Compound

Abstract

The present disclosure relates generally to compounds, methods for their synthesis, and their use in treating psychiatric or central nervous system disorders.

Description

[Technical Field]

[0001] This application claims priority to Australian Provisional Application No. 2021 / 904274 (filed on 24 December 2021), which is incorporated herein by reference in its entirety.

[0002] The present disclosure relates generally to novel compounds, methods for their synthesis, and their use in treating psychiatric or central nervous system disorders. [Background technology]

[0003] Mental illness encompasses many neuropsychiatric disorders that place a significant burden on the lives of those affected. Diagnoses such as treatment-resistant depression, major depressive disorder, eating disorders, substance abuse disorders, post-traumatic stress disorder, obsessive-compulsive disorder, attention deficit disorder, and schizophrenia can cause devastating symptoms that disrupt the ability of many affected individuals to lead normal lives.

[0004] A variety of serotonergic medications, including antidepressants, serotonin reuptake inhibitors, monoamine oxidase inhibitors, and selective serotonin reuptake inhibitors, are commercially available to treat psychiatric disorders. Unfortunately, in many indications, these medications offer limited benefit compared to placebo. Additionally, these medications can result in a wide range of side effects, including loss of libido, insomnia, fatigue, and weight gain. Despite their limited efficacy, these medications continue to be used to treat neuropsychiatric conditions and a wide range of adjunctive medical indications. Since the launch of many of these medications, progress in new treatment options has been limited, and the pharmaceutical industry is facing increasing financial pressure to fully deemphasize neuroscience programs. There is a growing unmet need for more effective mental health treatments, and the global COVID-19 pandemic may increase the burden of disease worldwide.

[0005] The use of psychedelic drugs to treat various mental illnesses was widely studied in the 1950s and 1960s, and these substances showed promise as treatments for many disorders of the central nervous system (CNS). After decades of prohibition, scientific research into the application of psychedelics as treatments for mental illness is gaining momentum. The serotonergic psychedelic agent psilocybin has been designated a breakthrough therapy by the FDA for the treatment of major depressive disorder (2019) and treatment-resistant depression (2018). Psilocybin is a prodrug compound produced by the many species of mushrooms collectively known as psilocybin mushrooms or "magic mushrooms." Psilocybin is rapidly metabolized into the bioactive compound psilocin, which produces states of altered consciousness, including altered perceptions, visual hallucinations, and distorted senses of space, time, and self. Many patients report spiritual or "mystical" experiences that have profound and lasting effects on their mood and behavior. Psilocybin has shown promise in over 50 clinical trials for neuropsychiatric indications, including numerous anxiety disorders, obsessive-compulsive disorder, anorexia nervosa, alcoholism, and tobacco dependence. Psilocybin, as well as other psychedelic compounds such as N,N-dimethyltryptamine (DMT) and 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT), have both immediate and persistent effects on mental state, the latter continuing well beyond the duration of action, likely as a result of their ability to induce increased neuroplasticity in the brain, promote neuronal proliferation, and increase spine density of synaptic neurons.

[0006] To date, psilocybin is classified as a controlled substance and / or drug of abuse in most countries under national drug laws. However, recently, clinical research has led to increased awareness of the potential of psychedelic drugs as breakthrough therapies for treating CNS disorders with enormous unmet medical need.

[0007] Despite their therapeutic potential, psilocybin and other psychedelics remain scheduled as drugs of abuse in most countries, and the commercial path to market for these drugs as medicines is uncertain. As adjuncts to psychotherapy, the long duration of action of psilocybin and LSD makes treatment sessions expensive and impractical for widespread implementation. Despite a long history of safe human use, several adverse events have been reported in clinical trials, which may be attributed to signaling bias at the 5-HT2A (primary target) or to off-target activity at, for example, the 5-HT2B receptor (cardiac liability antitarget), the 5-HT1A (anxiolytic target), or the 5-HT2C receptor (disease-associated target, e.g., obesity and some genetic epilepsies). Naturally occurring psychedelics provide important leads for a new generation of neurotherapeutics with novel mechanisms of action and / or superior clinical efficacy to currently available neuropsychiatric drugs.

[0008] In view of the foregoing, there is a continuing need to develop new compounds that may be useful in the treatment of psychiatric or central nervous system disorders.

[0009] The reference to any prior art herein is not an admission or suggestion that this prior art forms part of the common general knowledge in any jurisdiction, or that this prior art would be understood by, considered relevant, and / or could reasonably be expected to be incorporated into other pieces of prior art by a person skilled in the art. Summary of the Invention

[0010] In one aspect, the present disclosure provides a compound of formula (I): [ka] or a pharmaceutically acceptable salt, solvate, tautomer, N-oxide, stereoisomer, metabolite, polymorph, and / or prodrug thereof, During the ceremony, R1 and R 2 But hydrogen, C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkenyl, C 2~6 Haloalkenyl, C 2~6 Alkynyl, C 2~6 Haloalkynyl, C 3~8 Cycloalkyl, C 4~14 Alkylenecycloalkyl, C3-C8 heterocycloalkyl, C4-C 14 Alkyleneheterocycloalkyl, C 6~12 Aryl, C 7~18 Alkylene aryl, C 5~10 Heteroaryl, and C 6~16 alkyleneheteroaryl; The C in question 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkenyl, C 2~6 Haloalkenyl, C 2~6 Alkynyl, C 2~6 Haloalkynyl, C 3~8 Cycloalkyl, C 4~14 Alkylenecycloalkyl, C3-C8 heterocycloalkyl, C4-C 14 Alkyleneheterocycloalkyl, C 6~12 Aryl, C 7~18 Alkylene aryl, C 5~10 Heteroaryl, and C 6~16 The alkylene heteroaryl is selected from halogen, CN, C 1~8 Alkoxy, C 1~8 Alkylamino, C 1~8 Alkyl sulfonyl, CO2R 4 , C(O)N(R 4 )2, OR 4 , N(R 4 )2, NO2, SR 4 , and SO2R 4 each optionally substituted with one or more substituents independently selected from The C in question 3~8 Cycloalkyl, C 4~14 Alkylenecycloalkyl, C3-C8 heterocycloalkyl, C6~12 Aryl, C 7~18 Alkylene aryl, C 5~10 Heteroaryl, and C 6~16 The alkylene heteroaryl is (O), C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkenyl, C 2~6 Haloalkenyl, C 2~6 Alkynyl, C 2~6 Haloalkynyl, C 3~6 Cycloalkyl, as well as O, S, N, S(O), SO2 and NR 4 C containing one or two ring hetero moieties selected from 3~6 each optionally further substituted with substituents independently selected from heterocycloalkyl; Alternatively, R 1 and R 2 combine with the atoms to which they are attached to form O, S, S(O), SO2, N, and NR 4 C containing one or two additional ring hetero moieties selected from 3~8 forming a heterocycloalkyl, The C in question 3~8 Heterocycloalkyl is halogen, (O), CN, C 1~8 Alkoxy, C 1~8 Alkylamino, C 1~8 Alkyl sulfonyl, CO2R 4 , C(O)N(R 4 )2, OR 4 , N(R 4 )2, NO2, SR 4 , SO2R 4 , C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkenyl, C 2~6 Haloalkenyl, C 2~6 Alkynyl, C 2~6 Haloalkynyl, C 1~8 Alkylamino, C 1~8 Alkylsulfonyl, C 3~6 Cycloalkyl, as well as O, S, N, S(O), SO2 and NR 4 C containing one or two ring hetero moieties selected from3~6 and optionally further substituted with substituents selected from heterocycloalkyl; R 3 But hydrogen, C 1~6 Alkyl, C 3~8 Cycloalkyl, or C 4~14 alkylenecycloalkyl; Alternatively, R 3 , and R 1 and R 2 When one of these atoms combines with the atom to which it is attached, it forms C 3~12 forming a heterocycloalkyl, The C in question 3~12 Heterocycloalkyl is halogen, (O), CN, C 1~8 Alkoxy, C 1~8 Alkylamino, C 1~8 Alkyl sulfonyl, CO2R 4 , C(O)N(R 4 )2, OR 4 , N(R 4 )2, NO2, SR 4 , SO2R 4 , C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkenyl, C 2~6 Haloalkenyl, C 2~6 Alkynyl, C 2~6 Haloalkynyl, C 3~6 Cycloalkyl, as well as O, S, N, S(O), SO2 and NR 4 C containing one or two ring hetero moieties selected from 3~6 and optionally further substituted with substituents selected from heterocycloalkyl; Each R 4 But hydrogen, C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkenyl, C 2~6 Haloalkenyl, C 2~6 Alkynyl, C 2~6 Haloalkynyl, C 3~7 Cycloalkyl, as well as O, S, S(O), SO2, N, and NR 5C containing one or two ring hetero moieties selected from 3~7 heterocycloalkyl; The C in question 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkenyl, C 2~6 Haloalkenyl, C 2~6 Alkynyl, C 2~6 Haloalkynyl, C 3~7 Cycloalkyl, and C 3~7 Heterocycloalkyl is halogen, CN, C 1~8 Alkoxy, C 1~8 Alkylamino, C 1~8 Alkyl sulfonyl, CO2R 5 , C(O)N(R 5 )2, OR 5 , N(R 5 )2, NO2, SR 5 , and SO2R 5 each optionally substituted with one or more substituents independently selected from The C3-C7 cycloalkyl and C 3~7 Heterocycloalkyl is (O), C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkenyl, C 2~6 Haloalkenyl, C 2~6 Alkynyl, C 2~6 Haloalkynyl, C 3~6 Cycloalkyl, as well as O, S, S(O), SO2, N, and NR 5 C containing one or two ring hetero moieties selected from 3~6 each optionally further substituted with substituents independently selected from heterocycloalkyl; Each R 5 But hydrogen, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Haloalkyl, C 3~8 Cycloalkyl, C 5~10 Heterocycloalkyl, C 6~12 Aryl, and C 5~10heteroaryl; The C in question 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Haloalkyl, C 3~8 Cycloalkyl, C 5~10 Heterocycloalkyl, C 6~12 Aryl, and C 5~10 Heteroaryl is halogen, CN, C 1~8 Alkoxy, C 1~8 Alkylamino, C 1~8 Alkyl sulfonyl, CO2H, CO2CH3, C(O)NH2, C(O)N(CH3)2, C(O)NHCH3, OH, NH2, N(CH3)2, NHCH3, NO2, SH, SCH3, SO2CH3, SOCH3, C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkenyl, C 2~6 Haloalkenyl, C 2~6 Alkynyl, C 2~6 Haloalkynyl, C 3~6 C containing cycloalkyl and one or two ring hetero moieties selected from O, S, S(O), SO, N, NH, and NCH 3~6 each optionally substituted with one or more substituents independently selected from heterocycloalkyl; L is C 1~4 selected from alkylene, C2-C4 alkenylene, and C2-C4 alkynylene; R 6 But hydrogen, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Alkylene P(O)(OR 12 )2, C(O)R 12 , CO2R 12 , C(O)N(R 12 )2, S(O)R 12 and SO2R 12 , C 3~6 Cycloalkyl, C 6~9 Alkylenecycloalkyl, C 3~6 Heterocyclyl, C6~9 Alkyleneheterocycloalkyl, C 4~7 Heterocyclyl, C 7~10 Alkyleneheterocycloalkyl, C 6~12 Aryl, C 7~18 Alkylene aryl, C 5~10 Heteroaryl, and C 6~16 alkyleneheteroaryl; The C in question 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 6~9 Alkylenecycloalkyl, C 3~6 Heterocyclyl, C 6~9 Alkyleneheterocycloalkyl, C 4~7 Heterocyclyl, C 7~10 Alkyleneheterocycloalkyl, C 6~12 Aryl, C 7~18 Alkylene aryl, C 5~10 Heteroaryl, and C 6~16 The alkylene heteroaryl is selected from halogen, CN, C 1~8 Alkoxy, C 1~8 Alkylamino, C 1~8 Alkyl sulfonyl, CO2R 12 , C(O)N(R 12 )2, OR 12 , N(R 12 )2, NO2, SR 12 , and SO2R 12 each optionally substituted with one or more substituents independently selected from The C in question 3~6 Cycloalkyl, C 6~9 Alkylenecycloalkyl, C 3~6 Heterocyclyl, C 6~9 Alkyleneheterocycloalkyl, C 4~7 Heterocyclyl, C 7~10 Alkyleneheterocycloalkyl, C 6~12 Aryl, C 7~18 Alkylene aryl, C 5~10 Heteroaryl, and C 6~16 The alkylene heteroaryl is (O), C1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkenyl, C 2~6 Haloalkenyl, C 2~6 Alkynyl, C 2~6 Haloalkynyl, C 3~6 Cycloalkyl, as well as O, S, N, S(O), SO2 and NR 12 C containing one or two ring hetero moieties selected from 3~6 each optionally further substituted with substituents independently selected from heterocycloalkyl; Each R 12 But hydrogen, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Haloalkyl, C 3~8 Cycloalkyl, C 4~14 Alkylenecycloalkyl, C 3~10 Heterocycloalkyl, C 4~16 Alkyleneheterocycloalkyl, C 6~12 Aryl, C 7~18 Alkylene aryl, C 5~10 Heteroaryl, and C 6~16 alkyleneheteroaryl; The C in question 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Haloalkyl, C 3~8 Cycloalkyl, C 4~14 Alkylenecycloalkyl, C 3~10 Heterocycloalkyl, C 4~16 Alkyleneheterocycloalkyl, C 6~12 Aryl, C 7~18 Alkylene aryl, C 5~10 Heteroaryl, and C 6~16 The alkylene heteroaryl is selected from halogen, CN, C 1~8 Alkoxy, C 1~8 Alkylamino, C 1~8Alkyl sulfonyl, CO2H, CO2CH3, C(O)NH2, C(O)N(CH3)2, C(O)NHCH3, OH, NH2, N(CH3)2, NHCH3, NO2, SH, SCH3, SO2CH3, SOCH3, C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkenyl, C 2~6 Haloalkenyl, C 2~6 Alkynyl, C 2~6 Haloalkynyl, C 3~6 C containing cycloalkyl and one or two ring hetero moieties selected from O, S, S(O), SO, N, NH, and NCH 3~6 each optionally substituted with one or more substituents independently selected from heterocycloalkyl; (B) and (C): (B) (i)R 7 , R 8 , R 9 , R 10 , and R 11 One of the following is OR 13 , N(R 13 )2, SR 13 , C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkenyl, C2-C6 haloalkenyl, C 2~6 Alkynyl, C 2~6 Haloalkynyl, C 1~6 Alkylamines, C 1~6 Alkoxy, C 1~6 Haloalkoxy, CO2R 13 , C(O)R 13 , C(O)N(R 13 )2, C(O)C(O)N(R 13 )2, OC(O)R 13 ,OC(O)OR 13 , OC(O)N(R 13 )2, OS(O)R 13 , OS(O)N(R 13 )2, OSO2R 13 , OP(O)(OR 13 )2, O.C. 1~6 Alkylene P(O)(OR 13)2, S(O)R 13 , S(O)N(R 13 )2, SO2R 13 , N(R 13 )2, N(R 13 )C(O)R 13 , N(R 13 )C(O)OR 13 , N(R 13 )C(O)N(R 13 )2, NO2, C 3~8 Cycloalkyl, C 3~14 Alkylenecycloalkyl, C 3~10 Heterocycloalkyl, C 4~16 Alkyleneheterocycloalkyl, C 6~12 Aryl, C 7~18 Alkylene aryl, C 5~10 Heteroaryl, C 4~16 alkyleneheteroaryl; The C in question 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkenyl, C2-C6 haloalkenyl, C 2~6 Alkynyl, C 2~6 Haloalkynyl, C 1~6 Alkylamines, C 1~6 Alkoxy, C 1~6 Haloalkoxy, C 3~8 Cycloalkyl, C 3~14 Alkylenecycloalkyl, C 3~10 Heterocycloalkyl, C 4~16 Alkyleneheterocycloalkyl, C 6~12 Aryl, C 7~18 Alkylene aryl, C 5~10 Heteroaryl, and C 4~16 The alkylene heteroaryl is selected from halogen, CN, C 1~8 Alkoxy, C 1~8 Alkylamino, C 1~8 Alkyl sulfonyl, CO2R 13 , C(O)N(R 13 )2, OR 13 , N(R 13 )2, NO2, SR 13 , and SO2R 13and optionally substituted with one or more substituents independently selected from The C in question 3~8 Cycloalkyl, C 3~14 Alkylenecycloalkyl, C 3~10 Heterocycloalkyl, C 4~16 Alkyleneheterocycloalkyl, C 6~12 Aryl, C 7~18 Alkylene aryl, C 5~10 Heteroaryl, and C 4~16 The alkylene heteroaryl is (O), C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkenyl, C 2~6 Haloalkenyl, C 2~6 Alkynyl, C 2~6 Haloalkynyl, C 3~6 Cycloalkyl, as well as O, S, S(O), SO2, N, and NR 13 C containing one or two ring hetero moieties selected from 3~6 each optionally further substituted with a substituent selected from heterocycloalkyl; Each R 13 But hydrogen, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Haloalkyl, C 3~8 Cycloalkyl, C 4~14 Alkylenecycloalkyl, C 3~10 Heterocycloalkyl, C 4~16 Alkyleneheterocycloalkyl, C 6~12 Aryl, C 7~18 Alkylene aryl, C 5~10 Heteroaryl, and C 6~16 alkyleneheteroaryl; The C in question 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Haloalkyl, C 3~8 Cycloalkyl, C 4~14 Alkylenecycloalkyl, C 3~10 Heterocycloalkyl, C4~16 Alkyleneheterocycloalkyl, C 6~12 Aryl, C 7~18 Alkylene aryl, C 5~10 Heteroaryl, and C 6~16 The alkylene heteroaryl is selected from halogen, CN, C 1~8 Alkoxy, C 1~8 Alkylamino, C 1~8 Alkyl sulfonyl, CO2H, CO2CH3, C(O)NH2, C(O)N(CH3)2, C(O)NHCH3, OH, NH2, N(CH3)2, NHCH3, NO2, SH, SCH3, SO2CH3, SOCH3, C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkenyl, C 2~6 Haloalkenyl, C 2~6 Alkynyl, C 2~6 Haloalkynyl, C 3~6 C containing cycloalkyl and one or two ring hetero moieties selected from O, S, S(O), SO, N, NH, and NCH 3~6 each optionally substituted with one or more substituents independently selected from heterocycloalkyl; (ii)R 7 , R 8 , R 9 , R 10 , and R 11 are each hydrogen; Alternatively, R 6 and R 7 These are combined with the atoms to which they are bonded to form C 4~10 Heterocycloalkyl or C 5~10 forming a heteroaryl, The C in question 4~10 Heterocycloalkyl and C 5~10 Heteroaryl is halogen, (O), CN, C 1~8 Alkoxy, C 1~8 Alkylamino, C 1~8 Alkyl sulfonyl, CO2R 14 , C(O)N(R 14 )2, OR 14 , N(R 14 )2, NO2, SR14 , SO2R 14 , C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkenyl, C 2~6 Haloalkenyl, C 2~6 Alkynyl, C 2~6 Haloalkynyl, C 3~6 Cycloalkyl, as well as O, S, N, S(O), SO2 and NR 14 C containing one or two ring hetero moieties selected from 3~6 each optionally further substituted with a substituent selected from heterocycloalkyl; Alternatively, R 7 , and R 1 , R 2 or R 3 One of these will combine with the atom to which it is attached to form C 5~8 forming a heterocycloalkyl, The C in question 5~8 Heterocyclylalkyl is halogen, (O), CN, C 1~8 Alkoxy, C 1~8 Alkylamino, C 1~8 Alkyl sulfonyl, CO2R 14 , C(O)N(R 14 )2, OR 14 , N(R 14 )2, NO2, SR 14 , SO2R 14 , C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkenyl, C 2~6 Haloalkenyl, C 2~6 Alkynyl, C 2~6 Haloalkynyl, C 3~6 Cycloalkyl, as well as O, S, N, S(O), SO2 and NR 14 C containing one or two ring hetero moieties selected from 3~6 and optionally further substituted with one or more substituents selected from heterocycloalkyl; Each R 14 But hydrogen, C 1~6Alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C3-C7 cycloalkyl, C 3~10 Heterocycloalkyl, C 6~12 Aryl, and C 5~10 heteroaryl; The C in question 1~6 Alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C3-C7 cycloalkyl, C 3~10 Heterocycloalkyl, C 6~12 Aryl, and C 5~10 Heteroaryl is halogen, CN, C 1~8 Alkoxy, C 1~8 Alkylamino, C 1~8 Alkyl sulfonyl, CO2H, CO2CH3, C(O)NH2, C(O)N(CH3)2, C(O)NHCH3, OH, NH2, N(CH3)2, NHCH3, NO2, SH, SCH3, SO2CH3, SOCH3, C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkenyl, C 2~6 Haloalkenyl, C 2~6 Alkynyl, C 2~6 Haloalkynyl, C 3~6 C containing cycloalkyl and one or two ring hetero moieties selected from O, S, S(O), SO, N, NH, and NCH 3~6 each optionally substituted with one or more substituents independently selected from heterocycloalkyl; R 1 and R 2 are each methyl, and R 3 and R 6 are each hydrogen, then R 8 But not OH or OCH3, R 9 But instead of OH, R 1 and R 2 are each ethyl, isobutyl, or (sec)butyl, and R 3 and R 6 are each hydrogen, then R 8 But instead of OH, R1 and R 2 are each isopropyl, and R 3 and R 6 are each hydrogen, then R 9 But instead of OH, R 1 and R 2 But together with the nitrogen to which they are bound, [ka] and R 3 and R 6 are each hydrogen, then R 9 But not OCH3, R 1 and R 2 But together with the nitrogen to which they are bound, [ka] and R 3 and R 6 are each hydrogen, then R 8 But instead of OH, R 1 and R 2 But together with the nitrogen to which they are bound, [ka] and R 3 and R 6 are each hydrogen, then R 8 But instead of OH, it's R 9 But not CH3 or OCH3, R 10 But not OCH3, R 1 and R 2 But together with the nitrogen to which they are bound, [ka] and R 3 and R 6are each hydrogen, then R 7 , R 8 , R 9 , R 10 , and R 11 is not selected from OH, OCH3, OC(O)CH3, OP(O)(OH)2, NH2, halogen, CH3, CN, and CF3; R 1 and R 2 But together with the nitrogen to which they are bound, [ka] and R 3 is hydrogen and R 6 is methyl, R 8 But not OH or OBn, R 1 and R 2 are each methyl, and R 3 is hydrogen and R 6 is selected from ethyl, CH2CHF2, propyl, isopropyl, butyl, cyclopropyl, methylenecyclopropyl, cyclobutyl, oxetanyl, and butenyl; 8 But not OH or OBn, R 1 and R 2 are each methyl, and R 3 is hydrogen and R 6 is hydrogen or CH2P(O)(OH)2, then R 8 but, [ka] and OC(O)N(CH3)2, R 1 , R 2 , and R 3 But together with the atoms to which they are bonded, [ka] and R6 is hydrogen or CH2P(O)(OH)2, then R 8 but, [ka] and OC(O)N(CH3)2, (C)R 7 , R 8 , R 9 , R 10 , and R 11 are each hydrogen, R 3 and R 6 are each hydrogen, then R 1 and R 2 are each methyl, ethyl, propyl, isopropyl, cyclopropyl, or [ka] Instead, R 1 and R 2 do not, together with the nitrogen to which they are attached, form pyrrolidyl, piperidyl, or 2,5-dimethylpyrrolyl; R 6 is hydrogen and R 3 is methyl, R 1 and R 2 However, each is not hydrogen, R 3 and R 6 are each hydrogen, and R 1 and R 2 When one of R 1 and R 2 the other of which is propyl, isopropyl, cyclopropyl, methylenecyclopropyl, [ka] Instead, R 3 and R 6 are each hydrogen, and R 1 and R 2When one of R is ethyl or propyl, 1 and R 2 the other of which is isopropyl, cyclopropyl, methylenecyclopropyl, [ka] Instead, R 3 and R 6 are each hydrogen, and R 1 and R 2 When one of R 1 and R 2 the other of which is propyl, cyclopropyl, methylenecyclopropyl, [ka] is not one of the following applies:

[0011] The disclaimers of the first aspect of the invention, and any selection or combination of these disclaimers, may also be applied to other embodiments.

[0012] In another aspect of the present disclosure, there is provided a pharmaceutical product comprising a compound of Formula (I) as set forth in any one of the embodiments disclosed herein, or a pharmaceutically acceptable salt, solvate, tautomer, N-oxide, stereoisomer, metabolite, polymorph, or prodrug thereof.

[0013] In another aspect of the present disclosure, there is provided a pharmaceutical composition comprising a compound of Formula (I) as set forth in any one of the embodiments disclosed herein, or a pharmaceutically acceptable salt, solvate, tautomer, N-oxide, stereoisomer, metabolite, polymorph, or prodrug thereof, and a pharmaceutically acceptable excipient.

[0014] In another aspect, the present disclosure provides a pharmaceutical composition comprising a compound according to any one of the embodiments disclosed herein, or a pharmaceutically acceptable salt, solvate, tautomer, N-oxide, stereoisomer, metabolite, polymorph, or prodrug thereof, an additional therapeutic agent, and a pharmaceutically acceptable excipient.

[0015] In another aspect of the disclosure, there is provided a method of treating a disease, disorder, or condition through activation of a serotonin receptor, the method comprising administering to a subject in need thereof a compound of formula (I): [ka] or a pharmaceutically acceptable salt, solvate, tautomer, N-oxide, stereoisomer, metabolite, polymorph, or prodrug thereof, During the ceremony, R 1 and R 2 But hydrogen, C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkenyl, C 2~6 Haloalkenyl, C 2~6 Alkynyl, C 2~6 Haloalkynyl, C 3~8 Cycloalkyl, C 4~14 Alkylenecycloalkyl, C3-C8 heterocycloalkyl, C4-C 14 Alkyleneheterocycloalkyl, C 6~12 Aryl, C 7~18 Alkylene aryl, C 5~10 Heteroaryl, and C 6~16 alkyleneheteroaryl; The C in question 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkenyl, C 2~6 Haloalkenyl, C 2~6 Alkynyl, C 2~6 Haloalkynyl, C 3~8 Cycloalkyl, C 4~14Alkylenecycloalkyl, C3-C8 heterocycloalkyl, C4-C 14 Alkyleneheterocycloalkyl, C 6~12 Aryl, C 7~18 Alkylene aryl, C 5~10 Heteroaryl, and C 6~16 The alkylene heteroaryl is selected from halogen, CN, C 1~8 Alkoxy, C 1~8 Alkylamino, C 1~8 Alkyl sulfonyl, CO2R 4 , C(O)N(R 4 )2, OR 4 , N(R 4 )2, NO2, SR 4 , and SO2R 4 each optionally substituted with one or more substituents independently selected from The C in question 3~8 Cycloalkyl, C 4~14 Alkylenecycloalkyl, C3-C8 heterocycloalkyl, C 6~12 Aryl, C 7~18 Alkylene aryl, C 5~10 Heteroaryl, and C 6~16 The alkylene heteroaryl is (O), C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkenyl, C 2~6 Haloalkenyl, C 2~6 Alkynyl, C 2~6 Haloalkynyl, C 3~6 Cycloalkyl, as well as O, S, N, S(O), SO2 and NR 4 C containing one or two ring hetero moieties selected from 3~6 each optionally further substituted with substituents independently selected from heterocycloalkyl; Alternatively, R 1 and R 2 combine with the atoms to which they are attached to form O, S, S(O), SO2, N, and NR 4 C containing one or two additional ring hetero moieties selected from 3~8 forming a heterocycloalkyl, The C in question3~8 Heterocycloalkyl is halogen, (O), CN, C 1~8 Alkoxy, C 1~8 Alkylamino, C 1~8 Alkyl sulfonyl, CO2R 4 , C(O)N(R 4 )2, OR 4 , N(R 4 )2, NO2, SR 4 , SO2R 4 , C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkenyl, C 2~6 Haloalkenyl, C 2~6 Alkynyl, C 2~6 Haloalkynyl, C 1~8 Alkylamino, C 1~8 Alkylsulfonyl, C 3~6 Cycloalkyl, as well as O, S, N, S(O), SO2 and NR 4 C containing one or two ring hetero moieties selected from 3~6 and optionally further substituted with substituents selected from heterocycloalkyl; R 3 But hydrogen, C 1~6 Alkyl, C 3~8 Cycloalkyl, or C 4~14 alkylenecycloalkyl; Alternatively, R 3 , and R 1 and R 2 When one of these atoms combines with the atom to which it is attached, it forms C 3~12 forming a heterocycloalkyl, The C in question 3~12 Heterocycloalkyl is halogen, (O), CN, C 1~8 Alkoxy, C 1~8 Alkylamino, C 1~8 Alkyl sulfonyl, CO2R 4 , C(O)N(R 4 )2, OR 4 , N(R 4 )2, NO2, SR 4 , SO2R 4 , C 1~6 Alkyl, C1~6 Haloalkyl, C 2~6 Alkenyl, C 2~6 Haloalkenyl, C 2~6 Alkynyl, C 2~6 Haloalkynyl, C 3~6 Cycloalkyl, as well as O, S, N, S(O), SO2 and NR 4 C containing one or two ring hetero moieties selected from 3~6 and optionally further substituted with substituents selected from heterocycloalkyl; Each R 4 But hydrogen, C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkenyl, C 2~6 Haloalkenyl, C 2~6 Alkynyl, C 2~6 Haloalkynyl, C 3~7 Cycloalkyl, as well as O, S, S(O), SO2, N, and NR 5 C containing one or two ring hetero moieties selected from 3~7 heterocycloalkyl; The C in question 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkenyl, C 2~6 Haloalkenyl, C 2~6 Alkynyl, C 2~6 Haloalkynyl, C 3~7 Cycloalkyl, and C 3~7 Heterocycloalkyl is halogen, CN, C 1~8 Alkoxy, C 1~8 Alkylamino, C 1~8 Alkyl sulfonyl, CO2R 5 , C(O)N(R 5 )2, OR 5 , N(R 5 )2, NO2, SR 5 , and SO2R 5 each optionally substituted with one or more substituents independently selected from The C3-C7 cycloalkyl and C 3~7 Heterocycloalkyl is (O), C 1~6 Alkyl, C1~6 Haloalkyl, C 2~6 Alkenyl, C 2~6 Haloalkenyl, C 2~6 Alkynyl, C 2~6 Haloalkynyl, C 3~6 Cycloalkyl, as well as O, S, S(O), SO2, N, and NR 5 C containing one or two ring hetero moieties selected from 3~6 each optionally further substituted with substituents independently selected from heterocycloalkyl; Each R 5 But hydrogen, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Haloalkyl, C 3~8 Cycloalkyl, C 5~10 Heterocycloalkyl, C 6~12 Aryl, and C 5~10 heteroaryl; The C in question 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Haloalkyl, C 3~8 Cycloalkyl, C 5~10 Heterocycloalkyl, C 6~12 Aryl, and C 5~10 Heteroaryl is halogen, CN, C 1~8 Alkoxy, C 1~8 Alkylamino, C 1~8 Alkyl sulfonyl, CO2H, CO2CH3, C(O)NH2, C(O)N(CH3)2, C(O)NHCH3, OH, NH2, N(CH3)2, NHCH3, NO2, SH, SCH3, SO2CH3, SOCH3, C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkenyl, C 2~6 Haloalkenyl, C 2~6 Alkynyl, C 2~6 Haloalkynyl, C 3~6 C containing cycloalkyl and one or two ring hetero moieties selected from O, S, S(O), SO, N, NH, and NCH3~6 each optionally substituted with one or more substituents independently selected from heterocycloalkyl; L is C 1~4 selected from alkylene, C2-C4 alkenylene, and C2-C4 alkynylene; R 6 But hydrogen, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Alkylene P(O)(OR 12 )2, C(O)R 12 , CO2R 12 , C(O)N(R 12 )2, S(O)R 12 and SO2R 12 , C 3~6 Cycloalkyl, C 6~9 Alkylenecycloalkyl, C 3~6 Heterocyclyl, C 6~9 Alkyleneheterocycloalkyl, C 4~7 Heterocyclyl, C 7~10 Alkyleneheterocycloalkyl, C 6~12 Aryl, C 7~18 Alkylene aryl, C 5~10 Heteroaryl, and C 6~16 alkyleneheteroaryl; The C in question 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 6~9 Alkylenecycloalkyl, C 3~6 Heterocyclyl, C 6~9 Alkyleneheterocycloalkyl, C 4~7 Heterocyclyl, C 7~10 Alkyleneheterocycloalkyl, C 6~12 Aryl, C 7~18 Alkylene aryl, C 5~10 Heteroaryl, and C 6~16 The alkylene heteroaryl is selected from halogen, CN, C 1~8 Alkoxy, C 1~8 Alkylamino, C 1~8Alkyl sulfonyl, CO2R 12 , C(O)N(R 12 )2, OR 12 , N(R 12 )2, NO2, SR 12 , and SO2R 12 each optionally substituted with one or more substituents independently selected from The C in question 3~6 Cycloalkyl, C 6~9 Alkylenecycloalkyl, C 3~6 Heterocyclyl, C 6~9 Alkyleneheterocycloalkyl, C 4~7 Heterocyclyl, C 7~10 Alkyleneheterocycloalkyl, C 6~12 Aryl, C 7~18 Alkylene aryl, C 5~10 Heteroaryl, and C 6~16 The alkylene heteroaryl is (O), C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkenyl, C 2~6 Haloalkenyl, C 2~6 Alkynyl, C 2~6 Haloalkynyl, C 3~6 Cycloalkyl, as well as O, S, N, S(O), SO2 and NR 12 C containing one or two ring hetero moieties selected from 3~6 each optionally further substituted with substituents independently selected from heterocycloalkyl; Each R 12 But hydrogen, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Haloalkyl, C 3~8 Cycloalkyl, C 4~14 Alkylenecycloalkyl, C 3~10 Heterocycloalkyl, C 4~16 Alkyleneheterocycloalkyl, C 6~12 Aryl, C 7~18 Alkylene aryl, C 5~10 Heteroaryl, and C 6~16alkyleneheteroaryl; The C in question 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Haloalkyl, C 3~8 Cycloalkyl, C 4~14 Alkylenecycloalkyl, C 3~10 Heterocycloalkyl, C 4~16 Alkyleneheterocycloalkyl, C 6~12 Aryl, C 7~18 Alkylene aryl, C 5~10 Heteroaryl, and C 6~16 The alkylene heteroaryl is selected from halogen, CN, C 1~8 Alkoxy, C 1~8 Alkylamino, C 1~8 Alkyl sulfonyl, CO2H, CO2CH3, C(O)NH2, C(O)N(CH3)2, C(O)NHCH3, OH, NH2, N(CH3)2, NHCH3, NO2, SH, SCH3, SO2CH3, SOCH3, C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkenyl, C 2~6 Haloalkenyl, C 2~6 Alkynyl, C 2~6 Haloalkynyl, C 3~6 C containing cycloalkyl and one or two ring hetero moieties selected from O, S, S(O), SO, N, NH, and NCH 3~6 each optionally substituted with one or more substituents independently selected from heterocycloalkyl; (B) and (C): (B) (i)R 7 , R 8 , R 9 , R 10 , and R 11 One of the following is OR 13 , N(R 13 )2, SR 13 , C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkenyl, C2-C6 haloalkenyl, C2~6 Alkynyl, C 2~6 Haloalkynyl, C 1~6 Alkylamines, C 1~6 Alkoxy, C 1~6 Haloalkoxy, CO2R 13 , C(O)R 13 , C(O)N(R 13 )2, C(O)C(O)N(R 13 )2, OC(O)R 13 ,OC(O)OR 13 , OC(O)N(R 13 )2, OS(O)R 13 , OS(O)N(R 13 )2, OSO2R 13 , OP(O)(OR 13 )2, O.C. 1~6 Alkylene P(O)(OR 13 )2, S(O)R 13 , S(O)N(R 13 )2, SO2R 13 , N(R 13 )2, N(R 13 )C(O)R 13 , N(R 13 )C(O)OR 13 , N(R 13 )C(O)N(R 13 )2, NO2, C 3~8 Cycloalkyl, C 3~14 Alkylenecycloalkyl, C 3~10 Heterocycloalkyl, C 4~16 Alkyleneheterocycloalkyl, C 6~12 Aryl, C 7~18 Alkylene aryl, C 5~10 Heteroaryl, C 4~16 alkyleneheteroaryl; The C in question 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkenyl, C2-C6 haloalkenyl, C 2~6 Alkynyl, C 2~6 Haloalkynyl, C 1~6 Alkylamines, C 1~6 Alkoxy, C 1~6 Haloalkoxy, C 3~8 Cycloalkyl, C3~14 Alkylenecycloalkyl, C 3~10 Heterocycloalkyl, C 4~16 Alkyleneheterocycloalkyl, C 6~12 Aryl, C 7~18 Alkylene aryl, C 5~10 Heteroaryl, and C 4~16 The alkylene heteroaryl is selected from halogen, CN, C 1~8 Alkoxy, C 1~8 Alkylamino, C 1~8 Alkyl sulfonyl, CO2R 13 , C(O)N(R 13 )2, OR 13 , N(R 13 )2, NO2, SR 13 , and SO2R 13 and optionally substituted with one or more substituents independently selected from The C in question 3~8 Cycloalkyl, C 3~14 Alkylenecycloalkyl, C 3~10 Heterocycloalkyl, C 4~16 Alkyleneheterocycloalkyl, C 6~12 Aryl, C 7~18 Alkylene aryl, C 5~10 Heteroaryl, and C 4~16 The alkylene heteroaryl is (O), C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkenyl, C 2~6 Haloalkenyl, C 2~6 Alkynyl, C 2~6 Haloalkynyl, C 3~6 Cycloalkyl, as well as O, S, S(O), SO2, N, and NR 13 C containing one or two ring hetero moieties selected from 3~6 each optionally further substituted with a substituent selected from heterocycloalkyl; Each R 13 But hydrogen, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Haloalkyl, C 3~8Cycloalkyl, C 4~14 Alkylenecycloalkyl, C 3~10 Heterocycloalkyl, C 4~16 Alkyleneheterocycloalkyl, C 6~12 Aryl, C 7~18 Alkylene aryl, C 5~10 Heteroaryl, and C 6~16 alkyleneheteroaryl; The C in question 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Haloalkyl, C 3~8 Cycloalkyl, C 4~14 Alkylenecycloalkyl, C 3~10 Heterocycloalkyl, C 4~16 Alkyleneheterocycloalkyl, C 6~12 Aryl, C 7~18 Alkylene aryl, C 5~10 Heteroaryl, and C 6~16 The alkylene heteroaryl is selected from halogen, CN, C 1~8 Alkoxy, C 1~8 Alkylamino, C 1~8 Alkyl sulfonyl, CO2H, CO2CH3, C(O)NH2, C(O)N(CH3)2, C(O)NHCH3, OH, NH2, N(CH3)2, NHCH3, NO2, SH, SCH3, SO2CH3, SOCH3, C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkenyl, C 2~6 Haloalkenyl, C 2~6 Alkynyl, C 2~6 Haloalkynyl, C 3~6 C containing cycloalkyl and one or two ring hetero moieties selected from O, S, S(O), SO, N, NH, and NCH 3~6 each optionally substituted with one or more substituents independently selected from heterocycloalkyl; (ii)R 7 , R 8 , R 9 , R 10 , and R 11are each hydrogen; Alternatively, R 6 and R 7 These are combined with the atoms to which they are bonded to form C 4~10 Heterocycloalkyl or C 5~10 forming a heteroaryl, The C in question 4~10 Heterocycloalkyl and C 5~10 Heteroaryl is halogen, (O), CN, C 1~8 Alkoxy, C 1~8 Alkylamino, C 1~8 Alkyl sulfonyl, CO2R 14 , C(O)N(R 14 )2, OR 14 , N(R 14 )2, NO2, SR 14 , SO2R 14 , C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkenyl, C 2~6 Haloalkenyl, C 2~6 Alkynyl, C 2~6 Haloalkynyl, C 3~6 Cycloalkyl, as well as O, S, N, S(O), SO2 and NR 14 C containing one or two ring hetero moieties selected from 3~6 each optionally further substituted with a substituent selected from heterocycloalkyl; Alternatively, R 7 , and R 1 , R 2 or R 3 One of these will combine with the atom to which it is attached to form C 5~8 forming a heterocycloalkyl, The C in question 5~8 Heterocyclylalkyl is halogen, (O), CN, C 1~8 Alkoxy, C 1~8 Alkylamino, C 1~8 Alkyl sulfonyl, CO2R 14 , C(O)N(R 14 )2, OR 14 , N(R 14 )2, NO2, SR14 , SO2R 14 , C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkenyl, C 2~6 Haloalkenyl, C 2~6 Alkynyl, C 2~6 Haloalkynyl, C 3~6 Cycloalkyl, as well as O, S, N, S(O), SO2 and NR 14 C containing one or two ring hetero moieties selected from 3~6 and optionally further substituted with one or more substituents selected from heterocycloalkyl; Each R 14 But hydrogen, C 1~6 Alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C3-C7 cycloalkyl, C 3~10 Heterocycloalkyl, C 6~12 Aryl, and C 5~10 heteroaryl; The C in question 1~6 Alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C3-C7 cycloalkyl, C 3~10 Heterocycloalkyl, C 6~12 Aryl, and C 5~10 Heteroaryl is halogen, CN, C 1~8 Alkoxy, C 1~8 Alkylamino, C 1~8 Alkyl sulfonyl, CO2H, CO2CH3, C(O)NH2, C(O)N(CH3)2, C(O)NHCH3, OH, NH2, N(CH3)2, NHCH3, NO2, SH, SCH3, SO2CH3, SOCH3, C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkenyl, C 2~6 Haloalkenyl, C 2~6 Alkynyl, C 2~6 Haloalkynyl, C 3~6 C containing cycloalkyl and one or two ring hetero moieties selected from O, S, S(O), SO, N, NH, and NCH 3~6each optionally substituted with one or more substituents independently selected from heterocycloalkyl; R 1 and R 2 are each methyl, and R 3 and R 6 are each hydrogen, then R 8 But not OH or OCH3, R 9 But instead of OH, R 1 and R 2 are each ethyl, isobutyl, or (sec)butyl, and R 3 and R 6 are each hydrogen, then R 8 But instead of OH, R 1 and R 2 are each isopropyl, and R 3 and R 6 are each hydrogen, then R 9 But instead of OH, R 1 and R 2 But together with the nitrogen to which they are bound, [ka] and R 3 and R 6 are each hydrogen, then R 9 But not OCH3, R 1 and R 2 But together with the nitrogen to which they are bound, [ka] and R 3 and R 6 are each hydrogen, then R 8 But instead of OH, R 1 and R 2 But together with the nitrogen to which they are bound, [ka] and R 3 and R 6 are each hydrogen, then R 8 But instead of OH, it's R 9 But not CH3 or OCH3, R 10 But not OCH3, R 1 and R 2 But together with the nitrogen to which they are bound, [ka] and R 3 is hydrogen and R 6 is methyl, R 8 But instead of OH, R 1 and R 2 are each methyl, and R 3 is hydrogen and R 6 is selected from ethyl, CH2CHF2, propyl, isopropyl, butyl, cyclopropyl, methylenecyclopropyl, cyclobutyl, oxetanyl, and butenyl; 8 But instead of OH, R 1 and R 2 are each methyl, and R 3 is hydrogen and R 6 is hydrogen or CH2P(O)(OH)2, then R 8 but, [ka] and OC(O)N(CH3)2, R 1 , R 2 , and R 3 But together with the atoms to which they are bonded, [ka] and R6 is hydrogen or CH2P(O)(OH)2, then R 8 but, [ka] and OC(O)N(CH3)2, (C)R 7 , R 8 , R 9 , R 10 , and R 11 are each hydrogen, R 6 and R 3 are each hydrogen, then R 1 and R 2 However, each is not methyl, but R 1 and R 2 But together with the nitrogen to which they are bound, [ka] does not form pyrrolidyl, piperidyl, or 2,5-dimethylpyrrolyl; R 6 is hydrogen and R 3 is methyl, R 1 and R 2 and each is not hydrogen.

[0016] Further aspects of the invention and further embodiments of the aspects described in the preceding paragraphs will become apparent from the following description, given by way of example and with reference to the accompanying drawings, in which: DETAILED DESCRIPTION OF THE INVENTION

[0017] The invention disclosed and defined herein will be understood to extend to all alternative combinations of two or more of the individual features mentioned or made apparent from the text or drawings, all of which different combinations constitute various alternative aspects of the invention.

[0018] In a first aspect, the present disclosure provides a compound of formula (I) above.

[0019] In some embodiments, (i)R 7 , R 8 , R 9 , R 10 , and R 11 One of them is OR 13 , N(R 13 )2, SR 13 , C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkenyl, C2-C6 haloalkenyl, C 2~6 Alkynyl, C 2~6 Haloalkynyl, C 1~6 Alkylamines, C 1~6 Alkoxy, C 1~6 Haloalkoxy, CO2R 13 , C(O)R 13 , C(O)N(R 13 )2, C(O)C(O)N(R 13 )2, OC(O)R 13 ,OC(O)OR 13 , OC(O)N(R 13 )2, OS(O)R 13 , OS(O)N(R 13 )2, OSO2R 13 , OP(O)(OR 13 )2, O.C. 1~6 Alkylene P(O)(OR 13 )2, S(O)R 13 , S(O)N(R 13 )2, SO2R 13 , N(R 13 )2, N(R 13 )C(O)R 13 , N(R 13 )C(O)OR 13 , N(R 13 )C(O)N(R 13 )2, NO2, C 3~8 Cycloalkyl, C 3~14 Alkylenecycloalkyl, C 3~10 Heterocycloalkyl, C 4~16 Alkyleneheterocycloalkyl, C6~12 Aryl, C 7~18 Alkylene aryl, C 5~10 Heteroaryl, C 4~16 alkyleneheteroaryl; The C in question 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkenyl, C2-C6 haloalkenyl, C 2~6 Alkynyl, C 2~6 Haloalkynyl, C 1~6 Alkylamines, C 1~6 Alkoxy, C 1~6 Haloalkoxy, C 3~8 Cycloalkyl, C 3~14 Alkylenecycloalkyl, C 3~10 Heterocycloalkyl, C 4~16 Alkyleneheterocycloalkyl, C 6~12 Aryl, C 7~18 Alkylene aryl, C 5~10 Heteroaryl, and C 4~16 Alkyleneheteroaryl is substituted with halogen, CN, C 1~8 Alkoxy, C 1~8 Alkylamino, C 1~8 Alkyl sulfonyl, CO2R 13 , C(O)N(R 13 )2, OR 13 , N(R 13 )2, NO2, SR 13 , and SO2R 13 and optionally substituted with one or more substituents independently selected from The C in question 3~8 Cycloalkyl, C 3~14 Alkylenecycloalkyl, C 3~10 Heterocycloalkyl, C 4~16 Alkyleneheterocycloalkyl, C 6~12 Aryl, C 7~18 Alkylene aryl, C 5~10 Heteroaryl, and C 4~16 Alkyleneheteroaryl is (O), C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkenyl, C 2~6Haloalkenyl, C 2~6 Alkynyl, C 2~6 Haloalkynyl, C 3~6 Cycloalkyl, as well as O, S, S(O), SO2, N, and NR 13 C containing one or two ring hetero moieties selected from 3~6 each optionally further substituted with a substituent selected from heterocycloalkyl; Each R 13 is hydrogen, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Haloalkyl, C 3~8 Cycloalkyl, C 4~14 Alkylenecycloalkyl, C 3~10 Heterocycloalkyl, C 4~16 Alkyleneheterocycloalkyl, C 6~12 Aryl, C 7~18 Alkylene aryl, C 5~10 Heteroaryl, and C 6~16 alkyleneheteroaryl; The C in question 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Haloalkyl, C 3~8 Cycloalkyl, C 4~14 Alkylenecycloalkyl, C 3~10 Heterocycloalkyl, C 4~16 Alkyleneheterocycloalkyl, C 6~12 Aryl, C 7~18 Alkylene aryl, C 5~10 Heteroaryl, and C 6~16 Alkyleneheteroaryl is substituted with halogen, CN, C 1~8 Alkoxy, C 1~8 Alkylamino, C 1~8 Alkyl sulfonyl, CO2H, CO2CH3, C(O)NH2, C(O)N(CH3)2, C(O)NHCH3, OH, NH2, N(CH3)2, NHCH3, NO2, SH, SCH3, SO2CH3, SOCH3, C 1~6 Alkyl, C 1~6Haloalkyl, C 2~6 Alkenyl, C 2~6 Haloalkenyl, C 2~6 Alkynyl, C 2~6 Haloalkynyl, C 3~6 C containing cycloalkyl and one or two ring hetero moieties selected from O, S, S(O), SO, N, NH, and NCH 3~6 each optionally substituted with one or more substituents independently selected from heterocycloalkyl; (ii)R 7 , R 8 , R 9 , R 10 , and R 11 the others are each hydrogen; Alternatively, R 6 and R 7 are combined with the atoms to which they are bonded to form C 4~10 Heterocycloalkyl or C 5~10 forming a heteroaryl, The C in question 4~10 Heterocycloalkyl and C 5~10 Heteroaryl is a group that includes halogen, (O), CN, C 1~8 Alkoxy, C 1~8 Alkylamino, C 1~8 Alkyl sulfonyl, CO2R 14 , C(O)N(R 14 )2, OR 14 , N(R 14 )2, NO2, SR 14 , SO2R 14 , C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkenyl, C 2~6 Haloalkenyl, C 2~6 Alkynyl, C 2~6 Haloalkynyl, C 3~6 Cycloalkyl, as well as O, S, N, S(O), SO2 and NR 14 C containing one or two ring hetero moieties selected from 3~6 each optionally further substituted with a substituent selected from heterocycloalkyl; Alternatively, R 7, and R 1 , R 2 or R 3 One of these will combine with the atom to which it is attached to form C 5~8 forming a heterocycloalkyl, The C in question 5~8 Heterocyclylalkyl is a group that includes halogen, (O), CN, C 1~8 Alkoxy, C 1~8 Alkylamino, C 1~8 Alkyl sulfonyl, CO2R 14 , C(O)N(R 14 )2, OR 14 , N(R 14 )2, NO2, SR 14 , SO2R 14 , C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkenyl, C 2~6 Haloalkenyl, C 2~6 Alkynyl, C 2~6 Haloalkynyl, C 3~6 Cycloalkyl, as well as O, S, N, S(O), SO2 and NR 14 C containing one or two ring hetero moieties selected from 3~6 and optionally further substituted with one or more substituents selected from heterocycloalkyl; Each R 14 is hydrogen, C 1~6 Alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C3-C7 cycloalkyl, C 3~10 Heterocycloalkyl, C 6~12 Aryl, and C 5~10 heteroaryl; The C in question 1~6 Alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C3-C7 cycloalkyl, C 3~10 Heterocycloalkyl, C 6~12 Aryl, and C 5~10 Heteroaryl is a group containing halogen, CN, C 1~8 Alkoxy, C 1~8 Alkylamino, C 1~8Alkyl sulfonyl, CO2H, CO2CH3, C(O)NH2, C(O)N(CH3)2, C(O)NHCH3, OH, NH2, N(CH3)2, NHCH3, NO2, SH, SCH3, SO2CH3, SOCH3, C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkenyl, C 2~6 Haloalkenyl, C 2~6 Alkynyl, C 2~6 Haloalkynyl, C 3~6 C containing cycloalkyl and one or two ring hetero moieties selected from O, S, S(O), SO, N, NH, and NCH 3~6 each optionally substituted with one or more substituents independently selected from heterocycloalkyl; R 1 and R 2 are each methyl, and R 3 and R 6 are each hydrogen, then R 8 is not OH or OCH3, but R 9 is not OH, R 1 and R 2 are each ethyl, isobutyl, or (sec)butyl, and R 3 and R 6 are each hydrogen, then R 8 is not OH, R 1 and R 2 are each isopropyl, and R 3 and R 6 are each hydrogen, then R 9 is not OH, R 1 and R 2 But together with the nitrogen to which they are bound, [ka] and R 3 and R 6 are each hydrogen, then R 9 is not OCH3, R1 and R 2 But together with the nitrogen to which they are bound, [ka] and R 3 and R 6 are each hydrogen, then R 8 is not OH, R 1 and R 2 But together with the nitrogen to which they are bound, [ka] and R 3 and R 6 are each hydrogen, then R 8 is not OH, but R 9 is not CH3 or OCH3, but R 10 is not OCH3, R 1 and R 2 But together with the nitrogen to which they are bound, [ka] and R 3 and R 6 are each hydrogen, then R 7 , R 8 , R 9 , R 10 , and R 11 is not selected from OH, OCH3, OC(O)CH3, OP(O)(OH)2, NH2, halogen, CH3, CN, and CF3; R 1 and R 2 But together with the nitrogen to which they are bound, [ka] and R 3 is hydrogen and R6 is methyl, R 8 is not OH or OBn, R 1 and R 2 are each methyl, and R 3 is hydrogen and R 6 is selected from ethyl, CH2CHF2, propyl, isopropyl, butyl, cyclopropyl, methylenecyclopropyl, cyclobutyl, oxetanyl, and butenyl; 8 is not OH or OBn, R 1 and R 2 are each methyl, and R 3 is hydrogen and R 6 is hydrogen or CH2P(O)(OH)2, then R 8 teeth, [ka] and OC(O)N(CH3)2, R 1 , R 2 , and R 3 But together with the atoms to which they are bonded, [ka] and R 6 is hydrogen or CH2P(O)(OH)2, then R 8 teeth, [ka] and OC(O)N(CH3)2.

[0020] In some embodiments, (i)R 7 , R 8 , R 9 , R 10 , and R 11 One of them is OR 13 , N(R 13)2, SR 13 , C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkenyl, C2-C6 haloalkenyl, C 2~6 Alkynyl, C 2~6 Haloalkynyl, C 1~6 Alkylamines, C 1~6 Alkoxy, C 1~6 Haloalkoxy, CO2R 13 , C(O)R 13 , C(O)N(R 13 )2, C(O)C(O)N(R 13 )2, OC(O)R 13 ,OC(O)OR 13 , OC(O)N(R 13 )2, OS(O)R 13 , OS(O)N(R 13 )2, OSO2R 13 , OP(O)(OR 13 )2, O.C. 1~6 Alkylene P(O)(OR 13 )2, S(O)R 13 , S(O)N(R 13 )2, SO2R 13 , N(R 13 )2, N(R 13 )C(O)R 13 , N(R 13 )C(O)OR 13 , N(R 13 )C(O)N(R 13 )2, NO2, C 3~8 Cycloalkyl, C 3~14 Alkylenecycloalkyl, C 3~10 Heterocycloalkyl, C 4~16 Alkyleneheterocycloalkyl, C 6~12 Aryl, C 7~18 Alkylene aryl, C 5~10 Heteroaryl, C 4~16 alkyleneheteroaryl; The C in question 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkenyl, C2-C6 haloalkenyl, C 2~6 Alkynyl, C 2~6Haloalkynyl, C 1~6 Alkylamines, C 1~6 Alkoxy, C 1~6 Haloalkoxy, C 3~8 Cycloalkyl, C 3~14 Alkylenecycloalkyl, C 3~10 Heterocycloalkyl, C 4~16 Alkyleneheterocycloalkyl, C 6~12 Aryl, C 7~18 Alkylene aryl, C 5~10 Heteroaryl, and C 4~16 Alkyleneheteroaryl is substituted with halogen, CN, C 1~8 Alkoxy, C 1~8 Alkylamino, C 1~8 Alkyl sulfonyl, CO2R 13 , C(O)N(R 13 )2, OR 13 , N(R 13 )2, NO2, SR 13 , and SO2R 13 and optionally substituted with one or more substituents independently selected from The C in question 3~8 Cycloalkyl, C 3~14 Alkylenecycloalkyl, C 3~10 Heterocycloalkyl, C 4~16 Alkyleneheterocycloalkyl, C 6~12 Aryl, C 7~18 Alkylene aryl, C 5~10 Heteroaryl, and C 4~16 Alkyleneheteroaryl is (O), C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkenyl, C 2~6 Haloalkenyl, C 2~6 Alkynyl, C 2~6 Haloalkynyl, C 3~6 Cycloalkyl, as well as O, S, S(O), SO2, N, and NR 13 C containing one or two ring hetero moieties selected from 3~6 each optionally further substituted with a substituent selected from heterocycloalkyl; Each R 13is hydrogen, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Haloalkyl, C 3~8 Cycloalkyl, C 4~14 Alkylenecycloalkyl, C 3~10 Heterocycloalkyl, C 4~16 Alkyleneheterocycloalkyl, C 6~12 Aryl, C 7~18 Alkylene aryl, C 5~10 Heteroaryl, and C 6~16 alkyleneheteroaryl; The C in question 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Haloalkyl, C 3~8 Cycloalkyl, C 4~14 Alkylenecycloalkyl, C 3~10 Heterocycloalkyl, C 4~16 Alkyleneheterocycloalkyl, C 6~12 Aryl, C 7~18 Alkylene aryl, C 5~10 Heteroaryl, and C 6~16 Alkyleneheteroaryl is substituted with halogen, CN, C 1~8 Alkoxy, C 1~8 Alkylamino, C 1~8 Alkyl sulfonyl, CO2H, CO2CH3, C(O)NH2, C(O)N(CH3)2, C(O)NHCH3, OH, NH2, N(CH3)2, NHCH3, NO2, SH, SCH3, SO2CH3, SOCH3, C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkenyl, C 2~6 Haloalkenyl, C 2~6 Alkynyl, C 2~6 Haloalkynyl, C 3~6 C containing cycloalkyl and one or two ring hetero moieties selected from O, S, S(O), SO, N, NH, and NCH 3~6each optionally substituted with one or more substituents independently selected from heterocycloalkyl; (ii)R 7 , R 8 , R 9 , R 10 , and R 11 the others are each hydrogen; R 1 and R 2 are each methyl, and R 3 and R 6 are each hydrogen, then R 8 is not OH or OCH3, but R 9 is not OH, R 1 and R 2 are each ethyl, isobutyl, or (sec)butyl, and R 3 and R 6 are each hydrogen, then R 8 is not OH, R 1 and R 2 are each isopropyl, and R 3 and R 6 are each hydrogen, then R 9 is not OH, R 1 and R 2 But together with the nitrogen to which they are bound, [ka] and R 3 and R 6 are each hydrogen, then R 9 is not OCH3, R 1 and R 2 But together with the nitrogen to which they are bound, [ka] and R 3 and R 6 are each hydrogen, then R 8is not OH, R 1 and R 2 But together with the nitrogen to which they are bound, [ka] and R 3 and R 6 are each hydrogen, then R 8 is not OH, but R 9 is not CH3 or OCH3, but R 10 is not OCH3, R 1 and R 2 But together with the nitrogen to which they are bound, [ka] and R 3 and R 6 are each hydrogen, then R 7 , R 8 , R 9 , R 10 , and R 11 is not selected from OH, OCH3, OC(O)CH3, OP(O)(OH)2, NH2, halogen, CH3, CN, and CF3; R 1 and R 2 But together with the nitrogen to which they are bound, [ka] and R 3 is hydrogen and R 6 is methyl, R 8 is not OH or OBn, R 1 and R 2 are each methyl, and R 3 is hydrogen and R 6is selected from ethyl, CH2CHF2, propyl, isopropyl, butyl, cyclopropyl, methylenecyclopropyl, cyclobutyl, oxetanyl, and butenyl; 8 is not OH or OBn, R 1 and R 2 are each methyl, and R 3 is hydrogen and R 6 is hydrogen or CH2P(O)(OH)2, then R 8 teeth, [ka] and OC(O)N(CH3)2, R 1 , R 2 , and R 3 But together with the atoms to which they are bonded, [ka] and R 6 is hydrogen or CH2P(O)(OH)2, then R 8 teeth, [ka] and OC(O)N(CH3)2.

[0021] In some embodiments, (i)R 7 , R 8 , R 9 , R 10 , and R 11 One of them is C 1~6 Haloalkyl and OC 1~6 haloalkyl; C 1~6 Haloalkyl is R 1 and R 2 But together with the nitrogen to which they are bound, [ka] and R 3 and R 6 If each is hydrogen, then instead of CF3, (ii)R 7 , R 8 , R 9 , R 10 , and R 11 The others of each are hydrogen.

[0022] In some embodiments, R 7 , R 8 , R 9 , R 10 , and R 11 is hydrogen, halogen, C 1~6 Alkyl, C 1~6 Haloalkyl and OR 13 R 13 is hydrogen, C 1~6 Alkyl, and C 1~6 haloalkyl; R 1 and R 2 are each methyl, and R 3 is hydrogen and R 6 is selected from hydrogen, methyl, ethyl, and propyl, and R 9 , R 10 , and R 11 One of the groups is fluoro and R 9 , R 10 , and R 11 If the other of 8 is not selected from OH, OCH3, OCH2CH3, and OCH2CH2CH3, R 1 and R 2 are each methyl, and R 3 is hydrogen and R 6 is selected from hydrogen, methyl, ethyl, and propyl; R 9 is fluoro and R 11 is hydrogen, R 10 is not selected from OH, OCH3, OCH2CH3, and OCH2CH2CH3.

[0023] In some embodiments, R 7 , R 8 , R 9 , R 10 , and R 11 is hydrogen, halogen, C 1~6 Alkyl, C 1~6 Haloalkyl and OR 13 R 13 is hydrogen, C 1~6 Alkyl, and C 1~6 haloalkyl; R 7 , R 8 , R 9 , R 10 , and R 11 At least two of these are not hydrogen, R 1 and R 2 are each methyl, and R 3 is hydrogen and R 6 is selected from hydrogen, methyl, ethyl, and propyl, and R 9 , R 10 , and R 11 One of the groups is fluoro and R 9 , R 10 , and R 11 If the other of 8 is not selected from OH, OCH3, OCH2CH3, and OCH2CH2CH3, R 1 and R 2 are each methyl, and R 3 is hydrogen and R 6 is selected from hydrogen, methyl, ethyl, and propyl; R 9 is fluoro and R 11 is hydrogen, R 10 is not selected from OH, OCH3, OCH2CH3, and OCH2CH2CH3.

[0024] In some embodiments, R 7 , R 8 , R 9 , R10 , and R 11 are each hydrogen.

[0025] In some embodiments, R 7 , R 8 , R 9 , R 10 , and R 11 are each hydrogen, R 3 and R 6 are each hydrogen, then R 1 and R 2 are each methyl, ethyl, propyl, isopropyl, cyclopropyl, or [ka] Instead, R 1 and R 2 do not form, together with the nitrogen to which they are attached, pyrrolidyl, piperidyl, or 2,5-dimethylpyrrolyl; R 6 is hydrogen and R 3 is methyl, R 1 and R 2 are not hydrogen, R 3 and R 6 are each hydrogen, and R 1 and R 2 When one of R 1 and R 2 the other of which is propyl, isopropyl, cyclopropyl, methylenecyclopropyl, [ka] Instead, R 3 and R 6 are each hydrogen, and R 1 and R 2 When one of R is ethyl or propyl, 1 and R 2 The other of these is isopropyl, cyclopropyl, methylenecyclopropyl, [ka] Instead, R 3 and R 6 are each hydrogen, and R 1 and R 2 When one of R 1 and R 2 the other of which is propyl, cyclopropyl, methylenecyclopropyl, [ka] isn't it.

[0026] In some embodiments, R 1 and R 2 is C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkenyl, C 2~6 Haloalkenyl, C 2~6 Alkynyl, C 2~6 Haloalkynyl, C 3~8 Cycloalkyl, and C 4~14 alkylenecycloalkyl.

[0027] In some embodiments, R 1 and R 2 is C 1~4 Alkyl, C 3~8 cycloalkyl, and C-C heterocycloalkyl. In some embodiments, R 1 and R 2 is C 1~4 alkyl.

[0028] In some embodiments, R 1 and R 2 are the same.

[0029] In some embodiments, R 1 and R2 is different.

[0030] In some embodiments, one or both of R1 and R2 is a branched C1-C6 alkyl.

[0031] In some embodiments, R 1 and R 2 At least one of is methyl.

[0032] In some embodiments, R 1 and R 2 At least one of the groups is ethyl.

[0033] In some embodiments, R 1 and R 2 At least one of is propyl, preferably isopropyl.

[0034] In some embodiments, R 1 and R 2 At least one of the groups is butyl.

[0035] In some embodiments, R 1 and R 2 together with the nitrogen to which they are attached, form: [ka] Form one of the following:

[0036] In some embodiments, R 1 and R 2 together with the nitrogen to which they are attached, form: [ka] Form one of the following:

[0037] In some embodiments, R 1 and R2 are combined with the atoms to which they are bonded to form C 3~6 Forming a heterocycloalkyl, the C 3~6 Heterocycloalkyl is a group that is substituted with halogen, CN, C 1~8 Alkoxy, C 1~8 Alkylamino, C 1~8 Alkyl sulfonyl, CO2R 4 , C(O)N(R 4 )2, OR 4 , N(R 4 )2, NO2, SR 4 and SO2R 4 , (O), C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkenyl, C 2~6 Haloalkenyl, C 2~6 Alkynyl, C 2~6 Haloalkynyl, C 3~6 Cycloalkyl, as well as O, S, N, S(O), SO2 and NR 4 C containing one or two ring hetero moieties selected from 3~6 heterocycloalkyl; and R 4 is as defined in any one of the preceding paragraphs.

[0038] In some embodiments, R 3 is hydrogen.

[0039] In some embodiments, R 3 , and R 1 and R 2 One of them combines with the atom to which it is attached to form C 3~8 Forming a heterocycloalkyl, the C 5~8 Heterocycloalkyl is a group that includes halogen, (O), CN, C 1~8 Alkoxy, C 1~8 Alkylamino, C 1~8 Alkyl sulfonyl, CO2R 4 , C(O)N(R 4 )2, OR 4 , N(R 4)2, NO2, SR 4 , SO2R 4 , C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkenyl, C 2~6 Haloalkenyl, C 2~6 Alkynyl, C 2~6 Haloalkynyl, C 3~6 Cycloalkyl, as well as O, S, N, S(O), SO2 and NR 4 C containing one or two ring hetero moieties selected from 3~6 heterocycloalkyl; R 4 is as defined in any one of the preceding paragraphs.

[0040] In some embodiments, L is C 1~4 It is alkylene.

[0041] In some embodiments, L is methylene.

[0042] In some embodiments, R 6 is hydrogen and C 1~6 alkyl.

[0043] In some embodiments, R 6 is hydrogen.

[0044] In some embodiments, the compound of Formula (I) is selected from the compounds of Table 1, e.g., any one of compounds P4-P5, P15-P61, and P119-P164, or a pharmaceutically acceptable salt, solvate, tautomer, N-oxide, stereoisomer, metabolite, polymorph, or prodrug thereof. In some embodiments, the compound of Formula (I) is selected from any one of compounds P4-P5, P15-P19, P23-P61, and P119-P164, or a pharmaceutically acceptable salt, solvate, tautomer, N-oxide, stereoisomer, metabolite, polymorph, or prodrug thereof. In some embodiments, the compound of Formula (I) is selected from any one of compounds P20-P22, or a pharmaceutically acceptable salt, solvate, tautomer, N-oxide, stereoisomer, metabolite, polymorph, or prodrug thereof. In some embodiments, the compound of Formula (I) is selected from any one of compounds P136, P137, P162, and P163, or a pharmaceutically acceptable salt, solvate, tautomer, N-oxide, stereoisomer, metabolite, polymorph, or prodrug thereof.

[0045] In some embodiments, the compound of formula (I) is the following compound: [ka] isn't it.

[0046] In another aspect of the present disclosure, there is provided a pharmaceutical product comprising a compound of Formula (I) as set forth in any one of the embodiments disclosed herein, or a pharmaceutically acceptable salt, solvate, tautomer, N-oxide, stereoisomer, metabolite, polymorph, or prodrug thereof.

[0047] In another aspect of the present disclosure, there is provided a pharmaceutical composition comprising a compound of Formula (I) as set forth in any one of the embodiments disclosed herein, or a pharmaceutically acceptable salt, solvate, tautomer, N-oxide, stereoisomer, metabolite, polymorph, or prodrug thereof, and a pharmaceutically acceptable excipient.

[0048] In another aspect, the present disclosure provides a pharmaceutical composition comprising a compound according to any one of the embodiments disclosed herein, or a pharmaceutically acceptable salt, solvate, tautomer, N-oxide, stereoisomer, metabolite, polymorph, or prodrug thereof, an additional therapeutic agent, and a pharmaceutically acceptable excipient.

[0049] In another aspect of the disclosure, there is provided a method of treating a disease, disorder, or condition through activation of a serotonin receptor, the method comprising administering to a subject in need thereof a compound of formula (I): [ka] or a pharmaceutically acceptable salt, solvate, tautomer, N-oxide, stereoisomer, metabolite, polymorph, or prodrug thereof, During the ceremony, R 1 and R 2 But hydrogen, C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkenyl, C 2~6 Haloalkenyl, C 2~6 Alkynyl, C 2~6 Haloalkynyl, C 3~8 Cycloalkyl, C 4~14 Alkylenecycloalkyl, C3-C8 heterocycloalkyl, C4-C 14 Alkyleneheterocycloalkyl, C 6~12 Aryl, C 7~18 Alkylene aryl, C 5~10 Heteroaryl, and C 6~16 alkyleneheteroaryl; The C in question 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkenyl, C 2~6 Haloalkenyl, C 2~6 Alkynyl, C 2~6 Haloalkynyl, C 3~8 Cycloalkyl, C 4~14Alkylenecycloalkyl, C3-C8 heterocycloalkyl, C4-C 14 Alkyleneheterocycloalkyl, C 6~12 Aryl, C 7~18 Alkylene aryl, C 5~10 Heteroaryl, and C 6~16 The alkylene heteroaryl is selected from halogen, CN, C 1~8 Alkoxy, C 1~8 Alkylamino, C 1~8 Alkyl sulfonyl, CO2R 4 , C(O)N(R 4 )2, OR 4 , N(R 4 )2, NO2, SR 4 , and SO2R 4 each optionally substituted with one or more substituents independently selected from The C in question 3~8 Cycloalkyl, C 4~14 Alkylenecycloalkyl, C3-C8 heterocycloalkyl, C 6~12 Aryl, C 7~18 Alkylene aryl, C 5~10 Heteroaryl, and C 6~16 The alkylene heteroaryl is (O), C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkenyl, C 2~6 Haloalkenyl, C 2~6 Alkynyl, C 2~6 Haloalkynyl, C 3~6 Cycloalkyl, as well as O, S, N, S(O), SO2 and NR 4 C containing one or two ring hetero moieties selected from 3~6 each optionally further substituted with substituents independently selected from heterocycloalkyl; Alternatively, R 1 and R 2 combine with the atoms to which they are attached to form O, S, S(O), SO2, N, and NR 4 C containing one or two additional ring hetero moieties selected from 3~8 forming a heterocycloalkyl, The C in question3~8 Heterocycloalkyl is halogen, (O), CN, C 1~8 Alkoxy, C 1~8 Alkylamino, C 1~8 Alkyl sulfonyl, CO2R 4 , C(O)N(R 4 )2, OR 4 , N(R 4 )2, NO2, SR 4 , SO2R 4 , C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkenyl, C 2~6 Haloalkenyl, C 2~6 Alkynyl, C 2~6 Haloalkynyl, C 1~8 Alkylamino, C 1~8 Alkylsulfonyl, C 3~6 Cycloalkyl, as well as O, S, N, S(O), SO2 and NR 4 C containing one or two ring hetero moieties selected from 3~6 and optionally further substituted with substituents selected from heterocycloalkyl; R 3 But hydrogen, C 1~6 Alkyl, C 3~8 Cycloalkyl, or C 4~14 alkylenecycloalkyl; Alternatively, R 3 , and R 1 and R 2 When one of these atoms combines with the atom to which it is attached, it forms C 3~12 forming a heterocycloalkyl, The C in question 3~12 Heterocycloalkyl is halogen, (O), CN, C 1~8 Alkoxy, C 1~8 Alkylamino, C 1~8 Alkyl sulfonyl, CO2R 4 , C(O)N(R 4 )2, OR 4 , N(R 4 )2, NO2, SR 4 , SO2R 4 , C 1~6 Alkyl, C1~6 Haloalkyl, C 2~6 Alkenyl, C 2~6 Haloalkenyl, C 2~6 Alkynyl, C 2~6 Haloalkynyl, C 3~6 Cycloalkyl, as well as O, S, N, S(O), SO2 and NR 4 C containing one or two ring hetero moieties selected from 3~6 and optionally further substituted with substituents selected from heterocycloalkyl; Each R 4 But hydrogen, C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkenyl, C 2~6 Haloalkenyl, C 2~6 Alkynyl, C 2~6 Haloalkynyl, C 3~7 Cycloalkyl, as well as O, S, S(O), SO2, N, and NR 5 C containing one or two ring hetero moieties selected from 3~7 heterocycloalkyl; The C in question 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkenyl, C 2~6 Haloalkenyl, C 2~6 Alkynyl, C 2~6 Haloalkynyl, C 3~7 Cycloalkyl, and C 3~7 Heterocycloalkyl is halogen, CN, C 1~8 Alkoxy, C 1~8 Alkylamino, C 1~8 Alkyl sulfonyl, CO2R 5 , C(O)N(R 5 )2, OR 5 , N(R 5 )2, NO2, SR 5 , and SO2R 5 each optionally substituted with one or more substituents independently selected from The C3-C7 cycloalkyl and C 3~7 Heterocycloalkyl is (O), C 1~6 Alkyl, C1~6 Haloalkyl, C 2~6 Alkenyl, C 2~6 Haloalkenyl, C 2~6 Alkynyl, C 2~6 Haloalkynyl, C 3~6 Cycloalkyl, as well as O, S, S(O), SO2, N, and NR 5 C containing one or two ring hetero moieties selected from 3~6 each optionally further substituted with substituents independently selected from heterocycloalkyl; Each R 5 But hydrogen, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Haloalkyl, C 3~8 Cycloalkyl, C 5~10 Heterocycloalkyl, C 6~12 Aryl, and C 5~10 heteroaryl; The C in question 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Haloalkyl, C 3~8 Cycloalkyl, C 5~10 Heterocycloalkyl, C 6~12 Aryl, and C 5~10 Heteroaryl is halogen, CN, C 1~8 Alkoxy, C 1~8 Alkylamino, C 1~8 Alkyl sulfonyl, CO2H, CO2CH3, C(O)NH2, C(O)N(CH3)2, C(O)NHCH3, OH, NH2, N(CH3)2, NHCH3, NO2, SH, SCH3, SO2CH3, SOCH3, C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkenyl, C 2~6 Haloalkenyl, C 2~6 Alkynyl, C 2~6 Haloalkynyl, C 3~6 C containing cycloalkyl and one or two ring hetero moieties selected from O, S, S(O), SO, N, NH, and NCH3~6 each optionally substituted with one or more substituents independently selected from heterocycloalkyl; L is C 1~4 selected from alkylene, C2-C4 alkenylene, and C2-C4 alkynylene; R 6 But hydrogen, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Alkylene P(O)(OR 12 )2, C(O)R 12 , CO2R 12 , C(O)N(R 12 )2, S(O)R 12 and SO2R 12 , C 3~6 Cycloalkyl, C 6~9 Alkylenecycloalkyl, C 3~6 Heterocyclyl, C 6~9 Alkyleneheterocycloalkyl, C 4~7 Heterocyclyl, C 7~10 Alkyleneheterocycloalkyl, C 6~12 Aryl, C 7~18 Alkylene aryl, C 5~10 Heteroaryl, and C 6~16 alkyleneheteroaryl; The C in question 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 6~9 Alkylenecycloalkyl, C 3~6 Heterocyclyl, C 6~9 Alkyleneheterocycloalkyl, C 4~7 Heterocyclyl, C 7~10 Alkyleneheterocycloalkyl, C 6~12 Aryl, C 7~18 Alkylene aryl, C 5~10 Heteroaryl, and C 6~16 The alkylene heteroaryl is selected from halogen, CN, C 1~8 Alkoxy, C 1~8 Alkylamino, C 1~8Alkyl sulfonyl, CO2R 12 , C(O)N(R 12 )2, OR 12 , N(R 12 )2, NO2, SR 12 , and SO2R 12 each optionally substituted with one or more substituents independently selected from The C in question 3~6 Cycloalkyl, C 6~9 Alkylenecycloalkyl, C 3~6 Heterocyclyl, C 6~9 Alkyleneheterocycloalkyl, C 4~7 Heterocyclyl, C 7~10 Alkyleneheterocycloalkyl, C 6~12 Aryl, C 7~18 Alkylene aryl, C 5~10 Heteroaryl, and C 6~16 The alkylene heteroaryl is (O), C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkenyl, C 2~6 Haloalkenyl, C 2~6 Alkynyl, C 2~6 Haloalkynyl, C 3~6 Cycloalkyl, as well as O, S, N, S(O), SO2 and NR 12 C containing one or two ring hetero moieties selected from 3~6 each optionally further substituted with substituents independently selected from heterocycloalkyl; Each R 12 But hydrogen, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Haloalkyl, C 3~8 Cycloalkyl, C 4~14 Alkylenecycloalkyl, C 3~10 Heterocycloalkyl, C 4~16 Alkyleneheterocycloalkyl, C 6~12 Aryl, C 7~18 Alkylene aryl, C 5~10 Heteroaryl, and C 6~16alkyleneheteroaryl; The C in question 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Haloalkyl, C 3~8 Cycloalkyl, C 4~14 Alkylenecycloalkyl, C 3~10 Heterocycloalkyl, C 4~16 Alkyleneheterocycloalkyl, C 6~12 Aryl, C 7~18 Alkylene aryl, C 5~10 Heteroaryl, and C 6~16 The alkylene heteroaryl is selected from halogen, CN, C 1~8 Alkoxy, C 1~8 Alkylamino, C 1~8 Alkyl sulfonyl, CO2H, CO2CH3, C(O)NH2, C(O)N(CH3)2, C(O)NHCH3, OH, NH2, N(CH3)2, NHCH3, NO2, SH, SCH3, SO2CH3, SOCH3, C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkenyl, C 2~6 Haloalkenyl, C 2~6 Alkynyl, C 2~6 Haloalkynyl, C 3~6 C containing cycloalkyl and one or two ring hetero moieties selected from O, S, S(O), SO, N, NH, and NCH 3~6 each optionally substituted with one or more substituents independently selected from heterocycloalkyl; (B) and (C): (B) (i)R 7 , R 8 , R 9 , R 10 , and R 11 One of the following is OR 13 , N(R 13 )2, SR 13 , C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkenyl, C2-C6 haloalkenyl, C2~6 Alkynyl, C 2~6 Haloalkynyl, C 1~6 Alkylamines, C 1~6 Alkoxy, C 1~6 Haloalkoxy, CO2R 13 , C(O)R 13 , C(O)N(R 13 )2, C(O)C(O)N(R 13 )2, OC(O)R 13 ,OC(O)OR 13 , OC(O)N(R 13 )2, OS(O)R 13 , OS(O)N(R 13 )2, OSO2R 13 , OP(O)(OR 13 )2, O.C. 1~6 Alkylene P(O)(OR 13 )2, S(O)R 13 , S(O)N(R 13 )2, SO2R 13 , N(R 13 )2, N(R 13 )C(O)R 13 , N(R 13 )C(O)OR 13 , N(R 13 )C(O)N(R 13 )2, NO2, C 3~8 Cycloalkyl, C 3~14 Alkylenecycloalkyl, C 3~10 Heterocycloalkyl, C 4~16 Alkyleneheterocycloalkyl, C 6~12 Aryl, C 7~18 Alkylene aryl, C 5~10 Heteroaryl, C 4~16 alkyleneheteroaryl; The C in question 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkenyl, C2-C6 haloalkenyl, C 2~6 Alkynyl, C 2~6 Haloalkynyl, C 1~6 Alkylamines, C 1~6 Alkoxy, C 1~6 Haloalkoxy, C 3~8 Cycloalkyl, C3~14 Alkylenecycloalkyl, C 3~10 Heterocycloalkyl, C 4~16 Alkyleneheterocycloalkyl, C 6~12 Aryl, C 7~18 Alkylene aryl, C 5~10 Heteroaryl, and C 4~16 The alkylene heteroaryl is selected from halogen, CN, C 1~8 Alkoxy, C 1~8 Alkylamino, C 1~8 Alkyl sulfonyl, CO2R 13 , C(O)N(R 13 )2, OR 13 , N(R 13 )2, NO2, SR 13 , and SO2R 13 and optionally substituted with one or more substituents independently selected from The C in question 3~8 Cycloalkyl, C 3~14 Alkylenecycloalkyl, C 3~10 Heterocycloalkyl, C 4~16 Alkyleneheterocycloalkyl, C 6~12 Aryl, C 7~18 Alkylene aryl, C 5~10 Heteroaryl, and C 4~16 The alkylene heteroaryl is (O), C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkenyl, C 2~6 Haloalkenyl, C 2~6 Alkynyl, C 2~6 Haloalkynyl, C 3~6 Cycloalkyl, as well as O, S, S(O), SO2, N, and NR 13 C containing one or two ring hetero moieties selected from 3~6 each optionally further substituted with a substituent selected from heterocycloalkyl; Each R 13 But hydrogen, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Haloalkyl, C 3~8Cycloalkyl, C 4~14 Alkylenecycloalkyl, C 3~10 Heterocycloalkyl, C 4~16 Alkyleneheterocycloalkyl, C 6~12 Aryl, C 7~18 Alkylene aryl, C 5~10 Heteroaryl, and C 6~16 alkyleneheteroaryl; The C in question 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Haloalkyl, C 3~8 Cycloalkyl, C 4~14 Alkylenecycloalkyl, C 3~10 Heterocycloalkyl, C 4~16 Alkyleneheterocycloalkyl, C 6~12 Aryl, C 7~18 Alkylene aryl, C 5~10 Heteroaryl, and C 6~16 The alkylene heteroaryl is selected from halogen, CN, C 1~8 Alkoxy, C 1~8 Alkylamino, C 1~8 Alkyl sulfonyl, CO2H, CO2CH3, C(O)NH2, C(O)N(CH3)2, C(O)NHCH3, OH, NH2, N(CH3)2, NHCH3, NO2, SH, SCH3, SO2CH3, SOCH3, C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkenyl, C 2~6 Haloalkenyl, C 2~6 Alkynyl, C 2~6 Haloalkynyl, C 3~6 C containing cycloalkyl and one or two ring hetero moieties selected from O, S, S(O), SO, N, NH, and NCH 3~6 each optionally substituted with one or more substituents independently selected from heterocycloalkyl; (ii)R 7 , R 8 , R 9 , R 10 , and R 11are each hydrogen; Alternatively, R 6 and R 7 These are combined with the atoms to which they are bonded to form C 4~10 Heterocycloalkyl or C 5~10 forming a heteroaryl, The C in question 4~10 Heterocycloalkyl and C 5~10 Heteroaryl is halogen, (O), CN, C 1~8 Alkoxy, C 1~8 Alkylamino, C 1~8 Alkyl sulfonyl, CO2R 14 , C(O)N(R 14 )2, OR 14 , N(R 14 )2, NO2, SR 14 , SO2R 14 , C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkenyl, C 2~6 Haloalkenyl, C 2~6 Alkynyl, C 2~6 Haloalkynyl, C 3~6 Cycloalkyl, as well as O, S, N, S(O), SO2 and NR 14 C containing one or two ring hetero moieties selected from 3~6 each optionally further substituted with a substituent selected from heterocycloalkyl; Alternatively, R 7 , and R 1 , R 2 or R 3 One of these will combine with the atom to which it is attached to form C 5~8 forming a heterocycloalkyl, The C in question 5~8 Heterocyclylalkyl is halogen, (O), CN, C 1~8 Alkoxy, C 1~8 Alkylamino, C 1~8 Alkyl sulfonyl, CO2R 14 , C(O)N(R 14 )2, OR 14 , N(R 14 )2, NO2, SR14 , SO2R 14 , C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkenyl, C 2~6 Haloalkenyl, C 2~6 Alkynyl, C 2~6 Haloalkynyl, C 3~6 Cycloalkyl, as well as O, S, N, S(O), SO2 and NR 14 C containing one or two ring hetero moieties selected from 3~6 and optionally further substituted with one or more substituents selected from heterocycloalkyl; Each R 14 But hydrogen, C 1~6 Alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C3-C7 cycloalkyl, C 3~10 Heterocycloalkyl, C 6~12 Aryl, and C 5~10 heteroaryl; The C in question 1~6 Alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C3-C7 cycloalkyl, C 3~10 Heterocycloalkyl, C 6~12 Aryl, and C 5~10 Heteroaryl is halogen, CN, C 1~8 Alkoxy, C 1~8 Alkylamino, C 1~8 Alkyl sulfonyl, CO2H, CO2CH3, C(O)NH2, C(O)N(CH3)2, C(O)NHCH3, OH, NH2, N(CH3)2, NHCH3, NO2, SH, SCH3, SO2CH3, SOCH3, C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkenyl, C 2~6 Haloalkenyl, C 2~6 Alkynyl, C 2~6 Haloalkynyl, C 3~6 C containing cycloalkyl and one or two ring hetero moieties selected from O, S, S(O), SO, N, NH, and NCH 3~6each optionally substituted with one or more substituents independently selected from heterocycloalkyl; R 1 and R 2 are each methyl, and R 3 and R 6 are each hydrogen, then R 8 But not OH or OCH3, R 9 But instead of OH, R 1 and R 2 are each ethyl, isobutyl, or (sec)butyl, and R 3 and R 6 are each hydrogen, then R 8 But instead of OH, R 1 and R 2 are each isopropyl, and R 3 and R 6 are each hydrogen, then R 9 But instead of OH, R 1 and R 2 But together with the nitrogen to which they are bound, [ka] and R 3 and R 6 are each hydrogen, then R 9 But not OCH3, R 1 and R 2 But together with the nitrogen to which they are bound, [ka] and R 3 and R 6 are each hydrogen, then R 8 But instead of OH, R 1 and R 2 But together with the nitrogen to which they are bound, [ka] and R 3 and R 6 are each hydrogen, then R 8 But instead of OH, it's R 9 But not CH3 or OCH3, R 10 But not OCH3, R 1 and R 2 But together with the nitrogen to which they are bound, [ka] and R 3 is hydrogen and R 6 is methyl, R 8 But instead of OH, R 1 and R 2 are each methyl, and R 3 is hydrogen and R 6 is selected from ethyl, CH2CHF2, propyl, isopropyl, butyl, cyclopropyl, methylenecyclopropyl, cyclobutyl, oxetanyl, and butenyl; 8 But instead of OH, R 1 and R 2 are each methyl, and R 3 is hydrogen and R 6 is hydrogen or CH2P(O)(OH)2, then R 8 but, [ka] and OC(O)N(CH3)2, R 1 , R 2 , and R 3 But together with the atoms to which they are bonded, [ka] and R6 is hydrogen or CH2P(O)(OH)2, then R 8 but, [ka] and OC(O)N(CH3)2, (C)R 7 , R 8 , R 9 , R 10 , and R 11 are each hydrogen, R 6 and R 3 are each hydrogen, then R 1 and R 2 However, each is not methyl, but R 1 and R 2 But together with the nitrogen to which they are bound, [ka] does not form pyrrolidyl, piperidyl, or 2,5-dimethylpyrrolyl; R 6 is hydrogen and R 3 is methyl, R 1 and R 2 and each is not hydrogen.

[0050] In some embodiments of this method, R 7 , R 10 , and R 11 is hydrogen, halogen, CN, OR 13 , N(R 13 )2, SR 13 , C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkenyl, C2-C6 haloalkenyl, C 2~6 Alkynyl, C 2~6 Haloalkynyl, C 1~6 Alkylamines, C 1~6 Alkoxy, C 1~6 Haloalkoxy, CO2R13 , C(O)N(R 13 )2, OC(O)R 13 , OSO2R 13 , OP(O)(OR 13 )2, O.C. 1~6 Alkylene P(O)(OR 13 )2, S(O)R 13 , SO2R 13 , N(R 13 )2, NO2, C 3~8 Cycloalkyl, C 3~14 Alkylenecycloalkyl, C 3~10 Heterocycloalkyl, C 4~16 Alkyleneheterocycloalkyl, C 6~12 Aryl, C 7~18 Alkylene aryl, C 5~10 Heteroaryl, C 4~16 alkyleneheteroaryl; The C in question 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkenyl, C2-C6 haloalkenyl, C 2~6 Alkynyl, C 2~6 Haloalkynyl, C 1~6 Alkylamines, C 1~6 Alkoxy, C 1~6 Haloalkoxy, C 3~8 Cycloalkyl, C 3~14 Alkylenecycloalkyl, C 3~10 Heterocycloalkyl, C 4~16 Alkyleneheterocycloalkyl, C 6~12 Aryl, C 7~18 Alkylene aryl, C 5~10 Heteroaryl, and C 4~16 Alkyleneheteroaryl is substituted with halogen, CN, C 1~8 Alkoxy, C 1~8 Alkylamino, C 1~8 optionally substituted with one or more substituents independently selected from alkylsulfonyl, COH, COCH, C(O)NH, C(O)N(CH), C(O)NHCH, OH, NH, N(CH), NO, NHCH, SH, SCH, SOCH, and SOCH; The C in question 3~8 Cycloalkyl, C 3~14 Alkylenecycloalkyl, C 3~10 Heterocycloalkyl, C 4~16 Alkyleneheterocycloalkyl, C 6~12 Aryl, C 7~18 Alkylene aryl, C 5~10 Heteroaryl, and C 4~16 Alkyleneheteroaryl is (O), C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkenyl, C 2~6 Haloalkenyl, C 2~6 Alkynyl, C 2~6 Haloalkynyl, C 3~6 C containing cycloalkyl and one or two ring hetero moieties selected from O, S, S(O), SO, N, NH, and NCH 3~6 each optionally further substituted with a substituent selected from heterocycloalkyl; In the formula, R 13 is as defined in any one of the preceding paragraphs.

[0051] In some embodiments of this method, R 7 , R 10 , and R 11 is hydrogen, halogen, C 1~6 Alkyl, C 1~6 Haloalkyl and OR 13 R 13 is hydrogen, C 1~6 Alkyl, and C 1~6 haloalkyl.

[0052] In some embodiments of this method, R 7 , R 10 , and R 11 are each hydrogen.

[0053] In some embodiments of this method, R 8 is a halogen, C 1~6 Alkyl and OR 13Selected from R 13 is hydrogen, C 1~6 Alkyl, and C 1~6 haloalkyl.

[0054] In some embodiments of this method, R 9 is a halogen, C 1~6 Alkyl and OR 13 Selected from R 13 is hydrogen, C 1~6 Alkyl, and C 1~6 haloalkyl.

[0055] In some embodiments of this method, (i)R 7 , R 8 , R 9 , R 10 , and R 11 One of them is OR 13 , N(R 13 )2, SR 13 , C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkenyl, C2-C6 haloalkenyl, C 2~6 Alkynyl, C 2~6 Haloalkynyl, C 1~6 Alkylamines, C 1~6 Alkoxy, C 1~6 Haloalkoxy, CO2R 13 , C(O)R 13 , C(O)N(R 13 )2, C(O)C(O)N(R 13 )2, OC(O)R 13 ,OC(O)OR 13 , OC(O)N(R 13 )2, OS(O)R 13 , OS(O)N(R 13 )2, OSO2R 13 , OP(O)(OR 13 )2, O.C. 1~6 Alkylene P(O)(OR 13 )2, S(O)R 13 , S(O)N(R 13 )2, SO2R 13 , N(R13 )2, N(R 13 )C(O)R 13 , N(R 13 )C(O)OR 13 , N(R 13 )C(O)N(R 13 )2, NO2, C 3~8 Cycloalkyl, C 3~14 Alkylenecycloalkyl, C 3~10 Heterocycloalkyl, C 4~16 Alkyleneheterocycloalkyl, C 6~12 Aryl, C 7~18 Alkylene aryl, C 5~10 Heteroaryl, C 4~16 alkyleneheteroaryl; The C in question 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkenyl, C2-C6 haloalkenyl, C 2~6 Alkynyl, C 2~6 Haloalkynyl, C 1~6 Alkylamines, C 1~6 Alkoxy, C 1~6 Haloalkoxy, C 3~8 Cycloalkyl, C 3~14 Alkylenecycloalkyl, C 3~10 Heterocycloalkyl, C 4~16 Alkyleneheterocycloalkyl, C 6~12 Aryl, C 7~18 Alkylene aryl, C 5~10 Heteroaryl, and C 4~16 Alkyleneheteroaryl is substituted with halogen, CN, C 1~8 Alkoxy, C 1~8 Alkylamino, C 1~8 Alkyl sulfonyl, CO2R 13 , C(O)N(R 13 )2, OR 13 , N(R 13 )2, NO2, SR 13 , and SO2R 13 and optionally substituted with one or more substituents independently selected from The C in question 3~8 Cycloalkyl, C 3~14Alkylenecycloalkyl, C 3~10 Heterocycloalkyl, C 4~16 Alkyleneheterocycloalkyl, C 6~12 Aryl, C 7~18 Alkylene aryl, C 5~10 Heteroaryl, and C 4~16 Alkyleneheteroaryl is (O), C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkenyl, C 2~6 Haloalkenyl, C 2~6 Alkynyl, C 2~6 Haloalkynyl, C 3~6 Cycloalkyl, as well as O, S, S(O), SO2, N, and NR 13 C containing one or two ring hetero moieties selected from 3~6 each optionally further substituted with a substituent selected from heterocycloalkyl; Each R 13 is hydrogen, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Haloalkyl, C 3~8 Cycloalkyl, C 4~14 Alkylenecycloalkyl, C 3~10 Heterocycloalkyl, C 4~16 Alkyleneheterocycloalkyl, C 6~12 Aryl, C 7~18 Alkylene aryl, C 5~10 Heteroaryl, and C 6~16 alkyleneheteroaryl; The C in question 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Haloalkyl, C 3~8 Cycloalkyl, C 4~14 Alkylenecycloalkyl, C 3~10 Heterocycloalkyl, C 4~16 Alkyleneheterocycloalkyl, C 6~12 Aryl, C 7~18 Alkylene aryl, C 5~10Heteroaryl, and C 6~16 Alkyleneheteroaryl is substituted with halogen, CN, C 1~8 Alkoxy, C 1~8 Alkylamino, C 1~8 Alkyl sulfonyl, CO2H, CO2CH3, C(O)NH2, C(O)N(CH3)2, C(O)NHCH3, OH, NH2, N(CH3)2, NHCH3, NO2, SH, SCH3, SO2CH3, SOCH3, C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkenyl, C 2~6 Haloalkenyl, C 2~6 Alkynyl, C 2~6 Haloalkynyl, C 3~6 C containing cycloalkyl and one or two ring hetero moieties selected from O, S, S(O), SO, N, NH, and NCH 3~6 each optionally substituted with one or more substituents independently selected from heterocycloalkyl; (ii)R 7 , R 8 , R 9 , R 10 , and R 11 the others are each hydrogen; Alternatively, R 6 and R 7 are combined with the atoms to which they are bonded to form C 4~10 Heterocycloalkyl or C 5~10 forming a heteroaryl, The C in question 4~10 Heterocycloalkyl and C 5~10 Heteroaryl is a group that includes halogen, (O), CN, C 1~8 Alkoxy, C 1~8 Alkylamino, C 1~8 Alkyl sulfonyl, CO2R 14 , C(O)N(R 14 )2, OR 14 , N(R 14 )2, NO2, SR 14 , SO2R 14 , C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6Alkenyl, C 2~6 Haloalkenyl, C 2~6 Alkynyl, C 2~6 Haloalkynyl, C 3~6 Cycloalkyl, as well as O, S, N, S(O), SO2 and NR 14 C containing one or two ring hetero moieties selected from 3~6 each optionally further substituted with a substituent selected from heterocycloalkyl; Alternatively, R 7 , and R 1 , R 2 or R 3 One of these will combine with the atom to which it is attached to form C 5~8 forming a heterocycloalkyl, The C in question 5~8 Heterocyclylalkyl is a group that includes halogen, (O), CN, C 1~8 Alkoxy, C 1~8 Alkylamino, C 1~8 Alkyl sulfonyl, CO2R 14 , C(O)N(R 14 )2, OR 14 , N(R 14 )2, NO2, SR 14 , SO2R 14 , C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkenyl, C 2~6 Haloalkenyl, C 2~6 Alkynyl, C 2~6 Haloalkynyl, C 3~6 Cycloalkyl, as well as O, S, N, S(O), SO2 and NR 14 C containing one or two ring hetero moieties selected from 3~6 and optionally further substituted with one or more substituents selected from heterocycloalkyl; Each R 14 is hydrogen, C 1~6 Alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C3-C7 cycloalkyl, C 3~10 Heterocycloalkyl, C 6~12 Aryl, and C 5~10heteroaryl; The C in question 1~6 Alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C3-C7 cycloalkyl, C 3~10 Heterocycloalkyl, C 6~12 Aryl, and C 5~10 Heteroaryl is a group containing halogen, CN, C 1~8 Alkoxy, C 1~8 Alkylamino, C 1~8 Alkyl sulfonyl, CO2H, CO2CH3, C(O)NH2, C(O)N(CH3)2, C(O)NHCH3, OH, NH2, N(CH3)2, NHCH3, NO2, SH, SCH3, SO2CH3, SOCH3, C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkenyl, C 2~6 Haloalkenyl, C 2~6 Alkynyl, C 2~6 Haloalkynyl, C 3~6 C containing cycloalkyl and one or two ring hetero moieties selected from O, S, S(O), SO, N, NH, and NCH 3~6 each optionally substituted with one or more substituents independently selected from heterocycloalkyl; R 1 and R 2 are each methyl, and R 3 and R 6 are each hydrogen, then R 8 is not OH or OCH3, but R 9 is not OH, R 1 and R 2 are each ethyl, isobutyl, or (sec)butyl, and R 3 and R 6 are each hydrogen, then R 8 is not OH, R 1 and R 2 are each isopropyl, and R 3 and R 6 are each hydrogen, then R 9 is not OH, R 1 and R 2 But together with the nitrogen to which they are bound, [ka] and R 3 and R 6 are each hydrogen, then R 9 is not OCH3, R 1 and R 2 But together with the nitrogen to which they are bound, [ka] and R 3 and R 6 are each hydrogen, then R 8 is not OH, R 1 and R 2 But together with the nitrogen to which they are bound, [ka] and R 3 and R 6 are each hydrogen, then R 8 is not OH, but R 9 is not CH3 or OCH3, but R 10 is not OCH3, R 1 and R 2 But together with the nitrogen to which they are bound, [ka] and R 3 is hydrogen and R 6 is methyl, R 8 is not OH, R 1 and R 2 are each methyl, and R3 is hydrogen and R 6 is selected from ethyl, CH2CHF2, propyl, isopropyl, butyl, cyclopropyl, methylenecyclopropyl, cyclobutyl, oxetanyl, and butenyl; 8 is not OH, R 1 and R 2 are each methyl, and R 3 is hydrogen and R 6 is hydrogen or CH2P(O)(OH)2, then R 8 teeth, [ka] and OC(O)N(CH3)2, R 1 , R 2 , and R 3 But together with the atoms to which they are bonded, [ka] and R 6 is hydrogen or CH2P(O)(OH)2, then R 8 teeth, [ka] and OC(O)N(CH3)2.

[0056] In some embodiments of this method, (i)R 7 , R 8 , R 9 , R 10 , and R 11 One of them is OR 13 , N(R 13 )2, SR 13 , C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkenyl, C2-C6 haloalkenyl, C 2~6Alkynyl, C 2~6 Haloalkynyl, C 1~6 Alkylamines, C 1~6 Alkoxy, C 1~6 Haloalkoxy, CO2R 13 , C(O)R 13 , C(O)N(R 13 )2, C(O)C(O)N(R 13 )2, OC(O)R 13 ,OC(O)OR 13 , OC(O)N(R 13 )2, OS(O)R 13 , OS(O)N(R 13 )2, OSO2R 13 , OP(O)(OR 13 )2, O.C. 1~6 Alkylene P(O)(OR 13 )2, S(O)R 13 , S(O)N(R 13 )2, SO2R 13 , N(R 13 )2, N(R 13 )C(O)R 13 , N(R 13 )C(O)OR 13 , N(R 13 )C(O)N(R 13 )2, NO2, C 3~8 Cycloalkyl, C 3~14 Alkylenecycloalkyl, C 3~10 Heterocycloalkyl, C 4~16 Alkyleneheterocycloalkyl, C 6~12 Aryl, C 7~18 Alkylene aryl, C 5~10 Heteroaryl, C 4~16 alkyleneheteroaryl; The C in question 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkenyl, C2-C6 haloalkenyl, C 2~6 Alkynyl, C 2~6 Haloalkynyl, C 1~6 Alkylamines, C 1~6 Alkoxy, C 1~6 Haloalkoxy, C 3~8 Cycloalkyl, C 3~14Alkylenecycloalkyl, C 3~10 Heterocycloalkyl, C 4~16 Alkyleneheterocycloalkyl, C 6~12 Aryl, C 7~18 Alkylene aryl, C 5~10 Heteroaryl, and C 4~16 Alkyleneheteroaryl is substituted with halogen, CN, C 1~8 Alkoxy, C 1~8 Alkylamino, C 1~8 Alkyl sulfonyl, CO2R 13 , C(O)N(R 13 )2, OR 13 , N(R 13 )2, NO2, SR 13 , and SO2R 13 and optionally substituted with one or more substituents independently selected from The C in question 3~8 Cycloalkyl, C 3~14 Alkylenecycloalkyl, C 3~10 Heterocycloalkyl, C 4~16 Alkyleneheterocycloalkyl, C 6~12 Aryl, C 7~18 Alkylene aryl, C 5~10 Heteroaryl, and C 4~16 Alkyleneheteroaryl is (O), C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkenyl, C 2~6 Haloalkenyl, C 2~6 Alkynyl, C 2~6 Haloalkynyl, C 3~6 Cycloalkyl, as well as O, S, S(O), SO2, N, and NR 13 C containing one or two ring hetero moieties selected from 3~6 each optionally further substituted with a substituent selected from heterocycloalkyl; Each R 13 is hydrogen, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Haloalkyl, C 3~8 Cycloalkyl, C4~14 Alkylenecycloalkyl, C 3~10 Heterocycloalkyl, C 4~16 Alkyleneheterocycloalkyl, C 6~12 Aryl, C 7~18 Alkylene aryl, C 5~10 Heteroaryl, and C 6~16 alkyleneheteroaryl; The C in question 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 1~6 Haloalkyl, C 3~8 Cycloalkyl, C 4~14 Alkylenecycloalkyl, C 3~10 Heterocycloalkyl, C 4~16 Alkyleneheterocycloalkyl, C 6~12 Aryl, C 7~18 Alkylene aryl, C 5~10 Heteroaryl, and C 6~16 Alkyleneheteroaryl is substituted with halogen, CN, C 1~8 Alkoxy, C 1~8 Alkylamino, C 1~8 Alkyl sulfonyl, CO2H, CO2CH3, C(O)NH2, C(O)N(CH3)2, C(O)NHCH3, OH, NH2, N(CH3)2, NHCH3, NO2, SH, SCH3, SO2CH3, SOCH3, C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkenyl, C 2~6 Haloalkenyl, C 2~6 Alkynyl, C 2~6 Haloalkynyl, C 3~6 C containing cycloalkyl and one or two ring hetero moieties selected from O, S, S(O), SO, N, NH, and NCH 3~6 each optionally substituted with one or more substituents independently selected from heterocycloalkyl; (ii)R 7 , R 8 , R 9 , R 10 , and R 11the others are each hydrogen; R 1 and R 2 are each methyl, and R 3 and R 6 are each hydrogen, then R 8 is not OH or OCH3, but R 9 is not OH, R 1 and R 2 are each ethyl, isobutyl, or (sec)butyl, and R 3 and R 6 are each hydrogen, then R 8 is not OH, R 1 and R 2 are each isopropyl, and R 3 and R 6 are each hydrogen, then R 9 is not OH, R 1 and R 2 But together with the nitrogen to which they are bound, [ka] and R 3 and R 6 are each hydrogen, then R 9 is not OCH3, R 1 and R 2 But together with the nitrogen to which they are bound, [ka] and R 3 and R 6 are each hydrogen, then R 8 is not OH, R 1 and R 2 But together with the nitrogen to which they are bound, [ka] and R 3 and R 6 are each hydrogen, then R 8 is not OH, but R 9 is not CH3 or OCH3, but R 10 is not OCH3, R 1 and R 2 But together with the nitrogen to which they are bound, [ka] and R 3 is hydrogen and R 6 is methyl, R 8 is not OH, R 1 and R 2 are each methyl, and R 3 is hydrogen and R 6 is selected from ethyl, CH2CHF2, propyl, isopropyl, butyl, cyclopropyl, methylenecyclopropyl, cyclobutyl, oxetanyl, and butenyl; 8 is not OH, R 1 and R 2 are each methyl, and R 3 is hydrogen and R 6 is hydrogen or CH2P(O)(OH)2, then R 8 teeth, [ka] and OC(O)N(CH3)2, R 1 , R 2 , and R 3 But together with the atoms to which they are bonded, [ka] and R 6is hydrogen or CH2P(O)(OH)2, then R 8 teeth, [ka] and OC(O)N(CH3)2.

[0057] In some embodiments of this method, (i)R 7 , R 8 , R 9 , R 10 , and R 11 One of them is C 1~6 Haloalkyl and OC 1~6 haloalkyl; (ii)R 7 , R 8 , R 9 , R 10 , and R 11 The others of each are hydrogen.

[0058] In some embodiments of this method, R 7 , R 8 , R 9 , R 10 , and R 11 are each hydrogen, R 6 and R 3 are each hydrogen, then R 1 and R 2 are not methyl, but R 1 and R 2 together with the nitrogen to which they are attached, [ka] does not form pyrrolidyl, piperidyl, or 2,5-dimethylpyrrolyl; and R 6 is hydrogen and R 3 is methyl, R 1 and R 2 are not hydrogen.

[0059] In some embodiments of this method, R 1 and R 2 is C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkenyl, C 2~6 Haloalkenyl, C 2~6 Alkynyl, C 2~6 Haloalkynyl, C 3~8 Cycloalkyl, and C 4~14 alkylenecycloalkyl.

[0060] In some embodiments of this method, R 1 and R 2 is C 1~4 alkyl.

[0061] In some embodiments of this method, R 1 and R 2 together with the nitrogen to which they are attached, form: [ka] Form one of the following:

[0062] In some embodiments of this method, R 1 and R 2 are combined with the atoms to which they are bonded to form C 3~6 Forming a heterocycloalkyl, the C 3~6 Heterocycloalkyl is a group that is substituted with halogen, CN, C 1~8 Alkoxy, C 1~8 Alkylamino, C 1~8 Alkyl sulfonyl, CO2R 4 , C(O)N(R 4 )2, OR 4 , N(R 4 )2, NO2, SR 4 and SO2R 4 , (O), C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkenyl, C2~6 Haloalkenyl, C 2~6 Alkynyl, C 2~6 Haloalkynyl, C 3~6 Cycloalkyl, as well as O, S, N, S(O), SO2 and NR 4 C containing one or two ring hetero moieties selected from 3~6 heterocycloalkyl; and R 4 is as defined in any one of the preceding paragraphs.

[0063] In some embodiments of this method, R 3 is hydrogen.

[0064] In some embodiments of this method, R 3 , and R 1 and R 2 One of them combines with the atom to which it is attached to form C 3~8 Forming a heterocycloalkyl, the C 5~8 Heterocycloalkyl is a group that includes halogen, (O), CN, C 1~8 Alkoxy, C 1~8 Alkylamino, C 1~8 Alkyl sulfonyl, CO2R 4 , C(O)N(R 4 )2, OR 4 , N(R 4 )2, NO2, SR 4 , SO2R 4 , C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkenyl, C 2~6 Haloalkenyl, C 2~6 Alkynyl, C 2~6 Haloalkynyl, C 3~6 Cycloalkyl, as well as O, S, N, S(O), SO2 and NR 4 C containing one or two ring hetero moieties selected from 3~6 heterocycloalkyl; R 4 is as defined in any one of the preceding paragraphs.

[0065] In some embodiments of this method, L is C 1~4 It is alkylene.

[0066] In some embodiments of this method, L is methylene.

[0067] In some embodiments of this method, R 6 is hydrogen and C 1~6 alkyl.

[0068] In some embodiments of this method, R 6 is hydrogen.

[0069] In some embodiments of this method, the compound of Formula (I) is selected from any one of the compounds in Table 1, or a pharmaceutically acceptable salt, solvate, tautomer, N-oxide, stereoisomer, metabolite, polymorph, or prodrug thereof.

[0070] In some embodiments of this method, the compound of formula (I) is: [ka] or a pharmaceutically acceptable salt, solvate, tautomer, N-oxide, stereoisomer, metabolite, polymorph, or prodrug thereof.

[0071] In some embodiments of this method, the compound of formula (I) is: [ka] or a pharmaceutically acceptable salt, solvate, tautomer, N-oxide, stereoisomer, metabolite, polymorph, or prodrug thereof.

[0072] In another aspect of the present disclosure, there is provided a method of treating a disease, disorder, or condition through activation of a serotonin receptor, the method comprising administering to a subject in need thereof a compound of formula (I) according to any one of the embodiments disclosed herein, or a pharmaceutically acceptable salt, solvate, tautomer, N-oxide, stereoisomer, metabolite, polymorph, or prodrug thereof, in combination with another known agent useful in treating a disease, disorder, or condition through activation of a serotonin receptor.

[0073] In another aspect of the present disclosure, there is provided a method of treating psychosis, the method comprising administering to a subject in need thereof a compound of formula (I) according to any one of the embodiments disclosed herein, or a pharmaceutically acceptable salt, solvate, tautomer, N-oxide, stereoisomer, metabolite, polymorph, or prodrug thereof.

[0074] In embodiments, the mental illness is selected from anxiety disorders; depression; mood disorders; psychotic disorders; impulse control and addiction disorders; substance addiction; obsessive-compulsive disorder (OCD); post-traumatic stress disorder (PTSD); stress response syndromes; dissociative disorders; depersonalization disorder; factitious disorder; sexual and gender disorders; somatic symptom disorders; hallucinations; delusions; psychotic disorders; and combinations thereof.

[0075] In another aspect of the present disclosure, there is provided a method for treating a disease, disorder or condition of the central nervous system (CNS) and / or a disease, disorder or condition of the nervous system, the method comprising administering to a subject in need thereof a compound of formula (I) according to any one of the embodiments disclosed herein, or a pharmaceutically acceptable salt, solvate, tautomer, N-oxide, stereoisomer, metabolite, polymorph, or prodrug thereof.

[0076] In embodiments, the CNS disease, disorder or condition and / or nervous system disease, disorder or condition is selected from the group consisting of neurodevelopmental diseases and neurodegenerative diseases such as Alzheimer's disease; presenile dementia; senile dementia; vascular dementia; Lewy body dementia, cognitive impairment, Parkinson's disease, and Parkinson's disease-related disorders, such as Parkinsonism, corticobasal degeneration, and supranuclear palsy; epilepsy; CNS trauma; CNS infection; CNS inflammation; stroke; multiple sclerosis; Huntington's disease; mitochondrial disorders; fragile X syndrome; Angelman syndrome; hereditary ataxia; The neurodegenerative disorders are selected from disorders of the nervous system including transotic and oculomotor disorders; neurodegenerative diseases of retinal amyotrophic lateral sclerosis; tardive dyskinesia; hyperactivity disorder; attention deficit hyperactivity disorder and attention deficit disorder; restless legs syndrome; Tourette's syndrome; schizophrenia; autism spectrum disorders; tuberous sclerosis; Rett's syndrome; cerebral palsy; disorders of the reward system including eating disorders such as anorexia nervosa and bulimia nervosa; binge eating disorder, trichotillomania, excoriation disorder, nail biting; migraine; fibromyalgia; and peripheral neuropathy of any etiology, and combinations thereof.

[0077] In another aspect of the present disclosure, there is provided a method for increasing neuroplasticity and / or increasing dendritic spine density, the method comprising contacting a neuronal cell with a compound of Formula (I) as described in any one of the embodiments disclosed herein, or a pharmaceutically acceptable salt, solvate, tautomer, N-oxide, stereoisomer, metabolite, polymorph, or prodrug thereof, in an amount sufficient to increase neuroplasticity and / or increase dendritic spine density of the neuronal cell.

[0078] In another aspect, the present disclosure provides a method for treating body weight, comprising administering an effective amount of a compound of the present invention to a subject in need thereof.The treatment of body weight can include the treatment of weight gain; weight loss; metabolic disorders; weight gain associated with pharmaceutical intervention; weight gain associated with psychiatric illness (including those described herein); eating disorders such as anorexia nervosa, bulimia, cachexia; eating behavior; obesity; diabetes; insulin resistance; prediabetes; glucose intolerance; hyperlipidemia; and cardiovascular disease.

[0079] In another aspect, the present disclosure provides a method for activating serotonin receptors in cells, either in a biological sample or in a patient, comprising administering to the cells a compound of formula (I) as defined in any one of the embodiments disclosed herein.

[0080] Any embodiment in this specification should be applied mutatis mutandis to any other embodiment unless otherwise specified.

[0081] The present disclosure is not to be limited in scope by the specific embodiments described herein, which are intended as examples only. Functionally equivalent products, compositions, and methods are clearly within the scope of the invention as described herein.

[0082] definition For purposes of interpreting this specification, terms used in the singular will also include the plural and vice versa.

[0083] As used herein, unless the context otherwise requires, the term "comprise" and variations thereof such as "comprising," "comprises," and "comprised" are not intended to exclude additional additives, components, integers, or steps.

[0084] The term "treatment" or "treating" a subject includes delaying, slowing, stabilizing, curing, curing, mitigating, alleviating, altering, repairing, making less severe, improving, ameliorating, or affecting a disease or condition, a sign or symptom of a disease or condition, or the risk of (or susceptibility to) a disease or condition. The term "treating" refers to any indication of success in treating or improving an injury, condition, or condition, including any objective or subjective parameter such as decline; remission; slowing the rate of deterioration; reducing the severity of the disease; stabilization; reducing signs or symptoms or making the injury more tolerable to the individual; slowing the rate of degeneration or decline; or making the end point of degeneration less debilitating.

[0085] In particularly preferred embodiments, the methods of the invention may prevent or reduce the severity of, or inhibit or minimize the progression of, the signs or symptoms of the diseases or conditions described herein, and thus have therapeutic and prophylactic utility.

[0086] As used herein, "preventing" or "prevention" is intended to refer at least to a reduction in the likelihood of the risk (or susceptibility) of acquiring a disease or disorder (i.e., preventing at least one clinical sign or symptom of the disease from developing in an individual who may be exposed to or susceptible to the disease, but who has not yet experienced or displayed a sign or symptom of the disease). Biological and physiological parameters for identifying such patients are provided herein and are well known to physicians.

[0087] As used herein, the terms "subject" and "patient" can be used interchangeably. The terms "individual" and "patient," respectively, refer to animals treatable by the compounds and / or methods, including, but not limited to, for example, dogs, cats, horses, sheep, pigs, cows, etc., as well as humans and non-human primates. Unless otherwise specified, "subject" or "patient" can include both male and female genders. Furthermore, this also includes subjects or patients, preferably humans, suitable for receiving treatment with the pharmaceutical compositions and / or methods of the present invention.

[0088] The term "selective" refers to greater activity for a first target (e.g., a 5-HT receptor subtype) compared to a second target (e.g., a second 5-HT receptor subtype). In some embodiments, the compounds have at least 1.25-fold, at least 1.5-fold, at least 2-fold, at least 3-fold, at least 4-fold, at least 5-fold, at least 6-fold, at least 10-fold, or at least 100-fold greater selectivity for a first target compared to a second target. In some embodiments, the compounds described herein have at least 1.25-fold, at least 1.5-fold, at least 2-fold, at least 3-fold, at least 4-fold, at least 5-fold, at least 6-fold, at least 10-fold, or at least 100-fold greater selectivity for a first target compared to a second target. 2B and / or 5-HT 2C , preferably 5-HT 2B 5-HT receptor subtypes compared to one or more other 5-HT receptor subtypes, such as 2A In some embodiments, the compounds described herein are selective for the 5-HT receptor. 2A and / or 5-HT 2B , preferably 5-HT 2B 5-HT receptor subtypes compared to one or more other 5-HT receptor subtypes, such as 2C It is selective for the receptor.

[0089] As used herein when referring to a measurable value, such as an amount, duration over time, etc., "about" is meant to encompass variations of ±20% or ±10%, in some instances ±5%, in some instances ±1%, and in some instances ±0.1% from the specified value, where such variations are appropriate for practicing the disclosed methods.

[0090] Ranges: Throughout this disclosure, various aspects of the invention may be presented in a range format. It should be understood that the description in range format is merely for convenience and brevity and should not be construed as an inflexible limitation on the scope of the invention. Accordingly, the description of a range should be considered to have specifically disclosed all possible subranges and individual numerical values ​​within that range. For example, the description of a range such as 1 to 6 should be considered to have specifically disclosed subranges such as 1 to 3, 1 to 4, 1 to 5, 2 to 4, 2 to 6, 3 to 6, etc., as well as individual numbers within that range, e.g., 1, 2, 2.7, 3, 4, 5, 5.3, and 6. This applies regardless of the breadth of the range.

[0091] As used herein, the term "alkyl" refers to a straight or branched chain hydrocarbon radical having 1 to 12 carbon atoms, or any range therebetween, i.e., it contains 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 carbon atoms. Alkyl groups are optionally substituted with substituents. Examples of "alkyl" as used herein include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, n-pentyl, isopentyl, and the like.

[0092] As used herein, the terms "C1-C2 alkyl," "C1-C3 alkyl," and "C1-C6 alkyl" refer to an alkyl group, as defined herein, each containing at least 1 and at most 2, 3, or 6 carbon atoms, or any range therebetween (e.g., an alkyl group containing 2 to 5 carbon atoms is also within the C1-C6 range).

[0093] The term "alkylene" refers to a straight-chain or branched saturated aliphatic radical having the number of carbon atoms indicated and linking at least two other groups, i.e., divalent hydrocarbon radicals. The two moieties linked to the alkylene can be attached to the same atom or different atoms of the alkylene group. For example, a straight-chain alkylene is -(CH2) n- where n is 1, 2, 3, 4, 5, or 6. Representative alkylene groups include, but are not limited to, methylene, ethylene, propylene, isopropylene, butylene, isobutylene, sec-butylene, pentylene, and hexylene.

[0094] The term "alkenyl," whether used alone or as part of another group, refers to a straight-chain or branched saturated alkylene group, i.e., a saturated carbon chain containing substituents at two of its termini. The number of possible carbon atoms in the referenced alkylene group is indicated by the prefix "C n1~n2 For example, C 2~6 The term alkylene refers to an alkylene group having 2, 3, 4, 5, or 6 carbon atoms. Examples of alkenyl groups include, but are not limited to, vinyl (ethenyl), propenyl, isopropenyl, 1-butenyl, 2-butenyl, isobutenyl, butadienyl, 1-pentenyl, 2-pentenyl, isopentenyl, 1,3-pentadienyl, 1,4-pentadienyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 1,3-hexadienyl, 1,4-hexadienyl, 1,5-hexadienyl, 2,4-hexadienyl, or 1,3,5-hexatrienyl.

[0095] As used herein, the term "alkynyl," whether used alone or as part of another group, means a straight or branched chain unsaturated alkynyl group containing at least one triple bond. The number of carbon atoms possible in the referenced alkyl group is indicated by the prefix "C n1~n2 For example, C 2~6The term alkynyl refers to an alkynyl group having 2, 3, 4, 5, or 6 carbon atoms. Examples of alkynyl groups include, but are not limited to, acetylenyl, propynyl, 1-butynyl, 2-butynyl, butadinyl, 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.

[0096] The term "cycloalkyl" is intended to include monocyclic, bicyclic, or tricyclic alkyl groups. The number of possible carbon atoms in the referenced cycloalkyl group is determined by the prefix "C n1~n2 For example, C 3~8 The term cycloalkyl refers to a cycloalkyl group having 3, 4, 5, 6, 7, or 8 carbon atoms. In some embodiments, the cycloalkyl group has 3 to 12, 3 to 10, 3 to 8, 3 to 6, or 3 to 5 carbon atoms in the ring. In some embodiments, the cycloalkyl group has 5 or 6 ring carbon atoms. Examples of monocyclic cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. In some embodiments, the cycloalkyl group has 3 to 8, 3 to 7, 3 to 6, 4 to 6, 3 to 5, or 4 to 5 ring carbon atoms. Bicyclic and tricyclic ring systems include bridged, spiro, and fused cycloalkyl ring systems. Examples of bicyclic and tricyclic cycloalkyl systems include, but are not limited to, bicyclo[2.1.1]hexanyl, bicyclo[2.2.1]heptanyl, adamantyl, and decalinyl.

[0097] The term "alkylenecycloalkyl" refers to a radical having an alkyl component and a cycloalkyl component, where the alkyl component connects the cycloalkyl component to the point of attachment. The alkyl component is as defined above, except that the alkyl component is at least a divalent alkylene and connects the cycloalkyl component to the point of attachment. In some cases, the alkyl component may be absent. The alkyl component may be any of C 1~6 , C 1~2 , C 1~3 , C 1~4 , C 1~5 , C 2~3 , C 2~4 , C 2~5 , C 2~6 , C 3~4 , C 3~5 , C 3~6 , C 4~5 , C 4~6 , and C 5~6 The cycloalkyl moiety is as defined herein. x~y Alkylenecycloalkyl 」 The numerical range of x to y relates to the total number of alkyl carbons and cycloalkyl ring atoms. Exemplary alkylenecycloalkyl groups include, but are not limited to, methylenecyclopropyl, methylenecyclobutyl, methylenecyclopentyl, and methylenecyclohexyl.

[0098] The term "aryl" refers to an aromatic ring system having any suitable number of ring atoms and any suitable number of rings. The number of possible carbon atoms in the referenced aryl group can be determined by the prefix "C n1~n2 For example, C 6~12The term aryl refers to an aryl group having 6, 7, 8, 9, 10, 11, or 12 carbon atoms. The aryl group can contain any suitable number of ring atoms, for example, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16 ring atoms, and 6 to 10, 6 to 12, or 6 to 14 ring members. Aryl groups can be monocyclic, fused to form bicyclic or tricyclic groups, or linked by bonds to form biaryl groups. Representative aryl groups include phenyl, naphthyl, and biphenyl. Other aryl groups include benzyl with a methylene linking group. Some aryl groups have 6 to 12 ring members, such as phenyl, naphthyl, or biphenyl. Other aryl groups have 6 to 10 ring members, such as phenyl or naphthyl. Some other aryl groups have 6 ring members, such as phenyl.

[0099] The term "alkylenearyl" refers to a radical having an alkyl and aryl moiety, where the alkyl moiety connects the aryl moiety to the point of attachment. The alkyl moiety is as defined above, except that the alkyl moiety is at least divalent alkylene and connects the aryl moiety to the point of attachment. The alkyl moiety is selected from the group consisting of C 1~6 , 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. x~yThe numerical range of x to y in "alkylenearyl" relates to the total number of alkyl carbon and aryl ring atoms. Examples of alkylenearyl groups include, but are not limited to, benzyl and ethylenephenyl.

[0100] As used herein, the term "alkoxy" refers to an alkyl group, as defined herein, covalently attached via an O linkage. Alkoxy groups are optionally substituted with substituents. Examples of "alkoxy" as used herein include, but are not limited to, methoxy, ethoxy, propoxy, isoproxy, butoxy, isobutoxy, tert-butoxy, and pentoxy.

[0101] As used herein, the terms "C1-C2 alkoxy," "C1-C3 alkoxy," and "C1-C6 alkoxy" refer to an alkoxy group, as defined herein, each containing at least 1 and at most 2, 3, or 6 carbon atoms, or any range therebetween (e.g., an alkoxy group containing 2 to 5 carbon atoms is also within the C1-C6 range).

[0102] As used herein, the term "alkylamine" refers to an alkyl group, as defined herein, bearing one or more amino groups. The amino groups can be primary, secondary, or tertiary. The alkylamine can be further substituted with a hydroxy group to form an amino-hydroxy group. Examples of alkylamines include, but are not limited to, ethylamine, propylamine, isopropylamine, ethylenediamine, and ethanolamine. The amino group can link the alkylamine to the point of attachment to the rest of the compound, be in the omega position of the alkyl group, or link at least two carbon atoms of the alkyl group together.

[0103] As used herein, the terms "C1-C2 alkylamine," "C1-C3 alkylamine," and "C1-C6 alkylamine" refer to an alkylamine group, as defined herein, each containing at least 1 and at most 2, 3, or 6 carbon atoms, or any range therebetween (e.g., an alkylamine group containing 2 to 5 carbon atoms is also within the C1-C6 range).

[0104] As used herein, the term "alkylsulfonyl" refers to an alkyl group, as defined herein, bearing one or more sulfonyl groups. The sulfonyl group may be linked to the alkylsulfonyl at its point of attachment to the remainder of the compound, may be at the omega position of the alkyl group, or may link at least two carbon atoms of the alkyl group together.

[0105] As used herein, the terms "C1-C2 alkylsulfonyl," "C1-C3 alkylsulfonyl," and "C1-C6 alkylsulfonyl" refer to alkylsulfonyl groups, as defined herein, each containing at least 1, and up to 2, 3, or 6 carbon atoms, or any range therebetween (e.g., an alkylsulfonyl group containing 2 to 5 carbon atoms is also within the C1-C6 range).

[0106] As used herein, the term "heteroatom" means an atom of any element other than carbon or hydrogen. Examples of heteroatoms include nitrogen, oxygen, sulfur, and phosphorus. Preferred heteroatoms include N, O, and S, preferably N and O.

[0107] As used herein, the term "hetero moiety" refers to a chemical group that includes a heteroatom. Examples of hetero moieties include O, S, S(O), SO, N, and NH.

[0108] As used herein, "substituent" refers to a molecular moiety that is covalently bonded to an atom in the molecule of interest. For example, a "ring substituent" may be a moiety such as a halogen, an alkyl group, or other substituents described herein that are covalently bonded to a ring member atom, preferably a carbon atom or a nitrogen atom. As used herein, the term "substituted" means that any one or more hydrogens on the designated atom are replaced with a selection from the designated substituents, provided that the replacement does not exceed the normal valence of the designated atom, and that the replacement results in a stable compound, i.e., a compound that can be isolated, characterized, and tested for biological activity.

[0109] Terms such as "optionally substituted" or "can be substituted," as used throughout this specification, indicate that a group may or may not be further substituted or fused (so as to form a polycyclic ring system) with one or more non-hydrogen substituents. Suitable chemically feasible substituents for a particular functional group will be apparent to one of ordinary skill in the art.

[0110] Examples of the substituent include, but are not limited to, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 hydroxyalkyl, C3-C7 heterocyclyl, C3-C7 cycloalkyl, C1-C6 alkoxy, C1-C6 alkylsulfanyl, C1-C6 alkylsulfenyl, C1-C6 alkylsulfonylamino, arylsulfonoamino, alkylcarboxy, alkylcarboxyamido, oxo, hydroxy, mercapto, amino, acyl, carboxy, carbamoyl, aryl, aryloxy, heteroaryl, aminosulfonyl, aroyl, aroylamino, heteroaroyl, acyloxy, aroyloxy, heteroaroyloxy, alkoxycarbonyl, nitro, cyano, halo, ureido, and C1-C6 perfluoroalkyl. Preferably, the substituent includes amino, halo, C1-C6 alkyl, amido, or hydroxyl.

[0111] As used herein, the term "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br), or iodine (I), and the term "halo" refers to the halogen radicals fluoro (-F), chloro (-Cl), bromo (-Br), and iodine (-I). Preferably, "halo" is fluoro or chloro.

[0112] As used herein, the term "haloalkyl" refers to an alkyl group, as defined herein, in which one or more (up to all) available hydrogen atoms are replaced with halogen. In some cases, the term "perfluoro" can be used to define a compound or radical in which all hydrogen atoms are replaced with fluorine. For example, perfluoromethyl refers to 1,1,1-trifluoromethyl.

[0113] As used herein, the terms "C1-C2 haloalkyl," "C1-C3 haloalkyl," and "C1-C6 haloalkyl" refer to a haloalkyl group, as defined herein, each containing at least 1, and up to 2, 3, or 6 carbon atoms, or any range therebetween (e.g., a haloalkyl group containing 2 to 5 carbon atoms is also within the C1-C6 range).

[0114] For example, but not limited to, a C1 haloalkyl group can be fluoromethyl, or difluoromethyl, or trifluoromethyl.

[0115] As used herein, the term "haloalkenyl" refers to an alkenyl group as defined above in which one or more available hydrogen atoms has been replaced with a halogen. Thus, for example, "C 1~6 "Haloalkenyl" (or "C1-C6 haloalkenyl") refers to a C1-C6 linear or branched alkenyl group as defined above having one or more halogen substituents.

[0116] As used herein, the term "haloalkynyl" refers to an alkynyl group as defined above in which one or more available hydrogen atoms has been replaced with a halogen. Thus, for example, "C 1~6 "Haloalkynyl" (or "C1-C6 haloalkynyl") refers to a C1-C6 linear or branched alkynyl group as defined above having one or more halogen substituents.

[0117] As used herein, the term haloalkoxy refers to an alkoxy group, as defined herein, substituted with at least one halogen.

[0118] The term "amino" or "amine" refers to the group --NH.sub.2.

[0119] The term "substituted amino" or "secondary amino" refers to an amino group in which a hydrogen has been replaced, for example, by a C1-C6 alkyl group ("C1-C6 alkylamino"), an aryl or aralkyl group ("arylamino", "aralkylamino"), etc. Preferred are C1-C3 alkylamino groups such as methylamino (NHMe), ethylamino (NHEt), and propylamino (NHPr).

[0120] The term "disubstituted amino" or "tertiary amino" refers to an amino group in which two hydrogens have been replaced, for example, by a C1-C6 alkyl group ("dialkylamino"), an aryl and alkyl group ("aryl(alkyl)amino"), which may be the same or different. Di(C1-C3 alkyl)amino groups are preferred, for example, dimethylamino (NMe2), diethylamino (NEt2), dipropylamino (NPr2), and variations thereof (e.g., N(Me)(Et)).

[0121] The term "nitro" refers to the group -NO2.

[0122] The terms "cyano" and "nitrile" refer to the group --CN.

[0123] The terms "amido" or "amide" refer to the group -C(O)NH2.

[0124] The term "substituted amido" or "substituted amide" refers to an amide group in which a hydrogen has been replaced with, for example, a C1-C6 alkyl group ("C1-C6 alkylamido" or "C1-C6 alkylamido"), an aryl ("arylamido"), an aralkyl group ("aralkylamido"), etc. For example, C1-C3 alkylamido groups such as methylamido (-C(O)NHMe), ethylamido (-C(O)NHEt), and propylamido (-C(O)NHPr) are preferred, including their reverse amides (e.g., NHMeC(O)-, -NHEtC(O)-, and -NHPrC(O)-).

[0125] The term "disubstituted amido" or "disubstituted amide" refers to an amide group in which two hydrogens have been replaced, for example, by a C1-C6 alkyl group ("di(C1-C6 alkyl)amide" or "di(C1-C6 alkyl)amide"), an aralkyl and alkyl group ("alkyl(aralkyl)amide"). For example, di(C1-C3 alkyl)amide groups such as dimethylamide (-C(O)NMe2), diethylamide (-C(O)NEt2), and dipropylamide (-C(O)NPr2), as well as variations thereof (e.g., C(O)N(Me)Et, etc.), are preferred, including reverse amides thereof.

[0126] The term "sulfonyl" refers to the group -SO2H.

[0127] The term "substituted sulfonyl" refers to a group in which the hydrogen is replaced with, for example, C 1~ C6 alkyl group (sulfonyl C 1~ It refers to a sulfonyl group substituted with an aryl ("C alkyl"), an aryl ("arylsulfonyl"), an aralkyl ("aralkylsulfonyl"), or the like. For example, sulfonyl C groups such as -SOMe, -SOEt, and -SOPr are also included.1~ C3 alkyl groups are preferred.

[0128] The term "sulfonylamido" or "sulfonamide" refers to the group -SO2NH2.

[0129] The term "substituted sulfonamide" or "substituted sulfonamide" refers to a group in which hydrogen is replaced with, for example, C 1~ C6 alkyl group ("sulfonyl amide C 1~ C6 alkyl"), aryl ("arylsulfonamido"), aralkyl ("aralkylsulfonamido"), etc. For example, sulfonylamide C groups such as SO2NHMe, SO2NHEt, and SO2NHPr. 1~ C3 alkyl groups are preferred, including their reverse sulfonamides (e.g., -NHSO2Me, NHSO2Et, and -NHSO2Pr).

[0130] The term "disubstituted sulfonamide" or "disubstituted sulphonamide" refers to a disubstituted sulfonamide in which the two hydrogens are, for example, C 1~ C6 alkyl group ("sulfonylamide di(C 1~ It refers to sulfonylamido groups substituted with sulfonylamide di(C alkyl)), aralkyl, and alkyl groups ("sulfonamido(aralkyl)alkyl"), etc. For example, sulfonylamido di(C alkyl) groups such as -SONMe, -SONNEt, and -SONPr, and variations thereof (e.g., SON(Me)Et, etc.). 1~ C3 alkyl) groups are preferred, including their reverse sulfonamides (e.g., -N(Me)SO2Me, etc.).

[0131] The term "sulfate" refers to the group OS(O)OH, where the hydrogen is, for example, C 1~These include groups substituted with C alkyl groups ("alkyl sulfates"), aryl ("aryl sulfates"), aralkyl ("aralkyl sulfates"), etc. For example, C groups such as OS(O)2OMe, OS(O)2OEt, and OS(O)2OPr. 1~ C3 alkyl sulfates are preferred.

[0132] The term "sulfonate" refers to the group SO3H, where the hydrogen is, for example, C 1~ These include groups substituted with C alkyl groups ("alkyl sulfonates"), aryls ("aryl sulfonates"), aralkyls ("aralkyl sulfonates"), etc. For example, C groups such as SO3Me, SO3Et, and SO3Pr. 1~ C3 alkyl sulfonates are preferred.

[0133] The term "amino acid" as defined herein refers to a moiety containing an amino group and a carboxyl group linked by at least one carbon. The amino acid may refer to a natural or unnatural amino acid, preferably a natural amino acid such as alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, and valine; preferably, the amino acid is arginine, lysine, or histidine, most preferably lysine.

[0134] The term "carboxylate" or "carboxyl" refers to the group --COO-- or --COOH.

[0135] The term "carbamate" or "carbomyl" refers to the group -OC(O)NH. Carbamates can be substituted or disubstituted, for example with alkyl groups such as, but not limited to, C1-C6 alkyl.

[0136] The term "carbonate" refers to the group -OC(O)O- or -OC(O)OH.

[0137] The term "alkyl carbonate," as defined herein, refers to a carbonate group in which a hydrogen has been replaced, for example, by a C1-C6 alkyl group, an aryl or aralkyl group ("aryl carbonate" or "aralkyl carbonate"). Preferred are CO3C1-C3 alkyl groups, such as methyl carbonate (CO3Me), ethyl carbonate (CO3Et), and propyl carbonate (CO3Pr).

[0138] The term "ester" refers to an ester in which the hydrogen is present in an ester, e.g., C 1~ It refers to a carboxyl group substituted with a C alkyl group ("carboxyl C-C alkyl" or "alkyl ester"), an aryl or aralkyl group ("aryl ester" or "aralkyl ester"), or the like. For example, CO2C1-C3 alkyl groups such as methyl ester (CO2Me), ethyl ester (CO2Et), and propyl ester (CO2Pr) are preferred, including their reverse esters (e.g., -OC(O)Me, -OC(O)Et, and -OC(O)Pr).

[0139] The term "heterocyclyl" (unless otherwise specified) refers to a moiety obtained by removing a hydrogen atom from a ring atom of a heterocyclic compound having 3 to 12 ring atoms (1, 2, 3, 4 or more of which are ring heteroatoms independently selected from, e.g., O, S, and N, or ring heteromoieties independently selected from, e.g., O, S, S(O), SO, N, and NH). A heterocyclyl group may be denoted by the prefix C. n1~n2 or "n1-n2", this prefix indicates the number of carbon atoms in the corresponding carbocyclic group, where one or more, preferably 1, 2, 3, 4 or more, of the ring atoms are replaced with a heteroatom or heteromoiety.

[0140] In this context, the prefixes 3-, 4-, 5-, 6-, 7-, 8-, 9-, and 10- denote the number of ring atoms, or range of ring atoms, whether carbon atoms or heteroatoms. For example, as used herein, "C3~10 The term "heterocyclyl" or "3- to 10-membered heterocyclyl" refers to a heterocyclyl group having 3, 4, 5, 6, 7, 8, 9, or 10 ring atoms. Examples of heterocyclyl groups include 5- to 6-membered monocyclic heterocyclyl and 9- to 10-membered fused bicyclic heterocyclyl.

[0141] Examples of monocyclic heterocyclyl groups include those containing one nitrogen atom, such as aziridine (3-membered ring), azetidine (4-membered ring), pyrrolidine (tetrahydropyrrole), pyrroline (e.g., 3-pyrroline, 2,5-dihydropyrrole), 2H-pyrrole or 3H-pyrrole (isopyrrole, isoazole) or pyrrolidinone (5-membered ring), piperidine, dihydropyridine, tetrahydropyridine (6-membered ring), and azepine (7-membered ring); imidazoline, pyrazolidine (diazolidine), imidazoline, pyrazoline, pyrazolidine ... Those containing two nitrogen atoms, such as phosphorus (dihydropyrazole) (5-membered ring) and piperazine (6-membered ring); those containing one oxygen atom, such as oxirane (3-membered ring), oxetane (4-membered ring), oxolane (tetrahydrofuran), oxole (dihydrofuran) (5-membered ring), oxane (tetrahydropyran), dihydropyran, pyran (6-membered ring), and oxepin (7-membered ring); those containing two oxygen atoms, such as dioxolane (5-membered ring), dioxane (6-membered ring), and dioxepane (7-membered ring); trioxane Those containing three oxygen atoms, such as thiirane (6-membered ring); those containing one sulfur, such as thiirane (3-membered ring), thietane (4-membered ring), thiolane (tetrahydrothiophene) (5-membered ring), thiane (tetrahydrothiopyran) (6-membered ring), and thiepane (7-membered ring); those containing one nitrogen and one oxygen, such as tetrahydrooxazole, dihydrooxazole, tetrahydroisoxazole, dihydroisoxazole (5-membered ring), morpholine, tetrahydrooxazine, dihydrooxazine, and oxazine (6-membered ring). those containing one nitrogen and one sulfur atom, such as thiazoline, thiazolidine (5-membered ring), and thiomorpholine (6-membered ring); those containing two nitrogen and one oxygen atom, such as oxadiazine (6-membered ring); those containing one oxygen and one sulfur atom, such as oxathiol (5-membered ring) and oxathiane (thioxane) (6-membered ring); and those containing one nitrogen, one oxygen, and one sulfur atom, such as oxathiazine (6-membered ring).

[0142] Heterocyclyl also encompasses heteroaryl (aromatic heterocyclyl) and heterocycloalkyl (non-aromatic heterocyclyl). Such groups may be substituted or unsubstituted.

[0143] The term "aromatic heterocyclyl" can be used interchangeably with the term "heteroaromatic" or the terms "heteroaryl" or "hetaryl." The heteroatoms in an aromatic heterocyclyl group can be independently selected from N, S, and O. An aromatic heterocyclyl group can contain 1, 2, 3, 4, or more ring heteroatoms. A heteroaryl group can be denoted by the prefix C n1~n2 or "n1-n2", this prefix indicates the number of carbon atoms in the corresponding aryl group, where one or more, preferably 1, 2, 3, 4 or more, of the ring atoms are replaced with a heteroatom. In the case of fused aromatic heterocyclyl groups, only one of the rings may contain a heteroatom, and all rings need not be aromatic.

[0144] As used herein, "heteroaryl" is used to refer to a heterocycle having aromatic character and includes aromatic monocyclic ring systems and polycyclic (e.g., bicyclic) ring systems containing one or more aromatic rings. The term aromatic heterocyclyl also includes pseudoaromatic heterocyclyl. The term "pseudoaromatic" refers to a ring system that is not strictly aromatic but is stabilized by electron delocalization and behaves in a manner similar to an aromatic ring. Thus, the term aromatic heterocyclyl includes polycyclic ring systems in which all of the fused rings are aromatic, provided that at least one ring is aromatic, as well as ring systems in which one or more rings are non-aromatic. In polycyclic ring systems containing both aromatic and non-aromatic rings fused together, groups may be attached to another moiety by either the aromatic ring or the non-aromatic ring.

[0145] Examples of heteroaryl groups are monocyclic and bicyclic groups containing 5 to 10 ring members. Heteroaryl groups can be, for example, 5- or 6-membered monocyclic rings, or bicyclic structures formed from fused 5- and 6-membered rings, or two fused 6-membered rings, or two fused 5-membered rings. Each ring can contain up to about four heteroatoms, typically selected from nitrogen, sulfur, and oxygen. Heteroaryl rings contain up to four heteroatoms, more typically up to three heteroatoms, and more usually up to two heteroatoms, e.g., a single heteroatom. In one embodiment, a heteroaryl ring contains at least one ring nitrogen atom. The nitrogen atoms in a heteroaryl ring can be basic, as in the case of imidazole or pyridine, or essentially non-basic, as in the case of indole or pyrrole nitrogens. Generally, the number of basic nitrogen atoms present in a heteroaryl group, including any amino group substituents on the ring, is less than five.

[0146] An aromatic heterocyclyl group can be a 5- or 6-membered monocyclic aromatic ring system.

[0147] Examples of 5-membered monocyclic heteroaryl groups include, but are not limited to, furanyl, thienyl, pyrrolyl, oxazolyl, oxadiazolyl (including 1,2,3 and 1,2,4 oxadiazolyl and furazanyl, i.e., 1,2,5-oxadiazolyl), thiazolyl, isoxazolyl, isothiazolyl, pyrazolyl, imidazolyl, triazolyl (including 1,2,3, 1,2,4 and 1,3,4 triazolyl), oxatriazolyl, tetrazolyl, thiadiazolyl (including 1,2,3 and 1,3,4 thiadiazolyl), and the like.

[0148] Examples of 6-membered monocyclic heteroaryl groups include, but are not limited to, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, pyranyl, oxazinyl, dioxinyl, thiazinyl, thiadiazinyl, etc. Examples of 6-membered aromatic heterocyclyls containing nitrogen include pyridyl (one nitrogen), pyrazinyl, pyrimidinyl, and pyridazinyl (two nitrogens).

[0149] The aromatic heterocyclyl group may also be a bicyclic or polycyclic heteroaromatic ring system, such as a fused ring system (including purine, pteridinyl, naphthyridinyl, 1H-thieno[2,3-c]pyrazolyl, thieno[2,3-b]furyl, etc.) or a linked ring system (oligothiophene, polypyrrole, etc.). Fused ring systems may also include 5- or 6-membered heterocyclyls fused to a carbocyclic aromatic ring such as phenyl, naphthyl, indenyl, azulenyl, fluorenyl, anthracenyl, etc., e.g., a 5-membered aromatic heterocyclyl containing a nitrogen atom fused to a phenyl ring, a 5-membered aromatic heterocyclyl containing one or two nitrogen atoms fused to a phenyl ring.

[0150] Bicyclic heteroaryl groups include, for example, a) a benzene ring fused to a 5- or 6-membered ring containing 1, 2, or 3 ring heteroatoms, b) a pyridine ring fused to a 5- or 6-membered ring containing 1, 2, or 3 ring heteroatoms, c) a pyrimidine ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms, d) a pyrrole ring fused to a 5- or 6-membered ring containing 1, 2, or 3 ring heteroatoms, e) a pyrazole ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms, f) an imidazole ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms, g) an oxazole ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms. h) an isoxazole ring fused to a 5- or 6-membered ring containing one or two ring heteroatoms; i) a thiazole ring fused to a 5- or 6-membered ring containing one or two ring heteroatoms; j) an isothiazole ring fused to a 5- or 6-membered ring containing one or two ring heteroatoms; k) a thiophene ring fused to a 5- or 6-membered ring containing one, two, or three ring heteroatoms; l) a furan ring fused to a 5- or 6-membered ring containing one, two, or three ring heteroatoms; m) a cyclohexyl ring fused to a 5- or 6-membered ring containing one, two, or three ring heteroatoms; and n) a cyclopentyl ring fused to a 5- or 6-membered ring containing one, two, or three ring heteroatoms.

[0151] Particular examples of bicyclic heteroaryl groups containing a 5-membered ring fused to another 5-membered ring include, but are not limited to, imidazothiazoles (e.g., imidazo[2,1-b]thiazole) and imidazoimidazoles (e.g., imidazo[1,2-a]imidazole).

[0152] Specific examples of bicyclic heteroaryl groups containing a 6-membered ring fused to a 5-membered ring include, but are not limited to, benzofuran, benzothiophene, benzimidazole, benzoxazole, isobenzoxazole, benzisoxazole, benzothiazole, benzisothiazole, isobenzofuran, indole, isoindole, indolizine, indoline, isoindoline, purine (e.g., adenine, guanine), indazole, pyrazolopyrimidine (e.g., pyrazolo[1,5-a]pyrimidine), benzodioxole, and pyrazolopyridine (e.g., pyrazolo[1,5-a]pyridine) groups. A further example of a 6-membered ring fused to a 5-membered ring is a pyrrolopyridine group, such as a pyrrolo[2,3-b]pyridine group.

[0153] Particular examples of bicyclic heteroaryl groups containing two fused six-membered rings include, but are not limited to, quinoline, isoquinoline, chroman, thiochroman, chromene, isochromene, isochroman, benzodioxane, quinolizine, benzoxazine, benzodiazine, pyridopyridine, quinoxaline, quinazoline, cinnoline, phthalazine, naphthyridine, and pteridine groups.

[0154] Examples of heteroaryl groups containing aromatic and non-aromatic rings include tetrahydronaphthalene, tetrahydroisoquinoline, tetrahydroquinoline, dihydrobenzothiophene, dihydrobenzofuran, 2,3-dihydro-benzo[1,4]dioxine, benzo[1,3]dioxole, 4,5,6,7-tetrahydrobenzofuran, indoiine, isoindoline, and indane groups.

[0155] Thus, examples of aromatic heterocycles fused to carbocyclic aromatic rings include, but are not limited to, benzothiophenyl, indolyl, isoindolyl, benzofuranyl, isobenzofuranyl, benzimidazolyl, indazolyl, benzoxazolyl, benzisoxazolyl, isobenzoxazolyl, benzothiazolyl, benzisothiazolyl, quinolinyl, isoquinolinyl, quinoxalinyl, quinazolinyl, cinnolinyl, benzotriazinyl, phthalazinyl, carbolinyl, and the like.

[0156] The term "heterocycloalkyl" or "non-aromatic heterocyclyl" includes optionally substituted saturated and unsaturated rings containing at least one heteroatom, such as N, S, and O, or heteromoiety, such as O, S, S(O), SO, N, and NH. The ring may contain 1, 2, 3, 4, or more heteroatoms or heteromoieties. Heterocycloalkyl groups are denoted by the prefix C. n1~n2 or "n1-n2," the prefix indicates the number of carbon atoms in the corresponding carbocyclic group, with one or more, preferably one, two, three, four, or more, of the ring atoms being replaced with a heteroatom or heteromoiety. A ring can be a monocyclic ring or part of a polycyclic ring system. Polycyclic ring systems include fused rings and spiro rings. Not all rings in a non-aromatic heterocyclic polycyclic ring system must contain heteroatoms, provided that at least one ring contains one or more heteroatoms.

[0157] The non-aromatic heterocyclyl can be a 3- to 8-membered monocyclic ring.

[0158] Examples of 5-membered non-aromatic heterocyclyl rings include 2H-pyrrolyl, 1-pyrrolinyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrrolidinyl, 1-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrazolinyl, 2-pyrazolinyl, 3-pyrazolinyl, pyrazolidinyl, 2-pyrazolidinyl, 3-pyrazolidinyl, imidazolidinyl, 3-dioxalanyl, thiazolidinyl, isoxazolidinyl, 2-imidazolinyl, and the like.

[0159] Examples of 6-membered non-aromatic heterocyclyls include piperidinyl, piperidinonyl, pyranyl, dihydropyranyl, tetrahydropyranyl, 2H-pyranyl, 4H-pyranyl, thianyl, thianyloxide, thianyldioxide, piperazinyl, diozanyl, 1,4-dioxinyl, 1,4-dithianyl, 1,3,5-triozalanyl, 1,3,5-trithianyl, 1,4-morpholinyl, thiomorpholinyl, 1,4-oxathianyl, triazinyl, 1,4-thiazinyl, and the like.

[0160] Examples of 7-membered non-aromatic heterocyclyls include azepanyl, oxepanyl, thiepanyl, and the like.

[0161] Non-aromatic heterocyclyl rings can also be bicyclic heterocyclyl rings, such as linked ring systems (e.g., uridinyl, etc.) or fused ring systems. Fused ring systems include non-aromatic 5-, 6-, or 7-membered heterocyclyls fused to a carbocyclic aromatic ring, such as phenyl, naphthyl, indenyl, azulenyl, fluorenyl, anthracenyl, etc. Examples of non-aromatic 5-, 6-, or 7-membered heterocyclyls fused to a carbocyclic aromatic ring include indolinyl, benzodiazepinyl, benzazepinyl, dihydrobenzofuranyl, etc.

[0162] The term "alkyleneheteroaryl" refers to a radical having an alkyl component and a heteroaryl component, where the alkyl component connects the heteroaryl component to the point of attachment. The alkyl component is as defined above, except that the alkyl component is at least a divalent alkylene and connects the heteroaryl component to the point of attachment. In some cases, the alkyl component may be absent. The alkyl component may be any of C 1~6 , C 1~2 , C 1~3 , C 1~4 , C 1~5 , C 2~3 , C 2~4 , C 2~5 , C 2~6 , C 3~4 , C3~5 , C 3~6 , C 4~5 , C 4~6 , and C 5~6 The heteroaryl moiety is as defined herein. x~y Alkylene Heteroaryl 」 The numerical range of x to y relates to the total number of alkyl carbon and heteroaryl ring atoms (carbon and heteroatoms combined).

[0163] The term "alkyleneheterocycloalkyl" refers to a radical having an alkyl component and a heterocycloalkyl component, where the alkyl component connects the heterocycloalkyl component to the point of attachment. The alkyl component is as defined above, except that the alkyl component is at least a divalent alkylene and connects the heterocycloalkyl component to the point of attachment. In some cases, the alkyl component may be absent. The alkyl component may be any of C 1~6 , C 1~2 , C 1~3 , C 1~4 , C 1~5 , C 2~3 , C 2~4 , C 2~5 , C 2~6 , C 3~4 , C 3~5 , C 3~6 , C 4~5 , C 4~6 , and C 5~6 Heterocycloalkyl moieties are as defined herein. x~y The numerical range of x to y for "alkyleneheterocycloalkyl" relates to the total number of alkyl carbons and heterocycloalkyl ring atoms (carbons and heteroatoms combined).

[0164] As used herein, the term solvate refers to a complex of a compound with a solvent, either stoichiometric or non-stoichiometric.Solvates are often formed during the crystallization process using pharmaceutically acceptable solvents such as water, ethanol, etc. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol.

[0165] As used herein, the term "polymorph" refers to different crystal packing arrangements of a compound with the same elemental composition. Polymorphs typically have different X-ray diffraction patterns, infrared spectra, melting points, densities, hardnesses, crystal shapes, optical and electrical properties, stability, and solubility. Depending on various factors such as the recrystallization solvent, crystallization rate, and storage temperature, a single crystalline form may predominate.

[0166] As used herein, the term "metabolite" refers to a derivative of a compound that is formed when the compound is metabolized. The term "active metabolite" refers to a biologically active derivative of a compound that is formed when the compound is metabolized. As used herein, the term "metabolized" refers to the sum of processes by which a particular substance is transformed by an organism, including, but not limited to, hydrolysis reactions and reactions catalyzed by enzymes. Thus, enzymes may cause specific structural changes to the compound. Metabolites of the compounds disclosed herein are optionally identified by either administering the compound to a host and analyzing tissue samples from the host, or by incubating the compound with hepatocytes in vitro and analyzing the resulting compound.

[0167] The definitions and conventions of stereochemistry used herein generally follow those of S.P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York, and Eliel, E. and Wilen, S., "Stereochemistry of Organic Compounds", John Wiley & Sons, Inc., New York, 1994. The compounds of the present invention may contain asymmetric or chiral centers and, therefore, exist in different stereoisomeric forms. The term "stereoisomers" refers to compounds that have identical chemical constitution but differ with regard to the arrangement of atoms or groups in space. As used herein, the term "stereoisomers" includes, but is not limited to, diastereomers, enantiomers, and atropisomers, as well as mixtures thereof, such as racemic mixtures.

[0168] As used herein, the term "pharmaceutically acceptable salt" refers to a salt that is, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic reaction, etc., commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, S.M. Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences 1977, 66, 1-19, incorporated herein by reference. Pharmaceutically acceptable salts of the compounds of this invention include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable non-toxic acid addition salts are salts of amino groups formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid, or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid, or by using other methods used in the art, such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, nate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like.

[0169] Compound form For compounds that are solids, it will be understood by those skilled in the art that the compounds, agents, and salts of the invention may exist in different crystalline or polymorphic forms, all of which are intended to be within the scope of the invention and the specified formulas.

[0170] The present invention includes all crystalline forms of the compounds of formula (I), including anhydrous crystalline forms, hydrates, solvates, and mixed solvates. If any of these crystalline forms exhibit polymorphism, all polymorphs are within the scope of the invention.

[0171] Formula (I) is intended to encompass solvated and unsolvated forms of the compounds, where applicable. Thus, Formula (I) includes compounds having the indicated structure, including hydrated or solvated forms, as well as unhydrated and unsolvated forms.

[0172] The compound of formula (I), or its salt, tautomer, N-oxide, polymorph, or prodrug, may be provided in the form of a solvate. Solvates contain either stoichiometric or non-stoichiometric amounts of solvent and may be formed during the crystallization process using pharmaceutically acceptable solvents such as water, alcohols such as methanol, ethanol, or isopropyl alcohol, DMSO, acetonitrile, dimethylformamide (DMF), acetic acid, etc., where the solvate forms a part of the crystalline lattice either by non-covalent bonding or by occupying holes in the crystalline lattice. Hydrates are formed when the solvent is water, and alcoholates are formed when the solvent is alcohol. Solvates of the compounds of the present invention may be conveniently prepared or formed during the processes described herein. In general, solvated forms are considered equivalent to unsolvated forms for the purposes of the present invention.

[0173] Basic nitrogen-containing groups include C groups such as methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides. 1~6 It may be quaternized with agents such as alkyl halides; dialkyl sulfates such as dimethyl and diethyl sulfate.

[0174] Nitrogen-containing groups can also be oxidized to form N-oxides.

[0175] Compounds of formula (I), or salts, tautomers, N-oxides, solvates, and / or prodrugs thereof, that form crystalline solids may exhibit polymorphism. All polymorphic forms of the compounds, salts, tautomers, N-oxides, solvates, and / or prodrugs are within the scope of the present invention.

[0176] The compounds of formula (I) may exhibit tautomerism. Tautomers are two interchangeable forms of a molecule that typically exist in equilibrium. It should be understood that any tautomer of the compounds of formula (I) is within the scope of the present invention.

[0177] The compound of formula (I) may contain one or more stereocenters. All stereoisomers of the compound of formula (I) are within the scope of the present invention. Stereoisomers include enantiomers, diastereomers, geometric isomers (E and Z olefin forms and cis and trans substitution patterns), and atropisomers. In some embodiments, the compound is a stereoisomerically enriched form of the compound of formula (I) at any stereocenter. The compound may be enriched in one stereoisomer by at least about 60, 70, 80, 90, 95, 98, or 99% over another stereoisomer.

[0178] The compounds of formula (I), or salts, tautomers, solvates, N-oxides, and / or stereoisomers thereof, may be isotopically enriched with one or more of the isotopes of atoms present in the compounds. For example, the compounds may be enriched with one or more of the following minor isotopes: 2 H, 3 H, 13 C. 14 C. 15 N, and / or 17 O, preferably 2 H. An isotope can be considered enriched if its abundance is greater than its natural abundance.

[0179] A "prodrug" is a compound that may not fully meet the structural requirements of the compounds provided herein, but is modified in vivo after administration to a subject or patient to produce a compound of Formula (I) provided herein. For example, a prodrug can be an acylated derivative of a compound provided herein. Prodrugs include compounds in which a hydroxy, carboxy, amine, or sulfhydryl group is bonded to any group that cleaves upon administration to a mammalian subject to form a free hydroxy, carboxy, amino, or sulfhydryl group, respectively. Examples of prodrugs include, but are not limited to, acetate, formate, phosphate, and benzoate derivatives of alcohol and amine functional groups within the compounds provided herein. Prodrugs of the compounds provided herein can be prepared by modifying functional groups present in the compound in such a way that the modifications are cleaved in vivo to produce the parent compound.

[0180] Prodrugs include compounds in which an amino acid residue, or a polypeptide chain of two or more (e.g., two, three, or four) amino acid residues, is covalently bonded to the free amino and amide groups of a compound of Formula (I). Amino acid residues include the 20 naturally occurring amino acids commonly designated by their three-letter symbols, and also include 4-hydroxyproline, hydroxylysine, demosin, isodesin, 3-methylhistidine, norbuline, beta-alanine, gamma-aminobutyric acid, citrulline, homocysteine, homoserine, ornithine, and methionine sulfone. Prodrugs also include compounds in which carbonates, carbamates, amides, and alkyl esters are covalently bonded to the foregoing substituents of Formula (I) via the carbonyl carbon prodrug side chain.

[0181] Compositions, Formulations, and Modes of Administration The compound of formula (I) can be administered alone or in the form of a pharmaceutical composition. In practice, the compound of formula (I) is usually administered in the form of a pharmaceutical composition, i.e., mixed with at least one pharmaceutically acceptable excipient. The proportion and nature of any pharmaceutically acceptable excipient are determined by the properties of the selected compound of the invention, the selected route of administration, and standard pharmaceutical practice.

[0182] In another embodiment, there is provided a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate, metabolite, or polymorph thereof, and at least one pharmaceutically acceptable excipient.

[0183] Pharmaceutical compositions of the present disclosure typically contain a therapeutically effective amount of one or more active ingredients in admixture with one or more pharmaceutically and physiologically acceptable formulation materials. Suitable formulation materials include, but are not limited to, antioxidants, preservatives, colorants, flavorings and diluents, emulsifiers, suspending agents, solvents, fillers, extenders, buffers, delivery vehicles, diluents, excipients, and / or pharmaceutical adjuvants. For example, a suitable vehicle can be water for injection, physiological saline solution, or artificial perineal fluid, optionally supplemented with other materials common to compositions for parenteral administration. Neutral buffered saline or saline mixed with serum albumin are further exemplary vehicles.

[0184] The pharmaceutical compositions of the present disclosure further comprise a pharmaceutically acceptable carrier, including any solvents, diluents, or other liquid vehicles, dispersing or suspending aids, surfactants, isotonicity agents, thickening or emulsifying agents, preservatives, solid binders, lubricants, and the like, as used herein, appropriate for the particular dosage form desired. Remington's Pharmaceutical Sciences, Sixteenth Edition, E.W. Martin (Mack Publishing Co., Easton, Pa., 1980) discloses various carriers used in formulating pharmaceutical compositions and known techniques for their preparation. Except insofar as any conventional carrier medium is incompatible with the compounds of the present invention, such as by producing any undesirable biological effects or otherwise interacting in a deleterious manner with other components of the pharmaceutical composition, its use is contemplated within the scope of the present disclosure. Some examples of materials which can function as pharmaceutically acceptable carriers include sugars such as lactose, glucose, and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethylcellulose, ethyl cellulose, and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients such as cocoa butter and suppository wax; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; glycols such as protease inhibitors; isotonic saline; Ringer's solution; ethyl alcohol, and phosphate buffer, as well as other non-toxic compatible lubricants, such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, releasing agents, coating agents, sweetening agents, flavoring agents, and perfuming agents, but are not limited to, preservatives and antioxidants can also be present in the composition, according to the judgment of the formulator.

[0185] The various dosage units are preferably each provided as separate dosage tablets, capsules, troches, dragees, gums, or other types of solid formulations. Capsules may encapsulate powders, liquids, or gels. Solid formulations may be swallowed or may be of the slurpable or chewable type (either friable or gummy). The present invention contemplates dosage unit-holding devices other than blister packs, such as bottles, tubes, canisters, packets, and other packaging. The dosage units may further comprise conventional excipients well known in the practice of pharmaceutical formulation, such as binders, gelling agents, fillers, tableting lubricants, disintegrants, surfactants, and colorants, as well as slurpable or chewable formulations.

[0186] The compounds of formula (I) may be administered in any form and by any route that makes the compound bioavailable.

[0187] The compositions disclosed herein can be administered systemically or directly to the site of the condition or disease.

[0188] The compositions described herein can be formulated from the compounds according to Formula (I) for any suitable route of administration, including, for example, oral, rectal, nasal, vaginal, topical (including transdermal, buccal, ocular, and sublingual), parenteral (subcutaneous, intraperitoneal, intradermal, intravascular (e.g., intravenous), intramuscular, spinal, intracranial, intrathecal, intraocular, periocular, intraorbital, intrasynovial, and intraperitoneal injection, intracisternal injection, and other similar injection or infusion techniques), inhalation, insufflation, injection, or implantation techniques (e.g., as a sterile injectable aqueous or non-aqueous solution or suspension). In some embodiments, the compositions described herein can be administered orally, nasally, intravenously, intramuscularly, topically, subcutaneously, rectally, vaginally, or by urethral application.

[0189] Compositions intended for oral use may further contain one or more ingredients, such as sweeteners, flavoring agents, coloring agents, and / or preservatives, to provide an attractive and palatable preparation. Tablets contain the active ingredient in admixture with physiologically acceptable excipients suitable for tablet manufacture. Such excipients include, for example, inert diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate, or sodium phosphate; granulating and disintegrating agents such as corn starch or alginic acid; binders such as starch, gelatin, or acacia; and lubricants such as magnesium stearate, stearic acid, or talc. Tablets may be uncoated or may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract, thereby providing a sustained action over a longer period. For example, a time-delay material, such as glyceryl monostearate or glyceryl distearate, may be used.

[0190] Formulations for oral use may also be presented as hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent such as calcium carbonate, calcium phosphate, or kaolin, or as soft gelatin capsules in which the active ingredient is mixed with water or an oil medium such as peanut oil, liquid paraffin, or olive oil.

[0191] Oily suspensions can be formulated by suspending the active ingredient in vegetable oils such as arachis oil, olive oil, sesame oil or coconut oil, or mineral oils such as liquid paraffin.Oily suspensions can contain thickening agents such as beeswax, hard paraffin or cetyl alcohol.Sweeteners and / or flavoring agents such as those described above can be added to provide a palatable oral preparation.Such suspensions can be preserved by adding antioxidants such as ascorbic acid.

[0192] Dispersible powders and granules suitable for preparing an aqueous suspension by adding water provide the active ingredient in admixture with a dispersing or wetting agent, a suspending agent, and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients such as sweeteners, flavoring agents, and coloring agents may also be present.

[0193] The pharmaceutical composition can also be in the form of an oil-in-water emulsion.The oil phase can be vegetable oil such as olive oil or arachis oil, mineral oil such as liquid paraffin, or a mixture thereof.Suitable emulsifiers include naturally occurring gums such as acacia gum or tragacanth gum, naturally occurring phosphatides such as soybean lecithin, and esters or partial esters derived from fatty acids and hexitols, anhydrides such as sorbitan monooleate, and condensation products of partial esters derived from fatty acids and hexitols with ethylene oxide such as polyoxyethylene sorbitan monooleate.The emulsion can also contain one or more sweeteners and / or flavoring agents.

[0194] Syrups and elixirs may be formulated with sweetening agents, such as glycerol, propylene glycol, sorbitol or sucrose, and may also contain one or more analgesic agents, preservatives, flavorings, and / or coloring agents.

[0195] The composition may further comprise one or more ingredients adapted to improve the stability or effectiveness of the applied formulation, such as stabilizers, suspending agents, emulsifiers, viscosity adjusters, gelling agents, preservatives, antioxidants, skin penetration enhancers, moisturizers, and sustained-release materials. Examples of such ingredients are described in Martindale-The Extra Pharmacopoeia (Pharmaceutical Press, London 1993) and Martin (ed.), Remington's Pharmaceutical Sciences. The formulation may comprise microcapsules, such as hydroxymethylcellulose or gelatin microcapsules, liposomes, albumin microparticles, microemulsions, nanoparticles, or nanocapsules.

[0196] Preservatives include, but are not limited to, antibacterial agents such as methylparaben, propylparaben, sorbic acid, benzoic acid, and formaldehyde, as well as physical stabilizers and antioxidants such as vitamin E, sodium ascorbate / ascorbic acid, and propyl gallate. Suitable moisturizers include, but are not limited to, lactic acid and other hydroxy acids and their salts, glycerin, propylene glycol, and butylene glycol. Suitable emollients include lanolin alcohol, lanolin, lanolin derivatives, cholesterol, petrolatum, isostearyl neopentanoate, and mineral oil. Suitable fragrances and colors include, but are not limited to, FD&C Red No. 40 and FD&C Yellow No. 5. Other suitable additional ingredients that may be included in topical formulations include, but are not limited to, abrasives, absorbents, anti-caking agents, anti-foaming agents, anti-static agents, astringents (such as witch hazel), alcohols and herbal extracts such as chamomile extract, binders / excipients, buffers, chelating agents, film formers, conditioning agents, propellants, opacifying agents, pH adjusters, and protectants.

[0197] Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs. In addition to the active compound, liquid dosage forms may contain inert diluents commonly used in the art, such as water or other solvents, solubilizers, and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (e.g., cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, and sesame oil), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycol, and fatty acid esters of sorbitan, and mixtures thereof. In addition to inert diluents, oral compositions may also contain adjuvants, such as wetting agents, emulsifiers and suspending agents, sweeteners, flavoring agents, and flavoring agents.

[0198] Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions, can be formulated by known techniques using suitable dispersing or wetting agents and suspending agents. Sterile injectable preparations can also be sterile injectable solutions, suspensions, or emulsions in non-toxic parenterally acceptable diluents or solvents, for example, as solutions in 1,3-butanediol. Acceptable vehicles and solvents that can be used include water, Ringer's solution, USP, and isotonic sodium chloride solution. In addition, sterile fixed oils are conventionally used as solvents or suspending media. For this purpose, any non-irritating fixed oil can be used, including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid can be used in the preparation of injectables.

[0199] Injectable formulations can be sterilized, for example, by filtration through a bacteria-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium before use.

[0200] Pharmaceutical compositions can be formulated as inhalation formulations, including sprays, mists, or aerosols. In the case of inhalation formulations, the compositions or combinations provided herein can be delivered via any inhalation method known to those skilled in the art. Such inhalation methods and devices include, but are not limited to, metered-dose inhalers with propellants such as CFCs or HFAs or physiologically and environmentally acceptable propellants. Other suitable devices are breath-actuated inhalers, multi-dose dry powder inhalers, and aerosol nebulizers. Aerosol formulations for use in the subject methods typically contain propellants, surfactants, and cosolvents and can be filled into conventional aerosol containers closed with a suitable metering valve.

[0201] Inhalant compositions may include liquid or powder compositions containing the active ingredient suitable for nebulization and intrabronchial use, or aerosol compositions administered via an aerosol unit that dispenses a metered dose. Suitable liquid compositions contain the active ingredient in an aqueous, pharmaceutically acceptable inhalant solvent, such as isotonic saline or bacteriostatic water. The solution is administered by a pump or push-actuated atomizing spray dispenser, or by other conventional means that cause or enable the required dosage of the liquid composition to be inhaled into the patient's lungs. For example, suitable formulations in which the carrier is a liquid for administration as a nasal spray or nasal drops include aqueous or oily solutions of the active ingredient.

[0202] Compositions suitable for rectal administration are preferably presented as unit-dose suppositories, which may be prepared by at least partially dispersing the active ingredient in one or more lipophilic bases and then forming a mixture.

[0203] Pharmaceutical compositions can be formulated as sustained-release formulations, such as capsules, that produce a sustained release of the active substance after administration. Such formulations can generally be prepared using well-known techniques and can be administered, for example, by oral, rectal, or subcutaneous implantation, or by implantation at the desired target site. The carriers used in such formulations can be biocompatible and biodegradable. Preferably, the formulation provides a relatively constant level of active substance release. The amount of active substance contained in a sustained-release formulation depends, for example, on the implantation site, the rate and expected duration of release, and the nature of the condition to be treated.

[0204] Those skilled in the art can readily select an appropriate dosage form and route of administration depending on the particular characteristics of the compound selected, the disease or condition to be treated, the stage of the disease or condition, and other relevant circumstances.

[0205] It will be understood that the specific dose level for any particular patient will depend on a variety of factors, including the activity of the particular compound used, age, body weight, general health, sex, diet, time of administration, route of administration, number of doses, and rate of excretion, drug concomitant use (i.e., other drugs being used to treat the patient), and the severity of the particular disorder being treated.

[0206] The phrase "therapeutically effective amount" generally refers to an amount of one or more active ingredients of the present invention that (i) treats a particular disease, condition, or disorder, (ii) attenuates, ameliorate, or eliminates one or more signs or symptoms of a particular disease, condition, or disorder, or (iii) delays the onset of one or more signs or symptoms of a particular disease, condition, or disorder described herein.

[0207] Typically, therapeutically effective dosages are formulated to include concentrations (by weight) of at least about 0.1% up to about 50% or more, and all combinations and subcombinations of ranges therein. Compositions may be formulated to contain one or more actives described herein in a concentration of about 0.1 to less than about 50%, e.g., about 49, 48, 47, 46, 45, 44, 43, 42, 41, or 40%, with concentrations greater than about 0.1%, e.g., about 0.2, 0.3, 0.4, or 0.5%, to less than about 40%, e.g., about 39, 38, 37, 36, 35, 34, 33, 32, 31, or 30%. Exemplary compositions may contain from about 0.5% to less than about 30%, e.g., about 29, 28, 27, 26, 25, 25, 24, 23, 22, 21, or 20%, with concentrations greater than about 0.5%, e.g., about 0.6, 0.7, 0.8, 0.9, or 1% to less than about 20%, e.g., about 19, 18, 17, 16, 15, 14, 13, 12, 11, or 10%. Compositions may contain greater than about 1%, e.g., about 2% to less than about 10%, e.g., about 9 or 8%, including concentrations greater than about 2%, e.g., about 3 or 4% to less than about 8%, e.g., about 7 or 6%. Active agents may be present, for example, at a concentration of about 5%. In all cases, amounts may be adjusted to compensate for differences in the amount of active ingredient actually delivered to the treated cells or tissue.

[0208] The frequency of administration can be once daily, two, three, or four times daily. The duration of treatment can be for the duration of detectable disease.

[0209] In some embodiments, the pharmaceutical composition comprises a compound according to any one of the embodiments disclosed herein, or a pharmaceutically acceptable salt, solvate, tautomer, N-oxide, stereoisomer, metabolite, polymorph, or prodrug thereof, an additional therapeutic agent, and a pharmaceutically acceptable excipient.

[0210] The additional agent can be any suitable agent described herein. In some embodiments, the additional agent is a psychoactive agent, including those described herein. In some embodiments, the additional agent is useful for treating a disease, disorder, or condition caused by activation of a serotonin receptor, including those described herein. In some embodiments, the additional agent is selected from any one of the following, including those described herein: an agent for a psychotic and / or neuropsychiatric condition; an agent for a psychotic and / or psychotic condition; an agent for attention deficit hyperactivity disorder and / or attention deficit disorder; an agent for dementia and / or Alzheimer's disease; and an agent for an addictive disorder.

[0211] Purpose The present disclosure provides methods of using the compounds and compositions of formula (I) described in any one of the preceding paragraphs. The present disclosure also provides methods of delivering a compound or composition of formula (I) of the present disclosure (e.g., an effective amount of the compound or composition) to a subject in need thereof.

[0212] In another aspect, the present disclosure provides a method of treating a disease in a subject in need thereof, comprising administering to the subject in need thereof an effective amount (e.g., a therapeutically effective amount) of a compound or composition (e.g., a pharmaceutical composition) of the present disclosure.

[0213] In another aspect, the present disclosure provides a method of preventing a disease in a subject in need of such treatment, comprising administering to a subject in need thereof an effective amount (e.g., a therapeutically effective amount) of a compound of formula (I) or a composition (e.g., a pharmaceutical composition) of the present disclosure.

[0214] Provided herein, in another aspect, is the use of a compound of formula (I) or composition of the present disclosure in the manufacture of a medicament for use in a method of the present disclosure (e.g., a method of delivering an active agent to a subject in need thereof, a method of treating a disease in a subject in need thereof, a method of preventing a disease in a subject in need thereof).

[0215] Provided herein, in another aspect, is the use of a compound of formula (I) or composition of the present disclosure in a method of the present disclosure (e.g., a method of delivering an active agent to a subject in need thereof, a method of treating a disease in a subject in need thereof, a method of preventing a disease in a subject in need thereof).

[0216] In certain embodiments, the effective amount is effective in treating a disease. In certain embodiments, the effective amount is effective in preventing a disease.

[0217] In another aspect, the present disclosure provides a method of treating a disease, disorder, or condition through activation of a serotonin receptor, the method comprising administering to a subject in need thereof a compound of formula (I) or a pharmaceutical composition described herein.

[0218] In another aspect, the present disclosure provides a method for preventing a disease, disorder, or condition through activation of a serotonin receptor, the method comprising administering to a subject in need thereof a compound of formula (I) or a pharmaceutical composition described herein.

[0219] In another aspect, the present disclosure provides a method of treating a disease, disorder, or condition through activation of a serotonin receptor, the method comprising administering to a subject in need thereof a compound of Formula (I) or a pharmaceutical composition described herein in combination with another known agent useful for treating a disease, disorder, or condition through activation of a serotonin receptor. The other known agent useful for treating a disease, disorder, or condition through activation of a serotonin receptor can be any suitable agent known in the art, including those described herein.

[0220] In another aspect, the disclosure provides a method for preventing a disease, disorder, or condition through activation of a serotonin receptor, the method comprising administering to a subject in need thereof a compound of formula (I) or a pharmaceutical composition described herein in combination with another known agent useful for preventing a disease, disorder, or condition through activation of a serotonin receptor.

[0221] In certain embodiments, the serotonin receptor is 5-HT 2A is.

[0222] In certain embodiments, the serotonin receptor is 5-HT 2A and 5-HT 2C Additionally or alternatively, in some embodiments, the serotonin receptor is one or both of 5-HT 2B isn't it.

[0223] In some embodiments, the compounds of formula (I) of the present disclosure are 5-HT 2C Receptors and 5-HT 2B Preferably 5-HT relative to one or both of the receptors 2B Compared to receptors, 5-HT 2A In some embodiments, the compounds of formula (I) are selective for the 5-HT receptor. 2A Receptors and 5-HT 2B Preferably 5-HT relative to one or both of the receptors 2B Compared to receptors, 5-HT 2CIn some embodiments, the compounds of formula (I) are selective for the 5-HT receptor. 2B Compared to receptors, 5-HT 2A Receptors and 5-HT 2C It is selective for the receptor.

[0224] In some embodiments, compounds of formula (I) of the present disclosure have a 5-HT activity of less than about 1 mM, less than about 100 μM, less than about 10 μM, less than about 1 μM, or less than about 100 nM, or less than about 10 nM, as determined by an assay described herein, e.g., an assay of calcium flux activity, such as measuring changes in intracellular calcium. 2A EC for receptors 50 In some embodiments, the compounds of Formula (I) exhibit a calcium flux activity of less than about 1 mM, less than about 900 μM, less than about 800 μM, less than about 700 μM, less than about 600 μM, less than about 500 μM, less than about 400 μM, less than about 300 μM, less than about 200 μM, less than about 100 μM, less than about 90 μM, less than about 80 μM, less than about 70 μM, less than about 60 μM, less than about 50 μM, less than about 40 μM, less than about 30 μM, as determined by an assay for calcium flux activity. less than about 20 μM, less than about 10 μM, less than about 9 μM, less than about 8 μM, less than about 7 μM, less than about 6 μM, less than about 5 μM, less than about 4 μM, less than about 3 μM, less than about 2 μM, less than about 1 μM, less than about 900 nM, less than about 800 nM, less than about 700 nM, less than about 600 nM, less than about 500 nM, less than about 400 nM, less than about 300 nM, less than about 200 nM, or less than about 100 nM, or any equivalent unit of measure (e.g., mol / L) of 5-HT 2A EC for receptors 50 It presents.

[0225] In some embodiments, compounds of formula (I) of the present disclosure have a 5-HT activity of less than about 1 mM, less than about 100 μM, less than about 10 μM, less than about 1 μM, or less than about 100 nM, or less than about 10 nM, as determined by an assay described herein, e.g., an assay of calcium flux activity, such as measuring changes in intracellular calcium. 2C EC for receptors 50In some embodiments, the compounds of Formula (I) exhibit a calcium flux activity of less than about 1 mM, less than about 900 μM, less than about 800 μM, less than about 700 μM, less than about 600 μM, less than about 500 μM, less than about 400 μM, less than about 300 μM, less than about 200 μM, less than about 100 μM, less than about 90 μM, less than about 80 μM, less than about 70 μM, less than about 60 μM, less than about 50 μM, less than about 40 μM, less than about 30 μM, as determined by an assay for calcium flux activity. less than about 20 μM, less than about 10 μM, less than about 9 μM, less than about 8 μM, less than about 7 μM, less than about 6 μM, less than about 5 μM, less than about 4 μM, less than about 3 μM, less than about 2 μM, less than about 1 μM, less than about 900 nM, less than about 800 nM, less than about 700 nM, less than about 600 nM, less than about 500 nM, less than about 400 nM, less than about 300 nM, less than about 200 nM, or less than about 100 nM, or any equivalent unit of measure (e.g., mol / L) of 5-HT 2C EC for receptors 50 It presents.

[0226] In some embodiments, compounds of formula (I) of the present disclosure have a 5-HT activity greater than about 1 μM, greater than about 10 μM, or greater than about 100 μM as determined by an assay described herein, e.g., an assay of calcium flux activity, such as measuring changes in intracellular calcium. 2B EC for receptors 50 It presents value.

[0227] In some embodiments, the disease, disorder, or condition treated by activation of serotonin receptors is a psychotic or neuropsychiatric condition. Accordingly, the present application also includes a method for treating a psychotic or neuropsychiatric condition, comprising administering to a subject in need thereof a compound of Formula (I) or a composition described herein. The present application also includes the use of a compound of Formula (I) of the present disclosure for treating a psychotic or neuropsychiatric condition, and the use of a compound of Formula (I) of the present disclosure for preparing a medicament for treating a psychotic or neuropsychiatric condition. The present application further includes a compound of Formula (I) of the present disclosure for use in treating a psychotic or neuropsychiatric condition.

[0228] In some embodiments, the disease, disorder, or condition treated by activation of serotonin receptors is a psychotic or neuropsychiatric condition, and the compound of Formula (I) of the present disclosure is administered in combination with one or more additional medications for the psychotic or neuropsychiatric condition. The one or more additional medications for the psychotic or neuropsychiatric condition can be any suitable medication known in the art, including those described herein. In some embodiments, the additional medication for a psychotic or neuropsychiatric condition is selected from antipsychotics, including typical antipsychotics and atypical antipsychotics; antidepressants, including selective serotonin reuptake inhibitors (SSRIs) and selective norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants, and monoamine oxidase inhibitors (MAOIs) (e.g., bupropion); anti-anxiety medications, including benzodiazepines such as alprazolam; medications for addiction disorders, such as alcoholism (e.g., disulfiram), nicotine dependence (e.g., varenicline), and opioid use disorder (e.g., methadone, buprenorphine, buprenorphine-naloxone, and buprenorphine long-acting injection); mood stabilizers, e.g., lithium, and anticonvulsants, such as carbamazepine, divalproex (valproic acid), lamotrigine, gabapentin, and topiramate.

[0229] In some embodiments, the disease, disorder, or condition treated by activation of serotonin receptors is neurodegeneration. Accordingly, the present application also includes a method of treating neurodegeneration, comprising administering to a subject in need thereof a compound of Formula (I) or a composition described herein. The present application also includes the use of a compound of Formula (I) of the present disclosure for treating neurodegeneration, and the use of a compound of Formula (I) of the present disclosure for preparing a medicament for treating neurodegeneration. The present application further includes a compound of Formula (I) of the present disclosure for use in treating neurodegeneration. In some embodiments, the disease, disorder, or condition treated by activation of serotonin receptors is brain-derived neurotrophic factor (BDNF), mammalian target of rapamycin (mTOR) activation, and / or reduced inflammation.

[0230] In some embodiments, the disease, disorder, or condition treated by activation of serotonin receptors comprises cognitive impairment; ischemia, including stroke; neurodegeneration; refractory substance use disorders; sleep disorders; pain, e.g., social pain, acute pain, cancer pain, chronic pain, breakthrough pain, bone pain, soft tissue pain, neuralgia, referred pain, phantom pain, neuropathic pain, cluster headaches, and migraines; obesity and eating disorders; epilepsy and seizure disorders, neuronal cell death; excitotoxic cell death; or combinations thereof.

[0231] In some embodiments, the disease, disorder, or condition treated by activation of serotonin receptors is a psychotic or psychotic condition. Accordingly, the present application also includes a method of treating a psychotic or psychotic condition, comprising administering to a subject in need thereof a compound of Formula (I) or a composition described herein. The present application also includes the use of a compound of Formula (I) of the present disclosure for treating a psychotic or psychotic condition, and the use of a compound of Formula (I) of the present disclosure for preparing a medicament for treating a psychotic or psychotic condition. The present application further includes a compound of Formula (I) of the present disclosure for use in treating a psychotic or psychotic condition.

[0232] In some embodiments, the disease, disorder, or condition treated by activation of serotonin receptors is a psychotic or psychotic condition, and the compound of Formula (I) of the present disclosure is administered in combination with one or more additional medications for the psychotic or psychotic condition. The one or more additional medications for the psychotic or psychotic condition can be any suitable medication known in the art, including those described herein. In some embodiments, the additional medication for the psychotic or psychotic condition is selected from a typical antipsychotic and an atypical antipsychotic. Typical antipsychotics include acepromazine, acetophenazine, benperidol, bromperidol, butaperazine, carphenazine, chlorproethazine, chlorpromazine, chlorprothixene, clopenthixol, cyamemazine, dixyrazine, droperidol, fluanisone, flupenthixol, fluphenazine, fluspirilene, haloperidol, levomepromazine, lenperone, loxapine, mesoridazine, methytepin, molindone, moperone, and oxycodone. It may be selected from pertin, oxyprothepin, penfluridol, perazine, pericyazine, perphenazine, pimozide, pipamperone, piperacetazine, pipotiazine, prochlorperazine, promazine, prothipendyl, spiperone, sulforidazine, thiopropazate, thioproperazine, thioridazine, thiothixene, timiperone, trifluoperazine, trifluperidol, triflupromazine, and zuclopenthixol, and combinations thereof. The atypical antipsychotic may be selected from amoxapine, amisulpride, aripiprazole, asenapine, blonanserin, brexpiprazole, cariprazine, carpipramine, clocapramine, chlorothepine, clotiapine, clozapine, iloperidone, levosulpiride, lurasidone, melperone, mosapramine, nemonapride, olanzapine, paliperidone, perospirone, quetiapine, remoxipride, reserpine, risperidone, sertindole, sulpiride, sultopride, tiapride, veralipride, ziprasidone, and zotepine, and combinations thereof.

[0233] In some embodiments, administering a therapeutically effective amount of a compound of Formula (I) of the present disclosure to a subject in need thereof does not result in a worsening of psychotic or psychotic symptoms, such as, but not limited to, hallucinations and delusions. In some embodiments, administering a therapeutically effective amount of a compound of Formula (I) to a subject in need thereof results in an improvement of psychotic or psychotic symptoms, such as, but not limited to, hallucinations and delusions. In some embodiments, administering a therapeutically effective amount of a compound of Formula (I) to a subject in need thereof results in an improvement of psychotic or psychotic symptoms.

[0234] In some embodiments, the disease, disorder, or condition treated by activating serotonin receptors is a central nervous system (CNS) disease, disorder, or condition and / or a disease, disorder, or condition of the nervous system. Accordingly, the present application also includes a method of treating a CNS disease, disorder, or condition and / or a disease, disorder, or condition of the nervous system, comprising administering a therapeutically effective amount of a compound of Formula (I) or composition of the present disclosure to a subject in need thereof. The present application also includes the use of a compound of Formula (I) of the present disclosure for the treatment of a CNS disease, disorder, or condition and / or a disease, disorder, or condition of the nervous system, as well as the use of a compound of Formula (I) of the present disclosure for the preparation of a medicament for treating a CNS disease, disorder, or condition and / or a disease, disorder, or condition of the nervous system. The present application further includes a compound of Formula (I) of the present disclosure of the present application for use in the treatment of a CNS disease, disorder, or condition and / or a disease, disorder, or condition of the nervous system.

[0235] In some embodiments, the disease, disorder, or condition treated by activation of serotonin receptors is a central nervous system (CNS) disease, disorder, or condition and / or a nervous system disease, disorder, or condition, and the compound of Formula (I) of the present disclosure is administered in combination with one or more additional agents for a central nervous system (CNS) disease, disorder, or condition and / or a nervous system disease, disorder, or condition. The one or more additional agents for a central nervous system (CNS) disease, disorder, or condition and / or a nervous system disease, disorder, or condition can be any suitable agent known in the art, including those described herein. In some embodiments, the additional medication for a disease, disorder, or condition of the central nervous system (CNS) and / or a disease, disorder, or condition of the nervous system is selected from lithium, olanzapine, quetiapine, risperidone, ariprazole, ziprasidone, clozapine, divalproex sodium, lamotrigine, valproic acid, carbamazepine, topiramate, levomilnacipran, duloxetine, venlafaxine, citalopram, fluvoxamine, escitalopram, fluoxetine, paroxetine, sertraline, clomipramine, amitriptyline, desipramine, imipramine, nortriptyline, phenelzine, tranylcypromine, diazepam, alprazolam, clonazepam, or any combination thereof. Non-limiting examples of standard care therapies for depression are sertraline, fluoxetine, escitalopram, venlafaxine, or aripiprazole. Non-limiting examples of standard care treatments for depression are citralopram, escitalopram, fluoxetine, paroxetine, diazepam, or sertraline.

[0236] In some embodiments, the disease, disorder, or condition treated by activating serotonin receptors is selected from attention-deficit hyperactivity disorder and attention-deficit disorder, and combinations thereof. Accordingly, the present application also includes a method for treating attention-deficit hyperactivity disorder and / or attention-deficit disorder, comprising administering to a subject in need thereof a compound or composition of formula (I) described herein. The present application also includes the use of a compound of formula (I) of the present disclosure for treating attention-deficit hyperactivity disorder and / or attention-deficit disorder, as well as the use of a compound of formula (I) of the present disclosure for preparing a medicament for treating attention-deficit hyperactivity disorder and / or attention-deficit disorder. The present application further includes a compound of formula (I) of the present disclosure for use in treating attention-deficit hyperactivity disorder and / or attention-deficit disorder.

[0237] In some embodiments, the disease, disorder or condition that is treated by activating serotonin receptor is attention deficit hyperactivity disorder and / or attention deficit disorder and combinations thereof, and the compound of formula (I) of the present disclosure is administered in combination with one or more additional drugs for attention deficit hyperactivity disorder and / or attention deficit disorder and combinations thereof.The one or more additional drugs for attention deficit hyperactivity disorder and / or attention deficit disorder can be any suitable drug known in the art, including those described herein.In some embodiments, the additional drugs for attention deficit hyperactivity disorder and / or attention deficit disorder and combinations thereof are selected from methylphenidate, dexamphetamine, lisdexamphetine, atomoxetine and amphetamine, and combinations thereof.

[0238] In some embodiments, the disease, disorder, or condition treated by activating serotonin receptors is selected from dementia and Alzheimer's disease, and combinations thereof. Accordingly, the present application also includes a method for treating dementia and / or Alzheimer's disease, comprising administering to a subject in need thereof a compound of Formula (I) or a composition described herein. The present application also includes the use of a compound of Formula (I) of the present disclosure for treating dementia and / or Alzheimer's disease, as well as the use of a compound of Formula (I) of the present disclosure for preparing a medicament for treating dementia and / or Alzheimer's disease. The present application further includes a compound of Formula (I) of the present disclosure for use in treating dementia and / or Alzheimer's disease.

[0239] In some embodiments, the disease, disorder, or condition treated by activating serotonin receptors is dementia or Alzheimer's disease, and the compound of Formula (I) of the present disclosure is administered in combination with one or more additional medications for dementia or Alzheimer's disease. The one or more additional medications for dementia or Alzheimer's disease can be any suitable medication known in the art, including those described herein. In some embodiments, the additional medication for dementia and Alzheimer's disease is selected from an acetylcholinesterase inhibitor, an NMDA antagonist, and a nicotinic agonist. The acetylcholinesterase inhibitor can be selected from donepezil, galantamine, rivastigmine, and phenserine, and combinations thereof. The NMDA antagonist can be selected from MK-801, ketamine, phencyclidine, and memantine, and combinations thereof. The nicotinic agonist can be selected from nicotine, nicotinic acid, a nicotinic alpha7 agonist, or an alpha2beta4 agonist, or combinations thereof.

[0240] In another aspect, the present disclosure provides a method of treating psychosis, the method comprising administering to a subject in need thereof a compound of Formula (I) or a pharmaceutical composition described herein. In another aspect, the present disclosure provides a method of preventing psychosis, the method comprising administering to a subject in need thereof a compound of Formula (I) or a pharmaceutical composition described herein. The psychosis can be a neuropsychiatric condition.

[0241] In certain embodiments, the mental illness is an anxiety disorder such as generalized anxiety disorder, panic disorder, social anxiety disorder, and specific phobia; depression such as hopelessness, anhedonia, fatigue, and suicidal ideation; mood disorders such as depression, bipolar disorder, cancer-related depression, anxiety, and cyclothymic disorder; psychotic disorders such as hallucinations, delusions, mania, schizophrenia, schizoaffective disorder, and schizophreniform disorder; impulse control and addiction disorders such as pyromania (pyromania), kleptomania (kleptomania), and compulsive gambling; alcoholism; drug addiction such as opioid addiction / dependence, nicotine addiction, cocaine addiction, marijuana abuse, etc.; smoking cessation; antisocial personality disorders such as personality disorder, aggression, obsessive-compulsive personality disorder, and paranoid personality disorder; obsessive-compulsive disorder (OCD), such as thoughts or fears that cause a subject to perform certain recurring actions or routines; post-traumatic stress disorder (PTSD); stress response syndrome (formerly called adjustment disorder); dissociative disorder, formerly called multiple personality disorder or "split personality," and depersonalization disorder; factitious disorder; sexual and gender disorders, such as sexual dysfunction, gender identity disorder, and paraphilias; somatic symptom disorders, formerly known as psychosomatic or somatoform disorders.

[0242] In certain embodiments, the psychosis is selected from hallucinations and delusions, and combinations thereof. In these embodiments, the hallucinations may be selected from visual hallucinations, auditory hallucinations, olfactory hallucinations, gustatory hallucinations, tactile hallucinations, proprioceptive hallucinations, equilibrioceptive hallucinations, nociceptive hallucinations, thermoceptive hallucinations, and chronoceptive hallucinations, and combinations thereof.

[0243] In another aspect, the present disclosure provides a method for treating a central nervous system (CNS) disease, disorder or condition and / or a disease, disorder or condition of the nervous system, the method comprising administering to a subject in need thereof a compound of formula (I) or a pharmaceutical composition described herein.

[0244] In another aspect, the present disclosure provides a method for preventing a central nervous system (CNS) disease, disorder or condition and / or a nervous system disease, disorder or condition, the method comprising administering to a subject in need thereof a compound of formula (I) or a pharmaceutical composition described herein.

[0245] In some embodiments, the CNS disease, disorder or condition and / or nervous system disease, disorder or condition is selected from the group consisting of neurodevelopmental diseases and neurodegenerative diseases such as Alzheimer's disease; presenile dementia; senile dementia; vascular dementia; Lewy body dementia, cognitive impairment, Parkinson's disease, and Parkinson's disease-related diseases, such as Parkinsonism, corticobasal degeneration, and supranuclear palsy; epilepsy; CNS trauma; CNS infection; CNS inflammation; stroke; multiple sclerosis; Huntington's disease; mitochondrial disorders; fragile X syndrome; Angelman syndrome; hereditary ataxias; neurological disorders. The disorder is selected from disorders of the nervous system including otological and oculomotor disorders; neurodegenerative diseases of retinal amyotrophic lateral sclerosis; tardive dyskinesia; hyperactivity disorder; attention deficit hyperactivity disorder and attention deficit disorder; restless legs syndrome; Tourette's syndrome; tic disorders; schizophrenia; autism spectrum disorders; tuberous sclerosis; Rett's syndrome; cerebral palsy; disorders of the reward system including eating disorders such as anorexia nervosa and bulimia nervosa; binge eating disorder, trichotillomania, excoriation disorder, nail biting; migraine; fibromyalgia; and peripheral neuropathy of any etiology, and combinations thereof.

[0246] In another aspect, the present disclosure provides a method for increasing neuroplasticity, the method comprising contacting a neuronal cell with a compound of Formula (I) or a pharmaceutical composition described herein in an amount sufficient to increase the neuroplasticity of the neuronal cell. "Neuroplasticity" refers to the brain's ability to continually change its structure and / or function throughout a subject's lifetime. Examples of changes to the brain include, but are not limited to, the ability to adapt or respond to internal and / or external stimuli, such as due to injury, and the ability to generate new neurites, dendritic spines, and synapses. Increased neuroplasticity includes, but is not limited to, enhanced nerve growth, enhanced neuritogenesis, enhanced synaptogenesis, enhanced dendritogenesis, increased dendritic arbor complexity, increased dendritic spine density, and increased excitatory synapses in the brain. In some embodiments, increasing neuroplasticity comprises promoting neural growth, promoting neuritogenesis, promoting synaptogenesis, promoting dendritogenesis, increasing dendritic branching complexity, and increasing dendritic spine density.

[0247] In some embodiments, increasing neuroplasticity can treat neurodegenerative disorders, Alzheimer's disease, Parkinson's disease, psychological disorders, depression, addiction, anxiety, post-traumatic stress disorder, treatment-resistant depression, suicidal ideation, major depressive disorder, bipolar disorder, schizophrenia, stroke, traumatic brain injury, or substance use disorders.

[0248] In another aspect, the present disclosure provides a method for treating body weight, comprising administering an effective amount of a compound of the present invention to a subject in need thereof.The treatment of body weight can include the treatment of weight gain; weight loss; metabolic disorders; weight gain associated with pharmaceutical intervention; weight gain associated with psychiatric illness (including those described herein); eating disorders such as anorexia nervosa, bulimia, cachexia; eating behavior; obesity; diabetes; insulin resistance; prediabetes; glucose intolerance; hyperlipidemia; and cardiovascular disease.

[0249] In another aspect, the disclosure provides a method for increasing dendritic spine density, the method comprising contacting a neuronal cell with a compound of formula (I) or a pharmaceutical composition described herein in an amount sufficient to increase dendritic spine density of the neuronal cell.

[0250] In certain embodiments, compounds of formula (I) produce the greatest number of dendritic intersections with a greater than 1.0-fold increase by Sholl analysis.

[0251] In another aspect, the present disclosure provides a method for activating serotonin receptors in cells, either in a biological sample or in a patient, comprising administering to the cells a compound of Formula (I) as defined in any one of the embodiments disclosed herein. The serotonin receptor may be a 5-HT receptor subtype, preferably a 5-HT 2A and 5-HT 2C It may be one or both of the above.

[0252] In some embodiments, an effective amount varies depending on factors such as the disease state, age, sex, and / or weight of the subject or species. In some embodiments, the amount of one or more given compounds that corresponds to an effective amount varies depending on factors such as the given drug or compound, pharmaceutical formulation, route of administration, condition, type of disease or disorder, identity of the subject being treated, etc., but can nevertheless be routinely determined by one of ordinary skill in the art.

[0253] In some embodiments, the compound of Formula (I) of the present disclosure is administered 1, 2, 3, or 4 times per year. In some embodiments, the compound of the present disclosure is administered at least once per week. However, in other embodiments, the compound is administered to a subject about once per two weeks, three weeks, or month. In other embodiments, the compound is administered about once per week to about once per day. In other embodiments, the compound is administered 1, 2, 3, 4, 5, or 6 times per day. The length of treatment period will depend on various factors, such as the severity of the disease, disorder, or condition, the age of the subject, the concentration, and / or activity of the compound of the present application, and / or a combination thereof. It will also be understood that the effective dosage of the compound used for treatment may increase or decrease over the course of a particular treatment regime. Changes in dosage may occur and be evident by standard diagnostic assays known in the art. In some cases, chronic administration is required. For example, the compound is administered to a subject in an amount and for a duration sufficient to treat the subject.

[0254] In some embodiments, the compounds of the present application are administered at a hallucinogenic or psychotomimetic dose in conjunction with psychotherapy or treatment, which may occur once, twice, three times, or four times per year, however, in some embodiments, the compounds are administered at a non-hallucinogenic or non-psychotomimetic dose to a subject once per day, every other day, every third day, once per week, once every two weeks, once per month, once every two months, or once per three months.

[0255] The compounds of formula (I) of the present disclosure can be used alone or in combination with other known drugs useful for treating diseases, disorders, or conditions through the activation of serotonin receptors, such as the compounds of the present disclosure. When used in combination with other known drugs useful for treating diseases, disorders, or conditions through the activation of serotonin receptors, this is an embodiment in which the compounds of formula (I) are administered simultaneously with those drugs. As used herein, "co-administration" of two substances to a subject means providing each of the two substances so that they are both active in an individual at the same time. The exact details of administration depend on the pharmacokinetics of the two substances in the presence of each other, and may include administering the two substances within a few hours of each other, or even administering one substance within 24 hours of the other, if the pharmacokinetics are favorable. Designing a suitable administration regimen is routine for those skilled in the art. In certain embodiments, the two substances are administered substantially simultaneously, i.e., within minutes of each other, or in a single composition containing both substances. A further embodiment of the present application is that the combination of drugs is administered to a subject non-concurrently. In some embodiments, the compounds of formula (I) of the present disclosure are administered with another therapeutic agent, either simultaneously or sequentially in separate unit dosage forms, or together in a single unit dosage form. Thus, the present application provides a single unit dosage form comprising one or more compounds of formula (I) described herein, an additional therapeutic agent, and a pharmaceutically acceptable carrier.

[0256] In some embodiments, the compounds of the present application are used or administered in effective amounts, including administration of doses or dosing regimens that do not produce clinically significant psychedelic / psychotic effects. In some embodiments, the compounds of the present application have a human plasma psilocin Cmax of 4 ng / mL or less and / or a human 5-HT 2A exhibited by human CNS receptor occupancy or a human plasma psilocin Cmax of 1 ng / mL or less and / or 30% or less of human 5-HT 2AThe compounds of the present application are used or administered in effective amounts, including administration of a dose or dosing regimen that provides a clinical effect similar to that exhibited by human CNS receptor occupancy. In some embodiments, the compounds of the present application are used or administered in effective amounts, including administration of a dose or dosing regimen that provides a clinical effect similar to that exhibited by human plasma psilocin Tmax in excess of 60 minutes, 120 minutes, or 180 minutes.

[0257] kit In another embodiment, a kit or article of manufacture is provided that includes one or more compounds, pharmaceutically acceptable salts, stereoisomers, solvates, metabolites, or polymorphs, and / or pharmaceutical compositions as described above.

[0258] In another embodiment, there is provided a kit for use in the above-described therapeutic applications, comprising: a container holding one or more compounds, pharmaceutically acceptable salts, stereoisomers, solvates, metabolites, or polymorphs, and / or pharmaceutical compositions described herein; - A label or package insert with instructions for use is provided.

[0259] The invention disclosed and defined herein will be understood to extend to all alternative combinations of two or more of the individual features mentioned or made apparent from the text or drawings, all of which different combinations constitute various alternative aspects of the invention. [Example]

[0260] Scheme 1: Compounds of general formula (I) can be synthesized from appropriately substituted anilines by following the sequence of steps outlined in Scheme 1 or similar to those contemplated by one skilled in the art. Hydrazine formation provided a suitable intermediate to undergo Fischer indole synthesis to generate substituted indole intermediates. Dehalogenation provided access to compounds of general formula (I) (exemplified by P-4). Those skilled in the art will recognize that the utilization of differentially substituted amines during the Fischer indole synthesis provides access to compounds of general formula (I) disclosed herein. [ka]

[0261] Example 1: N,N-dimethyl-2-(4-(trifluoromethoxy)-1H-indol-3-yl)ethan-1-amine (P-4) [ka] Step 1: (2-Bromo-5-(trifluoromethoxy)phenyl)hydrazine (12) To a cooled (0 °C) solution of 2-bromo-5-(trifluoromethoxy)aniline (9.0 g, 35.2 mmol) in concentrated HCl (90 mL) and water (31.5 mL) was added a solution of NaNO (2.7 g, 38.7 mmol) in HO (31.5 mL) over a 20 min period. The reaction mixture was stirred at 0 °C for 1 h, followed by the dropwise addition of a solution of SnCl (23.8 g, 106 mmol, 3.0 equiv.) in concentrated HCl (90 mL) over a 1 h period at 0 °C. After the 2-bromo-5-(trifluoromethoxy)aniline was consumed, as indicated by TLC analysis, the reaction was basified with 50% aqueous NaOH (approximately 250 mL) at 0 °C to a pH of ≈14. The mixture was extracted with CHCl (200 mL × 3), and the combined organic layers were dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The crude material was purified by flash chromatography (EtOAc / hexane, 1:10) to afford (2-bromo-5-(trifluoromethoxy)phenyl)hydrazine (7.4 g, 78%) as a yellow oil. 1 H NMR (300MHz, CDCl3): δ 7.38 (d, J = 8.7 Hz, 1H), 7.04 (s, 1H), 6.52 (d, J = 8.4 Hz, 1H), 5.80 (br s, 1H), 3.62 (br s, 2H).

[0262] Step 2: 2-(7-bromo-4-(trifluoromethoxy)-1H-indol-3-yl)-N,N-dimethylethan-1-amine (13) A solution of (2-bromo-5-(trifluoromethoxy)phenyl)hydrazine (6.0 g, 22.1 mmol, 1.0 equiv.) and 4,4-dimethoxy-N,N-dimethylbutan-1-amine (3.9 g, 24.4 mmol, 1.1 equiv.) in toluene (90 mL) was stirred at 60 °C for 30 min. Phosphoric acid (90 mL, 85%) was added to the mixture at 60 °C and stirred for 1 h. The mixture was cooled to ambient temperature and poured into ice water (450 mL). The mixture was basified to pH ≈ 13 with 50% (w / v) aqueous NaOH solution (130 mL) and subsequently extracted with EtOAc (300 mL × 2). The combined organic layers were dried over anhydrous NaSO, filtered, and evaporated under reduced pressure. The crude product was purified by column chromatography (SiO, CHCl / MeOH, 100:1 to 30:1) to give 2-(7-bromo-4-(trifluoromethoxy)-1H-indol-3-yl)-N,N-dimethylethan-1-amine (680 mg, 8.7%) as an off-white solid. 1 H NMR (300MHz, DMSO-d6): δ 11.6 (brs, 1H), 7.46-7.36 (m, 2H), 6.96-6.93 (m, 1H), 3.18-2.95 (m, 4H), 2.46 (s, 6H).

[0263] Step 3: N,N-dimethyl-2-(4-(trifluoromethoxy)-1H-indol-3-yl)ethan-1-amine (P-4) A stirred mixture of 2-(7-bromo-4-(trifluoromethoxy)-1H-indol-3-yl)-N,N-dimethylethan-1-amine (680 mg, 1.51 mmol, 1.0 equiv), KCO (418 mg, 3.03 mmol, 2.0 equiv), and 10% Pd / C (80 mg) in MeOH (15 mL) was hydrogenated under 0.5 MPa of H at 40 °C for 3 h and then filtered through a pad of Celite. The filter cake was washed with EtOAc (10 mL × 3), and the combined filtrates were concentrated in vacuo. The residue was dissolved in EtOAc (500 mL) and washed with HO (200 mL × 2). The organic layer was dried over anhydrous NaSO, filtered, and the solvent was evaporated to give a yellow oil. Purification by preparative HPLC provided N,N-dimethyl-2-(4-(trifluoromethoxy)-1H-indol-3-yl)ethan-1-amine as a solid (170 mg, 32%). 1 H NMR (300MHz, DMSO-d6): δ 11.61 (br s, 1H), 7.36-7.42 (m, 2H), 6.94 (d, J = 8.3Hz, 1H), 2.87-3.07 (m, 4H), 2.52 (s, 6H). LCMS(ESI+):m / z273.0[M+H] + . HPLC purity (220nm): 97.8%

[0264] Scheme 2: Compounds of general formula (I) can be synthesized from appropriately substituted hydrazines by following the sequence of steps outlined in Scheme 2 or similar to those contemplated by one skilled in the art. Fischer indole synthesis provides access to appropriately substituted indoles that provide access to compounds of general formula (I) (exemplified by P-5). Those skilled in the art will recognize that the use of differentially substituted amines provides access to compounds of general formula (I) disclosed herein. [ka]

[0265] Example 7: N,N-dimethyl-2-(5-(trifluoromethoxy)-1H-indol-3-yl)ethan-1-amine (P-5) [ka] Step 1: N,N-dimethyl-2-(5-(trifluoromethoxy)-1H-indol-3-yl)ethan-1-amine (P-5) To a solution of (4-(trifluoromethoxy)phenyl)hydrazine hydrochloride (458 mg, 2.0 mmol) in 4 wt% aqueous H2SO4 solution (12 mL) at ambient temperature, 4,4-dimethoxy-N,N-dimethylbutan-1-amine (387 mg, 2.4 mmol) was added in one portion. The reaction was stirred under reflux for 4 hours. The cooled reaction mixture was basified to pH 8 with NH4OH (12 g, 87 mmol) and extracted with EtOAc (25 mL x 3). The combined organic phases were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by preparative HPLC to give N,N-dimethyl-2-(5-(trifluoromethoxy)-1H-indol-3-yl)ethan-1-amine (186 mg) as an oil, which rapidly formed the carbonate salt. The solid was dissolved in methanol (2 mL) and treated with a solution of 2 M HCl in EtO to give its HCl salt. After concentration in vacuo and trituration with EtO, N,N-dimethyl-2-(5-(trifluoromethoxy)-1H-indol-3-yl)ethan-1-amine hydrochloride (140 mg) was obtained as a light brown solid. 1 H NMR(300MHz,DMSO-d6):δ 11.31(s,1H),10.24-10.51(br,1H),7.64(s,1H),7.39-7.47(m,2H),7. 07(d,J=8.7Hz,1H),3.27-3.33(m,2H),3.10-3.15(m,2H),2.82(s,6H). LCMS(ESI+):m / z273.0[M+H] + . HPLC purity (220nm): 99.3%.

[0266] Scheme 3: Compounds of general formula (I) can be synthesized from an appropriately substituted tryptamine by following the sequence of steps outlined in Scheme 3 or similar to those contemplated by one skilled in the art. Boc protection of the pendant amine within the tryptamine scaffold, followed by reduction, provides access to a methyltryptamine intermediate that can undergo subsequent reductive alkylation with a variety of aldehydes and ketones to generate compounds of general formula (I) (exemplified by P-34). One skilled in the art will recognize that utilizing alternating aldehydes and ketones during the reductive alkylation transformation will generate alternating compounds of general formula (I) disclosed herein. [ka]

[0267] Example 10: N-methyl-N-(2-(5-(trifluoromethoxy)-1H-indol-3-yl)ethyl)propan-1-amine (P-34) [ka] Step 1: tert-butyl (2-(5-(trifluoromethoxy)-1H-indol-3-yl)ethyl)carbamate (73) To an ice-cooled (0 °C) solution of 5-(trifluoromethoxy)tryptamine hydrochloride (1.40 g, 5 mmol, 1.0 equiv.) and triethylamine (2.1 mL, 15 mmol, 3.0 equiv.) in THF (45 mL) was added a solution of BocO (1.31 g, 6 mmol, 1.2 equiv.) in THF (5 mL), and the reaction was stirred for 2 h. The reaction was poured into ice-water (50 mL) and extracted with EtOAc (50 mL × 3). The combined organic layers were washed with brine (50 mL), dried (MgSO), filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by column chromatography (SiO, hexane / EtOAc, v / v, 1 / 1) to afford tert-butyl (2-(5-(trifluoromethoxy)-1H-indol-3-yl)ethyl)carbamate as a light brown solid (1.72 g, 100%).1 H NMR(400MHz,DMSO-d6):δ 11.10(s,1H),7.46(s,1H),7.41(d,J=8.8Hz,1H),7.31-7.26(m,1H),7.02(dd,J=8.8,1 .2Hz,1H),6.88(t,J=5.8Hz,1H),3.22-3.12(m,2H),2.78(t,J=7.2Hz,2H),1.37(s,9H).

[0268] Step 2: N-methyl-2-(5-(trifluoromethoxy)-1H-indol-3-yl)ethan-1-amine (74) To an ice-cooled (0 °C) solution of tert-butyl (2-(5-(trifluoromethoxy)-1H-indol-3-yl)ethyl)carbamate (1.5 g, 4.36 mmol) in THF (50 mL) under N was added LiAlH (496 mg, 13.1 mmol), and the mixture was heated to reflux for 1 h. The mixture was then cooled to 0 °C and quenched by the successive dropwise addition of cold water (0.5 mL), 3.75 M aqueous NaOH (0.5 mL), and water (1.5 mL). The suspension was then stirred with approximately 1 g of anhydrous NaSO for 15 min and then filtered through a pad of Celite. The Celite plug was washed with hot THF (20 mL × 2) and the combined filtrates were concentrated to give N-methyl-2-(5-(trifluoromethoxy)-1H-indol-3-yl)ethan-1-amine as an off-white solid (1.05 g, 93%). 1 H NMR(400MHz,DMSO-d6):δ 11.07(s,1H),7.46(s,1H),7.40(d,J=8.8Hz,1H),7.28(d,J=2.0Hz,1H), 7.02(d,J=8.8Hz,1H),2.83-2.75(m,2H),2.75-2.67(m,2H),2.30(s,3H). 13 C NMR (101 MHz, DMSO-d): δ 141.3, 134.6, 127.4, 125.1, 114.4, 113.5, 112.3, 110.7, 52.3, 36.1, 25.0 (OCF3 carbon peak unresolved).

[0269] Step 3: N-methyl-N-(2-(5-(trifluoromethoxy)-1H-indol-3-yl)ethyl)propan-1-amine (P-34) To a solution of N-methyl-2-(5-(trifluoromethoxy)-1H-indol-3-yl)ethan-1-amine (0.2 g, 0.77 mmol) and propanal (66.6 μL, 1.2 equivalents, 0.93 mmol) in 1,2-dichloroethane (5 mL) was added NaBH(OAc) (246 mg, 1.5 equivalents, 1.16 mmol) at ambient temperature. The mixture was stirred for 16 h, then quenched with 1 M aqueous NaOH (5 mL) and extracted with CHCl (10 mL × 3). The combined organic layers were washed with brine (20 mL), dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (SiO, 0.1% to 6% MeOH / NH (aqueous) in CHCl) to give N-ethyl-N-methyl-2-(5-(trifluoromethoxy)-1H-indol-3-yl)ethan-1-amine (114 mg) as a yellow oil, which was used in the next step without further purification.

[0270] Step 3a: N-methyl-N-(2-(5-(trifluoromethoxy)-1H-indol-3-yl)ethyl)propan-1-amine fumarate (P-34 fumarate) To a solution of fumaric acid (44 mg, 0.38 mmol) in minimal refluxing acetone was added a solution of N-methyl-N-(2-(5-(trifluoromethoxy)-1H-indol-3-yl)ethyl)propan-1-amine (114 mg) in minimal warm acetone. The resulting solution was cooled to ambient temperature and allowed to stand at 4° C. overnight to afford N-methyl-N-(2-(5-(trifluoromethoxy)-1H-indol-3-yl)ethyl)propan-1-amine as the fumarate salt (115 mg, 41% over two steps) as off-white crystals. 1H NMR(400MHz,DMSO-d6):δ 11.15(s,1H),7.55-7.46(m,1H),7.41(d,J=8.8Hz,1H),7.32(d,J=2.4Hz,1H),7.03(dd,J=8.8,1.2Hz,1H),6.52(s,1H) ,2.95-2.85(m,2H),2.84-2.74(m,2H),2.59-2.52(m,2H),2.41(s,3H),1.51(sextet,J=7.4Hz,2H),0.86(t,J=7.4Hz,3H). 13 C NMR(101MHz,DMSO-d6):δ 167.4,141.4,134.8,134.6,127.2,125.2,120.5(d,J=253.8Hz),114.4,112.5,112.3,110.6,58.1,56.9,40.8,21.5,18.9,11.5. qNMR purity (ERETIC): 100%.

[0271] Scheme 4: Compounds of general formula (I) can be synthesized from an appropriately substituted indole in a single step similar to that outlined in Scheme 4 or that may be contemplated by one skilled in the art. The substituted tryptamine core could undergo reductive alkylation to provide access to compounds of general formula (I) (exemplified by P-15). Those skilled in the art will recognize that protecting the amine with a suitable protecting group such as benzyl, followed by alkylation, followed by deprotection, and a second alkylation, provides access to the differentially alkylated compounds of general formula (I) disclosed herein. [ka]

[0272] Example 14: N,N-dimethyl-2-(5-(trifluoromethyl)-1H-indol-3-yl)ethan-1-amine (P-15) Step 1: N,N-dimethyl-2-(5-(trifluoromethyl)-1H-indol-3-yl)ethan-1-amine (P-15) [ka] A solution of 2-(5-(trifluoromethyl)-1H-indol-3-yl)ethan-1-amine (0.2 g, 876 μmol) in MeOH (5 mL) was treated with AcOH (52.6 mg, 876 μmol), 37% aqueous formaldehyde solution (356 mg, 5 equiv., 4.38 mmol), and NaBHCN (220 mg, 4 equiv., 3.51 mmol) and stirred at ambient temperature for 12 h. The reaction was diluted with HO:EtOAc (1:1—100 mL), the layers were separated, and the organic layer was dried over anhydrous NaSO, filtered, and concentrated in vacuo. The crude product was purified by preparative HPLC to give N,N-dimethyl-2-(5-(trifluoromethyl)-1H-indol-3-yl)ethan-1-amine (54 mg, 24%) as a pale yellow solid. HPLC purity:96.6%(220nm);LCMS(ESI+) m / z 257.1[M+H] + ; 1 H NMR (400MHz, CDCl3): δ 8.23(br.s,1H),7.90(s,1H),7.42(s,2H),7.18-7.12(m,1H),3.01-2.93(m,2H),2.70-2.62(m,2H),2.36(s,6H).

[0273] Scheme 13: Compounds of general formula (I) can be synthesized from an appropriately substituted indole by following the sequence of steps outlined in Scheme 13 or similar to those that one skilled in the art would consider. An appropriately substituted indole could be glyoxylated with oxalyl chloride followed by treatment with an appropriately substituted amine to give a glyoxamide intermediate. Such intermediates could then be subjected to reducing conditions to provide access to compounds of general formula (I) (exemplified by P-16, P-17, and P-18). [ka]

[0274] Example 19: N-(2-(5-methoxy-1H-indol-3-yl)ethyl)-N-methylbutan-2-amine (P-16) [ka] Step 1: 2-(5-Methoxy-1H-indol-3-yl)-2-oxoacetyl chloride (52) To a solution of (COCl) (2 g, 15.7 mmol) in EtO (36 mL) at 0 °C was added dropwise a solution of 5-methoxy-1H-indole (2 g, 13.6 mmol) in minimal EtO. The reaction was stirred at 0 °C for 30 min, and the resulting precipitate was collected by filtration. The crude solid was dried under vacuum to provide 2-(5-methoxy-1H-indol-3-yl)-2-oxoacetyl chloride (2.9 g, 78%). 1 H NMR (300MHz, CDCl3): δ 8.88(s,1H),8.26(d,J=3.2Hz,1H),7.89(s,1H),7.36(d,J=8.9Hz,1H),7.00(d,J=7.6Hz,1H),3.91(s,3H).

[0275] Step 2: N-(sec-butyl)-2-(5-methoxy-1H-indol-3-yl)-N-methyl-2-oxoacetamide (53) To a solution of 2-(5-methoxy-1H-indol-3-yl)-2-oxoacetyl chloride (300 mg, 1.26 mmol) in CHCl (10 mL) was added N-methylbutan-2-amine (331 mg, 3.79 mmol). The reaction mixture was stirred at ambient temperature for 2 hours. The reaction mixture was quenched with HO (20 mL). The layers were separated, and the aqueous phase was extracted with CHCl (2 × 20 mL). The combined organics were dried over anhydrous NaSO, filtered, and the filtrate was concentrated in vacuo to provide N-(sec-butyl)-2-(5-methoxy-1H-indol-3-yl)-N-methyl-2-oxoacetamide (300 mg, 81%) as a yellow solid. 1H NMR(300MHz,DMSO-d6):δ 12.17(s,1H),7.96(m,1H),7.60(s,1H),7.43(dd,J=8.9,5.9Hz,1H),6.90(dt,J=8.8,2.7Hz,1H),3.80( s,3H),3.34(s,3H),3.12-2.96(m,1H),1.81-1.32(m,2H),1.16(d,J=6.6Hz,3H),0.90(t,J=7.5Hz,3H).

[0276] Step 3: N-(2-(5-methoxy-1H-indol-3-yl)ethyl)-N-methylbutan-2-amine (P-16) To a solution of LiAlH (395 mg, 10.4 mmol) in THF (10 mL) was added N-(sec-butyl)-2-(5-methoxy-1H-indol-3-yl)-N-methyl-2-oxoacetamide (300 mg, 1.04 mmol) in THF (10 mL) under reflux. The reaction mixture was stirred under reflux for 1 h. The resulting mixture was quenched with HO (0.4 mL), 15% aqueous NaOH (0.4 mL), and HO (1.2 mL), followed by the addition of MgSO and EtOAc. The mixture was stirred at ambient temperature for 30 min. The mixture was filtered through a Celite pad. The filtrate was concentrated to give the crude product. The resulting residue was purified by flash column chromatography with isocratic elution with CH2Cl2 (95%) and MeOH (5%) to provide N-(2-(5-methoxy-1H-indol-3-yl)ethyl)-N-methylbutan-2-amine (120 mg, 44%) as an off-white solid. 1 H NMR(300MHz,MeOH-d4):δ 7.28(d,J=9.0Hz,1H),7.20(s,1H),7.09(d,J=1.8Hz,1H),6.80(dd,J=2.4,9.0Hz,1H),3.84(s,3H), 3.60-3.33(m,3H),3.20-3.18(m,2H),2.86(s,3H),1.88-1.74(m,2H),1.31(brs,3H),0.99(brs,3H). LCMS(ESI+):m / z261.1[M+H] + . HPLC purity (220nm): 97.1%

[0277] Example 20: N-isopropyl-N-(2-(5-methoxy-1H-indol-3-yl)ethyl)propan-1-amine (P-17) [ka] Step 1: N-isopropyl-2-(5-methoxy-1H-indol-3-yl)-2-oxo-N-propylacetamide (54) To a solution of 2-(5-methoxy-1H-indol-3-yl)-2-oxoacetyl chloride (300 mg, 1.27 mmol) in CHCl (12 mL) was added N-isopropylpropan-1-amine (639 mg, 6.33 mmol). The reaction was stirred at 0 °C for 1 h. The resulting mixture was quenched with HO (15 mL) and extracted with CHCl (3 × 15 mL). The combined organics were dried over anhydrous NaSO, filtered, and concentrated in vacuo to provide crude N-isopropyl-2-(5-methoxy-1H-indol-3-yl)-2-oxo-N-propylacetamide (387 mg) as a white solid. 1 H NMR(300MHz,CDCl3):δ 9.06(br s,1H),7.82(s,1H),7.78-7.73(m,1H),7.30(d,J=9.0Hz,1H),6.93(dd,J=9.0,2.5Hz,1H),4.10-4.04(m,1H),3.90(s,3H),3.43-3.1 2(m,2H),1.85-1.67(m,2H),1.33(d,J=6.9Hz,2H),1.19(d,J=6.6Hz,4H),1.00(t,J=7.4Hz,2H),0.77(t,J=7.3Hz,1H) [mixture of rotamers].

[0278] Step 2: N-isopropyl-N-(2-(5-methoxy-1H-indol-3-yl)ethyl)propan-1-amine (P-17) To a refluxing solution of LiAlH (289 mg, 7.62 mmol) in THF (10 mL) was added dropwise a solution of N-isopropyl-2-(5-methoxy-1H-indol-3-yl)-2-oxo-N-propylacetamide (230 mg, 0.762 mmol) in THF (10 mL) under N. The reaction mixture was stirred under reflux for 30 min. After cooling to 0 °C, the reaction mixture was quenched by the addition of HO (0.29 mL), followed by 15% aqueous NaOH solution (0.29 mL) and HO (0.87 mL). The mixture was dried over anhydrous MgSO, filtered, and the filtrate was concentrated in vacuo. The resulting mixture was purified by flash column chromatography with isocratic elution (EtOAc) to provide N-isopropyl-N-(2-(5-methoxy-1H-indol-3-yl)ethyl)propan-1-amine (145 mg, 70%) as a yellow oil. 1 HNMR(300MHz,MeOD-d4):δ 7.27(d,J=9.0Hz,1H),7.20(s,1H),7.07(d,J=2.1Hz,1H),6.82-6.78(m,1H),3.84(s,3H),3.82-3.77(m ,1H),3.44-3.33(m,2H),3.23-3.10(m,4H),1.82-1.76(m,2H),1.38-1.34(m,6H),1.02(t,J=7.2Hz,3H). LCMS(ESI+):m / z275.3[M+H] + . HPLC purity (200nm): 97.7%

[0279] Example 21: N-ethyl-N-(2-(5-methoxy-1H-indol-3-yl)ethyl)-2-methylpropan-1-amine (P-18) [ka] Step 1: N-ethyl-N-isobutyl-2-(5-methoxy-1H-indol-3-yl)-2-oxoacetamide (55) To a solution of 2-(5-methoxy-1H-indol-3-yl)-2-oxoacetyl chloride (300 mg, 1.26 mmol) in CHCl (10 mL) was added N-ethyl-2-methylpropan-1-amine hydrochloride (520 mg, 3.79 mmol) and triethylamine (1.92 g, 18.99 mmol) at ambient temperature. The reaction mixture was stirred at ambient temperature for 16 h. The reaction mixture was quenched with HO (20 mL). The layers were separated, and the aqueous phase was extracted with CHCl (2 × 20 mL). The combined organics were dried over anhydrous NaSO, filtered, and concentrated in vacuo to provide N-ethyl-N-isobutyl-2-(5-methoxy-1H-indol-3-yl)-2-oxoacetamide (200 mg, 52%) as a yellow solid, which was used immediately in the next step without further purification.

[0280] Step 2: N-ethyl-N-(2-(5-methoxy-1H-indol-3-yl)ethyl)-2-methylpropan-1-amine (P-18) To a solution of LiAlH (250 mg, 6.6 mmol) in THF (10 mL) was added N-ethyl-N-isobutyl-2-(5-methoxy-1H-indol-3-yl)-2-oxoacetamide (200 mg, 0.66 mmol) in THF (10 mL) under reflux. The reaction mixture was stirred under reflux for 1 hour. The resulting mixture was quenched with HO (0.3 mL), 15% aqueous NaOH (0.3 mL), and HO (0.9 mL), followed by the addition of MgSO and EtOAc. The mixture was stirred at ambient temperature for 30 minutes. The mixture was filtered through a Celite pad. The filtrate was concentrated to give the crude product, which was purified by flash column chromatography with isocratic elution with CH2Cl2:MeOH (19:1 v / v) to provide N-ethyl-N-(2-(5-methoxy-1H-indol-3-yl)ethyl)-2-methylpropan-1-amine (45 mg, 11%) as a yellow oil. 1H NMR(300MHz,MeOD-d4):δ 7.26(d,J=9.0Hz,1H),7.19(s,1H),7.06(d,J=2.1Hz,1H),6.81(dd,J=9.0,2.4Hz,1H), 3.84(s,3H),3.48-3.36(m,4H),3.22-3.16(m,2H),3.11-3.04(m,2H),2.18-2.10(m,1H) 1.36(t,J=7.2Hz,3H),1.03(t,J=6.3Hz,6H). LCMS(ESI+):m / z275.4[M+H] + . HPLC purity (220nm): 95.9%.

[0281] Scheme 14: Compounds of general formula (I) can be synthesized from appropriately substituted tryptamines by following the sequence of steps outlined in Scheme 14 or similar to those that one skilled in the art would consider. The appropriately substituted tryptamines can undergo sequential one-pot reductive alkylation to provide compounds of general formula (I) (exemplified by P-19). [ka]

[0282] Example 22: N-ethyl-N-(2-(5-methoxy-1H-indol-3-yl)ethyl)butan-2-amine (P-19) [ka] Step 1: N-ethyl-N-(2-(5-methoxy-1H-indol-3-yl)ethyl)butan-2-amine (P-19) To a solution of 2-(5-methoxy-1H-indol-3-yl)ethan-1-amine (500 mg, 2.63 mmol) in MeOH (10 mL) was added butan-2-one (576 mg, 7.89 mmol), NaBHCN (663 mg, 10.52 mmol), and AcOH (80 mg, 1.33 mmol). The reaction mixture was stirred at ambient temperature for 2 hours. Then, acetaldehyde (463 mg, 10.52 mmol) and NaBHCN (663 mg, 10.52 mmol) were added. The reaction mixture was stirred at 45 °C for 2 hours. The reaction was concentrated in vacuo to give the crude product. The resulting residue was purified by flash column chromatography (SiO 2、 Purification by CHCl / MeOH (v / v, 91 / 9) provided the crude product (400 mg), which was dissolved in methanol (1 mL) and treated with HCl in EtO (8 mL, 1 M). The reaction was stirred at ambient temperature for 10 minutes and then concentrated in vacuo. The resulting solid was washed with EtO (3 × 3 mL) to give N-ethyl-N-(2-(5-methoxy-1H-indol-3-yl)ethyl)butan-2-amine as the hydrochloride salt (50.2 mg, 6%) as a pale yellow solid. 1 H NMR(300MHz,MeOD-d4):δ 7.27(d,J=9.0Hz,1H),7.20(s,1H),7.08-7.04(m,1H),6.82-6.79(m,1H),3.83(s,3H),3.50-3.34(m,5H),3.24- 3.19(m,2H),1.94-1.74(m,1H),1.68-1.55(m,1H),1.38(t,J=7.2Hz,3H),1.36-1.31(m,3H),1.05-0.94(m,3H). LCMS(ESI+):m / z275.3[M+H] + . HPLC purity (254nm): 99.6%.

[0283] Scheme 15: Compounds of general formula (I) can be synthesized from appropriately substituted tryptamines by following the sequence of steps outlined in Scheme 15 or similar to those that one skilled in the art would consider. Appropriately substituted tryptamines can undergo sequential one-pot reductive alkylations to provide compounds of general formula (I) (exemplified by P-20 and P-21). [ka]

[0284] Example 23: N-(2-(1H-indol-3-yl)ethyl)-N-methylbutan-2-amine (P-20) [ka] Step 1: N-(2-(1H-indol-3-yl)ethyl)-N-methylbutan-2-amine (P-20) To a solution of tryptamine (200 mg, 1.25 mmol) in MeOH (12 mL) was added butan-2-one (270 mg, 3.75 mmol), NaBHCN (315 mg, 5.00 mmol), and AcOH (23 mg, 0.38 mmol). The reaction was stirred at ambient temperature for 3 h. Then, aqueous formaldehyde solution (0.37 mL, 5.00 mmol, 37-40%) and NaBHCN (315 mg, 5.00 mmol) were added to the reaction. The mixture was stirred at ambient temperature for 1 h, then quenched with HO (30 mL) and extracted with EtOAc (30 mL × 2). The combined organic layers were washed with brine (40 mL), dried over NaSO (15 g), filtered, and concentrated. The resulting residue was purified by flash silica chromatography (CHCl-MeOH, 30:1 to 20:1) to give the crude product, which was dissolved in CHCl (5 mL), treated dropwise over 2 min with HCl in EtO (4 mL, 1 N), and stirred at ambient temperature for 30 min. The mixture was then concentrated, and the resulting solid was purified by preparative HPLC to give N-(2-(1H-indol-3-yl)ethyl)-N-methylbutan-2-amine as the hydrochloride salt (89 mg, 27%) as an off-white solid. 1 H NMR(300MHz,DMSO-d6):δ 11.03(br s,1H),10.05(br s,1H),7.69(m,1H),7.36(d,J=7.8Hz,1H),7.26(s,1H),7.11-6.98(m,2H),3.41-3.18(m,5H), 2.78-2.70(m,3H),2.04-1.82(m,1H),1.58-1.39(m,1H),1.31-1.20(m,3H),1.00-0.85(m,3H). LCMS(ESI+):m / z231.2[M+H] + . HPLC purity (220nm): 99.9%.

[0285] Example 24: N-(2-(1H-indol-3-yl)ethyl)-N-ethylbutan-2-amine (P-21) [ka] Step 1: N-(2-(1H-indol-3-yl)ethyl)-N-ethylbutan-2-amine (P-21) To a solution of tryptamine (250 mg, 1.56 mmol) in MeOH (12 mL) was added butan-2-one (337 mg, 4.68 mmol), NaBHCN (393 mg, 6.24 mmol), and AcOH (28 mg, 0.47 mmol). The reaction was stirred at ambient temperature for 3 hours, and then acetaldehyde (274 mg, 6.24 mmol), NaBHCN (393 mg, 6.24 mmol), and AcOH (28 mg, 0.47 mmol) were added to the reaction. The mixture was stirred at ambient temperature for 1 hour, quenched with HO (30 mL), and extracted with EtOAc (30 mL × 2). The combined organic layers were washed with brine (40 mL), dried over NaSO (15 g), filtered, and concentrated. The resulting residue was purified by flash silica chromatography (CHCl-MeOH, 30:1 to 20:1) to give the crude product (126 mg), which was dissolved in DCM (5 mL), treated dropwise over 2 min with HCl in EtO (4 mL, 1 N), and stirred at ambient temperature for 30 min. The precipitate was then collected by filtration to give N-(2-(1H-indol-3-yl)ethyl)-N-ethylbutan-2-amine as the hydrochloride salt (126 mg, 29%) as an off-white solid. 1 H-NMR(300MHz,DMSO-d6) δ 11.01(br s,1H),9.73(br s,1H),7.61(t,J=7.2Hz,1H),7.37(d,J=7.8Hz,1H),7.30(s,1H),7.11-6.98(m,2H),3.51 -3.12(m,7H),1.98-1.82(m,1H),1.61-1.48(m,1H),1.38-1.20(m,6H),1.00-0.89(m,3H). LCMS(ESI+):m / z245.2[M+H] + . HPLC purity (220nm): 99.8%.

[0286] Scheme 16: Compounds of general formula (I) can be synthesized from appropriately substituted tryptamines by following the sequence of steps outlined in Scheme 16 or similar to those that one skilled in the art would consider. The appropriately substituted tryptamines can undergo successive reductive alkylations to provide access to compounds of general formula (I) (exemplified by P-22). [ka]

[0287] Example 25: N-(2-(1H-indol-3-yl)ethyl)-N-ethyl-2-methylpropan-1-amine (P-22) [ka] Step 1: N-(2-(1H-indol-3-yl)ethyl)-2-methylpropan-1-amine (60) To a solution of 2-(1H-indol-3-yl)ethan-1-amine (600 mg, 3.74 mmol) in MeOH (10 mL) was added isobutyraldehyde (283 mg, 3.93 mmol), NaBHCN (232 mg, 6.48 mmol), and catalytic AcOH (3 drops). The reaction was stirred at ambient temperature for 2 hours, then quenched with water (50 mL) and extracted with EtOAc (50 mL × 2). The combined organic phases were washed with saturated aqueous NaHCO solution (50 mL) and brine (50 mL), dried over NaSO (15 g), filtered, and concentrated. The resulting residue was purified by flash silica chromatography (CH2Cl2-MeOH 30:1 to 20:1) to give N-(2-(1H-indol-3-yl)ethyl)-2-methylpropan-1-amine (350 mg, 43% yield). LCMS (ESI+): m / z 217.4 [M+H] + .

[0288] Step 2: N-(2-(1H-indol-3-yl)ethyl)-N-ethyl-2-methylpropan-1-amine (P-22) To a solution of N-(2-(1H-indol-3-yl)ethyl)-2-methylpropan-1-amine (350 mg, 1.62 mmol) in MeOH (10 mL) was added acetaldehyde (285 mg, 6.48 mmol), NaBHCN (408 mg, 6.48 mmol), and AcOH (29 mg, 0.48 mmol). The reaction was stirred at ambient temperature for 2 hours. After the reaction was complete, as indicated by TLC, the mixture was quenched with water (30 mL) and extracted with EtOAc (30 mL × 2). The combined organic layers were washed with brine (40 mL), dried over sodium sulfate (15 g), filtered, and concentrated. The resulting residue was purified by flash silica chromatography (CHCl-MeOH, 30:1 to 20:1) to give the crude product (170 mg), which was dissolved in DCM (3 mL), treated dropwise over 2 min with HCl in EtO (4 mL, 1 N), and stirred at ambient temperature for 30 min. The reaction mixture was then concentrated, and the residue was purified by preparative HPLC to give N-(2-(1H-indol-3-yl)ethyl)-N-ethyl-2-methylpropan-1-amine as the hydrochloride salt (87 mg, 10%) as an off-white solid. 1 H-NMR(300MHz,DMSO-d6):δ 11.01(br s,1H),9.89(br s,1H),7.65(d,J=7.8Hz,1H),7.37(d,J=8.1Hz,1H),7.27(s,1H),7.15-6.97(m,2H),3. 32-3.12(m,6H),3.09-2.92(m,2H),2.12(m,1H),1.31-1.20(m,3H),1.08-0.98(m,6H). LCMS(ESI+):m / z245.2[M+H] + . HPLC purity (220nm): 98.7%.

[0289] Scheme 17: Compounds of general formula (I) can be synthesized from appropriately substituted indoles by following the sequence of steps outlined in Scheme 17 or similar to those that one skilled in the art would consider. The substituted indole core could be condensed with dimethylamino-2-nitroethylene to give nitrovinyl indoles. Reduction of such indoles has proven feasible to provide unsubstituted ethylamine analogs, which can subsequently undergo successive reductive alkylation reactions to provide compounds of general formula (I) (exemplified by P-23, P-24, P-25, and P-26). [ka]

[0290] Example 26: N-(2-(4-methoxy-1H-indol-3-yl)ethyl)-N-methylbutan-2-amine (P-23) [ka] Step 1: (E)-4-Methoxy-3-(2-nitrovinyl)-1H-indole (62) A mixture of 4-methoxy-1H-indole (15.0 g, 102 mmol), N,N-dimethyl-2-nitroethen-1-amine (11.8 g, 102 mmol) in TFA (105 mL) was degassed and purged with N three times, and then the mixture was stirred at 25° C. for 1 h under a N atmosphere. The reaction mixture was quenched by adding it to a rapidly stirred solution of saturated aqueous NaHCO (105 mL × 5), and the resulting slurry was extracted with EtOAc (105 mL × 5), dried over NaSO, filtered, and concentrated under reduced pressure to give (£)-4-methoxy-3-(2-nitrovinyl)-1H-indole (16.0 g, 72% yield) as a red solid. 1H NMR:(400MHz,CDCl3)δ 8.72-8.81(m,1H),8.44-8.54(m,1H),7.93-8.00(m,1H),7.51-7.61(m,1H),7 .20-7.26(m,1H),7.04(d,J=8.0Hz,1H),6.64-6.73(m,1H),4.01-4.03(m,3H).

[0291] Step 2: 2-(4-Methoxy-1H-indol-3-yl)ethan-1-amine (63) A mixture of LiAlH (25.8 g, 680 mmol) in THF (47.0 mL) was degassed and purged with N three times, then a solution of (£)-4-methoxy-3-(2-nitrovinyl)-1H-indole (13.5 g, 61.8 mmol) in THF (47.0 mL) was added dropwise. Stirring was maintained at 0 °C for 1 h. The reaction was then warmed to 25 °C and heated to 80 °C for 2 h. The reaction mixture was quenched with NaSO·10H O, filtered, and concentrated under reduced pressure to give crude 2-(4-methoxy-1H-indol-3-yl)ethan-1-amine (8.00 g, 68% yield), which was used without further purification.

[0292] Step 3: N-(2-(4-methoxy-1H-indol-3-yl)ethyl)butan-2-amine (64) A solution of 2-(4-methoxy-1H-indol-3-yl)ethan-1-amine (0.50 g, 2.63 mmol), butan-2-one (284 mg, 3.94 mmol, 352 μL), and NEt (1.33 g, 13.1 mmol, 1.83 mL) in DCE (25 mL) was treated with NaBH(OAc) (2.79 g, 13.1 mmol) at 0 °C. The mixture was stirred at 25 °C for 12 h. The residue was diluted with HO (20 mL), extracted with EtOAc (10 mL × 3), dried over NaSO, filtered, and concentrated under reduced pressure to give N-(2-(4-methoxy-1H-indol-3-yl)ethyl)butan-2-amine (600 mg, 93%) as a brown solid, which was used in the subsequent reaction without further purification.

[0293] Step 3: N-(2-(4-methoxy-1H-indol-3-yl)ethyl)-N-methylbutan-2-amine (P-23) A solution of N-(2-(4-methoxy-1H-indol-3-yl)ethyl)butan-2-amine (500 mg, 2.03 mmol), formaldehyde (91.4 mg, 3.04 mmol, 83.8 μL), and NEt (1.03 g, 10.1 mmol, 1.41 mL) in DCE (20 mL) was treated with NaBH(OAc) (2.15 g, 10.1 mmol) at 0 °C. The mixture was stirred at 25 °C for 12 h. The residue was diluted with HO (30 mL), extracted with EtOAc (20 mL × 3), dried over NaSO, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (column: C18-1 150*30mm, 5um); mobile phase: [water (TFA)-ACN]; B%: 5%~50%, 8 min) to give N-(2-(4-methoxy-1H-indol-3-yl)ethyl)-N-methylbutan-2-amine (50.0 mg, yield 9.5%) as a yellow solid. 1 H NMR:(400MHz,CDCl3) δ 11.42-11.50(br.s,1H),8.26-8.32(br.s,1H),7.12(t,J=8.0Hz,1H),7.00(m,2H),6.51(d,J=8.0Hz,1H),3.94(s,3H) 3.28-3.45(m,4H),3.15-3.25(m,1H),2.68-2.87(m,3H),1.91-2.10(m,1H),1.40-1.57(m,1H),1.24-1.37(m,3H),0.95-1.06(m,3H). LCMS(ESI+):m / z261.1[M+H] + . HPLC purity (220nm): 95.5%

[0294] Example 27: N-ethyl-N-(2-(4-methoxy-1H-indol-3-yl)ethyl)butan-2-amine (P-24) [ka] Step 1: N-ethyl-N-(2-(4-methoxy-1H-indol-3-yl)ethyl)butan-2-amine (P-24) A solution of N-(2-(4-methoxy-1H-indol-3-yl)ethyl)butan-2-amine (1.00 g, 4.06 mmol), acetaldehyde (268 mg, 6.09 mmol, 341 μL), and NEt (2.05 g, 20.3 mmol, 2.83 mL) in DCE (40 mL) was treated with NaBH(OAc) (4.30 g, 20.3 mmol) at 0 °C. The mixture was stirred at 25 °C for 12 h. The residue was diluted with HO (15 mL), extracted with EtOAc (10 mL × 3), dried over NaSO, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (column: Phenomenex luna C18 250 * Purification by HPLC (50 mm, 10 μm; mobile phase: [water (TFA)-ACN]; B%: 10%-40%, 10 min) gave N-ethyl-N-(2-(4-methoxy-1H-indol-3-yl)ethyl)butan-2-amine (0.33 g, 30% yield) as the trifluoroacetate salt, which was a yellow solid. 1 H NMR(400MHz,CDCl3):δ 10.39-10.74(br.,1H),8.34(br.s,1H),7.11(t,J=8.0Hz,1H),7.01(m,2H),6.52(d,J=7.6Hz,1H),3.93(s,3H),3.29-3.55(m,4 H),3.11-3.28(m,3H),1.92-2.09(m,1H),1.48-1.57(m,1H),1.41-1.47(t,J=7.2Hz,3H),1.31-1.39(m,3H),0.96-1.06(m,3H). LCMS(ESI+):m / z274.1[M+H] + . HPLC purity (220nm): 95.5%.

[0295] Example 28: N-ethyl-N-(2-(4-methoxy-1H-indol-3-yl)ethyl)propan-2-amine (P-25) [ka] Step 1: N-(2-(4-methoxy-1H-indol-3-yl)ethyl)propan-2-amine (65) To a solution of 2-(4-methoxy-1H-indol-3-yl)ethan-1-amine (1.00 g, 5.26 mmol) in NEt (2.66 g, 26.3 mmol, 3.66 mL) was added acetone (458 mg, 7.88 mmol, 580 μL), and the cooled (0 °C) solution was treated with NaBH(OAc) (5.57 g, 26.3 mmol). The mixture was stirred at 25 °C for 12 h. The reaction mixture was diluted with HO (10 mL) and extracted with EtOAc (10 mL). The organic layer was concentrated under reduced pressure to give N-(2-(4-methoxy-1H-indol-3-yl)ethyl)propan-2-amine (980 mg, 80% yield) as a brown oil.

[0296] Step 2: N-ethyl-N-(2-(4-methoxy-1H-indol-3-yl)ethyl)propan-2-amine (P-25) To a solution of N-(2-(4-methoxy-1H-indol-3-yl)ethyl)propan-2-amine (780 mg, 3.36 mmol) in NEt (1.70 g, 16.8 mmol, 2.34 mL) was added acetaldehyde (222 mg, 5.04 mmol, 283 uL), and the cooled (0 °C) solution was treated with NaBH(OAc) (3.56 g, 16.8 mmol). The mixture was stirred at 25 °C for 12 h. The reaction mixture was diluted with HO (30 mL) and extracted with EtOAc (30 mL). The organic layer was concentrated under reduced pressure to give a residue. The crude product was purified by preparative HPLC (column: Phenomenex luna C18 250 × 50 mm × 10 μm; mobile phase: [water (TFA)-ACN]; B: 10–40%, 10 min) to give N-ethyl-N-(2-(4-methoxy-1H-indol-3-yl)ethyl)propan-2-amine (40.0 mg, 4% over two steps) as the trifluoroacetate salt, which was a yellow oil. 1H NMR(400MHz,CDCl3) δ 11.20-11.36(m,1H),8.01-8.20(m,1H),7.09-7.16(m,1H),6.99-7.05(m,2H),6.47-6.58(m,1H),3.89-4.02(m,3H),3. 73-3.85(m,1H),3.14-3.41(m,6H),1.44-1.48(m,3H),1.41-1.44(m,3H),1.36-1.39(m,3H)LCMS(ESI+):m / z261.1[M+H] + . HPLC purity (220nm): 98.6%.

[0297] Example 29: N-isopropyl-N-(2-(4-methoxy-1H-indol-3-yl)ethyl)propan-1-amine (P-26) [ka] Step 1: N-isopropyl-N-(2-(4-methoxy-1H-indol-3-yl)ethyl)propan-1-amine (P-26) To a solution of N-(2-(4-methoxy-1H-indol-3-yl)ethyl)propan-2-amine (930 mg, 4.00 mmol) in NEt (2.03 g, 20.0 mmol, 2.79 mL) was added propanal (349 mg, 6.00 mmol, 437 μL), and the cooled (0 °C) solution was treated with NaBH(OAc) (4.24 g, 20.0 mmol). The mixture was stirred at 25 °C for 12 h. The reaction mixture was diluted with HO (30.0 mL) and extracted with EtOAc (30.0 mL). The organic layer was concentrated under reduced pressure to give a residue that was purified by preparative HPLC (column: Phenomenex luna C18 250 × 50 mm × 10 μm; mobile phase: [water (TFA)-ACN]; B: 10–40%, 10 min) to give N-isopropyl-N-(2-(4-methoxy-1H-indol-3-yl)ethyl)propan-1-amine (70.0 mg, 5.8% yield) as the trifluoroacetate salt, which was a yellow oil. 1H NMR(400MHz,CDCl3):δ 11.20-11.10(m,1H),8.87-8.80(m,1H),7.12-7.06(m,1H),7.04-6.99(m,1H),6.97-6.93(m,1H),6.54-6.44(m,1H),3.91 (s,3H),3.75-3.72(m,1H),3.35-3.14(m,4H),3.00-2.95(m,2H),1.95-1.81(m,2H),1.40-1.01(m,6H),0.94-1.06(m,3H). LCMS(ESI+):m / z275.1[M+H] + . HPLC purity (220nm): 99.5%.

[0298] Scheme 18: Compounds of general formula (I) can be synthesized from appropriately substituted tryptamines by following the sequence of steps outlined in Scheme 18 or similar to those contemplated by one skilled in the art. Substituted tryptamine 63 can be derivatized to tert-butyl carbamate 238, which can be chemoselectively reduced to provide access to N-methylated tryptamine 239. Subsequent reductive alkylation provides access to compounds of general formula (I) (exemplified by P-136). [ka]

[0299] Example 30: N-(2-(4-methoxy-1H-indol-3-yl)ethyl)-N,2-dimethylpropan-1-amine (P-136) [ka] Step 1: tert-butyl (2-(4-methoxy-1H-indol-3-yl)ethyl)carbamate (238) A solution of 2-(4-methoxy-1H-indol-3-yl)ethan-1-amine (2.00 g, 10.5 mmol) and BocO (2.41 g, 11.0 mmol) in THF (14 mL) was degassed and purged with N three times, then stirred at ambient temperature for 2 h under N. Upon completion, the reaction mixture was diluted with HO (25 mL) and extracted with EtOAc (15 mL × 3). The organic layer was dried over anhydrous NaSO and concentrated to give crude tert-butyl (2-(4-methoxy-1H-indol-3-yl)ethyl)carbamate (3.00 g) as a brown oil, which was used in the next step without further purification.

[0300] Step 2: 2-(4-Methoxy-1H-indol-3-yl)-N-methylethan-1-amine (239) A solution of tert-butyl (2-(4-methoxy-1H-indol-3-yl)ethyl)carbamate (1.00 g, 3.44 mmol) in THF (3.50 mL) was added to a stirred mixture of LiAlH (653 mg, 17.2 mmol) in THF (3.50 mL), which was degassed and purged with N three times at 0 °C. The resulting mixture was heated at 70 °C for 3 h. Upon completion, the reaction was quenched by the addition of NaSO·10H O and then filtered. The filtrate was concentrated in vacuo to give crude 2-(4-methoxy-1H-indol-3-yl)-N-methylethan-1-amine (700 mg) as a brown oil, which was used in the next step without further purification.

[0301] Step 3: N-(2-(4-methoxy-1H-indol-3-yl)ethyl)-N,2-dimethylpropan-1-amine (P-136) A solution of 2-(4-methoxy-1H-indol-3-yl)-N-methylethan-1-amine (600 mg) and 3-methylbutanal (379 mg, 4.41 mmol) in EtN (1.49 g, 14.7 mmol) was treated with NaBH(OAc) (3.11 g, 14.7 mmol) at 0 °C. The reaction mixture was stirred at ambient temperature for 12 h. Upon completion, the reaction mixture was diluted with HO (10 mL) and extracted with EtOAc (15 mL × 3). The organic layer was dried over anhydrous NaSO and concentrated in vacuo. The residue was purified by preparative HPLC (column: C18-1 (150 × 30 mm × 5 μm); mobile phase: [water (TFA)-ACN; B: 10–55%, 8 min) to give N-(2-(4-methoxy-1H-indol-3-yl)ethyl)-N,2-dimethylpropan-1-amine trifluoroacetate (56.0 mg, 1% over three steps) as a yellow solid. 1 H NMR(400MHz,CDCl3):δ 11.35-11.75(br.,1H),8.28(br s,1H),7.12(t,J=8.0Hz,1H),7.00(d,J=8.0Hz,1H),6.97(s,1H),6.52(d,J=7.6Hz,1H),3.94(s,3H),3.37-3. 50(m,1H),3.23-3.36(m,3H),2.97-3.05(m,1H),2.77-2.96(m,4H),2.04-2.22(m,1H),1.08(d,J=6.8Hz,6H). LCMS(ESI+):m / z261.1[M+H] + . HPLC purity (220nm): 100%

[0302] Scheme 19: Compounds of general formula (I) can be synthesized from appropriately substituted tryptamines by following the sequence of steps outlined in Scheme 19 or similar to those contemplated by one skilled in the art. Substituted tryptamine 63 can be acetylated to give 240 before chemoselective reduction, providing access to N-ethylated tryptamine 241. Subsequent reductive alkylation provides access to compounds of general formula (I) (exemplified by P-137). [ka]

[0303] Example 31: N-(2-(4-methoxy-1H-indol-3-yl)ethyl)-N,2-dimethylpropan-1-amine (P-137) [ka] Step 1: N-(2-(4-methoxy-1H-indol-3-yl)ethyl)acetamide (240) A solution of 2-(4-methoxy-1H-indol-3-yl)ethan-1-amine (2.00 g, 10.5 mmol) in pyridine (9.30 mL) was treated with AcO (4.60 mL) and the reaction was stirred at ambient temperature for 12 hours. The reaction was then concentrated in vacuo to give crude N-(2-(4-methoxy-1H-indol-3-yl)ethyl)acetamide (2.44 g) as a brown solid, which was used in the next step without further purification.

[0304] Step 2: N-ethyl-2-(4-methoxy-1H-indol-3-yl)ethan-1-amine (241) A solution of crude N-(2-(4-methoxy-1H-indol-3-yl)ethyl)acetamide (2.30 g) and LiAlH (1.88 g, 49.5 mmol) in THF (16.1 mL) was degassed and purged with N three times at 0 °C and stirred at 0 °C for 10 min. The reaction was then warmed to ambient temperature and then heated at 50 °C for 5 h under N. The reaction was quenched by the addition of NaSO·10H O (2.00 g), filtered, and the filtrate was concentrated in vacuo to give crude N-ethyl-2-(4-methoxy-1H-indol-3-yl)ethan-1-amine (2.16 g) as a brown solid.

[0305] Step 3: N-ethyl-N-(2-(4-methoxy-1H-indol-3-yl)ethyl)-2-methylpropan-1-amine (P-137) A solution of crude N-ethyl-2-(4-methoxy-1H-indol-3-yl)ethan-1-amine (2.06 g) and isobutyraldehyde (1.02 g, 14.2 mmol) in EtN (4.77 g, 47.2 mmol) was treated with NaBH(OAc) (10.0 g, 47.2 mmol) at 0 °C. The reaction was then stirred at ambient temperature for 12 h. The reaction was quenched with water (30 mL) and extracted with EtOAc (20 mL × 3). The combined organic layers were dried over anhydrous NaSO and concentrated in vacuo. The residue was purified by preparative HPLC to give N-ethyl-N-(2-(4-methoxy-1H-indol-3-yl)ethyl)-2-methylpropan-1-amine trifluoroacetate (2.00 g, 49% over three steps) as a yellow oil. 1 H NMR(400MHz,CDCl3):δ 11.10(br.s,1H),8.30(br.s,1H),7.12(t,J=7.8Hz,1H),7.03-6.97(m,2H),6.52(d,J=7.8Hz,1H),3. 93(s,3H),3.38-3.25(m,6H),2.93(m,2H),2.15(m,1H),1.38(t,J=7.2Hz,3H),1.08(d,J=6.4Hz,6H). LCMS(ESI+):m / z275.1[M+H] + . HPLC purity (220nm): 98.8%.

[0306] Example 32: 3-(2-(ethyl(isopropyl)amino)ethyl)-1H-indol-4-ol (P-138) [ka] Step 1: 3-(2-(ethyl(isopropyl)amino)ethyl)-1H-indol-4-ol (P-138) A solution of N-ethyl-N-(2-(4-methoxy-1H-indol-3-yl)ethyl)propan-2-amine (400 mg, 1.54 mmol) in CHCl (2.80 mL) was treated with AlCl (1.23 g, 9.22 mmol) and EtSH (1.72 g, 27.7 mmol) at 0 °C. The resulting mixture was stirred at ambient temperature for 1 h. Upon completion, the reaction was cooled to 0 °C, quenched by the addition of saturated aqueous NaHCO solution (15 mL), and extracted with CHCl (10 mL × 3). The combined organics were washed with brine (30 mL), dried over anhydrous NaSO, and concentrated in vacuo. The residue was purified by preparative HPLC (column: C18-1 (150 × 30 mm × 5 μm); mobile phase: [water (TFA)-ACN]; B: 1–25%, 8 min) to give 3-(2-(ethyl(isopropyl)amino)ethyl)-1H-indol-4-ol trifluoroacetate (16.9 mg, 3%) as a brown oil. 1 H NMR (400MHz, MeOD4) δ 7.03(s,1H),6.90(m,2H),6.37(d,J=7.6Hz,1H),3.75(m,1H),3.60(m,1H),3.24-3.37(m,5H),1.36(m,9H). LCMS(ESI+):m / z247.1[M+H] + . HPLC purity (220nm): 100%

[0307] Example 33: 3-(2-(sec-butyl(ethyl)amino)ethyl)-1H-indol-4-ol (P-139) [ka] Step 1: 3-(2-(sec-butyl(ethyl)amino)ethyl)-1H-indol-4-ol (P-139) A solution of N-ethyl-N-(2-(4-methoxy-1H-indol-3-yl)ethyl)butan-2-amine (875 mg, 2.25 mmol) in CHCl (4.2 mL) was treated with AlCl (2.7 g, 9 equiv., 20.3 mmol) and EtSH (2.52 g, 18 equiv., 40.5 mmol) at 0 °C. The resulting mixture was purged with N three times and stirred at ambient temperature for 1 h. The reaction was cooled to 0 °C and quenched by the addition of saturated aqueous NaHCO solution (15 mL) and then extracted with CHCl (10 mL × 3). The combined organic layers were washed with brine (30 mL), dried over anhydrous NaSO, filtered, and the filtrate was concentrated in vacuo. The residue was purified by preparative HPLC (column: C18-1, 150 × 30 mm × 5 μm; mobile phase: [water (TFA)-ACN]; B%: 5% to 50%, 8 min) to give 3-(2-(sec-butyl(ethyl)amino)ethyl)-1H-indol-4-ol as the trifluoroacetate salt (9.4 mg, 1%), which was a yellow oil. 1 H NMR(400MHz,MeOD-d4):δ 7.03(s,1H),6.83-6.93(m,2H),6.37(d,J=7.2Hz,1H),3.31-3.48(m,4H),3.24-3.30 (m,3H),1.75-1.83(m,1H),1.55-1.68(m,1H),1.24-1.42(m,6H),0.93-1.05(m,3H). LCMS(ESI+):m / z261.1[M+H] + . HPLC purity (220nm): 96.7%.

[0308] Example 34: 3-(2-(ethyl(isobutyl)amino)ethyl)-1H-indol-4-ol (P-140) [ka] Step 1: 3-(2-(ethyl(isobutyl)amino)ethyl)-1H-indol-4-ol (P-140) A solution of N-ethyl-N-(2-(4-methoxy-1H-indol-3-yl)ethyl)-2-methylpropan-1-amine (0.8 g, 2.92 mmol) in CHCl (5 mL) was treated with AlCl (3.5 g, 9 equiv., 26.2 mmol) and EtSH (3.26 g, 18 equiv., 52.5 mmol) at 0 °C. The resulting mixture was purged with N three times and stirred at ambient temperature for 1 h. The reaction was cooled to 0 °C and quenched by the addition of saturated aqueous NaHCO solution (15 mL) and then extracted with CHCl (10 mL × 3). The combined organic layers were washed with brine (30 mL), dried over anhydrous NaSO, filtered, and the filtrate was concentrated in vacuo. The residue was purified by preparative HPLC (column: C18-1 150*30mm*5μm; mobile phase: [water (TFA)-ACN]; B%: 1%~45%, 8 min) to give 3-(2-(ethyl(isobutyl)amino)ethyl)-1H-indol-4-ol as the trifluoroacetate salt (38.2 mg, 4%), which was a yellow oil. 1 H NMR(400MHz,MeOD-d4):δ 7.03(s,1H),6.94-6.83(m,2H),6.38(d,J=7.2Hz,1H),3.64-3.41(m,2H),3.38-3.29(m ,4H),3.10(m,1H),2.99(m,1H),2.15(m,1H),1.38(t,J=7.2Hz,3H),1.05-1.00(m,6H). LCMS(ESI+):m / z261.1[M+H] + . HPLC purity (220nm): 97.7%.

[0309] Example 35: 3-(2-(isopropyl(propyl)amino)ethyl)-1H-indol-4-ol (P-141) [ka] Step 1: 3-(2-(isopropyl(propyl)amino)ethyl)-1H-indol-4-ol (P-141) A solution of N-isopropyl-N-(2-(4-methoxy-1H-indol-3-yl)ethyl)propan-1-amine (0.5 g, 1.82 mmol) in CHCl (3.5 mL) was treated with AlCl (1.46 g, 6 equiv., 10.9 mmol) and EtSH (2.04 g, 18 equiv., 32.8 mmol) at 0 °C. The resulting mixture was purged with N three times and stirred at ambient temperature for 1 h. The reaction was cooled to 0 °C and quenched by the addition of saturated aqueous NaHCO solution (20 mL) and then extracted with CHCl (20 mL × 3). The combined organic layers were washed with brine (50 mL), dried over anhydrous NaSO, filtered, and the filtrate was concentrated in vacuo. The residue was purified by preparative HPLC (column: C18-1 150*30mm*5μm; mobile phase: [water (TFA)-ACN]; B%: 5%~50%, 8 min) to give 3-(2-(isopropyl(propyl)amino)ethyl)-1H-indol-4-ol as the trifluoroacetate salt (230 mg, 34%), which was a brown oil. 1 H NMR(400MHz,MeOD-d4):δ 7.04(s,1H),6.85-6.94(m,2H),6.38(dd,J=7.4,0.8Hz,1H),3.71-3.81(m,1H),3.56-3.65(m,1H),3.35-3.40 (m,1H),3.24-3.29(m,2H),3.08-3.20(m,2H),1.72-1.90(m,2H),1.36(d,J=6.4Hz,6H),1.02(t,J=7.2Hz,3H). LCMS(ESI+):m / z261.1[M+H] + . HPLC purity (220nm): 100%.

[0310] Scheme 20: Compounds of general formula (I) can be synthesized from appropriately substituted indoles by following the outlined sequence of steps in Scheme 20 or similar to those contemplated by one skilled in the art. Amidation of the pendant acetic acid with an appropriately substituted secondary amine provided access to intermediates such as 301, which when subjected to reducing conditions, provided access to the desired compounds of general formula (I), exemplified by P-137. One skilled in the art will recognize that utilization of differentially substituted amines provides access to compounds of general formula (I) disclosed herein. [ka]

[0311] Example 36: N-(2-(5-methoxy-1H-indol-3-yl)ethyl)-N-methylcyclopropanamine (P-162) [ka] Step 1: N-cyclopropyl-2-(5-methoxy-1H-indol-3-yl)-N-methylacetamide (301) To a solution of 2-(5-methoxy-1H-indol-3-yl)acetic acid (500 mg, 2.44 mmol, 1.0 equiv) in CHCl (5 mL), EtN (370 mg, 3.65 mmol, 509 μL, 1.5 equiv), HATU (1.39 g, 3.65 mmol, 1.5 equiv), and N-methylcyclopropanamine (173 mg, 2.44 mmol, 1.0 equiv) were added, and the mixture was stirred for 2 h at 25° C. The reaction mixture was diluted with HO (10 mL) and extracted with EtOAc (15 mL × 3). The combined organic layers were washed with brine (10 mL x 2), dried over Na2SO4, filtered, and concentrated under reduced pressure to give crude N-cyclopropyl-2-(5-methoxy-1H-indol-3-yl)-N-methylacetamide (500 mg) as a yellow oil, which was used in the subsequent step without further purification. LCMS (ESI+): m / z 259.0 [M+H] + .

[0312] Step 2: N-(2-(5-methoxy-1H-indol-3-yl)ethyl)-N-methylcyclopropanamine (P-162) A cooled (0 °C) solution of crude N-cyclopropyl-2-(5-methoxy-1H-indol-3-yl)-N-methylacetamide (300 mg) in THF (3.00 mL) was degassed and purged with N three times, then treated dropwise with a solution of LiAlH in THF (2.50 M, 2.32 mL). The mixture was stirred at 25 °C under N for 3 h, then cooled to 0 °C and quenched by the addition of NaSO·10H O (3.00 g). The mixture was filtered, the filter cake was washed with EtOAc (15 mL × 3), and the combined organic phase was concentrated under reduced pressure. The residue was purified by preparative HPLC (neutral conditions: column: Waters Xbridge 150 × 25 mm × 5 μm; mobile phase: [water (NH4HCO3)-ACN]; gradient: 35% to 65% B, 9 min) to give N-(2-(5-methoxy-1H-indol-3-yl)ethyl)-N-methylcyclopropanamine (25.0 mg, 4% over two steps) as a yellow solid. 1 H NMR(400MHz,CDCl3):δ 7.86(br s,1H),7.26-7.24(m,1H),7.07(d,J=2.4Hz,1H),7.01(d,J=2.0Hz,1H),6.87(dd,J=8.8,2.4Hz,1H),3.88( s,3H),3.01-2.85(m,4H),2.49(s,3H),1.74-1.73(m,1H),0.56-0.52(m,4H);LCMS(ESI+):m / z245.0[M+H] + ; HPLC purity (220nm): 99.6%.

[0313] Example 37: N-(2-(5-methoxy-1H-indol-3-yl)ethyl)-N-methylcyclobutanamine (P-163) [ka] Step 1: N-cyclobutyl-2-(5-methoxy-1H-indol-3-yl)-N-methylacetamide (302) To a solution of 2-(5-methoxy-1H-indol-3-yl)acetic acid (0.50 g, 2.44 mmol, 1.0 equiv) and N-methylcyclobutanamine (249 mg, 2.92 mmol, 1.2 equiv) in CHCl (10 mL) was added EtN (370 mg, 3.65 mmol, 509 μL, 1.5 equiv) and HATU (1.39 g, 3.65 mmol, 1.5 equiv), and the mixture was stirred at 25° C. for 2 h. The reaction mixture was washed with HO (10 mL × 2), brine (10 mL), dried over NaSO, and concentrated in vacuo to give crude N-cyclobutyl-2-(5-methoxy-1H-indol-3-yl)-N-methylacetamide (0.70 g) as a light brown oil, which was used in the subsequent step without further purification. LCMS(ESI+):m / z273.0[M+H] + .

[0314] Step 2: N-(2-(5-methoxy-1H-indol-3-yl)ethyl)-N-methylcyclobutanamine (P-163) A cooled (0 °C) solution of crude N-cyclobutyl-2-(5-methoxy-1H-indol-3-yl)-N-methylacetamide (700 mg) in THF (7 mL) was degassed and purged with N three times, then treated dropwise with a solution of LiAlH in THF (2.50 M, 5.14 mL) and stirred at 25 °C for 3 h. The reaction mixture was cooled to 0 °C and quenched by the addition of NaSO·H0 (7.50 g). The mixture was filtered, the filter cake was washed with EtOAc (30 mL × 3), and the combined organic phases were concentrated under reduced pressure. The residue was purified by preparative HPLC [Column: Waters Xbridge Prep OBD C18 150 × 40 mm × 10 μm; Mobile phase: [water (NH4HCO3)-ACN]; Gradient: 20% to 50% B over 15 min] to give N-(2-(5-methoxy-1H-indol-3-yl)ethyl)-N-methylcyclobutanamine (259 mg, 41% over two steps) as a yellow solid. 1H NMR(400MHz,MeOD-d4):δ 7.22(d,J=8.8Hz,1H),7.03-6.98(m,2H),6.75(dd,J=8.8,2.4Hz,1H),3.82(s,3H),3.06-2.95(m,1H),2.94-2.87(m,2H) ),2.69-2.61(m,2H),2.30(s,3H),2.16-2.07(m,2H),2.03-1.91(m,2H),1.78-1.64(m,2H);LCMS(ESI+):m / z259.0[M+H] + ; HPLC purity (254nm): 98.4%.

[0315] Example 38: N-(2-(5-methoxy-1H-indol-3-yl)ethyl)-N-methyloxetan-3-amine (P-164) [ka] Step 1: 2-(5-methoxy-1H-indol-3-yl)-N-methyl-N-(oxetan-3-yl)acetamide (303) To a solution of 2-(5-methoxy-1H-indol-3-yl)acetic acid (500 mg, 2.44 mmol, 1.0 equiv) and N-methyloxetan-3-amine (254 mg, 2.92 mmol, 1.2 equiv) in CHCl (10 mL) was added EtN (370 mg, 3.65 mmol, 509 μL, 1.5 equiv), HATU (1.39 g, 3.65 mmol, 1.5 equiv), and the mixture was stirred at 25 °C for 2 h. The reaction mixture was washed with HO (10 mL x 2), brine (10 mL), dried over NaSO, filtered, and the filtrate was concentrated in vacuo to give crude 2-(5-methoxy-1H-indol-3-yl)-N-methyl-N-(oxetan-3-yl)acetamide (0.70 g) as a brown oil, which was used in the subsequent step without further purification. LCMS (ESI+): m / z 275.2 [M+H] + .

[0316] Step 2: N-(2-(5-methoxy-1H-indol-3-yl)ethyl)-N-methyloxetan-3-amine (P-164) A cooled (0 °C) solution of crude 2-(5-methoxy-1H-indol-3-yl)-N-methyl-N-(oxetan-3-yl)acetamide (0.70 g) in THF (10 mL) was treated dropwise with a solution of LiAlH in THF (2.50 M, 5.10 mL) under N, and the mixture was stirred at 25 °C for 5 h. The reaction mixture was cooled to 0 °C, quenched with NaSO·10H O (10.0 g), and stirred for 30 min. The mixture was filtered, the filter cake was washed with EtOAc (20 mL × 5), and the combined organic layers were concentrated in vacuo. The residue was purified by preparative HPLC (column: Waters Xbridge Prep OBD C18 150 × 40 mm × 10 μm; mobile phase: [water (NH4HCO3)-ACN]; gradient: 15 to 45% B in 15 min) to give N-(2-(5-methoxy-1H-indol-3-yl)ethyl)-N-methyloxetan-3-amine (20.0 mg, 3% over two steps) as a yellow solid. 1 H NMR(400MHz,CDCl3):δ 7.96(br s,1H),7.29(s,1H),7.06-7.04(m,2H),6.90(dd,J=8.8,2.4Hz,1H),4.68(d,J=6.8Hz,4H),3.90(s,3H) ),3.72-3.63(m,1H),2.95-2.85(m,2H),2.63-2.53(m,2H),2.31(s,3H);LCMS(ESI+):m / z261.0[M+H] + ; HPLC purity (220nm): 99.5%.

[0317] Scheme 21: Compounds of general formula (I) can be synthesized from an appropriately substituted tryptamine by following the sequence of steps outlined in Scheme 21 or similar to those contemplated by one skilled in the art. Attachment of a carbamate onto the pendant amine followed by reduction produces the monomethyl analog 402. This intermediate can be condensed with a variety of aldehydes or ketones under reductive alkylation conditions to produce compounds of general formula (I), as exemplified by compound P-42. One skilled in the art will recognize that utilizing alternating aldehydes and ketones provides access to alternating compounds of general formula (I) disclosed herein. [ka]

[0318] Example 39: N-methyl-N-(2-(4-methyl-1H-indol-3-yl)ethyl)propan-2-amine (P-42) [ka] Step 1: tert-butyl (2-(4-methyl-1H-indol-3-yl)ethyl)carbamate (401) To an ice-cold solution of 2-(4-methyl-1H-indol-3-yl)ethan-1-amine (2.0 g, 11.5 mmol) in THF (100 mL, 1.23 mol) was added triethylamine (2.4 mL, 1.5 equiv., 17.2 mmol) and BocO (3.01 g, 1.2 equiv., 13.8 mmol) predissolved in 20 mL of THF. The reaction was stirred at ambient temperature for 16 h and then diluted with cold water (50 mL). The solvent volume was reduced to half under a stream of N gas. The resulting solution was then extracted with EtO (50 mL × 3), and the combined organic layers were washed with 0.1 M aqueous HCl (50 mL × 3) and brine (100 mL × 1). The organic layer was concentrated in vacuo to give a solid, which was then triturated with hexane and filtered. The collected solid was washed with additional hexane (10 mL x 1) to give, after drying, tert-butyl (2-(4-methyl-1H-indol-3-yl)ethyl)carbamate as a red solid (2.9 g, 92%). 1 H NMR(400MHz,DMSO-d6):δ 10.77(s,1H),7.14(d,J=8.0Hz,1H),7.06(s,1H),6.95-6.86(m,2H),6.68(d,J= 7.0Hz, 1H), 3.25-3.14 (m, 2H), 2.95 (t, J=7.6Hz, 2H), 2.61 (s, 3H), 1.39 (s, 9H).

[0319] Step 2: N-methyl-2-(4-methyl-1H-indol-3-yl)ethan-1-amine (402) To an ice-cooled solution of anhydrous THF (100 mL) was added LiAlH (1.16 g, 3 equiv., 30.6 mmol) in small portions under N, followed by the addition of tert-butyl (2-(4-methyl-1H-indol-3-yl)ethyl)carbamate (2.8 g, 10.2 mmol) predissolved in minimal anhydrous THF at a rate that maintained a gentle reflux. After the addition, the reaction was heated to reflux for 1 h. The completed reaction was cooled in an ice bath and quenched with cold water (1.2 mL), 3.75 M aqueous NaOH (1.2 mL), and water (3.6 mL). The resulting suspension was stirred at low temperature for 15 min, then dried over approximately 1 g of anhydrous NaSO, filtered through a pad of Celite, and the filter cake was washed with several volumes of hot THF (50 mL × 2). The combined filtrates were concentrated in vacuo to give N-methyl-2-(4-methyl-1H-indol-3-yl)ethan-1-amine (1.59 g, 83%) as an off-white solid. 1 H NMR(400MHz,DMSO-d6):δ 10.75(s,1H),7.14(d,J=8.0Hz,1H),7.05(d,J=2.2Hz,1H),6.97-6.84(m,1H),6.68(d ,J=6.8Hz,1H),2.96(t,J=7.6Hz,2H),2.73(t,J=7.6Hz,2H),2.61(s,3H),2.33(s,3H). 13 C NMR (101MHz, DMSO-d6): δ 136.7,129.5,125.6,122.6,120.7,119.8,113.4,109.3,53.9,36.2,27.1,20.0.

[0320] Step 3: N-methyl-N-(2-(4-methyl-1H-indol-3-yl)ethyl)propan-2-amine (P-162) To a solution of N-methyl-2-(4-methyl-1H-indol-3-yl)ethan-1-amine (250 mg, 1.33 mmol) and acetone (84.8 mg, 1.1 equiv., 1.46 mmol) in 1,2-dichloroethane (5 mL) was added NaBH(OAc) (422 mg, 1.5 equiv., 1.99 mmol) at ambient temperature. The reaction was stirred at ambient temperature for 16 hours and then extracted with 1 M aqueous NaOH (5 mL) and CHCl (10 mL × 3). The combined organic layers were washed with brine (20 mL) and then concentrated under reduced pressure. The residue was purified by flash chromatography (0.1% to 6% MeOH / NH (aqueous) in CH2Cl2) to give N-methyl-N-(2-(4-methyl-1H-indol-3-yl)ethyl)propan-2-amine (190 mg) as a yellow oil, which was used in the next step without further purification.

[0321] Step 3a: N-methyl-N-(2-(4-methyl-1H-indol-3-yl)ethyl)propan-2-amine fumarate (P-162 fumarate) To a solution of fumaric acid (96 mg, 0.83 mmol) in minimal refluxing acetone was added a solution of N-methyl-N-(2-(4-methyl-1H-indol-3-yl)ethyl)propan-2-amine (190 mg) in minimal warm acetone. The resulting solution was cooled to ambient temperature and allowed to stand at 4° C. overnight to afford N-methyl-N-(2-(4-methyl-1H-indol-3-yl)ethyl)propan-2-amine as the fumarate salt (48 mg, 12% over two steps) as colorless crystals. 1 H NMR(400MHz,DMSO-d6):δ 10.83(s,1H),7.20-7.05(m,2H),7.01-6.84(m,1H),6.69(d,J=7.2Hz,1H),6.48(s,1H) ,3.23-2.95(m,3H),2.89-2.68(m,2H),2.61(s,3H),2.41(s,3H),1.07(d,J=6.8Hz,6H). 13C NMR (101MHz, DMSO-d6): δ 167.6,136.6,135.0,129.3,125.5,122.9,120.8,119.9,112.3,109.4,54.9,53.9,35.7,24.2,19.8,17.0. qNMR purity (ERETIC): 95.5%.

[0322] Functional assay 5-HT 2A , 5-HT 2B , and 5-HT 2C receptor Activity at 5-HT2A, 5-HT2B, and 5-HT2C receptors was determined using the FLIPR Ca2+ flux assay at the Discovery Biology Unit of WuXi AppTec Co., Ltd. (Hong Kong) according to their standard protocol. Briefly, stably transfected cells expressing the receptors of interest (HEK293 for 5-HT2A and 5-HT2C, CHO-K1 for 5-HT2B) were grown, plated into 384-well plates, and incubated overnight at 37°C and 5% CO2. A 250 mM stock solution of probenecid in FLIPR calcium assay buffer (10 mL) was freshly prepared and combined with the fluorescent dye (Fluo-4 Direct) to give a final assay concentration of 2.5 mM. The reference compound was serially diluted 4-fold, and the screening compound was serially diluted 3-fold in 100% DMSO for 10 points using an Agilent Bravo, and 750 nL was added to a 384-well compound plate using an Echo along with 30 μL of assay buffer. The fluorescent dye was then added to the assay plate along with the assay buffer to a final volume of 40 μL. The cell plate was incubated at 37°C and 5% CO2 for 50 minutes and placed in a FLIPR Tetra along with the compound plate. 10 μL of the reference and compound were then transferred from the compound plate to the cell plate, and the fluorescent signal was read. [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4]

[0323] In vivo pharmacokinetic experiments Prospective in vivo pharmacokinetic studies are conducted using established procedures in accordance with the Australian Code of Practice for the Care and Use of Animals for Scientific Purposes, and study protocols are reviewed and approved by the Monash Institute of Pharmaceutical Sciences Animal Ethics Committee. A brief summary of the standard methods previously used is provided below: Systemic exposure of selected examples will be investigated in non-fasted male C57BL / 6 mice weighing between 18.9 and 25.5 g. Mice will have free access to food and water throughout the pre-dose and post-dose sampling periods.

[0324] On the day of administration, each compound formulation is prepared by dissolving the solid compound in the appropriate solvent using a vortex.

[0325] Compounds are administered to mice via IP injection (10 mL / kg dose volume via a 27G needle; n = 9 mice per compound), and blood samples are collected at various time points (e.g., 5 and 30 minutes, 1, 2, and 4 hours post-dose (n = 3 mice per time point for each compound)). Up to three blood samples are obtained from each mouse, and plasma samples are collected via submandibular bleeding (approximately 120 μL). Once collected, blood samples are processed by standard methods and analyzed by LCMS. In addition, immediately after blood collection, whole brain samples are collected by rapid removal from the carcass. Whole brains are blotted to remove excess blood and placed in pre-weighed polypropylene vials and weighed. Brains are snap-frozen in dry ice and then stored frozen (-80°C) until analysis.

[0326] Overview of bioanalytical methods: The concentrations of test compounds in plasma and tissue samples are determined using an LCMS / MS method validated for linearity, precision, accuracy, matrix factor, and recovery. Test compound standard solutions are diluted from concentrated stock solutions (32 mM in HO) using 50% ACN (v / v) in HO, and a calibration curve is prepared in a matrix matched to the test samples.

[0327] Plasma: Plasma calibration curves are prepared by spiking aliquots (25 μL) of blank mouse plasma with test compound standard solution (5 μL) and internal standard solution (5 μL of diazepam, 5 μg / mL in 50% acetonitrile in water). Test plasma samples (25 μL) are thawed, mixed, and then spiked with internal standard solution (5 μL). Plasma protein precipitation can be performed by adding acetonitrile (3x volume ratio) and thorough vortex mixing. Samples are centrifuged (RCF = 9391 × g) for 3 minutes, and the supernatant (90 μL) is collected for analysis.

[0328] Tissue: Pre-weighed tissue samples (brain) were prepared according to standard methods, for example, homogenized using a glass rod in a buffer containing EDTA / potassium fluoride solution (0.1 M / 4 mg / mL) as a stabilizing cocktail to minimize the possibility of ex vivo degradation (3 mL cocktail / g tissue). The tissue homogenate was briefly centrifuged for 10 seconds (RCF = 79 × g) to separate the foam layer, and then an aliquot (200 μL) of the tissue homogenate was transferred to a fresh Eppendorf tube for sample extraction. Calibration standards were prepared by spiking blank brain homogenate (200 μL) with the solution standard (10 μL) and the internal standard (10 μL). Investigational samples were prepared similarly, except that acetonitrile (10 μL) was added instead of the solution standard to maintain the same volume. Protein precipitation can be performed by adding 3 volumes of acetonitrile, followed by vortex mixing and centrifugation (RCF=9391×g) for 3 minutes, and the supernatant can be collected for analysis.

[0329] Analytical Replicates: Triplicate analytical replicate (AR) samples are prepared as well as standards of each sample type at three concentrations (50, 500, and 2,000 ng / mL), and repeat injections of these ARs are included throughout the analytical run to assess assay performance. Extraction of test compounds from standards and ARs is performed as described above.

[0330] All test samples are quantified within the calibration range of the assay, and the stability of each test compound is confirmed in the homogenate for the duration of sample processing (15 min; less than 15% loss).

[0331] Biotelemetry and Head Twitch Response (HTR) Experiments Psychedelic potential is assessed via the industry-standard head-twitch response in mice (C57BL / 6J males). The study is conducted via standard procedures, summarized below. Mice are purchased from Jackson Laboratory (Bar Harbor, ME, USA) at 5-6 weeks of age and allowed to acclimate to the animal research facility for at least 1-2 weeks. During acclimation, mice are grouped 3-5 per cage and housed on a 12-h light-dark cycle throughout the study, with lights on at 0700 h. Food and water will be available ad libitum, except during testing. Cohorts of 20-24 mice are used for each test drug. Mice are subjected to experimental testing once every 1-2 weeks over a 2-3 month period to complete dose-effect curves and antagonist experiments. A minimum of 7 days between treatments is utilized to avoid tolerance to the effects of repeated drug administration. All drug doses represent the weight of the salt dissolved in 0.9% saline vehicle. Mice are first tested in dose-response studies to assess the effects of each compound at subcutaneous doses of 0.03 to 30 mg / kg, followed by antagonist reversal studies utilizing pretreatment with M100907 and WAY100635. All experiments are performed during the light phase, between 0900 and 1700 local time, because rodent sensitivity to other tryptamine psychedelics is diurnal, with maximum HTR observed in the middle of the light phase. Experiments are also performed during the light phase to avoid potential effects of melatonin receptor activity on HTR, because melatonin and related agonists are known to reduce DOI-induced HTR in rats. For each experiment, mice are allowed to acclimate to the testing room in their home cages for at least 1 h before the experimental session. Behavioral testing sessions are conducted in a TruScan mouse locomotor arena equipped with a photobeam array (Coulbourn Instruments, Holliston, Mass., USA), modified with a cylindrical insert and transparent floor useful for detecting mouse HTR.

[0332] Subcutaneous temperature transponder implantation. At least 1 week before the start of the experiment, mice received subcutaneously implanted temperature transponders (14 x 2 mm, model IPTT-300, BioMedic Data Systems, Inc., Seaford, DE, USA) under brief isoflurane anesthesia. Mice were single-housed after implantation for the remainder of the study to protect the transponders from removal by cagemates. Temperature was determined noninvasively using a handheld receiver sensitive to the signal emitted from the implanted transponder.

[0333] Before each experiment, mouse weight and body temperature were recorded. The mice were then placed in the testing room for acclimation. For dose-response studies, after a brief 5-minute acclimation period, mouse body temperature was recorded for baseline measurements, the mice received a subcutaneous injection of the test substance or vehicle, and the animals were returned to the testing arena for 30 minutes. During the session, locomotor activity was monitored via photobeam tracking of movement in the horizontal plane, yielding distance traveled in centimeters. HTR was monitored by analyzing GoPro Hero Black 7 video recordings (120 frames / s and 960p resolution) using a commercially available software package from Clever Sys Inc. (Reston, VA, USA). Post-treatment body temperature values ​​were also recorded, and temperature data were expressed as the change from the pretreatment baseline.

[0334] In the antagonist reversal experiment, mice received a subcutaneous injection of either receptor antagonist or vehicle and were returned to the testing chamber for 30 minutes. During this period, locomotor activity was monitored to examine potential effects of antagonist treatment on general behavior or movement. Thirty minutes after antagonist administration, mice were given the test drug or vehicle and returned to the chamber for an additional 30 minutes of video recording, which was used for analysis.

[0335] All statistical analyses are performed using GraphPad Prism 9 (La Jolla, CA, USA). Dose-response data from mouse experiments are analyzed using nonlinear regression, and efficacy values ​​are determined from the ascending phase of the curve for HTR measurements. For mouse studies, one-way ANOVA with Dunnett's post-hoc test is used to compare all conditions with the vehicle control (0 or 0.0) in dose-response and antagonist experiments. The mean HTR counts, distance traveled, and temperature change for each condition are used for statistical comparison. For all analyses, alpha is set to 0.05.

[0336] Acute restraint stressor (ASR) tail suspension test (TST) in mice Compounds are evaluated in a validated model of depression conducted by Europhins Panlabs, a leading contract research organization. Evaluations are performed according to standard conditions, briefly outlined here: Male ICR mice (23 ± 3 g) are purchased from BioLASCO (Taipei, Taiwan) at 4–5 weeks of age and acclimated for 5–7 days to the animal research facility at Pharmacology Discovery Services (Taipei, Taiwan). Mice are housed in groups of 10 in large cages (47 × 25 × 15 cm) on a 12-hour light cycle (lights on: 07:00) and provided with food and water ad libitum, except during acute restraint stress and tail suspension testing. Temperature was maintained at 20–24 °C, and all rooms (colony and testing room) had similar lighting intensities. All aspects of this work, including housing, experimentation, and animal disposal, were conducted in a facility certified by the Association for Assessment and Accreditation of Laboratory Animal Care in accordance with the "Guide for the Care and Use of Laboratory Animals: Eighth Edition" (The National Academies Press, Washington, DC, 2011). All experiments were conducted during the light phase between 09:00 and 17:00 local time. Each mouse underwent a single behavioral experiment in which mice were randomly assigned to receive a single treatment with vehicle (50 mM phosphate-buffered saline, pH = 6.5), ketamine (10 mg / kg, diluted in 0.9% saline from a 50 mg / ml stock) as a positive control, or one dose of test drug (n = 10 per dose of test drug; n = 12 for vehicle, n = 12 for ketamine). All drug doses represent the free base dose of the salt form dissolved in vehicle. All solutions are delivered via intraperitoneal injection at 5 ml / kg.

[0337] Acute Restraint Stress (ARS) Procedure: Mice were moved from the colony room to the treatment room where ARS was performed. To prevent dehydration, mice were given 10 ml / kg of water by oral gavage. They were then individually restrained for 5 hours in a clear plastic cylinder (a 50 mL centrifuge tube with air holes drilled for ventilation) placed horizontally on a bench with a bench towel to absorb urine. This restraint prevented physical movement without causing pain. The restrainer was cleaned with veterinary disinfectant between mice.

[0338] Drug administration: Immediately after the 5-hour ARS procedure, mice are removed from the restrainer, placed in their home cages, and transferred to the room where the tail suspension test is performed. Mice are then intraperitoneally injected with vehicle, ketamine (10 mg / kg), or test compound (a range of doses), and returned to their home cages. Then, 10 minutes after treatment, animals undergo the tail suspension test.

[0339] Tail Suspension Test (TST) Procedure: Mice are individually suspended from the end of a 58 cm shelf on a table surface using adhesive tape placed approximately 1 cm from the tip of the tail for a total duration of 7 min. Using a stopwatch, an experimenter blinded to treatment group records the duration of immobility (defined as passively hanging and not moving) for 5 min over a period of 2–7 min. Data from 0–2 min are not recorded. Mice undergoing the TST are never within sight of other mice. After the TST, mice are euthanized by carbon dioxide inhalation.

[0340] Statistical analysis: Statistical analysis was performed using GraphPad Prism 9 (La Jolla, CA, USA) using a priori simple effects comparisons within a one-way ANOVA to compare test compounds with vehicle conditions for time spent immobile (seconds).

Claims

1. Formula (I): 【Chemistry 1】 or a pharmaceutically acceptable salt, solvate, tautomer, N-oxide, stereoisomer, metabolite, polymorph, or prodrug thereof, During the ceremony, R １ and R ２ But hydrogen, C １～６ Alkyl, C １～６ Haloalkyl, C ２～６ Alkenyl, C ２～６ Haloalkenyl, C ２～６ Alkynyl, C ２～６ Haloalkynyl, C ３～８ Cycloalkyl, C ４～１４ Alkylenecycloalkyl, C ３ ~C ８ Heterocycloalkyl, C ４ ~C １４ Alkyleneheterocycloalkyl, C ６～１２ Aryl, C ７～１８ Alkylene aryl, C ５～１０ Heteroaryl, and C ６～１６ alkyleneheteroaryl; Said C １～６ Alkyl, C １～６ Haloalkyl, C ２～６ Alkenyl, C ２～６ Haloalkenyl, C ２～６ Alkynyl, C ２～６ Haloalkynyl, C ３～８ Cycloalkyl, C ４～１４ Alkylenecycloalkyl, C ３ ~C ８ Heterocycloalkyl, C ４ ~C １４ Alkyleneheterocycloalkyl, C ６～１２ Aryl, C ７～１８ Alkylene aryl, C ５～１０ Heteroaryl, and C ６～１６ The alkylene heteroaryl is selected from halogen, CN, C １～８ Alkoxy, C １～８ Alkylamino, C １～８ Alkyl sulfonyl, CO ２ R ４ , C(O)N(R ４ ) ２ , OR ４ , N(R ４ ) ２ , NO ２ , S.R. ４ , and SO ２ R ４ each optionally substituted with one or more substituents independently selected from Said C ３～８ Cycloalkyl, C ４～１４ Alkylenecycloalkyl, C ３ ~C ８ Heterocycloalkyl, C ６～１２ Aryl, C ７～１８ Alkylene aryl, C ５～１０ Heteroaryl, and C ６～１６ The alkylene heteroaryl is (O), C １～６ Alkyl, C １～６ Haloalkyl, C ２～６ Alkenyl, C ２～６ Haloalkenyl, C ２～６ Alkynyl, C ２～６ Haloalkynyl, C ３～６ Cycloalkyl, as well as O, S, N, S(O), SO ２ and NR ４ C containing one or two ring hetero moieties selected from ３～６ each optionally further substituted with substituents independently selected from heterocycloalkyl; Or, R １ and R ２ are combined with the atoms to which they are bonded to form O, S, S(O), SO ２ , N, and NR ４ C containing one or two additional ring hetero moieties selected from ３～８ forming a heterocycloalkyl, Said C ３～８ Heterocycloalkyl is selected from halogen, (O), CN, C １～８ Alkoxy, C １～８ Alkylamino, C １～８ Alkyl sulfonyl, CO ２ R ４ , C(O)N(R ４ ) ２ , OR ４ , N(R ４ ) ２ , NO ２ , S.R. ４ , S.O. ２ R ４ , C １～６ Alkyl, C １～６ Haloalkyl, C ２～６ Alkenyl, C ２～６ Haloalkenyl, C ２～６ Alkynyl, C ２～６ Haloalkynyl, C １～８ Alkylamino, C １～８ Alkylsulfonyl, C ３～６ Cycloalkyl, as well as O, S, N, S(O), SO ２ and NR ４ C containing one or two ring hetero moieties selected from ３～６ and optionally further substituted with substituents selected from heterocycloalkyl; R ３ But hydrogen, C １～６ Alkyl, C ３～８ cycloalkyl, or C ４～１４ alkylenecycloalkyl; Or, R ３ , and R １ and R ２ In combination with the atom to which they are attached, one of ３～１２ forming a heterocycloalkyl, Said C ３～１２ Heterocycloalkyl is selected from halogen, (O), CN, C １～８ Alkoxy, C １～８ Alkylamino, C １～８ Alkyl sulfonyl, CO ２ R ４ , C(O)N(R ４ ) ２ , OR ４ , N(R ４ ) ２ , NO ２ , S.R. ４ , S.O. ２ R ４ , C １～６ Alkyl, C １～６ Haloalkyl, C ２～６ Alkenyl, C ２～６ Haloalkenyl, C ２～６ Alkynyl, C ２～６ Haloalkynyl, C ３～６ Cycloalkyl, as well as O, S, N, S(O), SO ２ and NR ４ C containing one or two ring hetero moieties selected from ３～６ and optionally further substituted with substituents selected from heterocycloalkyl; Each R ４ But hydrogen, C １～６ Alkyl, C １～６ Haloalkyl, C ２～６ Alkenyl, C ２～６ Haloalkenyl, C ２～６ Alkynyl, C ２～６ Haloalkynyl, C ３～７ Cycloalkyl, as well as O, S, S(O), SO ２ , N and NR ５ C containing one or two ring hetero moieties selected from ３～７ heterocycloalkyl; Said C １～６ Alkyl, C １～６ Haloalkyl, C ２～６ Alkenyl, C ２～６ Haloalkenyl, C ２～６ Alkynyl, C ２～６ Haloalkynyl, C ３～７ Cycloalkyl, and C ３～７ Heterocycloalkyl is halogen, CN, C １～８ Alkoxy, C １～８ Alkylamino, C １～８ Alkyl sulfonyl, CO ２ R ５ , C(O)N(R ５ ) ２ , OR ５ , N(R ５ ) ２ , NO ２ , S.R. ５ , and SO ２ R ５ each optionally substituted with one or more substituents independently selected from Said C ３ ~C ７ Cycloalkyl and C ３～７ Heterocycloalkyl is (O), C １～６ Alkyl, C １～６ Haloalkyl, C ２～６ Alkenyl, C ２～６ Haloalkenyl, C ２～６ Alkynyl, C ２～６ Haloalkynyl, C ３～６ Cycloalkyl, as well as O, S, S(O), SO ２ , N and NR ５ C containing one or two ring hetero moieties selected from ３～６ each optionally further substituted with substituents independently selected from heterocycloalkyl; Each R ５ But hydrogen, C １～６ Alkyl, C ２～６ Alkenyl, C ２～６ Alkynyl, C １～６ Haloalkyl, C ３～８ Cycloalkyl, C ５～１０ Heterocycloalkyl, C ６～１２ Aryl, and C ５～１０ heteroaryl; Said C １～６ Alkyl, C ２～６ Alkenyl, C ２～６ Alkynyl, C １～６ Haloalkyl, C ３～８ Cycloalkyl, C ５～１０ Heterocycloalkyl, C ６～１２ Aryl, and C ５～１０ Heteroaryl is halogen, CN, C １～８ Alkoxy, C １～８ Alkylamino, C １～８ Alkyl sulfonyl, CO ２ H, CO ２ CH ３ , C(O)NH ２ , C(O)N(CH ３ ) ２ , C(O)NHCH ３ , OH, NH ２ , N(CH ３ ) ２ , NHCH ３ , NO ２ , S.H., S.C.H. ３ , S.O. ２ CH ３ , SOCH ３ , C １～６ Alkyl, C １～６ Haloalkyl, C ２～６ Alkenyl, C ２～６ Haloalkenyl, C ２～６ Alkynyl, C ２～６ Haloalkynyl, C ３～６ Cycloalkyl, as well as O, S, S(O), SO ２ , N, NH and NCH ３ C containing one or two ring hetero moieties selected from ３～６ each optionally substituted with one or more substituents independently selected from heterocycloalkyl; L is C １～４ Alkylene, C ２ ~C ４ Alkenylene, and C ２ ~C ４ alkynylene, R ６ But hydrogen, C １～６ Alkyl, C ２～６ Alkenyl, C ２～６ Alkynyl, C １～６ Alkylene P(O)(OR １２ ) ２ , C(O)R １２ , CO ２ R １２ , C(O)N(R １２ ) ２ , S(O)R １２ and SO ２ R １２ , C ３～６ Cycloalkyl, C ６～９ Alkylenecycloalkyl, C ３～６ Heterocyclyl, C ６～９ Alkyleneheterocycloalkyl, C ４～７ Heterocyclyl, C ７～１０ Alkyleneheterocycloalkyl, C ６～１２ Aryl, C ７～１８ Alkylene aryl, C ５～１０ Heteroaryl, and C ６～１６ alkyleneheteroaryl; Said C １～６ Alkyl, C ２～６ Alkenyl, C ２～６ Alkynyl, C ３～６ Cycloalkyl, C ６～９ Alkylenecycloalkyl, C ３～６ Heterocyclyl, C ６～９ Alkyleneheterocycloalkyl, C ４～７ Heterocyclyl, C ７～１０ Alkyleneheterocycloalkyl, C ６～１２ Aryl, C ７～１８ Alkylene aryl, C ５～１０ Heteroaryl, and C ６～１６ The alkylene heteroaryl is selected from halogen, CN, C １～８ Alkoxy, C １～８ Alkylamino, C １～８ Alkyl sulfonyl, CO ２ R １２ , C(O)N(R １２ ) ２ , OR １２ , N(R １２ ) ２ , NO ２ , S.R. １２ , and SO ２ R １２ each optionally substituted with one or more substituents independently selected from Said C ３～６ Cycloalkyl, C ６～９ Alkylenecycloalkyl, C ３～６ Heterocyclyl, C ６～９ Alkyleneheterocycloalkyl, C ４～７ Heterocyclyl, C ７～１０ Alkyleneheterocycloalkyl, C ６～１２ Aryl, C ７～１８ Alkylene aryl, C ５～１０ Heteroaryl, and C ６～１６ The alkylene heteroaryl is (O), C １～６ Alkyl, C １～６ Haloalkyl, C ２～６ Alkenyl, C ２～６ Haloalkenyl, C ２～６ Alkynyl, C ２～６ Haloalkynyl, C ３～６ Cycloalkyl, as well as O, S, N, S(O), SO ２ and NR １２ C containing one or two ring hetero moieties selected from ３～６ each optionally further substituted with substituents independently selected from heterocycloalkyl; Each R １２ But hydrogen, C １～６ Alkyl, C ２～６ Alkenyl, C ２～６ Alkynyl, C １～６ Haloalkyl, C ３～８ Cycloalkyl, C ４～１４ Alkylenecycloalkyl, C ３～１０ Heterocycloalkyl, C ４～１６ Alkyleneheterocycloalkyl, C ６～１２ Aryl, C ７～１８ Alkylene aryl, C ５～１０ Heteroaryl, and C ６～１６ alkyleneheteroaryl; Said C １～６ Alkyl, C ２～６ Alkenyl, C ２～６ Alkynyl, C １～６ Haloalkyl, C ３～８ Cycloalkyl, C ４～１４ Alkylenecycloalkyl, C ３～１０ Heterocycloalkyl, C ４～１６ Alkyleneheterocycloalkyl, C ６～１２ Aryl, C ７～１８ Alkylene aryl, C ５～１０ Heteroaryl, and C ６～１６ The alkylene heteroaryl is selected from halogen, CN, C １～８ Alkoxy, C １～８ Alkylamino, C １～８ Alkyl sulfonyl, CO ２ H, CO ２ CH ３ , C(O)NH ２ , C(O)N(CH ３ ) ２ , C(O)NHCH ３ , OH, NH ２ , N(CH ３ ) ２ , NHCH ３ , NO ２ , S.H., S.C.H. ３ , S.O. ２ CH ３ , SOCH ３ , C １～６ Alkyl, C １～６ Haloalkyl, C ２～６ Alkenyl, C ２～６ Haloalkenyl, C ２～６ Alkynyl, C ２～６ Haloalkynyl, C ３～６ Cycloalkyl, as well as O, S, S(O), SO ２ , N, NH and NCH ３ C containing one or two ring hetero moieties selected from ３～６ each optionally substituted with one or more substituents independently selected from heterocycloalkyl; (B) and (C): (B) (i) R ７ , R ８ , R ９ , R １０ , and R １１ One of them is OR １３ , N(R １３ ) ２ , S.R. １３ , C １～６ Alkyl, C １～６ Haloalkyl, C ２～６ Alkenyl, C ２ ~C ６ Haloalkenyl, C ２～６ Alkynyl, C ２～６ Haloalkynyl, C １～６ Alkylamines, C １～６ Alkoxy, C １～６ Haloalkoxy, CO ２ R １３ , C(O)R １３ , C(O)N(R １３ ) ２ , C(O)C(O)N(R １３ ) ２ , O.C.(O.)R １３ , OC(O)OR １３ , OC(O)N(R １３ ) ２ , OS(O)R １３ , OS(O)N(R １３ ) ２ , OSO ２ R １３ , OP(O)(OR １３ ) ２ , O.C. １～６ Alkylene P(O)(OR １３ ) ２ , S(O)R １３ , S(O)N(R １３ ) ２ , S.O. ２ R １３ , N(R １３ ) ２ , N(R １３ ) C(O)R １３ , N(R １３ )C(O)OR １３ , N(R １３ )C(O)N(R １３ ) ２ , NO ２ , C ３～８ Cycloalkyl, C ３～１４ Alkylenecycloalkyl, C ３～１０ Heterocycloalkyl, C ４～１６ Alkyleneheterocycloalkyl, C ６～１２ Aryl, C ７～１８ Alkylene aryl, C ５～１０ Heteroaryl, C ４～１６ alkyleneheteroaryl; Said C １～６ Alkyl, C １～６ Haloalkyl, C ２～６ Alkenyl, C ２ ~C ６ Haloalkenyl, C ２～６ Alkynyl, C ２～６ Haloalkynyl, C １～６ Alkylamines, C １～６ Alkoxy, C １～６ Haloalkoxy, C ３～８ Cycloalkyl, C ３～１４ Alkylenecycloalkyl, C ３～１０ Heterocycloalkyl, C ４～１６ Alkyleneheterocycloalkyl, C ６～１２ Aryl, C ７～１８ Alkylene aryl, C ５～１０ Heteroaryl, and C ４～１６ The alkylene heteroaryl is selected from halogen, CN, C １～８ Alkoxy, C １～８ Alkylamino, C １～８ Alkyl sulfonyl, CO ２ R １３ , C(O)N(R １３ ) ２ , OR １３ , N(R １３ ) ２ , NO ２ , S.R. １３ , and SO ２ R １３ and optionally substituted with one or more substituents independently selected from Said C ３～８ Cycloalkyl, C ３～１４ Alkylenecycloalkyl, C ３～１０ Heterocycloalkyl, C ４～１６ Alkyleneheterocycloalkyl, C ６～１２ Aryl, C ７～１８ Alkylene aryl, C ５～１０ Heteroaryl, and C ４～１６ The alkylene heteroaryl is (O), C １～６ Alkyl, C １～６ Haloalkyl, C ２～６ Alkenyl, C ２～６ Haloalkenyl, C ２～６ Alkynyl, C ２～６ Haloalkynyl, C ３～６ Cycloalkyl, as well as O, S, S(O), SO ２ , N, and NR １３ C containing one or two ring hetero moieties selected from ３～６ each optionally further substituted with a substituent selected from heterocycloalkyl; Each R １３ But hydrogen, C １～６ Alkyl, C ２～６ Alkenyl, C ２～６ Alkynyl, C １～６ Haloalkyl, C ３～８ Cycloalkyl, C ４～１４ Alkylenecycloalkyl, C ３～１０ Heterocycloalkyl, C ４～１６ Alkyleneheterocycloalkyl, C ６～１２ Aryl, C ７～１８ Alkylene aryl, C ５～１０ Heteroaryl, and C ６～１６ alkyleneheteroaryl; Said C １～６ Alkyl, C ２～６ Alkenyl, C ２～６ Alkynyl, C １～６ Haloalkyl, C ３～８ Cycloalkyl, C ４～１４ Alkylenecycloalkyl, C ３～１０ Heterocycloalkyl, C ４～１６ Alkyleneheterocycloalkyl, C ６～１２ Aryl, C ７～１８ Alkylene aryl, C ５～１０ Heteroaryl, and C ６～１６ The alkylene heteroaryl is selected from halogen, CN, C １～８ Alkoxy, C １～８ Alkylamino, C １～８ Alkyl sulfonyl, CO ２ H, CO ２ CH ３ , C(O)NH ２ , C(O)N(CH ３ ) ２ , C(O)NHCH ３ , OH, NH ２ , N(CH ３ ) ２ , NHCH ３ , NO ２ , S.H., S.C.H. ３ , S.O. ２ CH ３ , SOCH ３ , C １～６ Alkyl, C １～６ Haloalkyl, C ２～６ Alkenyl, C ２～６ Haloalkenyl, C ２～６ Alkynyl, C ２～６ Haloalkynyl, C ３～６ Cycloalkyl, as well as O, S, S(O), SO ２ , N, NH and NCH ３ C containing one or two ring hetero moieties selected from ３～６ each optionally substituted with one or more substituents independently selected from heterocycloalkyl; (ii) R ７ , R ８ , R ９ , R １０ , and R １１ are each hydrogen; Or, R ６ and R ７ These are combined with the atoms to which they are bonded to form C ４～１０ Heterocycloalkyl or C ５～１０ forming a heteroaryl, Said C ４～１０ Heterocycloalkyl and C ５～１０ Heteroaryl is halogen, (O), CN, C １～８ Alkoxy, C １～８ Alkylamino, C １～８ Alkyl sulfonyl, CO ２ R １４ , C(O)N(R １４ ) ２ , OR １４ , N(R １４ ) ２ , NO ２ , S.R. １４ , S.O. ２ R １４ , C １～６ Alkyl, C １～６ Haloalkyl, C ２～６ Alkenyl, C ２～６ Haloalkenyl, C ２～６ Alkynyl, C ２～６ Haloalkynyl, C ３～６ Cycloalkyl, as well as O, S, N, S(O), SO ２ and NR １４ C containing one or two ring hetero moieties selected from ３～６ each optionally further substituted with a substituent selected from heterocycloalkyl; Or, R ７ , and R １ , R ２ or R ３ One of these is combined with the atom to which it is attached to form C ５～８ forming a heterocycloalkyl, Said C ５～８ Heterocyclylalkyl is selected from halogen, (O), CN, C １～８ Alkoxy, C １～８ Alkylamino, C １～８ Alkyl sulfonyl, CO ２ R １４ , C(O)N(R １４ ) ２ , OR １４ , N(R １４ ) ２ , NO ２ , S.R. １４ , S.O. ２ R １４ , C １～６ Alkyl, C １～６ Haloalkyl, C ２～６ Alkenyl, C ２～６ Haloalkenyl, C ２～６ Alkynyl, C ２～６ Haloalkynyl, C ３～６ Cycloalkyl, as well as O, S, N, S(O), SO ２ and NR １４ C containing one or two ring hetero moieties selected from ３～６ and optionally further substituted with one or more substituents selected from heterocycloalkyl; Each R １４ But hydrogen, C １～６ Alkyl, C ２ ~C ６ Alkenyl, C ２ ~C ６ Alkynyl, C １ ~C ６ Haloalkyl, C ３ ~C ７ Cycloalkyl, C ３～１０ Heterocycloalkyl, C ６～１２ Aryl, and C ５～１０ heteroaryl; Said C １～６ Alkyl, C ２ ~C ６ Alkenyl, C ２ ~C ６ Alkynyl, C １ ~C ６ Haloalkyl, C ３ ~C ７ Cycloalkyl, C ３～１０ Heterocycloalkyl, C ６～１２ Aryl, and C ５～１０ Heteroaryl is halogen, CN, C １～８ Alkoxy, C １～８ Alkylamino, C １～８ Alkyl sulfonyl, CO ２ H, CO ２ CH ３ , C(O)NH ２ , C(O)N(CH ３ ) ２ , C(O)NHCH ３ , OH, NH ２ , N(CH ３ ) ２ , NHCH ３ , NO ２ , S.H., S.C.H. ３ , S.O. ２ CH ３ , SOCH ３ , C １～６ Alkyl, C １～６ Haloalkyl, C ２～６ Alkenyl, C ２～６ Haloalkenyl, C ２～６ Alkynyl, C ２～６ Haloalkynyl, C ３～６ Cycloalkyl, as well as O, S, S(O), SO ２ , N, NH and NCH ３ C containing one or two ring hetero moieties selected from ３～６ each optionally substituted with one or more substituents independently selected from heterocycloalkyl; R １ and R ２ are each methyl, and R ３ and R ６ are each hydrogen, then R ８ is OH or OCH ３ Instead, R ９ But instead of OH, R １ and R ２ are each ethyl, isobutyl, or (sec)butyl, and R ３ and R ６ are each hydrogen, then R ８ But instead of OH, R １ and R ２ are each isopropyl, and R ３ and R ６ are each hydrogen, then R ９ But instead of OH, R １ and R ２ But together with the nitrogen to which they are bound, 【Chemistry 2】 and R ３ and R ６ are each hydrogen, then R ９ But OCH ３ Instead, R １ and R ２ But together with the nitrogen to which they are bound, 【Transformation 3】 and R ３ and R ６ are each hydrogen, then R ８ But instead of OH, R １ and R ２ But together with the nitrogen to which they are bound, 【Chemistry 4】 and R ３ and R ６ are each hydrogen, then R ８ But it's not OH, it's R ９ But CH ３ or OCH ３ Instead, R １０ But OCH ３ Instead, R １ and R ２ But together with the nitrogen to which they are bound, 【Transformation 5】 and R ３ and R ６ are each hydrogen, then R ７ , R ８ , R ９ , R １０ , and R １１ But, OH, OCH ３ , OC(O)CH ３ ,OP(O)(OH) ２ , N.H. ２ , halogen, CH ３ , CN, and CF ３ is not selected from R １ and R ２ But together with the nitrogen to which they are bound, 【Transformation 6】 and R ３ is hydrogen, and R ６ is methyl, then R ８ but not OH or OBn, R １ and R ２ are each methyl, and R ３ is hydrogen, and R ６ But ethyl, CH ２ CHF ２ , propyl, isopropyl, butyl, cyclopropyl, methylenecyclopropyl, cyclobutyl, oxetanyl, and butenyl, R ８ but not OH or OBn, R １ and R ２ are each methyl, and R ３ is hydrogen, and R ６ is hydrogen or CH ２ P(O)(OH) ２ If R ８ but, 【Transformation 7】 and OC(O)N(CH ３ ) ２ is not selected from R １ , R ２ , and R ３ But together with the atoms to which they are bonded, 【Transformation 8】 and R ６ is hydrogen or CH ２ P(O)(OH) ２ If R ８ but, 【Chemistry 9】 and OC(O)N(CH ３ ) ２ Not selected from (C)R ７ , R ８ , R ９ , R １０ , and R １１ are each hydrogen, R ３ and R ６ are each hydrogen, then R １ and R ２ are each methyl, ethyl, propyl, isopropyl, cyclopropyl, or 【Chemistry 10】 Instead, R １ and R ２ do not, together with the nitrogen to which they are attached, form pyrrolidyl, piperidyl, or 2,5-dimethylpyrrolyl; R ６ is hydrogen and R ３ is methyl, R １ and R ２ However, each is not hydrogen, R ３ and R ６ are each hydrogen, and R １ and R ２ When one of R １ and R ２ the other of which is propyl, isopropyl, cyclopropyl, methylenecyclopropyl, 【Chemistry 11】 Instead, R ３ and R ６ are each hydrogen, and R １ and R ２ When one of R is ethyl or propyl, １ and R ２ the other of which is isopropyl, cyclopropyl, methylenecyclopropyl, 【Chemistry 12】 Instead, R ３ and R ６ are each hydrogen, and R １ and R ２ When one of R １ and R ２ the other of which is propyl, cyclopropyl, methylenecyclopropyl, 【Chemistry 13】 or a pharmaceutically acceptable salt, solvate, tautomer, N-oxide, stereoisomer, metabolite, polymorph, or prodrug thereof, wherein one of:

2. R ７ , R ８ , R ９ , R １０ , and R １１ But hydrogen, halogen, CN, OR １３ , N(R １３ ) ２ , S.R. １３ , C １～６ Alkyl, C １～６ Haloalkyl, C ２～６ Alkenyl, C ２ ~C ６ Haloalkenyl, C ２～６ Alkynyl, C ２～６ Haloalkynyl, C １～６ Alkylamines, C １～６ Alkoxy, C １～６ Haloalkoxy, CO ２ R １３ , C(O)R １３ , C(O)N(R １３ ) ２ , C(O)C(O)N(R １３ ) ２ , O.C.(O.)R １３ , OC(O)OR １３ , OC(O)N(R １３ ) ２ , OS(O)R １３ , OS(O)N(R １３ ) ２ , OSO ２ R １３ , OP(O)(OR １３ ) ２ , O.C. １～６ Alkylene P(O)(OR １３ ) ２ , S(O)R １３ , S(O)N(R １３ ) ２ , S.O. ２ R １３ , N(R １３ ) ２ , N(R １３ ) C(O)R １３ , N(R １３ )C(O)OR １３ , N(R １３ )C(O)N(R １３ ) ２ , NO ２ , C ３～８ Cycloalkyl, C ３～１４ Alkylenecycloalkyl, C ３～１０ Heterocycloalkyl, C ４～１６ Alkyleneheterocycloalkyl, C ６～１２ Aryl, C ７～１８ Alkylene aryl, C ５～１０ Heteroaryl, C ４～１６ alkyleneheteroaryl; Said C １～６ Alkyl, C １～６ Haloalkyl, C ２～６ Alkenyl, C ２ ~C ６ Haloalkenyl, C ２～６ Alkynyl, C ２～６ Haloalkynyl, C １～６ Alkylamines, C １～６ Alkoxy, C １～６ Haloalkoxy, C ３～８ Cycloalkyl, C ３～１４ Alkylenecycloalkyl, C ３～１０ Heterocycloalkyl, C ４～１６ Alkyleneheterocycloalkyl, C ６～１２ Aryl, C ７～１８ Alkylene aryl, C ５～１０ Heteroaryl, and C ４～１６ The alkylene heteroaryl is selected from halogen, CN, C １～８ Alkoxy, C １～８ Alkylamino, C １～８ Alkyl sulfonyl, CO ２ R １３ , C(O)N(R １３ ) ２ , OR １３ , N(R １３ ) ２ , NO ２ , S.R. １３ , and SO ２ R １３ and optionally substituted with one or more substituents independently selected from Said C ３～８ Cycloalkyl, C ３～１４ Alkylenecycloalkyl, C ３～１０ Heterocycloalkyl, C ４～１６ Alkyleneheterocycloalkyl, C ６～１２ Aryl, C ７～１８ Alkylene aryl, C ５～１０ Heteroaryl, and C ４～１６ The alkylene heteroaryl is (O), C １～６ Alkyl, C １～６ Haloalkyl, C ２～６ Alkenyl, C ２～６ Haloalkenyl, C ２～６ Alkynyl, C ２～６ Haloalkynyl, C ３～６ Cycloalkyl, as well as O, S, S(O), SO ２ , N, and NR １３ C containing one or two ring hetero moieties selected from ３～６ each optionally further substituted with a substituent selected from heterocycloalkyl; Each R １３ But hydrogen, C １～６ Alkyl, C ２～６ Alkenyl, C ２～６ Alkynyl, C １～６ Haloalkyl, C ３～８ Cycloalkyl, C ４～１４ Alkylenecycloalkyl, C ３～１０ Heterocycloalkyl, C ４～１６ Alkyleneheterocycloalkyl, C ６～１２ Aryl, C ７～１８ Alkylene aryl, C ５～１０ Heteroaryl, and C ６～１６ alkyleneheteroaryl; Said C １～６ Alkyl, C ２～６ Alkenyl, C ２～６ Alkynyl, C １～６ Haloalkyl, C ３～８ Cycloalkyl, C ４～１４ Alkylenecycloalkyl, C ３～１０ Heterocycloalkyl, C ４～１６ Alkyleneheterocycloalkyl, C ６～１２ Aryl, C ７～１８ Alkylene aryl, C ５～１０ Heteroaryl, and C ６～１６ The alkylene heteroaryl is selected from halogen, CN, C １～８ Alkoxy, C １～８ Alkylamino, C １～８ Alkyl sulfonyl, CO ２ H, CO ２ CH ３ , C(O)NH ２ , C(O)N(CH ３ ) ２ , C(O)NHCH ３ , OH, NH ２ , N(CH ３ ) ２ , NHCH ３ , NO ２ , S.H., S.C.H. ３ , S.O. ２ CH ３ , SOCH ３ , C １～６ Alkyl, C １～６ Haloalkyl, C ２～６ Alkenyl, C ２～６ Haloalkenyl, C ２～６ Alkynyl, C ２～６ Haloalkynyl, C ３～６ Cycloalkyl, as well as O, S, S(O), SO ２ , N, NH and NCH ３ C containing one or two ring hetero moieties selected from ３～６ each optionally substituted with one or more substituents independently selected from heterocycloalkyl; Or, R ６ and R ７ These are combined with the atoms to which they are bonded to form C ４～１０ Heterocycloalkyl or C ５～１０ forming a heteroaryl, Said C ４～１０ Heterocycloalkyl and C ５～１０ Heteroaryl is halogen, (O), CN, C １～８ Alkoxy, C １～８ Alkylamino, C １～８ Alkyl sulfonyl, CO ２ R １４ , C(O)N(R １４ ) ２ , OR １４ , N(R １４ ) ２ , NO ２ , S.R. １４ , S.O. ２ R １４ , C １～６ Alkyl, C １～６ Haloalkyl, C ２～６ Alkenyl, C ２～６ Haloalkenyl, C ２～６ Alkynyl, C ２～６ Haloalkynyl, C ３～６ Cycloalkyl, as well as O, S, N, S(O), SO ２ and NR １４ C containing one or two ring hetero moieties selected from ３～６ each optionally further substituted with a substituent selected from heterocycloalkyl; Or, R ７ , and R １ , R ２ or R ３ One of these is combined with the atom to which it is attached to form C ５～８ forming a heterocycloalkyl, Said C ５～８ Heterocyclylalkyl is selected from halogen, (O), CN, C １～８ Alkoxy, C １～８ Alkylamino, C １～８ Alkyl sulfonyl, CO ２ R １４ , C(O)N(R １４ ) ２ , OR １４ , N(R １４ ) ２ , NO ２ , S.R. １４ , S.O. ２ R １４ , C １～６ Alkyl, C １～６ Haloalkyl, C ２～６ Alkenyl, C ２～６ Haloalkenyl, C ２～６ Alkynyl, C ２～６ Haloalkynyl, C ３～６ Cycloalkyl, as well as O, S, N, S(O), SO ２ and NR １４ C containing one or two ring hetero moieties selected from ３～６ and optionally further substituted with one or more substituents selected from heterocycloalkyl; Each R １４ But hydrogen, C １～６ Alkyl, C ２ ~C ６ Alkenyl, C ２ ~C ６ Alkynyl, C １ ~C ６ Haloalkyl, C ３ ~C ７ Cycloalkyl, C ３～１０ Heterocycloalkyl, C ６～１２ Aryl, and C ５～１０ heteroaryl; Said C １～６ Alkyl, C ２ ~C ６ Alkenyl, C ２ ~C ６ Alkynyl, C １ ~C ６ Haloalkyl, C ３ ~C ７ Cycloalkyl, C ３～１０ Heterocycloalkyl, C ６～１２ Aryl, and C ５～１０ Heteroaryl is halogen, CN, C １～８ Alkoxy, C １～８ Alkylamino, C １～８ Alkyl sulfonyl, CO ２ H, CO ２ CH ３ , C(O)NH ２ , C(O)N(CH ３ ) ２ , C(O)NHCH ３ , OH, NH ２ , N(CH ３ ) ２ , NHCH ３ , NO ２ , S.H., S.C.H. ３ , S.O. ２ CH ３ , SOCH ３ , C １～６ Alkyl, C １～６ Haloalkyl, C ２～６ Alkenyl, C ２～６ Haloalkenyl, C ２～６ Alkynyl, C ２～６ Haloalkynyl, C ３～６ Cycloalkyl, as well as O, S, S(O), SO ２ , N, NH and NCH ３ C containing one or two ring hetero moieties selected from ３～６ each optionally substituted with one or more substituents independently selected from heterocycloalkyl; R ７ , R ８ , R ９ , R １０ , and R １１ At least two of these are not hydrogen, R １ and R ２ are each methyl, and R ３ is hydrogen, and R ６ is selected from hydrogen, methyl, ethyl, and propyl, and R ９ , R １０ , or R １１ is fluoro, and R ９ , R １０ , or R １１ If the other of R is hydrogen, ８ But, OH, OCH ３ , OCH ２ CH ３ , OCH ２ CH ２ CH ３ , and OBn are not selected, R １ and R ２ are each methyl, and R ３ is hydrogen, and R ６ is selected from hydrogen, methyl, ethyl, and propyl; R ９ is fluoro and R １１ is hydrogen, R １０ But, OH, OCH ３ , OCH ２ CH ３ , OCH ２ CH ２ CH ３ 2. The compound of claim 1, wherein the compound is not selected from:

3. R ７ , R ８ R ９ , R １０ , and R １１ But hydrogen, halogen, CN, OR １３ , N(R １３ ) ２ , S.R. １３ , C １～６ Alkyl, C １～６ Haloalkyl, C ２～６ Alkenyl, C ２ ~C ６ Haloalkenyl, C ２～６ Alkynyl, C ２～６ Haloalkynyl, C １～６ Alkylamines, C １～６ Alkoxy, C １～６ Haloalkoxy, CO ２ R １３ , C(O)N(R １３ ) ２ , O.C.(O.)R １３ , OSO ２ R １３ , OP(O)(OR １３ ) ２ , O.C. １～６ Alkylene P(O)(OR １３ ) ２ , S(O)R １３ , S.O. ２ R １３ , N(R １３ ) ２ , NO ２ , C ３～８ Cycloalkyl, C ３～１４ Alkylenecycloalkyl, C ３～１０ Heterocycloalkyl, C ４～１６ Alkyleneheterocycloalkyl, C ６～１２ Aryl, C ７～１８ Alkylene aryl, C ５～１０ Heteroaryl, C ４～１６ alkyleneheteroaryl; Said C １～６ Alkyl, C １～６ Haloalkyl, C ２～６ Alkenyl, C ２ ~C ６ Haloalkenyl, C ２～６ Alkynyl, C ２～６ Haloalkynyl, C １～６ Alkylamines, C １～６ Alkoxy, C １～６ Haloalkoxy, C ３～８ Cycloalkyl, C ３～１４ Alkylenecycloalkyl, C ３～１０ Heterocycloalkyl, C ４～１６ Alkyleneheterocycloalkyl, C ６～１２ Aryl, C ７～１８ Alkylene aryl, C ５～１０ Heteroaryl, and C ４～１６ The alkylene heteroaryl is selected from halogen, CN, C １～８ Alkoxy, C １～８ Alkylamino, C １～８ Alkyl sulfonyl, CO ２ H, CO ２ CH ３ , C(O)NH ２ , C(O)N(CH ３ ) ２ , C(O)NHCH ３ , OH, NH ２ , N(CH ３ ) ２ , NO ２ , NHCH ３ , S.H., S.C.H. ３ , S.O. ２ CH ３ , and SOCH ３ and optionally substituted with one or more substituents independently selected from Said C ３～８ Cycloalkyl, C ３～１４ Alkylenecycloalkyl, C ３～１０ Heterocycloalkyl, C ４～１６ Alkyleneheterocycloalkyl, C ６～１２ Aryl, C ７～１８ Alkylene aryl, C ５～１０ Heteroaryl, and C ４～１６ The alkylene heteroaryl is (O), C １～６ Alkyl, C １～６ Haloalkyl, C ２～６ Alkenyl, C ２～６ Haloalkenyl, C ２～６ Alkynyl, C ２～６ Haloalkynyl, C ３～６ Cycloalkyl, as well as O, S, S(O), SO ２ , N, NH, and NCH ３ C containing one or two ring hetero moieties selected from ３～６ each optionally further substituted with a substituent selected from heterocycloalkyl; R １３ is as defined in claim 2, R ７ , R ８ , R ９ , R １０ , and R １１ At least two of these are not hydrogen, R １ and R ２ are each methyl, and R ３ is hydrogen, and R ６ is selected from hydrogen, methyl, ethyl, and propyl, and R ９ , R １０ , and R １１ is fluoro, and R ９ , R １０ , and R １１ If the other of R is hydrogen, ８ But, OH, OCH ３ , OCH ２ CH ３ , OCH ２ CH ２ CH ３ , or not selected from OBn, R １ and R ２ are each methyl, and R ３ is hydrogen, and R ６ is selected from hydrogen, methyl, ethyl, and propyl; R ９ is fluoro and R １１ is hydrogen, R １０ But, OH, OCH ３ , OCH ２ CH ３ , OCH ２ CH ２ CH ３ 3. The compound of claim 2, wherein the compound is not selected from:

4. R ７ , R ８ , R ９ , R １０ , and R １１ But hydrogen, halogen, C １～６ Alkyl, C １～６ Haloalkyl, and OR １３ and R １３ But hydrogen, C １～６ Alkyl, and C １～６ The compound of claim 3 selected from haloalkyl.

5. R ８ But halogen, C １～６ Alkyl, and OR １３ and R １３ But hydrogen, C １～６ Alkyl, and C １～６ The compound of claim 4 selected from haloalkyl.

6. R ９ But halogen, C １～６ Alkyl, and OR １３ and R １３ But hydrogen, C １～６ Alkyl, and C １～６ The compound of claim 4 selected from haloalkyl.

7. (i) R ７ , R ８ , R ９ , R １０ , and R １１ One of them is OR １３ , N(R １３ ) ２ , S.R. １３ , C １～６ Alkyl, C １～６ Haloalkyl, C ２～６ Alkenyl, C ２ ~C ６ Haloalkenyl, C ２～６ Alkynyl, C ２～６ Haloalkynyl, C １～６ Alkylamines, C １～６ Alkoxy, C １～６ Haloalkoxy, CO ２ R １３ , C(O)R １３ , C(O)N(R １３ ) ２ , C(O)C(O)N(R １３ ) ２ , O.C.(O.)R １３ , OC(O)OR １３ , OC(O)N(R １３ ) ２ , OS(O)R １３ , OS(O)N(R １３ ) ２ , OSO ２ R １３ , OP(O)(OR １３ ) ２ , O.C. １～６ Alkylene P(O)(OR １３ ) ２ , S(O)R １３ , S(O)N(R １３ ) ２ , S.O. ２ R １３ , N(R １３ ) ２ , N(R １３ ) C(O)R １３ , N(R １３ )C(O)OR １３ , N(R １３ )C(O)N(R １３ ) ２ , NO ２ , C ３～８ Cycloalkyl, C ３～１４ Alkylenecycloalkyl, C ３～１０ Heterocycloalkyl, C ４～１６ Alkyleneheterocycloalkyl, C ６～１２ Aryl, C ７～１８ Alkylene aryl, C ５～１０ Heteroaryl, C ４～１６ alkyleneheteroaryl; Said C １～６ Alkyl, C １～６ Haloalkyl, C ２～６ Alkenyl, C ２ ~C ６ Haloalkenyl, C ２～６ Alkynyl, C ２～６ Haloalkynyl, C １～６ Alkylamines, C １～６ Alkoxy, C １～６ Haloalkoxy, C ３～８ Cycloalkyl, C ３～１４ Alkylenecycloalkyl, C ３～１０ Heterocycloalkyl, C ４～１６ Alkyleneheterocycloalkyl, C ６～１２ Aryl, C ７～１８ Alkylene aryl, C ５～１０ Heteroaryl, and C ４～１６ The alkylene heteroaryl is selected from halogen, CN, C １～８ Alkoxy, C １～８ Alkylamino, C １～８ Alkyl sulfonyl, CO ２ R １３ , C(O)N(R １３ ) ２ , OR １３ , N(R １３ ) ２ , NO ２ , S.R. １３ , and SO ２ R １３ and optionally substituted with one or more substituents independently selected from Said C ３～８ Cycloalkyl, C ３～１４ Alkylenecycloalkyl, C ３～１０ Heterocycloalkyl, C ４～１６ Alkyleneheterocycloalkyl, C ６～１２ Aryl, C ７～１８ Alkylene aryl, C ５～１０ Heteroaryl, and C ４～１６ The alkylene heteroaryl is (O), C １～６ Alkyl, C １～６ Haloalkyl, C ２～６ Alkenyl, C ２～６ Haloalkenyl, C ２～６ Alkynyl, C ２～６ Haloalkynyl, C ３～６ Cycloalkyl, as well as O, S, S(O), SO ２ , N, and NR １３ C containing one or two ring hetero moieties selected from ３～６ each optionally further substituted with a substituent selected from heterocycloalkyl; Each R １３ But hydrogen, C １～６ Alkyl, C ２～６ Alkenyl, C ２～６ Alkynyl, C １～６ Haloalkyl, C ３～８ Cycloalkyl, C ４～１４ Alkylenecycloalkyl, C ３～１０ Heterocycloalkyl, C ４～１６ Alkyleneheterocycloalkyl, C ６～１２ Aryl, C ７～１８ Alkylene aryl, C ５～１０ Heteroaryl, and C ６～１６ alkyleneheteroaryl; Said C １～６ Alkyl, C ２～６ Alkenyl, C ２～６ Alkynyl, C １～６ Haloalkyl, C ３～８ Cycloalkyl, C ４～１４ Alkylenecycloalkyl, C ３～１０ Heterocycloalkyl, C ４～１６ Alkyleneheterocycloalkyl, C ６～１２ Aryl, C ７～１８ Alkylene aryl, C ５～１０ Heteroaryl, and C ６～１６ The alkylene heteroaryl is selected from halogen, CN, C １～８ Alkoxy, C １～８ Alkylamino, C １～８ Alkyl sulfonyl, CO ２ H, CO ２ CH ３ , C(O)NH ２ , C(O)N(CH ３ ) ２ , C(O)NHCH ３ , OH, NH ２ , N(CH ３ ) ２ , NHCH ３ , NO ２ , S.H., S.C.H. ３ , S.O. ２ CH ３ , SOCH ３ , C １～６ Alkyl, C １～６ Haloalkyl, C ２～６ Alkenyl, C ２～６ Haloalkenyl, C ２～６ Alkynyl, C ２～６ Haloalkynyl, C ３～６ Cycloalkyl, as well as O, S, S(O), SO ２ , N, NH and NCH ３ C containing one or two ring hetero moieties selected from ３～６ each optionally substituted with one or more substituents independently selected from heterocycloalkyl; (ii) R ７ , R ８ , R ９ , R １０ , and R １１ are each hydrogen; Or, R ６ and R ７ These are combined with the atoms to which they are bonded to form C ４～１０ Heterocycloalkyl or C ５～１０ forming a heteroaryl, Said C ４～１０ Heterocycloalkyl and C ５～１０ Heteroaryl is halogen, (O), CN, C １～８ Alkoxy, C １～８ Alkylamino, C １～８ Alkyl sulfonyl, CO ２ R １４ , C(O)N(R １４ ) ２ , OR １４ , N(R １４ ) ２ , NO ２ , S.R. １４ , S.O. ２ R １４ , C １～６ Alkyl, C １～６ Haloalkyl, C ２～６ Alkenyl, C ２～６ Haloalkenyl, C ２～６ Alkynyl, C ２～６ Haloalkynyl, C ３～６ Cycloalkyl, as well as O, S, N, S(O), SO ２ and NR １４ C containing one or two ring hetero moieties selected from ３～６ each optionally further substituted with a substituent selected from heterocycloalkyl; Or, R ７ , and R １ , R ２ or R ３ One of these is combined with the atom to which it is attached to form C ５～８ forming a heterocycloalkyl, Said C ５～８ Heterocyclylalkyl is selected from halogen, (O), CN, C １～８ Alkoxy, C １～８ Alkylamino, C １～８ Alkyl sulfonyl, CO ２ R １４ , C(O)N(R １４ ) ２ , OR １４ , N(R １４ ) ２ , NO ２ , S.R. １４ , S.O. ２ R １４ , C １～６ Alkyl, C １～６ Haloalkyl, C ２～６ Alkenyl, C ２～６ Haloalkenyl, C ２～６ Alkynyl, C ２～６ Haloalkynyl, C ３～６ Cycloalkyl, as well as O, S, N, S(O), SO ２ and NR １４ C containing one or two ring hetero moieties selected from ３～６ and optionally further substituted with one or more substituents selected from heterocycloalkyl; Each R １４ But hydrogen, C １～６ Alkyl, C ２ ~C ６ Alkenyl, C ２ ~C ６ Alkynyl, C １ ~C ６ Haloalkyl, C ３ ~C ７ Cycloalkyl, C ３～１０ Heterocycloalkyl, C ６～１２ Aryl, and C ５～１０ heteroaryl; Said C １～６ Alkyl, C ２ ~C ６ Alkenyl, C ２ ~C ６ Alkynyl, C １ ~C ６ Haloalkyl, C ３ ~C ７ Cycloalkyl, C ３～１０ Heterocycloalkyl, C ６～１２ Aryl, and C ５～１０ Heteroaryl is halogen, CN, C １～８ Alkoxy, C １～８ Alkylamino, C １～８ Alkyl sulfonyl, CO ２ H, CO ２ CH ３ , C(O)NH ２ , C(O)N(CH ３ ) ２ , C(O)NHCH ３ , OH, NH ２ , N(CH ３ ) ２ , NHCH ３ , NO ２ , S.H., S.C.H. ３ , S.O. ２ CH ３ , SOCH ３ , C １～６ Alkyl, C １～６ Haloalkyl, C ２～６ Alkenyl, C ２～６ Haloalkenyl, C ２～６ Alkynyl, C ２～６ Haloalkynyl, C ３～６ Cycloalkyl, as well as O, S, S(O), SO ２ , N, NH and NCH ３ C containing one or two ring hetero moieties selected from ３～６ each optionally substituted with one or more substituents independently selected from heterocycloalkyl; R １ and R ２ are each methyl, and R ３ and R ６ are each hydrogen, then R ８ is OH or OCH ３ Instead, R ９ But instead of OH, R １ and R ２ are each ethyl, isobutyl, or (sec)butyl, and R ３ and R ６ are each hydrogen, then R ８ But instead of OH, R １ and R ２ are each isopropyl, and R ３ and R ６ are each hydrogen, then R ９ But instead of OH, R １ and R ２ But together with the nitrogen to which they are bound, 【Chemistry 14】 and R ３ and R ６ are each hydrogen, then R ９ But OCH ３ Instead, R １ and R ２ But together with the nitrogen to which they are bound, 【Chemistry 15】 and R ３ and R ６ are each hydrogen, then R ８ But instead of OH, R １ and R ２ But together with the nitrogen to which they are bound, 【Chemistry 16】 and R ３ and R ６ are each hydrogen, then R ８ But it's not OH, it's R ９ But CH ３ or OCH ３ Instead, R １０ But OCH ３ Instead, R １ and R ２ But together with the nitrogen to which they are bound, 【Chemistry 17】 and R ３ and R ６ are each hydrogen, then R ７ , R ８ , R ９ , R １０ , and R １１ But, OH, OCH ３ , OC(O)CH ３ ,OP(O)(OH) ２ , N.H. ２ , halogen, CH ３ , CN, and CF ３ is not selected from R １ and R ２ But together with the nitrogen to which they are bound, [Chemistry 18] and R ３ is hydrogen, and R ６ is methyl, then R ８ but not OH or OBn, R １ and R ２ are each methyl, and R ３ is hydrogen, and R ６ But ethyl, CH ２ CHF ２ , propyl, isopropyl, butyl, cyclopropyl, methylenecyclopropyl, cyclobutyl, oxetanyl, and butenyl, R ８ but not OH or OBn, R １ and R ２ are each methyl, and R ３ is hydrogen, and R ６ is hydrogen or CH ２ P(O)(OH) ２ If R ８ but, 【Chemistry 19】 and OC(O)N(CH ３ ) ２ is not selected from R １ , R ２ , and R ３ But together with the atoms to which they are bonded, 【Chemistry 20】 and R ６ is hydrogen or CH ２ P(O)(OH) ２ If R ８ but, 【Chemistry 21】 and OC(O)N(CH ３ ) ２ The compound of claim 1, which is not selected from:

8. (i) R ７ , R ８ , R ９ , R １０ , and R １１ One of them is OR １３ , N(R １３ ) ２ , S.R. １３ , C １～６ Alkyl, C １～６ Haloalkyl, C ２～６ Alkenyl, C ２ ~C ６ Haloalkenyl, C ２～６ Alkynyl, C ２～６ Haloalkynyl, C １～６ Alkylamines, C １～６ Alkoxy, C １～６ Haloalkoxy, CO ２ R １３ , C(O)R １３ , C(O)N(R １３ ) ２ , C(O)C(O)N(R １３ ) ２ , O.C.(O.)R １３ , OC(O)OR １３ , OC(O)N(R １３ ) ２ , OS(O)R １３ , OS(O)N(R １３ ) ２ , OSO ２ R １３ , OP(O)(OR １３ ) ２ , O.C. １～６ Alkylene P(O)(OR １３ ) ２ , S(O)R １３ , S(O)N(R １３ ) ２ , S.O. ２ R １３ , N(R １３ ) ２ , N(R １３ ) C(O)R １３ , N(R １３ )C(O)OR １３ , N(R １３ )C(O)N(R １３ ) ２ , NO ２ , C ３～８ Cycloalkyl, C ３～１４ Alkylenecycloalkyl, C ３～１０ Heterocycloalkyl, C ４～１６ Alkyleneheterocycloalkyl, C ６～１２ Aryl, C ７～１８ Alkylene aryl, C ５～１０ Heteroaryl, C ４～１６ alkyleneheteroaryl; Said C １～６ Alkyl, C １～６ Haloalkyl, C ２～６ Alkenyl, C ２ ~C ６ Haloalkenyl, C ２～６ Alkynyl, C ２～６ Haloalkynyl, C １～６ Alkylamines, C １～６ Alkoxy, C １～６ Haloalkoxy, C ３～８ Cycloalkyl, C ３～１４ Alkylenecycloalkyl, C ３～１０ Heterocycloalkyl, C ４～１６ Alkyleneheterocycloalkyl, C ６～１２ Aryl, C ７～１８ Alkylene aryl, C ５～１０ Heteroaryl, and C ４～１６ The alkylene heteroaryl is selected from halogen, CN, C １～８ Alkoxy, C １～８ Alkylamino, C １～８ Alkyl sulfonyl, CO ２ R １３ , C(O)N(R １３ ) ２ , OR １３ , N(R １３ ) ２ , NO ２ , S.R. １３ , and SO ２ R １３ and optionally substituted with one or more substituents independently selected from Said C ３～８ Cycloalkyl, C ３～１４ Alkylenecycloalkyl, C ３～１０ Heterocycloalkyl, C ４～１６ Alkyleneheterocycloalkyl, C ６～１２ Aryl, C ７～１８ Alkylene aryl, C ５～１０ Heteroaryl, and C ４～１６ The alkylene heteroaryl is (O), C １～６ Alkyl, C １～６ Haloalkyl, C ２～６ Alkenyl, C ２～６ Haloalkenyl, C ２～６ Alkynyl, C ２～６ Haloalkynyl, C ３～６ Cycloalkyl, as well as O, S, S(O), SO ２ , N, and NR １３ C containing one or two ring hetero moieties selected from ３～６ each optionally further substituted with a substituent selected from heterocycloalkyl; Each R １３ But hydrogen, C １～６ Alkyl, C ２～６ Alkenyl, C ２～６ Alkynyl, C １～６ Haloalkyl, C ３～８ Cycloalkyl, C ４～１４ Alkylenecycloalkyl, C ３～１０ Heterocycloalkyl, C ４～１６ Alkyleneheterocycloalkyl, C ６～１２ Aryl, C ７～１８ Alkylene aryl, C ５～１０ Heteroaryl, and C ６～１６ alkyleneheteroaryl; Said C １～６ Alkyl, C ２～６ Alkenyl, C ２～６ Alkynyl, C １～６ Haloalkyl, C ３～８ Cycloalkyl, C ４～１４ Alkylenecycloalkyl, C ３～１０ Heterocycloalkyl, C ４～１６ Alkyleneheterocycloalkyl, C ６～１２ Aryl, C ７～１８ Alkylene aryl, C ５～１０ Heteroaryl, and C ６～１６ The alkylene heteroaryl is selected from halogen, CN, C １～８ Alkoxy, C １～８ Alkylamino, C １～８ Alkyl sulfonyl, CO ２ H, CO ２ CH ３ , C(O)NH ２ , C(O)N(CH ３ ) ２ , C(O)NHCH ３ , OH, NH ２ , N(CH ３ ) ２ , NHCH ３ , NO ２ , S.H., S.C.H. ３ , S.O. ２ CH ３ , SOCH ３ , C １～６ Alkyl, C １～６ Haloalkyl, C ２～６ Alkenyl, C ２～６ Haloalkenyl, C ２～６ Alkynyl, C ２～６ Haloalkynyl, C ３～６ Cycloalkyl, as well as O, S, S(O), SO ２ , N, NH and NCH ３ C containing one or two ring hetero moieties selected from ３～６ each optionally substituted with one or more substituents independently selected from heterocycloalkyl; (ii) R ７ , R ８ , R ９ , R １０ , and R １１ are each hydrogen; R １ and R ２ are each methyl, and R ３ and R ６ are each hydrogen, then R ８ is OH or OCH ３ Instead, R ９ But instead of OH, R １ and R ２ are each ethyl, isobutyl, or (sec)butyl, and R ３ and R ６ are each hydrogen, then R ８ But instead of OH, R １ and R ２ are each isopropyl, and R ３ and R ６ are each hydrogen, then R ９ But instead of OH, R １ and R ２ But together with the nitrogen to which they are bound, 【Chemistry 22】 and R ３ and R ６ are each hydrogen, then R ９ But OCH ３ Instead, R １ and R ２ But together with the nitrogen to which they are bound, 【Chemistry 23】 and R ３ and R ６ are each hydrogen, then R ８ But instead of OH, R １ and R ２ But together with the nitrogen to which they are bound, 【Chemistry 24】 and R ３ and R ６ are each hydrogen, then R ８ But it's not OH, it's R ９ But CH ３ or OCH ３ Instead, R １０ But OCH ３ Instead, R １ and R ２ But together with the nitrogen to which they are bound, 【Chemistry 25】 and R ３ and R ６ are each hydrogen, then R ７ , R ８ , R ９ , R １０ , and R １１ But, OH, OCH ３ , OC(O)CH ３ ,OP(O)(OH) ２ , N.H. ２ , halogen, CH ３ , CN, and CF ３ is not selected from R １ and R ２ But together with the nitrogen to which they are bound, 【Chemistry 26】 and R ３ is hydrogen, and R ６ is methyl, then R ８ but not OH or OBn, R １ and R ２ are each methyl, and R ３ is hydrogen, and R ６ But ethyl, CH ２ CHF ２ , propyl, isopropyl, butyl, cyclopropyl, methylenecyclopropyl, cyclobutyl, oxetanyl, and butenyl, R ８ but not OH or OBn, R １ and R ２ are each methyl, and R ３ is hydrogen, and R ６ is hydrogen or CH ２ P(O)(OH) ２ If R ８ but, 【Chemistry 27】 and OC(O)N(CH ３ ) ２ is not selected from R １ , R ２ , and R ３ But together with the atoms to which they are bonded, 【Chemistry 28】 and R ６ is hydrogen or CH ２ P(O)(OH) ２ If R ８ but, 【Chemistry 29】 and OC(O)N(CH ３ ) ２ is not selected from Preferably, (i) one of R 7 , R 8 , R 9 , R 10 , and R 11 is selected from C 1-6 haloalkyl and OC 1-6 haloalkyl; The C 1-6 haloalkyl is defined as R 1 and R 2 taken together with the nitrogen to which they are attached: 【Transformation 30】 and when R 3 and R 6 are each hydrogen, then it is not CF 3 ; (ii) The compound of claim 7, wherein the others of R 7 , R 8 , R 9 , R 10 , and R 11 are each hydrogen.

9. R ７ , R ８ , R ９ , R １０ , and R １１ are each hydrogen, R ３ and R ６ are each hydrogen, then R １ and R ２ are each methyl, ethyl, propyl, isopropyl, cyclopropyl, or 【Chemistry 31】 Instead, R １ and R ２ do not, together with the nitrogen to which they are attached, form pyrrolidyl, piperidyl, or 2,5-dimethylpyrrolyl; R ６ is hydrogen and R ３ is methyl, R １ and R ２ However, each is not hydrogen, R ３ and R ６ are each hydrogen, and R １ and R ２ When one of R １ and R ２ the other of which is propyl, isopropyl, cyclopropyl, methylenecyclopropyl, 【Chemistry 32】 Instead, R ３ and R ６ are each hydrogen, and R １ and R ２ When one of R is ethyl or propyl, １ and R ２ the other of which is isopropyl, cyclopropyl, methylenecyclopropyl, 【Transformation 33】 Instead, R ３ and R ６ are each hydrogen, and R １ and R ２ When one of R １ and R ２ the other of which is propyl, cyclopropyl, methylenecyclopropyl, 【Transformation 34】 The compound of claim 1 which is not

10. R １ and R ２ But C １～６ Alkyl, C １～６ Haloalkyl, C ２～６ Alkenyl, C ２～６ Haloalkenyl, C ２～６ Alkynyl, C ２～６ Haloalkynyl, C ３～８ Cycloalkyl, and C ４～１４ alkylenecycloalkyl; Preferably, R 1 and R 2 are each independently selected from C 1-4 alkyl; More preferably, R 1 and R 2 together with the nitrogen to which they are attached represent: 【Chemistry 35】 The compound according to any one of claims 1 to 9,

11. R ３ The compound of any one of claims 1 to 9, wherein is hydrogen.

12. L is C １～４ A compound according to any one of claims 1 to 9, wherein L is alkylene, preferably methylene.

13. R ６ is hydrogen and C １～６ A compound according to any one of claims 1 to 9, wherein R 6 is selected from alkyl, preferably R 6 is hydrogen.

14. The following table: Table 1-1 Table 1-2 Table 1-3 Table 1-4 2. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, tautomer, N-oxide, stereoisomer, metabolite, polymorph, or prodrug thereof, selected from:

15. 10. A pharmaceutical product comprising the compound of any one of claims 1 to 9, or a pharmaceutically acceptable salt, solvate, tautomer, N-oxide, stereoisomer, metabolite, polymorph, or prodrug thereof.

16. 10. A pharmaceutical composition comprising the compound of any one of claims 1 to 9, or a pharmaceutically acceptable salt, solvate, tautomer, N-oxide, stereoisomer, metabolite, polymorph, or prodrug thereof, and a pharmaceutically acceptable excipient.

17. Formula (I): 【Transformation 36】 or a pharmaceutically acceptable salt, solvate, N-oxide, stereoisomer, metabolite, polymorph, or prodrug thereof, for treating a disease, disorder, or condition caused by activation of a serotonin receptor, comprising: During the ceremony, R １ and R ２ But hydrogen, C １～６ Alkyl, C １～６ Haloalkyl, C ２～６ Alkenyl, C ２～６ Haloalkenyl, C ２～６ Alkynyl, C ２～６ Haloalkynyl, C ３～８ Cycloalkyl, C ４～１４ Alkylenecycloalkyl, C ３ ~C ８ Heterocycloalkyl, C ４ ~C １４ Alkyleneheterocycloalkyl, C ６～１２ Aryl, C ７～１８ Alkylene aryl, C ５～１０ Heteroaryl, and C ６～１６ alkyleneheteroaryl; Said C １～６ Alkyl, C １～６ Haloalkyl, C ２～６ Alkenyl, C ２～６ Haloalkenyl, C ２～６ Alkynyl, C ２～６ Haloalkynyl, C ３～８ Cycloalkyl, C ４～１４ Alkylenecycloalkyl, C ３ ~C ８ Heterocycloalkyl, C ４ ~C １４ Alkyleneheterocycloalkyl, C ６～１２ Aryl, C ７～１８ Alkylene aryl, C ５～１０ Heteroaryl, and C ６～１６ The alkylene heteroaryl is selected from halogen, CN, C １～８ Alkoxy, C １～８ Alkylamino, C １～８ Alkyl sulfonyl, CO ２ R ４ , C(O)N(R ４ ) ２ , OR ４ , N(R ４ ) ２ , NO ２ , S.R. ４ , and SO ２ R ４ each optionally substituted with one or more substituents independently selected from Said C ３～８ Cycloalkyl, C ４～１４ Alkylenecycloalkyl, C ３ ~C ８ Heterocycloalkyl, C ６～１２ Aryl, C ７～１８ Alkylene aryl, C ５～１０ Heteroaryl, and C ６～１６ The alkylene heteroaryl is (O), C １～６ Alkyl, C １～６ Haloalkyl, C ２～６ Alkenyl, C ２～６ Haloalkenyl, C ２～６ Alkynyl, C ２～６ Haloalkynyl, C ３～６ Cycloalkyl, as well as O, S, N, S(O), SO ２ and NR ４ C containing one or two ring hetero moieties selected from ３～６ each optionally further substituted with substituents independently selected from heterocycloalkyl; Or, R １ and R ２ are combined with the atoms to which they are bonded to form O, S, S(O), SO ２ , N, and NR ４ C containing one or two additional ring hetero moieties selected from ３～８ forming a heterocycloalkyl, Said C ３～８ Heterocycloalkyl is selected from halogen, (O), CN, C １～８ Alkoxy, C １～８ Alkylamino, C １～８ Alkyl sulfonyl, CO ２ R ４ , C(O)N(R ４ ) ２ , OR ４ , N(R ４ ) ２ , NO ２ , S.R. ４ , S.O. ２ R ４ , C １～６ Alkyl, C １～６ Haloalkyl, C ２～６ Alkenyl, C ２～６ Haloalkenyl, C ２～６ Alkynyl, C ２～６ Haloalkynyl, C １～８ Alkylamino, C １～８ Alkylsulfonyl, C ３～６ Cycloalkyl, as well as O, S, N, S(O), SO ２ and NR ４ C containing one or two ring hetero moieties selected from ３～６ and optionally further substituted with substituents selected from heterocycloalkyl; R ３ But hydrogen, C １～６ Alkyl, C ３～８ cycloalkyl, or C ４～１４ alkylenecycloalkyl; Or, R ３ , and R １ and R ２ In combination with the atom to which they are attached, one of ３～１２ forming a heterocycloalkyl, Said C ３～１２ Heterocycloalkyl is selected from halogen, (O), CN, C １～８ Alkoxy, C １～８ Alkylamino, C １～８ Alkyl sulfonyl, CO ２ R ４ , C(O)N(R ４ ) ２ , OR ４ , N(R ４ ) ２ , NO ２ , S.R. ４ , S.O. ２ R ４ , C １～６ Alkyl, C １～６ Haloalkyl, C ２～６ Alkenyl, C ２～６ Haloalkenyl, C ２～６ Alkynyl, C ２～６ Haloalkynyl, C ３～６ Cycloalkyl, as well as O, S, N, S(O), SO ２ and NR ４ C containing one or two ring hetero moieties selected from ３～６ and optionally further substituted with substituents selected from heterocycloalkyl; Each R ４ But hydrogen, C １～６ Alkyl, C １～６ Haloalkyl, C ２～６ Alkenyl, C ２～６ Haloalkenyl, C ２～６ Alkynyl, C ２～６ Haloalkynyl, C ３～７ Cycloalkyl, as well as O, S, S(O), SO ２ , N and NR ５ C containing one or two ring hetero moieties selected from ３～７ heterocycloalkyl; Said C １～６ Alkyl, C １～６ Haloalkyl, C ２～６ Alkenyl, C ２～６ Haloalkenyl, C ２～６ Alkynyl, C ２～６ Haloalkynyl, C ３～７ Cycloalkyl, and C ３～７ Heterocycloalkyl is halogen, CN, C １～８ Alkoxy, C １～８ Alkylamino, C １～８ Alkyl sulfonyl, CO ２ R ５ , C(O)N(R ５ ) ２ , OR ５ , N(R ５ ) ２ , NO ２ , S.R. ５ , and SO ２ R ５ each optionally substituted with one or more substituents independently selected from Said C ３ ~C ７ Cycloalkyl and C ３～７ Heterocycloalkyl is (O), C １～６ Alkyl, C １～６ Haloalkyl, C ２～６ Alkenyl, C ２～６ Haloalkenyl, C ２～６ Alkynyl, C ２～６ Haloalkynyl, C ３～６ Cycloalkyl, as well as O, S, S(O), SO ２ , N and NR ５ C containing one or two ring hetero moieties selected from ３～６ each optionally further substituted with substituents independently selected from heterocycloalkyl; Each R ５ But hydrogen, C １～６ Alkyl, C ２～６ Alkenyl, C ２～６ Alkynyl, C １～６ Haloalkyl, C ３～８ Cycloalkyl, C ５～１０ Heterocycloalkyl, C ６～１２ Aryl, and C ５～１０ heteroaryl; Said C １～６ Alkyl, C ２～６ Alkenyl, C ２～６ Alkynyl, C １～６ Haloalkyl, C ３～８ Cycloalkyl, C ５～１０ Heterocycloalkyl, C ６～１２ Aryl, and C ５～１０ Heteroaryl is halogen, CN, C １～８ Alkoxy, C １～８ Alkylamino, C １～８ Alkyl sulfonyl, CO ２ H, CO ２ CH ３ , C(O)NH ２ , C(O)N(CH ３ ) ２ , C(O)NHCH ３ , OH, NH ２ , N(CH ３ ) ２ , NHCH ３ , NO ２ , S.H., S.C.H. ３ , S.O. ２ CH ３ , SOCH ３ , C １～６ Alkyl, C １～６ Haloalkyl, C ２～６ Alkenyl, C ２～６ Haloalkenyl, C ２～６ Alkynyl, C ２～６ Haloalkynyl, C ３～６ Cycloalkyl, as well as O, S, S(O), SO ２ , N, NH and NCH ３ C containing one or two ring hetero moieties selected from ３～６ each optionally substituted with one or more substituents independently selected from heterocycloalkyl; L is C １～４ Alkylene, C ２ ~C ４ Alkenylene, and C ２ ~C ４ alkynylene, R ６ But hydrogen, C １～６ Alkyl, C ２～６ Alkenyl, C ２～６ Alkynyl, C １～６ Alkylene P(O)(OR １２ ) ２ , C(O)R １２ , CO ２ R １２ , C(O)N(R １２ ) ２ , S(O)R １２ and SO ２ R １２ , C ３～６ Cycloalkyl, C ６～９ Alkylenecycloalkyl, C ３～６ Heterocyclyl, C ６～９ Alkyleneheterocycloalkyl, C ４～７ Heterocyclyl, C ７～１０ Alkyleneheterocycloalkyl, C ６～１２ Aryl, C ７～１８ Alkylene aryl, C ５～１０ Heteroaryl, and C ６～１６ alkyleneheteroaryl; Said C １～６ Alkyl, C ２～６ Alkenyl, C ２～６ Alkynyl, C ３～６ Cycloalkyl, C ６～９ Alkylenecycloalkyl, C ３～６ Heterocyclyl, C ６～９ Alkyleneheterocycloalkyl, C ４～７ Heterocyclyl, C ７～１０ Alkyleneheterocycloalkyl, C ６～１２ Aryl, C ７～１８ Alkylene aryl, C ５～１０ Heteroaryl, and C ６～１６ The alkylene heteroaryl is selected from halogen, CN, C １～８ Alkoxy, C １～８ Alkylamino, C １～８ Alkyl sulfonyl, CO ２ R １２ , C(O)N(R １２ ) ２ , OR １２ , N(R １２ ) ２ , NO ２ , S.R. １２ , and SO ２ R １２ each optionally substituted with one or more substituents independently selected from Said C ３～６ Cycloalkyl, C ６～９ Alkylenecycloalkyl, C ３～６ Heterocyclyl, C ６～９ Alkyleneheterocycloalkyl, C ４～７ Heterocyclyl, C ７～１０ Alkyleneheterocycloalkyl, C ６～１２ Aryl, C ７～１８ Alkylene aryl, C ５～１０ Heteroaryl, and C ６～１６ The alkylene heteroaryl is (O), C １～６ Alkyl, C １～６ Haloalkyl, C ２～６ Alkenyl, C ２～６ Haloalkenyl, C ２～６ Alkynyl, C ２～６ Haloalkynyl, C ３～６ Cycloalkyl, as well as O, S, N, S(O), SO ２ and NR １２ C containing one or two ring hetero moieties selected from ３～６ each optionally further substituted with substituents independently selected from heterocycloalkyl; Each R １２ But hydrogen, C １～６ Alkyl, C ２～６ Alkenyl, C ２～６ Alkynyl, C １～６ Haloalkyl, C ３～８ Cycloalkyl, C ４～１４ Alkylenecycloalkyl, C ３～１０ Heterocycloalkyl, C ４～１６ Alkyleneheterocycloalkyl, C ６～１２ Aryl, C ７～１８ Alkylene aryl, C ５～１０ Heteroaryl, and C ６～１６ alkyleneheteroaryl; Said C １～６ Alkyl, C ２～６ Alkenyl, C ２～６ Alkynyl, C １～６ Haloalkyl, C ３～８ Cycloalkyl, C ４～１４ Alkylenecycloalkyl, C ３～１０ Heterocycloalkyl, C ４～１６ Alkyleneheterocycloalkyl, C ６～１２ Aryl, C ７～１８ Alkylene aryl, C ５～１０ Heteroaryl, and C ６～１６ The alkylene heteroaryl is selected from halogen, CN, C １～８ Alkoxy, C １～８ Alkylamino, C １～８ Alkyl sulfonyl, CO ２ H, CO ２ CH ３ , C(O)NH ２ , C(O)N(CH ３ ) ２ , C(O)NHCH ３ , OH, NH ２ , N(CH ３ ) ２ , NHCH ３ , NO ２ , S.H., S.C.H. ３ , S.O. ２ CH ３ , SOCH ３ , C １～６ Alkyl, C １～６ Haloalkyl, C ２～６ Alkenyl, C ２～６ Haloalkenyl, C ２～６ Alkynyl, C ２～６ Haloalkynyl, C ３～６ Cycloalkyl, as well as O, S, S(O), SO ２ , N, NH and NCH ３ C containing one or two ring hetero moieties selected from ３～６ each optionally substituted with one or more substituents independently selected from heterocycloalkyl; (B) and (C): (B) (i) R ７ , R ８ , R ９ , R １０ , and R １１ One of them is OR １３ , N(R １３ ) ２ , S.R. １３ , C １～６ Alkyl, C １～６ Haloalkyl, C ２～６ Alkenyl, C ２ ~C ６ Haloalkenyl, C ２～６ Alkynyl, C ２～６ Haloalkynyl, C １～６ Alkylamines, C １～６ Alkoxy, C １～６ Haloalkoxy, CO ２ R １３ , C(O)R １３ , C(O)N(R １３ ) ２ , C(O)C(O)N(R １３ ) ２ , O.C.(O.)R １３ , OC(O)OR １３ , OC(O)N(R １３ ) ２ , OS(O)R １３ , OS(O)N(R １３ ) ２ , OSO ２ R １３ , OP(O)(OR １３ ) ２ , O.C. １～６ Alkylene P(O)(OR １３ ) ２ , S(O)R １３ , S(O)N(R １３ ) ２ , S.O. ２ R １３ , N(R １３ ) ２ , N(R １３ ) C(O)R １３ , N(R １３ )C(O)OR １３ , N(R １３ )C(O)N(R １３ ) ２ , NO ２ , C ３～８ Cycloalkyl, C ３～１４ Alkylenecycloalkyl, C ３～１０ Heterocycloalkyl, C ４～１６ Alkyleneheterocycloalkyl, C ６～１２ Aryl, C ７～１８ Alkylene aryl, C ５～１０ Heteroaryl, C ４～１６ alkyleneheteroaryl; Said C １～６ Alkyl, C １～６ Haloalkyl, C ２～６ Alkenyl, C ２ ~C ６ Haloalkenyl, C ２～６ Alkynyl, C ２～６ Haloalkynyl, C １～６ Alkylamines, C １～６ Alkoxy, C １～６ Haloalkoxy, C ３～８ Cycloalkyl, C ３～１４ Alkylenecycloalkyl, C ３～１０ Heterocycloalkyl, C ４～１６ Alkyleneheterocycloalkyl, C ６～１２ Aryl, C ７～１８ Alkylene aryl, C ５～１０ Heteroaryl, and C ４～１６ The alkylene heteroaryl is selected from halogen, CN, C １～８ Alkoxy, C １～８ Alkylamino, C １～８ Alkyl sulfonyl, CO ２ R １３ , C(O)N(R １３ ) ２ , OR １３ , N(R １３ ) ２ , NO ２ , S.R. １３ , and SO ２ R １３ and optionally substituted with one or more substituents independently selected from Said C ３～８ Cycloalkyl, C ３～１４ Alkylenecycloalkyl, C ３～１０ Heterocycloalkyl, C ４～１６ Alkyleneheterocycloalkyl, C ６～１２ Aryl, C ７～１８ Alkylene aryl, C ５～１０ Heteroaryl, and C ４～１６ The alkylene heteroaryl is (O), C １～６ Alkyl, C １～６ Haloalkyl, C ２～６ Alkenyl, C ２～６ Haloalkenyl, C ２～６ Alkynyl, C ２～６ Haloalkynyl, C ３～６ Cycloalkyl, as well as O, S, S(O), SO ２ , N, and NR １３ C containing one or two ring hetero moieties selected from ３～６ each optionally further substituted with a substituent selected from heterocycloalkyl; Each R １３ But hydrogen, C １～６ Alkyl, C ２～６ Alkenyl, C ２～６ Alkynyl, C １～６ Haloalkyl, C ３～８ Cycloalkyl, C ４～１４ Alkylenecycloalkyl, C ３～１０ Heterocycloalkyl, C ４～１６ Alkyleneheterocycloalkyl, C ６～１２ Aryl, C ７～１８ Alkylene aryl, C ５～１０ Heteroaryl, and C ６～１６ alkyleneheteroaryl; Said C １～６ Alkyl, C ２～６ Alkenyl, C ２～６ Alkynyl, C １～６ Haloalkyl, C ３～８ Cycloalkyl, C ４～１４ Alkylenecycloalkyl, C ３～１０ Heterocycloalkyl, C ４～１６ Alkyleneheterocycloalkyl, C ６～１２ Aryl, C ７～１８ Alkylene aryl, C ５～１０ Heteroaryl, and C ６～１６ The alkylene heteroaryl is selected from halogen, CN, C １～８ Alkoxy, C １～８ Alkylamino, C １～８ Alkyl sulfonyl, CO ２ H, CO ２ CH ３ , C(O)NH ２ , C(O)N(CH ３ ) ２ , C(O)NHCH ３ , OH, NH ２ , N(CH ３ ) ２ , NHCH ３ , NO ２ , S.H., S.C.H. ３ , S.O. ２ CH ３ , SOCH ３ , C １～６ Alkyl, C １～６ Haloalkyl, C ２～６ Alkenyl, C ２～６ Haloalkenyl, C ２～６ Alkynyl, C ２～６ Haloalkynyl, C ３～６ Cycloalkyl, as well as O, S, S(O), SO ２ , N, NH and NCH ３ C containing one or two ring hetero moieties selected from ３～６ each optionally substituted with one or more substituents independently selected from heterocycloalkyl; (ii) R ７ , R ８ , R ９ , R １０ , and R １１ are each hydrogen; Or, R ６ and R ７ These are combined with the atoms to which they are bonded to form C ４～１０ Heterocycloalkyl or C ５～１０ forming a heteroaryl, Said C ４～１０ Heterocycloalkyl and C ５～１０ Heteroaryl is halogen, (O), CN, C １～８ Alkoxy, C １～８ Alkylamino, C １～８ Alkyl sulfonyl, CO ２ R １４ , C(O)N(R １４ ) ２ , OR １４ , N(R １４ ) ２ , NO ２ , S.R. １４ , S.O. ２ R １４ , C １～６ Alkyl, C １～６ Haloalkyl, C ２～６ Alkenyl, C ２～６ Haloalkenyl, C ２～６ Alkynyl, C ２～６ Haloalkynyl, C ３～６ Cycloalkyl, as well as O, S, N, S(O), SO ２ and NR １４ C containing one or two ring hetero moieties selected from ３～６ each optionally further substituted with a substituent selected from heterocycloalkyl; Or, R ７ , and R １ , R ２ or R ３ One of these is combined with the atom to which it is attached to form C ５～８ forming a heterocycloalkyl, Said C ５～８ Heterocyclylalkyl is selected from halogen, (O), CN, C １～８ Alkoxy, C １～８ Alkylamino, C １～８ Alkyl sulfonyl, CO ２ R １４ , C(O)N(R １４ ) ２ , OR １４ , N(R １４ ) ２ , NO ２ , S.R. １４ , S.O. ２ R １４ , C １～６ Alkyl, C １～６ Haloalkyl, C ２～６ Alkenyl, C ２～６ Haloalkenyl, C ２～６ Alkynyl, C ２～６ Haloalkynyl, C ３～６ Cycloalkyl, as well as O, S, N, S(O), SO ２ and NR １４ C containing one or two ring hetero moieties selected from ３～６ and optionally further substituted with one or more substituents selected from heterocycloalkyl; Each R １４ But hydrogen, C １～６ Alkyl, C ２ ~C ６ Alkenyl, C ２ ~C ６ Alkynyl, C １ ~C ６ Haloalkyl, C ３ ~C ７ Cycloalkyl, C ３～１０ Heterocycloalkyl, C ６～１２ Aryl, and C ５～１０ heteroaryl; Said C １～６ Alkyl, C ２ ~C ６ Alkenyl, C ２ ~C ６ Alkynyl, C １ ~C ６ Haloalkyl, C ３ ~C ７ Cycloalkyl, C ３～１０ Heterocycloalkyl, C ６～１２ Aryl, and C ５～１０ Heteroaryl is halogen, CN, C １～８ Alkoxy, C １～８ Alkylamino, C １～８ Alkyl sulfonyl, CO ２ H, CO ２ CH ３ , C(O)NH ２ , C(O)N(CH ３ ) ２ , C(O)NHCH ３ , OH, NH ２ , N(CH ３ ) ２ , NHCH ３ , NO ２ , S.H., S.C.H. ３ , S.O. ２ CH ３ , SOCH ３ , C １～６ Alkyl, C １～６ Haloalkyl, C ２～６ Alkenyl, C ２～６ Haloalkenyl, C ２～６ Alkynyl, C ２～６ Haloalkynyl, C ３～６ Cycloalkyl, as well as O, S, S(O), SO ２ , N, NH and NCH ３ C containing one or two ring hetero moieties selected from ３～６ each optionally substituted with one or more substituents independently selected from heterocycloalkyl; R １ and R ２ are each methyl, and R ３ and R ６ are each hydrogen, then R ８ is OH or OCH ３ Instead, R ９ But instead of OH, R １ and R ２ are each ethyl, isobutyl, or (sec)butyl, and R ３ and R ６ are each hydrogen, then R ８ But instead of OH, R １ and R ２ are each isopropyl, and R ３ and R ６ are each hydrogen, then R ９ But instead of OH, R １ and R ２ But together with the nitrogen to which they are bound, 【Chemistry 37】 and R ３ and R ６ are each hydrogen, then R ９ But OCH ３ Instead, R １ and R ２ But together with the nitrogen to which they are bound, 【Transformation 38】 and R ３ and R ６ are each hydrogen, then R ８ But instead of OH, R １ and R ２ But together with the nitrogen to which they are bound, 【Chemistry 39】 and R ３ and R ６ are each hydrogen, then R ８ But it's not OH, it's R ９ But CH ３ or OCH ３ Instead, R １０ But OCH ３ Instead, R １ and R ２ But together with the nitrogen to which they are bound, 【Chemistry 40】 and R ３ is hydrogen, and R ６ is methyl, then R ８ But instead of OH, R １ and R ２ are each methyl, and R ３ is hydrogen, and R ６ But ethyl, CH ２ CHF ２ , propyl, isopropyl, butyl, cyclopropyl, methylenecyclopropyl, cyclobutyl, oxetanyl, and butenyl, R ８ But instead of OH, R １ and R ２ are each methyl, and R ３ is hydrogen, and R ６ is hydrogen or CH ２ P(O)(OH) ２ If R ８ but, 【Chemistry 41】 and OC(O)N(CH ３ ) ２ is not selected from R １ , R ２ , and R ３ But together with the atoms to which they are bonded, 【Chemistry 42】 and R ６ is hydrogen or CH ２ P(O)(OH) ２ If R ８ but, 【Chemistry 43】 and OC(O)N(CH ３ ) ２ Not selected from (C)R ７ , R ８ , R ９ , R １０ , and R １１ are each hydrogen, R ６ and R ３ are each hydrogen, then R １ and R ２ However, each is not methyl, but R １ and R ２ But together with the nitrogen to which they are bound, 【Chemistry 44】 does not form pyrrolidyl, piperidyl, or 2,5-dimethylpyrrolyl; R ６ is hydrogen and R ３ is methyl, R １ and R ２ and each is not hydrogen.

18. The pharmaceutical composition of claim 17, wherein the compound, or a pharmaceutically acceptable salt, solvate, tautomer, N-oxide, stereoisomer, metabolite, polymorph, or prodrug thereof, is for administration in combination with another known agent useful for treating a disease, disorder, or condition through activation of a serotonin receptor.

19. The pharmaceutical composition of claim 17, wherein the compound, or a pharmaceutically acceptable salt, solvate, tautomer, N-oxide, stereoisomer, metabolite, polymorph, or prodrug thereof, is for one of the following: Treatment of psychosis, preferably wherein said psychosis is selected from anxiety disorders; depression; mood disorders; psychotic disorders; impulse control and addiction disorders; substance addiction; obsessive-compulsive disorder (OCD); post-traumatic stress disorder (PTSD); stress response syndromes; dissociative disorders; depersonalization disorder; factitious disorder; sexual and gender disorders; somatic symptom disorders; hallucinations; delusions; psychotic disorders; and combinations thereof. Treatment of diseases, disorders or conditions of the central nervous system (CNS) and / or nervous system, preferably wherein said CNS disease, disorder or condition and / or nervous system disease, disorder or condition is a neurodevelopmental disease and neurodegenerative disease such as Alzheimer's disease; presenile dementia; senile dementia; vascular dementia; Lewy body dementia, cognitive impairment, Parkinson's disease and Parkinson's disease related disorders, e.g., Parkinsonism, corticobasal degeneration and supranuclear palsy; epilepsy; CNS trauma; CNS infection; CNS inflammation; stroke; Multiple sclerosis; Huntington's disease; mitochondrial disorders; Fragile X syndrome; Angelman syndrome; hereditary ataxia; neuro-otologic and oculomotor disorders; retinal amyotrophic lateral sclerosis neurodegenerative disorders; tardive dyskinesia; hyperactivity disorder; attention deficit hyperactivity disorder and attention deficit disorder; restless legs syndrome; Tourette's syndrome; schizophrenia; autism spectrum disorder; tuberous sclerosis; Rett syndrome; cerebral palsy; Treatment of diseases, disorders or conditions of the central nervous system (CNS) and / or nervous system, including disorders of the reward system, including eating disorders such as anorexia nervosa and bulimia nervosa; binge eating disorders, trichotillomania, dermatillomania, nail biting; migraine headaches; fibromyalgia; and diseases of the nervous system, including peripheral neuropathies of all etiologies, and combinations thereof; Increasing neuroplasticity and / or increasing dendritic spine density.

20. The pharmaceutical composition of any one of claims 17 to 19, wherein the compound of formula (I) is a compound of any one of claims 1 to 9, or a pharmaceutically acceptable salt, solvate, tautomer, N-oxide, stereoisomer, metabolite, polymorph, or prodrug thereof.

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