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 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; R 7 , R 8 , R 9 , R 10 , and R 11 But 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, 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(R13 )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 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 3~8 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, C6~12 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; 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, C2~6 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; Alternatively, R 8 and R 9 , or R 9 and R 10 , or R 10 and R 11 These are combined with the atoms to which they are bonded to form C 4~8 Cycloalkyl, C 5~8 Heterocycloalkyl, C 6~12 Aryl, or C 5~10forming a heteroaryl, The C in question 4~8 Cycloalkyl, C 5~8 Heterocycloalkyl, C 6~12 Aryl, 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; 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 1~8Alkyl 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 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, OCH2CH2CH3, or 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 is not selected from OH, OCH3, OCH2CH3, OCH2CH2CH3, and OBn; The compound is: [ka] or a pharmaceutically acceptable salt, solvate, tautomer, N-oxide, stereoisomer, metabolite, polymorph, and / or prodrug thereof, wherein the compound of formula (I) is not selected from:

[0011] 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.

[0012] 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.

[0013] 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.

[0014] 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 1and 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, C 6~12Aryl, 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 from 3~6and 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 5 C containing one or two ring hetero moieties selected from3~7 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 5~10 heteroaryl; The C in question1~6 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, C 6~9 Alkyleneheterocycloalkyl, C 4~7Heterocyclyl, 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), C 1~6 Alkyl, C 1~6 Haloalkyl, C2~6 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 1~8 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, 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 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 7 , R 8 , R 9 , R 10 , and R 11 But 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, 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 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 4~16Alkyleneheterocycloalkyl, 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, 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, C1~8 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; 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 3~6each 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; Alternatively, R 8 and R 9 , or R 9 and R 10 , or R 10 and R 11 These are combined with the atoms to which they are bonded to form C 4~8 Cycloalkyl, C 5~8 Heterocycloalkyl, C 6~12 Aryl, or C 5~10 forming a heteroaryl, The C in question 4~8 Cycloalkyl, C 5~8 Heterocycloalkyl, C 6~12 Aryl, and C 5~10Heteroaryl 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; 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 2~6Alkenyl, 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 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, OCH2CH2CH3, or 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 is not selected from OH, OCH3, OCH2CH3, OCH2CH2CH3, and OBn; The compound is: [ka] A method is provided in which the method is not selected from

[0015] In some embodiments, the compound is: [ka] is not selected from.

[0016] In some embodiments, the compound is: [ka] In some embodiments, the compounds of this embodiment may be included in pharmaceutical compositions or methods of treatment or use described herein.

[0017] 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: [Brief explanation of the drawings]

[0018] [Figure 1] Plasma concentrations of a subset of exemplary compounds P-37, P-42, and P-51 in male C57BL / 6 mice after IP administration at 10 mg / kg [Figure 2] Time binning and mean ± SD (n=3) HTR counts for a subset of exemplary compounds P-42 and P-51 in male C57BL / 6 mice after SC administration across several doses. Psilocin data from Glatfelter, et al. "Structure-Activity Relationships for Psilocybin, Baeocystin, Aeruginascin, and Related Analogues to Produce Pharmacological Effects in Mice." ACS Pharmacology & Translational Science 5, no. 11 (November 2022): 1181-96. [Figure 3]Temperature and locomotor activity results shown as mean ± SD (n=3) HTR counts for exemplary compounds P-42 and P-51 in male C57BL / 6 mice after SC administration across several doses. Psilocin data from Glatfelter, et al. “Structure-Activity Relationships for Psilocybin, Baeocystin, Aeruginascin, and Related Analogues to Produce Pharmacological Effects in Mice.” ACS Pharmacology & Translational Science 5, no. 11 (November 2022): 1181-96. [Figure 4] Average time spent immobile in the ASR-TST model of depression in male ICR mice following administration of some selected exemplary compounds P-42 and P-52. DETAILED DESCRIPTION OF THE INVENTION

[0019] 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.

[0020] A first aspect of the present disclosure provides a compound of formula (I) as defined herein.

[0021] In embodiments, 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, C1~6 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, C4~16 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; 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 5~10Heteroaryl 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 NR14 C containing one or two ring hetero moieties selected from 3~6 and optionally further substituted with one or more substituents selected from heterocycloalkyl; R 8 and R 9 are combined with the atoms to which they are bonded to form C 4~8 Cycloalkyl, C 5~8 Heterocycloalkyl, C 6~12 Aryl, or C 5~10 forming a heteroaryl, The C in question 4~8 Cycloalkyl, C 5~8 Heterocycloalkyl, C 6~12 Aryl, 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; 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, C4~16 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; 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;

[0022] In some embodiments, R 8 and R 9 are combined with the atoms to which they are bonded to form C 5~8 Heterocycloalkyl or C 5~10 Forming a heteroaryl, 5~8 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, 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, C2~6 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 is further optionally substituted with a substituent selected from heterocycloalkyl.

[0023] In some embodiments, R 8 and R 9 are combined to: [ka] C selected from 5~8 Heterocycloalkyl or C 5~10 form a heteroaryl, where the dashed bond is R 8 and R 9 represents a covalent bond with the aromatic ring to which it is attached, The C in question 5~8 Heterocycloalkyl and C 5~10 Heteroaryl is a halogen atom, (O), CN, 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, and C 1~6 each further optionally substituted with a substituent selected from haloalkyl.

[0024] In some embodiments, R 8 and R 9 are combined to: [ka] C selected from 5~8 Heterocycloalkyl or C 5~10 form a heteroaryl, where the dashed bond is R 8 and R9 indicates a covalent bond with the aromatic ring to which it is attached.

[0025] Typically, R 8 and R 9 These, together with the atoms to which they are bonded, form C 5~8 Heterocycloalkyl or C 5~10 The heteroaryl moiety, the depicted moiety, and the depicted moiety for the embodiment when forming formula (I) are connected in the orientation as depicted for both formulas.

[0026] In some embodiments, R 8 and R 9 together with the atom to which they are attached form a C5 heterocycloalkyl or C5 heteroaryl moiety. In some embodiments, the compound of formula (I) has formula (II): [ka] and L, R 1 , R 2 , R 3 , and R 6 is as defined for any aspect or embodiment herein; A 1 and A 2 , O, NR 16 , C(H) m are independently selected from R 15 is hydrogen, oxo (=O), C 1~4 Alkyl, HaloC 1~4 alkyl, [ka] denotes a single or double covalent bond, R 16 is hydrogen and C 1~6 alkyl, m is 1 or 2 and is selected according to valence requirements.

[0027] In some embodiments, A 1 is O.

[0028] In some embodiments, A 2 is C(H) m , N, or NH.

[0029] In some embodiments, A 1 is O and A 2 is NH and R 15 is oxo.

[0030] In some embodiments, A 1 is O and A 2 is N and R 15 is H.

[0031] In some embodiments, A 1 is O and A 2 is N and R 15 is C 1~6 It is alkyl, preferably methyl.

[0032] In some embodiments, A 1 is NH and A 2 is NH and R 15 is oxo.

[0033] In some embodiments, R 9 and R 10 together with the atom to which they are attached form a C5 heterocycloalkyl or C5 heteroaryl moiety. In some embodiments, the compound of formula (I) has formula (III): [ka] and L, R 1 , R 2 , R 3 , and R 6 is as defined for any aspect or embodiment herein; A1 and A 2 , O, NR 18 , C(H) m are independently selected from R 17 is hydrogen, oxo (=O), C 1~4 Alkyl, HaloC 1~4 is alkyl, [ka] denotes a single or double covalent bond, R 18 is hydrogen and C 1~6 alkyl, m is 1 or 2 and is selected according to valence requirements.

[0034] In some embodiments, 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, CO2R 13 , 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 4~16Alkyleneheterocycloalkyl, 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 2~6Haloalkenyl, 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; R 13 is as defined in any aspect or embodiment herein.

[0035] In some embodiments, 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.

[0036] In some embodiments, R 7 , R 10 , and R 11 are each hydrogen.

[0037] In some embodiments, R 7 , R 8 , R 9 , 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, CO2R 13 , C(O)R 13 , C(O)N(R13 )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 5~10Heteroaryl, 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, C 4~14 Alkylenecycloalkyl, C 3~10 Heterocycloalkyl, C 4~16 Alkyleneheterocycloalkyl, C 6~12 Aryl, C 7~18 Alkylene aryl, C5~10 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; 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 1~8Alkylamino, 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 3~6and 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 1~8 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 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 6is selected from hydrogen, methyl, ethyl, and propyl, and R 9 , R 10 , or R 11 One of the groups is fluoro and R 9 , R 10 , or R 11 If the other of 8 is not selected from OH, OCH3, OCH2CH3, OCH2CH2CH3, and 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 is not selected from OH, OCH3, OCH2CH3, OCH2CH2CH3, and OBn.

[0038] In some embodiments, R 7 , R 8 R 9 , 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, CO2R 13 , 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 C4~16 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; R 13 is as defined in any one of the preceding paragraphs, 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, OCH2CH2CH3, or 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 is not selected from OH, OCH3, OCH2CH3, OCH2CH2CH3, and OBn.

[0039] 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.

[0040] In some embodiments, R 8 is a halogen, C 1~6 Alkyl and OR 13 Selected from R 13is hydrogen, C 1~6 Alkyl, and C 1~6 haloalkyl.

[0041] In some embodiments, 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.

[0042] In some embodiments, R 6 is hydrogen.

[0043] In some embodiments, R 7 is hydrogen.

[0044] In some embodiments, R 7 is selected from hydrogen and methyl, R 8 , R 9 , R 10 , and R 11 are also H, and the others are as defined for any aspect or embodiment herein. In some embodiments, R 7 is hydrogen and R 8 , R 9 , R 10 , and R 11 are also H, and the others are as defined for any aspect or embodiment herein.

[0045] In some embodiments, R 8 is hydrogen.

[0046] In some embodiments, R 9 is hydrogen.

[0047] In some embodiments, R 10 is hydrogen.

[0048] In some embodiments, R11 is hydrogen.

[0049] In some embodiments, R 6 and R 7 are each hydrogen.

[0050] In some embodiments, R 7 , R 8 , R 9 , R 10 , and R 11 is defined according to any one of embodiments 1 to 18: [Table 1]

[0051] In some embodiments, R 8 and R 9 One of the two is OR 13 is.

[0052] In some embodiments, R 7 , R 10 , and R 11 Any one or more of the following must be OR 13 isn't it.

[0053] In some embodiments, R 13 is H or C 1~6 In embodiments, R 13 is H. In an embodiment, R 13 is C 1~6 Alkyl, preferably C 1~4 It is preferably alkyl, more preferably methyl.

[0054] In some embodiments, R 8 , R 9 , R 10 , and R 11 One or two of R are halo, preferably fluoro. 8 , R 9 , R 10 , and R 11In some embodiments, one of R 8 , R 9 , R 10 , and R 11 Two of are halo, preferably fluoro, and the other is H.

[0055] In some embodiments, R 7 , R 8 , R 9 , R 10 , and R 11 One of the following is C 1~6 Alkyl, preferably C 1~4 It is preferably alkyl, more preferably methyl.

[0056] 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.

[0057] In some embodiments, R 1 and R 2 is C 1~4 alkyl.

[0058] In some embodiments, R 1 and R 2 In some embodiments, at least one of R 1 and R 2 are not both methyl.

[0059] In some embodiments, R 1 and R 2 together with the nitrogen to which they are attached, form: [ka] Form one of the following:

[0060] In some embodiments, R 1 and R 2 together with the nitrogen to which they are attached, form: [ka] Form one of the following:

[0061] In some embodiments, 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 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.

[0062] In some embodiments, R 3is hydrogen.

[0063] 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.

[0064] In some embodiments, L is C 1~4 It is alkylene.

[0065] In some embodiments, L is methylene.

[0066] In some embodiments, R 6 is hydrogen and C 1~6 alkyl.

[0067] In some embodiments, R 6 is hydrogen.

[0068] In some embodiments, the compound of formula (I) is selected from any one of compounds P-1 to P-161 described herein, e.g., compounds P-1 to P-7 and P-37 to P-161.

[0069] In some embodiments, the compound of Formula (I) is selected from any one of compounds P1 through P4 and P-125 through P-135, or a pharmaceutically acceptable salt, solvate, tautomer, N-oxide, stereoisomer, metabolite, polymorph, or prodrug thereof.

[0070] In some embodiments, the compound of Formula (I) is selected from any one of compounds P-5 to P-7, P-37 to P-124, and P-136 to P161, or a pharmaceutically acceptable salt, solvate, tautomer, N-oxide, stereoisomer, metabolite, polymorph, or prodrug thereof.

[0071] In some embodiments, the compound is selected from any one of P1 to P3, P7 to P9, P11 to P14, and P-37 to P49, P51 to P-152, P-153 to P-155, P-157 to P-158, and P-160 to P-161.

[0072] 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.

[0073] 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.

[0074] 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.

[0075] 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; R 7 , R 8 , R 9 , R 10 , and R 11 But 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 2~6Haloalkynyl, 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 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 3~8 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 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; Alternatively, R 6 and R 7 These are combined with the atoms to which they are bonded to form C 4~10 Heterocycloalkyl or C5~10 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, SR 14 , SO2R 14 , C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkenyl, C 2~6 Haloalkenyl, C 2~6Alkynyl, 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; Alternatively, R 8 and R 9 , or R 9 and R 10 , or R 10 and R 11 These are combined with the atoms to which they are bonded to form C 4~8 Cycloalkyl, C 5~8 Heterocycloalkyl, C 6~12 Aryl, or C 5~10 forming a heteroaryl, The C in question 4~8 Cycloalkyl, C 5~8 Heterocycloalkyl, C 6~12 Aryl, 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; 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 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, OCH2CH2CH3, or 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 is not selected from OH, OCH3, OCH2CH3, OCH2CH2CH3, and OBn; The compound is: [ka] A method is provided in which the method is not selected from

[0076] In some embodiments of this method, the compound is: [ka] is not selected from.

[0077] 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, CO2R 13 , C(O)R 13 , C(O)N(R13 )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 5~10Heteroaryl, 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; 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 1~8Alkyl 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 3~6and optionally further substituted with one or more substituents selected from heterocycloalkyl; R 8 and R 9 are combined with the atoms to which they are bonded to form C 4~8 Cycloalkyl, C 5~8 Heterocycloalkyl, C 6~12 Aryl, or C 5~10 forming a heteroaryl, The C in question 4~8 Cycloalkyl, C 5~8 Heterocycloalkyl, C 6~12 Aryl, 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; 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, C7~18 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; 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 1~6Alkyl, 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 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;

[0078] In some embodiments of this method, R 8 and R 9 are combined with the atoms to which they are bonded to form C 5~8 Heterocycloalkyl or C 5~10 Forming a heteroaryl, 5~8 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, 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, C2~6 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 is further optionally substituted with a substituent selected from heterocycloalkyl.

[0079] In some embodiments of this method, R 8 and R 9 are combined to: [ka] C selected from 5~8 Heterocycloalkyl or C 5~10 form a heteroaryl, where the dashed bond is R 8 and R 9 represents a covalent bond with the aromatic ring to which it is attached, The C in question 5~8 Heterocycloalkyl and C 5~10 Heteroaryl is a halogen atom, (O), CN, 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, and C 1~6 each further optionally substituted with a substituent selected from haloalkyl.

[0080] In some embodiments of this method, R 8 and R 9 are combined to: [ka] C selected from 5~8 Heterocycloalkyl or C 5~10 form a heteroaryl, where the dashed bond is R 8 and R 9 indicates a covalent bond with the aromatic ring to which it is attached.

[0081] 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, CO2R 13 , 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 3~14Alkylenecycloalkyl, 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 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; R 13 is as defined in any one of the preceding paragraphs.

[0082] In some embodiments of this method, R 7 , R 10 , and R 11 is hydrogen, halogen, C1~6 Alkyl, C 1~6 Haloalkyl and OR 13 R 13 is hydrogen, C 1~6 Alkyl, and C 1~6 haloalkyl.

[0083] In some embodiments of this method, R 7 , R 10 , and R 11 are each hydrogen.

[0084] In some embodiments of this method, R 7 , R 8 , R 9 , 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, 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 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 3~10Heterocycloalkyl, 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 5~10 Heteroaryl, and C 6~16Alkyleneheteroaryl 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; 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 14C 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 6~12Aryl, 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 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, OCH2CH2CH3, or 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 R11 is hydrogen, R 10 is not selected from OH, OCH3, OCH2CH3, OCH2CH2CH3, and OBn.

[0085] In some embodiments of this method, R 7 , R 8 R 9 , 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, CO2R 13 , 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, C1~6 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; R 13 is as defined in any one of the preceding paragraphs, R7 , 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, OCH2CH2CH3, or 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 is not selected from OH, OCH3, OCH2CH3, OCH2CH2CH3, and OBn.

[0086] In some embodiments of this method, 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 11At 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.

[0087] In some embodiments of this method, R 8 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.

[0088] 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.

[0089] In some embodiments of this method, R 1 and R 2is 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.

[0090] In some embodiments of this method, R 1 and R 2 is C 1~4 alkyl.

[0091] 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:

[0092] 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:

[0093] 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 substituted with halogen, CN, C 1~8 Alkoxy, C 1~8 Alkylamino, C 1~8 Alkyl sulfonyl, CO2R 4 , C(O)N(R4 )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.

[0094] In some embodiments of this method, R 3 is hydrogen.

[0095] 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 3~6Cycloalkyl, 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.

[0096] In some embodiments of this method, L is C 1~4 It is alkylene.

[0097] In some embodiments of this method, L is methylene.

[0098] In some embodiments of this method, R 6 is hydrogen and C 1~6 alkyl.

[0099] In some embodiments of this method, R 6 is hydrogen.

[0100] In some embodiments of this method, the compound of formula (I) is as defined in any aspect or embodiment herein.

[0101] In some embodiments, the compound of formula (I) is selected from any one of claims 1-3, 6-14, and 37-161. In some embodiments, the compound is selected from any one of claims 1-3, 7-9, 11-14, 37-49, 51-152, 153-155, 157-158, and 160-161.

[0102] 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.

[0103] 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.

[0104] 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.

[0105] 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.

[0106] 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.

[0107] 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.

[0108] 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.

[0109] 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.

[0110] Any embodiment in this specification should be applied mutatis mutandis to other embodiments unless otherwise specified.

[0111] 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.

[0112] definition For purposes of interpreting this specification, terms used in the singular will also include the plural and vice versa.

[0113] 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.

[0114] 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.

[0115] 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.

[0116] 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.

[0117] 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.

[0118] 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.

[0119] 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.

[0120] 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.

[0121] 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.

[0122] 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).

[0123] 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.

[0124] 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.

[0125] 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.

[0126] 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.

[0127] 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.

[0128] 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 is indicated 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.

[0129] 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.

[0130] 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.

[0131] 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).

[0132] 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.

[0133] 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).

[0134] 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.

[0135] 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).

[0136] 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.

[0137] 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.

[0138] 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.

[0139] 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.

[0140] 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.

[0141] 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.

[0142] 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.

[0143] 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).

[0144] For example, but not limited to, a C1 haloalkyl group can be fluoromethyl, or difluoromethyl, or trifluoromethyl.

[0145] 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.

[0146] 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.

[0147] As used herein, the term haloalkoxy refers to an alkoxy group, as defined herein, substituted with at least one halogen.

[0148] The term "amino" or "amine" refers to the group --NH.sub.2.

[0149] The term "substituted amino" or "secondary amino" refers to a group in which hydrogen is replaced with, for example, C 1~ It refers to an amino group substituted with a C6 alkyl group ("C1-C6 alkylamino"), an aryl or aralkyl group ("arylamino", "aralkylamino"), etc. For example, C1-C3 alkylamino groups such as methylamino (NHMe), ethylamino (NHEt), and propylamino (NHPr) are preferred.

[0150] 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)).

[0151] The term "nitro" refers to the group -NO2.

[0152] The terms "cyano" and "nitrile" refer to the group --CN.

[0153] The terms "amido" or "amide" refer to the group -C(O)NH2.

[0154] 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)-).

[0155] 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.

[0156] The term "sulfonyl" refers to the group -SO2H.

[0157] The term "substituted sulfonyl" refers to a sulfonyl group in which the hydrogen has been replaced with, for example, a C1-C6 alkyl group ("sulfonyl C1-C6 alkyl"), aryl ("arylsulfonyl"), aralkyl ("aralkylsulfonyl"), etc. Preferred are sulfonyl C1-C3 alkyl groups such as, for example, -SO2Me, -SO2Et, and -SO2Pr.

[0158] The term "sulfonylamido" or "sulfonamide" refers to the group -SO2NH2.

[0159] The terms "substituted sulfonamide" or "substituted sulfonamide" refer to sulfonylamide groups in which the hydrogen has been replaced, for example, by a C1-C6 alkyl group ("sulfonylamide C1-C6 alkyl"), aryl ("arylsulfonamide"), aralkyl ("aralkylsulfonamide"), etc. Sulfonylamide C1-C3 alkyl groups, such as, for example, -SONHMe, -SONHEt, and SONHPr, are preferred, including their reverse sulfonamides (e.g., -NHSOMe, -NHSOEt, and -NHSOPr).

[0160] The term "disubstituted sulfonamide" or "disubstituted sulphonamide" refers to a disubstituted sulfonamide in which the two hydrogens are, for example, C1-C6 alkyl groups ("sulfonylamide di(C 1~ It refers to sulfonylamido groups substituted with, for example, -C alkyl), aralkyl, and alkyl groups ("sulfonamido(aralkyl)alkyl"). For example, sulfonylamido di(C-C alkyl) groups such as -SONMe, -SONNEt, and -SONPr, and variations thereof (e.g., -SON(Me)Et, etc.) are preferred, including their reverse sulfonamides (e.g., -N(Me)SOMe, etc.).

[0161] The term "sulfate" refers to the group OS(O)OH and includes groups in which the hydrogen has been replaced, for example, by a C-C alkyl group ("alkyl sulfate"), aryl ("aryl sulfate"), aralkyl ("aralkyl sulfate"), etc. Preferred are C-C alkyl sulfates such as, for example, OS(O)OMe, OS(O)OEt, and OS(O)OPr.

[0162] The term "sulfonate" refers to the group SO3H and includes groups in which the hydrogen has been replaced, for example, by a C1-C6 alkyl group ("alkylsulfonate"), aryl ("arylsulfonate"), aralkyl ("aralkylsulfonate"), etc. Preferred are C1-C3 alkylsulfonates such as, for example, SO3Me, SO3Et, and SO3Pr.

[0163] 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.

[0164] The term "carboxylate" or "carboxyl" refers to the group --COO-- or --COOH.

[0165] 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.

[0166] The term "carbonate" refers to the group -OC(O)O- or -OC(O)OH.

[0167] 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).

[0168] 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).

[0169] 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.

[0170] 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, "C 3~10The 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.

[0171] 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).

[0172] Heterocyclyl also encompasses heteroaryl (aromatic heterocyclyl) and heterocycloalkyl (non-aromatic heterocyclyl). Such groups may be substituted or unsubstituted.

[0173] 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.

[0174] 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.

[0175] 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.

[0176] An aromatic heterocyclyl group can be a 5- or 6-membered monocyclic aromatic ring system.

[0177] 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.

[0178] 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).

[0179] 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.

[0180] 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.

[0181] 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).

[0182] 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.

[0183] Specific 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.

[0184] 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.

[0185] 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.

[0186] 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.

[0187] The non-aromatic heterocyclyl can be a 3- to 8-membered monocyclic ring.

[0188] 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.

[0189] 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.

[0190] Examples of 7-membered non-aromatic heterocyclyls include azepanyl, oxepanyl, thiepanyl, and the like.

[0191] 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.

[0192] 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 Alkylenecycloalkyl 」 The numerical range of x to y relates to the total number of alkyl carbon and heteroaryl ring atoms (carbon and heteroatoms combined).

[0193] 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).

[0194] 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.

[0195] 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.

[0196] 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.

[0197] 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.

[0198] 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.

[0199] 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 formula.

[0200] 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.

[0201] 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.

[0202] 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.

[0203] Basic nitrogen-containing groups include C, such as methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides. 1~6 They may be quaternized with agents such as alkyl halides; dialkyl sulfates such as dimethyl and diethyl sulfate.

[0204] Nitrogen-containing groups can also be oxidized to form N-oxides.

[0205] 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.

[0206] 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.

[0207] 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.

[0208] 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.

[0209] 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.

[0210] 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.

[0211] Compositions, Formulations, and Modes of Administration Any of the compounds described herein may be for use as a pharmaceutical, and thus the compounds may be for use in the treatment of any of the indications disclosed herein.

[0212] 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.

[0213] 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.

[0214] 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.

[0215] 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.

[0216] 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.

[0217] The compounds of formula (I) may be administered in any form and by any route that makes the compound bioavailable.

[0218] The compositions disclosed herein can be administered systemically or directly to the site of the condition or disease.

[0219] 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.

[0220] 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.

[0221] 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.

[0222] 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.

[0223] 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.

[0224] 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.

[0225] 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.

[0226] 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.

[0227] 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.

[0228] 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.

[0229] 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.

[0230] 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.

[0231] 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.

[0232] 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.

[0233] 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.

[0234] 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.

[0235] Those skilled in the art can readily select appropriate dosage forms and routes 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.

[0236] 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.

[0237] 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.

[0238] 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.

[0239] 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.

[0240] 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.

[0241] 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.

[0242] 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.

[0243] 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.

[0244] In another aspect, the present disclosure provides a method of preventing a disease in a subject in need thereof, 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.

[0245] 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).

[0246] 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).

[0247] In certain embodiments, the effective amount is effective in treating a disease. In certain embodiments, the effective amount is effective in preventing a disease.

[0248] 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.

[0249] 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.

[0250] 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.

[0251] 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.

[0252] In certain embodiments, the serotonin receptor is 5-HT 2A is.

[0253] 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.

[0254] 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.

[0255] 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.

[0256] 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.

[0257] 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.

[0258] 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.

[0259] 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.

[0260] 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.

[0261] 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.

[0262] 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.

[0263] 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.

[0264] 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.

[0265] 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 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.

[0266] 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 therapies for depression are citralopram, escitalopram, fluoxetine, paroxetine, diazepam, or sertraline.

[0267] 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.

[0268] 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.

[0269] 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.

[0270] 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.

[0271] 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.

[0272] 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.

[0273] 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.

[0274] 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.

[0275] 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.

[0276] 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.

[0277] 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.

[0278] 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.

[0279] 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.

[0280] 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.

[0281] 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.

[0282] 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.

[0283] 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.

[0284] 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.

[0285] 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.

[0286] 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.

[0287] 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.

[0288] 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.

[0289] 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; Kits are provided that include a label or package insert with instructions for use.

[0290] 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]

[0291] Scheme 1: Compounds of general formula (I) can be synthesized from an appropriately substituted aniline by following the sequence of steps outlined in Scheme 1 or similar to those contemplated by one skilled in the art. Fischer indole synthesis utilizing an appropriately substituted aniline provided access to a tetracyclic intermediate, which, after subsequent ring opening and decarboxylation, allowed for the formation of intermediate 5. Reductive alkylation of the pendant amine provided access to compounds of general formula (I) (exemplified by P-1 and P-2). One skilled in the art will recognize that the use of differentially substituted amines provides access to compounds of general formula (I) disclosed herein. [ka]

[0292] Example 1: 2-(1,6-dihydro-2H-furo[3,2-e]indol-8-yl)-N,N-dimethylethan-1-amine (P-1) [ka] Step 1: (E)-3-(2-(2,3-dihydrobenzofuran-5-yl)hydrazinylidene)piperidin-2-one (2) A solution of ethyl 2-oxopiperidine-3-carboxylate (12.7 g, 74 mmol) in HO (120 mL) was treated with KOH (4.15 g, 74 mmol) and stirred at ambient temperature for 16 hours. In a separate flask, 2,3-dihydro-1-benzofuran-5-amine (10.0 g, 74 mmol) in HO (120 mL) and 12 M aqueous HCl (21.5 mL) was cooled to 0 °C and treated dropwise with a solution of NaNO (5.1 g, 74 mmol) in HO (10 mL). This mixture was stirred at 0 °C for 30 minutes, then adjusted to pH 4 with 10% w / v aqueous NaCO and then added to the first solution containing the oxopiperidine. The pH of the combined reaction mixture was adjusted to pH 4 with AcOH and stirred at 0 °C for 16 hours. Upon completion, the insoluble material was collected by filtration and washed with water (200 mL). The solid was dried under vacuum to give crude (£)-3-(2-(2,3-dihydrobenzofuran-5-yl)hydrazinylidene)piperidin-2-one (10 g) as a red solid, which was used without further purification.

[0293] Step 2: 2,3,5,7,8,9-Hexahydro-6H-furo[2,3-f]pyrido[3,4-b]indol-6-one (3) A solution of crude (£)-3-(2-(2,3-dihydrobenzofuran-5-yl)hydrazineylidene)piperidin-2-one (20.0 g) in HCOOH (120 mL) was stirred at 105° C. for 1 h. The reaction mixture was diluted with HO (200 mL) and extracted with EtOAc (200 mL × 2). The combined organic layers were washed with brine (100 mL), dried over NaSO, filtered, and concentrated under reduced pressure to give crude 2,3,5,7,8,9-hexahydro-6H-furo[2,3-f]pyrido[3,4-b]indol-6-one (8.00 g) as a brown solid, which was used in the subsequent step without further purification.

[0294] Step 3: 7-(2-aminoethyl)-3,5-dihydro-2H-furo[2,3-f]indole-6-carboxylic acid (4) To a solution of crude 2,3,5,7,8,9-hexahydro-6H-furo[2,3-f]pyrido[3,4-b]indol-6-one (7.50 g) in EtOH (20 mL) was added KOH (18.4 g, 328 mmol) and HO (20 mL). The mixture was stirred at 90 °C for 12 h. The solvent was removed, and the residue was diluted with HO (25 mL) and then filtered. The filtrate was acidified with AcOH to produce a precipitate, which was collected, washed with HO, and dried to give crude 7-(2-aminoethyl)-3,5-dihydro-2H-furo[2,3-f]indole-6-carboxylic acid (5.00 g) as a brown solid, which was used in the subsequent step without further purification.

[0295] Step 4: 2-(3,5-dihydro-2H-furo[2,3-f]indol-7-yl)ethan-1-amine (5) To a solution of crude 7-(2-aminoethyl)-3,5-dihydro-2H-furo[2,3-f]indole-6-carboxylic acid (5.00 g, 20.3 mmol) in HCl (12 M aqueous, 10 mL) was added HO (20 mL), and the resulting mixture was stirred at 100° C. for 1 h. The reaction mixture was adjusted to pH 10 with 30% aqueous NaOH. HO was removed by lyophilization to give crude 2-(3,5-dihydro-2H-furo[2,3-f]indol-7-yl)ethan-1-amine (3.00 g) as a brown solid, which was used in the subsequent step without further purification.

[0296] Step 5: 2-(3,5-dihydro-2H-furo[2,3-f]indol-7-yl)-N,N-dimethylethan-1-amine (P-1) To a solution of crude 2-(3,5-dihydro-2H-furo[2,3-f]indol-7-yl)ethan-1-amine (3.00 g) in MeOH (15 mL) was added AcOH (3.56 g, 59.3 mmol, 3.39 mL), NaBHCN (1.86 g, 29.6 mmol), and 37% w / w aqueous formaldehyde (3.01 g, 37.0 mmol). The mixture was stirred at 20 °C for 2 h. The reaction mixture was then concentrated under reduced pressure, and the residue was adjusted to pH 8 with saturated aqueous NaHCO and extracted with CHCl (50 mL × 2). The combined organic layers were washed with brine (50 mL), dried over anhydrous NaSO, filtered, and the filtrate was concentrated in vacuo 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: 1–40%, 10 min) to give 2-(3,5-dihydro-2H-furo[2,3-f]indol-7-yl)-N,N-dimethylethan-1-amine as the trifluoroacetate salt (0.75 g, 3% over five steps). 1 H NMR(400MHz,DMSO-d6):δ 10.70(s,1H),9.42(br s,1H),7.19(s,1H),7.11(d,J=2.4Hz,1H),6.89(s,1H),4.47(d,J=8.4Hz, 2H), 3.28-3.25(m, 2H), 3.22-3.18(m, 2H), 2.99-2.95(m, 2H), 2.84(s, 6H). LCMS(ESI+):m / z=231.0[M+H] + . HPLC purity (220nm): 98.2%.

[0297] Step 6: 2-(5H-furo[2,3-f]indol-7-yl)-N,N-dimethylethan-1-amine (P-2) To a solution of 2-(3,5-dihydro-2H-furo[2,3-f]indol-7-yl)-N,N-dimethylethan-1-amine (0.50 g, 2.17 mmol) in dioxane (3 mL) was added DDQ (591 mg, 2.61 mmol). The mixture was stirred at 105 °C for 2 h. The reaction mixture was then concentrated under reduced pressure, and the residue was purified by preparative HPLC (column: Waters Xbridge Prep OBD C18 150 × 40 mm × 10 μm; mobile phase: [water (NH + NHHCO)-ACN]; B: 1–45%, 8 min) to give 2-(5H-furo[2,3-f]indol-7-yl)-N,N-dimethylethan-1-amine (68 mg, 14%) as an off-white solid. 1 H NMR(400MHz,CD3CN-d3):δ 8.93(s,1H),7.65(d,J=2.4Hz,1H),7.61(s,1H),7.52(s,1H),7.14(d,J=2.4H z,1H),6.84-6.83(m,1H),2.91-2.87(m,2H),2.60-2.56(m,2H),2.25(s,6H). LCMS(ESI+):m / z=229.1[M+H] + . HPLC purity (220nm): 99.7%.

[0298] Scheme 2: Compounds of general formula (I) can be synthesized from an appropriately substituted aniline by following the sequence of steps outlined in Scheme 2 or similar to those contemplated by one skilled in the art. Fischer indole synthesis utilizing an appropriately substituted aniline provided access to tetracyclic intermediate 292, which, after subsequent ring opening and hydrogenation, produced intermediate 9. Decarboxylation produced intermediate 10. Reductive alkylation of the pendant amine provided access to compounds of general formula (I) (exemplified by P-3). Those skilled in the art will recognize that alternately utilizing aldehydes or ketones provides access to compounds of general formula (I) disclosed herein. [ka]

[0299] Example 2: 2-(3,6-dihydro-2H-furo[2,3-e]indol-8-yl)-N,N-dimethylethan-1-amine (P-3) [ka] Step 1: (E)-3-(2-(benzofuran-6-yl)hydrazineylidene)piperidin-2-one (281) A solution of ethyl 2-oxopiperidine-3-carboxylate (6.43 g, 37.6 mmol) in HO (11 mL) was treated with KOH (2.11 g, 37.6 mmol) and stirred at ambient temperature for 16 h. In a separate flask, a solution of 1-benzofuran-6-amine (5 g, 37.6 mmol) in HO (11 mL) and 12 M aqueous HCl (2.74 g, 2 equivalents, 75.1 mmol) was cooled to 0 °C and treated with NaNO (2.59 g, 37.6 mmol) predissolved in HO (11 mL). This mixture was stirred at 0 °C for 30 min, then adjusted to pH 4 with 10% w / v aqueous NaCO and then added to the first solution containing oxopiperidine. The pH of the resulting mixture was adjusted to pH 5 with AcOH and stirred at 0 °C for 16 h. Upon completion, the insoluble material was collected by filtration and washed with HO (30 mL). The solid was dried in vacuo to give crude (£)-3-(2-(benzofuran-6-yl)hydrazinylidene)piperidin-2-one (5 g) as a brown solid, which was used without further purification.

[0300] Step 2: 6,8,9,10-Tetrahydro-7H-furo[2,3-e]pyrido[3,4-b]indol-7-one (292) A solution of crude (£)-3-(2-(benzofuran-6-yl)hydrazinylidene)piperidin-2-one (5.0 g) in EtOH (17.5 mL) was treated with a solution of 3 M HCl in MeOH (17.5 mL) and stirred at 80 °C for 3 h. The pH of the reaction mixture was adjusted to 8 with saturated aqueous NaCO, and the organic solvent was removed under reduced pressure. The residue was diluted with HO (20 mL) and then extracted with CHCl (30 mL × 2). The combined organic layers were washed with brine (5 mL), dried over NaSO, filtered, and the filtrate was concentrated under reduced pressure to give crude 6,8,9,10-tetrahydro-7H-furo[2,3-e]pyrido[3,4-b]indol-7-one (4.00 g) as a brown solid, which was used in the subsequent step without further purification.

[0301] Step 3: 8-(2-aminoethyl)-6H-furo[2,3-e]indole-7-carboxylic acid (293) To a solution of crude 6,8,9,10-tetrahydro-7H-furo[2,3-e]pyrido[3,4-b]indol-7-one (4.0 g) in EtOH (14 mL) was added KOH (19.8 g, 353 mmol) and HO (14 mL). The mixture was stirred at 90 °C for 16 h. The solvent was removed, and the residue was diluted with HO (25 mL) and extracted with MTBE (30 mL × 2). The aqueous layer was then filtered, and the filtrate was acidified with AcOH to produce a precipitate, which was collected, washed with HO, and then dried to give crude 8-(2-aminoethyl)-6H-furo[2,3-e]indole-7-carboxylic acid (4.00 g) as a brown solid, which was used in the subsequent step without further purification.

[0302] Step 4: 8-(2-aminoethyl)-3,6-dihydro-2H-furo[2,3-e]indole-7-carboxylic acid (9) A solution of crude 8-(2-aminoethyl)-6H-furo[2,3-e]indole-7-carboxylic acid (200 mg) in MeOH (10 mL) was treated with 10% Pd / C (87.1 mg, 0.82 mmol). The resulting mixture was stirred at 30 °C for 36 hours under an atmosphere of H at 50 PSI. The suspension was then filtered through a pad of Celite, and the filter cake was eluted with MeOH (5 mL × 3). The combined filtrates were concentrated in vacuo to give crude 8-(2-aminoethyl)-3,6-dihydro-2H-furo[2,3-e]indole-7-carboxylic acid (200 mg) as a brown oil, which was used in the subsequent step without further purification.

[0303] Step 5: 2-(3,6-dihydro-2H-furo[2,3-e]indol-8-yl)ethan-1-amine (10) To a solution of crude 8-(2-aminoethyl)-3,6-dihydro-2H-furo[2,3-e]indole-7-carboxylic acid (200 mg) in HO (6 mL) was added HCl (12 M aqueous, 2 mL). The mixture was stirred at 100° C. for 1 hour. The reaction mixture was adjusted to pH 13 with 10% aqueous NaOH. The HO was then removed by lyophilization to give crude 2-(3,6-dihydro-2H-furo[2,3-e]indol-8-yl)ethan-1-amine (100 mg) as a brown solid, which was used in the subsequent step without further purification.

[0304] Step 6: 2-(3,6-dihydro-2H-furo[2,3-e]indol-8-yl)-N,N-dimethylethan-1-amine (P-3) To a solution of crude 2-(3,6-dihydro-2H-furo[2,3-e]indol-8-yl)ethan-1-amine (100 mg) in MeOH (3 mL) was added AcOH (118 mg, 1.98 mmol), NaBHCN (62.1 mg, 0.99 mmol), and 37% w / w aqueous formaldehyde (100 mg, 1.24 mmol). The mixture was stirred at 20 °C for 12 h. The pH of the reaction mixture was then adjusted to 8 with saturated aqueous NaHCO, and then the methanol was removed under reduced pressure. The aqueous residue was extracted with CHCl (3 mL × 2). The organic layer was washed with brine (1 mL × 2), dried over anhydrous NaSO, filtered, and the filtrate was 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]; B%: 1% to 35%, 8 min) to give 2-(3,6-dihydro-2H-furo[2,3-e]indol-8-yl)-N,N-dimethylethan-1-amine (9.34 mg, 0.1% over six steps) as a yellow solid. 1 H NMR(400MHz,CD3CN-d3):δ 8.89-8.93(br.s,1H),6.97-6.92(m,2H),6.85(d,J=8.0Hz,1H),4.63(t,J=8.8H z, 2H), 3.22 (t, J=8.8Hz, 2H), 2.90-2.85 (m, 2H), 2.56-2.52 (m, 2H), 2.21 (s, 6H). LCMS(ESI+) m / z 231.2[M+H] + . HPLC purity (220nm): 99.4%

[0305] Scheme 3: Compounds of general formula (I) can be synthesized by a similar sequence of steps outlined in Schemes 1 and 2. Performing a Fischer indole synthesis on an appropriately decorated aniline provided access to tetracyclic intermediate 282, which, after subsequent ring-opening and decarboxylation, allowed for the formation of intermediate 284. Reductive alkylation of the pendant amine provided access to compounds of general formula (I) (exemplified by P-4). Those skilled in the art will recognize that alternately utilizing aldehydes or ketones provides access to compounds of general formula (I) disclosed herein. [ka]

[0306] Example 3: 2-(7H-furo[3,2-f]indol-5-yl)-N,N-dimethylethan-1-amine (P-4) [ka] Step 1: (E)-3-(2-(benzofuran-6-yl)hydrazineylidene)piperidin-2-one (281) A solution of ethyl 2-oxopiperidine-3-carboxylate (6.43 g, 37.6 mmol) in HO (11 mL) was treated with KOH (2.11 g, 37.6 mmol) and stirred at ambient temperature for 16 h. In a separate flask, a solution of 1-benzofuran-6-amine (5 g, 37.6 mmol) in HO (11 mL) and 12 M aqueous HCl (2.74 g, 2 equivalents, 75.1 mmol) was cooled to 0 °C and treated with NaNO (2.59 g, 37.6 mmol) predissolved in HO (11 mL). This mixture was stirred at 0 °C for 30 min, then adjusted to pH 4 with 10% w / v aqueous NaCO and then added to the first solution containing oxopiperidine. The pH of the resulting mixture was adjusted to pH 5 with AcOH and stirred at 0 °C for 16 h. Upon completion, the insoluble material was collected by filtration and washed with HO (30 mL). The solid was dried in vacuo to give crude (£)-3-(2-(benzofuran-6-yl)hydrazinylidene)piperidin-2-one (5 g) as a brown solid, which was used without further purification.

[0307] Step 2: 5,6,7,9-Tetrahydro-8H-furo[3,2-f]pyrido[3,4-b]indol-8-one (282) A solution of crude (£)-3-(2-(benzofuran-6-yl)hydrazinylidene)piperidin-2-one (5.0 g, 20.5 mmol) in EtOH (17.5 mL) was treated with a solution of 3 M HCl in MeOH (17.5 mL) and stirred at 80 °C for 3 h. The pH of the reaction mixture was adjusted to 8 with saturated aqueous NaCO, and the organic solvent was removed under reduced pressure. The residue was diluted with HO (20 mL) and then extracted with CHCl (30 mL × 2). The combined organic layers were washed with brine (5 mL), dried over NaSO, filtered, and the filtrate was concentrated under reduced pressure to give crude 5,6,7,9-tetrahydro-8H-furo[3,2-f]pyrido[3,4-b]indol-8-one (4.00 g) as a brown solid, which was used in the subsequent step without further purification.

[0308] Step 3: 5-(2-aminoethyl)-7H-furo[3,2-f]indole-6-carboxylic acid (283) To a solution of crude 5,6,7,9-tetrahydro-8H-furo[3,2-f]pyrido[3,4-b]indol-8-one (4.0 g) in EtOH (14 mL) was added KOH (19.8 g, 353 mmol) and HO (14 mL). The mixture was stirred at 90 °C for 16 h. The solvent was removed, and the residue was diluted with HO (25 mL) and extracted with MTBE (30 mL × 2). The aqueous layer was then filtered, and the filtrate was acidified with AcOH to produce a precipitate, which was collected, washed with HO, and then dried to give crude 5-(2-aminoethyl)-7H-furo[3,2-f]indole-6-carboxylic acid (4.00 g) as a brown solid, which was used in the subsequent step without further purification.

[0309] Step 4: 2-(7H-furo[3,2-f]indol-5-yl)ethan-1-amine (284) A solution of crude 5-(2-aminoethyl)-7H-furo[3,2-f]indole-6-carboxylic acid (4 g) in 12 M aqueous HCl (7 mL) and HO (21 mL) was stirred at 100 °C for 3.5 h. Upon completion, the pH of the reaction mixture was adjusted to 13 with 10% w / v aqueous NaOH and extracted with CHCl (50 mL × 2). The combined organic layers were washed with brine (5 mL × 2), dried over anhydrous NaSO, filtered, and the filtrate was concentrated in vacuo to give crude 2-(7H-furo[3,2-f]indol-5-yl)ethan-1-amine (1 g) as a yellow solid, which was used in the subsequent step without further purification.

[0310] Step 5: 2-(7H-furo[3,2-f]indol-5-yl)-N,N-dimethylethan-1-amine (P-4) A solution of crude 2-(7H-furo[3,2-f]indol-5-yl)ethan-1-amine (1 g) in MeOH (7 mL) was treated sequentially with acetic acid (1.2 g, 20 mmol), NaBHCN (628 mg, 9.99 mmol), and 37% w / w aqueous formaldehyde (1.01 g, 12.5 mmol) at 0 °C. The resulting mixture was stirred at ambient temperature for 2 h. Upon completion, the pH of the reaction mixture was adjusted to 8 with saturated aqueous NaHCO, and the volatile components were removed in vacuo. The residue was diluted with HO (5 mL) and extracted with CHCl (10 mL × 2). The combined organic layers were washed with brine (3 mL × 2), dried over anhydrous NaSO, filtered, and the filtrate was concentrated in vacuo. The residue was purified by preparative HPLC (column: Waters Xbridge Prep OBD C18 150 × 40 mm × 10 μm; mobile phase: [water (NH3 + NH4HCO3)-ACN]; B: 5–45%, 8 min) to give 2-(7H-furo[3,2-f]indol-5-yl)-N,N-dimethylethan-1-amine (4.9 mg, 0.1% over five steps) as an off-white solid. 1 H NMR(400MHz,CD3CN-d3):δ 7.70(d,J=2.0Hz,1H),7.35-7.29(m,2H),7.10(d,J=1.6Hz,1H),6.90(d,J=2.4Hz,1H),3.11-3.07(m,2H),2.69-2.65(m,2H),2.28(s,6H). LCMS(ESI+):m / z 229.0[M+H] + . HPLC purity (220nm): 89.2%.

[0311] Scheme 4: Compounds of general formula (I) can be synthesized from appropriately substituted nitrotoluenes by following the sequence of steps outlined in Scheme 4 or similar to those contemplated by one skilled in the art. A modified version of the Leimgruber-Batcho indole synthesis via conversion of an appropriately substituted nitroarene to a substituted styrene followed by reductive cyclization provided access to indole intermediates (as in Example 17). Glyoxylation of such indoles with oxalyl chloride followed by treatment with an appropriately substituted amine afforded glyoxamide intermediates that, when subjected to reducing conditions, provided compounds of general formula (I) (exemplified by P-6). One skilled in the art will recognize that the use of differentially substituted amines provides access to compounds of general formula (I) disclosed herein. [ka]

[0312] Example 4: 2-(5-Methoxy-4-methyl-1H-indol-3-yl)-N,N-dimethylethan-1-amine (P-6) Step 1: (E)-1-(3-Methoxy-2-methyl-6-nitrostyryl)pyrrolidine (16) To a solution of 1-methoxy-2,3-dimethyl-4-nitrobenzene (30.0 g, 166 mmol) in DMF (300 mL) was added DMF-DMA (39.4 g, 331 mmol) and pyrrolidine (14.1 g, 199 mmol). The reaction mixture was stirred at 130° C. for 12 hours. The mixture was concentrated under reduced pressure to give crude (£)-1-(3-methoxy-2-methyl-6-nitrostyryl)pyrrolidine (39.1 g) as a black oil, which was used in the subsequent step without further purification.

[0313] Step 2: 5-Methoxy-4-methyl-1H-indole (17) To a solution of crude (E)-1-(3-methoxy-2-methyl-6-nitrostyryl)pyrrolidine (39.1 g) in AcOH (390 mL) was added Fe (92.4 g, 1.66 mol) in small portions at 50 °C. The reaction mixture was stirred at 80 °C for 4 h. The mixture was then filtered, and the filter cake was washed with EtOAc (80 mL). 6 N aqueous NaOH was added to the filtrate with stirring until the pH of the aqueous layer reached 6–7. The layers were separated, and the aqueous layer was further extracted with EtOAc (400 mL × 3). The combined organic layers were washed with brine (300 mL), dried over NaSO, filtered, and the filtrate was concentrated. The residue was purified by column chromatography (SiO, 1–5% EtOAc in petroleum ether) to give 5-methoxy-4-methyl-1H-indole (11.9 g, 45%) as a purple solid. 1 H NMR (400MHz, CDCl3): δ 8.03(s,1H),7.21-7.19(m,2H),6.94(d,J=8.8Hz,1H),6.55-6.53(m,1H),3.89(s,3H),2.48(s,3H).

[0314] Step 3: 2-(5-methoxy-4-methyl-1H-indol-3-yl)-2-oxoacetyl chloride (18) A solution of oxalyl chloride (319 μL, 3.72 mmol) in anhydrous EtO (300 μL) was added dropwise under N to an ice-cooled (0 °C) stirred solution of 5-methoxy-4-methyl-1H-indole (0.5 g, 3.1 mmol) in anhydrous EtO (20 mL). The reaction was stirred at 0 °C for 30 min, and the dark red precipitate was collected by filtration. The precipitate was washed with cold EtO (5 mL × 2). After cooling the filtrate, a second crop of the title compound was obtained; the precipitate was filtered and added to the first batch to give 2-(5-methoxy-4-methyl-1H-indol-3-yl)-2-oxoacetyl chloride (620 mg, 79%) as a red solid. 1 H NMR (400MHz, DMSO-d6): δ 12.32(s,1H),8.19(d,J=3.6Hz,1H),7.32(d,J=8.8Hz,1H),7.03(d,J=8.8Hz,1H),3.79(s,3H),2.67(s,3H).13 C NMR (101MHz, DMSO-d6): δ 181.4,167.3,153.4,140.5,133.0,125.6,118.8,113.1,110.3,110.0,56.7,14.5.

[0315] Step 4: 2-(5-methoxy-4-methyl-1H-indol-3-yl)-N,N-dimethyl-2-oxoacetamide (19) To a solution of 2-(5-methoxy-4-methyl-1H-indol-3-yl)-2-oxoacetyl chloride (7.80 g, 27.8 mmol) dissolved in THF (50 mL) was added MeNH (2 M in THF, 35 mL) at 0 °C. The reaction mixture was stirred at 25 °C for 12 h. The mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (SiO, 10–100% EtOAc in petroleum ether) to give 2-(5-methoxy-4-methyl-1H-indol-3-yl)-N,N-dimethyl-2-oxoacetamide (1.50 g, 21%) as a yellow solid. 1 H NMR (400MHz, MeOD-d4): δ 7.93(s,1H),7.27(d,J=8.8Hz,1H),7.03(d,J=8.8Hz,1H),3.85(s,3H),3.08(s,3H),3.04(s,3H),2.76(s,3H).

[0316] Step 5: 2-(5-methoxy-4-methyl-1H-indol-3-yl)-N,N-dimethylethan-1-amine (P-6) To an ice-cooled, stirred solution of 2-(5-methoxy-4-methyl-1H-indol-3-yl)-N,N-dimethyl-2-oxoacetamide (0.50 g, 1.92 mmol) in anhydrous THF (5 mL) was added LiAlH (875 mg, 23.0 mmol) in small portions under N. The reaction mixture was then heated to reflux and stirring was continued for 3 h. The mixture was cooled to 10 °C and quenched by the portionwise addition of NaSO·10H O (3.00 g). The mixture was filtered, the filter cake was washed with THF (20 mL), and the filtrate was concentrated under reduced pressure. The crude product was purified by preparative HPLC (column: Waters Xbridge Prep OBD C18 (150 × 40 mm × 10 μm); mobile phase: [water (NH4HCO3)-ACN]; B: 1–36%, 8 min) to give 2-(5-methoxy-4-methyl-1H-indol-3-yl)-N,N-dimethylethan-1-amine (110 mg, 24%) as an off-white solid. 1 H NMR(400MHz,MeOD-d4):δ 7.10(d,J=8.8Hz,1H),7.00(s,1H),6.84(d,J=8.4Hz,1H),3.80(s,3H),3.11-3.07(m,2H),2.68-2.64(m,2H),2.55(s,3H),2.38(s,6H). LCMS(ESI+):m / z 233.1[M+H] + . HPLC purity (220nm): 97.6%.

[0317] Example 5: N-ethyl-2-(5-methoxy-4-methyl-1H-indol-3-yl)-N-methylethan-1-amine (P-37) [ka] Step 1: N-ethyl-2-(5-methoxy-4-methyl-1H-indol-3-yl)-N-methyl-2-oxoacetamide (75) A suspension of 2-(5-methoxy-4-methyl-1H-indol-3-yl)-2-oxoacetyl chloride (360 mg, 1.43 mmol) in CHCl (10 mL) was treated with ethyl(methyl)amine (0.31 mL, 2.5 equiv., 3.58 mmol) at 0 °C. The reaction was stirred at ambient temperature for 30 min and then concentrated under a stream of N gas. The oily residue was taken up in EtOAc (20 mL) and washed with 0.1 M aqueous HCl (10 mL × 3), H0 (10 mL), and then brine (20 mL). The organic layer was dried over NaSO, filtered, and the filtrate was concentrated in vacuo. The residue was purified by trituration with CH2Cl2 / Et2O to give N-ethyl-2-(5-methoxy-4-methyl-1H-indol-3-yl)-N-methyl-2-oxoacetamide (380 mg, 97%) as a white solid that was a mixture of rotamers (A:B, 2:3). 1 H NMR(400MHz,MeOD-d4):δ 7.92(s,0.6H, rotamer B),7.88(s,0.4H,rotamer A),7.27(d,J=8.8Hz,1H),7.04 (d,J=8.8Hz,1H),3.85(s,3H),3.56(q,J=7.2Hz,0.8H,rotamer A),3.39(q,J= 7.2Hz, 1.2H, rotamer B), 3.06 (s, 1.8H, rotamer B), 3.01 (s, 1.2H, rotamer A), 2.76 (m,3H), 1.26(t,J=7.2Hz,1.2H, rotamer A),1.19(t,J=7.2Hz,1.8H, rotamer B).

[0318] Step 2: N-ethyl-2-(5-methoxy-4-methyl-1H-indol-3-yl)-N-methylethan-1-amine (P-37) To an ice-cooled (0 °C) solution of N-ethyl-2-(5-methoxy-4-methyl-1H-indol-3-yl)-N-methyl-2-oxoacetamide (0.2 g, 0.73 mmol) in anhydrous THF (10 mL) was added LiAlH (221 mg, 8 equiv., 5.83 mmol) in small portions. The resulting ice-cooled suspension was then treated dropwise with a solution of N-ethyl-2-(5-methoxy-4-methyl-1H-indol-3-yl)-N-methyl-2-oxoacetamide (0.2 g, 0.73 mmol) in anhydrous THF (2 mL). The reaction mixture was refluxed under N for 3 h, cooled to 0 °C, and quenched by the successive dropwise addition of HO (0.2 mL), 3.75 M aqueous NaOH (0.2 mL), and HO (0.6 mL). The mixture was dried (NaSO) and filtered through a pad of Celite. The filter cake was washed with additional hot THF (20 mL × 2), and the combined filtrates were concentrated in vacuo to give N-ethyl-2-(5-methoxy-4-methyl-1H-indol-3-yl)-N-methylethan-1-amine (160 mg, 89%) as a pale oil. 1 H NMR(400MHz,CDCl3):δ 8.12(s,1H),7.12(d,J=8.8Hz,1H),6.98(d,J=1.8Hz,1H),6.88(d,J=8.8Hz,1H),3.84(s,3H) ,3.19-3.05(m,2H),2.82-2.70(m,2H),2.67-2.54(m,5H),2.41(s,3H),1.15(t,J=7.2Hz,3H). 13 C NMR (101MHz, CDCl3): δ 151.4,132.7,126.9,123.6,118.3,114.5,110.2,108.9,59.0,58.3,51.5,41.3,24.9,12.0,11.8.

[0319] Step 2a: N-ethyl-2-(5-methoxy-4-methyl-1H-indol-3-yl)-N-methylethan-1-amine fumarate (P-37 fumarate) Fumaric acid (75 mg, 0.65 mmol) was dissolved in a minimum of refluxing acetone and treated with N-ethyl-2-(5-methoxy-4-methyl-1H-indol-3-yl)-N-methylethan-1-amine (160 mg, 0.65 mmol) predissolved in a minimum of hot acetone. The resulting solution was cooled to ambient temperature and allowed to stand overnight at 4°C to afford N-ethyl-2-(5-methoxy-4-methyl-1H-indol-3-yl)-N-methylethan-1-amine as the fumarate salt (127 mg, 60%) as pale yellow crystals. 1 H NMR(400MHz,DMSO-d6):δ 10.63(s,1H),7.18-6.92(m,2H),6.82(d,J=8.8Hz,1H),6.49(s,1H),3.73(s,3H),3.04(dd,J=9.6,6.8Hz ,2H),2.77(dd,J=9.6,6.8Hz,2H),2.67(q,J=7.2Hz,2H),2.47(s,3H),2.41(s,3H),1.08(t,J=7.2Hz,3H). 13 C NMR (101MHz, DMSO-d6): δ 167.6,150.2,134.9,132.4,126.3,124.3,116.3,112.0,109.0,108.9,58.1,57.4,50.4,40.3,23.7,11.6,11.1. LCMS(ESI+):m / z:247.3[M+H] + . qNMR purity (ERETIC): 95.8%.

[0320] Example 6: N-(2-(5-methoxy-4-methyl-1H-indol-3-yl)ethyl)-N-methylpropan-2-amine (P-38) [ka] Step 1: N-isopropyl-2-(5-methoxy-4-methyl-1H-indol-3-yl)-N-methyl-2-oxoacetamide (76) To a solution of 2-(5-methoxy-4-methyl-1H-indol-3-yl)-2-oxoacetyl chloride (780 mg, 3.1 mmol) in THF (8 mL) was added N-methyl(propan-2-yl)amine (2.27 g, 31.0 mmol) in THF (5 mL) at 0 °C. The reaction mixture was warmed to 25 °C and stirring was continued for 12 h. The reaction mixture was then concentrated in vacuo, and the residue was purified by column chromatography (SiO, 10% to 100% EtOAc in petroleum ether) to give N-isopropyl-2-(5-methoxy-4-methyl-1H-indol-3-yl)-N-methyl-2-oxoacetamide (240 mg, 27%) as a yellow solid, which was a mixture of rotamers. 1 H NMR(400MHz,MeOD-d4):δ 7.92-7.85(m,1H),7.28(d,J=8.8Hz,1H),7.04(d,J=8.8Hz,1H),3.86(s,3H),3.49-3.43(m,1H),2.77(s,3H),2.01(s,3H),1.21-1.22(m,6H). LCMS(ESI+):m / z 289.3[M+H] + .

[0321] Step 2: N-(2-(5-methoxy-4-methyl-1H-indol-3-yl)ethyl)-N-methylpropan-2-amine (P-38) To an ice-cooled (0 °C) solution of N-isopropyl-2-(5-methoxy-4-methyl-1H-indol-3-yl)-N-methyl-2-oxoacetamide (240 mg, 0.832 mmol) in THF (2.4 mL) was added LiAlH (379 mg, 9.99 mmol) in small portions under N. The reaction mixture was then warmed to 70 °C and stirring was continued for 3 h. The reaction mixture was then cooled to 10 °C, quenched by the portionwise addition of NaSO·10H O (3 g), and filtered through a pad of Celite. The filter cake was washed with THF (20 mL), and the combined filtrates were concentrated under reduced pressure. The crude residue was purified by preparative HPLC (column: Waters Xbridge BEH C18 100 × 30 mm × 10 μm; mobile phase: [water (NH4HCO3)-ACN]; B: 5–40%, 8 min) to give N-(2-(5-methoxy-4-methyl-1H-indol-3-yl)ethyl)-N-methylpropan-2-amine (28 mg, 13%) as a brown solid. 1 H NMR(400MHz,MeOD-d4):δ 7.11(d,J=8.4Hz,1H),7.01(s,1H),6.84(d,J=8.8Hz,1H),3.81(s,3H),3.11-3.02(m,2H),2 .96(septet, J=6.4Hz, 1H), 2.75-2.66(m, 2H), 2.55(s, 3H), 2.36(s, 3H), 1.09(d, J=6.4Hz, 6H). LCMS(ESI+) m / z 261.3[M+H] + . HPLC purity (220nm): 96.1%.

[0322] Example 7: N-ethyl-N-(2-(5-methoxy-4-methyl-1H-indol-3-yl)ethyl)propan-2-amine (P-40) [ka] Step 1: N-ethyl-N-isopropyl-2-(5-methoxy-4-methyl-1H-indol-3-yl)-2-oxoacetamide (78) To an ice-cold solution of 2-(5-methoxy-4-methyl-1H-indol-3-yl)-2-oxoacetyl chloride (624 mg, 2.48 mmol) in THF (5 mL) was added N-ethylpropan-2-amine (2.16 g, 24.8 mmol) in THF (5 mL). The reaction mixture was warmed to 25 °C and stirring was continued for 12 h, at which point the volatiles were removed in vacuo and the resulting residue was purified by column chromatography (SiO, 10–100% EtOAc in petroleum ether) to afford N-ethyl-N-isopropyl-2-(5-methoxy-4-methyl-1H-indol-3-yl)-2-oxoacetamide (541 mg) as a yellow solid, which was used in the subsequent step without further purification.

[0323] Step 2: N-ethyl-N-(2-(5-methoxy-4-methyl-1H-indol-3-yl)ethyl)propan-2-amine (P-40) To an ice-cooled, stirred solution of crude N-ethyl-N-isopropyl-2-(5-methoxy-4-methyl-1H-indol-3-yl)-2-oxoacetamide (541 mg) in THF (7 mL) was added LiAlH (813 mg, 21.4 mmol) in portions under N. The reaction mixture was then heated to 70 °C and stirring was continued for 3 h. The reaction was then cooled to 10 °C and quenched by the portionwise addition of NaSO·10H O (3 g) and then filtered through a pad of Celite. The filter cake was washed with THF (20 mL), and the combined filtrates were concentrated under reduced pressure. The crude residue was purified by preparative HPLC (column: Waters Xbridge OBD C18 150 × 40 mm × 10 μm; mobile phase: [water (NH4HCO3)-ACN]; B: 15–45%, 8 min) to give N-ethyl-N-(2-(5-methoxy-4-methyl-1H-indol-3-yl)ethyl)propan-2-amine (67 mg, 10% over two steps) as an off-white solid. 1H NMR(400MHz,MeOD-d4):δ 7.15(d,J=8.8Hz,1H),7.07(s,1H),6.88(d,J=8.8Hz,1H),3.84(s,3H),3.33-3.24(m,1H),3. 18-3.10(m,2H),2.93-2.79(m,4H),2.56(s,3H),1.19(t,J=7.2Hz,3H),1.14(d,J=6.8Hz,6H). LCMS:m / z:275.1[M+H] + . HPLC purity (220nm): 99.5%.

[0324] Scheme 5: Compounds of general formula (I) can be synthesized from appropriately substituted nitrotoluenes similarly as outlined in Scheme 5. A modified version of the Leimgruber-Batcho indole synthesis via conversion to an appropriately substituted styrene provided access to indole intermediates. Glyoxylation of such indoles with oxalyl chloride, followed by treatment with an appropriately substituted amine, afforded glyoxamide intermediates that, when subjected to reducing conditions, provided access to compounds of general formula (I) (exemplified by P-7). 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]

[0325] Example 10: 2-(5-Methoxy-6-methyl-1H-indol-3-yl)-N,N-dimethylethan-1-amine (P-7) [ka] Step 1: 1-Methoxy-2,5-dimethyl-4-nitrobenzene (21) 2-Methoxy-1,4-dimethylbenzene (10.5 g, 76.7 mmol) was added dropwise to HNO (70 mL) at 0–5 °C, followed by the dropwise addition of NaNO (15.9 g, 230 mmol) in small portions at −5–2 °C. The resulting mixture was stirred at 0–5 °C for 5 h. The mixture was quenched by pouring into iced H2O (100 mL), and the pH was adjusted to 7–8 with 6 N aqueous NaOH. The aqueous phase was extracted with EtOAc (60 mL × 3). The organic layer was washed with brine (60 mL), dried over Na2SO4, filtered, and the filtrate was concentrated. The residue was purified by column chromatography (SiO2, 1–5% v / v EtOAc in petroleum ether) to give 1-methoxy-2,5-dimethyl-4-nitrobenzene (6.5 g, 47%) as an off-white solid. 1 H NMR (400MHz, CDCl3): δ 7.93 (s, 1H), 6.66 (s, 1H), 3.91 (s, 3H), 2.64 (s, 3H), 2.22 (s, 3H).

[0326] Step 2: (E)-1-(5-methoxy-4-methyl-2-nitrostyryl)pyrrolidine (22) To a solution of 1-methoxy-2,5-dimethyl-4-nitrobenzene (7.40 g, 40.8 mmol) in DMF (50 mL) was added DMF-DMA (7.30 g, 61.3 mmol) and pyrrolidine (3.49 g, 49.0 mmol). The reaction mixture was stirred at 130° C. for 12 hours. The reaction mixture was concentrated under reduced pressure to give crude (£)-1-(5-methoxy-4-methyl-2-nitrostyryl)pyrrolidine (9.60 g, crude) as a black solid, which was used in the subsequent step without further purification.

[0327] Step 3: 5-Methoxy-6-methyl-1H-indole (23) To a solution of crude (E)-1-(5-methoxy-4-methyl-2-nitrostyryl)pyrrolidine (9.60 g) in AcOH (65 mL) was added Fe (22.7 g, 406 mmol) in small portions at 50 °C. The reaction mixture was stirred at 80 °C for 4 h. The mixture was filtered, and the filter cake was washed with EtOAc (20 mL). The combined filtrate was diluted with 6 N aqueous NaOH until the pH was between 6 and 7. The layers were separated, and the aqueous phase was further extracted with EtOAc (100 mL × 3). The combined organic layers were washed with brine (100 mL), dried over NaSO, filtered, and the filtrate was concentrated. The residue was purified by column chromatography (SiO, 1–1.25% v / v EtOAc in petroleum ether) to give 5-methoxy-6-methyl-1H-indole (1.66 g, 25%) as an off-white solid. 1 H NMR (400MHz, CDCl3): δ 7.94(s,1H),7.17(s,1H),7.12(t,J=2.8Hz,1H),7.05(t,J=2.0Hz,1H),7.05(s,1H),3.88(s,3H),2.34(s,3H).

[0328] Step 4: 2-(5-methoxy-6-methyl-1H-indol-3-yl)-N,N-dimethyl-2-oxoacetamide (24) To a solution of 5-methoxy-6-methyl-1H-indole (2.43 g, 15.1 mmol) in THF (17 mL) was added (COCl) (2.87 g, 22.6 mmol) dropwise at 0 °C under N. The reaction mixture was stirred at 0 °C for 2 h, and then a solution of MeNH (2 M in THF, 26 mL) was added dropwise. The reaction mixture was then stirred at 25 °C for 12 h. The mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (SiO, 1 to 100% v / v EtOAc in petroleum ether) to give 2-(5-methoxy-6-methyl-1H-indol-3-yl)-N,N-dimethyl-2-oxoacetamide (2.30 g, 59%) as an off-white solid. 1H NMR (400MHz, MeOD-d4): δ 7.85 (s, 1H), 7.66 (s, 1H), 7.25 (s, 1H), 3.90 (s, 3H), 3.10 (s, 3H), 3.04 (s, 3H), 2.29 (s, 3H).

[0329] Step 5: 2-(5-methoxy-6-methyl-1H-indol-3-yl)-N,N-dimethylethan-1-amine (P-7) To a solution of 2-(5-methoxy-6-methyl-1H-indol-3-yl)-N,N-dimethyl-2-oxoacetamide (0.50 g, 1.92 mmol) in anhydrous THF (5 mL) was added LiAlH (875 mg, 23.1 mmol) in small portions under N. The mixture was stirred at 70 °C for 3 h, cooled to 0 °C, and quenched with NaSO 10H O (3 g). The mixture was filtered, and the filter cake was washed with THF (20 mL). The combined filtrate was concentrated, and the residue was purified by preparative HPLC (Column: Waters Xbridge BEH C18 (100 × 30 mm × 10 μm; Mobile phase: [water (NH4HCO3)-ACN]; B: 20–40%, 8 min) to give 2-(5-methoxy-6-methyl-1H-indol-3-yl)-N,N-dimethylethan-1-amine (101 mg, 23%) as an off-white solid. 1 H NMR: (400MHz, MeOD-d4): δ 7.08(s,1H),6.96(s,1H),6.93(s,1H),3.85(s,3H),2.93-2.89(m,2H),2.70-2.67(m,2H),2.38(s,6H),2.26(s,3H). LCMS(ESI+):m / z 233.2[M+H] + . HPLC purity (220nm): 97.1%.

[0330] Example 11: N-ethyl-2-(5-methoxy-6-methyl-1H-indol-3-yl)-N-methylethan-1-amine (P-42) [ka] Step 1: 2-(5-methoxy-6-methyl-1H-indol-3-yl)-2-oxoacetyl chloride (25) To an ice-cold solution of 5-methoxy-6-methyl-1H-indole (2 g, 12.4 mmol) in anhydrous Et2O (15 mL) was added dropwise a solution of (COCl2)2 (1.38 mL, 16.1 mmol) in anhydrous Et2O (10 mL). Stirring was continued for 2 h, at which point the precipitate was collected by filtration and washed with anhydrous Et2O (15 mL) to give 2-(5-methoxy-6-methyl-1H-indol-3-yl)-2-oxoacetyl chloride (2.6 g, 83%) as a red solid. 1 H NMR (400MHz, DMSO-d6): δ 12.19 (br.s, 1H), 8.24 (d, J = 3.2Hz, 1H), 7.63 (s, 1H), 7.38-7.24 (m, 1H), 3.83 (s, 3H), 2.25 (s, 3H). 13 C NMR (101MHz, DMSO-d6): δ 180.6,165.4,154.5,136.7,131.0,124.4,123.3,113.8,112.3,101.1,55.3,16.8.

[0331] Step 2: N-ethyl-2-(5-methoxy-6-methyl-1H-indol-3-yl)-N-methyl-2-oxoacetamide (80) To an ice-cold suspension of 2-(5-methoxy-6-methyl-1H-indol-3-yl)-2-oxoacetyl chloride (250 mg, 0.99 mmol) in CHCl (10 mL) was added ethyl(methyl)amine (0.26 mL, 2.98 mmol). Stirring was continued at ambient temperature for 3 h, at which point HCl (0.1 M, 10 mL) was added. The aqueous phase was separated and extracted with CHCl (10 mL), and the combined organic layers were washed successively with HO (20 mL) and brine (20 mL), then dried over MgSO, filtered, and the filtrate was concentrated in vacuo. The residue was triturated with CHCl / EtO (10 mL, v / v, 1 / 5), and the white precipitate was filtered to give N-ethyl-2-(5-methoxy-6-methyl-1H-indol-3-yl)-N-methyl-2-oxoacetamide (248 mg, 91%) as a mixture of rotamers (A:B, ca. 1:2). 1 H NMR(400MHz,CDCl3):δ 10.44(m,1H),7.71(s,1H),7.50-7.43(m,1H),6.98(s,1H),3.91(s,3H),3.54(q,J=7.2Hz,0.75H , rotamer A), 3.36 (q, J=7.2Hz, 1.25H, rotamer B), 3.03-2.99 (m, 3H), 2.21 (s, 3H), 1.24-1.16 (m, 3H).

[0332] Step 3: N-ethyl-2-(5-methoxy-6-methyl-1H-indol-3-yl)-N-methylethan-1-amine (P-42) To an ice-cold solution of N-ethyl-2-(5-methoxy-6-methyl-1H-indol-3-yl)-N-methyl-2-oxoacetamide (250 mg, 0.91 mmol) in anhydrous THF (15 mL) was added LiAlH (173 mg, 4.56 mmol) in small portions. The resulting suspension was then heated at reflux for 1 h. The suspension was cooled in an ice bath and quenched by the subsequent addition of HO (180 μL), 30% NaOH (w / v) (180 μL), and HO (300 μL). The suspension was stirred at 0° C. for another 1 h, NaSO was added, and the reaction mass was filtered through a pad of Celite. The filtrate was concentrated under a stream of N2 gas to give crude N-ethyl-2-(5-methoxy-6-methyl-1H-indol-3-yl)-N-methylethan-1-amine (0.2 g) as a colorless oil, which was used in the subsequent step without further purification.

[0333] Step 4a: N-ethyl-2-(5-methoxy-6-methyl-1H-indol-3-yl)-N-methylethan-1-amine (P-42 fumarate) A solution of N-ethyl-2-(5-methoxy-6-methyl-1H-indol-3-yl)-N-methylethan-1-amine (159 mg, 0.65 mmol) in hot acetone (2 mL) was added dropwise to a saturated solution of fumaric acid (74.9 mg, 0.65 mmol) in acetone at reflux. The colorless solution was cooled to ambient temperature and allowed to stand at this temperature for 16 hours. The resulting colorless needles were collected by vacuum filtration and dried in a vacuum oven to give N-ethyl-2-(5-methoxy-6-methyl-1H-indol-3-yl)-N-methylethan-1-amine as the fumarate salt (80 mg, 36% over two steps) as colorless crystals. 1 H NMR(400MHz,MeOD-d4):δ 7.14(s,1H),7.09(s,1H),7.03(s,1H),6.74(s,3H),3.89(s,3H),3.43(t,J =7.6Hz,2H),3.23(m,4H),2.91(s,3H),2.28(s,3H),1.34(t,J=7.2Hz,3H). LCMS(ESI+):m / z 247.1[M+H] +. qNMR purity (ERETIC): 99.9%.

[0334] Step 4b: N-ethyl-2-(5-methoxy-6-methyl-1H-indol-3-yl)-N-methylethan-1-amine (P-42 oxalate) A solution of N-ethyl-2-(5-methoxy-6-methyl-1H-indol-3-yl)-N-methylethan-1-amine (246 mg, 1.0 mmol) in hot acetone (2 mL) was added dropwise to a solution of oxalic acid (100 mg, 1.1 mmol) dissolved in minimal acetone at reflux. The colorless solution was cooled to ambient temperature and allowed to stand at this temperature for 16 hours. The resulting colorless needles were collected by vacuum filtration and dried in a vacuum oven to give N-ethyl-2-(5-methoxy-6-methyl-1H-indol-3-yl)-N-methylethan-1-amine oxalate (201 mg, 67%) as off-white crystals. 1 H NMR(400MHz,DMSO-d6):δ 10.66(s,1H),7.11(s,1H),7.09(d,J=2.4Hz,1H),7.03(s,1H),3.81(s,3H),3.30-3.22(m,2H ),3.16(q,J=7.2Hz,2H),3.09-3.00(m,2H),2.80(s,3H),2.22(s,3H),1.23(t,J=7.2Hz,3H). 13 C NMR (101MHz, DMSO-d6): δ 164.6,151.8,130.9,125.1,122.4,120.8,112.7,108.9,98.5,55.4,54.6,49.9,38.5,20.0,16.9,8.9. LCMS(ESI+):m / z 247.1[M+H] + . qNMR purity (ERETIC): 96.9%.

[0335] Example 12: N-(2-(5-methoxy-6-methyl-1H-indol-3-yl)ethyl)-N-methylpropan-1-amine (P-43) [ka] Step 1: 2-(5-methoxy-6-methyl-1H-indol-3-yl)-N-methyl-2-oxo-N-propylacetamide (81) Methyl(propyl)amine (0.31 mL, 2.98 mmol) was added dropwise to an ice-cold suspension of 2-(5-methoxy-6-methyl-1H-indol-3-yl)-2-oxoacetyl chloride (250 mg, 0.99 mmol) in CHCl (10 mL). Stirring was continued for 3 h, at which point aqueous HCl (0.1 M, 10 mL) was added. The aqueous phase was separated and extracted with CHCl (10 mL), and the combined organics were washed successively with HO (20 mL) and brine (20 mL), then dried over MgSO, filtered, and the filtrate was concentrated in vacuo to yield a yellow oil, which was purified by flash column chromatography (SiO, 0.5–1% v / v MeOH (10% aqueous NH)—CHCl) to give 2-(5-methoxy-6-methyl-1H-indol-3-yl)-N-methyl-2-oxo-N-propylacetamide (273 mg, 95%) as a mixture of rotamers (A:B). 1 H NMR(400MHz,CDCl3):δ 9.73(s,0.5H, rotamer A),9.68(s,0.5H,rotamer B),7.73(d,J=2.4Hz,1H),7.62(d,J=3 .2Hz,0.5H, rotamer B),7.56(d,J=3.2Hz,0.5H,rotamer A),7.09(s,1H),3.93(s,3H),3 .57-3.44(m,1H, rotamer A),3.34-3.26(m,1H, rotamer B),3.04(m,3H),2.27(s,3H),1. 77-1.56(m,2H), 1.01(t,J=7.2Hz,1.5H, rotamer A),0.82(t,J=7.2Hz,1.5H, rotamer B).

[0336] Step 2: N-(2-(5-methoxy-6-methyl-1H-indol-3-yl)ethyl)-N-methylpropan-1-amine (P-43) To an ice-cooled stirred solution of 2-(5-methoxy-6-methyl-1H-indol-3-yl)-N-methyl-2-oxo-N-propylacetamide (250 mg, 0.87 mmol) in anhydrous THF (15 mL) was added LiAlH (165 mg, 4.34 mmol) in small portions. The resulting suspension was then heated at reflux for 1 h. The suspension was cooled in an ice bath and quenched by the subsequent addition of HO (180 μL), 30% NaOH (w / v) (180 μL), and HO (300 μL). The suspension was stirred at 0° C. for an additional 1 h, then NaSO was added, and the reaction mass was filtered through a pad of Celite. The filter cake was washed with THF (20 mL × 2), and the combined filtrates were concentrated under a stream of N gas to give N-(2-(5-methoxy-6-methyl-1H-indol-3-yl)ethyl)-N-methylpropan-1-amine (180 mg, 80%) as a colorless oil.

[0337] Example 13: N-(2-(5-methoxy-6-methyl-1H-indol-3-yl)ethyl)-N-methylpropan-2-amine (P-44) [ka] Step 1: N-isopropyl-2-(5-methoxy-6-methyl-1H-indol-3-yl)-N-methyl-2-oxoacetamide (82) Methyl(propan-2-yl)amine (0.42 mL, 3.97 mmol) was added dropwise to an ice-cooled suspension of 2-(5-methoxy-6-methyl-1H-indol-3-yl)-2-oxoacetyl chloride (250 mg, 0.99 mmol) in CHCl (10 mL). Stirring was continued for 3 h, at which point aqueous HCl (0.1 M, 10 mL) was added. The aqueous phase was separated and extracted with CHCl (10 mL). The combined organic layers were washed successively with HO (20 mL) and brine (20 mL), then dried over MgSO, filtered, and the filtrate was concentrated in vacuo to yield a yellow oil. The oil was triturated with CHCl / EtO (10 mL of a 1 / 5 (v / v) solution) and the white precipitate was filtered to give N-isopropyl-2-(5-methoxy-6-methyl-1H-indol-3-yl)-N-methyl-2-oxoacetamide (258 mg, 90%) as a white powder that was a mixture of rotamers (A:B). 1 H NMR(400MHz,CDCl3):δ 9.65(s,0.7H, rotamer B),9.49(s,0.3H,rotamer A),7.73(s,1H),7.65(d,J=3.2Hz,0.3H,rotamer A),7.55(d,J=3.2Hz,0.7H,rotamer B),7.10(s,1H),4.9 3(p,J=6.8Hz,0.3H,rotamer A),4.08(h,J=6.8Hz,0.7H,rotamer B),3.93(s,3 H), 2.94 (s, 2H, rotamer B), 2.89 (s, 1H, rotamer A), 2.28 (s, 3H), 1.22 (m, 6H).

[0338] Step 2: N-(2-(5-methoxy-6-methyl-1H-indol-3-yl)ethyl)-N-methylpropan-2-amine (P-44) To an ice-cooled stirred solution of N-isopropyl-2-(5-methoxy-6-methyl-1H-indol-3-yl)-N-methyl-2-oxoacetamide (250 mg, 0.87 mmol) in anhydrous THF (15 mL) was added LiAlH (165 mg, 4.34 mmol) in small portions. The resulting suspension was then heated at reflux for 1 h. The suspension was cooled in an ice bath and quenched by the subsequent addition of HO (180 μL), 30% NaOH (w / v) (180 μL), and HO (300 μL). The suspension was stirred at 0° C. for an additional 1 h, then dried (NaSO), and the reaction mass was filtered through a pad of Celite. The residue was washed with THF (2 × 20 mL), and the combined filtrates were concentrated under a stream of N gas to give N-(2-(5-methoxy-6-methyl-1H-indol-3-yl)ethyl)-N-methylpropan-2-amine (180 mg, 79%) as a colorless oil, which was used in the subsequent step without further purification.

[0339] Step 2a: N-(2-(5-methoxy-6-methyl-1H-indol-3-yl)ethyl)-N-methylpropan-2-amine fumarate (P-44 fumarate) A solution of N-(2-(5-methoxy-6-methyl-1H-indol-3-yl)ethyl)-N-methylpropan-2-amine (168 mg, 0.65 mmol) in hot acetone (2 mL) was added dropwise to a saturated solution of fumaric acid (75 mg, 0.65 mmol) in acetone at reflux. The colorless solution was cooled to ambient temperature and allowed to stand at this temperature for 16 hours. The resulting colorless needles were collected by vacuum filtration and dried in a vacuum oven to give N-(2-(5-methoxy-6-methyl-1H-indol-3-yl)ethyl)-N-methylpropan-2-amine as the fumarate salt (127 mg, 53%) as colorless crystals. 1H NMR(400MHz,MeOD-d4):δ 7.14(s,1H),7.10(s,1H),7.03(s,1H),6.73(s,2H),3.88(s,3H),3.67(p,J=6.8Hz,1H),3.3 7(dd,J=9.6,6.0Hz,2H),3.23-3.15(m,2H),2.83(s,3H),2.28(s,3H),1.32(d,J=6.8Hz,6H). 13 C NMR (101MHz, MeOD-d4): δ 170.1,152.6,134.9,131.7,125.1,122.2,122.1,112.5,108.2,97.8,56.9,54.9,52.8,34.6,20.6,15.8,15.1. LCMS(ESI+):m / z 261.1[M+H] + . qNMR purity (ERETIC): 99.7%.

[0340] Example 14: N,N-diethyl-2-(5-methoxy-6-methyl-1H-indol-3-yl)ethan-1-amine (P-45) [ka] Step 1: N,N-Diethyl-2-(5-methoxy-6-methyl-1H-indol-3-yl)-2-oxoacetamide (83) A suspension of 2-(5-methoxy-6-methyl-1H-indol-3-yl)-2-oxoacetyl chloride (250 mg, 0.99 mmol) in anhydrous CHCl (10 mL) was added dropwise to an ice-cooled, stirred suspension of diethylamine (109 mg, 1.49 mmol) in CHCl (10 mL), followed by the dropwise addition of triethylamine (0.46 mL, 3.28 mmol). Stirring was continued for 3 h, at which point the reaction was diluted with HO (20 mL) and the organic layer was separated. The organic layer was washed with HO (2 × 25 mL) followed by brine (50 mL), then dried over MgSO, filtered, and the filtrate was concentrated under reduced pressure. The residue was triturated with CH2Cl2 / Et2O and then filtered to give N,N-diethyl-2-(5-methoxy-6-methyl-1H-indol-3-yl)-2-oxoacetamide (255 mg, 89%).1 H NMR(400MHz,MeOD-d4):δ 7.83(s,1H),7.67(s,1H),7.27(d,J=1.2Hz,1H),3.92(s,3H),3.57(q,J=7.2Hz,2H ),3.40(q,J=7.2Hz,2H),2.31(s,3H),1.30(t,J=7.2Hz,4H),1.20(t,J=7.2Hz,3H). 13 C NMR (101MHz, MeOD-d4): δ 186.6,168.5,155.3,135.3,131.7,124.5,124.0,113.5,113.1,100.9,54.6,42.5,38.8,15.8,13.0,11.6.

[0341] Step 2: N,N-Diethyl-2-(5-methoxy-6-methyl-1H-indol-3-yl)ethan-1-amine (P-45) To an ice-cooled stirred solution of N,N-diethyl-2-(5-methoxy-6-methyl-1H-indol-3-yl)-2-oxoacetamide (250 mg, 0.87 mmol) in anhydrous THF (15 mL) was added LiAlH (165 mg, 4.34 mmol) in small portions. The resulting suspension was then heated at reflux for 1 h. The suspension was cooled in an ice bath and quenched by the subsequent addition of HO (180 μL), 30% NaOH (w / v) (180 μL), and HO (300 μL). The suspension was stirred for another 1 h at 0 °C, then NaSO was added, and the reaction mass was filtered through a pad of Celite, and the residue was washed with THF (2 × 20 mL). The combined filtrates were concentrated under a stream of N gas to give N,N-diethyl-2-(5-methoxy-6-methyl-1H-indol-3-yl)ethan-1-amine (148 mg) as a colorless oil, which was used in the subsequent step without further purification.

[0342] Step 2a: N,N-Diethyl-2-(5-methoxy-6-methyl-1H-indol-3-yl)ethan-1-amine (P-45 fumarate) A solution of N,N-diethyl-2-(5-methoxy-6-methyl-1H-indol-3-yl)ethan-1-amine (140 mg, 0.54 mmol) in hot acetone (2 mL) was added dropwise to a saturated solution of fumaric acid (63 mg, 0.54 mmol) in acetone at reflux. The colorless solution was cooled to ambient temperature and allowed to stand at this temperature for 16 hours. The resulting colorless needles were collected by vacuum filtration and dried in a vacuum oven to give N,N-diethyl-2-(5-methoxy-6-methyl-1H-indol-3-yl)ethan-1-amine as the fumarate salt (120 mg, 53% over two steps) as colorless crystals. 1 H NMR(400MHz,MeOD-d4):δ 7.14(d,J=1.2Hz,1H),7.10(s,1H),7.01(s,1H),6.74(s,2H),3.88(s,3H),3. 46-3.37(m,2H),3.28(m,4H),3.17(m,2H),2.28(s,3H),1.33(t,J=7.2Hz,6H). 13 C NMR (101MHz, MeOD-d4): δ 168.9,152.6,134.5,131.7,125.0,122.25,122.24,112.6,108.2,97.7,54.8,51.7,46.9,20.0,15.8,7.7. LCMS(ESI+):m / z 261.1[M+H] + . qNMR purity (ERETIC): 100%.

[0343] Example 15: N-ethyl-N-(2-(5-methoxy-6-methyl-1H-indol-3-yl)ethyl)propan-1-amine (P-46) [ka] Step 1: N-ethyl-2-(5-methoxy-6-methyl-1H-indol-3-yl)-2-oxo-N-propylacetamide (84) Ethyl(propyl)amine (0.46 mL, 3.97 mmol) was added dropwise to an ice-cooled suspension of 2-(5-methoxy-6-methyl-1H-indol-3-yl)-2-oxoacetyl chloride (250 mg, 0.99 mmol) in CHCl (10 mL). Stirring was continued for 3 h, at which point 0.1 M aqueous HCl (10 mL) was added. The aqueous phase was separated and extracted with CHCl (10 mL), and the combined organic layers were washed successively with HO (20 mL) and brine (20 mL), then dried over MgSO, filtered, and the filtrate was concentrated in vacuo to yield a yellow oil. The oil was triturated with CHCl / EtO (10 mL of a 1 / 5 (v / v) solution) and the white precipitate was collected by filtration to give N-ethyl-2-(5-methoxy-6-methyl-1H-indol-3-yl)-2-oxo-N-propylacetamide (278 mg, 93%) as a white powder as a mixture of rotamers (A:B). 1 H NMR(400MHz,CDCl3):δ 10.02(s,1H),7.72(s,1H),7.51(m,1H),7.05(s,1H),3.93(s,3H),3.55-3.52(m,1H),3.49-3.32(m,2H),3.31-3.22(m,1 H),2.25(s,3H),1.78-1.55(m,2H),1.28-1.16(m,3H),1.01(t,J=7.4Hz,1.6H, rotamer B),0.81(t,J=7.4Hz,1.4H, rotamer A).

[0344] Step 2: N-ethyl-N-(2-(5-methoxy-6-methyl-1H-indol-3-yl)ethyl)propan-1-amine (P-46) To an ice-cooled stirred solution of N-ethyl-2-(5-methoxy-6-methyl-1H-indol-3-yl)-2-oxo-N-propylacetamide (262 mg, 0.87 mmol) in anhydrous THF (15 mL) was added LiAlH (165 mg, 0.87 mmol) in small portions. The resulting suspension was then heated at reflux for 1 h. The suspension was cooled in an ice bath and quenched by the sequential addition of HO (180 μL), 30% NaOH (w / v) (180 μL), and HO (300 μL). The suspension was stirred at 0° C. for an additional 1 h, then NaSO was added and the reaction mass was filtered through a pad of Celite. The residue was washed with THF (2 × 10 mL), and the combined filtrates were concentrated under a stream of N gas to give N-ethyl-N-(2-(5-methoxy-6-methyl-1H-indol-3-yl)ethyl)propan-1-amine (185 mg, 78%) as a colorless oil, which was used in the subsequent step without further purification.

[0345] Step 2a: N-ethyl-N-(2-(5-methoxy-6-methyl-1H-indol-3-yl)ethyl)propan-1-amine fumarate (P-46 fumarate) A solution of N-ethyl-N-(2-(5-methoxy-6-methyl-1H-indol-3-yl)ethyl)propan-1-amine (177 mg, 0.65 mmol) in hot acetone (2 mL) was added dropwise to a saturated solution of fumaric acid (75 mg, 0.65 mmol) in acetone at reflux. The colorless solution was cooled to ambient temperature and allowed to stand at this temperature for 16 hours. The resulting colorless needles were collected by vacuum filtration and dried in a vacuum oven to give N-ethyl-N-(2-(5-methoxy-6-methyl-1H-indol-3-yl)ethyl)propan-1-amine as the fumarate salt (163 mg, 64%) as colorless crystals. 1H NMR(400MHz,MeOD-d4):δ 7.13(s,1H),7.07(s,1H),7.01(s,1H),6.73(s,1H),3.87(s,3H),3.38-3.30(m,2H),3.24(q,J=7.2Hz ,2H),3.18-3.04(m,4H),2.28(s,3H),1.80-1.66(m,2H),1.31(t,J=7.2Hz,3H),0.99(t,J=7.2Hz,3H). 13 C NMR(101MHz,MeOD-d4):δ 173.1,152.6,135.9,131.6,125.1,122.1,122.0,112.5,108.7,97.7,54.9,53.5,52.1,47.3,20.0,17.0,15.9,9.9,7.7. LCMS(ESI+):m / z 275.2[M+H] + . qNMR purity (ERETIC): 98.7%.

[0346] Example 16: N-ethyl-N-(2-(5-methoxy-6-methyl-1H-indol-3-yl)ethyl)propan-2-amine (P-47) [ka] Step 1: N-ethyl-N-isopropyl-2-(5-methoxy-6-methyl-1H-indol-3-yl)-2-oxoacetamide (85) Ethyl(isopropyl)amine (463 μL, 3.97 mmol) was added dropwise to an ice-cooled suspension of 2-(5-methoxy-6-methyl-1H-indol-3-yl)-2-oxoacetyl chloride (250 mg, 0.99 mmol) in CHCl (10 mL). Stirring was continued for 3 h, at which point aqueous HCl (0.1 M, 10 mL) was added. The aqueous phase was separated and extracted with CHCl (10 mL), and the combined organics were washed successively with HO (20 mL) and brine (20 mL), then dried over anhydrous MgSO, filtered, and concentrated in vacuo. The oil was triturated with CHCl / EtO (10 mL of a 1 / 5 (v / v) solution) and the white precipitate was filtered to give N-ethyl-2-(5-methoxy-6-methyl-1H-indol-3-yl)-2-oxo-N-(propan-2-yl)acetamide (280 mg, 93%) as a white powder that was a mixture of rotamers (A:B). 1 H NMR(400MHz,CDCl3):δ 9.69(s,0.7H, rotamer B),9.54(s,0.3H,rotamer A),7.73(s,1H),7.62(d,J=3.2Hz,0.3H,rotamer A),7.55(d,J=3.2Hz,0.7H,rotamer B),7.1 2(m,1H), 4.62(p,J=6.8Hz,0.3H, rotamer A), 4.11-4.00(m,0.7H, rotamer B), 3.93(s,3H),3.39(m,2H),2.29(s,3H),1.39-1.16(m,9H).

[0347] Step 2: N-ethyl-N-(2-(5-methoxy-6-methyl-1H-indol-3-yl)ethyl)propan-2-amine (P-47) To an ice-cooled stirred solution of N-ethyl-N-isopropyl-2-(5-methoxy-6-methyl-1H-indol-3-yl)-2-oxoacetamide (262 mg, 0.87 mmol) in anhydrous THF (15 mL) was added LiAlH (165 mg, 4.34 mmol) in small portions. The resulting suspension was then heated at reflux for 1 h. The suspension was cooled in an ice bath and quenched by the subsequent addition of HO (180 μL), 30% NaOH (w / v) (180 μL), and HO (300 μL). The suspension was stirred at 0°C for another 1 h, then NaSO was added, the reaction mass was filtered through a pad of Celite, the filter cake was washed with THF (15 mL x 2), and the combined filtrate was concentrated under a stream of N gas to give N-ethyl-N-(2-(5-methoxy-6-methyl-1H-indol-3-yl)ethyl)propan-2-amine (220 mg, 92%) as a colorless oil, which was used in the subsequent step without further purification.

[0348] Step 2a: N-Ethyl-N-(2-(5-methoxy-6-methyl-1H-indol-3-yl)ethyl)propan-2-amine fumarate (P-47 fumarate) A solution of N-ethyl-N-(2-(5-methoxy-6-methyl-1H-indol-3-yl)ethyl)propan-2-amine (177 mg, 0.65 mmol) in hot acetone (2 mL) was added dropwise to a saturated solution of fumaric acid (75 mg, 0.65 mmol) in acetone at reflux. The colorless solution was cooled to ambient temperature and allowed to stand at this temperature for 16 hours. The resulting colorless needles were collected by vacuum filtration and dried in a vacuum oven to give N-ethyl-N-(2-(5-methoxy-6-methyl-1H-indol-3-yl)ethyl)propan-2-amine as the fumarate salt (220 mg, 87%) as colorless crystals. 1H NMR(400MHz,MeOD-d4):δ 7.15(s,1H),7.11(s,1H),7.01(s,1H),6.72(s,2H),3.88(s,3H),3.80(septet,J=6.8Hz,1H),3 .42-3.37(m,2H),3.29(q,J=7.2Hz,2H),3.24-3.16(m,2H),2.28(s,3H),1.42-1.33(m,9H). 13 C NMR(101MHz,MeOD-d4):δ 171.4,154.0,136.3,133.1,126.4,123.63,123.56,114.0,109.7,99.0,56.2,56.0,51.1,46.7,22.5,17.2,16.8,10.6. LCMS(ESI+):m / z 275.2[M+H] + . qNMR purity (ERETIC): 99.6%.

[0349] Example 17: N,N-dipropyl-2-(5-methoxy-6-methyl-1H-indol-3-yl)ethan-1-amine (P-48) [ka] Step 1: N,N-Dipropyl-2-(5-methoxy-6-methyl-1H-indol-3-yl)-2-oxoacetamide (86) A suspension of 2-(5-methoxy-6-methyl-1H-indol-3-yl)-2-oxoacetyl chloride (250 mg, 0.99 mmol) in anhydrous CHCl (10 mL) was added dropwise to an ice-cooled, stirred suspension of dipropylamine (151 mg, 1.49 mmol) in CHCl (10 mL), followed by the dropwise addition of NEt (457 μL, 3.28 mmol). Stirring was continued for 3 h, at which point the reaction was diluted with HO (20 mL) and the organic layer was separated. The organic layer was washed with HO (2 × 25 mL) followed by brine (50 mL), then dried over MgSO, filtered, and the filtrate was concentrated under reduced pressure. The residue was triturated with CH2Cl2 / Et2O and filtered to give N,N-dipropyl-2-(5-methoxy-6-methyl-1H-indol-3-yl)-2-oxoacetamide (280 mg, 89%) as a white powder. 1 H NMR(400MHz,MeOD-d4):δ 7.81(s,1H),7.67(s,1H),7.27(d,J=1.2Hz,1H),3.92(s,3H),3.52-3.44(m,2H),3.33-3 .26(m,2H),2.31(s,3H),1.82-1.58(m,4H),1.03(t,J=7.6Hz,3H),0.82(t,J=7.6Hz,3H). 13 C NMR (101MHz, MeOD-d4): δ 186.5,169.0,155.3,135.3,131.6,124.5,124.0,113.6,113.1,100.9,54.6,49.6,45.9,21.5,20.2,15.8,10.3,9.9.

[0350] Step 2: N,N-dipropyl-2-(5-methoxy-6-methyl-1H-indol-3-yl)ethan-1-amine (P-48) To an ice-cooled stirred solution of 2-(5-methoxy-6-methyl-1H-indol-3-yl)-2-oxo-N,N-dipropylacetamide (250 mg, 0.79 mmol) in anhydrous THF (15 mL) was added LiAlH (150 mg, 3.95 mmol) in small portions. The resulting suspension was then heated at reflux for 1 h. The suspension was cooled in an ice bath and quenched by the subsequent addition of HO (180 μL), 30% NaOH (w / v) (180 μL), and HO (300 μL). The suspension was stirred at 0° C. for an additional 1 h, then NaSO was added and the reaction mass was filtered through a pad of Celite. The residue was washed with THF (2 × 20 mL), and the combined filtrates were concentrated under a stream of N gas to give N,N-dipropyl-2-(5-methoxy-6-methyl-1H-indol-3-yl)ethan-1-amine (200 mg, 88%) as a colorless oil, which was used in the subsequent step without further purification.

[0351] Step 2a: N,N-Dipropyl-2-(5-methoxy-6-methyl-1H-indol-3-yl)ethan-1-amine fumarate (P-48 fumarate) A solution of N,N-dipropyl-2-(5-methoxy-6-methyl-1H-indol-3-yl)ethan-1-amine (186 mg, 0.65 mmol) in hot acetone (2 mL) was added dropwise to a saturated solution of fumaric acid (75 mg, 0.65 mmol) in acetone at reflux. The colorless solution was cooled to ambient temperature and allowed to stand at this temperature for 16 hours. The resulting colorless needles were collected by vacuum filtration and dried in a vacuum oven to give N,N-dipropyl-2-(5-methoxy-6-methyl-1H-indol-3-yl)ethan-1-amine as the fumarate salt (110 mg, 34% over two steps) as colorless crystals. 1H NMR(400MHz,DMSO-d6):δ 10.50(s,1H),7.09(s,1H),7.02(d,J=2.4Hz,1H),6.94(s,1H),6.51(s,1H),3.79(s,3H), 2.84(s,4H),2.62(t,J=7.6Hz,4H),2.22(s,3H),1.58-1.44(m,4H),0.88(t,J=7.2Hz,6H). 13 C NMR (101MHz, DMSO-d6): δ 167.7,152.0,135.2,131.4,126.0,122.4,120.9,113.1,112.0,98.8,55.7,55.2,54.1,22.2,19.5,17.4,12.1. LCMS(ESI+):m / z 289.2[M+H] + . qNMR purity (ERETIC): 99.8%.

[0352] Example 18: N-isopropyl-N-(2-(5-methoxy-6-methyl-1H-indol-3-yl)ethyl)propan-2-amine (P-49) [ka] Step 1: N,N-Diisopropyl-2-(5-methoxy-6-methyl-1H-indol-3-yl)-2-oxoacetamide (87) A solution of 2-(5-methoxy-6-methyl-1H-indol-3-yl)-2-oxoacetyl chloride (250 mg, 0.99 mmol) in anhydrous THF (5 mL) was cooled in an ice bath and treated dropwise with diisopropylamine (418 μL, 2.98 mmol) under N. The reaction was stirred at ambient temperature overnight. The reaction was diluted with CHCl (20 mL) and filtered through a pad of Celite under vacuum. The filtrate was concentrated in vacuo, and the residue was purified by flash chromatography (0% to 2% MeOH in CHCl) to give N,N-diisopropyl-2-(5-methoxy-6-methyl-1H-indol-3-yl)-2-oxoacetamide (150 mg, 48%). 1H NMR(400MHz,MeOD-d4):δ 7.79(s,1H),7.63(s,1H),7.26(s,1H),3.72-3.96(m,4H),3.69(p,J=6.8Hz,1H),2.29(s,3H),1.57(d,J=6.8Hz,6H),1.21(d,J=6.8Hz,6H); 13 C NMR(101MHz,MeOD-d4):δ 188.2,156.7,149.3,136.3,125.9,125.4,116.0,114.6,110.7,102.2,56.1,52.3,47.2,20.6,20.6,17.2;LRMS(ESI,-ve):m / z=315.4[MH] - .

[0353] Step 2: N-isopropyl-N-(2-(5-methoxy-6-methyl-1H-indol-3-yl)ethyl)propan-2-amine (P-49) To an ice-cold solution of N,N-diisopropyl-2-(5-methoxy-6-methyl-1H-indol-3-yl)-2-oxoacetamide (150 mg, 0.47 mmol) in anhydrous THF (10 mL) was added LiAlH (144 mg, 3.79 mmol) in small portions under N. The reaction was then stirred at room temperature for 16 h and then at reflux for 1 h. The suspension was cooled in an ice bath and quenched by the subsequent addition of HO (150 μL), 30% NaOH (w / v) (150 μL), and HO (300 μL). The suspension was stirred at 0° C. for a further 15 min, then MgSO was added and the reaction mass was filtered through a pad of Celite. The pad was further eluted with several volumes of EtOAc and the combined filtrates were concentrated in vacuo to give N-isopropyl-N-(2-(5-methoxy-6-methyl-1H-indol-3-yl)ethyl)propan-2-amine (90 mg, 66%) as a white solid. 1 H NMR(400MHz,MeOD-d4):δ 7.09(s,1H),6.97-6.89(m,2H),3.84(s,3H),3.29-3.17(m,2H),2.93-2.76(m,4H),2.26(s,3H),1.18(d,J=6.8Hz,12H). 13C NMR (101MHz, MeOD-d4): δ 153.6,133.0,127.0,122.9,122.5,113.7,113.6,99.5,56.1,51.8,48.6,28.3,20.2,17.2.

[0354] Step 2a: N-Isopropyl-N-(2-(5-methoxy-6-methyl-1H-indol-3-yl)ethyl)propan-2-amine hydrochloride (P-49 HCl) A solution of N-isopropyl-N-(2-(5-methoxy-6-methyl-1H-indol-3-yl)ethyl)propan-2-amine in anhydrous EtO (1 mL) and anhydrous isopropanol (2 mL) was cooled to −10° C., and then 0.5 M HCl in anhydrous EtO (2 mL) was added dropwise over 10 min. The solvent volume was then reduced with a stream of N gas while still in the cold bath, and a white precipitate slowly formed. The suspension was then diluted with anhydrous EtO (10 mL) at ambient temperature to promote precipitation. The precipitate was collected by filtration under an N atmosphere, and the solid residue was washed with EtO (1 mL) to give N-isopropyl-N-(2-(5-methoxy-6-methyl-1H-indol-3-yl)ethyl)propan-2-amine as the hydrochloride salt (40 mg, 64%) as a white solid. 1 H NMR(400MHz,D2O):δ 7.26(s,1H),7.15(s,1H),7.06(s,1H),3.82(s,3H),3.70(pent,J=6.8Hz,2H ),3.34-3.26(m,2H),3.17-3.06(m,2H),2.23(s,3H),1.28(d,J=6.8Hz,12H). 13 C NMR (101MHz, D2O): δ 152.0,131.5,124.5,123.7,123.1,113.4,108.7,99.7,56.4,55.1,47.2,22.9,17.9,16.0. LCMS(ESI+):m / z 289.2[M+H] + . qNMR purity (ERETIC): 99.4%.

[0355] Scheme 6: Compounds of general formula (I) can be synthesized from appropriately substituted indoles similarly as outlined in Scheme 6. Glyoxylation of an appropriately substituted indole with oxalyl chloride, followed by treatment with an appropriately substituted amine, afforded a glyoxamide intermediate that, when subjected to reducing conditions, provided access to compounds of general formula (I) (exemplified by P-50). 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]

[0356] Example 19: 2-(5-Methoxy-7-methyl-1H-indol-3-yl)-N,N-dimethylethan-1-amine (P-50) [ka] Step 1: 2-(5-Methoxy-7-methyl-1H-indol-3-yl)-2-oxoacetyl chloride (89) A stirred solution of 5-methoxy-7-methyl-1H-indole (5.0 g, 31.0 mmol) in anhydrous EtO (35 mL) was cooled to 0 °C and treated dropwise with a solution of oxalyl chloride (3.46 mL, 40.3 mmol) dissolved in anhydrous EtO (35 mL). Stirring was continued at this temperature for 1 h, and then the red precipitate was collected by filtration and washed with cold anhydrous EtO (2 × 5 mL) to give 2-(5-methoxy-7-methyl-1H-indol-3-yl)-2-oxoacetyl chloride (6.5 g, 83%) as a red powder. 1 H NMR (400MHz, DMSO-d6): δ 12.36(s,1H),8.27(d,J=3.2Hz,1H),7.51(d,J=2.4Hz,1H),6.73(d,J=2.4Hz,1H),3.77(s,3H),2.47(s,3H). 13C NMR (101MHz, DMSO-d6): δ 180.7,165.4,156.2,137.3,131.0,126.2,123.2,113.9,112.5,100.5,55.3,16.7.

[0357] Step 2: 2-(5-methoxy-7-methyl-1H-indol-3-yl)-N,N-dimethyl-2-oxoacetamide (90) A suspension of 2-(5-methoxy-7-methyl-1H-indol-3-yl)-2-oxoacetyl chloride (0.4 g, 1.59 mmol) in anhydrous CHCl (10 mL) was added dropwise to an ice-cooled, stirred suspension of dimethylamine hydrochloride (389 mg, 4.77 mmol) in CHCl (10 mL), followed by the dropwise addition of triethylamine (731 μL, 5.24 mmol). Stirring was continued for 3 h, at which point the reaction was diluted with HO (20 mL) and the organic layer was separated. The organic layer was washed with HO (2 × 25 mL) followed by brine (50 mL), then dried over MgSO, filtered, and the filtrate was concentrated under reduced pressure. The residue was triturated with CH2Cl2 / Et2O and filtered to give 2-(5-methoxy-7-methyl-1H-indol-3-yl)-N,N-dimethyl-2-oxoacetamide (373 mg, 90%) as a white powder. 1 H NMR (400MHz, MeOD-d4): δ 7.95 (s, 1H), 7.58 (s, 1H), 6.79 (s, 1H), 3.87 (s, 3H), 3.12 (s, 3H), 3.06 (s, 3H), 2.53 (s, 3H).

[0358] Step 3: 2-(5-methoxy-7-methyl-1H-indol-3-yl)-N,N-dimethylethan-1-amine (P-50) To an ice-cooled stirred solution of 2-(5-methoxy-7-methyl-1H-indol-3-yl)-N,N-dimethyl-2-oxoacetamide (450 mg, 1.73 mmol) in anhydrous THF (15 mL) was added LiAlH (197 mg, 5.19 mmol) in small portions. The resulting suspension was then heated at reflux for 1 h. The suspension was cooled in an ice bath and quenched by the subsequent addition of HO (100 μL), 30% aqueous NaOH (w / v) (100 μL), and HO (300 μL). The suspension was stirred at 0° C. for an additional 1 h, then NaSO was added, and the reaction mass was filtered through a pad of Celite. The filter cake was washed with THF (2 × 20 mL), and the combined filtrates were concentrated under a stream of N gas to give 2-(5-methoxy-7-methyl-1H-indol-3-yl)-N,N-dimethylethan-1-amine (0.3 g) as a colorless oil, which was used in the subsequent step without further purification.

[0359] Step 3a: 2-(5-Methoxy-7-methyl-1H-indol-3-yl)-N,N-dimethylethan-1-amine fumarate (P-50 fumarate) A solution of 2-(5-methoxy-7-methyl-1H-indol-3-yl)-N,N-dimethylethan-1-amine (300 mg) in hot acetone (2 mL) was added dropwise to a saturated acetone solution of fumaric acid (150 mg, 1.29 mmol) in acetone at reflux. The colorless solution was cooled to ambient temperature and allowed to stand at this temperature for 16 hours. The resulting colorless needles were collected by vacuum filtration and dried in a vacuum oven to give 2-(5-methoxy-7-methyl-1H-indol-3-yl)-N,N-dimethylethan-1-amine as the fumarate salt (280 mg, 46% over two steps). 1 H NMR(400MHz,DMSO-d6):δ 10.74(d,J=2.8Hz,1H),7.14(d,J=2.4Hz,1H),6.91(d,J=2.4Hz,1H),6.5 8-6.50(m,3H),3.75(s,3H),3.11-2.93(m,4H),2.66(s,6H),2.40(s,3H). 13C NMR (101MHz, DMSO-d6): δ 168.4,153.7,135.5,131.5,127.2,123.7,122.0,112.3,110.8,98.1,57.7,55.8,43.0,21.4,17.2. LCMS(ESI+):m / z 233.2[M+H] + . qNMR purity (ERETIC): 98.9%.

[0360] Example 20: N-ethyl-2-(5-methoxy-7-methyl-1H-indol-3-yl)-N-methylethan-1-amine (P-51) [ka] Step 1: N-ethyl-2-(5-methoxy-7-methyl-1H-indol-3-yl)-N-methyl-2-oxoacetamide (91) A solution of ethyl(methyl)amine (207 mg, 3.5 mmol) in CHCl (5 mL) was added dropwise to an ice-cold suspension of 2-(5-methoxy-7-methyl-1H-indol-3-yl)-2-oxoacetyl chloride (0.4 g, 1.59 mmol). Stirring was continued for 3 h, at which point the reaction was diluted with HO (20 mL) and the organic layer was separated. The organic layer was then washed with dilute HCl (0.1 M aqueous, 25 mL), HO (2 × 25 mL), followed by brine (50 mL), then dried over MgSO, filtered, and the filtrate was concentrated under reduced pressure. The residue was triturated with CH2Cl2 / Et2O and filtered to give N-ethyl-2-(5-methoxy-7-methyl-1H-indol-3-yl)-N-methyl-2-oxoacetamide (378 mg, 87%) as a white powder as a mixture of rotamers (A:B). 1H NMR(400MHz,CDCl3):δ 9.55(s,1H),7.75-7.70(m,1H),7.65-7.63(m,1H),6.74(s,1H),3.89(s,3H),3.58(q,J=7.2Hz,0.8H,Rotamer A),3 .39(q,J=7.2Hz,1.2H, rotamer B), 3.07(s,1.8H, rotamer B), 3.03(s,1.2H, rotamer A), 2.46(s,3H),1.28-1.17(m,3H).

[0361] Step 2: N-ethyl-2-(5-methoxy-7-methyl-1H-indol-3-yl)-N-methylethan-1-amine (P-51) To an ice-cooled stirred solution of N-ethyl-2-(5-methoxy-7-methyl-1H-indol-3-yl)-N-methyl-2-oxoacetamide (425 mg, 1.55 mmol) in anhydrous THF (15 mL) was added LiAlH (176 mg, 3 equiv., 4.65 mmol) in small portions. The resulting suspension was then heated at reflux for 1 h. The suspension was cooled in an ice bath and quenched by the subsequent addition of HO (180 μL), 30% NaOH (w / v) (180 μL), and HO (360 μL). The suspension was stirred at 0° C. for an additional 1 h, then NaSO was added, and the reaction mass was filtered through a pad of Celite. The filtrate was concentrated under a stream of N2 gas to give N-ethyl-2-(5-methoxy-7-methyl-1H-indol-3-yl)-N-methylethan-1-amine (0.3 g) as a colorless oil, which was used in the subsequent step without further purification.

[0362] Step 2a: N-ethyl-2-(5-methoxy-7-methyl-1H-indol-3-yl)-N-methylethan-1-amine fumarate (P-51 fumarate) A solution of N-ethyl-2-(5-methoxy-7-methyl-1H-indol-3-yl)-N-methylethan-1-amine (159 mg, 0.65 mmol) in hot acetone (2 mL) was added dropwise to a saturated solution of fumaric acid (75 mg, 0.65 mmol) in acetone at reflux. The colorless solution was cooled to ambient temperature and allowed to stand at this temperature for 16 hours. The resulting colorless needles were collected by vacuum filtration and dried in a vacuum oven to give N-ethyl-2-(5-methoxy-7-methyl-1H-indol-3-yl)-N-methylethan-1-amine as the fumarate salt (148 mg, 31% over two steps). 1 H NMR(400MHz,DMSO-d6):δ 10.67(s,1H),7.11(d,J=2.4Hz,1H),6.86(d,J=2.4Hz,1H),6.56-6.53(m,1H),6.50(s,1H),3.74( s,3H),2.95-2.81(m,4H),2.75(q,J=7.2Hz,2H),2.46(s,3H),2.39(s,3H),1.10(t,J=7.2Hz,3H). 13 C NMR (101MHz, DMSO-d6): δ 168.2,153.1,135.2,131.0,126.9,123.0,121.4,111.6,111.5,97.6,56.0,55.3,50.0,30.6,21.5,16.7,10.6. LCMS(ESI+):m / z 247.1[M+H] + . qNMR purity (ERETIC): 99.0%.

[0363] Example 21: N-(2-(5-methoxy-7-methyl-1H-indol-3-yl)ethyl)-N-methylpropan-1-amine (P-52) [ka] Step 1: 2-(5-methoxy-7-methyl-1H-indol-3-yl)-N-methyl-2-oxo-N-propylacetamide (92) A solution of methyl(propyl)amine (256 mg, 3.50 mmol) in CHCl (5 mL) was added dropwise to an ice-cooled, stirred suspension of 2-(5-methoxy-7-methyl-1H-indol-3-yl)-2-oxoacetyl chloride (0.4 g, 1.59 mmol). Stirring was continued for 3 h, at which point the reaction was diluted with HO (20 mL) and the organic layer was separated. The organic layer was then washed with dilute HCl (0.1 M aqueous, 25 mL), HO (2 × 25 mL), followed by brine (50 mL), then dried over MgSO, filtered, and the filtrate was concentrated under reduced pressure. The residue was triturated with CH2Cl2 / Et2O and filtered to give 2-(5-methoxy-7-methyl-1H-indol-3-yl)-N-methyl-2-oxo-N-propylacetamide (320 mg, 70%) as a white powder as a mixture of rotamers (A:B). 1 H NMR(400MHz,MeOD-d4):δ 7.90-7.86(m,1H),7.57(d,J=2.4Hz,1H),6.76(d,J=2.4,1H),3.85(s ,3H),3.56-3.48(m,1H),3.34-3.27(m,1H),3.35-3.30(m,1H),3.09(s ,1.8H, rotamer B), 3.03(s,1.2H, rotamer A),2.50(s,3H),1.81-1.59(m,2H),1.03(t,J=7.2Hz,1.2H,rotamer A),0.83(t,J=7.2Hz,1.8H,rotamer B).

[0364] Step 2: N-(2-(5-methoxy-7-methyl-1H-indol-3-yl)ethyl)-N-methylpropan-1-amine (P-52) To an ice-cooled stirred solution of 2-(5-methoxy-7-methyl-1H-indol-3-yl)-N-methyl-2-oxo-N-propylacetamide (395 mg, 1.37 mmol) in anhydrous THF (15 mL) was added LiAlH (156 mg, 4.11 mmol) in small portions. The resulting suspension was then heated at reflux for 1 h. The suspension was cooled in an ice bath and quenched by the subsequent addition of HO (100 μL), 30% NaOH (w / v) (100 μL), and HO (300 μL). The suspension was stirred at 0° C. for an additional 1 h, then NaSO was added, and the reaction mass was filtered through a pad of Celite, and the filter cake was washed with THF (2×20 mL). The filtrate was concentrated under a stream of N2 gas to give N-(2-(5-methoxy-7-methyl-1H-indol-3-yl)ethyl)-N-methylpropan-1-amine (295 mg) as a colorless oil, which was used in the subsequent step without further purification.

[0365] Step 2a: N-(2-(5-methoxy-7-methyl-1H-indol-3-yl)ethyl)-N-methylpropan-1-amine (P-52 fumarate) A solution of N-(2-(5-methoxy-7-methyl-1H-indol-3-yl)ethyl)-N-methylpropan-1-amine (168 mg, 0.65 mmol) in hot acetone (2 mL) was added dropwise to a saturated solution of fumaric acid (74.9 mg, 0.65 mmol) in acetone at reflux. The colorless solution was cooled to ambient temperature and held at this temperature overnight. The resulting colorless needles were collected by vacuum filtration and dried overnight in a vacuum oven to yield N-(2-(5-methoxy-7-methyl-1H-indol-3-yl)ethyl)-N-methylpropan-1-amine as the fumarate salt (219 mg, 42% over two steps). 1H NMR(400MHz,DMSO-d6):δ 10.66(s,1H),7.11(d,J=2.4Hz,1H),6.85(d,J=2.4Hz,1H),6.55-6.52(m,1H),6.51(s,1H),3.74(s,3H),2.9 8-2.78(m,4H),2.65-2.58(m,2H),2.46(s,3H),2.39(s,3H),1.55(septet,J=7.4Hz,2H),0.88(t,J=7.4Hz,3H). 13 C NMR (101MHz, DMSO-d6): δ 168.0,153.1,135.1,131.0,126.9,123.0,121.4,111.6,111.6,97.6,57.7,56.7,55.3,40.5,21.5,18.6,16.7,11.5. LCMS(ESI+):m / z 261.1[M+H] + . qNMR purity (ERETIC): 97.9%.

[0366] Example 22: N-(2-(5-methoxy-7-methyl-1H-indol-3-yl)ethyl)-N-methylpropan-2-amine (P-53) [ka] Step 1: N-isopropyl-2-(5-methoxy-7-methyl-1H-indol-3-yl)-N-methyl-2-oxoacetamide (93) A solution of methyl(propan-2-yl)amine (256 mg, 3.5 mmol) in CHCl (5 mL) was added dropwise to an ice-cold suspension of 2-(5-methoxy-7-methyl-1H-indol-3-yl)-2-oxoacetyl chloride (0.4 g, 1.59 mmol). Stirring was continued for 3 h, at which point the reaction was diluted with HO (20 mL) and the organic layer was separated. The organic layer was then washed with dilute HCl (0.1 M aqueous, 25 mL), HO (2 × 25 mL), followed by brine (50 mL), then dried over MgSO, filtered, and the filtrate was concentrated under reduced pressure. The residue was triturated with CH2Cl2 / Et2O and filtered to give N-isopropyl-2-(5-methoxy-7-methyl-1H-indol-3-yl)-N-methyl-2-oxoacetamide (401 mg, 88%) as a white powder that was a mixture of rotamers (A:B). 1 H NMR(400MHz,MeOD-d4):δ 7.95 (s, 0.7H, rotamer B), 7.90 (s, 0.3H, rotamer A), 7.57 (m, 1H), 6.79 (m, 1H), 4.8 (septet, J=6.8Hz, 0.3H, rotamer A), 4.02 (septet, J=6.8Hz, 0.7H, rotation Isomer B), 3.87 (s, 3H), 2.98 (s, 2H, rotamer B), 2.90 (s, 1H, rotamer A), 2.52 (s, 3H), 1.29 (d, J = 6.8 Hz, 2H, rotamer A), 1.23 (d, J = 6.8 Hz, 4H, rotamer B).

[0367] Step 2: N-(2-(5-methoxy-7-methyl-1H-indol-3-yl)ethyl)-N-methylpropan-2-amine (P-53) To an ice-cooled stirred solution of 2-(5-methoxy-7-methyl-1H-indol-3-yl)-N-methyl-2-oxo-N-(propan-2-yl)acetamide (475 mg, 1.65 mmol) in anhydrous THF (15 mL) was added LiAlH (188 mg, 4.94 mmol) in small portions. The resulting suspension was then heated at reflux for 1 h. The suspension was cooled in an ice bath and quenched by the subsequent addition of HO (180 μL), 30% NaOH (w / v) (180 μL), and HO (300 μL). The suspension was stirred at 0° C. for another 1 h, then NaSO was added, and the reaction mass was filtered through a pad of Celite. The filtrate was concentrated under a stream of N2 gas to give N-(2-(5-methoxy-7-methyl-1H-indol-3-yl)ethyl)-N-methylpropan-2-amine (340 mg, 79%) as a colorless oil, which was used in the subsequent step without further purification.

[0368] Step 2a: N-(2-(5-methoxy-7-methyl-1H-indol-3-yl)ethyl)-N-methylpropan-2-amine oxalate (P-53 oxalate) A solution of N-(2-(5-methoxy-7-methyl-1H-indol-3-yl)ethyl)-N-methylpropan-2-amine (168 mg, 0.65 mmol) in hot acetone (2 mL) was added dropwise to a saturated solution of oxalic acid (75 mg, 0.65 mmol) in acetone at reflux. The colorless solution was cooled to ambient temperature and allowed to stand at this temperature for 16 hours. The resulting colorless needles were collected by vacuum filtration and dried in a vacuum oven to give N-(2-(5-methoxy-7-methyl-1H-indol-3-yl)ethyl)-N-methylpropan-2-amine as the oxalate salt (180 mg, 31% over two steps). 1H NMR(400MHz,DMSO-d6):δ 10.78(s,1H),7.19(d,J=2.4Hz,1H),6.90(d,J=2.4Hz,1H),6.61-6.42(m,1H),3.75(s,3H),3.60(Septet ,J=6.4Hz,1H),3.27-3.17(m,2H),3.11-2.98(m,2H),2.73(s,3H),2.39(s,3H),1.24(d,J=6.4Hz,6H). qNMR purity (ERETIC): 98.3%.

[0369] Example 23: N,N-diethyl-2-(5-methoxy-7-methyl-1H-indol-3-yl)ethan-1-amine (P-54) [ka] Step 1: N,N-Diethyl-2-(5-methoxy-7-methyl-1H-indol-3-yl)-2-oxoacetamide (94) A solution of diethylamine (174 mg, 2.38 mmol) in CHCl (5 mL) was added dropwise to an ice-cold suspension of 2-(5-methoxy-7-methyl-1H-indol-3-yl)-2-oxoacetyl chloride (0.4 g, 1.59 mmol) in CHCl (10 mL). Stirring was continued for 3 h, at which point the reaction was diluted with HO (20 mL) and the organic layer was separated. The organic layer was then washed with dilute HCl (0.1 M aqueous, 25 mL), HO (2 × 25 mL), followed by brine (50 mL), then dried over MgSO, filtered, and the filtrate concentrated under reduced pressure. The residue was triturated with CHCl / EtO and filtered to give N,N-diethyl-2-(5-methoxy-7-methyl-1H-indol-3-yl)-2-oxoacetamide (330 mg, 72%) as a white powder. 1H NMR(400MHz,CDCl3):δ 9.98(s,1H),7.63-7.59(m,2H),6.73-6.71(m,1H),3.88(s,3H),3.52(q,J=7.2Hz,2 H),3.36(q,J=7.2Hz,2H),2.43(s,3H),1.25(t,J=7.2Hz,3H),1.17(t,J=7.2Hz,3H). 13 C NMR (101MHz, CDCl3): δ 186.2,167.9,156.8,134.9,131.2,125.7,122.6,115.2,114.6,100.7,55.7,42.5,39.1,16.5,14.3,12.8.

[0370] Step 2: N,N-Diethyl-2-(5-methoxy-7-methyl-1H-indol-3-yl)ethan-1-amine (P-54) To an ice-cooled stirred solution of N,N-diethyl-2-(5-methoxy-7-methyl-1H-indol-3-yl)-2-oxoacetamide (489 mg, 1.70 mmol) in anhydrous THF (15 mL) was added LiAlH (193 mg, 5.09 mmol) in small portions. The resulting suspension was then heated at reflux for 1 h. The suspension was cooled in an ice bath and quenched by the subsequent addition of HO (200 μL), 30% NaOH (w / v) (200 μL), and HO (300 μL). The suspension was stirred at 0° C. for an additional 1 h, then NaSO was added and the reaction mass was filtered through a pad of Celite. The filtrate was concentrated under a stream of N2 gas to give N,N-diethyl-2-(5-methoxy-7-methyl-1H-indol-3-yl)ethan-1-amine (320 mg) as a colorless oil, which was used in the subsequent step without further purification.

[0371] Step 2a: N,N-Diethyl-2-(5-methoxy-7-methyl-1H-indol-3-yl)ethan-1-amine fumarate (P-54 fumarate) A solution of N,N-diethyl-2-(5-methoxy-7-methyl-1H-indol-3-yl)ethan-1-amine (310 mg, 1.19 mmol) in hot acetone (2 mL) was added dropwise to a saturated solution of fumaric acid (138 mg, 1.19 mmol) in acetone at reflux. The colorless solution was cooled to ambient temperature and allowed to stand at this temperature for 16 hours. The resulting colorless needles were collected by vacuum filtration and dried in a vacuum oven to give N,N-diethyl-2-(5-methoxy-7-methyl-1H-indol-3-yl)ethan-1-amine as the fumarate salt (296 mg, 67% over two steps). 1 H NMR(400MHz,DMSO-d6):δ 10.68(s,1H),7.13(d,J=2.4Hz,1H),6.85(d,J=2.4Hz,1H),6.57-6.51(m,1H),6 .49(s,1H),3.74(s,3H),2.98-2.77(m,8H),2.39(s,3H),1.10(t,J=7.2Hz,6H). 13 C NMR (101MHz, DMSO-d6): δ 168.2,153.1,135.2,131.0,126.9,123.0,121.4,111.6,111.5,97.5,55.2,52.1,45.8,21.2,16.7,10.3. LCMS(ESI+):m / z 261.1[M+H] + . qNMR purity (ERETIC): 99.8%.

[0372] Example 24: N-ethyl-N-(2-(5-methoxy-7-methyl-1H-indol-3-yl)ethyl)propan-1-amine (P-55) [ka] Step 1: N-ethyl-2-(5-methoxy-7-methyl-1H-indol-3-yl)-2-oxo-N-propylacetamide (95) A solution of ethyl(propyl)amine (305 mg, 3.5 mmol) in CHCl (5 mL) was added dropwise to an ice-cold suspension of 2-(5-methoxy-7-methyl-1H-indol-3-yl)-2-oxoacetyl chloride (0.4 g, 1.59 mmol) in CHCl (10 mL). Stirring was continued for 3 h, at which point the reaction was diluted with HO (20 mL) and the organic layer was separated. The organic layer was then washed with dilute HCl (0.1 M aqueous, 25 mL), HO (2 × 25 mL), followed by brine (50 mL), then dried over MgSO, filtered, and the filtrate was concentrated under reduced pressure. The residue was triturated with CH2Cl2 / Et2O and filtered to give crude N-ethyl-2-(5-methoxy-7-methyl-1H-indol-3-yl)-2-oxo-N-propylacetamide (486 mg, quantitative) as a white powder.

[0373] Step 2: N-ethyl-N-(2-(5-methoxy-7-methyl-1H-indol-3-yl)ethyl)propan-1-amine (P-55) To an ice-cooled stirred solution of N-ethyl-2-(5-methoxy-7-methyl-1H-indol-3-yl)-2-oxo-N-propylacetamide (481 mg, 1.59 mmol) in anhydrous THF (15 mL) was added LiAlH (181 mg, 4.77 mmol) in small portions. The resulting suspension was then heated at reflux for 1 h. The suspension was cooled in an ice bath and quenched by the subsequent addition of HO (200 μL), 30% NaOH (w / v) (200 μL), and HO (300 μL). The suspension was stirred at 0° C. for an additional 1 h, then NaSO was added, and the reaction mass was filtered through a pad of Celite. The residue was washed with THF (2 × 20 mL), and the combined filtrates were concentrated under a stream of N gas to give crude N-ethyl-N-(2-(5-methoxy-7-methyl-1H-indol-3-yl)ethyl)propan-1-amine (428 mg) as a colorless oil, which was used in the subsequent step without further purification.

[0374] Step 2a: N-ethyl-N-(2-(5-methoxy-7-methyl-1H-indol-3-yl)ethyl)propan-1-amine fumarate (P-55 fumarate) A solution of N-ethyl-N-(2-(5-methoxy-7-methyl-1H-indol-3-yl)ethyl)propan-1-amine (295 mg, 1.08 mmol) in hot acetone (2 mL) was added dropwise to a saturated solution of fumaric acid (125 mg, 1.08 mmol) in acetone at reflux. The colorless solution was cooled to ambient temperature and allowed to stand at this temperature for 16 hours. The resulting colorless needles were collected by vacuum filtration and dried in a vacuum oven to give N-ethyl-N-(2-(5-methoxy-7-methyl-1H-indol-3-yl)ethyl)propan-1-amine as the fumarate salt (219 mg, 42% over three steps). 1 H NMR(400MHz,DMSO-d6):δ 10.65-10.60(m,1H),7.12(d,J=2.4Hz,1H),6.81(d,J=2.4Hz,1H),6.54(d,J=2.4Hz,1H),6.49(s,1H),3.74(s,3H),2.82(s ,4H),2.74(q,J=7.2Hz,2H),2.61(t,J=7.6Hz,2H),2.39(s,3H),1.51(m,2H),1.06(t,J=7.2Hz,3H),0.89(t,J=7.2Hz,3H). LCMS(ESI+):m / z 275.2[M+H] + . qNMR purity (ERETIC): 97.5%.

[0375] Example 25: N-ethyl-N-(2-(5-methoxy-7-methyl-1H-indol-3-yl)ethyl)propan-2-amine (P-56) [ka] Step 1: N-ethyl-N-isopropyl-2-(5-methoxy-7-methyl-1H-indol-3-yl)-2-oxoacetamide (96) To a suspension of 2-(5-methoxy-7-methyl-1H-indol-3-yl)-2-oxoacetyl chloride (200 mg, 0.80 mmol) in CHCl (5 mL) was added ethyl(propan-2-yl)amine (0.48 mL, 3.97 mmol) at ambient temperature. The reaction was stirred at ambient temperature for 16 h, then diluted with CHCl (10 mL), and 0.2 M aqueous HCl was added dropwise until the aqueous layer was acidic. The layers were separated, and the organic layer was further washed with 1 M aqueous HCl (1 mL × 2) and brine (5 mL × 1). The organic layer was dried over Na2SO4, filtered, the filtrate was concentrated, and the residue was purified by flash chromatography (0% to 5% MeOH in CHCl2, v / v) to give crude N-ethyl-N-isopropyl-2-(5-methoxy-7-methyl-1H-indol-3-yl)-2-oxoacetamide (157 mg) as a brown solid, which was used in the subsequent step without further purification.

[0376] Step 2: N-ethyl-N-(2-(5-methoxy-7-methyl-1H-indol-3-yl)ethyl)propan-2-amine (P-56) To an ice-cold solution of N-ethyl-N-isopropyl-2-(5-methoxy-7-methyl-1H-indol-3-yl)-2-oxoacetamide (150 mg, 0.47 mmol) in anhydrous THF (10 mL) was added LiAlH (151 mg, 3.97 mmol) in small portions under N. The reaction was then stirred at ambient temperature for 16 h and then at reflux for 1 h. The suspension was cooled in an ice bath and quenched by the subsequent addition of HO (150 μL), 30% NaOH (w / v) (150 μL), and HO (300 μL). The suspension was stirred at 0° C. for a further 15 min, then MgSO was added, and the reaction mass was filtered through a pad of Celite. The pad was further eluted with several volumes of EtOAc, and the combined filtrates were concentrated in vacuo. The residue was purified by flash chromatography (0-5% MeOH (10% NH 3(水性)) / CH2Cl2, v / v) to give N-ethyl-N-(2-(5-methoxy-7-methyl-1H-indol-3-yl)ethyl)propan-2-amine (78 mg, 35% over two steps) as a pale oil. 1 H NMR(400MHz,MeOD-d4):δ 7.05(s,1H),6.85(d,J=2.4Hz,1H),6.63-6.57(m,1H),3.80(s,3H),3.29-3.21(m,1H),2.97-2.76(m,6H),2.43(s,3H),1.23-1.09(m,9H).

[0377] Step 2a: N-Ethyl-N-(2-(5-methoxy-7-methyl-1H-indol-3-yl)ethyl)propan-2-amine hydrochloride (P-56 HCl) A solution of N-ethyl-N-(2-(5-methoxy-7-methyl-1H-indol-3-yl)ethyl)propan-2-amine (60 mg, 0.22 mmol) in minimal anhydrous i-PrOH was cooled to −10 °C under an inert atmosphere (N), and then 0.5 M HCl in anhydrous EtO was added dropwise until the pH of the reaction medium was acidic. The resulting suspension was stirred cold for 15 min and then diluted with anhydrous EtO (10 mL) at ambient temperature to promote precipitation. The precipitate was allowed to settle, and the solvent was removed by decanting. The remaining suspension was triturated with anhydrous EtO (1 mL), the solvent was removed by decantation twice, and the solid residue was dried under vacuum to give N-ethyl-N-(2-(5-methoxy-7-methyl-1H-indol-3-yl)ethyl)propan-2-amine as the hydrochloride salt (23 mg, 38%) as a white solid. 1 H NMR(400MHz,D2O):δ 7.27(s,1H),6.97(d,J=2.4Hz,1H),6.80-6.70(m,1H),3.86(s,3H),3.70(septet,J= 6.8Hz, 1H), 3.46-3.31 (m, 1H), 3.30-3.00 (m, 5H), 2.45 (s, 3H), 1.34-1.20 (m, 9H). 13C NMR(101MHz,D2O):δ NMR purity (ERETIC): 97.1%.

[0378] Example 26: N,N-dipropyl-2-(5-methoxy-7-methyl-1H-indol-3-yl)ethan-1-amine (P-57) [ka] Step 1: N,N-Dipropyl-2-(5-methoxy-7-methyl-1H-indol-3-yl)-2-oxoacetamide (97) A solution of dipropylamine (354 mg, 3.5 mmol) in CHCl (5 mL) was added dropwise to an ice-cold suspension of 2-(5-methoxy-7-methyl-1H-indol-3-yl)-2-oxoacetyl chloride (0.4 g, 1.59 mmol). Stirring was continued for 3 h, at which point the reaction was diluted with HO (20 mL) and the organic layer was separated. The organic layer was then washed with dilute HCl (0.1 M aqueous, 25 mL), HO (2 × 25 mL), followed by brine (50 mL), then dried over MgSO, filtered, and the filtrate concentrated under reduced pressure. The residue was triturated with CHCl / EtO and filtered to give N,N-dipropyl-2-(5-methoxy-7-methyl-1H-indol-3-yl)-2-oxoacetamide (340 mg, 68%) as a white powder. 1 H NMR(400MHz,MeOD-d4):δ 7.85(s,1H),7.56(s,1H),6.77-6.74(m,1H),3.85(s,3H),3.53-3.43(m,2H),3.33-3.2 5(m,2H),2.49(s,3H),1.82-1.57(m,4H),1.02(t,J=7.4Hz,3H),0.80(t,J=7.4Hz,3H). 13C NMR(101MHz,MeOD-d4):δ 186.6,168.9,156.9,135.8,131.5,125.7,122.9,114.3,113.8,100.3,54.6,49.6,45.9,21.5,20.2,15.4,10.3,9.9.

[0379] Step 2: N,N-dipropyl-2-(5-methoxy-7-methyl-1H-indol-3-yl)ethan-1-amine (P-57) To an ice-cooled stirred solution of N,N-dipropyl-2-(5-methoxy-7-methyl-1H-indol-3-yl)-2-oxoacetamide (340 mg, 1.07 mmol) in anhydrous THF (15 mL) was added LiAlH (122 mg, 3.22 mmol) in small portions. The resulting suspension was then heated at reflux for 1 h. The suspension was cooled in an ice bath and quenched by the subsequent addition of HO (100 μL), 30% NaOH (w / v) (100 μL), and HO (300 μL). The suspension was stirred at 0° C. for an additional 1 h, then NaSO was added and the reaction mass was filtered through a pad of Celite. The filter cake was washed twice with THF (2 × 20 mL), and the combined filtrates were concentrated under a stream of N gas to give N,N-dipropyl-2-(5-methoxy-7-methyl-1H-indol-3-yl)ethan-1-amine (310 mg) as a colorless oil, which was used in the subsequent step without further purification.

[0380] Step 2a: N,N-Dipropyl-2-(5-methoxy-7-methyl-1H-indol-3-yl)ethan-1-amine fumarate (P-57 fumarate) A solution of N,N-dipropyl-2-(5-methoxy-7-methyl-1H-indol-3-yl)ethan-1-amine (186 mg, 0.65 mmol) in hot acetone (2 mL) was added dropwise to a saturated solution of fumaric acid (75 mg, 0.65 mmol) in acetone at reflux. The colorless solution was cooled to ambient temperature and allowed to stand at this temperature for 16 hours. The resulting colorless needles were collected by vacuum filtration and dried in a vacuum oven to give N,N-dipropyl-2-(5-methoxy-7-methyl-1H-indol-3-yl)ethan-1-amine as the fumarate salt (172 mg, 47% over two steps). 1 H NMR(400MHz,DMSO-d6):δ 10.68-10.63(m,1H),7.12(d,J=2.4Hz,1H),6.83(d,J=2.4Hz,1H),6.56-6.52(m,1H),6.52(s,1H), 3.74(s,3H),2.86(s,4H),2.70-2.62(m,4H),2.39(s,3H),1.60-1.46(m,4H),0.89(t,J=7.2Hz,6H). 13 C NMR (101MHz, DMSO-d6): δ 168.1,153.6,135.4,131.5,127.4,123.4,121.9,112.3,112.1,98.0,55.7,55.1,54.0,22.0,19.3,17.2,12.1. LCMS(ESI+):m / z 289.2[M+H] + . qNMR purity (ERETIC): 99.5%.

[0381] Example 27: N-isopropyl-N-(2-(5-methoxy-7-methyl-1H-indol-3-yl)ethyl)propan-2-amine (P-58) [ka] Step 1: N,N-Diisopropyl-2-(5-methoxy-7-methyl-1H-indol-3-yl)-2-oxoacetamide (98) A solution of bis(propan-2-yl)amine (804 mg, 7.95 mmol) in CHCl (5 mL) was added dropwise to an ice-cold suspension of 2-(5-methoxy-7-methyl-1H-indol-3-yl)-2-oxoacetyl chloride (0.4 g, 1.59 mmol). Stirring was continued for 3 h, at which point the reaction was diluted with HO (20 mL) and the organic layer was separated. The organic layer was then washed with dilute HCl (0.1 M aqueous, 25 mL), HO (2 × 25 mL), followed by brine (50 mL), then dried over MgSO, filtered, and the filtrate concentrated under reduced pressure. The residue was triturated with CHCl / EtO and filtered to give N,N-diisopropyl-2-(5-methoxy-7-methyl-1H-indol-3-yl)-2-oxoacetamide (358 mg, 71%) as a white powder. 1 H NMR(400MHz,CDCl3):δ 10.72(s,1H),7.56(d,J=2.4Hz,1H),7.47(d,J=3.3Hz,1H),6.65-6.62(m,1H),3.93(septet,J=6.8Hz,1 H),3.85(s,3H),3.54(septet,J=6.8Hz,1H),2.34(s,3H),1.54(d,J=6.8Hz,6H),1.13(d,J=6.8Hz,6H).

[0382] Step 2: N-Isopropyl-N-(2-(5-methoxy-7-methyl-1H-indol-3-yl)ethyl)propan-2-amine (P-58) To an ice-cooled stirred solution of N,N-diisopropyl-2-(5-methoxy-7-methyl-1H-indol-3-yl)-2-oxoacetamide (455 mg, 1.44 mmol) in anhydrous THF (15 mL) was added LiAlH (164 mg, 4.31 mmol) in small portions. The resulting suspension was then heated at reflux for 1 h. The suspension was cooled in an ice bath and quenched by the subsequent addition of HO (150 μL), 30% NaOH (w / v) (150 μL), and HO (450 μL). The suspension was stirred at 0° C. for an additional 1 h, then NaSO was added and the reaction mass was filtered through a pad of Celite. The filter cake was washed twice with THF (2 × 20 mL), and the combined filtrates were concentrated under a stream of N gas to give N-isopropyl-N-(2-(5-methoxy-7-methyl-1H-indol-3-yl)ethyl)propan-2-amine (358 mg) as a colorless oil, which was used in the subsequent step without further purification.

[0383] Step 2a: N-Isopropyl-N-(2-(5-methoxy-7-methyl-1H-indol-3-yl)ethyl)propan-2-amine fumarate (P-58 fumarate) A solution of N-isopropyl-N-(2-(5-methoxy-7-methyl-1H-indol-3-yl)ethyl)propan-2-amine (358 mg, 1.24 mmol) in hot acetone (2 mL) was added dropwise to a saturated solution of fumaric acid (144 mg, 1.24 mmol) in acetone at reflux. The colorless solution was cooled to ambient temperature and allowed to stand at this temperature for 16 hours. The resulting colorless needles were collected by vacuum filtration and dried in a vacuum oven to give N-isopropyl-N-(2-(5-methoxy-7-methyl-1H-indol-3-yl)ethyl)propan-2-amine as the fumarate salt (379 mg, 75% over two steps). 1H NMR(400MHz,DMSO-d6):δ 10.74(d,J=2.4Hz,1H),7.20(d,J=2.4Hz,1H),6.82(d,J=2.4Hz,1H),6.60-6.54(m,3H),3. 74(s,3H),3.46(septet,J=6.8Hz,2H),3.01-2.91(m,4H),2.40(s,3H),1.22(d...

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; 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; Or, R ８ and R ９ , or R ９ and R １０ , or R １０ and R １１ These are combined with the atoms to which they are bonded to form C ４～８ Cycloalkyl, C ５～８ Heterocycloalkyl, C ６～１２ Aryl, or C ５～１０ forming a heteroaryl, Said C ４～８ Cycloalkyl, C ５～８ Heterocycloalkyl, C ６～１２ Aryl, 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; 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 , 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 , and OBn are not selected, The compound is selected from the group consisting of: 【Chemistry 2】 or a pharmaceutically acceptable salt, solvate, tautomer, N-oxide, stereoisomer, metabolite, polymorph, or prodrug thereof, which is not selected from:

2. R ７ , 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; 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; R ８ and R ９ These are combined with the atoms to which they are bonded to form C ４～８ Cycloalkyl, C ５～８ Heterocycloalkyl, C ６～１２ Aryl, or C ５～１０ forming a heteroaryl, Said C ４～８ Cycloalkyl, C ５～８ Heterocycloalkyl, C ６～１２ Aryl, 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; 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; 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 10. The compound of claim 1, each optionally substituted with one or more substituents independently selected from heterocycloalkyl.

3. R ８ and R ９ These are combined with the atoms to which they are bonded to form C ５～８ Heterocycloalkyl or C ５～１０ forming a heteroaryl, ５～８ 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 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 3. The compound of claim 2, each optionally further substituted with a substituent selected from heterocycloalkyl.

4. R ８ and R ９ are combined into the following: 【Transformation 3】 C selected from ５～８ Heterocycloalkyl or C ５～１０ form a heteroaryl, wherein the dashed bond is R ８ and R ９ represents a covalent bond with the aromatic ring to which it is attached, Said C ５～８ Heterocycloalkyl and C ５～１０ Heteroaryl is halogen, (O), CN, 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, and C １～６ 4. The compound of claim 3, each optionally further substituted with a substituent selected from haloalkyl.

5. R ８ and R ９ are combined into the following: 【Chemistry 4】 C selected from ５～８ Heterocycloalkyl or C ５～１０ form a heteroaryl, wherein the dashed bond is R ８ and R ９ The compound of claim 4 , wherein represents a covalent bond to the aromatic ring to which it is attached.

6. R ７ , 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 above, Preferably, R 7 , R 10 and R 11 are each independently selected from hydrogen, halogen, C 1-6 alkyl, C 1-6 haloalkyl and OR 13 , and R 13 is selected from hydrogen, C 1-6 alkyl and C 1-6 haloalkyl; More preferably, the compound according to any one of claims 2 to 5, wherein R 7 , R 10 and R 11 are each hydrogen.

7. 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:

8. 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 above, 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 8. The compound of claim 7, wherein the compound is not selected from:

9. 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 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 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 , and OCH ２ CH ２ CH ３ is not selected from 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 , and OCH ２ CH ２ CH ３ is not selected from Preferably, R 8 is selected from halogen, C 1-6 alkyl and OR 13 , R 13 is selected from hydrogen, C 1-6 alkyl and C 1-6 haloalkyl, and / or More preferably, R 8 is selected from halogen, C 1-6 alkyl, and OR 13 , and R 13 is selected from hydrogen, C 1-6 alkyl, and C 1-6 haloalkyl.

10. R ７ , R ８ , R ９ , R １０ , and R １１ is defined by any one of embodiments 1 to 18. Table 1

11. 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 form: 【Transformation 5】 The compound according to any one of claims 1 to 5,

12. R ３ A compound according to any one of claims 1 to 5, wherein is hydrogen and / or L is C 1-4 alkylene, preferably L is methylene.

13. R ６ is hydrogen and C １～６ A compound according to any one of claims 1 to 5, wherein R 6 is hydrogen, preferably selected from alkyl.

14. The following table: Table 1-1 Table 1-2 Table 1-3 Table 1-4 Table 1-5 Table 1-6 Table 1-7 Table 1-8 Table 1-9 Table 1-10 Table 1-11 Table 1-12 Table 1-13 2. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, tautomer, N-oxide, stereoisomer, metabolite, polymorph, or prodrug thereof, selected from:

15. A pharmaceutical product comprising the compound of any one of claims 1 to 5, or a pharmaceutically acceptable salt, solvate, tautomer, N-oxide, stereoisomer, metabolite, polymorph, or prodrug thereof.

16. 6. A pharmaceutical composition comprising the compound of any one of claims 1 to 5, or a pharmaceutically acceptable salt, solvate, tautomer, N-oxide, stereoisomer, metabolite, polymorph, or prodrug thereof, and a pharmaceutically acceptable excipient.

17. Formula (I): 【Transformation 6】 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; 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; Or, R ８ and R ９ , or R ９ and R １０ , or R １０ and R １１ These are combined with the atoms to which they are bonded to form C ４～８ Cycloalkyl, C ５～８ Heterocycloalkyl, C ６～１２ Aryl, or C ５～１０ forming a heteroaryl, Said C ４～８ Cycloalkyl, C ５～８ Heterocycloalkyl, C ６～１２ Aryl, 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; 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 , 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 , and OBn are not selected, The compound is selected from the group consisting of: 【Transformation 7】 A pharmaceutical composition not selected from:

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; for the treatment of diseases, disorders or conditions of the central nervous system (CNS) and / or diseases, disorders or conditions of the nervous system selected from 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 any etiology, and combinations thereof; or Increasing neuroplasticity and / or increasing dendritic spine density.

20. 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 5, or a pharmaceutically acceptable salt, solvate, tautomer, N-oxide, stereoisomer, metabolite, polymorph, or prodrug thereof.

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