or, R 2 and R 3 These are combined with the atoms to which they are attached, resulting in C 6-12 Can an aryl group be formed? Or, R 4 and R 5 , R 5 and R 6 , or R 6 and R 7 These are combined with the atoms to which they are attached, resulting in C 3-6 Cycloalkyl or C 3-6 It can form heterocycloalkyl groups; and L is C 1-6 The present invention provides compounds of alkylene, or salts and isomers thereof.

[0073] In some embodiments, the present invention relates to the following formula I: [ka] {In the formula, X is N or CR} 3 And; R 1a , R 1b , and R 1c These are, independently, hydrogen and C 1-6 Alkyl, C 3-8 Cycloalkyl, or C 4-14 It is alkyl-cycloalkyl; or, R 1a , R 1b , and R 1c Two of them are combined with the atom to which they are attached to C 3-12 Forms heterocycloalkyl groups; R 2 , R 3 , R 4 , R 5 , R 6 and R 7 These are, independently, hydrogen and C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkynyl, halogen, C 1-6 Haloalkyl, C 1-6 Alkylamine, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -OR 8a -NO2, -CN, -C(O)R 8b , -C(O)OR 8b -OC(O)R 8b , -OC(O)OR 8b , -N(R 8b R 8c ), -N(R 8b )C(O)R 8c ,-C(O)N(R 8b R 8c ), -N(R 8b )C(O)OR 8c ,-OC(O)N(R 8b R 8c ), -N(R 8b )C(O)N(R 8c R 8d ), -C(O)C(O)N(R 8b R 8c), -S(O2)R 8b -S(O)2N(R 8b R 8c ), C 3-8 Cycloalkyl, C 3-14 Alkyl-cycloalkyl, C 4-10 Heterocycloalkyl, C 4-16 Alkyl-heterocycloalkyl, C 6-12 Ariel, C 7-18 Alkyl-aryl, C 5-10 Heteroaryl, or C 4-16 It is an alkyl-heteroaryl; R 8a C 3-8 Cycloalkyl, C 3-14 Alkyl-cycloalkyl, C 4-10 Heterocycloalkyl, C 4-16 Alkyl-heterocycloalkyl, C 6-12 Ariel, C 7-18 Alkyl-aryl, C 5-10 Heteroaryl, or C 4-16 It is an alkyl-heteroaryl; R 8b , R 8c , and R 8d Each of these is independently H or C 1-6 Is it 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 Forms a heterocycloalkyl group; or, R 2 and R 3 These are combined with the atoms to which they are attached, resulting in C 4-8 Cycloalkyl, C 4-10 Heterocycloalkyl, or C 6-12 To form an aryl group; or, R 4 and R 5 , R 5 and R 6 , or R 6 and R 7These are combined with the atoms to which they are attached, resulting in C 3-6 Cycloalkyl, C 3-6 Heterocycloalkyl, C 6-12 Aryl, or C 5-10 Forms a heteroaryl group; and L is C 1-6 A compound of alkylene, or a pharmaceutically acceptable salt or isomer thereof, where R 1a and R 1b Both are Me, and R 1c When is hydrogen and L is methylene, R 2 , R 3 , R 4 , R 5 , R 6 and R 7 At least one of them is not hydrogen, and the compound is as follows: [ka] It is the result of excluding R; here, 1a and R 1b If 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 them is not hydrogen; here, R 1c is hydrogen, and R 5 is Br, Cl, F, -NH2, -NO2, or C 1-3 When it is an alkoxy, R 2 , R 3 , R 4 , R 6 , or R 7 At least one of them is not hydrogen; here, R 1c is hydrogen, R 5 When F, R 2 , R 3 , R 4 , R 6 , or R 7 At least one of them is not hydrogen, and R 6is not F; and here, R 1a , R 1b and R 1c These are Me, L is methylene, and X is CR. 3 And R 2 , R 3 , R 4 , R 5 , R 6 and R 7 When is hydrogen, the compound is [ka] The present invention provides a compound, or a pharmaceutically acceptable salt or isomer thereof.

[0074] In some embodiments, the present invention relates to formula I: [ka] {In the formula, X is CR 3 And; R 1a and R 1b These are, independently, hydrogen and C 1-6 Alkyl, C 3-8 Cycloalkyl, or C 4-14 It is alkyl-cycloalkyl; R 1c C 1-6 Alkyl, C 3-8 Cycloalkyl, or C 4-14 It is alkyl-cycloalkyl; or, R 1a , R 1b , and R 1c Two of them are combined with the atom to which they are attached to C 3-12 Forms heterocycloalkyl groups; R 2 , R 3 , R 4 , R 5 , R 6 and R 7 These are, independently, hydrogen and C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkynyl, halogen, C 1-6 Haloalkyl, C 1-6 Alkylamine, C1-6 alkoxy, C 1-6 haloalkoxy, -OR 8a , -NO2, -CN, -C(O)R 8b , -C(O)OR 8b , -OC(O)R 8b , -OC(O)OR 8b , -N(R 8b R 8c , -N(R 8b )C(O)R 8c , -C(O)N(R 8b R 8c , -N(R 8b )C(O)OR 8c , -OC(O)N(R 8b R 8c , -N(R 8b )C(O)N(R 8c R 8d , -C(O)C(O)N(R 8b R 8c , -S(O2)R 8b , -S(O)2N(R 8b R 8c , C 3-8 cycloalkyl, C 3-14 alkyl-cycloalkyl, C 4-10 heterocycloalkyl, C 4-16 alkyl-heterocycloalkyl, C 6-12 aryl, C 7-18 alkyl-aryl, C 5-10 heteroaryl, or C 4-16 alkyl-heteroaryl; R 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 [[ID=9*]]alkyl; or, R 1a, R 1b , or R 1c One of them is R 2 Combined with C 5-12 Forms a heterocycloalkyl group; or, R 2 and R 3 These are combined with the atoms to which they are attached, resulting in C 4-8 Cycloalkyl, C 4-10 Heterocycloalkyl, or C 6-12 To form an aryl group; or, R 4 and R 5 , R 5 and R 6 , or R 6 and R 7 These are combined with the atoms to which they are attached, resulting in C 4-6 Cycloalkyl, C 4-6 Heterocycloalkyl, C 6-12 Aryl, or C 5-10 Forms a heteroaryl group; and L is C 1-6 A compound of alkylene, or a pharmaceutically acceptable salt or isomer thereof, where R 1a , R 1b , and R 1c These are Me, L is methylene, and X is CR. 3 And, R 2 , R 3 , R 4 , R 5 , R 6 and R 7 When is hydrogen, the compound is as follows: [ka] And, here, the compound is as follows: [ka] The present invention provides compounds, or pharmaceutically acceptable salts or isomers thereof, excluding the specified compound.

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

[0076] In some embodiments, the present invention provides a 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 alkylamine, C 1-6 alkoxy, C 1-6 haloalkoxy, -OR 8a , -NO2, -CN, -C(O)R 8b , -C(O)OR 8b , -OC(O)R 8b , -OC(O)OR 8b , -N(R 8b R 8c ), -N(R 8b )C(O)R 8c , -C(O)N(R 8b R 8c ), -N(R 8b )C(O)OR 8c , -OC(O)N(R 8b R 8c ), -N(R 8b )C(O)N(R 8c R 8d ), -C(O)C(O)N(R 8b R 8c ), -S(O2)R 8b , -S(O)2N(R 8b R 8c ), C 3-8 cycloalkyl, C<00oo996>alkyl-cycloalkyl, C 4-10 heterocycloalkyl, C 4-16 alkyl-heterocycloalkyl, C 6-12 aryl, C 7-18 alkyl-aryl, C5-10 Heteroaryl, or C 4-16 It is an alkyl-heteroaryl; R 8a C 3-8 Cycloalkyl, C 3-14 Alkyl-cycloalkyl, C 4-10 Heterocycloalkyl, C 4-16 Alkyl-heterocycloalkyl, C 6-12 Ariel, C 7-18 Alkyl-aryl, C 5-10 Heteroaryl, or C 4-16 It is an alkyl-heteroaryl; and R 8b , R 8c , and R 8d Each of these is independently H or C 1-6 We provide an alkyl or pharmaceutically acceptable salt thereof, where R 1a , R 1b and R 1c Each of these is Me, L is methylene, and R 2 , R 3 , R 4 , R 5 , R 6 and R 7 When is hydrogen, the compound is as follows: [ka] That is the case.

[0077] In some embodiments, the present invention provides compounds or pharmaceutically acceptable salts thereof, wherein the compound of formula I has the following structure: [ka] It holds.

[0078] In some embodiments, the present invention relates to a compound {wherein R 1a , R 1b , or R 1c Each is independent of C 1-6 Alkyl, C 3-8 Cycloalkyl, or C 4-14 It is alkyl-cycloalkyl; or, R1a , R 1b , and R 1c Two of them are combined with the atom to which they are attached to C 3-12 Forms heterocycloalkyl groups; R 2 , R 3 , R 4 , R 6 and R 7 These are, independently, hydrogen and C. 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkynyl, halogen, C 1-6 Haloalkyl, C 1-6 Alkylamine, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -OR 8a -NO2, -CN, -C(O)R 8b , -C(O)OR 8b -OC(O)R 8b , -OC(O)OR 8b , -N(R 8b R 8c ), -N(R 8b )C(O)R 8c ,-C(O)N(R 8b R 8c ), -N(R 8b )C(O)OR 8c ,-OC(O)N(R 8b R 8c ), -N(R 8b )C(O)N(R 8c R 8d ), -C(O)C(O)N(R 8b R 8c ), -S(O2)R 8b -S(O)2N(R 8b R 8c ), C 3-8 Cycloalkyl, C 3-14 Alkyl-cycloalkyl, C 4-10 Heterocycloalkyl, C 4-16 Alkyl-heterocycloalkyl, C 6-12 Ariel, C 7-18 Alkyl-aryl, C 5-10 Heteroaryl, or C 4-16 It is an alkyl-heteroaryl; R 5C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkynyl, halogen, C 1-6 Haloalkyl, C 1-6 Alkylamine, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -OR 8a -NO2, -CN, -C(O)R 8b , -C(O)OR 8b -OC(O)R 8b , -OC(O)OR 8b , -N(R 8b R 8c ), -N(R 8b )C(O)R 8c ,-C(O)N(R 8b R 8c ), -N(R 8b )C(O)OR 8c ,-OC(O)N(R 8b R 8c ), -N(R 8b )C(O)N(R 8c R 8d ), -C(O)C(O)N(R 8b R 8c ), -S(O2)R 8b -S(O)2N(R 8b R 8c ), C 3-8 Cycloalkyl, C 3-14 Alkyl-cycloalkyl, C 4-10 Heterocycloalkyl, C 4-16 Alkyl-heterocycloalkyl, C 6-12 Ariel, C 7-18 Alkyl-aryl, C 5-10 Heteroaryl, or C 4-16 It is an alkyl-heteroaryl; R 8a C 3-8 Cycloalkyl, C 3-14 Alkyl-cycloalkyl, C 4-10 Heterocycloalkyl, C 4-16 Alkyl-heterocycloalkyl, C 6-12 Ariel, C 7-18 Alkyl-aryl, C 5-10 Heteroaryl, or C 4-16It is an alkyl-heteroaryl; and R 8b , R 8c , and R 8d Each of these is 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 These are combined with the atoms to which they are attached, resulting in C 4-6 Cycloalkyl, C 4-6 Heterocycloalkyl, C 6-12 Aryl, or C 5-10 The present invention provides a heteroaryl compound or a pharmaceutically acceptable salt thereof.

[0079] In some embodiments, the present invention relates to a compound {wherein R 1a and R 1b Each of them independently consists of hydrogen or C 1-6 Alkyl; R 1c is C 1-6 Alkyl; R 2 and R 3 These are, independently, hydrogen and 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 These are, independently, hydrogen and C. 1-6 Alkyl, halogen, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, or -OR 8a And here, R 4 , R 5 , R 6 and R 7 At least one of them is not H; and R 8a is C 7-18 It is alkyl-aryl; or, R 5 and R 6These are combined with the atoms to which they are attached, resulting in C 4-6 The present invention provides a salt thereof that forms a heterocycloalkyl group or is pharmaceutically acceptable.

[0080] In some embodiments, the present invention relates to a compound {wherein X is CR}. 3 And; R 1a , R 1b and R 1c Each of them independently consists of hydrogen or C 1-6 Alkyl; R 2 and R 3 These are, independently, hydrogen and C. 1-6 Alkyl, or -C(O)C(O)N(R) 8b R 8c ) or R 2 and R 3 These are combined with the atoms to which they are attached, resulting in C 6-12 Forming an aryl group; R 4 , R 5 , R 6 and R 7 These are, independently, hydrogen and C. 1-6 Alkyl, halogen, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, or -OR 8a And here, R 4 , R 5 , R 6 and R 7 At least one of them is not H; and R 8a is C 7-18 It is alkyl-aryl; or, R 5 and R 6 These are combined with the atoms to which they are attached, resulting in C 3-6 It provides a heterocycloalkyl group.

[0081] In some embodiments, the present invention relates to a compound {wherein R 1a and R 1b These are, independently, hydrogen and C. 1-6 Alkyl, C 3-8 Cycloalkyl, or C4-14 It is alkyl-cycloalkyl; or, R 1a , R 1b , and R 1c Two of them are combined with the atom to which they are attached to C 3-12 The present invention provides a heterocycloalkyl group or a pharmaceutically acceptable salt thereof. In some embodiments, R 1a and R 1b Each of these is independently hydrogen or C 1-6 It is alkyl. In some embodiments, R 1a and R 1b Each is independently hydrogen, methyl, ethyl, or propyl. In some embodiments, R 1a and R 1b Each of these is independently either hydrogen or methyl.

[0082] In some embodiments, the present invention relates to a compound {wherein R 1a and R 1b R is independently hydrogen or methyl, and 1c Is it methyl; or, R 1a , R 1b , and R 1c Two of them are combined with the atom to which they are attached to C 3-8 The present invention provides a compound {wherein R} that forms a heterocycloalkyl group or a pharmaceutically acceptable salt thereof. In some embodiments, the present invention provides a compound {wherein R}. 1a and R 1b Each is independently hydrogen or methyl; and R 1c Is it methyl; or, R 1a , R 1b , and R 1c Two of them are combined with the atom to which they are attached to C 3-8 The present invention provides a salt thereof that forms a heterocycloalkyl group or is pharmaceutically acceptable.

[0083] In some embodiments, the present invention relates to a compound {wherein R 1c is C 1-6 Alkyl, C 3-8Cycloalkyl, or C 4-14 The present invention provides a compound {wherein R} which is alkyl-cycloalkyl or a pharmaceutically acceptable salt thereof. In some embodiments, the present invention provides a compound {wherein R} 1c is C 1-6 Provides alkyl or pharmaceutically acceptable salts thereof. In some embodiments, R 1c is methyl, ethyl, or propyl. In some embodiments, the present invention relates to a compound {wherein R}. 1c The present invention provides a salt thereof which is methyl or pharmaceutically acceptable. In some embodiments, R 1c It is methyl.

[0084] In some embodiments, the present invention relates to a compound {wherein R 1a , R 1b , and R 1c Each is methyl; or, R 1a , R 1b , and R 1c Two of them are combined with the atom to which they are attached to C 3-8 The present invention provides a compound {wherein R} that forms a heterocycloalkyl group or a pharmaceutically acceptable salt thereof. In some embodiments, the present invention provides a compound {wherein R}. 1a , R 1b , and R 1c Each is either Me or R 1a , R 1b , and R 1c Two of them are combined with the atom to which they are attached to C 3-8 The present invention provides a salt thereof that forms a heterocycloalkyl group or is pharmaceutically acceptable.

[0085] In some embodiments, the present invention relates to a compound {wherein 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 C5-12 The present invention provides a compound {wherein R} that forms a heterocycloalkyl group or a pharmaceutically acceptable salt thereof. 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 The present invention provides a compound {wherein R} that forms a heterocycloalkyl group or a pharmaceutically acceptable salt thereof. 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 The present invention provides a salt thereof that forms a heterocycloalkyl group or is pharmaceutically acceptable.

[0086] In some embodiments, the present invention relates to a compound {wherein R 2 , R 3 , R 4 , R 5 , R 6 and R 7 These are, independently, hydrogen and C. 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkynyl, halogen, C 1-6 Haloalkyl, C 1-6 Alkylamine, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -OR 8a -NO2, -CN, -C(O)R 8b , -C(O)OR 8b -OC(O)R 8b , -OC(O)OR 8b , -N(R 8b R 8c ), -N(R 8b )C(O)R 8c ,-C(O)N(R 8b R 8c ), -N(R 8b )C(O)OR 8c ,-OC(O)N(R 8b R 8c ), -N(R8b )C(O)N(R 8c R 8d ), -C(O)C(O)N(R 8b R 8c ), -S(O2)R 8b -S(O)2N(R 8b R 8c ), C 3-8 Cycloalkyl, C 3-14 Alkyl-cycloalkyl, C 4-10 Heterocycloalkyl, C 4-16 Alkyl-heterocycloalkyl, C 6-12 Ariel, C 7-18 Alkyl-aryl, C 5-10 Heteroaryl, or C 4-16 The present invention provides alkyl-heteroaryl or pharmaceutically acceptable salts thereof. In some embodiments, R 8a C 3-8 Cycloalkyl, C 3-14 Alkyl-cycloalkyl, C 4-10 Heterocycloalkyl, C 4-16 Alkyl-heterocycloalkyl, C 6-12 Ariel, C 7-18 Alkyl-aryl, C 5-10 Heteroaryl, or C 4-16 It is an alkyl-heteroaryl; and R 8b , R 8c and R 8d Each of these is independently H or C 1-6 It is alkyl.

[0087] In some embodiments, the present invention relates to a compound {wherein R 2 and R 3 These are, independently, hydrogen and C. 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkynyl, halogen, C 1-6 Haloalkyl, C 1-6 Alkylamine, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -OR 8a -NO2, -CN, -C(O)R 8b , -C(O)OR8b -OC(O)R 8b , -OC(O)OR 8b , -N(R 8b R 8c ), -N(R 8b )C(O)R 8c ,-C(O)N(R 8b R 8c ), -N(R 8b )C(O)OR 8c ,-OC(O)N(R 8b R 8c ), -N(R 8b )C(O)N(R 8c R 8d ), -C(O)C(O)N(R 8b R 8c ), -S(O2)R 8b -S(O)2N(R 8b R 8c ), C 3-8 Cycloalkyl, C 3-14 Alkyl-cycloalkyl, C 4-10 Heterocycloalkyl, C 4-16 Alkyl-heterocycloalkyl, C 6-12 Ariel, C 7-18 Alkyl-aryl, C 5-10 Heteroaryl, or C 4-16 The present invention provides alkyl heteroaryl compounds or pharmaceutically acceptable salts thereof.

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

[0089] In some embodiments, the present invention relates to a compound {wherein 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 Each of these is independently H or C 1-6 The present invention provides a compound {wherein R} that is alkyl or a pharmaceutically acceptable salt thereof. In some embodiments, the present invention provides a compound {wherein R}. 3 This 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 Each of these independently provides methyl, ethyl, or propyl or a pharmaceutically acceptable salt thereof.

[0090] In some embodiments, the present invention relates to a compound {wherein 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 Each of these is independently H or C 1-6 The present invention provides a compound {wherein R} which is alkyl or a pharmaceutically acceptable salt thereof. In some embodiments, the present invention provides a compound {wherein R} 3 The present invention provides hydrogen, Me, F, -OMe or -C(O)C(O)NMe2 or a pharmaceutically acceptable salt thereof.

[0091] In some embodiments, the present invention provides compounds or pharmaceutically acceptable salts thereof, wherein the compound of formula I has the following structure: [ka] It holds.

[0092] In some embodiments, the present invention provides compounds or pharmaceutically acceptable salts thereof, wherein the compound of formula I has the following structure: [ka] It holds.

[0093] In some embodiments, the present invention relates to a compound {wherein R 1a and R 1b They are combined with the atoms to which they are attached and C 3-12 The present invention provides a compound {wherein R} that forms a heterocycloalkyl group or a pharmaceutically acceptable salt thereof. In some embodiments, the present invention provides a compound {wherein R}. 1a and R 1b They are combined with the atoms to which they are attached and C 3-8 The present invention provides a compound {wherein R} that forms a heterocycloalkyl group or a pharmaceutically acceptable salt thereof. In some embodiments, the present invention provides a compound {wherein R}. 1a and R 1b They are combined with the atoms to which they are attached and C 3-8 The present invention provides a salt thereof that forms a heterocycloalkyl group or is pharmaceutically acceptable.

[0094] In some embodiments, the present invention relates to a compound {wherein R 1a and R 1c They are combined with the atoms to which they are attached and C 5-12 The present invention provides a compound {wherein R} that forms a heterocycloalkyl group or a pharmaceutically acceptable salt thereof. In some embodiments, the present invention provides a compound {wherein R}. 1a and R 1c They are combined with the atoms to which they are attached and C 5-8 The present invention provides a compound {wherein R} that forms a heterocycloalkyl group or a pharmaceutically acceptable salt thereof. In some embodiments, the present invention provides a compound {wherein R}. 1a and R 1c They are combined with the atoms to which they are attached and C 5-6The present invention provides a compound {wherein R} that forms a heterocycloalkyl group or a pharmaceutically acceptable salt thereof. In some embodiments, the present invention provides a compound {wherein R}. 1a and R 1c They are combined with the atoms to which they are attached and C 5-8 The present invention provides a salt thereof that forms a heterocycloalkyl group or is pharmaceutically acceptable.

[0095] In some embodiments, the present invention relates to formula (Ia): [ka] {where, R 1a and R 1b Each is independent of C 1-6 Alkyl, C 3-8 Cycloalkyl, or C 4-14 It is alkyl-cycloalkyl; R 1c is hydrogen, C 1-6 Alkyl, C 3-8 Cycloalkyl, or C 4-14 It is alkyl-cycloalkyl; or, R 1a , R 1b , and R 1c Two of them are combined with the atom to which they are attached to C 3-12 Forms heterocycloalkyl groups; R 2 , R 3 , R 4 , R 6 and R 7 These are, independently, hydrogen and C. 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkynyl, halogen, C 1-6 Haloalkyl, C 1-6 Alkylamine, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -OR 8a -NO2, -CN, -C(O)R 8b , -C(O)OR 8b -OC(O)R 8b , -OC(O)OR 8b , -N(R 8b R 8c ), -N(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 8b R 8c ), -S(O2)R 8b -S(O)2N(R 8b R 8c ), C 3-8 Cycloalkyl, C 3-14 Alkyl-cycloalkyl, C 4-10 Heterocycloalkyl, C 4-16 Alkyl-heterocycloalkyl, C 6-12 Ariel, C 7-18 Alkyl-aryl, C 5-10 Heteroaryl, or C 4-16 It is an alkyl-heteroaryl; R 5 F, Cl, Br, C 1-6 Alkyl, C 1-6 Haloalkoxy, -OR 8a -NO2, -CN, C 2-6 Alkenil, C 2-6 Alkinyl, -C(O)R 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 8c R 8c ), -S(O2)R 8b -S(O2)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 Ariel, C 7-18 Alkyl-aryl, or C 4-16 It is an alkyl-heteroaryl; R 8a C 3-8 Cycloalkyl, C 3-14 Alkyl-cycloalkyl, C 4-10 Heterocycloalkyl, C 4-16 Alkyl-heterocycloalkyl, C 6-12 Ariel, C 7-18 Alkyl-aryl, C 5-10 Heteroaryl, or C 4-16 It is an alkyl-heteroaryl; R 8b , R 8c and R 8d Each of these is independently H or C 1-6 Is it 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 heterocycloalkyl groups; and / or R 2 and R 3 These are combined with the atoms to which they are attached, resulting in C 6-12 To form an aryl group; or, R 4 and R 5 , R 5 and R 6 , or R 6 and R 7 These are combined with the atoms to which they are attached, resulting in C 3-6 It is cycloalkyl or C 3-6 A heterocycloalkyl group is formed, where R 1c H is H, and R 5 If R is Br, Cl, F, -NH2, -NO2, or C1-C3 alkoxy, 2 , R 3 , R4 , R 6 , or R 7 At least one of them is not H; and here, R 5 When F, R 6 The present invention provides compounds of {not F}, salts and isomers thereof, or pharmaceutically acceptable salts or solvates thereof.

[0096] In some embodiments, the present invention relates to formula (Ia) {wherein R 1a and R 1b Each is independent of C 1-6 Alkyl, C 3-8 Cycloalkyl, or C 4-14 It is alkyl-cycloalkyl; R 1c C 1-6 Alkyl, C 3-8 Cycloalkyl, or C 4-14 It is alkyl-cycloalkyl; or, R 1a , R 1b , and R 1c Two of them are combined with the atom to which they are attached to C 3-12 Forms heterocycloalkyl groups; R 2 , R 3 , R 4 , R 6 and R 7 These are, independently, hydrogen and C. 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkynyl, halogen, C 1-6 Haloalkyl, C 1-6 Alkylamine, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -OR 8a -NO2, -CN, -C(O)R 8b , -C(O)OR 8b -OC(O)R 8b , -OC(O)OR 8b , -N(R 8b R 8c ), -N(R 8b )C(O)R 8c ,-C(O)N(R 8b R 8c ), -N(R 8b)C(O)OR 8c ,-OC(O)N(R 8b R 8c ), -N(R 8b )C(O)N(R 8c R 8d ), -C(O)C(O)N(R 8b R 8c ), -S(O2)R 8b -S(O)2N(R 8b R 8c ), C 3-8 Cycloalkyl, C 3-14 Alkyl-cycloalkyl, C 4-10 Heterocycloalkyl, C 4-16 Alkyl-heterocycloalkyl, C 6-12 Ariel, C 7-18 Alkyl-aryl, C 5-10 Heteroaryl, or C 4-16 It is an alkyl-heteroaryl; R 5 C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkynyl, halogen, C 1-6 Haloalkyl, C 1-6 Alkylamine, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -OR 8a -NO2, -CN, -C(O)R 8b , -C(O)OR 8b -OC(O)R 8b , -OC(O)OR 8b , -N(R 8b R 8c ), -N(R 8b )C(O)R 8c ,-C(O)N(R 8b R 8c ), -N(R 8b )C(O)OR 8c ,-OC(O)N(R 8b R 8c ), -N(R 8b )C(O)N(R 8c R 8d ), -C(O)C(O)N(R 8b R 8c ), -S(O2)R 8b -S(O)2N(R8b R 8c ), C 3-8 Cycloalkyl, C 3-14 Alkyl-cycloalkyl, C 4-10 Heterocycloalkyl, C 4-16 Alkyl-heterocycloalkyl, C 6-12 Ariel, C 7-18 Alkyl-aryl, C 5-10 Heteroaryl, or C 4-16 It is an alkyl-heteroaryl; R 8a C 3-8 Cycloalkyl, C 3-14 Alkyl-cycloalkyl, C 4-10 Heterocycloalkyl, C 4-16 Alkyl-heterocycloalkyl, C 6-12 Ariel, C 7-18 Alkyl-aryl, C 5-10 Heteroaryl, or C 4-16 It is an alkyl-heteroaryl; R 8b , R 8c and R 8d Each of these is independently H or C 1-6 Is it 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 Forms a heterocycloalkyl group; or, R 2 and R 3 These are combined with the atoms to which they are attached, resulting in C 6-12 To form an aryl group; or, R 4 and R 5 , R 5 and R 6 , or R 6 and R 7 These are combined with the atoms to which they are attached, resulting in C 3-6 It is cycloalkyl or C 3-6 The present invention provides compounds that form heterocycloalkyl groups, salts and isomers thereof, or pharmaceutically acceptable salts or solvates thereof.

[0097] In some embodiments, the present invention provides compounds or pharmaceutically acceptable salts thereof, wherein the compound of formula I has the following structure: [ka] It holds.

[0098] In some embodiments, the present invention provides compounds or pharmaceutically acceptable salts thereof, wherein the compound of formula I has the following structure: [ka] It holds.

[0099] In some embodiments, the present invention provides compounds or pharmaceutically acceptable salts thereof, wherein the compound of formula I has the following structure: [ka] It holds.

[0100] In some embodiments, R 2 and R 3 These are combined with the atoms to which they are attached, resulting in C 4-8 Cycloalkyl, C 4-10 Heterocycloalkyl, or C 6-12 Form an aryl group.

[0101] In some embodiments, the present invention relates to a compound {wherein R 4 , R 5 , R 6 and R 7 These are, independently, hydrogen and C. 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkynyl, halogen, C 1-6 Haloalkyl, C 1-6 Alkylamine, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -OR 8a-NO2, -CN, -C(O)R 8b , -C(O)OR 8b -OC(O)R 8b , -OC(O)OR 8b , -N(R 8b R 8c ), -N(R 8b )C(O)R 8c ,-C(O)N(R 8b R 8c ), -N(R 8b )C(O)OR 8c ,-OC(O)N(R 8b R 8c ), -N(R 8b )C(O)N(R 8c R 8d ), -C(O)C(O)N(R 8b R 8c ), -S(O2)R 8b -S(O)2N(R 8b R 8c ), C 3-8 Cycloalkyl, C 3-14 Alkyl-cycloalkyl, C 4-10 Heterocycloalkyl, C 4-16 Alkyl-heterocycloalkyl, C 6-12 Ariel, C 7-18 Alkyl-aryl, C 5-10 Heteroaryl, or C 4-16 It is alkyl-heteroaryl; or, R 4 and R 5 , R 5 and R 6 , or R 6 and R 7 These are combined with the atoms to which they are attached, resulting in C 4-6 Cycloalkyl, C 4-6 Heterocycloalkyl, C 6-12 Aryl, or C 5-10 The present invention provides a compound or a pharmaceutically acceptable salt thereof that forms a heteroaryl compound. In some embodiments, the present invention provides a compound or a pharmaceutically acceptable salt thereof, where R 4 , R 5 , R 6 or R 7 These are, independently, hydrogen and C.1-6 Alkyl, halogen, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -OR 8a -NO2, -CN, C 3-8 Cycloalkyl, or C 3-14 It is an alkyl-cycloalkyl group.

[0102] In some embodiments, the present invention relates to a compound {wherein R 8a C 3-8 Cycloalkyl, C 3-14 Alkyl-cycloalkyl, C 4-10 Heterocycloalkyl, C 4-16 Alkyl-heterocycloalkyl, C 6-12 Ariel, C 7-18 Alkyl-aryl, C 5-10 Heteroaryl, or C 4-16 It is an alkyl-heteroaryl; and R 8b , R 8c and R 8d Each of these is independently H or C 1-6 The present invention provides a compound {wherein R} that is alkyl or a pharmaceutically acceptable salt thereof. In some embodiments, the present invention provides a compound {wherein R}. 8a C 3-8 Cycloalkyl, C 3-14 Alkyl-cycloalkyl, C 4-16 Alkyl-heterocycloalkyl, C 7-18 Alkyl-aryl, or C 4-16 The present invention provides alkyl heteroaryl compounds or pharmaceutically acceptable salts thereof.

[0103] In some embodiments, the present invention relates to a compound {wherein R 4 and R 5 , R 5 and R 6 , or R 6 and R 7 These are combined with the atoms to which they are attached, resulting in C 4-6 Cycloalkyl, C 4-6 Heterocycloalkyl, C 6-12 Aryl, or C5-10 The present invention provides a compound {wherein R} that forms a heteroaryl compound. 4 and R 5 These are combined with the atoms to which they are attached, resulting in C 4-6 The present invention provides a compound {wherein R} that forms a heterocycloalkyl group or a pharmaceutically acceptable salt thereof. In some embodiments, the present invention provides a compound {wherein R}. 5 and R 6 These are combined with the atoms to which they are attached, resulting in C 4-6 The present invention provides a compound {wherein R} that forms a heterocycloalkyl group or a pharmaceutically acceptable salt thereof. In some embodiments, the present invention provides a compound {wherein R}. 6 and R 7 These are combined with the atoms to which they are attached, resulting in C 4-6 The present invention provides a compound {wherein R} that forms a heterocycloalkyl group or a pharmaceutically acceptable salt thereof. In some embodiments, the present invention provides a compound {wherein R}. 5 and R 6 These are combined with the atoms to which they are attached, resulting in C 5-6 The present invention provides a compound {wherein R} that forms a heterocycloalkyl group or a pharmaceutically acceptable salt thereof. In some embodiments, the present invention provides a compound {wherein R}. 5 and R 6 The present invention provides salts thereof that, when combined with the atoms to which they are attached, form a 1,3-dioxole ring or a 1,4-dioxane ring, or are pharmaceutically acceptable.

[0104] In some embodiments, the present invention relates to a compound {wherein R 4 , R 5 , R 6 or R 7 These are, independently, hydrogen and C. 1-6 Alkyl, halogen, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -OR 8a -NO2, -CN, C 3-8 Cycloalkyl, or C3-14 It is alkyl-cycloalkyl; or, R 4 and R 5 , R 5 and R 6 , or R 6 and R 7 These are combined with the atoms to which they are attached, resulting in C 5-6 Forms heterocycloalkyl groups; and R 8a C 3-8 Cycloalkyl, C 3-14 Alkyl-cycloalkyl, C 4-16 Alkyl-heterocycloalkyl, C 7-18 Alkyl-aryl, or C 4-16 The present invention provides a compound {wherein R} which is alkyl-heteroaryl or a pharmaceutically acceptable salt thereof. In some embodiments, the present invention provides a compound {wherein R} 4 , R 5 , R 6 or R 7 These are, independently, hydrogen and C. 1-6 Alkyl, halogen, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -OR 8a , or -NO2; or, R 4 and R 5 , R 5 and R 6 , or R 6 and R 7 These combine with the atoms to which they are attached to form C5 heterocycloalkyl groups; and R 8a is C 7-18 The present invention provides a compound {wherein R} that is alkyl-aryl or a pharmaceutically acceptable salt thereof. In some embodiments, the present invention provides a compound {wherein R} 4 , R 6 or R 7 These are, independently, hydrogen and C. 1-6 Alkyl, halogen, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -OR 8a , or -NO2; R 5 C 1-6 Alkyl, halogen, C 1-6 Alkoxy, C 1-6Haloalkoxy, -OR 8a , or -NO2; or, R 4 and R 5 , R 5 and R 6 , or R 6 and R 7 These combine with the atoms to which they are attached to form C5 heterocycloalkyl groups; and R 8a is C 7-18 The present invention provides a compound {wherein R} that is alkyl-aryl or a pharmaceutically acceptable salt thereof. In some embodiments, the present invention provides a compound {wherein R} 4 , R 5 , R 6 or R 7 Each is independently hydrogen, Me, F, Cl, Br, -OMe, -OCF3, -O-CH2-phenyl, or -NO2; or R 5 and R 6 The present invention provides salts thereof that, when combined with the atoms to which they are attached, form a 1,3-dioxole ring or a 1,4-dioxane ring, or are pharmaceutically acceptable.

[0105] In some embodiments, the present invention relates to a compound {wherein R 5 C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkynyl, halogen, C 1-6 Haloalkyl, C 1-6 Alkylamine, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -OR 8a -NO2, -CN, -C(O)R 8b , -C(O)OR 8b -OC(O)R 8b , -OC(O)OR 8b , -N(R 8b R 8c ), -N(R 8b )C(O)R 8c ,-C(O)N(R 8b R 8c ), -N(R 8b )C(O)OR 8c ,-OC(O)N(R 8bR 8c ), -N(R 8b )C(O)N(R 8c R 8d ), -C(O)C(O)N(R 8b R 8c ), -S(O2)R 8b -S(O)2N(R 8b R 8c ), C 3-8 Cycloalkyl, C 3-14 Alkyl-cycloalkyl, C 4-10 Heterocycloalkyl, C 4-16 Alkyl-heterocycloalkyl, C 6-12 Ariel, C 7-18 Alkyl-aryl, C 5-10 Heteroaryl, or C 4-16 The present invention provides a compound {wherein R} which is alkyl-heteroaryl or a pharmaceutically acceptable salt thereof. In some embodiments, the present invention provides a compound {wherein R} 5 C 1-6 Alkyl, halogen, C 1-6 Alkoxy, C 1-6 The present invention provides a compound {wherein R} which is a haloalkoxy or -NO2, or a pharmaceutically acceptable salt thereof. In some embodiments, the present invention provides a compound {wherein R} 5 The present invention provides a compound {wherein R} which is methyl, ethyl, propyl, F, Cl, Br, I, methoxy, ethoxy, -OCF3, -O-benzyl, or -NO2} or a pharmaceutically acceptable salt thereof. In some embodiments, the present invention provides a compound {wherein R} 5 The present invention provides methyl, F, Cl, Br, methoxy, -OCF3, -O-benzyl, or -NO2, or pharmaceutically acceptable salts thereof.

[0106] In some embodiments, the present invention relates to a compound {wherein R 4 , R 6 and R 7 Each of them is hydrogen; and R 5 The present invention provides a compound {wherein R} which is Me, F, Cl, Br, -OMe, -CF3, -OCF3, -O-benzyl, or -NO2} or a pharmaceutically acceptable salt thereof. In some embodiments, the present invention provides a compound {wherein R} 5is Me, F, Cl, Br, -OMe, -CF3, -OCF3, -O-benzyl or -NO2; and R 6 and R 7 Each of these is independently hydrogen, Me, F, Cl, Br, -OMe, -OCF3, -O-CH2-phenyl, or -NO2, where R 6 and R 7 The invention provides at least one of which is not hydrogen, or a pharmaceutically acceptable salt thereof.

[0107] In some embodiments, the present invention is a compound {wherein X is CR}. 3 And; R 1a , R 1b and R 1c Each of them independently consists of hydrogen or C 1-6 Alkyl; R 2 and R 3 These are, independently, hydrogen and C. 1-6 Alkyl, or -C(O)C(O)N(R) 8b R 8c ) or R 2 and R 3 These are combined with the atoms to which they are attached, resulting in C 6-12 Forming an aryl group; R 4 , R 5 , R 6 and R 7 These are, independently, hydrogen and C. 1-6 Alkyl, halogen, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, or -OR 8a And here, R 4 , R 5 , R 6 and R 7 At least one of them is not H; and R 8a is C 7-18 It is alkyl-aryl; or, R 5 and R 6 These are combined with the atoms to which they are attached, resulting in C 3-6 It provides a heterocycloalkyl group.

[0108] In some embodiments, the present invention relates to a compound {wherein X is CR}. 3 And; R 1a and R 1b Each of these is Me; 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 These are combined to form a phenyl ring; R 4 , R 5 , R 6 and R 7 Each is independently H, F, Br, -NO2, -OMe, -CF3, -OCF3, or -O benzyl; or R 5 and R 6 This provides a combination that forms a 1,3-dioxole ring.

[0109] In some embodiments, the present invention relates to a compound {wherein X is CR}. 3 And; R 1a and R 1b Each of these is Me; 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 is H, F, Br, -OMe, -CF3OCF3 or -O-benzyl; R 6 is H, -NO2, -OMe, -OCF3, or -O-benzyl; or R 2 and R 3 They are combined to form a phenyl ring; or, R 5 and R 6 These are combined to form a 1,3-dioxole ring; and R 7 The material is H, F, -OMe, or -O-benzyl.

[0110] In some embodiments, the present invention relates to a compound {wherein X is CR}. 3 And; R1a and R 1b Each of these is Me; R 1c is 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 Each of these is independently H, Me, -F, -Cl, Br, -NO2, -OMe, -CF3, -OCF3, or -O benzyl; or R 5 and R 6 The present invention provides a compound {wherein X is CR} that can be combined to form a 1,3-dioxole ring or a 1,4-dioxane ring, or a pharmaceutically acceptable salt thereof. In some embodiments, the present invention provides a compound {wherein X is CR}. 3 And; R 1a and R 1b Each of these is Me; R 1c is Me, Et, or Pr; R 2 These are 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 is H, Me, -F, -Cl, Br, -OMe, -CF3OCF3 or -O-benzyl; R 6 is H, Me, -F, -NO2, -OMe, -OCF3, or -O-benzyl; or R 5 and R 6 These are combined to form a 1,3-dioxole ring or a 1,4-dioxane ring; and R 7 The present invention provides a salt thereof which is H, Me, -F, -OMe, or -O-benzyl, or a pharmaceutically acceptable salt thereof.

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

[0112] In some embodiments, the present invention provides compounds, wherein the compounds are as follows: [ka] Or it is the salt that is permitted as a medicine.

[0113] In some embodiments, the present invention provides compounds, wherein the compounds are as follows: [ka] Or it is the salt that is permitted as a medicine.

[0114] In some embodiments, the present invention provides compounds, wherein the compounds are as follows: [ka] Or it is the salt that is permitted as a medicine.

[0115] In some embodiments, the present invention provides compounds, wherein the compounds are as follows: [ka] Or it is the salt that is permitted as a medicine.

[0116] In some embodiments, the present invention relates to the following formula II: [ka] {In the formula, X is CR 3 And; R 1a and R 1b These are, independently, hydrogen and C 1-6 Alkyl, C 3-8 Cycloalkyl, or C 4-14 It is alkyl-cycloalkyl; or, R 1a and R 1b They are combined with the atoms to which they are attached and C 3-12 Forms heterocycloalkyl groups; R 2 , R 3 , R 4 , R 5 , R 6 , and R 7 These are, independently, hydrogen and C 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkynyl, halogen, C 1-6 Haloalkyl, C 1-6 Alkylamine, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -OR 8a -NO2, -CN, -C(O)R 8b , -C(O)OR 8b -OC(O)R 8b , -OC(O)OR 8b , -N(R 8b R 8c ), -N(R 8b )C(O)R 8c ,-C(O)N(R 8b R 8c ), -N(R 8b )C(O)OR 8c ,-OC(O)N(R 8b R 8c ), -N(R 8b )C(O)N(R 8c R 8d ), -C(O)C(O)N(R 8b R 8c ), -S(O2)R 8b -S(O)2N(R8b R 8c ), C 3-8 Cycloalkyl, C 3-14 Alkyl-cycloalkyl, C 4-10 Heterocycloalkyl, C 4-16 Alkyl-heterocycloalkyl, C 6-12 Ariel, C 7-18 Alkyl-aryl, C 5-10 Heteroaryl, or C 4-16 It is an alkyl-heteroaryl; R 8a C 3-8 Cycloalkyl, C 3-14 Alkyl-cycloalkyl, C 4-10 Heterocycloalkyl, C 4-16 Alkyl-heterocycloalkyl, C 6-12 Ariel, C 7-18 Alkyl-aryl, C 5-10 Heteroaryl, or C 4-16 It is an alkyl-heteroaryl; R 8b , R 8c , and R 8d Each of these is independently H or C 1-6 Is it alkyl; or R 1a or R 1b One of them is R 2 Combined with C 5-12 Forms a heterocycloalkyl group; or, R 2 and R 3 They are combined with the atoms to which they are attached and C 4-8 Cycloalkyl, C 4-10 Heterocycloalkyl, or C 6-12 To form an aryl group; or, R 4 and R 5 , R 5 and R 6 , or R 6 and R 7 These are combined with the atoms to which they are attached, resulting in C 4-6 Cycloalkyl, C 4-6 Heterocycloalkyl, C 6-12 Aryl, or C 5-10 Forms a heteroaryl group; and L is C 1-6A compound of alkylene, or a pharmaceutically acceptable salt or isomer thereof, where 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 At least one of them is not hydrogen, and the compound is as follows: [ka] It is the result of excluding R; here, 1a and R 1b If 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 them is not hydrogen; here, R 1c is hydrogen, and R 5 is Br, Cl, F, -NH2, -NO2, or C 1-3 When it is an alkoxy, R 2 , R 3 , R 4 , R 6 , or R 7 At least one of them is not hydrogen; and here, R 1c is hydrogen, R 5 When F, R 2 , R 3 , R 4 , R 6 , or R 7 At least one of them is not hydrogen, and R 6 The present invention provides a compound that is not F, or a pharmaceutically acceptable salt or isomer thereof.

[0117] In some embodiments, the present invention provides compounds or pharmaceutically acceptable salts thereof, wherein the compound of formula II has the following structure: [ka] It holds.

[0118] In some embodiments, the present invention provides compounds or pharmaceutically acceptable salts thereof, wherein the compound of formula II has the following structure: [ka] It holds.

[0119] In some embodiments, the present invention relates to a compound {wherein R 2 , R 3 , R 4 , R 5 , R 6 and R 7 The invention provides a salt thereof in which at least one of the members is not H, or a salt thereof that is pharmaceutically acceptable.

[0120] In some embodiments, the present invention relates to a compound {wherein R 4 , R 5 , R 6 or R 7 These are, independently, hydrogen and C. 1-6 Alkyl, halogen, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -OR 8a -NO2, -CN, C 3-8 Cycloalkyl, or C 3-14 It is alkyl-cycloalkyl; or, R 4 and R 5 , R 5 and R 6 , or R 6 and R 7 These are combined with the atoms to which they are attached, resulting in C 5-6 Forms heterocycloalkyl groups; and R 8a C 3-8 Cycloalkyl, C 3-14 Alkyl-cycloalkyl, C 4-16 Alkyl-heterocycloalkyl, C 7-18 Alkyl-aryl, or C 4-16The present invention provides a compound {wherein R} which is alkyl-heteroaryl or a pharmaceutically acceptable salt thereof. In some embodiments, the present invention provides a compound {wherein R} 4 , R 5 , R 6 or R 7 These are, independently, hydrogen and C. 1-6 Alkyl, halogen, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -OR 8a , or -NO2; or, R 4 and R 5 , R 5 and R 6 , or R 6 and R 7 These combine with the atoms to which they are attached to form C5 heterocycloalkyl groups; and R 8a is C 7-18 The present invention provides alkyl-aryl compounds or pharmaceutically acceptable salts thereof.

[0121] In some embodiments, the present invention relates to a compound {wherein R 4 , R 5 , R 6 or R 7 Each is independently hydrogen, F, Cl, -OMe, -OCF3, or -O-benzyl; or R 5 and R 6 The present invention provides compounds {wherein R} that, when combined with the atoms to which they are attached, form a 1,3-dioxole ring or a 1,4-dioxane ring} or pharmaceutically acceptable salts thereof. In some embodiments, the present invention provides compounds {wherein R} 5 is F, Cl, -OMe, -OCF3 or -O-benzyl; or R 5 and R 6 The present invention provides salts thereof that, when combined with the atoms to which they are attached, form a 1,3-dioxole ring or a 1,4-dioxane ring, or are pharmaceutically acceptable.

[0122] In some embodiments, the present invention relates to a compound {wherein R 5is F, Cl, -OMe, -OCF3 or -O-benzyl; R 6 and R 7 Each of these is independently hydrogen, F, Cl, -OMe, -OCF3, or -O-benzyl, where R 6 and R 7 At least one of them is not hydrogen; or R 5 and R 6 The present invention provides salts thereof that, when combined with the atoms to which they are attached, form a 1,3-dioxole ring or a 1,4-dioxane ring, or are pharmaceutically acceptable.

[0123] In some embodiments, the present invention provides compounds, wherein the compounds are as follows: [ka] Or it is the salt that is permitted as a medicine.

[0124] In some embodiments, the present invention provides compounds, wherein the compounds are as follows: [ka] Or it is the salt that is permitted as a medicine.

[0125] In some embodiments, the present invention relates to a compound {wherein R 1a and R 1b They are combined with the atoms to which they are attached and C 3-8 The present invention provides a salt thereof that forms a heterocycloalkyl group or is pharmaceutically acceptable.

[0126] In some embodiments, the present invention provides compounds, wherein the compounds are as follows: [ka] Or it is the salt that is permitted as a medicine.

[0127] In some embodiments, the present invention provides compounds, wherein the compounds are as follows: [ka] Or it is the salt that is permitted as a medicine.

[0128] The compounds of the present invention may also exist in the form of salts, such as acidic or basic salts. Exemplary examples of pharmaceutically acceptable salts are salts of mineral acids (e.g., hydrochloric acid, hydrobromic acid, phosphoric acid), salts of organic acids (e.g., fumaric acid, acetic acid, propionic acid, glutamic acid, citric acid), and salts of quaternary ammonium compounds (e.g., methyl iodide, ethyl iodide). Pharmaceutically acceptable salts are understood to be non-toxic. Further information regarding preferred 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 compounds of the present invention are salts containing fumaric acid. In some embodiments, the present invention provides compounds, wherein the compounds are salts containing fumaric acid or pharmaceutically acceptable salts.

[0130] The present invention also includes isotope-labeled compounds of the present invention, in which one or more atoms are replaced by one or more atoms having a specific atomic mass or mass number. Examples of isotopes that can be incorporated into the compounds of the present invention include, but are not limited to, isotopes of hydrogen, carbon, nitrogen, oxygen, fluorine, sulfur, and chlorine (e.g., 2 H, 3 H, 13 C, 14 C, 15 N, 18 O, 17 O, 18 F, 35 S and 36Examples include Cl. The isotope-labeled compounds of the present invention are useful for assays of the tissue distribution of the compounds, as well as their prodrugs and metabolites; preferred isotopes for such assays include 3 H 14 C is one example. In addition, under certain circumstances, heavier isotopes, such as deuterium ( 2 Substitution with H, etc., can provide high metabolic stability, which can lead to therapeutic benefits such as an extension of the half-life in vivo or a reduction in the required dose. Generally, the isotope-labeled compounds of the present invention can be prepared according to methods known to those skilled in the art by using an isotope-labeling reagent instead of a non-isotopically labeled reagent. The compounds of the present invention can be isotope-labeled at positions adjacent to the basic amine of the aromatic ring and the methyl group of the methoxy substituent.

[0131] The present invention comprises 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 a chiral center on a carbon atom, and therefore the compounds of the present invention may exist as diastereomers, enantiomers, or mixtures thereof. All conformational isomers (e.g., cis and trans isomers) and all optical isomers (e.g., enantiomers and diastereomers), racemates, diastereomers, and other mixtures of such isomers, as well as solvates, hydrates, isomorphs, polymorphs, and tautomers are within the scope of the present invention. The compounds of the present invention can be prepared using diastereomers, enantiomers, or racemic mixtures as starting materials. Furthermore, diastereomer and enantiomer products can be separated by chromatography, fractional crystallization, or other methods known to those skilled in the art. IV. Pharmaceutical Compositions and Compounds

[0132] In some embodiments, the present invention provides pharmaceutical compositions comprising the compound of the present invention and pharmaceutically acceptable excipients.

[0133] The compositions of the present invention can be prepared in a wide variety of oral, parenteral, and topical dosage forms. Oral preparations include tablets, pills, powders, capsules, liquids, licks, cachets, gels, syrups, slurries, and suspensions suitable for oral administration by patients. The compositions of the present invention can also be administered by injection, i.e., intravenously, intramuscularly, intradermally, subcutaneously, duodenally, or intraperitoneally. Furthermore, the compositions described herein can be administered by inhalation, for example, intranasally. In addition, the compositions of the present invention can be administered percutaneously. The compositions of the present invention can also be administered by intraocular, intravaginal, and intrarectal routes (including suppositories), gas infusion, powders, and aerosol formulations (for examples of inhaled steroids, see Rohatagi, J. Clin. Pharmacol. 35:1187-1193, 1995; Tjwa, Ann. Allergy Asthma Immunol. 75:107-111, 1995). Therefore, the present invention also provides pharmaceutical compositions comprising a pharmaceutically acceptable carrier or excipient and the compound of the present invention.

[0134] For preparing pharmaceutical compositions from the compounds of the present invention, pharmaceutically acceptable carriers may be solid or liquid. Preparations in solid form include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules. The solid carrier may be one or more substances that can act as diluents, flavorings, binders, preservatives, tablet disintegrants, or encapsulating materials. Detailed information regarding formulation and administration procedures is readily available in scientific literature and patent documents; for example, see the latest edition of Remington's Pharmaceutical Sciences, Maack Publishing Co, Easton PA (“Remington's”).

[0135] In the powder, the carrier is a pulverized solid, which is present in the mixture together with the pulverized active ingredient. In the tablet, the active ingredient is mixed in a suitable ratio with a carrier having the required binding properties and compressed into the desired shape and size. The powder and tablet 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-point wax; cocoa butter; carbohydrates; sugars (including, but not limited to, lactose, sucrose, mannitol or sorbitol, and starches derived from corn, wheat, rice, potato or other plants); cellulose (e.g., methylcellulose, hydroxypropylmethylcellulose or sodium carboxymethylcellulose); and gum (including arabic and tragacanth); and proteins (including, but not limited to, gelatin and collagen). If desired, disintegrants or solubilizers (e.g., cross-linked polyvinylpyrrolidone, agar, alginic acid or its salts (e.g., sodium alginate)) may be added.

[0137] To prepare the suppositories, a mixture of fatty acid glycerides or a low-melting-point wax such as cocoa butter is first melted, and the compound of the present invention is uniformly dispersed therein by stirring. Then, the melted homogeneous mixture is poured into a mold of a suitable size and cooled to solidify.

[0138] Preparations in liquid form include solutions, suspensions, and emulsions, such as water or water / propylene glycol solutions. For parenteral injection, liquid preparations may be formulated as solutions in aqueous polyethylene glycol solutions.

[0139] Aqueous solutions suitable for oral use can be prepared by dissolving the compounds of the present invention in water and adding suitable colorants, fragrances, stabilizers, and thickeners as desired. Aqueous suspensions suitable for oral use may contain the finely ground active components in a viscous material (e.g., natural or synthetic rubber, resin, methylcellulose, sodium carboxymethylcellulose, hydroxypropyl methylcellulose, sodium alginate, polyvinylpyrrolidone, tragacanth gum, and gum arabic) and a dispersant or wetting agent (e.g., naturally occurring phosphatides (e.g., lecithin), alkylene oxides and fatty acid condensates (e.g., polyoxyethylene stearate), ethylene oxides and long-chain aliphatic alcohol condensates (e.g., heptadecaethyleneoxycetanol), ethylene oxides and fatty acids and It can be produced by dispersing in water with a condensate of a partial ester derived from xitol (e.g., polyoxyethylene sorbitol mono-oleate) or a condensate of ethylene oxide with a partial ester derived from fatty acids and 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 colorants, one or more flavorings, and one or more sweeteners (e.g., sucrose, aspartame, or saccharin). The formulation can be adjusted in terms of osmolality.

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

[0141] An oily suspension may be formulated by suspending the compound of the present invention in a vegetable oil (e.g., peanut oil, olive oil, sesame oil, or coconut oil) or mineral oil (e.g., liquid paraffin); or a mixture thereof. The oily suspension may contain a thickener (e.g., beeswax, solid paraffin, or cetyl alcohol). A sweetener (e.g., glycerol, sorbitol, or sucrose) may be added to provide a palatable oral preparation. These formulations 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 formulation of the present invention may also be in the form of an oil-in-water emulsion. The oil phase may be a vegetable oil or mineral oil, or a mixture thereof, as described above. Suitable emulsifiers include naturally occurring gums (e.g., gum arabic and gum tragacanth), naturally occurring phosphatides (e.g., soy lecithin), esters or partial esters derived from fatty acids and hexitol anhydrides (e.g., sorbitan monooleate), and condensates of these partial esters with ethylene oxide (e.g., polyoxyethylene sorbitan monooleate). The emulsion may also contain sweeteners and flavorings, as in the formulations of syrups and elixirs. Such formulations may also contain lubricants, preservatives, or colorants.

[0142] The compositions of the present invention can also be delivered as microspheres for slow release within the body. For example, microspheres can be formulated for administration via intradermal injection of drug-containing microspheres that slowly release under the skin (see Rao, J. Biomater Sci. Polym. Ed. 7:623-645, 1995; as a biodegradable, injectable gel formulation (see, for example, Gao Pharm. Res. 12:857-863, 1995); or as microspheres for oral administration (see, for example, Eyles, J. Pharm. Pharmacol. 49:669-674, 1997). Both transdermal and intradermal routes provide consistent delivery over several 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 the lumen of a body cavity or organ). The formulation for administration typically comprises a solution of the composition of the present invention dissolved in a pharmaceutically acceptable carrier. Acceptable vehicles and solvents that can be used are water and Ringer's solution and isotonic sodium chloride. Furthermore, sterilized fixative oils may conventionally be used as solvents or suspension media. For this purpose, any non-irritating fixative oil containing synthetic mono- or diglycerides may be used. Furthermore, fatty acids such as oleic acid may similarly be used in the preparation of injectables. These solutions are sterile and typically do not contain undesirable substances. These formulations may be sterilized by conventional, well-known sterilization procedures. These formulations may contain pharmaceutically acceptable auxiliary substances (e.g., pH adjusters and buffers, toxicity modifiers, e.g., sodium acetate, sodium chloride, potassium chloride, calcium chloride, sodium lactate, etc.) as needed to approximate physiological conditions. The concentration of the composition of the present invention in these formulations can vary considerably and may be selected mainly based on the volume, viscosity, body weight, etc., according to the specific dosage mode selected and the patient's needs. For IV administration, the formulation may be a sterile injectable preparation (e.g., a sterile injectable aqueous or oily suspension). This suspension may be formulated according to known techniques using suitable dispersants or wetting agents and suspending agents. The sterile injectable formulation may also be a sterile injectable solution or suspension in a non-toxic, parenterally acceptable diluent or solvent (e.g., a solution of 1,3-butanediol).

[0144] In some embodiments, formulations of the compositions of the present invention may be delivered by using liposomes, which either fuse with the cell membrane or undergo endocytosis, i.e., delivery by using ligands attached to the liposomes or ligands directly attached to oligonucleotides that bind to cell surface membrane protein receptors, thereby facilitating endocytosis. In particular, the use of liposomes can be focused on delivering the compositions of the present invention to target cells in vivo, especially when the liposome surface has ligands specific to target cells or is otherwise preferentially oriented to specific organelles (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 methods. Transdermal administration methods via topical routes can be formulated as applicator sticks, solutions, suspensions, emulsions, gels, creams, ointments, pastes, jellies, paints, powders, and aerosols.

[0146] Pharmaceuticals are preferably available in unit dosage forms. In such forms, the preparation is subdivided into unit doses containing an appropriate amount of the compound of the present invention. A unit dosage form may be a packaged preparation, the packaging containing separate amounts of the preparation (e.g., packaged tablets, capsules, and powders in vials or ampoules). Alternatively, a unit dosage form may be the capsule, tablet, cachet or lollipop itself, or an appropriate number of these in packaged forms.

[0147] The compound of the present invention may be present in any suitable amount and may depend on various factors, including but not limited to the subject's body weight and age, and disease state. Suitable dosage ranges for the compound of the present invention include about 0.1 mg to about 10,000 mg, or about 1 mg to about 1,000 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 for the compound 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 1,000 mg.

[0148] The compounds of the present invention can be administered at any preferred frequency, interval, and duration. For example, the compounds of the present invention may be administered once per hour, twice per hour, three times per hour or more, once per day, twice per day, three times per day or more, or once every two, three, four, five, six, or seven days to provide a preferred dose level. When the compounds of the present invention are administered multiple times a day, typical intervals include 5, 10, 15, 20, 30, 45, and 60 minutes, and 1, 2, 4, 6, 8, 10, 12, 16, 20, and 24 hours. The compounds of the present invention may be administered once, twice, three times, or more over periods of one hour, one to six hours, one to twelve hours, one to twenty-four hours, six to twelve hours, twelve to twenty-four hours, one day, one to seven days, one week, one to four weeks, one month, one to twelve months, one year or more, or indefinitely.

[0149] The composition may also include other suitable therapeutic agents. The compounds described herein may be used in combination with other active agents known to be useful in modulating glucocorticoid receptors, or with adjuvants that may not be effective on their own but may contribute to the effectiveness of active agents.

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

[0151] In some embodiments, simultaneous administration can be achieved by simultaneous formulation, i.e., by preparing a single pharmaceutical composition containing both the compound of the present invention and the active substance. In other embodiments, the compound of the present invention and the active substance are formulated separately.

[0152] The compounds and active substances of the present invention may be provided in compositions of the present invention in any preferred 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 and other active substances of the present invention may be provided in any preferred 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 dosages and dose ratios of the compounds and active substances of the present invention are preferred in the compositions and methods of the present invention. VI. Treatment Methods

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

[0154] In some embodiments, the compounds of the present invention are used to treat neurological disorders. In some embodiments, the compounds have, for example, antitoxic, antidepressant, anxiolytic properties, or a combination thereof. In some embodiments, the neurological disorder is a neuropsychiatric disorder. In some embodiments, the neuropsychiatric disorder is a mood or anxiety disorder. In some embodiments, the neurological disorder is a 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 intoxication (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, neurological disorders are psychiatric disorders, 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, neuropsychiatric disorders are psychiatric disorders, 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, neuropsychiatric disorders or neurological disorders are post-traumatic stress disorder (PTSD), addiction (e.g., substance use disorder), schizophrenia, depression, or anxiety. In some embodiments, neuropsychiatric disorders or neurological disorders are addiction (e.g., substance use disorder). In some embodiments, neuropsychiatric disorders or neurological disorders are depression. In some embodiments, neuropsychiatric disorders or neurological disorders are anxiety. In some embodiments, neuropsychiatric disorders or neurological disorders are post-traumatic stress disorder (PTSD). In some embodiments, the neurological disorder is a stroke or traumatic brain injury. In some embodiments, the neuropsychiatric disorder 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 the translation, transcription, or secretion of neurotrophic factors.

[0156] In some embodiments, the compounds of the present invention are 5-HT 2A It has modulator activity. In some embodiments, the compounds of the present invention are 5-HT 2A It has activity as a modulator. In some embodiments, the compounds of the present invention are 5-HT 2A Activates receptors (e.g., allosteric regulation or 5-HT) 2A It induces a biological response by modulating the biological targets that activate receptors. 5-HT 2A The activity was associated with enhanced neural plasticity (Ly et al., 2018). As shown in Figure 7, 5-HT 2A The antagonist is 5-HT 2A Hallucinogenic compounds with agonist activity, such as DMT, LSD, and DOI, inhibit the neurite formation and spine formation effects. In some embodiments, the compounds of the present invention are 5-HT 2A It acts as a modulator and promotes neural plasticity (e.g., cortical plasticity). In some embodiments, the compounds of the present invention selectively promote 5-HT 2A It acts as a modulator and promotes neural plasticity (e.g., cortical structure plasticity). In some embodiments, the promotion of neural plasticity includes, for example, enhanced dendritic spine growth, increased synaptic protein synthesis, enhanced synaptic response, enhanced complexity of dendritic spread, enhanced dendritic branch content, enhanced spine formation, enhanced neurite formation, or any combination thereof. In some embodiments, enhanced neural plasticity includes, for example, enhanced cortical structure plasticity in the anterior part of the brain.

[0157] In some embodiments, 5-HT 2A Modulator (e.g., 5-HT) 2A The agonist is non-hallucinogenic. In some embodiments, non-hallucinogenic 5-HT 2A Modulator (e.g., 5-HT) 2A The agonist is used to treat neurological disorders, and its modulator does not induce dissociative side effects. In some embodiments, the hallucinogenic potential of the compounds described herein is evaluated in vitro. In some embodiments, the hallucinogenic potential of the compounds described herein, as evaluated in vitro, is compared to the hallucinogenic potential of a hallucinogenic homolog. In some embodiments, the compounds described herein induce lower in vitro hallucinogenic potential compared to a hallucinogenic homolog.

[0158] In some embodiments, non-hallucinogenic 5-HT 2A Modulator (e.g., 5-HT) 2A Agonists are used to treat neurological disorders. In some embodiments, neurological disorders are caused by reduced neuroplasticity, reduced cortical plasticity, and 5-HT 2A This includes reducing receptor content, reducing the complexity of dendritic spread, loss of dendritic spines, reducing dendritic branching content, reducing spine formation, reducing neurite formation, neurite stunting, or any combination thereof.

[0159] In some embodiments, non-hallucinogenic 5-HT 2A Modulator (e.g., 5-HT) 2A Agonists are used to enhance neuroplasticity. In some embodiments, non-hallucinogenic 5-HT 2A Modulator (e.g., 5-HT) 2A Agonists are used to treat brain disorders. In some embodiments, non-hallucinogenic 5-HT 2A Modulator (e.g., 5-HT) 2AAgonists are used to enhance at least one of the following: translation, transcription, or secretion of neurotrophic factors. A. Methods for enhancing neuroplasticity

[0160] Neuroplasticity refers to the brain's ability to alter its structure and / or function throughout an individual's life. New neurons can be produced and integrated into the central nervous system throughout an individual's life. Enhanced neuroplasticity includes, but is not limited to, increased neuronal proliferation, increased neurite formation, increased synapse formation, increased dendritic formation, increased complexity of dendritic spread, increased dendritic spine density, and increased excitatory synapses in the brain. In some embodiments, enhanced neuroplasticity includes increased neuronal proliferation, increased neurite formation, increased synapse formation, increased dendritic formation, increased complexity of dendritic spread, and increased dendritic spine density.

[0161] In some embodiments, enhanced neuronal plasticity may treat neurodegenerative disorders, Alzheimer's disease, Parkinson's disease, psychiatric disorders, 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 disorders.

[0162] In some embodiments, the present invention provides a method for enhancing neuroplasticity, comprising contacting nerve cells with any compound of the present invention. In some embodiments, the enhanced neuroplasticity improves 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, antitoxic, antidepressant, anxiolytic properties, or a combination thereof. In some embodiments, reduced neuroplasticity is associated with neuropsychiatry. In some embodiments, neuropsychiatry is a mood or anxiety disorder. In some embodiments, neuropsychiatry includes, for example, migraine, cluster headache, post-traumatic stress disorder (PTSD), schizophrenia, anxiety, depression, and addiction (e.g., substance abuse disorder). In some embodiments, brain disorders include, for example, migraine, addiction (e.g., substance use disorder), depression, and anxiety.

[0164] In some embodiments, experiments or assays measuring the enhanced neuronal plasticity of any compound of the present invention include phenotypic assays, dendritic formation assays, spine formation assays, synapse formation assays, Scholl analysis, concentration-response experiments, and 5-HT assays. 2A Agonist assay, 5-HT 2A Antagonist assay, 5-HT 2A Binding assay, or 5-HT 2A This involves a blockade experiment (e.g., a ketanserine blockade experiment). In some embodiments, an experiment or assay to measure the hallucinogenic potential of any compound of the present invention is a mouse head spasm response (HTR) assay.

[0165] In some embodiments, the present invention provides a method for enhancing neuronal plasticity, wherein a nerve cell is subjected to a sufficient amount of the following formula I: [ka] {In the formula, X is N or CR} 3 And; R 1a , R 1b , and R 1c These are, independently, hydrogen and C. 1-6 Alkyl, C 3-8 Cycloalkyl, or C 4-14It is alkyl-cycloalkyl; or, R 1a , R 1b , and R 1c Two of them are combined with the atom to which they are attached to C 3-12 Forms heterocycloalkyl groups; R 2 , R 3 , R 4 , R 5 , R 6 , and R 7 These are, independently, hydrogen and C. 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkynyl, halogen, C 1-6 Haloalkyl, C 1-6 Alkylamine, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -OR 8a -NO2, -CN, -C(O)R 8b , -C(O)OR 8b -OC(O)R 8b , -OC(O)OR 8b , -N(R 8b R 8c ), -N(R 8b )C(O)R 8c ,-C(O)N(R 8b R 8c ), -N(R 8b )C(O)OR 8c ,-OC(O)N(R 8b R 8c ), -N(R 8b )C(O)N(R 8c R 8d ), -C(O)C(O)N(R 8b R 8c ), -S(O2)R 8b -S(O)2N(R 8b R 8c ), C 3-8 Cycloalkyl, C 3-14 Alkyl-cycloalkyl, C 4-10 Heterocycloalkyl, C 4-16 Alkyl-heterocycloalkyl, C 6-12 Ariel, C 7-18 Alkyl-aryl, C 5-10 Heteroaryl, or C4-16 It is an alkyl-heteroaryl; R 8a C 3-8 Cycloalkyl, C 3-14 Alkyl-cycloalkyl, C 4-10 Heterocycloalkyl, C 4-16 Alkyl-heterocycloalkyl, C 6-12 Ariel, C 7-18 Alkyl-aryl, C 5-10 Heteroaryl, or C 4-16 It is an alkyl-heteroaryl; R 8b , R 8c and R 8d Each of these is 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 Forms a heterocycloalkyl group; or, R 2 and R 3 These are combined with the atoms to which they are attached, resulting in C 4-8 Cycloalkyl, C 4-10 Heterocycloalkyl, or C 6-12 To form an aryl group; or, R 4 and R 5 , R 5 and R 6 , or R 6 and R 7 These are combined with the atoms to which they are attached, resulting in C 3-6 Cycloalkyl, C 3-6 Heterocycloalkyl, C 6-12 Aryl, or C 5-10 Forms a heteroaryl group; and L is C 1-6 The present invention provides a method comprising contacting a compound or pharmaceutically acceptable salt thereof that is an alkylene.

[0166] In some embodiments, the present invention relates to a method for enhancing neuronal plasticity, wherein a nerve cell is subjected to a sufficient amount of formula I {wherein X is N or CR} to enhance the neuronal plasticity of the nerve cell. 3 And; R1a , R 1b , and R 1c These are, independently, hydrogen and C. 1-6 Alkyl, C 3-8 Cycloalkyl, or C 4-14 It is alkyl-cycloalkyl; or, R 1a , R 1b , and R 1c Two of them are combined with the atom to which they are attached to C 3-12 Forms heterocycloalkyl groups; R 2 , R 3 , R 4 , R 5 , R 6 , and R 7 These are, independently, hydrogen and C. 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkynyl, halogen, C 1-6 Haloalkyl, C 1-6 Alkylamine, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -OR 8a -NO2, -CN, -C(O)R 8b , -C(O)OR 8b -OC(O)R 8b , -OC(O)OR 8b , -N(R 8b R 8c ), -N(R 8b )C(O)R 8c ,-C(O)N(R 8b R 8c ), -N(R 8b )C(O)OR 8c ,-OC(O)N(R 8b R 8c ), -N(R 8b )C(O)N(R 8c R 8d ), -C(O)C(O)N(R 8b R 8c ), -S(O2)R 8b -S(O)2N(R 8b R 8c ), C 3-8 Cycloalkyl, C 3-14 Alkyl-cycloalkyl, C 4-10Heterocycloalkyl, C 4-16 Alkyl-heterocycloalkyl, C 6-12 Ariel, C 7-18 Alkyl-aryl, C 5-10 Heteroaryl, or C 4-16 It is an alkyl-heteroaryl; R 8a C 3-8 Cycloalkyl, C 3-14 Alkyl-cycloalkyl, C 4-10 Heterocycloalkyl, C 4-16 Alkyl-heterocycloalkyl, C 6-12 Ariel, C 7-18 Alkyl-aryl, C 5-10 Heteroaryl, or C 4-16 It is an alkyl-heteroaryl; R 8b , R 8c and R 8d Each of these is independently H or C 1-6 Is it 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 Forms a heterocycloalkyl group; or, R 2 and R 3 These are combined with the atoms to which they are attached, resulting in C 6-12 Can an aryl group be formed; or, R 4 and R 5 , R 5 and R 6 , or R 6 and R 7 These are combined with the atoms to which they are attached, resulting in C 3-6 Cycloalkyl, or C 3-6 It can form heterocycloalkyl groups; and L is C 1-6 The present invention provides a method comprising contacting a compound that is alkylene, or a salt or isomer thereof. B. Methods for treating brain damage

[0167] In some embodiments, the present invention provides a method for treating a disease, comprising administering a therapeutically effective amount of the compound of the present invention to a subject in need. In some embodiments, the present invention provides a method for treating a brain disorder, comprising administering a therapeutically effective amount of the compound of the present invention to a subject in need. In some embodiments, the present invention provides a method for treating a brain disorder in combination therapy, comprising administering a therapeutically effective amount of the compound of the present invention and at least one additional therapeutic agent to a subject in need.

[0168] In some embodiments, 5-HT 2A Modulator (e.g., 5-HT) 2A Agonists are used to treat brain damage. In some embodiments, brain damage is caused by reduced neuroplasticity, reduced cortical plasticity, and 5-HT 2A This includes reducing receptor content, reducing the complexity of dendritic spread, loss of dendritic spines, reduction of dendritic branching, reduction of spine formation, reduction of 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, antitoxic, antidepressant, anxiolytic 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, examples of brain disorders include migraines, cluster headaches, post-traumatic stress disorder (PTSD), anxiety, depression, schizophrenia, and intoxication (e.g., substance abuse disorder). In some embodiments, examples of brain disorders include migraines, intoxication (e.g., substance use disorder), depression, and anxiety.

[0170] In some embodiments, the present invention provides a method for enhancing neuronal plasticity, wherein a nerve cell is subjected to a sufficient amount of the following formula I: [ka] {In the formula, X is N or CR} 3 And; R 1a , R 1b , and R 1c These are, independently, hydrogen and C. 1-6 Alkyl, C 3-8 Cycloalkyl, or C 4-14 It is alkyl-cycloalkyl; or, R 1a , R 1b , and R 1c Two of them are combined with the atom to which they are attached to C 3-12 Forms heterocycloalkyl groups; R 2 , R 3 , R 4 , R 5 , R 6 , and R 7 These are, independently, hydrogen and C. 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkynyl, halogen, C 1-6 Haloalkyl, C 1-6 Alkylamine, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -OR 8a -NO2, -CN, -C(O)R 8b , -C(O)OR 8b -OC(O)R 8b , -OC(O)OR 8b , -N(R 8b R 8c ), -N(R 8b )C(O)R 8c ,-C(O)N(R 8b R 8c ), -N(R 8b )C(O)OR 8c ,-OC(O)N(R 8b R 8c ), -N(R 8b )C(O)N(R 8c R8d ), -C(O)C(O)N(R 8b R 8c ), -S(O2)R 8b -S(O)2N(R 8b R 8c ), C 3-8 Cycloalkyl, C 3-14 Alkyl-cycloalkyl, C 4-10 Heterocycloalkyl, C 4-16 Alkyl-heterocycloalkyl, C 6-12 Ariel, C 7-18 Alkyl-aryl, C 5-10 Heteroaryl, or C 4-16 It is an alkyl-heteroaryl; R 8a C 3-8 Cycloalkyl, C 3-14 Alkyl-cycloalkyl, C 4-10 Heterocycloalkyl, C 4-16 Alkyl-heterocycloalkyl, C 6-12 Ariel, C 7-18 Alkyl-aryl, C 5-10 Heteroaryl, or C 4-16 It is an alkyl-heteroaryl; R 8b , R 8c and R 8d Each of these is 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 Forms a heterocycloalkyl group; or, R 2 and R 3 These are combined with the atoms to which they are attached, resulting in C 4-8 Cycloalkyl, C 4-10 Heterocycloalkyl, or C 6-12 To form an aryl group; or, R 4 and R 5 , R 5 and R 6 , or R 6 and R 7 These are combined with the atoms to which they are attached, resulting in C 3-6Cycloalkyl, C 3-6 Heterocycloalkyl, C 6-12 Aryl, or C 5-10 Forms a heteroaryl group; and L is C 1-6 The present invention provides a method for treating brain disorders by contacting a compound or pharmaceutically acceptable salt thereof that is alkylene with another compound.

[0171] In some embodiments, the present invention relates to a method for treating brain injury, wherein a therapeutically effective amount of formula I{wherein X is N or CR} is given to a subject in need thereof. 3 And; R 1a , R 1b , and R 1c These are, independently, hydrogen and C. 1-6 Alkyl, C 3-8 Cycloalkyl, or C 4-14 It is alkyl-cycloalkyl; or, R 1a , R 1b , and R 1c Two of them are combined with the atom to which they are attached to C 3-12 Forms heterocycloalkyl groups; R 2 , R 3 , R 4 , R 5 , R 6 , and R 7 These are, independently, hydrogen and C. 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkynyl, halogen, C 1-6 Haloalkyl, C 1-6 Alkylamine, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -OR 8a -NO2, -CN, -C(O)R 8b , -C(O)OR 8b -OC(O)R 8b , -OC(O)OR 8b , -N(R 8b R 8c ), -N(R 8b )C(O)R 8c ,-C(O)N(R 8b R 8c ), -N(R8b )C(O)OR 8c ,-OC(O)N(R 8b R 8c ), -N(R 8b )C(O)N(R 8c R 8d ), -C(O)C(O)N(R 8b R 8c ), -S(O2)R 8b -S(O)2N(R 8b R 8c ), C 3-8 Cycloalkyl, C 3-14 Alkyl-cycloalkyl, C 4-10 Heterocycloalkyl, C 4-16 Alkyl-heterocycloalkyl, C 6-12 Ariel, C 7-18 Alkyl-aryl, C 5-10 Heteroaryl, or C 4-16 It is an alkyl-heteroaryl; R 8a C 3-8 Cycloalkyl, C 3-14 Alkyl-cycloalkyl, C 4-10 Heterocycloalkyl, C 4-16 Alkyl-heterocycloalkyl, C 6-12 Ariel, C 7-18 Alkyl-aryl, C 5-10 Heteroaryl, or C 4-16 It is an alkyl-heteroaryl; R 8b , R 8c and R 8d Each of these is independently H or C 1-6 Is it 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 Forms a heterocycloalkyl group; or, R 2 and R 3 These are combined with the atoms to which they are attached, resulting in C6-12 Can an aryl group be formed; or, R 4 and R 5 , R 5 and R 6 , or R 6 and R 7 These are combined with the atoms to which they are attached, resulting in C 3-6 Cycloalkyl, or C 3-6 It can form heterocycloalkyl groups; and L is C 1-6 The present invention provides a method for treating brain damage by administering a compound that is alkylene, or a salt or isomer thereof, thereby treating brain damage.

[0172] In some embodiments, the brain disorder is a neurodegenerative disorder, Alzheimer's disease, Parkinson's disease, a mental 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 mental 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 involves lithium, olanzapine (Zyprexa), quetiapine (Seroquel), risperidone (Risperdal), ariprazole (Abilify), ziprasidone (Geodon), clozapine (Clozaril), divalprox sodium (Depakote), lamotrigine (Lamictal), valproic acid (Depakene), carbamazepine (Equetro), topiramate (Topamax), levomilunacipran (Fetzima), duloxetine (Cymbalta, Yentreve), venlafaxine (Effexor), citalopram ( The treatment further includes administering one or more additional therapeutic agents, such as 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 neurological disorders as described herein. Non-limiting examples of standard care therapies include, for example, lithium, olanzapine, quetiapine, risperidone, ariprazole, ziprasidone, clozapine, divalprox sodium, lamotrigine, valproic acid, carbamazepine, topiramate, levomilunacipran, duloxetine, venlafaxine, citalopram, fluvoxamine, escitalopram, fluoxetine, paroxetine, sertraline, clomipramine, amitriptyline, desipramine, imipramine, nortriptyline, phenelzine, tranylcypromine, diazepam, alprazolam, clonazepam, or any combination thereof. Non-specific examples of standard care therapies for depression include sertraline, fluoxetine, escitalopram, venlafaxine, or aripiprazole. Non-specific examples of standard care therapies for depression include citralopram, escitalopram, fluoxetine, paroxetine, diazepam, or sertraline. C. Methods for enhancing at least one of the translation, transcription, or secretion of neurotrophic factors.

[0176] Neurotrophic factors refer to a family of soluble peptides or proteins that support the survival, growth, and differentiation of developing and maturing neurons. Enhancing at least one of the translation, transcription, or secretion of neurotrophic factors may be useful for enhancing neuronal plasticity, promoting neuronal proliferation, promoting neurite formation, promoting synapse formation, promoting dendritic formation, enhancing the complexity of dendritic spread, increasing dendritic spine density, and enhancing excitatory synapses in the brain, but is not limited to these effects. In some embodiments, enhancing at least one of the translation, transcription, or secretion of neurotrophic factors may enhance neuronal plasticity. In some embodiments, enhancing at least one of the translation, transcription, or secretion of neurotrophic factors may promote neuronal proliferation, promote neurite formation, promote synapse formation, promote dendritic formation, enhance the complexity of dendritic spread, and / or increase dendritic spine density.

[0177] In some embodiments, 5-HT 2A Modulator (e.g., 5-HT) 2A Agonists are used to increase at least one of the translation, transcription, or secretion of neurotrophic factors. In some embodiments, the compounds of 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 is used to treat migraines, headaches (e.g., cluster headaches), 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 intoxication (e.g., substance use disorder).

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

[0179] In some embodiments, the present invention relates to a method for enhancing at least one of the translation, transcription, or secretion of a neurotrophic factor, wherein a neuron is subjected to a sufficient amount of the following formula I: [ka] {In the formula, X is N or CR} 3 And; R 1a , R 1b , and R 1c These are, independently, hydrogen and C. 1-6 Alkyl, C 3-8 Cycloalkyl, or C 4-14 It is alkyl-cycloalkyl; or, R 1a , R 1b , and R 1c Two of them are combined with the atom to which they are attached to C 3-12 Forms heterocycloalkyl groups; R 2 , R 3 , R 4 , R 5 , R 6 , and R 7 These are, independently, hydrogen and C. 1-6 Alkyl, C 2-6 Alkenil, C 2-6 Alkynyl, halogen, C 1-6 Haloalkyl, C 1-6 Alkylamine, C 1-6 Alkoxy, C 1-6Haloalkoxy, -OR 8a -NO2, -CN, -C(O)R 8b , -C(O)OR 8b -OC(O)R 8b , -OC(O)OR 8b , -N(R 8b R 8c ), -N(R 8b )C(O)R 8c ,-C(O)N(R 8b R 8c ), -N(R 8b )C(O)OR 8c ,-OC(O)N(R 8b R 8c ), -N(R 8b )C(O)N(R 8c R 8d ), -C(O)C(O)N(R 8b R 8c ), -S(O2)R 8b -S(O)2N(R 8b R 8c ), C 3-8 Cycloalkyl, C 3-14 Alkyl-cycloalkyl, C 4-10 Heterocycloalkyl, C 4-16 Alkyl-heterocycloalkyl, C 6-12 Ariel, C 7-18 Alkyl-aryl, C 5-10 Heteroaryl, or C 4-16 It is an alkyl-heteroaryl; R 8a C 3-8 Cycloalkyl, C 3-14 Alkyl-cycloalkyl, C 4-10 Heterocycloalkyl, C 4-16 Alkyl-heterocycloalkyl, C 6-12 Ariel, C 7-18 Alkyl-aryl, C 5-10 Heteroaryl, or C 4-16 It is an alkyl-heteroaryl; R 8b , R 8c and R 8d Each of these is independently H or C 1-6 Is it alkyl; or, R 1a , R 1b , or R 1cOne of them is R 2 Combined with C 5-12 Forms a heterocycloalkyl group; or, R 2 and R 3 These are combined with the atoms to which they are attached, resulting in C 4-8 Cycloalkyl, C 4-10 Heterocycloalkyl, or C 6-12 To form an aryl group; or, R 4 and R 5 , R 5 and R 6 , or R 6 and R 7 These are combined with the atoms to which they are attached, resulting in C 3-6 Cycloalkyl, C 3-6 Heterocycloalkyl, C 6-12 Aryl, or C 5-10 Forms a heteroaryl group; and L is C 1-6 The present invention provides a method comprising contacting a compound or pharmaceutically acceptable salt thereof that is an alkylene.

[0180] In some embodiments, the present invention relates to a method for enhancing at least one of the translation, transcription, or secretion of a neurotrophic factor, wherein a neuron is subjected to a sufficient amount of a neuron of formula I {wherein X is N or CR} to enhance the neuronal plasticity of the neuron. 3 And; R 1a , R 1b , and R 1c These are, independently, hydrogen and C. 1-6 Alkyl, C 3-8 Cycloalkyl, or C 4-14 It is alkyl-cycloalkyl; or, R 1a , R 1b , and R 1c Two of them are combined with the atom to which they are attached to C 3-12 Forms heterocycloalkyl groups; R 2 , R 3 , R 4 , R 5 , R 6 , and R 7 These are, independently, hydrogen and C. 1-6Alkyl, C 2-6 Alkenil, C 2-6 Alkynyl, halogen, C 1-6 Haloalkyl, C 1-6 Alkylamine, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -OR 8a -NO2, -CN, -C(O)R 8b , -C(O)OR 8b -OC(O)R 8b , -OC(O)OR 8b , -N(R 8b R 8c ), -N(R 8b )C(O)R 8c ,-C(O)N(R 8b R 8c ), -N(R 8b )C(O)OR 8c ,-OC(O)N(R 8b R 8c ), -N(R 8b )C(O)N(R 8c R 8d ), -C(O)C(O)N(R 8b R 8c ), -S(O2)R 8b -S(O)2N(R 8b R 8c ), C 3-8 Cycloalkyl, C 3-14 Alkyl-cycloalkyl, C 4-10 Heterocycloalkyl, C 4-16 Alkyl-heterocycloalkyl, C 6-12 Ariel, C 7-18 Alkyl-aryl, C 5-10 Heteroaryl, or C 4-16 It is an alkyl-heteroaryl; R 8a C 3-8 Cycloalkyl, C 3-14 Alkyl-cycloalkyl, C 4-10 Heterocycloalkyl, C 4-16 Alkyl-heterocycloalkyl, C 6-12 Ariel, C 7-18 Alkyl-aryl, C 5-10 Heteroaryl, or C 4-16 It is an alkyl-heteroaryl; R8b , R 8c and R 8d Each of these is independently H or C 1-6 Is it 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 Forms a heterocycloalkyl group; or, R 2 and R 3 These are combined with the atoms to which they are attached, resulting in C 6-12 Can an aryl group be formed; or, R 4 and R 5 , R 5 and R 6 , or R 6 and R 7 These are combined with the atoms to which they are attached, resulting in C 3-6 Cycloalkyl, or C 3-6 It can form heterocycloalkyl groups; and L is C 1-6 The present invention provides a method comprising contacting a compound that is alkylene, or a salt or isomer thereof. [Examples]

[0181] VII. Examples General principles. Unless otherwise noted, all reagents were commercially sourced and used without purification. DMSO was purified by passing it through an activated alumina column under 12 psi N2. Reactions were carried out using glassware dried by heat under reduced pressure (~1 Torr). Compounds purified by chromatography were adsorbed onto silica gel before addition. Thin-layer chromatography was performed using Millipore silica gel 60 F 254The procedure was performed on a silica gel plate. Visualization of the developed chromatogram was performed by fluorescence quenching or by staining with ninhydrin or aqueous cerium ammonium molybdate (CAM).

[0182] Nuclear magnetic resonance (NMR) spectra, 1 H and 13 The C values ​​were acquired using either a Bruker400 operating at 400 and 100 MHz, a Varian600 operating at 600 and 150 MHz, or a Bruker800 operating at 800 and 200 MHz, and then internally standardized against the residual solvent signal. 1 The 1H NMR data was recorded as follows: chemical shift (δ, ppm), multiplicity (s, singlet; d, doublet; t, triplet; q, quadruplet; m, multiplet), integral value, and coupling constant (Hz). 13 We report the 13C NMR data in terms of chemical shift (δ, ppm). Infrared spectra were recorded using a Thermo Nicolet iS10 FT-IR spectrometer with a Smart iTX Accessory (diamond ATR), and the absorption frequencies are reported (ν, cm). -1Liquid chromatography-mass spectrometry (LC-MS) was performed using a Waters LC-MS equipped with an ACQUITY Arc QDa detector. Ketamine was purchased from Fagrone. DMT(1) and 6-F-DMT(29) were synthesized using previously established methods (purity >99% 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 (i.e., dendritic formation), all compounds were dissolved in DMSO and stored as a 10 mM solution in the dark at -20°C.

[0183] All compounds tested in the cell assay were confirmed to have a purity of >95% 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 5 μL volumes, and the column temperature was maintained at 40°C. One of three methods was used for specific compounds. Method A utilized a CORTECS C18, 2.7 μm, 4.6 x 50 mm column, a flow rate of 0.6 mL / min, and a gradient of mobile phase B from 10% to 90% over 3 minutes (and maintained for a further 2 minutes). Method B utilized an XBridge BEH C18 2.5 μm, 2.1 x 100 mm column, a flow rate of 0.6 mL / min, and a gradient of mobile phase B from 10% to 90% over 0.5 minutes (and maintained for a further 4.5 minutes). Method C utilized a CORTECS C18 2.7 μm, 4.6 x 50 mm column, a flow rate of 0.2 mL / min, and a gradient of mobile phase B from 10% to 90% over 4 minutes (and maintained for a further 2 minutes). Since most of the compounds reported in this study were isolated as fumarates, the UHPLC trace peaks corresponding to fumarate were not included in the purity calculations. isoDMT synthesis

[0184] Chemical reaction. A simple and robust method for synthesizing various isoDMTs under mild reaction conditions is described herein. Compound 2 was obtained in good yield via an in-situ Finkelstein reaction using KOH and KI as bases to enhance reactivity. Both higher and lower concentrations resulted in decreased yield, proving that maintaining the reaction at 0.4 M was optimal. Procedure A

[0185] In some embodiments, the intermediates used in the preparation of the 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 This is as described herein. In some embodiments, X is a halo or sulfone. In some embodiments, the halo is iodine, bromo, or chloro. In some embodiments, the halo is chloro. In some embodiments, the sulfone is tosylate, nosilate, brosilate, or mesylate. In some embodiments, X is chloro.

[0187] In some embodiments, indole I-1 is reacted with I-2 under suitable condensation conditions to provide substituted IsoDMT I-3, optionally followed by suitable salt formation conditions. In some embodiments, suitable condensation 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 aproton solvent. In some embodiments, the polar aproton solvent is dichloromethane (DCM), tetrahydrofuran (THF), ethyl acetate (¼), acetone, dimethylformamide (DMF), or acetonitrile (MeCN). In some embodiments, the polar aproton solvent is DMSO, DMF, MeCN, or acetone. In some embodiments, the polar aproton solvent is DMSO. In some embodiments, the appropriate time and temperature are overnight and about 25°C.

[0188] In some embodiments, suitable salt formation 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 0.4 M solution of each indole or related heterocyclic compound in DMSO, 2-chloro-N,N-dimethylethylamine hydrochloride (1.1 equiv), potassium iodide (1.1 equiv), and potassium hydroxide pellet (5.0 equiv) were added. The reaction mixture was stirred at room temperature for 24 hours, after which 1.0 M NaOH was added. (aq) The solution was diluted with [unclear]. The aqueous phase was extracted three times using DCM. The organic extracts were combined, dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the oil. The unrefined oil was dissolved in the smallest 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 the precipitate was stored overnight at -20°C. The resulting crystals were filtered and washed several times with ice-cold acetone to obtain the desired product. If the desired product did not readily crystallize as a fumarate, the oil was subjected to column chromatography (9:1 CH2Cl2:MeOH:1% NH4OH(aq)) unless otherwise noted. Example 1. N,N-dimethyltryptamine (DMT)

[0190] The following DMT compounds were prepared by methods known in the art. [ka] Example 2. 2-(1H-indole-1-yl)-N,N-dimethylethane-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 hours), as measured by TLC. The reaction mixture was then mixed with 1.0 M NaOH. (aq) Diluted with (100 mL). The aqueous phase was extracted three times with DCM (25 mL). The organic extracts were combined, dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain a colorless oil. The unrefined oil was dissolved in acetone (2 mL) and added dropwise to a boiling solution of fumaric acid (99 mg, 0.85 mmol, 1.0 equiv) in acetone (4 mL). The precipitate formed immediately afterward was stored overnight at -20°C. The crystals were filtered, washed several times with 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 CH2Cl2:MeOH:1% NH4OH) (aq) ); 1 H NMR (600 MHz, DMSO-d6) 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). 13C NMR (150 MHz, DMSO-d6) 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, 1705 cm -1 ;C 12 H 16 The calculated LRMS (ES+) value for N2+ was 188.13°C, and the measured value was 189.38°C (MH+); MP = 147-149°C. Example 3. 2-(4-methoxy-1H-indole-1-yl)-N,N-dimethylethane-1-amine fumarate (1:1)(3) [ka]

[0192] Synthesized according to Procedure A. The reaction was carried out using 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 CH2Cl2:MeOH:1% NH4OH) (aq) ); 1 H NMR (600 MHz, DMSO-d6) 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; 13C NMR (150 MHz, DMSO-d6) 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 Calculated LRMS (ES+) value for N2O+ was 219.15, measured value was 220.33 (MH+); MP = 140-145°C. Example 4. 2-(5-methoxy-1H-indole-1-yl)-N,N-dimethylethane-1-amine fumarate (1:1)(4) [ka]

[0193] Synthesized according to Procedure A. The reaction was carried out using 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 CH2Cl2:MeOH:1% NH4OH) (aq) ); 1 H NMR (600 MHz, DMSO-d6) 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; 13C NMR (150 MHz, DMSO-d6) 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 Calculated LRMS (ES+) value for N2O+ was 219.15, measured value was 220.19 (MH+); MP = 140-142°C. Example 5. 2-(6-methoxy-1H-indole-1-yl)-N,N-dimethylethane-1-amine(5) [ka]

[0194] Synthesized according to Procedure A. The reaction was carried out using 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 CH2Cl2:MeOH:1% NH4OH) (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 The calculated value for N2O+ using LRMS (ES+) was 219.15, and the measured value was 220.33 (MH+). Free bases were used in the dendritic formation assay. Example 5'. 2-(6-methoxy-1H-indole-1-yl)-N,N-dimethylethane-1-amine oxalate (5')

[0195] The compound was synthesized according to Procedure A. The reaction was carried out using 6-methoxyindole (250 mg, 1.7 mmol), and the compound was purified by crystallization. Yield = 221 mg, 42%. Purity = 98%. 1 H NMR (600 MHz, CD3OD) 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, CD3OD) 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 The calculated value of LRMS (ES+) for N2O+ was 219.15, and the measured value was 220.05 (MH+). MP = 165-167°C. Oxalate salt was used in the HTR assay. Example 6. 2-(7-methoxy-1H-indole-1-yl)-N,N-dimethylethane-1-amine fumarate (1:1)(6) [ka]

[0196] Synthesized according to Procedure A. The reaction was carried out using 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 CH2Cl2:MeOH:1% NH4OH) (aq) ); 1 H NMR (600 MHz, DMSO-d6) 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-d6) 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 Calculated value of LRMS (ES+) for N2O+: 219.15, measured value: 220.40 (MH+); Mp 120-123°C. Example 7. Benzyl oxyindole

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

[0198] Synthesized according to Procedure A. The reaction was carried out using 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 CH2Cl2:MeOH:1% NH4OH) (aq) ); 1 H NMR (400 MHz, CD3OD) 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, CD3OD) 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 . C 19 H 22 Calculated LRMS (ES+) value for N2O+ was 294.17, measured value was 295.24 (MH+); MP = 145-150°C. Example 9. 2-(5-(benzyloxy)-1H-indole-1-yl)-N,N-dimethylethane-1-amine fumarate (1:1)(9) [ka]

[0199] Synthesized according to Procedure A. The reaction was carried out using 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 CH2Cl2:MeOH:1% NH4OH) (aq) ); 1 H NMR (400 MHz, CD3OD) 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, CD3OD) 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 Calculated LRMS (ES+) value for N2O+ was 294.17°C, and the measured value was 295.17°C (MH+); MP = 133-135°C. Example 10. 2-(6-(benzyloxy)-1H-indole-1-yl)-N,N-dimethylethane-1-amine(10) [ka]

[0200] Synthesized according to Procedure A. The reaction was carried out using 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 CH2Cl2:MeOH:1% NH4OH) (aq) ); 1 H NMR (600 MHz, CD3OD) 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 The calculated value of LRMS (ES+) for N2O+ was 294.17, and the measured value was 295.10 (MH+). Example 11. 2-(7-(benzyloxy)-1H-indole-1-yl)-N,N-dimethylethane-1-amine(11) [ka]

[0201] Synthesized according to Procedure A. The reaction was carried out using 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 CH2Cl2:MeOH:1% NH4OH) (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 The calculated value of LRMS (ES+) for N2O+ was 294.17, and the measured value was 295.24 (MH+). Example 12. 2-(4-fluoro-1H-indole-1-yl)-N,N-dimethylethane-1-amine fumarate (1:1)(12) [ka]

[0202] Synthesized according to Procedure A. The reaction was carried out using 4-fluoroindole (135 mg, 1.0 mmol), and purified by crystallization. Yield = 164 mg, 51%. Purity > 99%. TLC Rf (Free base) = 0.39 (9:1 CH2Cl2:MeOH:1% NH4OH) (aq) ); 1 H NMR (400 MHz, DMSO-d6) 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-d6) 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 Calculated LRMS (ES+) value for FN2+ is 207.13, measured value is 208.32 (MH+); MP = 145-149°C. Example 13. 2-(5-fluoro-1H-indole-1-yl)-N,N-dimethylethane-1-amine fumarate (1:1)(13) [ka]

[0203] Synthesized according to Procedure A. The reaction was carried out using 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 CH2Cl2:MeOH:1% NH4OH) (aq) ); 1H NMR (400 MHz, DMSO-d6) 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-d6) 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 Calculated LRMS (ES+) value for FN2+ is 207.13, measured value is 207.40 (MH+); MP = 145-148°C. Example 14. 2-(6-fluoro-1H-indole-1-yl)-N,N-dimethylethane-1-amine fumarate (1:1) (14) [ka]

[0204] Synthesized according to Procedure A. The reaction was carried out using 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 CH2Cl2:MeOH:1% NH4OH) (aq) ); 1H NMR (600 MHz, DMSO-d6) 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-d6) 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 Calculated LRMS (ES+) value for FN2+ is 207.13, measured value is 208.39 (MH+); MP = 141-147°C. Example 15. 2-(7-fluoro-1H-indole-1-yl)-N,N-dimethylethane-1-amine fumarate (1:1)(15) [ka]

[0205] Synthesized according to Procedure A. The reaction was carried out using 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 CH2Cl2:MeOH:1% NH4OH) (aq) ); 1H NMR (400 MHz, DMSO-d6) 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, CD3OD) 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 The calculated LRMS (ES+) value for FN2+ is 207.13, and the measured value is 207.33 (MH+); MP = 168-170°C. Example 16. N,N-dimethyl-2-(2-methyl-1H-indole-1-yl)ethane-1-amine fumarate (1:1) (16) [ka]

[0206] Synthesized according to Procedure A. The reaction was carried out using 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 CH2Cl2:MeOH:1% NH4OH) (aq) ); 1H NMR (400 MHz, DMSO-d6) 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 ¹³C NMR (150 MHz, DMSO-d6) 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 -1 . C 13 H 18 The calculated LRMS (ES+) value for N2+ was 203.15°C, and the measured value was 204.43°C (MH+); MP = 131-133°C. Example 17. 2-(5,6-difluoro-1H-indole-1-yl)-N,N-dimethylethane-1-amine fumarate (1:1) (17) [ka]

[0207] Synthesized according to Procedure A. The reaction was carried out using 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 CH2Cl2:MeOH:1% NH4OH) (aq) ); 1H NMR (400 MHz, DMSO-d6) 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-d6) 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 The calculated LRMS (ES+) value for F2N2+ was 224.11°C, and the measured value was 225.28°C (MH+); MP = 162-165°C. Example 18. 2-(4,6-difluoro-1H-indole-1-yl)-N,N-dimethylethane-1-amine fumarate (1:1) (18) [ka]

[0208] Synthesized according to Procedure A. The reaction was carried out using 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 CH2Cl2:MeOH:1% NH4OH) (aq) ); 1H NMR (400 MHz, DMSO-d6) 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 ¹³C NMR (150 MHz, DMSO-d6) 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 The calculated LRMS (ES+) value for F2N2+ was 224.11°C, and the measured value was 225.28°C (MH+); MP = 141-145°C. Example 19. N,N-dimethyl-2-(6-nitro-1H-indole-1-yl)ethane-1-amine fumarate (1:1) (19) [ka]

[0209] Synthesized according to Procedure A. The reaction was carried out using 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 CH2Cl2:MeOH:1% NH4OH) (aq) ); 1H NMR (400 MHz, DMSO-d6) 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-d6) 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, 1607 cm -1 . C 12 H 16 Calculated LRMS (ES+) value for N3O2+ was 233.12°C, measured value was 234.25°C (MH+); MP = 159-164°C. Example 20. 2-(5-bromo-1H-indole-1-yl)-N,N-dimethylethane-1-amine fumarate (1:1)(20) [ka]

[0210] Synthesized according to Procedure A. The reaction was carried out using 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 CH2Cl2:MeOH:1% NH4OH) (aq) ); 1H NMR (600 MHz, DMSO-d6) 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-d6) 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 Calculated LRMS (ES+) value for BrN2+ was 266.04, measured value was 267.26 (MH+); MP = 140-142°C. Example 21. 2-(1-(2-(dimethylamino)ethyl)-1H-indole-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 using a 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) (200 mg, 0.92 mmol), and purified by chromatography). Yield = 92 mg, 35%. Purity = 98%. TLC R f(Free base) = 0.38 (9:1 CH2Cl2:MeOH:1% NH4OH) (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 The calculated value of LRMS (ES+) for N3O2+ was 287.16, and the measured value was 288.25 (MH+). Example 22. 2-(1H-benzo[d]imidazole-1-yl)-N,N-dimethylethane-1-amine fumarate (1:1)(22) [ka]

[0212] Synthesized according to Procedure A. The reaction was carried out using 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 CH2Cl2:MeOH:1% NH4OH) (aq) ); 1H NMR (400 MHz, DMSO-d6) 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, CD3OD) 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; ATR) ν 3054, 2384, 1707, 1654 cm -1 . C 11 H 15 The calculated LRMS (ES+) value for N3+ was 189.13, and the measured value was 190.23 (MH+); MP = 171-178°C. Example 23. N,N-dimethyl-2-(1H-pyrrole-1-yl)ethane-1-amine fumarate (1:1) (23)

[0213] Synthesized according to Procedure A. The reaction was carried out using 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 CH2Cl2:MeOH:1% NH4OH) (aq) ); 1 H NMR (600 MHz, CD3OD) 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, CD3OD) 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 -1C8H 14 The calculated LRMS (ES+) value for N2+ was 138.12, and the measured value was 139.29 (MH+); MP = 174-180°C. Example 24. 2-(9H-carbazol-9-yl)-N,N-dimethylethane-1-amine fumarate (1:1) (24) [ka]

[0214] Synthesized according to Procedure A. The reaction was carried out using 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 CH2Cl2:MeOH:1% NH4OH) (aq) ); 1 H NMR (600 MHz, DMSO-d6) 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-d6) 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 The calculated LRMS (ES+) value for N2+ was 238.15, and the measured value was 239.34 (MH+); MP = 182-184°C. Example 25. 1-Isopentyl-1H-Indole (25)

[0215] The compound was synthesized according to Procedure A. The reaction was carried out using indole (100 mg, 0.85 mmol) and 1-chloro-3-methylbutane (0.11 mL mg, 0.94 mmol, 1.1 equiv), and the mixture was purified by chromatography (4:1 hexane:RINKAN). Yield = 85 mg, 53%. Purity = 97%. TLC R f = 0.70 (7:3 hexanes: siRNA); 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; 13 C 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 The calculated LRMS (ES+) value for N+ was 187.14, while the measured value was 188.39 (MH+). Example 26. 3-(1H-indole-1-yl)-N,N-dimethylpropane-1-amine fumarate (1:1) (26) [ka]

[0216] Synthesized according to Procedure A. The reaction was carried out using 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 CH2Cl2:MeOH:1% NH4OH) (aq) ); 1 H NMR (600 MHz, DMSO-d6) 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; 13 C NMR (150 MHz, DMSO-d6) 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 Calculated LRMS (ES+) value for N2+ was 203.15°C, measured value 204.36°C (MH+); MP = 129-131°C. Example 27. N,N-dimethyl-2-(1-methyl-1H-indole-3-yl)ethane-1-amine fumarate (1:1) (1-Me-DMT 27)

[0217] To a chilled solution of N-methyl-2-(1-methyl-1H-indole-3-yl)ethane-1-amine (0.14 g, 0.70 mmol) and glacial acetic acid (0.22 mL, 11 mmol, 5.0 equiv) in MeOH (12 mL), sodium borohydride (0.10 g, 1.6 mmol, 2 equiv) was added, followed by 37% formaldehyde. (aq) (0.16 mL, 1.9 mmol, 6 equiv) was added. The reaction mixture was stirred at room temperature for 5 hours, and then concentrated under reduced pressure. Next, the unpurified material was mixed with CH2Cl2 (50 mL) and 1 M NaOH. (aq) Diluted with (100 mL). The phases were separated, and the aqueous phase was extracted with CH2Cl2 (2 x 50 mL). The organic extracts were combined, dried over Na2SO4, filtered, and concentrated under reduced pressure. The unpurified 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). The precipitate and solution formed immediately afterward were cooled to room temperature and then filtered. The resulting white solid was dried under reduced pressure to obtain the pure compound as fumarate (1:1). Yield = 0.108 g, 65%. Purity > 99%. TLC R f (Free base) = 0.19 (9:1 CH2Cl2:MeOH:1% NH4OH) (aq) ); 1 H NMR (600 MHz, CD3OD) 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; 13C NMR (150 MHz, CD3OD) 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 The calculated LRMS (ES+) m / z value for N2+ is 202.15, and the measured value is 203.37 (MH+); MP = 167-170°C. Example 28. 2-(5-methoxy-1H-indole-3-yl)-N,N-dimethylethane-1-amine fumarate (2:1) (DMT-5-MeO, 28)

[0218] To an ice-cold solution of 5-methoxytryptoamine (0.50 g, 2.2 mmol) and glacial acetic acid (0.60 mL, 11 mmol, 5.0 equiv) in MeOH (44 mL), sodium borohydride (0.305 g, 4.8 mmol, 2.2 equiv) was added, followed by 37% formaldehyde. (aq) (0.46 mL, 5.7 mmol, 2.6 equiv) was added. The reaction mixture was stirred at room temperature for 5 hours, and then concentrated under reduced pressure. The residue was collected in CH2Cl2 (50 mL) and 1 M NaOH. (aq) Diluted with (100 mL). The phases were separated, and the aqueous phase was extracted with CH2Cl2 (2 x 50 mL). The organic extracts were combined, dried over Na2SO4, filtered, and concentrated under reduced pressure. The unpurified 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). The precipitate and solution formed immediately afterward were cooled to room temperature and then filtered. The resulting white solid was dried under reduced pressure to obtain the pure compound as fumarate (2:1) (1:1). Yield = 0.49 g, 80%. Purity = 98%. TLC R f (Free base) = 0.20 (9:1 CH2Cl2:MeOH:1% NH4OH) (aq) ); 1H NMR (600 MHz, CD3OD) 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, CD3OD) 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 The calculated LRMS (ES+) m / z value for N2O+ was 218.14, and the measured value was 219.34 (MH+); MP = 175-177°C. Example 29. 2-(6-fluoro-1H-indole-3-yl)-N,N-dimethylethane-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-indole-3-yl)-N,N-dimethylethane-1-amine fumarate (2:1) (DMT-6-MeO, 30)

[0220] To an ice-cold solution of 6-methoxytryptoamine (0.40 g, 2.1 mmol) and glacial acetic acid (0.60 mL, 10 mmol, 5.0 equiv) in MeOH (42 mL), sodium borohydride (0.29 g, 4.6 mmol, 2.2 equiv) was added, followed by 37% formaldehyde. (aq) (0.44 mL, 5.5 mmol, 2.6 equiv) was added. The reaction mixture was stirred at room temperature for 5 hours, and then concentrated under reduced pressure. The residue was collected in CH2Cl2 (45 mL) and 1 M NaOH. (aq)Diluted with (100 mL). The phases were separated, and the aqueous phase was extracted with CH2Cl2 (2 x 45 mL). The organic extracts were combined, dried over Na2SO4, filtered, and concentrated under reduced pressure. The unpurified 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). The precipitate and solution formed immediately afterward were cooled to room temperature and then filtered. The resulting white solid was dried under reduced pressure to obtain the pure compound as fumarate (2:1). Yield = 0.320 g, 55%. Purity = 95%. TLC R f (Free base) = 0.31 (9:1 CH2Cl2:MeOH:1% NH4OH) (aq) ); 1 H NMR (600MHz, CD3OD) 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, CD3OD) 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 The calculated LRMS (ES+) m / z value for N2O+ was 218.14, and the measured value was 219.29 (MH+); MP = 173-176°C. Example 31. 2-(1H-indole-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), 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 pellet (280 mg, 5 mmol, 5.0 equiv) were added. The reaction mixture was stirred at room temperature for 24 hours, after which 1.0 M NaOH was added. (aq) Diluted with [amount]. The aqueous phase was extracted three times with DCM. The organic extracts were combined, dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the oil. The oil was purified by chromatography (3:2 hexane: Depositphotos). Yield = 175 mg, 57%. Purity = 99%. TLC R f = 0.15 (3:2 hexanes: Â); 1 H NMR (600 MHz, CD3OD) 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 Calculated LRMS (ES+) value for N2O+: 202.11°C; measured value: 203.17°C (MH+); MP = 58-61°C. Example 32. (R)-1-(5-methoxy-1H-indole-1-yl)-N,N-dimethylpropan-2-amine, fumarate [ka]

[0222] 5-Methoxyindole (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 then mixed with 1.0 M NaOH. (aq) The solution was diluted with (800 mL). The aqueous phase was extracted three times with DCM (75 mL). The organic extracts were combined, dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain a colorless oil. The unrefined oil was diluted with 1% ammonium hydroxide. (aq) The oil was purified by flash chromatography eluting with 9:1 DCM:MeOH. 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 formed immediately afterward was filtered and washed several times with ice-cold acetone to obtain the desired product. If no precipitate formed, the mixture was concentrated until crystallization was promoted to obtain the desired product (1:1 hybrid:fumaric acid). 1 H NMR (400 MHz, DMSO-d6) 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-indole-1-yl)-N,N-dimethylpropan-2-amine, fumarate [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 then mixed with 1.0 M NaOH. (aq) The solution was diluted with (100 mL). The aqueous phase was extracted three times with DCM (25 mL). The organic extracts were combined, dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain a colorless oil. The unrefined oil was diluted with 1% ammonium hydroxide. (aq) The oil was purified by flash chromatography eluting with 9:1 DCM:MeOH. 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 formed immediately afterward was filtered and washed several times with ice-cold acetone to obtain the desired product. If no precipitate formed, the mixture was concentrated until crystallization was promoted to obtain the desired product (1:1 mixture:fumaric acid) (111 mg, 68%). 11H 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). 13 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-indole-1-yl)-N,N-dimethylpropane-2-amine

Chem.

[0224] Synthesized according to Procedure A. 1 1H NMR (600 MHz, CD3OD) 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-indole-1-yl)-N,N-dimethylpropane-2-amine

Chem.

[0225] It was synthesized according to procedure A. 1 H 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-indole-1-yl)-N,N-dimethylpropane-2-amine [ka]

[0226] It was 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-indole-1-yl)-N,N-dimethylpropane-2-amine [ka]

[0227] It was 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-indole-1-yl)-N,N-dimethylpropane-2-amine [ka]

[0228] It was 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-dimethylpropane-2-amine [ka]

[0229] It was synthesized according to procedure A. 11H 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]imidazole-1-yl)-N,N-dimethylpropane-2-amine

Chem.

[0230] It was synthesized according to Procedure A. 1 1H 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-indole-3-yl)ethane-1-amine

Chem.

[0231] tert-butyl(2-(1H-indole-3-yl)ethyl) carbamate. Boc2O (0.77 g, 3.7 mmol, 1.2 equiv) was added to an ice-cold solution of tryptamine (0.50 g, 3.1 mmol) and triethylamine (0.68 mL, 9.4 mmol, 3 equiv) in CH2Cl2 (44 mL). The reaction mixture was warmed to room temperature, stirred overnight, and then quenched with H2O (200 mL). The organic phase was separated, and the aqueous phase was extracted with CH2Cl2 (2 x 50 mL). The organic extracts were combined, dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain an oil purified by silica gel chromatography (8:2 hexane:siRNA); a white solid (0.69 g, 85%).

[0232] N-methyl-2-(1-methyl-1H-indole-3-yl)ethane-1-amine. To an ice-cold solution of sodium hydride (0.23 g, 5.8 mmol, 2.2 equiv) in DMF (3 mL), tert-butyl(2-(1H-indole-3-yl)ethyl) carbamate (0.69 g, 2.6 mmol) in DMF (3 mL) was added. 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 mixture was stirred at room temperature for 20 hours. Next, the reaction mixture was cooled to 0°C, quenched with TFA (2 mL), and stirred for 30 minutes. The mixture was then mixed with 1.0 M NaOH. (aq) The solution was diluted with (600 mL) and extracted with CH2Cl2 (3 x 75 mL). The organic phase was combined, dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain an oil usable without further purification (0.45 g, 90%). Procedure B General synthesis scheme [ka]

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

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

[0235] General Procedure-3 (GP-B3): To a stirred solution of A (1.0 eq) in DMF (10 vol), K2CO3 (3.0 eq) was added, followed by the addition of reagent B (2.0 eq) and NaI (1.0 eq) at room temperature. The contents were then heated at 70°C for 16 hours. The reaction was observed by TLC.

[0236] General Workup / Purification Procedure - B1: The reactants were diluted and quenched with ice-cold water. 2N HCl aqueous solution was added until the pH of the solution reached 2. The resulting aqueous layer was washed with SiO2 until all unreacted starting materials were completely removed (TLC). The aqueous layer was then basicized with NaHCO3 aqueous solution and extracted with SiO2. The combined organic layers were then washed with water, followed by brine, dried over anhydrous Na2SO4, and concentrated to obtain the expected product which was sufficiently pure (>95% LC-MS and HPLC purity).

[0237] General Workup / Purification Procedure - B2: The reaction mixture was quenched with ice-cold water and extracted with ethyl acetate. The combined organic layer was washed with ice-cold water, followed by washing with brine. The organic layer was separated, dried over Na2SO4, and concentrated under reduced pressure to obtain starting material to be purified by combi-flash chromatography using either Depositphotos / heptane or CH2Cl2 / MeOH gradients based on the polarity of the compound. The pure fraction was removed by distillation and dried to obtain the compound with >95% LC-MS and HPLC purity. Example 42. 2-(5-methoxy-1H-indole-1-yl)-N,N-dimethylethane-1-amine [ka]

[0238] The compound was synthesized according to procedure B. GP-1 and work-up / purification procedure-1 were followed. Yield: 44% (brown liquid). LC-MS: 97.8%, m / z=219.2 [M+H] + 1 H NMR (DMSO-d6, 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-indole-1-yl)-N,N-dimethylethane-1-amine [ka]

[0239] The compound was synthesized according to procedure B. GP-1 and work-up / purification procedure-1 were followed. Yield: 44% (brown liquid). LC-MS: 95.4%, m / z=219.2 [M+H] + 1H NMR (DMSO-d6, 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-(pyrrolidine-1-yl)ethyl)-1H-indole [ka]

[0240] The compound was synthesized according to procedure B. GP-1 and work-up / purification procedure-1 were followed. Yield: 16% (yellow semi-solid). LC-MS: 98.2%, m / z=245.2 [M+H] + 1 H NMR (DMSO-d6, 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-(piperidine-1-yl)ethyl)-1H-indole [ka]

[0241] Synthesized according to procedure B. GP-1 and workup / purification procedure-1 were followed. Yield: 34% (brown solid). LC-MS: 99.5%, m / z=259.2 [M+H] + 1H NMR (DMSO-d6, 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-indole-1-yl)ethyl)morpholine [ka]

[0242] Synthesized according to procedure B. GP-1 and work-up / purification procedure-1 were followed. Yield: 28% (brown solid). LC-MS: 99.5%, m / z=261.2 [M+H] + 1 H NMR (DMSO-d6, 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-(pyrrolidine-1-yl)ethyl)-1H-indole [ka]

[0243] The compound was synthesized according to procedure B. GP-1 and work-up / purification procedure-1 were followed. Yield: 28% (brown liquid). LC-MS: 97%, m / z=248.11 [M+H] + 1H NMR (DMSO-d6, 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-(piperidine-1-yl)ethyl)-1H-indole [ka]

[0244] The compound was synthesized according to procedure B. GP-1 and work-up / purification procedure-2 were followed. Yield: 20% (yellow semi-solid). LC-MS: 95.18%, m / z=263.2 [M+H] + 1 H NMR (DMSO-d6, 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-indole-1-yl)ethyl)morpholine [ka]

[0245] The compound was synthesized according to procedure B. GP-1 and work-up / purification procedure-1 were followed. Yield: 28% (colorless liquid). LC-MS: 98.9%, m / z=265.2 [M+H]+ 1 H NMR (DMSO-d6, 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-(pyrrolidine-1-yl)ethyl)-5-(trifluoromethoxy)-1H-indole [ka]

[0246] The compound was synthesized according to procedure B. GP-2 and work-up / purification procedure-2 were followed. Yield: 22% (brown semi-solid). LC-MS: 99.8%, m / z=299.2 [M+H] + 1 H NMR (CD3OD, 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-(piperidine-1-yl)ethyl)-5-(trifluoromethoxy)-1H-indole [ka]

[0247] The compound was synthesized according to procedure B. GP-1 and work-up / purification procedure-2 were followed. Yield: 25% (brown liquid). LC-MS: 99.6%, m / z=313.2 [M+H] + 1H NMR (DMSO-d6, 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-indole-1-yl)ethyl)morpholine [ka]

[0248] The compound was synthesized according to procedure B. GP-2 and work-up / purification procedure-2 were followed. Yield: 22% (brown liquid). LC-MS: 98.27%, m / z=315.2 [M+H] + 1 H NMR (DMSO-d6, 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-indole-1-yl)-N,N-dimethylethane-1-amine [ka]

[0249] The compound was synthesized according to procedure B. GP-1 and work-up / purification procedure-1 were followed. Yield: 27% (brown liquid). LC-MS: 98.9%, m / z=219.2 [M+H] + 1H NMR (DMSO-d6, 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-indole-1-yl)-N,N-dimethylethane-1-amine [ka]

[0250] The compound was synthesized according to procedure B. GP-1 and work-up / purification procedure-1 were followed. Yield: 27% (brown liquid). LC-MS: 98.8%, m / z=219.2 [M+H] + 1 H NMR (DMSO-d6, 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]imidazole-1-yl)-N,N-dimethylethane-1-amine [ka] Example 56. 2-(6-methoxy-1H-benzo[d]imidazole-1-yl)-N,N-dimethylethane-1-amine [ka]

[0251] The compound was synthesized according to Procedure B. The reaction was attempted in Example 55 using GP-2 with slight modification (using 1 eq of NaI). A mixture of legomers was obtained by Workup / Purification Procedure-2. The mixture was separated by positive-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% (pale yellow solid). LCMS: 99.8%, m / z = 220.1 [M+H] + 1 H NMR (DMSO-d6, 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]imidazole-1-yl)-N,N-dimethylethane-1-amine [ka]

[0253] The compound was synthesized according to procedure B. GP-1 and work-up / purification procedure-2 were followed. Yield: 4% (colorless liquid). LCMS: 99.7%, m / z = 190.2 [M+H] + 1H NMR (DMSO-d6, 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]imidazole-1-yl)ethane-1-amine [ka]

[0254] The compound was synthesized according to procedure B. GP-3 and work-up / purification procedure-2 were followed. Yield: 15% (yellow liquid). LCMS: 98.3%, m / z = 204.2 [M+H] + 1 H NMR (DMSO-d6, 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 Common synthesis scheme: [ka] General synthesis procedure:

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

[0256] Workup and purification after Step-C1: The reaction mixture was quenched with ice-cold water and extracted with ethyl acetate. The combined organic layer was washed with ice-cold water, followed by washing with aqueous NaCl solution. The organic layer was separated, dried over Na2SO4, and concentrated to obtain the starting material. The starting material was purified by combi-flash purification using 10-20% toluene in hexane, then the washing fraction (by TLC) was removed by distillation, and the mixture was dried under reduced pressure to obtain compound F.

[0257] Step C2: Triethylamine (2.5 eq) was added to a stirred solution of compound F (1 eq) in CH2Cl2 (10 vol), and the resulting solution was cooled to 0°C. Mesylchloride (1.5 eq) was added, the mixture was heated to room temperature, and stirred for 1-2 hours. The reaction was observed by TLC.

[0258] Workup after Step-C2: The reaction mixture was quenched with ice-cold water and extracted with CH2Cl2. The combined organic layer was washed with saturated bicarbonate aqueous solution, followed by washing with water. The organic layer was separated, dried over Na2SO4, and concentrated to obtain unpurified compound G, which was used in the next step without further purification.

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

[0260] Workup and purification after step C3: The reaction was quenched with water and extracted with Â. The organic layer was separated, washed with water, and then with brine. The separated organic layer was dried over anhydrous Na₂SO₄ and removed by distillation to obtain the unpurified product. The unpurified product was purified by combi-flash purification using 5–10% Â in CH₂Cl₂ / 5–10% MeOH in CH₂Cl₂, and the washing fraction (by TLC) was then removed by distillation under reduced pressure and dried to obtain the target compound. Example 59. (R)-1-(5-methoxy-1H-indole-1-yl)-N,N-dimethylpropane-2-amine [ka]

[0261] Step-C1: Yield: 71% (light brown liquid). 1 H NMR (DMSO-d6, 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-d6, 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, CH2Cl2). LC-MS: 99.4%, m / z=233.2 [M+H] + 1H NMR (DMSO-d6, 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-indole-1-yl)-N,N-dimethylpropane-2-amine

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[0264] Structural-C1: Yield: 50% (thin brown liquid). 1 H NMR (DMSO-d6, 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: Mesitate was prepared using the general procedure described above, and then treated with NaN3 (1.5 eq) in DMF (10 vol) at 70°C for 2 hours. The reaction was observed by TLC. After the reaction was complete, the reaction mixture was diluted with water and extracted with siRNA. The combined organic layers were washed twice with cold water and then removed by distillation to obtain the unpurified product. This was treated with 10% Pd / C (50% water) in MeOH under a hydrogen atmosphere to obtain the unpurified amine. The unpurified product was purified by combi-flush using 1% MeOH in CH2Cl2, and the washing fraction was removed by distillation to obtain the amine. This was treated with paraformaldehyde (10 eq) in MeOH / DCM (10 vol, 2:1), then with AcOH (Cat), followed by the addition of NaBH3CN (6.0 eq), and stirred for 1 hour. The reaction was observed by TLC. After aqueous workup, the unpurified material was purified by preparation HPLC, followed by combi-flush purification, to obtain the above compound with an isolation yield of 30%.

[0266] The HPLC purification method for preparation is shown below: 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, CH2Cl2). LC-MS: 99.5%, m / z=221.2 [M+H] + 1H NMR (DMSO-d6, 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-d6, 376 MHz): δ -127.18 (s, 1F). Example 61. (R)-1-(6-fluoro-5-methoxy-1H-indole-1-yl)-N,N-dimethylpropane-2-amine

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[0268] Structural-C1: Yield: 74% (brown liquid). 1 H NMR (DMSO-d6, 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] Structural-C2: brown solid. 1 H NMR (DMSO-d6, 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] Suppressor C3: Yield: 14% (2 Suppressor, brown liquid). [α] D 20 = -19.7 (C 0.5, CH2Cl2). LC-MS: 98.5%, 251.2 [M+H] + 1 H NMR (DMSO-d6, 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-d6, 376 MHz): δ -142.08 (s, 1F). Example 62. (R)-1-(5,6-dimethoxy-1H-indole-1-yl)-N,N-dimethylpropane-2-amine

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[0271] Structural-C1: Yield: 50% (thin brown liquid). 1 H NMR (DMSO-d6, 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] Structural-C2: Thin brown semi-solid. 1H NMR (DMSO-d6, 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-d6, 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-indole-1-yl)-N,N-dimethylpropane-2-amine [ka]

[0274] Step C1: Yield: 35% (colorless liquid). 1 H NMR (DMSO-d6, 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: Pale yellow semi-solid. 1H NMR (DMSO-d6, 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, CH2Cl2). LC-MS: 99.25%, 263.2 [M+H] + 1 H NMR (DMSO-d6, 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-indole-1-yl)-N,N-dimethylpropane-2-amine

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[0277] Structural-C1: Yield: 83% (colorless liquid). 1H NMR (DMSO-d6, 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] ステップ-C2: Thin yellow semi-solid. 1 H NMR (DMSO-d6, 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] Suppressor C3: Yield: 8% (2 Suppressor, thin brown liquid). [α] D 20 = -19.10 (C 0.125, CH2Cl2). LC-MS: 99%, 247.2 [M+H] + 1 H NMR (DMSO-d6, 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-indole-1-yl)-N,N-dimethylpropane-2-amine

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[0280] Step-C1: Yield: 75% (light brown liquid). 1 H NMR (DMSO-d6, 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: Pale yellow syrup. 1 H NMR (DMSO-d6, 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 two steps, brown liquid). [α] D 20 = -6.34 (C 0.5, CH2Cl2). LC-MS: 99.43%, 247.2 [M+H] + 1H NMR (DMSO-d6, 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-indole-1-yl)-N,N-dimethylpropane-2-amine [ka]

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

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

[0285] Step C3: Yield: 19% (over two steps). [α] D 20 = -1.82 (C 0.5, CH2Cl2). LC-MS: 99.76%, 247.1 [M+H] + 1 H NMR (DMSO-d6, 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-indole-1-yl)-N,N-dimethylpropane-2-amine [ka]

[0286] Step-C1: Yield: 58% (light brown liquid). 1 H NMR (DMSO-d6, 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-d6, 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, CH2Cl2). LC-MS: 99.08%, m / z=239.2 [M+H] + 1 H NMR (DMSO-d6, 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-indole-1-yl)-N,N-dimethylpropane-2-amine [ka]

[0289] Step-C1: Yield: 63% (light brown liquid). 1 H NMR (DMSO-d6, 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] Step-C2: Pale yellow semi-solid. 1 H NMR (DMSO-d6, 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, CH2Cl2). LC-MS: 96.1%, m / z=239.2 [M+H] + 1H NMR (DMSO-d6, 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-d6, 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-indole-1-yl)-N,N-dimethylpropane-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% (a colorless liquid produced over two steps). [α] D 20 = -28.5 (C 0.5, CH2Cl2). LC-MS: 99.2%, m / z=239.1 [M+H] + 1H NMR (DMSO-d6, 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-d6, 376 MHz): δ -124.28 (s, 1F), -132.87 (s, 1F). Example 70. (R)-1-(5-fluoro-6-methoxy-1H-indole-1-yl)-N,N-dimethylpropane-2-amine

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

[0296] ステップ-C2: Yellow semi-solid.

[0297] Structural C3: Yield: 32% (2 ステップにわたる, colorless liquid). [α] D 20 = -8.05 (C 0.5, CH2Cl2). LC-MS: 98.4%, m / z=235.1 [M+H] + 1 H NMR (DMSO-d6, 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-d6, 376 MHz): δ -146.29 (s, 1F). Example 71. (R)-1-(5-fluoro-6-methyl-1H-indole-1-yl)-N,N-dimethylpropane-2-amine [ka]

[0298] Step-C1: Yield: 69% (light brown liquid). 1 H NMR (DMSO-d6, 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] Step-C2: Pale yellow solid. 1 H NMR (DMSO-d6, 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] Step C3: Yield: 24% (a light brown liquid obtained over two steps). [α] D 20 = -20.50 (C 0.5, CH2Cl2). LC-MS: 99.3%, m / z=235.1 [M+H] + 1H NMR (DMSO-d6, 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-d6, 376 MHz): δ -130.78 (s, 1F). Example 72. (R)-1-(5-fluoro-7-methyl-1H-indole-1-yl)-N,N-dimethylpropane-2-amine

change

[0301] Structural-C1: Yield: 72%, thin brown liquid. 1 H NMR (DMSO-d6, 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-d6, 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] Structural C3: Yield: 19% (2 ステップにわたる, thin brown liquid). [α] D 20 = -2.43 (C 0.5, CH2Cl2). LC-MS: 99.8%, m / z=235.1 [M+H] + 1 H NMR (DMSO-d6, 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-d6, 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 method (4-fluoro-2-methyl-1-nitrobenzene in THF (10 vol) was treated with 4 eq of 1 M magnesium vinyl bromide at -40°C for 3 hours). After the reaction was completed by TLC, the reaction mixture was quenched with saturated NH4Cl and extracted with siRNA. The combined organic layers were washed with brine and then with water to obtain the unpurified product. The unpurified product was purified by combi-flush with 5% siRNA in hexane, and the washing fraction was removed by distillation to obtain 5-fluoro-7-methyl-1H-indole in an isolated yield of 27%. Example 73. (R)-1-(5-fluoro-2-methyl-1H-indole-1-yl)-N,N-dimethylpropane-2-amine [ka]

[0305] Step C1: Yield: 33% (colorless liquid). 1 H NMR (DMSO-d6, 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% (a colorless liquid, performed over two steps). [α] D 20 = -36.86 (C 0.25, CH2Cl2). LC-MS: 94.4%, m / z=235.2 [M+H] + 1H NMR (DMSO-d6, 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-d6, 376 MHz): δ -127.21 (s, 1F). Example 74. (R)-1-(5-fluoro-3-methyl-1H-indole-1-yl)-N,N-dimethylpropane-2-amine

change

[0308] Structural-C1: Yield: 35% (thin brown liquid). 1 H NMR (DMSO-d6, 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-d6, 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, CH2Cl2). LC-MS: 95%, m / z=235.2 [M+H] + 1 H NMR (DMSO-d6, 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-d6, 376 MHz): δ -127.47 (s, 1F). Example 75. (R)-1-(5-methoxy-1H-indole-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 described in the general procedure. Yield: 44% (light brown solid). 1 H NMR (DMSO-d6, 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, 0.88 (t, J=7.40Hz, 3H).

[0312] Step-C2: Pale yellow solid. 1H NMR (DMSO-d6, 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] Step C3: Yield: 26% (over two steps, brown solid). [α] D 20 = -22.57 (C 0.5, CH2Cl2). LC-MS: 96.7%, m / z=247.2 [M+H] + 1 H NMR (DMSO-d6, 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=7.40Hz, 3H). Example 76. (S)-1-(5-methoxy-1H-indole-1-yl)-N,N-dimethylbutan-2-amine [ka]

[0314] Step C1: The epoxide used in the reaction is (R)-2-ethyloxirane, and the rest of the procedure is the same as described in the general procedure. Yield: 34% (light brown liquid). 1H NMR (DMSO-d6, 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), 0.88 (t, J=7.40 Hz, 3H).

[0315] Structural-C2: Thin brown solid. 1 H NMR (DMSO-d6, 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] Suppressor C3: Yield: 52% (2 Suppressor, brown solid). [α] D 20 = + 24.8 (C 0.5, CH2Cl2). LC-MS: 99.68%, m / z=247.2 [M+H] + 1H NMR (DMSO-d6, 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-indole-1-yl)-N,N-dimethylpropane-2-amine [ka]

[0317] Step-C1: Yield: 75% (light brown liquid). 1 H NMR (DMSO-d6, 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, CH2Cl2). LC-MS: 99.83%, m / z=263.1 [M+H] + 1H NMR (DMSO-d6, 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=6.60Hz, 3H). Example 78. (R)-1-(5-fluoro-3-methoxy-1H-indole-1-yl)-N,N-dimethylpropane-2-amine [ka]

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

[0321] Step-C2: Pale yellow solid.

[0322] Step C3: Yield: 3% (a light brown liquid obtained over two steps). [α] D 20 = -17.6 (C 0.25, CH2Cl2). LC-MS: 99.13%, m / z=251.1 [M+H] + 1H NMR (DMSO-d6, 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-indole-1-yl)-N,N-dimethylpropane-2-amine [ka] Step-C1: Yield: 45% (light brown solids). 1 H NMR (DMSO-d6, 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: Pale yellow semi-solid. Step C3: Yield: 30% (a light brown liquid obtained over two steps). [α] D 20 = -24.14 (C 0.25, CH2Cl2). LC-MS: 96.9%, m / z=271.0 [M+H] + 1H NMR (DMSO-d6, 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 Common synthesis scheme: [ka] General synthesis procedure:

[0323] Step-D1: To a stirred solution of compound J (1 eq) in CHCl3 (10 vol), SOCl2 (5 eq) was added at 0°C, and the resulting solution was heated under reflux temperature for 12 hours. The reaction was observed by TLC.

[0324] Workup after Step-D1: The reaction mixture was removed by distillation, and then removed twice with toluene (10 vol). The resulting unpurified product 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), NaH (60% in mineral oil, 1.5 eq) was added at 0°C. The reaction mixture was stirred for 30 minutes, then compound I (1.0 eq) was added, followed by NaI (cat.). The reaction mixture was slowly heated to room temperature, then heated to 65°C, and stirred for 16 hours. The reaction was observed by TLC.

[0326] Workup and Purification: The reaction mixture was cooled to RT, quenched with ice-cold water, and extracted with ethyl acetate. The combined organic layer was washed with ice-cold water, followed by washing with aqueous NaCl solution. The organic layer was separated, dried over Na2SO4, and concentrated to obtain the starting material. The starting material was purified by combi-flash purification using 2–5% MeOH in CH2Cl2, then the washing fraction (by TLC) was removed by distillation, and the mixture was dried under reduced pressure to obtain the desired product. Example 80. (S)-5-Methoxy-1-((1-methylpiperidine-2-yl)methyl)-1H-indole [ka]

[0327] Step D1: (S)-(1-methylpiperidine-2-yl)methanol was treated with SOCl2 using the general procedure described above to obtain the respective chlorides.

[0328] Step D2: Yield: 13% (semi-solid, light brown, over two steps). [α] D 20 = -85.8 (C 0.25, CH2Cl2). LC-MS: 99%, m / z=259.1 [M+H] + 1 H NMR (DMSO-d6, 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-methylpyrrolidine-2-yl)methyl)-1H-indole [ka]

[0329] Step D1: (S)-(1-methylpyrrolidine-2-yl)methanol was treated with SOCl2 using the general procedure described above to obtain the respective chlorides.

[0330] Step D2: Yield: 11% (over two steps, brown liquid). [α] D 20 = -62.7 (C 0.45, CH2Cl2). 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-methylpiperidine-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, CH2Cl2). LC-MS: 97.4%, m / z=259.2 [M+H] + 1H NMR (DMSO-d6, 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-methylpyrrolidine-2-yl)methyl)-1H-indole [ka]

[0332] Step-D1: (R)-(1-methylpyrrolidine-2-yl)methanol was treated with SOCl2 using the general procedure described above to obtain the respective chlorides.

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

[0334] Details of the HPLC purification process for preparation are shown 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% (colorless solid, obtained in two steps). [α] D 20 = + 79.47 (C 0.5, CH2Cl2). LC-MS: 99.9%, m / z=245.1 [M+H] + 1 H NMR (DMSO-d6, 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 Common synthesis scheme: [ka] General synthesis procedure:

[0336] Step E1: To a stirred solution of K (1.0 eq) in DMF (10 vol), NaH (60% in mineral oil, 1.2 eq) was added at 0°C, and the reaction mixture was stirred for 20 minutes. Reagent L (1.0 eq) was added to the reactant, and the mixture was then slowly heated to room temperature and stirred for 16 hours. The reaction was observed by TLC. The TLC showed nonpolar spots with respect to K.

[0337] Workup after step E1: The reaction mixture was quenched with ice-cold water and extracted with ethyl acetate. The combined organic layer was washed with ice-cold water, followed by washing with brine. The organic layer was separated, dried over Na2SO4, and concentrated under reduced pressure to obtain the starting material. The starting material was purified by combi-flash chromatography using toluene / heptane, and the washing fraction was then removed by distillation to obtain M.

[0338] Step E2: To a stirred solution of M (1.0 eq) in DMF (10 vol), K2CO3 (3 eq) was added at room temperature, followed by the addition of reagents N (1.2 eq) and NaI (1 eq). The reaction mixture was then heated at 70°C for 16 hours. The reaction was observed by TLC. The TLC showed polar spots with respect to M.

[0339] Workup after Step E2: The reaction mixture was quenched with ice-cold water and extracted with ethyl acetate. The combined organic layer was washed with ice-cold water, followed by washing with brine. The organic layer was separated, dried over Na2SO4, and concentrated under reduced pressure to obtain the starting material. The starting material was purified by combi-flash chromatography using a CH2Cl2 / MeOH-based system, and the washing fraction (by TLC) was removed by distillation. The mixture was dried to obtain the target compound with >95% LC-MS and HPLC purity. Example 84. 6-(2-(5-methoxy-1H-indole-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-d6, 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-indole-1-yl)ethyl)-2-oxa-6-azaspiro[3.3]heptane [ka]

[0341] Prepared according to procedure E. Yield: 25% (over two steps), brown liquid. LC-MS: 97.3%, m / z=277.0 [M+H] + . 1 H NMR (DMSO-d6, 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-indole-1-yl)-N,N-dimethylpropane-2-amine [ka]

[0342] It was prepared according to procedure C. 1 H NMR (DMSO-d6, 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] The SAR study was conducted by comparing the effects of DMT(1) with those of 1-Me-DMT(27) and isoDMT(2). While DMT has the potential to act as a hydrogen bond donor when binding to its target receptor, 27 and 2 did not. Since both 27 and 2 enhanced the complexity of dendritic extension to a degree comparable to 1, despite the lack of indole N-H bonds (Figure 2), this potential hydrogen bond interaction may not be important for inducing plasticity in the compounds.

[0344] 5-MeO-DMT (28) and 6-F-DMT (29) were selected as electron-rich and electron-deficient DMT analogs, respectively. Compound 28 promotes neurite formation in the dentate gyrus and alleviates symptoms of depression and anxiety in humans. Compound 29 was predicted to be non-hallucinogenic because fluorination of the DMT analog reduces its hallucinogenic potential. Examples 5 and 13 of the isoDMT analog were carried out in the same manner as 28 and 29 (Figure 3), and SAR data related to neuronal proliferation obtained using derivatives of the isoDMT scaffold can be applied to derivatives of the DMT scaffold due to the similarity resulting from the isometric volume properties of the two structures.

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

[0346] Modification of the aromatic ring was generally well tolerated (Figure 4C). Conversion of indole to benzimidazole (22), pyrrole (23), or carbazole (24) had minimal effect on the ability of these molecules to promote neuronal proliferation. Furthermore, substitutions at the 2 and 3 positions of indole (16 and 21, respectively) were well tolerated. Taken together, it appears that minimal amounts of psychoplastogen pharmacophores are involved in modifiable aromatic rings separated from basic nitrogen by short linkers.

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

[0348] To measure whether DMT and isoDMT derivatives exhibited differences in psychoplastogenic potency, concentration-response experiments were conducted (Figure 6). The isoDMT analogs (2 and Example 5) produced comparable maximal potency and exhibited similar potency as isometric volume DMT (1 and 28). Furthermore, they were able to enhance the complexity of dendritic spreading at concentrations as low as 1 nM. These compounds showed comparable potency and potency 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 identification and head spasm response (HTR) assays (Figure 8).

[0349] DMT and other hallucinogenic compounds are 5-HT 2A -Through a dependent process, it promotes enhanced dendritic spread complexity, dendritic spine density, and synapse formation. 5-HT 2A Pretreatment of cortical cultures with antagonists 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, and their mechanisms of action were influenced by 5-HT 2A The receptors were also involved (Figure 7).

[0350] Hallucinogenic potential. The hallucinogenic compound 5-MeO-DMT (28) produced a more robust, dose-dependent HTR in female mice. However, the isometric compound 6-MeO-isoDMT (Example 5) was not significantly potent (Figure 8). As expected based on drug identification data, 6-MeO-DMT (30) did not produce HTR. Finally, compounds that promote potent plasticity (Examples 4, 59, and 60) did not produce any HTR at all (Figures 8 and 9), demonstrating that hallucinogenic potential and psychoplastogenicity cannot be separated.

[0351] Hallucinogenic substances (e.g., LSD and 5-MeO-DMT) are agonist-induced in 5HT mode. 2AThese compounds activate the sensor assay, but their non-hallucinogenic congeners (lislid (LIS) and 6-MeO-DMT) do not (Figure 10). Furthermore, compounds that are hallucinogenic in animals (e.g., humans), such as 5-MeO-DMT, LSD, DMT, and DOI, are activated in 5HT mode. 2A Compounds that activate sensor assays but are non-hallucinogenic in animals (e.g., humans), such as 6-MeO-DMT, LIS, 6-F-DET, L-MDMA, R-MDMA, Ketanserin, and BOL148, are agonist-activated in 5HT mode. 2A The sensor assay is not activated (Figure 11, with 10 μM compound). In some embodiments, the hallucinogenic potential of the compound of the present invention is determined in vitro. In some embodiments, the hallucinogenic potential of the compound of the present invention is 5HT 2A Determined using a sensor assay. In some embodiments, 5HT 2A The sensor assay is either agonist mode or antagonist mode. In some embodiments, 5HT 2A The sensor assay is in agonist mode. In some embodiments, the compounds of the present invention that do not activate the sensor in agonist mode are non-hallucinogenic. In some embodiments, the compounds of the present invention that do not activate the sensor in agonist mode are non-hallucinogenic compounds.

[0352] Table 1 shows the hallucinogenic potential of compounds evaluated in agonist mode in several embodiments. Table 1 [Table 3-1] [Table 3-2]

[0353] Furthermore, non-hallucinogenic compounds (e.g., lithlid and 6-MeO-DMT) are 5HT 2AWhen the sensor assay is operated in antagonist mode, it competes with 5-HT (Figures 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 the antagonist mode sensor assay. 2A It competes with 5HT that binds to it (Figure 13, in the 10 μM compound). In some embodiments, the compounds of the present invention compete with 5HT 2A It prevents the binding of 5-HT to 5HT. In some embodiments, 2A The sensor assay is in antagonist mode. In some embodiments, 5HT 2A Compounds of the present invention that prevent the binding of 5-HT to 5HT may be non-hallucinogenic. In some embodiments, compounds of the present invention prevent the binding of 5-HT to 5HT 2A It inhibits the binding of 5-HT to and is a non-hallucinogenic compound. In some embodiments, it acts as an antagonist to 5HT 2A Compounds of the present invention that inhibit the binding of 5-HT to 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 indicated that the compound of the present invention is 5HT 2A This suggests that the compound is a non-hallucinogenic ligand for the receptor. In some embodiments, the results of antagonist mode sensor assays indicate that the compound of the present invention is 5-HT 2A This suggests that the compound is a non-hallucinogenic ligand for the receptor. In some embodiments, the results of sensor assays in agonist and antagonist modes indicate that the compound of the present invention is 5-HT 2A This also suggests that it is a non-hallucinogenic ligand for the receptor.

[0355] Table 2 shows the hallucinogenic potential of compounds evaluated in antagonist mode in several embodiments. Table 2 [Table 4]

[0356] Calcium flux assay. Calcium secondary transporter pathway. Calcium No Wash PLUS The assay is a non-image assay that uses signaling of Gq secondary signaling molecules in living cells to detect GPCRs (e.g., 5HT). 2A Observe the activation of PathHunter® cell line or Gq-linked GPCR (e.g., 5HT). 2A Calcium mobilization in other cell lines that stably express (e.g., 5HT) was observed using calcium-sensitive dyes taken up into cells. 2A ) Activation results in the release of calcium from intracellular storage and an increase in dye fluorescence, which 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, the activation of the calcium flux assay is due to the compounds of the present invention being 5-HT 2A This indicates adjusting the function.

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

[0358] Compulsory swimming test. Enhanced cortical plasticity in the anterior brain mediates the sustained (>24-hour) antidepressant-like effect of ketamine, and 5-HT 2ABecause it plays a role in the therapeutic effect of agonists, the effect of isoDMT analogs on forced swimming test (FST) behavior (Figures 14A and 14B) was evaluated. First, a preliminary study was used to induce a depressive phenotype. The compound was administered 24 hours after the preliminary study, 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 (Figure 14A vs. Figure 14B).

[0359] Neurite growth assay. Changes in neurite growth patterns were associated with neurodegenerative disorders and trauma. The discovery of novel therapeutic agents that can positively influence neurite formation is crucial for developing new therapeutic agents for neurological diseases. Automated image-based assays were used to measure neurite growth in rat cortical neurons to assess the neuroplastic effects of the compounds of the present invention. In some embodiments, the compounds of the present invention enhance the neurite growth pattern. In some embodiments, the compounds of the present invention increase the mean length of neurites compared to controls. In some embodiments, the compounds of the present invention increase the number of neurite branching points compared to controls. In some embodiments, the compounds of the present invention increase both the mean length of neurites and the number of neurite branching points compared to controls.

[0360] Table 4 shows the potential plastogenicity of compounds in several embodiments. Table 4 [Table 6] Assay

[0361] Dendritic formation assay. Historically, phenotypic screening has provided a better opportunity to identify drugs with novel mechanisms of action compared to target-based approaches. Having established a simple and robust method for obtaining isoDMT analogs, we then used phenotypic assays to test their ability to enhance the complexity of dendritic spread in central neuron cultures. Following treatment, neurons were fixed and visualized using an antibody against the cytoskeletal protein-MAP2-a localized in the somatic dendritic compartment of the neurons. Scholl analysis was then performed, and the intersections (N max The maximum number of ) was used as the quantitative distance for the complexity of dendritic spread. For statistical comparisons between specific compounds, raw N max The values ​​were compared. Percentage efficacy was measured against the vehicle (DMSO) and positive (ketamine) control, which corresponded to 0% and 100%, respectively. max It was determined by setting a value.

[0362] Animals. For dendritic formation experiments, time-pregnancy Sprague Dawley rats were obtained from Charles River Laboratories (Wilmington, MA). For head spasm response assays, male and female C57BL / 6J mice were obtained from Jackson Laboratory (Sacramento, CA). Mice were housed in groups of 4-5 individuals (same sex) in temperature and humidity-controlled rooms maintained on a 12-hour light / dark cycle. Animals weighed 17-30 g at the time of the experiment. 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. The University of California, Davis and the University of California, San Francisco are accredited by the Association for Assessment and Accreditation of Laboratory Animal Care International (AAALAC).

[0363] Dendritic formation - Sholl analysis. Dendritic formation experiments were performed according to previously established methods with minor modifications. Neurons were cultured in a 96-well system (200 μL of medium per well) at a density of approximately 15,000 cells / well in Neurobasal (Life Technologies) containing 1% penicillin-streptomycin, 10% thermoinactivated 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. Cells were treated with compounds in vitro after 3 days (DIV3). Unless otherwise noted, all compounds tested in the dendritic formation assay were treated at 10 μM. The stock solution of the compound in DMSO was first diluted 100-fold with Neurobasal, and then further diluted 10-fold in each well (total dilution = 1:1000, 0.1% DMSO concentration). Treatment was 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 a further 71 hours. At that time, neurons were fixed by removing 80% of the medium and replacing it with 4% aqueous paraformaldehyde (Alfa Aesar) in a volume equivalent to 50% of the usable range of the well. The cells were then incubated at room temperature for 20 minutes, after which the fixative was aspirated, and each well was washed twice with DPBS. The cells were permeabilized at room temperature for 20 minutes without shaking using 0.2% Triton X-100 (ThermoFisher) in DPBS. The plates were blocked at room temperature for 1 hour using antibody dilution buffer (ADB) containing 2% bovine serum albumin (BSA) in DPBS. Next, the plates were incubated overnight at 4°C with gentle shaking in ADB containing chicken anti-MAP2 antibody (1:10,000; EnCor, CPCA-MAP2).The following day, the plates were washed three times with DPBS and then once with 2% ADB in DPBS. The plates were incubated at room temperature for 1 hour with ADB containing anti-chicken IgG secondary antibody conjugated to Alexa Fluor 488 (Life Technologies, 1:500), and then washed five times with DPBS. After the final wash, 100 μL of DPBS was added to each well, and the images were scanned using an ImageXpress Micro XL High-Content Screening System (Molecular Devices, Sunnyvale, CA) with a 20x objective lens. The images were analyzed using ImageJ Fiji (version 1.51W). First, the images corresponding to each treatment were sorted into individual folders and then blinded for data analysis. Plate controls (both positive and negative) were used not only to ensure that the assay was working correctly, but also to ensure that appropriate values ​​for brightness / contrast and thresholds were visually determined so that they could be applied generally to the remaining randomized 0 images. Next, I applied the brightness / contrast settings, and then, using the rectangular selection tool, I selected approximately 1-2 individual pyramidal neurons per image (i.e., those without bipolar neurons) and saved them as separate files. I selected neurons that did not significantly overlap with other cells or extend far beyond the field of view. Next, I applied threshold settings to the individual images. I used the paintbrush tool to remove any artificial influences and dendrites arising from adjacent neurons (cleanup phase).Next, the center of the neuron was selected using the point tool, the image was saved, and then 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”); The radius of the Sholl analysis circle was 2 pixels, with an increment of 0.67 μm. All images were captured and analyzed by experimenters blinded to the treatment conditions. The average number of intersections for each neuron at each different radius was averaged to create an average Sholl plot for each treatment. max The values ​​were simply determined by identifying the maximum in each plot. For each treatment, neurons were selected from 6 wells (9 sites / well x 3 wells / plate x 2 plates) distributed across at least two plates. Each plate was prepared using neurons obtained from independent pregnant mothers. Table 5. Effectiveness of Sholl [Table 7-1] [Table 7-2]

[0364] Ketanserine blockade experiment. A slightly modified method was used for the ketanserine blockade experiment (Figure 7). In DIV3, neurons were first treated with ketanserine (10 μM) for 1 hour, followed by incubation with drug (1 μM) and ketanserine (10 μM) (final concentration of DMSO = 0.2%) for 1 hour. After 1 hour, the medium was removed and replaced with fresh Neurobasal medium containing 1 x B27 supplement, 1% penicillin-streptomycin, 0.5 mM glutamine, and 12.5 μM glutamic acid. Cells were grown for a further 71 hours, then fixed, stained, and imaged.

[0365] Neurite Growth Assay. Rat cortical neurons (20,000 cells / well) were freshly isolated from 18-day-old embryonic rats and cultured in Neurobasal Medium (+ B27). The cultured cells were plate-cultured in 96-well plates (avoiding the outer wells). Neurons were treated with a compound or control (10 μM) for 1 hour in DIV4, followed by complete washing of the compound. Neurons were analyzed in DIV7. The experiment was performed in triplicate. Neurite growth was measured by analyzing the following parameters: cell body number, total neurite length (pixels), root count, segments, tip count, and node point. Changes in the pattern of neuronal neurite growth were analyzed by immunocytology against βIII tubulin. Images were acquired from Thermo Fisher using CellInsight CX7 and analyzed using its software. The instrument-generated results were maximum neurite length, tip count, root count, dendritic branching point, and total neurite length. The results were compared with the DMSO control group to show the magnification change in neuronal growth.

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

[0367] For screening 41 compounds, sLight1.3s cells were cultured in 96-well plates at a density of 40,000 cells 24 hours prior to imaging. On the day of imaging, compounds solubilized with DMSO were diluted from a 100 mM stock solution to working concentrations of 1 mM, 100 μM, and 1 μM in 1% DMSO. Immediately before 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 adding 20 μL of compound working solution to wells containing 180 μL of HBSS. This produced final compound concentrations of 100 μM, 10 μM, and 100 nM in 0.1% DMSO. For the 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 prepare final concentrations of 100 μM, 10 μM, and 100 nM of the compound with 100 nM 5HT and 0.1% DMSO. Each compound was performed in triplicate (3 wells) for each concentration (100 μM, 10 μM, and 100 nM). In addition, a control with 100 nM 5HT and 0.1% DMSO was also imaged within each plate.

[0368] Imaging was performed using a Leica DMi8 inverted microscope with a 40x objective lens and pre-set FITC with excitation at 460nm and emission at 512–542nm. For each well, 5HT 2A The sensor targeted the cell membrane, which was then autofocused using an adaptive focus control system. Five images were then taken from different regions within the well, and each image was processed using 2x2 binning.

[0369] For data processing, the film from each image was segmented and analyzed using a custom algorithm written in MATLAB® to generate a single unprocessed fluorescence intensity value. For each well, the five unprocessed fluorescence intensity values ​​from 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 value in HBSS before compound addition is F apo The value used is F, while the fluorescence intensity value after compound addition is used. sat Used as a value.

[0371] For the agonist mode, data is presented as percentage activation relative to 5HT, where 0 is the average of the DMSO wells and 100 is the average of the 5HT wells with 100 μM. For the antagonist mode, the inactivation score was calculated as follows: Inactivation score = (dFFF(compound + 5HT) - dFF(5HT)) / dFF(5HT)

[0372] Calcium secondary signaling pathway. Cell lines were propagated from frozen stocks according to standard procedures. Cells were seeded in 20 μL of the total volume into poly-D-lysine coated 384-well microplates with black walls and clear bottoms, and incubated at 37°C for an appropriate time prior to the assay. The assay was performed in a 1x dye-supplemented buffer consisting of 1x dye, 1x additive A, and 2.5 mM Probenecid in HBSS / 20 mM Hepes. Probenecid was freshly prepared. Cells were added with the dye prior to the assay. The medium was aspirated from the cells and replaced with 20 μL of dye-supplemented buffer. Cells were incubated at 37°C for 30–60 minutes.

[0373] For agonist measurement, cells were incubated with the sample to induce a response. After dye addition, the cells were removed from the incubator and 10 μL of HBSS / 20 mM Hepes was added. A calibration curve for the agonist was performed for subsequent antagonist assays. 80 When defining the sample, a 3x vehicle was included in the buffer. Cells were incubated in the dark at room temperature for 30 minutes to equilibrate the plate temperature. Intermediate dilutions of the sample stock were performed to prepare 4X samples with assay buffer. The agonist activity of the compound was measured by FLIPR Tetra (MDS). Calcium mobilization was observed for 2 minutes, and then 10 μL of the 4X sample in HBSS / 20 mM Hepes was added to the cells, and the assay was performed after 5 seconds.

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

[0375] Cranial spasm response experiment. Mice (9-10 weeks old) were intraperitoneally injected with a compound (5 ml / kg), placed in empty cages, and filmed for 20 minutes. During the experiment, the cages were cleaned with 70% ethanol. Each video was scored for the number of cranial spasms by two trained observers blinded to the treatment condition, and these results were averaged (Pearson correlation coefficient = 0.91 and 0.99 for males and females, respectively).

[0376] Forced swimming test (FST). Male C57 / BL6J mice (9-10 weeks old at the time of the experiment) were obtained from Jackson Lab and housed in a UCD vivarium in groups of 4-5 mice / cage according to a protocol approved by IACUC. After one week in the vivarium, each mouse was handled by a male experimenter for approximately 1 minute over three consecutive days before the first FST. All experiments were conducted by the same male experimenter who performed the initial handling. During the FST, mice underwent a 6-minute swimming session in a clear plexiglass cylinder, 40 cm high and 20 cm in diameter, filled with 30 cm of 24±1°C water. Fresh water was used for all mice. Following handling and experimenter training, drug-untreated mice were first subjected to a preliminary swimming test to more reliably induce a depressive phenotype in subsequent FST sessions. Immobility scores were determined for all mice after a preliminary test, and the mice were randomly assigned to treatment groups to create groups with similar mean immobility scores for use in the following two FST sessions. The following day, the animals were given intraperitoneal injections of the experimental compound (20 mg / kg), a positive control (ketamine, 3 mg / kg), or a vehicle (physiological saline). Thirty minutes after injection, the animals were subjected to FST and then returned to their home cages. All FSTs were conducted over several hours between 8 a.m. and 1 p.m. The experiments were videotaped and scored manually offline. Immobility time—defined as the maintenance of a stationary state with no activity other than passive floating or the activity required to keep the mouse's head above water—was scored over the last four minutes of each six-minute trial.

[0377] Statistical analysis. Data were analyzed by experimenters who randomized treatment and blinded to treatment conditions. 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 shown in the legend of the figures, where necessary. All comparisons were planned before each experiment was conducted. For the dendritic formation 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 assay was performed correctly.

[0378] While the present invention has been described in some detail by illustrations and examples for the purpose of clarifying understanding, those skilled in the art will recognize that certain changes and modifications may be implemented within the scope of the appended claims. Furthermore, each reference provided herein is referred to by reference to the same extent as each individual reference is referred to by reference. In the event of any conflict between the present application and the references provided herein, the present application shall prevail.

Claims

1. The following equation I: 【Chemistry 1】 {During the ceremony, X is CR ３ And; R １ａ and R １ｂ These are, independently, hydrogen and C １－６ Alkyl, C ３－８ Cycloalkyl, or C ４－１４ It is alkyl-cycloalkyl; R １ｃ is C １－６ alkyl, C ３－８ cycloalkyl, or C ４－１４ alkyl-cycloalkyl; or Or, R １ａ , R １ｂ , and R １ｃ Two of them are combined with the atom to which they are attached to C ３－１２ Forms heterocycloalkyl groups; R ２ , R ３ , R ４ , R ５ , R ６ and R ７ These are, independently, hydrogen and C １－６ Alkyl, C ２－６ Alkenil, C ２－６ Alkynyl, halogen, C １－６ Haloalkyl, C １－６ Alkylamine, 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 Ariel, C ７－１８ Alkyl-aryl, C ５－１０ Heteroaryl, or C ４－１６ It is an alkyl-heteroaryl; R ８ａ C ３－８ Cycloalkyl, C ３－１４ Alkyl-cycloalkyl, C ４－１０ Heterocycloalkyl, C ４－１６ Alkyl-heterocycloalkyl, C ６－１２ Ariel, C ７－１８ Alkyl-aryl, C ５－１０ Heteroaryl, or C ４－１６ It is an alkyl-heteroaryl; R ８ｂ , R ８ｃ , and R ８ｄ Each of these is 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 Does it form a heterocycloalkyl group? Or, R ２ and R ３ These are combined with the atoms to which they are attached, resulting in C ４－８ Cycloalkyl, C ４－１０ Heterocycloalkyl, or C ６－１２ Does it form an aryl group? Alternatively, R ４ and R ５ or R ５ and R ６ or R ６ and R ７ are combined with the atoms to which they are respectively attached to form C ４－６ cycloalkyl, C ４－６ heterocycloalkyl, C ６－１２ aryl, or C ５－１０ heteroaryl; and L is C １－６ A compound that is alkylene, or a pharmaceutically acceptable salt or isomer thereof, Here, R １ａ , R １ｂ , and R １ｃ are each Me, L is methylene, X is CR ３ , and when R ２ , R ３ , R ４ , R ５ , R ６ and R ７ are hydrogen, the compound is the following: 【Chemistry 2】 And, Here, the compound is as follows: 【Transformation 3】 Compounds, or their pharmaceutically acceptable salts or isomers, excluding the compound.

2. Compound {wherein, X is CR ３ And; R ２ and R ３ These are, independently, hydrogen and C １－６ Alkyl, C ２－６ Alkenil, C ２－６ Alkynyl, halogen, C １－６ Haloalkyl, C １－６ Alkylamine, 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 Ariel, C ７－１８ Alkyl-aryl, C ５－１０ Heteroaryl, or C ４－１６ It is an alkyl-heteroaryl; R ８ａ C ３－８ Cycloalkyl, C ３－１４ Alkyl-cycloalkyl, C ４－１０ Heterocycloalkyl, C ４－１６ Alkyl-heterocycloalkyl, C ６－１２ Ariel, C ７－１８ Alkyl-aryl, C ５－１０ Heteroaryl, or C ４－１６ It is an alkyl-heteroaryl; and R ８ｂ , R ８ｃ , and R ８ｄ Each of these is independently H or C １－６ Alkyl or a pharmaceutically acceptable salt thereof, Here, R １ａ , R １ｂ and R １ｃ Each of these is Me, L is methylene, and R ２ , R ３ , R ４ , R ５ , R ６ and R ７ When is hydrogen, the compound is as follows: 【Chemistry 4】 The compound described in claim 1 or a pharmaceutically acceptable salt thereof.

3. The compound of formula I has the following structure: 【Transformation 5】 A compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, having the above.

4. In the above formula, R １ａ , R １ｂ , or R １ｃ Each is independent of C １－６ Alkyl, C ３－８ Cycloalkyl, or C ４－１４ Is it alkyl-cycloalkyl? Or, R １ａ , R １ｂ , and R １ｃ Two of them are combined with the atom to which they are attached to C ３－１２ Forms heterocycloalkyl groups; R ２ , R ３ , R ４ , R ６ and R ７ These are, independently, hydrogen and C １－６ Alkyl, C ２－６ Alkenil, C ２－６ Alkynyl, halogen, C １－６ Haloalkyl, C １－６ Alkylamine, 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 Ariel, C ７－１８ Alkyl-aryl, C ５－１０ Heteroaryl, or C ４－１６ It is an alkyl-heteroaryl; R ５ C １－６ Alkyl, C ２－６ Alkenil, C ２－６ Alkynyl, halogen, C １－６ Haloalkyl, C １－６ Alkylamine, 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 Ariel, C ７－１８ Alkyl-aryl, C ５－１０ Heteroaryl, or C ４－１６ It is an alkyl-heteroaryl; R ８ａ C ３－８ Cycloalkyl, C ３－１４ Alkyl-cycloalkyl, C ４－１０ Heterocycloalkyl, C ４－１６ Alkyl-heterocycloalkyl, C ６－１２ Ariel, C ７－１８ Alkyl-aryl, C ５－１０ Heteroaryl, or C ４－１６ It is an alkyl-heteroaryl; and R ８ｂ , R ８ｃ , and R ８ｄ Each of these is 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 These are combined with the atoms to which they are attached, resulting in C ４－６ Cycloalkyl, C ４－６ Heterocycloalkyl, C ６－１２ Aryl, or C ５－１０ Forms heteroaryls A compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof.

5. In the above formula, R １ａ and R １ｂ Each of them independently consists of hydrogen or C １－６ It is alkyl; R １ｃ is C １－６ It is alkyl; R ２ and R ３ These are, independently, hydrogen and 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 These are, independently, hydrogen and C １－６ Alkyl, halogen, C １－６ Haloalkyl, C １－６ Alkoxy, C １－６ Haloalkoxy, or -OR ８ａ And here, R ４ , R ５ , R ６ and R ７ At least one of them is not H; and R ８ａ is C ７－１８ Is it alkyl-aryl? Or, R ５ and R ６ These are combined with the atoms to which they are attached, resulting in C ４－６ Forms heterocycloalkyl groups, A compound or a pharmaceutically acceptable salt thereof as described in any one of claims 1 to 3.

6. In the above formula, R １ａ and R １ｂ Each is independently hydrogen or methyl, and R １ｃ Is it methyl? Or, R １ａ , R １ｂ , and R １ｃ Two of them are combined with the atom to which they are attached to C ３－８ Forms heterocycloalkyl groups, A compound or a pharmaceutically acceptable salt thereof as described in any one of claims 1 to 3.

7. In the above formula, R １ａ , R １ｂ , and R １ｃ Is each of them Me? Or, R １ａ , R １ｂ , and R １ｃ Two of them are combined with the atom to which they are attached to C ３－８ Forms heterocycloalkyl groups, A compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 6.

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

9. In the above formula, R ２ However, it is hydrogen, Me, F, or -OMe. A compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof.

10. In the above formula, R ３ However, 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 Each of these is independently H or C １－６ It is alkyl. A compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 9.

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

12. The compound of formula I has the following structure: 【Transformation 6】 A compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 11, having the properties of the compound.

13. The compound of formula I has the following structure: 【Transformation 7】 A compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 11, having the properties of the compound.

14. The compound of formula I has the following structure: 【Transformation 8】 A compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 11, having the properties of the compound.

15. The compound of formula I has the following structure: 【Chemistry 9】 A compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 12 or 14, having the properties of the compound.

16. The compound of formula I has the following structure: 【Chemistry 10】 A compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 11, 13, or 14, having the properties of the compound.

17. In the above formula, R １ａ and R １ｂ However, when combined with the atoms to which they are attached, C ３－８ Forms heterocycloalkyl groups, A compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 13.

18. In the above formula, R １ａ and R １ｃ However, when combined with the atoms to which they are attached, C ５－８ Forms heterocycloalkyl groups, A compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 13.

19. In the above formula, R ４ , R ５ , R ６ or R ７ These are, independently, hydrogen and 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 Is it alkyl-cycloalkyl? Or, R ４ and R ５ , R ５ and R ６ , or R ６ and R ７ These are combined with the atoms to which they are attached, resulting in C ５－６ Forming heterocycloalkyl groups; and R ８ａ C ３－８ Cycloalkyl, C ３－１４ Alkyl-cycloalkyl, C ４－１６ Alkyl-heterocycloalkyl, C ７－１８ Alkyl-aryl, or C ４－１６ It is an alkyl-heteroaryl, A compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 18.

20. In the above formula, R ４ , R ５ , R ６ or R ７ These are, independently, hydrogen and 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 These are combined with the atoms to which they are attached, resulting in C ５ Forming heterocycloalkyl groups; and R ８ａ is C ７－１８ It is an alkyl-aryl, A compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 19.

21. In the above formula, R ４ , R ６ or R ７ These are, independently, hydrogen and C １－６ Alkyl, halogen, C １－６ Alkoxy, C １－６ Haloalkoxy, -OR ８ａ , or -NO ２ And; R ５ 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 These are combined with the atoms to which they are attached, resulting in C ５ Forming heterocycloalkyl groups; and R ８ａ is C ７－１８ It is an alkyl-aryl, A compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 19.

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

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

24. In the above formula, R ５ The elements are Me, F, Cl, Br, -OMe, -CF ３ , -OCF ３ , -O-benzyl or -NO ２ and R ６ and R ７ These are, independently, hydrogen, Me, F, Cl, Br, -OMe, and -OCF. ３ , -O-CH ２ -phenyl or -NO ２ And here, R ６ and R ７ At least one of them is not hydrogen. A compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 22.

25. In the above formula, X is CR ３ And; R １ａ and R １ｂ Each of these is Me; 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 These are H, Me, -F, -Cl, -Br, and -NO, respectively, independently. ２ -OMe, -CF ３ , -OCF ３ , or -O benzyl; Or, R ５ and R ６ These are combined to form a 1,3-dioxole ring or a 1,4-dioxane ring. A compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 2.

26. In the above formula, X is CR ３ And; R １ａ and R １ｂ Each of these is Me; R １ｃ is Me, Et, or Pr; R ２ These are 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 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 These 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. A compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 2 or 25.

27. The aforementioned compound is as follows: 【Chemistry 11】 The compound according to any one of claims 1 to 26, or a salt thereof that is pharmaceutically acceptable.

28. The aforementioned compound is as follows: 【Chemistry 12】 The compound according to any one of claims 1 to 26, or a salt thereof that is pharmaceutically acceptable.

29. The aforementioned compound is as follows: 【Chemistry 13】 The compound according to any one of claims 1 to 26, or a salt thereof that is pharmaceutically acceptable.

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

31. The following equation II: 【Chemistry 14】 {During the ceremony, X is CR ３ And; R １ａ and R １ｂ These are, independently, hydrogen and C １－６ Alkyl, C ３－８ Cycloalkyl, or C ４－１４ Is it alkyl-cycloalkyl? Or, R １ａ and R １ｂ They are combined with the atoms to which they are attached and C ３－１２ Forms heterocycloalkyl groups; R ２ , R ３ , R ４ , R ５ , R ６ , and R ７ These are, independently, hydrogen and C １－６ Alkyl, C ２－６ Alkenil, C ２－６ Alkynyl, halogen, C １－６ Haloalkyl, C １－６ Alkylamine, 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 Ariel, C ７－１８ Alkyl-aryl, C ５－１０ Heteroaryl, or C ４－１６ It is an alkyl-heteroaryl; R ８ａ C ３－８ Cycloalkyl, C ３－１４ Alkyl-cycloalkyl, C ４－１０ Heterocycloalkyl, C ４－１６ Alkyl-heterocycloalkyl, C ６－１２ Ariel, C ７－１８ Alkyl-aryl, C ５－１０ Heteroaryl, or C ４－１６ It is an alkyl-heteroaryl; R ８ｂ , R ８ｃ , and R ８ｄ Each of these is independently H or C １－６ Is it alkyl? Or R １ａ or R １ｂ One of them is R ２ Combined with C ５－１２ Does it form a heterocycloalkyl group? Or, R ２ and R ３ They are combined with the atoms to which they are attached, and C ４－８ Cycloalkyl, C ４－１０ Heterocycloalkyl, or C ６－１２ Does it form an aryl group? Or, R ４ and R ５ , R ５ and R ６ , or R ６ and R ７ These are combined with the atoms to which they are attached, resulting in C ４－６ Cycloalkyl, C ４－６ Heterocycloalkyl, C ６－１２ Aryl, or C ５－１０ Forming heteroaryls; and L is C １－６ A compound that is alkylene, or a pharmaceutically 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 At least one of them is not hydrogen, and the compound is as follows: 【Chemistry 15】 It is the one that excludes; 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 them is not hydrogen; Here, R １ｃ is hydrogen, and R ５ is Br, Cl, F, -NH ２ , -NO ２ , or C １－３ When it is an alkoxy, R ２ , R ３ , R ４ , R ６ , or R ７ At least one of them is not hydrogen; and Here, R １ｃ is hydrogen, R ５ When F, R ２ , R ３ , R ４ , R ６ , or R ７ At least one of them is not hydrogen, and R ６ F is not a compound, or a pharmaceutically acceptable salt or isomer thereof.

32. The compound of formula II has the following structure: 【Chemistry 16】 A compound according to claim 31 or a pharmaceutically acceptable salt thereof, having the properties of the compound according to claim 31.

33. The compound of formula II has the following structure: 【Chemistry 17】 A compound according to claim 31 or 32, or a pharmaceutically acceptable salt thereof, having the properties of the compound according to claim 31 or 32.

34. In the above formula, R ２ , R ３ , R ４ , R ５ , R ６ and R ７ A compound or pharmaceutically acceptable salt thereof according to any one of claims 31 to 33, wherein at least one of the compounds is not H.

35. In the above formula, R ４ , R ５ , R ６ or R ７ These are, independently, hydrogen and 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 Is it alkyl-cycloalkyl? Or, R ４ and R ５ , R ５ and R ６ , or R ６ and R ７ These are combined with the atoms to which they are attached, resulting in C ５－６ Forming heterocycloalkyl groups; and R ８ａ C ３－８ Cycloalkyl, C ３－１４ Alkyl-cycloalkyl, C ４－１６ Alkyl-heterocycloalkyl, C ７－１８ Alkyl-aryl, or C ４－１６ It is an alkyl-heteroaryl, A compound or a pharmaceutically acceptable salt thereof as described in any one of claims 31 to 34.

36. In the above formula, R ４ , R ５ , R ６ or R ７ These are, independently, hydrogen and 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 These are combined with the atoms to which they are attached, resulting in C ５ Forming heterocycloalkyl groups; and R ８ａ is C ７－１８ It is an alkyl-aryl, A compound or a pharmaceutically acceptable salt thereof as described in any one of claims 31 to 35.

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

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

39. In the above formula, R ５ F, Cl, -OMe, -OCF ３ or -O-benzyl; R ６ and R ７ These are, independently, hydrogen, F, Cl, -OMe, and -OCF. ３ or -O-benzyl, where R ６ and R ７ Isn't at least one of them hydrogen? Or, R ５ and R ６ These combine with the atoms to which they are attached to form a 1,3-dioxole ring or a 1,4-dioxane ring. A compound or a pharmaceutically acceptable salt thereof according to any one of claims 31 to 37.

40. The aforementioned compound is as follows: [Chemistry 18] The compound according to any one of claims 31 to 37, or a salt thereof that is pharmaceutically acceptable.

41. The aforementioned compound is as follows: 【Chemistry 19】 The compound according to any one of claims 31 to 39, or a salt thereof that is pharmaceutically acceptable.

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

43. The aforementioned compound is as follows: 【Chemistry 20】 The compound according to any one of claims 31 to 39 or 42, or a salt thereof that is pharmaceutically acceptable.

44. The aforementioned compound is as follows: 【Chemistry 21】 The compound according to any one of claims 31 to 37, or a salt thereof that is pharmaceutically acceptable.

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

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

47. A method for enhancing neuronal plasticity, comprising a nerve cell and a sufficient amount of the following formula I: 【Chemistry 22】 {During the ceremony, X is N or CR ３ And; R １ａ , R １ｂ , and R １ｃ These are, independently, hydrogen and C １－６ Alkyl, C ３－８ Cycloalkyl, or C ４－１４ Is it alkyl-cycloalkyl? Or, R １ａ , R １ｂ , and R １ｃ Two of them are combined with the atom to which they are attached to C ３－１２ Forms heterocycloalkyl groups; R ２ , R ３ , R ４ , R ５ , R ６ and R ７ These are, independently, hydrogen and C １－６ Alkyl, C ２－６ Alkenil, C ２－６ Alkynyl, halogen, C １－６ Haloalkyl, C １－６ Alkylamine, 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 Ariel, C ７－１８ Alkyl-aryl, C ５－１０ Heteroaryl, or C ４－１６ It is an alkyl-heteroaryl; R ８ａ C ３－８ Cycloalkyl, C ３－１４ Alkyl-cycloalkyl, C ４－１０ Heterocycloalkyl, C ４－１６ Alkyl-heterocycloalkyl, C ６－１２ Ariel, C ７－１８ Alkyl-aryl, C ５－１０ Heteroaryl, or C ４－１６ It is an alkyl-heteroaryl; R ８ｂ , R ８ｃ and R ８ｄ Each of these is 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 Does it form a heterocycloalkyl group? Or, R ２ and R ３ These are combined with the atoms to which they are attached, resulting in C ４－８ Cycloalkyl, C ４－１０ Heterocycloalkyl, or C ６－１２ Does it form an aryl group? Or, R ４ and R ５ , R ５ and R ６ , or R ６ and R ７ These are combined with the atoms to which they are attached, resulting in C ３－６ Cycloalkyl, C ３－６ Heterocycloalkyl, C ６－１２ Aryl, or C ５－１０ Forming heteroaryls; and L is C １－６ A method comprising contacting a compound or pharmaceutically acceptable salt thereof that is an alkylene.

48. A method for treating brain damage, for a patient in need of it, with a therapeutically effective dose calculated using the following formula I: 【Chemistry 23】 {During the ceremony, X is N or CR ３ And; R １ａ , R １ｂ , and R １ｃ These are, independently, hydrogen and C １－６ Alkyl, C ３－８ Cycloalkyl, or C ４－１４ Is it alkyl-cycloalkyl? Or, R １ａ , R １ｂ , and R １ｃ Two of them are combined with the atom to which they are attached to C ３－１２ Forms heterocycloalkyl groups; R ２ , R ３ , R ４ , R ５ , R ６ and R ７ These are, independently, hydrogen and C １－６ Alkyl, C ２－６ Alkenil, C ２－６ Alkynyl, halogen, C １－６ Haloalkyl, C １－６ Alkylamine, 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 Ariel, C ７－１８ Alkyl-aryl, C ５－１０ Heteroaryl, or C ４－１６ It is an alkyl-heteroaryl; R ８ａ C ３－８ Cycloalkyl, C ３－１４ Alkyl-cycloalkyl, C ４－１０ Heterocycloalkyl, C ４－１６ Alkyl-heterocycloalkyl, C ６－１２ Ariel, C ７－１８ Alkyl-aryl, C ５－１０ Heteroaryl, or C ４－１６ It is an alkyl-heteroaryl; R ８ｂ , R ８ｃ and R ８ｄ Each of these is 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 Does it form a heterocycloalkyl group? Or, R ２ and R ３ These are combined with the atoms to which they are attached, resulting in C ４－８ Cycloalkyl, C ４－１０ Heterocycloalkyl, or C ６－１２ Does it form an aryl group? Or, R ４ and R ５ , R ５ and R ６ , or R ６ and R ７ These are combined with the atoms to which they are attached, resulting in C ３－６ Cycloalkyl, C ３－６ Heterocycloalkyl, C ６－１２ Aryl, or C ５－１０ Forming heteroaryls; and L is C １－６ A method comprising administering a compound that is alkylene, thereby treating brain damage.

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

50. The method according to claim 48, wherein the brain disorder is a mental disorder, depression, addiction, anxiety, or post-traumatic stress disorder.

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

52. The method according to claim 50, wherein the brain damage is due to poisoning.

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

54. The method according to claim 48, wherein the brain injury is a stroke or traumatic brain injury.

55. 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), levomilunacipran (Fetzima), duloxetine (Cymbalta, Yentreve), venlafaxine (Effexor), citalopram (Celexa), fluvoxamine (Luv The method according to any one of claims 48 to 54, comprising administering one or more additional therapeutic agents, which are ox), escitalopram (Lexapro), fluoxetine (Prozac), paroxetine (Paxil), sertraline (Zoloft), clomipramine (Anafranil), amitriptyline (Elavil), desipramine (Norpramine), imipramine (Tofranil), nortriptyline (Pamelor), phenelzine (Nardil), tranylcypromine (Parnate), diazepam (Valium), alprazolam (Xanax), or clonazepam (Klonopin).

56. A method for enhancing at least one of the translation, transcription, or secretion of a neurotrophic factor, wherein a neuron contains a sufficient amount of the following formula I to enhance the neuronal plasticity of the neuron: 【Chemistry 24】 {During the ceremony, X is N or CR ３ And; R １ａ , R １ｂ , and R １ｃ These are, independently, hydrogen and C １－６ Alkyl, C ３－８ Cycloalkyl, or C ４－１４ Is it alkyl-cycloalkyl? Or, R １ａ , R １ｂ , and R １ｃ Two of them are combined with the atom to which they are attached to C ３－１２ Forms heterocycloalkyl groups; 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 alkylamine, 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<\(0000910\)>、-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; (注:原文中 ８ｂ 翻译为<\(0000910\)>是为了显示格式,实际书写时应保持为 ８ｂ ) R ８ａ C ３－８ Cycloalkyl, C ３－１４ Alkyl-cycloalkyl, C ４－１０ Heterocycloalkyl, C ４－１６ Alkyl-heterocycloalkyl, C ６－１２ Ariel, C ７－１８ Alkyl-aryl, C ５－１０ Heteroaryl, or C ４－１６ It is an alkyl-heteroaryl; R ８ｂ , R ８ｃ and R ８ｄ Each of these is 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 Does it form a heterocycloalkyl group? Or, R ２ and R ３ These are combined with the atoms to which they are attached, resulting in C ４－８ Cycloalkyl, C ４－１０ Heterocycloalkyl, or C ６－１２ Does it form an aryl group? Or, R ４ and R ５ , R ５ and R ６ , or R ６ and R ７ These are combined with the atoms to which they are attached, resulting in C ３－６ Cycloalkyl, C ３－６ Heterocycloalkyl, C ６－１２ Aryl, or C ５－１０ Forming heteroaryls; and L is C １－６ A method comprising contacting a compound that is alkylene with another compound.

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