N-substituted indole and other heterocyclic compounds used to treat brain diseases

Abstract

This invention provides N-substituted indole and other heterocycles, as well as methods for treating brain diseases with said compounds.

Description

[0001] This application is a divisional application of the invention patent application filed on February 26, 2020, with application number 2020800174967 and entitled "N-substituted indole and other heterocyclic compounds for treating brain diseases".

[0002] Cross-reference to related applications This patent application is based on priority to U.S. Provisional Application No. 62 / 811,206, filed February 27, 2019, and U.S. Provisional Application No. 62 / 958,220, filed January 7, 2020, the contents of which are incorporated herein by reference for all purposes. Background of the Invention Ketamine, N,N-dimethyltryptamine (DMT), and other plasticizers have potential for neurotherapeutic effects due to their ability to promote neuronal growth.

[0003] This article discloses several key characteristics of pharmacophores that act as plasticizers. It also discloses iso-DMT plasticizers that are easier to synthesize, have better physicochemical properties, and lower hallucinogenic potential compared to their DMT counterparts.

[0004] Major depressive disorder and related neuropsychiatric disorders are among the leading causes of disability worldwide. Recently, the U.S. Food and Drug Administration (FDA) approved ketamine, a dissociative anesthetic, for the treatment of treatment-resistant depression, making it the first mechanically unique drug to be introduced into psychiatry in nearly 30 years. In some cases, ketamine can correct harmful changes in neuronal structure associated with depression. These structural changes include, for example, the loss of dendritic spines and synapses in the prefrontal cortex (PFC), and a reduction in dendritic tree complexity. However, ketamine is an imperfect drug; for example, there is a possibility of abuse, and its dissociative effects require hospitalization during treatment. Clinically, there is a need for a treatment method without these side effects.

[0005] Compounds known as plastids promote neuronal growth through mechanisms that activate AMPA receptors, tropomyosin receptor kinase B (TrkB), and the target of rapamycin (mTOR). Besides ketamine, tropane alkaloids such as scopolamine and GLYX-13 (rapastine) have shown plastidating properties, and these compounds hold promise for treating a variety of neuropsychiatric disorders. Because pyramidal neurons in the PFC exhibit top-down control over brain regions that regulate motivation, fear, and reward, these results offer an explanation for the psychedelic effects of compounds with clinical antidepressant, anti-anxiety, and anti-addictive properties.

[0006] The pharmacophore commonly found in psychedelic compounds appears to be N,N-dimethyltryptamine (DMT,1) Figure 1Because DMT produces antidepressant and anti-anxiety behavioral effects in rodents, and because decoctions containing DMT have demonstrated clinical efficacy in treating antidepressant depression, DMT was used as a starting point for identifying the novel psychoplastic compounds described in this invention.

[0007] Therefore, there is a need for new compounds to treat major depressive disorder and neuropsychiatric disorders. This invention fulfills this and other needs. Summary of the Invention

[0008] In one embodiment, the present invention provides a compound of formula I or a pharmaceutically acceptable salt thereof, and isomers thereof: (I) Where: X is CR 3 ;R 1a and R 1b Each independently is hydrogen, C 1-6 Alkyl, C 3-8 cycloalkyl, or C 4-14 Alkyl-cycloalkyl; R 1c C 1-6 Alkyl, C 3-8 cycloalkyl, or C 4-14 alkyl-cycloalkyl; or, R 1a R 1b and R 1c Two atoms bonded together form C. 3-12 Heterocyclic alkyl; R 2 R 3 R 4 R 5 R 6 and R 7 Each independently is hydrogen, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkyne, halogen, C 1-6 Haloalkyl, C 1-6 Alkylamine, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, –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 Heterocyclic alkyl, C 4-16 Alkyl-heterocyclic alkyl, C 6-12 Aryl, C 7-18 Alkyl-aryl, C 5-10 heteroaryl, or C 4-16 alkyl heteroaryl; R 8a C 3-8 cycloalkyl, C 3-14 Alkyl-cycloalkyl, C 4-10 Heterocyclic alkyl, C 4-16 Alkyl-heterocyclic alkyl, 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 Each independently is H or C 1-6 Alkyl; or, R 1a R 1b Or R 1c One of them is with R 2 Combining to form C 5-12 Heterocyclic alkyl; or, R 2 and R 3 They combine with their respective atoms to form C 4-8 cycloalkyl, C 4-10 Heterocyclic alkyl, or C 6-12 aryl; or, R 4 and R 5 R 5 and R 6 , or R 6 and R 7 They combine with their respective atoms to form C 4-6 cycloalkyl, C 4-6 Heterocyclic alkyl, C 6-12Aryl, or C 5-10 heteroaryl; L is C 1-6 alkylene, wherein, when R 1a R 1b and R 1c When each is Me, L is methylene and X is CR. 3 and R 2 R 3 R 4 R 5 R 6 and R 7 If it's hydrogen, then the compound is... or And the compound said compound is not .

[0009] In another embodiment, the present invention provides a compound of formula II or a pharmaceutically acceptable salt thereof and its isomers: (II) Where: X is CR 3 ;R 1a and R 1b Each independently represents H and C. 1-6 Alkyl, C 3-8 cycloalkyl, or C 4-14 alkyl-cycloalkyl; or, R 1a and R 1b They combine with the atoms they are attached to to form C 3-12 Heterocyclic alkyl; R 2 R 3 R 4 R 5 R 6 and R 7 Each independently is hydrogen, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkyne, halogen, C 1-6 Haloalkyl, C 1-6 Alkylamine, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, –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 Heterocyclic alkyl, C 4-16 Alkyl-heterocyclic alkyl, C 6-12 Aryl, C 7-18 Alkyl-aryl, C 5-10 heteroaryl, or C 4-16 alkyl heteroaryl; R 8a C 3-8 cycloalkyl, C 3-14 Alkyl-cycloalkyl, C 4-10 Heterocyclic alkyl, C 4-16 Alkyl-heterocyclic alkyl, 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 Each independently is H or C 1-6 Alkyl; or, R 1a Or R 1b One of them with R 2 Combining to form C 5-12 Heterocyclic alkyl; or, R 2 and R 3 They combine with their respective atoms to form C 4-8 cycloalkyl, C 4-10 Heterocyclic alkyl, or C 6-12 aryl; or, R 4 and R 5 R 5 and R 6 , or R 6 and R 7 They combine with their respective atoms to form C 4-6cycloalkyl, C 4-6 Heterocyclic alkyl, C 6-12 Aryl, or C 5-10 heteroaryl; L is C 1-6 alkylene, wherein, when R 1a and R 1b When both are Me, L represents methylene, then 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 not: ; Where R 1a and R 1b When Me is , L is ethylene, and X is CR. 3 When, then R 2 R 3 R 4 R 5 R 6 and R 7 At least one of them is not hydrogen; where, when R 1c For H, R 5 For Br, Cl, F, -NH2, -NO2, or C 1-3 When alkoxy is present, then R 2 R 3 R 4 R 6 , or R 7 At least one of them is not hydrogen; where, when R 1c It is hydrogen and R 5 When it is F, then R 2 R 3 R 4 R 6 , or R 7 At least one of them is not hydrogen, R 6 It's not F.

[0010] In another embodiment, the present invention provides a pharmaceutical composition comprising the compounds of the present invention and pharmaceutically acceptable excipients.

[0011] In another embodiment, the present invention provides a method for increasing neuronal plasticity, comprising contacting neuronal cells with a compound of formula I or a pharmaceutically acceptable salt thereof: (I) Its dosage is sufficient to increase neuronal plasticity in neurons, where: X is N or CR 3 ;R 1a R1b and R 1c Each independently represents H and C. 1-6 Alkyl, C 3-8 cycloalkyl, or C 4-14 alkyl-cycloalkyl; or, R 1a R 1b and R 1c Two atoms bonded to them combine to form C. 3-12 Heterocyclic alkyl; R 2 R 3 R 4 R 5 R 6 and R 7 Each independently is hydrogen, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkyne, halogen, C 1-6 Haloalkyl, C 1-6 Alkylamine, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, –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 Heterocyclic alkyl, C 4-16 Alkyl-heterocyclic alkyl, C 6-12 Aryl, C 7-18 Alkyl-aryl, C 5-10 heteroaryl, or C4-16 alkyl heteroaryl; R 8a C 3-8 cycloalkyl, C 3-14 Alkyl-cycloalkyl, C 4-10 Heterocyclic alkyl, C 4-16 Alkyl-heterocyclic alkyl, 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 Each independently is H or C 1-6 Alkyl; or, R 1a R 1b Or R 1c One of them is with R 2 Combining to form C 5-12 Heterocyclic alkyl; or, R 2 and R 3 They combine with their respective atoms to form C 4-8 cycloalkyl, C 4-10 Heterocyclic alkyl, or C 6-12 aryl; or, R 4 and R 5 R 5 and R 6 , or R 6 and R 7 They combine with their respective atoms to form C 3-6 cycloalkyl, C 3-6 Heterocyclic alkyl, C 6-12 Aryl, or C 5-10 heteroaryl; and L is C 1-6 Alkylene.

[0012] In another embodiment, the present invention provides a method for treating a brain disease, comprising administering to a subject in need a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof: (I) This is used to treat brain diseases, where X is N or CR. 3 ;R 1a R 1b and R 1c Each independently represents H and C. 1-6 Alkyl, C 3-8 cycloalkyl, or C 4-14 alkyl-cycloalkyl; or, R 1a R 1b and R 1cAny two atoms bonded to them combine to form C. 3-12 Heterocyclic alkyl; R 2 R 3 R 4 R 5 R 6 and R 7 Each independently is hydrogen, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkyne, halogen, C 1-6 Haloalkyl, C 1-6 Alkylamine, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, –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 Heterocyclic alkyl, C 4-16 Alkyl-heterocyclic alkyl, C 6-12 Aryl, C 7-18 Alkyl-aryl, C 5-10 heteroaryl, or C 4-16 alkyl heteroaryl; R 8a C 3-8 cycloalkyl, C 3-14 Alkyl-cycloalkyl, C 4-10 Heterocyclic alkyl, C 4-16 Alkyl-heterocyclic alkyl, C 6-12 Aryl, C7-18 Alkyl-aryl, C 5-10 heteroaryl, or C 4-16 alkyl-heteroaryl; R 8b R 8c and R 8d Each independently is H or C 1-6 Alkyl; or, R 1a R 1b Or R 1c One of them is with R 2 Combining to form C 5-12 Heterocyclic alkyl; or, R 2 and R 3 They combine with their respective atoms to form C 4-8 cycloalkyl, C 4-10 Heterocyclic alkyl, or C 6-12 aryl; or, R 4 and R 5 R 5 and R 6 , or R 6 and R 7 They combine with their respective atoms to form C 3-6 cycloalkyl, C 3-6 Heterocyclic alkyl, C 6-12 Aryl, or C 5-10 heteroaryl; and L is C 1-6 Alkylene.

[0013] In another embodiment, the present invention provides a method for enhancing at least one of the translation, transcription, or secretion of neurotrophic factors, comprising contacting neuronal cells with a compound of formula I or a pharmaceutically acceptable salt thereof: (I) Its dosage is sufficient to increase neuronal plasticity in neurons, where: X is N or CR 3 ;R 1a R 1b and R 1c Each independently represents H and C. 1-6 Alkyl, C 3-8 cycloalkyl, or C 4-14 alkyl-cycloalkyl; or, R 1a R 1b and R 1c Any two atoms bonded to them combine to form C. 3-12 Heterocyclic alkyl; R 2 R 3 R 4 R 5 R 6 and R 7Each independently is hydrogen, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkyne, halogen, C 1-6 Haloalkyl, C 1-6 Alkylamine, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, –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 Heterocyclic alkyl, C 4-16 Alkyl-heterocyclic alkyl, C 6-12 Aryl, C 7-18 Alkyl-aryl, C 5-10 heteroaryl, or C 4-16 alkyl heteroaryl; R 8a C 3-8 cycloalkyl, C 3-14 Alkyl-cycloalkyl, C 4-10 Heterocyclic alkyl, C 4-16 Alkyl-heterocyclic alkyl, 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 Each independently is H or C 1-6Alkyl; or, R 1a R 1b Or R 1c One of them is with R 2 Combining to form C 5-12 Heterocyclic alkyl; or, R 2 and R 3 They combine with their respective atoms to form C 4-8 cycloalkyl, C 4-10 Heterocyclic alkyl, or C 6-12 aryl; or, R 4 and R 5 R 5 and R 6 , or R 6 and R 7 They combine with their respective atoms to form C 3-6 cycloalkyl, C 3-6 Heterocyclic alkyl, C 6-12 Aryl, or C 5-10 heteroaryl; and L is C 1-6 Alkylene. Brief description of the attached figures Figure 1 A and Figure 1 B shows the structure of a compound having a DMT pharmacophore. Figure 1 A shows that the DMT structure (highlighted in black) is the core structure of several known psychoplastic compounds. Figure 1 B shows that the only difference between the chemical structures of DMT(1) and iso-DMT(2) is that the C1 and C3 atoms of indole are transposed. The predicted chemical properties and calculated MPO values ​​are shown. clogD = calculated logarithm D; TPSA = total polar surface area; HBD = hydrogen bond donor; MPO = multi-parameter optimized value.

[0014] Figure 2 A, Figure 2 B and Figure 2 C indicates that the indole NH of tryptophan derivatives is not essential for promoting dendrite formation. Figure 2 A shows a representative image of a cortical neuron (DIV6) treated with the compound. Figure 2 B shows a Sholl analysis, which indicates that 1-ME-DMT(27) and hetero-DMT(2) increase dendritic spine complexity to a level comparable to DMT(1) (n=46-79 neurons). Figure 2C shows the maximum number of crossovers (Nmax) in the Sholl plot of B. Data are presented as mean ± SEM. One-way ANOVA using Dunnett post-hoc multiple detection was performed. Compared with the vector, *p<0.05, **p<0.01, ***p<0.001, *****p<0.0001 (F=9.702; DFn=4; DFd=304; p-value<0.0001). VEH = vector, KET = ketamine. Scale bar: 20 μm.

[0015] Figure 3 A and Figure 3 B shows that DMT and its analogues have similar effects on dendritic spine complexity. Figure 3 A shows the chemical structures of DMT derivatives and analogues, specifically DMT. Figure 3 B shows the maximum number of crossovers (Nmax) in the Sholll analysis of cortical neurons treated with the compound (n = 82–95 neurons). Data are expressed as mean ± SEM. One-way ANOVA using Dunnett post-hoc multiple detection was performed. Compared with the vector control, *p < 0.05, **p < 0.01, ***p < 0.001, *****p < 0.0001 (F = 11.17; DFn = 5; DFd = 524; p < 0.0001). VEH = vector, KET = ketamine.

[0016] Figure 4 A to Figure 4 C illustrates the establishment of the essential psychoactive plasticizer pharmacophore. Figure 4 A: The chemical structure of the non-basic analogue iso-DMT2. Figure 4 B and Figure 4 C shows the maximum number of crossovers (Nmax) in the Sholl plots of cortical neurons treated with the compound (n = 46–85 neurons). [The remaining text appears to be incomplete and requires further context.] Figure 4 B and Figure 4 The effects of nitrogen basicity and aromatic ring modification were evaluated in C. Data are expressed as mean ± SEM. One-way ANOVA with post-hoc multiple detections by Dunnett was used. Compared with the vector, *p<0.05, **p<0.01, ***p<0.001, *****p<0.0001 (For B: F=19.03; DFn=4; DFd=273; P<0.0001. For C: F=6.933; DFn=8; DFd=599; P<0.0001). VEH = vector, KET = ketamine.

[0017] Figure 5This study illustrates the effect of indole substitution on the neuronal growth-promoting ability of different DMTs. The maximum number of crossovers (Nmax) in the Sholl plots of cortical neurons treated with the compound is shown (n = 39–93 neurons). Data are expressed as mean ± SEM. One-way ANOVA using Dunnett post-hoc multiple detection methods was performed. Compared with the vector control, *p < 0.05, **p < 0.01, ***p < 0.001, *****p < 0.0001 (For R = OMe: F = 13.85; DFn = 5; DFd = 493; P < 0.0001. For R = OBn: F = 15.44; DFn = 5; DFd = 372; P < 0.0001. For R = F: F = 13.24; DFn = 5; DFd = 506; P < 0.0001). VEH = vector, KET = ketamine.

[0018] Figure 6 The concentration-response experiments showed that DMT and iso-DMT have similar plasticity potential. The maximum number of crossovers (Nmax) in the Sholl plots of cortical neurons treated with compounds at concentrations ranging from 10 μM to 10 pM (n = 66–123 neurons) was used. Data are expressed as mean ± SEM. One-way ANOVA using Dunnett post-hoc multiple detections was performed. Compared with the carrier, *p < 0.05, **p < 0.01, ***p < 0.001, *****p < 0.0001 (F = 15.40; DFn = 24; DFd = 2,276; p < 0.0001). V = carrier, K = ketamine.

[0019] Figure 7 The psychoplasticizing effect of heterodoxane (DMT) was demonstrated to be blocked by a 5-HT2A antagonist. The maximum number of crossovers (Nmax) in the Shol charts of cortical neurons treated with the compound (n = 45–63 neurons) was measured in the presence (+) and absence (–) of the 5-HT2A antagonist ketoserin. Data are expressed as mean ± SEM. One-way ANOVA with post-hoc multiple tests by Dunnett was performed, with ***** p < 0.0001 compared to the vector control (F = 13.92; DFn = 8; DFd = 461; p < 0.0001). V = vector, K = ketamine, KTSN = ketoserin.

[0020] Figure 8The HTR assay in mice showed that plastinated iso-ODMT exhibited reduced hallucinogenic potential. Male and female mice were administered the drug via intraperitoneal injection, and the number of head twitches was recorded over the next 20 minutes (n = 3–8 mice in each case). Data are expressed as mean ± SEM. One-way ANOVA using Dunnett post-hoc multiple test results was performed. Compared with the vector control, *p < 0.05, **p < 0.01, ***p < 0.001, *****p < 0.0001. V = vector.

[0021] Figure 9 The ability of the compounds of the present invention to reduce head twitching behavioral responses in head twitching response analysis is demonstrated.

[0022] Figure 10 The effects of hallucinogenic and non-hallucinogenic compounds on agonist modes were shown, with 5HT 2A The dose-response curve measured by the sensor.

[0023] Figure 11 The effects of hallucinogenic and non-hallucinogenic compounds (10 μm) on 5HT in the agonist mode were shown. 2A The reaction curve measured by the sensor.

[0024] Figure 12A The dose-response curves for 5HT and 6-MEO-DMT are shown, and Figure 12B This demonstrates the effect of lysylurea on 5HT in antagonist mode. 2A Dose response measured by sensing.

[0025] Figure 13 The study showed the effects of hallucinogenic and non-hallucinogenic compounds (10 μm) on the antagonist mode, 5HT 2A The reaction curve measured by the sensor.

[0026] Figure 14 A and Figure 14 B illustrates the antidepressant properties of the compound of the present invention in two pre-test mandatory swimming trials. Figure 14 A) and acute ( Figure 14 B) Application of the compound. Detailed Implementation

[0027] I.General This invention provides N-substituted indole and other heterocyclic non-halogenated compounds for the treatment of various brain diseases and other conditions, as well as for increasing neuronal plasticity and increasing at least one of the translation, transcription or secretion of neurotrophic factors.

[0028] Compounds capable of altering neural circuits controlling motivation, anxiety, and drug-seeking behavior have the potential to treat depression, post-traumatic stress disorder (PTSD), and substance use disorder (SUD). Furthermore, these plastylinogenin drugs may produce sustained therapeutic effects because, for example, they have the potential to treat underlying circuit lesions. Psychedelic compounds are unique in this regard; for example, they promote structural and functional neuroplasticity in key circuits, eliciting therapeutic responses in a variety of neuropsychiatric disorders and producing beneficial effects that can last for months after a single dose.

[0029] In some cases, hallucinogenic 5-HT 2A Agonists (such as DMT, LSD, DOI, etc.) are potential drugs for treating neurological disorders, such as neuropsychiatric disorders. (Ly et al., 2018) However, the hallucinogenic and dissociative potentials of these compounds limit their clinical application. 5-HT 2A Antagonist elimination has 5-HT 2A The agonist-active hallucinogenic compounds, such as DMT, LSD, and DOI, have demonstrated the effects of 5-HT on neuronal generation and spinogenesis. 2A The correlation between excitation and promotion of neural plasticity (Ly et al., 2018; Dunlap et al., 2020).

[0030] This article provides non-hallucinogenic serotonin analogues. Furthermore, several iso-DMT compounds exhibit comparable affinity for serotonin receptors compared to their DMT counterparts. In some embodiments, the iso-DMT analogues described herein exhibit improved physicochemical properties due to the loss of hydrogen bond donors, resulting in a reduced total polar surface area and improved central nervous system multiparameter optimization (MPO) values. Figure 1 In some embodiments described herein, non-hallucinogenic compounds are described that exhibit similarities to hallucinogenic 5-HT. 2A Agonist-like therapeutic potential. In some implementations, the non-hallucinogenic compounds described herein offer greater therapeutic benefits than hallucinogenic 5-HT. 2A Agonists have greater potential for treating neurological disorders.

[0031] II. Definition Unless otherwise stated, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. Furthermore, any methods or materials similar to or equivalent to those described or made herein may be used in the practice of this invention. For the purposes of this invention, the following terms are defined.

[0032] The terms “a,” “an,” or “the” refer not only to an aspect having one member but also to an aspect having multiple members. For example, unless the context clearly specifies otherwise, the singular forms “a,” “an,” and “the” include the plural forms. Thus, for example, referring to “cell” includes multiple such cells, while referring to “reagent” includes one or more reagents known to those skilled in the art, and so on.

[0033] Abbreviation used: DMT N,N - Dimethyltryptamine; PFC, prefrontal cortex; 5-HT2A, serotonin 2A; MPO, multi-parameter optimization; LSD, psychedelic drug; TPSA, total polar surface area; MAP2, total polar surface area; microtubule-associated protein 2; N max Maximum number of cross-sections; 5-HT2B, 5-hydroxytryptamine 2B; DIV, days in vitro; VEH, carrier; KET, ketamine; SEM; standard error of mean; ANOVA; DOM, 2,5-dimethoxy-4-methylamphetamine; OMe, methoxy; OBn, benzyloxy; F, fluorine; M, micromolar; nM, nanomolar; pM, picomolar; V, carrier; K, ketamine; ATR, attenuated total reflectance coefficient; FT-IR, Fourier transform infrared spectroscopy; UHPLC, ultra-high performance liquid chromatography; low resolution mass spectrometry; IACUC, Institutional Animal Care and Use Committee; AAALAC, Association for Assessment and Accreditation of Laboratory Animal Care; BSA, bovine serum albumin; DPBS, Durbeco phosphate-buffered saline; mTOR, target of rapamycin; AMPA, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid; TrkB, tropomyosin receptor kinase B; HTR, head twitching response.

[0034] "alkyl" refers to a straight-chain or branched saturated aliphatic free group having the indicated number of carbon atoms. Alkyl groups can include any number of carbons, for example, C10, C20, C30, C40, C50, C60, C7 ... 12 C 13 C 14 C 15 C 16 C 17 C 18 C 19 C 110 C 23 C 24 C 25 C 26 C 34 C 35 C 36 C 45 C 46 and C 56 For example, C 1-6Alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, and hexyl. Alkyl groups can also refer to alkyl groups having up to 20 carbon atoms, such as, but not limited to, heptyl, octyl, nonyl, and decyl. Alkyl groups may be substituted or unsubstituted.

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

[0036] "Alkenyl" refers to a straight-chain or branched hydrocarbon compound having at least two carbon atoms and at least one double bond. Alkenes can include any number of carbon atoms, for example, C2, C3, C4, C5, C6, C7, C8, C9 ... 23 C 24 C 25 C 26 C 27 C 28 C 29 C 210 C3, C 34 C 35 C 36 C4, C 45 C 46 C5, C 56 And C6. The alkenyl group has 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 (vinyl), propenyl, isopropenyl, 1-butenyl, 2-butenyl, isobutenyl, butadienyl, 1-pentenyl, 2-pentenyl, isopentenyl, 1,3-pentadienyl, 1,4-pentadienyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 1,3-hexadienyl, 1,4-hexadienyl, 1,5-hexadienyl, 2,4-hexadienyl, or 1,3,5-hexatrienyl. The alkenyl group may be substituted or unsubstituted.

[0037] "Alynyl" refers to a straight-chain or branched hydrocarbon compound having at least two carbon atoms and at least one triple bond. Alynyl groups can include any number of carbon atoms, such as C2, C3, etc. 23 C 24 C 25 C 26 C 27 C 28 C 29C 210 C3, C 34 C 35 C 36 C4, C 45 C 46 C5, C 56 And C6. Examples of alkynyl groups include, but are not limited to, ethynyl, propynyl, 1-butynyl, 2-butynyl, butyrynyl, 1-pentynyl, 2-pentynyl, isopentenynyl, 1,3-pentadiynyl, 1,4-pentadiynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 1,3-hexadiynyl, 1,4-hexadiynyl, 1,5-hexadiynyl, 2,4-hexadiynyl, or 1,3,5-hextriynyl. The alkynyl group can be substituted or unsubstituted.

[0038] "Cycloalkyl" refers to a saturated or partially unsaturated, monocyclic, bicyclic, fused bicyclic, or polycyclic bridged ring combination containing 3-12 ring atoms or a specified number of ring atoms. Cycloalkyl groups can include any number of carbon atoms, such as C64. 3-6 C 4-6 C 5-6 C 3-8 C 4-8 C 5-8 C 6-8 C 39- C 3-10 C 3-11 and C 3-12 Saturated monocyclic cycloalkyl rings include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cyclooctyl. Bicyclic compounds include spirocyclic compounds, fused bicyclic compounds, and bridged bicyclic compounds. Saturated bicyclic and polycyclic cycloalkyl rings include, for example, norbornene, [2.2.2]bicyclooctane, decahydronaphthalene, and adamantane. Cycloalkyl groups can also be partially unsaturated, having one or more double or triple bonds on 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 norbornene. When the cycloalkyl group is a saturated monocyclic C 3-8 When cycloalkyl is used, exemplary groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. When the cycloalkyl group is a saturated monocyclic C 3-6 When cycloalkyl is used, exemplary groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. The cycloalkyl group may be substituted or unsubstituted.

[0039] "alkyl-cycloalkyl" refers to a group having an alkyl component and a cycloalkyl component, wherein the alkyl component is attached to a linker with an aryl component. The alkyl component is as defined above, except that the alkyl component is at least divalent, alkylene, to be attached to the cycloalkyl component and to the linker. In some cases, the alkyl component may be absent. The alkyl component comprises any number of carbons, such as C10. 1-6 C 1-2 C 1-3 C 1-4 C 1-5 C 2-3 C 2-4 C 2-5 C 2-6 C 3-4 C 3-5 C 3-6 C 4-5 C 4-6 and C 5-6 The cycloalkyl 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] "Heterocyclic alkyl" refers to a cycloalkyl group having 3 to 12 ring members and 1 to 4 heteroatoms selected from N, O, and S, as described above. Heterocyclic alkyl groups include bicyclic compounds containing heteroatoms. Bicyclic compounds include spirocyclic compounds, fused bicyclic compounds, and bridged bicyclic compounds. Heteroatoms may also be oxidized, for example, but not limited to, -S(O)- and -S(O)2-. Heterocyclic alkyl groups include any number of ring atoms, for example, 3-6, 4-6, 5-6, 3-8, 4-8, 5-8, 6-8, 3-9, 3-10, 3-11, or 3-12 ring members. Any suitable number of heteroatoms is included in the heterocyclic alkyl group, for example, 1, 2, 3, or 4, or 1-2, 1-3, 1-4, 2-3, 2-4, or 3-4. The heterocyclic alkyl group includes, for example, aziridine, aziridine butadiene, pyrrolidine, piperidine, cyclohexylimine, azaocane, quinine ring, pyrazolidine, imidazoline, piperazine (1,2-, 1,3- and 1,4-isomers), ethylene oxide, oxazolidinyl butane, tetrahydrofuran, tetrahydropyran-4-acetyl chloride, hexane oxide, thiaprocyclo, thiophene, thiophene (tetrahydrothiophene), thiazolidine (tetrahydrothiaran), oxazolidine, isoxazolidine, thiazoline, isothiazolidine, dioxolane, dithiopentane, morpholine, thiomorpholine, dioxane, or dithiazolidine. The heterocyclic alkyl group may also incorporate aromatic or non-aromatic ring systems to form members including, but not limited to, indoline. The heterocyclic alkyl group may be unsubstituted or substituted. For example, the heterocyclic alkyl group is C 1-6 Alkyl or oxo (=O) substitution, etc.

[0041] "alkyl-heterocyclic alkyl" refers to a group having an alkyl component and a heterocyclic alkyl component, wherein the alkyl component and the heterocyclic alkyl component are attached to a connection point. The alkyl component is as defined above, except that the alkyl component is at least divalent, alkylene, to be attached to the heterocyclic alkyl component and to the connection point. The alkyl component includes any number of carbons, such as C10. 0-6 C 1-2 C 1-3 C 1-4 C 1-5 C 1-6 C 2-3 C 2-4 C 2-5 C 2-6 C 3-4 C 3-5 C 3-6 C 4-5 C 4-6 and C 5-6 In some cases, the alkyl component may be absent. The heterocyclic alkyl component is as defined above. The alkyl-heterocyclic alkyl group may be substituted or unsubstituted.

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

[0043] "Haloalkyl" refers to an alkyl group as defined above, wherein some or all of the hydrogen atoms are replaced by halogen atoms. For alkyl groups, haloalkyl groups have any suitable number of carbon atoms, such as C0. 1-6 For example, alkyl halides include trifluoromethyl, fluoromethyl, etc. In some cases, the term "perfluorinated" can be used to define all compounds or free radicals in which hydrogen is replaced by fluorine. For example, perfluoromethyl refers to 1,1,1-trifluoromethyl. Alkylamines.

[0044] "Alkoxy" refers to an alkyl group having an oxygen atom connecting the alkyl group to the junction point: alkyl-O-. For alkyl groups, the alkoxy group has any suitable number of carbon atoms, such as C. 1-6 Alkoxy groups include, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, 2-butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentoxy, hexoxy, etc. Alkoxy groups may be further substituted with various substituents described below. Alkoxy groups may be substituted or unsubstituted.

[0045] "Haloalkoxy" refers to an alkoxy group in which some or all of the hydrogen atoms are replaced by halogen atoms. For alkyl groups, haloalkoxy groups have any suitable number of carbon atoms, such as C10. 1-6Alkoxy groups can be substituted with one, two, three, or more halogens. When all hydrogen atoms are substituted with halogens, such as fluorine, these compounds are fully substituted, such as perfluorinated compounds. Haloalkoxy groups include, but are not limited to, trifluoromethoxy, 2,2,2-trifluoroethoxy, perfluoroethoxy, etc.

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

[0047] "Alkylamine" is defined as an alkyl group having one or more amino groups. The amino group can be a primary, secondary, or tertiary amine. Alkylamines can be further substituted with hydroxyl groups to form an amino-hydroxy group. Alkylamines used in this invention include, but are not limited to, ethylamine, propylamine, isopropylamine, ethylenediamine, and ethanolamine. The amino group can be attached to the alkylamine at a connection point with the rest of the compound, at the ω-position of the alkyl group, or attached to at least two carbon atoms on the alkyl group. Those skilled in the art will recognize that other alkylamines can also be used in this invention.

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

[0049] "alkyl-aryl" refers to a group having an alkyl component and an aryl component, wherein the alkyl component and the aryl component are attached to a connection point. The alkyl component is as defined above, except that the alkyl component is at least divalent, an alkylene group, to be attached to the aryl component and to the connection point. The alkyl component includes any number of carbons, such as C10. 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 C3-5 C 3-6 C 4-5 C 4-6 and C 5-6 In some cases, the alkyl component may be absent. The aryl component is as defined above. Examples of alkyl-aryl groups include, but are not limited to, benzyl and ethylbenzene. The alkyl-aryl group may be substituted or unsubstituted.

[0050] "Heteroaryl" refers to a monocyclic or fused bicyclic or tricyclic aromatic ring composition containing 5-16 ring atoms, wherein 1-5 ring atoms are heteroatoms, such as N, O, or S. Heteroaryl can include any number of ring atoms, such as 5-6, 3-8, 4-8, 5-8, 6-8, 3-9, 3-10, 3-11, or 3-12 ring members. Heteroaryl can contain any suitable number of heteroatoms, such as 1, 2, 3, 4, or 5, or 1-2, 1-3, 1-4, 1-5, 2-3, 2-4, 2-5, 3-4, or 3-5. Heteroaryl can have 5 to 8 ring members and 1 to 4 heteroatoms, or 5 to 8 ring members and 1 to 3 heteroatoms, or 5 to 6 ring members and 1 to 4 heteroatoms, or 5 to 6 ring members and 1 to 3 heteroatoms. Heteroaryl groups can include groups such as pyrrole, pyridine, imidazole, pyrazole, triazole, tetraazole, pyrazine, pyrimidine, pyridazine, triazine (1,2,3-, 1,2,4- and 1,3,5-isomers), thiophene, furan, thiazole, isothiazole, oxazole, and isoxazole. Heteroaryl groups can also fuse to form aromatic ring systems, such as benzene rings, forming 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., o-phenylenediamine and sinoline), benzothiophene, and benzofuran. Other heteroaryl groups include heteroaryl rings linked by bonds, such as bipyridine. Heteroaryl groups can be substituted or unsubstituted.

[0051] "alkyl-heteroaryl" refers to a group having an alkyl component and a heteroaryl component, wherein the alkyl component and the heteroaryl component are attached to a connection point. The alkyl component is as defined above, except that the alkyl component is at least divalent, alkylene, to be attached to the heteroaryl component and to the connection point. The alkyl component includes any number of carbons, such as C10. 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 C4-6 and C 5-6 In some cases, the alkyl component may be absent. The heteroaryl component is as defined herein. The alkyl-heteroaryl group may be substituted or unsubstituted.

[0052] “Salt” means an acid salt or base salt of a compound used in the methods of this invention. Illustrative examples of pharmaceutically acceptable salts are inorganic acid (hydrochloric acid, hydrobromic acid, phosphoric acid, etc.) salts, organic (fumaric acid, acetic acid, oleic acid, propionic acid, glutamic acid, citric acid, etc.) salts, and quaternary ammonium (methyl iodide, ethyl iodide, etc.) salts. It should be understood that pharmaceutically acceptable salts are non-toxic. Further information on suitable pharmaceutically acceptable salts can be found in Remington's Pharmaceutical Sciences (17th edition, Mack Publishing Company, Easton, PA, 1985), which is incorporated herein by reference.

[0053] The neutral form of the compound can be regenerated by contacting the salt with a base or acid and separating the parent compound in a conventional manner. The parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents; however, for the purposes of this invention, the salt is equivalent to the parent form of the compound.

[0054] "Pharmaceutically acceptable salts" refer to compounds in salt form that are suitable for administration to a subject. Representative pharmaceutically acceptable salts include acetates, ascorbic acid salts, benzenesulfonates, benzoates, camphorsulfonates, citrates, ethanesulfonates, oxalates, fumarates, gentianates, gluconates, gluconates, glutamates, hippurates, hydrobromide salts, hydrochlorides, isothiocyanates, lactates, lactobionic acid salts, maleates, malates, mandelates, methanesulfonates, mucilage salts, naphthalenesulfonates, naphthalene-1,5-disulfonates, naphthalene-2,6-disulfonates, nicotinates, nitrates, orotates, papoic acid salts, pantothenates, phosphates, succinates, sulfates, tartrates, p-toluenesulfonates, and xinafoic acid salts, etc. "Pharmaceutically acceptable excipients" are substances that facilitate administration to and absorption of an active pharmaceutical ingredient by a subject. Pharmaceutical excipients used in this invention include, but are not limited to, binders, fillers, disintegrants, lubricants, coatings, sweeteners, flavorings, and colorings. Those skilled in the art will recognize that other pharmaceutically acceptable excipients may also be used in this invention.

[0055] "Composition" means a product containing a specific amount of a specific ingredient, and any product produced directly or indirectly from a combination of specific amounts of a specific ingredient. "Pharmaceutically acceptable" means that the carrier, diluent, or excipient must be compatible with the other components of the formulation.

[0056] "Isomers" are compounds with the same chemical formula but different atomic connections, resulting in different chemical structures. Isomers include structural isomers and stereoisomers. Examples of structural isomers include, but are not limited to, tautomers and regioisomers. Examples of stereoisomers include, but are not limited to, diastereomers and enantiomers.

[0057] "Administration" refers to oral administration, suppository administration, external contact, parenteral administration, intravenous administration, intraperitoneal administration, intramuscular administration, intradermal administration, intranasal administration, subcutaneous administration, intrathecal administration, or implantation of a slow-release device, such as implanting a micro-osmotic pump into the subject.

[0058] "Subjects" refers to animals such as mammals, including but not limited to primates (e.g., mammals). ， Animals including humans, cattle, sheep, goats, horses, dogs, cats, rabbits, rats, and mice. In some embodiments, the object is a human.

[0059] "Therapeutic effective dose," "therapeutic adequate dose," or "effective or adequate dose" refers to a dose that produces a therapeutic effect on the recipient. The specific dose will depend on the therapeutic purpose and will be determined by someone 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: pharmacy The Science and Practice of Pharmacy. 20th edition, 2003, edited by Gennaro, LWW Publishing. In sensitized cells, the effective dose of treatment for sensitized cells is often lower than the effective dose of conventional treatment.

[0060] "Neuronal plasticity" refers to the brain's ability to continuously change its structure and / or function throughout a subject's life. Examples of brain changes include, but are not limited to, the ability to adapt to or respond to internal and / or external stimuli such as those caused by injury, and the ability to generate new neurites, dendritic spines, and synapses.

[0061] "Brain diseases" refer to neurological disorders that affect the structure and function of the brain. Brain diseases include, but are not limited to, 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.

[0062] "Combination therapy" refers to a method of treating a disease or disorder in which two or more different drugs are administered in an overlapping regimen so that the subject is simultaneously exposed to both drugs. For example, the compounds of the present invention can be used in combination with other pharmaceutically active compounds. The compounds of the present invention can be administered simultaneously (as a single formulation or a single formulation) or sequentially to other drug treatments. Generally, combination therapy envisions administering two or more drugs in one cycle or course of treatment.

[0063] "Neurotrophic factors" refer to a family of soluble peptides or proteins that support the survival, growth, and differentiation of developing and maturing neurons.

[0064] "Modulate," "modulating," or "modulation" refers to increasing or decreasing the quantity, quality, or effect of a particular activity, function, or molecule. As an illustration and not a limitation, G protein-coupled receptors (e.g., 5HT) 2A Agonists, partial agonists, antagonists, and allosteric modulators (e.g., orthoallosteric modulators) of the receptor are regulators of the receptor.

[0065] "Arousal" refers to the activation of receptors or enzymes by regulators or agonists to produce a biological response.

[0066] An "agonist" is a regulator that binds to a receptor or enzyme and activates the receptor to produce a biological response. For example, "5HT..." 2A "Agonist" can be used to refer to EC 50 Approximately 5HT, not exceeding approximately 100 μM 2A The active chemical substance exhibited. In some embodiments, the term "agonist" includes full agonists or partial agonists. A "full agonist" is a regulator that binds to the receptor and activates the receptor with the maximum response that the agonist can elicit on the receptor. A "partial agonist" is a regulator that binds to and activates a given receptor, but has only partial potency on that receptor, i.e., less than the maximum response, compared to a full agonist.

[0067] "Orthoallosteric modulators" are modulators that bind to sites different from orthoallosteric binding sites and enhance or amplify the effects of agonists.

[0068] "Antagonism" refers to the inactivation of a receptor or enzyme by a regulator or antagonist. For example, receptor antagonism prevents a molecule from becoming active when it binds to the receptor.

[0069] "Antagonists" or "neutral antagonists" are regulators that bind to receptors or enzymes and block biological responses. In the absence of agonists or antiagonists, antagonists are inactive, but they can block the activity of either without altering the biological response.

[0070] III. Compounds This invention provides N-substituted indole and other heterocyclic compounds for the treatment of various brain diseases and other ailments. In some embodiments, the N-substituted indole and other heterocyclic compounds provided herein are 5-HT 2A Modulators that promote neural plasticity (such as cortical structural plasticity).

[0071] In some embodiments, the present invention provides a compound of formula I or a salt and isomer thereof: (I) Where X is N or CR 3 ;R 1a R 1b and R 1c Each independently represents H and C. 1-6 Alkyl, C 3-8 cycloalkyl, or C 4-14 alkyl-cycloalkyl; or, R 1a R 1b and R 1c The two atoms in the mixture combine with the atoms they are attached to to form C. 3-6 Heterocyclic alkyl; R 2 R 3 R 4 R 5 R 6 and R 7 Each independently is hydrogen, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkyne, halogen, C 1-6 Haloalkyl, C 1-6 Alkylamine, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, –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 Heterocyclic alkyl, C 4-16 Alkyl-heterocyclic alkyl, C 6-12 Aryl, C 7-18 Alkyl-aryl, C 5-10 heteroaryl, or C 4-16 alkyl heteroaryl; R 8a C 3-8 cycloalkyl, C 3-14 Alkyl-cycloalkyl, C 4-10 Heterocyclic alkyl, C 4-16 Alkyl-heterocyclic alkyl, 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 Each independently is H or C 1-6 Alkyl; or, R 1a R 1b Or R 1c One of them is with R 2 R 3 R 4 R 5 R 6 and R 7 A combination of these elements forms C 5-6 cycloalkyl or C 5-6 Heterocyclic alkyl; or, R 2 and R 3 They combine with their respective atoms to form C 6-12 aryl; or, R 4 and R5 R 5 and R 6 , or R 6 and R 7 They combine with their respective atoms to form C 3-6 cycloalkyl or C 3-6 Heterocyclic alkyl; L is C 1-6 Alkylene.

[0072] In some embodiments, the present invention provides a compound of formula I or a pharmaceutically acceptable salt thereof and its isomers: (I) Where: X is N or CR 3 ;R 1a R 1b and R 1c Each independently represents H and C. 1-6 Alkyl, C 3-8 cycloalkyl, or C 4-14 alkyl-cycloalkyl; or, R 1a R 1b and R 1c The two atoms in the mixture combine with the atoms they are attached to to form C. 3-12 Heterocyclic alkyl; R 2 R 3 R 4 R 5 R 6 and R 7 Each independently is hydrogen, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkyne, halogen, C 1-6 Haloalkyl, C 1-6 Alkylamine, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, –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 Heterocyclic alkyl, C 4-16 Alkyl-heterocyclic alkyl, C 6-12 Aryl, C 7-18 Alkyl-aryl, C 5-10 heteroaryl, or C 4-16 alkyl heteroaryl; R 8a C 3-8 cycloalkyl, C 3-14 Alkyl-cycloalkyl, C 4-10 Heterocyclic alkyl, C 4-16 Alkyl-heterocyclic alkyl, 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 Each independently is H or C 1-6 Alkyl; or, R 1a R 1b Or R 1c One of them is with R 2 R 3 R 4 R 5 R 6 and R 7 A combination of these elements forms C 5-12 Heterocyclic alkyl; or, R 2 and R 3 They combine with their respective atoms to form C 4-8 cycloalkyl, C 4-10 Heterocyclic alkyl, or C 6-12 aryl; or, R 4 and R 5 R 5 and R 6 , or R 6 and R 7 They combine with their respective atoms to form C 3-6 cycloalkyl, C 3-6 Heterocyclic alkyl, C 6-12Aryl, or C 5-10 heteroaryl; L is C 1-6 alkylene, wherein, when R 1a and R 1b Both are Me, R 1c When L is a hydrogen atom and L is a methylene group, 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 not: ; Where R 1a and R 1b For Me, R 1c L represents hydrogen atoms, L represents ethylene, and X represents CR. 3 When, then R 2 R 3 R 4 R 5 R 6 and R 7 At least one of them is not hydrogen; among them, when R 1c For H, R 5 For Br, Cl, F, -NH2, -NO2, or C 1-3 When alkoxy is present, then R 2 R 3 R 4 R 6 , or R 7 At least one of them is not hydrogen; where, when R 1c For hydrogen and R 5 When it is F, then R 2 R 3 R 4 R 6 , or R 7 At least one of them is not hydrogen, R 6 Not F; where, when R 1a R 1b and R 1c Each is Me, L is methylene, and X is CR. 3 R 2 R 3 R 4 R 5 R 6 and R 7 When all components are hydrogen, then the compound is: or .

[0073] In some embodiments, the present invention provides a compound of formula I or a pharmaceutically acceptable salt thereof and its isomers: (I) Where: X is CR 3 ;R 1a and R 1b Each independently is hydrogen, C 1-6 Alkyl, C 3-8 cycloalkyl, or C 4-14 Alkyl-cycloalkyl; R 1c C 1-6 Alkyl, C 3-8 cycloalkyl, or C 4-14 alkyl-cycloalkyl; or, R 1a R 1b and R 1c Two atoms in the matrix combine through the atoms they are attached to to form C. 3-12 Heterocyclic alkyl; R 2 R 3 R 4 R 5 R 6 and R 7 Each independently is hydrogen, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkyne, halogen, C 1-6 Haloalkyl, C 1-6 Alkylamine, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, –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)R8b -S(O)2N(R) 8b R 8c C 3-8 cycloalkyl, C 3-14 Alkyl-cycloalkyl, C 4-10 Heterocyclic alkyl, C 4-16 Alkyl-heterocyclic alkyl, C 6-12 Aryl, C 7-18 Alkyl-aryl, C 5-10 heteroaryl, or C 4-16 alkyl heteroaryl; R 8a C 3-8 cycloalkyl, C 3-14 Alkyl-cycloalkyl, C 4-10 Heterocyclic alkyl, C 4-16 Alkyl-heterocyclic alkyl, 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 Each independently is H or C 1-6 Alkyl; or, R 1a R 1b Or R 1c One of them is with R 2 Combining to form C 5-12 Heterocyclic alkyl; or, R 2 and R 3 They combine with their respective atoms to form C 4-8 cycloalkyl, C 4-10 Heterocyclic alkyl, or C 6-12 aryl; or, R 4 and R 5 R 5 and R 6 , or R 6 and R 7 They combine with their respective atoms to form C 4-6 cycloalkyl, C 4-6 Heterocyclic alkyl, C 6-12 Aryl, or C 5-10 heteroaryl; L is C 1-6 alkylene, wherein, when R 1a R 1b and R 1c Each is Me, L is methylene, and X is CR. 3 and R 2 R 3 R 4 R 5R 6 and R 7 If it is hydrogen, then the compound is or And the compound said compound is not .

[0074] In some embodiments, the present invention provides a compound or a pharmaceutically acceptable salt thereof, wherein X is N or CR. 3 In some embodiments, the present invention provides a compound or a pharmaceutically acceptable salt thereof, where X is a CR. 3 In some embodiments, the present invention provides a compound or a pharmaceutically acceptable salt thereof, where X is N.

[0075] In some embodiments, the present invention provides a compound or a pharmaceutically acceptable salt thereof, wherein X is a CR 3 ;R 2 and R 3 Each independently is hydrogen, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkyne, halogen, C 1-6 Haloalkyl, C 1-6 Alkylamine, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, –OR 8a -NO2, -CN, -C(O)R 8b -C(O)OR 8b -OC(O)R 8b -OC(O)OR 8b -N(R) 8b R 8c ), -N(R 8b )C(O)R 8c -C(O)N(R) 8b R 8c ), -N(R 8b )C(O)OR 8c -OC(O)N(R) 8b R 8c ), -N(R 8b )C(O)N(R 8c R 8d -C(O)C(O)N(R) 8b R 8c -S(O2)R 8b -S(O)2N(R) 8b R 8c C 3-8 cycloalkyl, C3-14 Alkyl-cycloalkyl, C 4-10 Heterocyclic alkyl, C 4-16 Alkyl-heterocyclic alkyl, C 6-12 Aryl, C 7-18 Alkyl-aryl, C 5-10 heteroaryl, or C 4-16 alkyl heteroaryl; R 8a C 3-8 cycloalkyl, C 3-14 Alkyl-cycloalkyl, C 4-10 Heterocyclic alkyl, C 4-16 Alkyl-heterocyclic alkyl, C 6-12 Aryl, C 7-18 Alkyl-aryl, C 5-10 heteroaryl, or C 4-16 alkyl-heteroaryl; and R 8b R 8c and R 8d Each independently is H or C 1-6 Alkyl; wherein, when R 1a R 1b and R 1c Each is Me, L is methylene, and R 2 R 3 R 3 R 4 R 5 R 6 and R 7 Both are hydrogen, then the compound is or .

[0076] In some embodiments, the present invention provides a compound or a pharmaceutically acceptable salt thereof, wherein the compound of formula I has the following structure: .

[0077] In some embodiments, the present invention provides a compound or a pharmaceutically acceptable salt thereof, wherein R 1a R 1b and R 1c Each independently is C 1-6 Alkyl, C 3-8 cycloalkyl, or C 4-14 alkyl-cycloalkyl; or, R 1a R 1b and R 1c Any two atoms bonded to them combine to form C. 3-12 Heterocyclic alkyl; R 2 R 3 R4 R 6 and R 7 Each independently is hydrogen, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkyne, halogen, C 1-6 Haloalkyl, C 1-6 Alkylamine, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, –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 Heterocyclic alkyl, C 4-16 Alkyl-heterocyclic alkyl, C 6-12 Aryl, C 7-18 Alkyl-aryl, C 5-10 heteroaryl, or C 4-16 alkyl heteroaryl; R 5 C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkyne, halogen, C 1-6 Haloalkyl, C 1-6 Alkylamine, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, –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 Heterocyclic alkyl, C 4-16 Alkyl-heterocyclic alkyl, C 6-12 Aryl, C 7-18 Alkyl-aryl, C 5-10 heteroaryl, or C 4-16 alkyl-heteroaryl; R 8a C 3-8 cycloalkyl, C 3-14 Alkyl-cycloalkyl, C 4-10 Heterocyclic alkyl, C 4-16 Alkyl-heterocyclic alkyl, 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 Each independently is H or C 1-6 Alkyl; or, R 4 and R 5 R 5 and R 6 , or R 6 and R 7 They combine with their respective atoms to form C 4-6 cycloalkyl, C 4-6 Heterocyclic alkyl, C 6-12 Aryl, or C 5-10 Mixed aromatics; In some embodiments, the present invention provides a compound or a pharmaceutically acceptable salt thereof, wherein R 1a and R 1b Each is independently hydrogen or C 1-6 Alkyl; R 1c C 1-6 Alkyl; R 2 and R 3 Each is independently hydrogen, C 1-6 Alkyl, C 1-6 Alkoxy, halogen, or -C(O)C(O)N(R) 8b R 8c ); R 4 R 5 R 6 and R 7 Each independently is hydrogen, C 1-6 Alkyl, halogen, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, or –OR 8a , where R 4 R 5 R 6 and R 7 At least one of them is not H; and R 8a It is C 7-18 alkyl-aryl; or, R 5 and R 6 They combine with their respective atoms to form C 4-6 Heterocyclic alkyl groups.

[0078] In some embodiments, the present invention provides a compound, wherein X is a CR 3 ;R 1a R 1b and R 1c Each independently is either hydrogen or C. 1-6 Alkyl; R 2 and R 3 Each is independently hydrogen, C 1-6 Alkyl group, or -C(O)C(O)N(R) 8b R 8c ); R 4 R 5 R 6 and R 7 Each independently is hydrogen, C 1-6 Alkyl, halogen, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, or –OR 8a , where R4 R 5 R 6 and R 7 At least one of them is not H; and R 8a It is C 7-18 alkyl-aryl; or, R 5 and R 6 They combine with their respective atoms to form C 3-6 Heterocyclic alkyl groups.

[0079] In some embodiments, the present invention provides a compound or a pharmaceutically acceptable salt thereof, R 1a and R 1b Each independently represents H and C. 1-6 Alkyl, C 3-8 cycloalkyl, or C 4-14 alkyl-cycloalkyl; or, R 1a R 1b and R 1c The two atoms in the mixture combine with the atoms they are attached to to form C. 3-12 Heterocyclic alkyl groups. In some embodiments, R 1a and R 71b Each is independently hydrogen or C 1-6 Alkyl group. 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 is independently hydrogen or methyl.

[0080] In some embodiments, the present invention provides a compound or a pharmaceutically acceptable salt thereof, R 1a and R 1b Each is independently H or methyl, R 1c It is methyl; or, R 1a R 1b and R 1c The two atoms in the mixture combine with the atoms they are attached to to form C. 3-8 Heterocyclic alkyl groups. In some embodiments, the present invention provides a compound or a pharmaceutically acceptable salt thereof, wherein R 1a and R 1b Each is independently H or methyl; R 1c It is methyl; or, R 1a R 1b and R 1c The two atoms in the mixture combine with the atoms they are attached to to form C. 3-8 Heterocyclic alkyl groups.

[0081] In some embodiments, the present invention provides a compound or a pharmaceutically acceptable salt thereof, wherein R1c C 1-6 Alkyl, C 3-8 cycloalkyl, or C 4-14 Alkyl-cycloalkyl. In some embodiments, the present invention provides a compound or a pharmaceutically acceptable salt thereof, wherein R 1c C 1-6 Alkyl group. In some embodiments, R 1c It is methyl, ethyl, or propyl. In some embodiments, the invention provides a compound or a pharmaceutically acceptable salt thereof, wherein R 1c methyl. In some embodiments, R 1c It is a methyl group.

[0082] In some embodiments, the present invention provides a compound or a pharmaceutically acceptable salt thereof, wherein R 1a R 1b and R 1c Each is a methyl group; or, R 1a R 1b and R 1c The two atoms in the mixture combine with the atoms they are attached to to form C. 3-8 Heterocyclic alkyl groups. In some embodiments, the present invention provides a compound or a pharmaceutically acceptable salt thereof, wherein R 1a R 1b and R 1c Each is Me; or, R 1a R 1b and R 1c The two atoms in the mixture combine with the atoms they are attached to to form C. 3-8 Heterocyclic alkyl groups.

[0083] In some embodiments, the present invention provides a compound or a pharmaceutically acceptable salt thereof, wherein R 1a R 1b Or R 1c One of them with R 2 R 3 R 4 R 5 R 6 Or R 7 One of them combines to form C 5-12 Heterocyclic alkyl groups. In some embodiments, the present invention provides a compound or a pharmaceutically acceptable salt thereof, wherein R 1a R 1b Or R 1c One of them with R 2 Or R 7 One of them combines to form C 5-8 Heterocyclic alkyl groups. In some embodiments, the present invention provides a compound or a pharmaceutically acceptable salt thereof, wherein R1a R 1b , or R 1c One of them with R 2 Combining to form C 5-8 Heterocyclic alkyl groups.

[0084] In some embodiments, the present invention provides a compound or a pharmaceutically acceptable salt thereof, wherein R 2 R 3 R 4 R 5 R 6 and R 7 Each independently is hydrogen, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkyne, halogen, C 1-6 Haloalkyl, C 1-6 Alkylamine, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, –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 Heterocyclic alkyl, C 4-16 Alkyl-heterocyclic alkyl, C 6-12 Aryl, C 7-18 Alkyl-aryl, C 5-10 heteroaryl, or C 4-16 Alkyl heteroaryl. In some embodiments, R8a C 3-8 cycloalkyl, C 3-14 Alkyl-cycloalkyl, C 4-10 Heterocyclic alkyl, C 4-16 Alkyl-heterocyclic alkyl, C 6-12 Aryl, C 7-18 Alkyl-aryl, C 5-10 heteroaryl, or C 4-16 alkyl-heteroaryl; and R 8b R 8c and R 8d Each independently is H or C 1-6 alkyl; In some embodiments, the present invention provides a compound or a pharmaceutically acceptable salt thereof, wherein R 2 and R 3 Each independently is hydrogen, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkyne, halogen, C 1-6 Haloalkyl, C 1-6 Alkylamine, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, –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 Heterocyclic alkyl, C 4-16 Alkyl-heterocyclic alkyl, C6-12 Aryl, C 7-18 Alkyl-aryl, C 5-10 heteroaryl, or C 4-16 Alkyl-heteroaryl.

[0085] In some embodiments, the present invention provides a compound, or a pharmaceutically acceptable salt thereof, wherein R 2 For hydrogen, C 1-6 Alkyl, halogen, or C 1-6 Alkyl group. In some embodiments, the present invention provides a compound or a pharmaceutically acceptable salt thereof, wherein R 2 It is hydrogen, methyl, ethyl, propyl, F, Cl, Br, I, methoxy, or ethoxy. In some embodiments, the invention provides a compound or a pharmaceutically acceptable salt thereof, wherein R 2 It can be hydrogen, Me, F or -OMe.

[0086] In some embodiments, the present invention provides a compound or a pharmaceutically acceptable salt thereof, wherein R 3 For 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 independently is H or C 1-6 Alkyl group. In some embodiments, the present invention provides a compound or a pharmaceutically acceptable salt thereof, wherein R 3 It can be 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 can be methyl, ethyl, or propyl.

[0087] In some embodiments, the present invention provides a compound or a pharmaceutically acceptable salt thereof, wherein R 3 For 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 independently is H or C 1-6 Alkyl group. In some embodiments, the present invention provides a compound or a pharmaceutically acceptable salt thereof, wherein R 3 It can be hydrogen, Me, F, -OMe or -C(O)C(O)NMe2.

[0088] In some embodiments, the present invention provides a compound or a pharmaceutically acceptable salt thereof, wherein the compound of formula I has the following structure: .

[0089] In some embodiments, the present invention provides a compound or a pharmaceutically acceptable salt thereof, wherein the compound of formula I has the following structure: .

[0090] In some embodiments, the present invention provides a compound or a pharmaceutically acceptable salt thereof, wherein R 1a and R 1b They combine with the atoms to which they are attached to form C 3-12 Heterocyclic alkyl groups. In some embodiments, the present invention provides a compound or a pharmaceutically acceptable salt thereof, wherein R 1a and R 1b They combine with the atoms to which they are attached to form C 3-8 Heterocyclic alkyl groups. In some embodiments, the present invention provides a compound or a pharmaceutically acceptable salt thereof, wherein R 1a and R 1b They combine with the atoms they are attached to to form C 3-8 Heterocyclic alkyl groups.

[0091] In some embodiments, the present invention provides a compound or a pharmaceutically acceptable salt thereof, wherein, R 1a and R 1c They combine with the atoms they are attached to to form C 5-12 Heterocyclic alkyl groups. In some embodiments, the present invention provides a compound or a pharmaceutically acceptable salt thereof, wherein R 1a and R 1c They combine with the atoms they are attached to to form C 5-8 Heterocyclic alkyl groups. In some embodiments, the present invention provides a compound or a pharmaceutically acceptable salt thereof, wherein R 1a and R 1c They combine with the atoms they are attached to to form C 5-6 Heterocyclic alkyl groups. In some embodiments, the present invention provides a compound or a pharmaceutically acceptable salt thereof, wherein R 1a and R 1c They combine with the atoms they are attached to to form C 5-8 Heterocyclic alkyl groups.

[0092] In some embodiments, the present invention provides a compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof: (Ia); Where: R 1a and R 1b Each independently is C 1-6 Alkyl, C 3-8 cycloalkyl, or C 4-14 Alkyl-cycloalkyl; R 1c For hydrogen, C 1-6 Alkyl, C 3-8 cycloalkyl, or C 4-14 alkyl-cycloalkyl; or, R 1a R 1b and R 1c Any two atoms in the middle combine through the atoms to which they are attached to form C. 3-12 Heterocyclic alkyl; R 2 R 3 R 4 R 6 and R 7 Each independently is hydrogen, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkyne, halogen, C 1-6 Haloalkyl, C 1-6 Alkylamine, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, –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 Heterocyclic alkyl, C4-16 Alkyl-heterocyclic alkyl, C 6-12 Aryl, C 7-18 Alkyl-aryl, C 5-10 heteroaryl, or C 4-16 alkyl heteroaryl; R 5 For F, Cl, Br, C 1-6 Alkyl, C 1-6 Halogenated alkoxy groups, OR 8a -NO2, -CN, C 2-6 alkenyl, C 2-6 alkynyl group, –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 3-8 cycloalkyl, C 3-14 Alkyl-cycloalkyl, C 4-10 Heterocyclic alkyl, C 4-16 Alkyl-heterocyclic alkyl, C 6-12 Aryl, C 7-18 alkyl-aryl or C 4-16 alkyl-heteroaryl; R 8a C 3-8 cycloalkyl, C 3-14 Alkyl-cycloalkyl, C 4-10 Heterocyclic alkyl, C 4-16 Alkyl-heterocyclic alkyl, 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 Each independently is H or C 1-6 Alkyl; or, R 1a R1b and R 1c One of them with R 2 Or R 7 One of them combines to form C 5-6 cycloalkyl or C 5-6 Heterocyclic alkyl; or, R 2 and R 3 They combine with their respective atoms to form C 6-12 aryl; or, R 4 and R 5 R 5 and R 6 , or R 6 and R 7 They combine with their respective atoms to form C 3-6 cycloalkyl or C 3-6 Heterocyclic alkyl groups; or their salts and isomers; wherein, if R 1c For H and R 5 If it is Br, Cl, F, -NH2, -NO2, or C1-C3 alkoxy, then R 2 R 3 R 4 R 6 Or R 7 At least one of them is not H; where, when R 5 If F is the denominator, then R is the denominator. 6 It's not F.

[0093] In some embodiments, the present invention provides a compound of formula (Ia), or a pharmaceutically acceptable salt or solvate thereof: wherein: R 1a and R 1b Each independently is C 1-6 Alkyl, C 3-8 cycloalkyl, or C 4-14 Alkyl-cycloalkyl; R 1c C 1-6 Alkyl, C 3-8 cycloalkyl, or C 4-14 alkyl-cycloalkyl; or, R 1a R 1b and R 1c Any two atoms in the middle combine through the atoms they are connected to form C. 3-12 Heterocyclic alkyl; R 2 R 3 R 4 R 6 and R 7 Each independently is hydrogen, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkyne, halogen, C 1-6Haloalkyl, C 1-6 Alkylamine, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, –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 Heterocyclic alkyl, C 4-16 Alkyl-heterocyclic alkyl, C 6-12 Aryl, C 7-18 Alkyl-aryl, C 5-10 heteroaryl, or C 4-16 alkyl heteroaryl; R 5 C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkyne, halogen, C 1-6 Haloalkyl, C 1-6 Alkylamine, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, –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)R8c -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 Heterocyclic alkyl, C 4-16 Alkyl-heterocyclic alkyl, C 6-12 Aryl, C 7-18 Alkyl-aryl, C 5-10 heteroaryl, or C 4-16 alkyl-heteroaryl; R 8a C 3-8 cycloalkyl, C 3-14 Alkyl-cycloalkyl, C 4-10 Heterocyclic alkyl, C 4-16 Alkyl-heterocyclic alkyl, 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 Each independently is H or C 1-6 Alkyl; or, R 1a R 1b Or R 1c One of them is with R 2 Or R 7 A combination of these elements forms C 5-6 cycloalkyl or C 5-6 Heterocyclic alkyl; or, R 2 and R 3 They combine with the atoms attached to them to form C 6-12 aryl; or, R 4 and R 5 R 5 and R 6 , or R 6 and R 7 They combine with the atoms attached to them to form C3-6 cycloalkyl or C 3-6 Heterocyclic alkyl groups; or their salts and isomers.

[0094] In some embodiments, the present invention provides a compound or a pharmaceutically acceptable salt thereof, wherein the compound of formula I has the following structure: .

[0095] In some embodiments, the present invention provides a compound or a pharmaceutically acceptable salt thereof, wherein the compound of formula I has the following structure: .

[0096] In some embodiments, the present invention provides a compound or a pharmaceutically acceptable salt thereof, wherein the compound of formula I has the following structure: .

[0097] In some embodiments, R 2 and R 3 They combine with their respective atoms to form C 4-8 cycloalkyl, C 4-10 Heterocyclic alkyl, or C 6-12 Aryl.

[0098] In some embodiments, the present invention provides a compound or a pharmaceutically acceptable salt thereof, wherein R 4 R 5 R 6 and R 7 Each independently is hydrogen, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkyne, halogen, C 1-6 Haloalkyl, C 1-6 Alkylamine, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, –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 Heterocyclic alkyl, C 4-16 Alkyl-heterocyclic alkyl, C 6-12 Aryl, C 7-18 Alkyl-aryl, C 5-10 heteroaryl, or C 4-16 alkyl-heteroaryl; or, R 4 and R 5 R 5 and R 6 , or R 6 and R 7 They combine with their respective atoms to form C 4-6 cycloalkyl, C 4-6 Heterocyclic alkyl, C 6-12 Aryl, or C 5-10 Heteroaryl. In some embodiments, the present invention provides a compound or a pharmaceutically acceptable salt thereof, wherein R 4 R 5 R 6 and R 7 Each independently is hydrogen, C 1-6 Alkyl, halogen, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, –OR 8a -NO2, -CN, C 3-8 cycloalkyl, or C 3-14 Alkyl-cycloalkyl.

[0099] In some embodiments, the present invention provides a compound or a pharmaceutically acceptable salt thereof, wherein R 8a C 3-8 cycloalkyl, C 3-14 Alkyl-cycloalkyl, C 4-10 Heterocyclic alkyl, C 4-16 Alkyl-heterocyclic alkyl, C 6-12 Aryl, C 7-18 Alkyl-aryl, C 5-10 heteroaryl, C4-16 alkyl-heteroaryl; and R 8b R 8c and R 8d Each independently is H or C 1-6 Alkyl group. In some embodiments, the present invention provides a compound or a pharmaceutically acceptable salt thereof, wherein R 8a C 3-8 cycloalkyl, C 3-14 Alkyl-cycloalkyl, C 4-16 Alkyl-heterocyclic alkyl.

[0100] In some embodiments, the present invention provides a compound or a pharmaceutically acceptable salt thereof, wherein R 4 and R 5 R 5 and R 6 , or R 6 and R 7 They combine with their respective atoms to form C 4-6 cycloalkyl, C 4-6 Heterocyclic alkyl, C 6-12 Aryl, or C 5-10 Heteroaryl. In some embodiments, the present invention provides a compound or a pharmaceutically acceptable salt thereof, wherein R 4 and R 5 They combine with the atoms they are attached to to form C 4-6 Heterocyclic alkyl groups. In some embodiments, the present invention provides a compound or a pharmaceutically acceptable salt thereof, wherein R 5 and R 6 They combine with their respective atoms to form C 4-6 Heterocyclic alkyl groups. In some embodiments, the present invention provides a compound or a pharmaceutically acceptable salt thereof, wherein R 6 and R 7 They combine with their respective atoms to form C 4-6 Heterocyclic alkyl groups. In some embodiments, the present invention provides a compound or a pharmaceutically acceptable salt thereof, wherein R 5 and R 6 They combine with the atoms they are attached to to form C 5-6 Heterocyclic alkyl groups. In some embodiments, the present invention provides a compound or a pharmaceutically acceptable salt thereof, wherein R 5 and R 6 They combine with the atoms to which they are attached to form 1,3-m-dioxacyclopentene rings or 1,4-dioxane rings.

[0101] In some embodiments, the present invention provides a compound or a pharmaceutically acceptable salt thereof, wherein R 4 R 5 R6 and R 7 Each is independently hydrogen, C 1-6 Alkyl, halogen, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, -OR 8a -NO2, -CN, C 3-8 cycloalkyl, or C 3-14 alkyl-cycloalkyl; or, R 4 and R 5 R 5 and R 6 , or R 6 and R 7 It can combine with the atoms they are attached to to form C 56 Heterocyclic alkyl groups; and R 8a It is C 3-8 cycloalkyl 3-14 alkyl-cycloalkyl 4-16 alkyl heterocyclic alkyl 7-18 alkylaryl 4-16 alkyl heteroaryl; or, R 4 and R 5 R 5 and R 6 , or R 6 and R 7 They combine with their respective atoms to form C 5-6 Heterocyclic alkyl groups. And R 8a C 3-8 cycloalkyl, C 3-14 Alkyl-cycloalkyl, C 4-16 Alkyl-heterocyclic alkyl, C 7-18 alkyl-aryl, or C 4-16 Alkyl-heteroaryl. In some embodiments, the present invention provides a compound or a pharmaceutically acceptable salt thereof, wherein R 4 R 5 R 6 and R 7 Each independently is hydrogen, C 1-6 Alkyl, halogen, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, -OR 8a Or -NO2; or, R 4 and R 5 R 5 and R 6 , or R 6 and R 7 They combine with their respective attached atoms to form C5 heterocyclic alkyl groups. And R 8a C7-18 Alkyl-aryl. In some embodiments, the present invention provides a compound or a pharmaceutically acceptable salt thereof, wherein R 4 R 6 and R 7 Each independently is hydrogen, C 1-6 Alkyl, halogen, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, -OR 8a Or -NO2; R 5 C 1-6 Alkyl, halogen, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, -OR 8a Or -NO2; or, R 4 and R 5 R 5 and R 6 , or R 6 and R 7 They combine with their respective attached atoms to form C5 heterocyclic alkyl groups. And R 8a C 7-18 Alkyl-aryl. In some embodiments, the present invention provides a compound or a pharmaceutically acceptable salt thereof, wherein, R 4 R 5 R 6 and R 7 Each can be independently hydrogen, Me, F, Cl, Br, -OMe, -OCF3, -O-CH2-phenyl, or -NO2; or, R 5 and R 6 They combine with the atoms to which they are attached to form 1,3-m-dioxacyclopentene rings or 1,4-dioxane rings.

[0102] In some embodiments, the present invention provides a compound or a pharmaceutically acceptable salt thereof, wherein R 5 C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkyne, 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 Heterocyclic alkyl, C 4-16 Alkyl-heterocyclic alkyl, C 6-12 Aryl, C 7-18 Alkyl-aryl, C 5-10 heteroaryl, or C 4-16 Alkyl-heteroaryl. In some embodiments, the present invention provides a compound or a pharmaceutically acceptable salt thereof, wherein R 5 It is C 1-6 Alkyl, halogen, C 1-6 Alkoxy, C 1-6 Haloalkoxy, or –NO2. In some embodiments, the present invention provides a compound or a pharmaceutically acceptable salt thereof, wherein R 5 The compounds are methyl, ethyl, propyl, F, Cl, Br, I, methoxy, ethoxy, -OCF3, -O-benzyl, or -NO2. In some embodiments, the invention provides a compound or a pharmaceutically acceptable salt thereof, wherein R 5 It can be methyl, F, Cl, Br, methoxy, -OCF3, -O-benzyl, or -NO2.

[0103] In some embodiments, the present invention provides a compound or a pharmaceutically acceptable salt thereof, wherein R 4 R 6 and R 7 Each is independently hydrogen; and R 5 It can be Me, F, Cl, Br, -OMe, -CF3, -OCF3, -O-benzyl, or -NO2. In some embodiments, the present invention provides a compound or a pharmaceutically acceptable salt thereof, wherein R 5 For Me, F, Cl, Br, -OMe, -CF3, -OCF3, -O-benzyl, or -NO2; and R6 and R 7 Each can be independently hydrogen, Me, F, Cl, Br, -OMe, -OCF3, -O-CH2-phenyl, or -NO2, wherein R 6 and R 7 At least one of them is not hydrogen.

[0104] In some embodiments, the present invention provides a compound, wherein X is a CR 3 ;R 1a R 1b and R 1c Each independently is either hydrogen or C. 1-6 Alkyl; R 2 and R 3 Each is independently hydrogen, C 1-6 Alkyl group, or -C(O)C(O)N(R) 8b R 8c ); or, R 2 and R 3 They combine with the atoms they are attached to to form C 6-12 Aryl; R 4 R 5 R 6 and R 7 Each independently is hydrogen, C 1-6 Alkyl, halogen, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, or –OR 8a , where R 4 R 5 R 6 and R 7 At least one of them is not H; and R 8a It is C 7-18 alkyl-aryl; or, R 5 and R 6 They combine with their respective atoms to form C 3-6 Heterocyclic alkyl groups.

[0105] In some embodiments, the present invention provides a compound, wherein X is a CR 3 ;R 1a and R 1b Each is Me; R 1c For hydrogen or Me; R 2 For H, Me, or -C(O)-C(O)N(Me)2; or, R 2 and R 3 They combine to form a benzene ring; and R 4 R 5 R6 and R 7 Each of the following is independently H, F, Br, -NO2, -OMe, -CF 3、 -OCF3, or -O-benzyl; or, R 5 and R 6 They combine to form a 1,3-m-dioxacyclopentene ring.

[0106] In some embodiments, the present invention provides a compound, wherein X is a CR 3 ;R 1a and R 1b Each is Me; R 1c For hydrogen or Me; R 2 For H or Me; R 3 For H or -C(O)-C(O)N(Me)2; R 4 It is H, F, -OMe or -O-benzyl; R 5 For H, F, Br, -OMe, -CF3, -OCF3 or -O-benzyl; R 6 It can be H, -NO2, -OMe, -OCF3, or -O-benzyl; or, R 2 and R 3 Combine to form a benzene ring; or, R 5 and R 6 The combination forms a 1,3-m-dioxacyclopentene ring; and R 7 It can be H, F, -OMe, or -O-benzyl.

[0107] In some embodiments, the present invention provides a compound or a pharmaceutically acceptable salt thereof, wherein X is a CR 3 ;R 1a and R 1b Each is Me, Et, or Pr; R 2 For H, Me, -OMe, -F or -C(O)-C(O)N(Me)2; R 3 For H, Me, -OMe, -F, or C(O)-C(O)N(Me)2; and R 4 R 5 R 6 and R 7 Each can be independently H, Me, -F, -Cl, -Br, -NO2, -OMe, -CF3, -OCF3, or -O-benzyl; or, R 5 and R 6 This combination forms a 1,3-m-dioxacyclopentene ring or a 1,4-dioxane. In some embodiments, the present invention provides a compound or a pharmaceutically acceptable salt thereof, wherein X is a CR 3 ;R 1a and R1b Both are Me; R 1c For Me, Et, or Pr; R 2 For H, Me, -F, -OMe; R 3 For H, Me, -F, -OMe or -C(O)-C(O)N(Me)2; R 4 For H, Me, -F, -OMe, or -O-benzyl; R 5 It can be H, Me, -F, -Cl, -Br, -OMe, -CF3, -OCF3, or -O-benzyl; R 6 For H, Me, -F, -NO2, -OMe, -OCF3, or -O-benzyl; or, R 5 and R 6 Combined to form a 1,3-me-dioxacyclopentene ring or a 1,4-dioxane ring; and R 7 It can be H, Me, F, -OMe, or -O-benzyl.

[0108] In some embodiments, the present invention provides a compound or a pharmaceutically acceptable salt thereof, wherein L is C 1-6 Alkylene. In some embodiments, the present invention provides a compound or a pharmaceutically acceptable salt thereof, wherein L is methylene, ethylene, propylene, or butylene. In some embodiments, the present invention provides a compound or a pharmaceutically acceptable salt thereof, wherein L is methylene or ethylene. In some embodiments, the present invention provides a compound or a pharmaceutically acceptable salt thereof, wherein L is ethylene. In some embodiments, the present invention provides a compound or a pharmaceutically acceptable salt thereof, wherein L is methylene.

[0109] In some embodiments, the present invention provides a compound, wherein the compound is... Or, or a pharmaceutically acceptable salt thereof.

[0110] In some embodiments, the present invention provides a compound, wherein the compound is... Or, or a pharmaceutically acceptable salt thereof.

[0111] In some embodiments, the present invention provides a compound, wherein the compound is... , , , , , , , , , , , , , , or Or, or a pharmaceutically acceptable salt thereof.

[0112] In some embodiments, the present invention provides that the compound is , , , , , , , , , , , , , , , , , , , , , , , or Or, or a pharmaceutically acceptable salt thereof.

[0113] In some embodiments, the present invention provides a compound of formula II or a pharmaceutically acceptable salt and isomer thereof: (II) Where: X is CR 3 ;R 1a and R 1b Each independently represents H and C. 1-6 Alkyl, C 3-8 cycloalkyl, or C 4-14 alkyl-cycloalkyl; or, R 1a and R 1b They combine with the atoms they are attached to to form C 3-12 Heterocyclic alkyl; R 2 R 3 R 4 R 5 R 6 and R 7 Each independently is hydrogen, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkyne, halogen, C 1-6 Haloalkyl, C 1-6 Alkylamine, C1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, –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 Heterocyclic alkyl, C 4-16 Alkyl-heterocyclic alkyl, C 6-12 Aryl, C 7-18 Alkyl-aryl, C 5-10 heteroaryl, or C 4-16 alkyl heteroaryl; R 8a C 3-8 cycloalkyl, C 3-14 Alkyl-cycloalkyl, C 4-10 Heterocyclic alkyl, C 4-16 Alkyl-heterocyclic alkyl, 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 Each independently is H or C 1-6 Alkyl; or, R 1a Or R 1b One of them with R 2 Combining to form C 5-12 Heterocyclic alkyl; or, R 2 and R3 They combine with their respective atoms to form C 4-8 cycloalkyl, C 4-10 Heterocyclic alkyl, or C 6-12 aryl; or, R 4 and R 5 R 5 and R 6 , or R 6 and R 7 They combine with their respective atoms to form C 4-6 cycloalkyl, C 4-6 Heterocyclic alkyl, C 6-12 Aryl, or C 5-10 heteroaryl; L is C 1-6 alkylene, wherein, when R 1a and R 1b When all are Me and L is methylene, then 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 not: ; Where R 1a and R 1b Me, L is ethylene, and X is CR. 3 When, then R 2 R 3 R 4 R 5 R 6 and R 7 At least one of them is not hydrogen; among them, when R 1c For H, R 5 For Br, Cl, F, -NH2, -NO2, or C 1-3 When alkoxy is present, then R 2 R 3 R 4 R 6 Or R 7 At least one of them is not hydrogen; where, when R 1c It is hydrogen and R 5 When it is F, then R 2 R 3 R 4 R 6 Or R 7 At least one of them is not hydrogen, and R 6 It's not F.

[0114] In some embodiments, the present invention provides a compound or a pharmaceutically acceptable salt thereof, wherein the compound of formula II has the following structure: .

[0115] In some embodiments, the present invention provides a compound or a pharmaceutically acceptable salt thereof, wherein the compound of formula II has the following structure: .

[0116] In some embodiments, the present invention provides a compound or a pharmaceutically acceptable salt thereof, wherein R 2 R 3 R 4 R 5 R 6 and R 7 At least one of them is not H.

[0117] In some embodiments, the present invention provides a compound or a pharmaceutically acceptable salt thereof, wherein R 4 R 5 R 6 and R 7 Each is independently hydrogen, C 1-6 Alkyl, halogen, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, -OR 8a -NO2, -CN, C 3-8 cycloalkyl, or C 3-14 alkyl-cycloalkyl; or, R 4 and R 5 R 5 and R 6 , or R 6 and R 7 They combine with their respective atoms to form C 5-6 Heterocyclic alkyl groups; and R 8a It is C 3-8 cycloalkyl, C 3-14 Alkyl-cycloalkyl, C 4-16 alkyl heterocyclic alkyl, C 7-18 Alkyl-aryl, C 4-16 Alkyl-heteroaryl. In some embodiments, the present invention provides a compound or a pharmaceutically acceptable salt thereof, wherein R 4 R 5 R 6 and R 7 Each independently is hydrogen, C 1-6 Alkyl, halogen, C 1-6 Alkoxy, C1-6 Halogenated alkoxy groups, -OR 8a Or -NO2; or, R 4 and R 5 R 5 and R 6 , or R 6 and R 7 They combine with their respective attached atoms to form C5 heterocyclic alkyl groups; and R 8a C 7-18 Alkyl-aryl.

[0118] In some embodiments, the present invention provides a compound or a pharmaceutically acceptable salt thereof, wherein R 4 R 5 R 6 and R 7 Each can be independently hydrogen, F, Cl, -OMe, -OCF3, or -O-benzyl; or, R 5 and R 6 They combine with the atoms to form 1,3-m-dioxacyclopentene rings or 1,4-dioxane rings. In some embodiments, the invention provides compounds or pharmaceutically acceptable salts thereof, wherein R 5 It is F, Cl, -OMe, -OCF3 or -O-benzyl; or, R 5 and R 6 They combine with the atoms to which they are attached to form 1,3-m-dioxacyclopentene rings or 1,4-dioxane rings.

[0119] In some embodiments, the present invention provides a compound or a pharmaceutically acceptable salt thereof, wherein R 5 For F, Cl, -OMe, -OCF3 or -O-benzyl; R 6 and R 7 Each is independently hydrogen, F, Cl, -OMe, -OCF3, or -O-benzyl, wherein R 6 and R 7 At least one of them is not hydrogen; or, R 5 and R 6 They combine with the atoms to which they are attached to form 1,3-m-dioxacyclopentene rings or 1,4-dioxane rings.

[0120] In some embodiments, the present invention provides a compound, wherein the compound is... Or, or a pharmaceutically acceptable salt thereof.

[0121] In some embodiments, the present invention provides a compound, wherein the compound is... , ,or , Or its pharmaceutically acceptable salt.

[0122] In some embodiments, the present invention provides a compound or a pharmaceutically acceptable salt thereof, wherein R 1a and R 1b They combine with the atoms they are attached to to form C 3-8 Heterocyclic alkyl groups.

[0123] In some embodiments, the present invention provides a compound, wherein the compound is... , ,or Or, or a pharmaceutically acceptable salt thereof.

[0124] In some embodiments, the present invention provides a compound, wherein the compound is... , , , , , , , , , , , , ,or Or its pharmaceutically acceptable salt.

[0125] The compounds of the present invention may also be in salt form, such as acid salts or base salts of the compounds of the present invention. Illustrative examples of pharmaceutically acceptable salts are inorganic acid (hydrochloric acid, hydrobromic acid, phosphoric acid, etc.) salts, organic (fumaric acid, acetic acid, oleic acid, propionic acid, glutamic acid, citric acid, etc.) salts, and quaternary ammonium (methyl iodide, ethyl iodide, etc.) salts. It should be understood that pharmaceutically acceptable salts are non-toxic. Further information on suitable pharmaceutically acceptable salts can be found in Remington's Pharmaceutical Sciences (17th edition, Mack Publishing Company, Easton, PA, 1985), which is incorporated herein by reference.

[0126] 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.

[0127] The present invention also includes isotope-labeled compounds of the present invention, wherein one or more atoms are substituted with one or more atoms having a specific atomic mass or mass number. Examples of isotopes incorporated into the compounds of the present invention include, but are not limited to, isotopes of hydrogen, carbon, nitrogen, oxygen, fluorine, sulfur, and chlorine (e.g., 2 H, 3 H, 13 C 14 C 15 N、 18 O、 17 O、 18 F, 35 S and 36 Cl). The isotope-labeled compounds of the present invention can be used to analyze the tissue distribution of compounds, their prodrugs, and metabolites; preferred isotopes for such analyses include 3 H and 14 C. In addition, in some cases, heavier isotopes are substituted, such as deuterium ( 2 H), which can improve metabolic stability, thereby providing therapeutic advantages, such as increasing in vivo half-life or reducing dosage requirements. The isotopically labeled compounds of the present invention can generally be prepared by replacing non-isotopically labeled reagents with isotopically labeled reagents according to methods known to those skilled in the art. The compounds of the present invention can be isotopically labeled at the ortho position of a basic amine, the aromatic ring, and the methyl position of a methoxy substituent.

[0128] This invention encompasses all tautomers and stereoisomers of the compounds of this invention, in mixtures or in pure or substantially pure form. The compounds of this invention have an asymmetric center at the carbon atom, and therefore can exist in diastereomers or enantiomers or mixtures thereof. All conformational isomers (e.g., cis and trans isomers) and all optical isomers (e.g., enantiomers and diastereomers), racemic mixtures, diastereomers and other mixtures of such isomers, as well as solvates, hydrates, isomers, polymorphs and tautomers are within the scope of this invention. The compounds of this invention can be prepared using diastereomers, enantiomers or racemic mixtures as starting materials. Furthermore, diastereomers and enantiomeric products can be separated by chromatography, separate crystallization or other methods known to those skilled in the art.

[0129] IV. Pharmaceutical Compositions and Formulations In some embodiments, the present invention provides pharmaceutical compositions comprising the compounds of the present invention and pharmaceutically acceptable excipients.

[0130] The pharmaceutical compositions of the present invention can be prepared into various oral, parenteral, and topical dosage forms. Oral formulations include tablets, pills, powders, capsules, liquids, lozenges, cachets, gels, syrups, slurries, suspensions, etc., suitable for patient ingestion. The compositions of the present invention can also be administered by injection, i.e., intravenous, intramuscular, intradermal, subcutaneous, duodenal, or intraperitoneal administration. Furthermore, the compositions described herein can be administered by inhalation, such as intranasal administration. Additionally, the compositions of the present invention can be administered transdermally. The compositions of the present invention can also be administered via intraocular, intravaginal, and rectal routes, including suppositories, inhalers, powders, and aerosol formulations (e.g., steroid inhalers, see Rohatagi, Journal of Clinical Pharmacology J. Clin. Pharmacol. 35: 1187-1193, 1995; Tjwa, Annals of 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.

[0131] For the preparation of pharmaceutical compositions containing compounds as described in this invention, a pharmaceutically acceptable carrier may be solid or liquid. Solid forms of formulations include powders, tablets, pills, capsules, pouches, suppositories, and dispersible granules. A solid carrier may be one or more substances, which may also be used as a diluent, flavoring agent, binder, preservative, tablet disintegrant, or encapsulating material. Details regarding formulation and administration techniques are described in detail in scientific and patent literature, see, for example, the latest edition of the Remington Pharmaceutical Encyclopedia, Mack Publishing, Easton, PA (Remington).

[0132] For powders, the carrier is a finely separated solid mixed with the finely separated active ingredient. In tablets, the active ingredient is mixed with a carrier having the necessary binding properties in an appropriate proportion and compacted into the desired shape and size. Powders and tablets preferably contain 5%-70% or 10%-70% of the compounds of this invention.

[0133] Suitable solid excipients include, but are not limited to, magnesium carbonate; magnesium stearate; talc; pectin; dextrin; starch; astragalus gum; low-melting-point wax; cocoa butter; carbohydrates; sugars including but not limited to lactose, sucrose, mannitol or sorbitol, starch from corn, wheat, rice, potatoes or other plants; cellulose, such as methylcellulose, hydroxypropyl methylcellulose or sodium carboxymethylcellulose; and chewing gum, including gum arabic and astragalus gum; and proteins, including but not limited to gelatin and collagen. If desired, disintegrants or solubilizers, such as croscarmellose, agar, alginic acid or its salts, such as sodium alginate, may be added.

[0134] To prepare the suppositories, a mixture of low-melting-point waxes, such as fatty acid glycerides or cocoa butter, is first melted, and the compound of the present invention is uniformly dispersed therein by stirring. The molten, homogeneous mixture is then poured into a suitably sized mold and allowed to cool and solidify.

[0135] Liquid formulations include solutions, suspensions, and emulsions, such as water or water / propylene glycol solutions. For parenteral injection, liquid formulations can be prepared as solutions in aqueous polyethylene glycol solutions.

[0136] Aqueous solutions suitable for oral administration can be prepared by dissolving the compounds of the present invention in water and adding suitable colorants, flavoring agents, stabilizers and thickeners as needed. Aqueous suspensions suitable for oral administration can be prepared by combining finely crushed active ingredients with viscous materials (such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, hydroxypropyl methylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth, and gum arabic), and dispersing or wetting agents (such as naturally occurring phospholipids (e.g., lecithin), condensation products of alkyl esters and fatty acids (e.g., polyoxyethylene stearate), condensation products of ethylene oxide and long-chain aliphatic alcohols (e.g., heptadecaethyleneoxycetanol), condensation products of ethylene oxide and esters derived from fatty acids and hexitols (e.g., polyoxyethylene sorbitol monooleate), or ethylene oxide and esters derived from fatty acids and hexitol anhydrides (e.g., polyoxyethylene sorbitan monooleate). The aqueous suspension is prepared by dispersing the condensation product of a mono-oleate in water. The aqueous suspension may also contain one or more preservatives, such as ethyl, n-propyl, or p-hydroxybenzoate, one or more colorants, one or more flavoring agents, and one or more sweeteners, such as sucrose or saccharin. The osmotic pressure of the formulation can be adjusted.

[0137] This also includes solid formulations intended to be converted into liquid formulations for oral administration shortly before use. These liquid forms include solutions, suspensions, and emulsions. In addition to the active ingredient, these formulations may also contain colorants, flavoring agents, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizers, etc.

[0138] Oily suspensions can be formulated by suspending the compounds of the present invention in vegetable oils, such as peanut oil, olive oil, sesame oil, or coconut oil, or mineral oils (such as liquid paraffin), or combinations thereof. The oily suspension may contain a thickener, such as beeswax, hard paraffin, or hexadecyl alcohol. Sweeteners may be added to provide palatable oral formulations, such as glycerin, sorbitol, or sucrose. These formulations may be preserved by adding antioxidants such as ascorbic acid. As an example of an injectable oil carrier, see Minto, J. Pharmacol. Exp. Ther. 281:93-102, 1997. The pharmaceutical formulations of the present invention may also be in the form of an oil-in-water emulsion. The oil phase may be the aforementioned vegetable oils or mineral oils, or combinations thereof. Suitable emulsifiers include naturally occurring gums such as gum arabic and tragacanth, naturally occurring phospholipids such as soybean lecithin, fatty acids, and esters or metaesters derived from hexadiol anhydrides such as sorbitan monooleate, and condensation products of these metaesters with ethylene oxide such as polyoxyethylene sorbitan monooleate. The emulsion may also contain sweeteners and flavoring agents, such as formulations found in syrups and elixirs. The formulation may also contain modifiers, preservatives, or colorants.

[0139] The compositions of the present invention can also be used as microspheres for sustained release in vivo. For example, microspheres for drug delivery can be formulated as drug-containing microspheres that release slowly subcutaneously via intradermal injection (see Rao, Journal of Biomaterials Science, Polymer Edition 7:623-645, 1995); as biodegradable and injectable gel formulations (see, for example, Gao, Pharmaceutical Research Pharm. Res. 12:857-863, 1995); or as microspheres for oral administration (see, for example, Eyles, Journal of Pharmacy and Pharmacology J. Pharm. Pharmacol. 49:669-674, 1997). Both percutaneous and intradermal routes can provide continuous administration for weeks or months.

[0140] In some embodiments, the pharmaceutical compositions of the present invention can be formulated for parenteral administration, such as intravenous (IV) administration or administration into body cavities or organ cavities. Formulations for administration typically comprise a solution of the composition of the present invention dissolved in a pharmaceutically acceptable carrier. Among acceptable carriers and solvents, water, Ringer's solution, and isotonic sodium chloride solution may be used. Additionally, sterile, non-volatile oils are commonly used as solvents or suspension media. For this purpose, any mild fixed oil, including synthetic monoglycerides or diglycerides, may be used. Furthermore, fatty acids such as oleic acid may also be used to prepare injectable formulations. These solutions are sterile and generally free of excess substances. These formulations can be sterilized using conventional, well-known sterilization techniques. The formulations may contain pharmaceutically acceptable excipients required to approximate physiological conditions, such as pH adjusters and buffers, toxicity modifiers, such as sodium acetate, sodium chloride, potassium chloride, calcium chloride, sodium lactate, etc. The concentration of the compositions of the present invention varies widely in these formulations and will be selected primarily based on fluid volume, viscosity, body weight, etc., according to the specific administration modality chosen and the patient's needs. For intravenous injection, the formulation can be a sterile injectable formulation, such as a sterile injectable aqueous or oil-containing suspension. This suspension can be formulated with suitable dispersants or wetting agents and suspending agents used in known techniques. Sterile injectable formulations can also be sterile injectable solutions or suspensions in non-toxic, parenteral diluents or solvents, such as 1,3-butanediol solutions.

[0141] In some embodiments, formulations of the compositions of the present invention can be delivered using liposomes fused to or endocytosed with cell membranes, i.e., by using ligands attached to the liposomes or directly attached to oligonucleotides, which bind to protein receptors on the cell surface membrane, resulting in endocytosis. By using liposomes, particularly when the liposomes carry ligands specific to target cells or otherwise preferentially targeting specific organs, the compositions of the present invention can be delivered concentratedly to target cells in vivo. (See, for example, Al-Muhammed, Journal of Microcapsules, 13:293-306, 1996; Chonn, Current Opinions in Biotechnology, 6:698-708, 1995; Ostrov, Am. J. Hosp. Pharm. 46:1576-1587, 1989).

[0142] V. Application The compositions of the present invention can be delivered by any suitable method, including oral, parenteral, and external methods. Transdermal administration via a local route can be formulated as applicators, solutions, suspensions, emulsions, gels, creams, ointments, pastes, gels, coatings, powders, and aerosols.

[0143] The pharmaceutical formulation is preferably a unit dosage form. In this form, the formulation is further divided into unit doses containing an appropriate amount of the compound of the present invention. The unit dosage form can be a packaged formulation containing discrete amounts of the formulation, such as packaged tablets, capsules, and powder in vials or ampoules. Furthermore, the unit dosage form can be the capsule, tablet, sachets, or lozenges themselves, or it can be any suitable quantity of these packaged forms.

[0144] The compounds 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 weight and age, disease state, etc. Suitable dosage ranges for the compounds 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 of the compounds of the present invention include about 1 mg, 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 200, 300, 400, 500, 600, 700, 800, 900, or 1,000 mg.

[0145] The compounds of the present invention can be administered at any suitable frequency, interval, and period. For example, the compounds of the present invention can be administered once per hour, or twice, three or more times per hour, once daily, or twice, three or more times daily, or once every 2, 3, 4, 5, 6, or 7 days to provide preferred dose levels. When the compounds of the present invention are administered more than once daily, representative intervals include 5, 10, 15, 20, 30, 45, and 60 minutes, and 1, 2, 4, 6, 8, 10, 12, 16, 20, and 24 hours. The compounds of the present invention can be administered once, twice, three or more times, for 1 hour, 1-6 hours, 1-12 hours, 1-24 hours, 6-12 hours, 12-24 hours, 1 day, 1-7 days, 1 week, 1-4 weeks, 1 month, 1-12 months, 1 year or longer, or even indefinitely.

[0146] The composition may also contain other compatible therapeutic agents. The compounds described herein may be used in combination with each other, with other known active agents that can modulate glucocorticoid receptors, or with adjuvants that may not be effective when used alone but help to exert the efficacy of the active agents.

[0147] The compounds of the present invention can be co-administered with another active agent. Co-administration includes administering the compound and the active agent at intervals of 0.5, 1, 2, 4, 6, 8, 10, 12, 16, 20, or 24 hours. Co-administration solutions include the simultaneous, substantially simultaneous (e.g., within 1, 5, 10, 15, 20, or 30 minutes), or sequential administration of the compound and the active agent. Furthermore, the compound and the active agent can be administered once daily, or twice, three times, or more daily, to provide a preferred daily dose level.

[0148] In some embodiments, co-administration can be achieved through co-formulation, i.e., preparing a single pharmaceutical composition comprising the compound and the active agent described herein. In other embodiments, the compound and active agent of the present invention can be formulated separately.

[0149] The compounds and active agents of the present invention may be present in the compositions of the present invention in any suitable weight ratio, for example, about 1:100 to about 100:1 (w / w), or about 1:50 to about 50:1, or about 1:25 to about 25:1, or about 1:10 to about 10:1, or about 1:5 to about 5:1 (w / w). The compounds and other active agents of the present invention may be present in any suitable weight ratio, for example, 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 dosage ratios of the compounds and active agents of the present invention are applicable to the compositions and methods of the present invention.

[0150] VI. Treatment methods The compounds of this invention can be used to increase neuronal plasticity. The compounds of this invention can also be used to treat any brain disease. The compounds of this invention can also be used to increase at least one of the translation, transcription, or secretion of neurotrophic factors.

[0151] In some embodiments, the compounds of the present invention are used to treat neurological disorders. In some embodiments, the compounds have, for example, anti-addiction, antidepressant, anti-anxiety properties, or combinations thereof. In some embodiments, the neurological disorder is a neuropsychiatric disorder. In some embodiments, the neuropsychiatric disorder is a mood or anxiety disorder. In some embodiments, the neurological disorder is migraine, headache (e.g., cluster headache), post-traumatic stress disorder (PTSD), anxiety, depression, neurodegenerative disorders, Alzheimer's disease, Parkinson's disease, mental disorders, treatment-resistant depression, suicidal ideation, major depressive disorder, bipolar disorder, schizophrenia, stroke, traumatic brain injury, and addiction (e.g., substance use disorder). In some embodiments, the neurological disorder is migraine or cluster headache. In some embodiments, the neurological disorder is a neurodegenerative disease, Alzheimer's disease, or Parkinson's disease. In some embodiments, the neurological disorder is a mental disorder, treatment-resistant depression, suicidal ideation, major depressive disorder, bipolar disorder, schizophrenia, post-traumatic stress disorder (PTSD), addiction (e.g., substance use disorder), depression, or anxiety. In some embodiments, the neuropsychiatric disorder is a mental disorder, treatment-resistant depression, suicidal ideation, major depressive disorder, bipolar disorder, schizophrenia, post-traumatic stress disorder (PTSD), addiction (e.g., substance use disorder), depression, or anxiety. In some embodiments, the neuropsychiatric disorder or neurological disorder is post-traumatic stress disorder (PTSD), addiction (e.g., substance use disorder), schizophrenia, depression, or anxiety. In some embodiments, the neuropsychiatric disorder or neurological disorder is addiction (e.g., substance use disorder). In some embodiments, the neuropsychiatric disorder or neurological disorder is depression. In some embodiments, the neuropsychiatric disorder or neurological disorder is anxiety. In some embodiments, the neuropsychiatric disorder or neurological disorder is post-traumatic stress disorder (PTSD). In some embodiments, the neurological disorder is stroke or traumatic brain injury. In some embodiments, the neuropsychiatric disorder or neurological disorder is schizophrenia.

[0152] In some embodiments, the compounds of the present invention are used to increase neuronal plasticity. In some embodiments, the compounds described herein are used to treat brain diseases. In some embodiments, the compounds described herein are used to increase at least one of the translation, transcription, or secretion of neurotrophic factors.

[0153] In some embodiments, the compounds of the present invention have the function of 5-HT 2A The activity of the regulator. In some embodiments, the compounds of the present invention have the function of 5-HT 2A The activity of the modulator. In some embodiments, the compounds of the present invention activate 5-HT.2A Receptors (e.g., allosteric regulation or regulation of 5-HT activation) 2A (The biological target of the receptor) triggers a biological response. 5-HT 2A Excitatory disorders are associated with the promotion of neuroplasticity (Ly et al., 2018). For example... Figure 7 As shown, 5-HT 2A Antagonists can eliminate 5-HT 2A Agonist-active hallucinogenic compounds, such as DMT, LSD, and DOI, promote neuroticism and spinogenesis. In some embodiments, the compound of the present invention is 5-HT. 2A Modulators that promote neuroplasticity (e.g., cortical structural plasticity). In some embodiments, the compounds of the present invention are selective 5-HT. 2A Modulators and promoters of neural plasticity (e.g., cortical structural plasticity). In some embodiments, the promotion of neural plasticity includes, for example, increasing dendritic spine growth, increasing synaptic protein synthesis, strengthening synaptic responses, increasing dendritic complexity, increasing dendritic branching content, increasing spinous process generation, increasing neuronal generation, or any combination thereof. In some embodiments, increased neural plasticity includes, for example, increasing structural plasticity of the anterior cortex of the brain.

[0154] In some embodiments, the 5-HT 2A Modifiers (e.g., 5-HT) 2A Agonists are non-hallucinogens. In some implementations, the non-hallucinogen 5-HT... 2A Modifiers (e.g., 5-HT) 2A Agonists are used to treat neurological disorders, and the modulators do not cause dissociative side effects. In some embodiments, the hallucinogenic potential of the compounds described herein is evaluated in vitro. In some embodiments, the in vitro hallucinogenic potential of the compounds described herein is compared with that of their hallucinogenic homologues. In some embodiments, the compounds described herein induce less hallucinogenic potential in vitro than their hallucinogenic homologues.

[0155] In some implementation schemes, the non-hallucinogen 5-HT 2A Modifiers (e.g., 5-HT) 2A Agonists are used to treat neurological disorders. In some embodiments, the neurological disorders include decreased neural plasticity, decreased cortical structural plasticity, and 5-HT. 2A Decreased receptor content, reduced dendritic complexity, absence of dendritic spines, decreased dendritic branching, reduced spine formation, reduced neuronal generation, retraction of neurites, or any combination thereof.

[0156] In some implementation schemes, the non-hallucinogen 5-HT 2A Regulators (such as 5-HT)2a Agonists are used to enhance neuronal plasticity. In some implementations, the non-hallucinogenic 5-HT... 2A Regulators (such as 5-HT) 2a Agonists are used to treat brain diseases. In some implementations, the non-hallucinogenic 5-HT... 2A Regulators (such as 5-HT) 2a Agonists are used to increase at least one of the translation, transcription, or secretion of neurotrophic factors.

[0157] A. Methods to improve neuronal plasticity "Neuronal plasticity" refers to the brain's ability to continuously change its structure and / or function throughout a subject's life. During a subject's life, new neurons are generated and integrated into the central nervous system. Increasing neuronal plasticity includes, but is not limited to, promoting neuronal growth, promoting neurogenesis, promoting synapse formation, promoting dendrite formation, increasing dendritic complexity, increasing dendritic spine density, and increasing excitatory synapses in the brain. In some implementations, increasing neuronal plasticity includes promoting neuronal growth, promoting neurogenesis, promoting synapse formation, promoting dendrite formation, increasing dendritic complexity, and increasing dendritic spine density.

[0158] In some embodiments, increasing neuronal plasticity can treat neurodegenerative diseases, Alzheimer's disease, Parkinson's disease, mental disorders, depression, addiction, anxiety, post-traumatic stress disorder, treatment-resistant depression, suicidal ideation, major depressive disorder, bipolar disorder, schizophrenia, stroke, traumatic brain injury, or medication use disorder.

[0159] In some embodiments, the present invention provides a method for increasing neuronal plasticity, comprising contacting neuronal cells with any of the compounds of the present invention. In some embodiments, increasing neuronal plasticity improves the brain diseases described herein.

[0160] In some embodiments, the compounds of the present invention are used to increase neuronal plasticity. In some embodiments, the compounds for increasing neuronal plasticity have, for example, anti-addiction, antidepressant, anti-anxiety properties, or combinations thereof. In some embodiments, reduced neuronal plasticity is associated with neuropsychiatric disorders. In some embodiments, the neuropsychiatric disorders are mood or anxiety disorders. In some embodiments, the neuropsychiatric disorders include, for example, migraines, cluster headaches, post-traumatic stress disorder (PTSD), schizophrenia, anxiety, depression, and addiction (e.g., substance use disorder). In some embodiments, brain disorders include, for example, migraines, addiction (e.g., substance use disorder), depression, and anxiety.

[0161] In some embodiments, experiments or assays determining that any compound of the present invention increases neuronal plasticity include phenotypic analysis, dendrite formation analysis, spinogenesis analysis, synaptic formation analysis, Shore analysis, concentration-response experiments, and 5-HT. 2A Agonist analysis, 5-HT 2A Antagonist analysis, 5-HT 2A Combined analysis or 5-HT 2A Blocking experiments (e.g., ketoselin blocking experiments). In some embodiments, the experiment or assay for determining the hallucinogenic potential of any compound of the present invention is a mouse head twitching response (HTR) assay.

[0162] In some embodiments, the present invention provides a method for increasing neuronal plasticity, comprising contacting neuronal cells with a compound of formula I or a pharmaceutically acceptable salt thereof: (I) Its dosage is sufficient to increase neuronal plasticity in neurons, where: X is N or CR 3 ;R 1a R 1b and R 1c Each independently represents H and C. 1-6 Alkyl, C 3-8 cycloalkyl, or C 4-14 alkyl-cycloalkyl; or, R 1a R 1b and R 1c The two atoms in the mixture combine with the atoms they are attached to to form C. 3-12 Heterocyclic alkyl; R 2 R 3 R 4 R 5 R 6 and R 7 Each independently is hydrogen, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkyne, halogen, C 1-6 Haloalkyl, C 1-6 Alkylamine, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, –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 Heterocyclic alkyl, C 4-16 Alkyl-heterocyclic alkyl, C 6-12 Aryl, C 7-18 Alkyl-aryl, C 5-10 heteroaryl, or C 4-16 alkyl heteroaryl; R 8a C 3-8 cycloalkyl, C 3-14 Alkyl-cycloalkyl, C 4-10 Heterocyclic alkyl, C 4-16 Alkyl-heterocyclic alkyl, 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 Each independently is H or C 1-6 Alkyl; or, R 1a R 1b Or R 1c One of them is with R 2 Combining to form C 5-12 Heterocyclic alkyl; or, R 2 and R 3 They combine with their respective atoms to form C 4-8 cycloalkyl, C 4-10 Heterocyclic alkyl, or C 6-12 aryl; or, R 4 and R 5 R 5 and R 6 , or R 6 and R 7 They combine with their respective atoms to form C 3-6cycloalkyl, C 3-6 Heterocyclic alkyl, C 6-12 Aryl, or C 5-10 heteroaryl; and L is C 1-6 Alkylene.

[0163] In some embodiments, the present invention provides a method for increasing neuronal plasticity, comprising contacting neuronal cells with a compound of formula I or a salt and isomer thereof, wherein X is N or CR. 3 ;R 1a R 1b and R 1c Each independently represents H and C. 1-6 Alkyl, C 3-8 cycloalkyl, or C 4-14 alkyl-cycloalkyl; or, R 1a R 1b and R 1c The two atoms in the mixture combine with the atoms they are attached to to form C. 3-6 Heterocyclic alkyl; R 2 R 3 R 4 R 5 R 6 and R 7 Each independently is hydrogen, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkyne, halogen, C 1-6 Haloalkyl, C 1-6 Alkylamine, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, –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 Heterocyclic alkyl, C 4-16 Alkyl-heterocyclic alkyl, C 6-12 Aryl, C 7-18 Alkyl-aryl, C 5-10 heteroaryl, or C 4-16 alkyl heteroaryl; R 8a C 3-8 cycloalkyl, C 3-14 Alkyl-cycloalkyl, C 4-10 Heterocyclic alkyl, C 4-16 Alkyl-heterocyclic alkyl, 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 Each independently is H or C 1-6 Alkyl; or, R 1a R 1b Or R 1c One of them is with R 2 R 3 R 4 R 5 R 6 and R 7 A combination of these elements forms C 5-6 cycloalkyl or C 5-6 Heterocyclic alkyl; or, R 2 and R 3 They combine with their respective atoms to form C 6-12 aryl; or, R 4 and R 5 R 5 and R 6 , or R 6 and R 7 They combine with their respective atoms to form C 3-6 cycloalkyl or C 3-6 Heterocyclic alkyl; and L is C 1-6 Alkylene compounds, in doses sufficient to increase neuronal plasticity in neurons.

[0164] B. Methods of treating brain diseases In some embodiments, the present invention provides a method of 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 of treating a brain 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 of treating a brain disease with a 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 of treatment.

[0165] In some implementation schemes, 5-HT 2A Regulators (such as 5-HT) 2A Agonists are used to treat brain disorders. In some embodiments, the brain disorders include decreased neuroplasticity, decreased cortical structural plasticity, and 5-HT. 2A Decreased receptor content, reduced dendritic complexity, absence of dendritic spines, decreased dendritic branching, reduced spine formation, reduced neuronal generation, retraction of neurites, or any combination thereof.

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

[0167] In some embodiments, the present invention provides a method for treating a brain disease, comprising administering to a subject in need a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof: (I) This is used to treat brain diseases, where X is N or CR. 3 ;R 1a R 1b and R 1c Each independently represents H and C. 1-6 Alkyl, C 3-8 cycloalkyl, or C 4-14 alkyl-cycloalkyl; or, R 1a R 1b and R 1c The two atoms in the mixture combine with the atoms they are attached to to form C. 3-12 Heterocyclic alkyl; R 2 R 3 R4 R 5 R 6 and R 7 Each independently is hydrogen, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkyne, halogen, C 1-6 Haloalkyl, C 1-6 Alkylamine, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, –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 Heterocyclic alkyl, C 4-16 Alkyl-heterocyclic alkyl, C 6-12 Aryl, C 7-18 Alkyl-aryl, C 5-10 heteroaryl, or C 4-16 alkyl heteroaryl; R 8a C 3-8 cycloalkyl, C 3-14 Alkyl-cycloalkyl, C 4-10 Heterocyclic alkyl, C 4-16 Alkyl-heterocyclic alkyl, C 6-12 Aryl, C 7-18 Alkyl-aryl, C 5-10 heteroaryl, or C 4-16 alkyl-heteroaryl; R8b R 8c and R 8d Each independently is H or C 1-6 Alkyl; or, R 1a R 1b Or R 1c One of them is with R 2 Combining to form C 5-12 Heterocyclic alkyl; or, R 2 and R 3 They combine with their respective atoms to form C 4-8 cycloalkyl, C 4-10 Heterocyclic alkyl, or C 6-12 aryl; or, R 4 and R 5 R 5 and R 6 , or R 6 and R 7 They combine with their respective atoms to form C 3-6 cycloalkyl, C 3-6 Heterocyclic alkyl, C 6-12 Aryl, or C 5-10 heteroaryl; and L is C 1-6 Alkylene.

[0168] In some embodiments, the present invention provides a method for treating a brain disease, comprising administering to a subject in need a therapeutically effective amount of a compound of formula I or a salt and isomer thereof, wherein X is N or CR. 3 ;R 1a R 1b and R 1c Each independently represents H and C. 1-6 Alkyl, C 3-8 cycloalkyl, or C 4-14 alkyl-cycloalkyl; or, R 1a R 1b and R 1c The two atoms in the mixture combine with the atoms they are attached to to form C. 3-6 Heterocyclic alkyl; R 2 R 3 R 4 R 5 R 6 and R 7 Each independently is hydrogen, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkyne, halogen, C 1-6 Haloalkyl, C 1-6 Alkylamine, C 1-6 Alkoxy, C 1-6Halogenated alkoxy groups, –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 Heterocyclic alkyl, C 4-16 Alkyl-heterocyclic alkyl, C 6-12 Aryl, C 7-18 Alkyl-aryl, C 5-10 heteroaryl, or C 4-16 alkyl heteroaryl; R 8a C 3-8 cycloalkyl, C 3-14 Alkyl-cycloalkyl, C 4-10 Heterocyclic alkyl, C 4-16 Alkyl-heterocyclic alkyl, 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 Each independently is H or C 1-6 Alkyl; or, R 1a R 1b Or R 1c One of them is with R 2 R 3 R 4 R 5 R 6 and R7 A combination of these elements forms C 5-6 cycloalkyl or C 5-6 Heterocyclic alkyl; or, R 2 and R 3 They combine with their respective atoms to form C 6-12 aryl; or, R 4 and R 5 R 5 and R 6 , or R 6 and R 7 They combine with their respective atoms to form C 3-6 cycloalkyl or C 3-6 Heterocyclic alkyl; L is C 1-6 Alkyl groups, thereby treating brain diseases.

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

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

[0171] In some embodiments, the method further includes administering one or more additional therapeutic agents, said therapeutic agents being lithium, olanzapine (Zyprexa), quetiapine (Seroquel), risperidone (Risperdal), abilify, ziprasidone (Geodon), clozapine (Clozaril), sodium dihydrophenylalanine (Depakote), lamotrigine (Lamictal), sodium valproate (Depakene), carbamazepine (Equetro), topiramate (Topamax), levamisole (Fetzima), duloxetine (Cymbalta, Yentrev) e) Venlafaxine (Effexor), Celexa, Fluvoxamine (Luvox), Lexapro, Fluoxetine (Prozac), Paroxetine (Paxil), Sertraline (zolot), Anafranil, Elavil, Norpramine, Tofranil, Pamelor, Nardil, Parnate, Valium, Xanax, or Klonopin.

[0172] In some embodiments, the compounds of the present invention are used in combination with the nursing care standards for neurological disorders described herein. Non-limiting examples of nursing care standards include, for example, lithium, olanzapine, quetiapine, risperidone, aripiprazole, ziprasidone, clozapine, sodium dihydrophenylalanine, lamotrigine, sodium valproate, carbamazepine, topiramate, levamisole, duloxetine, venlafaxine, citalopram, fluvoxamine, escitalopram, fluoxetine, paroxetine, sertraline, clomipramine, amitriptyline, desipramine, nortriptyline, phenethylazine, tranicoprofen, diazepam, alprazolam, clonazepam, or any combination thereof. Non-limiting examples of nursing care standards for depression are sertraline, fluoxetine, escitalopram, venlafaxine, or aripiprazole. Non-limiting examples of standard care medications for depression include cetropril, escitalopram, fluoxetine, paroxetine, diazepam, or sertraline.

[0173] C. Methods that increase at least one of the translation, transcription, or secretion of neurotrophic factors. Neurotrophic factors are families of soluble peptides or proteins that support the survival, growth, and differentiation of developing and maturing neurons. Increasing at least one of the translation, transcription, or secretion of neurotrophic factors can be used, but is not limited to, increasing neuronal plasticity, promoting neuronal growth, promoting neurogenesis, promoting synapse formation, promoting dendrite formation, increasing dendritic complexity, increasing dendritic spine density, and increasing excitatory synapses in the brain. In some embodiments, increasing at least one of the translation, transcription, or secretion of neurotrophic factors can increase neuronal plasticity. In some embodiments, increasing at least one of the translation, transcription, or secretion of neurotrophic factors can promote neuronal growth, promote neurogenesis, promote synapse formation, promote dendrite formation, increase dendritic complexity, and / or increase dendritic spine density.

[0174] In some implementation schemes, 5-HT 2A Regulators (such as 5-HT) 2A Agonists) are used to increase at least one of the translation, transcription, or secretion of neurotrophic factors. In some embodiments, the compounds of the present invention are used to increase at least one of the translation, transcription, or secretion of neurotrophic factors. In some embodiments, increasing at least one of the translation, transcription, or secretion of neurotrophic factors is used to treat migraine, headache (e.g., cluster headache), post-traumatic stress disorder (PTSD), anxiety, depression, neurodegenerative disorders, Alzheimer's disease, Parkinson's disease, mental disorders, anti-treatment depression, suicidal ideation, major depressive disorder, bipolar disorder, schizophrenia, stroke, traumatic brain injury, and addiction (e.g., substance use disorder).

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

[0176] In some embodiments, the present invention provides a method for enhancing at least one of the translation, transcription, or secretion of neurotrophic factors, comprising contacting neuronal cells with a compound of formula I or a pharmaceutically acceptable salt thereof: (I) Its dosage is sufficient to increase neuronal plasticity in neurons, where: X is N or CR 3 ;R 1a R1b and R 1c Each independently represents H and C. 1-6 Alkyl, C 3-8 cycloalkyl, or C 4-14 alkyl-cycloalkyl; or, R 1a R 1b and R 1c The two atoms in the mixture combine with the atoms they are attached to to form C. 3-12 Heterocyclic alkyl; R 2 R 3 R 4 R 5 R 6 and R 7 Each independently is hydrogen, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkyne, halogen, C 1-6 Haloalkyl, C 1-6 Alkylamine, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, –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 Heterocyclic alkyl, C 4-16 Alkyl-heterocyclic alkyl, C 6-12 Aryl, C 7-18 Alkyl-aryl, C 5-10 heteroaryl, or C4-16 alkyl heteroaryl; R 8a C 3-8 cycloalkyl, C 3-14 Alkyl-cycloalkyl, C 4-10 Heterocyclic alkyl, C 4-16 Alkyl-heterocyclic alkyl, 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 Each independently is H or C 1-6 Alkyl; or, R 1a R 1b Or R 1c One of them is with R 2 Combining to form C 5-12 Heterocyclic alkyl; or, R 2 and R 3 They combine with their respective atoms to form C 4-8 cycloalkyl, C 4-10 Heterocyclic alkyl, or C 6-12 aryl; or, R 4 and R 5 R 5 and R 6 , or R 6 and R 7 They combine with their respective atoms to form C 3-6 cycloalkyl, C 3-6 Heterocyclic alkyl, C 6-12 Aryl, or C 5-10 heteroaryl; and L is C 1-6 Alkylene.

[0177] In some embodiments, the present invention provides a method for enhancing at least one of the translation, transcription, or secretion of neurotrophic factors, comprising contacting neuronal cells with a compound of formula I or a salt and isomer thereof, wherein X is N or CR. 3 ;R 1a R 1b and R 1c Each independently represents H and C. 1-6 Alkyl, C 3-8 cycloalkyl, or C 4-14 alkyl-cycloalkyl; or, R 1a R 1b and R 1c The two atoms in the mixture combine with the atoms they are attached to to form C. 3-6 Heterocyclic alkyl; R 2 R3 R 4 R 5 R 6 and R 7 Each independently is hydrogen, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkyne, halogen, C 1-6 Haloalkyl, C 1-6 Alkylamine, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, –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 Heterocyclic alkyl, C 4-16 Alkyl-heterocyclic alkyl, C 6-12 Aryl, C 7-18 Alkyl-aryl, C 5-10 heteroaryl, or C 4-16 alkyl heteroaryl; R 8a C 3-8 cycloalkyl, C 3-14 Alkyl-cycloalkyl, C 4-10 Heterocyclic alkyl, C 4-16 Alkyl-heterocyclic alkyl, C 6-12 Aryl, C 7-18 Alkyl-aryl, C 5-10 heteroaryl, or C 4-16alkyl-heteroaryl; R 8b R 8c and R 8d Each independently is H or C 1-6 Alkyl; or, R 1a R 1b Or R 1c One of them is with R 2 R 3 R 4 R 5 R 6 and R 7 A combination of these elements forms C 5-6 cycloalkyl or C 5-6 Heterocyclic alkyl; or, R 2 and R 3 They combine with their respective atoms to form C 6-12 aryl; or, R 4 and R 5 R 5 and R 6 , or R 6 and R 7 They combine with their respective atoms to form C 3-6 cycloalkyl or C 3-6 Heterocyclic alkyl; and L is C 1-6 Alkylene compounds, in doses sufficient to increase neuronal plasticity in neurons.

[0178] VII. Examples General Unless otherwise stated, all reagents were commercially available and used without purification. DMSO was purified by passing it through an activated alumina column at 12 psi N2. Reactions were carried out in flame-dried glassware under reduced pressure (~1 Torr). Compounds purified by chromatography were adsorbed onto silica gel prior to loading. The silica gel was then placed in microporous silica gel at 60°F. 254 Thin-layer chromatography was performed on silica gel plates. Visualization of the chromatography was achieved by fluorescence quenching or staining with ninhydrin or cerium ammonium molybdate (CAM).

[0179] 1 H and 13 C-NMR spectra were obtained by passing the Bruker 400 at 400 and 100 MHz, the Varian 600 at 600 and 150 MHz, or the Bruker 800 at 800 and 200 MHz, respectively, with the residual solvent signal used as an internal reference. 1 The H NMR data are recorded as follows: chemical shift (δ, ppm), multiply states (s, singlet; d, doublet; t, triplet; q, quartet; m, multiply), integral, and coupling constant (Hz). 13C10 NMR data are reported as chemical shifts (δ, ppm). Infrared spectra were recorded using a Nicolet iS10 FT-IR spectrometer equipped with a Smart iTXThermo plug-in (Diamond ATR) and reported as absorption frequencies (δ, ppm). ,cm -1 The effects of N-dimethyltryptamine (DMT) on rodent behavior associated with anxiety and depression were reported. Liquid chromatography-mass spectrometry (LC-MS) was performed using a Waters LC-MS and an ACQUITY Arc QDa detector. Ketamine was purchased from Fagron. DMT (1) and 6-F-DMT (29) were synthesized using previously published methods (purity >99% as determined by UHPLC) (Cameron, LP; Benson, CJ; Dunlap, LE; Olson, DE N, Effects of N-dimethyltryptamine (DMT) on rodent behavior associated with anxiety and depression. Chemical Neuroscience ACS Chemical Neuroscience . 2018, 97, 1582–1590; Tombari, RJ; Saunders, CM; Wu, CY; Dunlap, LE; Tantillo, DJ; Olson, DE. In vitro analysis of 19F NMR tryptophan metabolism. ACS Chemical Biology 2019, 14, 1866–1873.). For cell plasticity analysis (i.e. dendriticization), all compounds were dissolved in DMSO and stored as a 10 mM stock solution in the dark at -20°C.

[0180] Absorbance was measured at 254 and 280 nm using UHPLC (Waters ACQUITY Arc). All compounds tested in the cell analysis had a purity >95%. Mobile phase A was an aqueous solution of 0.01% formic acid, and mobile phase B was an acetonitrile solution of 0.01% formic acid. All sample injection volumes were 5 μL, and the column temperature was maintained at 40 °C. Depending on the specific compound, one of three methods was used. Method A used a CORTECS C18, 2.7 μm, 4.6 × 50 mm column at a flow rate of 0.6 mL / min, with a mobile phase B gradient of 10%–90%, for 3 min followed by a 2 min hold. Method B used an XBridge BEH C18, 2.5 μm, 2.1 × 100 mm column at a flow rate of 0.6 mL / min, with a mobile phase B gradient of 10%–90%, for 0.5 min followed by a 4.5 min hold. Method C used a CORTECS C18 2.7 μm, 4.6 × 50 mm column at a flow rate of 0.2 mL / min, with a mobile phase B gradient of 10%–90%, for 4 minutes followed by a maintenance period of 2 minutes. Since most of the compounds reported in this study were separated as fumarates, peaks in the UHPLC trace amounts corresponding to fumarate were not included in the purity calculations.

[0181] Synthesis of heterodyne DMT This paper describes a simple and robust method for synthesizing various iso-DMTs under mild reaction conditions. Compound 2 was obtained in high yield via an in-situ Finkelstein reaction using KOH as a base and KI to enhance reactivity. Maintaining the reaction at 0.4 M was shown to be optimal; both high and low concentrations resulted in decreased yields.

[0182] Step A In some embodiments, the intermediates used to prepare the compounds described herein are prepared according to Scheme 1.

[0183] Option 1 In Scheme 1, L, R 1a-1c , and R 2 -R 7 As described herein. In some embodiments, X is a halogen or a sulfonate. In some embodiments, the halogen is iodine, bromine, or chlorine. In some embodiments, the halogen is chlorine. In some embodiments, the sulfonate is toluenesulfonate, methanesulfonic acid, p-bromobenzenesulfonate, or methanesulfonate. In some embodiments, X is chlorine.

[0184] In some embodiments, indole I-1 reacts with I-2 under suitable condensation reaction conditions, optionally followed by suitable salting conditions, to provide the substituted isoDMTI-3. In some embodiments, suitable condensation reaction conditions include a suitable base, a suitable additive, a suitable solvent, and are carried out at a suitable temperature for a suitable time. In some embodiments, the suitable base is a hydroxide base, a carbonate base, or a bicarbonate base. In some embodiments, the suitable base is a hydroxide base or a hydride base. In some embodiments, the suitable hydroxide base is sodium hydroxide or potassium hydroxide. In some embodiments, the suitable hydroxide base is potassium hydroxide. In some embodiments, the suitable hydride base is sodium hydride. In some embodiments, the suitable additive is a salt. In some embodiments, the salt is potassium iodide, sodium iodide, or lithium iodide. In some embodiments, the suitable salt is potassium iodide. In some embodiments, the suitable solvent is a polar aprotic solvent. In some embodiments, the polar aprotic solvent is dichloromethane (DCM), tetrahydrofuran (THF), ethyl acetate (EtOAc), acetone, dimethylformamide (DMF), or acetonitrile (MeCN). In some embodiments, the polar aprotic solvent is DMSO, DMF, MeCN, or acetone. In some embodiments, the polar aprotic solvent is DMSO. In some embodiments, the appropriate time and appropriate temperature are overnight and about 25°C, respectively.

[0185] In some embodiments, the suitable salt-forming conditions include a suitable temperature, a suitable time, a suitable solvent, and a suitable acid. 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, respectively.

[0186] For example, adding 2-chloro- to a solution of indole or related heterocycles in DMSO (0.4 M) N,N - Dimethyl ethylamine hydrochloride (1.1 equivalents), potassium iodide (1.1 equivalents), and potassium hydroxide tablets (5.0 equivalents). The reaction was stirred at room temperature for 24 hours, and then dissolved in 1.0 M NaOH. (水性)Dilute. Extract the aqueous phase three times with DCM. Combine the organic extracts, dry with Na2SO4, filter, and concentrate under reduced pressure to obtain an oil. Dissolve the unpurified oil in a trace amount of acetone and add it dropwise to a boiling acetone solution of fumaric acid (1.0 equivalent). In most cases, a precipitate forms immediately and is stored overnight at -20°C. Filter the resulting crystals and wash with several portions of ice-cold acetone to obtain the desired product. In cases where the desired product does not readily crystallize to fumarate, unless otherwise specified, the oil is subjected to column chromatography (9:1 CH2Cl2:MeOH:1% NH4OH). (水性) ).

[0187] Example 1. N,N-Dimethyltryptamine (DMT) The following DMT compounds can be prepared using methods known in the art. Example 2. 2-(1H-indol-1-yl)-N,N-dimethylethane-1-amine fumarate (1:1) (2, iso-DMT) Indole (100 mg, 0.85 mmol), 2-chloro-N,N-dimethylethylamine hydrochloride (135 mg, 0.94 mmol, 1.1 equivalents), potassium iodide (156 mg, 0.94 mmol, 1.1 equivalents), and potassium hydroxide (140 mg, 4.2 mmol, 5.0 equivalents) were dissolved in DMSO (2.15 mL) and stirred. The reaction mixture was monitored by TLC until the 2-chloro-N,N-dimethylethylamine was completely consumed (17–24 h), indicating the reaction was complete. The reaction mixture was then diluted with 1.0 M NaOH. (水性) (100 mL) dilute. 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 unpurified oil was dissolved in acetone (2 mL) and added dropwise to a boiling acetone (4 mL) solution of fumaric acid (99 mg, 85 mmol, 1.0 equiv). A precipitate formed immediately and was then stored overnight at -20°C. The crystals were filtered and washed with several portions of ice-cold acetone to obtain the desired product. (1:1 iso-DMT: fumaric acid) (175 mg, 67%). Purity >99%. TLC R f (Free base) = 0.50 (9:1 CH2Cl2:MeOH:1%NH4OH) (水性) ); 1 H NMR (600 MHz, DMSO- d 6) δ 7.54 (d, 1H, J = 7.6 Hz), 7.48 (d, 1H, J= 7.6 Hz), 7.38 (d, 1H, J = 3.1 Hz), 7.13 (ddd, 1H, J = 7.6, 1.0 Hz), 7.01(dd, 1H, J = 7.6, 1.0 Hz), 6.61 (s, 2H), 6.42 (d, 1H J = 3.1Hz), 4.29 (t, 2H, J = 6.7 Hz), 2.70 (t, 2H, J = 6.7 Hz), 2.26 (s, 6H). 13 C NMR (150 MHz, DMSO- d 6 δ 166.32, 135.66, 134.20, 128.82, 128.06, 120.96, 120.38, 118.88, 109.68, 100.54, 58.09, 44.83, 43.11 ppm; IR (diamond, ATR) 3100, 2923, 2393, 1705cm -1 ; Calculated relative molecular mass C of LRMS (ES+) 12 H 16 N2+ 188.13, measured value 189.38 (MH+); MP = 147–149℃.

[0188] Example 3. 2-(4-methoxy-1H-indol-1-yl)-N,N-dimethylethane-1-amine fumarate (1:1) （3） Synthesized according to step A. The reaction was carried out with 4-methoxyindole (100 mg, 0.68 mmol) and purified by crystallization. Yield: 95 mg, 42%. Purity: 96%. TLC R f (Free base) = 0.35 (9:1 CH2Cl2:MeOH:1% NH4OH) (水性) ); 1 H NMR (600 MHz, DMSO-) D 6 )δ7.26(d, 1h, J =3.1Hz), 7.10(d, 1H, J =7.8Hz), 6.90(t, 1H, J =7.8Hz), 6.66(d, 1H, J=7.8Hz), 6.60(s, 2H), 6.35(d, 1H), J =3.1Hz), 4.49(t, 2H, J =7.0Hz),3.89(s,3H),2.76(t,2H), J =7.0Hz), 2.32(s, 6h)ppm; 13 C NMR (150 MHz, DMSO- d 6 δ 166.30, 146.96, 134.17, 130.46, 129.79, 124.94, 119.64, 113.33, 102.42, 100.93, 59.61, 55.32, 45.63, 44.63 ppm; IR (diamond, ATR) 2929, 2455, 1712, 1644 cm -1 LRMS (ES+) relative molecular mass calculation: C 13 H 18 N2O+ 219.15, measured value 220.33 (MH+); MP= 140–145℃.

[0189] Example 4. 2-(5-methoxy-1H-indol-1-yl)-N,N-dimethylethane-1-amine fumarate (1:1) （4） Synthesized according to step A. The reaction was carried out with 5-methoxyindole (100 mg, 0.68 mmol) and purified by crystallization. Yield: 111 mg, 49%. Purity: 98%. TLC R f (Free base) = 0.66 (9:1 CH2Cl2: MeOH: 1% NH4OH) (水性) ); 1 H NMR (600 MHz, DMSO-) D 6 )δ7.38(d, 1h, J =8.9Hz), 7.33(d, 1H, J =3.0Hz), 7.04(d, 1H, J =2.4Hz), 6.77 (dd, 1H, J =8.9, 2.4 Hz), 6.6 (s, 2h), 6.33 (d, 1h), J =3.0Hz), 4.29(t, 2H, J =6.8Hz),3.74(s,3H),2.79(t,2H),J =6.8Hz), 2.30(s, 6h)ppm; 13 C NMR (150 MHz, DMSO-) D 6 ) δ166.58, 153.42, 134.32, 130.90, 129.20, 128.48, 111.12, 110.39,102.13,100.34,57.68,55.30,44.44,42.91ppm 3035, 2923, 2446, 1715cm - 1. Calculated relative molecular mass of LRMS (ES+): C 13 H 18 N2O+ 219.15, measured value 220.19 (MH+); MP = 140-142℃.

[0190] Example 5. 2-(6-methoxy-1H-indol-1-yl)-N,N-dimethylethane-1-amine (5) Synthesized according to step A. The reaction was carried out with 6-methoxyindole (147 mg, 1.0 mmol) and purified by chromatographic chromatography. Yield: 148 mg, 68%. Purity: >99%. TLC R f (Free base) = 0.32 (9:1 CH2Cl2: Meoh: 1% NH4OH) (水性) ); 1 H NMR (600 MHz, CDCl3) δ7.49 (d, 1h, J =7.8Hz), 7.02(d, 1H, J =8.2Hz),6.82(s,2h),6.78(dd,1h, J =7.5Hz), 6.42(d, 1H, J =7.8Hz), 4.17(t, 2H, J =7.0Hz),2.31(s,3h),2.69(t,2h), J =7.0Hz), 2.31(s, 6h)ppm; 13 C NMR (150 MHz, CDCl3) δ156.30,136.77,127.04,123.00,121.67,109.22,101.31,93.14,59.00,55.91,45.94,44.91 ppm 2940, 2859, 2769, 1602cm -1Calculated relative molecular mass of LRMS (ES+): C 13 H 18 N2O+ 219.15, measured value: 220.33 (MH+). Used for dendrite generation analysis of free base.

[0191] Example 5'. 2-(6-methoxy-1H-indol-1-yl)-N,N-dimethylethane-1-oxalamide (5') Synthesized according to step A. The reaction was carried out with 6-methoxyindole (250 mg, 1.7 mmol), and purified by crystallization. Yield: 221 mg, 42%. Purity: 98%. 1 H NMR (600 MHz, CD3OD) δ7.42 (d, 1h, J =8.5Hz), 7.16(d, 1H, J =2.9Hz), 7.02(s, 2H), 6.74(d, 1H), J =8.5Hz), 6.44(d, 1H, J =2.9Hz), 4.58(t, 2H, J =6.8Hz), 3.87(s, 3H), 3.56(t, 2H), J =7.0Hz), 2.86(s,6h)ppm; 13 C NMR (150 MHz, CD3δ166.72,158.20,138.02,127.52,124.45,122.61,111.06,103.58,93.83,57.22,56.19,44.04,42.17ppm 3129, 3014, 2641, 1727cm -1 Calculated relative molecular mass of LRMS (ES+): C 13 H 18 N₂O⁺ 219.15, measured value: 220.05 (MH⁺). MP = 165-167℃. Oxalate is used for HTR determination.

[0192] Example 6. 2-(7-methoxy-1H-indol-1-yl)-N,N-dimethylethane-1-amine fumarate (1:1) （6） Synthesized according to step A. The reaction was carried out with 7-methoxyindole (100 mg, 0.68 mmol) and purified by crystallization. Yield: 162 mg, 72%. Purity >99%. TLC R f (Free base) = 0.44 (9:1 CH2Cl2:MeOH:1%NH4OH) (水性) ); 1H NMR (600 MHz, DMSO-) D 6 )δ7.26(d, 1h, J =3.1Hz),7.09-7.03(m,2H),6.60(s,2H),6.52(dd,1H), J =6.1, 1.3Hz), 6.41 (dd, 1h, J =3.0, 0.7Hz), 4.29 (t, 2H, J =6.8Hz), 3.86(s, 3H), 2.75(t, 2H), J =6.8Hz), 2.29(s,6h)ppm: 13 C NMR (150 MHz, DMSO-) D 6 ) δ166.46, 152.80, 137.02, 134.24, 127.14, 121.98, 118.38, 103.09, 99.16, 97.88, 57.83, 54.89, 44.60, 43.15ppm 3435, 3034, 2653, 1705cm -1 Calculated relative molecular mass of LRMS (ES+): C 13 H 18 N2O+ 219.15, measured value: 220.40 (MH+); MP=120–123℃.

[0193] Example 7. Benzyloxyindole 4-,5-,6- and 7-OBn indoles were synthesized using methods previously reported in the literature.

[0194] Example 8. 2-(4-(benzyloxy)-1H-indol-1-yl)-N,N-dimethylethane-1-amine fumarate (1: 1）（8） Synthesized according to step A. The reaction was carried out with 4-benzyloxyindole (200 mg, 0.89 mmol), followed by crystallization purification. Yield: 120 mg, 46%. Purity >99%. TLC R f (Free base) = 0.42 (9:1 CH2Cl2: Meoh: 1% NH4OH) (水性) ); 1 HNMR (400 MHz, CD3OD) δ7.49 (d, 2h, J =7.5Hz), 7.37(t, 2H, J =7.5Hz), 7.31(t, 1H, J=7.5Hz), 7.20(d, 1H, J =3.26Hz),7.12(m,2h),6.72(s,1h),6.66(m,1h),5.22(s,2h),4.57(t,2h), J =6.7Hz), 3.50(t, 2H, J =6.7Hz), 2.81(s, 6h)ppm; 13 C NMR (100 MHz, CD3δ169.90, 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 2918, 2493, 1701, 1639cm -1 Calculated relative molecular mass of LRMS (ES+): C 19 H 22 N2O+ 294.17, measured value 295.24 (MH+); MP = 145-150°C.

[0195] Example 9. 2-(5-(benzyloxy)-1H-indol-1-yl)-N,N-dimethylethane-1-amine fumarate (1: 1）（9） Synthesized according to step A. The reaction was carried out with 5-benzyloxyindole (287 mg, 1.3 mmol), followed by crystallization purification. Yield: 133 mg, 25%. Purity >99%. TLC R f (Free base) = 0.47 (9:1 CH2Cl2:MeOH:1% NH4OH) (水性 ); 1 HNMR (400 MHz, CD3OD) δ7.44 (d, 2h, J =7.5Hz), 7.36(m, 3H), 7.29(d, 2H), J =7.5Hz), 7.24(d, 1H, J =3.2Hz), 7.15(d, 1H, J =2.4Hz), 6.95 (dd, 1H, J =2.4,8.9Hz),6.72(s,2h),6.43(d,1h), J =3.2Hz), 5.07(s, 2H), 4.54(t, 2H), J=6.8Hz), 3.45(t, 2H, J =6.8Hz), 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) 2916, 2516, 1698, 1639 cm -1 Calculated relative molecular mass of LRMS (ES+): C 19 H 22 N2O+ 294.17, measured value 295.17 (MH+); MP = 133-135℃.

[0196] Example 10. 2-(6-(benzyloxy)-1H-indol-1-yl)-N,N-dimethylethane-1-amine (10) Synthesized according to step A. The reaction was carried out with 6-benzyloxyindole (370 mg, 1.7 mmol) and purified by chromatographic chromatography. Yield: 184 mg, 38%. Purity: >97%. TLC R f (Free base) = 0.45 (9:1 CH2Cl2:MeOH:1%NH4OH) (水性) ); 1 H NMR (600 MHz, CD3OD) δ7.47 (d, 2h, J =7.4Hz), 7.40(d, 2H, J =8.6Hz), 7.37(t, 1H) J =7.4Hz), 7.30(t, 1H, J =7.4Hz), 7.08 (d, 1H, J =3.8Hz), 6.96(s, 1H), 6.78(d, 1H), J =8.6Hz), 6.35 (d, 1H, J =3.8Hz), 5.15(s, 2H), 4.22(t, 2H), J =7.3Hz), 2.66(t, 2H, J =7.3Hz), 2.26(s, 6h)ppm; 13C NMR (150 MHz, CDCl3) δ156.39, 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 3030, 2952, 2768, 1621cm -1 Calculated relative molecular mass of LRMS (ES+): C 19 H 22 N2O+ 294.17, measured value: 295.10 (MH+). Example 11. 2-(7-(benzyloxy)-1H-indol-1-yl)-N,N-dimethylethane-1-amine (11) Synthesized according to step A. The reaction was carried out with 7-benzyloxyindole (119 mg, 0.53 mmol) and purified by chromatographic chromatography. Yield: 51 mg, 23%. Purity: >99%. TLC R f (Free base) = 0.48 (9:1 CH2Cl2:MeOH:1%NH4OH) (水性) ); 1 H NMR (600 MHz, CDCl3) δ7.49 (d, 2h, J =7.4Hz), 7.40(t, 2H, J =7.4Hz), 7.34(t, 1H, J =7.4Hz), 7.22(d, 1H, J =7.9Hz), 7.01(d, 1H, J =3.0Hz), 6.97(t, 1H, J =7.8Hz), 6.70(d, 1H, J =7.8Hz), 5.19(s, 2H), 4.45(t, 2H), J =7.4Hz), 2.62(t, 2H, J =7.4Hz), 2.09(s, 6h)ppm; 13 C NMR (150 MHz, CDCl3) δ150.59, 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 2940, 2821, 1575, 1439cm-1 Calculated relative molecular mass of LRMS (ES+): C 19 H 22 N2O+ 294.17, measured value: 295.24 (MH+). Example 12. 2-(4-fluoro-1H-indol-1-yl)-N,N-dimethylethane-1-amine fumarate (1:1) (12) Synthesized according to step A. The reaction was carried out with 4-fluoroindole (135 mg, 1.0 mmol), and purified by crystallization. Yield: 164 mg, 51%. Purity: >99%. TLC R f (Free base) = 0.39 (9:1 CH2Cl2:MeOH:1% NH4OH) (水性) ); 1 HNMR (400 MHz, DMSO- D 6 )δ7.44(d, 1h, J =2.3Hz), 7.35(d, 2H, J =8.3Hz), 7.10(dd, 2H, J =7.4,7.25Hz),6.79 (t,2H, J =9.5Hz), 6.60(s, 2H), 6.49(d, 2H), J =2.3Hz), 4.32(t, 2H, J =6.7Hz), 2.74(t, 2H, J =6.8Hz), 2.28(s, 6h)ppm; 13 C NMR (150 MHz, DMSO-) D 6 ) δ166.37, 156.67, 154.34, 138.56, 138.44, 134.21, 129.35, 121.63, 121.55, 1 16.74, 116.51, 106.48, 106.45, 103.70, 103.51, 96.24, 57.90, 44.73, 43.40ppm 3123, 2389, 1702, 1660cm - 1 Calculated relative molecular mass of LRMS (ES+): C 12 H 16 FN2+ 207.13, measured value: 208.32 (MH+); MP = 145–149℃.

[0197] Example 13. 2-(5-fluoro-1H-indol-1-yl)-N,N-dimethylethane-1-amine fumarate (1:1) (13) Synthesized according to step A. The reaction was carried out with 5-fluoroindole (135 mg, 1.0 mmol), and purified by crystallization. Yield: 145 mg, 45%. Purity: >99%. TLC R f (Free base) = 0.35 (9:1 CH2Cl2:MeOH:1% NH4OH) (水性) ); 1 HNMR (400 MHz, DMSO- D 6 )δ7.50(dd, 1h, J =4.5, 4.3Hz), 7.46 (d, 1H, J =2.1Hz), 7.29 (d, 1H, J =9.5Hz), 6.97(t, 1H, J =9.5Hz), 6.60(s, 2H), 6.41(d, 1H), J =2.1Hz), 4.32(t, 2H, J =6.7Hz), 2.79(t, 2H, J =6.7Hz), 2.31(s, 6h)ppm; 13 C NMR (150 MHz, DMSO-) D 6 ) δ166.59, 159.61,158.06,135.77,135.69,134.33,129.54,129.51,124.72,121.3 9,121.32,107.48,107.32,100.97,96.32,96.15,57.66,44.58,43.00ppm 3036, 2049, 1723, 1663cm -1 Calculated relative molecular mass of LRMS (ES+): C 12 H 16 FN2+ 207.13, measured value: 207.40 (MH+); MP = 145-148℃.

[0198] Example 14. 2-(6-fluoro-1H-indol-1-yl)-N,N-dimethylethane-1-amine fumarate (1:1) (14) Synthesized according to step A. The reaction was carried out with 6-fluoroindole (100 mg, 0.739 mmol), and purified by crystallization. Yield: 145 mg, 61%. Purity: 97%. TLC R f(Free base) = 0.45 (9:1 CH2Cl2:MeOH:1% NH4OH) (水性) ); 1 H NMR (600 MHz, DMSO-) D 6 )δ7.52(dd, 1h, J =7.0,3.0Hz),7.39-7.37(m,2h),6.88-6.85(m,1h),6.59(s,2h),6.44(d,1h), J =3.1Hz), 4.29(t, 2H, J =6.8Hz), 2.77(t, 2H, J =6.8Hz), 2.30(s, 6h)ppm; 13 C NMR (150 MHz, DMSO-) D 6 ) δ166.59, 159.61, 158.06, 136.16,134.75, 129.95,125.14,121.78,107.91,107.74,101.39,96.74,96.57,57.66,44.58,43.00ppm 3058, 2385, 1698, 1634cm -1 Calculated relative molecular mass of LRMS (ES+): C 12 H 16 FN2+207.13, measured value: 208.39 (MH+); MP = 141-147℃.

[0199] Example 15. 2-(7-fluoro-1H-indol-1-yl)-N,N-dimethylethane-1-amine fumarate (1:1) (15) Synthesized according to step A. The reaction was carried out with 7-fluoroindole (135 mg, 1.0 mmol), and purified by crystallization. Yield: 172 mg, 53%. Purity: 98%. (TLC-R) 1661 cm⁻¹ f (Free base) = 0.45 (9:1 CH2Cl2:MeOH:1%NH4OH) (水性) ); 1 H NMR (400 MHz, DMSO- D 6 δ7.41(s, 1h), 7.35(d, 1h) J =7.6Hz),6.98-6.88(m,2h),6.61(s,2h),6.48(s,1h,),4.37(t,2h,J =6.7Hz), 2.69(t, 2H, J =6.7Hz), 2.23(s, 6h)ppm; 13 C NMR(100 MHz, CD3δ169.37,134.60,133.26,129.51,119.90,119.46,116.82,116.79,107.06,106.88,102.78,57.61,57.61,43.71,43.67,42.90 ppm 3040, 2429, 1718. 1661cm -1 Calculated relative molecular mass of LRMS (ES+): C 12 H 16 FN2+ 207.13, measured value: 207.33 (MH+); MP = 168-170℃.

[0200] Example 16. N,N-Dimethyl-2-(2-methyl-1H-indol-1-yl)ethane-1-amine fumarate (1:1) （16） Synthesized according to step A. The reaction was carried out with 2-methylindole (100 mg, 0.76 mmol) and purified by crystallization. Yield: 172 mg, 71%. Purity: >99%. TLC R f (Free base) = 0.47 (9:1 CH2Cl2:MeOH:1% NH4OH) (水性) ); 1 HNMR (400 MHz, DMSO- D 6 )δ7.41(d, 1h, J =7.8Hz), 7.37 (d, 1H, J =7.8Hz), 7.06(t, 1H, J =7.8Hz), 6.96(t, 1H, J =7.8Hz), 6.61(s, 2H), 6.20(d, J =1.3Hz, 1H), 4.24(t, 2H, J =7.0Hz), 2.65(t, 2H, J =7.0Hz), 2.42(s,3H), 2.31(s,6H)ppm; 13 C NMR (150 MHz, DMSO-) D 6)167.03,137.08,136.72,134.75,128.09,120.58,119.65,119.62,119.40,109.61,100.14,57.82,45.18,12.76ppm 3040, 2489, 1700, 1606cm -1 Calculated relative molecular mass of LRMS (ES+): C 13 H 18 N2+ 203.15, measured value: 204.43 (MH+); MP = 131–133℃.

[0201] Example 17. 2-(5,6-difluoro-1H-indol-1-yl)-N,N-dimethylethane-1-amine fumarate (1:1) （17） Synthesized according to step A. The reaction was carried out with 5,6-difluoroindole (153 mg, 1.0 mmol), and purified by crystallization. Yield: 147 mg, 43%. Purity: 98%. TLC R f (Free base) = 0.35 (9:1 CH2Cl2:MeOH:1%NH4OH) (水性) ); 1 H NMR (400 MHz, DMSO- D 6 )δ7.64(dd, 1h, J =7.0, 4.7Hz), 7.51 (dd, 1h, J =8.5, 2.1Hz), 7.45 (d, 1H, J =2.1Hz), 6.60(s, 2H), 6.43(d, 1H), J =2.1Hz), 4.28(t, 2H, J =6.5Hz), 2.73(t, 2H, J =6.5Hz), 2.27(s, 6h)ppm; 13 C NMR (150 MHz, DMSO-) D 6 ) δ166.37,134.21, 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 3051, 2392, 1712, 1658cm -1Calculated relative molecular mass of LRMS (ES+): C 12 H 16 F2N2+ 224.11, measured value: 225.28 (MH+); MP = 162–165°C. Example 18. 2-(4,6-Difluoro-1H-indol-1-yl)-N,N-dimethylethane-1-amine fumarate (1:1) （18） Synthesized according to step A. The reaction was carried out with 4,6-difluoroindole (153 mg, 1.0 mmol), and purified by crystallization. Yield: 265 mg, 78%. Purity: >99%. TLC R f (Free base) = 0.35 (9:1 CH2Cl2:MeOH:1%NH4OH) (水性) ); 1 H NMR (400 MHz, DMSO- D 6 )δ7.44(d, 1h, J =2.8Hz), 7.32(d, 1H, J =10.1Hz), 6.83(t, 1H, J =10.1Hz), 6.60(s, 2H), 6.49(d, 1H), J =2.8Hz), 4.31(t, 2H, J =6.6Hz), 2.78(t, 2H, J =6.6Hz), 2.31(s, 6h)ppm; 13 C NMR (150 MHz, DMSO-) D 6 ) δ166.55, 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 3026, 2398, 1706, 1640cm -1 Calculated relative molecular mass of LRMS (ES+): C 12 H 16 F₂N₂⁺ 224.11, measured value: 225.28 (MH⁺); MP = 141-145℃. Example 19. N,N-Dimethyl-2-(6-nitro-1H-indol-1-yl)ethane-1-amine fumarate (1:1) （19） Synthesized according to step A. The reaction was carried out with 6-nitroindole (43.6 mg, 0.269 mmol), and purified by crystallization. Yield: 52 mg, 55%. Purity: >96%. TLC R f (Free base) = 0.48 (9:1 CH2Cl2:MeOH:1% NH4OH) (水性) ); 1 H NMR (400 MHz, DMSO- D 6 )δ8.54(d, 1h, J =2.0Hz), 7.90 (dd, 1H, J =8.8, 2.0 Hz), 7.82 (d, 1H, J =3.0Hz), 7.72(d, 1H, J =8.8Hz), 7.74(s, 1H), 6.65(d, 1H), J =3.0Hz), 6.60(s, 2H), 4.44(t, 2H), J =6.3Hz), 2.68(t, 2H, J =6.3Hz), 2.23(s, 6h)ppm; 13 C NMR (600 MHz, DMSO-) D 6 ) δ166.66, 136.18, 134.76, 134.59, 133.41, 121.04, 114.52, 107.53,102.25,58.98,45.50,44.18ppm 3048, 2922, 1704, 1607cm -1 Calculated relative molecular mass of LRMS (ES+): C 12 H 16 N3O2+ 233.12, measured value: 234.25 (MH+); MP = 159–164℃.

[0202] Example 20. 2-(5-bromo-1H-indol-1-yl)-N,N-dimethylethane-1-amine fumarate (1:1) (20) Synthesized according to step A. The reaction was carried out with 5-bromoindole (56.1 mg, 0.281 mmol), and purified by crystallization. Yield: 60 mg, 55%. Purity >99%. TLC R f(Free base) = 0.49 (9:1 CH2Cl2:MeOH:1% NH4OH) (水性) ); 1 HNMR (600 MHz, DMSO- D 6 )δ7.72(d, J =1.9 Hz, 1H), 7.48 (d, 1H, J =8.7Hz), 7.44(d, 1H, J =3.1Hz), 7.23 (dd, 1H, J =8.7,1.9Hz),6.60(s,3h),6.41(d,1h), J =3.1Hz), 4.27(t, 2H, J =6.6Hz), 2.67(t, 2H, J =6.6Hz), 2.22(s, 6h)ppm; 13 C NMR (600 MHz, DMSO-) D 6 ) δ166.24,134.47, 134.15,130.46,129.89,123.81,122.54,111.87,111.56,100.28,58.09,44.86,43.32 ppm 2959, 2443, 1705, 1661cm -1 Calculated relative molecular mass of LRMS (ES+): C 12 H 16 BrN2+ 266.04, measured value: 267.26 (MH+); MP = 140–142℃.

[0203] Example 21. 2-(1-(2-dimethylamino)ethyl)-1H-indol-3-yl)-N,N-dimethyl-2-oxoacetyl Amine (21) 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 effect of oxaloyl chloride on indole: A new pathway for tryptamines. Journal of the American Chemical Society) JOURNAL OF THE AMERICAN CHEMICAL SOCIETY (1954, 76, 6208-6210.) (200 mg, 0.92 mmol), purified by chromatographic chromatography. Yield: 92 mg, yield: 35%. Purity: 98%. TLC R f (Free base) = 0.38 (9:1 CH2Cl2:MeOH:1% NH4OH)(水性) ); 1 H NMR (600 MHz, CDCl3) δ8.32(s,1h), 7.92(s,1h), 7.37-7.29(m,3h), 4.21(t,2h), J =7.0Hz), 3.08(s,3H), 3.04(s,3H), 2.71(t,2H), J =7.0Hz), 2.27(s, 6h)ppm; 13 C NMR (150 MHz, CDCl3) δ185.64, 167.70, 138.82,137.01,126.36,124.00,123.28,122.48,113.45,110.06,58.40,45.68,45.42,37.59,34.51ppm 2981,1734 1631,1525cm -1 Calculated relative molecular mass of LRMS (ES+): C 16 H 21 N3O2+ 287.16, measured value: 288.25 (MH+). Example 22. 2-(1H-benzo[d]imidazol-1-yl)-N,N-dimethylethane-1-amine fumarate (1:1) （22） Synthesized according to step A. The reaction was carried out with benzimidazole (200 mg, 1.6 mmol), and purified by crystallization. Yield: 218 mg, 45%. Purity: 98%. TLC R f (Free base) = 0.42 (9:1 CH2Cl2:MeOH:1% NH4OH) (水性) ); 1 HNMR (400 MHz, DMSO- D 6 ) δ8.23(s,1h), 7.71-7.56(m,2h), 7.34-7.10(m,2h), 6.61(s,2h), 4.41(t,2h), J =6.5Hz), 2.83(dd, 2H, J =7.0, 6.0 Hz), 2.32 (s, 6h) ppm; 13 C NMR (100 MHz, CD3δ170.14, 144.78,143.90,135.81,134.62,124.80,124.04,120.36,111.29,57.46,44.39,41.80 ppm 3054, 2384, 1707, 1654cm -1 Calculated relative molecular mass of LRMS (ES+): C 11 H 15 N3+ 189.13, measured value: 190.23 (MH+); MP = 171–178℃.

[0204] Example 23. N,N-Dimethyl-2-(1H-pyrrolo-1-yl)ethane-1-amine fumarate (1:1) (23) Synthesized according to step A. The reaction was carried out with pyrrole (0.103 mL, 1.5 mmol), and purified by crystallization. Yield: 126 mg, 33%. Purity: >99%. TLC R f (Free base) = 0.45 (9:1 CH2Cl2:MeOH:1% NH4OH) (水性) ); 1 H NMR (600 MHz, CD3OD) δ6.80 (t, 2h, J =2.2, Hz), 6.72 (s, 2H), 6.14 (t, 2H. J =2.2,Hz), 4.34(t,2H, J =6.4Hz), 3.50(dd, 2H, J =6.4Hz), 2.78(s, 6h)ppm; 13 C NMR (100 MHz, CD3δ170.26,136.21, 122.18, 110.89,59.35,45.83,44.45ppm 2998, 2532, 1662, 1421cm -1 Calculated relative molecular mass of LRMS(ES+) for C8H 14 N2+ 138.12, measured value: 139.29 (MH+); MP = 174-180℃.

[0205] Example 24. 2-(9H-carbazole-9-yl)-N,N-dimethylethane-1-amine fumarate (1:1) (24) Synthesized according to step A. The reaction was carried out with carbazole (100 mg, 0.57 mmol), and purified by crystallization. Yield was 102 mg, 51%. Purity >99%. TLC R f (Free base) = 0.42 (9:1 CH2Cl2:MeOH:1% NH4OH) (水性) ); 1 H NMR (600 MHz, DMSO-) D 6 )δ8.15(d, 2h, J=7.8Hz), 7.61(d, 2H, J =8.2Hz), 7.48-7.44(m,2h),7.23-7.19(m,2h), 6.61(s,2h), 4.52(t,2h), J =7.0Hz), 2.73(t, 2H, J =7.0Hz), 2.31(s, 6h)ppm; 13 C NMR (100 MHz, DMSO-) D 6 ) δ169.78, 139.86, 134.76, 125.83, 123.17,119.99, 119.39, 108.34,54.39,42.61,37.85 ppm 3053, 2405, 1720, 1660cm -1 Calculated relative molecular mass of LRMS(ES+): C 16 H 18 N2+ 238.15, measured value: 239.34 (MH+); MP = 182-184°C.

[0206] Example 25. 1-Isopentyl-1H-indole (25) Synthesized according to step A. The reaction was carried out with indole (100 mg, 0.85 mmol) and 1-chloro-3-methylbutane (0.11 mL mg, 0.94 mmol, 1.1 equivalents), and purified by chromatography (4:1 hexane: ethyl acetate). Yield: 85 mg, 53%. Purity: 97%. TLC R f = 0.70 (7:3 hexane: ethyl acetate); 1 H NMR (600 MHz, CDCl3) δ7.65 (d, 1H, J = 8.0 Hz), 7.36 (d, 1H, J = 8.0 Hz), 7.22 (t, 1H, J = 6.9Hz), 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) 3054, 2955, 2927, 2869 cm -1 Calculated relative molecular mass of LRMS (ES+): C 13 H 17 N+187.14, measured value: 188.39 (MH+). Example 26. 3-(1H-indol-1-yl)-N,N-dimethylpropane-1-amine fumarate (1:1) (26) Synthesized according to step A. Using indole (100 mg, 0.85 mmol) and 3-chloro- N,N The reaction was carried out with 1-dimethylpropane-1-amine (160 mg, 0.98 mmol, 1.1 equivalents), followed by crystallization and purification, yielding 107 mg, a yield of 48%. Purity = 98%. TLC R f (Free base) = 0.38 (9:1 CH2Cl2:MeOH:1% NH4OH) (水性) ); 1 H NMR (600 MHz, DMSO- d 6 ) δ 7.54(d, 1H, J = 7.8 Hz), 7.48 (d, 1H, J = 7.8 Hz), 7.36 (d, 1H, J = 3.1 Hz), 7.13 (td, 1H, J = 7.4, 1.0 Hz), 7.01 (td, 1H, J = 7.4, 1.0 Hz), 6.55 (s, 2H), 6.43 (dd, 1H, J = 3.1, 1.0 Hz), 4.21 (t, 2H, J = 6.8 Hz), 2.56 (t, 2H, J =7.4 Hz), 2.40 (s, 6H), 2.00 (tt, 2H, J = 7.4, 6.8 Hz) ppm;13 C NMR (150 MHz, DMSO- d 6 δ 167.19, 135.60, 134.62, 128.49, 128.07, 120.99, 120.41, 118.90, 109.67, 100.61, 54.88, 43.41, 43.07, 26.26 ppm; IR (diamond, ATR) 3435, 3034, 2653, 1705 cm -1 Calculated relative molecular mass of LRMS (ES+): C 13 H 18 N2+ 203.15, measured value: 204.36 (MH+); MP = 129-131℃.

[0207] Example 27. N,N-Dimethyl-2-(1-methyl-1H-indol-3-yl)ethane-1-amine fumarate (1:1) (1-ME-DMT 27) Add N-methyl-2-(1-methyl-1H-indol-3-yl)ethane-1-amine (0.14 g, 0.70 mmol), glacial acetic acid (0.22 mL, 11 mmol, 5.0 equivalents), sodium cyanoborohydride (0.10 g, 1.6 mmol, 2.1 equivalents), and 37% formaldehyde to a 12 mL solution of glacial methanol. (水性) (0.16 mL, 1.9 mmol, 2.6 equivalents). The reaction was stirred at room temperature for 5 hours, then concentrated under reduced pressure. The solution was then reacted with CH₂Cl₂ (50 mL) and 1 M NaOH. (水性) Dilute the unpurified material (100 mL). Perform phase separation, extracting the aqueous phase with CH2Cl2 (2 x 50 mL). Combine the organic extracts, dry with Na2SO4, filter, and concentrate under reduced pressure. Dissolve the unpurified material in acetone (5 mL), and add a boiling solution of fumaric acid (0.088 g, 1 mmol, 1 equivalent) in acetone (20 mL). A precipitate forms immediately; cool the solution to room temperature and filter. Dry the resulting white solid under reduced pressure to give the pure compound of fumarate (1:1). Yield: 0.108 g, yield: 65%. Purity: >99%. TLC R f (Free base) = 0.19 (9:1 CH2Cl2:MeOH:1% NH4OH) (水性) ); 1 H NMR (600 MHz, CD3OD) δ7.60 (d, 1h, J =8.0Hz), 7.37(d, 1H, J =8.0Hz), 7.20(t, 1H, J=8.0Hz),7.14(s,1h),7.09(t,1h), J =8.0Hz),6.69(s,2h),3.78(s,3h),3.42(t,2h), J =7.8Hz), 3.20(t, 2H, J =7.8Hz), 2.91(s, 6h)ppm; 13 C 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 -1 Calculated relative molecular mass of LRMS (ES+) m / z: C 13 H 18 N2+ 202.15, measured value: 203.37 (MH+); MP = 167-170℃.

[0208] Example 28. 2-(5-methoxy-1H-indol-3-yl)-N,N-dimethylethane-1-amine fumarate (2:1) (5-MeO-DMT, 28) Add 5-methoxytryptamine (0.50 g, 2.2 mmol), glacial acetic acid (0.60 mL, 11 mmol, 5.0 equivalents), sodium cyanoborohydride (0.305 g, 4.8 mmol, 2.2 equivalents), and 37% formaldehyde to a 44 mL solution of glacial methanol. (水性) (0.46 mL, 5.7 mmol, 2.6 equivalents). The reaction was stirred at room temperature for 5 hours, then concentrated under reduced pressure. The residue was treated with CH2Cl2 (50 mL) and 1 M NaOH. (水性) (100 mL) dilution. Phase separation was performed, with the aqueous phase extracted with CH2Cl2 (2 x 50 mL). The organic extracts were combined, dried over Na2SO4, filtered, and concentrated under reduced pressure. The unpurified substance was dissolved in acetone (5 mL), and a boiling solution of fumaric acid (0.26 g, 2.2 mmol, 0.7 equivalent) in acetone (35 mL) was added. A precipitate formed immediately, and the solution was cooled to room temperature and then filtered. The resulting white solid was dried under reduced pressure to give the pure compound of fumarate (2:1). Yield: 0.49 g, 80%. Purity: 98%. TLC R f (Free base) = 0.20 (9:1 CH2Cl2:MeOH:1% NH4OH) (水性) ); 1H NMR (600 MHz, CD3OD) δ7.24 (d, 1h, J =8.8Hz),7.14(s,1h),7.07(s,1h),6.78(d,1h), J =8.8Hz),6.70(s,1h),3.83(s,3h),3.29(m,2h),3.13(t,2h), J =7.9Hz), 2.83(s, 6h)ppm; 13 C NMR (150MHz, CD3δ174.36, 155.27, 137.09, 133.44, 128.49, 124.79, 113.20, 112.96,110.05, 101.05, 59.25, 56.37, 43.56, 22.12ppm 3436, 3034, 2654, 1705cm -1 .LRMS (ES+) m / z relative molecular mass calculation: C 13 H 18 N2O+ 218.14, , measured value: 219.34 (MH+); MP=175-177℃.

[0209] Example 29. 2-(6-Fluoro-1H-indol-3-yl)-N,N-dimethylethane-1-amine (6-F-DMT, 29) The following Example 29 can be prepared by methods known in the art. Example 30. 2-(6-methoxy-1H-indol-3-yl)-N,N-dimethylethane-1-amine fumarate (2:1) (6-MeO-DMT, 30) Sodium cyanoborohydride (0.29 g, 4.6 mmol, 2.2 equivalents) and 37% formaldehyde were added to a solution of 6-methoxytryptamine (0.40 g, 2.1 mmol) and glacial acetic acid (0.60 mL, 10 mmol, 5.0 equivalents) in 42 mL of MeOH. (水性) (0.44 mL, 5.5 mmol, 2.6 equivalents). The reaction was stirred at room temperature for 5 hours, then concentrated under reduced pressure. The residue was treated with CH2Cl2 (45 mL) and 1 M NaOH. (水性)(100 mL) dilution. Phase separation was performed, with the aqueous phase extracted with CH2Cl2 (2 x 45 mL). The organic extracts were combined, dried over Na2SO4, filtered, and concentrated under reduced pressure. The unpurified substance was dissolved in acetone (5 mL), and a boiling solution of fumaric acid (0.26 g, 2.2 mmol, 0.7 equivalent) in acetone (35 mL) was added. A precipitate formed immediately, and the solution was cooled to room temperature and then filtered. The resulting white solid was dried under reduced pressure to give the pure compound of fumarate (2:1). Yield: 0.320 g, yield: 55%. Purity: 95%. TLC R f (Free base) = 0.31 (9:1 CH2Cl2:MeOH:1% NH4OH) (水性) ); 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) 2915, 2836, 1691, 1559 cm -1 .LRMS (ES+) m / z relative molecular mass calculation: C 13 H 18 N2O+ 218.14, , measured value: 219.29 (MH+); MP=173-176℃.

[0210] Example 31. 2-(1H-indol-1-yl)-N,N-dimethylacetamide (31) 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 equivalents), potassium iodide (182 mg, 1.1 mmol, 1.1 equivalents), and potassium hydroxide granules (280 mg, 5 mmol, 5.0 equivalents) were added. The reaction was stirred at room temperature for 24 hours, and then dissolved in 1.0 M NaOH. (水性) Dilute. Extract the aqueous phase three times with DCM. Combine the organic extracts, dry with Na2SO4, filter, and concentrate under reduced pressure to obtain an oil. Purify the oil by chromatographic chromatography (3:2 n-hexane:ethyl acetate). Yield: 175 mg, 57%. Purity: 99%. TLC R f =0.15 (3:2 hexane: EtOAc); 1 H NMR (600 MHz, CD3OD) δ7.53 (d, 1h, J =7.9Hz), 7.27 (d, 1H, J =7.9Hz), 7.12(m, 2H), 7.01(t, 1H), J =7.5, Hz), 6.46 (d, 1H, J =2.9Hz), 5.01(s,2H), 3.15(s,3H), 2.96(s,3H)ppm; 13 C NMR (150 MHz, CDCl3) δ167.4, 136.7, 128.7, 128.5, 122.0,121.2, 119.8, 109.1, 102.4, 48.2, 36.7, 36.1 ppm 3021, 2922, 2877, 1648cm - 1 Calculated relative molecular mass of LRMS (ES+): C 12 H 14 N2O+ 202.11 Measured value: 203.17 (MH+); MP = 58–61℃.

[0211] Example 32. (R)-1-(5-methoxy-1H-indol-1-yl)-N,N-dimethylpropyl-2-amine fumarate 5-Methoxyindole (500 mg, 3.40 mmol), (R)-1-chloro-N,N-dimethylpropane-2-amine (1.074 g, 6.79 mmol, 2 equivalents), potassium iodide (1.128 mg, 6.79 mmol, 2 equivalents), and potassium hydroxide (0.953 g, 16.9 mmol, 5.0 equivalents) were placed in 8.49 mL of DMSO and stirred for 24 hours. The reaction mixture was then diluted with 1.0 M NaOH. (水性) Dilute (800ml). Extract the aqueous phase three times with DCM (75mL). Combine the organic extracts, dry with Na2SO4, filter, and concentrate under reduced pressure to obtain a colorless oil. Dilute the crude oil with 9:1 DCM:MeOH (containing 1% ammonium hydroxide). （水性） Rapid chromatographic elution purification was performed. 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). A precipitate formed immediately; the mixture was filtered and washed with ice-cold acetone to obtain the desired product. If no precipitate formed, the mixture was concentrated to promote crystal formation, thus obtaining the desired product. (1:1 mixture: fumaric acid) 1 H NMR (400 MHz, DMSO- d 6) δ 7.37 (d, 1H, J = 8.8 Hz), 7.30 (s, 1H), 7.03 (s, 1H, J = 3.1 Hz), 6.76(d, 1H, J = 8.8 Hz), 6.61 (s, 2H), 6.32 (s, 1H), 4.25 (dd, 1H J = 6.3, 7.8Hz), 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- d 4) δ171.0, 155.8, 136.1, 132.8, 130.9, 129.7, 113.3, 111.2, 103.8, 103.3, 61.6,56.2, 47.5, 39.9, 11.7 ppm. Example 33. (R)-1-(5-fluoro-1H-indol-1-yl)-N,N-dimethylpropane-2-amine fumarate 5-Fluoro-indole (100 mg, 0.739 mmol), (R)-1-chloro-N,N-dimethylpropane-2-amine (128 mg, 0.814 mmol, 1.1 equivalents), potassium iodide (135 mg, 0.814 mmol, 1.1 equivalents), and potassium hydroxide (166 mg, 15.8 mmol, 5.0 equivalents) were placed in 8.49 mL of DMSO and stirred for 24 hours. The reaction mixture was then diluted with 1.0 M NaOH. (水性) Dilute (100 ml). Extract the aqueous phase three times with DCM (25 mL). Combine the organic extracts, dry with Na2SO4, filter, and concentrate under reduced pressure to obtain a colorless oil. Dilute the crude oil with 9:1 DCM:MeOH (containing 1% ammonium hydroxide). （水性） Rapid chromatographic elution purification was performed. 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 equivalent) in acetone (5 mL). A precipitate formed immediately, which was filtered and washed with ice-cold acetone to obtain the desired product. If no precipitate formed, the mixture was concentrated to promote crystal formation, thus obtaining the desired product. (1:1 mixture: fumaric acid) (111 mg, 68%) 1 H NMR (400 MHz, MeOD- d 4) δ 7.50 (dd, 1H, J = 4.3, 4.6 Hz), 7.36 (d, 1H, J = 3.0 Hz), 7.28 (dd, 1H, J = 2.0, 9.2Hz), 7.01 (td, 1H, J = 2.0, 9.2 Hz),6.74 (s, 1H), 6.55 (d, 1H, J = 3.0 Hz), 4.63 (dd, 1H J = 6.9, 8.5, 5.2 Hz),4.38 (dd, 1H, J = 8.8, 5.7, 8.59 Hz), 3.92 (m, 1H,) 2.89 (s, 6H), 1.25 (d,3H, J = 6.7 Hz). 13C NMR (100 MHz, MeOD-d4) δ 170.9, 136.0, 131.0, 111.4,111.3, 111.1, 106.7, 106.5, 103.6, 103.5, 61.6, 47.7, 40.2, 11.8 ppm. Example 34. 1-(1H-indol-1-yl)-N,N-dimethylpropane-2-amine Synthesize according to step A. 1 H 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 = 7.6Hz), 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 = 6.7Hz). Example 35. (R)-1-(1H-indol-1-yl)-N,N-dimethylpropane-2-amine Synthesize according to step 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 =6.7Hz ). Example 36. (R)-1-(6-fluoro-1H-indol-1-yl)-N,N-dimethylpropane-2-amine Synthesize according to step A. 1H NMR (600 MHz, CDCL3) δ 7.40 (dd, 1H, J = 5.5, 3.1Hz), 6.98 (d, 1H, J = 3.1 Hz), 6.91 (d, 1H, J = 11.8 Hz), 6.74 (t, 1H, J =9.0 Hz), 6.35 (d, 1H, J = 3.1 Hz) 4.10 (dd, 1H, J = 8.5, 5.6 Hz), 3.74 (dd,1H, J = 8.5, 5.6 Hz), 2.91 (m, 1H), 2.20 (s, 6H), 0.79 (d, 3H, J = 6.6Hz). Example 37. (R)-1-(4-methoxy-1H-indol-1-yl)-N,N-dimethylpropane-2-amine Synthesize according to step A. 1 H 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 = 8.01Hz), 4.16 (dd, 1H, J = 8.5, 5.5 Hz), 3.83 (s, 3H), 3.77(dd, 1H, J = 8.5, 5.5Hz), 2.94 (m, 1H), 2.23 (s, 6H), 0.79 (d, 3H, J = 6.5Hz). Example 38. (R)-1-(7-methoxy-1H-indol-1-yl)-N,N-dimethylpropane-2-amine Synthesize according to step 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 = 6.7Hz). Example 39. (R)-1-(9H-carbazol-9-yl)-N,N-dimethylpropane-2-amine Synthesize according to step A. 1 H 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 = 6.6Hz). Example 40. (R)-1-(1H-benzo[d]imidazol-1-yl)-N,N-dimethylpropane-2-amine Synthesize according to step A. 1 H NMR (600 MHz, CDCL3) δ 7.72 (s, 1H), 7.16 (d, 1H, J= 7.6 Hz), 7.32 (d, 1H, J = 11.8 Hz), 6.91 (m, 3H), 4.05 (dd, 1H, J = 7.5,6.7 Hz), 4.10 (dd, 1H, J = 7.5, 6.7 Hz), 3.79 (dd, 1H, J = 8.5, 5.6 Hz), 2.86 (m, 1H), 2.06 (s, 6H), 0.69 (d, 3H, J = 6.6Hz). Example 41. N-Methyl-2-(1-methyl-1H-indol-3-yl)ethane-1-amine (2-(1H-indol-3-yl)ethyl)carbamate tert-butyl ester. Boc₂O (0.77 g, 3.7 mmol, 1.2 equivalents) was added to an ice-cold CH₂Cl₂ (44 mL) solution of tryptamine (0.50 g, 3.1 mmol) and triethylamine (0.68 mL, 9.4 mmol, 3 equivalents). The reaction was heated to room temperature and stirred overnight, then quenched with water (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 oily substance, which did not require further purification.

[0212] N-Methyl-2-(1-Methyl-1H-indol-3-yl)ethane-1-amine.To a solution of sodium hydride (0.23 g, 5.8 mmol, 2.2 equivalences) in ice-cold DMF (3 mL), tert-butyl (2-(1H-indol-3-yl)ethyl)carbamate (0.69 g, 2.6 mmol) was added. The reaction mixture was stirred at room temperature and cooled to 0 °C. Then, iodomethane (0.4 mL, 5.8 mmol, 2.2 equivalences) was added dropwise. The reaction was stirred at room temperature for 20 hours. Then, the reaction mixture was cooled to 0 °C, quenched with TFA (2 mL), and stirred for 30 minutes. The mixture was then treated with 1.0 M NaOH. (水性) Dilute (600 mL) and extract with CH2Cl2 (3 x 75 mL). Combine the organic phases, dry with Na2SO4, filter, and concentrate under reduced pressure to obtain an oily substance, which requires no further purification.

[0213] Step B General synthesis scheme General Step-1 (GP-B1): At 0°C, add NaH (60% mineral oil, 1.2 equivalents) to a stirred solution of A (1.0 equivalents) in DMF (10 vol). Stir the reaction mixture at 0°C for 20 minutes. Add reagent B (1.0 equivalents) and NaI (catalyst) to the resulting reaction mixture. Slowly raise the temperature to room temperature and stir for 16 hours. Monitor the reaction progress using thin-layer chromatography.

[0214] Step-2 (GP-B2): At 0°C, NaH (60% mineral oil, 1.2 equivalents) was added to a stirred solution of A (1.0 equivalents) in 10 vol DMF. The reaction mixture was stirred at 0°C for 20 minutes. Reagent B (1.0 equivalents) and NaI (catalyst) were added to the resulting reaction mixture. The reaction was slowly heated to room temperature and stirred at 60–65°C for 16 hours. The reaction progress was monitored by thin-layer chromatography.

[0215] Step-3 (GP-B3): At room temperature, K₂CO₃ (3 equivalents) was added to a stirred solution of A (1.0 equivalents) in DMF (10 vol), followed by reagent B (2.0 equivalents) and NaI (1.0 equivalents). The contents were then heated at 70°C for 16 hours. The reaction progress was monitored by thin-layer chromatography.

[0216] General Processing / Purification Steps - B1: Dilute and quench the reaction with ice-cold water. Add 2N HCl solution until the pH of the solution is 2. Wash the resulting aqueous layer with EtOAc until all unreacted starting material is removed (TLC). Adjust the aqueous layer to alkalinity with NaHCO3 solution and extract with ethyl acetate. Combine the organic layers and wash with water and saturated brine, then dry with anhydrous Na2SO4 and concentrate to obtain the desired product of sufficient purity (LC-MS and HPLC purity >95%).

[0217] General Processing / Purification Steps - B2: Quench the reaction mixture with ice water and extract with ethyl acetate. Combine the organic layers and wash with ice water, then with brine. Separate the organic phase, dry with Na₂SO₄, and concentrate under reduced pressure to obtain the crude product. Purify the crude product by combi-flash chromatography using an ethyl acetate / n-heptane or dichloromethane / methanol gradient, based on the polarity of the compound. Distill to obtain the pure fraction, dry to obtain the compound, with LC-MS and HPLC purity >95%.

[0218] Example 42. 2-(5-methoxy-1H-indol-1-yl)-N,N-dimethylethane-1-amine Synthesize according to step B, then proceed according to GP-1 and treatment / purification step 1. Yield: 44% (brown liquid). LC-MS: 97.8%, m / z = 219.2 [M+H] + 1 H NMR (DMSO- d 6, 400 MHz): δ 7.30-7.37 (m, 2H), 7.03(d, J =2.4 Hz, 1H), 6.76 (dd, J =2.4, 8.8 Hz, 1H), 6.30 (dd, J =0.4, 2.8 Hz, 1H), 4.19 (t, J =6.8 Hz, 2H), 3.74 (s, 3H), 2.57 (t, J =6.8 Hz, 2H), 2.17 (s, 6H). Example 43. 2-(6-methoxy-1H-indol-1-yl)-N,N-dimethylethane-1-amine Synthesize according to step B. Then proceed according to GP-1 and treatment / purification step-1. Yield: 44% (brown liquid). LC-MS: 95.4%, m / z = 219.2 [M+H] + 1 H 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-pyrrolidone-1-yl)ethyl)-1H-indole Synthesized according to step B. GP-1 and processing / purification procedure-1. Yield: 16% (yellow semi-solid). LC-MS: 98.2%, m / z = 245.2 [M+H] + 1 H NMR (DMSO- d 6, 400 MHz): δ 7.30-7.36 (m, 2H), 7.03 (d, J =2.45 Hz, 1H), 6.76 (dd, J = 2.38, 8.86 Hz, 1H), 6.31 (d, J = 3.06 Hz, 1H), 4.21 (t, J = 6.79 Hz, 2H), 3.74 (s, 3H), 2.75 (t, J = 6.72 Hz, 2H), 2.43-2.47(m, 4H), 1.65 (td, J =3.15, 6.66 Hz, 4H). Example 45. 5-Methoxy-1-(2-piperidin-1-yl)ethyl)-1H-indole Synthesize according to step B, then proceed according to GP-1 and treatment / purification step 1. Yield: 34% (brown solid). LC-MS: 99.5%, m / z = 259.2 [M+H] + 1 H NMR (DMSO- d 6,400 MHz): δ 7.30-7.36 (m, 2H), 7.02(d, J = 2.32 Hz, 1H), 6.75 (dd, J = 2.45, 8.80 Hz, 1H), 6.29-6.31 (m, 1H), 4.20 (t, J = 6.79 Hz, 2H), 3.74 (s, 3H), 2.55-2.60 (m, 2H), 2.32-2.42 (m,4H), 1.46 (quin, J = 5.41 Hz, 4H), 1.33-1.39 (m, 2H). Example 46. 4-(2-(5-methoxy-1H-indol-1-yl)ethyl)morpholine Synthesize according to step B, then proceed according to GP-1 and treatment / purification step-1. Yield: 28% (brown solid). LC-MS: 99.5%, m / z = 261.2 [M+H] + 1 H NMR (DMSO- d 6, 400 MHz): δ 7.31-7.37 (m, 2H), 7.02(d, J = 2.45 Hz, 1H), 6.76 (dd, J = 2.45, 8.80 Hz, 1H), 6.31 (dd, J = 0.67, 3.00 Hz, 1H), 4.23 (t, J = 6.66 Hz, 2H), 3.74 (s, 3H), 3.51-3.55 (m, 4H), 2.62 (t, J = 6.66 Hz, 2H), 2.38-2.42 (m, 4H). Example 47. 5-Chloro-1-(2-pyrrolidone-1-yl)ethyl)-1H-indole Synthesize according to step B. Then proceed according to GP-1 and treatment / purification step-1. Yield: 28% (brown liquid). LC-MS: 97%, m / z = 248.11 [M+H] + 1 H NMR (DMSO- d 6, 400 MHz): δ 7.57 (d, J= 1.96 Hz, 1H), 7.50 (d, J = 8.80 Hz, 1H), 7.46 (d, J = 3.06 Hz, 1H), 7.11 (dd, J = 2.08,8.80 Hz, 1H), 6.40 (dd, J = 0.61, 3.06 Hz, 1H), 4.27 (t, J = 6.60 Hz, 2H), 2.77 (t, J = 6.60 Hz, 2H), 2.45 (br s, 4H), 1.64 (td, J = 3.16, 6.76 Hz, 4H). Example 48. 5-Chloro-1-(2-piperidin-1-yl)ethyl)-1H-indole Synthesize according to step B. Then proceed according to GP-1 and treatment / purification step-2. Yield: 20% (yellow semi-solid). LC-MS: 95.18%, m / z = 263.2 [M+H] + 1 H NMR (DMSO- d 6, 400 MHz): δ 7.57 (d, J = 1.96 Hz, 1H), 7.50 (d, J = 8.68 Hz, 1H), 7.45 (d, J = 3.06 Hz, 1H), 7.11(dd, J = 1.77, 8.74 Hz, 1H), 6.40 (d, J = 2.81 Hz, 1H), 4.26 (br s, 2H), 2.53-2.62 (m, 2H), 2.32-2.43 (m, 4H), 1.32-1.50 (m, 6H). Example 49. 4-(2-(5-chloro-1H-indol-1-yl)ethyl)morpholine Synthesize according to step B. Then proceed according to GP-1 and treatment / purification step-1. Yield: 28% (colorless liquid). LC-MS: 98.9%, m / z = 265.2 [M+H] + 1 H NMR (DMSO- d 6,400 MHz): δ 7.57 (d, J = 1.83 Hz, 1H), 7.52 (d, J = 8.80 Hz, 1H), 7.47 (d, J = 3.18 Hz, 1H), 7.12 (dd, J =1.83, 8.68 Hz, 1H), 6.41 (d, J = 2.81 Hz, 1H), 4.28 (br t, J = 5.75 Hz, 2H), 3.52 (br s, 4H), 2.60-2.67 (m, 2H), 2.40 (br s, 4H). Example 50. 1-(2-(pyrrolidone-1-yl)ethyl)-5-(trifluoromethoxy)-1H-indole Synthesize according to step B, then proceed according to GP-2 and treatment / purification step-2. 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-(piperidin-1-yl)ethyl)-5-(trifluoromethoxy)-1H-indole Synthesize according to step B, then proceed according to GP-1 and treatment / purification step-2. Yield: 25% (brown liquid). LC-MS: 99.6%, m / z = 313.2 [M+H] + 1 H NMR (DMSO- d 6, 400 MHz): δ 7.54-7.59 (m, 1H), 7.51(d,J =3.06 Hz, 2H), 7.08 (dd, J =1.34, 8.93 Hz, 1H), 6.48 (dd, J =0.61, 3.06Hz, 1H), 4.28 (t, J =6.66 Hz, 2H), 2.60 (t, J =6.66 Hz, 2H), 2.37 (br d, J =4.40Hz, 4H), 1.45 (quin, J =5.41 Hz, 4H), 1.32-1.40 (m, 2H). Example 52. 4-(2-(5-trifluoromethoxy)-1H-indol-1-yl)ethyl)morpholine Synthesize according to step B. Then proceed according to GP-2 and treatment / purification step-2. Yield: 22% (brown liquid). LC-MS: 98.27%, m / z = 315.2 [M+H] + 1 H NMR (DMSO- d 6, 400 MHz): δ 7.59 (d, J =8.93 Hz, 1H),7.50-7.54 (m, 2H), 7.09 (dd, J =1.16, 8.99 Hz, 1H), 6.49 (d, J =2.93 Hz, 1H), 4.31 (t, J =6.54 Hz, 2H), 3.50-3.57 (m, 4H), 2.65 (br t, J =6.54 Hz, 2H), 2.42(br s, 4H). Example 53. 2-(4-methoxy-1H-indol-1-yl)-N,N-dimethylethane-1-amine Synthesize according to step B. Then proceed according to GP-1 and treatment / purification step-1. Yield: 27% (brown liquid). LC-MS: 98.9%, m / z = 219.2 [M+H] + 1 H NMR (DMSO- d 6,400 MHz): δ 7.25 (d, J=3.18 Hz, 1H),7.02-7.07 (m, 2H), 6.49-6.52 (m, 1H), 6.38-6.40 (m, 1H), 4.20 (t, J=6.72 Hz,2H), 3.85 (s, 3H), 2.55-2.60 (m, 2H), 2.17 (s, 6H). Example 54. 2-(7-methoxy-1H-indol-1-yl)-N,N-dimethylethane-1-amine Synthesize according to step B. Then proceed according to GP-1 and treatment / purification step-1. Yield: 27% (brown liquid). LC-MS: 98.8%, m / z = 219.2 [M+H] + 1 H NMR (DMSO- d 6, 400 MHz): δ 7.24 (d, J =3.06 Hz, 1H),7.07-7.11 (m, 1H), 6.89 (t, J =7.82 Hz, 1H), 6.64 (d, J =7.70 Hz, 1H), 6.33 (d, J =3.06 Hz, 1H), 4.42 (t, J =6.97 Hz, 2H), 3.88 (s, 3H), 2.56 (t, J =6.97 Hz, 2H), 2.18 (s, 6H). Example 55. 2-(5-methoxy-1H-benzo[d]imidazol-1-yl)-N,N-dimethylethane-1-amine Example 56. 2-(6-methoxy-1H-benzo[d]imidazol-1-yl)-N,N-dimethylethane-1-amine Synthesized according to step B. Example 55 was performed with a slight modification to CP-2 (using 1 eq NaI). Subsequent processing / purification step-2 yielded the regiomers of the mixture. The mixture was separated using the normal-phase chiral high-performance liquid chromatography purification method described below. NOE analysis confirmed the two structures.

[0219] Pillar: Chiralpak IC (250m x 4.6mm, 5μm) Mobile phase: 0.1% DEA / n-hexane Mobile phase B: DCM:MEOH (80:20) Option: A:B: 80:20 Flow rate: 1.0 ml / min.

[0220] Yield: 10% (pale yellow solid). LCMS: 99.8%, m / z = 220.1 [M+H] + 1 H NMR (DMSO- d 6, 400 MHz): δ 8.11 (s, 1H), 7.48 (d, J =8.80 Hz, 1H), 7.15 (d, J =2.32 Hz, 1H), 6.87 (dd, J =2.32, 8.80 Hz, 1H), 4.27 (t, J =6.30 Hz, 2H), 3.77 (s, 3H), 2.62(t, J =6.24 Hz, 2H), 2.17 (s, 6H). Example 57. 2-(1H-benzo[d]imidazol-1-yl)-N,N-dimethylethyl-1-amine Synthesize according to step B. Then proceed according to GP-2 and treatment / purification step-1. Yield: 4% (colorless liquid). LCMS: 99.7%, m / z = 190.2 [M+H] + 1 H NMR (DMSO- d 6, 400 MHz): δ 8.20 (s, 1H), 7.62 (dd, J =7.95, 12.47 Hz, 2H), 7.16-7.27 (m, 2H), 4.32 (t, J =6.36 Hz, 2H), 2.64 (t, J =6.30 Hz, 2H), 2.18 (s, 6H). Example 58. N,N-Dimethyl-2-(2-methyl-1H-benzo[d]imidazol-1-yl)ethane-1-amine Synthesize according to step B. Then proceed according to GP-3 and treatment / purification step-2. Yield: 15% (yellow liquid). LCMS: 98.3%, m / z = 204.2 [M+H] + 1 H NMR (DMSO- d 6,400 MHz): δ 7.44-7.51 (m, 2H), 7.09-7.19 (m, 2H), 4.24 (t, J =6.66 Hz, 2H), 2.53-2.57 (m, 5H), 2.19 (s, 6H). Step C General synthesis scheme: General synthesis steps: Step C1: At 0°C, add NaH (60% mineral oil, 1.2 equivalents) to a stirred DMF (10 mL) solution of compound D (1.0 equivalent). Stir the reaction mixture for 20 minutes, then add compound E (1.0 equivalent). Slowly heat the reaction to room temperature, then stir at the same temperature for 16 hours. Monitor the reaction progress using thin-layer chromatography.

[0221] Processing and purification after step C1: The reaction mixture was quenched with ice water and extracted with ethyl acetate. The organic layers were combined and washed with ice water, then with an aqueous NaCl solution. The organic layers were separated, dried with Na₂SO₄, and concentrated to obtain the crude product. The crude product was purified by combi-flash with 10-20% ethyl acetate / n-hexane, then the purer fraction was distilled (by TLC) and dried under reduced pressure to give compound F.

[0222] Step C2: Add triethylamine (2.5 equivalents) to a 10 vol solution of compound F (1 equivalent) in dichloromethane under stirring, and cool the resulting solution to 0°C. Add formyl chloride (1.5 equivalents) to the above solution, heat to room temperature, and stir for 1 to 2 hours. Monitor the reaction progress using thin-layer chromatography.

[0223] Post-treatment in step C2: Quench the reaction mixture with ice water and extract with dichloromethane. Combine the organic layers and wash successively with saturated aqueous bicarbonate solution and water. Separate the organic layers, dry with anhydrous Na₂SO₄, and concentrate the crude product compound G, which can be used directly in the next reaction without purification.

[0224] Step C3: Add compound G (1 eq), DMF (2 vol), and 40% dimethylamine aqueous solution (10 vol) sequentially to a sealed tube, and heat at 65°C for 1-2 days. Monitor the reaction progress using thin-layer chromatography.

[0225] Post-C3 processing and purification: The reaction was quenched with water and extracted with EtOAc. The organic layer was separated and washed successively with water and saturated brine. The organic layer was dried with anhydrous Na2SO4, and the concentrated crude product was purified by combi-flash extraction with 5-10% ethyl acetate / dichloromethane or 5-10% methanol / dichloromethane. Then, the purer fraction was distilled (by TLC) and dried under reduced pressure to obtain the target compound.

[0226] Example 59. (R)-1-(5-methoxy-1H-indol-1-yl)-N,N-dimethylpropane-2-amine Step-C1: Yield: 71% (light brown liquid). 1 H NMR (DMSO- d 6, 400 MHz): δ 7.35 (d, J =8.93 Hz, 1H), 7.27 (d, J =3.06 Hz, 1H), 7.02 (d, J =2.32 Hz, 1H), 6.74 (dd, J =2.45, 8.80 Hz, 1H), 6.29-6.32 (m, 1H), 4.85 (d, J =4.77 Hz, 1H), 3.99-4.07 (m,2H), 3.90-3.98 (m, 1H), 3.74 (s, 3H), 1.01 (d, J =6.11 Hz, 3H). Step-C2: Yellow solid. 1 H NMR (DMSO- d 6, 400 MHz): δ 7.45 (d, J =8.93 Hz, 1H), 7.33 (d, J =3.06 Hz, 1H), 7.04 (d, J =2.32 Hz, 1H), 6.80 (dd, J =2.32, 8.93 Hz, 1H), 6.38 (d, J =2.93 Hz, 1H), 4.92-5.01 (m, 1H), 4.34-4.40 (m, 2H), 3.75 (s, 3H), 2.54 (s, 3H), 1.33 (d, J =6.24 Hz, 3H). Step C3: Yield: 16% (after two steps, brown liquid). [α] D 20 = -14.6 (C 0.5, CH2Cl2). LC-MS: 99.4%, m / z=233.2 [M+H] + 1 H NMR (DMSO- d 6, 400 MHz): δ 7.27-7.36 (m, 2H),7.02 (d, J =2.32 Hz, 1H), 6.75 (dd, J =2.38, 8.86 Hz, 1H), 6.28-6.32 (m, 1H), 4.18 (dd, J =6.72, 14.18 Hz, 1H), 3.92-3.99 (m, 1H), 3.74 (s, 3H), 2.92-3.02(m, 1H), 2.19 (s, 6H), 0.79 (d, J =6.60 Hz, 3H). Example 60. (R)-1-(5-fluoro-1H-indol-1-yl)-N,N-dimethylpropane-2-amine Step-C1: Yield: 50% (light brown liquid). 1 H NMR (DMSO- d 6, 400 MHz): δ 7.50 (dd, J =4.52, 8.93 Hz, 1H), 7.41 (d, J =3.06 Hz, 1H), 7.26-7.31 (m, 1H), 6.92-6.99 (m,1H), 6.39-6.42 (m, 1H), 3.93-4.03 (m, 2H), 3.12-3.21 (m, 1H), 0.92 (d, J =6.36Hz, 3H). Step C2: Prepare methanesulfonate using the general method described above, then treat with NaN 3 (1.5 equivalents) in DMF (10 volumes) at 70°C for 2 hours. Monitor the reaction progress using thin-layer chromatography. After the reaction is complete, dilute the reaction mixture with water and extract with EtOAc. Combine the organic layers, wash twice with cold water, and concentrate to obtain the crude product. Treat the crude product with 10% Pd / C (50% wet) MeOH under hydrogen to obtain the crude amine. Purify the crude amine by combi-flas chromatography with 1% MeOH / CH2Cl2, and distill the purer fraction to obtain the amine. Treat the amine with a solution of paraformaldehyde (10 equivalents) in MeOH / DCM (10 vol, 2:1), then add AcOH (catalyst) and NaBH3CN (6.0 equivalents), and stir for 1 hour. Monitor the reaction progress using thin-layer chromatography. After water treatment, the compound was first purified by prep-HPLC and then by combi-flash chromatography to obtain the above compound with a separation yield of 30%.

[0227] The preparation-HPLC purification method is shown below: Preparative HPLC column; YMC Triat Actus C18 (250*20mm), 5µm Mobile phase A: Acetonitrile Mobile phase B: 5mM ammonium bicarbonate Flow rate: 15.0 mL / min Gradient table: Solvent used for dilution: Acetonitrile / MeOH Yield: 30% (brown liquid). [α] D 20 = -15.9 (C 0.5, CH2Cl2). LC-MS: 99.5%, m / z=221.2 [M+H] + 1 H NMR (DMSO- d 6, 400 MHz): δ 7.40-7.49 (m, 2H), 7.28 (dd, J =2.51,9.96 Hz, 1H), 6.92-6.98 (m, 1H), 6.39 (dd, J =0.61, 3.06 Hz, 1H), 4.18-4.25(m, 1H), 4.01 (dd, J=7.27, 14.24 Hz, 1H), 2.94-3.03 (m, 1H), 2.19 (s, 6H),0.81 (d, J =6.60 Hz, 3H). 19 F NMR (DMSO- d 6, 376 MHz): δ -127.18 (s, 1F). Example 61. (R)-1-(6-fluoro-5-methoxy-1H-indol-1-yl)-N,N-dimethylpropane-2-amine Step-C1: Yield: 74% (brown liquid). 1 H NMR (DMSO- d 6, 400 MHz): δ 7.39 (d, J =12.23 Hz, 1H), 7.27 (d, J =3.06 Hz, 1H), 7.18-7.22 (m, 1H), 6.34 (dd, J =0.61, 3.06 Hz, 1H), 4.84 (d, J =4.77 Hz, 1H), 3.88-4.06 (m, 3H), 3.81 (s, 3H), 1.02(d, J =6.11 Hz, 3H). Step-C2: Brown solid. 1 H NMR (DMSO- d 6, 400 MHz): δ 7.52 (d, J =12.23 Hz, 1H), 7.33 (d, J =3.06 Hz, 1H), 7.22 (d, J =8.56 Hz, 1H), 6.41 (dd, J =0.67, 3.12Hz, 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). Step C3: Yield: 14% (after two steps, brown liquid). [α] D 20 = -19.7 (C 0.5, CH2Cl2).LC-MS: 98.5%, 251.2 [M+H]+ 1 H NMR (DMSO- d 6, 400 MHz): δ 7.38-7.44 (m, 1H), 7.30(d, J =3.18 Hz, 1H), 7.22 (d, J =8.56 Hz, 1H), 6.35 (d, J =2.57 Hz, 1H), 4.15(dd, J =7.09, 14.18 Hz, 1H), 3.96 (dd, J =7.15, 14.24 Hz, 1H), 3.83 (s, 3H), 2.93-3.03 (m, 1H), 2.20 (s, 6H), 0.81 (d, J =6.60 Hz, 3H). 19 F NMR (DMSO-d 6, 376MHz): δ -142.08 (s, 1F). Example 62. (R)-1-(5,6-dimethoxy-1H-indol-1-yl)-N,N-dimethylpropane-2-amine Step-C1: Yield: 50% (light brown liquid). 1 H NMR (DMSO- d 6, 400 MHz): δ 7.13 (d, J =3.06 Hz, 1H), 7.03 (d, J =7.21 Hz, 2H), 6.23-6.26 (m, 1H), 4.84 (d, J =4.65 Hz,1H), 3.91-4.01 (m, 3H), 3.79 (s, 3H), 3.73 (s, 3H), 1.02 (d, J =5.99 Hz, 3H). Step-C2: Light brown semi-solid. 1 H NMR (DMSO- d 6, 400 MHz): δ 7.18 (d, J =3.18 Hz,1H), 7.14 (s, 1H), 7.04 (s, 1H), 6.32 (d, J=3.06 Hz, 1H), 4.93-5.02 (m, 1H), 4.30-4.42 (m, 2H), 3.81 (s, 3H), 3.74 (s, 3H), 2.56 (s, 3H), 1.34 (d, J =6.36Hz, 3H). Step C3: Yield: 18% (after two steps, brown liquid). LC-MS: 94.8%, 263.2 [M+H] + 1 H NMR (DMSO- d 6, 400 MHz): δ 7.14 (d, J =3.06 Hz, 1H), 6.99-7.03 (m, 2H), 6.25 (dd, J =0.61, 3.06 Hz, 1H), 4.12-4.19 (m, 1H), 3.91-3.98 (m, 1H), 3.72-3.81 (m, 6H), 2.93-3.02 (m, 1H), 2.21 (s, 6H), 0.81 (d, J =6.60 Hz, 3H). Example 63. (R)-1-(5,7-dimethoxy-1H-indol-1-yl)-N,N-dimethylpropane-2-amine Step-C1: Yield: 35% (colorless liquid). 1 H NMR (DMSO- d 6, 400 MHz): δ 7.10-7.16 (m,1H), 6.58-6.61 (m, 1H), 6.27-6.30 (m, 1H), 4.74 (d, J =5.14 Hz, 1H), 4.09-4.32(m, 2H), 3.83-3.92 (m, 4H), 3.71-3.73 (m, 3H), 0.91-1.00 (m, 3H). Step-C2: Pale yellow, semi-solid. 1 H NMR (DMSO- d 6, 400 MHz): δ 7.14-7.20 (m, 1H),6.61 (d, J =2.08 Hz, 1H), 6.35 (d, J=2.08 Hz, 1H), 6.29-6.32 (m, 1H), 4.87-4.95 (m, 1H), 4.41-4.52 (m, 2H), 3.85-3.89 (m, 3H), 3.72-3.74 (m, 3H), 2.56(s, 3H), 1.23-1.35 (m, 3H). Step C3: Yield: 25% (after two steps, brown liquid). [α] D 20 = -22.94 (C 0.25, CH2Cl2).LC-MS: 99.25%, 263.2 [M+H] + 1 H NMR (DMSO- d 6, 400 MHz): δ 7.13 (d, J =2.93 Hz, 1H), 6.58 (d, J =2.08 Hz, 1H), 6.29 (d, J =1.96 Hz, 1H), 6.23 (d, J =2.93 Hz, 1H), 4.38 (dd, J =6.30, 13.63 Hz, 1H), 4.06 (dd, J =7.83, 13.57 Hz, 1H), 3.85(s, 3H), 3.72 (s, 3H), 2.88-2.97 (m, 1H), 2.20 (s, 6H), 0.73 (d, J =6.72 Hz, 3H). Example 64. (R)-1-(5-methoxy-6-methyl-1H-indol-1-yl)-N,N-dimethylpropane-2-amine Step-C1: Yield: 83% (colorless liquid). 1 H NMR (DMSO- d 6, 400 MHz): δ 7.25 (s, 1H),7.19 (br d, J =2.81 Hz, 1H), 7.00 (s, 1H), 6.29 (br d, J =2.45 Hz, 1H), 4.84(br d, J=4.40 Hz, 1H), 3.92-4.03 (m, 3H), 3.79 (s, 3H), 2.26 (s, 3H), 1.03(br d, J =5.87 Hz, 3H). Step-C2: Pale yellow, semi-solid. 1 H NMR (DMSO- d 6, 400 MHz): δ 7.34 (s, 1H), 7.23(d, J =3.06 Hz, 1H), 7.00 (s, 1H), 6.34 (dd, J =0.73, 3.06 Hz, 1H), 4.91-4.98(m, 1H), 4.31-4.35 (m, 2H), 3.77 (s, 3H), 3.35 (s, 3H), 2.25 (s, 3H), 1.34(d, J =6.24 Hz, 3H). Step C3: Yield: 8% (after two steps, light brown liquid). [α] D 20 = -19.10 (C 0.125, CH2Cl2).LC-MS: 99%, 247.2 [M+H] + 1 H NMR (DMSO- d 6, 400 MHz): δ 7.17-7.22 (m, 2H), 6.98 (s, 1H), 6.26-6.27 (m, 1H), 4.14 (dd, J =6.66, 14.12 Hz, 1H), 3.93 (dd, J =7.58, 14.18 Hz, 1H), 3.77 (s, 3H), 2.93-3.02 (m, 1H), 2.25 (s, 3H), 2.20 (s,6H), 0.79 (d, J =6.60 Hz, 3H). Example 65. (R)-1-(5-methoxy-7-methyl-1H-indol-1-yl)-N,N-dimethylpropane-2-amine Step-C1: Yield: 75% (light brown liquid). 1 H NMR (DMSO- d 6,400 MHz): δ 7.18 (d, J =3.06 Hz, 1H), 6.84 (d, J =2.45 Hz, 1H), 6.49 (d, J =2.08 Hz, 1H), 6.27 (d, J =3.06 Hz, 1H), 4.87 (d, J =5.14 Hz, 1H), 4.16 (dd, J =2.14, 6.17 Hz, 2H), 3.81-3.89 (m, 1H), 3.71 (s, 3H), 2.60 (s, 3H), 1.02 (d, J =6.11 Hz, 3H). Step C2: Pale yellow syrup. 1 H NMR (DMSO- d 6, 400 MHz): δ 7.27 (d, J =3.06 Hz, 1H), 6.86 (d, J =2.45 Hz, 1H), 6.54-6.56 (m, 1H), 6.35-6.37 (m, 1H), 4.82-4.90(m, 1H), 4.48-4.52 (m, 2H), 3.72 (s, 3H), 2.61 (s, 3H), 2.41 (s, 3H), 1.34(d, J =6.36 Hz, 3H). Step C3: Yield: 11% (after two steps, brown liquid). [α] D 20 = -6.34 (C 0.5, CH2Cl2). LC-MS: 99.43%, 247.2 [M+H] + 1 H NMR (DMSO- d 6, 400 MHz): δ 7.17 (d, J =3.06 Hz, 1H), 6.84 (d, J =2.45 Hz, 1H), 6.50 (d, J =1.96 Hz, 1H), 6.26 (d, J =3.06 Hz, 1H), 4.35 (dd, J=6.05, 14.37 Hz, 1H), 4.05-4.12 (m, 1H), 3.71 (s, 3H), 2.81-2.90(m, 1H), 2.60 (s, 3H), 2.19 (s, 6H), 0.74 (d, J =6.60 Hz, 3H).

[0228] Example 66. (R)-1-(5-methoxy-3-methyl-1H-indol-1-yl)-N,N-dimethylpropane-2-amine Step-C1: Yield: 70% (light brown liquid).

[0229] Step-C2: Pale yellow, semi-solid.

[0230] Step C3: Yield: 19% (after two steps). [α] D 20 = -1.82 (C 0.5, CH2Cl2). LC-MS: 99.76%, 247.1 [M+H] + 1 H NMR (DMSO- d 6, 400 MHz): δ 7.28 (d, J =8.80 Hz, 1H),7.06 (s, 1H), 6.94 (d, J =2.45 Hz, 1H), 6.74 (dd, J =2.45, 8.80 Hz, 1H), 4.07-4.14 (m, 1H), 3.85-3.92 (m, 1H), 3.76 (s, 3H), 2.88-2.98 (m, 1H), 2.18-2.22(m, 9H), 0.78 (d, J =6.60 Hz, 3H).

[0231] Example 67. (R)-1-(4,5-difluoro-1H-indol-1-yl)-N,N-dimethylpropane-2-amine Step-C1: Yield: 58% (light brown liquid). 1 H NMR (DMSO- d 6, 400 MHz): δ 7.45 (d, J =3.18 Hz, 1H), 7.33 (dd, J=3.42, 9.05 Hz, 1H), 7.09-7.17 (m, 1H), 6.53 (dd, J =0.79, 3.12 Hz, 1H), 4.89 (d, J =4.77 Hz, 1H), 4.10-4.16 (m, 1H), 4.00-4.07 (m,1H), 3.90-3.99 (m, 1H), 1.04 (d, J =6.24 Hz, 3H).

[0232] Step-C2: Brown liquid. 1 H NMR (DMSO- d 6, 400 MHz): δ 7.51 (d, J =3.18 Hz, 1H),7.40-7.44 (m, 1H), 7.16-7.24 (m, 1H), 6.61 (dd, J =0.86, 3.18 Hz, 1H), 4.96-5.04 (m, 1H), 4.43-4.47 (m, 2H), 2.65 (s, 3H), 1.34 (d, J =6.36 Hz, 3H).

[0233] Step C3: Yield: 30% (after 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- d 6, 400 MHz): δ 7.48 (d, J =3.06Hz, 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).

[0234] Example 68. (R)-1-(5,6-difluoro-1H-indol-1-yl)-N,N-dimethylpropane-2-amine Step-C1: Yield: 63% (light brown liquid). 1 H NMR (DMSO- d 6, 400 MHz): δ 7.57-7.63(m, 1H), 7.50 (dd, J =8.07, 11.37 Hz, 1H), 7.39 (d, J =3.18 Hz, 1H), 6.41 (dd, J =0.73, 3.18 Hz, 1H), 4.86 (d, J =4.89 Hz, 1H), 4.06-4.12 (m, 1H), 3.89-4.02(m, 2H), 1.04 (d, J =6.11 Hz, 3H).

[0235] Step-C2: Pale yellow semi-solid. 1 H NMR (DMSO- d 6, 400 MHz): δ 7.71 (dd, J =6.97,11.62 Hz, 1H), 7.51-7.57 (m, 1H), 7.44-7.46 (m, 1H), 6.49 (dd, J =0.73, 3.18Hz, 1H), 4.94-5.02 (m, 1H), 4.39-4.43 (m, 2H), 2.61 (s, 3H), 1.34 (d, J =6.36Hz, 3H).

[0236] Step C3: Yield: 30% (after two steps, brown liquid). [α] D 20 = - 21.12 (C 0.5, CH2Cl2). LC-MS: 96.1%, m / z=239.2 [M+H] + 1 H NMR (DMSO- d 6, 400 MHz): δ 7.58-7.63 (m, 1H), 7.47-7.52 (m, 1H), 7.40-7.42 (m, 1H), 6.41 (dd,J =0.73, 3.06 Hz, 1H), 4.17(dd, J =7.52, 14.24 Hz, 1H), 3.96-4.03 (m, 1H), 2.94-3.04 (m, 1H), 2.18 (s,6H), 0.81 (d, J =6.60 Hz, 3H). 19 F NMR (DMSO- d 6, 376 MHz): δ -146.8 (d, J = 22.5Hz, 1F), -150.82 (d, J = 24.0 Hz, 1F).

[0237] Example 69. (R)-1-(5,7-difluoro-1H-indol-1-yl)-N,N-dimethylpropane-2-amine Step-C1: Yield: 57% (colorless liquid). 1 H NMR (CDCl 3, 400 MHz): δ 7.15 (d, J =3.06Hz, 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).

[0238] Step-C2: Yellow semi-solid.

[0239] Step C3: Yield: 50% (after two or more steps, colorless liquid). [α] D 20 = - 28.5 (C 0.5, CH2Cl2). LC-MS: 99.2%, m / z=239.1 [M+H] + 1 H NMR (DMSO- d 6, 400 MHz): δ 7.44 (d,J =3.06 Hz, 1H), 7.15-7.19 (m, 1H), 6.90-6.97 (m, 1H), 6.47 (t, J =2.69 Hz, 1H), 4.29-4.35 (m, 1H), 4.04-4.10 (m, 1H), 2.91-3.00 (m, 1H), 2.18 (s, 6H), 0.80(d, J =6.60 Hz, 3H). 19 F NMR (DMSO- d 6, 376 MHz): δ -124.28 (s, 1F), -132.87 (s, 1F).

[0240] Example 70. (R)-1-(5-fluoro-6-methoxy-1H-indol-1-yl)-N,N-dimethylpropane-2-amine Step-C1: Yield: 46% (colorless liquid).

[0241] Step-C2: Yellow semi-solid.

[0242] Step C3: Yield: 32% (after two steps, 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- d 6, 400 MHz): δ 7.24-7.32 (m, 2H), 7.17(d, J =7.34 Hz, 1H), 6.30 (d, J =2.93 Hz, 1H), 4.18 (dd, J =7.03, 14.24 Hz, 1H), 3.96-4.03 (m, 1H), 3.87 (s, 3H), 2.94-3.05 (m, 1H), 2.21 (s, 6H), 0.82 (d, J =6.60 Hz, 3H). 19 F NMR (DMSO- d 6, 376 MHz): δ -146.29 (s, 1F). Example 71. (R)-1-(5-fluoro-6-methyl-1H-indol-1-yl)-N,N-dimethylpropyl-2-amine Step-C1: Yield: 69% (light brown liquid). 1 H NMR (DMSO- d 6, 400 MHz): δ 7.33-7.37(m, 1H), 7.30 (d, J =3.06 Hz, 1H), 7.22 (d, J =10.64 Hz, 1H), 6.32-6.34 (m,1H), 4.84-4.87 (m, 1H), 3.91-4.08 (m, 3H), 2.32 (d, J =1.83 Hz, 3H), 1.03 (d, J =5.99 Hz, 3H).

[0243] Step-C2: Pale yellow solid. 1 H NMR (DMSO- d 6, 400 MHz): δ 7.46 (d, J =6.48 Hz, 1H), 7.36 (d, J =3.06 Hz, 1H), 7.25 (d, J =10.64 Hz, 1H), 6.39-6.41 (m, 1H), 4.94-5.02 (m, 1H), 4.32-4.43 (m, 2H), 2.56 (s, 3H), 2.33 (d, J =1.83 Hz, 3H), 1.34 (d, J =6.36 Hz, 3H).

[0244] Step C3: Yield: 24% (after two steps, light brown liquid). [α] D 20 = - 20.50 (C 0.5, CH2Cl2). LC-MS: 99.3%, m / z=235.1 [M+H] + . 1 H NMR (DMSO- d 6, 400 MHz): δ 7.30-7.35 (m, 2H),7.22 (d, J =10.64 Hz, 1H), 6.32 (d, J=3.06 Hz, 1H), 4.17 (dd, J =6.97, 14.18Hz, 1H), 3.97 (dd, J =7.34, 14.18 Hz, 1H), 2.95-3.04 (m, 1H), 2.33 (d, J =1.59Hz, 3H), 2.19 (s, 6H), 0.80 (d, J =6.60 Hz, 3H). 19 F NMR (DMSO- d 6, 376 MHz): δ -130.78 (s, 1F). Example 72. (R)-1-(5-fluoro-7-methyl-1H-indol-1-yl)-N,N-dimethylpropyl-2-amine Step-C1: Yield: 72%, light brown liquid. 1 H NMR (DMSO- d 6, 400 MHz): δ 7.30 (d, J =3.06 Hz, 1H), 7.09 (dd, J =2.51, 9.35 Hz, 1H), 6.72 (dd, J =2.20, 10.39 Hz, 1H), 6.36 (d, J =3.06 Hz, 1H), 4.89 (d, J =5.14 Hz, 1H), 4.16-4.25 (m, 2H), 3.81-3.91 (m, 1H), 2.65 (s, 3H), 1.04 (d, J =6.24 Hz, 3H).

[0245] Step-C2: Yellow semi-solid. 1 H NMR (DMSO- d 6, 400 MHz): δ 7.39 (d, J =3.06 Hz, 1H), 7.13 (dd, J =2.45, 9.29 Hz, 1H), 6.78 (dd, J =1.96, 10.27 Hz, 1H), 6.44-6.46 (m, 1H), 4.89 (sxt, J=6.24 Hz, 1H), 4.50-4.60 (m, 2H), 2.66 (s, 3H), 2.46 (s, 3H), 1.35 (d, J =6.24 Hz, 3H).

[0246] Step C3: Yield: 19% (after two steps, light 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- d 6, 400 MHz): δ 7.30 (d, J =3.06 Hz, 1H), 7.09 (dd, J =2.45, 9.29 Hz, 1H), 6.73 (dd, J =2.02, 10.33 Hz, 1H), 6.35(d, J =3.06 Hz, 1H), 4.38 (dd, J =6.30, 14.49 Hz, 1H), 4.11-4.18 (m, 1H), 2.82-2.92 (m, 1H), 2.65 (s, 3H), 2.19 (s, 6H), 0.76 (d, J =6.60 Hz, 3H). 19 F NMR (DMSO- d 6, 376 MHz): δ -127.62 (s, 1F). 5-Fluoro-7-methyl-1H-indole was synthesized from 4-fluoro-2-methyl-1-nitrobenzene via Bartoli indole. The reaction mixture was treated with 4 equivalents of 1M vinyl magnesium bromide in a 10 vol THF solution of 4-fluoro-2-methyl-1-nitrobenzene for 3 hours at -40 °C. After the reaction was completed as monitored by TLC, the reaction mixture was quenched with saturated NH4Cl and extracted with EtOAc. The combined organic layers were washed with saturated brine to obtain the crude product. The crude product was purified using a combi-flash reaction of 5% ethyl acetate / n-hexane, and the purer fraction was distilled to give 5-fluoro-7-methyl-1H-indole in a yield of 27%.

[0247] Example 73. (R)-1-(5-fluoro-2-methyl-1H-indol-1-yl)-N,N-dimethylpropane-2-amine Step-C1: Yield: 33% (colorless liquid). 1 H NMR (DMSO- d 6, 400 MHz): δ 7.36 (dd, J =4.52, 8.93 Hz, 1H), 7.13-7.17 (m, 1H), 6.81-6.87 (m, 1H), 6.17 (s, 1H), 4.86(d, J =4.77 Hz, 1H), 3.89-4.05 (m, 3H), 2.40 (d, J =0.73 Hz, 3H), 1.08 (d, J =5.99 Hz, 3H).

[0248] Step-C2: Light brown semi-solid.

[0249] Step C3: Yield: 10% (after two steps, colorless liquid). [α] D 20 = - 36.86 (C 0.25, CH2Cl2). LC-MS: 94.4%, m / z=235.2 [M+H] + 1 H NMR (DMSO- d 6, 400 MHz): δ 7.34 (dd, J =4.52, 8.80 Hz, 1H), 7.15 (dd, J =2.45, 9.90 Hz, 1H), 6.86 (dt, J =2.57, 9.23 Hz, 1H), 6.18 (s, 1H), 4.16 (dd, J =6.42, 14.73 Hz, 1H), 3.93 (dd, J =7.58, 14.67 Hz,1H), 2.92 (sxt, J =6.80 Hz, 1H), 2.40 (s, 3H), 2.22 (s, 6H), 0.81 (d, J =6.60Hz, 3H). 19 F NMR (DMSO-d 6, 376 MHz): δ -127.21 (s, 1F). Example 74. (R)-1-(5-fluoro-3-methyl-1H-indol-1-yl)-N,N-dimethylpropane-2-amine Step-C1: Yield: 35% (light brown liquid). 1 H NMR (DMSO- d 6, 400 MHz): δ 7.41 (dd, J =4.52, 8.93 Hz, 1H), 7.16-7.23 (m, 2H), 6.89-6.95 (m, 1H), 4.85 (d, J =4.65 Hz,1H), 3.87-4.04 (m, 3H), 2.20 (d, J =0.98 Hz, 3H), 1.02 (d, J =6.11 Hz, 3H).

[0250] Step-C2: Brown semi-solid. 1 H NMR (DMSO- d 6, 400 MHz): δ 7.49 (dd, J =4.46,8.92 Hz, 1H), 7.20-7.26 (m, 2H), 6.95-7.01 (m, 1H), 4.91-4.99 (m, 1H), 4.34(d, J =5.65 Hz, 2H), 2.63 (s, 3H), 2.21 (s, 3H), 1.31 (d, J =6.54 Hz, 3H).

[0251] Step C3: Yield: 44% (after 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- d 6, 400 MHz): δ 7.40 (dd, J =4.46, 8.86Hz, 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 =6.60Hz, 3H). 19 F NMR (DMSO-d 6, 376 MHz): δ -127.47 (s, 1F). Example 75. (R)-1-(5-methoxy-1H-indol-1-yl)-N,N-dimethylbutane-2-amine Step C1: The epoxide used in the reaction is (S)-2-ethylethylene oxide; the remaining steps are the same as the general steps described above. Yield: 44% (light brown solid). 1 H NMR (DMSO- d 6, 400 MHz): δ 7.34 (d, J =8.93 Hz, 1H), 7.27 (d, J =3.06 Hz, 1H), 7.02 (d, J =2.32 Hz, 1H), 6.73-6.77 (m, 1H), 6.30 (dd, J =0.73, 3.06 Hz, 1H), 4.81 (d, J =5.50 Hz, 1H), 3.95-4.10 (m, 2H), 3.74 (s, 3H), 3.63-3.70 (m, 1H), 1.21-1.42 (m, 2H), 0.88 (t, J =7.40 Hz, 3H).

[0252] Step-C2: Pale yellow solid. 1 H NMR (DMSO- d 6, 400 MHz): δ 7.43 (d, J =8.93 Hz, 1H), 7.34 (d, J =3.06 Hz, 1H), 7.04 (d, J =2.32 Hz, 1H), 6.80 (dd, J =2.45, 8.93Hz, 1H), 6.38 (dd, J =0.73, 3.06 Hz, 1H), 4.81-4.87 (m, 1H), 4.41 (d,J =5.75Hz, 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).

[0253] Step C3: Yield: 26% (after 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- d 6, 400 MHz): δ 7.27-7.33 (m, 2H),7.03 (d, J =2.32 Hz, 1H), 6.75-6.78 (m, 1H), 6.31 (dd, J =0.73, 3.06 Hz, 1H), 4.17-4.24 (m, 1H), 3.94-4.00 (m, 1H), 3.74 (s, 3H), 2.69-2.76 (m, 1H), 2.23 (s, 6H), 1.40-1.51 (m, 1H), 1.07-1.19 (m, 1H), 0.81 (t, J =7.40 Hz, 3H).

[0254] Example 76. (S)-1-(5-methoxy-1H-indol-1-yl)-N,N-dimethylbutane-2-amine Step C1: The epoxide used in the reaction is (R)-2-ethylethylene oxide; the remaining steps are the same as the general steps described above. Yield: 34% (light brown liquid). 1 H NMR (DMSO- d 6, 400 MHz): δ 7.34 (d, J =8.93 Hz, 1H), 7.27 (d, J =2.93 Hz, 1H), 7.02 (d, J =2.32 Hz, 1H), 6.75 (dd, J =2.45, 8.93Hz, 1H), 6.30 (d, J=2.93 Hz, 1H), 4.82 (d, J =5.50 Hz, 1H), 3.95-4.10 (m, 2H), 3.74 (s, 3H), 3.62-3.70 (m, 1H), 1.21-1.42 (m, 2H), 0.88 (t, J =7.40 Hz, 3H).

[0255] Step-C2: Light brown solid. 1 H NMR (DMSO- d 6, 400 MHz): δ 7.45 (d, J =8.93 Hz, 1H), 7.36 (d, J =3.06 Hz, 1H), 7.06 (d, J =2.45 Hz, 1H), 6.82 (dd, J =2.45, 8.93Hz, 1H), 6.40 (dd, J =0.61, 3.06 Hz, 1H), 4.82-4.90 (m, 1H), 4.43 (d, J =5.75Hz, 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).

[0256] Step C3: Yield: 52% (after two steps, brown solid). [α] D 20 = +24.8(C0.5,CH2CL2). LC-MS: 99.68%, m / z=247.2 [M+H] + 1 H NMR (DMSO- d 6, 400 MHz): δ 7.27-7.33 (m, 2H), 7.02(d, J =2.38 Hz, 1H), 6.76 (dd, J =2.38, 8.80 Hz, 1H), 6.30-6.32 (m, 1H), 4.21(dd, J=6.79, 14.31 Hz, 1H), 3.94-4.01 (m, 1H), 3.74 (s, 3H), 2.68-2.76 (m,1H), 2.23 (s, 6H), 1.41-1.51 (m, 1H), 1.07-1.18 (m, 1H), 0.81 (t, J =7.43 Hz, 3H).

[0257] Example 77. (R)-1-(4,5-dimethoxy-1H-indol-1-yl)-N,N-dimethylpropane-2-amine Step-C1: Yield: 75% (light brown liquid). 1 H NMR (DMSO- d 6, 400 MHz): δ 7.24 (d, J=3.18 Hz, 1H), 7.12 (dd, J=0.61, 8.80 Hz, 1H), 6.89-6.92 (m, 1H), 6.39 (dd, J=0.67, 3.12 Hz, 1H), 4.84 (d, J=4.65 Hz, 1H), 3.91-4.01 (m, 3H), 3.88 (s, 3H), 3.77 (s, 3H), 1.03 (d, J=5.99 Hz, 3H).

[0258] Step-C2: Light brown liquid.

[0259] Step C3: Yield: 18% (after two steps, brown liquid). [α] D 20 = -11.7 (C 0.25, CH2CL2). LC-MS: 99.83%, m / z=263.1[m+h] + 1 H NMR (DMSO-) D 6, 400 MHz): δ7.28(d,j=3.06 Hz,1H),7.11(d,j=8.80 Hz,1H),6.93(d,j=8.80 Hz,1H),6.41(d,j=3.06 Hz,1H),4.17(dd,j=6.85,14.18 Hz,1H), 3.96(dd,j=7.40,14.24 Hz,1H), 3.90(s,3H), 3.79(s,3H), 2.97-3.03(m,1H), 2.19(s,6H),0.83(d,j=6.60 Hz,3H).

[0260] Example 78. (R)-1-(5-fluoro-3-methoxy-1H-indol-1-yl)-N,N-dimethylpropane-2-amine Step-C1: Yield: 50% (brown liquid).

[0261] Step-C2: Pale yellow solid.

[0262] Step C3: Yield: 3% (after two steps, light brown liquid). [α] D 20 = -17.6 (C 0.25, CH2CL2). LC-MS: 99.13%, m / z=251.1 [M+H] + 1 H NMR (DMSO- d 6, 400 MHz): δ 7.41 (dd, J=4.28, 9.05Hz, 1H), 7.15 (dd, J=2.51, 9.48 Hz, 1H), 7.06 (s, 1H), 6.95 (dt, J=2.57, 9.23Hz, 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). 19 F NMR (DMSO- d 6, 376 MHz): δ -127.6 (s, 1F).

[0263] Example 79. (R)-1-(5,6-dichloro-1H-indol-1-yl)-N,N-dimethylpropane-2-amine Step-C1: Yield: 45% (light brown solid). 1 H NMR (DMSO- d 6, 400 MHz): δ 7.85 (s,1H), 7.78 (s, 1H), 7.45 (d, J =3.18 Hz, 1H), 6.43 (dd, J =0.67, 3.12 Hz, 1H), 4.85 (d, J=4.89 Hz, 1H), 4.11-4.16 (m, 1H), 3.99-4.05 (m, 1H), 3.90-3.97 (m,1H), 1.05 (d, J =6.24 Hz, 3H).

[0264] Step-C2: Pale yellow semi-solid.

[0265] Step C3: Yield: 30% (after two steps, light brown liquid). [α] D 20 = -24.14 (C 0.25, CH2CL2). LC-MS: 96.9%, m / z=271.0 [M+H] + 1 H NMR (DMSO- d 6, 400 MHz): δ 7.86 (s, 1H), 7.79 (s, 1H), 7.49 (d, J =3.06 Hz, 1H), 6.45 (d, J =3.06 Hz, 1H), 4.21 (dd, J =7.76,14.37 Hz, 1H), 4.07 (dd, J =6.60, 14.31 Hz, 1H), 2.98-3.04 (m, 1H), 2.19 (s,6H), 0.84 (d, J =6.60 Hz, 3H).

[0266] Step D General synthesis scheme: General synthesis steps: Step D1: At 0°C, add SOCl2 (5 equivalents) to a chloroform solution (10 volumes) of compound J (1 equivalent) under stirring, and heat the resulting solution at reflux temperature for 12 hours. Monitor the reaction progress using thin-layer chromatography.

[0267] Post-processing in step D1: The reaction mixture is evaporated, and then co-evaporated twice with toluene (10 volumes). The resulting crude product is then used directly in the next step.

[0268] Step D2: The stirred compound solution h (1.0 equivalent) was added to DMF (10 volumes) with NaH (60% mineral oil, 1.5 equivalent) at 0°C. The reaction mixture was stirred for 30 minutes, followed by the addition of compound I (1.0 equivalent) and then NaI (catalyst). The reaction mixture was stirred for another 30 minutes, followed by the addition of NaI (catalytic amount) and then compound I (1.0 equivalent). The reaction mixture was slowly heated to room temperature, then to 65°C and stirred for 16 hours. The reaction progress was monitored using thin-layer chromatography.

[0269] Processing and purification: The reaction mixture was cooled to room temperature, quenched in ice water, and extracted with ethyl acetate. The organic layers were combined and washed with ice water, then with an aqueous NaCl solution. The organic layers were separated, dried with Na₂SO₄, and concentrated to obtain the crude product. The crude product was purified by combi-flash with 2–5% methanol / dichloromethane, followed by distillation of the purer fraction (by TLC), and drying under reduced pressure to obtain the desired product.

[0270] Example 80. (S)-5-methoxy-1-((1-methylpiperidin-2-yl)methyl)-1H-indole Step-D1: Treat (S)-(1-methylpiperidin-2-yl)methanol with SOCl2 and obtain the corresponding chloride using the general steps described above.

[0271] Step D2: Yield: 13% (two steps, light brown semi-solid). [α] D 20 = -85.8 (C 0.25, CH2CL2). LC-MS: 99%, m / z=259.1 [M+H] + 1 H NMR (DMSO- d 6, 400 MHz): δ 7.28-7.35 (m, 2H), 7.03(d, J =2.32 Hz, 1H), 6.76 (dd, J =2.45, 8.80 Hz, 1H), 6.32 (d, J =2.81 Hz, 1H),4.44-4.50 (m, 1H), 3.89-3.96 (m, 1H), 3.74 (s, 3H), 2.75-2.82 (m, 1H), 2.36(br s, 3H), 2.24-2.31 (m, 1H), 1.97-2.08 (m, 1H), 1.37-1.58 (m, 3H), 1.05 (brd, J=9.05 Hz, 3H).

[0272] Example 81. (S)-5-methoxy-1-((1-methylpyrrolidone-2-yl)methyl)-1H-indole Step-D1: Treat (S)-(1-methylpiperidin-2-yl)methanol with SOCl2 and obtain the corresponding chloride using the general steps described above.

[0273] Step-D2: Yield: 11% (after 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- d 6, 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).

[0274] Example 82. (R)-5-methoxy-1-((1-methylpiperidin-2-yl)methyl)-1H-indole Prepared according to step D. Yield: 6% (after two steps, brown solid). [α] D 20 = +101.19(C0.5,CH2CL2). LC-MS: 97.4%, m / z=259.2 [M+H] + 1 H NMR (DMSO- d 6,400 MHz): δ 7.27-7.35 (m, 2H),7.03 (d, J=2.45 Hz, 1H), 6.76 (dd, J=2.45, 8.93 Hz, 1H), 6.32 (d, J=2.93 Hz,1H), 4.46 (dd, J=4.28, 14.06 Hz, 1H), 3.92 (dd, J=8.50, 14.12 Hz, 1H), 3.74(s, 3H), 2.76-2.81 (m, 1H), 2.35 (s, 3H), 2.25-2.30 (m, 1H), 1.99-2.06 (m,1H), 1.36-1.57 (m, 3H), 1.00-1.10 (m, 3H).

[0275] Example 83. (R)-5-methoxy-1-((1-methylpyrrolidone-2-yl)methyl)-1H-indole Step-D1: Treat (R)-(1-methylpiperidin-2-yl)methanol with SOCl2 and obtain the corresponding chloride using the general steps described above.

[0276] Step D2: After purification by combi-flash column chromatography, a product with a purity of 80% was obtained, which was further purified by preparative-HPLC to obtain a cleaner final compound.

[0277] The details of Prep-HPLC purification are as follows: HPLC column preparation: Chiralpak IG (250*30mm, 5μm) Mobile phase A: 0.1% n-hexane DEA Mobile phase B: EtOH: MeOH (50:50) Flow rate: 35.0 mL / min isometry table: Solvent used for dilution: methanol / ethanol Yield: 11% (after two steps, colorless solid). [α] D 20 = +79.47(C0.5,CH2CL2). LC-MS: 99.9%, m / z=245.1[m+h] + 1 H NMR (DMSO-) D 6, 400 MHz): δ7.29-7.38(m, 2H), 7.02(d, J=2.32Hz, 1H), 6.76 (dd, J =2.38, 8.86 Hz, 1H), 6.31 (d, J =2.93Hz,1H),4.16-4.22(m,1H),3.95-4.01(m,1H),3.74(s,3H),2.94(td, J =4.37,9.11Hz,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).

[0278] Step E General synthesis scheme: General synthesis steps: Step E1: At 0°C, add NaH (60% mineral oil, 1.2 equivalents) to a stirred solution of K (1.0 equivalents) in DMF (10 volumes), and stir the reaction mixture for 20 minutes. Add reagent L to the reaction mixture, slowly heat to room temperature, and stir for 16 hours. Monitor the reaction progress using thin-layer chromatography. Thin-layer chromatography shows a nonpolar spot corresponding to K.

[0279] Post-treatment of step E1: The reaction mixture was quenched with ice water and extracted with ethyl acetate. The organic layers were combined and washed with ice water, then with brine. The organic phase was separated, dried over Na₂SO₄, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by combi-flash with ethyl acetate / n-hexane, and then the purer fraction was distilled to obtain M.

[0280] Step E2: At room temperature, K₂CO₃ (3 equivalents) was added to a stirred solution of M (1.0 equivalents) in DMF (10 volumes), followed by reagent N (1.2 equivalents) and NaI (1 equivalent). The reaction mixture was then heated at 70°C for 16 hours. The reaction progress was monitored by thin-layer chromatography. Thin-layer chromatography showed a polar spot corresponding to M.

[0281] Step-E2 Post-processing: The reaction mixture was quenched with ice water and extracted with ethyl acetate. The organic layers were combined and washed with ice water, then with brine. The organic phase was separated, dried over Na2SO4, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by CH2Cl2 / MeOH chromatography using a combi-flash column, and the purer fraction was distilled (by TLC). After drying, the target compound was obtained with LC-MS and HPLC purity >95%.

[0282] Example 84. 6-(2-(5-methoxy-1H-indol-1-yl)ethyl)-2-oxa-6-azaspiro[3.3]heptane Prepared according to step E. Yield: 38% (2+ steps), colorless liquid. LC-MS: 99%, m / z = 273.2.1 [M+H] + . 1 H NMR (DMSO- d 6, 400 MHz): δ 7.32 (d, J =8.93 Hz, 1H), 7.26 (d, J =3.06 Hz, 1H), 7.02 (d, J =2.32 Hz, 1H), 6.75 (dd, J =2.38, 8.86 Hz, 1H), 6.30 (d, J =2.93 Hz,1H), 4.52 (s, 4H), 4.04 (t, J =6.30 Hz, 2H), 3.74 (s, 3H), 3.17 (s, 4H), 2.63-2.67 (m, 2H).

[0283] Example 85. 6-(2-(5-chloro-1H-indol-1-yl)ethyl)-2-oxa-6-azaspiro[3.3]heptane Prepared according to step E. Yield: 25% (2+ steps), brown liquid. LC-MS: 97.3%, m / z = 277.0 [M+H] + 1 H NMR (DMSO- d 6, 400 MHz): δ 7.57 (d, J=1.96 Hz, 1H), 7.46-7.49 (m, 2H),7.40J=6.90 Hz, 1H), 7.09-7.12 (m, 1H), 6.40 (D, J=3.06 Hz, 2H), 4.52 (s, 4H), 4.08-4.11 (m, 2H), 3.18 (s, 4H).

[0284] Example 86. (R)-1-(5-methoxy-2-methyl-1H-indol-1-yl)-N,N-dimethylpropane-2-amine Prepare according to step C. 1 H NMR (DMSO- d 6, 400 MHz): δ 7.20 (d, J =8.8 Hz, 1H), 6.95 (d,J = 2.4 Hz, 1H), 6.73 (dd, J =8.8 Hz, J =2.4 Hz, 1H), 6.14 (s, 1H), 4.29(dd, J =4.8, 14.4 Hz, 1H), 4.06-3.99 (m, 1H), 3.79 (s, 3H), 3.25-3.10 (m, 1H), 2.48 (s, 6H), 2.42 (d, J=0.4 Hz, 3H), 0.92 (d, J =6.4 Hz, 3H). LCMS: 247.1 [M+H] + .

[0285] Results and discussion SAR studies were conducted by comparing the effects of DMT(1) with 1-ME-DMT(27) and iso-DMT(2). DMT has the potential to act as a hydrogen bond donor when it binds to the target receptor, while 27 and 2 do not. Therefore, this potential hydrogen bond interaction may not be critical for compounds that induce plasticity, as 27 and 2, despite lacking indole NH bonds, increase dendritic spine complexity to a level comparable to 1 (…). Figure 2 ).

[0286] 5-MEO-DMT (28) and 6-F-DMT (29) were selected as electron-rich and electron-poor DMT analogs, respectively. Compound 28 promotes neuronal generation in the dentate gyrus and alleviates symptoms of depression and anxiety in humans. Compound 29 is not expected to be hallucinogenic because the fluorination of the DMT analog reduces its hallucinogenic potential. The performance of the iso-DMT analogs in Examples 5 and 13 was similar to that of 28 and 29 ( Figure 3 The fact that the two structures are isomorphic indicates that, due to their isomorphic nature, the SAR data related to neuronal growth obtained from the hetero-DMT scaffold derivative can be used analogously for the DMT scaffold derivative.

[0287] Key features of the pharmacophore of psychoactive substances were determined using various iso-DMT analogs. Figure 4 Removing the alkaline amine from iso-DMT to prepare 25 yielded a molecule that does not promote dendrite development. Furthermore, compound 31—an N,N-dimethylamide analog of iso-DMT—does not promote neuronal growth, confirming the hypothesis that basic nitrogen is necessary for promoting plasticity. Figure 4 A and 4B). Expanding the distance between the aromatic ring and the amine by a single carbon atom (26) can only cause N. max A slight decrease in value ( Figure 4 B).

[0288] Modification of aromatic rings is generally well tolerated. Figure 4 C). Converting indole to benzimidazole (22), pyrrole (23), or carbazole (24) has the least effect on the ability of these molecules to promote neuronal growth. Furthermore, substitutions at the 2- and 3-positions of indole (16 and 21, respectively) are well tolerated. In summary, the minimal psychoplasticizer pharmacophore appears to possess a modifiable aromatic ring separated from the basic nitrogen via a short linker.

[0289] Substitution on the benzene ring of both DMTs and iso-DMTs affects their hallucinogenic potential. For example, 5-MEO-DMT (28) was used in rats to replace the psychedelic 2,5-dimethoxy-4-methylamphetamine (DOM) to differentiate DOM from saline, whereas 6-MEO-DMT did not. Similarly, 6-MEO-iso-DMT (5) was used to replace the hallucinogenic training drug, whereas 5-MEO-iso-DMT (Example 5) did not. Therefore, methoxy (electron-donating; Examples 3-6), benzyloxy (electron-donating, but requiring steric hindrance; Examples 8-11), or fluorine group (electron-withdrawing; Examples 12-15) were synthesized respectively. Figure 5 Three series of analogues with substituents were tested. Substitutions at positions 5, 6, and 7 were well tolerated, regardless of the substituent. However, substitution at position 4 prevented the compound from increasing the complexity of the dendritic spines. Even fluorine substituents with small van der Waals radii (H and F = 1.2 and 1.47, respectively) were not tolerated.

[0290] To determine whether DMT and iso-DMT derivatives exhibit differences in psychoplasticity potency, a concentration-response experiment was conducted. Figure 6 The iso-DMT analogues (2 and Example 5) produced similar maximum efficacy and potency to allo-DMT (1 and 28). Furthermore, at low concentrations of 1 nM, they were able to increase dendritic spine complexity. These compounds exhibited efficacy and potency comparable to ketamine, further highlighting their potential as antidepressants. Finally, Compound Example 4 was demonstrated to be a particularly important psychoshaping agent due to its low hallucinogenic potential in drug identification and head twitching response (HTR) tests. Figure 8 ).

[0291] DMT and other psychedelic compounds via 5-HT 2A - Related processes promote increased dendritic spine complexity, dendritic spine density, and synapse formation. Using 5-HT 2A Antagonist pretreatment of cortical cultures to block the ability of 5-MeO-DMT (28) to promote dendritic growth ( Figure 7 Importantly, under these conditions, the psychoplasticity of iso-DMTs was also blocked, indicating that 5-HT... 2AReceptors are involved in its mechanism of action ( Figure 7 ).

[0292] Hallucinogenic potential. The hallucinogenic compound 5-MEO-DMT (28) produces a potent, dose-related HTR, which is greater in female mice. However, the potency of the allotropic compound 6-MeO-isoDMT (Example 5) is significantly lower. Figure 8 According to drug identification data, 6-MEO-DMT (30) did not produce HTR. Finally, the potent plasticity-promoting compounds (Examples 4, 59, and 60) did not produce any HTR. Figure 8 and Figure 9 This indicates that hallucinogenic potential and mental volition can be separated.

[0293] Hallucinogens (such as LSD and 5-MEO-DMT) activate 5HT in arousal mode. 2A Sensor analysis was performed, but its non-hallucinogenic homologs (risolide (LIS) and 6-MEO-DMT) were not included. Figure 10 Furthermore, hallucinogenic compounds in animals (e.g., humans), such as 5-MEO-DMT, LSD, DMT, and DOI, activate 5HT in an agonistic mode. 2A Sensor analysis revealed that compounds that are non-hallucinogenic in animals (e.g., humans), such as 6-MEO-DMT, LIS, 6-F-DET, L-MDMA, R-MDMA, ketoselin, and BOL148, do not activate 5HT in agonistic mode. 2A Sensor analysis ( Figure 11 (Compound 10 μM). In some embodiments, the hallucinogenic potential of the compounds of the present invention is determined in vitro. In some embodiments, the hallucinogenic potential of the compounds of the present invention is measured using 5HT. 2A Sensor analysis and measurement. In some embodiments, the 5HT 2A Sensor analysis is performed in agonist or antagonist mode. In some embodiments, the 5HT 2A Sensor analysis is performed in agonist mode. In some embodiments, the inventive compounds that do not activate the sensor in agonist mode have non-hallucinogenic potential. In some embodiments, the inventive compounds that do not activate the sensor in agonist mode are non-hallucinogenic compounds.

[0294] In some implementations, the hallucinogenic potential of compounds evaluated in agonist mode is shown in Table 1.

[0295] Table 1 A: Activation of 5HT in agonist mode 2A Sensor analysis; B: 5HT is not activated in agonist mode.2A Sensor analysis. Percentages correlated with positive control (100 uM 5-HT in agonist mode). Compounds producing a response >15% were considered to activate the sensor in agonist mode.

[0296] In addition, 5HT 2A Sensor analysis during antagonist mode ( Figure 12A and Figure 12B Non-hallucinogenic compounds (such as lisuradil and 6-MeO-DMT) compete with 5-HT. Furthermore, compounds that are non-hallucinogenic in animals (e.g., humans), such as 6-F-DET, ketoselin, and BOL148, compete with 5-HT in sensor analysis under antagonist mode. 2A Combined 5HT competition ( Figure 13 (at a compound concentration of 10 μM). In some embodiments, 5-HT is blocked from reacting with 5-HT. 2A The compounds of the present invention are combined. In some embodiments, the 5HT 2A Sensor analysis indicates an antagonist mode. In some implementations, it blocks 5-HT and 5HT. 2A The compounds of this invention are combined and possess non-hallucinogenic potential. In some embodiments, they block 5-HT from reacting with 5-HT. 2A The compounds of this invention are combined and are non-hallucinogenic. In some embodiments, they block 5-HT and 5HT in antagonist mode. 2A The compounds of the present invention, when combined, have non-hallucinogenic potential. In some embodiments, the compounds of the present invention that block 5-HT binding in antagonist mode are non-hallucinogenic compounds. In some embodiments, the compounds of the present invention that suppress sensor assay response in antagonist mode have non-hallucinogenic potential. In some embodiments, the compounds of the present invention that suppress sensor assay response in antagonist mode are non-hallucinogenic compounds.

[0297] In some embodiments, agonist mode sensor analysis results indicate that the compound of the present invention is 5-HT. 2A Non-hallucinogenic ligands for receptors. In some embodiments, antagonist modality sensor analysis results indicate that the compounds of the present invention are 5-HT. 2A Non-hallucinogenic ligands for receptors. In some embodiments, results from agonist and antagonist mode sensor analyses collectively indicate that the compounds of the present invention are 5-HT. 2A Non-hallucinogenic ligands of receptors.

[0298] In some implementations, the hallucinogenic potential of compounds evaluated in antagonist mode is shown in Table 2.

[0299] Table 2 A: 5HT response inhibition >100%; B: 5HT response inhibition 75%–100%; 5HT response inhibition <75%. Percentages are related to the positive control (100 nM 5-HT in antagonist mode).

[0300] Calcium flux determination. Calcium secondary messenger pathway. Calcium No Wash PLUS Assay for monitoring GPCRs (e.g., 5HT) using Gq secondary messenger signals in a live-cell non-imaging analysis format. 2A Activation of calcium in PathHunter cells. Calcium levels were monitored in cells loaded with calcium-sensitive dyes. ® Metabolism in cell lines and other cell lines, stable expression of Gq-coupled GPCRs (e.g., 5HT) 2A Compounds that activate GPCRs (such as 5HT) 2A This causes the release of intracellularly stored calcium, and the dye fluorescence is enhanced as measured in real time. In some embodiments, the compounds of the present invention regulate 5-HT. 2A The functional capability was determined by calcium flux assay. In some embodiments, the compound of the present invention activates the calcium flux assay. In some embodiments, activation of the calcium flux assay indicates that the compound of the present invention regulates 5-HT. 2A Function.

[0301] In some embodiments, the compounds of the present invention regulate 5-HT 2A The functional capacity was assessed based on the results of calcium flux measurement (Table 3).

[0302] Table 3 A: >10 µM; B: <10 µM.

[0303] Forced swimming test. Due to increased plasticity in the anterior cortical structure of the brain, ketamine mediates a sustained (>24 hours) antidepressant effect, and in 5-HT... 2A The effects of agonists on the therapeutic effects of iso-DMT analogues on forced swimming test (FST) behavior ( ) Figure 14 A and Figure 14 B) Evaluation was conducted. First, a pre-test was performed to induce a depressive phenotype. The compound was administered 24 hours after the pre-test, and FST was performed 24 hours and 7 days after administration. The positive control (ketamine) and Example 59 showed a significant reduction in fixation 24 hours after administration. Figure 14 A vs. Figure 14 B).

[0304] Neuronal spur growth assay. Alterations in neuronal spur growth patterns are associated with neurodegenerative diseases and trauma. The discovery of novel compounds capable of positively influencing neuronal development is of great significance for the development of new therapies for neurological diseases. Neuronal spur growth in rat cortical neurons was measured using an image-based automated analysis method to determine the neuroplasticity effects of the compounds of this invention. In some embodiments, the compounds of this invention increase the pattern of neuronal exogenous growth. In some embodiments, the compounds of this invention increase the mean length of nerve axons compared to a control. In some embodiments, the compounds of this invention increase the number of nerve axonal branching points compared to a control. In some embodiments, the compounds of this invention increase both the number of nerve axonal branching points and the mean length of nerve axons compared to a control.

[0305] In some implementations, the plastic potential of the compound is shown in Table 4.

[0306] Table 4 A: Compared to controlling DMSO, the increase is >3 times; B: Compared to controlling DMSO, the increase is 1.5 to 3 times; C: Compared to controlling DMSO, the increase is <1.5 times.

[0307] test Dendriticization assay: Historically, phenotypic screening has proven more successful than target-based methods in identifying drugs with novel mechanisms of action. After establishing a simple and robust method for evaluating iso-DMT analogs, the next step was to test its ability to increase dendritic spine complexity using phenotypic analysis in cortical neuron culture. Following treatment, neurons were fixed and visually observed using an antibody against MAP2 (a neuronal somatic cartilage chamber cytoskeletal protein). Sholl analysis was then performed, and the results were compared using the maximum number of crossovers (N...). max () as a quantitative measure of dendritic spine complexity. For statistical comparisons between specific compounds, the original N is compared. max Value. By comparing the N values ​​of the vector (DMSO) and the positive control (ketamine). max The values ​​were set to 0% and 100% respectively to determine the percentage of efficacy.

[0308] Animals. For dendritic development experiments, timed-pregnancy SD mice were purchased from Charles River Laboratories (Wilmington, Massachusetts). For head twitching response experiments, male and female C57BL / 6J mice were obtained from Jackson Laboratory (Sacramento, California). Each group consisted of 4-5 mice (same sex), housed in a temperature- and humidity-controlled room with a 12-hour light / dark cycle. Animals weighed 17-30g during the experiments. All procedures involving rodents were approved by the Institutional Animal Care and Use Committee (IACUC) of the University of California, Davis, and adhered to the principles outlined in the National Institutes of Health's Guidelines for the Care and Use of Laboratory Animals. The University of California, Davis, and the University of California, San Francisco are accredited by the International Association for the Care of Laboratory Animals (AAALAC).

[0309] Dendriticization-Sholl Analysis. The dendriticization assay was performed according to previously published methods with minor modifications. Neurons were seeded at a density of 15,000 cells / well in 96-well plates (200 μL of medium per well) containing basal glomerulonephrine (Biotech) with 1% penicillin-streptomycin, 10% heat-inactivated fetal bovine serum, and 0.5 mM glutamine. After 24 hours, the medium was refreshed with basal glomerulonephrine containing 1x B27 supplement (Biotech), 1% penicillin-streptomycin, 0.5 mM glutamine, and 12.5 μM glutamate. After 3 days of in vitro culture (DIV3), cells were treated with compounds. Unless otherwise specified, all compounds tested in the dendriticization assay were 10 μM. The DMSO stock solution of these compounds was first diluted 100-fold with basal glomerulonephrine, and then further diluted 10-fold in each well (total dilution = 1:1000; 0.1% DMSO concentration). Treatment was randomized. One hour later, the culture medium was removed and replaced with fresh neural base medium containing 1x B27 supplement, 1% penicillin-streptomycin, 0.5mM glutamine, and 12.5%... M-glutamate. These cells continued to grow for 71 hours. Neurons were then immobilized by removing 80% of the culture medium and replacing it with 4% paraformaldehyde aqueous solution (Alpha Esar) equivalent to 50% of the working volume of each 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 with DPBS containing 0.2% Triton X-100 (Thermo Fisher Scientific) at room temperature for 20 minutes without shaking. The culture plates were blocked with antibody dilution buffer (ADB) containing 2% bovine serum albumin (BSA) at room temperature for 1 hour. Then, the culture plates containing ADB containing chicken anti-MAP2 antibody (1:10,000; EnCor, CPCA-MAP2) were incubated overnight at 4°C with gentle shaking. The next day, the culture plates were washed three times with DPBS and once with 2% ADB / DPBS. Culture plates were incubated for one hour at room temperature in an ADB containing Alexa Fluor 488 (LifeTech) coupled with anti-chicken IgG antibodies and washed five times with DPBS. After the final wash, 100 μL of DPBS was added to each well, and the plates were imaged on an ImageXpress Micro XL high-content screening system (Molecular Devices, Sunnyvale, CA) with a 20x objective. Images were analyzed using ImageJ Fiji (version 1.51W). First, images corresponding to each treatment were categorized into separate folders, followed by blinded data analysis. Culture plate controls (positive and negative) were used to ensure proper analysis, while visually determining appropriate values ​​for brightness / contrast and thresholds generally applicable to the remaining random images. Next, brightness / contrast settings were applied, and approximately 1–2 individual pyramidal neurons (i.e., no bipolar neurons) were selected for each image using the rectangular selection tool and saved as separate files. The selected neurons did not extensively overlap with other cells or extend beyond the field of view. Threshold settings were then applied to each image. Use the brush tool to remove artifacts and dendritic protrusions originating from adjacent neurons (cleanup phaseNext), the point tool to select the center of neurons, and save and process the image using the following Sholl analysis batch macro (Table 5): Run ("Sholl Analysis...", "Start=0 End=NaN Radius Step=2#_Sample=1 Integral=Mean Boundary=1#_Initial=4 Inference Fit Linear Polynomial=[Best Fit] Semilog Normalizer=Area Create Background=228 Save") Sholl analysis circle radius = 2 pixels increment = 0.67 m. All images were taken and analyzed by an experimenter unaware of the treatment conditions. The average number of crossovers per neuron at each different radius was used to generate the average Sholll plot for each treatment. N maxThe values ​​were determined solely by identifying the maximum value for each graph. For each treatment, neurons were selected from at least 6 wells on 2 plates (9 sites / well × 3 wells / plate × 2 plates). Each culture plate was prepared using neurons obtained from independently pregnant female mice.

[0310] Table 5. The efficacy of Sholls Ketoseripine blocking test. For the ketoseripine blocking test ( Figure 7 A slightly modified method was used. In DIV3, neurons were first treated with ketoserine (10... M)1h, then with medication (1 M) and Ketoselin (10 Co-incubate with DMSO (final concentration = 0.2%) for 1 hour. After 1 hour, remove the medium and replace it with fresh neural base medium containing 1x B27 supplement, 1% penicillin-streptomycin, 0.5mM glutamine, and 12.5% ​​sodium bicarbonate. M glutamate. Cells continued to grow for 71 hours prior to fixation, staining, and imaging.

[0311] Neuronal neurite growth assay. Cortical neurons (20,000 cells / well) were isolated from rats at 18 days of gestation and cultured in neurobasal medium (+B27). The cultured cells were seeded in 96-well plates (avoiding the outer wells). In DIV4, neurons were treated with either the compound or a control (10 μM) for 1 h, followed by complete washing away of the compound. In DIV7, neurons were analyzed. Each experiment had three replicates. Neuronal neurite growth was measured by analyzing the following parameters: cell body number, total neurite length (pixels), number of roots, segments, limbs, and nodes. Changes in neuronal neurite growth patterns were analyzed using immunocytochemistry against β-III-tubulin. Images were acquired using a Thermo Fisher Scientific CellInsight CX7 and analyzed using its software. Results generated by the device included maximum axon length, number of terminals, number of roots, dendritic branching points, and total axon length. Results compared to the DMSO control showed changes in neuronal folding.

[0312] 5HT 2A Sensor Analysis. The HEK293T(ATCC)5HT2A sensor stable system (Slink1.3s) was derived from HIV-EF1-Slink1.3 lentivirus transduced and propagated from a single colony. The lentivirus was produced using second-generation lentiviral plasmids pHIV-EF1-1.3, pHCMV-G, and pCMV-deltaR8.2.

[0313] To screen 41 compounds, Slight1.3S cells were seeded in 96-well plates at a density of 40,000 cells 24 hours prior to imaging. On the day of imaging, the compounds dissolved in DMSO were diluted from 100 mM stock solution to 1 mM, 100 mM. M and 1 The working concentration of M was 1% DMSO. Before imaging, cells grown in DMEM (Gibco) were washed twice with HBSS (Gibco). After the final wash, 180 μL of HBSS was added to each well in agonist mode or 160 μL of HBSS in antagonist mode. In agonist mode, images were taken before and after adding 20 μL of the compound working solution to the wells containing 180 μL of HBSS. This resulted in a final compound concentration of 100%. M, 10 M and 100 nM, with DMSO concentration of 0.1%. In 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 the compound working solution, resulting in a final 5-HT concentration of 100 nM. Compound concentrations were 100 μM, 10 μM, and 100 nM, with DMSO concentration of 0.1%. Each compound was tested three times (3 wells) at each concentration (100 μM, 10 μM, and 100 nM). In addition, the 100 nM 5-HT and 0.1% DMSO controls were also imaged within each culture plate.

[0314] Imaging was performed using a Leica DMi8 inverted microscope with a 40x objective lens, FITC presets, excitation wavelength of 460 nm, and emission wavelength of 512-542 nm. For each aperture, an adaptive focusing control was used to focus on the 5HT aperture. 2A The sensor automatically focuses on the cell membrane and takes five images of different areas within the pore, with each image processed in a 2x2 bin.

[0315] For data processing, a custom algorithm written in MATLAB was used to segment and analyze the membrane in each image, generating a single raw fluorescence intensity value. For each well, the average of the five raw fluorescence intensity values ​​generated from five images was taken. The formula for calculating the change in fluorescence intensity (dFF) is as follows: dFF = (F sat – F apo ) / F apo In both agonist and antagonist modes, the fluorescence intensity value of HBSS before the addition of the compound is used only as F. apo The fluorescence intensity value after adding the compound was used as the F value. sat value.

[0316] For the agonist mode, the data are activation percentages relative to 5HT, where 0 is the average value from DMSO wells and 100 is the average value from 100 μM 5HT wells. For the antagonist mode, the inactivation value is calculated as follows: Inactivation value = (dFFF(compound + 5HT) – dFF(5HT)) / dFF(5HT) Calcium secondary messenger pathway. Cell lines were expanded from cryopreservation according to standard procedures. 20 μL of cells were seeded into 384-well microplates with black walls, clear bottoms, and poly-D-lysine coating, and incubated at 37°C for an appropriate time prior to assay. Analysis was performed in 1x dye-loading buffer, which was HBSS / 20 mM Hepes containing 1x dye, 1x additive A, and 2.5 mM probenecid. Probenicid was freshly prepared. Cells were dye-loaded prior to assay. Culture medium was aspirated from cells and replaced with 20 μL of dye-loading buffer. Cells were incubated at 37°C for 30–60 minutes.

[0317] To determine the agonist, cells were incubated with the sample to induce the reaction. After loading the dye, the cells were removed from the incubator and 10 µL of HBSS / 20 mM Hepes was added. The buffer contained 3x carriers when performing agonist dose-proportioning to determine the EC80 for subsequent antagonist analysis. Cells were incubated in the dark at room temperature for 30 min to equilibrate the plate temperature. The sample solution was moderately diluted to produce 4x samples in the test buffer. The agonist activity of the compound was measured on a FLIPR Tetra (MDS). Calcium flow was detected for 2 min, and 4x samples containing 10 µL of HBSS / 20 mM Hepes were added to the experiment within 5 s.

[0318] Compound activity was analyzed using the CBIS data analysis suite (Chemical Innovation, CA). For agonist mode assays, the percentage of activity was calculated using the following formula: % Activity = 100% x (mean RFU of test sample - mean RFU of vector control) / (mean MAX RFU of control ligand - mean RFU of vector control).

[0319] Head twitching response test. Mice (9–10 weeks old) were intraperitoneally injected with the compound (5 ml / kg) and placed in empty cages for 20 minutes. The cages were cleaned with 70% ethanol between tests. Two trained observers unaware of the treatment conditions rated the number of head twitches in each video segment (Pearson correlation coefficients for males and females were 0.91 and 0.99, respectively), and the average of these results was taken.

[0320] Forced swimming test (FST). Male C57 / BL6J mice (9-10 weeks old at the time of the experiment) were purchased from Jackson Laboratory. Following an IACUC-approved protocol, 4-5 mice per cage were housed in a UCD ecosphere. After one week of live animal housing, the male experimenter treated each mouse for approximately 1 minute for three consecutive days until the first FST. All experiments were performed by the same male experimenter. During the FST, mice swam for 6 minutes in a transparent plexiglass cylinder 40 cm high, 20 cm in diameter, and with a water level of 30 cm. Fresh water was used for each mouse. After experimenter treatment and habituation, the drug-addicted mice underwent a pre-test swim to more reliably induce a depressive phenotype during the subsequent FST. After the pre-test, immobility values ​​were determined for all mice, and mice were randomly assigned to treatment groups to produce groups with similar mean immobility values ​​for the following two FST cycles. On the second day, animals were intraperitoneally injected with the experimental compound (20 mg / kg), a positive control (ketamine, 3 mg / kg), or a carrier (saline). These animals underwent free floaters (FSTs) 30 minutes after injection and were then returned to their cages. All FSTs were performed between 8:00 AM and 1:00 PM. The experiments were video-recorded and manually scored offline. Immobility time was scored during the last 4 minutes of the 6-minute test; immobility time was defined as passive floating or remaining motionless except for activities necessary to keep the mouse's head above water.

[0321] Statistical Analysis. Treatment was randomized, and data analysis was performed by participants unaware of the treatment conditions. Statistical analysis was performed using GraphPad Prism (version 8.1.2). The specific tests used, F-statistics, degrees of freedom, and main effect p-values ​​are shown in the legend where appropriate. All comparisons were planned prior to each experiment. For the dendriticization experiment, a one-way ANOVA with Dunnett's post-hoc test was considered most appropriate. Ketamine was used as a positive control to ensure the test was performed correctly.

[0322] Although the foregoing invention has been described in detail by way of illustration and examples for purposes of clarity, those skilled in the art will understand that certain changes and modifications may be made within the scope of the appended claims. Furthermore, each reference provided herein is incorporated by way of citation as if it were incorporated individually. In the event of any conflict between this application and the references provided herein, this application shall prevail.

Claims

1. A compound of formula I or a pharmaceutically acceptable salt and isomer thereof: (I) Its features are: X is CR 3 ; R 1a and R 1b Each independently is hydrogen, C 1-6 Alkyl, C 3-8 cycloalkyl, or C 4-14 Alkyl-cycloalkyl; R 1c C 1-6 Alkyl, C 3-8 cycloalkyl, or C 4-14 Alkyl-cycloalkyl; Or, R 1a R 1b and R 1c The two atoms in the mixture combine with the atoms they are attached to to form C. 3-12 Heterocyclic alkyl groups; R 2 R 3 R 4 R 5 R 6 and R 7 Each independently is hydrogen, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkyne, halogen, C 1-6 Haloalkyl, C 1-6 Alkylamine, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, –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 Heterocyclic alkyl, C 4-16 Alkyl-heterocyclic alkyl, C 6-12 Aryl, C 7-18 Alkyl-aryl, C 5-10 heteroaryl, or C 4-16 Alkyl heteroaryl; R 8a C 3-8 cycloalkyl, C 3-14 Alkyl-cycloalkyl, C 4-10 Heterocyclic alkyl, C 4-16 Alkyl-heterocyclic alkyl, 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 Each independently is H or C 1-6 alkyl; Or, R 1a R 1b or R 1c One of them with R 2 Combine to form C 5-12 Heterocyclic alkyl groups; Or, R 2 and R 3 They combine with their respective atoms to form C 4-8 cycloalkyl, C 4-10 Heterocyclic alkyl, or C 6-12 Aryl; Or, R 4 and R 5 R 5 and R 6 , or R 6 and R 7 They combine with their respective atoms to form C 4-6 cycloalkyl, C 4-6 Heterocyclic alkyl, C 6-12 Aryl, or C 5-10 Mixed aromatics, and L is C 1-6 Alkylene Where R 1a R 1b and R 1c Each is Me, L is methylene, and X is CR. 3 , and R 2 R 3 R 4 R 5 R 6 and R 7 Both are hydrogen, then the compound is or ,as well as The compound mentioned is not 。 2. The compound of claim 1 or a pharmaceutically acceptable salt thereof, characterized in that, X is CR 3 ; R 2 and R 3 Each independently is hydrogen, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkyne, halogen, C 1-6 Haloalkyl, C 1-6 Alkylamine, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, –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 Heterocyclic alkyl, C 4-16 Alkyl-heterocyclic alkyl, C 6-12 Aryl, C 7-18 Alkyl-aryl, C 5-10 heteroaryl, or C 4-16 Alkyl heteroaryl; R 8a C 3-8 cycloalkyl, C 3-14 Alkyl-cycloalkyl, C 4-10 Heterocyclic alkyl, C 4-16 Alkyl-heterocyclic alkyl, C 6-12 Aryl, C 7-18 Alkyl-aryl, C 5-10 heteroaryl, or C 4-16 alkyl-heteroaryl; and R 8b R 8c and R 8d Each independently is H or C 1-6 alkyl; Where R 1a R 1b and R 1c Each is Me, L is methylene, and R 2 R 3 R 3 R 4 R 5 R 6 and R 7 Both are hydrogen, then the compound is or .

3. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, characterized in that, The compound of formula I has the following structure: 。 4. The compound or a pharmaceutically acceptable salt thereof as described in any one of claims 1-3, characterized in that, R 1a R 1b and R 1c Each independently is C 1-6 Alkyl, C 3-8 cycloalkyl, or C 4-14 Alkyl-cycloalkyl; Or, R 1a R 1b and R 1c The two atoms in the mixture combine with the atoms they are attached to to form C. 3-12 Heterocyclic alkyl groups; R 2 R 3 R 4 R 6 and R 7 Each independently is hydrogen, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkyne, halogen, C 1-6 Haloalkyl, C 1-6 Alkylamine, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, –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 Heterocyclic alkyl, C 4-16 Alkyl-heterocyclic alkyl, C 6-12 Aryl, C 7-18 Alkyl-aryl, C 5-10 heteroaryl, or C 4-16 Alkyl heteroaryl; R 5 C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkyne, halogen, C 1-6 Haloalkyl, C 1-6 Alkylamine, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, –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 Heterocyclic alkyl, C 4-16 Alkyl-heterocyclic alkyl, C 6-12 Aryl, C 7-18 Alkyl-aryl, C 5-10 heteroaryl, or C 4-16 alkyl-heteroaryl; R 8a C 3-8 cycloalkyl, C 3-14 Alkyl-cycloalkyl, C 4-10 Heterocyclic alkyl, C 4-16 Alkyl-heterocyclic alkyl, C 6-12 Aryl, C 7-18 Alkyl-aryl, C 5-10 heteroaryl, or C 4-16 alkyl-heteroaryl; and R 8b R 8c and R 8d Each independently is H or C 1-6 alkyl; Or, R 4 and R 5 R 5 and R 6 , or R 6 and R 7 They combine with their respective atoms to form C 4-6 cycloalkyl, C 4-6 Heterocyclic alkyl, C 6-12 Aryl, or C 5-10 Mixed aromatic compounds.

5. The compound or a pharmaceutically acceptable salt thereof as described in any one of claims 1-3, characterized in that, R 1a and R 1b Each is independently hydrogen or C 1-6 alkyl; R 1c C 1-6 alkyl; R 2 and R 3 Each independently is hydrogen, C 1-6 Alkyl, C 1-6 Alkoxy, halogen, or -C(O)C(O)N(R) 8b R 8c ); R 4 R 5 R 6 and R 7 Each independently is hydrogen, C 1-6 Alkyl, halogen, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, or –OR 8a , where R 4 R 5 R 6 and R 7 At least one of them is not H; and R 8a C 7-18 alkyl-aryl; Or, R 5 and R 6 They combine with their respective atoms to form C 4-6 Heterocyclic alkyl groups.

6. The compound according to any one of claims 1-3 or 5, or a pharmaceutically acceptable salt thereof, characterized in that, R 1a and R 1b Each is independently hydrogen or methyl; and R 1c It is methyl; Or, R 1a R 1b and R 1c The two atoms in the mixture combine with the atoms they are attached to to form C. 3-8 Heterocyclic alkyl groups.

7. The compound according to any one of claims 1-6, or a pharmaceutically acceptable salt thereof, characterized in that, R 1a R 1b and R 1c Each for Me; Or, R 1a R 1b and R 1c The two atoms in the mixture combine with the atoms they are attached to to form C. 3-8 Heterocyclic alkyl groups.

8. The compound according to any one of claims 1-7, or a pharmaceutically acceptable salt thereof, characterized in that, R 2 For hydrogen, C 1-6 Alkyl, halogen or C 1-6 Alkyl group.

9. The compound according to any one of claims 1-8, or a pharmaceutically acceptable salt thereof, characterized in that, R 2 It can be hydrogen, Me, F or -OMe.

10. The compound according to any one of claims 1-9, or a pharmaceutically acceptable salt thereof, characterized in that, R 3 For 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 independently is H or C 1-6 alkyl.

11. The compound according to any one of claims 1-10, or a pharmaceutically acceptable salt thereof, characterized in that, R 3 It can be hydrogen, Me, F, -OMe or -C(O)C(O)NMe2.

12. The compound according to any one of claims 1-11, or a pharmaceutically acceptable salt thereof, characterized in that, The compound of formula I has the following structure: 。 13. The compound according to any one of claims 1-11, or a pharmaceutically acceptable salt thereof, characterized in that, The compound of formula I has the following structure: 。 14. The compound according to any one of claims 1-11, or a pharmaceutically acceptable salt thereof, characterized in that, The compound of formula I has the following structure: 。 15. The compound according to any one of claims 1-12 or 14, or a pharmaceutically acceptable salt thereof, characterized in that, The compound of formula I has the following structure: 。 16. The compound according to any one of claims 1-11, 13 or 14, or a pharmaceutically acceptable salt thereof, characterized in that, The compound of formula I has the following structure: 。 17. The compound according to any one of claims 1-13, or a pharmaceutically acceptable salt thereof, characterized in that, R 1a and R 1b They combine with the atoms they are attached to to form C 3-8 Heterocyclic alkyl groups.

18. The compound according to any one of claims 1-13, or a pharmaceutically acceptable salt thereof, characterized in that, R 1a and R 1c They combine with the atoms they are attached to to form C 5-8 Heterocyclic alkyl groups.

19. The compound according to any one of claims 1-18, or a pharmaceutically acceptable salt thereof, characterized in that, R 4 R 5 R 6 and R 7 Each independently is hydrogen, C 1-6 Alkyl, halogen, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, –OR 8a -NO2, -CN, C 3-8 cycloalkyl, or C 3-14 Alkyl-cycloalkyl; Or, R 4 and R 5 R 5 and R 6 , or R 6 and R 7 They combine with their respective atoms to form C 5-6 Heterocyclic alkyl groups; and R 8a C 3-8 cycloalkyl, C 3-14 Alkyl-cycloalkyl, C 4-16 Alkyl-heterocyclic alkyl, C 7-18 alkyl-aryl, or C 4-16 Alkyl-heteroaryl.

20. The compound according to any one of claims 1-19, or a pharmaceutically acceptable salt thereof, characterized in that, R 4 R 5 R 6 and R 7 Each independently represents H and C. 1-6 Alkyl, halogen, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, -OR 8a Or -NO2; Or, R 4 and R 5 R 5 and R 6 , or R 6 and R 7 They combine with their respective attached atoms to form C5 heterocyclic alkyl groups; and R 8a C 7-18 Alkyl-aryl.

21. The compound according to any one of claims 1-19, or a pharmaceutically acceptable salt thereof, characterized in that, R 4 R 6 and R 7 Each independently represents H and C. 1-6 Alkyl, halogen, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, -OR 8a Or -NO2; R 5 C 1-6 Alkyl, halogen, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, -OR 8a Or -NO2; Or, R 4 and R 5 R 5 and R 6 , or R 6 and R 7 They combine with their respective attached atoms to form C5 heterocyclic alkyl groups; and R 8a C 7-18 Alkyl-aryl.

22. The compound according to any one of claims 1-20, or a pharmaceutically acceptable salt thereof, characterized in that, R 4 R 5 R 6 and R 7 Each can be independently hydrogen (H, Me, F, Cl, Br, -OMe, -OCF3, -O-CH2-phenyl, or -NO2); Or, R 5 and R 6 They combine with the atoms to which they are attached to form 1,3-m-dioxacyclopentene rings or 1,4-dioxane rings.

23. The compound according to any one of claims 1-22, or a pharmaceutically acceptable salt thereof, characterized in that, R 4 R 6 and R 7 Each is hydrogen; and R 5 It can be Me, F, Cl, Br, -OMe, -CF3, -OCF3, -O-benzyl, or -NO2.

24. The compound according to any one of claims 1-22, or a pharmaceutically acceptable salt thereof, characterized in that, R 5 For Me, F, Cl, Br, -OMe, -CF3, -OCF3, -O-benzyl, or -NO2; and R 6 and R 7 Each can be independently hydrogen, Me, F, Cl, Br, -OMe, -OCF3, -O-CH2-phenyl, or -NO2, wherein R 6 and R 7 At least one of them is not hydrogen.

25. The compound according to any one of claims 1-2, or a pharmaceutically acceptable salt thereof, characterized in that, X is CR 3 ; R 1a and R 1b Each for Me; R 1c For Me, Et, or Pr; R 2 For H, Me, -OMe, F or -C(O)-C(O)N(Me)2; R 3 For H, Me, -OMe, F, or -C(O)-C(O)N(Me)2; and R 4 R 5 R 6 and R 7 Each can be independently H, Me, -F, -Cl, -Br, -NO2, -OMe, -CF3, -OCF3, or -O-benzyl; Or, R 5 and R 6 They combine to form 1,3-me-dioxacyclopentene rings or 1,4-dioxane rings.

26. The compound as described in claims 1-2 or 25, or a pharmaceutically acceptable salt thereof, characterized in that, X is CR 3 ; R 1a and R 1b Each for Me; R 1c For Me, Et, or Pr; R 2 is H, Me, -F, -OMe; R 3 For H, Me, -F, -OMe or -C(O)-C(O)N(Me)2; R 4 It can be H, Me, -F, -OMe or -O-benzyl; R 5 It can be H, Me, -F, -Cl, -Br, -OMe, -CF3, -OCF3, or -O-benzyl; R 6 It can be H, Me, -F, -NO2, -OMe, -OCF3, or -O-benzyl; Or, R 5 and R 6 Combined to form a 1,3-me-dioxacyclopentene ring or a 1,4-dioxane ring; and R 7 It can be H, Me, -F, -OMe or -O-benzyl.

27. The compound according to any one of claims 1-26, characterized in that, The compound is ， Or its pharmaceutically acceptable salt.

28. The compound according to any one of claims 1-26, characterized in that, The compound is , , , , , , , , , , , , , , or Or, or a pharmaceutically acceptable salt thereof.

29. The compound according to any one of claims 1-26, characterized in that, The compound is , , , , , , , , , , , , , , , , , , , , , , , or Or, or a pharmaceutically acceptable salt thereof.

30. The compound according to any one of claims 1-29, characterized in that, The compound is a salt containing fumaric acid or a pharmaceutically acceptable salt.

31. A compound of formula II or a pharmaceutically acceptable salt thereof and its isomers: (II) in: X is CR 3 ; R 1a and R 1b Each independently is hydrogen, C 1-6 Alkyl, C 3-8 cycloalkyl, or C 4-14 Alkyl-cycloalkyl; Or, R 1a and R 1b They combine with the atoms they are attached to to form C 3-12 Heterocyclic alkyl groups; R 2 R 3 R 4 R 5 R 6 and R 7 Each independently is hydrogen, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkyne, halogen, C 1-6 Haloalkyl, C 1-6 Alkylamine, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, –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 Heterocyclic alkyl, C 4-16 Alkyl-heterocyclic alkyl, C 6-12 Aryl, C 7-18 Alkyl-aryl, C 5-10 heteroaryl, or C 4-16 Alkyl heteroaryl; R 8a C 3-8 cycloalkyl, C 3-14 Alkyl-cycloalkyl, C 4-10 Heterocyclic alkyl, C 4-16 Alkyl-heterocyclic alkyl, 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 Each independently is H or C 1-6 alkyl; Or, R 1a or R 1b One of them with R 2 Combine to form C 5-12 Heterocyclic alkyl groups; Or, R 2 and R 3 They combine with their respective atoms to form C 4-8 cycloalkyl, C 4-10 Heterocyclic alkyl, or C 6-12 Aryl; Or, R 4 and R 5 R 5 and R 6 , or R 6 and R 7 They combine with their respective atoms to form C 4-6 cycloalkyl, C 4-6 Heterocyclic alkyl, C 6-12 Aryl, or C 5-10 Mixed aromatics; and L is C 1-6 Alkylene Where R 1a and R 1b When all are Me and L is methylene, then 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 not: ； Where R 1a and R 1b All are Me, L is ethylene, and X is CR. 3 Then R 2 R 3 R 4 R 5 R 6 and R 7 At least one of them is not hydrogen; Where R 1c For hydrogen, and R 5 For Br, Cl, F, -NH2, -NO2, or C 1-3 Alkoxy, then R 2 R 3 R 4 R 6 or R 7 At least one of them is not hydrogen; and Where R 1c For hydrogen and R 5 If F is the value of R, then R 2 R 3 R 4 R 6 or R 7 At least one of them is not hydrogen and R 6 It's not F.

32. The compound of claim 31, or a pharmaceutically acceptable salt thereof, characterized in that, The compound of formula II has the following structure: 。 33. The compound of claim 31 or 32, or a pharmaceutically acceptable salt thereof, characterized in that, The compound of formula II has the following structure: 。 34. The compound according to any one of claims 31-33, or a pharmaceutically acceptable salt thereof, characterized in that, R 2 R 3 R 4 R 5 R 6 and R 7 At least one of them is not H.

35. The compound according to any one of claims 31-34, or a pharmaceutically acceptable salt thereof, characterized in that, R 4 R 5 R 6 and R 7 Each independently is hydrogen, C 1-6 Alkyl, halogen, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, –OR 8a -NO2, -CN, C 3-8 cycloalkyl, or C 3-14 Alkyl-cycloalkyl; Or, R 4 and R 5 R 5 and R 6 , or R 6 and R 7 They combine with their respective atoms to form C 5-6 Heterocyclic alkyl groups; and R 8a C 3-8 cycloalkyl, C 3-14 Alkyl-cycloalkyl, C 4-16 Alkyl-heterocyclic alkyl, C 7-18 alkyl-aryl, or C 4-16 Alkyl-heteroaryl.

36. The compound according to any one of claims 31-35, or a pharmaceutically acceptable salt thereof, characterized in that, R 4 R 5 R 6 and R 7 Each independently represents H and C. 1-6 Alkyl, halogen, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, -OR 8a Or -NO2; Or, R 4 and R 5 R 5 and R 6 , or R 6 and R 7 They combine with their respective attached atoms to form C5 heterocyclic alkyl groups; and R 8a C 7-18 Alkyl-aryl.

37. The compound according to any one of claims 31-36, or a pharmaceutically acceptable salt thereof, characterized in that, R 4 R 5 R 6 and R 7 Each can be independently hydrogen, F, Cl, -OMe, -OCF3, or -O-benzyl; Or, R 5 and R 6 They combine with the atoms to which they are attached to form 1,3-m-dioxacyclopentene rings or 1,4-dioxane rings.

38. The compound according to any one of claims 31-37, or a pharmaceutically acceptable salt thereof, characterized in that, R 5 It can be F, Cl, -OMe, -OCF3, or -O-benzyl; Or, R 5 and R 6 They combine with the atoms to which they are attached to form 1,3-m-dioxacyclopentene rings or 1,4-dioxane rings.

39. The compound according to any one of claims 31-37, or a pharmaceutically acceptable salt thereof, characterized in that, R 5 For F, Cl, -OMe, -OCF3, or -O-benzyl; R 6 and R 7 Each is independently hydrogen, F, Cl, -OMe, -OCF3, or -O-benzyl, wherein R 6 and R 7 At least one of them is not hydrogen; Or, R 5 and R 6 They combine with the atoms to which they are attached to form 1,3-m-dioxacyclopentene rings or 1,4-dioxane rings.

40. The compound according to any one of claims 31-37, characterized in that, The compound is ， Or its pharmaceutically acceptable salt.

41. The compound according to any one of claims 31-39, characterized in that, The compound is , or its pharmaceutically acceptable salt.

42. The compound according to any one of claims 31-39, characterized in that, R 1a and R 1b They combine with the atoms they are attached to to form C 3-8 Heterocyclic alkyl groups.

43. The compound according to any one of claims 31-39 or 42, characterized in that, The compound is , ,or Or its pharmaceutically acceptable salt.

44. The compound according to any one of claims 31-37, characterized in that, The compound is 、 、 、 , , , , , , , , , or Or, or a pharmaceutically acceptable salt thereof.

45. The compound according to any one of claims 31-44, characterized in that, The compound is a salt containing fumaric acid or a pharmaceutically acceptable salt.

46. ​​A pharmaceutical composition comprising the compound as described in any one of claims 1-45 and a pharmaceutically acceptable excipient.

47. A method for increasing neuronal plasticity, comprising contacting neuronal cells with a compound of formula I or a pharmaceutically acceptable salt thereof, at a dose sufficient to increase neuronal plasticity of the neuronal cells: (I) in: X is N or CR 3 ; R 1a R 1b and R 1c Each independently is hydrogen, C 1-6 Alkyl, C 3-8 cycloalkyl, or C 4-14 Alkyl-cycloalkyl; Or, R 1a R 1b and R 1c The two atoms in the mixture combine with the atoms they are attached to to form C. 3-12 Heterocyclic alkyl groups; R 2 R 3 R 4 R 5 R 6 and R 7 Each independently is hydrogen, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkyne, halogen, C 1-6 Haloalkyl, C 1-6 Alkylamine, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, –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 Heterocyclic alkyl, C 4-16 Alkyl-heterocyclic alkyl, C 6-12 Aryl, C 7-18 Alkyl-aryl, C 5-10 heteroaryl, or C 4-16 Alkyl heteroaryl; R 8a C 3-8 cycloalkyl, C 3-14 Alkyl-cycloalkyl, C 4-10 Heterocyclic alkyl, C 4-16 Alkyl-heterocyclic alkyl, 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 Each independently is H or C 1-6 alkyl; Or, R 1a R 1b or R 1c One of them with R 2 Combine to form C 5-12 Heterocyclic alkyl groups; Or, R 2 and R 3 They combine with their respective atoms to form C 4-8 cycloalkyl, C 4-10 Heterocyclic alkyl, or C 6-12 Aryl; Or, R 4 and R 5 R 5 and R 6 , or R 6 and R 7 They combine with their respective atoms to form C 3-6 cycloalkyl, C 3-6 Heterocyclic alkyl, C 6-12 Aryl, or C 5-10 heteroaryl; and L is C 1-6 Alkylene.

48. A method of treating a brain disease, comprising administering to a subject in need a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof, thereby treating the brain disease: (I) in: X is N or CR 3 ; R 1a R 1b and R 1c Each independently is hydrogen, C 1-6 Alkyl, C 3-8 cycloalkyl, or C 4-14 Alkyl-cycloalkyl; Or, R 1a R 1b and R 1c The two atoms in the mixture combine with the atoms they are attached to to form C. 3-12 Heterocyclic alkyl groups; R 2 R 3 R 4 R 5 R 6 and R 7 Each independently is hydrogen, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkyne, halogen, C 1-6 Haloalkyl, C 1-6 Alkylamine, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, –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 Heterocyclic alkyl, C 4-16 Alkyl-heterocyclic alkyl, C 6-12 Aryl, C 7-18 Alkyl-aryl, C 5-10 heteroaryl, or C 4-16 Alkyl heteroaryl; R 8a C 3-8 cycloalkyl, C 3-14 Alkyl-cycloalkyl, C 4-10 Heterocyclic alkyl, C 4-16 Alkyl-heterocyclic alkyl, 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 Each independently is H or C 1-6 alkyl; Or, R 1a R 1b or R 1c One of them with R 2 Combine to form C 5-12 Heterocyclic alkyl groups; Or, R 2 and R 3 They combine with their respective atoms to form C 4-8 cycloalkyl, C 4-10 Heterocyclic alkyl, or C 6-12 Aryl; Or, R 4 and R 5 R 5 and R 6 , or R 6 and R 7 They combine with their respective atoms to form C 3-6 cycloalkyl, C 3-6 Heterocyclic alkyl, C 6-12 Aryl, or C 5-10 heteroaryl; and L is C 1-6 Alkylene.

49. The method as described in claim 48, characterized in that, The brain disease mentioned is a neurodegenerative disease, Alzheimer's disease, or Parkinson's disease.

50. The method as described in claim 48, characterized in that, The brain disorders mentioned are mental disorders, depression, addiction, anxiety, or post-traumatic stress disorder.

51. The method as described in claim 50, characterized in that, The brain disease mentioned is depression.

52. The method as described in claim 50, characterized in that, The brain disease mentioned is addiction.

53. The method as described in claim 48, characterized in that, The brain disorders mentioned are treatment-resistant depression, suicidal ideation, major depressive disorder, bipolar disorder, schizophrenia, or substance use disorder.

54. The method as described in claim 48, characterized in that, The brain disease referred to is stroke or traumatic brain injury.

55. The method according to any one of claims 48-54, characterized in that, This includes the administration of one or more additional therapeutic agents, such as lithium, olanzapine (Zyprexa), quetiapine (Seroquel), risperidone (Risperdal), aripiprazole (Abilify), ziprasidone (Geodon), clozapine (Clozaril), sodium dihydrophenylalanine (Depakote), lamotrigine (Lamictal), sodium valproate (Depakene), carbamazepine (Equetro), topiramate (Topamax), levamisole (Fetzima), duloxetine (Cymbalta, Yentreve), and venlafaxine. Effexor, Celexa, Luvox, Lexapro, Prozac, Paxil, Zolot, Anafranil, Elavil, Norpramine, Tofranil, Pamelor, Nardil, Parnate, Valium, Xanax, or Klonopin.

56. A method for enhancing at least one of the translation, transcription, or secretion of neurotrophic factors, comprising contacting neuronal cells with a compound of formula I or a pharmaceutically acceptable salt thereof, in a dose sufficient to increase neuronal plasticity of the neuronal cells: (I) in: X is N or CR 3 ; R 1a R 1b and R 1c Each independently is hydrogen, C 1-6 Alkyl, C 3-8 cycloalkyl, or C 4-14 Alkyl-cycloalkyl; Or, R 1a R 1b and R 1c The two atoms in the mixture combine with the atoms they are attached to to form C. 3-12 Heterocyclic alkyl groups; R 2 R 3 R 4 R 5 R 6 and R 7 Each independently is hydrogen, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkyne, halogen, C 1-6 Haloalkyl, C 1-6 Alkylamine, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, –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 Heterocyclic alkyl, C 4-16 Alkyl-heterocyclic alkyl, C 6-12 Aryl, C 7-18 Alkyl-aryl, C 5-10 heteroaryl, or C 4-16 Alkyl heteroaryl; R 8a C 3-8 cycloalkyl, C 3-14 Alkyl-cycloalkyl, C 4-10 Heterocyclic alkyl, C 4-16 Alkyl-heterocyclic alkyl, 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 Each independently is H or C 1-6 alkyl; Or, R 1a R 1b or R 1c One of them with R 2 Combine to form C 5-12 Heterocyclic alkyl groups; Or, R 2 and R 3 They combine with their respective atoms to form C 4-8 cycloalkyl, C 4-10 Heterocyclic alkyl, or C 6-12 Aryl; Or, R 4 and R 5 R 5 and R 6 , or R 6 and R 7 They combine with their respective atoms to form C 3-6 cycloalkyl, C 3-6 Heterocyclic alkyl, C 6-12 Aryl, or C 5-10 heteroaryl; and L is C 1-6 Alkylene.

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