Neuroactive steroids and methods of use thereof

Abstract

To provide neuroactive steroids and methods of using the same.SOLUTION: Provided herein are compounds of Formula (I): (I) or pharmaceutically acceptable salts thereof, wherein R2a, R2b, R3, R4a, R4b, R5, R6a, R6b, R11a,,,,,,, wetter, wetter, wetter, wetter, wetter, wetter, wetter, wetter, wetter, wetter, wetter, wetter, wetter, wetter, wetter, wetter, wetter, wetter, wetter, wetter, wetter, wetter, wetter, wetter, wetter, wetter, wetter, wetter, wetter, wetter, wetter, wetter, wetter, wetter, wetter, wetter, wetter, wetter, wetter, wetter, wetter, wetter, wetter, wetter, wetter, wetter, wetter, wetter, wetter, wetter, wetter R18 R11b R20b R19 R16b R15a R20a R16a R15b. Also provided herein are pharmaceutical compositions comprising compounds of Formula (I), and methods of using the compounds, for example, in the treatment of CNS-related disorders.SELECTED DRAWING: None

Description

[Background technology]

[0001] Brain excitability is defined as the level of alertness of an animal, a continuum from coma to seizures, and is regulated by various neurotransmitters. Generally, neurotransmitters serve to regulate the conductance of ions across the neuronal membrane. At rest, the neuronal membrane has an electrical potential (or membrane potential) of approximately -70 mV, making the interior of the cell negative compared to the exterior of the cell. The electrical potential (voltage) is determined by the flow of ions (K) across the neuronal semipermeable membrane. + , Na + , Cl - Neurotransmitters are the result of an equilibrium between synaptic and non-synaptic substances (organic anions). Neurotransmitters are stored in presynaptic vesicles and are released under the influence of a neuronal action potential. When released into the synaptic cleft, excitatory chemical transmitters such as acetylcholine cause membrane depolarization (a change in potential from -70 mV to -50 mV occurs). This effect is mediated by postsynaptic nicotinic receptors stimulated by acetylcholine, leading to the release of Na + Increases membrane permeability to ions. Reduction of membrane potential stimulates neuronal excitability in the form of postsynaptic action potentials.

[0002] In the case of the GABA receptor complex (GRC), its effects on brain excitability are mediated by the neurotransmitter gamma-aminobutyric acid (GABA). Because up to 40% of brain neurons utilize GABA as a neurotransmitter, GABA has a profound influence on global brain excitability. GABA regulates the excitability of individual neurons by modulating the conductance of chloride ions across neuronal membranes. GABA interacts with its recognition site on the GRC, promoting the influx of chloride ions into the cell down the GRC's electrochemical gradient. Increased intracellular levels of this anion cause hyperpolarization of the transmembrane potential, reducing neuronal sensitivity to excitatory inputs and thus neuronal excitability. In other words, the higher the chloride ion concentration in neurons, the lower the brain excitability and arousal levels.

[0003] The GRC is well documented to be involved in mediating anxiety, seizure activity, and sedation. Thus, GABA and drugs that act like or potentiate the actions of GABA, such as therapeutically useful barbiturates and benzodiazepines (BZs) (e.g., Valium®), exert their therapeutically useful effects by interacting with specific regulatory sites on the GRC. Accumulating evidence now suggests that the GRC contains unique sites for neuroactive steroids in addition to benzodiazepine and barbiturate binding sites. See, e.g., Lan, NC et al., Neurochem. Res. (1991) 16:347-356.

[0004] Neuroactive steroids can occur endogenously. The most potent endogenous neuroactive steroids are 3α-hydroxy-5-reduced pregnan-20-one and 3α-21-dihydroxy-5-reduced pregnan-20-one (metabolites of the hormonal steroids progesterone and deoxycorticosterone, respectively). The ability of these steroid metabolites to alter brain excitability was recognized in 1986 (Majewska, MD et al., Science 232:1004-1007 (1986); Harrison, NL et al., J Pharmacol. Exp. Ther. 241:346-353 (1987)). There is a need for new and improved compounds that act as modulators of brain excitability and as agents for the prevention and treatment of CNS-related disorders. The compounds, compositions, and methods described herein are directed to this end. [Prior art documents] [Patent documents]

[0005] [Non-Patent Document 1] Lan, NC et al., Neurochem. Res. (1991) 16:347-356 [Non-patent document 2] Majewska, MDet al., Science 232:1004-1007(1986) [Non-patent document 3] Harrison,NLet al.,J Pharmacol.Exp.Ther.241:346-353(1987) Summary of the Invention [Means for solving the problem]

[0006] Provided herein are compounds designed to act as GABA receptor modulators. In some embodiments, such compounds are expected to be useful as therapeutic agents for treating CNS-related disorders.

[0007] In one aspect, Formula I: [ka] [In formula: m is 0, 1, 2, or 3; m1 is 0, 1, or 2; n is 1, 2, 3 or 4; n1 is 0, 1, 2, 3, 4 or 5; q is independently 0, 1, 2, or 3; r is independently 0, 1, or 2; s is independently 0, 1, or 2; t is independently 0, 1, 2, or 3; u is independently 1 or 2; X is hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -OR A1 , -SR A1 , -N(R A1 )2, -OC(=O)R A1 , -OC(=O)OR A1 , -OC(=O)SRA1 , -OC(=O)N(R A1 )2, -SC(=O)R A2 , -SC(=O)OR A1 , -SC(=O)SR A1 , -SC(=O)N(R A1 )2, -NHC(=O)R A1 , -NHC(=O)OR A1 , -NHC(=O)SR A1 , -NHC(=O)N(R A1 )2, -OS(=O)2R A2 , -OS(=O)2OR A1 , -SS(=O)2R A2 , -SS(=O)2OR A1 , -S(=O)R A2 , -SO2R A2 , or -S(=O)2OR A1 and R A1 Each occurrence is independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, oxygen protecting groups (oxygen protecting groups), R is a protecting group (when attached to a sulfur atom), a protecting group (when attached to a nitrogen atom), or a protecting group (when attached to a nitrogen atom); A2 each occurrence is independently substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; A is CR 17 or N and R 17is selected from the group consisting of a hydrogen atom, a deuterium atom, an alkyl group, a deuterated alkyl group, a hydroxyl group, an amino group, an alkenyl group, an alkynyl group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group, wherein the alkyl group, the cycloalkyl group, the heterocyclyl group, the aryl group, and the heteroaryl group are optionally further substituted with one or more substituents selected from the group consisting of a deuterium atom, a substituted or unsubstituted alkyl group, a halogen, a hydroxyl group, a substituted or unsubstituted amino group, an oxo group, a nitro group, a cyano group, an alkenyl group, an alkynyl group, an alkoxy group, a hydroxyalkyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted heterocyclic group, a substituted or unsubstituted aryl group, and a substituted or unsubstituted heteroaryl group; [ka] is a double bond, then A is C; [ka] is a double bond, R 5 and R 6a or R 6b one of them is not present; R 3 , R 2a , R 2b , R 4a , R 4b , R 5 , R 6a , R 6b , R 11a , R 11b , R 15a , R 15b , R 16a , R 16b , R 18 , R 19 , R 20a , or R 20bare each independently a hydrogen atom, a deuterium atom, an alkyl group, a deuterated alkyl group, an alkoxy group, a halogenated alkoxy group, a halogen, an amino group, a mercapto group, a nitro group, a hydroxyl group, a cyano group, an alkenyl group, an alkynyl group, a cycloalkyl group, a heterocyclyl group, an aryl group, a heteroaryl group, -(CH2) n1 R 23 , -(CH2) n1 OR 23 , -(CH2) n1 SR 23 , -(CH2) n1 C(O)R 23 , -(CH2) n1 C(O)OR 23 , -(CH2) n1 S(O) m1 R 23 , -(CH2) n1 NR 23 R 24 , -(CH2) n1 C(O)NR 23 R 24 , -(CH2) n1 NR 23 C(O)R 24 or -(CH2) n1 NR 23 S(O) m1 R 24 and the alkyl group, the haloalkyl group, the cycloalkyl group, the heterocyclic group, the aryl group, and the heteroaryl group are selected from the group consisting of a deuterium atom, an alkyl group, a halogen, an amino group, a mercapto group, an oxo group, a nitro group, a cyano group, a hydroxyl group, an alkenyl group, an alkynyl group, an alkoxy group, a halogenated alkoxy group, a hydroxyalkyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted heterocyclic group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, -(CH2) n1 R 25 , -(CH2) n1 OR 25 , -(CH2) n1 SR 25 , -(CH2) n1 C(O)R 25 , -(CH2) n1 C(O)OR25 , -(CH2) n1 S(O) m1 R 25 , -(CH2) n1 NR 25 R 26 , -(CH2) n1 C(O)NR 25 R 26 , -(CH2) n1 C(O)NHR 25 , -(CH2) n1 NR 25 C(O)R 26 , and -(CH2) n1 NR 25 S(O) m1 R 26 or optionally further substituted with one or more of the substituents selected from the group consisting of: Or R 3 , R 2a , R 2b , R 4a , R 4b , R 5 , R 6a , R 6b , R 11a , R 11b , R 15a , R 15b , R 16a , R 16b , R 18 , R 19 , R 20a , or R 20b Any two adjacent or non-adjacent groups among these may form a cycloalkyl group, a heteroalkyl group, an aryl group, and a heteroaryl group, and the cycloalkyl group, the heterocyclic group, the aryl group, and the heteroaryl group may be substituted with a deuterium atom, an alkyl group, a halogen atom, an amino group, a mercapto group, an oxo group, a nitro group, a cyano group, a hydroxyl group, an alkenyl group, an alkynyl group, an alkoxy group, a halogenated alkoxy group, a hydroxyalkyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted heterocyclic group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, -(CH2) n1 R 25 , -(CH2) n1 OR25 , -(CH2) n1 SR 25 , -(CH2) n1 C(O)R 25 , -(CH2) n1 C(O)OR 25 , -(CH2) n1 S(O) m1 R 25 , -(CH2) n1 NR 25 R 26 , -(CH2) n1 C(O)NR 25 R 26 , -(CH2) n1 C(O)NHR 25 , -(CH2) n1 NR 25 C(O)R 26 , and -(CH2) n1 NR 25 S(O) m1 R 26 or optionally further substituted with one or more of the substituents selected from the group consisting of: Or R 15a and R 15b , or R 16a and R 16b together form an oxo (=O) group; Or R 15a or R 15b One of the two and R 16a or R 16b one of which is absent, forming a double bond; R 22 , R 23 , R 24 , R 25 , and R 26are each independently selected from a hydrogen atom, a deuterium atom, an alkyl group, a deuterated alkyl group, a hydroxyl group, an amino group, an alkenyl group, an alkynyl group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group, wherein the alkyl group, the cycloalkyl group, the heterocyclyl group, the aryl group, and the heteroaryl group are optionally further substituted with one or more substituents selected from a deuterium atom, a substituted or unsubstituted alkyl group, a halogen, a hydroxyl group, a substituted or unsubstituted amino group, an oxo group, a nitro group, a cyano group, an alkenyl group, an alkynyl group, an alkoxy group, a hydroxyalkyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted heterocyclic group, a substituted or unsubstituted aryl group, and a substituted or unsubstituted heteroaryl group; however, If m is 0, R 15a or R 15b Any of the is not -H] or a pharmaceutically acceptable salt thereof.

[0008] In some embodiments, the compound has Formula II: [ka] [In formula: m is 0, 1, 2, or 3; m1 is 0, 1, or 2; n is 1 or 2; n1 is 0, 1, 2, 3, 4 or 5; q is independently 0, 1, 2, or 3; r is independently 0, 1, or 2; s is independently 0, 1, or 2; t is independently 0, 1, 2, or 3; u is independently 1 or 2; X is hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -OR A1 , -SR A1 , -N(R A1 )2, -OC(=O)R A1 , -OC(=O)OR A1 , -OC(=O)SR A1 , -OC(=O)N(R A1 )2, -SC(=O)R A2 , -SC(=O)OR A1 , -SC(=O)SR A1 , -SC(=O)N(R A1 )2, -NHC(=O)R A1 , -NHC(=O)OR A1 , -NHC(=O)SR A1 , -NHC(=O)N(R A1 )2, -OS(=O)2R A2 , -OS(=O)2OR A1 , -SS(=O)2R A2 , -SS(=O)2OR A1 , -S(=O)R A2 , -SO2R A2 , or -S(=O)2OR A1 and R A1 each occurrence is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, an oxygen protecting group (when attached to an oxygen atom), a sulfur protecting group (when attached to a sulfur atom), or a nitrogen protecting group (when attached to a nitrogen atom); R A2 each occurrence is independently substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; Z is independently -CR 23 R24 -, -NR 23 -or -O-; A is CR 17 or N and R 17 is selected from the group consisting of a hydrogen atom, a deuterium atom, an alkyl group, a deuterated alkyl group, a hydroxyl group, an amino group, an alkenyl group, an alkynyl group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group, wherein the alkyl group, the cycloalkyl group, the heterocyclyl group, the aryl group, and the heteroaryl group are optionally further substituted with one or more substituents selected from the group consisting of a deuterium atom, a substituted or unsubstituted alkyl group, a halogen, a hydroxyl group, a substituted or unsubstituted amino group, an oxo group, a nitro group, a cyano group, an alkenyl group, an alkynyl group, an alkoxy group, a hydroxyalkyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted heterocyclic group, a substituted or unsubstituted aryl group, and a substituted or unsubstituted heteroaryl group; [ka] is a double bond, then A is C; [ka] is a double bond, R 5 and R 6a or R 6b one of them is not present; R 3 , R 2a , R 2b , R 4a , R 4b , R 5 , R 6a , R 6b , R 11a , R 11b , R 15a , R 15b , R 16a , R 16b , R 18 , R 19 , R 20a , or R 20 bare each independently a hydrogen atom, a deuterium atom, an alkyl group, a deuterated alkyl group, an alkoxy group, a halogenated alkoxy group, a halogen, an amino group, a mercapto group, a nitro group, a hydroxyl group, a cyano group, an alkenyl group, an alkynyl group, a cycloalkyl group, a heterocyclyl group, an aryl group, a heteroaryl group, -(CH2) n1 R 23 , -(CH2) n1 OR 23 , -(CH2) n1 SR 23 , -(CH2) n1 C(O)R 23 , -(CH2) n1 C(O)OR 23 , -(CH2) n1 S(O) m1 R 23 , -(CH2) n1 NR 23 R 24 , -(CH2) n1 C(O)NR 23 R 24 , -(CH2) n1 NR 23 C(O)R 24 or -(CH2) n1 NR 23 S(O) m1 R 24 and the alkyl group, the haloalkyl group, the cycloalkyl group, the heterocyclic group, the aryl group, and the heteroaryl group are selected from the group consisting of a deuterium atom, an alkyl group, a halogen, an amino group, a mercapto group, an oxo group, a nitro group, a cyano group, a hydroxyl group, an alkenyl group, an alkynyl group, an alkoxy group, a halogenated alkoxy group, a hydroxyalkyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted heterocyclic group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, -(CH2) n1 R 25 , -(CH2) n1 OR 25 , -(CH2) n1 SR 25 , -(CH2) n1 C(O)R 25 , -(CH2) n1 C(O)OR25 , -(CH2) n1 S(O) m1 R 25 , -(CH2) n1 NR 25 R 26 , -(CH2) n1 C(O)NR 25 R 26 , -(CH2) n1 C(O)NHR 25 , -(CH2) n1 NR 25 C(O)R 26 , and -(CH2) n1 NR 25 S(O) m1 R 26 or optionally further substituted with one or more of the substituents selected from the group consisting of: Or R 3 , R 2a , R 2b , R 4a , R 4b , R 5 , R 6a , R 6b , R 11a , R 11b , R 15a , R 15b , R 16a , R 16b , R 18 , R 19 , R 20a , or R 20b Any two adjacent or non-adjacent groups among these may form a cycloalkyl group, a heteroalkyl group, an aryl group, and a heteroaryl group, and the cycloalkyl group, the heterocyclic group, the aryl group, and the heteroaryl group may be substituted with a deuterium atom, an alkyl group, a halogen atom, an amino group, a mercapto group, an oxo group, a nitro group, a cyano group, a hydroxyl group, an alkenyl group, an alkynyl group, an alkoxy group, a halogenated alkoxy group, a hydroxyalkyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted heterocyclic group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, -(CH2) n1 R 25 , -(CH2) n1 OR 25, -(CH2) n1 SR 25 , -(CH2) n1 C(O)R 25 , -(CH2) n1 C(O)OR 25 , -(CH2) n1 S(O) m1 R 25 , -(CH2) n1 NR 25 R 26 , -(CH2) n1 C(O)NR 25 R 26 , -(CH2) n1 C(O)NHR 25 , -(CH2) n1 NR 25 C(O)R 26 , and -(CH2) n1 NR 25 S(O) m1 R 26 or optionally further substituted with one or more of the substituents selected from the group consisting of: Or R 15a and R 15b , or R 16a and R 16b together form an oxo (=O) group; Or R 15a or R 15b and R 16a or R 16b one of which is absent, forming a double bond; R 22 , R 23 , R 24 , R 25 , and R 26are each independently selected from a hydrogen atom, a deuterium atom, an alkyl group, a deuterated alkyl group, a hydroxyl group, an amino group, an alkenyl group, an alkynyl group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group, wherein the alkyl group, the cycloalkyl group, the heterocyclyl group, the aryl group, and the heteroaryl group are optionally further substituted with one or more substituents selected from a deuterium atom, a substituted or unsubstituted alkyl group, a halogen, a hydroxyl group, a substituted or unsubstituted amino group, an oxo group, a nitro group, a cyano group, an alkenyl group, an alkynyl group, an alkoxy group, a hydroxyalkyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted heterocyclic group, a substituted or unsubstituted aryl group, and a substituted or unsubstituted heteroaryl group; however, When m is 0 and Z is -CH2-, R 15a or R 15b Any of the is not -H] or a pharmaceutically acceptable salt thereof.

[0009] In one aspect, a compound of formula III: [ka] [In formula: m is 0, 1, 2, or 3; m1 is 0, 1, or 2; n is 1 or 2; n1 is 0, 1, 2, 3, 4 or 5; q is independently 0, 1, 2, or 3; r is independently 0, 1, or 2; s is independently 0, 1, or 2; t is independently 0, 1, 2, or 3; u is independently 1 or 2; X is hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -OR A1 , -SR A1 , -N(R A1 )2, -OC(=O)R A1 , -OC(=O)OR A1 , -OC(=O)SR A1 , -OC(=O)N(R A1 )2, -SC(=O)R A2 , -SC(=O)OR A1 , -SC(=O)SR A1 , -SC(=O)N(R A1 )2, -NHC(=O)R A1 , -NHC(=O)OR A1 , -NHC(=O)SR A1 , -NHC(=O)N(R A1 )2, -OS(=O)2R A2 , -OS(=O)2OR A1 , -SS(=O)2R A2 , -SS(=O)2OR A1 , -S(=O)R A2 , -SO2R A2 , or -S(=O)2OR A1 and R A1 each occurrence is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, an oxygen protecting group (when attached to an oxygen atom), a sulfur protecting group (when attached to a sulfur atom), or a nitrogen protecting group (when attached to a nitrogen atom); R A2 each occurrence is independently substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; Z is independently -CR 23 R24 -, -NR 23 -or -O-; Each W is independently -S(CH2) n1 -, [ka] Selected from; A is CR 17 or N and R 17 is selected from the group consisting of a hydrogen atom, a deuterium atom, an alkyl group, a deuterated alkyl group, a hydroxyl group, an amino group, an alkenyl group, an alkynyl group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group, wherein the alkyl group, the cycloalkyl group, the heterocyclyl group, the aryl group, and the heteroaryl group are optionally further substituted with one or more substituents selected from the group consisting of a deuterium atom, a substituted or unsubstituted alkyl group, a halogen, a hydroxyl group, a substituted or unsubstituted amino group, an oxo group, a nitro group, a cyano group, an alkenyl group, an alkynyl group, an alkoxy group, a hydroxyalkyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted heterocyclic group, a substituted or unsubstituted aryl group, and a substituted or unsubstituted heteroaryl group; [ka] is a double bond, then A is C; [ka] is a double bond, R 5 and R 6a or R 6b one of them is not present; R 3 , R 2a , R 2b , R 4a , R 4b , R 5 , R 6a , R 6b , R 11a , R 11b , R 15a , R 15b, R 16a , R 16b , R 18 , R 19 , R 20a , or R 20b are each independently a hydrogen atom, a deuterium atom, an alkyl group, a deuterated alkyl group, an alkoxy group, a halogenated alkoxy group, a halogen, an amino group, a mercapto group, a nitro group, a hydroxyl group, a cyano group, an alkenyl group, an alkynyl group, a cycloalkyl group, a heterocyclyl group, an aryl group, a heteroaryl group, -(CH2) n1 R 23 , -(CH2) n1 OR 23 , -(CH2) n1 SR 23 , -(CH2) n1 C(O)R 23 , -(CH2) n1 C(O)OR 23 , -(CH2) n1 S(O) m1 R 23 , -(CH2) n1 NR 23 R 24 , -(CH2) n1 C(O)NR 23 R 24 , -(CH2) n1 NR 23 C(O)R 24 or -(CH2) n1 NR 23 S(O) m1 R 24 and the alkyl group, the haloalkyl group, the cycloalkyl group, the heterocyclic group, the aryl group, and the heteroaryl group are selected from the group consisting of a deuterium atom, an alkyl group, a halogen, an amino group, a mercapto group, an oxo group, a nitro group, a cyano group, a hydroxyl group, an alkenyl group, an alkynyl group, an alkoxy group, a halogenated alkoxy group, a hydroxyalkyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted heterocyclic group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, -(CH2) n1 R 25 , -(CH2) n1 OR 25 , -(CH2)n1 SR 25 , -(CH2) n1 C(O)R 25 , -(CH2) n1 C(O)OR 25 , -(CH2) n1 S(O) m1 R 25 , -(CH2) n1 NR 25 R 26 , -(CH2) n1 C(O)NR 25 R 26 , -(CH2) n1 C(O)NHR 25 , -(CH2) n1 NR 25 C(O)R 26 , and -(CH2) n 1NR 25 S(O) m1 R 26 or optionally further substituted with one or more of the substituents selected from the group consisting of: Or R 3 , R 2a , R 2b , R 4a , R 4b , R 5 , R 6a , R 6b , R 11a , R 11b , R 15a , R 15b , R 16a , R 16b , R 18 , R 19 , R 20a , or R 20bAny two adjacent or non-adjacent groups among these may form a cycloalkyl group, a heteroalkyl group, an aryl group, and a heteroaryl group, and the cycloalkyl group, the heterocyclic group, the aryl group, and the heteroaryl group may be substituted with a deuterium atom, an alkyl group, a halogen atom, an amino group, a mercapto group, an oxo group, a nitro group, a cyano group, a hydroxyl group, an alkenyl group, an alkynyl group, an alkoxy group, a halogenated alkoxy group, a hydroxyalkyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted heterocyclic group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, -(CH2) n1 R 25 , -(CH2) n1 OR 25 , -(CH2) n1 SR 25 , -(CH2) n1 C(O)R 25 , -(CH2) n1 C(O)OR 25 , -(CH2) n1 S(O) m1 R 25 , -(CH2) n1 NR 25 R 26 , -(CH2) n1 C(O)NR 25 R 26 , -(CH2) n1 C(O)NHR 25 , -(CH2) n1 NR 25 C(O)R 26 , and -(CH2) n1 NR 25 S(O) m1 R 26 and optionally further substituted with one or more of the substituents selected from the group consisting of: R 22 , R 23 , R 24 , R 25 , and R 26are each independently selected from a hydrogen atom, a deuterium atom, an alkyl group, a deuterated alkyl group, a hydroxyl group, an amino group, an alkenyl group, an alkynyl group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group, wherein the alkyl group, the cycloalkyl group, the heterocyclyl group, the aryl group, and the heteroaryl group are optionally further substituted with one or more substituents selected from a deuterium atom, a substituted or unsubstituted alkyl group, a halogen, a hydroxyl group, a substituted or unsubstituted amino group, an oxo group, a nitro group, a cyano group, an alkenyl group, an alkynyl group, an alkoxy group, a hydroxyalkyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted heterocyclic group, a substituted or unsubstituted aryl group, and a substituted or unsubstituted heteroaryl group; however, If m is 0; Z is -CH2-; W is [ka] and; n1 is 0; R 15a or R 15b [Either -H or -H is not] or a pharmaceutically acceptable salt thereof.

[0010] In some embodiments, the compound has formula IV-A or IV-B: [ka] [In formula: m is 0, 1, 2, or 3; m1 is 0, 1, or 2; n is 1 or 2; n1 is 0, 1, 2, 3, 4 or 5; p is 0, 1, 2, 3 or 4; q is independently 0, 1, 2, or 3; r is independently 0, 1, or 2; s is independently 0, 1, or 2; t is independently 0, 1, 2, or 3; u is independently 1 or 2; X is hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -OR A1 , -SR A1 , -N(R A1 )2, -OC(=O)R A1 , -OC(=O)OR A1 , -OC(=O)SR A1 , -OC(=O)N(R A1 )2, -SC(=O)R A2 , -SC(=O)OR A1 , -SC(=O)SR A1 , -SC(=O)N(R A1 )2, -NHC(=O)R A1 , -NHC(=O)OR A1 , -NHC(=O)SR A1 , -NHC(=O)N(R A1 )2, -OS(=O)2R A2 , -OS(=O)2OR A1 , -SS(=O)2R A2 , -SS(=O)2OR A1 , -S(=O)R A2 , -SO2R A2 , or -S(=O)2OR A1 and R A1 each occurrence is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, an oxygen protecting group (when attached to an oxygen atom), a sulfur protecting group (when attached to a sulfur atom), or a nitrogen protecting group (when attached to a nitrogen atom); R A2each occurrence is independently substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; Z is independently -CR 23 R 24 -, -NR 23 -or -O-; Each W is independently -S(CH2) n1 -, [ka] Selected from; Y is -C(R 23 )2- or oxygen atom; R D are each independently a hydrogen atom, a deuterium atom, an alkyl group, a deuterated alkyl group, an alkoxy group, a halogenated alkoxy group, a halogen, an amino group, a mercapto group, a nitro group, a hydroxyl group, a cyano group, an alkenyl group, an alkynyl group, a cycloalkyl group, a heterocyclyl group, an aryl group, a heteroaryl group, -(CH2) n1 R 23 , -(CH2) n1 OR 23 , -(CH2) n1 SR 23 , -(CH2) n1 C(O)R 23 , -(CH2) n1 C(O)OR 23 , -(CH2) n1 S(O) m1 R 23 , -(CH2) n1 S(O)(NR 23 )R 24 , -(CH2) n1 NR 23 R 24 , -(CH2) n1 C(O)NR 23 R 24 , -(CH2) n1 NR 23 C(O)R 24 or -(CH2)n1 NR 23 S(O) m1 R 24 and the alkyl group, the haloalkyl group, the cycloalkyl group, the heterocyclic group, the aryl group, and the heteroaryl group are selected from the group consisting of a deuterium atom, an alkyl group, a halogen, an amino group, a mercapto group, an oxo group, a nitro group, a cyano group, a hydroxyl group, an alkenyl group, an alkynyl group, an alkoxy group, a halogenated alkoxy group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclic group, an aryl group, a heteroaryl group, -(CH2) n1 R 25 , -(CH2) n1 OR 25 , -(CH2) n1 SR 25 , -(CH2) n1 C(O)R 25 , -(CH2) n1 C(O)OR 25 , -(CH2) n1 S(O) m1 R 25 , -(CH2) n1 NR 25 R 26 , -(CH2) n1 C(O)NR 25 R 26 , -(CH2) n1 C(O)NHR 25 , -(CH2) n1 NR 25 C(O)R 26 , and -(CH2) n1 NR 25 S(O) m1 R 26 and optionally further substituted with one or more of the substituents selected from the group consisting of: [ka] is a double bond, R 5 and R 6a or R 6b one of them is not present; R 3 , R 2a , R 2b , R4a , R 4b , R 5 , R 6a , R 6b , R 11a , R 11b , R 15a , R 15b , R 16a , R 16b , R 18 , R 19 , R 20a , or R 20b are each independently a hydrogen atom, a deuterium atom, an alkyl group, a deuterated alkyl group, an alkoxy group, a halogenated alkoxy group, a halogen, an amino group, a mercapto group, a nitro group, a hydroxyl group, a cyano group, an alkenyl group, an alkynyl group, a cycloalkyl group, a heterocyclyl group, an aryl group, a heteroaryl group, -(CH2) n1 R 23 , -(CH2) n1 OR 23 , -(CH2) n1 SR 23 , -(CH2) n1 C(O)R 23 , -(CH2) n1 C(O)OR 23 , -(CH2) n1 S(O) m1 R 23 , -(CH2) n1 NR 23 R 24 , -(CH2) n1 C(O)NR 23 R 24 , -(CH2) n1 NR 23 C(O)R 24 or -(CH2) n1 NR 23 S(O) m1 R 24and the alkyl group, the haloalkyl group, the cycloalkyl group, the heterocyclic group, the aryl group, and the heteroaryl group are selected from the group consisting of a deuterium atom, an alkyl group, a halogen, an amino group, a mercapto group, an oxo group, a nitro group, a cyano group, a hydroxyl group, an alkenyl group, an alkynyl group, an alkoxy group, a halogenated alkoxy group, a hydroxyalkyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted heterocyclic group, a substituted or unsubstituted is an unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, -(CH2) n1 R 25 , -(CH2) n1 OR 25 , -(CH2) n1 SR 25 , -(CH2) n1 C(O)R 25 , -(CH2) n1 C(O)OR 25 , -(CH2) n1 S(O) m1 R 25 , -(CH2) n1 NR 25 R 26 , -(CH2) n1 C(O)NR 25 R 26 , -(CH2) n1 C(O)NHR 25 , -(CH2) n1 NR 25 C(O)R 26 , and -(CH2) n1 NR 25 S(O) m1 R 26 or optionally further substituted with one or more of the substituents selected from the group consisting of: Or R 3 , R 2a , R 2b , R 4a , R 4b , R 5 , R 6a , R 6b , R 11a , R 11b , R 15a , R 15b , R 16a, R 16b , R 18 , R 19 , R 20a , or R 20b Any two adjacent or non-adjacent groups among these may form a cycloalkyl group, a heteroalkyl group, an aryl group, and a heteroaryl group, and the cycloalkyl group, the heterocyclic group, the aryl group, and the heteroaryl group may be substituted with a deuterium atom, an alkyl group, a halogen atom, an amino group, a mercapto group, an oxo group, a nitro group, a cyano group, a hydroxyl group, an alkenyl group, an alkynyl group, an alkoxy group, a halogenated alkoxy group, a hydroxyalkyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted heterocyclic group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, -(CH2) n1 R 25 , -(CH2) n1 OR 25 , -(CH2) n1 SR 25 , -(CH2) n1 C(O)R 25 , -(CH2) n1 C(O)OR 25 , -(CH2) n1 S(O) m1 R 25 , -(CH2) n1 NR 25 R 26 , -(CH2) n1 C(O)NR 25 R 26 , -(CH2) n1 C(O)NHR 25 , -(CH2) n1 NR 25 C(O)R 26 , and -(CH2) n1 NR 25 S(O) m1 R 26 or optionally further substituted with one or more of the substituents selected from the group consisting of: Or R 15a and R 15b , or R 16a and R 16b together form an oxo (=O) group; Or R 15a or R 15b and R 16a or R 16b one of which is absent, forming a double bond; R 22 , R 23 , R 24 , R 25 , and R 26 are each independently selected from a hydrogen atom, a deuterium atom, an alkyl group, a deuterated alkyl group, a hydroxyl group, an amino group, an alkenyl group, an alkynyl group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group, wherein the alkyl group, the cycloalkyl group, the heterocyclyl group, the aryl group, and the heteroaryl group are optionally further substituted with one or more substituents selected from a deuterium atom, a substituted or unsubstituted alkyl group, a halogen, a hydroxyl group, a substituted or unsubstituted amino group, an oxo group, a nitro group, a cyano group, an alkenyl group, an alkynyl group, an alkoxy group, a hydroxyalkyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted heterocyclic group, a substituted or unsubstituted aryl group, and a substituted or unsubstituted heteroaryl group. or a pharmaceutically acceptable salt thereof.

[0011] In some embodiments, Formula V: [ka] [In formula: m is 0, 1, 2, or 3; n is 1 or 2; q is independently 0, 1, 2, or 3; r is independently 0, 1, or 2; s is independently 0, 1, or 2; t is independently 0, 1, 2, or 3; u is independently 1 or 2; X is hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -OR A1 , -SR A1 , -N(R A1 )2, -OC(=O)R A1 , -OC(=O)OR A1 , -OC(=O)SR A1 , -OC(=O)N(R A1 )2, -SC(=O)R A2 , -SC(=O)OR A1 , -SC(=O)SR A1 , -SC(=O)N(R A1 )2, -NHC(=O)R A1 , -NHC(=O)OR A1 , -NHC(=O)SR A1 , -NHC(=O)N(R A1 )2, -OS(=O)2R A2 , -OS(=O)2OR A1 , -SS(=O)2R A2 , -SS(=O)2OR A1 , -S(=O)R A2 , -SO2R A2 , or -S(=O)2OR A1 and R A1 each occurrence is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, an oxygen protecting group (when attached to an oxygen atom), a sulfur protecting group (when attached to a sulfur atom), or a nitrogen protecting group (when attached to a nitrogen atom); R A2 each occurrence is independently substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 5 is hydrogen or methyl, or [ka] is a double bond, R 5 and R 6a or R 6b one of them is not present; R 19 is hydrogen or substituted or unsubstituted alkyl; R 18 is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl; R 3 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 6a and R 6b each is independently hydrogen, halogen, cyano, hydroxyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl; or R 6a and R 6b together form an oxo (=O) group; R 2a , R 2b , R 4a , R 4b , R 11a , R 11b , R 16a , or R 16b each independently represents hydrogen, halogen, cyano, hydroxyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted alkynyl, -OR D1 , -OC(=O)R D1 , -NH2, -N(R D1 )2, or -NR D1 C(=O)R D1 and R D1each occurrence is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, an oxygen protecting group (when attached to an oxygen atom), a nitrogen protecting group (when attached to a nitrogen atom), or two R D1 groups taken together form a substituted or unsubstituted heterocyclic ring; or R 2a and R 2b , or R 4a and R 4b , or R 11a and R 11b , or R 16a and R 16b any one of which taken together form an oxo (=O) group; however, q, s, r, u, and t cannot simultaneously be 1] or a pharmaceutically acceptable salt thereof.

[0012] In some embodiments, Formula VI: [ka] [In formula: m is 0, 1, 2, 3, or 4; n is 0, 1, 2, 3, or 4; However, if m is 0, then n is not 0 or 1; X is hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 1a , R 1b , R 2a , R 2b , R 4a , R 4b , R 7a , R 7b , R 11a , R11b , R 12a , R 12b , R 15a , R 15b , R 16a , and R 16b Each of independently hydrogen, halogen, cyano, -NO2, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -OR A1 , -N(R A1 )2, -SR A1 , -C(=O)R A1 , -C(=O)OR A1 , -C(=O)SR A1 , -C(=O)N(R A1 )2, -OC(=O)R A1 , -OC(=O)OR A1 , -OC(=O)N(R A1 )2, -OC(=O)SR A1 , -OS(=O)2R A1 , -OS(=O)2OR A1 , -OS(=O)2N(R A1 )2, -N(R A1 )C(=O)R A1 , -N(R A1 )C(=NR A1 )R A1 , -N(R A1 )C(=O)OR A1 , -N(R A1 )C(=O)N(R A1 )2, -N(R A1 )C(=NR A1 )N(R A1 )2, -N(R A1 )S(=O)2R A1 , -N(R A1 )S(=O)2OR A1 , -N(R A1 )S(=O)2N(R A1 )2, -SC(=O)R A1 , -SC(=O)OR A1 , -SC(=O)SR A1 , -SC(=O)N(RA1 )2, -S(=O)2R A1 , -S(=O)2OR A1 , or -S(=O)2N(R A1 )2 and R A1 each occurrence of is independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, or substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, an oxygen protecting group (when oxygen is attached), a nitrogen protecting group (when nitrogen is attached), or a sulfur protecting group (when sulfur is attached); or R 11a and R 11b together form an oxo (=O) group; or R 12a and R 12b together form an oxo (=O) group; or R 15a and R 15b together form an oxo (=O) group; or R 16a and R 16b together form an oxo (=O) group; or R 4a and R 4b together form an oxo (=O) group; or R 7a and R 7b together form an oxo (=O) group; or R 2a and R 2b together form an oxo (=O) group; or R 1a and R 1b together form an oxo (=O) group; R 3 is hydrogen, substituted or unsubstituted alkyl; R 5 is hydrogen or methyl; R 6a and R 6b each is independently hydrogen, halogen, cyano, —NO, —OH, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl; or R 6a and R 6btogether form an oxo (=O) group; R 18 is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl; R 19 is hydrogen or substituted or unsubstituted alkyl; And R 20a , R 20b , R 23a , or R 23b are each independently selected from the group consisting of a hydrogen atom, an alkyl group, a halogenated alkyl group, an alkoxy group, and a halogenated alkoxy group. or a pharmaceutically acceptable salt thereof. DETAILED DESCRIPTION OF THE INVENTION

[0013] As generally described herein, the present invention provides compounds designed to act, for example, as GABA receptor modulators. In certain embodiments, such compounds are expected to be useful as therapeutic agents for treating CNS-related disorders (e.g., disorders described herein, e.g., depression, such as postpartum depression or major depressive disorder).

[0014] I. Definition

[0015] Specific functional groups and chemical term definitions are explained in detail below. Chemical elements are defined by the Periodic Table of Elements. (CAS method, Handbook of Chemistry and Physics, 75 th (Ed., inside cover), and specific functional groups are generally defined as described therein. Further, general principles of organic chemistry, as well as specific functional moieties and reactivities, are described in Thomas Sorrell, Organic Chemistry, University Science Books, Sausalito, 1999; Smith and March, March's Advanced Organic Chemistry, 5 thEdition, John Wiley & Sons, Inc., New York, 2001; Larock, Comprehensive Organic Transformations, VCH Publishers, Inc., New York, 1989; and Carruthers, Some Modern Methods of Organic Synthesis, 3 rd Edition, Cambridge University Press, Cambridge, 1987.

[0016] Isomers, e.g., stereoisomers, can be isolated from mixtures by methods known to those skilled in the art, including chiral high-pressure liquid chromatography (HPLC) and chiral salt formation and crystallization, or preferred isomers can be prepared by asymmetric synthesis. See, for example, Jacques et al., Enantiomers, Racemates, and Resolutions (Wiley Interscience, New York, 1981); Wilen et al., Tetrahedron 33:2725 (1977); Eliel, Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); and Wilen, Tables of Resolving Agents and Optical Resolutions p. 268 (EL Eliel, Ed., University of Notre Dame Press, Notre Dame, IN 1972). The present invention further encompasses the compounds described herein as individual isomers substantially free of other isomers, or as mixtures of various isomers.

[0017] "Stereoisomers": It should also be understood that compounds that have the same molecular formula but differ in the nature or bonding sequence of their atoms or the arrangement of their atoms in space are referred to as "isomers." Isomers that differ in the arrangement of their atoms in space are referred to as "stereoisomers." Stereoisomers that are not mirror images of each other are referred to as "diastereomers," and those that are non-superimposable mirror images of each other are referred to as "enantiomers." For example, if a compound has an asymmetric center and is bonded to four different groups, a set of enantiomers is possible. Enantiomers can be characterized by the absolute configuration of their asymmetric center, described by the R- and S-sequencing rules of Cahn and Prelog, or by the way the molecule rotates the plane of polarized light, described as dextrorotatory or levorotatory (i.e., (+) or (-) isomers, respectively). Chiral compounds can exist as individual enantiomers or as mixtures thereof. A mixture containing equal proportions of enantiomers is called a "racemic mixture."

[0018] As used herein, a pure enantiomer compound is substantially free of other enantiomers or stereoisomers of a compound (i.e., in enantiomeric excess). In other words, the "S" form of a compound is substantially free of the "R" form of the compound and is thus in enantiomeric excess of the "R" form. The terms "enantiomerically pure" or "pure enantiomer" indicate that a compound contains more than 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 98.5%, 99%, 99.2%, 99.5%, 99.6%, 99.7%, 99.8%, or 99.9% by weight of an enantiomer. In certain embodiments, the weight is based on the total weight of all enantiomers or stereoisomers of the compound.

[0019] As used herein, the term "diastereomerically pure" refers to the amount of a compound having the depicted absolute stereochemistry, expressed as a ratio of the total amount of the depicted compound and its diastereomer. The term "diastereomerically pure" indicates that a compound contains greater than 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 98.5%, 99%, 99.2%, 99.5%, 99.6%, 99.7%, 99.8%, or 99.9% by weight of a diastereomer. Methods for determining diastereomeric and enantiomeric purity are well known in the art. Diastereomeric purity can be determined by any analytical method capable of quantitatively distinguishing between a compound and its diastereomer, such as high-performance liquid chromatography (HPLC).

[0020] In the compositions provided herein, the enantiomerically pure compound can be present together with other active or inactive ingredients. For example, a pharmaceutical composition containing an enantiomerically pure R position / center / carbon compound can contain, for example, about 90% excipients and about 10% enantiomerically pure R compound. In certain embodiments, the enantiomerically pure R compound in such a composition can contain, for example, at least about 95% by weight of the R compound and up to about 5% by weight of the S compound, based on the total weight of the compound. For example, a pharmaceutical composition containing an enantiomerically pure S compound can contain, for example, about 90% excipients and about 10% of the enantiomerically pure S compound. In certain embodiments, the enantiomerically pure S compound in such a composition can contain, for example, at least about 95% by weight of the S compound and up to about 5% by weight of the R compound, based on the total weight of the compound. In certain embodiments, the active ingredient can be formulated with little or no excipients or carriers.

[0021] The articles "a" and "an" may be used herein to refer to one or to more than one (i.e., to at least one) of the grammatical object of the article. By way of example, "an analogue" means one analogue or multiple analogues.

[0022] When a range of values ​​is listed, it is intended to encompass each value and subrange within the range. For example, "C 1~6 "Alkyl" refers to C1, C2, C3, C4, C5, C6, C 1~6 , C 1~5 , C 1~4 , C 1~3 , C 1~2 , C 2~6 , C 2~5 , C 2~4 , C 2~3 , C 3~6 , C 3~5 , C 3~4 , C 4~6 , C 4~5 , and C 5~6 Alkyl is intended to be included.

[0023] The following terms are intended to have the meanings provided below and are useful in understanding the specification and the intended scope of the invention.

[0024] "Alkyl" means the radical of a linear or branched saturated hydrocarbon group having 1 to 20 carbon atoms ("C 1~20 In some embodiments, an alkyl group has 1 to 12 carbon atoms ("C 1~12 In some embodiments, an alkyl group has 1 to 10 carbon atoms ("C 1~10 In some embodiments, an alkyl group has 1 to 9 carbon atoms ("C 1~9 In some embodiments, the alkyl group has 1 to 8 carbon atoms ("C 1~8 In some embodiments, the alkyl group has 1 to 7 carbon atoms ("C 1~7In some embodiments, an alkyl group has 1 to 6 carbon atoms (also referred to herein as "lower alkyl" or "C 1~6 In some embodiments, an alkyl group has 1 to 5 carbon atoms ("C 1~5 In some embodiments, an alkyl group has 1 to 4 carbon atoms ("C 1~4 Al In some embodiments, the alkyl group has 1 to 3 carbon atoms ("C 1~3 In some embodiments, the alkyl group has 1 to 2 carbon atoms ("C 1~2 In some embodiments, the alkyl group has 1 carbon atom ("C alkyl"). In some embodiments, the alkyl group has 2 to 6 carbon atoms ("C 2~6 alkyl). C 1~6 Examples of alkyl groups include methyl (C1), ethyl (C2), n-propyl (C3), isopropyl (C3), n-butyl (C4), tert-butyl (C4), sec-butyl (C4), iso-butyl (C4), n-pentyl (C5), 3-pentanyl (C5), amyl (C5), neopentyl (C5), 3-methyl-2-butanyl (C5), tertiary amyl (C5), and n-hexyl (C6). Further examples of alkyl groups include n-heptyl (C7), n-octyl (C8), and the like. Unless otherwise specified, each occurrence of an alkyl group is independently optionally substituted, i.e., unsubstituted ("unsubstituted alkyl") or substituted with one or more substituents, e.g., 1 to 5 substituents, 1 to 3 substituents, or 1 substituent ("substituted alkyl"). In certain embodiments, an alkyl group is an unsubstituted C 1~10 In certain embodiments, the alkyl group is a substituted C 1~10 Common abbreviations for alkyl include Me(-CH), Et(-CHCH), iPr(-CH(CH)), nPr(-CHCHCH), n-Bu(-CHCHCHCHCH), or i-Bu(-CHCH(CH)).

[0025] "Alkylene" refers to an alkyl group in which two hydrogens are removed to provide a divalent radical, which can be substituted or unsubstituted. Unsubstituted alkylene groups include, but are not limited to, methylene (-CH-), ethylene (-CHCH-), propylene (-CHCHCH-), butylene (-CHCHCHCHCH-), pentylene (-CHCHCHCHCHCH-), hexylene (-CHCHCHCHCHCHCH-), and the like. Examples of substituted alkylene groups, e.g., substituted with one or more alkyl (methyl) groups, include, but are not limited to, substituted methylene (-CH(CH)-, (-C(CH)-), substituted ethylene (-CH(CH)CH-, -CHCH(CH)-, -C(CH)CH-, -CHC(CH)-), substituted propylene (-CH(CH)CHCH-, -CHCH(CH)CH-, -CHCHCH(CH)CH-, -CHCHCH(CH)-, -C(CH)CHCH-, -CHC(CH)CH-, -CHCHC(CH)-), and the like. When a range or number of carbons is given for a particular alkylene group, it is understood that the range or number refers to the range or number of carbons in a divalent linear carbon chain. An alkylene group can be substituted or unsubstituted with one or more substituents described herein.

[0026] "Alkenyl" refers to the radical of a straight-chain or branched hydrocarbon group having 2 to 20 carbon atoms, one or more carbon-carbon double bonds (e.g., 1, 2, 3, or 4 carbon-carbon double bonds), and optionally one or more carbon-carbon triple bonds (e.g., 1, 2, 3, or 4 carbon-carbon triple bonds) ("C 2~20 In certain embodiments, alkenyl does not contain any triple bonds. In some embodiments, alkenyl groups have 2 to 10 carbon atoms ("C 2~10 In some embodiments, an alkenyl group has 2 to 9 carbon atoms ("C 2~9 In some embodiments, an alkenyl group has 2 to 8 carbon atoms ("C2~8 In some embodiments, an alkenyl group has 2 to 7 carbon atoms ("C 2~7 In some embodiments, an alkenyl group has 2 to 6 carbon atoms ("C 2~6 In some embodiments, an alkenyl group has 2 to 5 carbon atoms ("C 2~5 In some embodiments, an alkenyl group has 2 to 4 carbon atoms ("C 2~4 In some embodiments, an alkenyl group has 2 to 3 carbon atoms ("C2 ~3 In some embodiments, an alkenyl group has two carbon atoms ("C2 alkenyl"). The one or more carbon-carbon double bonds can be internal (such as 2-butenyl) or terminal (such as 1-butenyl). C 2~4 Examples of alkenyl groups include ethenyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), and the like. 2~6 Examples of alkenyl groups include the above-mentioned C 2~4 Alkenyl groups include pentenyl (C5), pentadienyl (C5), hexenyl (C6), and the like. Further examples of alkenyl include heptenyl (C7), octenyl (C8), octatrienyl (C8), and the like. Unless otherwise specified, each occurrence of an alkenyl group is independently optionally substituted, i.e., unsubstituted ("unsubstituted alkenyl") or substituted with one or more substituents, e.g., 1 to 5 substituents, 1 to 3 substituents, or 1 substituent ("substituted alkenyl"). In certain embodiments, an alkenyl group is an unsubstituted C 2~10 In certain embodiments, the alkenyl group is a substituted C 2~10 It is alkenyl.

[0027] "Alkynyl" refers to the radical of a straight-chain or branched hydrocarbon group having 2 to 20 carbon atoms, one or more carbon-carbon triple bonds (e.g., 1, 2, 3, or 4 carbon-carbon triple bonds), and, optionally, one or more carbon-carbon double bonds (e.g., 1, 2, 3, or 4 carbon-carbon double bonds) ("C 2~20 In certain embodiments, alkynyl groups contain no double bonds. In some embodiments, alkynyl groups have 2 to 10 carbon atoms ("C 2~10 In some embodiments, an alkynyl group has 2 to 9 carbon atoms ("C 2~9 In some embodiments, an alkynyl group has 2 to 8 carbon atoms ("C 2~8 In some embodiments, an alkynyl group has 2 to 7 carbon atoms ("C 2~7 In some embodiments, an alkynyl group has 2 to 6 carbon atoms ("C 2~6 In some embodiments, an alkynyl group has 2 to 5 carbon atoms ("C 2~5 In some embodiments, an alkynyl group has 2 to 4 carbon atoms ("C 2~4 In some embodiments, an alkynyl group has 2 to 3 carbon atoms ("C 2~3 In some embodiments, an alkynyl group has two carbon atoms ("C2 alkynyl"). The one or more carbon-carbon triple bonds can be internal (such as 2-butynyl) or terminal (such as 1-butynyl). C 2~4 Examples of alkynyl groups include, but are not limited to, ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), and the like. 2~6 Examples of alkynyl groups include the above-mentioned C 2~4Alkynyl groups include pentynyl (C5), hexynyl (C6), and the like. Further examples of alkynyl include heptynyl (C7), octynyl (C8), and the like. Unless otherwise specified, each occurrence of an alkynyl group is independently optionally substituted, i.e., unsubstituted ("unsubstituted alkynyl") or substituted with one or more substituents, e.g., 1 to 5 substituents, 1 to 3 substituents, or 1 substituent ("substituted alkynyl"). In certain embodiments, an alkynyl group is an unsubstituted C 2~10 In certain embodiments, the alkynyl group is a substituted C 2~10 It is alkynyl.

[0028] The term "heteroalkyl," as used herein, refers to an alkyl group, as defined herein, further comprising one or more (e.g., 1, 2, 3, or 4) heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus) in the parent chain, wherein one or more heteroatoms are inserted between adjacent carbon atoms in the parent carbon chain and / or between a carbon atom and the parent molecule, i.e., between the points of attachment. In certain embodiments, a heteroalkyl group is a saturated group having 1 to 10 carbon atoms and 1, 2, 3, or 4 heteroatoms ("heteroC 1~10 Some In embodiments, a heteroalkyl group is a saturated group having 1 to 9 carbon atoms and 1, 2, 3, or 4 heteroatoms ("heteroC"). 1~9 In some embodiments, a heteroalkyl group is a saturated group having 1 to 8 carbon atoms and 1, 2, 3, or 4 heteroatoms ("heteroC 1~8 In some embodiments, a heteroalkyl group is a saturated group having 1 to 7 carbon atoms and 1, 2, 3, or 4 heteroatoms ("heteroC 1~7 In some embodiments, a heteroalkyl group is a group having 1 to 6 carbon atoms and 1, 2, or 3 heteroatoms ("heteroC 1~6In some embodiments, a heteroalkyl group is a saturated group having 1 to 5 carbon atoms and 1 or 2 heteroatoms ("heteroC 1~5 In some embodiments, a heteroalkyl group is a saturated group having 1 to 4 carbon atoms and 1 or 2 heteroatoms ("heteroC 1~4 In some embodiments, a heteroalkyl group is a saturated group having 1 to 3 carbon atoms and 1 heteroatom ("heteroC 1~3 In some embodiments, a heteroalkyl group is a saturated group having 1 to 2 carbon atoms and 1 heteroatom ("heteroC 1~2 In some embodiments, the heteroalkyl group is a saturated group having 1 carbon atom and 1 heteroatom ("heteroC1 alkyl"). In some embodiments, the heteroalkyl group is a saturated group having 2-6 carbon atoms and 1 or 2 heteroatoms ("heteroC 2~6 Unless otherwise specified, each occurrence of a heteroalkyl group is independently unsubstituted ("unsubstituted heteroalkyl") or substituted with one or more substituents ("substituted heteroalkyl"). In certain embodiments, a heteroalkyl group is an unsubstituted heteroC 1~10 In certain embodiments, the heteroalkyl group is a substituted heteroC 1~10 It is alkyl.

[0029] "Aryl" refers to a radical of a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 (e.g., having 6, 10, or 14 pi electrons shared in a cyclic arrangement) aromatic ring system having 6 to 14 ring carbon atoms and 0 heteroatoms provided in the aromatic ring system ("C 6~14 In some embodiments, an aryl group has 6 ring carbon atoms ("C aryl"; e.g., phenyl). In some embodiments, an aryl group has 10 ring carbon atoms ("C 10aryl"; e.g., naphthyl, such as 1-naphthyl and 2-naphthyl). In some embodiments, an aryl group has 14 ring carbon atoms ("C 14 "Aryl"; e.g., anthracyl). "Aryl" also includes ring systems in which an aryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups, in which case the bonding radical or point of attachment is on the aryl ring, and in such cases the number of carbon atoms continues to refer to the number of carbon atoms in the aryl ring system. Typical aryl groups include, but are not limited to, groups derived from aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, coronene, fluoranthene, fluorene, hexacene, hexaphene, hexalene, as-indacene, s-indacene, indane, indene, naphthalene, octacene, octaphene, octalene, ovalene, penta-2,4-diene, pentacene, pentalene, pentaphene, perylene, phenalene, phenanthrene, picene, pleiadene, pyrene, pyranthrene, rubicene, triphenylene, and trinaphthalene. Particularly, aryl groups include phenyl, naphthyl, indenyl, and tetrahydronaphthyl. Unless otherwise specified, each occurrence of the aryl group is independently optionally substituted, i.e., unsubstituted ("unsubstituted aryl"), or substituted with one or more substituents ("substituted aryl"). In certain embodiments, the aryl group is an unsubstituted C 6~14 In certain embodiments, the aryl group is a substituted C 6~14 It is aryl.

[0030] In certain embodiments, the aryl group is selected from the group consisting of halogen, C1-C8 alkyl, C1-C8 It is substituted with one or more groups selected from haloalkyl, cyano, hydroxy, C1-C8 alkoxy, and amino.

[0031] Representative examples of substituted aryl include the following: [ka] are listed, In the formula, R 56 and R 57 can be hydrogen, and R 56 and R 57 At least one of the following is independently C 1~8 Alkyl, C 1~8 Haloalkyl, 4-10 membered heterocyclyl, alkanoyl, C 1~8 Alkoxy, heteroaryloxy, alkylamino, arylamino, heteroarylamino, -NR 58 COR 59 , -NR 58 SOR 59 , -NR 58 SO2R 59 , -COO alkyl, -COO aryl, -CONR 58 R 59 , -CONR 58 OR 59 , -NR 58 R 59 , -SO2NR 58 R 59 , -S-alkyl, -SO-alkyl, -SO2-alkyl, -S-aryl, -SO-aryl, -SO2-aryl, or R 56 and R 57 may be linked to form a cyclic ring (saturated or unsaturated) of 5 to 8 atoms (optionally containing one or more heteroatoms selected from the group N, O, or S). 60 and R 61 are independently hydrogen, C 1~8 Alkyl, C 1~4 Haloalkyl, C 3~10 Cycloalkyl, 4-10 membered heterocyclyl, C 6~10 Aryl, substituted C6 10 It is aryl, 5- to 10-membered heteroaryl, or substituted 5- to 10-membered heteroaryl.

[0032] "Fused aryl" refers to an aryl having two of its ring carbons in common with a second aryl or heteroaryl ring, or a carbocyclyl or heterocyclyl ring.

[0033] "Heteroaryl" refers to a radical of a 5- to 10-membered monocyclic or bicyclic 4n+2 (e.g., having 6 or 10 π-electrons shared in the cyclic arrangement) aromatic ring system in which ring carbon atoms and 1 to 4 ring heteroatoms are provided in the aromatic ring system, with each heteroatom independently selected from nitrogen, oxygen, and sulfur ("5- to 10-membered heteroaryl"). In heteroaryl groups containing one or more nitrogen atoms, the point of attachment can be at a carbon atom or a nitrogen atom, as long as the valence allows. Heteroaryl bicyclic ring systems can contain one or more heteroatoms in one or both rings. "Heteroaryl" includes ring systems in which a heteroaryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups, in which case the point of attachment is on the heteroaryl ring; in such cases, the ring member number continues to refer to the number of ring members in the heteroaryl ring system. "Heteroaryl" also includes ring systems in which a heteroaryl ring, as defined above, is fused to one or more aryl groups, in which case the point of attachment can be on either the aryl ring or the heteroaryl ring, and in such cases the ring member count refers to the number of ring members in the fused (aryl / heteroaryl) ring system. In bicyclic heteroaryl groups in which one ring does not contain a heteroatom (e.g., indolyl, quinolinyl, carbazolyl, etc.), the point of attachment can be on either ring, i.e., on the heteroatom-bearing ring. The heteroatom may be present on a ring containing a heteroatom (eg, 2-indolyl) or on a ring containing no heteroatoms (eg, 5-indolyl).

[0034] In some embodiments, heteroaryl groups are 5- to 10-membered aromatic ring systems having ring carbon atoms and 1-4 ring heteroatoms independently selected from nitrogen, oxygen, and sulfur ("5- to 10-membered heteroaryl"). In some embodiments, heteroaryl groups are 5- to 8-membered aromatic ring systems having ring carbon atoms and 1-4 ring heteroatoms independently selected from nitrogen, oxygen, and sulfur ("5- to 8-membered heteroaryl"). In some embodiments, heteroaryl groups are 5- to 6-membered aromatic ring systems having carbon atoms and 1-4 ring heteroatoms independently selected from nitrogen, oxygen, and sulfur ("5- to 6-membered heteroaryl"). In some embodiments, 5- to 6-membered heteroaryls have 1-3 ring heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, 5- to 6-membered heteroaryls have 1-2 ring heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, a 5- to 6-membered heteroaryl has one ring heteroatom selected from nitrogen, oxygen, and sulfur. Unless otherwise specified, each occurrence of a heteroaryl group is independently optionally substituted, i.e., unsubstituted ("unsubstituted heteroaryl") or substituted with one or more substituents ("substituted heteroaryl"). In certain embodiments, a heteroaryl group is an unsubstituted 5- to 14-membered heteroaryl. In certain embodiments, a heteroaryl group is a substituted 5- to 14-membered heteroaryl.

[0035] Exemplary 5-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyrrolyl, furanyl, and thiophenyl. Exemplary 5-membered heteroaryl groups containing two heteroatoms include, but are not limited to, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered heteroaryl groups containing three heteroatoms include, but are not limited to, triazolyl, oxadiazolyl, and thiadiazolyl. Exemplary 5-membered heteroaryl groups containing four heteroatoms include, but are not limited to, tetrazolyl. Exemplary 6-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyridinyl. Exemplary 6-membered heteroaryl groups containing two heteroatoms include, but are not limited to, pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6-membered heteroaryl groups containing three or four heteroatoms include, but are not limited to, triazinyl and tetrazinyl, respectively. Exemplary 7-membered heteroaryl groups containing one heteroatom include, but are not limited to, azepinyl, oxepinyl, and thiepinyl. Exemplary 5,6-bicyclic heteroaryl groups include, but are not limited to, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzothiazolyl, benzisothiazolyl, benzothiadiazolyl, indolizinyl, and purinyl. Exemplary 6,6-bicyclic heteroaryl groups include, but are not limited to, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl.

[0036] Representative examples of heteroaryls include: [ka] are listed, where each Z is a carbonyl, N, NR 65 , O, and S; R 65 are independently hydrogen, C1-8 alkyl, C3- 10 Cycloalkyl, 4-10 membered heterocyclyl, C6-C 10 aryl, and 5- to 10-membered heteroaryl.

[0037] "Carbocyclyl" or "carbocyclic" means a ring system having 3 to 10 ring carbon atoms ("C 3~10 In some embodiments, a carbocyclyl group has 3 to 8 ring carbon atoms ("C 3~8 In some embodiments, a carbocyclyl group has 3 to 6 ring carbon atoms ("C 3~6 In some embodiments, a carbocyclyl group has 3 to 6 ring carbon atoms ("C 3~6 In some embodiments, a carbocyclyl group has 5 to 10 ring carbon atoms ("C 5~10 carbocyclyl). Exemplary C 3~6 Carbocyclyl groups include, but are not limited to, cyclopropyl (C), cyclopropenyl (C), cyclobutyl (C), cyclobutenyl (C), cyclopentyl (C), cyclopentenyl (C), cyclohexyl (C), cyclohexenyl (C), cyclohexadienyl (C), and the like. 3~8 The carbocyclyl group includes the above-mentioned C 3~6 Examples of carbocyclyl groups include, but are not limited to, cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (C8), and the like. 3~10 As the carbocyclyl group, the above-mentioned C 3~8 Carbocyclyl groups, as well as cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C10 ), cyclodecenyl (C 10 ), octahydro-1H-indenyl (C9), decahydronaphthalenyl (C 10 ), spiro[4.5]decanyl (C 10 ), and the like. Illustrating the foregoing examples, in certain embodiments, a carbocyclyl group is monocyclic ("monocyclic carbocyclyl") or contains a fused, bridged, or spiro ring system (e.g., a bicyclic system ("bicyclic carbocyclyl")), which may be saturated or partially unsaturated. "Carbocyclyl" also includes ring systems in which a carbocyclyl ring, as defined above, is fused with one or more aryl or heteroaryl groups, in which case the point of attachment is on the carbocyclyl ring, and in such cases the number of carbons continues to refer to the number of carbons in the carbocyclyl ring system. Unless otherwise specified, each occurrence of a carbocyclyl group is Independently, it is optionally substituted, i.e., unsubstituted ("unsubstituted carbocyclyl") or substituted with one or more substituents ("substituted carbocyclyl"). In certain embodiments, a carbocyclyl group is an unsubstituted C 3~10 In certain embodiments, the carbocyclyl group is a substituted C 3~10 It is a carbocyclyl.

[0038] In some embodiments, "carbocyclyl" refers to a monocyclic saturated carbocyclyl group having 3 to 10 ring carbon atoms ("C 3~10 In some embodiments, a cycloalkyl group has 3 to 8 ring carbon atoms ("C 3~8 In some embodiments, a cycloalkyl group has 3 to 6 ring carbon atoms ("C 3~6 In some embodiments, a cycloalkyl group has 5 to 6 ring carbon atoms ("C 5~6 In some embodiments, a cycloalkyl group has 5 to 10 ring carbon atoms ("C 5~10 Cycloalkyl). C 5~6Examples of cycloalkyl groups include cyclopentyl (C5) and cyclohexyl (C5). 3~6 Examples of cycloalkyl groups include the above-mentioned C 5~6 Cycloalkyl groups include cyclopropyl (C3) and cyclobutyl (C4). 3~8 Examples of cycloalkyl groups include the above-mentioned C 3~6 Cycloalkyl groups include cycloalkyl groups, as well as cycloheptyl (C7) and cyclooctyl (C8). Unless otherwise specified, each occurrence of a cycloalkyl group is independently unsubstituted ("unsubstituted cycloalkyl") or substituted with one or more substituents ("substituted cycloalkyl"). In certain embodiments, a cycloalkyl group is an unsubstituted C 3~10 In certain embodiments, the cycloalkyl group is a substituted C 3~10 It is cycloalkyl.

[0039] "Heterocyclyl" or "heterocyclic" refers to a radical of a 3- to 10-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, each heteroatom independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon ("3- to 10-membered heterocyclyl"). In heterocyclyl groups containing one or more nitrogen atoms, the point of attachment can be at a carbon atom or a nitrogen atom, where valence allows. Heterocyclyl groups can be monocyclic ("monocyclic heterocyclyl") or can be fused, bridged, or spiro ring systems (e.g., bicyclic systems ("bicyclic heterocyclyl")), and can be saturated or partially unsaturated. Heterocyclyl bicyclic ring systems can contain one or more heteroatoms in one or both rings. "Heterocyclyl" also includes ring systems in which a heterocyclyl ring, as defined above, is fused to one or more carbocyclyl groups, with the point of attachment located on either the carbocyclyl or heterocyclyl ring, or in which a heterocyclyl ring, as defined above, is fused to one or more aryl or heteroaryl groups, with the point of attachment located on the heterocyclyl ring; in such cases, the number of ring members continues to refer to the number of ring members in the heterocyclyl ring system. Unless otherwise specified, each occurrence of a heterocyclyl group is independently optionally substituted, i.e., unsubstituted ("unsubstituted heterocyclyl") or substituted with one or more substituents ("substituted heterocyclyl"). In certain embodiments, a heterocyclyl group is an unsubstituted 3- to 10-membered heterocyclyl. In certain embodiments, a heterocyclyl group is a substituted 3- to 10-membered heterocyclyl.

[0040] In some embodiments, a heterocyclyl group is a 5- to 10-membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, each heteroatom independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon (a "5- to 10-membered heterocyclyl"). In some embodiments, a heterocyclyl group is a 5- to 8-membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, each heteroatom independently selected from nitrogen, oxygen, and sulfur (a "5- to 8-membered heterocyclyl"). In some embodiments, a heterocyclyl group is a 5- to 6-membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, each heteroatom independently selected from nitrogen, oxygen, and sulfur (a "5- to 6-membered heterocyclyl"). In some embodiments, a 5- to 6-membered heterocyclyl is selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5- or 6-membered heterocyclyl has 1 to 2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5- or 6-membered heterocyclyl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur.

[0041] Exemplary 3-membered heterocyclyl groups containing one heteroatom include, but are not limited to, aziridinyl, oxiranyl, and thiorenyl. Exemplary 4-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azetidinyl, oxetanyl, and thietanyl. Exemplary 5-membered heterocyclyl groups containing one heteroatom include, but are not limited to, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2,5-dione. Exemplary 5-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, dioxolanyl, oxasulfuranyl, disulfuranyl, and oxazolidin-2-one. Exemplary 5-membered heterocyclyl groups containing three heteroatoms include, but are not limited to, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclyl groups containing one heteroatom include, but are not limited to, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary 6-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, piperazinyl, morpholinyl, dithianyl, and dioxanyl. Exemplary 6-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, triazinanyl. Exemplary 7-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azepanyl, oxepanyl, and thiepanyl. Exemplary 8-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azocanyl, oxecanyl, and thiocanyl. Exemplary 5-membered heterocyclyl groups (also referred to herein as 5,6-bicyclic heterocycles) fused to a C6 aryl ring include, but are not limited to, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, benzoxazolinonyl, etc. Exemplary 6-membered heterocyclyl groups (also referred to herein as 6,6-bicyclic heterocycles) fused to an aryl ring include, but are not limited to, tetrahydroquinolinyl, tetrahydroisoquinolinyl, etc.

[0042] A "nitrogen-containing heterocyclyl" group refers to a 4- to 7-membered non-aromatic ring group containing at least one nitrogen atom, such as, but not limited to, morpholine, piperidine (e.g., 2-piperidinyl, 3-piperidinyl, and 4-piperidinyl), pyrrolidine (e.g., 2-pyrrolidinyl and 3-pyrrolidinyl), azetidine, pyrrolidone, imidazoline, imidazolidinone, 2-pyrazoline, pyrazolidine, piperazine, and N-alkylpiperazine (e.g., N-methylpiperazine). Specific examples include azetidine, piperidone, and piperazone.

[0043] "Hetero," when used to describe a compound or a group present on a compound, means that one or more carbon atoms of the compound or group are replaced with a nitrogen, oxygen, or sulfur heteroatom. Hetero can apply to any of the hydrocarbyl groups described above having 1 to 5, and especially 1 to 3, heteroatoms, such as alkyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkenyl, cycloheteroalkenyl, etc.

[0044] "Acyl" means -C(O)R 20 Refers to the radical, R 20 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, as defined herein. "Alkanoyl" is R 20 is an acyl group where the carbon atom is a group other than hydrogen. Representative acyl groups include formyl (-CHO), acetyl (-C(=O)CH3), cyclohexylcarbonyl, cyclohexylmethylcarbonyl, benzoyl (-C(=O)Ph), benzylcarbonyl (-C(=O)CH2Ph), and -C(O)-C 1~8 Alkyl, -C(O)-(CH2) t (C 6~10aryl), -C(O)-(CH2) t (5-10 membered heteroaryl), -C(O)-(CH2)t(C 3~10 cycloalkyl), and -C(O)-(CH2) t (4-10 membered heterocyclyl) (t is an integer from 0 to 4). 21 is a C substituted with halogen or hydroxy 1~8 Alkyl; or C 3~10 Cycloalkyl, 4-10 membered heterocyclyl, C 6~10 aryl, arylalkyl, 5- to 10-membered heteroaryl, or heteroarylalkyl (each of which is an unsubstituted C 1~4 Alkyl, halogen, unsubstituted C 1~4 Alkoxy, unsubstituted C 1~4 Haloalkyl, unsubstituted C 1~4 Hydroxyalkyl or unsubstituted C 1~4 substituted with haloalkoxy or hydroxy).

[0045] "Alkoxy" means -OR 29 R refers to the group 29 is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. Particular alkoxy groups are methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, and 1,2-dimethylbutoxy. Particular alkoxy groups are lower alkoxy, i.e., having 1 to 6 carbon atoms. Further particular alkoxy groups have 1 to 4 carbon atoms.

[0046] In certain embodiments, R 29 is amino, substituted amino, C 6~10 Aryl, aryloxy, carboxyl, cyano, C 3~10A group having one or more substituents selected from the group consisting of cycloalkyl, 4- to 10-membered heterocyclyl, halogen, 5- to 10-membered heteroaryl, hydroxyl, nitro, thioalkoxy, thioaryloxy, thiol, alkyl-S(O)-, aryl-S(O)-, alkyl-S(O)2-, and aryl-S(O)2-, for example, 1 to 5 substituents, particularly 1 to 3 substituents, and particularly 1 substituent. Exemplary "substituted alkoxy" groups include, but are not limited to, -O-(CH2) t (C 6~10 aryl), -O-(CH2) t (5-10 membered heteroaryl), -O-(CH2) t (C 3~10 cycloalkyl), and -O-(CH2) t (4-10 membered heterocyclyl), where t is an integer from 0 to 4, and any aryl, heteroaryl, cycloalkyl, or heterocyclyl group present is itself an unsubstituted C 1~4 Alkyl, halogen, unsubstituted C 1~4 Alkoxy, unsubstituted C 1~4 Haloalkyl, unsubstituted C 1~4 Hydroxyalkyl, or unsubstituted C 1~4 It may be substituted with haloalkoxy or hydroxy. Particularly exemplary "substituted alkoxy" groups are -OCF3, -OCH2CF3, -OCH2Ph, -OCH2-cyclopropyl, -OCH2CH2OH, and -OCH2CH2NMe2.

[0047] "Amino" refers to the -NH2 radical.

[0048] An "oxo group" refers to -C(=O)-.

[0049] "Substituted amino" refers to a group of the formula -N(R 38 )2, and R 38is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or an amino protecting group; R 38 At least one of R is not hydrogen. 38 is independent, Hydrogen, C 1~8 Alkyl, C 3~8 Alkenyl, C 3~8 Alkynyl, C 6~10 Aryl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocyclyl, or C 3~10 cycloalkyl; or C substituted with halogen or hydroxy 3~8 Alkyl; C substituted with halogen or hydroxy 3~8 Alkenyl; C substituted with halogen or hydroxy 3~8 Alkynyl, or -(CH2) t (C 6~10 aryl), -(CH2) t (5-10 membered heteroaryl), -(CH2) t (C 3~10 cycloalkyl), or -(CH2) t (4- to 10-membered heterocyclyl) (where t is an integer 0 to 8), each of which is selected from unsubstituted C 1~4 Alkyl, halogen, unsubstituted C 1~4 Alkoxy, unsubstituted C 1~4 Haloalkyl, unsubstituted C 1~4 Hydroxyalkyl or unsubstituted C 1~4 substituted with haloalkoxy, or hydroxy, or both R 38 The groups are linked to form an alkylene group.

[0050] Exemplary "substituted amino" groups include, but are not limited to, -NR 39 -C1-C8 alkyl, -NR 39 -(CH2) t (C6~C 10 aryl), -NR 39-(CH2) t (5-10 membered heteroaryl), -NR 39 -(CH2) t (C 3~10 cycloalkyl), and -NR 39 -(CH2) t (4-10 membered heterocyclyl), where t is an integer from 0 to 4, e.g., 1 or 2, and each R 39 are independently H or C 1~8 any alkyl group present may itself be substituted with halogen, substituted or unsubstituted amino, or hydroxy; any aryl, heteroaryl, cycloalkyl, or heterocyclyl group present may itself be an unsubstituted C 1~4 Alkyl, halogen, unsubstituted C 1~4 Alkoxy, unsubstituted C 1~4 Haloalkyl, unsubstituted C 1~4 Hydroxyalkyl, or unsubstituted C 1~4 It may be substituted with haloalkoxy or hydroxy. For the avoidance of doubt, the term "substituted amino" includes alkylamino, substituted alkylamino, alkylarylamino, substituted alkylarylamino, arylamino, substituted arylamino, dialkylamino, and substituted dialkylamino groups, as defined below. Substituted amino includes both mono- and di-substituted amino groups.

[0051] "Carboxy" refers to the -C(O)OH radical.

[0052] "Cyano" refers to the -CN radical.

[0053] "Halo" or "halogen" refers to fluoro (F), chloro (Cl), bromo (Br), and iodo (I). In certain embodiments, the halogen group is either fluoro or chloro.

[0054] "Haloalkyl" refers to an alkyl radical in which the alkyl group is substituted with one or more halogens. Typical haloalkyl groups include, but are not limited to, trifluoromethyl, difluoromethyl, fluoromethyl, chloromethyl, dichloromethyl, dibromoethyl, tribromomethyl, tetrafluoroethyl, and the like.

[0055] "Hydroxy" refers to the -OH radical.

[0056] "Nitro" refers to the -NO2 radical.

[0057] "Thioketo" refers to the group =S.

[0058] The alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl groups defined herein are optionally substituted (e.g., "substituted" or "unsubstituted" alkyl groups, "substituted" or "unsubstituted" alkenyl groups). "substituted" or "unsubstituted" alkynyl groups, "substituted" or "unsubstituted" carbocyclyl groups, "substituted" or "unsubstituted" heterocyclyl groups, "substituted" or "unsubstituted" aryl groups, or "substituted" or "unsubstituted" heteroaryl groups). In general, the term "substituted," whether preceded by the term "optionally," means that at least one hydrogen atom present in a group (e.g., a carbon or nitrogen atom) is replaced with a permissible substituent, e.g., a substituent that, when substituted, results in a stable compound, e.g., a compound that does not undergo spontaneous transformation (e.g., by rearrangement, cyclization, elimination, or other reaction). Unless otherwise specified, a "substituted" group has a substituent at one or more substitutable positions of the group; when more than one position in any given structure is substituted, the substituents are either the same or different at each position. The term "substituted" is intended to include substitution with all permissible substituents of organic compounds, i.e., any of the substituents described herein that result in the formation of a stable compound. The present invention contemplates all combinations that result in stable compounds. For purposes of this invention, heteroatoms such as nitrogen may have hydrogen substituents and / or any suitable substituents described herein that satisfy the valence of the heteroatom and result in the formation of a stable moiety.

[0059] Exemplary carbon atom substituents include halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OR aa , -ON(R bb )2, -N(R bb )2, -N(R bb )3 + X - , -N(OR cc )R bb , -SH, -SR aa , -SSR cc , -C(=O)R aa , -CO2H, -CHO, -C(OR cc )2, -CO2R aa , -OC(=O)R aa , -OCO2R aa , -C(=O)N(R bb )2, -OC(=O)N(Rbb )2、-NR bb C(=O)R aa 、-NR bb CO2R aa 、-NR bb C(=O)N(R bb )2、-C(=NR bb )R aa 、-C(=NR bb )OR aa 、-OC(=NR bb )R aa 、-OC(=NR bb )OR aa 、-C(=NR bb )N(R bb )2、-OC(=NR bb )N(R bb )2、-NR bb C(=NR bb )N(R bb )2、-C(=O)NR bb SO2R aa 、-NR bb SO2R aa 、-SO2N(R bb )2、-SO2R aa 、-SO2OR aa 、-OSO2R aa 、-S(=O)R aa 、-OS(=O)R aa 、-Si(R aa )3、-OSi(R aa )3-C(=S)N(R bb )2、-C(=O)SR aa 、-C(=S)SR aa 、-SC(=S)SR aa 、-SC(=O)SR aa 、-OC(=O)SR aa 、-SC(=O)OR aa 、-SC(=O)R aa 、-P(=O)2R aa 、-OP(=O)2R aa 、-P(=O)(R aa )2、-OP(=O)(R aa )2、-OP(=O)(OR cc )2、-P(=O)2N(R bb )2、-OP(=O)2N(R bb)2, -P(=O)(NR bb )2, -OP(=O)(NR bb )2, -NR bb P(=O)(OR cc )2, -NR bb P(=O)(NR bb )2, -P(R cc )2, -P(R cc )3, -OP(R cc )2, -OP(R cc )3, -B(R aa )2, -B(OR cc )2, -BR aa (OR cc ), C 1~10 Alkyl, C 1~10 Haloalkyl, C 2~10 Alkenyl, C 2~10 Alkynyl, C 3~10 Carbocyclyl, 3- to 14-membered heterocyclyl, C 6~14 aryl, and 5- to 14-membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently has 0, 1, 2, 3, 4, or 5 R dd groups, or two geminal hydrogens on the carbon atom are substituted with ═O, ═S, ═NN(R bb )2, =NNR bb C(=O)R aa , =NNR bb C(=O)OR aa , =NNR bb S(=O)2R aa , =NR bb , or =NOR cc substituted with a group; R aa Each occurrence of is independently 1~10 Alkyl, C 1~10 Haloalkyl, C 2~10 Alkenyl, C 2~10 Alkynyl, C 3~10 Carbocyclyl, 3- to 14-membered heterocyclyl, C 6~14 aryl, and 5- to 14-membered heteroaryl; or two R aagroups are linked to form a 3- to 14-membered heterocyclyl or 5- to 14-membered heteroaryl ring, and each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently contains 0, 1, 2, 3, 4, or 5 R dd substituted with a group; R bb Each occurrence of is independently hydrogen, -OH, -OR aa , -N(R cc )2, -CN, -C(=O)R aa , -C(=O)N(R cc )2, -CO2R aa , -SO2R aa , -C(=NR cc ) OR aa , -C(=NR cc )N(R cc )2, -SO2N(R cc )2, -SO2R cc , -SO2OR cc , -SOR aa , -C(=S)N(R cc )2, -C(=O)SR cc , -C(=S)SR cc , -P(=O)2R aa , -P(=O)(R aa )2, -P(=O)2N(R cc )2, -P(=O)(NR cc )2, C 1~10 Alkyl, C 1~10 Haloalkyl, C 2~10 Alkenyl, C 2~10 Alkynyl, C 3~10 Carbocyclyl, 3- to 14-membered heterocyclyl, C 6~14 aryl, and 5- to 14-membered heteroaryl; or two R bb groups are linked to form a 3- to 14-membered heterocyclyl or 5- to 14-membered heteroaryl ring, and each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently contains 0, 1, 2, 3, 4, or 5 R dd substituted with a group; R cc Each occurrence of is independently hydrogen, C1~10 Alkyl, C 1~10 Haloalkyl, C 2~10 Alkenyl, C 2~10 Alkynyl, C 3~10 Carbocyclyl, 3- to 14-membered heterocyclyl, C 6~14 aryl, and 5- to 14-membered heteroaryl; or two R cc groups are linked to form a 3- to 14-membered heterocyclyl or 5- to 14-membered heteroaryl ring, and each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently contains 0, 1, 2, 3, 4, or 5 R dd substituted with a group; R dd Each occurrence of is independently a halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OR ee , -ON(R ff )2, -N(R ff )2, -N(R ff )3 + X - , -N(OR ee )R ff , -SH, -SR ee , -SSR ee , -C(=O)R ee , -CO2H, -CO2R ee , -OC(=O)R ee , -OCO2R ee , -C(=O)N(R ff )2, -OC(=O)N(R ff )2, -NR ff C(=O)R ee , -NR ff CO2R ee , -NR ff C(=O)N(R ff )2, -C(=NR ff ) OR ee , -OC(=NR ff )R ee , -OC(=NR ff ) OR ee , -C(=NR ff )N(R ff )2, -OC(=NR ff )N(R ff )2, -NRff C(=NR ff )N(R ff )2,-NR ff SO2R ee , -SO2N(R ff )2, -SO2R ee , -SO2OR ee , -OSO2R ee , -S(=O)R ee , -Si(R ee )3, -OSi(R ee )3, -C(=S)N(R ff )2, -C(=O)SR ee , -C(=S)SR ee , -SC(=S)SR ee , -P(=O)2R ee , -P(=O)(R ee )2, -OP(=O)(R ee )2, -OP(=O)(OR ee )2, C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~10 Carbocyclyl, 3-10 membered heterocyclyl, C 6~10 aryl, and 5- to 10-membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently selected from 0, 1, 2, 3, 4, or 5 R gg or substituted with two geminal R dd the substituents can be linked to form =O or =S; R ee Each occurrence of C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~10 Carbocyclyl, C 6~10 aryl, 3- to 10-membered heterocyclyl, and 3- to 10-membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently selected from 0, 1, 2, 3, 4, or 5 R gg substituted with a group; R ff Each occurrence of is independently hydrogen, C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~10 Carbocyclyl, 3-10 membered heterocyclyl, C 6~10 aryl, and 5- to 10-membered heteroaryl, or two R ff groups are linked to form a 3- to 14-membered heterocyclyl or 5- to 14-membered heteroaryl ring, and each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently contains 0, 1, 2, 3, 4, or 5 R gg substituted with a group; R gg Each occurrence of is independently a halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OC 1~6 Alkyl, -ON(C 1~6 alkyl)2, -N(C 1~6 alkyl)2, -N(C 1~6 alkyl)3 + X - , -NH(C 1~6 alkyl)2 + X - , -NH2(C 1~6 alkyl) + X - , -NH3 + X - , -N(OC 1~6 Alkyl)(C 1~6 alkyl), -N(OH)(C 1~6 alkyl), -NH(OH), -SH, -SC 1~6 Alkyl, -SS(C 1~6 alkyl), -C(=O)(C 1~6 alkyl), -CO2H, -CO2(C 1~6 alkyl), -OC(=O)(C 1~6 alkyl), -OCO2(C 1~6 alkyl), -C(=O)NH2, -C(=O)N(C 1~6 alkyl)2, -OC(=O)NH(C 1~6alkyl), -NHC(=O)(C 1~6 alkyl), -N(C 1~6 alkyl)C(=O)(C 1~6 alkyl), -NHCO2(C 1~6 alkyl), -NHC(=O)N(C 1~6 alkyl)2, -NHC(=O)NH(C 1~6 alkyl), -NHC(=O)NH2, -C(=NH)O(C 1~6 alkyl), -OC(=NH)(C 1~6 alkyl), -OC(=NH)OC 1~6 Alkyl, -C(=NH)N(C 1~6 alkyl)2, -C(=NH)NH(C 1~6 alkyl), -C(=NH)NH2, -OC(=NH)N(C 1~6 alkyl)2, -OC(NH)NH(C 1~6 alkyl), -OC(NH)NH2, -NHC(NH)N(C 1~6 alkyl)2, -NHC(=NH)NH2, -NHSO2(C 1~6 alkyl), -SO2N(C 1~6 alkyl)2, -SO2NH(C 1~6 alkyl), -SO2NH2, -SO2C 1~6 Alkyl, -SO2OC 1~6 Alkyl, -OSO2C 1~6 Alkyl, -SOC 1~6 Alkyl, -Si(C 1~6 alkyl)3, -OSi(C 1~6 alkyl)3-C(=S)N(C 1~6 alkyl)2, -C(=S)NH(C 1~6 alkyl), -C(=S)NH2, -C(=O)S(C 1~6 alkyl), -C(=S)SC 1~6 Alkyl, -SC(=S)SC 1~6 Alkyl, -P(=O)2(C 1~6 alkyl), -P(=O)(C 1~6 alkyl)2, -OP(=O)(C 1~6 alkyl)2, -OP(=O)(OC 1~6 alkyl)2, -C 1~6 Alkyl, -C 1~6 Haloalkyl, -C2~6 Alkenyl, -C 2~6 Alkynyl, C 3~10 Carbocyclyl, C 6~10 aryl, 3- to 10-membered heterocyclyl, 5- to 10-membered heteroaryl, or two geminal R gg The substituents can be linked to form =O or =S; X - is the counter ion.

[0060] In some embodiments, the carbon atom substituents include halogen, —CN, —OH, —OR aa , -N(R bb )2, -CO2H, -CO2R aa , -OC(=O)R aa , -C(=O)N(R bb )2, -SO2R aa , C 1~6 Alkyl, C 1~6 Haloalkyl, C 3~10 carbocyclyl, 5- to 6-membered heterocyclyl, phenyl, and 5- to 6-membered heteroaryl; R aa Each occurrence of is independently hydrogen, C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~10 Alkenyl, C 2~10 Alkynyl, C 3~10 selected from carbocyclyl, 5- to 6-membered heterocyclyl, phenyl, and 5- to 6-membered heteroaryl; R bb Each occurrence of is independently hydrogen, C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~10 Alkenyl, C 2~10 Alkynyl, C 3~10 It is selected from carbocyclyl, 5- to 6-membered heterocyclyl, phenyl, and 5- to 6-membered heteroaryl.

[0061] A "counterion" or "anionic counterion" is a negatively charged group that associates with a cationic quaternary amino group to maintain electroneutrality. Exemplary counterions include halide ions (e.g., F - , Cl - , Br -, I - ), NO3 - , ClO4 - , O.H. - , H2PO4 - , HSO4 - , sulfonate ions (e.g., methanesulfonate, trifluoromethanesulfonate, p-toluenesulfonate, benzenesulfonate, 10-camphorsulfonate, naphthalene-2-sulfonate, naphthalene-1-sulfonic acid-5-sulfonate, ethane-1-sulfonic acid-2-sulfonate, etc.), and carboxylate ions (e.g., acetate, ethanoate, propanoate, benzoate, glycerol, etc.). Examples include lactate, tartrate, glycolate, etc.

[0062] These and other exemplary substituents are described in detail in the detailed description and claims. The present invention is not intended to be limited in any way by the exemplary substituents listed above.

[0063] As used herein, the term "modulation" refers to the A A "modulator" (e.g., a modulator compound) refers to the inhibition or enhancement of receptor function, e.g., GABA A It can be an agonist, partial agonist, antagonist, or partial antagonist of the receptor.

[0064] "Pharmaceutically acceptable" means approved or approvable by a regulatory authority of a federal or state government, or a corresponding authority in a country other than the United States, or listed in the United States Pharmacopoeia or other generally recognized pharmacopoeia for use in animals (more specifically, humans).

[0065] "Pharmaceutically acceptable salt" refers to a salt of the compound of the present invention that is pharmaceutically acceptable and has the desired pharmacological activity of the parent compound. In particular, such salts are non-toxic and can be inorganic acid addition salts or organic acid addition salts, and inorganic base addition salts or organic base addition salts. Specifically, such salts include (1) salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc.; or salts formed with organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, or (2) salts formed when an acidic proton present in the parent compound is replaced by a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion; or when coordinated with an organic base, e.g., ethanolamine, diethanolamine, triethanolamine, N-methylglucamine, etc. Salts further include, by way of example only, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, etc.; and, if the compound contains a basic functional group, salts of non-toxic organic or inorganic acids, e.g., hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate, oxalate, etc. The term "pharmaceutically acceptable cation" refers to an acceptable cationic counterion of an acidic functional group. Such cations are exemplified by sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium cations, and the like.See, e.g., Berge, et al., J. Pharm. Sci. (1977) 66(1):1-79.

[0066] The term "prodrug" is intended to encompass therapeutically inactive compounds that are converted under physiological conditions into the therapeutically active agents of the present invention. One method for creating a prodrug is to design a selected moiety that is hydrolyzed or cleaved at the target in vivo site of action under physiological conditions to expose the molecule of interest, which then produces a therapeutic effect. In certain embodiments, the prodrug is converted by the enzymatic activity of the subject.

[0067] In an alternative embodiment, the present invention provides a prodrug of a compound of formula (I), As shown in Figure 1, a prodrug containing a cleavable moiety at the C3 hydroxy is provided.

[0068] "Tautomers" refer to compounds that are interchangeable forms of a particular compound structure, with changes in the displacement of hydrogen atoms and electrons. Thus, two structures can be in equilibrium through the displacement of π electrons and atoms (usually H). For example, enols and ketones are tautomers because they are rapidly interconverted by treatment with either acid or base. Another example of tautomerism is the acid and nitro forms of phenylnitromethane, which are similarly formed by treatment with acid or base. Tautomers can be relevant to achieving optimal chemical reactivity and biological activity of a compound of interest.

[0069] "Subjects" to which administration is contemplated include, but are not limited to, humans (i.e., men and women of any age group, e.g., pediatric subjects (e.g., infants, children, adolescents) or adult subjects (e.g., young adults, middle-aged adults, or elderly adults)) and / or non-human animals, e.g., mammals (e.g., primates (e.g., cynomolgus monkeys, rhesus monkeys), cows, pigs, horses, sheep, goats, rodents, cats, and / or dogs). In certain embodiments, the subject is a human. In certain embodiments, the subject is a non-human animal.

[0070] In certain embodiments, the substituent present on the oxygen atom is an oxygen protecting group (also referred to as a hydroxyl protecting group). Oxygen protecting groups include, but are not limited to, -R aa , -N(R bb )2, -C(=O)SR aa , -C(=O)R aa , -CO2R aa , -C(=O)N(R bb )2, -C(=NR bb )R aa , -C(=NR bb ) OR aa , -C(=NR bb )N(R bb )2, -S(=O)R aa , -SO2R aa , -Si(R aa )3, -P(R cc )2, -P(R cc )3, -P(=O)2R aa , -P(=O)(R aa )2, -P(=O)(OR cc )2, -P(=O)2N(R bb )2, and -P(=O)(NR bb )2 is mentioned, and R aa , R bb , and R cc is as defined herein. Oxygen protecting groups are well known in the art and are described in Protecting Groups in Organic Synthesis, T.W. Greene and P.G.M. Buts, 3, incorporated herein by reference. rd edition, John Wiley & Sons, 1999.

[0071] Exemplary oxygen protecting groups include, but are not limited to, methyl, methoxylmethyl (MOM), 2-methoxyethoxymethyl (MEM), benzyl (Bn), triisopropylsilyl (TIPS), t-butyldimethylsilyl (TBDMS), t-butylmethoxyphenylsilyl (TBMPS), methanesulfonate (mesylate), and tosylate (Ts).

[0072] In certain embodiments, the substituent present on the sulfur atom is a sulfur protecting group (also referred to as a thiol protecting group). Sulfur protecting groups include, but are not limited to, -R aa , -N(R bb )2, -C(=O)SR aa , -C(=O)R aa , -CO2R aa , -C(=O)N(R bb )2, -C(=NR bb )R aa , -C(=NR bb ) OR aa , -C(=NR bb )N(R bb )2, -S(=O)R aa , -SO2R aa , -Si(R aa )3, -P(R cc )2, -P(R cc )3, -P(=O)2R aa , -P(=O)(R aa )2, -P(=O)(OR cc )2, -P(=O)2N(R bb )2, and -P(=O)(NR bb )2 is mentioned, and R aa , R bb , and R cc is as defined herein. Sulfur protecting groups are well known in the art and are described in Protecting Groups in Organic Synthesis, T.W. Greene and P.G.M. Buts, 3, incorporated herein by reference. rd edition,John Including those described in detail in Wiley & Sons, 1999.

[0073] In certain embodiments, the substituent present on the nitrogen atom is an amino protecting group (nitrogen protecting group Amino protecting groups include, but are not limited to, -OH, -OR aa , -N(R cc )2, -C(=O)R aa , -C(=O)OR aa, -C(=O)N(R cc )2, -S(=O)2R aa , -C(=NR cc )R aa , -C(=NR cc ) OR aa , -C(=NR cc )N(R cc )2, -SO2N(R cc )2, -SO2R cc , -SO2OR cc , -SOR aa , -C(=S)N(R cc )2, -C(=O)SR cc , -C(=S)SR cc , C 1~10 Alkyl, C 2~10 Alkenyl, C 2~10 Alkynyl, C 3~10 Carbocyclyl, 3- to 14-membered heterocyclyl, C 6~14 and 5- to 14-membered heteroaryl groups, each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently having 0, 1, 2, 3, 4, or 5 R dd substituted with R aa , R bb , R cc , and R dd is as defined herein. Amino protecting groups are well known in the art and are described in Protecting Groups in Organic Synthesis, T.W. Greene and P.G.M. Buts, 3, incorporated herein by reference. rd edition, John Wiley & Sons, 1999.

[0074] Exemplary amino protecting groups include, but are not limited to, amide groups (e.g., —C(═O)R aa ) (including, but not limited to, formamide and acetamide); carbamate groups (e.g., —C(═O)OR aa) (including, but not limited to, 9-fluorenylmethyl carbamate (Fmoc), t-butyl carbamate (BOC), and benzyl carbamate (Cbz); sulfonamide groups (e.g., —S(═O)R aa ) (including, but not limited to, p-toluenesulfonamide (Ts), methanesulfonamide (Ms), and N-[2-(trimethylsilyl)ethoxy]methylamine (SEM)).

[0075] Disease, disorder, and condition are used interchangeably herein.

[0076] As used herein, unless otherwise specified, the terms "treat," "treating," and "treatment" contemplate actions taken while a subject is afflicted with a particular disease, disorder, or condition to reduce the severity of the disease, disorder, or condition or to delay or slow the progression of the disease, disorder, or condition. In an alternative embodiment, the present invention contemplates administering a compound of the invention as a prophylactic, before a subject is afflicted with a particular disease, disorder, or condition.

[0077] Generally, the "effective amount" of a compound refers to an amount sufficient to induce a desired biological response, for example, to treat a CNS-related disorder, and is sufficient to induce anesthesia or sedation.As will be understood by those skilled in the art, the "effective amount" of the compound of the present invention may vary depending on factors such as the biological endpoint of interest, the pharmacokinetics of the compound, the disease to be treated, the mode of administration, and the age, weight, health status, and pathology of the subject.The effective amount includes therapeutic treatment and prophylactic treatment.

[0078] As used herein, unless otherwise specified, a "therapeutically effective amount" of a compound is an amount sufficient to provide a therapeutic benefit in the treatment of a disease, disorder, or condition, or to delay or minimize one or more symptoms associated with the disease, disorder, or condition. A therapeutically effective amount of a compound means the amount of therapeutic agent alone, or in combination with other therapies, that provides a therapeutic benefit in the treatment of the disease, disorder, or condition. The term "therapeutically effective amount" can encompass an amount that improves overall treatment, an amount that alleviates or avoids the symptoms or causes of a disease or condition, or an amount that enhances the therapeutic efficacy of another therapeutic agent.

[0079] As used herein, unless otherwise specified, a "prophylactically effective amount" of a compound is an amount sufficient to prevent or prevent the recurrence of a disease, disorder, or condition, or one or more symptoms associated with the disease, disorder, or condition. A prophylactically effective amount of a compound refers to the amount of therapeutic agent alone, or in combination with other agents, that provides a prophylactic benefit in the prevention of the disease, disorder, or condition. The term "prophylactically effective amount" can encompass an amount that improves overall prophylaxis or an amount that enhances the prophylactic efficacy of another prophylactic agent.

[0080] In alternative embodiments, the compounds described herein may also contain one or more isotopic substitutions. For example, hydrogen may be: 2 H (D or deuterium) or 3 H (T or tritium). Carbon can be, for example, 13 C or 14 C. Oxygen can be, for example, 18 O. Nitrogen can be, for example, 15 In other embodiments, a specific isotope (e.g., 3 H, 13 C. 14 C. 18 O, or 15N) may occur in at least 1%, at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or at least 99.9% of the total isotopic abundance of the element occupying a particular site in the compound.

[0081] As used herein, an "episodic dosing regimen" refers to a dosing regimen in which a compound of Formula (I) or a composition comprising a compound of Formula (I) is administered to a subject in a finite cycle depending on the diagnosis of a disorder or a symptom thereof, e.g., a diagnosis or symptom of an episode of depression, major depressive disorder, bipolar depression, anxiety, or postpartum depression. In some embodiments, the major depressive disorder is moderate major depressive disorder. In some embodiments, the major depressive disorder is severe major depressive disorder. In some embodiments, the compound is formulated as individual dosage units, each unit comprising a compound of Formula (I) and one or more suitable excipients. In some embodiments, the episodic dosing regimen has a duration of several weeks, e.g., about 8 weeks. In contrast to chronic administration as defined herein, episodic dosing of a compound is administered for a finite period of about 2 weeks to about 8 weeks depending on the diagnosis of a disorder, e.g., depression, or a symptom thereof. In some embodiments, the episodic dosing is administered once daily for several weeks, e.g., about 2 weeks to about 6 weeks. In one embodiment, the episodic dosing has a duration of 2 weeks. In some embodiments, the subject is administered more than one episodic dosing regimen over the course of the subject's lifetime, for example, two or more episodic regimens.

[0082] II. Compounds

[0083] It should be understood that the formulae set forth herein may refer to particular carbon atoms, for example, C17, C3, C19, etc. These references are as follows: [ka] The nomenclature is based on the carbon atom position according to known steroid nomenclature used in the industry, as shown in Figure 1. For example, C17 refers to the 17th carbon and C3 refers to the 3rd carbon.

[0084] In some embodiments, the compound has Formula I: [ka] [In formula: m is 0, 1, 2, or 3; m1 is 0, 1, or 2; n is 1, 2, 3 or 4; n1 is 0, 1, 2, 3, 4 or 5; q is independently 0, 1, 2, or 3; r is independently 0, 1, or 2; s is independently 0, 1, or 2; t is independently 0, 1, 2, or 3; u is independently 1 or 2; X is hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -OR A1 , -SR A1 , -N(R A1 )2, -OC(=O)R A1 , -OC(=O)OR A1 , -OC(=O)SR A1 , -OC(=O)N(R A1 )2, -SC(=O)R A2 , -SC(=O)OR A1 , -SC(=O)SR A1 , -SC(=O)N(R A1 )2, -NHC(=O)R A1 , -NHC(=O)OR A1 , -NHC(=O)SR A1 , -NHC(=O)N(R A1 )2, -OS(=O)2R A2 , -OS(=O)2OR A1 , -SS(=O)2R A2 , -SS(=O)2OR A1 , -S(=O)R A2 , -SO2R A2 , or -S(=O)2OR A1 and R A1 each occurrence is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, an oxygen protecting group (when attached to an oxygen atom), a sulfur protecting group (when attached to a sulfur atom), or a nitrogen protecting group (when attached to a nitrogen atom); R A2 each occurrence is independently substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; A is CR 17 or N and R 17 is selected from the group consisting of a hydrogen atom, a deuterium atom, an alkyl group, a deuterated alkyl group, a hydroxyl group, an amino group, an alkenyl group, an alkynyl group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group, wherein the alkyl group, the cycloalkyl group, the heterocyclyl group, the aryl group, and the heteroaryl group are optionally further substituted with one or more substituents selected from the group consisting of a deuterium atom, a substituted or unsubstituted alkyl group, a halogen, a hydroxyl group, a substituted or unsubstituted amino group, an oxo group, a nitro group, a cyano group, an alkenyl group, an alkynyl group, an alkoxy group, a hydroxyalkyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted heterocyclic group, a substituted or unsubstituted aryl group, and a substituted or unsubstituted heteroaryl group; [ka] is a double bond, then A is C; [ka] is a double bond, R 5 and R 6a or R 6b one of them is not present; R 3 , R 2a , R 2b , R 4a , R 4b , R 5 , R 6a , R 6b , R 11a , R 11b , R 15a , R 15b , R 16a , R 16b , R 18 , R 19 , R 20a , or R 20b are each independently a hydrogen atom, a deuterium atom, an alkyl group, a deuterated alkyl group, an alkoxy group, a halogenated alkoxy group, a halogen, an amino group, a mercapto group, a nitro group, a hydroxyl group, a cyano group, an alkenyl group, an alkynyl group, a cycloalkyl group, a heterocyclyl group, an aryl group, a heteroaryl group, -(CH2) n1 R 23 , -(CH2) n1 OR 23 , -(CH2) n1 SR 23 , -(CH2) n1 C(O)R 23 , -(CH2) n1 C(O)OR 23 , -(CH2) n1 S(O) m1 R 23 , -(CH2) n1 NR 23 R 24 , -(CH2) n1 C(O)NR 23 R 24 , -(CH2) n1 NR 23 C(O)R 24 , or -(CH2)n1 NR 23 S(O) m1 R 24 and the alkyl group, the haloalkyl group, the cycloalkyl group, the heterocyclic group, the aryl group, and the heteroaryl group are selected from the group consisting of a deuterium atom, an alkyl group, a halogen, an amino group, a mercapto group, an oxo group, a nitro group, a cyano group, a hydroxyl group, an alkenyl group, an alkynyl group, an alkoxy group, a halogenated alkoxy group, a hydroxyalkyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted heterocyclic group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, -(CH2) n1 R 25 , -(CH2) n1 OR 25 , -(CH2) n1 SR 25 , -(CH2) n1 C(O)R 25 , -(CH2) n1 C(O)OR 25 , -(CH2) n1 S(O) m1 R 25 , -(CH2) n1 NR 25 R 26 , -(CH2) n1 C(O)NR 25 R 26 , -(CH2) n1 C(O)NHR 25 , -(CH2) n1 NR 25 C(O)R 26 , and -(CH2) n1 NR 25 S(O) m1 R 26 or optionally further substituted with one or more of the substituents selected from the group consisting of: Or R 3 , R 2a , R 2b , R 4a , R 4b , R 5 , R 6a , R 6b , R 11a , R11b , R 15a , R 15b , R 16a , R 16b , R 18 , R 19 , R 20a , or R 20b Any two adjacent or non-adjacent groups among these may form a cycloalkyl group, a heteroalkyl group, an aryl group, and a heteroaryl group, and the cycloalkyl group, the heterocyclic group, the aryl group, and the heteroaryl group may be substituted with a deuterium atom, an alkyl group, a halogen atom, an amino group, a mercapto group, an oxo group, a nitro group, a cyano group, a hydroxyl group, an alkenyl group, an alkynyl group, an alkoxy group, a halogenated alkoxy group, a hydroxyalkyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted heterocyclic group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, -(CH2) n1 R 25 , -(CH2) n1 OR 25 , -(CH2) n1 SR 25 , -(CH2) n1 C(O)R 25 , -(CH2) n1 C(O)OR 25 , -(CH2) n1 S(O) m1 R 25 , -(CH2) n1 NR 25 R 26 , -(CH2) n1 C(O)NR 25 R 26 , -(CH2) n1 C(O)NHR 25 , -(CH2) n1 NR 25 C(O)R 26 , and -(CH2) n1 NR 25 S(O) m1 R 26 or optionally further substituted with one or more of the substituents selected from the group consisting of: Or R 15a and R 15b , or R16a and R 16b together form an oxo (=O) group; Or R 15a or R 15b and R 16a or R 16b one of which is absent, forming a double bond; R 22 , R 23 , R 24 , R 25 , and R 26 are each independently selected from a hydrogen atom, a deuterium atom, an alkyl group, a deuterated alkyl group, a hydroxyl group, an amino group, an alkenyl group, an alkynyl group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group, wherein the alkyl group, the cycloalkyl group, the heterocyclyl group, the aryl group, and the heteroaryl group are optionally further substituted with one or more substituents selected from a deuterium atom, a substituted or unsubstituted alkyl group, a halogen, a hydroxyl group, a substituted or unsubstituted amino group, an oxo group, a nitro group, a cyano group, an alkenyl group, an alkynyl group, an alkoxy group, a hydroxyalkyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted heterocyclic group, a substituted or unsubstituted aryl group, and a substituted or unsubstituted heteroaryl group; however, If m is 0, R 15a or R 15b is not H] or a pharmaceutically acceptable salt thereof.

[0085] In some embodiments, the compound has Formula II: [ka] [In formula: m is 0, 1, 2, or 3; m1 is 0, 1, or 2; n is 1 or 2; n1 is 0, 1, 2, 3, 4 or 5; q is independently 0, 1, 2, or 3; r is independently 0, 1, or 2; s is independently 0, 1, or 2; t is independently 0, 1, 2, or 3; u is independently 1 or 2; X is hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -OR A1 , -SR A1 , -N(R A1 )2, -OC(=O)R A1 , -OC(=O)OR A1 , -OC(=O)SR A1 , -OC(=O)N(R A1 )2, -SC(=O)R A2 , -SC(=O)OR A1 , -SC(=O)SR A1 , -SC(=O)N(R A1 )2, -NHC(=O)R A1 , -NHC(=O)OR A1 , -NHC(=O)SR A1 , -NHC(=O)N(R A1 )2, -OS(=O)2R A2 , -OS(=O)2OR A1 , -SS(=O)2R A2 , -SS(=O)2OR A1 , -S(=O)R A2 , -SO2R A2 , or -S(=O)2OR A1 and R A1 each occurrence is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, an oxygen protecting group (when attached to an oxygen atom), a sulfur protecting group (when attached to a sulfur atom), or a nitrogen protecting group (when attached to a nitrogen atom); R A2each occurrence is independently substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; Z is independently -CR 23 R 24 -, -NR 23 -, or -O-; A is CR 17 or N and R 17 is selected from the group consisting of a hydrogen atom, a deuterium atom, an alkyl group, a deuterated alkyl group, a hydroxyl group, an amino group, an alkenyl group, an alkynyl group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group, and the alkyl group, the cycloalkyl group, the heterocyclyl group, the aryl group, and the heteroaryl group are each independently selected from the group consisting of a deuterium atom, a substituted or unsubstituted alkyl group, a halogen atom, a hydroxyl group, a substituted or unsubstituted amino group, an oxo group, a nitro group, a cyano group, an alkenyl group, an alkynyl group, an alkoxy group, a hydroxyalkyl group, a substituted or unsubstituted is optionally further substituted with one or more substituents selected from the group consisting of unsubstituted cycloalkyl groups, substituted or unsubstituted heterocyclic groups, substituted or unsubstituted aryl groups, and substituted or unsubstituted heteroaryl groups; [ka] is a double bond, then A is C; [ka] is a double bond, R 5 and R 6a or R 6b one of them is not present; R 3 , R 2a , R 2b , R 4a , R 4b , R 5 , R 6a , R 6b, R 11a , R 11b , R 15a , R 15b , R 16a , R 16b , R 18 , R 19 , R 20a , or R 20b are each independently a hydrogen atom, a deuterium atom, an alkyl group, a deuterated alkyl group, an alkoxy group, a halogenated alkoxy group, a halogen, an amino group, a mercapto group, a nitro group, a hydroxyl group, a cyano group, an alkenyl group, an alkynyl group, a cycloalkyl group, a heterocyclyl group, an aryl group, a heteroaryl group, -(CH2) n1 R 23 , -(CH2) n1 OR 23 , -(CH2) n1 SR 23 , -(CH2) n1 C(O)R 23 , -(CH2) n1 C(O)OR 23 , -(CH2) n1 S(O) m1 R 23 , -(CH2) n1 NR 23 R 24 , -(CH2) n1 C(O)NR 23 R 24 , -(CH2) n1 NR 23 C(O)R 24 , or -(CH2) n1 NR 23 S(O) m1 R 24 and the alkyl group, the haloalkyl group, the cycloalkyl group, the heterocyclic group, the aryl group, and the heteroaryl group are selected from the group consisting of a deuterium atom, an alkyl group, a halogen, an amino group, a mercapto group, an oxo group, a nitro group, a cyano group, a hydroxyl group, an alkenyl group, an alkynyl group, an alkoxy group, a halogenated alkoxy group, a hydroxyalkyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted heterocyclic group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, -(CH2)n1 R 25 , -(CH2) n1 OR 25 , -(CH2) n1 SR 25 , -(CH2) n1 C(O)R 25 , -(CH2) n1 C(O)OR 25 , -(CH2) n1 S(O) m1 R 25 , -(CH2) n1 NR 25 R 26 , -(CH2) n1 C(O)NR 25 R 26 , -(CH2) n1 C(O)NHR 25 , -(CH2) n1 NR 25 C(O)R 26 , and -(CH2) n1 NR 25 S(O) m1 R 26 or optionally further substituted with one or more of the substituents selected from the group consisting of: Or R 3 , R 2a , R 2b , R 4a , R 4b , R 5 , R 6a , R 6b , R 11a , R 11b , R 15a , R 15b , R 16a , R 16b , R 18 , R 19 , R 20a , or R 20bAny two adjacent or non-adjacent groups among these may form a cycloalkyl group, a heteroalkyl group, an aryl group, and a heteroaryl group, and the cycloalkyl group, the heterocyclic group, the aryl group, and the heteroaryl group may be substituted with a deuterium atom, an alkyl group, a halogen atom, an amino group, a mercapto group, an oxo group, a nitro group, a cyano group, a hydroxyl group, an alkenyl group, an alkynyl group, an alkoxy group, a halogenated alkoxy group, a hydroxyalkyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted heterocyclic group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, -(CH2) n1 R 25 , -(CH2) n1 OR 25 , -(CH2) n1 SR 25 , -(CH2) n1 C(O)R 25 , -(CH2) n1 C(O)OR 25 , -(CH2) n1 S(O) m1 R 25 , -(CH2) n1 NR 25 R 26 , -(CH2) n1 C(O)NR 25 R 26 , -(CH2) n1 C(O)NHR 25 , -(CH2) n1 NR 25 C(O)R 26 , and -(CH2) n1 NR 25 S(O) m1 R 26 or optionally further substituted with one or more of the substituents selected from the group consisting of: Or R 15a and R 15b , or R 16a and R 16b together form an oxo (=O) group; Or R 15a or R 15b and R 16aor R 16b one of which is absent, forming a double bond; R 22 , R 23 , R 24 , R 25 , and R 26 are each independently selected from a hydrogen atom, a deuterium atom, an alkyl group, a deuterated alkyl group, a hydroxyl group, an amino group, an alkenyl group, an alkynyl group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group, wherein the alkyl group, the cycloalkyl group, the heterocyclyl group, the aryl group, and the heteroaryl group are optionally further substituted with one or more substituents selected from a deuterium atom, a substituted or unsubstituted alkyl group, a halogen, a hydroxyl group, a substituted or unsubstituted amino group, an oxo group, a nitro group, a cyano group, an alkenyl group, an alkynyl group, an alkoxy group, a hydroxyalkyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted heterocyclic group, a substituted or unsubstituted aryl group, and a substituted or unsubstituted heteroaryl group; however, When m is 0 and Z is -CH2-, R 15a or R 15b Any of the is not -H] or a pharmaceutically acceptable salt thereof.

[0086] In some embodiments, the compound has Formula III: [ka] [In formula: m is 0, 1, 2, or 3; m1 is 0, 1, or 2; n is 1 or 2; n1 is 0, 1, 2, 3, 4 or 5; q is independently 0, 1, 2, or 3; r is independently 0, 1, or 2; s is independently 0, 1, or 2; t is independently 0, 1, 2, or 3; u is independently 1 or 2; X is hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -OR A1 , -SR A1 , -N(R A1 )2, -OC(=O)R A1 , -OC(=O)OR A1 , -OC(=O)SR A1 , -OC(=O)N(R A1 )2, -SC(=O)R A2 , -SC(=O)OR A1 , -SC(=O)SR A1 , -SC(=O)N(R A1 )2, -NHC(=O)R A1 , -NHC(=O)OR A1 , -NHC(=O)SR A1 , -NHC(=O)N(R A1 )2, -OS(=O)2R A2 , -OS(=O)2OR A1 , -SS(=O)2R A2 , -SS(=O)2OR A1 , -S(=O)R A2 , -SO2R A2 , or -S(=O)2OR A1 and R A1 each occurrence is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, an oxygen protecting group (when attached to an oxygen atom), a sulfur protecting group (when attached to a sulfur atom), or a nitrogen protecting group (when attached to a nitrogen atom); R A2each occurrence is independently substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; Z is independently -CR 23 R 24 -, -NR 23 -, or -O-; Each W is independently -S(CH2) n1 -, [ka] Selected from; A is CR 17 or N and R 17 is selected from the group consisting of a hydrogen atom, a deuterium atom, an alkyl group, a deuterated alkyl group, a hydroxyl group, an amino group, an alkenyl group, an alkynyl group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group, wherein the alkyl group, the cycloalkyl group, the heterocyclyl group, the aryl group, and the heteroaryl group are optionally further substituted with one or more substituents selected from the group consisting of a deuterium atom, a substituted or unsubstituted alkyl group, a halogen, a hydroxyl group, a substituted or unsubstituted amino group, an oxo group, a nitro group, a cyano group, an alkenyl group, an alkynyl group, an alkoxy group, a hydroxyalkyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted heterocyclic group, a substituted or unsubstituted aryl group, and a substituted or unsubstituted heteroaryl group; [ka] is a double bond, then A is C; [ka] is a double bond, R 5 and R 6a or R 6b one of them is not present; R3 , R 2a , R 2b , R 4a , R 4b , R 5 , R 6a , R 6b , R 11a , R 11b , R 15a , R 15b , R 16a , R 16b , R 18 , R 19 , R 20a , or R 20b are each independently a hydrogen atom, a deuterium atom, an alkyl group, a deuterated alkyl group, an alkoxy group, a halogenated alkoxy group, a halogen, an amino group, a mercapto group, a nitro ... Toro group, hydroxyl group, cyano group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclyl group, aryl group, heteroaryl group, -(CH2) n1 R 23 , -(CH2) n1 OR 23 , -(CH2) n1 SR 23 , -(CH2) n1 C(O)R 23 , -(CH2) n1 C(O)OR 23 , -(CH2) n1 S(O) m1 R 23 , -(CH2) n1 NR 23 R 24 , -(CH2) n1 C(O)NR 23 R 24 , -(CH2) n1 NR 23 C(O)R 24 , or -(CH2) n1 NR 23 S(O) m1 R 24and the alkyl group, the haloalkyl group, the cycloalkyl group, the heterocyclic group, the aryl group, and the heteroaryl group are selected from the group consisting of a deuterium atom, an alkyl group, a halogen, an amino group, a mercapto group, an oxo group, a nitro group, a cyano group, a hydroxyl group, an alkenyl group, an alkynyl group, an alkoxy group, a halogenated alkoxy group, a hydroxyalkyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted heterocyclic group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, -(CH2) n1 R 25 , -(CH2) n1 OR 25 , -(CH2) n1 SR 25 , -(CH2) n1 C(O)R 25 , -(CH2) n1 C(O)OR 25 , -(CH2) n1 S(O) m1 R 25 , -(CH2) n1 NR 25 R 26 , -(CH2) n1 C(O)NR 25 R 26 , -(CH2) n1 C(O)NHR 25 , -(CH2) n1 NR 25 C(O)R 26 , and -(CH2) n1 NR 25 S(O) m1 R 26 or optionally further substituted with one or more of the substituents selected from the group consisting of: Or R 3 , R 2a , R 2b , R 4a , R 4b , R 5 , R 6a , R 6b , R 11a , R 11b , R 15a , R 15b , R 16a , R 16b, R 18 , R 19 , R 20a , or R 20b Any two adjacent or non-adjacent groups among these may form a cycloalkyl group, a heteroalkyl group, an aryl group, and a heteroaryl group, and the cycloalkyl group, the heterocyclic group, the aryl group, and the heteroaryl group may be substituted with a deuterium atom, an alkyl group, a halogen atom, an amino group, a mercapto group, an oxo group, a nitro group, a cyano group, a hydroxyl group, an alkenyl group, an alkynyl group, an alkoxy group, a halogenated alkoxy group, a hydroxyalkyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted heterocyclic group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, -(CH2) n1 R 25 , -(CH2) n1 OR 25 , -(CH2) n1 SR 25 , -(CH2) n1 C(O)R 25 , -(CH2) n1 C(O)OR 25 , -(CH2) n1 S(O) m1 R 25 , -(CH2) n1 NR 25 R 26 , -(CH2) n1 C(O)NR 25 R 26 , -(CH2) n1 C(O)NHR 25 , -(CH2) n1 NR 25 C(O)R 26 , and -(CH2) n1 NR 25 S(O) m1 R 26 and optionally further substituted with one or more of the substituents selected from the group consisting of: R 22 , R 23 , R 24 , R 25 , and R 26are each independently selected from a hydrogen atom, a deuterium atom, an alkyl group, a deuterated alkyl group, a hydroxyl group, an amino group, an alkenyl group, an alkynyl group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group, wherein the alkyl group, the cycloalkyl group, the heterocyclyl group, the aryl group, and the heteroaryl group are optionally further substituted with one or more substituents selected from a deuterium atom, a substituted or unsubstituted alkyl group, a halogen, a hydroxyl group, a substituted or unsubstituted amino group, an oxo group, a nitro group, a cyano group, an alkenyl group, an alkynyl group, an alkoxy group, a hydroxyalkyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted heterocyclic group, a substituted or unsubstituted aryl group, and a substituted or unsubstituted heteroaryl group; however, If m is 0; Z is -CH2-; W is [ka] and; n1 is 0; R 15a or R 15b Any of the is not -H] or a pharmaceutically acceptable salt thereof.

[0087] In some embodiments, the compound has formula IV-A or IV-B: [ka] [In formula: m is 0, 1, 2, or 3; m1 is 0, 1, or 2; n is 1 or 2; n1 is 0, 1, 2, 3, 4 or 5; p is 0, 1, 2, 3 or 4; q is independently 0, 1, 2, or 3; r is independently 0, 1, or 2; s is independently 0, 1, or 2; t is independently 0, 1, 2, or 3; u is independently 1 or 2; X is hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -OR A1 , -SR A1 , -N(R A1 )2, -OC(=O)R A1 , -OC(=O)OR A1 , -OC(=O)SR A1 , -OC(=O)N(R A1 )2, -SC(=O)R A2 , -SC(=O)OR A1 , -SC(=O)SR A1 , -SC(=O)N(R A1 )2, -NHC(=O)R A1 , -NHC(=O)OR A1 , -NHC(=O)SR A1 , -NHC(=O)N(R A1 )2, -OS(=O)2R A2 , -OS(=O)2OR A1 , -SS(=O)2R A2 , -SS(=O)2OR A1 , -S(=O)R A2 , -SO2R A2 , or -S(=O)2OR A1 and R A1 each occurrence is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, an oxygen protecting group (when attached to an oxygen atom), a sulfur protecting group (when attached to a sulfur atom), or a nitrogen protecting group (when attached to a nitrogen atom); R A2each occurrence is independently substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; Z is independently -CR 23 R 24 -, -NR 23 -, or -O-; Each W is independently -S(CH2) n1 -, [ka] Selected from; Y is -C(R 23 )2- or -O-; R D are each independently a hydrogen atom, a deuterium atom, an alkyl group, a deuterated alkyl group, an alkoxy group, a halogenated alkoxy group, a halogen, an amino group, a mercapto group, a nitro group, a hydroxyl group, a cyano group, an alkenyl group, an alkynyl group, a cycloalkyl group, a heterocyclyl group, an aryl group, a heteroaryl group, -(CH2) n1 R 23 , -(CH2) n1 OR 23 , -(CH2) n1 SR 23 , -(CH2) n1 C(O)R 23 , -(CH2) n1 C(O)OR 23 , -(CH2) n1 S(O) m1 R 23 , -(CH2) n1 S(O)(NR 23 )R 24 , -(CH2) n1 NR 23 R 24 , -(CH2) n1 C(O)NR 23 R 24 , -(CH2) n1 NR 23 C(O)R 24 or -(CH2)n1 NR 23 S(O) m1 R 24 and the alkyl group, the haloalkyl group, the cycloalkyl group, the heterocyclic group, the aryl group, and the heteroaryl group are selected from the group consisting of a deuterium atom, an alkyl group, a halogen, an amino group, a mercapto group, an oxo group, a nitro group, a cyano group, a hydroxyl group, an alkenyl group, an alkynyl group, an alkoxy group, a halogenated alkoxy group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclic group, an aryl group, a heteroaryl group, -(CH2) n1 R 25 , -(CH2) n1 OR 25 , -(CH2) n1 SR 25 , -(CH2) n1 C(O)R 25 , -(CH2) n1 C(O)OR 25 , -(CH2) n1 S(O) m1 R 25 , -(CH2) n1 NR 25 R 26 , -(CH2) n1 C(O)NR 25 R 26 , -(CH2) n1 C(O)NHR 25 , -(CH2) n1 NR 25 C(O)R 26 , and -(CH2) n1 NR 25 S(O) m1 R 26 and optionally further substituted with one or more of the substituents selected from the group consisting of: [ka] is a double bond, R 5 and R 6a or R 6b one of them is not present; R 3 , R 2a , R 2b , R4a , R 4b , R 5 , R 6a , R 6b , R 11a , R 11b , R 15a , R 15b , R 16a , R 16b , R 18 , R 19 , R 20a , or R 20b are each independently a hydrogen atom, a deuterium atom, an alkyl group, a deuterated alkyl group, an alkoxy group, a halogenated alkoxy group, a halogen, an amino group, a mercapto group, a nitro group, a hydroxyl group, a cyano group, an alkenyl group, an alkynyl group, a cycloalkyl group, a heterocyclyl group, an aryl group, a heteroaryl group, -(CH2) n1 R 23 , -(CH2) n1 OR 23 , -(CH2) n1 SR 23 , -(CH2) n1 C(O)R 23 , -(CH2) n1 C(O)OR 23 , -(CH2) n1 S(O) m1 R 23 , -(CH2) n 1NR 23 R 24 , -(CH2) n1 C(O)NR 23 R 24 , -(CH2) n1 NR 23 C(O)R 24 , or -(CH2) n1 NR 23 S(O) m1 R 24and the alkyl group, the haloalkyl group, the cycloalkyl group, the heterocyclic group, the aryl group, and the heteroaryl group are selected from the group consisting of a deuterium atom, an alkyl group, a halogen, an amino group, a mercapto group, an oxo group, a nitro group, a cyano group, a hydroxyl group, an alkenyl group, an alkynyl group, an alkoxy group, a halogenated alkoxy group, a hydroxyalkyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted heterocyclic group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, -(CH2) n1 R 25 , -(CH2) n1 OR 25 , -(CH2) n1 SR 25 , -(CH2) n1 C(O)R 25 , -(CH2) n1 C(O)OR 25 , -(CH2) n1 S(O) m1 R 25 , -(CH2) n1 NR 25 R 26 , -(CH2) n1 C(O)NR 25 R 26 , -(CH2) n1 C(O)NHR 25 , -(CH2) n1 NR 25 C(O)R 26 , and -(CH2) n1 NR 25 S(O) m1 R 26 or optionally further substituted with one or more of the substituents selected from the group consisting of: Or R 3 , R 2a , R 2b , R 4a , R 4b , R 5 , R 6a , R 6b , R 11a , R 11b , R 15a , R 15b , R 16a , R 16b, R 18 , R 19 , R 20a , or R 20b Any two adjacent or non-adjacent groups among these may form a cycloalkyl group, a heteroalkyl group, an aryl group, and a heteroaryl group, and the cycloalkyl group, the heterocyclic group, the aryl group, and the heteroaryl group may be substituted with a deuterium atom, an alkyl group, a halogen atom, an amino group, a mercapto group, an oxo group, a nitro group, a cyano group, a hydroxyl group, an alkenyl group, an alkynyl group, an alkoxy group, a halogenated alkoxy group, a hydroxyalkyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted heterocyclic group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, -(CH2) n1 R 25 , -(CH2) n1 OR 25 , -(CH2) n1 SR 25 , -(CH2) n1 C(O)R 25 , -(CH2) n1 C(O)OR 25 , -(CH2) n1 S(O) m1 R 25 , -(CH2) n1 NR 25 R 26 , -(CH2) n1 C(O)NR 25 R 26 , -(CH2) n1 C(O)NHR 25 , -(CH2) n1 NR 25 C(O)R 26 , and -(CH2) n1 NR 25 S(O) m1 R 26 or optionally further substituted with one or more of the substituents selected from the group consisting of: Or R 15a and R 15b , or R 16a and R 16b together form an oxo (=O) group; Or R15a or R 15b and R 16a or R 16b one of which is absent, forming a double bond; R 22 , R 23 , R 24 , R 25 , and R 26 are each independently selected from a hydrogen atom, a deuterium atom, an alkyl group, a deuterated alkyl group, a hydroxyl group, an amino group, an alkenyl group, an alkynyl group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group, wherein the alkyl group, the cycloalkyl group, the heterocyclyl group, the aryl group, and the heteroaryl group are optionally further substituted with one or more substituents selected from a deuterium atom, a substituted or unsubstituted alkyl group, a halogen, a hydroxyl group, a substituted or unsubstituted amino group, an oxo group, a nitro group, a cyano group, an alkenyl group, an alkynyl group, an alkoxy group, a hydroxyalkyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted heterocyclic group, a substituted or unsubstituted aryl group, and a substituted or unsubstituted heteroaryl group. or a pharmaceutically acceptable salt thereof.

[0088] In some embodiments, the compound has formula IV-C or formula IV-D: [ka] or a pharmaceutically acceptable salt thereof.

[0089] In some embodiments, the compound has formula IV-E: [ka] or a pharmaceutically acceptable salt thereof.

[0090] In some embodiments, the compound has formula IA: [ka] or a pharmaceutically acceptable salt thereof.

[0091] In some embodiments, the compound has formula IB: [ka] or a pharmaceutically acceptable salt thereof.

[0092] In some embodiments, the compound has formula IC: [ka] or a pharmaceutically acceptable salt thereof.

[0093] In some embodiments, the compound has formula ID: [ka] or a pharmaceutically acceptable salt thereof.

[0094] In some embodiments, the compound has the formula IE: [ka] or a pharmaceutically acceptable salt thereof.

[0095] In some embodiments, the compound has the formula IF: [ka] or a pharmaceutically acceptable salt thereof.

[0096] In some embodiments, the compound has formula IG: [ka] or a pharmaceutically acceptable salt thereof.

[0097] In some embodiments, the compound has formula IH: [ka] or a pharmaceutically acceptable salt thereof.

[0098] In some embodiments, the compound has Formula V: [ka] [In formula: m is 0, 1, 2, or 3; n is 1 or 2; q is independently 0, 1, 2, or 3; r is independently 0, 1, or 2; s is independently 0, 1, or 2; t is independently 0, 1, 2, or 3; u is independently 1 or 2; X is hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -OR A1 , -SR A1 , -N(R A1 )2, -OC(=O)R A1 , -OC(=O)OR A1 , -OC(=O)SR A1 , -OC(=O)N(R A1 )2, -SC(=O)R A2 , -SC(=O)OR A1 , -SC(=O)SR A1 , -SC(=O)N(R A1 )2, -NHC(=O)R A1 , -NHC(=O)OR A1 , -NHC(=O)SR A1 , -NHC(=O)N(R A1 )2, -OS(=O)2R A2 , -OS(=O)2OR A1 , -SS(=O)2R A2, -SS(=O)2OR A1 , -S(=O)R A2 , -SO2R A2 , or -S(=O)2OR A1 and R A1 Each occurrence is independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, oxygen protecting groups (oxygen protecting groups), R is a protecting group (when attached to a sulfur atom), a protecting group (when attached to a nitrogen atom), or a protecting group (when attached to a nitrogen atom); A2 each occurrence is independently substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 5 is hydrogen or methyl, or [ka] is a double bond, R 5 and R 6a or R 6b one of them is not present; R 19 is hydrogen or substituted or unsubstituted alkyl; R 18 is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl; R 3 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 6a and R 6beach is independently hydrogen, halogen, cyano, hydroxyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl; or R 6a and R 6b together form an oxo (=O) group; R 2a , R 2b , R 4a , R 4b , R 11a , R 11b , R 16a , or R 16b each independently represents hydrogen, halogen, cyano, hydroxyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted alkynyl, -OR D1 , -OC(=O)R D1 , -NH2, -N(R D1 )2, or -NR D1 C(=O)R D1 and R D1 each occurrence is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, an oxygen protecting group (when attached to an oxygen atom), a nitrogen protecting group (when attached to a nitrogen atom), or two R D1 groups taken together form a substituted or unsubstituted heterocyclic ring; or R 2a and R 2b , or R 4a and R 4b , or R 11a and R 11b , or R 16a and R 16b taken together form an oxo (=O) group; however, q, s, r, u, and t cannot be 1 simultaneously] or a pharmaceutically acceptable salt thereof.

[0099] In some embodiments, the compound has Formula VI: [ka] [In formula: m is 0, 1, 2, 3, or 4; n is 0, 1, 2, 3, or 4; However, if m is 0, then n is not 0 or 1; X is hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 1a , R 1b , R 2a , R 2b , R 4a , R 4b , R 7a , R 7b , R 11a , R 11b , R 12a , R 12b , R 15a , R 15b , R 16a , and R 16b each independently represents hydrogen, halogen, cyano, -NO2, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -OR A1 , -N(R A1 )2, -SR A1 , -C(=O)R A1 , -C(=O)OR A1 , -C(=O)SR A1 , -C(=O)N(R A1 )2, -OC(=O)R A1 , -OC(=O)OR A1 , -OC(=O)N(R A1 )2, -OC(=O)SR A1 , -OS(=O)2R A1 , -OS(=O)2ORA1 , -OS(=O)2N(R A1 )2, -N(R A1 )C(=O)R A1 , -N(R A1 )C(=NR A1 )R A1 , -N(R A1 )C(=O)OR A1 , -N(R A1 )C(=O)N(R A1 )2, -N(R A1 )C(=NR A1 )N(R A1 )2, -N(R A1 )S(=O)2R A1 , -N(R A1 )S(=O)2OR A1 , -N(R A1 )S(=O)2N(R A1 )2, -SC(=O)R A1 , -SC(=O)OR A1 , -SC(=O)SR A1 , -SC(=O)N(R A1 )2, -S(=O)2R A1 , -S(=O)2OR A1 , or -S(=O)2N(R A1 )2 and R A1 each occurrence of is independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, or substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, an oxygen protecting group (when oxygen is attached), a nitrogen protecting group (when nitrogen is attached), or a sulfur protecting group (when sulfur is attached); or R 11a and R 11b together form an oxo (=O) group; or R 12a and R 12b together form an oxo (=O) group; or R 15a and R 15b together form an oxo (=O) group; or R 16a and R 16b together form an oxo (=O) group; or R 4aand R 4b together form an oxo (=O) group; or R 7a and R 7b together form an oxo (=O) group; or R 2a and R 2b together form an oxo (=O) group; or R 1a and R 1b Let's get together and forming an xo(=O) group; R 3 is hydrogen, substituted or unsubstituted alkyl; R 5 is hydrogen or methyl; R 6a and R 6b each is independently hydrogen, halogen, cyano, —NO, —OH, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl; or R 6a and R 6b together form an oxo (=O) group; R 18 is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl; R 19 is hydrogen or substituted or unsubstituted alkyl; And R 20a , R 20b , R 23a , or R 23b are each independently selected from the group consisting of a hydrogen atom, an alkyl group, a halogenated alkyl group, an alkoxy group, and a halogenated alkoxy group. or a pharmaceutically acceptable salt thereof.

[0100] In some embodiments, [ka] is a single bond. In another embodiment, [ka] is a double bond.

[0101] In some embodiments, the compound has Formula VII: [ka] [In formula: R 3 is C 1~6 Alkyl or C 1~6 is an alkoxyalkyl; R 30 teeth, [ka] and; R 28 is -H or unsubstituted C 1~3 is alkyl; Each R 29 are independently -H or unsubstituted C 1~3 is alkyl; R 31 is -OH, -CN, or -CF3; n is 2, 3, or 4] or a pharmaceutically acceptable salt thereof.

[0102] In some embodiments, R 30 teeth, [ka] and R 28 is -H or -CH3. In some embodiments, R 31 is -CN.

[0103] In some embodiments, R 30 teeth, [ka] and each R 29 is independently -H or -CH3. In some embodiments, each R 29is -CH3. In some embodiments, R 29 One occurrence of is -CH3. And, in some embodiments, each R 29 is —H. In other embodiments, R 31 is -CN.

[0104] In some embodiments, R 30 teeth, [ka] where n is 2 or 3, and R 31 is -CN.

[0105] In some embodiments, R 3 is the unsubstituted C 1~3 Alkyl or unsubstituted C 1~3 Alkyl-OC 1~3 It is alkyl.

[0106] In some embodiments, the compound of Formula (I) is a compound of Formula (IA), Formula (IB), Formula (IC), Formula (ID), Formula (IE), Formula (IF), Formula (IG), Formula (IH), or Formula (VII). In some embodiments, the compound of Formula (IV-A) or (IV-A) is a compound of Formula (IV-C), Formula (IV-D), or Formula (IV-E). In some embodiments, the compound of Formula (VI) is a compound of Formula (VI-A), Formula (VI-B), Formula (VI-C), Formula (VI-D), Formula (VI-E), Formula (VI-F), Formula (VI-G), Formula (VI-H), Formula (VI-IA).

[0107] A.R. 1a and R 1b base

[0108] In some embodiments, R 1a and R 1bare each independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl.

[0109] In some embodiments, R 1a and R 1b are each independently hydrogen, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl.

[0110] In some embodiments, R 1a and R 1b are each independently substituted carbocyclyl, substituted heterocyclyl, substituted aryl, or substituted heteroaryl, each of which is further substituted with substituted carbocyclyl, substituted heterocyclyl, substituted aryl, or substituted heteroaryl.

[0111] In some embodiments, R 1a and R 1b are, independently: [ka] [In formula: R a Each occurrence of is independently hydrogen, halogen, -NO2, -CN, -OR A1 , -OC(=O)R A1 , -OS(=O)2OR A1 , -N(R A1 )2, or -N(R A1 )C(=O)R A1 , -N(R A1 )S(=O)2R A1 , -N(R A1 )S(=O)2OR A1 , substituted or unsubstituted C 1~6 Alkyl, substituted or unsubstituted C 2~6 Alkenyl, substituted or unsubstituted C 2~6 Alkynyl, substituted or unsubstituted C3~6 Carbocyclyl, substituted or unsubstituted 3- to 6-membered heterocyclyl, substituted or unsubstituted C 5~10 aryl, substituted or unsubstituted 5-10 membered heteroaryl; R A1 Each occurrence is independently hydrogen, substituted or unsubstituted C 1~6 Alkyl, substituted or unsubstituted C 2~6 Alkenyl, substituted or unsubstituted C 2~6 Alkynyl, substituted or unsubstituted C 3~6 Carbocyclyl, substituted or unsubstituted 3- to 6-membered heterocyclyl, substituted or is unsubstituted C 5~10 aryl, substituted or unsubstituted 5- to 10-membered heteroaryl, oxygen protecting group (when oxygen is bonded), nitrogen protecting group (when nitrogen is bonded), or two R A1 the group, together with the intervening atoms, forms a substituted or unsubstituted heterocyclic ring; p is an integer selected from 0 to 11. is selected from the group consisting of:

[0112] In some embodiments, R 1a and R 1b are, independently: [ka] [In formula: R a Each occurrence of is independently hydrogen, halogen, -NO2, -CN, -OR A1 , -OC(=O)R A1 , -OS(=O)2OR A1 , -N(R A1 )2, or -N(R A1 )C(=O)R A1 , -N(R A1 )S(=O)2R A1 , -N(R A1 )S(=O)2OR A1 , substituted or unsubstituted C 1~6 Alkyl, substituted or unsubstituted C 2~6 Alkenyl, substituted or unsubstituted C 2~6 Alkynyl, substituted or unsubstituted C3~6 Carbocyclyl, substituted or unsubstituted 3- to 6-membered heterocyclyl, substituted or unsubstituted C 5~10 aryl, substituted or unsubstituted 5-10 membered heteroaryl; R A1 Each occurrence is independently hydrogen, substituted or unsubstituted C 1~6 Alkyl, substituted or unsubstituted C 2~6 Alkenyl, substituted or unsubstituted C 2~6 Alkynyl, substituted or unsubstituted C 3~6 Carbocyclyl, substituted or unsubstituted 3- to 6-membered heterocyclyl, substituted or unsubstituted C 5~10 aryl, substituted or unsubstituted 5- to 10-membered heteroaryl, oxygen protecting group (when oxygen is bonded), nitrogen protecting group (when nitrogen is bonded), or two R A1 the group, together with the intervening atoms, forms a substituted or unsubstituted heterocyclic ring; p is an integer selected from 0 to 11. is selected from the group consisting of:

[0113] In some embodiments, R 1a and R 1b are both hydrogen.

[0114] B.R. 2a and R 2b base

[0115] In some embodiments, R 2a and R 2b are each independently hydrogen, halogen, —CN, —NO2, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, -OR A1 , -OC(=O)R A1 , -OS(=O)2OR A1 , -N(R A1 )2, or -N(R A1 )C(=O)R A1 , -N(R A1 )S(=O)2R A1 , -N(R A1 )S(=O)2OR A1and;R A1 each occurrence is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, or two R A1 The groups, together with the intervening atoms, form a substituted or unsubstituted heterocyclic ring.

[0116] In some embodiments, R 2a and R 2b are each independently hydrogen, halogen, -CN, -NO2, -OR A1 , -OC(=O)R A1 , -N(R A1 )2, or -N(R A1 )C(=O)R A1 and;R A1 each occurrence is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, or two R A1 The groups, together with the intervening atoms, form a substituted or unsubstituted heterocyclic ring.

[0117] In some embodiments, R 2a and R 2b are independently hydrogen, —OH, or substituted or unsubstituted C 1~6 It is alkyl.

[0118] In some embodiments, R 2a and R 2b Each of the is independently -H, -OH, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy, or C 1~6 It is haloalkoxy.

[0119] In some embodiments, R 2a and R 2bare independently -CH3, -CH2CH3, -OH, -OCH3, or -CH(CH3)2.

[0120] In some embodiments, R 2a and R 2b are both hydrogen.

[0121] In some embodiments, R 2a and R 2b together form an oxo (=O) group.

[0122] C.R. 3 base

[0123] In some embodiments, R 3 is substituted or unsubstituted alkyl. In some embodiments, R 3 is substituted alkyl. In some embodiments, R 3 is an unsubstituted alkyl.

[0124] In some embodiments, R 3 is a substituted or unsubstituted C 1~6 In some embodiments, R 3 is a substitution C 1~6 In some embodiments, R 3 is the unsubstituted C 1~6 It is alkyl.

[0125] In some embodiments, R 3 is a substituted or unsubstituted C 2~6 In some embodiments, R 3 is a substitution C 2~6 In some embodiments, R 3 is the unsubstituted C 2~6 It is alkyl.

[0126] In some embodiments, R 3 is methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl. In some embodiments, R 3is methyl. In some embodiments, R 3 is ethyl. In some embodiments, R 3 is propyl. In some embodiments, R 3 is n-butyl. In some embodiments, R 3 is a substituted methyl. In some embodiments, R 3 is unsubstituted methyl In some embodiments, R 3 is substituted ethyl. In some embodiments, R 3 is unsubstituted ethyl.

[0127] In some embodiments, R 3 is -CH2C3H5.

[0128] In some embodiments, R 3 is C 1~6 It is an alkoxy.

[0129] In some embodiments, R 3 is —CH2OCH3. In some embodiments, R 3 is -CH2CH2OCH3. In some embodiments, R 3 is -CH2CH2CH2OCH3.

[0130] In some embodiments, R 3 is -CH2OCH2CH3, -CH2CH2OCH2CH3, or -CH2CH2CH2OCH2CH3.

[0131] In some embodiments, R 3 is -CH2OCH2CH2CH3, -CH2CH2OCH2CH2CH3, or -CH2CH2CH2OCH2CH2CH3.

[0132] In some embodiments, R 3 is hydrogen.

[0133] In some embodiments, R 3is -CH3.

[0134] D.R. 4a and R 4b base

[0135] In some embodiments, R 4a and R 4b are each independently hydrogen, halogen, —CN, —NO2, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, —OR A1 , -OC(=O)R A1 , -OS(=O)2OR A1 , -N(R A1 )2, or -N(R A1 )C(=O)R A1 , -N(R A1 )S(=O)2R A1 , -N(R A1 )S(=O)2OR A1 and;R E5 each occurrence is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, or two R A1 The groups, together with the intervening atoms, form a substituted or unsubstituted heterocyclic ring.

[0136] In some embodiments, R 4a and R 4b are each independently -H, halogen, -CN, -NO2, -OR A1 , -OC(=O)R A1 , -N(R A1 )2, or -N(R A1 )C(=O)R A1 and;R A1 each occurrence is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, or two R A1The groups, together with the intervening atoms, form a substituted or unsubstituted heterocyclic ring.

[0137] In some embodiments, R 4a and R 4b are each independently -H, -OH, or substituted or unsubstituted C 1~6 It is alkyl.

[0138] In some embodiments, R 4a and R 4b Each of the is independently -H, -OH, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy, or C 1~6 It is haloalkoxy.

[0139] In some embodiments, R 4a and R 4b are each independently -CH3, -CH2CH3, -OH, -OCH3, or -CH(CH3)2.

[0140] In some embodiments, R 4a and R 4b are both -H.

[0141] In some embodiments, R 4a and R 4b together form an oxo (=O) group.

[0142] E.R. 5 base

[0143] In some embodiments, R 5 is —H. In some embodiments, R 5 is methyl.

[0144] In some embodiments, R 5 is R 19 cis or R 19 is a hydrogen or methyl in the trans position relative to

[0145] In some embodiments, R 5 is R 19 cis or R 19 In some embodiments, R 5 is R 19 In some embodiments, R 5 is R 19 is a hydrogen atom in the trans position relative to

[0146] In some embodiments, R 5 is R 19 cis or R 19 In some embodiments, R 5 is R 19 In some embodiments, R 5 is R 19 The methyl is in the trans position relative to the

[0147] F.R. 6a and R 6b base

[0148] In some embodiments, R 6a and R 6b are each independently -H, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl.

[0149] In some embodiments, R 6a and R 6b Each of is independently —H or substituted alkyl.

[0150] In some embodiments, R 6a and R 6b Each of is independently —H or unsubstituted alkyl.

[0151] In some embodiments, R 6a is halogen or alkyl, and R6b is -H.

[0152] In some embodiments, R 6a and R 6b Both are halogens.

[0153] In some embodiments, R 6a and R 6b are both unsubstituted alkyl.

[0154] In some embodiments, R 6a is hydrogen and R 6b does not exist.

[0155] In some embodiments, R 6a and R 6b are both -H.

[0156] G.R. 7a and R 7b base

[0157] In some embodiments, R 7a and R 7b each independently represents -H, a halogen, -CN, -NO2, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, -OR A1 , -OC(=O)R A1 , -OS(=O)2OR A1 , -N(R A1 )2, or -N(R A1 )C(=O)R A1 , -N(R A1 )S(=O)2R A1 , -N(R A1 )S(=O)2OR A1 and;R A1 each occurrence is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, or two RA1 The groups, together with the intervening atoms, form a substituted or unsubstituted heterocyclic ring.

[0158] In some embodiments, R 7a and R 7b each independently represents -H, halogen, -CN, -NO2, -OR A1 , -OC(=O)R A1 , -N(R A1 )2, or -N(R A1 )C(=O)R A1 and;R A1 each occurrence is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, or two R A1 The groups, together with the intervening atoms, form a substituted or unsubstituted heterocyclic ring.

[0159] In some embodiments, R 7a and R 7b each independently represents -H, -OH, or a substituted or unsubstituted C 1~6 It is alkyl.

[0160] In some embodiments, R 7a and R 7b Each of the is independently -H, -OH, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy, or C 1~6 It is haloalkoxy.

[0161] In some embodiments, R 7a and R 7b each is independently —CH 3 , —CH 2 CH 3 , —OH, —OCH 3 , or —CH(CH 3 ) 2 .

[0162] In some embodiments, R 7a and R 7b are both -H.

[0163] In some embodiments, R 7a and R 7b together form an oxo (=O) group.

[0164] H.R. 11a and R 11b base

[0165] In some embodiments, R 11a and R 11b each independently represents -H, halogen, -CN, -NO2, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, -OR A1 , -OC(=O)R A1 , -OS(=O)2OR A1 , -N(R A1 )2, or -N(R A1 )C(=O)R A1 , -N(R A1 )S(=O)2R A1 , -N(R A1 )S(=O)2OR A1 and;R A1 each occurrence is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, or two R A1 The groups, together with the intervening atoms, form a substituted or unsubstituted heterocyclic ring.

[0166] In some embodiments, R 11a and R 11b each independently represents -H, halogen, -CN, -NO2, -OR A1 , -OC(=O)R A1 , -N(R A1 )2, or -N(R A1 )C(=O)R A1 and;R A1each occurrence is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, or 2 R's A1 The groups, together with the intervening atoms, form a substituted or unsubstituted heterocyclic ring.

[0167] In some embodiments, R 11a and R 11b each independently represents -H, -OH, or a substituted or unsubstituted C 1~6 It is alkyl.

[0168] In some embodiments, R 11a and R 11b Each of the is independently -H, -OH, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy, or C 1~6 It is haloalkoxy.

[0169] In some embodiments, R 11a and R 11b each independently is hydrogen, —OH, or R 11a and R 11b together form an oxo (=O) group.

[0170] In some embodiments, R 11a and R 11b each is independently —CH 3 , —CH 2 CH 3 , —OH, —OCH 3 , or —CH(CH 3 ) 2 .

[0171] In some embodiments, R 11a and R 11b are both hydrogen.

[0172] In some embodiments, R 11a and R 11b together form an oxo (=O) group.

[0173] I.R. 12a and R 12b base

[0174] In some embodiments, R 12a and R 12b each independently represents -H, halogen, -CN, -NO2, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, -OR A1 , -OC(=O)R A1 , -OS(=O)2OR A1 , -N(R A1 )2, or -N(R A1 )C(=O)R A1 , -N(R A1 )S(=O)2R A1 , -N(R A1 )S(=O)2OR A1 and;R A1 each occurrence is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, or two R A1 The groups, together with the intervening atoms, form a substituted or unsubstituted heterocyclic ring.

[0175] In some embodiments, R 12a and R 12b each independently represents -H, halogen, -CN, -NO2, -OR A1 , -OC(=O)R A1 , -N(R A1 )2, or -N(R A1 )C(=O)R A1 and;R A1 each occurrence is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, or two R A1 The groups, together with the intervening atoms, form a substituted or unsubstituted heterocyclic ring.

[0176] In some embodiments, R 12a and R 12b each independently represents -H, -OH, or a substituted or unsubstituted C 1~6 It is alkyl.

[0177] In some embodiments, R 12a and R 12b are independently hydrogen, -OH, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy, or C 1~6 It is haloalkoxy.

[0178] In some embodiments, R 12a and R 12b each is independently —CH 3 , —CH 2 CH 3 , —OH, —OCH 3 , or —CH(CH 3 ) 2 .

[0179] In some embodiments, R 12a and R 12b are both hydrogen.

[0180] In some embodiments, R 12a and R 12b together form an oxo (=O) group.

[0181] J.R. 15a and R 15b base

[0182] In some embodiments, R 15a and R 15b each independently represents -H, halogen, -CN, -NO2, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -OR A1 , -N(R A1 )2, -SR A1 , -C(=O)R A1, -C(=O)OR A1 , -C(=O)SR A1 , -C(=O)N(R A1 )2, -OC(=O)R A1 , -OC(=O)OR A1 , -OC(=O)N(R A1 )2, -OC(=O)SR A1 , -OS(=O)2R A1 , -OS(=O)2OR A1 , -OS(=O)2N(R A1 )2, -N(R A1 )C(=O)R A1 , -N(R A1 )C(=NR A1 )R A1 , -N(R A1 )C(=O)OR A1 , -N(R A1 )C(=O)N(R A1 )2, -N(R A1 )C(=NR A1 )N(R A1 )2, -N(R A1 )S(=O)2R A1 , -N(R A1 )S(=O)2OR A1 , -N(R A1 )S(=O)2N(R A1 )2, -SC(=O)R A1 , -SC(=O)OR A1 , -SC(=O)SR A1 , -SC(=O)N(R A1 )2, -S(=O)2R A1 , -S(=O)2OR A1 , or -S(=O)2N(R A1 )2 and R A1 each occurrence is independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, or substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, an oxygen protecting group (when oxygen is attached), a nitrogen protecting group (when nitrogen is attached), or a sulfur protecting group (when sulfur is attached), or two R A1The groups, together with the intervening atoms, form a substituted or unsubstituted heterocyclic ring; or R 15a and R 15b together form an oxo (=O) group.

[0183] In some embodiments, R 15a and R 15b Each of is independently -H, halogen, -CN, substituted or unsubstituted alkyl, or substituted or unsubstituted carbocyclyl.

[0184] In some embodiments, R 15a and R 15b are both hydrogen. In some embodiments, R 15a is hydrogen. In some embodiments, R 15b is hydrogen.

[0185] In some embodiments, R 15a and R 15b and R are both substituted alkyl. In some embodiments, R 15a and R 15b and R are both unsubstituted alkyl. In some embodiments, R 15a and R 15b and R are both methyl. 15a and R 15b and R are both unsubstituted methyl. In some embodiments, R 15a and R 15b and R are both substituted methyl. In some embodiments, R 15a and R 15b One of R is substituted methyl and the other is unsubstituted methyl. In some embodiments, R 15a and R 15b and R are both ethyl. 15a is unsubstituted methyl. In some embodiments, R 15a is a substituted methyl. In some embodiments, R 15a and R 15bOne of R is substituted ethyl and the other is unsubstituted ethyl. 15b is unsubstituted methyl. In some embodiments, R 15b is a substituted methyl.

[0186] In some embodiments, R 15a and R 15b together form an oxo (=O) group.

[0187] In some embodiments, R 15a and R 15b Each of R is independently hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted carbocyclyl. 15a and R 15b are each independently hydrogen, unsubstituted alkyl, or unsubstituted carbocyclyl. In some embodiments, R 15a and R 15b are each independently hydrogen, methyl, or cyclopropyl.

[0188] K.R. 16a and R 16b base

[0189] In some embodiments, R 16a and R 16b each independently represents hydrogen, halogen, —CN, —NO, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —OR A1 , -N(R A1 )2, -SR A1 , -C(=O)R A1 , -C(=O)OR A1 , -C(=O)SR A1 , -C(=O)N(R A1 )2, -OC(=O)R A1 , -OC(=O)OR A1 , -OC(=O)N(R A1)2, -OC(=O)SR A1 , -OS(=O)2R A1 , -OS(=O)2OR A1 , -OS(=O)2N(R A1 )2, -N(R A1 )C(=O)R A1 , -N(R A1 )C(=NR A1 )R A1 , -N(R A1 )C(=O)OR A1 , -N(R A1 )C(=O)N(R A1 )2, -N(R A1 )C(=NR A1 )N(R A1 )2, -N(R A1 )S(=O)2R A1 , -N(R A1 )S(=O)2OR A1 , -N(R A1 )S(=O)2N(R A1 )2, -SC(=O)R A1 , -SC(=O)OR A1 , -SC(=O)SR A1 , -SC(=O)N(R A1 )2, -S(=O)2R A1 , -S(=O)2OR A1 , or -S(=O)2N(R A1 )2 and R A1 each occurrence is independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, or substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, an oxygen protecting group (when oxygen is attached), a nitrogen protecting group (when nitrogen is attached), or a sulfur protecting group (when sulfur is attached), or two R A1 The groups, together with the intervening atoms, form a substituted or unsubstituted heterocyclic ring; or R 15a and R 15b together form an oxo (=O) group.

[0190] In some embodiments, R 16a and R 16bEach of is independently hydrogen, halogen, —CN, substituted or unsubstituted alkyl, or substituted or unsubstituted carbocyclyl.

[0191] In some embodiments, R 16a and R 16b are both hydrogen. In some embodiments, R 16a is hydrogen. In some embodiments, R 16b is hydrogen.

[0192] In some embodiments, R 16a and R 16b and R are both substituted alkyl. In some embodiments, R 16a and R 16b and R are both unsubstituted alkyl. In some embodiments, R 16a and R 16b and R are both methyl. 16a and R 16b and R are both unsubstituted methyl. In some embodiments, R 16a and R 16b and R are both substituted methyl. In some embodiments, R 16a and R 16b and R are both ethyl. 16a is unsubstituted methyl. In some embodiments, R 16a is a substituted methyl. In some embodiments, R 16b is unsubstituted methyl. In some embodiments, R 15b is a substituted methyl.

[0193] In some embodiments, R 16a and R 16b together form an oxo (=O) group.

[0194] In some embodiments, R 16a and R 16bEach of R is independently hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted carbocyclyl. 16a and R 16b are each independently hydrogen, unsubstituted alkyl, or unsubstituted carbocyclyl. In some embodiments, R 16a and R 16b is independently hydrogen, methyl, or cyclopropyl.

[0195] L.R. 18 base

[0196] In some embodiments, R 18 is substituted alkyl. In some embodiments, R 18 is a substitution C 1~6 alkyl (eg, substituted methyl, substituted ethyl, substituted propyl, or substituted iso-propyl).

[0197] In some embodiments, R 18 is unsubstituted alkyl. In some embodiments, R 18 is the unsubstituted C 1~6 alkyl (e.g., unsubstituted methyl, unsubstituted ethyl, unsubstituted propyl, or unsubstituted iso-propyl). In some embodiments, R 18 is methyl. In some embodiments, R 18 is ethyl.

[0198] In some embodiments, R 18 is unsubstituted alkenyl. In some embodiments, R 18 is the unsubstituted C 2~6 In some embodiments, R is alkenyl. 18 is substituted alkenyl. In some embodiments, R 18 is a substitution C 2~4 In some embodiments, R is alkenyl. 18 is an unsubstituted alkynyl (e.g., C 2~6 alkynyl). In some embodiments, R 18 is a substituted alkynyl.

[0199] M.R. 19 base

[0200] In some embodiments, R 19 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl.

[0201] In some embodiments, R 19 is hydrogen or substituted or unsubstituted alkyl.

[0202] In some embodiments, R 19 is a substituted alkyl.

[0203] In some embodiments, R 19 is a substitution C 2~6 In some embodiments, R 19 is the unsubstituted C 2~6 It is alkyl.

[0204] In some embodiments, R 19 is —CH2OCH3. In some embodiments, R 19 is -CH2OCH2CH3.

[0205] In some embodiments, R 19 is hydrogen or unsubstituted alkyl.

[0206] In some embodiments, R 19 is an unsubstituted alkyl.

[0207] In some embodiments, R 19 is a substitution C 1~6 In some embodiments, R 19 is the unsubstituted C 1~6 It is alkyl.

[0208] In some embodiments, R 19 is methyl. In some embodiments, R19 is ethyl.

[0209] In some embodiments, R 19 is hydrogen. In some embodiments, R 19 is hydrogen or substituted or unsubstituted C 1~6 It is alkyl.

[0210] In some embodiments, R 19 is hydrogen, methyl, ethyl, or methoxymethyl.

[0211] N.R. 20a and R 20b base

[0212] In some embodiments, R 20a and R 20b is independently hydrogen or substituted alkyl. In some embodiments, R 20a and R 20b are independently hydrogen or unsubstituted alkyl. In some embodiments, R 20a and R 20b are independently -CH3, -CH2CH3, -OH, -OCH3, or -CH(CH3)2.

[0213] In some embodiments, R 20a is -CH3 and R 20b is hydrogen. In some embodiments, R 20a and R 20b are both -CH3. In some embodiments, R 20a and R 20b and R are both unsubstituted alkyl. In some embodiments, R 20a and R 20b and R are both substituted alkyl. In some embodiments, R 20a and R 20b are both unsubstituted C 1~6 In some embodiments, R 20a and R 20b are both substitutions C 1~6It is alkyl.

[0214] In some embodiments, R 20a and R 20b are both hydrogen. In some embodiments, R 20a is hydrogen. In some embodiments, R 20a is -CH3. In some embodiments, R 20a is -CH2CH3. In some embodiments, R 20b is hydrogen. In some embodiments, R 20b is -CH3. In some embodiments, R 20b is -CH2CH3.

[0215] O.R. 23a and R 23b base

[0216] In some embodiments, R 23a and R 23b are independently hydrogen or substituted alkyl. In some embodiments, R 23a and R 23b are independently hydrogen or unsubstituted alkyl. In some embodiments, R 23a and R 23b each is independently —CH 3 , —CH 2 CH 3 , —OH, —OCH 3 , or —CH(CH 3 ) 2 .

[0217] In some embodiments, R 23a is -CH3 and R 23b is hydrogen. In some embodiments, R 23a and R 23b are both -CH3. In some embodiments, R 23a and R 23b and R are both unsubstituted alkyl. In some embodiments, R 23a and R 23b and R are both substituted alkyl. In some embodiments, R 23a and R 23b are both unsubstituted C 1~6In some embodiments, R 23a and R 23b are both substitutions C 1~6 It is alkyl.

[0218] In some embodiments, R 23a and R 23b are both hydrogen. In some embodiments, R 23a is hydrogen. In some embodiments, R 23a is -CH3. In some embodiments, R 23a is -CH2CH3. In some embodiments, R 23b is hydrogen. In some embodiments, R 23b is -CH3. In some embodiments, R 23b is -CH2CH3.

[0219] P. Integers m and n

[0220] In some embodiments, n is 0, 1, 2, 3, or 4. In some embodiments, n is 0, 1, 2, or 3. In some embodiments, n is 0, 1, or 2. In some embodiments, n is 0 or 1. In some embodiments, n is 1 or 2. In some embodiments, n is 3 or 4. In some embodiments, n is 0. In some embodiments, n is 1. In another embodiment, n is 2. In another embodiment, n is 3. In another embodiment, n is 4.

[0221] In some embodiments, m is 0, 1, 2, 3, or 4. In some embodiments, m is 0, 1, 2, or 3. In some embodiments, m is 0, 1, or 2. In some embodiments, m is 0 or 1. In some embodiments, m is 1 or 2. In some embodiments, m is 3 or 4. In some embodiments, m is 0. In some embodiments, m is 1. In another embodiment, m is 2. In another embodiment, m is 3. In another embodiment, m is 4.

[0222] In some embodiments, m is 0 and n is 2. In some embodiments, m is 0 and n is 3. In some embodiments, m is 0 and n is 4.

[0223] In some embodiments, m is 1 and n is 0. In some embodiments, m is 1 and n is 1. In some embodiments, m is 1 and n is 2. In some embodiments, m is 1 and n is 3. In some embodiments, m is 1 and n is 4.

[0224] In some embodiments, m is 2 and n is 0. In some embodiments, m is 2 and n is 1. In some embodiments, m is 2 and n is 2. In some embodiments, m is 2 and n is 3. In some embodiments, m is 2 and n is 4.

[0225] In some embodiments, m is 3 and n is 0. In some embodiments, m is 3 and n is 1. In some embodiments, m is 3 and n is 2. In some embodiments, m is 3 and n is 3. In some embodiments, m is 3 and n is 4.

[0226] In some embodiments, m is 4 and n is 0. In some embodiments, m is 4 and n is 1. In some embodiments, m is 4 and n is 2. In some embodiments, m is 4 and n is 3. In some embodiments, m is 4 and n is 4.

[0227] In some embodiments, when m is 0, R 15a or R 15b None of these are H.

[0228] In some embodiments, when m is 0, n is not 0. In some embodiments, when m is 0, n is not 1.

[0229] Q. Integers q, r, s, t, and u

[0230] In some embodiments, q is 0, 1, 2, or 3. In some embodiments, q is 0, 1, or 2. In some embodiments, q is 0 or 1. In some embodiments, q is 1 or 2. In some embodiments, q is 0. In some embodiments, q is 1. In other embodiments, q is 2. In other embodiments, q is 3.

[0231] In some embodiments, r is 0, 1, or 2. In some embodiments, r is 0 or 1. In some embodiments, r is 1 or 2. In some embodiments, r is 0. In some embodiments, r is 1. In other embodiments, r is 2.

[0232] In some embodiments, s is 0, 1, or 2. In some embodiments, s is 0 or 1. In some embodiments, s is 1 or 2. In some embodiments, s is 0. In some embodiments, s is 1. In other embodiments, s is 2.

[0233] In some embodiments, t is 0, 1, 2, or 3. In some embodiments, t is 0, 1, or 2. In some embodiments, t is 0 or 1. In some embodiments, t is 1 or 2. In some embodiments, t is 0. In some embodiments, t is 1. In another embodiment, t is 2. In another embodiment, t is 3.

[0234] In some embodiments, u is 1 or 2. In some embodiments, u is 1. In some embodiments, u is 2.

[0235] In some embodiments, r is 1 and s is 1.

[0236] In some embodiments, q is 0, 2, or 3; and t is 0, 2, or 3. In other embodiments, q is 2, t is 2, and u is 1.

[0237] In some embodiments, q is 0, 2, or 3; and u is 1. In other embodiments, q is 0, 2, or 3; t is 0, 2, or 3, and u is 1.

[0238] In another embodiment, q is 1, t is 0, 2, or 3, and u is 2.

[0239] In some embodiments, q, u, r, s, and t are not all 1 at the same time. In some embodiments, when t is 0, 2, or 3, q, u, s, and r are not all 1 at the same time. In some embodiments, when q is 0 or 2 and u is 1, t, s, and r are not all 1 at the same time. In some embodiments, when u is 2 and q is 1, t, s, and r are not all 1 at the same time. In some embodiments, when r is 0 or 2, q, u, s, and t are not all 1 at the same time. In some embodiments, when s is 0 or 2, q, u, r, and t are not all 1 at the same time.

[0240] R. Integers p, m1 and n1

[0241] In some embodiments, n1 is 1 or 2. In some embodiments, n1 is 0. In some embodiments, n1 is 1. In another embodiment, n1 is 2. In another embodiment, n1 is 3. In another embodiment, n1 is 4. In another embodiment, n1 is 5.

[0242] In some embodiments, m1 is 1 or 2. In some embodiments, m1 is 0. In some embodiments, m1 is 1. In other embodiments, m1 is 2.

[0243] In some embodiments, p is 1 or 2. In some embodiments, p is 0. In some embodiments, p is 1. In another embodiment, p is 2. In another embodiment, p is 3. In another embodiment, p is 4.

[0244] S.X group

[0245] In some embodiments, X is -H, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl, or substituted or unsubstituted heteroaryl.

[0246] In some embodiments, X is hydrogen, substituted or unsubstituted heteroaryl, or substituted or unsubstituted alkyl.

[0247] In another embodiment, X is substituted or unsubstituted heteroaryl.

[0248] In one embodiment, X is a substituted or unsubstituted 5-10 membered heteroaryl.

[0249] In one embodiment, X is hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or -OR A1 and;R A1 is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0250] In some embodiments, X is hydrogen or substituted or unsubstituted heteroaryl.

[0251] For example, in some instances, X is a substituted or unsubstituted N-linked heteroaryl.

[0252] In one embodiment, the N-linked heteroaryl is a 5-6 membered N-linked heteroaryl.

[0253] In some embodiments, X is [ka] is.

[0254] In some embodiments, X is [ka] is.

[0255] In some embodiments, X is -CH3.

[0256] In some embodiments, X is [ka] [In formula: R 20 Each occurrence of is independently a halogen, -NO2, -CN, -OR GA , -N(R GA )2, -C(=O)R GA , -C(=O)OR GA , -OC(=O)R GA , -OC(=O)OR GA , -C(=O)N(R GA )2, -N(R GA )C(=O)R GA , -OC(=O)N(R GA )2, -N(R GA )C(=O)OR GA , -S(=O)2R GA , -S(=O)2OR GA , -OS(=O)2R GA , -S(=O)2N(R GA )2, or -N(R GA )S(=O)2R GA ;Substituted or unsubstituted C 1~6 Alkyl, substituted or unsubstituted C 2~6 Alkenyl, substituted or unsubstituted C 2~6 Alkynyl, substituted or unsubstituted C 3~4 carbosilyl, or substituted or unsubstituted 3- to 4-membered heterosilyl; R GA Each occurrence is independently hydrogen, substituted or unsubstituted C 1~6 Alkyl, substituted or unsubstituted C 2~6 Alkenyl, substituted or unsubstituted C 2~6 Alkynyl, substituted or unsubstituted substitution C 3~6 carbosilyl, substituted or unsubstituted 3- to 6-membered heterosilyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, oxygen protecting group (when oxygen is bonded), or nitrogen protecting group (when nitrogen is bonded); or two RGA the group, together with the intervening atoms, forms a substituted or unsubstituted carbocyclic or substituted or unsubstituted heterocyclic ring; e is 0, 1, 2, 3, 4, or 5] is.

[0257] In some embodiments, X is: [ka] [In formula: R 20 Each occurrence of is independently a halogen, -NO2, -CN, -OR GA , -N(R GA )2, -C(=O)R GA , -C(=O)OR GA , -C(=O)N(R GA )2, -N(R GA )C(=O)R GA , -OC(=O)N(R GA )2, substituted or unsubstituted C 1~6 alkyl, substituted or unsubstituted 3- to 4-membered carbosilyl, substituted or unsubstituted 3- to 4-membered heterocyclyl; R GA Each occurrence is independently hydrogen, substituted or unsubstituted C 1~6 alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, oxygen protecting group (when oxygen is bonded), nitrogen protecting group (when nitrogen is bonded), or two R GA the group, together with the intervening atoms, forms a substituted or unsubstituted carbocyclic or heterocyclic ring; e is 0, 1, 2, or 3] is.

[0258] In some embodiments, X is [ka] [In formula: R 20 Each occurrence of is independently a halogen, -NO2, -CN, -OR GA , -N(R GA )2, -C(=O)R GA, -C(=O)OR GA , -C(=O)N(R GA )2, -N(R GA )C(=O)R GA , -OC(=O)N(R GA )2, substituted or unsubstituted C 1~6 alkyl, substituted or unsubstituted 3- to 4-membered carbosilyl, substituted or unsubstituted 3- to 4-membered heterocyclyl; R GA Each occurrence is independently hydrogen, substituted or unsubstituted C 1~6 alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or two R GA base together with the intervening atoms form a substituted or unsubstituted carbocyclic or heterocyclic ring; e is 0, 1, 2, or 3] is.

[0259] T. A, Z, W, and Y groups

[0260] In some embodiments, A is CR 17 and R 17 is selected from the group consisting of a hydrogen atom, a deuterium atom, an alkyl group, a deuterated alkyl group, a hydroxyl group, an amino group, an alkenyl group, an alkynyl group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group, wherein the alkyl group, the cycloalkyl group, the heterocyclyl group, the aryl group, and the heteroaryl group are optionally further substituted with one or more substituents selected from the group consisting of a deuterium atom, a substituted or unsubstituted alkyl group, a halogen, a hydroxyl group, a substituted or unsubstituted amino group, an oxo group, a nitro group, a cyano group, an alkenyl group, an alkynyl group, an alkoxy group, a hydroxyalkyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted heterocyclic group, a substituted or unsubstituted aryl group, and a substituted or unsubstituted heteroaryl group.

[0261] In some embodiments, A is N. In some embodiments, A is CH. In some embodiments, A is C(CH). In some embodiments, A is C(CHCH). In some embodiments, [ka] is a double bond, then A is C.

[0262] In some embodiments, Z is -CH2-. In some embodiments, Z is -C(CH2CH3)2-. In some embodiments, Z is -C(CH3)2-. In some embodiments, Z is -NH-. In some embodiments, Z is -O-.

[0263] In some embodiments, W is -S(CH2)2-. In some embodiments, W is [ka] In some embodiments, W is [ka] In some embodiments, W is [ka] In some embodiments, W is [ka] In some embodiments, W is [ka] In some embodiments, W is [ka] is.

[0264] In some embodiments, Z is -CH2-. In some embodiments, Z is -C(CH2CH3)2-. In some embodiments, Z is -C(CH3)2-. In some embodiments, Z is -NH-. In some embodiments, Z is -O-.

[0265] In some embodiments, Y is oxygen. In some embodiments, Y is —CH—.

[0266] U.R. 20 base

[0267] In some embodiments, R 20 is -CN.

[0268] In some embodiments, R 20 is an unsubstituted alkyl.

[0269] In another embodiment, R 20 is the unsubstituted C 1~6 It is alkyl.

[0270] In one embodiment, R 20 is methyl.

[0271] V.R. 55 base

[0272] In some embodiments, R 55 is hydrogen, halogen, cyano, or substituted or unsubstituted alkyl.

[0273] In some embodiments, R 55 is cyano. In another embodiment, R 55 is methyl. In one example, R 55 is hydrogen. 55 is a halogen.

[0274] W.R. D base

[0275] In some embodiments, R D are independently hydrogen, halogen, —CN, —NO2, oxo, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —OR C3 , -N(R C3 )2, -SR C3 , -C(=O)R C3 , -C(=O)OR C3 , -C(=O)SR C3 , -C(=O)N(R C3 )2, -OC(=O)R C3 , -OC(=O)OR C3 , -OC(=O)N(R C3 )2, -OC(=O)SR C3 , -OS(=O)2R C3 , -OS(=O)2OR C3 , -OS(=O)2N(R C3 )2, -N(R C3 )C(=O)R C3 , -N(R C3 )C(=NR C3 )R C3 , -N(R C3 )C(=O)OR C3 , -N(R C3 )C(=O)N(R C3 )2, -N(R C3 )C(=NR C3 )N(R C3 )2, -N(R C3 )S(=O)2R C3 , -N(R C3 )S(=O)2OR C3 , -N(R C3 )S(=O)2N(R C3 )2, -SC(=O)R C3 , -SC(=O)OR C3 , -SC(=O)SR C3 , -SC(=O)N(R C3 )2, -S(=O)2R C3 , -S(=O)2OR C3 , or -S(=O)2N(R C3 )2 and RC3 Each occurrence is independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted carbocyclyl, or substituted or unsubstituted heterocyclyl.

[0276] In some embodiments, each R D is independently hydrogen, halogen, —CN, —NO 2 , oxo, hydroxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, or substituted or unsubstituted carbocyclyl.

[0277] In some embodiments, each R D is independently hydrogen, oxo, substituted or unsubstituted alkyl, hydroxy, or substituted or unsubstituted carbocyclyl.

[0278] In some embodiments, each R D is independently hydrogen, oxo, methyl, ethyl, hydroxy, or cyclopropyl.

[0279] In some embodiments, a method for treating a CNS-related disorder in a subject in need thereof comprises administering to the subject an effective amount of a compound described herein or a pharmaceutically acceptable salt thereof. In some embodiments, the CNS-related disorder is a sleep disorder, a mood disorder, a schizophrenia spectrum disorder, a seizure disorder, a memory and / or cognition disorder, a movement disorder, a personality disorder, an autism spectrum disorder, pain, a traumatic brain injury, a vascular disease, a substance abuse disorder and / or withdrawal syndrome, tinnitus, or status epilepticus. In some embodiments, the CNS-related disorder is depression. In some embodiments, the CNS-related disorder is postpartum depression. In some embodiments, the CNS-related disorder is major depressive disorder. In some embodiments, the major depressive disorder is moderate major depressive disorder. In some embodiments, the major depressive disorder is severe major depressive disorder.

[0280] In some embodiments, the compound has formula VI-A: [ka] or a pharmaceutically acceptable salt thereof.

[0281] In some embodiments, the compound has formula VI-B: [ka] or a pharmaceutically acceptable salt thereof.

[0282] In some embodiments, the compound has formula VI-C: [ka] or a pharmaceutically acceptable salt thereof.

[0283] In some embodiments, the compound has formula VI-D: [ka] or a pharmaceutically acceptable salt thereof.

[0284] In some embodiments, the compound has formula VI-E: [ka] or a pharmaceutically acceptable salt thereof.

[0285] In some embodiments, the compound has formula VI-F: [ka] or a pharmaceutically acceptable salt thereof.

[0286] In some embodiments, the compound has formula VI-G: [ka] or a pharmaceutically acceptable salt thereof.

[0287] In some embodiments, the compound has formula VI-H: [ka] or a pharmaceutically acceptable salt thereof.

[0288] In some embodiments, the compound has formula VI-IA: [ka] or a pharmaceutically acceptable salt thereof.

[0289] In some embodiments, the compound has formula VI-IB: [ka] or a pharmaceutically acceptable salt thereof.

[0290] In some embodiments, the compound is selected from the group consisting of the compounds identified in Table 1 below.

[0291] [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] or a pharmaceutically acceptable salt thereof.

[0292] In one aspect, provided herein are pharmaceutically acceptable salts of the compounds described herein (e.g., compounds of Formula (I) and compounds of Formula (VI)).

[0293] In one aspect, provided herein is a pharmaceutical composition comprising a compound described herein (e.g., a compound of Formula (I) and a compound of Formula (VI)) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. In certain embodiments, the compound of the invention is provided in an effective amount in the pharmaceutical composition. In certain embodiments, the compound of the invention is provided in a therapeutically effective amount.

[0294] The compounds of the invention as described herein may, in certain embodiments, be used in combination with GAB A Acting as a modulator, i.e., GABA, in either a positive or negative way A These compounds act on GABA receptors. A They are predicted to have central nervous system (CNS) activity as modulators of CNS excitability as mediated by their ability to modulate receptors.

[0295] Therefore, in another aspect, there is provided a method for treating a CNS-related disorder in a subject in need thereof, comprising administering to the subject an effective amount of a compound of the present invention.In certain embodiments, the CNS-related disorder is a sleep disorder, a mood disorder, a schizophrenia spectrum disorder, a seizure disorder, a memory and / or cognitive disorder, a movement disorder, a personality disorder, an autism spectrum disorder, pain, a traumatic brain injury, a vascular disease, a substance abuse disorder and / or withdrawal syndrome, tinnitus, or status epilepticus.In certain embodiments, the CNS-related disorder is depression.In certain embodiments, the CNS-related disorder is postpartum depression.In certain embodiments, the CNS-related disorder is major depressive disorder.In certain embodiments, the CNS-related disorder is major depressive disorder. is moderate major depressive disorder. In certain embodiments, the major depressive disorder is severe major depressive disorder. In certain embodiments, the compound is administered orally, subcutaneously, intravenously, or intramuscularly. In certain embodiments, the compound is administered orally. In certain embodiments, the compound is administered chronically. In certain embodiments, the compound is administered continuously, for example, by continuous intravenous infusion.

[0296] Exemplary compounds of the invention can be synthesized from the following known starting materials using methods known to those skilled in the art or methods from specific references: In one aspect, provided herein are pharmaceutically acceptable salts of the compounds described herein (e.g., compounds of Formula (I), and compounds of Formula (VI)).

[0297] III. Alternative Embodiments

[0298] In alternative embodiments, the compounds described herein may also contain one or more isotopic substitutions. For example, hydrogen may be: 2 H (D or deuterium) or 3 H (T or tritium); carbon can be, for example, 13 C or 14 C; oxygen can be, for example, 18 O; nitrogen can be, for example, 15 In other embodiments, a specific isotope (e.g., 3 H, 13 C. 14 C. 18 O, or 15 N) may occur in at least 1%, at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or at least 99.9% of the total isotopic abundance of the element occupying a particular site in the compound.

[0299] IV. Pharmaceutical Compositions

[0300] In one aspect, provided herein is a pharmaceutical composition comprising a compound described herein (e.g., a compound of Formula (I)) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. In certain embodiments, the compound of the invention is provided in an effective amount as a pharmaceutical composition. In certain embodiments, the compound of the invention is provided in a therapeutically effective amount.

[0301] In certain embodiments, the pharmaceutical composition comprises an effective amount of the active ingredient. In certain embodiments, the pharmaceutical composition comprises a therapeutically effective amount of the active ingredient.

[0302] The pharmaceutical compositions provided herein can be administered by a variety of routes, including, but not limited to, oral (enteral), parenteral (by injection), rectal, transdermal, intradermal, intrathecal, subcutaneous (SC), intravenous (IV), intramuscular (IM), and intranasal administration.

[0303] Generally, the compounds provided herein are administered in an effective amount. The amount of compound actually administered will typically be determined by a physician in light of the relevant circumstances, including the condition being treated, the selected route of administration, the actual compound being administered, the age, weight, and response of the individual patient, the severity of the patient's symptoms, etc.

[0304] When used to prevent the development of a CNS disorder, the compounds provided herein will typically be administered to a subject at risk of developing the condition at the dosage levels described above, under the advice and supervision of a physician. Subjects at risk of developing a particular condition generally include those with a family history of the condition or those identified by genetic testing or screening as being particularly susceptible to developing the condition.

[0305] The pharmaceutical compositions provided herein can also be administered chronically ("chronic administration"). Chronic administration refers to the administration of a compound or pharmaceutical composition thereof for an extended period of time, for example, 3 months, 6 months, 1 year, 2 years, 3 years, 5 years, etc., or can continue indefinitely, for example, for the remaining life span of the subject. In certain embodiments, chronic administration is intended to provide a constant level of the compound in the blood, for example, within the therapeutic range, for an extended period of time.

[0306] The pharmaceutical composition of the present invention can also be delivered using various administration methods.For example, in certain embodiments, the pharmaceutical composition can be given as a bolus, for example, to raise the blood concentration of the compound to an effective level.The location of the bolus administration depends on the systemic level of the active ingredient desired throughout the body; for example, intramuscular or subcutaneous bolus administration allows for a slow release of the active ingredient, while a bolus delivered directly into a vein (for example, by IV drip) allows for much faster delivery, and the blood concentration of the active ingredient can quickly rise to an effective level.In other embodiments, the pharmaceutical composition can be administered as a continuous infusion, for example, by IV drip, to maintain the steady-state concentration of the active ingredient in the subject's body.In addition, in still other embodiments, the pharmaceutical composition can be administered as a bolus first, and then by continuous infusion.

[0307] Compositions for oral administration can take the form of bulk liquid solutions or suspensions or bulk powders. However, more commonly, compositions are provided in unit dosage forms to facilitate accurate dosing. The term "unit dosage form" refers to a physically discrete unit suitable as a unitary dosage for human subjects and other mammals, each unit containing a predetermined amount of active ingredient calculated to achieve a desired therapeutic effect, along with suitable pharmaceutical excipients. Typical unit dosage forms include prefilled ampoules or syringes containing premeasured amounts of liquid compositions, or pills, tablets, capsules, etc., for solid compositions. In such compositions, the compound is typically a minor component (about 0.1 to about 50% by weight, or preferably about 1 to about 40% by weight), with the remainder consisting of various vehicles or excipients and processing aids useful in forming the desired dosage form.

[0308] For oral administration, a typical regimen is 1 to 5 times, particularly 2 to 4 times, and typically 3 times per day. When using such a dosing pattern, each dose provides about 0.01 to about 20 mg / kg of the compound provided herein, with preferred doses being about 0.1 to about 10 mg / kg, particularly about 1 to about 5 mg / kg.

[0309] Transdermal doses are generally selected to produce blood levels that are comparable to or lower than those achieved using injection doses, and are generally amounts ranging from about 0.01 to about 20% by weight, preferably from about 0.1 to about 20% by weight, preferably from about 0.1 to about 10% by weight, and more preferably from about 0.5 to about 15% by weight.

[0310] Injection dose levels range from about 0.1 mg / kg / hour to at least 20 mg / kg / hour, all for about 1 to about 120 hours, particularly 24 to 96 hours. A preloading bolus of about 0.1 mg / kg to about 10 mg / kg or more may also be administered to achieve adequate steady-state levels. The maximum total dose is expected to not exceed about 5 g / day for a 40-80 kg human patient.

[0311] Liquid forms suitable for oral administration may include a suitable aqueous or nonaqueous vehicle with buffers, suspending and dispersing agents, colorants, flavors, etc. Solid forms may include, for example, any of the following ingredients or compounds of a similar nature: binders (such as microcrystalline cellulose, gum tragacanth, or gelatin); excipients (such as starch or lactose); disintegrating agents (such as alginic acid, Primogel, or corn starch); lubricants (stearin a lubricant (such as colloidal silicon dioxide); a sweetener (such as sucrose or saccharin); or a flavoring agent (such as peppermint, methyl salicylate, or orange flavor).

[0312] Injectable compositions are typically based on injectable sterile saline or phosphate-buffered saline, or other injectable vehicles known in the art. As noted above, the active compound in such compositions is typically a minor component, often about 0.05 to 10% by weight, with the remainder being the injectable vehicle or the like.

[0313] Transdermal compositions are typically formulated as topical ointments or creams containing active ingredient(s). When formulated as an ointment, the active ingredient is typically mixed with a paraffinic ointment base or a water-miscible ointment base. Alternatively, the active ingredient may be formulated as a cream, for example, with an oil-in-water cream base. Such transdermal formulations are well known in the art and generally contain additional ingredients that enhance the skin penetration or stability of the active ingredient or formulation. All such known transdermal formulations and ingredients are encompassed within the scope provided herein.

[0314] The compounds provided herein can also be administered by a transdermal device. Accordingly, transdermal administration can be accomplished using a patch either of the reservoir or porous membrane type or of a solid matrix variety.

[0315] The ingredients listed above for oral, injectable, or topical compositions are merely representative. Other materials and processing techniques are described in Part 8 of Remington's Pharmaceutical Sciences, 17th edition, 1985, Mack Publishing Company, Easton, Pennsylvania, which is incorporated herein by reference.

[0316] The compounds of this invention can also be administered in sustained release forms or from sustained release drug delivery systems. A description of representative sustained release materials can be found in Remington's Pharmaceutical Sciences.

[0317] The present invention also relates to pharmaceutically acceptable acid addition salts of the compounds of the present invention. Acids that can be used to prepare pharmaceutically acceptable salts are those that form non-toxic acid addition salts, i.e., salts containing pharmacologically acceptable anions (e.g., hydrochloride, hydroiodide, hydrobromide, nitrate, sulfate, bisulfate, phosphate, acetate, lactate, citrate, tartrate, succinate, maleate, fumarate, benzoate, para-toluenesulfonate, etc.).

[0318] In another aspect, the present invention provides pharmaceutical compositions comprising a compound of the present invention and a pharmaceutically acceptable excipient, e.g., a composition suitable for injection, such as intravenous (IV) administration.

[0319] Pharmaceutically acceptable excipients include any diluents or other liquid vehicles suitable for the particular dosage form desired, e.g., injection, dispersing or suspending aids, surfactants, isotonicity agents, preservatives, lubricants, etc. General considerations in the formulation and / or manufacture of pharmaceutical compositions can be found, for example, in Remington's Pharmaceutical Sciences, Sixteenth Edition, E.W. Martin (Mack Publishing Co., Easton, Pa., 1980), and Remington: The Science and Practice of Pharmacy, 21 st Edition(Lippincott Williams & Wi For more information, see lkins, 2005.

[0320] For example, injectable preparations, such as sterile injectable aqueous suspensions, can be formulated according to known techniques using suitable dispersing or wetting agents and suspending agents. Exemplary excipients that can be used include, but are not limited to, water, sterile saline or phosphate-buffered saline, or Ringer's solution.

[0321] In certain embodiments, the pharmaceutical composition further comprises a cyclodextrin derivative. The most common cyclodextrins are α-, β-, and γ-cyclodextrins, which consist of six, seven, and eight α-1,4-linked glucose units, respectively, optionally containing one or more substituents on the attached sugar moiety (including, but not limited to, substituted or unsubstituted methylation, hydroxyalkylation, acylation, and sulfoalkyl ether substitution). In certain embodiments, the cyclodextrin is a sulfoalkyl ether β-cyclodextrin, such as sulfobutyl ether β-cyclodextrin, also known as CAPTISOL®. See, e.g., U.S. Patent No. 5,376,645. In certain embodiments, the composition comprises hexapropyl-β-cyclodextrin. In more specific embodiments, the composition comprises hexapropyl-β-cyclodextrin (10-50% aqueous solution).

[0322] Injectable compositions can be sterilized, for example, by filtration through a bacterial-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 prior to use.

[0323] Generally, the compounds provided herein are administered in an effective amount. The amount of compound actually administered will typically be determined by a physician in light of the relevant circumstances, including the condition being treated, the selected route of administration, the actual compound being administered, the age, weight, and response of the individual patient, the severity of the patient's symptoms, etc.

[0324] The compositions are provided in unit dosage forms to facilitate accurate administration. The term "unit dosage form" refers to a physically discrete unit suitable as a unitary dosage for human subjects and other mammals, each unit containing a predetermined amount of active ingredient calculated to achieve a desired therapeutic effect together with suitable pharmaceutical excipients. Typical unit dosage forms include prefilled ampoules or syringes containing a premeasured liquid composition. In such compositions, the compound is usually a minor component (about 0.1% to about 50% by weight, or preferably about 1% to about 40% by weight), with the remainder consisting of various vehicles or carriers and processing aids useful for forming the desired dosage form.

[0325] The compounds provided herein can be administered as a single active agent or in combination with other active agents. In one aspect, the present invention provides a combination of a compound of the present invention with another pharmacologically active agent. The administration of the combination can be carried out by any technique apparent to those skilled in the art, including, for example, separate administration, sequential administration, simultaneous administration, and alternating administration.

[0326] While the description of pharmaceutical compositions provided herein is primarily directed to pharmaceutical compositions suitable for administration to humans, those skilled in the art will understand that such compositions are generally suitable for administration to all types of animals. Modifications of pharmaceutical compositions suitable for administration to humans to make them suitable for administration to a variety of animals are well understood, and veterinary pharmacologists of ordinary skill in the art can design and / or perform such modifications using routine experimentation. General considerations in formulating and / or manufacturing pharmaceutical compositions can be found, for example, in Remington: The Science and Practice of Pharmacy, 1999, pp. 111-114, 1999. twenty one st ed., Lippincott Williams & Wilkins, 2005.

[0327] In one embodiment, a kit is provided that includes a composition (e.g., a solid composition) comprising a compound of formula (I). In one embodiment, a kit is provided that includes a composition (e.g., a solid composition) comprising a compound of formula (VI).

[0328] V. Methods of Use and Treatment

[0329] In one aspect, the compounds described herein, e.g., compounds of Formula (I) or Formula (VI), are contemplated to be useful as therapeutic agents for treating a CNS-related disorder (e.g., a sleep disorder, a mood disorder such as depression, a schizophrenia spectrum disorder, a seizure disorder, an epileptic seizure, a disorder of memory and / or cognition, a movement disorder, a personality disorder, an autism spectrum disorder, pain, a traumatic brain injury, a vascular disease, a substance abuse disorder and / or withdrawal syndrome, or tinnitus) in a subject in need thereof (e.g., a subject having Rett syndrome, Fragile X syndrome, or Angelman syndrome). Exemplary CNS conditions associated with GABA modulation include sleep disorders [e.g., insomnia], mood disorders [e.g., depression (e.g., major depressive disorder (MDD)), dysthymic disorder (e.g., mild depression), bipolar disorder (e.g., Type I and / or Type II), anxiety disorders (e.g., generalized anxiety disorder (GAD), social anxiety disorder), stress, post-traumatic stress disorder (PTSD), obsessive-compulsive disorder (OCD))], schizophrenia spectrum disorders [e.g., schizophrenia, schizoaffective disorder], seizure disorders [e.g., epilepsy (e.g., status epilepticus (SE)), seizures], memory and / or cognition disorders [e.g., attention disorders (e.g., attention deficit hyperactivity disorder (ADHD))], dementia (e.g., These conditions include, but are not limited to, Alzheimer's disease, dementia with Lewy bodies, vascular dementia), movement disorders (e.g., Huntington's disease, Parkinson's disease), personality disorders (e.g., antisocial personality disorder, obsessive-compulsive personality disorder), autism spectrum disorders (ASD) (e.g., autism, monogenic cases of autism such as synaptic degeneration, e.g., Rett syndrome, Fragile X syndrome, Angelman syndrome), pain (e.g., neuropathic pain, injury-related pain syndrome, acute pain, chronic pain), traumatic brain injury (TBI), cerebrovascular disease (e.g., stroke, ischemia, vascular malformation), substance abuse disorders and / or withdrawal syndromes (e.g., addiction to opiates, cocaine, and / or alcohol), and tinnitus.

[0330] In certain embodiments, the CNS-related disorder is a sleep disorder, a mood disorder, a schizophrenia spectrum disorder, a seizure disorder, a memory and / or cognitive disorder, a movement disorder, a personality disorder, an autism spectrum disorder, pain, a traumatic brain injury, a vascular disease, a substance abuse disorder and / or withdrawal syndrome, tinnitus, or status epilepticus. In certain embodiments, the CNS-related disorder is depression. In certain embodiments, the CNS-related disorder is postpartum depression. In certain embodiments, the CNS-related disorder is major depressive disorder. In certain embodiments, the major depressive disorder is moderate major depressive disorder. In certain embodiments, the major depressive disorder is severe major depressive disorder.

[0331] In one aspect, there is provided a method of reducing or preventing seizure activity in a subject, comprising administering to a subject in need of such treatment an effective amount of a compound of the invention, hi some embodiments, the method reduces or prevents epileptic seizures.

[0332] In yet another aspect, the present invention provides a combination of a compound of the present invention with another pharmacologically active agent. The compounds provided herein can be administered as a single active agent or in combination with other agents. The administration of the combination can be carried out by any technique that is apparent to those skilled in the art, including, for example, separate administration, sequential administration, simultaneous administration, and alternating administration.

[0333] In another aspect, there is provided a method for treating or preventing brain excitability in a subject susceptible to or suffering from a condition associated with brain excitability, comprising administering to the subject an effective amount of a compound of the invention.

[0334] In yet another aspect, there is provided a method for treating or preventing stress or anxiety in a subject, comprising administering to a subject in need of such treatment an effective amount of a compound of the invention, or a composition thereof.

[0335] In yet another aspect, there is provided a method for reducing or preventing insomnia in a subject, comprising administering to a subject in need of such treatment an effective amount of a compound of the present invention, or a composition thereof.

[0336] In yet another aspect, there is provided a method for inducing sleep and substantially maintaining the level of REM sleep seen in normal sleep, without inducing substantial rebound insomnia, comprising administering an effective amount of a compound of the invention.

[0337] In yet another aspect, there is provided a method for alleviating or preventing premenstrual syndrome (PMS) or postpartum depression (PND) in a subject, comprising administering to a subject in need of such treatment an effective amount of a compound of the invention.

[0338] In yet another aspect, there is provided a method of treating or preventing a mood disorder in a subject, comprising administering to a subject in need of such treatment an effective amount of a compound of the invention, hi certain embodiments, the mood disorder is depression.

[0339] In yet another aspect, the present invention provides a method for cognitive enhancement or treating memory impairment by administering a therapeutically effective amount of the compound of the present invention to a subject.In certain embodiments, the disorder is Alzheimer's disease.In certain embodiments, the disorder is Rett syndrome.

[0340] In yet another aspect, there is provided a method for treating attention disorders by administering to a subject a therapeutically effective amount of a compound of the invention. In certain embodiments, the attention disorder is ADHD.

[0341] In certain embodiments, the compound is administered chronically to the subject. In certain embodiments, the compound is administered orally, subcutaneously, intramuscularly, or intravenously to the subject.

[0342] A. Neuroendocrine Disorders and Dysfunctions

[0343] Methods are provided herein that can be used to treat neuroendocrine disorders and dysfunctions. As used herein, "neuroendocrine disorder" or "neuroendocrine dysfunction" refers to various conditions caused by an imbalance in the body's hormone production that is directly related to the brain. Neuroendocrine disorders involve interactions between the nervous system and the endocrine system. Because the hypothalamus and pituitary gland are two areas of the brain that control hormone production, damage to the hypothalamus or pituitary gland, for example, due to traumatic brain injury, can affect hormone production and other neuroendocrine functions of the brain. In some embodiments, the neuroendocrine disorder or dysfunction is associated with a women's health disorder or condition (e.g., a women's health disorder or condition described herein). In some embodiments, the neuroendocrine disorder or dysfunction associated with a women's health disorder or condition is polycystic ovary syndrome.

[0344] Symptoms of neuroendocrine disorders include, but are not limited to, behavioral, emotional, and sleep-related symptoms, reproductive symptoms, and physical symptoms, including, but not limited to: , fatigue, poor memory, anxiety, depression, weight gain or loss, emotional lability, lack of concentration, difficulty paying attention, decreased libido, infertility, amenorrhea, loss of muscle mass, increased abdominal body fat, low blood pressure, low heart rate, hair loss, anemia, constipation, cold intolerance, and dry skin.

[0345] B. Neurodegenerative Diseases and Disorders

[0346] The methods described herein can be used to treat neurodegenerative diseases and disorders. The term "neurodegenerative disease" encompasses diseases and disorders associated with the progressive loss of neuronal structure or function, or the death of neurons. Neurodegenerative diseases and disorders include Alzheimer's disease (including associated symptoms of mild, moderate, or severe cognitive impairment); amyotrophic lateral sclerosis (ALS); anoxic and ischemic injury; ataxia and seizures (including for the treatment and prevention, and for the prevention of seizures caused by schizoaffective disorder or medications used to treat schizophrenia); benign amnesia; cerebral edema; cerebellar ataxia, including McLeod neuroacanthocytosis syndrome (MLS); closed head injury; coma; contusion injury (e.g., spinal cord injury and head injury); dementia, including multi-infarct dementia and senile dementia; impairment of consciousness; Down's syndrome; drug-induced or medication-induced Parkinson's disease (such as neuroleptic-induced acute akathisia, acute dystonia, parkinsonism, or tardive dyskinesia, neuroleptic malignant syndrome, or medication-induced postural tremor); epilepsy; Fragile X syndrome; Gilles de la Tourette syndrome; head trauma; deafness and hearing impairment; Huntington's disease; Lennox syndrome; levodopa-induced Dyskinesias; mental retardation; movement disorders, including akinesia and akinesia (rigidity) syndromes (including brainstem neurocalcification, corticobasal degeneration, multiple system atrophy, Parkinsonism-ALS dementia complex, Parkinson's disease, postencephalitic parkinsonism, and progressive supranuclear palsy); muscle spasms and disorders associated with muscle spasms or weakness (chorea (e.g., benign hereditary chorea, drug-induced chorea, hemiballismus, Huntington's disease, neuroacanthocytosis, Sydenham's chorea, and symptomatic chorea), dyskinesias (complex chorea), tics, including tics such as tics, simple tics, and asymptomatic tics), myoclonus, including generalized myoclonus and focal cycloclonic jerks, tremors, such as rest tremor, postural tremor, and intention tremor, and dystonia, such as truncal dystonia, dystonic writer's cramp, hemiplegic dystonia, paroxysmal dystonia, and focal dystonia, including blepharospasm, temporomandibular dystonia, and spasmodic dysphonia and spasmodic torticollis; neuronal damage, including eye damage, retinopathy, or macular degeneration of the eye;Neurodegenerative diseases include, but are not limited to, stroke, thromboembolic stroke, hemorrhagic stroke, cerebral ischemia, cerebral vasospasm, hypoglycemia, amnesia, hypoxia, anoxia, perinatal asphyxia, and neurotoxicity following cardiac arrest; Parkinson's disease; seizures; status epilepticus; stroke; tinnitus; tuberous sclerosis; and viral infection-induced neurodegeneration (e.g., those caused by acquired immunodeficiency syndrome (AIDS) and encephalopathy). Neurodegenerative diseases also include, but are not limited to, stroke, thromboembolic stroke, hemorrhagic stroke, cerebral ischemia, cerebral vasospasm, hypoglycemia, amnesia, hypoxia, anoxia, perinatal asphyxia, and neurotoxicity following cardiac arrest. Methods for treating or preventing neurodegenerative diseases also include treating or preventing the loss of neuronal function characteristic of neurodegenerative disorders.

[0347] C. Mood disorders

[0348] Also provided herein are methods of treating mood disorders, such as clinical depression, postpartum or postpartum depression, perinatal depression, atypical depression, melancholic depression, major psychotic depression, catatonic depression, seasonal affective disorder, dysthymia, bipolar depression, depressive personality disorder, recurrent brief depression, minor depressive disorder, bipolar or manic-depressive disorder, depression due to a chronic medical condition, treatment-resistant depression, refractory depression, suicidal, suicidal ideation, or suicidal behavior. In some embodiments, the methods described herein provide a therapeutic benefit to a subject suffering from depression (e.g., moderate or severe depression). In some embodiments, the mood disorder is a disease or disorder described herein (e.g., neuroendocrine diseases and disorders, neurodegenerative disorders, and the like). Diseases and disorders (e.g., epilepsy), movement disorders, tremors (e.g., Parkinson's disease), women's health disorders or conditions).

[0349] Clinical depression, also known as major depression, major depressive disorder (MDD), severe depression, unipolar depression, unipolar disorder, and recurrent depression, refers to a mental disorder characterized by a pervasive and persistent low mood accompanied by low self-esteem and a loss of interest or pleasure in normally enjoyable activities. Some people with clinical depression experience sleep disturbances, weight loss, and generally feel agitated and irritable. Clinical depression affects how individuals feel, think, and behave, and can lead to a variety of emotional and physical problems. Individuals with clinical depression may have difficulty performing daily activities and may feel as if life is not worth living.

[0350] Perinatal depression refers to depression during pregnancy. Symptoms include irritability, tearfulness, restlessness, sleep disturbances, exhaustion (emotional and / or physical), changes in appetite, difficulty concentrating, increased anxiety and / or worry, feelings of disconnection from the baby and / or fetus, and loss of interest in previously enjoyed activities.

[0351] Postpartum depression (PND), also known as postpartum depression (PPD), refers to a type of clinical depression that women experience after giving birth. Symptoms may include sadness, fatigue, changes in sleep and eating habits, decreased libido, tearful episodes, anxiety, and irritability. In some embodiments, the PND is treatment-resistant depression (e.g., treatment-resistant depression as described herein). In some embodiments, the PND is treatment-refractory depression (e.g., treatment-refractory depression as described herein).

[0352] In some embodiments, the subject with PND also experiences depression or depressive symptoms during pregnancy.This depression is herein referred to as perinatal depression.In one embodiment, the subject who experiences perinatal depression has a high risk of experiencing PND.

[0353] Atypical depression (AD) is characterized by mood reactivity (e.g., paradoxical anhedonia) and aggressiveness, significant weight gain, or increased appetite. Patients with AD may also have significant social impairments as a result of excessive sleepiness or somnolence (hypersomnia), a feeling of heaviness in the limbs, and hypersensitivity to perceived interpersonal rejection.

[0354] Melancholic depression is characterized by loss of pleasure in most or all activities (anhedonia), unresponsiveness to pleasurable stimuli, depressed mood more pronounced than grief or loss, excessive weight loss, or excessive guilt.

[0355] Psychotic major depression (PMD) or psychotic depression refers to a major depressive episode, particularly one of a melancholic nature, in which an individual experiences psychotic symptoms such as delusions and hallucinations.

[0356] Catatonic depression refers to major depression accompanied by disturbances in motor behavior and other symptoms. Individuals may become mute and stuporous, become immobile, or exhibit purposeless or bizarre movements.

[0357] Seasonal affective disorder (SAD) refers to a type of seasonal depression in which an individual has a seasonal pattern of depressive episodes that occur in the fall or winter.

[0358] Dysthymia refers to a condition related to unipolar depression that causes the same physical and cognitive problems, but tends to be less severe and last longer (e.g., at least 2 years).

[0359] Double depression is defined as at least two years of significant depressed mood (dysthymia) interspersed with periods of major depression.

[0360] Depressive personality disorder (DPD) refers to a personality disorder with depressive traits.

[0361] Recurrent brief depression (RBD) refers to a condition in which an individual has depressive episodes approximately once per month, each lasting for a short period of time (less than two weeks), typically less than two to three days.

[0362] Minor depressive disorder or minor depression refers to depression in which at least two symptoms are present for two weeks.

[0363] Bipolar disorder or manic-depressive disorder causes extreme mood swings, including emotional highs (mania or hypomania) and lows (depression). During manic periods, individuals may experience unusual euphoria, energy, or irritability in their emotions or behavior. Such individuals often make ill-considered decisions with little regard for the consequences. They usually have a decreased need for sleep. During depressive periods, individuals may become tearful, make less eye contact with others, and become pessimistic about life. The risk of suicide for people with this disorder is high—more than 6% over a 20-year period—and 30–40% will self-harm. Other mental health problems, such as anxiety disorders and substance abuse disorders, often coexist with bipolar disorder.

[0364] Chronic condition-induced depression refers to depression caused by a chronic medical condition such as cancer, chronic pain, chemotherapy, or chronic stress.

[0365] Treatment-resistant depression refers to a condition in which an individual is treated for depression but the symptoms do not improve. For example, antidepressants or psychological counseling (psychotherapy) do not alleviate the depressive symptoms of individuals with treatment-resistant depression. In some cases, individuals with treatment-resistant depression improve but then relapse. Treatment-resistant depression occurs in patients with depression who are resistant to standard pharmacological treatments, including tricyclic antidepressants, MAOIs, SSRIs, and double and triple doses of inhibitors and / or anxiolytics, as well as non-pharmacological treatments (e.g., psychotherapy, electroconvulsive therapy, vagus nerve stimulation, and / or transcranial magnetic stimulation).

[0366] Postoperative depression refers to depressed feelings that continue after a surgical procedure (e.g., as a result of facing death). For example, patients may experience persistent feelings of sadness or emptiness, loss of pleasure or interest in hobbies and activities that they normally enjoy, or persistent feelings of worthlessness or hopelessness.

[0367] A mood disorder associated with a women's health condition or disorder refers to a mood disorder (eg, depression) that is associated with (eg, caused by) a women's health condition or disorder (eg, as described herein).

[0368] Suicidal tendencies, ideation, and behavior refer to an individual's tendency to attempt suicide. Suicidal ideation involves thoughts about or an abnormal preoccupation with suicide. The spectrum of suicidal ideation varies significantly, for example, from passing thoughts to widespread ideation, detailed plans, role-playing, and aborted attempts. Symptoms may include talking about suicide, obtaining the means to attempt suicide, withdrawing from social contacts, preoccupation with death, feeling trapped or hopeless about a situation, increased alcohol or drug use, engaging in risky or self-destructive behavior, and saying goodbye to people as if they will never see each other again.

[0369] Symptoms of depression include persistent anxiety or sadness, helplessness, hopelessness, pessimism, worthlessness, low energy, restlessness, difficulty sleeping, insomnia, irritability, fatigue, difficulty exercising, loss of interest in enjoyable activities or hobbies, poor concentration, low energy, low self-esteem, lack of positive thinking or planning, excessive sleep, overeating, loss of appetite, insomnia, self-harm, suicidal thoughts, and suicide attempts. The presence, severity, frequency, and duration of symptoms may vary from case to case. Depression symptoms and their relief can be confirmed by a doctor or psychologist (for example, by mental status examination).

[0370] In some embodiments, the method includes monitoring the subject using known depression rating scales, such as the Hamilton Depression Rating Scale (HAM-D), Clinical Global Impression-Improvement Scale (CGI), and Montgomery-Asberg Depression Rating Scale (MADRS). In some embodiments, the effectiveness of treatment can be determined by a reduction in the subject's Hamilton Depression Rating Scale (HAM-D) total score. A reduction in the HAM-D total score can occur within 4, 3, 2, or 1 day; or within 96, 84, 72, 60, 48, 24, 20, 16, 12, 10, or 8 hours. The effectiveness of treatment can be assessed over a specific treatment period. For example, therapeutic efficacy can be determined by a reduction from baseline in HAM-D total score after administration of a compound described herein, e.g., a compound of Formula (I) (e.g., 12, 24, or 48 hours after administration; or 24, 48, 72, or 96 hours or more; or 1 day, 2 days, 14 days, 21 days, or 28 days; or 1 week, 2 weeks, 3 weeks, or 4 weeks; or 1 month, 2 months, 6 months, or 10 months; or 1 year, 2 years, or lifetime).

[0371] In some embodiments, the subject has a mild depressive disorder, e.g., mild major depressive disorder. In some embodiments, the subject has a moderate depressive disorder, e.g., moderate major depressive disorder. In some embodiments, the subject has a severe depressive disorder, e.g., severe major depressive disorder. In some embodiments, the subject has a very severe depressive disorder, e.g., very severe major depressive disorder. In some embodiments, the subject's baseline HAM-D total score (i.e., before treatment with a compound described herein, e.g., a compound of Formula (I)) is at least 24. In some embodiments, the subject's baseline HAM-D total score is at least 18. In some embodiments, the subject's baseline HAM-D total score is 14 to 18, inclusive. In some embodiments, the subject's baseline HAM-D total score is 19 to 22, inclusive. In some embodiments, the subject's HAM-D total score before treatment with a compound described herein, e.g., a compound of Formula (I), is 23 or greater. In some embodiments, the baseline score is at least 10, 15, or 20. In some embodiments, the subject's HAM-D total score after treatment with a compound described herein, e.g., a compound of Formula (I), is about 0-10 (e.g., less than 10; 0-10, 0-6, 0-4, 0-3, 0-2, or 1.8). In some embodiments, the subject's HAM-D total score after treatment with a compound described herein, e.g., a compound of Formula (I), is less than 10, i.e., 7, 5, or 3. In some embodiments, after treatment with a compound described herein, e.g., a compound of Formula (I), the HAM-D total score is reduced from a baseline score of about 20-30 (e.g., 22-28, 23-27, 24-27, 25-27, 26-27) to a HAM-D total score of about 0-10 (e.g., less than 10; 0-10, 0-6, 0-4, 0-3, 0-2, or 1.8). In some embodiments, the reduction in HAM-D total score after treatment with a compound described herein, e.g., a compound of Formula (I), from baseline HAM-D total score is at least 1, 2, 3, 4, 5, 7, 10, 25, 40, 50, or 100-fold.In some embodiments, the reduction in HAM-D total score after treatment with a compound described herein, e.g., a compound of Formula (I), from baseline HAM-D total score is at least 50% (e.g., 60%, 70%, 80%, or 90%). In some embodiments, the therapeutic effect is a reduction in HAM-D total score from baseline. This is measured by a reduction in the HAM-D total score after treatment with a compound described herein, e.g., a compound of Formula (I) (e.g., 12, 24, 48 hours; or 24, 48, 72, 96 hours or more; or 1 day, 2 days, 14 days or more after administration), compared to the MD total score, which is at least 10, 15, or 20 points.

[0372] In some embodiments, the method for treating a depressive disorder, e.g., major depressive disorder, results in a therapeutic benefit (e.g., as measured by a reduction in the Hamilton Rating Scale for Depression (HAM-D)) within 14, 10, 4, 3, 2, or 1 day, or within 24, 20, 16, 12, 10, or 8 hours. In some embodiments, the method for treating a depressive disorder, e.g., major depressive disorder, results in a therapeutic benefit (e.g., as determined by a statistically significant reduction in the HAM-D total score) by the first or second day of treatment with a compound described herein, e.g., a compound of Formula (I). In some embodiments, the method for treating a depressive disorder, e.g., major depressive disorder, results in a therapeutic benefit (e.g., as determined by a statistically significant reduction in the HAM-D total score) within 14 days of initiating treatment with a compound described herein, e.g., a compound of Formula (I). In some embodiments, the method for treating a depressive disorder, e.g., major depressive disorder, results in a therapeutic benefit (e.g., as determined by a statistically significant reduction in the HAM-D total score) within 21 days of initiating treatment with a compound described herein, e.g., a compound of Formula (I). In some embodiments, the method of treating a depressive disorder, e.g., major depressive disorder, results in a therapeutic effect (e.g., as determined by a statistically significant decrease in HAM-D total score) within 28 days of initiating treatment with a compound described herein, e.g., a compound of Formula (I). In some embodiments, the therapeutic effect is a decrease in HAM-D total score from baseline after treatment with a compound described herein, e.g., a compound of Formula (I) (e.g., 14 days of once-daily treatment with a compound described herein, e.g., a compound of Formula (I)). In some embodiments, the subject's HAM-D total score before treatment with a compound described herein, e.g., a compound of Formula (I), is at least 24. In some embodiments, the subject's HAM-D total score before treatment with a compound described herein, e.g., a compound of Formula (I), is at least 18. In some embodiments, the subject's HAM-D total score before treatment with a compound described herein, e.g., a compound of Formula (I), is between 14 and 18, inclusive.In some embodiments, the reduction in HAM-D total score following treatment of a subject with a compound described herein, e.g., a compound of Formula (I), compared to the baseline HAM-D total score is at least 10. In some embodiments, the reduction in HAM-D total score following treatment of a subject with a compound described herein, e.g., a compound of Formula (I), compared to the baseline HAM-D total score is at least 15 (e.g., at least 17). In some embodiments, treatment of a subject with a compound described herein, e.g., a compound of Formula (I), results in a HAM-D total score of no more than a number in the range of 6 to 8. In some embodiments, treatment of a subject with a compound described herein, e.g., a compound of Formula (I), results in a HAM-D total score of no more than 7.

[0373] In some embodiments, the method provides a therapeutic benefit (e.g., as measured by a reduction in the Clinical Global Impression (CGI) score) within 14, 10, 4, 3, 2, or 1 day, or within 24, 20, 16, 12, 10, or 8 hours. In some embodiments, the CNS disorder is a depressive disorder, e.g., major depressive disorder. In some embodiments, the method of treating a depressive disorder, e.g., major depressive disorder, provides a therapeutic benefit by day 2 of the treatment period. In some embodiments, the therapeutic benefit is a reduction in CGI score from baseline at the end of the treatment period (e.g., day 14 after administration).

[0374] In some embodiments, the method provides a therapeutic effect (e.g., as measured by a reduction in the Montgomery-Asberg Depression Rating Scale (MADRS)) within 14, 10, 4, 3, 2, or 1 day, or within 24, 20, 16, 12, 10, or 8 hours. In some embodiments, the CNS disorder is a depressive disorder, e.g., major depressive disorder. In some embodiments, the method for treating a depressive disorder, e.g., major depressive disorder, provides a therapeutic benefit by day 2 of the treatment period. In some embodiments, the therapeutic benefit is a reduction from baseline in the MADRS score at the end of the treatment period (e.g., day 14 after administration).

[0375] The effectiveness of treatment for major depressive disorder can be determined by a reduction in a subject's Montgomery-Asberg Depression Rating Scale (MADRS) score. For example, MADRS scores can decrease within 4, 3, 2, or 1 day; or within 96, 84, 72, 60, 48, 24, 20, 16, 12, 10, or 8 hours. The Montgomery-Asberg Depression Rating Scale (MADRS) is a 10-item diagnostic questionnaire (referring to outward sadness, verbal sadness, internal tension, decreased sleep, decreased appetite, difficulty concentrating, inhibitions, lack of emotion, pessimistic thoughts, and suicidal thoughts) used by psychiatrists to measure the severity of depressive episodes in patients with mood disorders.

[0376] In some embodiments, the method results in a therapeutic effect (e.g., as measured by a reduction in the Edinburgh Postnatal Depression Scale (EPDS)) within 4, 3, 2, 1 day; 24, 20, 16, 12, 10, 8 hours. In some embodiments, the therapeutic effect is an improvement as measured by the EPDS.

[0377] In some embodiments, the method provides a therapeutic effect (e.g., as measured by a reduction in the Generalized Anxiety Disorder 7-item scale (GAD-7)) within 4, 3, 2, 1 day; 24, 20, 16, 12, 10, 8 hours.

[0378] D. Anxiety disorders

[0379] Provided herein are methods for treating anxiety disorders (e.g., generalized anxiety disorder, panic disorder, obsessive-compulsive disorder, phobias, and post-traumatic stress disorder). Anxiety disorder is an umbrella term that encompasses several different forms of abnormal and pathological fear and anxiety. Current psychiatric diagnostic criteria distinguish between a wide variety of anxiety disorders.

[0380] Generalized anxiety disorder (GAD) is a common chronic disorder characterized by long-term anxiety that is not focused on any one goal or situation. Those suffering from GAD experience persistent, nonspecific fear and worry, and become excessively concerned about minor everyday occurrences. GAD is the most common anxiety disorder affecting older adults.

[0381] In panic disorder, patients experience brief, intense attacks of fear and anxiety, often characterized by tremors, shaking, confusion, dizziness, nausea, and difficulty breathing. Defined by the APA as sudden onset of fear or discomfort that peaks in less than 10 minutes, these attacks can last for hours and can be triggered by stress, fear, or even exercise, although a specific cause is not always apparent. In addition to recurrent, unexpected panic attacks, a diagnosis of panic disorder also requires that the attacks have chronic consequences (either worry about the attack's potential impact, persistent fear of future attacks, or significant behavioral changes related to the attack). Thus, those suffering from panic disorder also experience symptoms outside of a specific panic episode. Often, when panic sufferers notice normal heart rate changes, they believe there is something wrong with their heart or that another panic attack is coming. In some cases, heightened perceptions of bodily functions (hyperarousal) occur during a panic attack, leading to interpretation of perceived physiological changes as potentially life-threatening illness (i.e., extreme hypochondriasis).

[0382] Obsessive-compulsive disorder is a type of anxiety disorder that is primarily characterized by recurrent obsessions (distressing, persistent, intrusive thoughts or images) and compulsions (attempts to perform specific actions or habitual behaviors). OCD is characterized by obsessions (compulsions to perform certain actions). OCD thought patterns are sometimes likened to superstition because they involve belief in nonexistent causal relationships. The process is often entirely illogical; for example, a person may adopt a compulsive behavior, such as walking in a particular pattern, to alleviate obsessive thoughts of impending harm. In many cases, the compulsions are entirely inexplicable and are simply urges to complete habitual behaviors triggered by nervousness. In a minority of cases, OCD patients may experience only obsessions without overt compulsions, and even fewer experience only compulsions.

[0383] The largest single category of anxiety disorders is that of phobias, which includes all cases in which fear and anxiety are provoked by a particular stimulus or situation. Patients typically anticipate frightening consequences from encountering their feared object (which can be anything from an animal to a place or bodily fluid).

[0384] Post-traumatic stress disorder, or PTSD, is an anxiety disorder that results from a traumatic experience. Post-traumatic stress can result from extreme situations, such as combat, rape, hostage situations, or even serious accidents. It can also result from prolonged (chronic) exposure to significant stressors (e.g., soldiers who can tolerate individual combat but are unable to cope with sustained combat). Common symptoms include flashbacks, avoidance behaviors, and depression.

[0385] E. Women's Health Disorders

[0386] Provided herein are methods for treating women's health-related conditions or disorders, including, but not limited to, gynecological health conditions and disorders (e.g., premenstrual syndrome (PMS), premenstrual dysphoric disorder (PMDD)), fertility issues (e.g., miscarriage, abortion), infertility and related disorders (e.g., polycystic ovary syndrome (PCOS)), other disorders and conditions, and issues related to women's overall health and wellness (e.g., menopause).

[0387] Gynecological conditions and disorders affecting women include menstruation and menstrual irregularities; urinary tract conditions, including urinary incontinence and pelvic floor disorders; and disorders such as bacterial vaginosis, vaginitis, uterine fibroids, and vulvodynia.

[0388] Premenstrual syndrome (PMS) refers to the physical and emotional symptoms that occur one to two weeks before a woman's period. Symptoms vary but can include bleeding, mood swings, breast tenderness, overeating, fatigue, irritability, acne, and depression.

[0389] Premenstrual dysphoric disorder (PMDD) is a severe form of PMS. Symptoms of PMDD are similar to those of PMS but are more severe and can interfere with work, social activities, and relationships. Symptoms of PMDD include mood swings, depressed mood or feelings of hopelessness, marked anger, increased interpersonal conflict, tension and anxiety, irritability, decreased interest in usual activities, difficulty concentrating, fatigue, appetite changes, uncontrollable or irresistible feelings, sleep disturbances, and physical problems (e.g., swelling, breast tenderness, edema, headaches, joint or muscle pain).

[0390] Pregnancy issues include preconception and prenatal care, pregnancy termination (miscarriage and stillbirth), preterm labor and delivery, sudden infant death syndrome (SIDS), breastfeeding, and congenital anomalies.

[0391] A miscarriage is a pregnancy that ends naturally within the first 20 weeks of pregnancy.

[0392] Abortion refers to the intentional interruption of a pregnancy, which can be performed during the first 28 weeks of pregnancy.

[0393] Infertility and related disorders include uterine fibroids, polycystic ovary syndrome, endometriosis, and primary ovarian insufficiency.

[0394] Polycystic ovary syndrome (PCOS) refers to an endocrine system disorder in women of reproductive age. PCOS is a group of symptoms resulting from elevated levels of male hormones in women. Most women with PCOS develop numerous small cysts on their ovaries. Symptoms of PCOS include irregular menstrual periods, amenorrhea, menorrhagia, excessive body and facial hair growth, acne, pelvic pain, difficulty conceiving, and thickened, dark, velvety patches of skin. PCOS can be associated with conditions including type 2 diabetes, obesity, obstructive sleep apnea, heart disease, mood disorders, and endometrial cancer.

[0395] Other disorders and conditions that affect only women include Turner syndrome, Rett syndrome, and ovarian and cervical cancer.

[0396] Issues relating to women's overall health and wellness include violence against women, women with disabilities and their particular challenges, osteoporosis and bone health, and menopause.

[0397] Menopause refers to the 12 months following a woman's last menstrual period and is characterized by the end of the menstrual cycle. Menopause usually occurs in women in their 40s or 50s. The physical (e.g., hot flushes) and emotional symptoms of menopause can disrupt sleep, reduce energy, and induce anxiety or feelings of sadness or loss. Menopause includes natural menopause and surgical menopause, which is a type of menopause induced by events such as surgery (e.g., hysterectomy, oophorectomy, cancer). It is induced when the ovaries are severely damaged, such as by radiation, chemotherapy, or other medications.

[0398] F. Epilepsy

[0399] A compound of formula (I) or a pharmaceutically acceptable salt, or a pharmaceutically acceptable composition, can be used in the methods described herein, e.g., for the treatment of a disorder described herein, such as epilepsy, status epilepticus, or seizures.

[0400] Epilepsy is a brain disorder characterized by recurrent seizures over time. Types of epilepsy can include, but are not limited to, generalized epilepsy, such as childhood absence epilepsy, juvenile myoclonic epilepsy, epilepsy with grand mal seizures on awakening, West syndrome, Lennox-Gastaut syndrome, partial epilepsy, such as temporal lobe epilepsy, frontal lobe epilepsy, and benign focal childhood epilepsy.

[0401] G. Epileptic seizures

[0402] The compounds and methods described herein can be used to treat or prevent epileptic seizures. Epileptic seizures are a sequential process in which a normal brain develops epilepsy (a chronic condition in which seizures occur). Epileptic seizures result from neuronal damage that is suddenly triggered by an initial injury (e.g., status epilepticus).

[0403] H. Status epilepticus (SE)

[0404] Status epilepticus (SE) can include, for example, convulsive status epilepticus, e.g., early status epilepticus, confirmed status epilepticus, refractory status epilepticus, very refractory status epilepticus; non-convulsive status epilepticus, e.g., generalized status epilepticus, complex partial status epilepticus; generalized periodic epileptiform discharges; and periodic unilateral epileptic discharges. Status epilepticus is characterized by the presence of convulsive status epilepticus and may include early status epilepticus, confirmed status epilepticus, refractory status epilepticus, and very refractory status epilepticus. Early status epilepticus is treated with first-line therapy. Confirmed status epilepticus is characterized by status epilepticus that persists despite treatment with first-line therapy and for which second-line therapy is implemented. Refractory status epilepticus is characterized by status epilepticus that persists despite treatment with first-line and second-line therapy and for which general anesthetics are administered systemically. Very refractory status epilepticus is characterized by status epilepticus that persists despite treatment with first-line therapy, second-line therapy, and general anesthetics for more than 24 hours.

[0405] Non-convulsive status epilepticus can include, for example, focal non-convulsive status epilepticus, e.g., complex partial non-convulsive status epilepticus, simple partial non-convulsive status epilepticus, latent non-convulsive status epilepticus; generalized non-convulsive status epilepticus, e.g., delayed absence non-convulsive status epilepticus, atypical absence non-convulsive status epilepticus, or typical absence non-convulsive status epilepticus.

[0406] The compounds of formula (I) or pharmaceutically acceptable salts, or pharmaceutically acceptable compositions thereof, may also be administered as a prophylactic agent before the onset of a seizure to subjects with a CNS disorder, such as traumatic brain injury, status epilepticus, e.g., convulsive status epilepticus, e.g., early status epilepticus, established status epilepticus, refractory status epilepticus, very refractory status epilepticus; non-convulsive status epilepticus, e.g., generalized status epilepticus, complex partial status epilepticus; generalized periodic epileptiform discharges; and periodic unilateral epileptic discharges.

[0407] The compound of formula (VI) or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable composition thereof, can also be administered as a prophylactic agent before the onset of a seizure to a subject with a CNS disorder, such as traumatic brain injury, status epilepticus, e.g., convulsive status epilepticus, e.g., early status epilepticus, established status epilepticus, refractory status epilepticus, very refractory status epilepticus; non-convulsive status epilepticus, e.g., generalized status epilepticus, complex partial status epilepticus; generalized periodic epileptiform discharges; and periodic unilateral epileptic discharges.

[0408] I. Seizures

[0409] A seizure is a physical finding or behavioral change that occurs after an episode of abnormal electrical activity in the brain. The term "seizure" is often used synonymously with "convulsion." A convulsion is when the human body shakes rapidly and uncontrollably. During a convulsion, a person's muscles repeatedly contract and relax.

[0410] Based on the type of behavior and brain activity, seizures are classified into two broad categories: generalized and partial (also called focal or focal). Classifying the type of seizure helps doctors diagnose whether a patient has epilepsy.

[0411] Generalized seizures are caused by electrical excitation throughout the brain, whereas partial seizures are caused (at least initially) by electrical excitation in a smaller part of the brain. The part of the brain that produces the seizure is sometimes called the focus.

[0412] There are six types of generalized seizures. The most common, most severe, and therefore best known is the generalized convulsion, also known as a grand mal seizure. In this type of seizure, the patient loses consciousness and usually passes out. Following the loss of consciousness, the patient experiences a 30-60 second period of generalized stiffening (called the "tonic" phase of the seizure), followed by another 30-60 second period of violent convulsions (the "clonic" phase), after which the patient enters a deep sleep state. During a grand mal seizure, injuries and accidents such as tongue biting and urinary incontinence may occur.

[0413] Absence seizures cause a brief loss of consciousness (only a few seconds) with little to no symptoms. Typically, the patient (mostly a child) stops moving and stares blankly. These seizures begin and end suddenly and may occur several times a day. Patients are usually unaware that a seizure is occurring, except for the ability to keep track of "time."

[0414] Myoclonic seizures consist of sporadic jerks, usually on both sides of the body. Patients may describe the jerks as brief electric shocks. These seizures, when severe, may cause dropping or involuntary throwing of objects.

[0415] Clonic seizures are recurrent rhythmic convulsions that involve both sides of the body simultaneously.

[0416] Tonic seizures are characterized by muscle stiffness.

[0417] Cataplexy consists of a sudden generalized loss of muscle tone, especially in the arms and legs, often causing falls.

[0418] The seizures described herein may include epileptic seizures; acute repetitive seizures; cluster seizures; continuous seizures; persistent seizures; prolonged seizures; recurrent seizures; status epilepticus seizures, e.g., refractory convulsive status epilepticus, non-convulsive status epilepticus seizures; refractory seizures; myoclonic seizures; tonic seizures; tonic-clonic seizures; simple partial seizures; complex partial seizures; secondarily generalized seizures; atypical absence seizures; absence seizures; atonic seizures; benign rolandic seizures; febrile convulsions; affective seizures; focal seizures; galactoceles; generalized onset seizures; infantile spasms; Jacksonian seizures; widespread bilateral myoclonic seizures; multifocal seizures; neonatal onset seizures; nocturnal seizures; occipital lobe seizures; post-traumatic seizures; latency seizures; Sylvan seizures; visual reflex seizures; or withdrawal seizures. In some embodiments, the seizures are generalized seizures associated with Dravet syndrome, Lennox-Gastaut syndrome, tuberous sclerosis complex, Rett syndrome, or PCDH19 female epilepsy.

[0419] J. Movement disorders

[0420] Also described herein are methods for treating movement disorders. As used herein, "movement disorder" refers to various diseases and disorders associated with hyperkinetic movement disorders and related to abnormalities in muscle control. Exemplary movement disorders include, but are not limited to, Parkinson's disease and parkinsonism (particularly defined by bradykinesia), dystonia, chorea and Huntington's disease, ataxia, tremor (e.g., essential tremor), myoclonus and startle reflex, tic disorders and Tourette's syndrome, restless legs syndrome, stiff person syndrome, and gait disorders.

[0421] K. Tremor

[0422] The methods described herein can be used to treat tremors, for example, compounds of Formula (I) can be used to treat cerebellar or intention tremor, dystonic tremor, essential tremor, orthostatic tremor, Parkinson's disease, physiological tremor, psychogenic tremor, or rubral tremor. Tremors can be caused by genetic, degenerative, and idiopathic disorders (such as Wilson's disease, Parkinson's disease, and essential tremor, respectively); metabolic diseases (e.g., thyroid disease, parathyroid disease, liver disease, and hypoglycemia); peripheral neuropathies (associated with Charcot-Marie-Tooth disease, Lucy-Lewy syndrome, diabetes mellitus, and complex regional pain syndrome); toxins (nicotine, hydrochloride, and the like); and tremors caused by steroids (e.g., steroids, steroid drugs, and the like). These include: silver, lead, CO, manganese, arsenic, toluene); drug-induced (sleep inducers, tricyclic antidepressants, lithium, cocaine, alcohol, adrenaline, bronchodilators, theophylline, caffeine, steroids, valproate, amiodarone, thyroid hormones, vincristine); and psychogenic disorders. Clinical tremor can be classified into physiological tremor, increased physiological tremor, essential tremor syndrome (including classic essential tremor, primary orthostatic tremor, and task-specific and position-specific tremor), dystonic tremor, Parkinson's tremor, cerebellar tremor, Holmes tremor (i.e., red nucleus tremor), palatal tremor, neuropathic tremor, toxic or drug-induced tremor, and psychogenic tremor.

[0423] Tremor is an involuntary, intermittent rhythmic movement, muscle contraction, and relaxation that may involve vibration or twitching of one or more body parts (e.g., hands, arms, eyes, face, head, vocal cords, trunk, legs).

[0424] Cerebellar tremor or intention tremor is a slow, widespread tremor of the limbs that occurs after intentional movement.Cerebellar tremor is caused by lesions or damage to the cerebellum, such as tumors, stroke, or diseases (e.g., multiple sclerosis, hereditary degenerative diseases).

[0425] Dystonic tremor occurs in individuals with dystonia and is a movement disorder in which sustained involuntary muscle contractions cause twisting and repetitive movements and / or painful, abnormal postures or positions. Dystonic tremor can affect any muscle in the body. Dystonic tremor occurs irregularly and is often relieved by complete rest.

[0426] Essential tremor, or benign essential tremor, is the most common type of tremor. Essential tremor can be mild and non-progressive or gradually develop, starting on one side of the body but affecting both sides within three years. It most often affects the hands, but can also affect the head, vocal cords, tongue, legs, and trunk. Tremor frequency may decrease with age, but severity may increase. Emotional arousal, stress, fever, physical fatigue, or hypoglycemia may trigger tremor and / or increase its severity. Symptoms generally evolve over time and can be visible and persistent after onset.

[0427] Orthostatic tremor is characterized by rapid (e.g., greater than 12 Hz) rhythmic muscle contractions in the legs and trunk immediately after standing. Patients may experience painful muscle spasms in the thighs and legs, and may tremble uncontrollably when asked to stand in one place. Patients with essential tremor may experience orthostatic tremor.

[0428] Parkinsonian tremor is caused by damage to structures in the brain that control movement. Parkinsonian tremor is often a precursor to Parkinson's disease and is typically seen as a "pill-rolling" movement of the hands, and may also affect the jaw, lips, legs, and trunk. Onset of Parkinsonian tremor usually begins after age 60. Movements may begin in one limb or side of the body and progress to involve the other side.

[0429] Physiologic tremor can occur in normal individuals and is not clinically significant. Physiologic tremor can be found in all voluntary muscle groups. Physiologic tremor can be caused by certain medications, alcohol withdrawal, or medical conditions including hyperthyroidism and hypoglycemia. Classic tremor has a frequency of approximately 10 Hz.

[0430] Psychogenic or hysterical tremor can occur at rest or during postural or motor activity. Patients with psychogenic tremor may have conversion disorder or another psychiatric illness.

[0431] Red nucleus tremor is characterized by a slow, coarse tremor that can occur at rest, posturally, and intentionally. It accompanies pathologies affecting the red nucleus of the midbrain, classic abnormal stroke.

[0432] Parkinson's disease affects the nerve cells in the brain that produce dopamine. Symptoms include muscle stiffness, tremors, and changes in speech and gait. Parkinsonism is characterized by tremors, bradykinesia, rigidity, and postural instability. Although Parkinsonism shares symptoms with Parkinson's disease, it is not a progressive neurodegenerative disease but rather a symptom complex.

[0433] Dystonia is a movement disorder characterized by sustained or intermittent muscle contractions, causing abnormal, often repetitive movements or postures. Dystonic movements can be stereotyped, twisting, and may be tremulous. Dystonia is often initiated by or exacerbated by voluntary movements and is associated with overflow of muscle activation.

[0434] Chorea is a neurological disorder characterized by intermittent involuntary movements that typically affect the shoulders, hips, and face. Huntington's disease is a genetic disorder that causes loss of nerve cells in the brain. Symptoms include uncontrollable movements, clumsiness, and balance problems. Huntington's disease can interfere with walking, speaking, and swallowing.

[0435] Ataxia refers to the complete loss of control of bodily movements and can affect fingers, hands, arms, legs, trunk, speech, and eye movements.

[0436] Myoclonus and startle reflexes are responses to sudden, unexpected stimuli, which may be auditory, tactile, visual, or vestibular.

[0437] Tics are involuntary movements that are usually sudden, brief, repetitive, and non-rhythmic, typically mimicking normal behavior and often occurring as a secondary cause of normal behavior. Tics can be classified as motor or vocal; motor tics involve movement, while vocal tics involve vocalization. Tics can be simple or complex. For example, simple motor tics involve only a few muscles confined to a specific body part. Tourette's syndrome is a childhood-onset, inherited neuropsychiatric disorder characterized by multiple motor tics and at least one vocal tic.

[0438] Restless legs syndrome is a neurosensorimotor disorder characterized by a strong desire to move the legs while at rest.

[0439] Stiff-person syndrome is a progressive movement disorder characterized by involuntary painful spasms and muscle stiffness, usually involving the lower back and legs. A stiff gait commonly occurs with lumbar hyperlordosis. Characteristic abnormalities in EMG recordings with continuous motor unit activity of the paraspinal axial muscles are commonly observed. Variants include "stiff limb syndrome," which causes focal stiffness usually affecting the distal legs and feet.

[0440] Gait disorders refer to abnormalities in the way or style of walking due to neuromuscular, arthritic, or other physical changes. Gaits are classified according to the system involved in the abnormal gait, including hemiplegic gait, diplegic gait, neuropathic gait, myopathic gait, parkinsonian gait, choreiform gait, ataxic gait, and sensory gait.

[0441] L. Anesthesia / Sedation

[0442] Anesthesia is a pharmacologically induced, reversible state of amnesia, analgesia, loss of responsiveness, loss of skeletal muscle reflexes, reduced stress response, or all of these simultaneously. Anesthesia can be obtained from a single drug that provides the right combination of effects alone, or in some cases through combinations of drugs (e.g., hypnotics, sedatives, paralytics, analgesics) that achieve extremely specific combinations of results. Anesthesia allows patients to undergo surgery and other procedures without the discomfort and pain that would otherwise be experienced by the patient.

[0443] Sedation is the reduction of irritability or excitement through the administration of pharmacological agents, generally to facilitate a medical or diagnostic procedure.

[0444] Sedation and analgesia encompass a continuum of states of consciousness ranging from minimal sedation (anxiolysis) to general anesthesia.

[0445] Minimal sedation is also known as anxiolysis. Minimal sedation is a drug-induced state during which the patient responds normally to verbal commands. Cognitive function and coordination may be impaired. Ventilatory and cardiovascular function are generally not affected.

[0446] Moderate sedation / analgesia (conscious sedation) is a drug-induced decrease in consciousness during which the patient responds purposefully to verbal commands alone or with mild tactile stimulation. No intervention is usually required to maintain a patent airway. Spontaneous ventilation is usually adequate. Cardiovascular function is usually preserved.

[0447] Deep sedation / analgesia is a drug-induced decrease in consciousness during which the patient cannot be easily aroused but responds purposefully following repetitive or painful stimuli (rather than reflex withdrawal from painful stimuli). Independent ventilation may be impaired, and the patient may require assistance to maintain a patent airway. Spontaneous ventilation may be inadequate. Cardiovascular function is usually preserved.

[0448] General anesthesia is a drug-induced loss of consciousness during which the patient cannot be aroused by painful stimuli. The ability to maintain independent ventilation is often impaired, and assistance is often required to maintain a patent airway. Positive pressure ventilation may be required due to decreased spontaneous ventilation or drug-induced neuromuscular depression. Cardiovascular function may be impaired.

[0449] Sedation in the intensive care unit (ICU) allows for decreased patient awareness of the environment and decreased patient reactivity to external stimuli. This allows for the care of critically ill patients and encompasses the management of a wide range of symptoms that vary across the course of the disease and between patients and individuals. Heavy sedation has been used in critical care to facilitate tolerance of endotracheal intubation and ventilator synchronization, often with the use of neuromuscular blockers.

[0450] In some embodiments, sedation (e.g., long-term sedation, continuous sedation) is induced and maintained in the ICU for an extended period of time (e.g., 1 day, 2 days, 3 days, 5 days, 1 week, 2 weeks, 3 weeks, 1 month, 2 months). Long-term sedative agents can have a long duration of action. Sedative agents in the ICU can have a short elimination half-life.

[0451] Procedural sedation and analgesia, also called conscious sedation, is a technique in which sedative or dissociative agents are administered with or without analgesics to induce a state that allows the subject to tolerate an unpleasant procedure while preserving cardiopulmonary function. [Example]

[0452] VI. Working Examples

[0453] In order that the invention described herein may be more fully understood, the following examples are set forth. The synthetic and biological examples described in this application are offered to illustrate the compounds, pharmaceutical compositions, and methods provided herein, and are not to be construed in any way as limiting the scope thereof.

[0454] Materials and Methods

[0455] The compounds provided herein can be prepared from readily available starting materials using the following general methods and procedures. Where typical or preferred process conditions (i.e., reaction temperature, time, molar ratio of reactants, solvent, pressure, etc.) are given, it is understood that other process conditions can also be used unless otherwise specified. Optimum reaction conditions may vary with the particular reactants or solvents used, but such conditions can be determined by one skilled in the art by routine optimization.

[0456] Additionally, as will be apparent to those skilled in the art, conventional protecting groups may be necessary to prevent certain functional groups from undergoing undesired reactions. The selection of a suitable protecting group for a particular functional group, as well as suitable conditions for protection and deprotection, are well known in the art. For example, numerous protecting groups and their introduction and removal are described in T.W. Greene and P.G.M. Buts, Protecting Groups in Organic Synthesis, Second Edition, Wiley, New York, 1991, and the references cited therein.

[0457] The compounds provided herein can be isolated and purified by known standard procedures. Such procedures include (but are not limited to) recrystallization, column chromatography, HPLC, or supercritical fluid chromatography (SFC). The following schemes are presented with details regarding the preparation of representative oxysterols listed herein. The compounds provided herein can be prepared from known or commercially available starting materials and reagents by those skilled in the art of organic synthesis. Exemplary chiral columns that can be used for the separation / purification of enantiomers / diastereomers provided herein include, but are not limited to, CHIRALPAK® AD-10, CHIRALCEL® OB, CHIRALCEL® OB-H, CHIRALCEL® OD, CHIRALCEL® OD-H, CHIRALCEL® OF, CHIRALCEL® OG, CHIRALCEL® OJ, and CHIRALCEL® OK.

[0458] As reported herein 1 It is understood that H-NMR (e.g., the region where δ (ppm) is from about 0.5 to about 4 ppm) is an exemplary interpretation of the NMR spectrum of a compound (e.g., exemplary peak integrals).

[0459] LC-ELSD / MS: (Mobile phase: 1.5ML / 4L TFA aqueous solution (solvent A) and 0.75ML / 4L TFA acetonitrile solution (solvent B), elution gradient 30%-90% (solvent B) over 0.9 min, held at 90% for 0.6 min at a flow rate of 1.2ml / min; Column: Xtimate C18 2.1*30mm, 3um; Wavelength: UV220nm; Column temperature: 50℃; MS ionization: ESI; Detector: PDA & ELSD.

[0460] Abbreviation

[0461] DCM: dichloromethane; DMF: dimethylformamide; DMP: Dess-Martin periodinane; DMSO: dimethyl sulfoxide; EtOAc: ethyl acetate; EtOH: ethanol; HATU: (1-[bis(dimethylamino)methylene]-1H-1,2,3- Triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate; MeI: methyl iodide; MeOH: methanol; t-BuOK: potassium tert-butoxide; i-PrMrCl: isopropylmagnesium chloride; PCC: pyridinium chlorochromate; PE: petroleum ether; TBAF: tetra-n-butylammonium fluoride; TBSCl: tert-butyl(chloro)dimethylsilane; TBSOTf: tert-butyldimethylsilyl trifluoromethanesulfonate; THF: tetrahydrofuran; 9-BBN dimer: 9-borabicyclo(3.3.1)nonane (dimer); Ts: p-toluenesulfonyl;

[0462] Example 1: Synthesis of 1-(3-((3R,5S,8R,9R,10S,13S,14S,17S)-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-3-oxopropyl)-1H-pyrazole-4-carbonitrile (1) [ka]

[0463] 1.1 Synthesis

[0464] To a solution of PPhMeBr (20.2 g, 56.6 mmol) in THF (200 mL) was added t-BuOK (6.35 g, 56.6 mmol). The reaction mixture was stirred for 0.5 h at 60 °C. A solution of 1.0 (5.5 g, 18.9 mmol) in THF (100 mL) was added to the reaction at 60 °C. After stirring the reaction mixture for 12 h at 60 °C, the mixture was poured into saturated NHCl (300 mL) and extracted with EtOAc (2 × 100 mL). The combined organic phases were washed with saturated brine (2 × 100 mL), dried over anhydrous NaSO, filtered, and concentrated in vacuo. The mixture was purified by silica gel chromatography (0–15% EtOAc in PE) to give 1.1 (4.8 g, 88%).

[0465] 1 H NMR (400 MHz, CDCl3) δ H 4.66-4.58 (m, 2H), 2.52-2.41 (m, 1H), 2.29-2.17 (m, 1H), 1.89-1.57 (m, 7H), 1.55-1.51 (m, 1H), 1.39-1.22 (m, 4H), 1.20 (s, 3H), 1.20-0.92 (m, 8H), 0.78 (s, 3H), 0.75-0.65 (m, 2H).

[0466] Synthesis of 1.2

[0467] To a solution of 1.1 (4.8 g, 16.6 mmol) in THF (100 mL) was added 9-BBN dimer (8.03 g, 33.2 mmol) under N. The reaction mixture was stirred at 60 °C under N for 2 h to give a colorless solution. The mixture was cooled to 0 °C, and EtOH (11.4 mL, 199 mmol) and aqueous NaOH (39.8 mL, 5 M, 199 mmol) were added to the mixture, followed by the dropwise addition of HO (19.9 mL, 10 M, 199 mmol) at 15 °C. After stirring the mixture at 60 °C for 2 h, the mixture was cooled, poured into NaSO (200 mL, saturated), and stirred for 30 min. The aqueous layer was extracted with EtOAc (2 × 200 mL). The combined organic layers were washed with saturated brine (2 x 100 mL), dried over anhydrous Na2SO4, filtered and concentrated to give 1.2 (5.5 g).

[0468] 1 H NMR (400 MHz, CDCl3) δ H 3.78-3.65 (m, 1H), 3.61-3.48 (m, 1H), 1.88-1.58 (m, 9H), 1.55-1.22 (m, 5H), 1.20 (s, 3H), 1.19-0.91 (m, 10H), 0.81-0.67 (m, 2H), 0.65 (s, 3H).

[0469] Synthesis of 1.3

[0470] To a solution of 1.2 (1.0 g, 3.26 mmol) in DCM (20 mL) was added PCC (1.4 g, 6.52 mmol) and silica gel (1.4 g). The mixture was stirred at 25 °C for 0.5 h, filtered, washed with EtOAc (2 × 50 mL), and concentrated. The residue was purified by silica gel chromatography (0 to 20% EtOAc in PE) to give 1.3 (740 mg, 75%).

[0471] 1 H NMR (400 MHz, CDCl3) δ H 9.77 (d, 1H), 2.57-1.94 (m, 4H), 1.84-1.57 (m, 8H), 1.43-1.26 (m, 5H), 1.20 (s, 3H), 1.14-0.98 (m, 6H), 0.76 (s, 3H), 0.75-0.63 (m, 2H).

[0472] Synthesis of 1.4

[0473] To a solution of 1.3 (740 mg, 2.43 mmol) in THF (20 mL) was added bromo(ethenyl)magnesium (17.2 mL, 0.7 M, 12.1 mmol) at 0 °C. After the mixture was stirred at 25 °C for 2 h, the mixture was poured into NH Cl (100 mL, saturated). The mixture was extracted with EtOAc (2 × 100 mL), and the combined organic phases were washed with water (2 × 100 mL), brine (200 mL), dried over anhydrous Na SO , filtered, and concentrated. The residue was purified by silica gel chromatography (0–20% EtOAc in PE) to give 1.4 (330 mg, 41%).

[0474] 1 H NMR (400 MHz, CDCl3) δ H 5.95-5.78 (m, 1H), 5.27-5.00 (m, 2H), 4.05-3.94 (m, 1H), 2.10-2.05 (m, 1H), 1.97-1.61 (m, 7H), 1.52-1.24 (m, 7H), 1.21-1.19 (m, 3H), 1.13-0.94 (m, 9H), 0.81-0.66 (m, 5H).

[0475] 1.5 Synthesis

[0476] To a solution of 1.4 (330 mg, 0.9923 mmol) in DCM (10 mL) was added DMP (839 mg, 1.98 mmol) at 40° C. The mixture was stirred at 40° C. for 1 h. After 2 min, the mixture was added to NaHCO (50 mL, saturated) and NaSO (50 mL, saturated). The aqueous phase was extracted with DCM (2 × 50 mL), and the combined organic phases were washed with NaHCO / NaSO (1:1, 2 × 100 mL, saturated), brine (100 mL), dried over anhydrous NaSO, filtered, and concentrated to give 1.5 (350 mg).

[0477] 1 H NMR (400 MHz, CDCl3) δ H 6.49-6.37 (m, 1H), 6.25-6.16 (m, 1H), 5.70-5.63 (m, 1H), 2.80 (t, 1H), 1.89-1.64 (m, 8H), 1.37-1.24 (m, 5H), 1.45-1.22 (m, 1H), 1.20 (s, 3H), 1.12-0.95 (m, 7H), 0.79-0.62 (m, 3H), 0.59 (s, 3H).

[0478] Synthesis of 1

[0479] A solution of 1.5 (350 mg, 1.05 mmol), 1-methyl-1H-imidazole (255 mg, 3.15 mmol), and 1H-pyrazole-4-carbonitrile (195 mg, 2.10 mmol) in DMSO (10 mL) was stirred at 70° C. for 16 h. The mixture was added to saturated brine (50 mL), and the aqueous layer was extracted with EtOAc (2×50 mL). The combined organic layers were washed with saturated brine (2×50 mL), dried over anhydrous NaSO, filtered, and concentrated. The residue was purified by silica gel chromatography (0-50% EtOAc in PE) and preparative HPLC (Column: Welch Xtimate C18 150*25mm*5um; Conditions: water (0.225% FA)-MeOH; Start B: 64; End B: 94; Gradient time (min): 8.5; 100% B retention time (min): 2; Flow rate (ml / min): 30; Injections: 8) to give 1 (84.5 mg, 19%).

[0480] 1H NMR (400 MHz, CDCl3) δ H 7.91 (s, 1H), 7.75 (s, 1H), 4.52-4.44 (m, 1H), 4.40-4.33 (m, 1H), 3.11-3.01 (m, 1H), 2.93-2.83 (m, 1H), 2.47 (t, 1H), 2.18-2.07 (m, 1H), 1.95-1.56 (m, 9H), 1.44-1.27 (m, 4H), 1.20 (s, 3H), 1.16-0.94 (m, 8H), 0.74-0.59 (m, 2H), 0.41 (s, 3H). LC-ELSD / MS: Purity 99%;C 26 H 38 MS ESI calculated for N3O2 [M+H] + 424.4, actual value 424.4.

[0481] Example 2: Synthesis of 1-(3-((3R,5S,8R,9R,10S,13S,14S,17S)-3-hydroxy-3-(methoxymethyl)-13-methylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-3-oxopropyl)-1H-pyrazole-4-carbonitrile (2) [ka]

[0482] 2.1 Synthesis

[0483] To a mixture of MePPhBr (22.2 g, 62.4 mmol) in THF (150 mL) was added t-BuOK (7.0 g, 48.4 mmol) at 25 °C under N. The resulting mixture was stirred at 50 °C for 30 min. Compound 2.0 (10.0 g, 31.2 mmol) was added portionwise below 50 °C. After stirring at 50 °C for 16 h, a yellow suspension was observed. The reaction mixture was quenched with 10% aqueous NHCl (150 mL) at 25 °C, and the aqueous phase was extracted with EtOAc (2 × 150 mL). The combined organic phases were separated, dried over NaSO, filtered, and concentrated, which was purified by trituration with MeOH / HO (1:1, 400 mL) at reflux to give 2.1 (11.1 g).

[0484] 1 H NMR (400 MHz, CDCl3) δ H 4.65-4.59 (m, 2 H), 3.42-3.35 (m, 3 H), 3.19 (s, 2 H), 2.53-2.42 (m, 1 H), 2.28-2.16 (m, 1 H), 2.00 (s, 1 H), 1.89-1.65 (m, 6 H), 1.50-1.36 (m, 1 H), 1.34-0.83 (m, 12 H), 0.78 (s, 3 H), 0.75-0.67 (m, 2 H).

[0485] 2.2 Synthesis

[0486] To a solution of 2.1 (11.1 g, 34.8 mmol) in anhydrous THF (150 mL) was added 9-BBN dimer (16.9 g, 69.6 mmol) at 25 °C under N 2 . The reaction mixture was stirred at 25 °C for 18 h. To the resulting mixture was added ethanol (24.6 mL, 417 mmol) at 25 °C, followed by aqueous NaOH (83.4 mL, 5.0 M, 417 mmol) and HO (41.7 mL, 10 M, 417 mmol) dropwise at 0 °C. After stirring at 80 °C for 3 h, the mixture was cooled and then poured into Na 2 SO 3 (300 mL, saturated aqueous solution). The aqueous phase was extracted with EtOAc (2 × 200 mL). The combined organic phase was washed with saturated brine (200 mL), dried over anhydrous Na 2 SO 4 , filtered, and concentrated in vacuo. The residue was purified by flash column (15-25% EtOAc in PE) to give 2.2 (8.6 g, 73.5%).

[0487] 1 H NMR (400 MHz, CDCl3) δ H 3.75-3.68 (m, 1 H), 3.38 (s, 3 H), 3.18 (s, 2 H), 2.03-1.93 (m, 1 H), 1.86-1.69 (m, 6 H), 1.6 6-1.62 (m, 2 H), 1.48-1.33 (m, 2 H), 1.29-1.14 (m, 6 H), 1.12-1.04 (m, 4 H), 1.03-0.96 (m, 3 H), 0.77-0.67 (m, 2 H), 0.65 (s, 3 H).

[0488] Synthesis of 2.3

[0489] To a mixture of 2.2 (8.6 g, 25.5 mmol) in DCM (100 mL) was added silica gel (8.23 g) and PCC (8.23 g, 38.2 mmol) at 0 °C. After stirring at 25 °C for 1 h, the mixture was filtered, washed with DCM (2 × 100 mL), and the solvent was evaporated. The residue was purified by column chromatography (15–35% EtOAc in PE) to give 2.3 (4.1 g, 48%).

[0490] 1 H NMR (400 MHz, CDCl3) δ H , 3.38 (s, 3 H), 3.18 (s, 2 H), 2.44-2.05 (m, 2 H), 2.02-1.94 (m, 1 H), 1.87-1.58 (m, 9 H), 1.52-1.36 (m, 2 H), 1.32-0.88 (m, 11 H), 0.82-0.65 (m, 5 H).

[0491] 2.4 Synthesis

[0492] To a solution of 2.3 (1.0 g, 2.98 mmol) in THF (5 mL) was added bromo(ethenyl)magnesium (1.95 g, 14.9 mmol) at 0 °C. After stirring at 25 °C for 16 h, the mixture was quenched with NH4Cl (10 mL, saturated) and extracted with EtOAc (2 × 10 mL). The organic layer was separated, dried over Na2SO4, filtered, concentrated, and purified by flash column (15–40% EtOAc in PE) to give 2.4 (460 mg, 43%).

[0493] 1 H NMR (400 MHz, CDCl3) δ H 5.95-5.75 (m, 1 H), 5.27-4.99 (m, 2 H), 4.06-3.91 (m, 1 H), 3.38 (s, 3 H), 3.20-3.15 (m, 2 H), 2.21-2.06 (m, 1 H), 2.02-1.61 (m, 8 H), 1.51-1.33 (m, 3 H), 1.29-1.17 (m, 5 H), 1.13-0.92 (m, 7 H), 0.81-0.64 (m, 5 H).

[0494] 2.5 Synthesis

[0495] To a solution of 2.4 (200 mg, 0.55 mmol) in DCM (2 mL) was added DMP (466 mg, 1.10 mmol) at 25 °C. After stirring at 25 °C for 1 h, NaHCO (10 mL, saturated) and NaSO (10 mL, saturated) were added to the mixture. The aqueous phase was extracted with DCM (2 × 10 mL), and the combined organic phases were washed with NaHCO / NaSO (1:1, 2 × 10 mL, saturated), brine (10 mL), dried over anhydrous NaSO, filtered, and concentrated to give 2.5 (140 mg, 71%).

[0496] 1 H NMR (400 MHz, CDCl3) δ H 6.48-6.36 (m, 1 H). 6.23-6.15 (m, 1 H), 5.72-5.62 (m, 1 H), 3.38 (s, 3 H), 3.18 (s, 2 H), 2.85-2.73 (m, 1 H), 2.31-2.17 (m, 1 H), 1.91-1.64 (m, 8 H), 1.45-1.35 (m, 2 H), 1.3 0-1.15 (m, 5 H), 1.13-0.93 (m, 6 H), 0.77-0.65 (m, 2 H), 0.59 (s, 3 H).

[0497] Synthesis of 2

[0498] A solution of 2.5 (140 mg, 0.39 mmol), 1-methyl-1H-imidazole (95.2 mg, 1.16 mmol), and 1H-pyrazole-4-carbonitrile (72.2 mg, 0.7766 mmol) in DMSO (5 mL) was stirred at 70 °C for 16 h. The mixture was added to saturated brine (10 mL), and the aqueous layer was subsequently extracted with EtOAc (3 × 10 mL). The combined organic layers were washed with saturated brine (2 × 10 mL), dried over anhydrous NaSO, filtered, and concentrated to give crude 2 (60 mg). Crude 2 (60 mg) was purified by SFC (DAICEL CHIRALCEL OJ-H (250 mm * 30 mm, 5 μm)); mobile phase: A:CO B:0.1% NH H O EtOH; gradient: 25% to 25% B, flow rate (ml / min): 60) to give 2 (10.6 mg).

[0499] 1 H NMR (400 MHz, CDCl3) δ H 7.91 (s, 1 H), 7.75 (s, 1 H), 4.52-4.43 (m, 1 H), 4.40- 4.32 (m, 1 H), 3.38 (s, 3 H), 3.18 (s, 2 H), 3.11-3.01 (m, 1 H), 2.92-2.84 (m, 1 H), 2.51-2.44 (m, 1 H), 2.18-2.05 (m, 1 H), 2.03-1.99 (m, 1 H), 1.85-1.70 (m, 4 H), 1.66-1.59 (m, 3 H), 1.44-1.33 (m, 2 H), 1.27-1.14 (m, 5H), 1.10-0.91 (m, 6 H), 0.75-0.63 (m, 2 H), 0.41 (s, 3 H). LC-ELSD / MS purity 99%, C 27 H 39 MS ESI calculated for N3O3 [M+H] + 454.3, actual value 454.3.

[0500] Example 3: Synthesis of 1-(4-((3R,5R,8R,9R,10S,13S,14S,17S)-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-4-oxobutyl)-1H-pyrazole-4-carbonitrile (3) [ka]

[0501] 3.1 Synthesis

[0502] To a suspension of Mg (2.52 g, 105 mmol) and I2 (20 mg) in THF (10 mL) was added dropwise a solution of 1-bromo-3-benzyloxypropane (12.0 g, 52.5 mmol) in THF (40 mL) at 35-40 °C under N2. The mixture was stirred at 35 °C for 1 h. To the freshly prepared Grignard reagent was added a solution of 3.0 (1.6 g, 3.28 mmol) in THF (20 mL) at 10 °C. After stirring at 25 °C for 1 h, the mixture was quenched with NH4Cl (40 mL, saturated) and extracted with EtOAc (100 mL). The organic layer was separated, dried over Na2SO4, filtered, concentrated, and purified by flash column (15-40% EtOAc in PE) to give 3.1 (2.3 g, 97%).

[0503] 3.2 Synthesis

[0504] To a solution of 3.1 (2.3 g, 5.05 mmol) in DMF (10 mL) was added imidazole (687 mg, 10.1 mmol) and TBSCl (1.14 g, 7.57 mmol). After stirring at 50 °C for 8 h, the mixture was quenched with water (20 mL) and extracted with EtOAc (20 mL). The organic layer was separated, dried over Na2SO4, filtered, concentrated, and purified by flash column (0-10% EtOAc in PE) to give 3.2 (1.3 g, 45%).

[0505] 3.3 Synthesis

[0506] To a solution of 3.2 (500 mg, 0.8787 mmol) in THF (20 mL) was added Pd / C (100 mg, wet, 10%) under N. After stirring at 25 °C under H (20 psi) for 20 h, the mixture was filtered through a pad of Celite and washed with THF (3 × 50 mL). The combined filtrate was concentrated to give 3.3 (400 mg).

[0507] 3.4 Synthesis

[0508] To a solution of 3.3 (400 mg, 0.83 mmol) in DCM (5 mL) was added N-methylimidazole (102 mg, 1.25 mmol), TEA (252 mg, 2.50 mmol), and TsCl (318 mg, 1.67 mmol). After stirring at 25 °C for 0.5 h, the mixture was poured into water (20 mL). The aqueous phase was extracted with EtOAc (2 × 30 mL). The combined organic phases were washed with water (2 × 20 mL), dried over anhydrous NaSO, filtered, and concentrated to give 3.4 (600 mg).

[0509] 3.5 Synthesis

[0510] To a solution of 3.4 (600 mg, 0.9478 mmol) in DMF (10 mL) was added CsCO (619 mg, 1.89 mmol) and 4-cyano-pyrazole (175 mg, 1.89 mmol). After stirring at 80 °C for 16 h, the mixture was diluted with EtOAc (2 × 30 mL), washed with water (30 mL), LiCl (5%, aq.), dried over NaSO, filtered, and purified by flash column (5-30% EtOAc in PE) to give 3.5 (400 mg, 76%).

[0511] 3.6 Synthesis

[0512] To a solution of 3.5 (400 mg, 0.7221 mmol) in THF (1 mL) was added TBAF (7.22 mL, 1 M in THF, 7.22 mmol, in-house). After stirring for 1 h, the mixture was concentrated in vacuo. The residue was dissolved in EtOAc (50 mL), washed with water (2×30 mL), brine (30 mL), dried over Na SO , filtered, and concentrated in vacuo to give crude 3.6 (360 mg).

[0513] Synthesis of 3

[0514] To a mixture of 3.6 (360 mg, 0.82 mmol) in DCM (5 mL) was added DMP (691 mg, 1.63 mmol) at 25 °C. After stirring at 20 °C for 3 h, NaHCO (10 mL, saturated) and NaSO (10 mL, saturated) were added to the mixture. The aqueous phase was extracted with DCM (2 × 30 mL), and the combined organic phases were washed with NaHCO / NaSO (1:1, 2 × 40 mL, saturated), brine (30 mL), dried over anhydrous NaSO, filtered, and concentrated. The residue was purified by column chromatography (15–35% EtOAc in PE) to give 3 (118.7 mg, 33%).

[0515] 1 H NMR (400 MHz, CDCl3) δ H 7.82-7.75 (m, 2H), 4.20 (t, 2H), 2.52-2.43 (m, 1H), 2.40-2.32 (m, 2H), 2.20-2.08 (m, 3H), 1.89-1.59 (m, 8H), 1.49-1.31 (m, 8H), 1.27 (s, 4H), 1.25-0.97 (m, 6H), 0.58 (s, 3H) LC-ELSD / MS purity >99%, C 27 H 38 MS ESI calculated value for NO [M-HO+H] + 420.2, actual value 420.2.

[0516] Example 4: Synthesis of 1-(5-((3R,5R,8R,9R,10S,13S,14S,17S)-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-5-oxopentyl)-1H-pyrazole-4-carbonitrile (4) [ka]

[0517] 4.1 Synthesis

[0518] To a solution of 4.0 (5 g, 19.4 mmol) in xylene (20 mL) was added PPh3 (5.58 g, 21.3 mmol). After stirring at 120 °C for 40 h, the clear xylene layer was separated and discarded. The residue was triturated in DCM (20 mL) and filtered. The filtrate was concentrated and purified by flash chromatography (0-4% MeOH in DCM) to give 4.1 (7 g, 70%).

[0519] 1 H NMR (400 MHz, CDCl3) δ H 7.90-7.60 (m, 18H), 7.35-7.25 (m, 2H), 4.42 (s, 2H), 3.95-3.80 (m, 2H), 3.45 (t, 2H), 1.80-1.60 (m, 6H).

[0520] 4.3 Synthesis

[0521] To a solution of 4.1 (7 g, 13.4 mmol) in THF (30 mL) was added t-BuOK (1.49 g, 13.3 mmol) under N2, and the mixture was stirred at 50 °C for 1 h. To this, 4.2 (3.0 g, 10.3 mmol) was added, and the reaction mixture was stirred at 50 °C for an additional 16 h. The mixture was quenched with NH4Cl (20 mL, saturated) and extracted with EtOAc (2 × 50 mL). The combined organic layers were dried over Na2SO4, filtered, concentrated in vacuo, and purified by flash column (0–10% EtOAc in PE) to give 4.3 (300 mg, 6%).

[0522] 1 H NMR (400 MHz, CDCl3) δ H 7:40-4:30 (m, 5H), 5.00 (t, 1H), 4.50 (s, 2H), 3.47 (t, 2H), 2.40-2.30 (m, 1H), 2.20-1.95 (m, 4H), 1.90-1.75 (m, 3H), 1.75-1.60 (m, 5H), 1.50-1.00 (m, 20H), 0.85 (s, 3H).

[0523] 4.4 Synthesis

[0524] To a solution of 4.3 (300 mg, 0.66 mmol) in THF (5 mL) was added BH3.Me2S (0.66 mL, 10 M, 6.65 mmol) under N2, and the reaction was stirred at 25 °C for 16 h. To the mixture was added EtOH (1.52 g, 33.2 mmol), NaOH (6.6 mL, 5 M, 33 mmol), and HO2 (0.66 mL, 10 M, 6.6 mmol), and the mixture was further stirred at 20 °C for 1 h. The mixture was quenched with Na2SO3 (10%, 10 mL) and extracted with EtOAc (2 × 50 mL). The combined organic layers were dried over Na2SO4, filtered, concentrated in vacuo, and purified by flash column (20–40% EtOAc in PE) to give 4.4 (300 mg, 96%).

[0525] 4.5 Synthesis

[0526] To a solution of 4.4 (300 mg, 0.64 mmol) in DCM (5 mL) was added silica gel (1.2 g) and PCC (275 mg, 1.28 mmol), and the mixture was stirred at 25° C. for 1 h. The mixture was concentrated and purified by flash column (10-20% EtOAc in PE) to give 4.5 (190 mg, 64%).

[0527] 4.6 Synthesis

[0528] To a solution of 4.5 (190 mg, 0.41 mmol) in THF (10 mL) was added Pd(OH) / C (anhydrous, 10%, 0.5 g) under N. The suspension was degassed under vacuum and The mixture was purged with H2 three times. The mixture was stirred under H2 (30 psi) at 30 °C for 20 h, resulting in a black suspension. The reaction mixture was filtered through a pad of Celite and washed with THF (3 × 10 mL). The filtrate was concentrated and purified by flash column (25-75% EtOAc in PE) to give 4.6 (100 mg, 65%).

[0529] 4.7 Synthesis

[0530] To a solution of 4.6 (70 mg, 0.1858 mmol) in DCM (3 mL) was added N-methylimidazole (45.7 mg, 0.5574 mmol), TEA (112 mg, 1.11 mmol), and TsCl (141 mg, 0.7432 mmol). After stirring at 25 °C for 3 h, the mixture was poured into saturated aqueous NaHCO (20 mL). The aqueous phase was extracted with EtOAc (2 × 30 mL). The combined organic phases were washed with water (2 × 20 mL), dried over anhydrous NaSO, filtered, and concentrated to give 4.7 (150 mg).

[0531] Synthesis of 4

[0532] To a solution of 4.7 (150 mg, 0.2826 mmol) in DMF (3 mL) was added CsCO (184 mg, 0.5652 mmol), 4-cyano-pyrazole (52.6 mg, 0.5652 mmol), and the mixture was stirred at 80 °C for 16 h. The mixture was diluted with EtOAc (2 × 30 mL), washed with water (30 mL), LiCl (5%, aq. 30 mL), dried over NaSO, filtered, and purified by flash column (5-40% EtOAc in PE) to give crude 4 (50 mg). 50 mg of crude 4 was purified by SFC (Column: DAICEL CHIRALCEL OJ-H (250 mm * 30 mm, 5 μm)); Mobile phase: A:CO B:0.1% NH H O EtOH; Gradient: 35% to 35% B, Flow rate (ml / min): 60) to give 4 (32.8 mg, 65.7%).

[0533] 1 H NMR (400 MHz, CDCl3) δ H 7.82 (s, 1H), 7.79 (s, 1H), 4.15 (t, 2H), 2.52-2.43 (m, 1H), 2.40 (t, 2H), 2.21-2.10 (m, 1H), 1.95-1.60 (m, 11H), 1.51-1.32 (m, 9H), 1.27 (s, 4H), 1.23-0.99 (m, 6H), 0.58 (s, 3H). LC-ELSD / MS purity >99%, C 29 H 41 MS for N3O2 ESI calculated value [M+H] + 452.3, actual value 452.3.

[0534] Examples 5 and 6: Synthesis of 1-(3-((3R,5R,8R,9R,10S,13R,14S,17R)-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-oxopropyl)-1H-pyrazole-4-carbonitrile (5) and (3R,5R,8R,9R,10S,13R,14S,17R)-17-(2-hydroxypropyl)-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-3-ol (6) [ka]

[0535] 5.1 Synthesis

[0536] To a suspension of NaH (2.75 g, 60% in mineral oil, 68.8 mmol) in THF (60 mL), (EtO)P(O)CHCOOEt (15.4 g, 68.8 mmol) was added dropwise at 0 °C, and the mixture was subsequently stirred at 20 °C for 10 min. A solution of 5.0 (10 g, 34.4 mmol) in THF (20 mL) was added dropwise at 20 °C. After refluxing at 70 °C for 16 h, the mixture was poured into NH Cl (200 mL, 10% aqueous solution) and extracted with EtOAc (200 mL). The organic layer was separated, dried over Na SO , filtered, concentrated, and purified by flash column (0-20% EtOAc in PE) to give 5.1 (12.0 g, 97%).

[0537] 1 H NMR (400 MHz, CDCl3) δ H 5.52 (t, 1H), 4.15 (q, 2H), 2.90-2.75 (m, 2H), 1.95-1.60 (m, 5H), 1.50-1.25 (m, 18H), 1.20-1.05 (m, 4H), 0.82 (s, 3H).

[0538] 5.2 Synthesis

[0539] To a solution of 5.1 (12 g, 33.2 mmol) in THF (150 mL) was added Pd / C (2 g, dry, 10%) under N. After stirring at 40 °C under H (40 psi) for 24 h, the mixture was filtered through a pad of Celite and washed with THF (3 × 50 mL). The combined filtrate was concentrated to give 5.2 (11.7 g, 98%).

[0540] 1 H NMR (400 MHz, CDCl) δ H 4.11 (q, 2H), 2.35 (dd, 1H), 2.10 (dd, 1H), 2.00-1.75 (m, 6H), 1.70-1.50 (m, 3H), 1.50-1.35 (m, 6H), 1.35-1.25 (m, 10H), 1.20-0.95 (m, 6H), 0.59 (s, 3H).

[0541] 5.3 Synthesis

[0542] To a suspension of LiAlH (6.0 g, 158 mmol) in THF (120 mL) was added a solution of 5.2 (11.1 g, 30.6 mmol) in THF (30 mL) at 0 °C under N. After stirring for 10 min at 0 °C, water / THF (6 mL / 200 mL) was added dropwise, followed by NaOH (6 mL, 10% aqueous solution) and water (18 mL). The mixture was filtered, and the precipitate was washed with THF (3 × 100 mL). The combined filtrate was concentrated and triturated in DCM (50 mL) to give 5.3 (9 g, 92%).

[0543] 1 H NMR (400 MHz, CDCl3) δ H 3.75-3.55 (m, 2H), 1.90-1.60 (m, 9H), 1.50-1.15 (m, 16H) 1.15-0.90 (m, 6H), 0.59 (s, 3H).

[0544] 5.4 Synthesis

[0545] To a solution of 5.3 (3 g, 9.3 mmol) in DCM (80 mL) was added DMP (7.92 g, 18.7 mmol). After stirring at 30 °C for 1 h, the mixture was washed twice with a mixed solution of NaHCO (160 mL, saturated aqueous solution) and NaSO (80 mL, saturated aqueous solution), dried over NaSO, filtered, concentrated, and purified by flash column (10-30% EtOAc in PE) to give 5.4 (2.2 g, 74%).

[0546] 1 H NMR (400 MHz, CDCl3) δ H 9.76 (t, 1H), 2.55-2.45 (m, 1H), 2.30-2.20 (m, 1H), 2.00-1.80 (m, 5H), 1.70-1.55 (m, 4H), 1.50-1.20 (m, 13H), 1.30-1.00 (m, 6H), 0.60 (s, 3H).

[0547] 5.5 Synthesis

[0548] To a solution of 5.4 (4 g, 12.5 mmol) in THF (40 mL) was added MeMgBr (20.8 mL, 7.19 mmol, 3 M) at 0 °C. After stirring for 1 h at 20 °C, a black suspension formed. The reaction mixture was added to saturated NH Cl (100 mL) and the aqueous layer was extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with saturated brine (100 mL), dried over anhydrous Na SO , filtered, and concentrated to give 5.5 (4 g).

[0549] 1 H NMR (400 MHz, CDCl3) δ 3.82-3.72 (m, 1H), 1.94-1.59 (m, 12H), 1.54-1.31 (m, 8H), 1.25-0.97 (m, 14H), 0.64-0.50 (m, 3H).

[0550] Synthesis of 6

[0551] To a solution of 5.5 (4 g, 11.9 mmol) in DCM (50 mL) was added silica gel (8 g) and PCC (5.11 g, 23.8 mmol) at 20 °C. After stirring for 1 h at 20 °C, a yellow suspension formed. The mixture was filtered, and the filter cake was washed with DCM (3 × 20 mL). The mother liquor was concentrated, and the residue was purified by flash column (0 to 40% EtOAc in PE) to give 6 (2.3 g, 58%).

[0552] 1 H NMR (400 MHz, CDCl3) δ 2.53-2.44 (m, 1H), 2.27-2.18 (m, 1H), 2.17-2.10 (m, 3H ), 1.82-1.74 (m, 3H), 1.69-1.57 (m, 7H), 1.48-1.38 (m, 5H), 1.34-1.25 (m, 6H), 1.19-0.97 (m, 7H), 0.58 (s, 3H). LC-ELSD / MS purity 99%, C 22 H 35 MS ESI calculated value for O [M-HO+H] + 315.2, actual value 315.2.

[0553] 5.6 Synthesis

[0554] To a solution of 6 (200 mg, 0.6014 mmol) and HBr (5.99 mg, 0.03007 mmol, 40%) in MeOH (10 mL) was added Br (105 mg, 0.6615 mmol) at 0 °C. After stirring at 25 °C for 2 h, the mixture was added to saturated NaHCO (20 mL). The aqueous layer was extracted with EtOAc (3 × 20 mL), and the combined organic layers were washed with saturated brine (30 mL), dried over anhydrous NaSO, filtered, and concentrated to give 5.6 (247 mg).

[0555] Synthesis of 5

[0556] To a solution of 5.6 (240 mg, 0.5833 mmol) in acetone (5 mL) was added KCO (160 mg, 1.16 mmol) and 1H-pyrazole-4-carbon (81.4 mg, 0.8749 mmol). After stirring at 25 °C for 2 h, the reaction mixture was poured into water and subsequently extracted with EtOAc (2 × 20 mL). The organic phase was dried over anhydrous NaSO, filtered, and concentrated to give the crude product, which was purified by flash column chromatography (0 to 40% EtOAc in PE) to give product 5 (200 mg). The crude product was purified by preparative HPLC (column: YMC Triart C18 150*25mm*5um; condition: water (10mM NH4HCO3)-ACN; start B: 70; end B: 100; gradient time (min): 9.5; 100% B retention time (min): 2) to give product 5 (100mg, 50%).

[0557] 1 H NMR (400 MHz, CDCl3) δ 7.90-7.76 (m, 2H), 5.09-4.91 (m, 2H), 2.61-2.49 (m, 1H), 2.39-2.18 (m, 1H), 2.03-1.75 (m, 5H), 1.68-1.58 (m, 6H), 1.42-1.37 (m, 4H), 1.33-0.93 (m, 13H), 0.59 (s, 3H). LC-ELSD / MS purity ≧99%, C 26 H 36 MS ESI calculated value for NO [M-HO+H] + 406.3, actual value 406.3.

[0558] Example 7: Synthesis of 1-(4-((3R,5R,8R,9R,10S,13R,14S,17R)-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-methyl-3-oxobutan-2-yl)-1H-pyrazole-4-carbonitrile (7) [ka]

[0559] Synthesis of 7

[0560] To a solution of 5 (200 mg, 0.47 mmol) in THF (2.0 mL) was added KOH (52.8 mg, 0.94 mmol) and MeI (134 mg, 0.94 mmol) at 25 °C. After stirring at 25 °C for 2 h, the reaction mixture was treated with water (50 mL) and extracted with EtOAc (3 × 30 mL). The organic phase was washed with brine (100 mL), dried over anhydrous NaSO, and concentrated in vacuo. The residue was purified by flash column chromatography (0–40% EtOAc in PE) to give 7 (100 mg). 100 mg of impure 7 was purified by HPLC (column: Phenomenex Gemini-NX 80*40 mm*3 um; condition: water (0.05% NH3H2O+10 mM NH4HCO3)-ACN; start B: 60; end B: 90) to give 7 (18.5 mg, 19%).

[0561] 1 H NMR (400 MHz, CDCl3) δ H 7.98 (s, 1 H) 7.88 (s, 1 H) 2.13-2.21 (m, 1 H) 1.77-1.93 (m, 5 H) 1.75 (d, 6 H) 1.59-1.65 (m, 3 H) 1.27-1.50 (m, 10 H) 1.25 (s, 3 H) 0.91-1.17 (m, 8 H) 0.43 (s, 3 H). LC-ELSD / MS: 99% purity, analytical SFC: 100% de;C 28 H 41 MS ESI calculated value for N3O2 [M-H2O+H] + 434.3, actual value 434.3.

[0562] Examples 8 and 9: Synthesis of 1-((R)-4-((3R,5R,8R,9R,10S,13R,14S,17R)-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-3-oxobutan-2-yl)-1H-pyrazole-4-carbonitrile (8) and 1-((S)-4-((3R,5R,8R,9R,10S,13R,14S,17R)-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-3-oxobutan-2-yl)-1H-pyrazole-4-carbonitrile (9) [ka]

[0563] Synthesis of 8 and 9

[0564] To a solution of 5 (400 mg, 0.94 mmol) in THF (10 mL) was added KOH (63.2 mg, 1.13 mmol) and MeI (200 mg, 1.41 mmol) at 25 °C. After stirring at 25 °C for 2 h, the reaction mixture was treated with water (20 mL) and extracted with EtOAc (3 × 10 mL). The organic phase was washed with brine (50 mL), dried over anhydrous NaSO, and concentrated in vacuo. The residue was purified by flash column chromatography (0–60% EtOAc in PE) to give a mixture of 8 and 9 (120 mg). The mixture product (120 mg) was purified by SFC (column: DAICEL CHIRALPAK AD (250 mm * 30 mm, 10 μm; condition: 0.1% NH3HO IPA); start B: 45; end B: 45) to give 8 (50 mg, 12%) and 9 (40 mg, 9.6%).

[0565] 8: 1 H NMR (400 MHz, CDCl3) δ 7.99-7.79 (m, 2H), 5.19-5.02 (m, 1H), 2.52-2.43 (m, 1H), 2.24-2.15 (m, 1H), 1.94-1.68 (m, 8H), 1.65-1.57 (m, 6H), 1.54-1.26 (m, 10H), 1.14-0.94 (m, 7H), 0.53 (s, 3H) LC-ELSD / MS: Purity ≧99%, C 27 H 38 MS ESI calculated value for NO [M-HO+H] + 454.3, actual value 454.3.

[0566] 9: 1 H NMR (400 MHz, CDCl3) δ 7.99-7.77 (m, 2H), 5.18-5.03 (m, 1H), 2.50-2.37 (m, 1H), 2.24-2.13(m, 1H), 1.93-1.58 (m, 12H), 1.50-1.23 (m, 12H), 1.15-0.94 (m, 7H), 0.52 (s, 3H).

[0567] Examples 10 and 11: Synthesis of 1-((S)-3-((3R,5R,8R,9R,10S,13S,14S,17R)-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-oxobutyl)-1H-pyrazole-4-carbonitrile (10) and 1-((R)-3-((3R,5R,8R,9R,10S,13S,14S,17R)-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-oxobutyl)-1H-pyrazole-4-carbonitrile (11) [ka]

[0568] 10.1 Synthesis

[0569] To a mixture of PPhEtBr (15.6 g, 42.3 mmol) in THF (65 mL) was added t-BuOK (4.74 g, 42.3 mmol) at 25 °C under N. The resulting mixture was stirred at 40 °C for 1 h. 10.0 (4.5 g, 14.1 mmol) in THF (5 mL) was added portionwise below 50 °C. After stirring at 40 °C for 12 h, the reaction mixture was poured into water (100 mL) at 25 °C. The aqueous phase was extracted with EtOAc (2 × 100 mL), and the organic layer was washed with water (100 mL), brine (100 mL), dried over NaSO, filtered, concentrated in vacuo, and the residue was purified by silica gel chromatography (0–10% EtOAc in PE) to give 10.1 (4.0 g, 86%).

[0570] 1 H NMR (400 MHz, CDCl3) δ H 5.47-5.21 (m, 1H), 2.04-1.97 (m, 1H), 1.90-1.72 (m, 5H), 1.71-1.61 (m, 4H), 1.61-1.53 ​​(m, 6H), 1.49-1.34 (m, 6H), 1.33-1.27 (m, 2H), 1.26 (s, 4H), 1.22-0.98 (m, 6H), 0.71-0.50 (m, 3H).

[0571] 10.2 Synthesis

[0572] To a solution of 10.1 (4.0 g, 12.1 mmol) in THF (80 mL) was added BH3.Me2S (3.63 mL, 36.3 mmol, 10 M), and the reaction mixture was stirred at 15 °C for 20 h. To the resulting mixture was added ethanol (6.27 mL, 108 mmol) at 15 °C, followed by aqueous NaOH (21.6 mL, 5.0 M, 108 mmol) at 0 °C. Hydrogen peroxide (10.8 mL, 10 M, 108 mmol) was added dropwise at 0 °C, and the reaction mixture was stirred at 70 °C for 1 h. The mixture was cooled to 15 °C, and Na2S2O3 (100 mL, saturated aqueous solution) was added. The aqueous phase was extracted with EtOAc (2 × 100 mL), and the combined organic phase was washed with saturated brine (2 × 100 mL), dried over anhydrous Na2SO4, and filtered to give 10.2 (2.8 g).

[0573] 1 H NMR (400 MHz, CDCl3) δ H 4.13-4.05 (m, 1H), 3.95-3.86 (m, 1H), 2.00-1.90 (m, 1H), 1.72-1.54 (m, 7H), 1.48-1.34 (m, 9H), 1.25 (s, 6H), 1.06-1.00 (m, 8H), 0.91-0.89 (m, 2H), 0.85-0.81 (m, 2H), 0.69-0.67 (m, 3H).

[0574] 10.3 Synthesis

[0575] To a solution of 10.2 (4.6 g, 13.1 mmol) in DCM (50 mL) was added Dess-Martin (11.1 g, 26.2 mmol) at 25 °C. After stirring at 25 °C for 5 min, the mixture was quenched with saturated aqueous NaHCO (50 mL), and the DCM phase was separated and washed with saturated aqueous NaHCO / NaSO (1:1, 2 × 50 mL), brine (50 mL), dried over anhydrous NaSO, filtered, and concentrated. The residue was purified by flash column (0-30% EtOAc in PE) to give 10.3 (2.7 g, 60%).

[0576] 10.4 Synthesis

[0577] To a solution of 10.3 (2.7 g, 7.79 mmol) in MeOH (30 mL) was added HBr (310 mg, 1.55 mmol, 40%) and Br (1.36 g, 8.56 mmol) dropwise at 25 °C, and the reaction mixture was stirred for 4 h. To the mixture was added NaHCO (50 ml, saturated aqueous solution) at 25 °C, and the aqueous phase was extracted with EtOAc (2 × 50 mL). The combined organic phase was washed with saturated brine (2 × 50 mL), dried over anhydrous NaSO, filtered, and concentrated to give 10.4 (3.2 g).

[0578] 1 H NMR (400 MHz, CDCl3) δ H 4.07 (d, 1H), 3.96 (s, 1H), 2.90-2.70 (m, 1H), 1.90-1.76 (m, 4H), 1.74-1.54 (m, 6H), 1.49-1.30 (m, 8H), 1.26-1.24 (m, 4H), 1.17 (d, 2H), 1.13-1.08 (m, 3H), 1.08-0.84 (m, 4H) , 0.72-0.64 (m, 3H).

[0579] 10.5 Synthesis

[0580] To a solution of 10.4 (3.2 g, 7.52 mmol) in acetone (50 mL) was added 1H-pyrazole-4-carbonitrile (769 mg, 8.27 mmol) and K2CO3 (3.10 mg, 22.5 mmol). After stirring at 25 °C for 4 h, a light yellow solution was observed. The mixture was diluted with water (50 mL) and extracted with EtOAc (2 × 20 mL). The combined organic phases were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by flash column (0-30% EtOAc in PE) to give 10.5 (2.4 g, 72.9%).

[0581] 1 H NMR (400 MHz, CDCl3) δH 7.87-7.85 (m, 1H), 7.81 (s, 1H), 5.15-4.92 (m, 2H), 2.66-2.53 (m, 1H), 1.95-1.76 (m, 5H), 1.72-1.57 (m, 6H), 1.51-1.31 (m, 8H), 1.26-1.25 (m, 3H), 1.23-1.19 (m, 2H), 1.16-1.13 (m, 2H), 1.11-0.90 (m, 5H), 0.71-0.65 (m, 3H).

[0582] Synthesis of 10 and 11

[0583] 10.5 (2.4 g, 5.48 mmol) was purified by SFC (column: DAICEL CHIRALCEL OD-H (250 mm * 30 mm, 5 um)); mobile phase: A:CO B:0.1% NH HO EtOH; gradient: 30% to B 30%, flow rate (ml / min): 50) to give 10 (1.05 g, 43.9%) and 11 (1.08 g, 45.1%).

[0584] 10: 1 H NMR (400 MHz, CDCl3) δ H 7.85 (s, 1H), 7.82 (s, 1H), 5.10-5.05 (m, 1H), 4.97-4.92 (m, 1H), 2.66-2.56 (m, 1H), 1.93-1.88 (m, 1H), 1.87-1.61 (m, 9H), 1.56-1.35 (m, 9H), 1.26 (s, 3H), 1.21 (d, 3H), 1.16-1.03 (m, 6H), 0.70 (s, 3H). LC-ELSD / MS: Purity >99%;C 27 H 39 MS ESI calculated value for N3O2 [M-H2O+H] + 420.3, actual value 420.3.

[0585] 11: 1 H NMR (400 MHz, CDCl3) δH 7.86 (s, 1H), 7.82 (s, 1H), 5.17-5.02 (m, 2H), 2.65-2.55 (m, 1H), 1.94-1.76 (m, 5H), 1.71-1.44 (m, 11H), 1.41-1.29 (m, 7H), 1.15 (d, 3H), 1.10-0.94 (m, 5H), 0.68 (s, 3H). LC-ELSD / MS: Purity >99%;C 27 H 39 MS ESI calculated value for N3O2 [M-H2O+H] + 420.3, actual value 420.3.

[0586] Example 12: Synthesis of 4-(2-((3R,5R,8R,9R,10S,13R,14S,17R)-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)acetyl)benzonitrile (12) [ka]

[0587] 12.1 Synthesis

[0588] To a solution of 5.2 (10 g, 27.5 mmol) and 2,6-lutidine (7.35 g, 68.7 mmol) in DCM (100 mL) was added TBSOTf (14.5 g, 55.0 mmol) at 0 °C. After stirring at 40 °C for 16 h, the mixture was diluted with DCM (50 mL) and washed with water (100 mL). The organic phase was separated, dried over Na2SO4, filtered, and concentrated. The crude product was purified by flash column (0-20% EtOAc in PE) to give product 12.1 (8 g, 61%).

[0589] 1 H NMR (400 MHz, CDCl3) δ 4.15-4.10 (m, 2H), 2.43-2.32 (m, 1H), 2.22-2.00 (m, 1H), 1.98-1.53 ​​(m, 9H), 1.48-1.25 (m, 3H), 1.24-1.19 (m, 12H), 1.16-0.98 (m, 6H), 0.86 (s, 9H), 0.59 (s, 3H), 0.07 (m, 6H).

[0590] 12.2 Synthesis

[0591] To a suspension of 12.1 (7.0 g, 14.6 mmol) and MeNHOMe.HCl (2.13 g, 21.9 mmol) in THF (70 mL) was added i-PrMgCl (2 M in THF, 29.2 mL, 58.4 mmol) at 0 °C under N. After stirring at 20 °C for 10 min, NHCl (10% aqueous solution, 70 mL) was added. The aqueous layer was extracted with DCM (2 × 50 mL) and the combined organic layers were washed with saturated brine (50 mL), dried over NaSO, filtered, and concentrated in vacuo to give 12.2 (7.7 g).

[0592] 1 H NMR (400 MHz, CDCl3) δ 3.68 (s, 3 H), 3.17 (s, 3 H), 2.44-2.54 (m, 1 H), 2.16-2.27 (m, 1 H), 1.56-1.98 (m, 11 H), 1.29-1.44 (m, 6 H), 1.22 (s, 3 H), 0.95-1.18 (m, 7 H), 0.86 (s, 9 H) 0.62 (s, 3 H), 0.07 (s, 6 H).

[0593] 12.3 Synthesis

[0594] To i-PrMgCl.LiCl (3.03 ml, 3.94 mmol, 1.3 M) was added 4-bromobenzonitrile (919 mg, 5.05 mmol) in THF (5 mL) slowly at 0 °C under N2. After stirring at 20 °C for 2 h, a yellow solution was observed. A solution of 12.2 (500 mg, 1.01 mmol) in THF (5 mL) was added dropwise. The mixture was stirred at -75 °C for 1 h, followed by 20 °C for 1 h. The mixture was added to saturated NH4Cl (30 mL), and the aqueous layer was extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with saturated brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by flash column (0-15% EtOAc in PE) and then triturated from MeOH / H2O (8 ml / 2 ml) at 20°C to give 12.3 (400 mg, 74%).

[0595] 1 H NMR (400 MHz, CDCl3) δ 8.02 (d, 2 H) 7.76 (d, 2H) 3.08 (dd, 3.20 Hz, 1 H) 2.74 (dd, 9.20 Hz, 1 H) 1.58-1.99 (m, 9 H) 1.23-1.47 (m, 9 H) 1.22 (s, 3 H) 0.99-1.17 (m, 6 H) 0.85 (s, 9 H) 0.68 (s, 3 H) 0.07 (s, 6 H)

[0596] Synthesis of 12

[0597] To a mixture of 12.3 (50 mg, 0...

Claims

[Claim 1] The invention described in the specification.

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