N-substituted indoles and other heterocyclic compounds for the treatment of brain disorders

Abstract

The invention provides N-substituted indoles and other heterocycles and methods of using the compounds to treat brain disorders.

Description

[0001] Cross Reference to Related Applications

[0002] This patent application is based on priority of U.S. provisional applications numbered 62 / 811,206 filed February 27, 2019 and 62 / 958,220 filed January 7, 2020, the contents of which are incorporated herein by reference for all purposes. BACKGROUND

[0004] Ketamine, N,N-dimethyltryptamine (DMT), and other psychoplastogenic agents have neurotherapeutic potential due to their ability to promote neuronal growth.

[0005] Several key features of psychoplastogenic pharmacophores are disclosed herein. Also disclosed herein are iso-DMT psychoplastogenic agents that are more synthetically accessible, have better physicochemical properties, and have lower psychedelic potential than their DMT counterparts.

[0006] 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 the dissociative anesthetic ketamine for the treatment of treatment-resistant depression, making it the first mechanistically unique drug introduced into psychiatry in nearly 30 years. In some cases, ketamine is able to correct deleterious changes in neuronal structure associated with depression. Such structural changes include, for example, loss of dendritic spines and synapses in the prefrontal cortex (PFC), and reduction in dendritic arbor complexity. However, ketamine is an imperfect drug, for example, it has potential for abuse, and its dissociative effects require patients to be hospitalized during treatment. There is a clinical need for a treatment without such side effects.

[0007] Compounds known as psychoplastogens promote neuronal growth through mechanisms that activate AMPA receptors, the TrkB and mTOR. In addition to ketamine, the tropane alkaloid scopolamine and GLYX-13 (i.e., rapastinel) have shown psychoplastogenic properties, and this class of compounds has the potential to treat a variety of neuropsychiatric disorders. These results provide an explanation for the psychedelic effects of compounds that have clinically relevant antidepressant, anxiolytic, and anti-addictive effects, as pyramidal neurons in the PFC exhibit top-down control over brain regions that control motivation, fear, and reward.

[0008] A common pharmacophore in psychedelic compounds appears to be N,N-dimethyltryptamine (DMT, 1) Figure 1 ). Since DMT produces antidepressant and anxiolytic behavioral effects in rodents, and a soup containing DMT has demonstrated clinical efficacy in the treatment of treatment-resistant depression, DMT was used as a starting point for the identification of new psychoplastogenic compounds described herein.

[0009] Thus, there is a need for new compounds to treat major depressive disorder and neuropsychiatric disorders. The present invention satisfies this and other needs. SUMMARY

[0010] In one embodiment, the present invention provides a compound of Formula I, or a pharmaceutically acceptable salt thereof, and isomers thereof:

[0011]

[0012] wherein: X is CR 3 ; R 1a and R 1b are each independently hydrogen, C 1-6 alkyl, C 3-8 cycloalkyl, or C 4-14 alkyl-cycloalkyl; R 1c is C 1-6 alkyl, C 3-8 cycloalkyl, or C 4-14 alkyl-cycloalkyl; or, two of R 1a , R 1b and R 1c combine with the atom to which they are attached to form a C 3-12 heterocycloalkyl; R 2 , R 3 , R 4 , R 5 , R 6 and R 7 are each independently hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, halogen, C 1-6 haloalkyl, C 1-6 alkylamine, C 1-6 alkoxy, C 1-6 haloalkoxy, -OR 8a , -NO2, -CN, -C(O)R 8b , -C(O)OR 8b , -OC(O)R 8b , -OC(O)OR 8b , -N(R 8b R 8c ), -N(R 8b )C(O)R 8c , -C(O)N(R 8b R 8c ), -N(R 8b )C(O)OR 8c , -OC(O)N(R 8b R 8c ), -N(R 8b)C(O)N(R 8c R 8d -C(O)C(O)N(R) 8b R 8c -S(O2)R 8b -S(O)2N(R) 8b R 8c C 3-8 cycloalkyl, C 3-14 Alkyl-cycloalkyl, C 4-10 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 When each is Me, L is methylene and X is CR. 3and R 2 , R 3 , R 4 , R 5 , R 6 and R 7 are hydrogen, then the compound is

[0013] and wherein the compound is not and

[0014] In another embodiment, the present application provides a compound of Formula II, or a pharmaceutically acceptable salt thereof, and isomers thereof:

[0015]

[0016] wherein: X is CR 3 ; R 1a and R 1b are each independently H, C 1-6 alkyl, C 3-8 cycloalkyl, or C 4-14 alkyl-cycloalkyl; or, R 1a and R 1b combine with the atoms to which they are attached to form C 3-12 heterocycloalkyl; R 2 , R 3 , R 4 , R 5 , R 6 and R 7 are each independently hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, halogen, C 1-6 haloalkyl, C 1-6 alkylamine, C 1-6 alkoxy, C 1-6 haloalkoxy, -OR 8a , -NO2, -CN, -C(O)R 8b , -C(O)OR 8b , -OC(O)R 8b , -OC(O)OR 8b , -N(R 8b R 8c ), -N(R 8b )C(O)R 8c , -C(O)N(R 8b R 8c ), -N(R 8b )C(O)OR 8c , -OC(O)N(R 8b R 8c), -N(R 8b )C(O)N(R 8c R 8d ), -C(O)C(O)N(R 8b R 8c ), -S(O2)R 8b , -S(O)2N(R 8b R 8c ), C 3-8 cycloalkyl, C 3-14 alkyl-cycloalkyl, C 4-10 heterocycloalkyl, C 4-16 alkyl-heterocycloalkyl, C 6-12 aryl, C 7-18 alkyl-aryl, C 5-10 heteroaryl, or C 4-16 alkyl-heteroaryl; R 8a is C 3-8 cycloalkyl, C 3-14 alkyl-cycloalkyl, C 4-10 heterocycloalkyl, C 4-16 alkyl-heterocycloalkyl, C 6-12 aryl, C 7-18 alkyl-aryl, C 5-10 heteroaryl, or C 4-16 alkyl-heteroaryl; R 8b , R 8c and R 8d are each independently H or C 1-6 alkyl; or, one of R 1a or R 1b in combination with R 2 forms a C 5-12 heterocycloalkyl; or, R 2 and R 3 in combination with the atoms to which they are each attached form a C 4-8 cycloalkyl, C 4-10 heterocycloalkyl, or C 6-12 aryl; or, R 4 and R 5 , R 5 and R 6 , or R 6 and R 7 in combination with the atoms to which they are each attached form a C 4-6 cycloalkyl, C 4-6 heterocycloalkyl, C 6-12 aryl, or C 5-10 heteroaryl; L is C 1-6 alkylene, wherein, when R 1a and R 1b are each Me, L is methylene, then R 2 , R3 , R 4 , R 5 , R 6 , and R 7 is not hydrogen and the compound is not:

[0017]

[0018] wherein, when R 1a and R 1b are Me, L is ethylene, X is CR 3 , then at least one of R 2 , R 3 , R 4 , R 5 , R 6 , and R 7 is not hydrogen; wherein, when R 1c is H, R 5 is Br, Cl, F, -NH2, -NO2, or C 1-3 alkoxy, then at least one of R 2 , R 3 , R 4 , R 6 , or R 7 is not hydrogen; wherein, when R 1c is hydrogen and R 5 is F, then at least one of R 2 , R 3 , R 4 , R 6 , or R 7 is not hydrogen, R 6 is not F.

[0019] In another embodiment, the present application provides a pharmaceutical composition comprising a compound of the present application and a pharmaceutically acceptable excipient.

[0020] In another embodiment, the present application provides a method for increasing neuronal plasticity comprising contacting a neuronal cell with a compound of Formula I, or a pharmaceutically acceptable salt thereof:

[0021]

[0022] in an amount sufficient to increase neuronal plasticity in the neuronal cell, wherein: X is N or CR 3 ; R 1a , R 1b , and R 1c are each independently H, C 1-6 alkyl, C 3-8 cycloalkyl, or C 4-14 alkyl-cycloalkyl; or, R 1aR 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 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 6-12aryl, C 7-18 alkyl-aryl, C 5-10 heteroaryl, or C 4-16 alkyl-heteroaryl; R 8b , R 8c and R 8d are each independently H or C 1-6 alkyl; or, R 1a , R 1b or R 1c one in combination with R 2 form a C 5-12 heterocycloalkyl; or, R 2 and R 3 in combination with the atoms to which they are respectively attached form a C 4-8 cycloalkyl, C 4-10 heterocycloalkyl, or C 6-12 aryl; or, R 4 and R 5 , R 5 and R 6 , or R 6 and R 7 in combination with the atoms to which they are respectively attached form a C 3-6 cycloalkyl, C 3-6 heterocycloalkyl, C 6-12 aryl, or C 5-10 heteroaryl; and L is C 1-6 alkylene.

[0023] In another embodiment, the present application provides a method of treating a brain disease, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof:

[0024]

[0025] thereby treating the brain disease, wherein: X is N or CR 3 ; R 1a , R 1b and R 1c are each independently H, C 1-6 alkyl, C 3-8 cycloalkyl, or C 4-14 alkyl-cycloalkyl; or, any two of R 1a , R 1b and R 1c in combination with the atoms to which they are attached form a C 3-12 heterocycloalkyl; R 2 , R 3 , R 4 , R 5 , R 6 and R 7 are each independently hydrogen, C1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, halogen, C 1-6 haloalkyl, C 1-6 alkylamine, C 1-6 alkoxy, C 1-6 haloalkoxy, -OR 8a , -NO2, -CN, -C(O)R 8b , -C(O)OR 8b , -OC(O)R 8b , -OC(O)OR 8b , -N(R 8b R 8c ), -N(R 8b )C(O)R 8c , -C(O)N(R 8b R 8c ), -N(R 8b )C(O)OR 8c , -OC(O)N(R 8b R 8c ), -N(R 8b )C(O)N(R 8c R 8d ), -C(O)C(O)N(R 8b R 8c ), -S(O2)R 8b , -S(O2)N(R 8b R 8c ), C 3-8 cycloalkyl, C 3-14 alkyl-cycloalkyl, C 4-10 heterocycloalkyl, C 4-16 alkyl-heterocycloalkyl, C 6-12 aryl, C 7-18 alkyl-aryl, C 5-10 heteroaryl, or C 4-16 alkyl-heteroaryl; R 8a is C 3-8 cycloalkyl, C 3-14 alkyl-cycloalkyl, C 4-10 heterocycloalkyl, C 4-16 alkyl-heterocycloalkyl, C 6-12 aryl, C 7-18 alkyl-aryl, C 5-10 heteroaryl, or C 4-16 alkyl-heteroaryl; R 8b , R 8c , and R 8d are each independently H or C 1-6 alkyl; or, R 1a , R 1bor R 1c wherein one of R 2 combines with the atom to which they are both attached to form a C 5-12 heterocycloalkyl; or, R 2 and R 3 combine to form a C 4-8 cycloalkyl, C 4-10 heterocycloalkyl, or C 6-12 aryl; or, R 4 and R 5 , R 5 and R 6 , or R 6 and R 7 combine to form a C 3-6 cycloalkyl, C 3-6 heterocycloalkyl, C 6-12 aryl, or C 5-10 heteroaryl; and L is C 1-6 alkylene.

[0026] In another embodiment, the present application provides a method of increasing at least one of translation, transcription, or secretion of a neurotrophic factor, comprising contacting a neuronal cell with a compound of Formula I, or a pharmaceutically acceptable salt thereof:

[0027]

[0028] in a dosage sufficient to increase neuronal plasticity of the neuronal cell, wherein: X is N or CR 3 ; R 1a , R 1b , and R 1c are each independently H, C 1-6 alkyl, C 3-8 cycloalkyl, or C 4-14 alkyl-cycloalkyl; or, any two of R 1a , R 1b , and R 1c combine with the atom to which they are attached to form a C 3-12 heterocycloalkyl; R 2 , R 3 , R 4 , R 5 , R 6 , and R 7 are each independently hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, halogen, C 1-6 haloalkyl, C 1-6 alkylamine, C 1-6 alkoxy, C 1-6 haloalkoxy, -OR 8a-NO2, -CN, -C(O)R 8b -C(O)OR 8b -OC(O)R 8b -OC(O)OR 8b -N(R) 8b R 8c ), -N(R 8b )C(O)R 8c -C(O)N(R) 8b R 8c ), -N(R 8b )C(O)OR 8c -OC(O)N(R) 8b R 8c ), -N(R 8b )C(O)N(R 8c R 8d -C(O)C(O)N(R) 8b R 8c -S(O2)R 8b -S(O)2N(R) 8b R 8c C 3-8 cycloalkyl, C 3-14 Alkyl-cycloalkyl, C 4-10 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 4-10heteroaryl; and L is C 6-12 aryl; or, R 4 and R 5 , R 5 and R 6 , or R 6 and R 7 combined with the atom to which they are each attached form a C 3-6 cycloalkyl, C 3-6 heterocycloalkyl, C 6-12 aryl, or C 5-10 heteroaryl; and L is C 1-6 alkylene.

[0029] BRIEF DESCRIPTION OF DRAWINGS

[0030] Figure 1 A and Figure 1 B show the structure of compounds with the DMT pharmacophore. Figure 1 A shows that the DMT structure (highlighted in black) is the core structure of several known psychoactive 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 the indole are transposed. Predicted chemical properties and calculated MPO values are shown. clogD = calculated log D; TPSA = total polar surface area; HBD = hydrogen bond donor; MPO = multi-parameter optimization value.

[0031] Figure 2 A, Figure 2 B and Figure 2 C show that the indole N-H of the tryptamine derivative is not necessary for promoting dendritogenesis. Figure 2 A shows representative images of cortical neurons (DIV6) treated with compounds. Figure 2 B shows sholl analysis indicating that 1-ME-DMT (27) and iso-DMT (2) increase dendritic spine complexity comparable to DMT (1) (n = 46-79 neurons). Figure 2 C shows the maximum number of intersections (Nmax) of the Sholl plot in B. Data represent mean ± SEM. One-way ANOVA with Dunnett’s post-hoc multiple comparisons, *p < 0.05, **p < 0.01, ***p < 0.001, *****p < 0.0001, (F = 9.702; DFN= 4; DFd= 304; p-value < 0.0001). VEH = vehicle, KET = ketamine. Scale bar: 20 μm.

[0032] Figure 3 A and Figure 3 B show that DMT and iso-DMT analogs produce similar effects on dendritic spine complexity. Figure 3A shows the chemical structure of DMT derivative and analog isoDMT. Figure 3 B shows the maximum number of intersections (Nmax) of cortical neurons Sholl analysis treated with compounds (n = 82-95 neurons). Data are expressed as mean ± SEM. One-way ANOVA with Dunnett’s post-hoc multiple testing, *p<0.05, **p<0.01, ***p<0.001, *****p<0.0001 vs vehicle control (F=11.17; DFn=5; DFd=524; p-value <0.0001). VEH = vehicle, KET = ketamine.

[0033] Figure 4 A to Figure 4 C shows the establishment of the essential psychoplastogen pharmacophore. Figure 4 A: Chemical structure of non-basic analog isoDMT2. Figure 4 B and Figure 4 C shows the maximum number of intersections (Nmax) of cortical neurons Sholl analysis treated with compounds (n = 46-85 neurons). Data are expressed as mean ± SEM. One-way ANOVA with Dunnett’s post-hoc multiple testing, *p<0.05, **p<0.01, ***p<0.001, *****p<0.0001 vs vehicle control (F=11.17; DFn=5; DFd=524; p-value <0.0001). VEH = vehicle, KET = ketamine. Figure 4 B and Figure 4 The effect of nitrogen basicity and aromatic ring modification was evaluated in B and C, respectively. Data are expressed as mean ± SEM. One-way ANOVA with Dunnett’s post-hoc multiple testing, *p<0.05, **p<0.01, ***p<0.001, *****p<0.0001 vs vehicle control (for B: F=19.03; DFn=4; DFd=273; p-value <0.0001. For C: F=6.933; DFn=8; DFd=599; p-value <0.0001). VEH = vehicle, KET = ketamine.

[0034] Figure 5 The effect of indole substitution on isoDMT’s ability to promote neuronal growth is shown. Maximum number of intersections (Nmax) of cortical neurons Sholl analysis treated with compounds (n = 39-93 neurons). Data are expressed as mean ± SEM. One-way ANOVA with Dunnett’s post-hoc multiple testing, *p<0.05, **p<0.01, ***p<0.001, *****p<0.0001 vs vehicle control (for R=OMe: F=13.85; DFn=5; DFd=493; p-value <0.0001. For R=OBn: F=15.44; DFn=5; DFd=372; p-value <0.0001. For R=F: F=13.24; DFn=5; DFd=506; p-value <0.0001). VEH = vehicle, KET = ketamine.

[0035] Figure 6Figure 6 shows that concentration-response experiments indicate that DMT and isoDMT have similar psychoplastogenic potential. Maximum number of intersections (Nmax) of Sholl plots of cortical neurons treated with compounds at concentrations ranging from 10 mM to 10 pM (n = 66-123 neurons). Data are expressed as mean ± SEM. One-way ANOVA with Dunnett’s post-hoc multiple testing, *p<0.05, **p<0.01, ***p<0.001, *****p<0.0001 vs vehicle control (F=15.40; DFn=24; DFd=2,276; p-value<0.0001). V = vehicle, K = ketamine.

[0036] Figure 7 Figure 8 shows that psychoplastogenic effects of isoDMT are blocked by 5-HT2A antagonists. Maximum number of intersections (Nmax) of Sholl plots of cortical neurons treated with compounds in the presence (+) and absence (-) of the 5-HT2A antagonist ketanserin (n = 45-63 neurons). Data are expressed as mean ± SEM. One-way ANOVA with Dunnett’s post-hoc multiple testing, *****p<0.0001 vs vehicle control (F=13.92; DFn=8; DFd=461; p-value<0.0001). V = vehicle, K = ketamine, KTSN = ketanserin.

[0037] Figure 8 Figure 9 shows that mouse HTR assay indicates that psychoplastogenic isoODMTs exhibit reduced hallucinogenic potential. Male and female mice were dosed by i.p. injection and the number of head twitches was recorded over the next 20 minutes (n = 3-8 mice per condition). Data are expressed as mean ± SEM. One-way ANOVA with Dunnett’s post-hoc multiple testing, *p<0.05, **p<0.01, ***p<0.001, *****p<0.0001 vs vehicle control. V = vehicle.

[0038] Figure 9 Figure 10 shows the ability of compounds of the invention to reduce head twitch behavioral responses in the head twitch response assay.

[0039] Figure 10 Figure 11 shows the effect of hallucinogenic and non-hallucinogenic compounds on 5HT 2A Dose response curves measured by sensor.

[0040] Figure 11 Figure 12 shows the effect of hallucinogenic and non-hallucinogenic compounds (10 mM) on 5HT 2A Response curves measured by sensor.

[0041] Figure 12AThe 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.

[0042] 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.

[0043] Figure 14 A and Figure 14 B illustrates the antidepressant properties of the compound of the present invention in a forced swimming test in two preliminary trials. Figure 14 A) and acute ( Figure 14 B) Application of the compound. Detailed Implementation

[0044] I.General

[0045] 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.

[0046] 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.

[0047] 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).

[0048] Provided herein are non-psychedelic plasticizers of the mind. Further, several iso-DMT compounds have comparable affinity for serotonin receptors relative to their DMT counterparts. In some embodiments, iso-DMT analogs described herein have improved physicochemical properties due to loss of hydrogen bond donors, reduced overall polar surface area, and improved central nervous system multi-parameter optimization (MPO) values Figure 1 ) In some embodiments described herein, non-psychedelic compounds are described that show similar therapeutic potential to psychedelic 5-HT 2A agonists. In some embodiments, non-psychedelic compounds described herein provide better therapeutic potential for neurological diseases than psychedelic 5-HT 2A agonists.

[0049] II. DEFINITIONS

[0050] Unless otherwise indicated, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs. Furthermore, any method or material similar or equivalent to those described herein can be used in the practice of the present application. For purposes of the present application, the following terms are defined with the following meanings.

[0051] “a,” “an,” or “the” refers to both the singular and plural aspects unless otherwise indicated by context. For example, the singular forms “a,” “an” and “the” include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to “a cell” includes a plurality of such cells, and reference to “an agent” includes reference to one or more agents known to one of skill in the art, and so forth.

[0052] Abbreviations used: DMT, N,N-dimethyltryptamine; PFC, prefrontal cortex; 5-HT2A, 5-hydroxytryptamine 2A; MPO, multi-parameter optimization; LSD, lysergic acid diethylamide; TPSA, total polar surface area; MAP2, microtubule-associated protein 2; N max, maximum number of intersections; 5-HT2B, 5-hydroxytryptamine 2B; DIV, days in vitro; VEH, vehicle; KET, ketamine; SEM; standard error of the mean; ANOVA, analysis of variance; DOM, 2,5-dimethoxy-4-methylamphetamine; OMe, methoxy; OBn, benzyloxy; F, fluoro; pM, picomolar; V, vehicle; K, ketamine; ATR, attenuated total reflectance; 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, Dulbecco's Phosphate Buffered Saline; mTOR, mammalian target of rapamycin; AMPA, a-amino-3-hydroxy-5-methyl-4- isoxazole propionic acid; TrkB, tropomyosin receptor kinase B; HTR, head twitch response.

[0053] "Alkyl" refers to a straight-chain or branched-chain saturated aliphatic radical having the indicated number of carbon atoms. Alkyl groups can include any number of carbons, for example, C 1-2 , C 1-3 , C 1-4 , C 1-5 , C 1-6 , C 1-7 , C 1-8 , C 1-9 , C 1-10 , C 2-3 , C 2-4 , C 2-5 , C 2-6 , C 3-4 , C 3-5 , C 3-6 , C 4-5 , C 4-6 , and C 5-6 . For example, C 1-6 alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, pentyl, isopentyl, hexyl, and the like. Alkyl groups can also refer to alkyl groups having up to 20 carbon atoms, for example, but not limited to, heptyl, octyl, nonyl, decyl, and the like. Alkyl groups can be substituted or unsubstituted.

[0054] "Alkylene" refers to a straight-chain or branched-chain saturated aliphatic group having the indicated number of carbons and linking at least two other groups, i.e., a divalent hydrocarbon radical. The two moieties attached to the alkylene group can be attached to the same atom or different atoms of the alkylene group. For example, a straight-chain alkylene group can be the divalent group -(CH2) n-wherein n is 1, 2, 3, 4, 5, or 6. Representative alkylene groups include, but are not limited to, methylene, ethylene, propylene, isopropylene, butylene, isobutylene, sec-butylene, amylene, and hexylene. The alkylene group can be substituted or unsubstituted.

[0055] "Alkenyl" refers to a straight or branched chain hydrocarbon having at least 2 carbon atoms and at least one double bond. Alkenyl groups can include any number of carbons, such as C2, C 2-3 , C 2-4 , C 2-5 , C 2-6 , C 2-7 , C 2-8 , C 2-9 , C 2-10 , C3, C 3-4 , C 3-5 , C 3-6 , C4, C 4-5 , C 4-6 , C5, C 5-6 , and C6. Alkenyl groups have any suitable number of double bonds, including but not limited to 1, 2, 3, 4, 5, or more. Examples of alkenyl groups include, but are not limited to, ethenyl (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 can be substituted or unsubstituted.

[0056] "Alkynyl" refers to a straight or branched chain hydrocarbon having at least 2 carbon atoms and at least one triple bond. Alkynyl groups can include any number of carbons, such as C2, C 2-3 , C 2-4 , C 2-5 , C 2-6 , C 2-7 , C 2-8 , C 2-9 , C 2-10 , C3, C 3-4 , C 3-5 , C 3-6 , C4, C 4-5 , C 4-6 , C5, C 5-6and C6. Examples of alkynyl groups include, but are not limited to, ethynyl, propynyl, 1 -butynyl, 2-butynyl, butadiynyl, 1-pentynyl, 2-pentynyl, isopentynyl, 1,3-pentadiynyl, 1,4-pentadiynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 1,3-hexadiynyl, 1,4-hexadiynyl, 1,5-hexadiynyl, 2,4-hexadiynyl, or 1,3,5-hexatriynyl. Alkynyl groups can be substituted or unsubstituted.

[0057] "Cycloalkyl" refers to saturated or partially unsaturated, monocyclic, bicyclic, fused bicyclic, or polycyclic bridged ring combinations containing 3 to 12 ring atoms or the number of atoms specified. Cycloalkyl groups can include any number of carbon atoms, such as C 3-6 , C 4-6 , C 5-6 , C 3-8 , C 4-8 , C 5-8 , C 6-8 , C 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 spiro compounds, fused bicyclic compounds, and bridged bicyclic compounds. Saturated bicyclic and polycyclic cycloalkyl rings include, for example, norbornane, [2.2.2]bicyclooctane, decalin, and adamantane. Cycloalkyl groups can also be partially unsaturated, having one or more double bonds or triple bonds in the ring. Representative partially unsaturated cycloalkyl groups include, but are not limited to, cyclobutene, cyclopentene, cyclohexene, cyclohexadiene (1,3- and 1,4-isomers), cycloheptene, cycloheptadiene, cyclooctene, cyclooctadiene (1,3-, 1,4-, and 1,5-isomers), norbornene, and norbornadiene. When the cycloalkyl is a saturated monocyclic C 3-8 cycloalkyl, exemplary groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. When the cycloalkyl is a saturated monocyclic C 3-6 cycloalkyl, exemplary groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Cycloalkyl groups can be substituted or unsubstituted.

[0058] "Alkyl-cycloalkyl" refers to a radical that has both an alkyl component and a cycloalkyl component, wherein the alkyl component is attached to the cycloalkyl component at a point of attachment. The alkyl component is as defined above, except that the alkyl component is at least divalent, an alkylene, to connect to the cycloalkyl component and to the point of attachment. In some cases, the alkyl component can be absent. The alkyl component includes any number of carbons, such as C 1-6 , C 1-2 , C 1-3 , C 1-4 , C1-5 , C 2-3 , C 2-4 , C 2-5 , C 2-6 , C 3-4 , C 3-5 , C 3-6 , C 4-5 , C 4-6 and C 5-6 . The cycloalkyl component is as defined herein. Exemplary alkyl-cycloalkyl groups include, but are not limited to, methyl-cyclopropyl, methyl-cyclobutyl, methyl-cyclopentyl, and methyl-cyclohexyl.

[0059] "Heterocycloalkyl" refers to a cycloalkyl group having from 3 to 12 ring members and from 1 to 4 heteroatoms selected from N, O, and S as described above. Heterocycloalkyl groups include bicyclic compounds containing heteroatoms. Bicyclic compounds include spirocyclic compounds, fused bicyclic compounds, and bridged bicyclic compounds. The heteroatoms can also be oxidized, for example, but not limited to, -S(O)- and -S(O)2-. Heterocycloalkyl 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 a heterocycloalkyl group, for example, 1, 2, 3, or 4, or 1-2, 1-3, 1-4, 2-3, 2-4, or 3-4. The heterocycloalkyl group includes groups such as aziridine, azetidine, pyrrolidine, piperidine, hexamethyleneimine, azocane, quinuclidine, pyrazolidine, imidazolidine, piperazine (1,2-, 1,3-, and 1,4-isomers), oxirane, oxetane, tetrahydrofuran, tetrahydropyran-4-acetyl chloride, hexamethylene oxide, thiirane, thietane, thiolane (tetrahydrothiophene), thiane (tetrahydrothiopyran), oxazolidine, isoxazolidine, thiazolidine, isothiazolidine, dioxolane, dithiolane, morpholine, thiomorpholine, dioxane, or dithiane. The heterocycloalkyl group can also be fused to an aromatic or non-aromatic ring system to form members including, but not limited to, indoline. The heterocycloalkyl group can be unsubstituted or substituted. For example, the heterocycloalkyl group is substituted with alkyl or oxo (=O), among others. 1-6 Alkyl or oxo (=O), among others.

[0060] "Alkyl-heterocycloalkyl" refers to a group having an alkyl component and a heterocycloalkyl component, wherein the alkyl component is attached to the heterocycloalkyl component to the point of attachment. The alkyl component is as defined above, except that the alkyl component is at least divalent, an alkylene, to attach to the heterocycloalkyl component and to the point of attachment. The alkyl component includes any number of carbons, such as C 0-6 , C 1-2 , C 1-3 , C 1-4 , C 1-5 , C1-6 , 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 can be absent. The heterocycloalkyl component is as defined above. The alkyl-heterocycloalkyl group can be substituted or unsubstituted.

[0061] "Halogen" means fluorine, chlorine, bromine, and iodine.

[0062] "Haloalkyl" means an alkyl group as defined above in which 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 C 1-6 For example, haloalkyl includes trifluoromethyl, fluoromethyl, and the like. In some cases, the term "perfluoro" can be used to define compounds or radicals in which all hydrogens are replaced by fluorines. For example, perfluoromethyl means 1,1,1 trifluoromethyl. Alkyl amines.

[0063] "Alkoxy" means an alkyl group as defined above attached through an oxygen atom: alkyl-O-. For alkyl groups, alkoxy groups have any suitable number of carbon atoms, such as C 1-6 Alkoxy includes, for example, methoxy, ethoxy, propyloxy, isopropoxy, butoxy, 2-butoxy, isobutoxy, sec-butoxy, t-butoxy, pentoxy, hexyloxy, and the like. Alkoxy groups can be further substituted with various substituents described below. Alkoxy groups can be substituted or unsubstituted.

[0064] "Haloalkoxy" means an alkoxy group as defined above 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 C 1-6 Alkoxy groups can be substituted with 1, 2, 3, or more halogens. When all of the hydrogen atoms are replaced by halogens, for example fluorine, these compounds are per-substituted, for example perfluorinated compounds. Haloalkoxy includes, but is not limited to, trifluoromethoxy, 2,2,2-trifluoroethoxy, perfluoroethoxy, and the like.

[0065] "Amine" means a -N(R)2 group, where the R groups are hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, and the like. The R groups can be the same or different. Amino groups can be primary (each R is hydrogen) amino, secondary (one R is hydrogen) amino, or tertiary (each R is not hydrogen) amino.

[0066] "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.

[0067] "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.

[0068] "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 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 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.

[0069] "Heteroaryl" refers to a monocyclic or fused bicyclic or tricyclic aromatic ring composition containing 5-16 ring atoms, of which 1-5 ring atoms are heteroatoms, such as N, O, or S. Heteroaryl groups 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 groups can include 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 groups can have 5 to 8 ring members and 1 to 4 heteroatoms, or 5 to 8 ring members and 1 to 3 heteroatoms, or 5 to 6 ring members and 1 to 4 heteroatoms, or 5 to 6 ring members and 1 to 3 heteroatoms. Heteroaryl groups can include groups such as pyrrole, pyridine, imidazole, pyrazole, triazole, tetrazole, pyrazine, pyrimidine, pyridazine, triazine (1,2,3-, 1,2,4- and 1,3,5-isomers), thiophene, furan, thiazole, isothiazole, oxazole, and isoxazole. Heteroaryl groups can also be fused to an aromatic ring system, such as a benzene ring, forming members including but not limited to benzopyrrole (e.g., indole and isoindole), benzopyridine (e.g., quinoline and isoquinoline), benzopyrazine (quinooxaline), benzopyrimidine (quinazoline), benzopyridazine (e.g., cinnoline and phthalazine), benzothiophene, and benzofuran. Other heteroaryl groups include heteroaromatic rings linked by a bond, such as bipyridine. Heteroaryl groups can be substituted or unsubstituted.

[0070] "Alkyl-heteroaryl" refers to a group having an alkyl component and a heteroaryl component, wherein the alkyl component is attached to the heteroaryl component at a point of attachment. The alkyl component is as defined above, except that the alkyl component is at least divalent, an alkylene, to attach to the heteroaryl component and to the point of attachment. The alkyl component includes any number of carbons, such as C 0-6 , C 1-2 , C 1-3 , C 1-4 , C 1-5 , C 1-6 , C 2-3 , C 2-4 , C 2-5 , C 2-6 , C 3-4 , C 3-5 , C 3-6 , C 4-5 , C 4-6 , and C 5-6 . In certain cases, the alkyl component can be absent. The heteroaryl component is as defined herein. The alkyl-heteroaryl group can be substituted or unsubstituted.

[0071] "Salt" refers to an acid or base salt of a compound used in the methods of the application. Illustrative examples of pharmaceutically acceptable salts are mineral (hydrochloric, hydrobromic, phosphoric, etc.) salts, organic (fumaric, acetic, oleic, propionic, glutamic, citric, etc.), quaternary ammonium (methyl iodide, ethyl iodide, etc.) salts. It will be appreciated that pharmaceutically acceptable salts are non-toxic. Additional information on suitable pharmaceutically acceptable salts can be found in Remington's Pharmaceutical Sciences (17th Ed., Mack Publishing Company, Easton, PA, 1985), which is incorporated herein by reference.

[0072] The neutral form of the compounds can be regenerated by contacting the salts with base or acid and isolating the parent compound in the conventional manner. The parent form of the compounds differs from the various salt forms in certain physical properties, such as solubility in polar solvents, but otherwise the salts are equivalent to the parent form of the compound for the purposes of the present application.

[0073] "Pharmaceutically acceptable salt" refers to a salt form of a compound wherein the compound is suitable for administration to a subject. Representative pharmaceutically acceptable salts include acetate, ascorbate, benzenesulfonate, benzoate, camphorsulfonate, citrate, ethanesulfonate, oxalate, fumarate, gentisate, gluconate, glutamate, hippurate, hydrobromate, hydrochlorate, isothionate, lactate, lactobionate, maleate, malate, mandelate, methanesulfonate, mucate, naphthalenesulfonate, naphthalene- 1,5-disulfonate, naphthalene-2,6-disulfonate, nicotinate, nitrate, orotate, pamoate, pantothenate, phosphate, succinate, sulfate, tartrate, p-toluenesulfonate, and xinafoic acid salts, among others

[0074] "Pharmaceutically acceptable excipient" refers to a substance that aids in the administration of an active agent to a subject and its absorption into the subject. Pharmaceutically acceptable excipients for use in the present application include, but are not limited to, binders, fillers, disintegrants, lubricants, coatings, sweeteners, flavorants, and colorants. Those of skill in the art will recognize that other pharmaceutically acceptable excipients can also be used in the present application.

[0075] "Composition" refers to a product comprising the specified ingredients in the specified amounts, as well as any product that results, directly or indirectly, from combinations of the specified ingredients in the specified amounts. "Pharmaceutically acceptable" means that the carrier, diluent or excipient must be compatible with the other ingredients of the formulation for the dosage form to be effective.

[0076] “Isomers” refer to compounds that have the same chemical formula but different connectivity between atoms in the molecule, resulting in different chemical structures. Isomers include structural isomers and stereoisomers. Examples of structural isomers include, but are not limited to, tautomers and regioisomers. Examples of stereoisomers include, but are not limited to, diastereomers and enantiomers.

[0077] “Administering” refers to oral administration, suppository administration, external contact, parenteral administration, intravenous, intraperitoneal administration, intramuscular administration, intralesional administration, intranasal administration or subcutaneous administration, intrathecal administration or implantation of slow release devices, e.g., implantation of a mini-osmotic pump into a subject.

[0078] “Subject” refers to an animal, such as a mammal, including, but not limited to, primates (e.g., humans), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice, and the like. In some embodiments, the subject is a human.

[0079] “Therapeutically effective amount” or “therapeutically sufficient amount” or “effective or sufficient amount” refers to a dose that produces therapeutic effects in an administered subject. The specific dose will depend on the purpose of the treatment, and will be determined by those of ordinary skill in the art using known techniques (see, e.g., Lieberman, Pharmaceutical Dosage Forms (vols. 1-3, 1992); Lloyd, The Art, Science and Technology of Pharmaceutical Compounding (1999); Pickar, Dosage Calculations (1999); and Remington: The Science and Practice of Pharmacy, 20th Edition, 2003, Gennaro, Ed., LWW). In sensitized cells, the therapeutically effective dose of sensitized cells is often lower than the conventional therapeutically effective dose.

[0080] “Neuronal plasticity” refers to the ability of the brain to change its structure and / or function throughout a subject’s life. Examples of brain changes include, but are not limited to, the ability to adapt or respond to internal and / or external stimuli, such as due to injury, and the ability to generate new neurites, dendritic spines, and synapses.

[0081] “Brain disease” refers to a neurological disease that affects the structure and function of the brain. Brain diseases include, but are not limited to, Alzheimer’s disease, Parkinson’s disease, a psychological disorder, depression, treatment-resistant depression, addiction, anxiety, post-traumatic stress disorder, suicidal ideation, major depressive disorder, bipolar disorder, schizophrenia, stroke, traumatic brain injury, and a drug use disorder.

[0082] "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.

[0083] "Neurotrophic factors" refer to a family of soluble peptides or proteins that support the survival, growth, and differentiation of developing and maturing neurons.

[0084] "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.

[0085] "Arousal" refers to the activation of receptors or enzymes by regulators or agonists to produce a biological response.

[0086] 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.

[0087] "Orthoallosteric modulators" are modulators that bind to sites different from orthoallosteric binding sites and enhance or amplify the effects of agonists.

[0088] "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.

[0089] "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.

[0090] III. Compounds

[0091] 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).

[0092] In some embodiments, the present invention provides a compound of formula I or a salt and isomer thereof:

[0093]

[0094] 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(O2)N(R 8b R 8c ), C 3-8 cycloalkyl, C 3-14 alkyl-cycloalkyl, C 4-10 heterocycloalkyl, C 4-16 alkyl-heterocycloalkyl, C 6-12 aryl, C 7-18 alkyl-aryl, C 5-10 heteroaryl, or C 4-16 alkyl-heteroaryl; R 8a is C 3-8 cycloalkyl, C 3-14 alkyl-cycloalkyl, C 4-10 heterocycloalkyl, C 4-16 alkyl-heterocycloalkyl, C 6-12 aryl, C 7-18 alkyl-aryl, C 5-10 heteroaryl, or C 4-16 alkyl-heteroaryl; R 8b , R 8c and R 8d are each independently H or C 1-6 alkyl; or, one of R 1a , R 1b or R 1c combines with one of R 2 , R 3 , R 4 , R 5 , R 6 and R 7 to form C 5-6 cycloalkyl or C 5-6 heterocycloalkyl; or, R 2 and R 3 combine with the atoms through which they are attached to form C 6-12 aryl; or, R 4 and R 5 , R 5 and R 6 , or R 6 and R 7They combine with their respective atoms to form C 3-6 cycloalkyl or C 3-6 Heterocyclic alkyl; L is C 1-6 Alkylene.

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

[0096]

[0097] 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(O2)N(R 8b R 8c ), C 3-8 cycloalkyl, C 3-14 alkyl-cycloalkyl, C 4-10 heterocycloalkyl, C 4-16 alkyl-heterocycloalkyl, C 6-12 aryl, C 7-18 alkyl-aryl, C 5-10 heteroaryl, or C 4-16 alkyl-heteroaryl; R 8a is C 3-8 cycloalkyl, C 3-14 alkyl-cycloalkyl, C 4-10 heterocycloalkyl, C 4-16 alkyl-heterocycloalkyl, C 6-12 aryl, C 7-18 alkyl-aryl, C 5-10 heteroaryl, or C 4-16 alkyl-heteroaryl; R 8b , R 8c and R 8d are each independently H or C 1-6 alkyl; or, one of R 1a , R 1b or R 1c combines with one of R 2 , R 3 , R 4 , R 5 , R 6 and R 7 to form C 5-12 heterocycloalkyl; or, R 2 and R 3 combine with the atoms to which they are each attached to form C 4-8 cycloalkyl, C 4-10 heterocycloalkyl, or C 6-12 aryl; or, R 4 and R 5 , R 5 and R 6 , or R 6 and R 7 combine with the atoms to which they are each attached to form C 3-6 cycloalkyl, C 3-6 heterocycloalkyl, C 6-12 aryl, or C 5-10 heteroaryl; L is C 1-6 alkylene, wherein, when R 1a and R 1b are both Me, R1c R is hydrogen, L is methylene, R 2 3 4 5 6 and R 7 is not hydrogen, and the compound is not:

[0098]

[0099] wherein, when R 1a and R 1b are Me, R 1c is hydrogen, L is ethylene, X is CR 3 , then at least one of R 2 , R 3 , R 4 , R 5 , R 6 , and R 7 is not hydrogen; wherein, when R 1c is H, R 5 is Br, CI, F, -NH2, -NO2, or C 1-3 alkoxy, then at least one of R 2 , R 3 , R 4 , R 6 , or R 7 is not hydrogen; wherein, when R 1c is hydrogen and R 5 is F, then at least one of R 2 , R 3 , R 4 , R 6 , or R 7 is not hydrogen, R 6 is not F; wherein, when R 1a , R 1b , and R 1c are each Me, L is methylene, X is CR 3 , R 2 , R 3 , R 4 , R 5 , R 6 , and R 7 are each hydrogen, then the compound is:

[0100]

[0101] In some embodiments, the present application provides a compound of Formula I, or a pharmaceutically acceptable salt thereof, and isomers thereof:

[0102] In some embodiments, the present application provides a compound of Formula I, or a pharmaceutically acceptable salt thereof, and isomers thereof:

[0102] In some embodiments, the present application provides a compound of Formula I, or a pharmaceutically acceptable salt thereof, and isomers thereof:

[0102] In some embodiments, the present application provides a compound of Formula I, or a pharmaceutically acceptable salt thereof, and isomers thereof:

[0102] In some embodiments, the present application provides a compound of Formula I, or a pharmaceutically acceptable salt thereof, and isomers thereof:

[0102] In some embodiments, the present application provides a compound of Formula I, or a pharmaceutically acceptable salt thereof, and isomers thereof:

[0102] In some embodiments, the present application provides a compound of Formula I, or a pharmaceutically acceptable salt thereof, and isomers thereof:

[0102] In some embodiments, the present application provides a compound of Formula I, or a pharmaceutically acceptable salt thereof, and isomers thereof:

[0102] In some embodiments, the present application provides a compound of Formula I, or a pharmaceutically acceptable salt thereof, and isomers thereof:

[0102] In some embodiments, the present application provides a compound of Formula I, or a pharmaceutically acceptable salt thereof, and isomers thereof:

[0102] In some embodiments, the present application provides a compound of Formula I, or a pharmaceutically acceptable salt thereof, and isomers thereof:

[0102] In some embodiments, the present application provides a compound of Formula I, or a pharmaceutically acceptable salt thereof, and isomers thereof:

[0102] In some embodiments, the present application provides a compound of Formula I, or a pharmaceutically acceptable salt thereof, and isomers thereof:

[0102] In some embodiments, the present application provides a compound of Formula I, or a pharmaceutically acceptable salt thereof, and isomers thereof:

[0102] In some embodiments, the present application provides a compound of Formula I, or a pharmaceutically acceptable salt thereof, and isomers thereof:

[0102] In some embodiments, the present application provides a compound of Formula I, or a pharmaceutically acceptable salt thereof, and isomers thereof:

[0102] In some embodiments, the present application provides a compound of Formula I, or a pharmaceutically acceptable salt thereof, and isomers thereof:

[0102] In some embodiments, the present application provides a compound of Formula I, or a pharmaceutically acceptable salt thereof, and isomers thereof:

[0102] In some embodiments, the present application provides a compound of Formula I, or a pharmaceutically acceptable salt thereof, and isomers thereof:

[0102] In some embodiments, the present application provides a compound of Formula I, or a pharmaceutically acceptable salt thereof, and isomers thereof:

[0102] In some embodiments, the present application provides a compound of Formula I, or a pharmaceutically acceptable salt thereof, and isomers thereof:

[0102] In some embodiments, the present application provides a compound of Formula I, or a pharmaceutically acceptable salt thereof, and isomers thereof:

[0102] In some embodiments, the present application provides a compound of Formula I, or a pharmaceutically acceptable salt thereof, and isomers thereof:

[0102] In some embodiments, the present application provides a compound of Formula I, or a pharmaceutically acceptable salt thereof, and isomers thereof:

[0102] In some embodiments, the present application provides a compound of Formula I, or a pharmaceutically acceptable salt thereof, and isomers thereof:

[0102] In some embodiments, the present application provides a compound of Formula I, or a pharmaceutically acceptable salt thereof, and isomers thereof:

[0102] In some embodiments, the present application provides a compound of Formula I, or a pharmaceutically acceptable salt thereof, and isomers thereof:

[0102] In some embodiments, the present application provides a compound of Formula I, or a pharmaceutically acceptable salt thereof, and isomers thereof:

[0102] In some embodiments, the present application provides a compound of Formula I, or a pharmaceutically acceptable salt thereof, and isomers thereof:

[0102] In some embodiments, the present application provides a compound of Formula I, or a pharmaceutically acceptable salt thereof, and isomers thereof:

[0102] In some embodiments, the present application provides a compound of Formula I, or a pharmaceutically acceptable salt thereof, and isomers thereof:

[0102] In some embodiments, the present application provides a compound of Formula I, or a pharmaceutically acceptable salt thereof, and isomers thereof:

[0102] In some embodiments, the present application provides a compound of Formula I, or a pharmaceutically acceptable salt thereof, and isomers thereof:

[0102] In some embodiments, the present application provides a compound of Formula I, or a pharmaceutically acceptable salt thereof, and isomers thereof:

[0102] In some embodiments, the present application provides a compound of Formula I, or a pharmaceutically acceptable salt thereof, and isomers thereof:

[0102] In some embodiments, the present application provides a compound of Formula I, or a pharmaceutically acceptable salt thereof, and isomers thereof:

[0102] In some embodiments, the present

[0103] wherein: X is CR 3 ; R 1a and R 1b are each independently hydrogen, C 1-6 alkyl, C 3-8 cycloalkyl, or C 4-14 alkyl-cycloalkyl; R 1c is C 1-6 alkyl, C 3-8 cycloalkyl, or C 4-14 alkyl-cycloalkyl; or, two of R 1a , R 1b and R 1c combine with the atom to which they are attached to form a C 3-12 heterocycloalkyl; R 2 , R 3 , R 4 , R 5 , R 6 and R 7 are each independently hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, halogen, C 1-6 haloalkyl, C 1-6 alkylamine, C 1-6 alkoxy, C 1-6 haloalkoxy, -OR 8a , -NO2, -CN, -C(O)R 8b , -C(O)OR 8b , -OC(O)R 8b , -OC(O)OR 8b , -N(R 8b R 8c ), -N(R 8b )C(O)R 8c , -C(O)N(R 8b R 8c ), -N(R 8b )C(O)OR 8c , -OC(O)N(R 8b R 8c ), -N(R 8b )C(O)N(R 8c R 8d ), -C(O)C(O)N(R 8b R 8c ), -S(O2)R 8b , -S(O2)N(R 8b R 8c ), C 3-8 cycloalkyl, C 3-14alkyl-cycloalkyl, C 4-10 heterocycloalkyl, C 4-16 alkyl-heterocycloalkyl, C 6-12 aryl, C 7-18 alkyl-aryl, C 5-10 heteroaryl, or C 4-16 alkyl-heteroaryl; R 8a is C 3-8 cycloalkyl, C 3-14 alkyl-cycloalkyl, C 4-10 heterocycloalkyl, C 4-16 alkyl-heterocycloalkyl, C 6-12 aryl, C 7-18 alkyl-aryl, C 5-10 heteroaryl, or C 4-16 alkyl-heteroaryl; R 8b , R 8c and R 8d are each independently H or C 1-6 alkyl; or, R 1a , R 1b or R 1c one of which combines with R 2 to form C 5-12 heterocycloalkyl; or, R 2 and R 3 in combination with the atoms to which they are each attached form C 4-8 cycloalkyl, C 4-10 heterocycloalkyl, or C 6-12 aryl; or, R 4 and R 5 , R 5 and R 6 , or R 6 and R 7 in combination with the atoms to which they are each attached form C 4-6 cycloalkyl, C 4-6 heterocycloalkyl, C 6-12 aryl, or C 5-10 heteroaryl; L is C 1-6 alkylene, wherein, when R 1a , R 1b and R 1c are each Me, L is methylene, and X is CR 3 and R 2 , R 3 , R 4 , R 5 , R 6 and R 7 are hydrogen, then the compound is

[0104] and wherein the compound is not

[0105]

[0106] In some embodiments, the present application provides a compound, or a pharmaceutically acceptable salt thereof, wherein X is N or CR 3 In some embodiments, the present application provides a compound, or a pharmaceutically acceptable salt thereof, wherein X is CR 3 In some embodiments, the present application provides a compound, or a pharmaceutically acceptable salt thereof, wherein X is N.

[0107] In some embodiments, the present application provides a compound, or a pharmaceutically acceptable salt thereof, wherein X is CR 3 ; R 2 and R 3 are each independently hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, halogen, C 1-6 haloalkyl, C 1-6 alkylamine, C 1-6 alkoxy, C 1-6 haloalkoxy, -OR 8a , -NO2, -CN, -C(O)R 8b , -C(O)OR 8b , -OC(O)R 8b , -OC(O)OR 8b , -N(R 8b R 8c ), -N(R 8b )C(O)R 8c , -C(O)N(R 8b R 8c ), -N(R 8b )C(O)OR 8c , -OC(O)N(R 8b R 8c ), -N(R 8b )C(O)N(R 8c R 8d ), -C(O)C(O)N(R 8b R 8c ), -S(O2)R 8b , -S(O)2N(R 8b R 8c ), C 3-8 cycloalkyl, C 3-14 alkyl-cycloalkyl, C 4-10 heterocycloalkyl, C 4-16 alkyl-heterocycloalkyl, C 6-12 aryl, C 7-18 alkyl-aryl, C 5-10 heteroaryl, or C4-16 alkyl heteroaryl; 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

[0108]

[0109] 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:

[0110]

[0111] 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 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 1-6alkylamine, C 1-6 alkoxy, C 1-6 haloalkoxy, -OR 8a , -NO2, -CN, -C(O)R 8b , -C(O)OR 8b , -OC(O)R 8b , -OC(O)OR 8b , -N(R 8b R 8c ), -N(R 8b )C(O)R 8c , -C(O)N(R 8b R 8c ), -N(R 8b )C(O)OR 8c , -OC(O)N(R 8b R 8c ), -N(R 8b )C(O)N(R 8c R 8d ), -C(O)C(O)N(R 8b R 8c ), -S(O2)R 8b , -S(O)2N(R 8b R 8c ), C 3-8 cycloalkyl, C 3-14 alkyl-cycloalkyl, C 4-10 heterocycloalkyl, C 4-16 alkyl-heterocycloalkyl, C 6-12 aryl, C 7-18 alkyl-aryl, C 5-10 heteroaryl, or C 4-16 alkylheteroaryl; R 5 is C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, halogen, C 1-6 haloalkyl, C 1-6 alkylamine, C 1-6 alkoxy, C 1-6 haloalkoxy, -OR 8a , -NO2, -CN, -C(O)R 8b , -C(O)OR 8b , -OC(O)R 8b , -OC(O)OR 8b , -N(R 8b R 8c ), -N(R 8b )C(O)R 8c , -C(O)N(R 8b R8c ), -N(R 8b )C(O)OR 8c , -OC(O)N(R 8b R 8c ), -N(R 8b )C(O)N(R 8c R 8d ), -C(O)C(O)N(R 8b R 8c ), -S(O2)R 8b , -S(O)2N(R 8b R 8c ), C 3-8 cycloalkyl, C 3-14 alkyl-cycloalkyl, C 4-10 heterocycloalkyl, C 4-16 alkyl-heterocycloalkyl, C 6-12 aryl, C 7-18 alkyl-aryl, C 5-10 heteroaryl, or C 4-16 alkyl-heteroaryl; R 8a is C 3-8 cycloalkyl, C 3-14 alkyl-cycloalkyl, C 4-10 heterocycloalkyl, C 4-16 alkyl-heterocycloalkyl, C 6-12 aryl, C 7-18 alkyl-aryl, C 5-10 heteroaryl, or C 4-16 alkyl-heteroaryl; R 8b , R 8c and R 8d are each independently H or C 1-6 alkyl; or, R 4 and R 5 , R 5 and R 6 , or R 6 and R 7 combine with the atom to which they are respectively attached to form a C 4-6 cycloalkyl, C 4-6 heterocycloalkyl, C 6-12 aryl, or C 5-10 heteroaryl;

[0112] In some embodiments, the present application provides compounds, or a pharmaceutically acceptable salt thereof, wherein R 1a and R 1b are each independently hydrogen or C 1-6 alkyl; R 1c is C 1-6 alkyl; R 2 and R 3each independently hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, C 8b alkoxy, halogen, or -C(O)C(O)N(R 8c R 4 ); R 5 , R 6 , and R 7 are each independently hydrogen, C 1-6 alkyl, halogen, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, or -OR 8a , wherein at least one of R 4 , R 5 , R 6 , and R 7 is other than H; and R 8a is C 7-18 alkyl-aryl; or, R 5 and R 6 , taken together with the atom to which they are each attached, form a C 4-6 heterocycloalkyl.

[0113] In some embodiments, the present application provides compounds, wherein X is CR 3 ; R 1a , R 1b , and R 1c are each independently hydrogen or C 1-6 alkyl; R 2 and R 3 are each independently hydrogen, C 1-6 alkyl, or -C(O)C(O)N(R 8b R 8c ); R 4 , R 5 , R 6 , and R 7 are each independently hydrogen, C 1-6 alkyl, halogen, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, or -OR 8a , wherein at least one of R 4 , R 5 , R 6 , and R 7 is other than H; and R 8a is C 7-18 alkyl-aryl; or, R 5 and R 6 , taken together with the atom to which they are each attached, form a C 3-6 heterocycloalkyl.

[0114] In some embodiments, the present application provides a compound, or a pharmaceutically acceptable salt thereof, wherein R 1a and R 1b are each independently H, C 1-6 alkyl, C 3-8 cycloalkyl, or C 4-14 alkyl-cycloalkyl; or, two of R 1a , R 1b , and R 1c , together with the atom to which they are attached, form a C 3-12 heterocycloalkyl. In some embodiments, the present application provides a compound, or a pharmaceutically acceptable salt thereof, wherein R 1a and R 71b are each independently hydrogen or C 1-6 alkyl. In some embodiments, R 1a and R 1b are each independently hydrogen, methyl, ethyl, or propyl. In some embodiments, R 1a and R 1b are each independently hydrogen or methyl.

[0115] In some embodiments, the present application provides a compound, or a pharmaceutically acceptable salt thereof, wherein R 1a and R 1b are each independently H or methyl, R 1c is methyl; or, two of R 1a , R 1b , and R 1c , together with the atom to which they are attached, form a C 3-8 heterocycloalkyl. In some embodiments, the present application provides a compound, or a pharmaceutically acceptable salt thereof, wherein R 1a and R 1b are each independently H or methyl; R 1c is methyl; or, two of R 1a , R 1b , and R 1c , together with the atom to which they are attached, form a C 3-8 heterocycloalkyl.

[0116] In some embodiments, the present application provides a compound, or a pharmaceutically acceptable salt thereof, wherein R 1c is C 1-6 alkyl, C 3-8 cycloalkyl, or C 4-14 alkyl-cycloalkyl. In some embodiments, the present application provides a compound, or a pharmaceutically acceptable salt thereof, wherein R 1c is C 1-6 alkyl. In some embodiments, R 1c is methyl, ethyl, or propyl. In some embodiments, the present application provides a compound, or a pharmaceutically acceptable salt thereof, wherein R1c is methyl. In some embodiments, R 1c is methyl.

[0117] In some embodiments, the present application provides compounds, or pharmaceutically acceptable salts thereof, wherein R 1a , R 1b , and R 1c are each methyl; or two of R 1a , R 1b , and R 1c combine with the atom to which they are attached to form a C 3-8 heterocycloalkyl. In some embodiments, the present application provides compounds, or pharmaceutically acceptable salts thereof, wherein R 1a , R 1b , and R 1c are each Me; or two of R 1a , R 1b , and R 1c combine with the atom to which they are attached to form a C 3-8 heterocycloalkyl.

[0118] In some embodiments, the present application provides compounds, or pharmaceutically acceptable salts thereof, wherein one of R 1a , R 1b , or R 1c combines with one of R 2 , R 3 , R 4 , R 5 , R 6 , or R 7 to form a C 5-12 heterocycloalkyl. In some embodiments, the present application provides compounds, or pharmaceutically acceptable salts thereof, wherein one of R 1a , R 1b , or R 1c combines with one of R 2 or R 7 to form a C 5-8 heterocycloalkyl. In some embodiments, the present application provides compounds, or pharmaceutically acceptable salts thereof, wherein one of R 1a , R 1b , or R 1c combines with R 2 to form a C 5-8 heterocycloalkyl.

[0119] In some embodiments, the present application provides compounds, or pharmaceutically acceptable salts thereof, wherein R 2 , R 3 , R 4 , R 5 , R 6and R 7 each independently is hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, halogen, C 1-6 haloalkyl, C 1-6 alkylamine, C 1-6 alkoxy, C 1-6 haloalkoxy, -OR 8a , -NO2, -CN, -C(O)R 8b , -C(O)OR 8b , -OC(O)R 8b , -OC(O)OR 8b , -N(R 8b R 8c ), -N(R 8b )C(O)R 8c , -C(O)N(R 8b R 8c ), -N(R 8b )C(O)OR 8c , -OC(O)N(R 8b R 8c ), -N(R 8b )C(O)N(R 8c R 8d ), -C(O)C(O)N(R 8b R 8c ), -S(O2)R 8b , -S(O)2N(R 8b R 8c ), C 3-8 cycloalkyl, C 3-14 alkyl-cycloalkyl, C 4-10 heterocycloalkyl, C 4-16 alkyl-heterocycloalkyl, C 6-12 aryl, C 7-18 alkyl-aryl, C 5-10 heteroaryl, or C 4-16 alkyl-heteroaryl. In some embodiments, R 8a is C 3-8 cycloalkyl, C 3-14 alkyl-cycloalkyl, C 4-10 heterocycloalkyl, C 4-16 alkyl-heterocycloalkyl, C 6-12 aryl, C 7-18 alkyl-aryl, C 5-10 heteroaryl, or C 4-16 alkyl-heteroaryl; and R 8b , R 8c and R 8d each independently is H or C 1-6alkyl;

[0120] In some embodiments, the present application provides a compound, or a pharmaceutically acceptable salt thereof, wherein R 2 and R 3 are each independently hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, halogen, C 1-6 haloalkyl, C 1-6 alkylamine, C 1-6 alkoxy, C 1-6 haloalkoxy, -OR 8a , -NO2, -CN, -C(O)R 8b , -C(O)OR 8b , -OC(O)R 8b , -OC(O)OR 8b , -N(R 8b R 8c ), -N(R 8b )C(O)R 8c , -C(O)N(R 8b R 8c ), -N(R 8b )C(O)OR 8c , -OC(O)N(R 8b R 8c ), -N(R 8b )C(O)N(R 8c R 8d ), -C(O)C(O)N(R 8b R 8c ), -S(O2)R 8b , -S(O)2N(R 8b R 8c ), C 3-8 cycloalkyl, C 3-14 alkyl-cycloalkyl, C 4-10 heterocycloalkyl, C 4-16 alkyl-heterocycloalkyl, C 6-12 aryl, C 7-18 alkyl-aryl, C 5-10 heteroaryl, or C 4-16 alkyl-heteroaryl.

[0121] In some embodiments, the present application provides a compound, or a pharmaceutically acceptable salt thereof, wherein R 2 is hydrogen, C 1-6 alkyl, halogen, or C 1-6 alkoxy. In some embodiments, the present application provides a compound, or a pharmaceutically acceptable salt thereof, wherein R 2hydrogen, methyl, ethyl, propyl, F, CI, Br, I, methoxy, or ethoxy. In some embodiments, the present application provides a compound, or a pharmaceutically acceptable salt thereof, wherein R 2 is hydrogen, Me, F, or -OMe.

[0122] In some embodiments, the present application provides a compound, or a pharmaceutically acceptable salt thereof, wherein R 3 is hydrogen, C 1-6 alkyl, C 1-6 alkoxy, halogen, or -C(O)C(O)N(R 8b R 8c ) and R 8b and R 8c are each independently H or C 1-6 alkyl. In some embodiments, the present application provides a compound, or a pharmaceutically acceptable salt thereof, wherein R 3 is hydrogen, methyl, ethyl, propyl, F, CI, Br, I, methoxy, ethoxy, or -C(O)C(O)N(R 8b R 8c ), and R 8b and R 8c are each independently methyl, ethyl, or propyl.

[0123] In some embodiments, the present application provides a compound, or a pharmaceutically acceptable salt thereof, wherein R 3 is hydrogen, C 1-6 alkyl, C 1-6 alkoxy, halogen, or -C(O)C(O)N(R 8b R 8c ); and R 8b and R 8c are each independently H or C 1-6 alkyl. In some embodiments, the present application provides a compound, or a pharmaceutically acceptable salt thereof, wherein R 3 is hydrogen, Me, F, -OMe, or -C(O)C(O)NMe2.

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

[0125]

[0126] In some embodiments, the present application provides a compound, or a pharmaceutically acceptable salt thereof, wherein the compound of Formula I has the structure:

[0127]

[0128] In some embodiments, the present application provides a compound, or a pharmaceutically acceptable salt thereof, wherein R 1a and R 1b combine with the atom to which they are attached to form a C 3-12 heterocycloalkyl group. In some embodiments, the present application provides a compound, or a pharmaceutically acceptable salt thereof, wherein R 1a and R 1b combine with the atom to which they are attached to form a C 3-8 heterocycloalkyl group. In some embodiments, the present application provides a compound, or a pharmaceutically acceptable salt thereof, wherein R 1a and R 1b combine with the atom to which they are attached to form a C 3-8 heterocycloalkyl group.

[0129] In some embodiments, the present application provides a compound, or a pharmaceutically acceptable salt thereof, wherein R 1a and R 1c combine with the atom to which they are attached to form a C 5-12 heterocycloalkyl group. In some embodiments, the present application provides a compound, or a pharmaceutically acceptable salt thereof, wherein R 1a and R 1c combine with the atom to which they are attached to form a C 5-8 heterocycloalkyl group. In some embodiments, the present application provides a compound, or a pharmaceutically acceptable salt thereof, wherein R 1a and R 1c combine with the atom to which they are attached to form a C 5-6 heterocycloalkyl group. In some embodiments, the present application provides a compound, or a pharmaceutically acceptable salt thereof, wherein R 1a and R 1c combine with the atom to which they are attached to form a C 5-8 heterocycloalkyl group.

[0130] In some embodiments, the present application provides a compound of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof:

[0131]

[0132] wherein: R 1a and R 1b are each independently C 1-6 alkyl, C 3-8 cycloalkyl, or C 4-14 alkyl-cycloalkyl; R 1c is hydrogen, C 1-6 alkyl, C 3-8 cycloalkyl, or C 4-14 alkyl-cycloalkyl; or, R 1a , R 1b , and R1c 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, 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 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 )2, -N(R 8b )C(O)R 8c , -C(O)N(R 8b R 8c )2, -N(R 8b )C(O)OR 8c , -OC(O)N(R 8b R 8c )2, -N(R 8b )C(O)N(R 8c R 8d )2, -C(O)C(O)N(R 8c R 8c )2, -S(O2)R 8b , -S(O2)N(R 8b R 8c )2, C3. 3-8 cycloalkyl, C 3-14 alkyl-cycloalkyl, C 4-10 heterocycloalkyl, C 4-16 alkyl-heterocycloalkyl, C 6-12 aryl, C 7-18 alkyl-aryl, or C 4-16 alkyl-heteroaryl; R 8a is C 3-8 cycloalkyl, C 3-14 alkyl-cycloalkyl, C 4-10 heterocycloalkyl, C 4-16 alkyl-heterocycloalkyl, C 6-12 aryl, C 7-18 alkyl-aryl, C 5-10 heteroaryl, or C 4-16 alkyl-heteroaryl; R 8b , R 8c and R 8d are each independently H or C 1-6 alkyl; or, one of R 1a , R 1b and R 1c is combined with one of R 2 or R 7 to form C 5-6 cycloalkyl or C 5-6 heterocycloalkyl; or, R 2 and R 3 are combined with the atoms to which they are each attached to form C 6-12 aryl; or, R 4 and R 5 , R 5 and R 6 , or R 6 and R 7 are combined to form a ring.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.

[0133] 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 1-6 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(R8b )C(O)OR 8c -OC(O)N(R) 8b R 8c ), -N(R 8b )C(O)N(R 8c R 8d -C(O)C(O)N(R) 8b R 8c -S(O2)R 8b -S(O)2N(R) 8b R 8c C 3-8 cycloalkyl, C 3-14 Alkyl-cycloalkyl, C 4-10 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 3-14alkyl-cycloalkyl, C 4-10 heterocycloalkyl, C 4-16 alkyl-heterocycloalkyl, C 6-12 aryl, C 7-18 alkyl-aryl, C 5-10 heteroaryl, or C 4-16 alkyl-heteroaryl; R 8a is C 3-8 cycloalkyl, C 3-14 alkyl-cycloalkyl, C 4-10 heterocycloalkyl, C 4-16 alkyl-heterocycloalkyl, C 6-12 aryl, C 7-18 alkyl-aryl, C 5-10 heteroaryl, or C 4-16 alkyl-heteroaryl; R 8b , R 8c , and R 8d are each independently H or C 1-6 alkyl; or, R 1a , R 1b , or R 1c one of which combines with one of R 2 or R 7 to form C 5-6 cycloalkyl or C 5-6 heterocycloalkyl; or, R 2 and R 3 combine with the atoms to which they are each attached to form C 6-12 aryl; or, R 4 and R 5 , R 5 and R 6 , or R 6 and R 7 combine with the atoms to which they are each attached to form C 3-6 cycloalkyl or C 3-6 heterocycloalkyl; or salts and isomers thereof.

[0134] In some embodiments, the present application provides a compound, or a pharmaceutically acceptable salt thereof, wherein the compound of Formula I has the structure:

[0135]

[0136] In some embodiments, the present application provides a compound, or a pharmaceutically acceptable salt thereof, wherein the compound of Formula I has the structure:

[0137]

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

[0139]

[0140] In some embodiments, R 2 and R 3 combine with the atom to which they are respectively attached to form a C 4-8 cycloalkyl, C 4-10 heterocycloalkyl, or C 6-12 aryl.

[0141] In some embodiments, the present application provides a compound, or a pharmaceutically acceptable salt thereof, wherein R 4 , R 5 , R 6 and R 7 are each independently hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, halogen, C 1-6 haloalkyl, C 1-6 alkylamine, C 1-6 alkoxy, C 1-6 haloalkoxy, -OR 8a , -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(O2)N(R 8b R 8c ), C 3-8 cycloalkyl, C 3-14 alkyl-cycloalkyl, C 4-10 heterocycloalkyl, C 4-16 alkyl-heterocycloalkyl, C 6-12 aryl, C 7-18 alkyl-aryl, or C 5-10heteroaryl, or C 4-16 alkyl-heteroaryl; or, R 4 and R 5 , R 5 and R 6 , or R 6 and R 7 combine with the atom to which they are respectively attached to form a C 4-6 cycloalkyl, C 4-6 heterocycloalkyl, C 6-12 aryl, or C 5-10 heteroaryl. In some embodiments, the present application provides compounds, or pharmaceutically acceptable salts thereof, wherein R 4 , R 5 , R 6 and R 7 are each independently hydrogen, C 1-6 alkyl, halogen, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, -OR 8a , -NO2, -CN, C 3-8 cycloalkyl, or C 3-14 alkyl-cycloalkyl.

[0142] In some embodiments, the present application provides compounds, or pharmaceutically acceptable salts thereof, wherein R 8a is C 3-8 cycloalkyl, C 3-14 alkyl-cycloalkyl, C 4-10 heterocycloalkyl, C 4-16 alkyl-heterocycloalkyl, C 6-12 aryl, C 7-18 alkyl-aryl, C 5-10 heteroaryl, C 4-16 alkyl-heteroaryl; and R 8b , R 8c and R 8d are each independently H or C 1-6 alkyl. In some embodiments, the present application provides compounds, or pharmaceutically acceptable salts thereof, wherein R 8a is C 3-8 cycloalkyl, C 3-14 alkyl-cycloalkyl, C 4-16 alkyl-heterocycloalkyl.

[0143] In some embodiments, the present application provides compounds, or pharmaceutically acceptable salts thereof, wherein R 4 and R 5 , R 5 and R 6 , or R 6 and R 7with the atom to which they are attached form C 4-6 cycloalkyl, C 4-6 heterocycloalkyl, C 6-12 aryl, or C 5-10 heteroaryl. In some embodiments, the present application provides compounds, or pharmaceutically acceptable salts thereof, wherein: 4 and R 5 with the atom to which they are attached form C 4-6 heterocycloalkyl. In some embodiments, the present application provides compounds, or pharmaceutically acceptable salts thereof, wherein: 5 and R 6 with the atom to which they are attached form C 4-6 heterocycloalkyl. In some embodiments, the present application provides compounds, or pharmaceutically acceptable salts thereof, wherein: 6 and R 7 with the atom to which they are attached form C 4-6 heterocycloalkyl. In some embodiments, the present application provides compounds, or pharmaceutically acceptable salts thereof, wherein: 5 and R 6 with the atom to which they are attached form C 5-6 heterocycloalkyl. In some embodiments, the present application provides compounds, or pharmaceutically acceptable salts thereof, wherein: 5 and R 6 with the atom to which they are attached form a 1,3- dioxole ring or a 1,4-dioxane ring.

[0144] In some embodiments, the present application provides compounds, or pharmaceutically acceptable salts thereof, wherein: 4 , R 5 , R 6 and R 7 are each independently hydrogen, C 1-6 alkyl, halogen, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, -OR 8a , -NO2, -CN, 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 may combine with the atom to which they are attached to form a C 56 heterocycloalkyl; and R 8a is C 3-8 cycloalkyl 3-14 alkyl-cycloalkyl4-16 alkylheteroaryl; or, R 7-18 alkylaryl 4-16 alkylheteroaryl; or, R 4 and R 5 , R 5 and R 6 , or R 6 and R 7 , together with the atoms to which they are respectively attached, form a C5 heterocycloalkyl group. and R 5-6 is C 8a alkyl-aryl. In some embodiments, the present application provides compounds, or pharmaceutically acceptable salts thereof, wherein R 3-8 is C 3-14 alkyl-cycloalkyl, C 4-16 alkyl-heterocycloalkyl, C 7-18 alkyl-aryl, or C 4-16 alkyl-heteroaryl. In some embodiments, the present application provides compounds, or pharmaceutically acceptable salts thereof, wherein R 4 , R 5 , R 6 and R 7 are each independently hydrogen, C 1-6 alkyl, halogen, C 1-6 alkoxy, C 1-6 haloalkoxy, -OR 8a , or -NO2; or, R 4 and R 5 , R 5 and R 6 , or R 6 and R 7 , together with the atoms to which they are respectively attached, form a C5 heterocycloalkyl group. and R 8a is C 7-18 alkyl-aryl. In some embodiments, the present application provides compounds, or pharmaceutically acceptable salts thereof, wherein R 4 , R 6 and R 7 are each independently hydrogen, C 1-6 alkyl, halogen, C 1-6 alkoxy, C 1-6 haloalkoxy, -OR 8a , or -NO2; R 5 is C 1-6 alkyl, halogen, C 1-6 alkoxy, C 1-6 haloalkoxy, -OR 8a , or -NO2; or, R 4 and R 5 , R 5 and R 6 , or R 6 and R 7with the atom to which they are attached to form a C5 heterocycloalkyl group. R 8a is C 7-18 alkyl-aryl. In some embodiments, the present application provides a compound, or a pharmaceutically acceptable salt thereof, wherein R 4 , R 5 , R 6 , and R 7 are each independently hydrogen, Me, F, Cl, Br, -OMe, -OCF3, -O-CH2-phenyl, or -NO2; or, R 5 and R 6 combine with the atom to which they are attached to form a 1,3- dioxolyl ring or a dioxane ring.

[0145] In some embodiments, the present application provides a compound, or a pharmaceutically acceptable salt thereof, wherein R 5 is C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, halogen, C 1-6 haloalkyl, C 1-6 alkylamine, C 1-6 alkoxy, C 1-6 haloalkoxy, -OR 8a , -NO2, -CN, -C(O)R 8b , -C(O)OR 8b , -OC(O)R 8b , -OC(O)OR 8b , -N(R 8b R 8c ), -N(R 8b )C(O)R 8c , -C(O)N(R 8b R 8c ), -N(R 8b )C(O)OR 8c , -OC(O)N(R 8b R 8c ), -N(R 8b )C(O)N(R 8c R 8d ), -C(O)C(O)N(R 8b R 8c ), -S(O2)R 8b , -S(O2)N(R 8b R 8c ), C 3-8 cycloalkyl, C 3-14 alkyl-cycloalkyl, C 4-10 heterocycloalkyl, C 4-16 alkyl-heterocycloalkyl, C 6-12aryl, C 7-18 alkyl-aryl, C 5-10 heteroaryl, or C 4-16 alkyl-heteroaryl. In some embodiments, the present application provides a compound, or a pharmaceutically acceptable salt thereof, wherein R 5 is C 1-6 alkyl, halo, C 1-6 alkoxy, C 1-6 haloalkoxy, or -NO2. In some embodiments, the present application provides a compound, or a pharmaceutically acceptable salt thereof, wherein R 5 is methyl, ethyl, propyl, F, Cl, Br, I, methoxy, ethoxy, -OCF3, -O-benzyl, or -NO2. In some embodiments, the present application provides a compound, or a pharmaceutically acceptable salt thereof, wherein R 5 is methyl, F, Cl, Br, methoxy, -OCF3, -O-benzyl, or -NO2.

[0146] In some embodiments, the present application provides a compound, or a pharmaceutically acceptable salt thereof, wherein R 4 , R 6 and R 7 are each independently hydrogen; and R 5 is Me, F, Cl, Br, -OMe, -CF3, -OCF3, -O-benzyl, or -NO2. In some embodiments, the present application provides a compound, or a pharmaceutically acceptable salt thereof, wherein R 5 is Me, F, Cl, Br, -OMe, -CF3, -OCF3, -O-benzyl, or -NO2; and R 6 and R 7 are each independently hydrogen, Me, F, Cl, Br, -OMe, -OCF3, -O-CH2-phenyl, or -NO2, wherein at least one of R 6 and R 7 is not hydrogen.

[0147] In some embodiments, the present application provides a compound, wherein X is CR 3 ; R 1a , R 1b and R 1c are each independently hydrogen or C 1-6 alkyl; R 2 and R 3 are each independently hydrogen, C 1-6 alkyl, or -C(O)C(O)N(R 8b R 8c ); or R 2 and R 3 , together with the atoms to which they are respectively attached, form a C 6-12 aryl; R4 , R 5 , R 6 , and R 7 are each independently hydrogen, C 1-6 alkyl, halogen, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, or -OR 8a , wherein R 4 , R 5 , R 6 , and R 7 are not H; and R 8a is C 7-18 alkyl-aryl; or, R 5 and R 6 , taken together with the atom to which they are each attached, form a C 3-6 heterocycloalkyl.

[0148] In some embodiments, the present application provides compounds, wherein X is CR 3 ; R 1a and R 1b are each Me; R 1c is hydrogen or Me; R 2 is H, Me, or -C(O)-C(O)N(Me)2; or, R 2 and R 3 , taken together with the atom to which they are each attached, form a phenyl ring; and R 4 , R 5 , R 6 , and R 7 are each independently H, F, Br, -NO2, -OMe, -CF3, -OCF3, or -O-benzyl; or, R 5 and R 6 , taken together with the atom to which they are each attached, form a 1,3- dioxole ring.

[0149] In some embodiments, the present application provides compounds, wherein X is CR 3 ; R 1a and R 1b are each Me; R 1c is hydrogen or Me; R 2 is H or Me; R 3 is H or -C(O)-C(O)N(Me)2; R 4 is H, F, -OMe, or -O-benzyl; R 5 is H, F, Br, -OMe, -CF3, -OCF3, or -O-benzyl; R 6 is H, -NO2, -OMe, -OCF3, or -O-benzyl; or, R 2 and R 3combine to form a phenyl ring; or, R 5 combine to form a 1,3-dioxolyl ring; and R 6 combine to form a 1,3-dioxolyl ring; and R 7 is H, F, -OMe, or -O-benzyl.

[0150] In some embodiments, the present application provides a compound, or a pharmaceutically acceptable salt thereof, wherein X is CR 3 ; R 1a and R 1b are each Me, Et, or Pr; R 2 is H, Me, -OMe, -F, or -C(O)-C(O)N(Me)2; R 3 is H, Me, -OMe, -F, or -C(O)-C(O)N(Me)2; and R 4 , R 5 , R 6 and R 7 are each independently H, Me, -F, -Cl, -Br, -NO2, -OMe, -CF3, -OCF3, or -O-benzyl; or, R 5 and R 6 combine to form a 1,3-dioxolyl ring or a 1,4-dioxanyl ring. In some embodiments, the present application provides a compound, or a pharmaceutically acceptable salt thereof, wherein X is CR 3 ; R 1a and R 1b are each Me; R 1c is Me, Et, or Pr; R 2 is H, Me, -F, -OMe; R 3 is H, Me, -F, -OMe, or -C(O)-C(O)N(Me)2; R 4 is H, Me, -F, -OMe, or -O-benzyl; R 5 is H, Me, -F, -Cl, -Br, -OMe, -CF3, -OCF3, or -O-benzyl; R 6 is H, Me, -F, -NO2, -OMe, -OCF3, or -O-benzyl; or, R 5 and R 6 combine to form a 1,3-dioxolyl ring or a 1,4-dioxanyl ring; and R 7 is H, Me, F, -OMe, or -O-benzyl.

[0151] In some embodiments, the present application provides a compound, or a pharmaceutically acceptable salt thereof, wherein L is C 1-6Alkylene. In some embodiments, the present application provides a compound, or a pharmaceutically acceptable salt thereof, wherein L is methylene, ethylene, propylene, or butylene. In some embodiments, the present application provides a compound, or a pharmaceutically acceptable salt thereof, wherein L is methylene or ethylene. In some embodiments, the present application provides a compound, or a pharmaceutically acceptable salt thereof, wherein L is ethylene. In some embodiments, the present application provides a compound, or a pharmaceutically acceptable salt thereof, wherein L is methylene.

[0152] In some embodiments, the present application provides a compound, wherein the compound is or a pharmaceutically acceptable salt thereof.

[0153] In some embodiments, the present application provides a compound, wherein the compound is

[0154] or a pharmaceutically acceptable salt thereof.

[0155] In some embodiments, the present application provides a compound, wherein the compound is

[0156] or a pharmaceutically acceptable salt thereof.

[0157] In some embodiments, the present application provides a compound, wherein the compound is

[0158] or a pharmaceutically acceptable salt thereof.

[0159] In some embodiments, the present application provides a compound of Formula II, or a pharmaceutically acceptable salt and isomer thereof:

[0160]

[0161] wherein: X is CR 3 ; R 1a and R 1b are each independently H, C 1-6 alkyl, C 3-8 cycloalkyl, or C 4-14 alkyl-cycloalkyl; or, R 1a and R 1b combine with the atom to which they are attached to form a C 3-12 heterocycloalkyl; R 2 , R 3 , R 4 , R5 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 8dEach 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 4-6 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:

[0162]

[0163] 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 R3 4 6 7 at least one of R 6 is not H.

[0164] In some embodiments, the present application provides a compound, or a pharmaceutically acceptable salt thereof, wherein the compound of Formula II has the structure:

[0165]

[0166] In some embodiments, the present application provides a compound, or a pharmaceutically acceptable salt thereof, wherein the compound of Formula II has the structure:

[0167]

[0168] In some embodiments, the present application provides a compound, or a pharmaceutically acceptable salt thereof, wherein at least one of R 2 3 4 5 6 7 is not H.

[0169] In some embodiments, the present application provides a compound, or a pharmaceutically acceptable salt thereof, wherein R 4 5 6 7 are each independently hydrogen, C 1-6 alkyl, halogen, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, -OR 8a , -NO2, -CN, 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 combine with the atom to which they are respectively attached to form C 5-6 heterocycloalkyl; and R 8a is C 3-8 cycloalkyl, C 3-14 alkyl-cycloalkyl, C 4-16 alkyl-heterocycloalkyl, 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, 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.

[0170] 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.

[0171] 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.

[0172] In some embodiments, the present invention provides a compound, wherein the compound is...

[0173] Or its pharmaceutically acceptable salt.

[0174] In some embodiments, the present invention provides a compound, wherein the compound is...

[0175]

[0176] Or its pharmaceutically acceptable salt.

[0177] 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.

[0178] In some embodiments, the present invention provides a compound, wherein the compound is...

[0179] Or its pharmaceutically acceptable salt.

[0180] In some embodiments, the present invention provides a compound, wherein the compound is...

[0181]

[0182] Or its pharmaceutically acceptable salt.

[0183] 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.

[0184] 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.

[0185] The present application also includes isotopically-labeled compounds of the present application, wherein one or more atoms are replaced by an atom having the same atomic number but an atomic mass or mass number different from the predominant mass or mass number of the atom which is replaced. Examples of isotopes that are included in the present application include, but are not limited to, isotopes of hydrogen, carbon, nitrogen, oxygen, fluorine, sulfur, and chlorine, such as 2 H, 3 H, 13 C, 14 C, 15 N, 18 O, 17 O, 18 F, 35 S, and 36 Cl). Isotopically-labeled compounds of the present application are useful in metabolic studies, as reversible inactivators of biological activity, as detectable labels, as probes for screening potential drug candidates, or simply because certain isotopically-labeled compounds can be useful in formulating compositions. 3 H, and 14 C. In addition, substitution with heavier isotopes such as deuterium ( 2 H) can afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements. Isotopically labeled compounds of the present application can generally be prepared by carrying out the procedures disclosed in the schemes and examples below, by either substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent, or by using an isotopically labeled reagent in a manner similar to the procedures disclosed in the schemes and examples below. The compounds of the present application can be isotopically labeled at the ortho position of the basic amine, at the aromatic ring, and at the methyl group of the methoxy substituent.

[0186] The present application includes all tautomers and stereoisomers of the compounds of the present application, in any mixture or in pure or substantially pure form. The compounds of the present application have asymmetric centers at the carbon atoms and are therefore capable of existing in the form of diastereomers or enantiomers or mixtures thereof. All conformational isomers (e.g., cis and trans isomers) and all optical isomers (e.g., enantiomeric and diastereomeric isomers), racemates, diastereomers and other mixtures of such isomers, as well as solvates, hydrates, isoforms, polymorphs and tautomers are within the scope of the present application. The compounds of the present application can be prepared using diastereomeric, enantiomeric or racemic mixtures as starting materials. In addition, diastereomeric and enantiomeric products can be separated by chromatography, fractional crystallization or other techniques known to those skilled in the art.

[0187] IV. Pharmaceutical Compositions and Formulations

[0188] In some embodiments, the present application provides pharmaceutical compositions comprising a compound of the present application and a pharmaceutically acceptable excipient.

[0189] The pharmaceutical compositions of the present application 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 and the like, suitable for ingestion by the patient. The compositions of the present application can also be administered by injection, that is, intravenously, intramuscularly, intradermally, subcutaneously, intraduodenally or intraperitoneally. In addition, the compositions described herein can be administered by inhalation, for example, intranasally. Further, the compositions of the present application can be administered transdermally. The compositions of the present application can also be administered by intraocular, intravaginal and intrarectal routes, including suppositories, insufflation, powders and aerosol formulations (e.g., steroid inhalers, see Rohatagi, J. Clin. Pharmacol. 35:1187-1193, 1995; Tjwa, Ann. Allergy Asthma Immunol. 75:107-111, 1995). Accordingly, the present application also provides pharmaceutical compositions comprising a pharmaceutically acceptable carrier or excipient and a compound of the present application.

[0190] For preparing the pharmaceutical compositions of the compounds as described herein, a pharmaceutically acceptable carrier can be a solid or a liquid. Solid form preparations include powders, tablets, capsules, cachets, suppositories, and dispersible granules. A solid carrier can be one or more substances which also function as diluents, flavoring agents, binding agents, preservatives, tablet disintegrating agents, or an encapsulating material. Details of suitable preparations and administration techniques for various dosage forms can be found in the scientific and patent literature, see, e.g., Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, PA (latest edition).

[0191] For a powder, the carrier is a finely divided solid, which is mixed with the finely divided active ingredient. In a tablet, the active ingredient combined with a carrier having the necessary binding capacity in suitable proportions is compressed into tablets of the desired shape and size. The powders and tablets preferably contain from 5% to 70% or from 10% to 70% of the compound of the present application.

[0192] Suitable solid excipients include, but are not limited to, magnesium carbonate; magnesium stearate; talc; pectin; dextrin; starch; tragacanth; low-melting waxes; cocoa butter; carbohydrates such as, but not limited to, lactose, sucrose, mannitol or sorbitol, corn, wheat, rice, potato, or other vegetable starches; celluloses such as, but not limited to, methyl cellulose, hydroxypropylmethyl cellulose or sodium carboxymethyl cellulose; and chewing gum, including gum arabic and tragacanth; and proteins, including, but not limited to, gelatin and collagen. If desired, disintegrating or solubilizing agents can be added, such as, but not limited to, cross-linked polyvinyl pyrrolidone, agar, alginic acid or a salt thereof such as sodium alginate.

[0193] For preparing suppositories, a low-melting wax, such as a mixture of fatty acid glycerides or cocoa butter, is first melted and the compound of the application is dispersed homogeneously therein, as by stirring. The molten homogeneous mixture is then poured into convenient sized molds, cooled, and ejected therefrom.

[0194] Liquid form preparations include solutions, suspensions, and emulsions, for example, water or water / propylene glycol solutions. For parenteral injection, liquid preparations can be formulated in solutions in aqueous polyethylene glycol ether.

[0195] aqueous suspensions can be prepared by dispersing the finely divided active component in the required amount of the chosen liquid to which it is unreactive, the resulting suspension then being maintained by the use of surfactants or wetting agents. The liquid phase is then generally a solvent or dispersion medium, such as water, an aliphatic ketone, e.g. acetone, or an aromatic solvent, e.g. liquid paraffin, or a mixture of these suitable solvents. The formulations can also contain other suitable flavouring or colouring agents. The formulations can be presented in unit dose or multi-dose containers, for example, sealed ampoules and vials, and can be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water, for injection. Alternatively, the formulations can be presented in a single-dose form, for example, as an aqueous sterile injection suspension in a pre-filled syringe.

[0196] Also included are solid form preparations which are intended to be converted to liquid form preparations shortly before use. Such liquid forms include solutions, suspensions, and emulsions. In addition to the active component, the liquid forms can contain coloring agents, flavoring agents, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizing agents, and the like.

[0197] Oil suspensions can be formulated by suspending a compound of the application in a vegetable oil, such as arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin or a combination of these. The oil suspension can contain a thickening agent, such as beeswax, hard paraffin or cetyl alcohol. Sweetening agents can be added to provide a palatable oral preparation, such as glycerol, sorbitol or sucrose. These formulations can be preserved by the addition of an antioxidant such as ascorbic acid. As an example of an injectable oil-based carrier, see Minto, J. Pharmacol. Exp. Ther. 281 :93-102, 1997. The pharmaceutical formulations of the application can also be in the form of oil-in-water emulsions. The oily phase can be a vegetable oil or a mineral oil, described above, or a combination of these. Suitable emulsifying agents include naturally occurring gums such as gum acacia and gum tragacanth, naturally occurring phosphatides such as soybean

[0198] The compositions of the application can also be administered in the form of microspheres for sustained release in vivo. For example, microspheres for administration can be formulated for slow subcutaneous release by intradermal injection of drug-containing microspheres that slowly release subcutaneously (see Rao, J. Biomaterials Appl. 7:623-645, 1995; as biodegradable and injectable gel formulations (see, e.g., Gao, Pharm. Res. 12:857-863, 1995); or as microspheres for oral administration (see, e.g., Eyles, J. Pharm. Pharmacol. 49:669-674, 1997). Both transdermal and intradermal routes provide for sustained drug administration for weeks or months.

[0199] In some embodiments, the pharmaceutical compositions of the present application can be formulated for parenteral administration, e.g., intravenous (IV) administration or administration into a body cavity or organ lumen. Formulations for administration generally include solutions of the compositions of the present application dissolved in a pharmaceutically acceptable carrier. Among the acceptable carriers that can be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil can be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables. These solutions are sterile and generally free of undesirable matter. These formulations can be sterilized by conventional, well-known sterilization techniques. The formulations can contain pharmaceutically acceptable auxiliary substances as required. These auxiliary substances include, for example, pH adjusting and buffering agents, toxicity adjusting agents, e.g., sodium acetate, sodium chloride, potassium chloride, calcium chloride, sodium lactate, and the like. The concentration of the compositions of the present application in these formulations can vary widely, and will be selected primarily based on fluid volumes, viscosities, body weight, and the like, in accordance with the particular mode of administration selected and the patient's needs. For IV injection, the formulations can be sterile injectable preparations, e.g., sterile injectable aqueous or oleaginous suspensions. This suspensions can be formulated according to techniques known in the art using those suitable dispersing or wetting agents and suspending agents. A sterile injectable preparation can also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, such as a solution in 1,3-butanediol.

[0200] In some embodiments, formulations of the compositions of the present application can be delivered by the use of liposomes which fuse with or are endocytosed by cell membranes, i.e., by the use of ligands attached to the liposome or directly to the oligonucleotide, which bind to protein receptors on the surface membrane of the cell, resulting in endocytosis. By the use of liposomes, particularly where the liposome surface bears ligands specific for target cells, or ligands which otherwise preferentially direct the liposome to a particular organ, one can focus the delivery of the compositions of the present application to target cells in vivo. (See, e.g., Al-Muhammed, JOURNAL OF MICROENCAPSULATION. 13:293-306, 1996; Chonn, CURRENT OPINION IN BIOTECHNOLOGY. 6:698-708, 1995; Ostro, Am. J. Hosp. Pharm. 46:1576-1587, 1989).

[0201] V. Administration

[0202] The compositions of the present application can be delivered by any suitable method, including oral, parenteral, and topical methods. Transdermal administration by topical routes can be formulated as applicator sticks, solutions, suspensions, emulsions, gels, creams, ointments, pastes, jellies, paints, powders, and aerosols.

[0203] The pharmaceutical preparations are preferably in unit dosage forms. In such form, the preparation is subdivided into unit doses containing appropriate quantities of the compounds of the present application. The unit dosage form can be a packaged preparation, the package containing discrete quantities of preparation, such as packeted tablets, capsules, and powders in vials or ampules. Also, the unit dosage form can be a capsule, tablet, cachet, or lozenge itself, or it can be the appropriate number of any of these in packaged form.

[0204] The compounds of the present application can be present in any suitable amount, and can depend on various factors including, but not limited to, the weight and age of the subject, the disease state, and the like. Suitable dosage ranges of the compounds of the present application 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 application 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.

[0205] The compounds of the present application can be administered at any suitable frequency, interval, and duration. For example, the compounds of the present application can be administered once per hour, or twice, three times, or more per hour, once per day, or twice, three times, or more per day, or once every 2, 3, 4, 5, 6, or 7 days, to provide the preferred dosage level. When the compounds of the present application are administered more than once per day, representative intervals include 5, 10, 15, 20, 30, 45, and 60 minutes, and 1, 2, 4, 6, 8, 10, 12, 16, 20, and 24 hours. The compounds of the present application can be administered once, twice, three times, or more than three times, for 1 hour, 1-6 hours, 1-12 hours, 1-24 hours, 6-12 hours, 12-24 hours, 1 day, 1-7 days, one week, 1-4 weeks, one month, 1-12 months, one year, or more, or even indefinitely.

[0206] The compositions can also contain other compatible therapeutic agents. The compounds described herein can be used in combination with each other, with other active agents known to be useful in modulating glucocorticoid receptors, or with adjunct agents that can not be useful per se, but which are helpful in potentiating the action of the active agents.

[0207] The compounds of the application can be co-administered with another active agent. Co-administration includes administration of the compound of the application and the active agent within 0.5, 1, 2, 4, 6, 8, 10, 12, 16, 20, or 24 hours of each other. Co-administration includes administration of the compound of the application and the active agent simultaneously, approximately simultaneously (e.g., within 1, 5, 10, 15, 20, or 30 minutes of each other), or sequentially. In addition, the compound of the application and the active agent can be administered separately once a day, or twice, three times, or more times a day to provide the preferred dosage level per day.

[0208] In some embodiments, co-administration can be achieved by co-formulation, i.e., preparing a single pharmaceutical composition that includes both the compound of the application and the active agent. In other embodiments, the compound of the application and the active agent can be formulated separately.

[0209] The compound of the application and the active agent can be present in the compositions of the application in any suitable weight ratio, such as 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 compound of the application and the other active agent can be present in any suitable weight ratio, such as about 1:100 (w / w), 1:50, 1:25, 1:10, 1:5, 1:4, 1:3, 1:2, 1:1, 2:1, 3:1, 4:1, 5:1, 10:1, 25:1, 50:1, or 100:1 (w / w). Other dosages and dosage ratios of the compound of the application and the active agent are suitable for use in the compositions and methods of the application.

[0210] VI. Methods of Treatment

[0211] The compounds of the application can be used to increase neuronal plasticity. The compounds of the application can also be used to treat any brain disease. The compounds of the application can also be used to increase at least one of translation, transcription, or secretion of a neurotrophic factor.

[0212] In some embodiments, the compounds of the application are used to treat a neurological disorder. In some embodiments, the compounds have, e.g., anti-addiction, anti-depression, anti-anxiety, or a combination thereof. In some embodiments, the neurological disorder is a neuropsychiatric disorder. In some embodiments, the neuropsychiatric disorder is a mood or anxiety disorder. In some embodiments, the neurological disorder is migraine, headache (e.g., cluster headache), post-traumatic stress disorder (PTSD), anxiety, depression, neurodegenerative disorder, Alzheimer’s disease, Parkinson’s disease, a psychological disorder, treatment-resistant depression, suicidal ideation, major depressive disorder, bipolar disorder, schizophrenia, stroke, traumatic brain injury, and addiction (e.g., a drug use disorder). In some embodiments, the neurological disorder is migraine or cluster headache. In some embodiments, the neurological disorder is a neurodegenerative disorder, Alzheimer’s disease, or Parkinson’s disease. In some embodiments, the neurological disorder is a psychological disorder, treatment-resistant depression, suicidal ideation, major depressive disorder, bipolar disorder, schizophrenia, post-traumatic stress disorder (PTSD), addiction (e.g., a drug use disorder), depression, or anxiety. In some embodiments, the neuropsychiatric disorder is a psychological disorder, treatment-resistant depression, suicidal ideation, major depressive disorder, bipolar disorder, schizophrenia, post-traumatic stress disorder (PTSD), addiction (e.g., a drug use disorder), depression, or anxiety. In some embodiments, the neuropsychiatric or neurological disorder is post-traumatic stress disorder (PTSD), addiction (e.g., a drug use disorder), schizophrenia, depression, or anxiety. In some embodiments, the neuropsychiatric or neurological disorder is addiction (e.g., a drug use disorder). In some embodiments, the neuropsychiatric or neurological disorder is depression. In some embodiments, the neuropsychiatric or neurological disorder is anxiety. In some embodiments, the neuropsychiatric or neurological disorder is post-traumatic stress disorder (PTSD). In some embodiments, the neurological disorder is stroke or traumatic brain injury. In some embodiments, the neuropsychiatric or neurological disorder is schizophrenia.

[0213] In some embodiments, the compounds of the application are used to increase neuronal plasticity. In some embodiments, the compounds described herein are used to treat a brain disorder. In some embodiments, the compounds described herein are used to increase at least one of translation, transcription, or secretion of a neurotrophic factor.

[0214] In some embodiments, the compounds of the application have activity as 5-HT 2A modulating agents. In some embodiments, the compounds of the application have activity as 5-HT 2A modulating agents. In some embodiments, the compounds of the application have activity as 5-HT2A receptors (e.g., allosterically modulate or modulate activation of 5-HT 2A receptors) to elicit biological responses. 5-HT 2A agonism is associated with promotion of neuroplasticity (Ly et al., 2018). As Figure 7 shown, 5-HT 2A antagonists can eliminate the hallucinogenic and spinogenesis effects of hallucinogenic compounds that are active as 5-HT 2A agonists, such as DMT, LSD, and DOI. In some embodiments, the compounds of the present invention are 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 promote neuroplasticity (e.g., cortical structural plasticity). In some embodiments, the promotion of neuroplasticity includes, for example, increasing dendritic spine growth, increasing synaptic protein synthesis, strengthening synaptic responses, increasing dendritic complexity, increasing dendritic branch content, increasing spinogenesis, increasing neurogenesis, or any combination thereof. In some embodiments, the increased neuroplasticity includes, for example, increasing prefrontal cortical structural plasticity.

[0215] In some embodiments, the 5-HT 2A modulators (e.g., 5-HT 2A agonists) are non-hallucinogenic. In some embodiments, the non-hallucinogenic 5-HT 2A modulators (e.g., 5-HT 2A agonists) are used to treat neurological diseases without causing dissociative side effects. In some embodiments, the hallucinogenic potential of the compounds described herein is assessed in vitro. In some embodiments, the in vitro hallucinogenic potential of the compounds described herein is compared to the in vitro hallucinogenic potential of hallucinogenic homologs. In some embodiments, the compounds described herein induce less hallucinogenic potential in vitro than the hallucinogenic homologs.

[0216] In some embodiments, the non-hallucinogenic 5-HT 2A modulators (e.g., 5-HT 2A agonists) are used to treat neurological diseases. In some embodiments, the neurological diseases include reduced neuroplasticity, reduced cortical structural plasticity, reduced 5-HT 2A receptor content, reduced dendritic complexity, absence of dendritic spines, reduced dendritic branch content, reduced spinogenesis, reduced neurogenesis, retraction of neurites, or any combination thereof.

[0217] In some embodiments, the non-hallucinogenic 5-HT 2A modulators (e.g., 5-HT 2aAgonists are used to enhance neuronal plasticity. In some implementations, the non-hallucinogenic 5-HT... 2A Modifiers (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.

[0218] A. Methods to improve neuronal plasticity

[0219] "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.

[0220] 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.

[0221] 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.

[0222] 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.

[0223] In some embodiments, the experiment or assay to determine that any of the compounds of the application increase neuronal plasticity is a phenotyping analysis, a dendritogenesis analysis, a spiny process analysis, a synaptogenesis analysis, a Sholl analysis, a concentration response experiment, a 5-HT 2A agonist assay, a 5-HT 2A antagonist assay, a 5-HT 2A binding assay, or a 5-HT 2A blockade experiment (e.g., ketanserin blockade experiment). In some embodiments, the experiment or assay to determine that any of the compounds of the application have a hallucinogenic potential is the mouse head twitch response (HTR) assay.

[0224] In some embodiments, the application provides a method for increasing neuronal plasticity comprising contacting a neuronal cell with a compound of Formula I:

[0225]

[0226] at a dosage sufficient to increase neuronal plasticity of the neuronal cell, wherein: X is N or CR 3 ; R 1a , R 1b , and R 1c are each independently H, C 1-6 alkyl, C 3-8 cycloalkyl, or C 4-14 alkyl-cycloalkyl; or two of R 1a , R 1b , and R 1c combine with the atoms to which they are attached to form a C 3-12 heterocycloalkyl; R 2 , R 3 , R 4 , R 5 , R 6 , and R 7 are each independently hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, halogen, C 1-6 haloalkyl, C 1-6 alkylamine, C 1-6 alkoxy, C 1-6 haloalkoxy, -OR 8a , -NO2, -CN, -C(O)R 8b , -C(O)OR 8b , -OC(O)R 8b , -OC(O)OR 8b , -N(R 8b R 8c ), -N(R 8b )C(O)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 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, C3-6 heteroaryl, or C 6-12 aryl, or C 5-10 heteroaryl; and L is C 1-6 alkylene.

[0227] In some embodiments, the present application provides a method for increasing neuronal plasticity comprising contacting a neuronal cell with a compound of Formula I or salts and isomers thereof, wherein X is N or CR 3 ; R 1a , R 1b , and R 1c are each independently H, C 1-6 alkyl, C 3-8 cycloalkyl, or C 4-14 alkyl-cycloalkyl; or two of R 1a , R 1b , and R 1c combine with the atom to which they are attached to form a C 3-6 heterocycloalkyl; R 2 , R 3 , R 4 , R 5 , R 6 , and R 7 are each independently hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, halogen, C 1-6 haloalkyl, C 1-6 alkylamine, C 1-6 alkoxy, C 1-6 haloalkoxy, -OR 8a , -NO2, -CN, -C(O)R 8b , -C(O)OR 8b , -OC(O)R 8b , -OC(O)OR 8b , -N(R 8b R 8c ), -N(R 8b )C(O)R 8c , -C(O)N(R 8b R 8c ), -N(R 8b )C(O)OR 8c , -OC(O)N(R 8b R 8c ), -N(R 8b )C(O)N(R 8c R 8d ), -C(O)C(O)N(R 8b R 8c ), -S(O2)R 8b-S(O)2N(R 8b R 8c ), C 3-8 cycloalkyl, C 3-14 alkyl-cycloalkyl, C 4-10 heterocycloalkyl, C 4-16 alkyl-heterocycloalkyl, C 6-12 aryl, C 7-18 alkyl-aryl, C 5-10 heteroaryl, or C 4-16 alkyl-heteroaryl; R 8a is C 3-8 cycloalkyl, C 3-14 alkyl-cycloalkyl, C 4-10 heterocycloalkyl, C 4-16 alkyl-heterocycloalkyl, C 6-12 aryl, C 7-18 alkyl-aryl, C 5-10 heteroaryl, or C 4-16 alkyl-heteroaryl; R 8b , R 8c and R 8d are each independently H or C 1-6 alkyl; or, one of R 1a , R 1b or R 1c combines with one of R 2 , R 3 , R 4 , R 5 , R 6 and R 7 to form C 5-6 cycloalkyl or C 5-6 heterocycloalkyl; or, R 2 and R 3 combine with the atoms to which they are respectively attached to form C 6-12 aryl; or, R 4 and R 5 , R 5 and R 6 , or R 6 and R 7 combine with the atoms to which they are respectively attached to form C 3-6 cycloalkyl or C 3-6 heterocycloalkyl; and L is C 1-6 alkylene, in a dose sufficient to increase neuronal plasticity of neuronal cells.

[0228] B. Methods of treating brain disorders

[0229] 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.

[0230] In some implementations, 5-HT 2A Modifiers (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.

[0231] 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.

[0232] 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:

[0233]

[0234] 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 R3 , R 4 , R 5 , R 6 , and R 7 are each independently hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, halogen, C 1-6 haloalkyl, C 1-6 alkylamine, C 1-6 alkoxy, C 1-6 haloalkoxy, -OR 8a , -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(O2)N(R 8b R 8c ), C 3-8 cycloalkyl, C 3-14 alkyl-cycloalkyl, C 4-10 heterocycloalkyl, C 4-16 alkyl-heterocycloalkyl, C 6-12 aryl, C 7-18 alkyl-aryl, C 5-10 heteroaryl, or C 4-16 alkyl-heteroaryl; R 8a is C 3-8 cycloalkyl, C 3-14 alkyl-cycloalkyl, C 4-10 heterocycloalkyl, C 4-16 alkyl-heterocycloalkyl, C 6-12 aryl, C 7-18 alkyl-aryl, C 5-10 heteroaryl, or C 4-16 alkyl-heteroaryl; R 8b , R8c and R 8d each independently is H or C 1-6 alkyl; or, R 1a , R 1b or R 1c where one is combined with R 2 to form a C 5-12 heterocycloalkyl; or, R 2 and R 3 are combined with the atoms to which they are respectively attached to form a C 4-8 cycloalkyl, C 4-10 heterocycloalkyl, or C 6-12 aryl; or, R 4 and R 5 , R 5 and R 6 , or R 6 and R 7 are combined with the atoms to which they are respectively attached to form a C 3-6 cycloalkyl, C 3-6 heterocycloalkyl, C 6-12 aryl, or C 5-10 heteroaryl; and L is C 1-6 alkylene.

[0235] In some embodiments, the present application provides a method of treating a brain disease, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula I or salts and isomers thereof, wherein X is N or CR 3 ; R 1a , R 1b and R 1c each independently is H, C 1-6 alkyl, C 3-8 cycloalkyl, or C 4-14 alkyl-cycloalkyl; or, two of R 1a , R 1b and R 1c are combined with the atoms to which they are attached to form a C 3-6 heterocycloalkyl; 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 alkynyl, halogen, C 1-6 haloalkyl, C 1-6 alkylamine, C 1-6 alkoxy, C 1-6 haloalkoxy, -OR 8a , -NO2, -CN, -C(O)R8b -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, R2 and R 3 with the atom to which they are each attached forming C 6-12 aryl; or, R 4 and R 5 , R 5 and R 6 , or R 6 and R 7 with the atom to which they are each attached forming C 3-6 cycloalkyl or C 3-6 heterocycloalkyl; L is C 1-6 alkylene, thereby treating a brain disease.

[0236] In some embodiments, the brain disease is a neurodegenerative disease, Alzheimer’s disease, Parkinson’s disease, a psychological disorder, depression, addiction, anxiety, post-traumatic stress disorder, treatment-resistant depression, suicidal ideation, major depressive disorder, bipolar disorder, schizophrenia, stroke, traumatic brain injury, or a substance use disorder.

[0237] In some embodiments, the brain disease is a neurodegenerative disease, Alzheimer’s disease, or Parkinson’s disease. In some embodiments, the brain disease is a psychological disorder, depression, addiction, anxiety, or post-traumatic stress disorder. In some embodiments, the brain disease is depression. In some embodiments, the brain disease is addiction. In some embodiments, the brain disease is treatment-resistant depression, suicidal ideation, major depressive disorder, bipolar disorder, schizophrenia, stroke, traumatic brain injury, or a substance use disorder. In some embodiments, the brain disease is treatment-resistant depression, suicidal ideation, major depressive disorder, bipolar disorder, schizophrenia, or a 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 a substance use disorder. In some embodiments, the brain disease is schizophrenia. In some embodiments, the brain disease is an alcohol use disorder.

[0238] In some embodiments, the method further comprises administering one or more additional therapeutic agents that is lithium, olanzapine (Zyprexa), quetiapine (Seroquel), risperidone (Risperdal), aripiprazole (Abilify), ziprasidone (Geodon), clozapine (Clozaril), divalproex sodium (Depakote), lamotrigine (Lamictal), valproic acid sodium (Depakene), carbamazepine (Equetro), topiramate (Topamax), levomilnacipran (Fetzima), duloxetine (Cymbalta, Yentreve), venlafaxine (Effexor), citalopram (Celexa), fluvoxamine (Luvox), escitalopram (Lexapro), fluoxetine (Prozac), paroxetine (Paxil), sertraline (zolot), clomipramine (Anafranil), amitriptyline (Elavil), desipramine (norpramine), imipramine (Tofranil), nortriptyline (Pamelor), phenelzine (Nardil), tranylcypromaine (Parnate), diazepam (Valium), alprazolam (Xanax), or clonazepam (Klonopin).

[0239] In some embodiments, the compounds of the application are used in combination with a standard of care treatment for a neurological disorder described herein. Non-limiting examples of a standard of care treatment include, for example, lithium, olanzapine, quetiapine, risperidone, aripiprazole, ziprasidone, clozapine, divalproex sodium, lamotrigine, valproic acid sodium, carbamazepine, topiramate, levomilnacipran, duloxetine, venlafaxine, citalopram, fluvoxamine, escitalopram, fluoxetine, paroxetine, sertraline, clomipramine, amitriptyline, desipramine, nortriptyline, phenelzine, tranylcypromaine, diazepam, alprazolam, clonazepam, or any combination thereof. Non-limiting examples of a standard of care treatment for depression are sertraline, fluoxetine, escitalopram, venlafaxine, or aripiprazole. Non-limiting examples of a standard of care treatment for depression are citalopram, escitalopram, fluoxetine, paroxetine, diazepam, or sertraline.

[0240] C. Methods of increasing at least one of translation, transcription, or secretion of a neurotrophic factor

[0241] Neurotrophins refer to a family of soluble peptides or proteins that support survival, growth, and differentiation of developing and mature neurons. Increasing at least one of translation, transcription, or secretion of a neurotrophin can be used, without limitation, to increase neuronal plasticity, promote neuronal growth, promote neurogenesis, promote synapse generation, promote dendrite generation, increase dendritic complexity, increase density of dendritic spines, and increase excitatory synapses in the brain. In some embodiments, increasing at least one of translation, transcription, or secretion of a neurotrophin can increase neuronal plasticity. In some embodiments, increasing at least one of translation, transcription, or secretion of a neurotrophin can promote neuronal growth, promote neurogenesis, promote synapse generation, promote dendrite generation, increase dendritic complexity, and / or increase density of dendritic spines.

[0242] In some embodiments, 5-HT 2A modulators (e.g., 5-HT 2A agonists) are used to increase at least one of translation, transcription, or secretion of a neurotrophin. In some embodiments, compounds of the present application are used to increase at least one of translation, transcription, or secretion of a neurotrophin. In some embodiments, increasing at least one of translation, transcription, or secretion of a neurotrophin is used to treat migraine, headache (e.g., cluster headache), post-traumatic stress disorder (PTSD), anxiety, depression, neurodegenerative disorder, Alzheimer’s disease, Parkinson’s disease, psychological disorder, treatment-resistant depression, suicidal ideation, major depressive disorder, bipolar disorder, schizophrenia, stroke, traumatic brain injury, and addiction (e.g., drug use disorder).

[0243] In some embodiments, experiments or assays used to determine an increase in translation of a neurotrophin include ELISA, western blot, immunofluorescence assay, proteomics experiment, and mass spectrometry analysis. In some embodiments, experiments or assays used to determine an increase in transcription of a neurotrophin include gene expression analysis, PCR, and microarray. In some embodiments, experiments or assays used to determine an increase in secretion of a neurotrophin include ELISA, western blot, immunofluorescence assay, proteomics experiment, and mass spectrometry analysis.

[0244] In some embodiments, the present application provides a method of increasing at least one of translation, transcription, or secretion of a neurotrophin, comprising contacting a neuronal cell with a compound of Formula I:

[0245]

[0246] in an amount sufficient to increase neuronal plasticity of the neuronal cell, wherein: X is N or CR 3 ; R1a R 1b and R 1c are each independently H, C 1-6 alkyl, C 3-8 cycloalkyl, or C 4-14 alkyl-cycloalkyl; or two of R 1a , R 1b and R 1c , together with the atom to which they are attached, form a C 3-12 heterocycloalkyl; R 2 , R 3 , R 4 , R 5 , R 6 and R 7 are each independently hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, halogen, C 1-6 haloalkyl, C 1-6 alkylamine, C 1-6 alkoxy, C 1-6 haloalkoxy, -OR 8a , -NO2, -CN, -C(O)R 8b , -C(O)OR 8b , -OC(O)R 8b , -OC(O)OR 8b , -N(R 8b R 8c ), -N(R 8b )C(O)R 8c , -C(O)N(R 8b R 8c ), -N(R 8b )C(O)OR 8c , -OC(O)N(R 8b R 8c ), -N(R 8b )C(O)N(R 8c R 8d ), -C(O)C(O)N(R 8b R 8c ), -S(O2)R 8b , -S(O2)N(R 8b R 8c ), C 3-8 cycloalkyl, C 3-14 alkyl-cycloalkyl, C 4-10 heterocycloalkyl, C 4-16 alkyl-heterocycloalkyl, C 6-12 aryl, C 7-18 alkyl-aryl, C 5-10 heteroaryl, or 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.

[0247] 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 R 3 R 4R 5 R 6 and R 7 are each independently hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, halogen, C 1-6 haloalkyl, C 1-6 alkylamine, C 1-6 alkoxy, C 1-6 haloalkoxy, -OR 8a , -NO2, -CN, -C(O)R 8b , -C(O)OR 8b , -OC(O)R 8b , -OC(O)OR 8b , -N(R 8b R 8c ), -N(R 8b )C(O)R 8c , -C(O)N(R 8b R 8c ), -N(R 8b )C(O)OR 8c , -OC(O)N(R 8b R 8c ), -N(R 8b )C(O)N(R 8c R 8d ), -C(O)C(O)N(R 8b R 8c ), -S(O2)R 8b , -S(O)2N(R 8b R 8c ), C 3-8 cycloalkyl, C 3-14 alkyl-cycloalkyl, C 4-10 heterocycloalkyl, C 4-16 alkyl-heterocycloalkyl, C 6-12 aryl, C 7-18 alkyl-aryl, C 5-10 heteroaryl, or C 4-16 alkyl-heteroaryl; R 8a is C 3-8 cycloalkyl, C 3-14 alkyl-cycloalkyl, C 4-10 heterocycloalkyl, C 4-16 alkyl-heterocycloalkyl, C 6-12 aryl, C 7-18 alkyl-aryl, C 5-10 heteroaryl, or C 4-16 alkyl-heteroaryl; R 8b , R 8c and R 8deach independently H or C 1-6 alkyl; or, R 1a , R 1b or R 1c wherein one is combined with R 2 , R 3 , R 4 , R 5 , R 6 and R 7 to form a C 5-6 cycloalkyl or C 5-6 heterocycloalkyl; or, R 2 and R 3 are combined with the atoms to which they are respectively attached to form a C 6-12 aryl; or, R 4 and R 5 , R 5 and R 6 , or R 6 and R 7 are combined with the atoms to which they are respectively attached to form a C 3-6 cycloalkyl or C 3-6 heterocycloalkyl; and L is C 1-6 alkylene, in an amount sufficient to increase neuronal plasticity of neuronal cells.

[0248] VII. Examples

[0249] General

[0250] Unless otherwise indicated, all reagents were obtained from commercial suppliers and used without further purification. DMSO was purified by passage through an activated alumina column under N2at 12 psi. Reactions were performed using flame-dried glassware under reduced pressure (~1 torr). Compounds purified by chromatography were adsorbed onto silica gel prior to loading. Thin layer chromatography was performed on micro-pore silica gel 60 F 254 Silica gel plates. Visualization of chromatography was achieved by fluorescence quenching or ninhydrin or cerium ammonium molybdate (CAM) staining.

[0251] 1 H and 13 H nuclear magnetic resonance (NMR) spectra were recorded on a Bruker 400 at 400 and 100 MHz, Varian 600 at 600 and 150 MHz, or Bruker 800 at 800 and 200 MHz, respectively, and referenced to residual solvent signals as internal standards. 1 H NMR data are recorded as follows: chemical shift (δ, ppm), multiplicity (s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet), integration, coupling constant (Hz). 13C NMR data are reported in chemical shifts (δ, ppm). Infrared spectra were recorded with a Nicolet iS10 FT-IR spectrometer equipped with a Smart iTX Thermo plug-in (Diamond ATR) and are reported in absorption frequencies (v, cm -1 ) 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, L. P.; Benson, C. J.; Dunlap, L. E.; Olson, D. E. Effects of N,N-Dimethyltryptamine (DMT) on Rodent Behaviors Related to Anxiety and Depression. ACS Chemical Neuroscience. 2018, 97, 1582-1590; Tombari, R. J.; Saunders, C. M.; Wu, C. Y.; Dunlap, L. E.; Tantillo, D. J.; Olson, D. E. In Vitro Analysis of Tryptophan Metabolism by19F NMR. ACS Chemical Biology, 2019, 14, 1866-1873.). For cellular plasticity assays (i.e., dendritogenesis), all compounds were dissolved in DMSO and stored as 10 mM stocks at -20 °C in the dark.

[0252] All compounds tested in cellular assays had purity >95% as measured by UHPLC analysis (Waters ACQUITY Arc) with absorbance at 254 and 280 nm. Mobile phase A was 0.01% formic acid in water and mobile phase B was 0.01% formic acid in acetonitrile. Injection volume was 5 μL for all samples and column temperature was maintained at 40 °C. One of three methods was used depending on the specific compound. Method A employed a CORTECS C18, 2.7 μm, 4.6 x 50 mm column with a flow rate of 0.6 mL / min and a gradient of mobile phase B from 10% to 90% over 3 min, followed by a 2 min hold. Method B employed an XBridge BEH C18 2.5 μm, 2.1 x 100 mm column with a flow rate of 0.6 mL / min and a gradient of mobile phase B from 10% to 90% over 0.5 min, followed by a 4.5 min hold. Method C employed a CORTECS C18, 2.7 μm, 4.6 x 50 mm column with a flow rate of 0.2 mL / min and a gradient of mobile phase B from 10% to 90% over 4 min, followed by a 2 min hold. Since most of the compounds reported in this study were isolated as fumarate salts, the peak corresponding to fumaric acid in the UHPLC trace was not included in the purity calculation.

[0253] Synthesis of iso-DMT

[0254] A simple and robust procedure for the synthesis of various isoDMTs under mild reaction conditions is described herein. Compound 2 was obtained in high yield by in situ Finkelstein reaction with KOH as base and KI to enhance the reactivity of the reaction. It was demonstrated that the reaction was optimal when maintained at 0.4 M, both high and low concentrations resulted in lower yields.

[0255] Step A

[0256] In some embodiments, the intermediates used to prepare the compounds described herein are prepared according to Scheme 1.

[0257] Scheme 1

[0258]

[0259] In Scheme 1, L, R 1a-1c , and R 2 -R 7 as described herein. In some embodiments, X is a halogen or a sulfo group. In some embodiments, the halogen is iodine, bromine, or chlorine. In some embodiments, the halogen is chlorine. In some embodiments, the sulfo group is tosylate, mesylate, brosylate, or mesylate. In some embodiments, X is chlorine.

[0260] In some embodiments, indole I-1 is reacted with I-2 under suitable condensation reaction conditions, optionally followed by appropriate salt forming conditions, to provide substituted isoDMTI-3. In some embodiments, suitable condensation reaction conditions include an appropriate base, an appropriate additive, an appropriate solvent, at an appropriate temperature, for an appropriate time. In some embodiments, the appropriate base is a hydroxide base, a carbonate base, or a bicarbonate base. In some embodiments, the appropriate base is a hydroxide base or a hydride base. In some embodiments, the appropriate hydroxide base is sodium hydroxide or potassium hydroxide. In some embodiments, the appropriate hydroxide base is potassium hydroxide. In some embodiments, the suitable hydride base is sodium hydride. In some embodiments, the appropriate additive is a salt. In some embodiments, the salt is potassium iodide, sodium iodide, or lithium iodide. In some embodiments, the appropriate salt is potassium iodide. In some embodiments, the appropriate 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.

[0261] In some embodiments, the appropriate salt forming conditions include an appropriate acid, in an appropriate solvent, at an appropriate temperature, for an appropriate time. In some embodiments, the appropriate acid is a carboxylic acid. In some embodiments, the carboxylic acid is fumaric acid. In some embodiments, the appropriate solvent is acetone. In some embodiments, the appropriate time and temperature are 5 minutes to 1 hour and 55 °C, respectively.

[0262] For example, to a solution of indole or related heterocycle in DMSO (0.4 M) is added 2-chloro-N,N-dimethylethanamine hydrochloride (1.1 eq), potassium iodide (1.1 eq), and potassium hydroxide pellets (5.0 eq). The reaction is stirred at room temperature for 24 hours, then quenched with 1.0 M NaOH (2.0 eq) and stirred for 1 hour. The reaction is acidified with 1.0 M HCl (2.0 eq) and extracted with ethyl acetate (3x). The combined organic layers are dried over sodium sulfate, filtered, and concentrated in vacuo. The residue is purified by flash chromatography (0-100% EtOAc in hexanes) to provide the desired product. (水性)Dilution. The aqueous phase was extracted three times with DCM. The organic extracts were combined, dried over Na2SO4, filtered, and concentrated under reduced pressure to yield an oil. The unpurified oil was dissolved in a small amount of acetone and added dropwise to a boiling acetone solution of fumaric acid (1.0 equiv). In most cases, a precipitate formed immediately and was stored overnight at -20 °C. The resulting crystals were filtered and washed with a few portions of ice-cold acetone to yield the desired product. In cases where the desired product did not crystallize readily as a fumarate salt, column chromatography (9:1 CH2Cl2:MeOH:1% NH4OH (水性) ) was performed on the oil unless otherwise noted.

[0263] Example 1. N,N-Dimethyltryptamine (DMT)

[0264] The following DMT compounds can be prepared by methods known in the art.

[0265]

[0266] Example 2. 2-(1H-Indol-1-yl)-N,N-dimethylethan-1-amine fumarate (1:1) (2, iso-DMT)

[0267]

[0268] Indole (100 mg, 0.85 mmol), 2-chloro-N,N-dimethylethanamine hydrochloride (135 mg, 0.94 mmol, 1.1 equiv), potassium iodide (156 mg, 0.94 mmol, 1.1 equiv), and potassium hydroxide (140 mg, 4.2 mmol, 5.0 equiv) were dissolved in DMSO (2.15 mL) and stirred, monitoring by TLC for complete consumption of 2-chloro-N,N-dimethylethanamine (17-24 h), at which point the reaction was complete. The reaction mixture was diluted with 1.0 M NaOH (水性) (100 mL). The aqueous phase was extracted three times with DCM (25 mL). The organic extracts were combined, dried over Na2SO4, filtered, and concentrated under reduced pressure to yield 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 stored overnight at -20 °C. The crystals were filtered and washed with a few portions of ice-cold acetone to yield the desired product. (1 : 1 isoDMT:fumaric acid) (175 mg, 67%). Purity >99%. TLC R f (free base) = 0.50 (9:1 CH2Cl2:MeOH:1% NH4OH (水性) ); 1H NMR (600 MHz, DMSO-d6) δ 7.54 (d, 1H, J = 7.6 Hz), 7.48 (d, 1H, J = 7.6 Hz), 7.38 (d, 1H, J = 3.1 Hz), 7.13 (ddd, 1H, J = 7.6, 1.0 Hz), 7.01 (dd, 1H, J = 7.6, 1.0 Hz), 6.61 (s, 2H), 6.42 (d, 1H J = 3.1 Hz), 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-d6) δ 166.32, 135.66, 134.20, 128.82, 128.06, 120.96, 120.38, 118.88, 109.68, 100.54, 58.09, 44.83, 43.11 ppm; IR (Diamond, ATR) v 3100, 2923, 2393, 1705 cm -1 ; LRMS (ES+) Relative Mass Calcd. for C 12 H 16 N2+ 188.13, found 189.38 (MH+); MP = 147-149 °C.

[0269] Example 3. 2-(4-Methoxy-1H-indol-1-yl)-N,N-dimethylethan-1-amine fumarate (1:1) (3)

[0270]

[0271] Synthesized according to Procedure A. Reaction was performed with 4-methoxyindole (100 mg, 0.68 mmol) and purified by crystallization. Yield = 95 mg, 42% yield. Purity = 96%. TLC R f (free base) = 0.35 (9:1 CH2Cl2: MeOH: 1% NH4OH (水性) ); 1 H NMR (600 MHz, DMSO-D6) δ 7.26 (d, 1h, J = 3.1 Hz), 7.10 (d, 1H, J = 7.8 Hz), 6.90 (t, 1H, J = 7.8 Hz), 6.66 (d, 1H, J = 7.8 Hz), 6.60 (s, 2H), 6.35 (d, 1H), J = 3.1 Hz), 4.49 (t, 2H, J = 7.0 Hz), 3.89 (s, 3H), 2.76 (t, 2H), J = 7.0 Hz), 2.32 (s, 6h) ppm; 13C NMR (150 MHz, DMSO-d6) δ 166.30, 146.96, 134.17, 130.46, 129.79, 124.94, 119.64, 113.33, 102.42, 100.93, 59.61, 55.32, 45.63, 44.63 ppm; IR (Diamond, ATR) v 2929, 2455, 1712, 1644 cm -1 LRMS (ES+) Relative Mass Calculated: C 13 H 18 N2O + 219.15, found 220.33 (MH+); MP = 140-145 °C.

[0272] Example 4. 2-(5-Methoxy-1H-indol-1-yl)-N,N-dimethylethan-1-amine fumarate (1:1) (4)

[0273]

[0274] Synthesized according to Procedure A. Reaction was performed with 5-methoxyindole (100 mg, 0.68 mmol) and purified by crystallization. Yield = 111 mg, 49% yield. Purity = 98%. TLC R f (free base) = 0.66 (9:1 CH2CI2: MeOH: 1% NH4OH (水性) ); 1 H NMR (600 MHz, DMSO-D6) δ 7.38 (d, 1 h, J = 8.9 Hz), 7.33 (d, 1 H, J = 3.0 Hz), 7.04 (d, 1 H, J = 2.4 Hz), 6.77 (dd, 1 H, J = 8.9, 2.4 Hz), 6.6 (s, 2 h), 6.33 (d, 1 h), J = 3.0 Hz), 4.29 (t, 2 H, J = 6.8 Hz), 3.74 (s, 3 H), 2.79 (t, 2 H), J = 6.8 Hz), 2.30 (s, 6 h) ppm; 13 C NMR (150 MHz, DMSO-D6) δ 166.58, 153.42, 134.32, 130.90, 129.20, 128.48, 111.12, 110.39, 102.13, 100.34, 57.68, 55.30, 44.44, 42.91 ppm v 3035, 2923, 2446, 1715 cm - 1. LRMS (ES+) Relative Mass Calculated: C 13 H 18 N2O + 219.15, found 220.19 (MH+); MP = 140-142 °C.

[0275] Example 5. 2-(6-Methoxy-1H-indol-1-yl)-N,N-dimethylethan-1-amine (5)

[0276]

[0277] Synthesized according to Procedure A. Reaction was performed with 6-methoxyindole (147 mg, 1.0 mmol) and purified by chromatography. Yield 148 mg, 68% yield. Purity >99%. TLC Rf= 0.45 (9:1 CH2CI2: Meoh: 1% NH4OH). f (Free base) = 0.32 (9:1 CH2CI2: Meoh: 1% NH4OH (水性) ); 1 H NMR (600 MHz, CD3OD) δ 7.42 (d, 1 h, J = 8.5 Hz), 7.16 (d, 1 H, J = 2.9 Hz), 7.02 (s, 2 H), 6.74 (d, 1 H), J = 8.5 Hz), 6.44 (d, 1 H, J = 2.9 Hz), 4.58 (t, 2 H, J = 6.8 Hz), 3.87 (s, 3 H), 3.56 (t, 2 H), J = 7.0 Hz), 2.86 (s, 6 h) ppm; 13 C NMR (150 MHz, CD3OD) δ 156.30, 136.77, 127.04, 123.00, 121.67, 109.22, 101.31, 93.14, 59.00, 55.91, 45.94, 44.91 ppm v 2940, 2859, 2769, 1602 cm -1 . LRMS (ES+) Relative Mass Calculated: C 13 H 18 N2O + 219.15, found: 220.33 (MH+). Used for free base for dendrimer generation analysis.

[0278] Example 5'. 2-(6-Methoxy-1H-indol-1-yl)-N,N-dimethylethan-1-amine oxalate (5')

[0279] Synthesized according to Procedure A. Reaction was performed with 6-methoxyindole (250 mg, 1.7 mmol) and purified by crystallization. Yield 221 mg, 42% yield. Purity = 98%. 1 H NMR (600 MHz, CD3OD) δ 7.42 (d, 1 h, J = 8.5 Hz), 7.16 (d, 1 H, J = 2.9 Hz), 7.02 (s, 2 H), 6.74 (d, 1 H), J = 8.5 Hz), 6.44 (d, 1 H, J = 2.9 Hz), 4.58 (t, 2 H, J = 6.8 Hz), 3.87 (s, 3 H), 3.56 (t, 2 H), J = 7.0 Hz), 2.86 (s, 6 h) ppm; 13C NMR (150 MHz, CD3OD) δ 166.72, 158.20, 138.02, 127.52, 124.45, 122.61, 111.06, 103.58, 93.83, 57.22, 56.19, 44.04, 42.17 ppm v 3129, 3014, 2641, 1727 cm -1 LRMS (ES+) Relative Mass Calculated for C 13 H 18 N2O + 219.15, found: 220.05 (MH+). MP = 165-167 °C. The oxalate salt was used for HTR determination.

[0280] Example 6. 2-(7-Methoxy-1H-indol-1-yl)-N,N-dimethylethan-1-amine fumarate (1:1) (6)

[0281]

[0282] Synthesized according to Procedure A. The reaction was performed with 7-methoxyindole (100 mg, 0.68 mmol) and purified by crystallization. Yield 162 mg, 72% yield. Purity >99%. TLC Rf (free base) = 0.44 (9:1 CH2Cl2:MeOH:1% NH4OH f (1:1) = 0.44 (9:1 CH2Cl2:MeOH:1% NH4OH (水性) ); 1 H NMR (600 MHz, DMSO-D6) δ 7.26 (d, 1h, J = 3.1 Hz), 7.09-7.03 (m, 2H), 6.60 (s, 2H), 6.52 (dd, 1H), J = 6.1, 1.3 Hz), 6.41 (dd, 1h, J = 3.0, 0.7 Hz), 4.29 (t, 2H, J = 6.8 Hz), 3.86 (s, 3H), 2.75 (t, 2H), J = 6.8 Hz), 2.29 (s, 6h) ppm: 13 C NMR (150 MHz, DMSO-D6) δ 166.46, 152.80, 137.02, 134.24, 127.14, 121.98, 118.38, 103.09, 99.16, 97.88, 57.83, 54.89, 44.60, 43.15 ppm v 3435, 3034, 2653, 1705 cm -1 LRMS (ES+) Relative Mass Calculated for C 13 H 18 N2O + 219.15, found: 220.40 (MH+); MP = 120-123 °C.

[0283] Example 7. Benzyloxyindole

[0284] 4-,5-,6- and 7-OBn indoles were synthesized using methods previously reported in the literature.

[0285] Example 8. 2-(4-(Benzyloxy)-1H-indol-1-yl)-N,N-dimethylethan-1-amine fumarate (1:1) (8)

[0286]

[0287] 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 (400MHz, 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 (100MHz, CD3δ169.90,153.99,139.05,138.85,135.75,129.47,128.78,128.47,127.21,12 4.18,121.16,103.87,102.67,101.07,70.95,57.32,43.90,42.46ppmν2918, 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℃.

[0288] Example 9. 2-(5-(Benzyloxy)-1H-indol-1-yl)-N,N-dimethylethan-1-amine fumarate (1:1) (9)

[0289]

[0290] 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) δ 7.44 (d, 2H, J = 7.5 Hz), 7.36 (m, 3H), 7.29 (d, 2H, J = 7.5 Hz), 7.24 (d, IH, J = 3.2 Hz), 7.15 (d, IH, J = 2.4 Hz), 6.95 (dd, IH, J = 2.4, 8.9 Hz), 6.72 (s, 2H), 6.43 (d, IH, J = 3.2 Hz), 5.07 (s, 2H), 4.54 (t, 2H, J = 6.8 Hz), 3.45 (t, 2H, J = 6.8 Hz), 2.78 (s, 6H) ppm; 13 C NMR (200 MHz, CD3OD) δ 171.06, 154.78, 139.26, 136.11, 132.77, 130.89, 130.81, 129.44, 128.73, 128.61, 113.97, 110.95, 105.71, 103.24, 71.86, 57.66, 44.16, 42.77 ppm; IR (diamond, ATR) v 2916, 2516, 1698, 1639 cm -1 LRMS (ES+) Relative Mass Calculated for C 19 H 22 N2O + 294.17, found 295.17 (MH+); MP = 133-135 °C.

[0291] Example 10. 2-(6-(Benzyloxy)-1H-indol-1-yl)-N,N-dimethylethan-1-amine (10)

[0292]

[0293] Synthesized according to Procedure A. Reaction was performed with 6-benzyloxyindole (370 mg, 1.7 mmol) and purified by chromatography. Yield 184 mg, 38% yield. Purity >97%. TLC R f (free base) = 0.45 (9:1 CH2Cl2: MeOH: 1% NH4OH (水性) ); 1H NMR (600 MHz, CD3OD) δ 7.47 (d, 2H, J = 7.4 Hz), 7.40 (d, 2H, J = 8.6 Hz), 7.37 (t, 1H J = 7.4 Hz), 7.30 (t, 1H, J = 7.4 Hz), 7.08 (d, 1H, J = 3.8 Hz), 6.96 (s, 1H), 6.78 (d, 1H), J = 8.6 Hz), 6.35 (d, 1H, J = 3.8 Hz), 5.15 (s, 2H), 4.22 (t, 2H), J = 7.3 Hz), 2.66 (t, 2H, J = 7.3 Hz), 2.26 (s, 6h) ppm; 13 C NMR (150 MHz, CDC13) δ 156.39, 137.60, 136.66, 128.69, 127.97, 127.67, 127.22, 123.24, 121.68, 109.95, 101.31, 94.71, 70.87, 58.92, 45.91, 44.90 ppm v 3030, 2952, 2768, 1621 cm -1 LRMS (ES+) Relative Mass Calculated for C 19 H 22 N2O + 294.17, found: 295.10 (MH+).

[0294] Example 11. 2-(7-(Benzyloxy)-1H-indol-1-yl)-N,N-dimethylethan-1-amine (11)

[0295]

[0296] Synthesized according to Procedure A. Reaction was performed with 7-benzyloxyindole (119 mg, 0.53 mmol) and purified by chromatography. Yield 51 mg, 23% yield. Purity >99%. TLC R f (free base) = 0.48 (9:1 CH2Cl2: MeOH: 1% NH4OH (水性) ); 1 H NMR (600 MHz, CDC13) δ 7.49 (d, 2H, J = 7.4 Hz), 7.40 (t, 2H, J = 7.4 Hz), 7.34 (t, 1H, J = 7.4 Hz), 7.22 (d, 1H, J = 7.9 Hz), 7.01 (d, 1H, J = 3.0 Hz), 6.97 (t, 1H, J = 7.8 Hz), 6.70 (d, 1H, J = 7.8 Hz), 5.19 (s, 2H), 4.45 (t, 2H), J = 7.4 Hz), 2.62 (t, 2H, J = 7.4 Hz), 2.09 (s, 6h) ppm; 13C NMR (150 MHz, CDC13) δ 150.59, 146.71, 137.11, 131.25, 129.45, 128.75, 128.24, 128.15, 119.82, 114.16, 103.35, 101.60, 70.55, 61.02, 47.54, 45.64 ppm v 2940, 2821, 1575, 1439 cm -1 LRMS (ES+) Relative Mass Calculated for C 19 H 22 N2O + 294.17, found: 295.24 (MH+).

[0297] Example 12. 2-(4-Fluoro-1H-indol-1-yl)-N,N-dimethylethan-1-amine fumarate (1:1) (12)

[0298]

[0299] Synthesized according to Procedure A. Reaction was performed with 4-fluoroindole (135 mg, 1.0 mmol) and purified by crystallization. Yield 164 mg, 51% yield. Purity >99%. TLC Rf (free base) = 0.39 (9:1 CH2Cl2:MeOH:1% NH4OH f (水性) ); 1 HNMR (400 MHz, DMSO-D6) δ 7.44 (d, 1 h, J = 2.3 Hz), 7.35 (d, 2H, J = 8.3 Hz), 7.10 (dd, 2H, J = 7.4, 7.25 Hz), 6.79 (t, 2H, J = 9.5 Hz), 6.60 (s, 2H), 6.49 (d, 2H), J = 2.3 Hz), 4.32 (t, 2H, J = 6.7 Hz), 2.74 (t, 2H, J = 6.8 Hz), 2.28 (s, 6h) ppm; 13 C NMR (150 MHz, DMSO-D6) δ 166.37, 156.67, 154.34, 138.56, 138.44, 134.21, 129.35, 121.63, 121.55, 116.74, 116.51, 106.48, 106.45, 103.70, 103.51, 96.24, 57.90, 44.73, 43.40 ppm v 3123, 2389, 1702, 1660 cm -1 LRMS (ES+) Relative Mass Calculated for C 12 H 16 FN2+ 207.13, found: 208.32 (MH+); MP = 145-149 °C.

[0300] Example 13. 2-(5-Fluoro-1H-indol-1-yl)-N,N-dimethylethan-1-amine fumarate (1:1) (13) ​

[0301]

[0302] Synthesized according to Procedure A. Reaction was performed with 5-fluoroindole (135 mg, 1.0 mmol) and purified by crystallization. Yield 145 mg, 45% yield. Purity >99%. TLC Rf (free base) = 0.45 (9:1 CH2Cl2:MeOH:1% NH4OH f (水性) 1 HNMR (400 MHz, DMSO-D6) δ 7.50 (dd, 1 h, J = 4.5, 4.3 Hz), 7.46 (d, 1 H, J = 2.1 Hz), 7.29 (d, 1 H, J = 9.5 Hz), 6.97 (t, 1 H, J = 9.5 Hz), 6.60 (s, 2 H), 6.41 (d, 1 H), J = 2.1 Hz), 4.32 (t, 2 H, J = 6.7 Hz), 2.79 (t, 2 H, J = 6.7 Hz), 2.31 (s, 6 h) ppm; 13 C NMR (150 MHz, DMSO-D6) δ 166.59, 159.61, 158.06, 135.77, 135.69, 134.33, 129.54, 129.51, 124.72, 121.39, 121.32, 107.48, 107.32, 100.97, 96.32, 96.15, 57.66, 44.58, 43.00 ppm v 3036, 2049, 1723, 1663 cm -1 LRMS (ES+) Relative Mass Calculated for C 12 H 16 FN2+ 207.13, found: 207.40 (MH+); MP = 145-148 °C.

[0303] Example 14. 2-(6-Fluoro-1H-indol-1-yl)-N,N-dimethylethan-1-amine fumarate (1:1) (14)

[0304]

[0305] Synthesized according to Procedure A. Reaction was performed with 5-fluoroindole (135 mg, 1.0 mmol) and purified by crystallization. Yield 145 mg, 45% yield. Purity >99%. TLC R f (水性) 1 ​​​​H NMR (600 MHz, DMSO-D6) δ 7.52 (dd, 1 h, J = 7.0, 3.0 Hz), 7.39-7.37 (m, 2 h), 6.88-6.85 (m, 1 h), 6.59 (s, 2 h), 6.44 (d, 1 h), J = 3.1 Hz), 4.29 (t, 2 H, J = 6.8 Hz), 2.77 (t, 2 H, J = 6.8 Hz), 2.30 (s, 6 h) ppm; 13 C NMR (150 MHz, DMSO-D6) δ 166.59, 159.61, 158.06, 136.16, 134.75, 129.95, 125.14, 121.78, 107.91, 107.74, 101.39, 96.74, 96.57, 57.66, 44.58, 43.00 ppm v 3058, 2385, 1698, 1634 cm -1 LRMS (ES+) Relative Mass Calculated: C 12 H 16 FN2+ 207.13, found: 208.39 (MH+); MP = 141-147 °C.

[0306] Example 15. 2-(7-Fluoro-1H-indol-1-yl)-N,N-dimethylethan-1-amine fumarate (1:1) (15)

[0307]

[0308] Synthesized according to Procedure A. Reaction was performed with 7-fluoroindole (135 mg, 1.0 mmol) and purified by crystallization. Yield = 172 mg, 53% yield. Purity = 98%. TLC Rf = 0.45 (9:1 CH2Cl2:MeOH:1% NH4OH f (Free base) = 0.45 (9:1 CH2Cl2:MeOH:1% NH4OH (水性) ); 1 H NMR (400 MHz, DMSO-D6) δ 7.41 (s, 1 h), 7.35 (d, 1 h), J = 7.6 Hz), 6.98-6.88 (m, 2 h), 6.61 (s, 2 h), 6.48 (s, 1 h,), 4.37 (t, 2 h, J = 6.7 Hz), 2.69 (t, 2 H, J = 6.7 Hz), 2.23 (s, 6 h) ppm; 13 C NMR (100 MHz, CD3 δ 169.37, 134.60, 133.26, 129.51, 119.90, 119.46, 116.82, 116.79, 107.06, 106.88, 102.78, 57.61, 57.61, 43.71, 43.67, 42.90 ppm v 3040, 2429, 1718. 1661 cm-1 LRMS (ES+) Relative molecular mass calculated for C 12 H 16 FN2+207.13, found: 207.33 (MH+); MP = 168-170 °C.

[0309] Example 16. N,N-Dimethyl-2-(2-methyl-1H-indol-1-yl)ethan-1-amine fumarate (1:1) (16)

[0310]

[0311] Synthesized according to Procedure A. Reaction was performed with 2-methylindole (100 mg, 0.76 mmol) and purified by crystallization. Yield 172 mg, 71% yield. Purity >99%. TLC Rf = 0.48 (9:1 CH2Cl2:MeOH:1% NH4OH f (free base) = 0.47 (9:1 CH2Cl2:MeOH:1% NH4OH (水性) ); 1 HNMR (400 MHz, DMSO-D6) δ 7.41 (d, 1 h, J = 7.8 Hz), 7.37 (d, 1 H, J = 7.8 Hz), 7.06 (t, 1 H, J = 7.8 Hz), 6.96 (t, 1 H, J = 7.8 Hz), 6.61 (s, 2 H), 6.20 (d, J = 1.3 Hz, 1 H), 4.24 (t, 2 H, J = 7.0 Hz), 2.65 (t, 2 H, J = 7.0 Hz), 2.42 (s, 3 H), 2.31 (s, 6 H) ppm; 13 C NMR (150 MHz, DMSO-D6) 167.03, 137.08, 136.72, 134.75, 128.09, 120.58, 119.65, 119.62, 119.40, 109.61, 100.14, 57.82, 45.18, 12.76 ppm v 3040, 2489, 1700, 1606 cm -1 LRMS (ES+) Relative molecular mass calculated for C 13 H 18 N2+203.15, found: 204.43 (MH+); MP = 131-133 °C.

[0312] Example 17. 2-(5,6-Difluoro-1H-indol-1-yl)-N,N-dimethylethan-1-amine fumarate (1:1) (17)

[0313]

[0314] Synthesized according to Procedure A. Reaction was performed with 5,6-difluoroindole (153 mg, 1.0 mmol) and purified by crystallization. Yield 147 mg, 43% yield. Purity = 98%. TLC Rf = 0.48 (9:1 CH2Cl2:MeOH:1% NH4OH f(Free base) = 0.35 (9: 1 CH2Cl2: MeOH: 1% NH4OH (水性) ) ; 1 H NMR (400 MHz, DMSO-D6) δ 7.64 (dd, 1 h, J = 7.0, 4.7 Hz), 7.51 (dd, 1 h, J = 8.5, 2.1 Hz), 7.45 (d, 1 H, J = 2.1 Hz), 6.60 (s, 2 H), 6.43 (d, 1 H), J = 2.1 Hz), 4.28 (t, 2 H, J = 6.5 Hz), 2.73 (t, 2 H, J = 6.5 Hz), 2.27 (s, 6 h) ppm; 13 C NMR (150 MHz, DMSO-D6) δ 166.37, 134.21, 131.09, 130.99, 134.70, 130.67, 123.21, 123.12, 106.86, 106.67, 100.98, 100.94, 98.30, 98.08, 57.86, 44.71, 43.36 ppm v 3051, 2392, 1712, 1658 cm -1 LRMS (ES+) Relative Mass Calculated: C 12 H 16 F2N2+ 224.11, found: 225.28 (MH+); MP = 162-165 °C.

[0315] Example 18. 2-(4,6-Difluoro-1H-indol-1-yl)-N,N-dimethylethan-1-amine fumarate (1:1) (18)

[0316]

[0317] Synthesized according to Procedure A. Reaction was performed with 4,6-difluoroindole (153 mg, 1.0 mmol) and purified by crystallization. Yield 265 mg, 78% yield. Purity = >99% TLC Rf (9: 1 CH2Cl2: MeOH) = 0.35 (free base). f (Free base) = 0.35 (9: 1 CH2Cl2: MeOH: 1% NH4OH (水性) ) ; 1 H NMR (400 MHz, DMSO-D6) δ 7.44 (d, 1 h, J = 2.8 Hz), 7.32 (d, 1 H, J = 10.1 Hz), 6.83 (t, 1 H, J = 10.1 Hz), 6.60 (s, 2 H), 6.49 (d, 1 H), J = 2.8 Hz), 4.31 (t, 2 H, J = 6.6 Hz), 2.78 (t, 2 H, J = 6.6 Hz), 2.31 (s, 6 h) ppm; 13C NMR (150 MHz, DMSO-D6) δ 166.55, 159.33, 159.21, 156.99, 156.87, 156.03, 155.88, 153.58, 153.43, 137.50, 137.36, 137.22, 134.29, 129.82, 129.79, 113.42, 113.20, 96.61, 94.53, 94.30, 94.24, 94.00, 93.32, 93.28, 93.06, 93.02, 57.49, 44.49, 43.23 ppm v 3026, 2398, 1706, 1640 cm -1 LRMS (ES+) Relative molecular mass calculated for C 12 H 16 F2N2+ 224.11, found: 225.28 (MH+); MP = 141-145 °C.

[0318] Example 19. N,N-Dimethyl-2-(6-nitro-lH-indol-l-yl)ethan-l-amine fumarate (1:1) (19)

[0319]

[0320] Synthesized according to Procedure A. Reaction with 6-nitroindole (43.6 mg, 0.269 mmol) and purified by crystallization. Yield 52 mg, 55% yield. Purity >96% TLC Rf (9:1 CH2Cl2:MeOH:1% NH4OH) = 0.48 (free base). f (水性) ); 1 H NMR (400 MHz, DMSO-D6) δ 8.54 (d, 1 h, J = 2.0 Hz), 7.90 (dd, 1 H, J = 8.8, 2.0 Hz), 7.82 (d, 1 H, J = 3.0 Hz), 7.72 (d, 1 H, J = 8.8 Hz), 7.74 (s, 1 H), 6.65 (d, 1 H), J = 3.0 Hz), 6.60 (s, 2 H), 4.44 (t, 2 H), J = 6.3 Hz), 2.68 (t, 2 H, J = 6.3 Hz), 2.23 (s, 6 h) ppm; 13 C NMR (600 MHz, DMSO-D6) δ 166.66, 136.18, 134.76, 134.59, 133.41, 121.04, 114.52, 107.53, 102.25, 58.98, 45.50, 44.18 ppm v 3048, 2922, 1704, 1607 cm -1 LRMS (ES+) Relative molecular mass calculated for C 12 H 16 ​N3O2+ 233.12, found: 234.25 (MH+); MP = 159-164 °C.

[0321] Example 20. 2-(5-Bromo-lH-indol-l-yl)-N,N-dimethylethan-l-amine fumarate (1:1) (20)

[0322]

[0323] Synthesized according to Procedure A. Reaction with 5-bromoindole (56.1 mg, 0.281 mmol) and purified by crystallization. Yield 60 mg, 55%. Purity >99%. TLC Rf (9:1 CH2Cl2:MeOH:1% NH4OH) = 0.49 (free base) f (水性) 1 HNMR (600 MHz, DMSO-D6) δ 7.72 (d, J = 1.9 Hz, 1H), 7.48 (d, 1H, J = 8.7 Hz), 7.44 (d, 1H, J = 3.1 Hz), 7.23 (dd, 1H, J = 8.7, 1.9 Hz), 6.60 (s, 3h), 6.41 (d, 1h), J = 3.1 Hz), 4.27 (t, 2H, J = 6.6 Hz), 2.67 (t, 2H, J = 6.6 Hz), 2.22 (s, 6h) ppm; 13 C NMR (600 MHz, DMSO-D6) δ 166.24, 134.47, 134.15, 130.46, 129.89, 123.81, 122.54, 111.87, 111.56, 100.28, 58.09, 44.86, 43.32 ppm v 2959, 2443, 1705, 1661 cm -1 LRMS (ES+) Relative Mass Calculated for C 12 H 16 BrN2+ 266.04, found: 267.26 (MH+); MP = 140-142 °C.

[0324] Example 21. 2-(l-(2-Dimethylamino)ethyl)-lH-indol-3-yl)-N,N-dimethyl-2-oxoacetamide (21) Example 22. 2-(lH-Benzo[d]imidazol-l-yl)-N,N-dimethylethan-l-amine fumarate (1:1)

[0325]

[0326] ​​Reaction with 2-(1 H-indol-3-yl)-N,N-dimethyl-2-oxoacetamide (synthesized using the method developed by Speeter et al.). (Speeter, M. E.; Anthony, W. C. Action of oxalyl chloride on indole: a new approach to tryptamines. JOURNAL OF THE AMERICAN CHEMICAL SOCIETY. 1954, 76, 6208-6210.) (200 mg, 0.92 mmol), purified by chromatography. Yield = 92 mg, 35% yield. Purity = 98%. TLC Rf (free base) = 0.38 (9:1 CH2CI2:MeOH:1% NH4OH f (水性) 1 H NMR (600 MHz, CDCI3) δ 8.32 (s, 1 h), 7.92 (s, 1 h), 7.37-7.29 (m, 3 h), 4.21 (t, 2 h), J = 7.0 Hz), 3.08 (s, 3H), 3.04 (s, 3H), 2.71 (t, 2H), J = 7.0 Hz), 2.27 (s, 6 h) ppm; 13 C NMR (150 MHz, CDCI3) δ 185.64, 167.70, 138.82, 137.01, 126.36, 124.00, 123.28, 122.48, 113.45, 110.06, 58.40, 45.68, 45.42, 37.59, 34.51 ppm v 2981, 1734 1631, 1525 cm -1 LRMS (ES+) Relative Mass Calculated for C 16 H 21 N3O2 + 287.16, Found: 288.25 (MH+).

[0327] Example 23. N,N-Dimethyl-2-(lH-pyrrol-l-yl)ethan-l-amine fumarate (1:1) (23) (22)

[0328]

[0329] Synthesized according to Step A. Reaction with benzimidazole (200 mg, 1.6 mmol), purified by crystallization. Yield = 218 mg, 45% yield. Purity = 98%. TLC Rf (free base) = 0.42 (9:1 CH2CI2:MeOH:1% NH4OH f (水性) 1 ​​​​HNMR (400 MHz, DMSO-D6) δ 8.23 (s, 1 h), 7.71-7.56 (m, 2 h), 7.34-7.10 (m, 2 h), 6.61 (s, 2 h), 4.41 (t, 2 h), J = 6.5 Hz), 2.83 (dd, 2 H, J = 7.0, 6.0 Hz), 2.32 (s, 6 h) ppm; 13 C NMR (100 MHz, CD3OD) δ 170.26, 136.21, 122.18, 110.89, 59.35, 45.83, 44.45 ppm v 2998, 2532, 1662, 1421 cm -1 LRMS (ES+) ) Relative molecular mass calculated for C8H 11 H 15 N3+ 189.13, found: 190.23 (MH+); MP = 171-178 °C.

[0330] Example 24. 2-(9H-Carbazol-9-yl)-N,N-dimethylethan-l-amine fumarate (1:1) (24)

[0331] Synthesized according to Step A. Reaction with pyrrole (0.103 ml, 1.5 mmol), purified by crystallization. Yield 126 mg, 33% yield. Purity >99%. TLC R f (free base) = 0.45 (9:1 CH2Cl2: MeOH: 1% NH4OH (水性) ); 1 HNMR (600 MHz, CD3OD) δ 6.80 (t, 2 h, J = 2.2, Hz), 6.72 (s, 2 H), 6.14 (t, 2 H. J = 2.2, Hz), 4.34 (t, 2 H, J = 6.4 Hz), 3.50 (dd, 2 H, J = 6.4 Hz), 2.78 (s, 6 h) ppm; 13 C NMR (100 MHz, CD3OD) δ 170.26, 136.21, 122.18, 110.89, 59.35, 45.83, 44.45 ppm v 2998, 2532, 1662, 1421 cm -1 LRMS (ES+) ) Relative molecular mass calculated for C8H 14 N2+ 138.12, found: 139.29 (MH+); MP = 174-180 °C.

[0332] Example 25. l-Isopentyl-lH-indole (25)

[0333]

[0334] Synthesized according to Procedure A. Reaction was performed with carbazole (100 mg, 0.57 mmol) and purified by crystallization. Yield 102 mg, 51% yield. Purity >99%. TLC Rf = 0.70 (7:3 n-hexane: ethyl acetate). f (Free base) = 0.42 (9:1 CH2Cl2: MeOH: 1% NH4OH (水性) ); 1 HNMR (600 MHz, DMSO-D6) δ 8.15 (d, 2h, J = 7.8 Hz), 7.61 (d, 2H, J = 8.2 Hz), 7.48-7.44 (m, 2h), 7.23-7.19 (m, 2h), 6.61 (s, 2h), 4.52 (t, 2h), J = 7.0 Hz), 2.73 (t, 2H, J = 7.0 Hz), 2.31 (s, 6h) ppm; 13 CNMR (100 MHz, DMSO-D6) δ 169.78, 139.86, 134.76, 125.83, 123.17, 119.99, 119.39, 108.34, 54.39, 42.61, 37.85 ppm v 3053, 2405, 1720, 1660 cm -1 LRMS (ES+) Relative Mass Calculated for C 16 H 18 N2+238.15, found: 239.34 (MH+); MP = 182-184 °C.

[0335] Example 26. 3-(lH-Indol-l-yl)-N,N-dimethylpropan-l-amine fumarate (1:1) (26)

[0336] Synthesized according to Procedure A. Reaction was performed with indole (100 mg, 0.85 mmol) and 1-chloro-3-methylbutane (0.11 mL mg, 0.94 mmol, 1.1 equiv) and purified by chromatography (4:1 n-hexane: ethyl acetate). Yield 85 mg, 53% yield. Purity = 97%. TLC Rf = 0.70 (7:3 n-hexane: ethyl acetate). f = 0.70 (7:3 n-hexane: ethyl acetate); 1 H NMR (600 MHz, CDCl3) δ 7.65 (d, 1H, J = 8.0 Hz), 7.36 (d, 1H, J = 8.0 Hz), 7.22 (t, 1H, J = 6.9 Hz), 7.11 (m, 2H), 6.49 (d, 1H, J = 3.1 Hz), 4.15 (t, 2H, J = 7.5 Hz), 1.74 (dd, 2H, J = 6.7 Hz), 1.62 (quint, 2H, J = 6.7 Hz), 0.98 (d, 1H, J = 6.7 Hz) ppm; 13C NMR (150 MHz, CDC13) 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) v 3054, 2955, 2927, 2869 cm -1 LRMS (ES+) Relative molecular mass calculated for C 13 H 17 N + 187.14, found: 188.39 (MH+).

[0337] Example 27. N,N-Dimethyl-2-(l-methyl-lH-indol-3-yl)ethan-l-amine fumarate (1:1) (1-

[0338]

[0339] Synthesized according to Procedure A. Reaction with indole (100 mg, 0.85 mmol) and 3-chloro-N,N-dimethylpropan-1 -amine (160 mg, 0.98 mmol, 1.1 equiv) and crystallization purification yielded 107 mg, 48% yield. Purity = 98%. TLC Rf (free base) = 0.38 (9:1 CH2CI2:MeOH:1 % NH4OH f ); (水性) 1 H NMR (600 MHz, DMSO-d6) δ 7.54 (d, 1 H, J = 7.8 Hz), 7.48 (d, 1 H, J = 7.8 Hz), 7.36 (d, 1 H, J = 3.1 Hz), 7.13 (td, 1 H, J = 7.4, 1.0 Hz), 7.01 (td, 1 H, J = 7.4, 1.0 Hz), 6.55 (s, 2H), 6.43 (dd, 1 H, J = 3.1, 1.0 Hz), 4.21 (t, 2H, J = 6.8 Hz), 2.56 (t, 2H, J = 7.4 Hz), 2.40 (s, 6H), 2.00 (tt, 2H, J = 7.4, 6.8 Hz) ppm; 13 C NMR (150 MHz, DMSO-d6) δ 167.19, 135.60, 134.62, 128.49, 128.07, 120.99, 120.41, 118.90, 109.67, 100.61, 54.88, 43.41, 43.07, 26.26 ppm; IR (diamond, ATR) v 3435, 3034, 2653, 1705 cm -1 LRMS (ES+) Relative molecular mass calculated for C 13 H 18 ​N2+ 203.15, found: 204.36 (MH+); MP = 129-131 °C.

[0340] ME-DMT 27) Example 28. 2-(5-Methoxy-lH-indol-3-yl)-N,N-dimethylethan-l-amine fumarate (2:1)

[0341] To an ice methanol (12 mL) solution was added N-methyl-2-(l-methyl-lH-indol-3- yl)ethan-l -amine (0.14 g, 0.70 mmol), glacial acetic acid (0.22 mL, 11 mmol, 5.0 eq), sodium cyanoborohydride (0.10 g, 1.6 mmol, 2.1 eq) and 37% formaldehyde (水性) (0.16 mL, 1.9 mmol, 2.6 eq). The reaction was stirred at room temperature for 5 h, then concentrated under reduced pressure. The unpurified material was then diluted with CH2Cl2(50 mL) and 1 M NaOH (水性) (100 mL). The phases were separated and the aqueous phase was extracted with CH2Cl2(2 x 50 mL). The organic extracts were combined, dried over Na2SO4, filtered and concentrated under reduced pressure. The unpurified material was dissolved in acetone (5 mL) and a boiling solution of fumaric acid (0.088 g, 1 mmol, 1 eq) in acetone (20 mL) was added. Precipitation occurred immediately and the solution was allowed to cool to room temperature before being filtered. The resulting white solid was dried under reduced pressure to give the pure fumarate salt (1 : 1). Yield 0.108 g, 65% yield. Purity >99%. TLC R f (free base) = 0.19 (9: 1 CH2Cl2: MeOH: 1% NH4OH (水性) ); 1 H NMR (600 MHz, CD3OD) δ 7.60 (d, 1 h, J = 8.0 Hz), 7.37 (d, 1 H, J = 8.0 Hz), 7.20 (t, 1 H, J = 8.0 Hz), 7.14 (s, 1 h), 7.09 (t, 1 h), J = 8.0 Hz), 6.69 (s, 2 h), 3.78 (s, 3 h), 3.42 (t, 2 h), J = 7.8 Hz), 3.20 (t, 2 H, J = 7.8 Hz), 2.91 (s, 6 h) 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) v 3435, 3034, 2653, 1705 cm -1 LRMS (ES+) m / z Relative molecular mass calculated: C 13H 18 N2+202.15, found: 203.37 (MH+); MP = 167-170 °C.

[0342] (5-MeO-DMT, 28) Example 29. 2-(6-Fluoro-lH-indol-3-yl)-N,N-dimethylethan-l-amine (6-F-DMT, 29)

[0343] To a solution of ice-methanol (44 mL) was added 5-methoxytryptamine (0.50 g, 2.2 mmol), glacial acetic acid (0.60 mL, 11 mmol, 5.0 equiv), sodium cyanoborohydride (0.305 g, 4.8 mmol, 2.2 equiv) and 37% formaldehyde (0.46 mL, 5.7 mmol, 2.6 equiv). The reaction was stirred at room temperature for 5 h, then concentrated under reduced pressure. The residue was diluted with CH2Cl2(50 mL) and 1 M NaOH (100 mL). The phases were separated and the aqueous phase was extracted with CH2Cl2(2 x 50 mL). The organic extracts were combined, dried over Na2SO4, filtered and concentrated under reduced pressure. The unpurified material was dissolved in acetone (5 mL) and a boiling solution of fumaric acid (0.26 g, 2.2 mmol, 0.7 equiv) in acetone (35 mL) was added. Precipitation occurred immediately and the solution was allowed to cool to room temperature before being filtered. The resulting white solid was dried under reduced pressure to give the pure fumarate salt (2:1). Yield 0.49 g, 80% yield. Purity = 98%. TLC Rf(free base) = 0.20 (9:1 CH2Cl2:MeOH:1% NH4OH (水性) (水性) f (9:1 CH2Cl2:MeOH:1% NH4OH (水性) ) = 0.20 (9:1 CH2Cl2:MeOH:1% NH4OH 1 H NMR (600 MHz, CD3OD) δ 7.24 (d, 1 h, J = 8.8 Hz), 7.14 (s, 1 h), 7.07 (s, 1 h), 6.78 (d, 1 h), J = 8.8 Hz), 6.70 (s, 1 h), 3.83 (s, 3 h), 3.29 (m, 2 h), 3.13 (t, 2 h), J = 7.9 Hz), 2.83 (s, 6 h) ppm; 13 C NMR (150 MHz, CD3OD) δ 174.36, 155.27, 137.09, 133.44, 128.49, 124.79, 113.20, 112.96, 110.05, 101.05, 59.25, 56.37, 43.56, 22.12 ppm v 3436, 3034 2654, 1705 cm -1 LRMS (ES+) m / z Calcd for C 13 H 18 N2O+218.14,, found: 219.34 (MH+); MP = 175-177 °C.​​

[0344] Example 30. 2-(6-Methoxy-lH-indol-3-yl)-N,N-dimethylethan-l-amine fumarate (2:1)

[0345] Example 29 below can be prepared by methods known in the art.

[0346]

[0347] (6-MeO-DMT, 30) Example 31. 2-(lH-Indol-l-yl)-N,N-dimethylacetamide (31)

[0348] To a solution of 6-methoxytryptamine (0.40 g, 2.1 mmol) and glacial acetic acid (0.60 mL, 10 mmol, 5.0 equiv) in MeOH (42 mL) was added sodium cyanoborohydride (0.29 g, 4.6 mmol, 2.2 equiv) and 37% formaldehyde (0.44 mL, 5.5 mmol, 2.6 equiv). The reaction was stirred at room temperature for 5 h, then concentrated under reduced pressure. The residue was diluted with CH2Cl2(45 mL) and 1 M NaOH (100 mL). The phases were separated and the aqueous phase was extracted with CH2Cl2(2 x 45 mL). The organic extracts were combined, dried over Na2SO4, filtered, and concentrated under reduced pressure. The unpurified material was dissolved in acetone (5 mL) and a boiling solution of fumaric acid (0.26 g, 2.2 mmol, 0.7 equiv) in acetone (35 mL) was added. Precipitation occurred immediately and the solution was allowed to cool to room temperature before being filtered. The resulting white solid was dried under reduced pressure to give the pure fumarate salt (2: 1). Yield = 0.320 g, 55% yield. Purity = 95%. TLC Rf(free base) = 0.31 (9: 1 CH2Cl2: MeOH: 1% NH4OH (水性) (水性) ;1H NMR (600 MHz, 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;13C 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) v 2915, 2836, 1691, 1559 cm f (水性) 1 ;1H NMR (600 MHz, 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;13C 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) v 2915, 2836, 1691, 1559 cm 13 -1 ​​​​Calculated relative molecular mass of LRMS(ES+) m / z: C 13 H 18 N2O+218.14,, Measured value: 219.29 (MH+); MP = 173-176℃.

[0349] Example 32. (R)-l-(5-Methoxy-lH-indol-l-yl)-N,N-dimethylpropan-2-amine fumarate

[0350] 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 (600MHz, 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 (150MHz, CDCl3) δ167.4,136.7,128.7,128.5,122.0,121.2,119.8,109.1,102.4,48.2,36.7,36.1ppmν3021,2922,2877,1648cm -1 Calculated relative molecular mass of LRMS(ES+): C 12 H 14 Measured value of N2O+202.11: 203.17 (MH+); MP = 58–61℃.

[0351] Example 33. (R)-l-(5-Fluoro-lH-indol-l-yl)-N,N-dimethylpropan-2-amine fumarate

[0352]

[0353] 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 (400MHz, DMSO-d6) δ7.37(d,1H,J=8.8Hz),7.30(s,1H),7.03(s,1H,J=3.1Hz),6.76(d,1H,J=8.8Hz),6.61(s,2H),6.32(s,1H),4.25(dd,1H J=6.3,7.8Hz),4.02(dd,1H,J=6.3,7.8Hz),3.74(s,3H,)3.11(q,1H,J=6.3,6.6Hz),2.30(s,6H),0.84(d,3H,J=6.6Hz). 13 C NMR (100MHz, MeOD-d4) δ171.0,155.8,136.1,132.8,130.9,129.7,113.3,111.2,103.8,103.3,61.6,56.2,47.5,39.9,11.7ppm.

[0354] Example 34. l-(lH-Indol-l-yl)-N,N-dimethylpropan-2-amine

[0355]

[0356] 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 (400MHz, MeOD-d4) δ7.50(dd,1H,J=4.3,4.6Hz),7.36(d,1H,J=3.0Hz),7.28(dd,1H,J=2.0,9.2Hz),7.01(td,1H,J=2.0,9.2Hz),6.74(s,1 H), 6.55 (d, 1H, J = 3.0Hz), 4.63 (dd, 1HJ = 6.9, 8.5, 5.2Hz), 4.38 (dd, 1H, J = 8.8, 5.7, 8.59Hz), 3.92 (m, 1H,) 2.89 (s, 6H), 1.25 (d, 3H, J = 6.7Hz). 13 C NMR (100MHz, MeOD-d4) δ170.9,136.0,131.0,111.4,111.3,111.1,106.7,106.5,103.6,103.5,61.6,47.7,40.2,11.8ppm.

[0357] Example 35. (R)-l-(lH-Indol-l-yl)-N,N-dimethylpropan-2-amine

[0358]

[0359] Synthesize according to step A. 1H NMR (600 MHz, CD3OD) δ 7.59 (d, 1H, J = 7.6 Hz), 7.50 (d, 1H, J = 7.6 Hz), 7.29 (d, 1H, J = 3.1 Hz), 7.23 (t, 1H, J = 7.6 Hz), 7.09 (t, 1H, J = 7.6 Hz), 6.56 (d, 1H, J = 3.1 Hz), 4.64 (dd, 1H, J = 8.5, 6.4 Hz), 4.40 (dd, 1H, J = 8.5, 6.8 Hz), 3.97 (m), 2.90 (s, 6H), 1.27 (d, 3H, J = 6.7 Hz).

[0360] Example 36. (R)-l-(6-Fluoro-lH-indol-l-yl)-N,N-dimethylpropan-2-amine

[0361]

[0362] Synthesized according to Procedure A. 1 H NMR (600 MHz, CDCL3) δ 7.40 (dd, 1H, J = 5.5, 3.1 Hz), 6.98 (d, 1H, J = 3.1 Hz), 6.91 (d, 1H, J = 11.8 Hz), 6.74 (t, 1H, J = 9.0 Hz), 6.35 (d, 1H, J = 3.1 Hz) 4.10 (dd, 1H, J = 8.5, 5.6 Hz), 3.74 (dd, 1H, J = 8.5, 5.6 Hz), 2.91 (m, 1H), 2.20 (s, 6H), 0.79 (d, 3H, J = 6.6 Hz).

[0363] Example 37. (R)-l-(4-Methoxy-lH-indol-l-yl)-N,N-dimethylpropan-2-amine

[0364]

[0365] Synthesized according to Procedure A. 1 H NMR (600 MHz, CDCL3) δ 7.40 (dd, 1H, J = 5.5, 3.1 Hz), 6.98 (d, 1H, J = 3.1 Hz), 6.91 (d, 1H, J = 11.8 Hz), 6.74 (t, 1H, J = 9.0 Hz), 6.35 (d, 1H, J = 3.1 Hz) 4.10 (dd, 1H, J = 8.5, 5.6 Hz), 3.74 (dd, 1H, J = 8.5, 5.6 Hz), 2.91 (m, 1H), 2.20 (s, 6H), 0.79 (d, 3H, J = 6.6 Hz).

[0366] Example 38. (R)-l-(7-Methoxy-lH-indol-l-yl)-N,N-dimethylpropan-2-amine

[0367]

[0368] Synthesized according to Procedure A. 1 H NMR (600 MHz, CDCL3) δ 7.02 (d, 1H, J = 7.8 Hz), 6.81 (m, 2H), 6.46 (t, 1H, J = 6.2 Hz), 6.25 (d, 1H, J = 3.0 Hz), 4.44 (dd, 1H, J = 8.2, 5.5 Hz), 3.96 (dd, 1H, J = 8.2, 5.5 Hz), 3.77 (s, 3H) 2.91 (m, 1H), 2.19 (s, 6H), 0.79 (d, 3H, J = 6.7 Hz).

[0369] Example 39. (R)-l-(9H-Carbazol-9-yl)-N,N-dimethylpropan-2-amine

[0370]

[0371] Synthesized according to Procedure A. 1 H NMR (600 MHz, CDCL3) δ 7.02 (d, 1H, J = 7.8 Hz), 6.81 (m, 2H), 6.46 (t, 1H, J = 6.2 Hz), 6.25 (d, 1H, J = 3.0 Hz), 4.44 (dd, 1H, J = 8.2, 5.5 Hz), 3.96 (dd, 1H, J = 8.2, 5.5 Hz), 3.77 (s, 3H) 2.91 (m, 1H), 2.19 (s, 6H), 0.79 (d, 3H, J = 6.7 Hz).

[0372] ​

[0373]

[0374] Synthesized according to Procedure A. 1 H NMR (600 MHz, CDCL3) δ 7.02 (d, 1H, J = 7.8 Hz), 6.81 (m, 2H), 6.46 (t, 1H, J = 6.2 Hz), 6.25 (d, 1H, J = 3.0 Hz), 4.44 (dd, 1H, J = 8.2, 5.5 Hz), 3.96 (dd, 1H, J = 8.2, 5.5 Hz), 3.77 (s, 3H) 2.91 (m, 1H), 2.19 (s, 6H), 0.79 (d, 3H, J = 6.7 Hz).

[0375] Example 40. (R)-1-(1 H-benzo[d]imidazol-1-yl)-N,N-dimethylpropan-2-amine

[0376]

[0377] Synthesized according to Procedure A. 1H NMR (600 MHz, CDC13) δ 7.72 (s, 1 H), 7.16 (d, 1 H, J = 7.6 Hz), 7.32 (d, 1 H, J = 11.8 Hz), 6.91 (m, 3 H), 4.05 (dd, 1 H, J = 7.5, 6.7 Hz), 4.10 (dd, 1 H, J = 7.5, 6.7 Hz), 3.79 (dd, 1 H, J = 8.5, 5.6 Hz), 2.86 (m, 1 H), 2.06 (s, 6 H), 0.69 (d, 3 H, J = 6.6 Hz).

[0378] Example 41. N-methyl-2-(1-methyl-1 H-indol-3-yl)ethan-1 -amine

[0379]

[0380] (2-(lH-indol-3-yl)ethyl)carbamic acid tert-butyl ester. To a solution of tryptamine (0.50 g, 3.1 mmol) and triethylamine (0.68 mL, 9.4 mmol, 3 equiv) in ice CH2Cl2(44 mL) was added Boc20 (0.77 g, 3.7 mmol, 1.2 equiv). The reaction was warmed 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 give an oil, which was used without further purification.

[0381] N-methyl-2-(l-methyl-lH-indol-3-yl)ethan-l-amine. To a solution of sodium hydride (0.23 g, 5.8 mmol, 2.2 equiv) in ice DMF (3 mL) was added (2-(lH-indol-3-yl)ethyl)carbamic acid tert-butyl ester (0.69 g, 2.6 mmol). The reaction mixture was stirred at room temperature and cooled to 0 °C. Then iodomethane (0.4 mL, 5.8 mmol, 2.2 equiv) was added dropwise. The reaction was stirred at room temperature for 20 h. Then, the reaction was cooled to 0 °C and quenched with TFA (2 mL) and stirred for 30 min. The mixture was diluted with 1.0 M NaOH (水性) (600 mL) and extracted with CH2Cl2(3 x 75 mL). The organic phases were combined, dried over Na2SO4, filtered, and concentrated under reduced pressure to give an oil, which was used without further purification.

[0382] Step B

[0383] General synthetic scheme

[0384]

[0385] General Procedure-1 (GP-B1): To a stirred solution of A (1.0 eq) in DMF (10 vol) was added NaH (60% in mineral oil, 1.2 eq) at 0 °C. The reaction mixture was stirred at 0 °C for 20 min. To the resulting reaction mixture was added reagent B (1.0 eq) and NaI (cat). The reaction was allowed to warm to rt slowly and stirred for 16 h. The progress of the reaction was monitored by TLC.

[0386] By Procedure-2 (GP-B2): To a stirred solution of A (1.0 eq) in DMF (10 vol) was added NaH (60% in mineral oil, 1.2 eq) at 0 °C. The reaction mixture was stirred at 0 °C for 20 min. To the resulting reaction mixture was added reagent B (1.0 eq) and NaI (cat). The reaction was allowed to warm to rt slowly and stirred at 60-65 °C for 16 h. The progress of the reaction was monitored by TLC.

[0387] By Procedure-3 (GP-B3): To a stirred solution of A (1.0 eq) in DMF (10 vol) was added K2CO3 (3 eq) followed by reagent B (2.0 eq) and NaI (1.0 eq) at rt. The contents were then heated at 70 °C for 16 h. The progress of the reaction was monitored by TLC.

[0388] General work-up / purification procedure-B1: The reaction was diluted and quenched with ice-cold water. 2N HCI solution was added until the pH of the solution was 2. The resulting aqueous layer was washed with EtOAc until all unreacted starting material was removed (TLC). The aqueous layer was made basic with NaHC03solution and extracted with ethyl acetate. The organic layers were combined and washed with water and brine, then dried over anhydrous Na2S04and concentrated to yield the desired product of sufficient purity (LC-MS and HPLC purity > 95%).

[0389] General work-up / purification procedure-B2: The reaction mixture was quenched with ice-cold water and extracted with ethyl acetate. The organic layers were combined and washed with ice-cold water, then brine. The organic phase was separated, dried over Na2S04and concentrated under reduced pressure to yield the crude product. The crude product was purified by combi-flash chromatography using ethyl acetate / n-hexane or dichloromethane / methanol gradient based on the polarity of the compound. The pure fractions were distilled to yield the compound, which was dried to yield the compound of > 95% LC-MS and HPLC purity.

[0390] Example 42. 2-(5-methoxy-1 H-indol-1-yl)-N,N-dimethylethan-1 -amine

[0391]

[0392] Synthesized according to step B, then according to GP-1 and work-up / purification procedure-1. Yield: 44% (brown liquid). LC-MS: 95.4%, m / z = 219.2 [M+H] +1 H NMR (DMSO-d6, 400 MHz): δ 7.30-7.37 (m, 2H), 7.03 (d, J = 2.4 Hz, 1H), 6.76 (dd, J = 2.4, 8.8 Hz, 1H), 6.30 (dd, J = 0.4, 2.8 Hz, 1H), 4.19 (t, J = 6.8 Hz, 2H), 3.74 (s, 3H), 2.57 (t, J = 6.8 Hz, 2H), 2.17 (s, 6H).

[0393] Example 43. 2-(6-methoxy-1 H-indol-1-yl)-N,N-dimethylethan-1 -amine

[0394]

[0395] Synthesized according to step B. Then according to GP-1 and work-up / purification procedure-1. Yield: 44% (brown liquid). LC-MS: 95.4%, m / z = 219.2 [M+H] +1 H NMR (DMSO-d6, 400 MHz): δ 7.30-7.37 (m, 2H), 7.03 (d, J = 2.4 Hz, 1H), 6.76 (dd, J = 2.4, 8.8 Hz, 1H), 6.30 (dd, J = 0.4, 2.8 Hz, 1H), 4.19 (t, J = 6.8 Hz, 2H), 3.74 (s, 3H), 2.57 (t, J = 6.8 Hz, 2H), 2.17 (s, 6H).

[0396] Example 44. 5-methoxy-1-(2-pyrrolidin-1-yl)ethyl)-1 H-indole

[0397]

[0398] Synthesized according to step B. GP-1 and work-up / purification procedure-1. Yield: 16% (yellow semi-solid). LC-MS: 98.2%, m / z = 245.2 [M+H] +1 H NMR (DMSO-d6, 400 MHz): δ 7.30-7.37 (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).

[0399] Example 45. 5-methoxy-1-(2-piperidin-1-yl)ethyl)-1 H-indole

[0400]

[0401] Synthesized according to step B, then according to GP-1 and work-up / purification step-1. Yield: 28% (brown solid). LC-MS: 99.5%, m / z = 261.2 [M+H] +1 H NMR (DMSO-d6, 400 MHz): δ 7.31-7.37 (m, 2H), 7.02 (d, J = 2.45 Hz, 1H), 6.76 (dd, J = 2.45, 8.80 Hz, 1H), 6.31 (dd, J = 0.67, 3.00 Hz, 1H), 4.23 (t, J = 6.66 Hz, 2H), 3.74 (s, 3H), 3.51-3.55 (m, 4H), 2.62 (t, J = 6.66 Hz, 2H), 2.38-2.42 (m, 4H).

[0402] Example 46. 4-(2-(5-methoxy-1 H-indol-1-yl)ethyl)morpholine

[0403]

[0404] Synthesized according to step B, then according to GP-1 and work-up / purification step-1. Yield: 28% (brown solid). LC-MS: 99.5%, m / z = 261.2 [M+H] +1 H NMR (DMSO-d6, 400 MHz): δ 7.31-7.37 (m, 2H), 7.02 (d, J = 2.45 Hz, 1H), 6.76 (dd, J = 2.45, 8.80 Hz, 1H), 6.31 (dd, J = 0.67, 3.00 Hz, 1H), 4.23 (t, J = 6.66 Hz, 2H), 3.74 (s, 3H), 3.51-3.55 (m, 4H), 2.62 (t, J = 6.66 Hz, 2H), 2.38-2.42 (m, 4H).

[0405] Example 47. 5-chloro-1-(2-pyrrolidin-1-yl)ethyl)-1 H-indole

[0406]

[0407] Synthesized according to step B. Then according to GP-1 and work-up / purification step-1. Yield: 28% (brown liquid). LC-MS: 97%, m / z = 248.11 [M+H] +1H NMR (DMSO-d6, 400 MHz): δ 7.57 (d, J = 1.96 Hz, 1H), 7.50 (d, J = 8.80 Hz, 1H), 7.46 (d, J = 3.06 Hz, 1H), 7.11 (dd, J = 2.08, 8.80 Hz, 1H), 6.40 (dd, J = 0.61, 3.06 Hz, 1H), 4.27 (t, J = 6.60 Hz, 2H), 2.77 (t, J = 6.60 Hz, 2H), 2.45 (br s, 4H), 1.64 (td, J = 3.16, 6.76 Hz, 4H).

[0408] Example 48. 5-chloro-1-(2-piperidin-1-yl)ethyl)-1 H-indole

[0409]

[0410] Synthesized according to Step B. Then according to GP-1 and work-up / purification Step-1. Yield: 28% (colorless liquid). LC-MS: 98.9%, m / z = 265.2 [M+H] +1 H NMR (DMSO-d6, 400 MHz): δ 7.57 (d, J = 1.96 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).

[0411] Example 49. 4-(2-(5-chloro-1 H-indol-1-yl)ethyl)morpholine

[0412]

[0413] Synthesized according to Step B. Then according to GP-1 and work-up / purification Step-1. Yield: 28% (colorless liquid). LC-MS: 98.9%, m / z = 265.2 [M+H] +1 H NMR (DMSO-d6, 400 MHz): δ 7.57 (d, J = 1.96 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).

[0414] Example 50. 1-(2-(pyrrolidin-1-yl)ethyl)-5-(trifluoromethoxy)-1 H-indole

[0415]

[0416] Synthesized according to step B, then GP-2 and work-up / 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).

[0417] Example 51. 1-(2-(piperidin-1-yl)ethyl)-5-(trifluoromethoxy)-1 H-indole

[0418]

[0419] Synthesized according to step B, then GP-1 and work-up / purification step-2. Yield: 25% (brown liquid). LC-MS: 99.6%, m / z = 313.2 [M+H] +1 H NMR (DMSO-d6, 400 MHz): δ 7.54-7.59 (m, 1H), 7.51 (d, J = 3.06 Hz, 2H), 7.08 (dd, J = 1.34, 8.93 Hz, 1H), 6.48 (dd, J = 0.61, 3.06 Hz, 1H), 4.28 (t, J = 6.66 Hz, 2H), 2.60 (t, J = 6.66 Hz, 2H), 2.37 (br d, J = 4.40 Hz, 4H), 1.45 (quin, J = 5.41 Hz, 4H), 1.32-1.40 (m, 2H).

[0420] Example 52. 4-(2-(5-trifluoromethoxy)-1 H-indol-1-yl)ethyl)morpholine

[0421]

[0422] Synthesized according to step B. Then GP-2 and work-up / purification step-2. Yield: 22% (brown liquid). LC-MS: 98.27%, m / z = 315.2 [M+H] +1H NMR (DMSO-d6, 400 MHz): δ 7.59 (d, J = 8.93 Hz, 1H), 7.50-7.54 (m, 2H), 7.09 (dd, J = 1.16, 8.99 Hz, 1H), 6.49 (d, J = 2.93 Hz, 1H), 4.31 (t, J = 6.54 Hz, 2H), 3.50-3.57 (m, 4H), 2.65 (br t, J = 6.54 Hz, 2H), 2.42 (br s, 4H).

[0423] Example 53. 2-(4-methoxy-1 H-indol-1-yl)-N,N-dimethylethan-1 -amine

[0424]

[0425] Synthesized according to Step B. Then according to GP-1 and work-up / purification Step-1. Yield: 27% (brown liquid). LC-MS: 98.8%, m / z = 219.2 [M+H] +1 H NMR (DMSO-d6, 400 MHz): δ 7.25 (d, J = 3.18 Hz, 1H), 7.02-7.07 (m, 2H), 6.49-6.52 (m, 1H), 6.38-6.40 (m, 1H), 4.20 (t, J = 6.72 Hz, 2H), 3.85 (s, 3H), 2.55-2.60 (m, 2H), 2.17 (s, 6H).

[0426] Example 54. 2-(7-methoxy-1 H-indol-1-yl)-N,N-dimethylethan-1 -amine

[0427]

[0428] Synthesized according to Step B. Then according to GP-1 and work-up / purification Step-1. Yield: 27% (brown liquid). LC-MS: 98.8%, m / z = 219.2 [M+H] +1 H NMR (DMSO-d6, 400 MHz): δ 7.24 (d, J = 3.06 Hz, 1H), 7.07-7.11 (m, 1H), 6.89 (t, J = 7.82 Hz, 1H), 6.64 (d, J = 7.70 Hz, 1H), 6.33 (d, J = 3.06 Hz, 1H), 4.42 (t, J = 6.97 Hz, 2H), 3.88 (s, 3H), 2.56 (t, J = 6.97 Hz, 2H), 2.18 (s, 6H).

[0429] Example 55. 2-(5-methoxy-1 H-benzo[d]imidazol-1-yl)-N,N-dimethylethan-1 -amine

[0430]

[0431] Example 56. 2-(6-methoxy-1 H-benzo[d]imidazol-1-yl)-N,N-dimethylethan-1 -amine

[0432]

[0433] Synthesized according to Step B. Example 55 was slightly modified (1 eq of Nal was used). Subsequent work-up / purification step-2 gave a mixture of regiomers. The mixture was separated using the following normal phase chiral HPLC purification method. NOE analysis confirmed the two structures.

[0434] Column: Chiralpak IC (250 m X 4.6 mm, 5 μm)

[0435] Mobile phase: 0.1% DEA / n-Hexane

[0436] Mobile phase B: DCM: MEOH (80:20)

[0437] Scheme: A: B: 80:20

[0438] Flow rate: 1.0 ml / min.

[0439] Yield: 10% (pale yellow solid). LCMS: 99.8%, m / z = 220.1 [M+H] +1 H NMR (DMSO-d6, 400 MHz): δ 8.11 (s, 1H), 7.48 (d, J = 8.80 Hz, 1H), 7.15 (d, J = 2.32 Hz, 1H), 6.87 (dd, J = 2.32, 8.80 Hz, 1H), 4.27 (t, J = 6.30 Hz, 2H), 3.77 (s, 3H), 2.62 (t, J = 6.24 Hz, 2H), 2.17 (s, 6H).

[0440] Example 57. 2-(1 H-benzo[d]imidazol-1-yl)-N,N-dimethylethan-1 -amine

[0441]

[0442] Synthesized according to Step B. Then according to GP-2 and work-up / purification step-1. Yield: 4% (colorless liquid). LCMS: 99.7%, m / z = 190.2 [M+H] +1 H NMR (DMSO-d6, 400 MHz): δ 8.20 (s, 1H), 7.62 (dd, J = 7.95, 12.47 Hz, 2H), 7.16 - 7.27 (m, 2H), 4.32 (t, J = 6.36 Hz, 2H), 2.64 (t, J = 6.30 Hz, 2H), 2.18 (s, 6H).

[0443] Example 58. N,N-dimethyl-2-(2-methyl-1 H-benzo[d]imidazol-1-yl)ethan-1 -amine

[0444]

[0445] Synthesized according to step B. Then according to GP-3 and work-up / purification step-2. Yield: 15% (yellow liquid). LCMS: 98.3%, m / z = 204.2 [M+H] +1 H NMR (DMSO-d6, 400 MHz): δ 7.44-7.51 (m, 2H), 7.09-7.19 (m, 2H), 4.24 (t, J = 6.66 Hz, 2H), 2.53-2.57 (m, 5H), 2.19 (s, 6H).

[0446] Step C

[0447] General synthetic scheme:

[0448]

[0449] General synthetic procedure:

[0450] Step-C1 : To a stirred solution of compound D (1.0 eq) in DMF (10 mL) was added NaH (60% in mineral oil, 1.2 eq) at 0 °C. The reaction mixture was stirred for 20 min, then compound E (1.0 eq) was added. The reaction was allowed to warm to room temperature slowly and stirred at the same temperature for 16 h. The progress of the reaction was monitored by thin layer chromatography.

[0451] Work-up and purification after step-C1 : The reaction mixture was quenched with ice cold water and extracted with ethyl acetate. The organic layers were combined and washed with ice cold water followed by aqueous NaCI solution. The organic layer was separated, dried over Na2S04and concentrated to get the crude product. The crude product was purified by combi-flash using 10-20% ethyl acetate in n-hexane followed by rectification of the purer fractions (by TLC) to get compound F.

[0452] Step-C2: To a stirred solution of compound F (1 eq) in dichloromethane (10 vol) was added triethylamine (2.5 eq) and the resulting solution was cooled to 0 °C. To this was added formyl chloride (1.5 eq) and the reaction mixture was allowed to warm to room temperature and stirred for 1-2 h. The progress of the reaction was monitored by thin layer chromatography.

[0453] Work-up after step-C2: The reaction mixture was quenched with ice cold water and extracted with dichloromethane. The organic layers were combined and washed with saturated aqueous bicarbonate solution followed by water. The organic layer was separated, dried over anhydrous Na2S04and the crude product compound G was concentrated and used as such in the next step without purification.

[0454] Step-C3: Into a sealed tube was added compound G (1 eq), DMF (2 vol) and 40% aqueous dimethylamine (10 vol) and heated at 65 °C for 1-2 days. The progress of the reaction was monitored by thin layer chromatography.

[0455] Workup and purification after step C3: The reaction was quenched with water and extracted with EtOAc. The organic layer was separated and washed with water and saturated brine. The organic layer was dried over anhydrous Na2SO4and concentrated. The crude product was purified by combi-flash using 5-10% ethyl acetate / dichloromethane or 5-10% methanol / dichloromethane and then the purer fractions were distilled under reduced pressure to obtain the target compound.

[0456] Example 59. (R)-1-(5-methoxy-1 H-indol-1-yl)-N,N-dimethylpropan-2-amine

[0457]

[0458] Step-C1: Yield: 71% (pale brown liquid). 1 H NMR (DMSO-d6, 400 MHz): δ 7.35 (d, J = 8.93 Hz, 1H), 7.27 (d, J = 3.06 Hz, 1H), 7.02 (d, J = 2.32 Hz, 1H), 6.74 (dd, J = 2.45, 8.80 Hz, 1H), 6.29-6.32 (m, 1H), 4.85 (d, J = 4.77 Hz, 1H), 3.99-4.07 (m, 2H), 3.90-3.98 (m, 1H), 3.74 (s, 3H), 1.01 (d, J = 6.11 Hz, 3H).

[0459] Step-C2: Yellow solid. 1 H NMR (DMSO-d6, 400 MHz): δ 7.45 (d, J = 8.93 Hz, 1H), 7.33 (d, J = 3.06 Hz, 1H), 7.04 (d, J = 2.32 Hz, 1H), 6.80 (dd, J = 2.32, 8.93 Hz, 1H), 6.38 (d, J = 2.93 Hz, 1H), 4.92-5.01 (m, 1H), 4.34-4.40 (m, 2H), 3.75 (s, 3H), 2.54 (s, 3H), 1.33 (d, J = 6.24 Hz, 3H).

[0460] Step-C3: Yield: 16% (over two steps, brown liquid).[α] D 20 = -14.6 (C 0.5, CH2Cl2). LC-MS: 99.4%, m / z = 233.2 [M+H] +1H NMR (DMSO-d6, 400 MHz): δ 7.27-7.36 (m, 2H), 7.02 (d, J = 2.32 Hz, 1H), 6.75 (dd, J = 2.38, 8.86 Hz, 1H), 6.28-6.32 (m, 1H), 4.18 (dd, J = 6.72, 14.18 Hz, 1H), 3.92-3.99 (m, 1H), 3.74 (s, 3H), 2.92-3.02 (m, 1H), 2.19 (s, 6H), 0.79 (d, J = 6.60 Hz, 3H).

[0461] Example 60. (R)-1-(5-fluoro-1 H-indol-1-yl)-N,N-dimethylpropan-2-amine

[0462]

[0463] Step-C1 : Yield: 50% (light brown liquid). 1 H NMR (DMSO-d6, 400 MHz): δ 7.50 (dd, J = 4.52, 8.93 Hz, 1H), 7.41 (d, J = 3.06 Hz, 1H), 7.26-7.31 (m, 1H), 6.92-6.99 (m, 1H), 6.39-6.42 (m, 1H), 3.93-4.03 (m, 2H), 3.12-3.21 (m, 1H), 0.92 (d, J = 6.36 Hz, 3H).

[0464] Step-C2: The mesylate was prepared using the general procedure described above and then treated with NaN3(1.5 eq) in DMF (10 vol) at 70 °C for 2 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with water and extracted with EtOAc. The organic layers were combined, washed with cold water twice and concentrated to get the crude. The crude was treated with 10% Pd / C (50% wet) in MeOH under hydrogen to get the crude amine. The crude amine was purified by combi-flas chromatography using 1% MeOH / CH2Cl2and the pure fractions were concentrated to get the amine. The above amine was treated with a solution of paraformaldehyde (10 eq) in MeOH / DCM (10 vol, 2:1) followed by the addition of AcOH (cat), NaBH3CN (6.0 eq) separately and stirred for 1 h. The progress of the reaction was monitored by TLC. After working up with water, the compound was purified first by prep-HPLC and then by combi-flash chromatography to get the above compound in 30% isolated yield.

[0465] Preparative-HPLC purification method is shown below:

[0466] Preparative HPLC column; Ymc triactus C18 (250*20 mm), 5 um

[0467] Mobile phase A: Acetonitrile

[0468] Mobile phase B: 5 mM ammonium bicarbonate

[0469] Flow rate: 15.0 mL / min

[0470] Gradient table:

[0471]

[0472]

[0473] Solvent for dilution: Acetonitrile / MeOH

[0474] Yield: 30% (brown liquid).[a] D 20 = -15.9 (C 0.5, CH2Cl2). LC-MS: 99.5%, m / z = 221.2 [M+H] +1 H NMR (DMSO-d6, 400 MHz): δ 7.40-7.49 (m, 2H), 7.28 (dd, J = 2.51, 9.96 Hz, 1H), 6.92-6.98 (m, 1H), 6.39 (dd, J = 0.61, 3.06 Hz, 1H), 4.18-4.25 (m, 1H), 4.01 (dd, J = 7.27, 14.24 Hz, 1H), 2.94-3.03 (m, 1H), 2.19 (s, 6H), 0.81 (d, J = 6.60 Hz, 3H). 19 F NMR (DMSO-d6, 376 MHz): δ -127.18 (s, 1F).

[0475] Example 61. (R)-1-(6-fluoro-5-methoxy-1 H-indol-1-yl)-N,N-dimethylpropan-2-amine

[0476]

[0477] Step-C1: Yield: 74% (brown liquid). 1 H NMR (DMSO-d6, 400 MHz): δ 7.39 (d, J = 12.23 Hz, 1H), 7.27 (d, J = 3.06 Hz, 1H), 7.18-7.22 (m, 1H), 6.34 (dd, J = 0.61, 3.06 Hz, 1H), 4.84 (d, J = 4.77 Hz, 1H), 3.88-4.06 (m, 3H), 3.81 (s, 3H), 1.02 (d, J = 6.11 Hz, 3H).

[0478] Step-C2: Brown solid. 1H NMR (DMSO-d6, 400 MHz): δ 7.52 (d, J = 12.23 Hz, 1H), 7.33 (d, J = 3.06 Hz, 1H), 7.22 (d, J = 8.56 Hz, 1H), 6.41 (dd, J = 0.67, 3.12 Hz, 1H), 4.91 - 5.00 (m, 1H), 4.30 - 4.39 (m, 2H), 3.82 (s, 3H), 2.56 (s, 3H), 1.32 - 1.35 (m, 3H).

[0479] Step-C3: Yield: 14% (over two steps, brown liquid).[a] D 20 = -19.7 (C 0.5, CH2Cl2). LC-MS: 98.5%, 251.2 [M+H] +1 H NMR (DMSO-d6, 400 MHz): δ 7.38 - 7.44 (m, 1H), 7.30 (d, J = 3.18 Hz, 1H), 7.22 (d, J = 8.56 Hz, 1H), 6.35 (d, J = 2.57 Hz, 1H), 4.15 (dd, J = 7.09, 14.18 Hz, 1H), 3.96 (dd, J = 7.15, 14.24 Hz, 1H), 3.83 (s, 3H), 2.93 - 3.03 (m, 1H), 2.20 (s, 6H), 0.81 (d, J = 6.60 Hz, 3H). 19 F NMR (DMSO-d6, 376 MHz): δ -142.08 (s, 1F).

[0480] Example 62. (R)-1-(5,6-dimethoxy-1 H-indol-1-yl)-N,N-dimethylpropan-2-amine

[0481]

[0482] Step-C1 : Yield: 50% (pale brown liquid). 1 H NMR (DMSO-d6, 400 MHz): δ 7.13 (d, J = 3.06 Hz, 1H), 7.03 (d, J = 7.21 Hz, 2H), 6.23 - 6.26 (m, 1H), 4.84 (d, J = 4.65 Hz, 1H), 3.91 - 4.01 (m, 3H), 3.79 (s, 3H), 3.73 (s, 3H), 1.02 (d, J = 5.99 Hz, 3H).

[0483] Step-C2: Pale brown semi-solid. 1H NMR (DMSO-d6, 400 MHz): δ 7.18 (d, J = 3.18 Hz, 1H), 7.14 (s, 1H), 7.04 (s, 1H), 6.32 (d, J = 3.06 Hz, 1H), 4.93-5.02 (m, 1H), 4.30-4.42 (m, 2H), 3.81 (s, 3H), 3.74 (s, 3H), 2.56 (s, 3H), 1.34 (d, J = 6.36 Hz, 3H).

[0484] Step-C3: Yield: 18% (over two steps, brown liquid). LC-MS: 94.8%, 263.2 [M+H] +1 H NMR (DMSO-d6, 400 MHz): δ 7.14 (d, J = 3.06 Hz, 1H), 6.99-7.03 (m, 2H), 6.25 (dd, J = 0.61, 3.06 Hz, 1H), 4.12-4.19 (m, 1H), 3.91-3.98 (m, 1H), 3.72-3.81 (m, 6H), 2.93-3.02 (m, 1H), 2.21 (s, 6H), 0.81 (d, J = 6.60 Hz, 3H).

[0485] Example 63. (R)-1-(5,7-dimethoxy-1 H-indol-1-yl)-N,N-dimethylpropan-2-amine

[0486]

[0487] Step-C1: Yield: 35% (colorless liquid). 1 H NMR (DMSO-d6, 400 MHz): δ 7.10-7.16 (m, 1H), 6.58-6.61 (m, 1H), 6.27-6.30 (m, 1H), 4.74 (d, J = 5.14 Hz, 1H), 4.09-4.32 (m, 2H), 3.83-3.92 (m, 4H), 3.71-3.73 (m, 3H), 0.91-1.00 (m, 3H).

[0488] Step-C2: Light yellow, semi-solid. 1 H NMR (DMSO-d6, 400 MHz): δ 7.14-7.20 (m, 1H), 6.61 (d, J = 2.08 Hz, 1H), 6.35 (d, J = 2.08 Hz, 1H), 6.29-6.32 (m, 1H), 4.87-4.95 (m, 1H), 4.41-4.52 (m, 2H), 3.85-3.89 (m, 3H), 3.72-3.74 (m, 3H), 2.56 (s, 3H), 1.23-1.35 (m, 3H).

[0489] Step-C3: Yield: 25% (over 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-d6, 400 MHz): δ 7.13 (d, J = 2.93 Hz, 1H), 6.58 (d, J = 2.08 Hz, 1H), 6.29 (d, J = 1.96 Hz, 1H), 6.23 (d, J = 2.93 Hz, 1H), 4.38 (dd, J = 6.30, 13.63 Hz, 1H), 4.06 (dd, J = 7.83, 13.57 Hz, 1H), 3.85 (s, 3H), 3.72 (s, 3H), 2.88-2.97 (m, 1H), 2.20 (s, 6H), 0.73 (d, J = 6.72 Hz, 3H).

[0490] Example 64. (R)-1-(5-methoxy-6-methyl-1H-indol-1-yl)-N,N-dimethylpropan-2- amine

[0491]

[0492] Step-C1: Yield: 83% (colorless liquid). 1 H NMR (DMSO-d6, 400 MHz): δ 7.25 (s, 1H), 7.19 (br d, J = 2.81 Hz, 1H), 7.00 (s, 1H), 6.29 (br d, J = 2.45 Hz, 1H), 4.84 (br d, J = 4.40 Hz, 1H), 3.92-4.03 (m, 3H), 3.79 (s, 3H), 2.26 (s, 3H), 1.03 (br d, J = 5.87 Hz, 3H).

[0493] Step-C2: Pale yellow, semi-solid. 1 H NMR (DMSO-d6, 400 MHz): δ 7.34 (s, 1H), 7.23 (d, J = 3.06 Hz, 1H), 7.00 (s, 1H), 6.34 (dd, J = 0.73, 3.06 Hz, 1H), 4.91-4.98 (m, 1H), 4.31-4.35 (m, 2H), 3.77 (s, 3H), 3.35 (s, 3H), 2.25 (s, 3H), 1.34 (d, J = 6.24 Hz, 3H).

[0494] Step-C3: Yield: 8% (over 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-d6, 400 MHz): δ 7.17-7.22 (m, 2H), 6.98 (s, 1H), 6.26-6.27 (m, 1H), 4.14 (dd, J = 6.66, 14.12 Hz, 1H), 3.93 (dd, J = 7.58, 14.18 Hz, 1H), 3.77 (s, 3H), 2.93-3.02 (m, 1H), 2.25 (s, 3H), 2.20 (s, 6H), 0.79 (d, J = 6.60 Hz, 3H).

[0495] Example 65. (R)-1-(5-methoxy-7-methyl-1H-indol-1-yl)-N,N-dimethylpropan-2- amine

[0496]

[0497] Step-C1: Yield: 75% (pale brown liquid). 1 H NMR (DMSO-d6, 400 MHz): δ 7.18 (d, J = 3.06 Hz, 1H), 6.84 (d, J = 2.45 Hz, 1H), 6.49 (d, J = 2.08 Hz, 1H), 6.27 (d, J = 3.06 Hz, 1H), 4.87 (d, J = 5.14 Hz, 1H), 4.16 (dd, J = 2.14, 6.17 Hz, 2H), 3.81-3.89 (m, 1H), 3.71 (s, 3H), 2.60 (s, 3H), 1.02 (d, J = 6.11 Hz, 3H).

[0498] Step-C2: Pale yellow syrup. 1 H NMR (DMSO-d6, 400 MHz): δ 7.27 (d, J = 3.06 Hz, 1H), 6.86 (d, J = 2.45 Hz, 1H), 6.54-6.56 (m, 1H), 6.35-6.37 (m, 1H), 4.82-4.90 (m, 1H), 4.48-4.52 (m, 2H), 3.72 (s, 3H), 2.61 (s, 3H), 2.41 (s, 3H), 1.34 (d, J = 6.36 Hz, 3H).

[0499] Step-C3: Yield: 11% (over two steps, brown liquid).[a] D 20 = -6.34 (C 0.5, CH2Cl2). LC-MS: 99.43%, 247.2 [M+H] +1H NMR (DMSO-d6, 400 MHz): δ 7.17 (d, J = 3.06 Hz, 1H), 6.84 (d, J = 2.45 Hz, 1H), 6.50 (d, J = 1.96 Hz, 1H), 6.26 (d, J = 3.06 Hz, 1H), 4.35 (dd, J = 6.05, 14.37 Hz, 1H), 4.05-4.12 (m, 1H), 3.71 (s, 3H), 2.81-2.90 (m, 1H), 2.60 (s, 3H), 2.19 (s, 6H), 0.74 (d, J = 6.60 Hz, 3H).

[0500] Example 66. (R)-1-(5-methoxy-3-methyl-1H-indol-1-yl)-N,N-dimethylpropan-2- amine

[0501]

[0502] Step-C1 : Yield: 70% (light brown liquid).

[0503] Step-C2: Light yellow, semi-solid.

[0504] Step-C3: Yield: 19% (over two steps).[α] D 20 = -1.82 (C 0.5, CH2Cl2). LC-MS: 99.76%, 247.1 [M+H] +1 H NMR (DMSO-d6, 400 MHz): δ 7.17 (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).

[0505] Example 67. (R)-1-(4,5-difluoro-1H-indol-1-yl)-N,N-dimethylpropan-2-amine

[0506]

[0507] Step-C1 : Yield: 70% (light brown liquid). 1H NMR (DMSO-d6, 400 MHz): δ 7.45 (d, J = 3.18 Hz, 1H), 7.33 (dd, J = 3.42, 9.05 Hz, 1H), 7.09-7.17 (m, 1H), 6.53 (dd, J = 0.79, 3.12 Hz, 1H), 4.89 (d, J = 4.77 Hz, 1H), 4.10-4.16 (m, 1H), 4.00-4.07 (m, 1H), 3.90-3.99 (m, 1H), 1.04 (d, J = 6.24 Hz, 3H).

[0508] Step-C2: Brown liquid. 1 H NMR (DMSO-d6, 400 MHz): δ 7.51 (d, J = 3.18 Hz, 1H), 7.40-7.44 (m, 1H), 7.16-7.24 (m, 1H), 6.61 (dd, J = 0.86, 3.18 Hz, 1H), 4.96-5.04 (m, 1H), 4.43-4.47 (m, 2H), 2.65 (s, 3H), 1.34 (d, J = 6.36 Hz, 3H).

[0509] Step-C3: Yield: 30% (over two steps, brown liquid).[α] D 20 = -25.0 (C 0.5, CH2Cl2). LC-MS: 99.08%, m / z = 239.2 [M+H] +1 H NMR (DMSO-d6, 400 MHz): δ 7.48 (d, J = 3.06 Hz, 1H), 7.30-7.34 (m, 1H), 7.13 (ddd, J = 7.89, 8.80, 11.19 Hz, 1H), 6.52 (dd, J = 0.73, 3.18 Hz, 1H), 4.19-4.25 (m, 1H), 4.01-4.07 (m, 1H), 2.95-3.04 (m, 1H), 2.18 (s, 6H), 0.82 (d, J = 6.60 Hz, 3H).

[0510] Example 68. (R)-1-(5,6-difluoro-1H-indol-1-yl)-N,N-dimethylpropan-2-amine

[0511]

[0512] Step-C1: Yield: 63% (pale brown liquid). 1H NMR (DMSO-d6, 400 MHz): δ 7.57-7.63 (m, 1H), 7.50 (dd, J = 8.07, 11.37 Hz, 1H), 7.39 (d, J = 3.18 Hz, 1H), 6.41 (dd, J = 0.73, 3.18 Hz, 1H), 4.86 (d, J = 4.89 Hz, 1H), 4.06-4.12 (m, 1H), 3.89-4.02 (m, 2H), 1.04 (d, J = 6.11 Hz, 3H).

[0513] Step-C2: Pale yellow semi solid. 1 H NMR (DMSO-d6, 400 MHz): δ 7.71 (dd, J = 6.97, 11.62 Hz, 1H), 7.51-7.57 (m, 1H), 7.44-7.46 (m, 1H), 6.49 (dd, J = 0.73, 3.18 Hz, 1H), 4.94-5.02 (m, 1H), 4.39-4.43 (m, 2H), 2.61 (s, 3H), 1.34 (d, J = 6.36 Hz, 3H).

[0514] Step-C3: Yield: 30% (over two steps, brown liquid).[α] D 20 = -21.12 (C 0.5, CH2Cl2). LC-MS: 96.1%, m / z = 239.2 [M+H] +1 H NMR (DMSO-d6, 400 MHz): δ 7.58-7.63 (m, 1H), 7.47-7.52 (m, 1H), 7.40-7.42 (m, 1H), 6.41 (dd, J = 0.73, 3.06 Hz, 1H), 4.17 (dd, J = 7.52, 14.24 Hz, 1H), 3.96-4.03 (m, 1H), 2.94-3.04 (m, 1H), 2.18 (s, 6H), 0.81 (d, J = 6.60 Hz, 3H). 19 F NMR (DMSO-d6, 376 MHz): δ -146.8 (d, J = 22.5 Hz, 1F), -150.82 (d, J = 24.0 Hz, 1F).

[0515] Example 69. (R)-1-(5,7-difluoro-1H-indol-1-yl)-N,N-dimethylpropan-2-amine

[0516]

[0517] Step-C1: Yield: 57% (colorless liquid). 1 H NMR (CDCI 3,H NMR (DMSO-d6, 400 MHz): δ 7.15 (d, J = 3.06 Hz, 1H), 7.05 (dd, J = 2.20, 9.05 Hz, 1H), 6.67-6.73 (m, 1H), 6.45-6.47 (m, 1H), 4.34 (ddd, J = 1.22, 3.30, 14.06 Hz, 1H), 4.14-4.19 (m, 1H), 4.03-4.10 (m, 1H), 1.65 (d, J = 4.03 Hz, 1H), 1.24 (d, J = 6.11 Hz, 3H).

[0518] Step-C2: Yellow semi-solid.

[0519] Step-C3: Yield: 32% (over two steps, colorless liquid).[a] D 20 = -28.5 (C 0.5, CH2Cl2). LC-MS: 99.2%, m / z = 239.1 [M+H] +1 H NMR (DMSO-d6, 400 MHz): δ 7.44 (d, J = 3.06 Hz, 1H), 7.15-7.19 (m, 1H), 6.90-6.97 (m, 1H), 6.47 (t, J = 2.69 Hz, 1H), 4.29-4.35 (m, 1H), 4.04-4.10 (m, 1H), 2.91-3.00 (m, 1H), 2.18 (s, 6H), 0.80 (d, J = 6.60 Hz, 3H). 19 F NMR (DMSO-d6, 376 MHz): δ -124.28 (s, 1F), -132.87 (s, 1F).

[0520] Example 70. (R)-1-(5-fluoro-6-methoxy-1H-indol-1-yl)-N,N-dimethylpropan-2- amine

[0521]

[0522] Step-C1: Yield: 46% (colorless liquid).

[0523] Step-C2: Yellow semi-solid.

[0524] Step-C3: Yield: 32% (over two steps, colorless liquid).[a] D 20 = -8.05 (C 0.5, CH2Cl2). LC-MS: 98.4%, m / z = 235.1 [M+H] +1H NMR (DMSO-d6, 400 MHz): δ 7.24-7.32 (m, 2H), 7.17 (d, J = 7.34 Hz, 1H), 6.30 (d, J = 2.93 Hz, 1H), 4.18 (dd, J = 7.03, 14.24 Hz, 1H), 3.96-4.03 (m, 1H), 3.87 (s, 3H), 2.94-3.05 (m, 1H), 2.21 (s, 6H), 0.82 (d, J = 6.60 Hz, 3H). 19 F NMR (DMSO-d6, 376 MHz): δ -146.29 (s, 1F).

[0525] Example 71. (R)-1-(5-fluoro-6-methyl-1H-indol-1-yl)-N,N-dimethylpropan-2-amine

[0526]

[0527] Step-C1: Yield: 69% (pale brown liquid). 1 H NMR (DMSO-d6, 400 MHz): δ 7.33-7.37 (m, 1H), 7.30 (d, J = 3.06 Hz, 1H), 7.22 (d, J = 10.64 Hz, 1H), 6.32-6.34 (m, 1H), 4.84-4.87 (m, 1H), 3.91-4.08 (m, 3H), 2.32 (d, J = 1.83 Hz, 3H), 1.03 (d, J = 5.99 Hz, 3H).

[0528] Step-C2: Pale yellow solid. 1 H NMR (DMSO-d6, 400 MHz): δ 7.46 (d, J = 6.48 Hz, 1H), 7.36 (d, J = 3.06 Hz, 1H), 7.25 (d, J = 10.64 Hz, 1H), 6.39-6.41 (m, 1H), 4.94-5.02 (m, 1H), 4.32-4.43 (m, 2H), 2.56 (s, 3H), 2.33 (d, J = 1.83 Hz, 3H), 1.34 (d, J = 6.36 Hz, 3H).

[0529] Step-C3: Yield: 24% (over two steps, pale brown liquid).[a] D 20 = -20.50 (C 0.5, CH2Cl2). LC-MS: 99.3%, m / z = 235.1 [M+H] + . 1H NMR (DMSO-d6, 400 MHz): δ 7.30-7.35 (m, 2H), 7.22 (d, J = 10.64 Hz, 1H), 6.32 (d, J = 3.06 Hz, 1H), 4.17 (dd, J = 6.97, 14.18 Hz, 1H), 3.97 (dd, J = 7.34, 14.18 Hz, 1H), 2.95-3.04 (m, 1H), 2.33 (d, J = 1.59 Hz, 3H), 2.19 (s, 6H), 0.80 (d, J = 6.60 Hz, 3H). 19 F NMR (DMSO-d6, 376 MHz): δ -130.78 (s, 1F).

[0530] Example 72. (R)-1-(5-fluoro-7-methyl-1H-indol-1-yl)-N,N-dimethylpropan-2-amine

[0531]

[0532] Step-C1: Yield: 72%, light brown liquid). 1 H NMR (DMSO-d6, 400 MHz): δ 7.30-7.35 (m, 2H), 7.22 (d, J = 10.64 Hz, 1H), 6.32 (d, J = 3.06 Hz, 1H), 4.17 (dd, J = 6.97, 14.18 Hz, 1H), 3.97 (dd, J = 7.34, 14.18 Hz, 1H), 2.95-3.04 (m, 1H), 2.33 (d, J = 1.59 Hz, 3H), 2.19 (s, 6H), 0.80 (d, J = 6.60 Hz, 3H).

[0533] Step-C2: Yellow semi-solid. 1 H NMR (DMSO-d6, 400 MHz): δ 7.30-7.35 (m, 2H), 7.22 (d, J = 10.64 Hz, 1H), 6.32 (d, J = 3.06 Hz, 1H), 4.17 (dd, J = 6.97, 14.18 Hz, 1H), 3.97 (dd, J = 7.34, 14.18 Hz, 1H), 2.95-3.04 (m, 1H), 2.33 (d, J = 1.59 Hz, 3H), 2.19 (s, 6H), 0.80 (d, J = 6.60 Hz, 3H).

[0534] Step-C3: Yield: 19% (over two steps, light brown liquid).[a] D 20 = -2.43 (C 0.5, CH2Cl2). LC-MS: 99.8%, m / z = 235.1 [M+H] +1H NMR (DMSO-d6, 400 MHz): δ 7.36 (dd, J = 4.52, 8.93 Hz, 1H), 7.13-7.17 (m, 1H), 6.81-6.87 (m, 1H), 6.17 (s, 1H), 4.86 (d, J = 4.77 Hz, 1H), 3.89-4.05 (m, 3H), 2.40 (d, J = 0.73 Hz, 3H), 1.08 (d, J = 5.99 Hz, 3H). 19 F NMR (DMSO-d6, 376 MHz): δ -127.62 (s, 1F).

[0535] Bartoli indole synthesis of 5-fluoro-7-methyl-lH-indole from 4-fluoro-2-methyl-l- nitrobenzene, a solution of 4-fluoro-2-methyl-l-nitrobenzene in THF (10 vol) was treated with 4 equivalents of 1M vinylmagnesium bromide at -40°C for 3 hours. The reaction was monitored by TLC and upon completion, the reaction mixture was quenched with saturated NH4C1 and extracted with EtOAc. The organic layers were combined and washed with saturated brine to give the crude product. The crude product was purified using a combi-flash with 5% ethyl acetate in n-hexane and the more pure fractions were distilled to give 5-fluoro-7-methyl-lH-indole in 27% isolated yield.

[0536] Example 73. (R)-1-(5-fluoro-2-methyl-1H-indol-1-yl)-N,N-dimethylpropan-2-amine

[0537]

[0538] Step-C1 : Yield: 33% (colorless liquid). 1 H NMR (DMSO-d6, 400 MHz): δ 7.36 (dd, J = 4.52, 8.93 Hz, 1H), 7.13-7.17 (m, 1H), 6.81-6.87 (m, 1H), 6.17 (s, 1H), 4.86 (d, J = 4.77 Hz, 1H), 3.89-4.05 (m, 3H), 2.40 (d, J = 0.73 Hz, 3H), 1.08 (d, J = 5.99 Hz, 3H).

[0539] Step-C2: Light brown semi-solid.

[0540] Step-C3: Yield: 10% (over two steps, colorless liquid).[a] D 20 = -36.86 (C 0.25, CH2Cl2). LC-MS: 94.4%, m / z = 235.2 [M+H] +1H NMR (DMSO-d6, 400 MHz): δ 7.34 (dd, J = 4.52, 8.80 Hz, 1H), 7.15 (dd, J = 2.45, 9.90 Hz, 1H), 6.86 (dt, J = 2.57, 9.23 Hz, 1H), 6.18 (s, 1H), 4.16 (dd, J = 6.42, 14.73 Hz, 1H), 3.93 (dd, J = 7.58, 14.67 Hz, 1H), 2.92 (sxt, J = 6.80 Hz, 1H), 2.40 (s, 3H), 2.22 (s, 6H), 0.81 (d, J = 6.60 Hz, 3H). 19 F NMR (DMSO-d6, 376 MHz): δ -127.21 (s, 1F).

[0541] Example 74. (R)-1-(5-fluoro-3-methyl-1H-indol-1-yl)-N,N-dimethylpropan-2-amine

[0542]

[0543] Step-C1 : Yield: 35% (light brown liquid). 1 H NMR (DMSO-d6, 400 MHz): δ 7.41 (dd, J = 4.52, 8.93 Hz, 1H), 7.16-7.23 (m, 2H), 6.89-6.95 (m, 1H), 4.85 (d, J = 4.65 Hz, 1H), 3.87-4.04 (m, 3H), 2.20 (d, J = 0.98 Hz, 3H), 1.02 (d, J = 6.11 Hz, 3H).

[0544] Step-C2: Brown semi-solid. 1 H NMR (DMSO-d6, 400 MHz): δ 7.49 (dd, J = 4.46, 8.92 Hz, 1H), 7.20-7.26 (m, 2H), 6.95-7.01 (m, 1H), 4.91-4.99 (m, 1H), 4.34 (d, J = 5.65 Hz, 2H), 2.63 (s, 3H), 2.21 (s, 3H), 1.31 (d, J = 6.54 Hz, 3H).

[0545] Step-C3: Yield: 44% (over two steps, brown liquid).[a] D 20 = -18.4 (C 0.5, CH2Cl2). LC-MS: 95%, m / z = 235.2 [M+H] +1H NMR (DMSO-d6, 400 MHz): δ 7.40 (dd, J = 4.46, 8.86 Hz, 1H), 7.17-7.23 (m, 2H), 6.89-6.96 (m, 1H), 4.14 (dd, J = 6.91, 14.24 Hz, 1H), 3.90-3.97 (m, 1H), 2.91-3.00 (m, 1H), 2.17-2.23 (m, 9H), 0.80 (d, J = 6.60 Hz, 3H). 19 F NMR (DMSO-d6, 376 MHz): δ -127.47 (s, 1F).

[0546] Example 75. (R)-1-(5-methoxy-1H-indol-1-yl)-N,N-dimethylbutan-2-amine

[0547]

[0548] Step-C1 : The epoxide used in the reaction was (S)-2-ethyl oxirane, and the remaining steps were the same as the general procedure. Yield: 44% (pale brown solid). 1 H NMR (DMSO-d6, 400 MHz): δ 7.34 (d, J = 8.93 Hz, 1H), 7.27 (d, J = 3.06 Hz, 1H), 7.02 (d, J = 2.32 Hz, 1H), 6.73-6.77 (m, 1H), 6.30 (dd, 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).

[0549] Step-C2: Pale yellow solid. 1 H NMR (DMSO-d6, 400 MHz): δ 7.34 (d, J = 8.93 Hz, 1H), 7.27 (d, J = 3.06 Hz, 1H), 7.02 (d, J = 2.32 Hz, 1H), 6.73-6.77 (m, 1H), 6.30 (dd, 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).

[0550] Step-C3: Yield: 26% (over two steps, brown solid).[a] D 20= -22.57 (C 0.5, CH2Cl2). LC-MS: 96.7%, m / z = 247.2 [M+H] +1 H NMR (DMSO-d6, 400 MHz): δ 7.27-7.33 (m, 2H), 7.03 (d, J = 2.32 Hz, 1H), 6.75-6.78 (m, 1H), 6.31 (dd, J = 0.73, 3.06 Hz, 1H), 4.17-4.24 (m, 1H), 3.94-4.00 (m, 1H), 3.74 (s, 3H), 2.69-2.76 (m, 1H), 2.23 (s, 6H), 1.40-1.51 (m, 1H), 1.07-1.19 (m, 1H), 0.81 (t, J = 7.40 Hz, 3H).

[0551] Example 76. (S)-1-(5-methoxy-1H-indol-1-yl)-N,N-dimethylbutan-2-amine

[0552]

[0553] Step-C1 : The epoxide used in the reaction was (R)-2-ethyl oxirane, the rest of the steps were the same as the general procedure. Yield: 34% (pale brown liquid). 1 H NMR (DMSO-d6, 400 MHz): δ 7.34 (d, J = 8.93 Hz, 1H), 7.27 (d, J = 2.93 Hz, 1H), 7.02 (d, J = 2.32 Hz, 1H), 6.75 (dd, J = 2.45, 8.93 Hz, 1H), 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).

[0554] Step-C2: Pale brown solid. 1 H NMR (DMSO-d6, 400 MHz): δ 7.45 (d, J = 8.93 Hz, 1H), 7.36 (d, J = 3.06 Hz, 1H), 7.06 (d, J = 2.45 Hz, 1H), 6.82 (dd, J = 2.45, 8.93 Hz, 1H), 6.40 (dd, J = 0.61, 3.06 Hz, 1H), 4.82-4.90 (m, 1H), 4.43 (d, J = 5.75 Hz, 2H), 3.77 (s, 3H), 2.55 (s, 3H), 1.67-1.78 (m, 1H), 1.55-1.64 (m, 1H), 0.98 (t, J = 7.46 Hz, 3H).

[0555] 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-d6, 400MHz): δ7.27-7.33(m,2H),7.02(d,J=2.38Hz,1H),6.76(dd,J=2.38,8.80Hz,1H),6.30-6.32(m,1H),4.21(dd,J=6.79,14 .31Hz,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=7.43Hz,3H).

[0556] Example 77. (R)-1-(4,5-dimethoxy-1H-indol-1-yl)-N,N-dimethylpropan-2-amine

[0557]

[0558] Step-C1: Yield: 75% (light brown liquid). 1 H NMR (DMSO-d6, 400MHz): δ7.24 (d, J=3.18Hz, 1H), 7.12 (dd, J=0.61, 8.80Hz, 1H), 6.89-6.92 (m, 1H), 6.39 (dd, J= 0.67, 3.12Hz, 1H), 4.84 (d, J = 4.65Hz, 1H), 3.91-4.01 (m, 3H), 3.88 (s, 3H), 3.77 (s, 3H), 1.03 (d, J = 5.99Hz, 3H).

[0559] Step-C2: Light brown liquid.

[0560] 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] +1H NMR (DMSO-D6, 400 MHz): δ 7.28 (d, J = 3.06 Hz, 1H), 7.11 (d, J = 8.80 Hz, 1H), 6.93 (d, J = 8.80 Hz, 1H), 6.41 (d, J = 3.06 Hz, 1H), 4.17 (dd, J = 6.85, 14.18 Hz, 1H), 3.96 (dd, J = 7.40, 14.24 Hz, 1H), 3.90 (s, 3H), 3.79 (s, 3H), 2.97 - 3.03 (m, 1H), 2.19 (s, 6H), 0.83 (d, J = 6.60 Hz, 3H).

[0561] Example 78. (R)-1-(5-fluoro-3-methoxy-1H-indol-1-yl)-N,N-dimethylpropan-2- amine

[0562]

[0563] Step-C1 : Yield: 50% (brown liquid).

[0564] Step-C2: Light yellow solid.

[0565] Step-C3: Yield: 3% (over two steps, light brown liquid).[a] D 20 = -17.6 (C 0.25, CH2CL2). LC-MS: 99.13%, m / z = 251.1 [M+H] +1 H NMR (DMSO-d6, 400 MHz): δ 7.41 (dd, J = 4.28, 9.05 Hz, 1H), 7.15 (dd, J = 2.51, 9.48 Hz, 1H), 7.06 (s, 1H), 6.95 (dt, J = 2.57, 9.23 Hz, 1H), 4.11 (dd, J = 6.60, 14.18 Hz, 1H), 3.91 (dd, J = 7.64, 14.24 Hz, 1H), 3.78 (s, 3H), 2.98 (sxt, J = 6.90 Hz, 1H), 2.20 (s, 6H), 0.79 (d, J = 6.60 Hz, 3H). 19 F NMR (DMSO-d6, 376 MHz): δ -127.6 (s, 1F).

[0566] Example 79. (R)-1-(5,6-dichloro-1H-indol-1-yl)-N,N-dimethylpropan-2-amine

[0567]

[0568] Step-C1 : Yield: 45% (light brown solid). 1H NMR (DMSO-d6, 400 MHz): δ 7.86 (s, 1H), 7.79 (s, 1H), 7.49 (d, J = 3.06 Hz, 1H), 6.45 (d, J = 3.06 Hz, 1H), 4.21 (dd, J = 7.76, 14.37 Hz, 1H), 4.07 (dd, J = 6.60, 14.31 Hz, 1H), 2.98 - 3.04 (m, 1H), 2.19 (s, 6H), 0.84 (d, J = 6.60 Hz, 3H).

[0569] Step-C2: Pale yellow semi-solid.

[0570] Step-C3: Yield: 30% (over two steps, pale 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-d6, 400 MHz): δ 7.86 (s, 1H), 7.79 (s, 1H), 7.49 (d, J = 3.06 Hz, 1H), 6.45 (d, J = 3.06 Hz, 1H), 4.21 (dd, J = 7.76, 14.37 Hz, 1H), 4.07 (dd, J = 6.60, 14.31 Hz, 1H), 2.98 - 3.04 (m, 1H), 2.19 (s, 6H), 0.84 (d, J = 6.60 Hz, 3H).

[0571] Step D

[0572] General synthetic scheme:

[0573]

[0574] General synthetic procedure:

[0575] Step-D1 : To a stirred solution of compound J (1 eq) in chloroform (10 vol) at 0 °C was added SOCl2(5 eq) and the resulting solution was heated at reflux temperature for 12 h. The progress of the reaction was monitored by thin layer chromatography.

[0576] Post-treatment at step D1 : The reaction mixture was evaporated and then co-evaporated twice with toluene (10 vol). The resulting crude product was then used directly in the next step.

[0577] Step-D2: To a stirred solution of compound solution h (1.0 eq) in DMF (10 vol) was added NaH (60% in mineral oil, 1.5 eq) at 0 °C. The reaction mixture was stirred for 30 min, then compound I (1.0 eq) was added followed by NaI (cat). The reaction mixture was stirred for 30 min, then NaI (cat) was added followed by compound I (1.0 eq). The reaction mixture was slowly warmed to rt, then warmed to 65 °C and stirred for 16 h. The progress of the reaction was monitored by TLC.

[0578] Workup and purification: The reaction mixture was cooled to rt, quenched with ice-cold water and extracted with ethyl acetate. The organic layers were combined and washed with ice-cold water, then with aqueous NaCl. The organic layer was separated, dried over Na2S04, and concentrated to give the crude product. The crude product was purified by combi-flash using 2-5% methanol / dichloromethane, then the purer fractions were distilled and dried under reduced pressure to give the desired product.

[0579] Example 80. (S)-5-methoxy-1-((1-methylpiperidin-2-yl)methyl)-1H-indole

[0580]

[0581] Step-D1: (S)-(1-methylpiperidin-2-yl)methanol was treated with SOCl2to give the corresponding chloride using the general procedure described above.

[0582] Step-D2: Yield: 13% (over two steps, light brown semi-solid). [a] D 20 = -85.8 (C 0.25, CH2CL2). LC-MS: 99%, m / z = 259.1 [M+H] +1 H NMR (DMSO-d6, 400 MHz): δ 7.28-7.35 (m, 2H), 7.03 (d, J = 2.32 Hz, 1H), 6.76 (dd, J = 2.45, 8.80 Hz, 1H), 6.32 (d, J = 2.81 Hz, 1H), 4.44-4.50 (m, 1H), 3.89-3.96 (m, 1H), 3.74 (s, 3H), 2.75-2.82 (m, 1H), 2.36 (br s, 3H), 2.24-2.31 (m, 1H), 1.97-2.08 (m, 1H), 1.37-1.58 (m, 3H), 1.05 (br d, J = 9.05 Hz, 3H).

[0583] Example 81. (S)-5-methoxy-1-((1-methylpyrrolidin-2-yl)methyl)-1H-indole

[0584]

[0585] Step-D1 : (S)-(1 -Methylpiperidin-2-yl)methanol was treated with SOCl2to give the corresponding chloride using the general procedure described above.

[0586] Step-D2: Yield: 11% (over two steps, brown liquid).[α] D 20 = -62.7 (C 0.45, CH2CL2). LC-MS: 98.14%, m / z = 245.2 [m+h] + . 1 H NMR (DMSO-d6, 400 MHz): δ 7.27-7.35 (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).

[0587] Example 82. (R)-5-methoxy-1-((1-methylpiperidin-2-yl)methyl)-1H-indole

[0588]

[0589] Step-D1 : (S)-(1 -Methylpiperidin-2-yl)methanol was treated with SOCl2to give the corresponding chloride using the general procedure described above. D 20 = +101.19 (C 0.5, CH2CL2). LC-MS: 97.4%, m / z = 259.2 [M+H] +1 H NMR (DMSO-d6, 400 MHz): δ 7.27-7.35 (m, 2H), 7.03 (d, J = 2.45 Hz, 1H), 6.76 (dd, J = 2.45, 8.93 Hz, 1H), 6.32 (d, J = 2.93 Hz, 1H), 4.46 (dd, J = 4.28, 14.06 Hz, 1H), 3.92 (dd, J = 8.50, 14.12 Hz, 1H), 3.74 (s, 3H), 2.76-2.81 (m, 1H), 2.35 (s, 3H), 2.25-2.30 (m, 1H), 1.99-2.06 (m, 1H), 1.36-1.57 (m, 3H), 1.00-1.10 (m, 3H).

[0590] Example 83. (R)-5-methoxy-1-((1-methylpyrrolidin-2-yl)methyl)-1H-indole Step-D1 : (S)-(1 -Methylpiperidin-2-yl)methanol was treated with SOCl2to give the corresponding chloride using the general procedure described above.

[0591]

[0592] Step-D1: (R)-(1-methylpiperidin-2-yl)methanol was treated with SOCl2to get the corresponding chloride using the general procedure described above.

[0593] Step-D2: After purification by combi-flash, the product was obtained with 80% purity and was further purified by Prep-HPLC to get cleaner final compound.

[0594] Prep-HPLC purification details are shown below:

[0595] Prep-HPLC column; Chiralpak IG (250*30mm, 5μ)

[0596] Mobile phase A: 0.1% n-hexane DEA

[0597] Mobile phase B: EtOH:MeOH (50:50)

[0598] Flow rate: 35.0 mL / min

[0599] Isocratic table:

[0600] Time ％A ％B 20 20 80 2.00 20 80

[0601] Solvent used for dilution: Methanol / Ethanol

[0602] Yield: 11% (over two steps, colorless solid).[α] D 20 = +79.47 (C 0.5, CH2CL2). LC-MS: 99.9%, m / z = 245.1 [m+h] +1 H NMR (DMSO-D6, 400 MHz): δ 7.29-7.38 (m, 2H), 7.02 (d, J = 2.32 Hz, 1H), 6.76 (dd, J = 2.38, 8.86 Hz, 1H), 6.31 (d, J = 2.93 Hz, 1H), 4.16-4.22 (m, 1H), 3.95-4.01 (m, 1H), 3.74 (s, 3H), 2.94 (td, J = 4.37, 9.11 Hz, 1H), 2.52-2.58 (m, 1H), 2.18 (s, 3H), 2.09-2.15 (m, 1H), 1.53-1.72 (m, 3H), 1.41-1.50 (m, 1H).

[0603] Step E

[0604] General synthetic scheme:

[0605]

[0606] General synthetic procedure:

[0607] Step-E1 : To a stirred solution of K (1.0 eq) in DMF (10 vol) was added NaH (60% in mineral oil, 1.2 eq) at 0 °C. The reaction mixture was stirred for 20 min. Reagent L was added to the reaction, slowly warmed to room temperature and stirred for 16 h. The progress of the reaction was monitored by TLC. TLC showed one non-polar spot corresponding to K.

[0608] Step-E1 work-up: The reaction mixture was quenched with ice-cold water and extracted with ethyl acetate. The organic layers were combined and washed with ice-cold water followed by brine. The organic phase was separated, dried over Na2S04and concentrated under reduced pressure to get the crude product. The crude product was purified over a combi-flash column using ethyl acetate / n-hexane and the more pure fractions were distilled to get M.

[0609] Step-E2: To a stirred solution of M (1.0 eq) in DMF (10 vol) was added K2C03(3 eq) at room temperature, followed by reagent N (1.2 eq) and NaI (1 eq). The reaction mixture was then heated at 70 °C for 16 h. The progress of the reaction was monitored by TLC. TLC showed one polar spot corresponding to M.

[0610] Step-E2 work-up: The reaction mixture was quenched with ice-cold water and extracted with ethyl acetate. The organic layers were combined and washed with ice-cold water followed by brine. The organic phase was separated, dried over Na2S04and concentrated under reduced pressure to get the crude product. The crude product was purified over a combi-flash column using CH2CI2 / MeOH and the more pure fractions were distilled (by TLC), dried to get the target compound with >95% LC-MS and HPLC purity.

[0611] Example 84. 6-(2-(5-methoxy-1H-indol-1-yl)ethyl)-2-oxa-6-azaspiro[3.3]heptane

[0612]

[0613] Prepared according to step E. Yield: 38% (over 2 steps), colorless liquid. LC-MS: 99%, m / z = 273.2.1 [M+H] + . 1H NMR (DMSO-d6, 400 MHz): δ 7.32 (d, J = 8.93 Hz, 1H), 7.26 (d, J = 3.06 Hz, 1H), 7.02 (d, J = 2.32 Hz, 1H), 6.75 (dd, J = 2.38, 8.86 Hz, 1H), 6.30 (d, J = 2.93 Hz, 1H), 4.52 (s, 4H), 4.04 (t, J = 6.30 Hz, 2H), 3.74 (s, 3H), 3.17 (s, 4H), 2.63-2.67 (m, 2H).

[0614] Example 85. 6-(2-(5-chloro-1H-indol-1-yl)ethyl)-2-oxa-6-azaspiro[3.3]heptane

[0615]

[0616] Prepared according to Step E. Yield: 25% (over 2 steps), brown liquid. LC-MS: 97.3%, m / z = 277.0 [M+H] + 1 H NMR (DMSO-d6, 400 MHz): δ 7.57 (d, J = 1.96 Hz, 1H), 7.46-7.49 (m, 2H), 7.40 J = 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).

[0617] Example 86. (R)-1-(5-methoxy-2-methyl-1H-indol-1-yl)-N,N-dimethylpropan-2-amine

[0618]

[0619] Prepared according to Step C. 1 H NMR (DMSO-d6, 400 MHz): δ 7.20 (d, J = 8.8 Hz, 1H), 6.95 (d, J = 2.4 Hz, 1H), 6.73 (dd, J = 8.8 Hz, J = 2.4 Hz, 1H), 6.14 (s, 1H), 4.29 (dd, J = 4.8, 14.4 Hz, 1H), 4.06-3.99 (m, 1H), 3.79 (s, 3H), 3.25-3.10 (m, 1H), 2.48 (s, 6H), 2.42 (d, J = 0.4 Hz, 3H), 0.92 (d, J = 6.4 Hz, 3H). LCMS: 247.1 [M+H] + .

[0620] Results and Discussion

[0621] SAR studies were conducted by comparing the effects of DMT (1) with 1-ME-DMT (27) and isoDMT (2). While DMT can act as a hydrogen bond donor when it binds to target receptors, 27 and 2 cannot. Thus, this potential hydrogen bond interaction can not be critical for compounds that induce plasticity, as 27 and 2 increase dendritic spine complexity to a comparable extent as 1, despite the absence of an indole N-H bond. Figure 2

[0622] As electron-rich and electron-poor DMT analogs, 5-MEO-DMT (28) and 6-F-DMT (29) were chosen. Compound 28 promotes neurogenesis in the dentate gyrus, alleviating symptoms of human depression and anxiety. Compound 29 is not expected to be hallucinogenic, as fluorination of DMT analogs attenuates the hallucinogenic potential. IsoDMT analogs Examples 5 and 13 behave the same as 28 and 29( Figure 3 ), indicating that SAR data obtained with isoDMT scaffold derivatives with respect to neuronal growth can be used by analogy for DMT scaffold derivatives, due to the isomorphic nature of the two structures.

[0623] Key features of the psychoplastogen pharmacophore were determined with various isoDMT analogs( Figure 4 ). Removal of the basic amine on isoDMT to make 25 resulted in a molecule that does not promote dendritogenesis. Furthermore, compound 31, the N,N-dimethylamide analog of isoDMT, does not promote neuronal growth, confirming the hypothesis that the basic nitrogen is necessary for promoting plasticity( Figure 4 A and 4B). Expanding the distance between the aromatic ring and the amine by one carbon atom (26) can only cause a slight decrease in N max values( Figure 4 B).

[0624] Modifications of the aromatic ring are generally well-tolerated( Figure 4 C). Conversion of the indole to a benzimidazole (22), pyrrole (23), or carbazole (24) has minimal effect on the ability of these molecules to promote neuronal growth. Furthermore, substitution of the indole 2- and 3-positions (16 and 21, respectively) is well-tolerated. In summary, the minimal psychoplastogen pharmacophore appears to have a modifiable aromatic ring separated from the basic nitrogen by a short linker.

[0625] ​Substitution on the DMT and isoDMT benzene ring affects the psychedelic potential. For example, 5-MEO-DMT (28) was used instead of the psychedelic 2,5-dimethoxy-4-methylamphetamme (DOM) in rats to distinguish DOM from saline, but not 6-MEO-DMT. Similarly, 6-MEO-isoDMT (5) was used instead of the psychedelic training drug, but not 5-MEO-isoDMT (Example 5). Therefore, three series of analogs substituted with methoxy (electron donating; Examples 3-6), benzyloxy (electron donating, but requiring steric hindrance; Examples 8-11), or fluorine (electron withdrawing; Examples 12-15) Figure 5 ) groups were synthesized and tested. Substitution at the 5-, 6-, and 7-positions was well tolerated regardless of the substituent. However, substitution at the 4-position rendered the compounds incapable of increasing dendritic spine complexity. Even the fluorine substituent, which has a very small van der Waals radius (1.2 and 1.47 for H and F, respectively), was not tolerated.

[0626] To determine whether DMT and isoDMT derivatives exhibit differences in their psychoplastogenic potency, concentration-response experiments Figure 6 ) were performed. The isoDMT analogs (2 and Example 5) produced similar maximum efficacy and potency as the equipotent DMT analogs (1 and 28). Furthermore, they were able to increase dendritic spine complexity at low concentrations of 1 nM. These compounds showed comparable efficacy and potency to ketamine, further emphasizing their potential as antidepressants. Finally, compound Example 4 proved to be a special psychoplastogen, which is of great importance due to its low psychedelic potential in drug discrimination and head twitch response (HTR) tests Figure 8 ).

[0627] DMT and other psychedelic compounds promote increased dendritic spine complexity, dendritic spine density, and synapse formation through 5-HT 2A -related processes. Pretreatment of cortical cultures with 5-HT 2A antagonists blocked the ability of 5-MeO-DMT (28) to promote dendritic growth Figure 7 ). Importantly, the psychoplastogenic effects of isoDMTs were also blocked under these conditions, indicating that 5-HT 2A receptors are involved in their mechanism of action Figure 7 ).

[0628] Psychedelic potential. The psychedelic compound 5-MeO-DMT (28) produced a robust, dose-dependent HTR, which was greater in female mice. However, the equipotent compound 6-MeO-isoDMT (Example 5) was significantly less potent Figure 8According 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.

[0629] Hallucinogens (such as LSD and 5-MEO-DMT) activate 5HT in stimulant mode. 2A Sensor analysis, but its non-hallucinogenic homologs (risolide (LIS) and 6-MEO-DMT) are not suitable. 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.

[0630] In some implementations, the hallucinogenic potential of compounds evaluated in agonist mode is shown in Table 1.

[0631] Table 1

[0632]

[0633]

[0634] A: Activation of 5HT in agonist mode 2A Sensor analysis; B: 5HT is not activated in agonist mode. 2A Sensor analysis. Percentages correlated with the positive control (100 μM 5-HT in agonist mode). Compounds producing a response >15% were considered to activate the sensor in agonist mode.

[0635] In addition, 5HT 2A Sensor assays run in agonist mode Figure 12A and Figure 12B non-hallucinogenic compounds (e.g., psilocin and 6-MeO-DMT) compete with 5-HT. In addition, non-hallucinogenic compounds in animals (e.g., humans), such as 6-F-DET, ketanserin, BOL148, compete with 5HT 2A binding in sensor assays run in antagonist mode Figure 13 at a compound concentration of 10 μM. In some embodiments, a compound of the application prevents 5-HT from binding to 5HT 2A In some embodiments, the 5HT 2A sensor assay is in antagonist mode. In some embodiments, a compound of the application prevents 5-HT from binding to 5HT 2A and has non-hallucinogenic potential. In some embodiments, a compound of the application prevents 5-HT from binding to 5HT 2A and is non-hallucinogenic. In some embodiments, a compound of the application prevents 5-HT from binding to 5HT 2A In some embodiments, a compound of the application that prevents 5-HT binding in antagonist mode has non-hallucinogenic potential. In some embodiments, a compound of the application that prevents 5-HT binding in antagonist mode is a non-hallucinogenic compound. In some embodiments, a compound of the application that inhibits sensor assay response in antagonist mode has non-hallucinogenic potential. In some embodiments, a compound of the application that inhibits sensor assay response in antagonist mode is a non-hallucinogenic compound.

[0636] In some embodiments, results from agonist mode sensor assays indicate that a compound of the application is a non-hallucinogenic ligand for 5-HT 2A receptors. In some embodiments, results from antagonist mode sensor assays indicate that a compound of the application is a non-hallucinogenic ligand for 5-HT 2A receptors. In some embodiments, results from agonist mode and antagonist mode sensor assays together indicate that a compound of the application is a non-hallucinogenic ligand for 5-HT 2A receptors.

[0637] In some embodiments, hallucinogenic potential of compounds evaluated in antagonist mode is as shown in Table 2.

[0638] Table 2

[0639]

[0640] A: 5HT response inhibition > 100%; B: 5HT response inhibition 75% - 100%; 5HT response inhibition < 75%. Percentages are relative to the positive control (100 nM 5-HT in antagonist mode).

[0641] Calcium flux assay. Calcium secondary messenger pathway. Calcium No Wash PLUS Assay to monitor activation of GPCRs (e.g., 5HT 2A ) by Gq secondary messenger signaling through live cell non-imaging assay formats. Cells loaded with a calcium sensitive dye are used to monitor the release of calcium from intracellular stores upon Metabolism in cell lines and other cell lines stably expressing Gq-coupled GPCRs (e.g., 5HT 2A ). Activation of the GPCR (e.g., 5HT 2A ) by compounds results in the release of calcium from intracellular stores and an increase in dye fluorescence that is measured in real time. In some embodiments, the ability of a compound of the present application to modulate 5-HT 2A function is determined by a calcium flux assay. In some embodiments, a compound of the present application activates a calcium flux assay. In some embodiments, activation of a calcium flux assay indicates that a compound of the present application modulates 5-HT 2A function.

[0642] In some embodiments, the ability of a compound of the present application to modulate 5-HT 2A function is assessed according to the results of a calcium flux assay (Table 3).

[0643] Table 3

[0644]

[0645] A: > 10 μΜ; B: < 10 μΜ.

[0646] Forced swim test. Since the sustained (>24h) anti-depressant-like effects of ketamine are mediated by increased plasticity of prefrontal cortical structures and play a role in the therapeutic effects of 5-HT 2A agonists, the effects of the hetero DMT analogs on forced swim test (FST) behavior (A and B) were evaluated. First, a pretest was performed to induce a depressive phenotype. Compounds were administered 24h after the pretest and FST was performed 24h and 7d after dosing. Positive controls (ketamine) and Example 59 significantly reduced immobility (A vs. B) 24h after dosing. Figure 14 Figure 14 Figure 14 Figure 14

[0647] ​​​​Neurite outgrowth assay. Changes in the pattern of neurite outgrowth are associated with neurodegenerative diseases and trauma. The discovery of new compounds that positively influence neurogenesis is of great interest for the development of new therapies for neurological diseases. The neurite outgrowth of rat cortical neurons was measured using an image-based automated analysis to determine the neuroplasticity effects of the compounds of the invention. In some embodiments, the compounds of the invention increase the pattern of neurite outgrowth. In some embodiments, the compounds of the invention increase the average length of the neurite axons compared to controls. In some embodiments, the compounds of the invention increase the branching points of the neurite axons compared to controls. In some embodiments, the compounds of the invention increase both the branching points of the neurite axons and the average length of the neurite axons compared to controls.

[0648] In some embodiments, the plasticity potential of the compounds is shown in Table 4.

[0649] Table 4

[0650]

[0651]

[0652] A: >3-fold increase compared to control DMSO; B: 1.5-3-fold increase compared to control DMSO; C: <1.5-fold increase compared to control DMSO.

[0653] Test

[0654] Dendritic arborization assay: It is historically proven that phenotypic screening is more successful than target-based approaches in identifying drugs with novel mechanisms of action. After establishing a simple and robust method to assess isoDMT analogs, the next step was to test their ability to increase dendritic spine complexity using phenotypic analysis in cortical neuron cultures. After treatment, neurons were fixed and visualized using an antibody against MAP2, a cytoskeletal protein localized to the soma of neurons. Sholl analysis was then performed and the maximum number of intersections (N max ) was used as a quantitative measure of dendritic spine complexity. For statistical comparisons between specific compounds, raw N max values were compared. Percent efficacy was determined by setting the N max values of vehicle (DMSO) and positive control (ketamine) to 0% and 100%, respectively.

[0655] Animals. For dendritogenesis experiments, timed pregnant SD rats were purchased from Charles River Laboratories (Wilmington, MA). For the head twitch response test, male and female C57BL / 6J mice were from Jackson Laboratories (Sacramento, CA). Mice were housed 4-5 per cage (same sex) in a temperature- and humidity-controlled room and maintained on a 12-h light / dark cycle. During the course of the experiments, animals weighed between 17 and 30 g. All experimental procedures involving rodents were approved by the Institutional Animal Care and Use Committee (IACUC) at the University of California, Davis, and followed the principles stated in the Guide for the Care and Use of Laboratory Animals by the National Institutes of Health. The University of California, Davis, and the University of California, San Francisco, are accredited by the Association for Assessment and Accreditation of Laboratory Animal Care (AAALAC).

[0656] Dendritogenesis - Sholl analysis. Dendritic outgrowth experiments were performed following previously published methods with minor modifications. Neurons were seeded at a density of 15000 cells / well in 96-well plates (200 μL of culture medium per well) containing NeuroBASAL (Life Technologies) containing 1% penicillin streptomycin, 10% heat inactivated fetal bovine serum and 0.5 mM glutamine. After 24 hours, the culture medium was refreshed with NeuroBASAL containing 1x B27 supplement (Life Technologies), 1% penicillin-streptomycin, 0.5 mM glutamine and 12.5 μM glutamate. After 3 days in vitro (DIV3), cells were treated with compounds. Unless otherwise stated, all compounds tested in the dendritogenesis assay were at 10 μM. DMSO stocks of these compounds were first diluted 100-fold with NeuroBASAL and then diluted 10-fold more in each well (total dilution = 1:1000; 0.1% DMSO concentration). Treatments were randomized. After 1 hour, the culture medium was removed and replaced with fresh NeuroBASAL medium containing 1x B27 supplement, 1% penicillin-streptomycin, 0.5 mM glutamine and 12.5 μM glutamate. Cells were allowed to grow for an additional 71 hours. Neurons were then fixed by removing 80% of the culture medium and replacing it with an equivalent volume of 4% paraformaldehyde aqueous solution (Alfa Aesar) corresponding to 50% of the working volume of the well. Cells were then incubated at room temperature for 20 minutes and then the fixative was aspirated and each well was washed twice with DPBS. Cells were permeabilized with DPBS containing 0.2% Triton X-100 (Thermo) for 20 minutes at room temperature without shaking. Plates were blocked with antibody dilution buffer (ADB) containing 2% bovine serum albumin (BSA) for 1 h at room temperature. Plates were then incubated overnight at 4°C with ADB containing chicken anti-MAP2 antibody (1:10,000; EnCor, CPCA-MAP2) with slow shaking. The next day, plates were washed three times with DPBS and once with 2% ADB / DPBS. Plates were incubated for one hour at room temperature with ADB containing AlexaFluor 488 coupled to anti-chicken IgG antibody (Life Technologies) and washed 5 times with DPBS. After the last wash, 100 μL of DPBS was added to each well and imaged with an ImageXpress Micro XL High Content Screening System (Molecular Devices, Sunnyvale, CA) at 20x objective. Images were analyzed using ImageJ Fiji (version 1.51W). First, images corresponding to each treatment were sorted into separate folders and then data analysis was performed in a blind fashion. Plate controls (positive and negative) were used to ensure that the analysis was working properly while visual determination of appropriate values for brightness / contrast and threshold values that were generally applicable to the remaining random images was determined.Next, brightness / contrast settings were applied and using the rectangular selection tool, approximately 1-2 individual pyramidal neurons (i.e., no bipolar neurons) were selected per image and saved as individual files. Selected neurons did not extensively overlap with other cells and did not extend outside the field of view. Threshold settings were then applied to the individual images. A paintbrush tool was used to clean up artifacts and dendritic protrusions originating from neighboring neurons (cleanup phase). The point tool was used to select the center of the neuron and the following Sholl analysis batch macro was used to save and process the images (Table 5).

[0657] Run ("sholl analysis...", "start=0 end=NaN radius_steps=2 #_samples=1 integral=mean encompass=1 #_prelim=4 extrapolate fit linear polynomial=[best fit] most half log normalize=area create background=228 save");

[0658] Sholl analysis circle radius=2 pixels increment=0.67 pm. All images were taken and analyzed by an experimenter who was blinded to treatment conditions. The number of intersections at each radius for each neuron was averaged to generate an average Sholl plot for each treatment. N max Values were determined by identifying the maximum value for each plot. For each treatment, neurons were selected from at least 6 wells on 2 plates (9 sites / well x 3 wells / plate x 2 plates). Each culture plate was prepared with neurons obtained from a separate pregnant dam.

[0659] Table 5 Sholls efficacy

[0660]

[0661]

[0662] Ketanserin blockade experiment. For the ketanserin blockade experiment ( Figure 7 ), a slightly modified approach was used. At DIV3, neurons were first treated with ketanserin (10 pM) for 1 h, then co-incubated with the drug (1 pM) and ketanserin (10 pM) (DMSO final concentration = 0.2%) for 1 h. After 1 h, the media was removed and replaced with fresh neural basal media containing 1 x B27 supplement, 1% penicillin-streptomycin, 0.5 mM glutamine, and 12.5 pM glutamate. Cells were allowed to continue growing for 71 h before fixation, staining, and imaging.

[0663] Neurite outgrowth assay. Rat cortical neurons (20,000 cells / well) were isolated from 18-day-old rat fetuses and cultured in neurobasal medium (+ B27). Cultured cells were seeded in 96-well plates (avoiding outer wells). At DIV4, neurons were treated with compounds or controls (10 mM) for 1 h, then the compounds were washed out completely. At DIV7, neurons were analyzed. There were three parallel groups for each experiment. Neurite outgrowth was measured by analyzing the following parameters: cell body number, total neurite length (pixels), root number, segments, limb number, and node. Changes in neurite outgrowth patterns were analyzed by immunocytochemistry with anti-beta-III-tubulin. Images were acquired with the CellInsight CX7 by Thermo Fisher and analyzed using its software. The results generated by the device were maximum axon length, end number, root number, dendritic branch points, and total axon length. The results were compared with DMSO controls, indicating the fold change in neuron growth.

[0664] 5HT 2A Sensor assay. HEK293T (ATCC) 5HT2A sensor stable line (Slink 1.3s) was derived by HIV-EF1-Slink 1.3 lentivirus transduction and propagated from a single colony. Lentivirus was produced with second generation lentivirus plasmids pHIV-EF1-1.3, pHCMV-G and pCMV-deltaR8.2.

[0665] For screening 41 compounds, Slight 1.3S cells were seeded in 96-well plates at a density of 40,000 24 hours prior to imaging. On the day of imaging, compounds dissolved in DMSO were diluted from a 100 mM stock to working concentrations of 1 mM, 100 mM and 1 mM with a DMSO concentration of 1%. Prior to imaging, cells grown in DMEM (Gibco) were washed twice with HBSS (Gibco) and after the final wash, 180 L of HBSS was added to each well in agonist mode or 160 L of HBSS was added in antagonist mode. In agonist mode, pictures were taken before and after the addition of 20 L of compound working solution to wells containing 180 L of HBSS. This resulted in a final compound concentration of 100 mM, 10 mM and 100 nM with a DMSO concentration of 0.1%. In antagonist mode, pictures were taken before and after the addition of 20 L of 900 nM 5-HT and then again after the addition of 20 L of compound working solution, resulting in a final 5-HT concentration of 100 nM and a compound concentration of 100 mM, 10 mM, 100 nM with a DMSO concentration of 0.1%. Each compound was tested at each concentration (100 mM, 10 mM and 100 nM) in triplicate (3 wells). Additionally, 100 nM 5HT and 0.1% DMSO controls were imaged within each plate, respectively.

[0666] Imaging was performed using a Leica DMi8 inverted microscope, 40x objective, FITC preset, excitation wavelength 460 nm, emission wavelength 512-542 nm. For each well, 5 images were taken of different areas within the well using an adaptive focus control device, and each image was processed using 2x2 binning. 2A The cell membrane targeted by the sensor was automatically focused, and 5 images were taken of different areas within the well, and each image was processed using 2x2 binning.

[0667] For data processing, custom algorithms written in MATLAB were used to segment and analyze the membrane in each image, generating a single raw fluorescence intensity value. For each well, the average of the 5 raw fluorescence intensity values generated from the 5 images was taken, and the change in fluorescence intensity (dFF) was calculated as follows:

[0668] dFF = (F sat – F apo ) / F apo

[0669] In both agonist and antagonist modes, the fluorescence intensity value before addition of compound in HBSS was used as F apo only, and the fluorescence intensity value after addition of compound was used as F sat .

[0670] For agonist mode, data was in terms of percent activation of 5HT, where 0 was the average of the DMSO wells, and 100 was the average of the 100 mM 5HT wells. For antagonist mode, the inactivation value was calculated as follows:

[0671] Inactivation value = (dFFF(compound + 5HT) - dFF(5HT)) / dFF(5HT)

[0672] Calcium secondary messenger pathway. Cell lines were expanded from frozen stocks according to standard procedures. Cells were seeded in a total volume of 20 pL into wall white, clear bottom, poly-D-lysine coated 384-well microplates and incubated at 37 °C for an appropriate time before testing. Assays were performed in lx dye loading buffer, which is HBSS / 20 mM Hepes containing lx dye, lx Additive A, and 2.5 mM probenecid. Probenecid was prepared fresh. Cells were loaded with dye prior to testing. Media was aspirated from the cells and replaced with 20 pL of dye loading buffer. Cells were incubated at 37 °C for 30-60 minutes.

[0673] To determine agonist activity, cells were incubated with samples to induce a response. After loading dye, cells were removed from the incubator and 10 μL HBSS / 20 mM Hepes was added. When performing agonist dose curves to determine EC80 for subsequent antagonist analysis, 3x vehicle was included in the buffer. Cells were incubated for 30 minutes at room temperature in the dark to equilibrate the plate temperature. Moderate dilutions were made for sample solutions, resulting in 4X samples in test buffer. Compound agonist activity was measured on the FLIPR Tetra (MDS). Calcium flux was detected for 2 min, and 10 μL of 4x sample in HBSS / 20 mM Hepes was added to the experiment over 5 s.

[0674] Compound activity was analyzed with the CBIS Data Analysis Package (Chemical Innovation, CA). For agonist mode testing, percent activity was calculated using the following formula:

[0675] % Activity = 100% x (average RFU of test sample - average RFU of vehicle control) / (average MAX RFU control ligand - average RFU of vehicle control).

[0676] Head twitch response test. Mice (9-10 weeks of age) were injected intraperitoneally with compounds (injection volume 5 ml / kg), placed in empty cages, and videoed for 20 min. Cages were cleaned with 70% ethanol between experiments. Head twitches were scored by two trained observers blinded to treatment conditions (Pearson's correlation coefficients for male and female were 0.91 and 0.99, respectively) for each video segment and the results averaged.

[0677] Forced swim test (FST). Male C57 / BL6J mice (9-10 weeks old at the time of experiment) were purchased from Jackson Laboratories and housed in UCD Eco-Cages at 4-5 mice / cage according to IACUC approved protocols. After one week of acclimation in the vivarium, male experimenters handled each mouse for approximately 1 minute for 3 consecutive days prior to the first FST. All experiments were performed by the same male experimenter. During the FST experiment, mice were allowed to swim in a 40 cm tall, 20 cm diameter, 30 cm water level, clear Plexiglas cylinder for 6 minutes. Each mouse was given fresh water. After acclimating the experimenter, drug-dependent mice were first given a pre-test swim to more reliably induce the depressive phenotype during the subsequent FSTs. After the pre-test, immobility values were determined for all mice and mice were randomly assigned to treatment groups to produce groups with similar average immobility values for the two FST sessions that followed. The next day, animals were injected intraperitoneally with experimental compounds (20 mg / kg), positive control (ketamine, 3 mg / kg), or vehicle (saline). These animals received the FST 30 minutes after injection and were then returned to their cages. All FTS were performed between 8 am and 1 pm. The experiments were video recorded and scored offline manually. Immobility time was scored for the last 4 minutes of the 6-minute test and was defined as passive floating or remaining immobile except for the movements necessary to keep the mouse’s head above water.

[0678] Statistical analysis. Treatments were randomized and data analysis was performed by experimenters blinded to treatment conditions. Statistical analysis was performed with GraphPad Prism (version 8.1.2). The specific tests used, F-statistic, degrees of freedom, and P values for main effects are shown in the figure legends where appropriate. All comparisons were planned before each experiment was performed. For the dendritogenesis experiment, one-way ANOVA with Dunnett’s post-hoc test was considered the most appropriate. Ketamine was used as a positive control to ensure that the assay was working properly.

[0679] While the foregoing application has been described in some detail by way of illustration and example for purposes of clarity and understanding, one skilled in the art will appreciate that certain changes and modifications can be practiced within the scope of the appended claims. In addition, each reference provided herein is incorporated by reference in its entirety to the extent that it is consistent with the description of this application. In the event of inconsistencies between the disclosure of the application and the references, the disclosure of the application will prevail.

Claims

1. A compound, characterized in that, The compounds are selected from the following group: Or its pharmaceutically acceptable salt.

2. The compound according to claim 1, characterized in that, The compound is a salt containing fumaric acid.

3. The compound according to claim 1, characterized in that, The compound is Or its pharmaceutically acceptable salt.

4. The compound according to claim 1, characterized in that, The compound is Or its pharmaceutically acceptable salt.

5. The compound according to claim 1, characterized in that, The compound is Or its pharmaceutically acceptable salt.

6. The compound according to claim 1, characterized in that, The compound is Or its pharmaceutically acceptable salt.

7. The compound according to claim 1, characterized in that, The compound is Or its pharmaceutically acceptable salt.

8. The compound according to claim 1, characterized in that, The compound is Or its pharmaceutically acceptable salt.

9. The compound according to claim 1, characterized in that, The compound is Or its pharmaceutically acceptable salt.

10. The compound according to claim 1, characterized in that, The compound is Or its pharmaceutically acceptable salt.

11. The compound according to claim 1, characterized in that, The compound is Or its pharmaceutically acceptable salt.

12. A pharmaceutical composition comprising the compound as described in any one of claims 1-11, or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient thereof.

13. Use of any compound of claims 1-11 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating brain diseases, wherein, The brain disease mentioned is either a neurodegenerative disease or depression.

14. The use as described in claim 13, characterized in that, The brain disease mentioned is either Alzheimer's disease or Parkinson's disease.

15. The use as described in claim 13, characterized in that, The brain disease mentioned is depression.

16. The use as described in claim 13, characterized in that, The brain disease in question is treatment-resistant depression.

17. The use as described in claim 13, characterized in that, The brain disease mentioned is severe depression.

Images