Neurostimulatory steroid and method of using the same

Abstract

To provide a neurostimulatory steroid and a method of using the same.SOLUTION: Provided is a compound of formula (I-1) or a pharmaceutically acceptable salt thereof. (R3a denotes methyl; R18 denotes methyl or ethyl; R19 denotes hydrogen, methyl or ethyl; RY denotes methyl or cyano; each RD denotes hydrogen; other groups R denote hydrogen; q denotes an integer of 0 to 5; R55a and R55b form pyrazole together with intervening atoms).SELECTED DRAWING: None

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Application No. 62 / 775,470, filed December 5, 2018, the entire contents of which are incorporated herein by reference. [Background technology]

[0002] 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.

[0003] 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.

[0004] 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.

[0005] 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]

[0006] [Non-Patent Document 1] Lan, NC et al., Neurochem. Res. (1991) 16:347-356 [Non-patent document 2] Majewska, MD et 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]

[0007] 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.

[0008] In one embodiment, a compound of formula (I): [ka] [In formula: [ka] represents a single or double bond, and if a double bond is present, R 6a or R 6b If one of the two does not exist, R 5 does not exist; L is [ka] wherein A represents the point of attachment to C17; X is -C(O)N(R 55a )(R 55b ), -N(R 55a )(R 55b ), -N(R 55b )C(O)(R 55a ), and R 55c selected from the group consisting of: R Y are each independently hydrogen, cyano, haloalkyl, or unsubstituted alkyl; R 55c is a carbon-bonded substituted or unsubstituted heteroaryl or substituted or unsubstituted aryl; R 55a and R 55b each independently represents 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 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 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, oxygen protecting group (when oxygen is attached), nitrogen protecting group (when nitrogen is attached), 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; Alternatively, R 55a and R 55bmay, together with the intervening atoms, form a substituted or unsubstituted heterocyclyl or a 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 , and R 12b 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)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)2ORA1 , -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 11a and R 11b are linked to form an oxo (=O) group; R 3a 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; R 5 is hydrogen or substituted or unsubstituted alkyl; R 6a and R 6b each is hydrogen, halogen, cyano, —NO, —OH, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl, or R 6a and R 6b are linked to form an oxo (=O) group; R Dare 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 R C3each 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, 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); R 18 is substituted or unsubstituted alkyl; R 19 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl; q is an integer from 0 to 5; However, the compound [ka] or a pharmaceutically acceptable salt thereof] or a pharmaceutically acceptable salt thereof.

[0009] In some embodiments, the compound has formula (II): [ka] [In the formula, R 15a , R 15b , 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, or 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 R C3 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, an oxygen protecting group (when oxygen is attached), a nitrogen protecting group (when nitrogen is attached), a sulfur protecting group (when sulfur is attached), or 15a and R 15b are linked to form an oxo (=O) group, or R 16a and R 16b are linked to form an oxo (=O) group] or a pharmaceutically acceptable salt thereof.

[0010] In some embodiments, the compound has formula (Ia): [ka] or a pharmaceutically acceptable salt thereof.

[0011] In some embodiments, the compound has formula (I-Ia): [ka] or a pharmaceutically acceptable salt thereof.

[0012] In some embodiments, the compound has formula (Ib), (Ic), (Id), (Ie), (Il), (Im), (In), or (Ip): [ka] [ka] or a pharmaceutically acceptable salt thereof.

[0013] In some embodiments, the compound has formula (If), (Ig), or (Ih): [ka] or a pharmaceutically acceptable salt thereof.

[0014] In some embodiments, the compound has formula (Ii), (Ij), or (Ik): [ka] [ka] or a pharmaceutically acceptable salt thereof.

[0015] In some embodiments, the compound has the formula (Io): [ka] or a pharmaceutically acceptable salt thereof.

[0016] In some embodiments, the compound has formula (I-qq), (Iq), (Is), (It), or (Iu): [ka] [ka] [In the formula, Q, Q', and Q'' are each independently CR w or N; R w is hydrogen, cyano, —NH2, or substituted or unsubstituted alkyl; At least one of Q, Q', and Q'' is CR w is] or a pharmaceutically acceptable salt thereof.

[0017] In some embodiments, the compound has the formula (Ir): [ka] [In the formula, k is an integer 1 or 2; R z is a substituted or unsubstituted alkyl or substituted or unsubstituted aryl, or two R on adjacent carbons z is attached to an intervening atom to form a substituted or unsubstituted aryl; j is an integer between 0 and 6. or a pharmaceutically acceptable salt thereof.

[0018] In some embodiments, the compound has formula (Iv), (Iw), or (Ix): [ka] [ka] or a pharmaceutically acceptable salt thereof.

[0019] In some embodiments, the compound has formula (I-Ib), (I-Ic), (I-Id), (I-Ie), (I-Il), (I-Im), (I-In), (I-Ip1), or (I-Ip2): [ka] [ka] or a pharmaceutically acceptable salt thereof.

[0020] In some embodiments, the compound has formula (I-If), (I-Ig), or (I-Ih): [ka] or a pharmaceutically acceptable salt thereof.

[0021] In some embodiments, the compound has formula (I-Ii), (I-Ij), or (I-Ik): [ka] or a pharmaceutically acceptable salt thereof.

[0022] In some embodiments, the compound has formula (I-Io1) or (I-Io2): [ka] or a pharmaceutically acceptable salt thereof.

[0023] In some embodiments, the compound has formula (I-Iqq), (I-Iq1), (I-Iq2), (I-It1), (I-It2), (I-Iu1), or (I-Iu2): [ka] [ka] [In the formula, Q, Q', and Q'' are each independently CR w or N; R w is hydrogen, cyano, —NH2, or substituted or unsubstituted alkyl; At least one of Q, Q', and Q'' is CR w is] or a pharmaceutically acceptable salt thereof.

[0024] In some embodiments, the compound has formula (I-Irr), (I-Ir1), or (I-Ir2): [ka] [ka] [In the formula, k is an integer 1 or 2; R z is a substituted or unsubstituted alkyl or substituted or unsubstituted aryl, or two R on adjacent carbons z is attached to an intervening atom to form a substituted or unsubstituted aryl; j is an integer between 0 and 6. or a pharmaceutically acceptable salt thereof.

[0025] In some embodiments, the compound has formula (I-Ir3) or (I-Ir4): [ka] wherein k is an integer 1 or 2; R z’ is substituted or unsubstituted alkyl or cyano; j' is an integer between 0 and 4. or a pharmaceutically acceptable salt thereof.

[0026] In some embodiments, the compound has formula (I-Iw1), (I-Iw2), (I-Ix1), or (I-Ix2): [ka] [ka] or a pharmaceutically acceptable salt thereof.

[0027] In some embodiments, the compound is selected from the group consisting of the compounds identified in Table 1 herein.

[0028] The compounds of the invention described herein may, in certain embodiments, be GABA A In certain embodiments, the compounds described herein act as receptor modulators at GABA receptors, e.g., GABA A It can act as a positive allosteric modulator of the receptor.

[0029] In one embodiment, the compounds described herein (e.g., compounds of Formula I or Table 1) are GABA A Compared to the α1β2γ2 structure of the GABA receptor, A It exhibits high selectivity for modulating the α4β3δ structure of the receptor.

[0030] 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. In certain embodiments, the compound of the invention is provided in a prophylactically effective amount.

[0031] In one aspect, provided herein are pharmaceutically acceptable salts of the compounds described herein (eg, compounds of Formula (I)).

[0032] 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.

[0033] The compounds of the invention described herein may, in certain embodiments, be used to treat, for example, GABA A These compounds act as GABA receptor modulators, affecting the GABA receptor in either a positive or negative way. A They are predicted to have central nervous system (CNS) activity as modulators of CNS excitability as mediated by their ability to modulate receptors.

[0034] In one aspect, there is provided a method of treating a CNS-related disorder in a subject in need thereof, comprising administering to the subject an effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof.

[0035] In some embodiments, the CNS-related disorder is a sleep disorder, a mood disorder, a schizophrenia spectrum disorder, a seizure disorder, 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, tinnitus, or status epilepticus.

[0036] 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. DETAILED DESCRIPTION OF THE INVENTION

[0037] Detailed Description of Certain Embodiments of the Invention 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).

[0038] definition chemical definition The definitions of specific functional groups and chemical terms are explained in detail below. Chemical elements are listed in the Periodic Table of Elements (CAS system, 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 th Edition, 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.

[0039] 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.

[0040] "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."

[0041] 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.

[0042] 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).

[0043] 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.

[0044] 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.

[0045] 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.

[0046] 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.

[0047] "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 1-7 In 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 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 1-6Examples 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)).

[0048] "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.

[0049] "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 ("C 2-8In 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, the alkenyl group has 2 to 3 carbon atoms ("C 2-3 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.

[0050] "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.

[0051] 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 In some embodiments, a heteroalkyl group refers to 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.

[0052] "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.

[0053] In certain embodiments, the aryl group is substituted with one or more groups selected from halogen, C1-C8 alkyl, C1-C8 haloalkyl, cyano, hydroxy, C1-C8 alkoxy, and amino.

[0054] 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 each independently represents C1-C8 alkyl, C1-C8 haloalkyl, 4- to 10-membered heterocyclyl, alkanoyl, C1-C8 alkoxy, heteroaryloxy, alkylamino, arylamino, heteroarylamino, NR 58 COR 59 , N.R. 58 SOR 59 NR 58 SO2R 59 , COO alkyl, COO aryl, CONR 58 R 59 ,CONR 58 OR 59 , N.R. 58 R 59 , SO2NR 58 R 59 , S-alkyl, SO alkyl, SO alkyl, S aryl, SO aryl, SO 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, C1-C8 alkyl, C1-C4 haloalkyl, C3-C 10 Cycloalkyl, 4-10 membered heterocyclyl, C6-C 10 Aryl, substituted C6-C 10 It is aryl, 5- to 10-membered heteroaryl, or substituted 5- to 10-membered heteroaryl.

[0055] "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.

[0056] "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 with 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 ring bearing a heteroatom (e.g., 2-indolyl) or on the ring without a heteroatom (e.g., 5-indolyl).

[0057] In some embodiments, heteroaryl groups are 5- to 10-membered aromatic ring systems having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, each heteroatom being 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 provided in the aromatic ring system, each heteroatom being 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 ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, each heteroatom being 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 selected from nitrogen, oxygen, and sulfur. In some embodiments, 5- to 6-membered heteroaryls have 1-2 ring heteroatoms 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.

[0058] 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.

[0059] 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-C8 alkyl, C3-C 10 Cycloalkyl, 4-10 membered heterocyclyl, C6-C 10 aryl, and 5- to 10-membered heteroaryl.

[0060] "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")), and can be saturated or partially unsaturated. "Carbocyclyl" also includes ring systems in which a carbocyclyl ring, as defined above, is fused to 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 represent the number of carbons in the carbocyclyl ring system. Unless otherwise specified, each occurrence of a carbocyclyl group is independently 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.

[0061] 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.

[0062] "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.

[0063] In some embodiments, a heterocyclyl group is a 5- to 10-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, each 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 to 4 ring heteroatoms, each 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 to 4 ring heteroatoms, each independently selected from nitrogen, oxygen, and sulfur (a "5- to 6-membered heterocyclyl"). In some embodiments, a 5- to 6-membered heterocyclyl has 1 to 3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5- to 6-membered heterocyclyl has 1 to 2 ring heteroatoms selected from nitrogen, oxygen, and sulfur, hi some embodiments, the 5- to 6-membered heterocyclyl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur.

[0064] 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.

[0065] 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.

[0066] "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.

[0067] "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" refers to a group in which R 20 is an acyl group where the aryl group 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), -C(O)-C1 to C8 alkyl, -C(O)-(CH2) t (C6~C 10 aryl), -C(O)-(CH2)t (5-10 membered heteroaryl), -C(O)-(CH2)t(C3-C 10 cycloalkyl), and -C(O)-(CH2) t (4-10 membered heterocyclyl) (t is an integer from 0 to 4). 21 is C1-C8 alkyl substituted with halogen or hydroxy; or C3-C 10 Cycloalkyl, 4-10 membered heterocyclyl, C6-C 10 Aryl, arylalkyl, 5-10 membered heteroaryl, or heteroarylalkyl (each of which is substituted with unsubstituted C1-C4 alkyl, halogen, unsubstituted C1-C4 alkoxy, unsubstituted C1-C4 haloalkyl, unsubstituted C1-C4 hydroxyalkyl, or unsubstituted C1-C4 haloalkoxy or hydroxy).

[0068] "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.

[0069] In certain embodiments, R 29 is amino, substituted amino, C6-C 10 Aryl, aryloxy, carboxyl, cyano, C3-C 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 (C6~C 10 aryl), -O-(CH2) t (5-10 membered heteroaryl), -O-(CH2) t (C3~C 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 may itself be substituted with unsubstituted C1-C4 alkyl, halogen, unsubstituted C1-C4 alkoxy, unsubstituted C1-C4 haloalkyl, unsubstituted C1-C4 hydroxyalkyl, or unsubstituted C1-C4 haloalkoxy or hydroxy. Particularly exemplary "substituted alkoxy" groups are -OCF3, -OCH2CF3, -OCH2Ph, -OCH2-cyclopropyl, -OCH2CH2OH, and -OCH2CH2NMe2.

[0070] "Amino" refers to the -NH2 radical.

[0071] An "oxo group" refers to -C(=O)-.

[0072] "Substituted amino" refers to a group of the formula -N(R 38 )2, and R 38 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, substituted or unsubstituted heteroaryl, or an amino protecting group; R 38At least one of R is not hydrogen. 38 are independently hydrogen, C1-C8 alkyl, C3-C8 alkenyl, C3-C8 alkynyl, C6-C 10 Aryl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocyclyl, or C3-C 10 Cycloalkyl; or C1-C8 alkyl substituted with halogen or hydroxy; C3-C8 alkenyl substituted with halogen or hydroxy; C3-C8 alkynyl substituted with halogen or hydroxy, or -(CH2) t (C6~C 10 aryl), -(CH2) t (5-10 membered heteroaryl), -(CH2) t (C3~C 10 cycloalkyl), or -(CH2) t (4-10 membered heterocyclyl) (where t is an integer from 0 to 8), each of which is substituted with unsubstituted C1-C4 alkyl, halogen, unsubstituted C1-C4 alkoxy, unsubstituted C1-C4 haloalkyl, unsubstituted C1-C4 hydroxyalkyl, or unsubstituted C1-C4 haloalkoxy, or hydroxy; or both R 38 The groups are linked to form an alkylene group.

[0073] 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 (C3~C 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 39independently represent H or C1-C8 alkyl; any alkyl group present may itself be substituted with halogen, substituted or unsubstituted amino, or hydroxy, and any aryl, heteroaryl, cycloalkyl, or heterocyclyl group present may itself be substituted with unsubstituted C1-C4 alkyl, halogen, unsubstituted C1-C4 alkoxy, unsubstituted C1-C4 haloalkyl, unsubstituted C1-C4 hydroxyalkyl, or unsubstituted C1-C4 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.

[0074] "Carboxy" refers to the -C(O)OH radical.

[0075] "Cyano" refers to the -CN radical.

[0076] "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.

[0077] "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.

[0078] "Hydroxy" refers to the -OH radical.

[0079] "Nitro" refers to the -NO2 radical.

[0080] "Thioketo" refers to the group =S.

[0081] 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 on 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, and when more than one position in any given structure is substituted, the substituents may be 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.

[0082] 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, -SRaa 、-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(R bb )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)Raa , -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 1-10Alkyl, 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 aa 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 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 bbgroups 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, 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 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(=NRff ) 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, -NR ff 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, C2-6 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)(C1-6 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 1-6 alkyl), -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 1-6Alkyl, -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, C 2-6 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.

[0083] 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.

[0084] 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, glycerate, lactate, tartrate, glycolate, etc.).

[0085] 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.

[0086] Other definitions 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.

[0087] "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).

[0088] "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.

[0089] 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.

[0090] In an alternative embodiment, the present invention provides prodrugs of compounds of formula (I), which include a cleavable moiety at the C3 hydroxy, as shown in formula (I).

[0091] "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.

[0092] "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.

[0093] 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.

[0094] 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).

[0095] 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 Wiley & Sons, 1999.

[0096] In certain embodiments, the substituent present on the nitrogen atom is an amino protecting group (also referred to as a 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(Rcc )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.

[0097] 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)).

[0098] Disease, disorder, and condition are used interchangeably herein.

[0099] 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.

[0100] 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.

[0101] 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.

[0102] 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.

[0103] Alternative Embodiments 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.

[0104] compound 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.

[0105] In one embodiment, a compound of formula (I): [ka] [In the formula, [ka] represents a single or double bond, and if a double bond is present, R 6a or R 6b If one of the two does not exist, R 5 does not exist; L is [ka] wherein A represents the point of attachment to C17; X is -C(O)N(R 55a )(R 55b ), -N(R 55a )(R 55b ), -N(R 55b)C(O)(R 55a ), and R 55c selected from the group consisting of: R Y are each independently hydrogen, cyano, haloalkyl, or unsubstituted alkyl; R 55c is a carbon-bonded substituted or unsubstituted heteroaryl or substituted or unsubstituted aryl; R 55a and R 55b each independently represents 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 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(RA1 )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, oxygen protecting group (when oxygen is attached), nitrogen protecting group (when nitrogen is attached), sulfur protecting group (when sulfur is attached), or two R A1 whether the groups, together with the intervening atoms, form a substituted or unsubstituted heterocyclic ring; Alternatively, R 55a and R 55b may, together with the intervening atoms, form a substituted or unsubstituted heterocyclyl or a 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 , and R 12b 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)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 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 11a and R 11b are linked to form an oxo (=O) group; R 12a and R 12b are linked to form an oxo (=O) group; R 4a and R4b are linked to form an oxo (=O) group; R 7a and R 7b are linked to form an oxo (=O) group; R 2a and R 2b are linked to form an oxo (=O) group; R 1a and R 1b are linked to form an oxo (=O) group; R 3a 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; R 5 is hydrogen or substituted or unsubstituted alkyl; R 6a and R 6b each is hydrogen, halogen, cyano, —NO, —OH, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl, or R 6a and R 6b are linked to form an oxo (=O) group; 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 R C3 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, 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); R 18 is substituted or unsubstituted alkyl; R 19 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl; q is an integer from 0 to 5; However, the compound [ka] or a pharmaceutically acceptable salt thereof] or a pharmaceutically acceptable salt thereof.

[0106] In some embodiments, the compound has formula (II): [ka] [In the formula, R 15a , R 15b , 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, or 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)2ORC3 , -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 R C3 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, an oxygen protecting group (when oxygen is attached), a nitrogen protecting group (when nitrogen is attached), a sulfur protecting group (when sulfur is attached), or 15a and R 15b are linked to form an oxo (=O) group, or R 16a and R 16b are linked to form an oxo (=O) group] or a pharmaceutically acceptable salt thereof.

[0107] In some embodiments, the compound has formula (Ia): [ka] or a pharmaceutically acceptable salt thereof.

[0108] In some embodiments, the compound has formula (I-Ia): [ka] or a pharmaceutically acceptable salt thereof.

[0109] R 55a Groups and R 55b basis In some embodiments, R 55a is hydrogen or methyl, and R 55bis 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.

[0110] In some embodiments, R 55a and R 55b are 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, or substituted or unsubstituted heteroaryl.

[0111] In some embodiments, R 55a and R 55b are each independently hydrogen, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0112] In some embodiments, R 55a and R 55b are each independently substituted carbocyclyl, substituted heterocyclyl, substituted aryl, or substituted heteroaryl.

[0113] In some embodiments, at least R 55a or R 55b But other than hydrogen.

[0114] In some embodiments, R 55a and R 55b each independently represents hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, [ka] [ka] and; During the ceremony, R a Each occurrence of is independently hydrogen, halogen, -NO2, -CN, -OR D4 , -N(R D4 )2, -C(=O)R D4 , -C(=O)OR D4 , -C(=O)N(R D4 )2, -OC(=O)R D4 , -OC(=O)OR D4 , -N(R D4 )C(=O)R D4 , -OC(=O)N(R D4 )2, -N(R D4 )C(=O)OR D4 , -S(=O)2R D4 , -S(=O)2OR D4 , -OS(=O)2R D4 , -S(=O)2N(R D4 )2, or -N(R D4 )S(=O)2R D4 , 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 5-10 membered heteroaryl; R D4 Each occurrence of 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 D4 the groups together with the intervening atoms form a substituted or unsubstituted heterocyclic ring; p is an integer selected from 0 to 11.

[0115] In some embodiments, R 55a and R 55b each independently represents hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, [ka] [ka] and; During the ceremony, R a Each occurrence of is independently hydrogen, halogen, -NO2, -CN, -OR D4 , -N(R D4 )2, -C(=O)R D4 , -C(=O)OR D4 , -C(=O)N(R D4 )2, -OC(=O)R D4 , -OC(=O)OR D4 , -N(R D4 )C(=O)R D4 , -OC(=O)N(R D4 )2, -N(R D4 )C(=O)OR D4 , -S(=O)2R D4 , -S(=O)2OR D4 , -OS(=O)2R D4 , -S(=O)2N(R D4 )2, or -N(R D4 )S(=O)2R D4 , 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 5-10 membered heteroaryl; R D4 Each occurrence of is independently hydrogen, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 2-6Alkenyl, 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 D4 the groups together with the intervening atoms form a substituted or unsubstituted heterocyclic ring; p is an integer selected from 0 to 3.

[0116] In some embodiments, R 55a and R 55b are each independently hydrogen, substituted or unsubstituted alkyl, [ka] and; During the ceremony, R a Each occurrence of is independently hydrogen, halogen, -NO2, -CN, -OR D4 , -N(R D4 )2, -C(=O)R D4 , -C(=O)OR D4 , -C(=O)N(R D4 )2, -OC(=O)R D4 , -OC(=O)OR D4 , -N(R D4 )C(=O)R D4 , -OC(=O)N(R D4 )2, -N(R D4 )C(=O)OR D4 , -S(=O)2R D4 , -S(=O)2OR D4 , -OS(=O)2R D4 , -S(=O)2N(R D4 )2, or -N(R D4 )S(=O)2R D4 , 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 3-6Carbocyclyl, substituted or unsubstituted 3- to 6-membered heterocyclyl, substituted or unsubstituted C 5-10 aryl, substituted or unsubstituted 5-10 membered heteroaryl; R D4 Each occurrence of 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 D4 the groups together with the intervening atoms form a substituted or unsubstituted heterocyclic ring; p is an integer selected from 0 to 5.

[0117] In some embodiments, R 55a and R 55b are independently hydrogen, substituted or unsubstituted alkyl, [ka] and; During the ceremony, R a Each occurrence of is independently hydrogen, halogen, -CN, -OR D4 , -N(R D4 )2, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted 3- to 6-membered heterocyclyl, substituted or unsubstituted 5- to 10-membered heteroaryl; R D4 Each occurrence of is independently hydrogen, or substituted or unsubstituted C 1-6 is alkyl; p is an integer selected from 0 to 2.

[0118] In some embodiments, R ais a substituted 3- to 6-membered heterocyclyl or a substituted 5- to 10-membered heteroaryl, the 3- to 6-membered heterocyclyl or the 5- to 10-membered heteroaryl is preferably C 1-6 substituted with one or more of alkyl, cyano, or oxo. For example, in certain embodiments, R a is C 1-6 5- to 6-membered heterocyclyl substituted with one or more of alkyl, cyano, or oxo, or C 1-6 It is a 5- to 6-membered heteroaryl substituted with one or more of alkyl, cyano, or oxo.

[0119] In some embodiments, R 55a and R 55b taken together with the intervening atoms form a substituted or unsubstituted heterocyclyl or substituted or unsubstituted heteroaryl.

[0120] In some embodiments, R 55a and R 55b together with the intervening atom, [ka] [ka] forming a substituted or unsubstituted heterocyclyl or substituted or unsubstituted heteroaryl selected from the group consisting of During the ceremony, R a Each occurrence of is independently hydrogen, oxo, halogen, -NO2, -CN, -OR D4 , -N(R D4 )2, -C(=O)R D4 , -C(=O)OR D4 , -C(=O)N(R D4 )2, -OC(=O)R D4 , -OC(=O)OR D4 , -N(R D4 )C(=O)R D4 , -OC(=O)N(R D4 )2, -N(R D4 )C(=O)OR D4, -S(=O)2R D4 , -S(=O)2OR D4 , -OS(=O)2R D4 , -S(=O)2N(R D4 )2, or -N(R D4 )S(=O)2R D4 , 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 5-10 membered heteroaryl; R D4 Each occurrence of 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 D4 the groups together with the intervening atoms form a substituted or unsubstituted heterocyclic ring; p is an integer selected from 0 to 10.

[0121] In some embodiments, R 55a and R 55b together with the intervening atom, [ka] forming a substituted or unsubstituted heterocyclyl or substituted or unsubstituted heteroaryl selected from the group consisting of During the ceremony, R a Each occurrence of is independently hydrogen, oxo, halogen, -NO2, -CN, -OR D4 , -N(R D4 )2, -C(=O)RD4 , -C(=O)OR D4 , -C(=O)N(R D4 )2, -OC(=O)R D4 , -OC(=O)OR D4 , -N(R D4 )C(=O)R D4 , -OC(=O)N(R D4 )2, -N(R D4 )C(=O)OR D4 , -S(=O)2R D4 , -S(=O)2OR D4 , -OS(=O)2R D4 , -S(=O)2N(R D4 )2, or -N(R D4 )S(=O)2R D4 , 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 5-10 membered heteroaryl; R D4 Each occurrence of 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 D4 the groups together with the intervening atoms form a substituted or unsubstituted heterocyclic ring; p is an integer selected from 0 to 10.

[0122] In some embodiments, R 55a and R 55b together with the intervening atom, [ka] forming a substituted or unsubstituted heterocyclyl or substituted or unsubstituted heteroaryl selected from the group consisting of During the ceremony, R a Each occurrence of is independently hydrogen, oxo, halogen, —CN, —OR D4 , -N(R D4 )2, or substituted or unsubstituted C 1-6 is alkyl; R D4 Each occurrence of is independently hydrogen, or substituted or unsubstituted C 1-6 is alkyl; p is an integer selected from 0 to 2.

[0123] R 1a Groups and R 1b basis In some embodiments, R 1a and R 1b are 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.

[0124] 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.

[0125] 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.

[0126] In some embodiments, R 1a and R1b are each independently [ka] [ka] selected from the group consisting of: During the ceremony, R a Each occurrence of is independently hydrogen, halogen, -NO2, -CN, -OR D4 , -N(R D4 )2, -C(=O)R D4 , -C(=O)OR D4 , -C(=O)N(R D4 )2, -OC(=O)R D4 , -OC(=O)OR D4 , -N(R D4 )C(=O)R D4 , -OC(=O)N(R D4 )2, -N(R D4 )C(=O)OR D4 , -S(=O)2R D4 , -S(=O)2OR D4 , -OS(=O)2R D4 , -S(=O)2N(R D4 )2, or -N(R D4 )S(=O)2R D4 , 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 5-10 membered heteroaryl; R D4 Each occurrence of 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 C5-10 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 D4 the groups together with the intervening atoms form a substituted or unsubstituted heterocyclic ring; p is an integer selected from 0 to 11.

[0127] In some embodiments, R 1a and R 1b are each independently [ka] selected from the group consisting of: During the ceremony, R a Each occurrence of is independently hydrogen, halogen, -NO2, -CN, -OR D4 , -N(R D4 )2, -C(=O)R D4 , -C(=O)OR D4 , -C(=O)N(R D4 )2, -OC(=O)R D4 , -OC(=O)OR D4 , -N(R D4 )C(=O)R D4 , -OC(=O)N(R D4 )2, -N(R D4 )C(=O)OR D4 , -S(=O)2R D4 , -S(=O)2OR D4 , -OS(=O)2R D4 , -S(=O)2N(R D4 )2, or -N(R D4 )S(=O)2R D4 , 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 5-10 membered heteroaryl; R D4Each occurrence of 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 D4 the groups together with the intervening atoms form a substituted or unsubstituted heterocyclic ring; p is an integer selected from 0 to 11.

[0128] In some embodiments, R 1a and R 1b are both hydrogen.

[0129] R 2a Groups and R 2b base 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 E5 , -OC(=O)R E5 , -OS(=O)2OR E5 , -N(R E5 )2, or -N(R E5 )C(=O)R E5 , -N(R E5 )S(=O)2R E5 , -N(R E5 )S(=O)2OR E5 where R E5 each occurrence of 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 E5The groups together with the intervening atoms form a substituted or unsubstituted heterocyclic ring.

[0130] In some embodiments, R 2a and R 2b are each independently hydrogen, halogen, -CN, -NO2, -OR F6 , -OC(=O)R F6 , -N(R F6 )2, or -N(R F6 )C(=O)R F6 where R F6 Each occurrence of 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 F6 The groups together with the intervening atoms form a substituted or unsubstituted heterocyclic ring.

[0131] In some embodiments, R 2a and R 2b are independently hydrogen, —OH, or substituted or unsubstituted C 1-6 It is alkyl.

[0132] In some embodiments, R 2a and R 2b each independently represents hydrogen, -OH, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, or C 1-6 It is an alkoxyhalo.

[0133] In some embodiments, R 2a and R 2b are independently -CH3, -CH2CH3, -OH, -OCH3, or -CH(CH3)2.

[0134] In some embodiments, R 2a and R 2b are both hydrogen.

[0135] In some embodiments, R 2aand R 2b are linked to form an oxo (=O) group.

[0136] R 3a base In some embodiments, R 3a is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl.

[0137] In some embodiments, R 3a is hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted carbocyclyl.

[0138] In some embodiments, R 3a is a substituted or unsubstituted carbocyclyl, a substituted or unsubstituted heterocyclyl, a substituted or unsubstituted aryl, or a substituted or unsubstituted heteroaryl.

[0139] In some embodiments, R 3a is substituted or unsubstituted carbocyclyl. In some embodiments, R 3a is cyclopropyl.

[0140] In some embodiments, R 3a is substituted or unsubstituted alkyl, or substituted or unsubstituted carbocyclyl.

[0141] In some embodiments, R 3a is a substituted or unsubstituted C 1-6 It is alkyl.

[0142] In some embodiments, R 3 is substituted alkyl. In some embodiments, R 3a is an unsubstituted alkyl.

[0143] In some embodiments, R 3a is methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl. In some embodiments, R 3ais methyl. In some embodiments, R 3a is ethyl. In some embodiments, R 3a is propyl. In some embodiments, R 3a is n-butyl.

[0144] In some embodiments, R 3a is a substitution C 1-6 It is alkyl.

[0145] In some embodiments, R 3a is -CH2C3H5.

[0146] In some embodiments, R 3a is C 1-6 It is an alkoxy.

[0147] In some embodiments, R 3a is -CH2OCH3, -CH2CH2OCH3, or -CH2CH2CH2OCH3.

[0148] In some embodiments, R 3a is -CH2OCH2CH3, -CH2CH2OCH2CH3, or -CH2CH2CH2OCH2CH3.

[0149] In some embodiments, R 3a is -CH2OCH2CH2CH3, -CH2CH2OCH2CH2CH3, or -CH2CH2CH2OCH2CH2CH3.

[0150] R 4a Groups and R 4b basis 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 E5 , -OC(=O)R E5 , -OS(=O)2OR E5 , -N(RE5 )2, or -N(R E5 )C(=O)R E5 , -N(R E5 )S(=O)2R E5 , -N(R E5 )S(=O)2OR E5 where R E5 each occurrence of 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 E5 The groups together with the intervening atoms form a substituted or unsubstituted heterocyclic ring.

[0151] In some embodiments, R 4a and R 4b are each independently hydrogen, halogen, -CN, -NO2, -OR F6 , -OC(=O)R F6 , -N(R F6 )2, or -N(R F6 )C(=O)R F6 where R F6 Each occurrence of 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 F6 The groups together with the intervening atoms form a substituted or unsubstituted heterocyclic ring.

[0152] In some embodiments, R 4a and R 4b are independently hydrogen, —OH, or substituted or unsubstituted C 1-6 It is alkyl.

[0153] In some embodiments, R 4a and R 4b each independently represents hydrogen, -OH, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, or C1-6 It is an alkoxyhalo.

[0154] In some embodiments, R 4a and R 4b are independently -CH3, -CH2CH3, -OH, -OCH3, or -CH(CH3)2.

[0155] In some embodiments, R 4a and R 4b are both hydrogen.

[0156] In some embodiments, R 4a and R 4b are linked to form an oxo (=O) group.

[0157] R 5 basis In some embodiments, R 5 is R 19 cis position relative to R 19 is a hydrogen or methyl in the trans position relative to

[0158] In some embodiments, R 5 is R 19 cis position relative to 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

[0159] In some embodiments, R 5 is R 19 cis position relative to 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

[0160] R 6a Groups and R 6b basis In some embodiments, R 6a and R 6b is independently hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl.

[0161] In some embodiments, R 6a and R 6b is independently hydrogen or substituted alkyl.

[0162] In some embodiments, R 6a and R 6b is independently hydrogen or unsubstituted alkyl.

[0163] In some embodiments, R 6a is halogen or alkyl, and R 6b is hydrogen.

[0164] In some embodiments, R 6a and R 6b are all halogens.

[0165] In some embodiments, R 6a and R 6b are both unsubstituted alkyl.

[0166] In some embodiments, R 6a is hydrogen and R 6b does not exist.

[0167] R 7a Groups and R 7b basis In some embodiments, R 7a and R 7b are each independently hydrogen, halogen, —CN, —NO2, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, —OR E5, -OC(=O)R E5 , -OS(=O)2OR E5 , -N(R E5 )2, or -N(R E5 )C(=O)R E5 , -N(R E5 )S(=O)2R E5 , -N(R E5 )S(=O)2OR E5 where R E5 each occurrence of 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 E5 The groups together with the intervening atoms form a substituted or unsubstituted heterocyclic ring.

[0168] In some embodiments, R 7a and R 7b are each independently hydrogen, halogen, -CN, -NO2, -OR F6 , -OC(=O)R F6 , -N(R F6 )2, or -N(R F6 )C(=O)R F6 where R F6 Each occurrence of 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 F6 The groups together with the intervening atoms form a substituted or unsubstituted heterocyclic ring.

[0169] In some embodiments, R 7a and R 7b are independently hydrogen, —OH, or substituted or unsubstituted C 1-6 It is alkyl.

[0170] In some embodiments, R 7a and R 7b each independently represents hydrogen, -OH, C 1-6Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, or C 1-6 It is an alkoxyhalo.

[0171] In some embodiments, R 7a and R 7b are independently -CH3, -CH2CH3, -OH, -OCH3, or -CH(CH3)2.

[0172] In some embodiments, R 7a and R 7b are both hydrogen.

[0173] In some embodiments, R 7a and R 7b are linked to form an oxo (=O) group.

[0174] R 11a Groups and R 11b base In some embodiments, R 11a and R 11b are each independently hydrogen, halogen, —CN, —NO2, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, —OR E5 , -OC(=O)R E5 , -OS(=O)2OR E5 , -N(R E5 )2, or -N(R E5 )C(=O)R E5 , -N(R E5 )S(=O)2R E5 , -N(R E5 )S(=O)2OR E5 where R E5 each occurrence of 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 E5 The groups together with the intervening atoms form a substituted or unsubstituted heterocyclic ring.

[0175] In some embodiments, R 11a and R 11b are each independently hydrogen, halogen, -CN, -NO2, -OR F6 , -OC(=O)R F6 , -N(R F6 )2, or -N(R F6 )C(=O)R F6 where R F6 Each occurrence of 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 F6 The groups together with the intervening atoms form a substituted or unsubstituted heterocyclic ring.

[0176] In some embodiments, R 11a and R 11b are independently hydrogen, —OH, or substituted or unsubstituted C 1-6 It is alkyl.

[0177] In some embodiments, R 11a and R 11b each independently represents hydrogen, -OH, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, or C 1-6 It is an alkoxyhalo.

[0178] In some embodiments, R 11a and R 11b are independently hydrogen, —OH, or R 11a and R 11b are linked to form an oxo (=O) group.

[0179] In some embodiments, R 11a and R 11b are independently -CH3, -CH2CH3, -OH, -OCH3, or -CH(CH3)2.

[0180] In some embodiments, R 11a and R 11b are both hydrogen.

[0181] In some embodiments, R 11a and R 11b are linked to form an oxo (=O) group.

[0182] R 12a Groups and R 12b basis In some embodiments, R 12a and R 12b are each independently hydrogen, halogen, —CN, —NO2, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, —OR E5 , -OC(=O)R E5 , -OS(=O)2OR E5 , -N(R E5 )2, or -N(R E5 )C(=O)R E5 , -N(R E5 )S(=O)2R E5 , -N(R E5 )S(=O)2OR E5 where R E5 each occurrence of 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 E5 The groups together with the intervening atoms form a substituted or unsubstituted heterocyclic ring.

[0183] In some embodiments, R 12a and R 12b are each independently hydrogen, halogen, -CN, -NO2, -OR F6 , -OC(=O)R F6 , -N(R F6 )2, or -N(R F6 )C(=O)R F6 where R F6Each occurrence of 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 F6 The groups together with the intervening atoms form a substituted or unsubstituted heterocyclic ring.

[0184] In some embodiments, R 12a and R 12b are independently hydrogen, —OH, or substituted or unsubstituted C 1-6 It is alkyl.

[0185] In some embodiments, R 12a and R 12b each independently represents hydrogen, -OH, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, or C 1-6 It is an alkoxyhalo.

[0186] In some embodiments, R 12a and R 12b are independently -CH3, -CH2CH3, -OH, -OCH3, or -CH(CH3)2.

[0187] In some embodiments, R 12a and R 12b are both hydrogen.

[0188] In some embodiments, R 12a and R 12b are linked to form an oxo (=O) group.

[0189] R 19 basis In some embodiments, R 19 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl.

[0190] In some embodiments, R 19is hydrogen or substituted or unsubstituted alkyl.

[0191] In some embodiments, R 19 is a substituted alkyl.

[0192] In some embodiments, R 19 is a substituted C2-C6 alkyl.

[0193] In some embodiments, R 19 is —CH2OCH3. In some embodiments, R 19 is -CH2OCH2CH3.

[0194] In some embodiments, R 19 is hydrogen or unsubstituted alkyl.

[0195] In some embodiments, R 19 is an unsubstituted alkyl.

[0196] In some embodiments, R 19 is unsubstituted C1-C6 alkyl.

[0197] In some embodiments, R 19 is methyl. In some embodiments, R 19 is ethyl.

[0198] In some embodiments, R 19 is hydrogen or substituted or unsubstituted C1-C6 alkyl.

[0199] In some embodiments, R 19 is hydrogen, methyl, ethyl, or methoxymethyl.

[0200] R 18 basis In some embodiments, R 18 is substituted alkyl. In some embodiments, R 18 is a substitution C 1-6 It is alkyl.

[0201] In some embodiments, R 18 is unsubstituted alkyl. In some embodiments, R 18 is an unsubstituted C1-C6 alkyl. In some embodiments, R 18 is methyl. In some embodiments, R 18 is ethyl.

[0202] R D basis 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, where R C3 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.

[0203] In some embodiments, R D are each 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.

[0204] In some embodiments, R D are each independently hydrogen, oxo, substituted or unsubstituted alkyl, hydroxy, or substituted or unsubstituted carbocyclyl.

[0205] In some embodiments, R D is independently hydrogen, oxo, methyl, ethyl, hydroxy, or cyclopropyl.

[0206] R 15a Groups and R 15b basis In some embodiments, R 15a and R 15beach 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 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, where R C3is 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, an oxygen protecting group (when oxygen is attached), a nitrogen protecting group (when nitrogen is attached), a sulfur protecting group (when sulfur is attached), or two R C3 groups taken together with the intervening atoms form a substituted or unsubstituted heterocyclic ring; or R 15a and R 15b are linked to form an oxo (=O) group.

[0207] In some embodiments, R 15a and R 15b is independently hydrogen, halogen, —CN, substituted or unsubstituted alkyl, or substituted or unsubstituted carbocyclyl.

[0208] In some embodiments, R 15a and R 15b are both hydrogen.

[0209] In some embodiments, R 15a and R 15b are linked to form an oxo (=O) group.

[0210] In some embodiments, R 15a and R 15b are each 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.

[0211] R 16a Groups and R 16b basis In some embodiments, R16a 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 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, where R C3 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, an oxygen protecting group (when oxygen is attached), a nitrogen protecting group (when nitrogen is attached), a sulfur protecting group (when sulfur is attached), or two R C3 groups taken together with the intervening atoms form a substituted or unsubstituted heterocyclic ring; or R 16a and R 16b are linked to form an oxo (=O) group.

[0212] In some embodiments, R 16a and R 16b is independently hydrogen, halogen, —CN, substituted or unsubstituted alkyl, or substituted or unsubstituted carbocyclyl.

[0213] In some embodiments, R 16a and R 16b are both hydrogen.

[0214] In some embodiments, R 16a and R 16b are linked to form an oxo (=O) group.

[0215] L In some embodiments, L is [ka] is.

[0216] In some embodiments, R Y is hydrogen, unsubstituted C 1-6 Alkyl, unsubstituted C 1-6 haloalkyl, or cyano. In certain embodiments, R Y is hydrogen, methyl, ethyl, -CF3, or cyano.

[0217] In some embodiments, L is [ka] is.

[0218] In some embodiments, L is [ka] is.

[0219] In some embodiments, L is [ka] is.

[0220] In some embodiments, L is [ka] is.

[0221] In some embodiments, L is [ka] is.

[0222] In some embodiments, L is [ka] is.

[0223] X In some embodiments, X is —NC(O)(R 55a )

[0224] In some embodiments, X is —N(R 55a )(R 55b )

[0225] In some embodiments, X is —C(O)N(R 55a )(R 55b )

[0226] In some embodiments, X is R 55c is.

[0227] R 55c basis In some embodiments, R 55c is a substituted or unsubstituted phenyl, or a carbon-linked substituted or unsubstituted heteroaryl containing at least one nitrogen in the heteroaryl ring.

[0228] In some embodiments, R 55c is a substituted or unsubstituted phenyl or a carbon-linked substituted or unsubstituted heteroaryl selected from the group consisting of pyridyl, isothiazolyl, thiazolyl, pyrimidyl, pyrazinyl, and oxazolyl.

[0229] In some embodiments, R 55c teeth, [ka] [In the formula, R a Each occurrence of is independently hydrogen, halogen, -CN, -OR D4 , -N(R D4 )2, -C(=O)R D4 , -C(=O)OR D4 , or substituted or unsubstituted C 1-6 is alkyl; R D4 Each occurrence of is independently hydrogen, or substituted or unsubstituted C 1-6 is alkyl; and p is an integer selected from 0 to 2.

[0230] In some embodiments, the compound has formula (Ib), (Ic), (Id), (Ie), (Il), (Im), (In), or (Ip): [ka] [ka] or a pharmaceutically acceptable salt thereof.

[0231] In some embodiments, the compound has formula (If), (Ig), or (Ih): [ka] or a pharmaceutically acceptable salt thereof.

[0232] In some embodiments, the compound has formula (Ii), (Ij), or (Ik): [ka] or a pharmaceutically acceptable salt thereof.

[0233] In some embodiments, the compound has the formula (Io): [ka] or a pharmaceutically acceptable salt thereof.

[0234] In some embodiments, the compound has formula (I-qq), (Iq), (Is), (It), or (Iu): [ka] [ka] [In the formula, Q, Q', and Q'' are each independently CR w or N; R w is hydrogen, cyano, —NH2, or substituted or unsubstituted alkyl; At least one of Q, Q', and Q'' is CR w is] or a pharmaceutically acceptable salt thereof.

[0235] In some embodiments, the compound has the formula (Ir): [ka] [In the formula, k is an integer 1 or 2; R z is a substituted or unsubstituted alkyl or substituted or unsubstituted aryl, or two R on adjacent carbons z is attached to an intervening atom to form a substituted or unsubstituted aryl; j is an integer between 0 and 6. or a pharmaceutically acceptable salt thereof.

[0236] In some embodiments, the compound has formula (Iv), (Iw), or (Ix): [ka] or a pharmaceutically acceptable salt thereof.

[0237] In some embodiments, the compound has formula (I-Ib), (I-Ic), (I-Id), (I-Ie), (I-Il), (I-Im), (I-In), (I-Ip1), or (I-Ip2): [ka] [ka] or a pharmaceutically acceptable salt thereof.

[0238] In some embodiments, the compound has formula (I-If), (I-Ig), or (I-Ih): [ka] [ka] or a pharmaceutically acceptable salt thereof.

[0239] In some embodiments, the compound has formula (I-Ii), (I-Ij), or (I-Ik): [ka] or a pharmaceutically acceptable salt thereof.

[0240] In some embodiments, the compound has formula (I-Io1) or (I-Io2): [ka] or a pharmaceutically acceptable salt thereof.

[0241] In some embodiments, the compound has formula (I-Iqq), (I-Iq1), (I-Iq2), (I-It1), (I-It2), (I-Iu1), or (I-Iu2): [ka] [In the formula, Q, Q', and Q'' are each independently CR w or N; R w is hydrogen, cyano, —NH2, or substituted or unsubstituted alkyl; At least one of Q, Q', and Q'' is CR w is] or a pharmaceutically acceptable salt thereof.

[0242] In some embodiments, the compound has formula (I-Irr), (I-Ir1), or (I-Ir2): [ka] [In the formula, k is an integer 1 or 2; R z is a substituted or unsubstituted alkyl or substituted or unsubstituted aryl, or two R on adjacent carbons zis attached to an intervening atom to form a substituted or unsubstituted aryl; j is an integer between 0 and 6. or a pharmaceutically acceptable salt thereof.

[0243] In some embodiments, the compound has formula (I-Ir3) or (I-Ir4): [ka] [In the formula, k is an integer 1 or 2; R z’ is substituted or unsubstituted alkyl or cyano; j' is an integer between 0 and 4. or a pharmaceutically acceptable salt thereof.

[0244] In some embodiments, the compound has formula (I-Iw1), (I-Iw2), (I-Ix1), or (I-Ix2): [ka] or a pharmaceutically acceptable salt thereof.

[0245] The configuration of C17 is as follows: [ka] It should be understood that the expression may be expressed in an equivalent manner.

[0246] The compounds of the invention described herein may, in certain embodiments, be GABA A In certain embodiments, the compounds described herein act as receptor modulators at GABA receptors, e.g., GABA A It can act as a positive allosteric modulator of the receptor.

[0247] In one embodiment, the compounds described herein (e.g., compounds of Formula I or Table 1) are GABAA Compared to the α1β2γ2 structure of the GABA receptor, A It exhibits high selectivity for modulating the α4β3δ structure of the receptor.

[0248] Such compounds include GABA A They are predicted to have central nervous system (CNS) activity as modulators of CNS excitability as mediated by their ability to modulate receptors.

[0249] In some embodiments, the compound is selected from the group consisting of the compounds identified in Table 1 below. [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7] [Table 1-8] [Table 1-9] [Table 1-10] [Table 1-11] [Table 1-12]

Table 1-13

Table 1-14

Table 1-15

Table 1-16

Table 1-17

Table 1-18

Table 1-19

Table 1-20

Table 1-21

Table 1-22

Table 1-23

Table 1-24

Table 1-25

Table 1-26

Table 1-27

Table 1-28

Table 1-29

Table 1-30

Table 1-31

Table 1-32

Table 1-33

Table 1-34

Table 1-35

Table 1-36

Table 1-37

Table 1-38

Table 1-39

Table 1-40

Table 1-41

Table 1-42

Table 1-43

Table 1-44

[0250] 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)).

[0251] Pharmaceutical Composition 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. In certain embodiments, the compound of the invention is provided in a prophylactically effective amount.

[0252] 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. In certain embodiments, the pharmaceutical composition comprises a prophylactically effective amount of the active ingredient.

[0253] 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.

[0254] 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.

[0255] 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.

[0256] 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.

[0257] 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.

[0258] 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.

[0259] 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.

[0260] 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.

[0261] 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.

[0262] 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 (such as magnesium stearate); glidants (such as colloidal silicon dioxide); sweetening agents (such as sucrose or saccharin); or flavoring agents (such as peppermint, methyl salicylate, or orange flavoring).

[0263] 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.

[0264] 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.

[0265] 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.

[0266] 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.

[0267] 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.

[0268] 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.).

[0269] 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.

[0270] 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 & Wilkins, 2005).

[0271] 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.

[0272] 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).

[0273] 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.

[0274] 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.

[0275] 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.

[0276] 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.

[0277] 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 21 st ed., Lippincott Williams & Wilkins, 2005.

[0278] In one aspect, a kit is provided that includes a composition (eg, a solid composition) comprising a compound of Formula (I).

[0279] Methods of Use and Treatment In one aspect, the compounds described herein, e.g., compounds of Formula (I), 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 regulation 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], convulsive 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., , 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.

[0280] 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.

[0281] 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.

[0282] 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.

[0283] 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.

[0284] 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.

[0285] 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 invention, or a composition thereof.

[0286] 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.

[0287] 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.

[0288] 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.

[0289] In yet another aspect, the present invention provides a method for cognitive enhancement or treating memory impairment by administering to a subject a therapeutically effective amount of the compound of the present invention.In certain embodiments, the disorder is Alzheimer's disease.In certain embodiments, the disorder is Rett syndrome.

[0290] 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.

[0291] 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.

[0292] Neuroendocrine disorders and dysfunction 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.

[0293] Symptoms of neuroendocrine disorders include, but are not limited to, behavioral, emotional, and sleep-related symptoms, symptoms related to reproductive function, 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.

[0294] Neurodegenerative Diseases and Disorders 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.

[0295] Mood disorders Also provided herein are methods for treating mood disorders, such as clinical depression, postpartum or postpartum depression, perinatal depression, atypical depression, melancholic depression, psychotic major 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, treatment-refractory depression, suicidal tendencies, 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 associated with a disease or disorder described herein (e.g., neuroendocrine diseases and disorders, neurodegenerative diseases and disorders (e.g., epilepsy), movement disorders, tremors (e.g., Parkinson's disease), or women's health disorders or conditions).

[0296] 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.

[0297] 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.

[0298] 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).

[0299] 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.

[0300] 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.

[0301] 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.

[0302] 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.

[0303] 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.

[0304] 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.

[0305] 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).

[0306] Double depression is defined as at least two years of significant depressed mood (dysthymia) interspersed with periods of major depression.

[0307] Depressive personality disorder (DPD) refers to a personality disorder with depressive traits.

[0308] 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.

[0309] Minor depressive disorder or minor depression refers to depression in which at least two symptoms are present for two weeks.

[0310] 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.

[0311] Chronic condition-induced depression refers to depression caused by a chronic medical condition such as cancer, chronic pain, chemotherapy, or chronic stress.

[0312] 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).

[0313] 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.

[0314] 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).

[0315] 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.

[0316] 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).

[0317] 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).

[0318] 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 percent 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 measured by a reduction in 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) of at least 10, 15, or 20 points compared to baseline HAM-D total score.

[0319] 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.

[0320] 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).

[0321] In some embodiments, the method provides a therapeutic benefit (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 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 the MADRS score from baseline at the end of the treatment period (e.g., day 14 after administration).

[0322] 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.

[0323] 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.

[0324] 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.

[0325] Anxiety disorders 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.

[0326] 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.

[0327] 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).

[0328] Obsessive-compulsive disorder (OCD) is a type of anxiety disorder characterized primarily by recurrent obsessions (distressing, persistent, intrusive thoughts or images) and compulsions (urges to perform specific actions or habitual behaviors). 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 patient may engage in 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 experience only obsessions without overt compulsions, and even fewer experience only compulsions.

[0329] 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).

[0330] 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.

[0331] Women's Health Disorders 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).

[0332] 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.

[0333] 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.

[0334] 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).

[0335] 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.

[0336] A miscarriage is a pregnancy that ends naturally within the first 20 weeks of pregnancy.

[0337] Abortion refers to the intentional interruption of a pregnancy, which can be performed during the first 28 weeks of pregnancy.

[0338] Infertility and related disorders include uterine fibroids, polycystic ovary syndrome, endometriosis, and primary ovarian insufficiency.

[0339] 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.

[0340] Other disorders and conditions that affect only women include Turner syndrome, Rett syndrome, and ovarian and cervical cancer.

[0341] 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.

[0342] 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.

[0343] epilepsy 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.

[0344] 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.

[0345] Epileptic seizures 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).

[0346] Status epilepticus (SE) Status epilepticus (SE) can include, for example, convulsive status epilepticus, e.g., early status epilepticus, confirmed status epilepticus, refractory status epilepticus, and 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. Convulsive status epilepticus is characterized by the presence of convulsive status epilepticus and can 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, leading to the implementation of second-line therapy. Refractory status epilepticus is characterized by status epilepticus that persists despite treatment with first-line and second-line therapies and for which general anesthetics are administered systemically. Super-refractory status epilepticus is characterized by status epilepticus that persists despite treatment with first-line, second-line therapies, and general anesthetics for more than 24 hours.

[0347] 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.

[0348] 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.

[0349] Seizures 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.

[0350] 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.

[0351] 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.

[0352] There are six types of generalized seizures. The most common, most severe, and therefore best known is a generalized convulsion, also known as a grand mal seizure. During this type of seizure, the patient loses consciousness and usually passes out. Following this loss of consciousness, there is a 30-60 second period of generalized rigidity (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 (the "postictal" or postictal period). During a grand mal seizure, injuries and accidents such as tongue biting and urinary incontinence can occur.

[0353] 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."

[0354] 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.

[0355] Clonic seizures are recurrent rhythmic convulsions that involve both sides of the body simultaneously.

[0356] Tonic seizures are characterized by muscle stiffness.

[0357] Cataplexy consists of a sudden generalized loss of muscle tone, especially in the arms and legs, often causing falls.

[0358] 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.

[0359] Movement disorders 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.

[0360] Tremor The methods described herein can be used to treat tremors, for example, the compounds of Formula (I) can be used to treat cerebellar or intention tremor, dystonic tremor, essential tremor, orthostatic tremor, Parkinson's tremor, physiological tremor, psychogenic tremor, or red nucleus tremor. Tremors include genetic, degenerative, and idiopathic disorders (such as Wilson's disease, Parkinson's disease, and essential tremor, respectively); metabolic disorders (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, mercury, lead, CO, manganese, arsenic, toluene); drug-induced (sleep-inducing drugs, tricyclic antidepressants, lithium, cocaine, alcohol, adrenaline, bronchodilators, theophylline, caffeine, steroids, valproate, amiodarone, thyroid hormones, vincristine); and psychogenic disorders. Clinical tremor can be classified as physiologic tremor, enhanced physiologic tremor, essential tremor syndrome (including classic essential tremor, primary orthostatic tremor, and task- 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.

[0361] 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).

[0362] 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).

[0363] 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.

[0364] 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.

[0365] 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.

[0366] 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.

[0367] 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.

[0368] 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.

[0369] Red nucleus tremor is characterized by a slow, coarse tremor that can occur at rest, posturally, and intentionally. Tremor is associated with conditions affecting the red nucleus of the midbrain, classic abnormal stroke.

[0370] 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.

[0371] 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.

[0372] 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.

[0373] Ataxia refers to the complete loss of control of bodily movements and can affect fingers, hands, arms, legs, trunk, speech, and eye movements.

[0374] Myoclonus and startle reflexes are responses to sudden, unexpected stimuli, which may be auditory, tactile, visual, or vestibular.

[0375] 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.

[0376] Restless legs syndrome is a neurosensorimotor disorder characterized by a strong desire to move the legs while at rest.

[0377] 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.

[0378] 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.

[0379] Anesthesia / Sedation 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. Such effects can be obtained from a single drug that provides a reasonable combination of effects alone, or in some cases, from a combination of drugs (e.g., hypnotics, sedatives, paralytics, analgesics) that achieve an extremely specific combination of results. Anesthesia allows patients to undergo surgery and other procedures without the discomfort and pain they would otherwise experience.

[0380] Sedation is the reduction of irritability or excitement through the administration of pharmacological agents, generally to facilitate a medical or diagnostic procedure.

[0381] Sedation and analgesia encompass a continuum of states of consciousness ranging from minimal sedation (anxiolysis) to general anesthesia.

[0382] 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.

[0383] 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.

[0384] 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.

[0385] 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.

[0386] 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.

[0387] 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.

[0388] 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]

[0389] 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.

[0390] Materials and Methods 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.

[0391] 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.

[0392] 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 provided 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.

[0393] 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).

[0394] Exemplary general method for LCMS / LC ELSD: 30-90 AB, 2 min. Lcm. (Mobile phase: 1.5 mL / 4 L TFA in water (solvent A) and 0.75 mL / 4 L TFA in acetonitrile (solvent B). Elution gradient: 30%-90% (solvent B) over 0.9 min, held at 90% for 0.6 min at a flow rate of 1.2 mL / min; Column: Xtimate C18 2.1*30 mm, 3 μm; Wavelength: UV 220 nm; Column temperature: 50°C; MS ionization: ESI; Detector: PDA & ELSD)

[0395] Abbreviations: PE: petroleum ether; EtOAc: ethyl acetate; THF: tetrahydrofuran; PCC: pyridinium chlorochromate; TLC: thin layer chromatography; PCC: pyridinium chlorochromate; t-BuOK: potassium tert-butoxide; 9-BBN: 9-borabicyclo[3.3.1]nonane; Pd(t-Bu3P)2: bis(tri-tert-butylphosphine)palladium(0); AcCl: acetyl chloride; i-PrMgCl: isopropylmagnesium chloride; TBSCl: tert-butyl(chloro)dimethyl Tisilane; (i-PrO)4Ti: Titanium tetraisopropoxide; BHT: 2,6-di-t-butyl-4-methylphenoxide; Me: Methyl; i-Pr: Isopropyl; t-Bu: Tert-butyl; Ph: Phenyl; Et: Ethyl; Bz: Benzoyl; BzCl: Benzoyl chloride; CsF: Cesium fluoride; DCC: Dicyclohexylcarbodiimide; DCM: Dichloromethane; DMAP: 4-Dimethylaminopyridine; DMP: Dess-Martin periodinane; EtMgBr: Ethyl magnesium bromide; EtO Ac: ethyl acetate; TEA: triethylamine; AlaOH: alanine; Boc: t-butoxycarbonyl; Py: pyridine; TBAF: tetra-n-butylammonium fluoride; THF: tetrahydrofuran; TBS: t-butyldimethylsilyl; TMS: trimethylsilyl; TMSCF3: (trifluoromethyl)trimethylsilane; Ts: p-toluenesulfonyl; Bu: butyl; Ti(OiPr)4: tetraisopropoxytitanium; LAH: lithium aluminum hydride; LDA: lithium diisopropylamine LiOH: Lithium hydroxide hydrate; MAD: Methylaluminum bis(2,6-di-t-butyl-4-methylphenoxide); MeCN: Acetonitrile; NBS: N-Bromosuccinimide; NaSO: Sodium sulfate; NaSO: Sodium thiosulfate; MeCN: Acetonitrile; MeOH: Methanol; Boc: t-Butoxycarbonyl; MTBE: Methyl tert-butyl ether; K-Selectride: Potassium tri(s-butyl)borohydride; 9-BBN dimer: 9-Borabicyclo(3.3.1) Nonane (dimer); DIPEA: diisopropylethylamine; DMF: dimethylformamide; FA: formic acid; SM: starting material.

[0396] Example 1: Synthesis of 1-(((3R,5R,8R,9R,10S,13S,14S,17S)-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)methyl)piperidin-2-one (A7) [ka] Synthesis of A2 To a solution of chloro(methoxymethyl)triphenylphosphorane (35.3 g, 103 mmol, 3.0 equiv.) in THF (100 mL) was added t-BuLi (79.2 mL, 103 mmol, 1.3 M n-hexane solution, 3.0 equiv.) at 0 °C. After stirring at 0 °C for 1 h, the mixture was added to A1 (10 g, 34.4 mmol, 1.0 equiv.) in THF (100 mL) in three portions. After slowly warming to room temperature over 12 h, the mixture was treated with NH4Cl (200 mL, 10%) and extracted with ethyl acetate (3 × 200 mL). The combined organic solution was washed with brine (300 mL), dried over Na2SO4, filtered, and concentrated in vacuo to give an oil, which was purified by flash column chromatography (0–20% EtOAc in PE) to give A2 (6.5 g, 59%) as an oil. 1 H NMR (400 MHz,CDCl3) δ 5.72-5.68 (t, J =2Hz,1H), 3.44 (s, 3H), 2.36-2.23 (m, 2H), 2.17-2.07(m, 1H), 1.92-1.74 (m, 3H), 1.71-1.59(m, 3H), 1.51-1.35 (m, 7H), 1.34-1.23(m, 6H),1.22-1.01 (m, 5H), 0.86 (s, 3H).

[0397] Synthesis of A3 To a solution of A2 (3 g, 9.41 mmol) in acetone (50 mL) was added p-TsOH (1.75 g, 9.41 mmol). After stirring at 25 °C for 2 h, the reaction was quenched with water (50 mL) and extracted with EtOAc (3 × 50 mL). The combined organics were washed with NaHCO (100 mL, 10%) and brine (100 mL), dried over NaSO, filtered, and concentrated. The residue was purified by flash column (0–20% EtOAc in PE) to give A3 (2.8 g) as an oil. 1 H NMR (400 MHz,CDCl3) δ 9.78-9.74 (m, 1H), 2.34-2.23(m, 1H), 2.18-2.08(m, 1H), 2.02-1.95 (m, 1H),1.88-1.61 (m, 9H), 1.49-1.38(m,6H), 1.28-1.21 (m, 6H), 1.15-1.06 (m, 3H), 0.94-0.89(m, 1H), 0.78-0.71 (m, 3H).

[0398] Synthesis of A4 To a solution of A3 (1.5 g, 4.92 mmol) in toluene (20 mL) was added phenylmethanamine (1.57 g, 14.7 mmol) and 4-methylbenzenesulfonic acid (137 mg, 0.73 mmol) at 25 °C under N2. After refluxing for 3 h, the reaction mixture was cooled to 25 °C, and a suspension of NaBH4 (556 mg, 14.7 mmol) in MeOH (20 mL) was added. After stirring for 1 h, the mixture was poured into water (20 mL) and extracted with EtOAc (3 × 20 mL). The combined organic solution was washed with NaHCO3 (30 mL, 10%) and brine (20 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography (0–20% EtOAc in PE, 0.5% NH3.HO in PE) to give A4 (1 g, 51%) as a solid. 1H NMR (400 MHz,CDCl3) δ 7.32 (s, 2H), 7.31 (s,2H), 7.25-7.22 (m, 1H), 3.87 (s, 1H), 3.78 (s, 2H),2.76-2.69 (m, 1H), 2.49-2.42(m,1H), 1.93-1.73 (m, 5H), 1.68-1.63 (m, 2H), 1.49-1.35(m, 6H), 1.34-1.23 (m,8H), 1.19-0.98 (m, 7H), 0.58 (s, 3H);LC-ELSD / MS purity 90%, MS ESIC 27 H 42 NO[M+H] + Calculated value 396, measured value 396.

[0399] Synthesis of A5 To a solution of A4 (1 g, 2.52 mmol) in EtOAc (20 mL) under N was added Pd / C (wet, 10%, 0.45 g). The suspension was degassed under vacuum and purged three times with H. After stirring for 12 h under H (15 psi) at 25 °C, the reaction mixture was filtered through a pad of Celite and washed with EtOAc (3 × 20 mL). The filtrate was concentrated to give the product (900 mg), which required further hydrogenation. To a solution of this material (900 mg, 2.27 mmol) in EtOAc / MeOH (10 mL / 10 mL) under N was added Pd / C (wet, 10%, 408 mg). The suspension was degassed under vacuum and purged three times with H. After stirring for 12 h under H (15 psi) at 25 °C, the reaction mixture was filtered through a pad of Celite and washed with EtOAc (3 × 20 mL). The filtrate was concentrated to give A5 (650 mg) as a solid, which was used without further purification. 1 H NMR (400 MHz,CDCl3) δ 2.86-2.78 (m, 1H), 2.57-2.45(m, 1H), 1.79(s, 5H), 1.68-1.61(m, 4H), 1.49-1.36(m, 8H), 1.28-1.23 (m, 5H),1.17-1.01 (m, 8H), 0.60 (s, 3H);LC-ELSD / MS purity 99%,MS ESIC 20 H36 NO[M+H] + Calculated value 306, measured value 306.

[0400] Synthesis of A6 To a solution of A5 (150 mg, 0.490 mmol) and DIPEA (189 mg, 1.47 mmol) in DCM (2 mL) was added 5-chloropentanoyl chloride (91.1 mg, 0.588 mmol). The mixture was stirred at 30 °C for 1 h. The reaction mixture was quenched with water (2 mL) and extracted with DCM (3 × 2 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography on silica gel (10% to 50% EtOAc in PE) to give A6 (120 mg, 58%) as a solid. 1 H NMR (400 MHz,CDCl3) δ 3.57-3.53 (m,2H), 3.38-3.30 (m, 1H), 3.20-3.10 (m, 1H), 2.22-2.15(m, 2H), 1.87-1.75 (m, 10H),1.69-1.61 (m, 4H), 1.54-1.38 (m, 8H), 1.35-1.27 (m,4H), 1.18-1.02 (m, 7H), 0.66(s, 3H).

[0401] Synthesis of A7 To a solution of A6 (70 mg, 0.165 mmol) in anhydrous DMF (2 mL) was added NaH (60%, 32.8 mg, 0.825 mmol). After stirring at 30 °C for 18 h, the reaction mixture was quenched with ice-water (10 mL) and extracted with EtOAc (2 × 10 mL). The combined organic solutions were washed with 3% aqueous LiCl (2 × 10 mL) and brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography on silica gel (10% to 80% EtOAc in PE, basified with aqueous ammonia) to give A7 as an oil. The oil was dissolved in MeCN (2 mL), diluted with deionized water (15 mL), concentrated, and lyophilized to give A7 (29 mg, 45%) as a solid. 1H NMR (400 MHz,CDCl3) δ 3.57-3.48 (m,1H), 3.32-3.18 (m, 3H), 2.35 (t, J = 6.0 Hz, 2H),1.89-1.69 (m, 10H), 1.68-1.62(m,2H), 1.48-1.36 (m, 7H), 1.35-1.21 (m, 7H), 1.16-0.98(m, 6H), 0.70 (s, 3H); LC-ELSD / MS purity 99%, MSESI C 25 H 42 NO2[M+H] + Calculated value 388, measured value 388.

[0402] Example 2: Synthesis of N-(((3R,5R,8R,9R,10S,13S,14S,17S)-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)methyl)-N-methylbenzamide (A9) [ka] Synthesis of A8 To a solution of A3 (200 mg, 0.65 mmol) in toluene (10 mL) was added methanamine (0.65 mL, 1.31 mmol, 2 M THF solution) and 4-methylbenzenesulfonic acid (18.2 mg, 0.098 mmol) under N at 25 °C. After refluxing at 110 °C for 3 h, the reaction mixture was cooled to 25 °C, and a suspension of NaBH (74.1 mg, 1.96 mmol) in MeOH (10 mL) was added. After stirring at 25 °C for 1 h, the mixture was poured into water (20 mL) and extracted with EtOAc (3 × 20 mL). The combined organic solution was washed with NaHCO (30 mL, 10% aqueous solution) and brine (20 mL), dried over NaSO, filtered, and concentrated in vacuo. The residue was purified by flash column (0-80% EtOAc in PE, 0.5% NH3.H2O in PE) to give A8 (160 mg) as an oil. LC-ELSD / MS purity 95%, MS ESI C 21 H 38 NO[M+H] + The calculated value is 320, and the measured value is 320.

[0403] Synthesis of A9 To a solution of benzoic acid (122 mg, 1 mmol) in DCM (3 mL) was added HATU (285 mg, 0.75 mmol) and EtN (252 mg, 2.5 mmol) at 25 °C. After stirring at 25 °C for 0.5 h, A8 (160 mg, 0.5 mmol) was added. After stirring at 25 °C for 10 h, the residue was diluted with water (10 mL) and then extracted with EtOAc (2 × 10 mL). The combined organic solution was washed with water (2 × 10 mL) and brine (10 mL), dried over anhydrous NaSO, filtered, and concentrated. The residue was purified by flash column (0-50% EtoAc in PE, 0.1% NH3.HO in PE) to give A9 (130 mg) as a solid, which was purified by HPLC (Column: Xtimate C18 150*25mm*5um, Conditioning solvent: water (0.225% FA)-ACN, Gradient: 78-100% B, Gradient time: 7 min, Retention time of 100% B: 1 min, Flow rate: 25 mL / min) to give A9 (38 mg, 18%) as a solid. 1 H NMR (400 MHz,CDCl3) δ 7.42-1.33 (m, 5H), 3.78-3.65(m, 0.6H), 3.51-3.38(m, 1.3H), 3.07 (s, 1.5H),2.92 (s, 1.5H), 1.92-1.76 (m, LC-ELSD / MS 99% purity, MS ESIC 28 H 42 NO2[M+H] + Calculated value 424, measured value 424.

[0404] Example 3: Synthesis of N-(((3R,5R,8R,9R,10S,13S,14S,17S)-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)methyl)benzamide (A10) [ka] To a solution of benzoic acid (158 mg, 1.3 mmol) in DCM (3 mL) was added HATU (494 mg, 1.3 mmol) and EtN (330 mg, 3.27 mmol) at 25 °C. After stirring for 0.5 h, A5 (200 mg, 0.65 mmol) was added to the reaction mixture. After stirring for 10 h, the mixture was treated with water (10 mL) and extracted with EtOAc (2 × 10 mL). The combined organic solution was concentrated in vacuo. The residue was dissolved in EtOAc and washed with water (2 × 10 mL), brine (10 mL), dried over anhydrous NaSO, filtered, and concentrated to give a solid (150 mg). The solid was purified by HPLC (Column: Xtimate C18 150*25mm*5um, Preparation solvent: water (0.225% FA)-ACN, Gradient: 63-93% B, Gradient time: 7 min, Retention time at 100% B: 2 min, Flow rate: 25 mL / min) to give A10 (6 mg, 4%) as a solid. 1 H NMR (400 MHz,CDCl3) δ 7.77-7.71 (m, 2H), 7.53-7.46(m, 1H), 7.45-7.39(m, 2H), 5.99(s, 1H), 3.61-3.51(m, 1H), 3.42-3.31 (m, 1H),2.01-1.79(m, 5H), 1.69-1.63 (m, 4H),1.49-1.29 (m, 10H),1.26 (s, 3H), 1.22-1.04(m, 6H), 0.72 (m, 3H);LC-ELSD / MS purity 99%,MSESI C 27 H 40 NO2[M+H] + Calculated value 410, measured value 410.

[0405] Example 4: Synthesis of N-(((3R,5R,8R,9R,10S,13S,14S,17S)-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)methyl)benzenesulfonamide (A11) [ka] To a solution of A5 (300 mg, 0.9819 mmol) in DCM (10 mL) was added EtN (247 mg, 2.45 mmol) and benzenesulfonyl chloride (259 mg, 1.47 mmol) at 20 °C. After stirring at 20 °C for 16 h, the reaction mixture was washed with water (3 × 100 mL). The combined organic solutions were dried over NaSO, filtered, and concentrated to give the desired product, which was purified by Combiflash (0–15% EtOAc in PE) to give A11 (180 mg, 41%) as a solid. 1 H NMR (400 MHz,CDCl3) δ 7.95-7.85 (m,2H), 7.65-7.51 (m, 3H), 4.31-4.15 (m, 1H), 3.11-3.00(m, 1H), 2.85-2.75 (m, 1H),1.91-1.75 (m, 5H), 1.74-1.59 (m, 3H), 1.45-1.28 (m, 9H),1.26 (s, 3H), 1.23-0.91(m, 8H),0.55 (s, 3H);LC-ELSD / MS purity 99%,MS ESI C 26 H 38 NO2S[M+H-H2O] + Calculated value 428, measured value 428.

[0406] Example 5: Synthesis of N-(((3R,5R,8R,9R,10S,13S,14S,17S)-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)methyl)-N-methylbenzenesulfonamide (A12) [ka] To a solution of A11 (142 mg, 0.3186 mmol) in DMF (5 mL) was added Cs2CO3 (207 mg, 0.6372 mmol) at 20 °C. After stirring for 20 min, MeI (70 mg, 0.4929 mmol) was added. After stirring at 20 °C for 16 h, the reaction mixture was added to water (50 mL) and extracted with EtOAc (2 × 50 mL). The combined organic solutions were washed with water (3 × 100 mL), dried over Na2SO4, filtered, and concentrated to give the desired product, which was purified by Combiflash (0–15% EtOAc in PE) to give A12 (64 mg, 44%) as a solid. 1 H NMR (400 MHz,CDCl3) δ 7.81-7.75 (m,2H), 7.55-7.52 (m,3H), 3.11-3.05 (m, 1H), 2.85-2.75(m, 1H), 2.69 (s, 3H), 1.91-1.59(m, 10H), 1.51-1.28 (m, 9H), 1.26 (s, 3H), 1.24-1.01(m, 6H), 0.71 (s, 3H); LC-ELSD / MS purity 99%, MS ESI C 27 H 42 NO3S[M+H] + The calculated value is 460, and the measured value is 460.

[0407] Examples 6 and 7: Synthesis of (S)-1-(((3R,5R,8R,9R,10S,13S,14S,17S)-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene)-17-yl)methyl)-6-methylpiperidin-2-one (A14) and (R)-1-(((3R,5R,8R,9R,10S,13S,14S,17S)-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)methyl)-6-methylpiperidin-2-one (A15) [ka] Synthesis of A13 To a solution of A5 (300 mg, 0.981 mmol) in toluene (10 mL) was added methyl 5-oxohexanoate (282 mg, 1.96 mmol). After stirring at 120 °C for 16 h, the reaction was cooled to 25 °C, and MeOH (20 mL) and sodium borane hydride (92.6 mg, 2.45 mmol) were added. After 30 min, the mixture was poured into ice water (50 mL) and extracted with EtOAc (2 × 30 mL). The combined organic solution was washed with brine (50 mL), dried over NaSO, filtered, and concentrated in vacuo. The residue was purified by silica gel column (PE / EtOAc = 10 / 1 to 3 / 1) to give A13 (300 mg, 70.5%) as an oil. 1 HNMR (400 MHz,CDCl3) δ 3.67 (s, 3H), 2.37-2.31(m, 2H), 1.96-1.74 (m,9H), 1.72-1.57 (m, 8H), 1.48-1.37(m, 9H), 1.30-1.22 (m,7H), 1.17-1.01 (m, 6H),0.61 (s, 3H)

[0408] Synthesis of A14 and A15 To a solution of A13 (300 mg, 0.691 mmol) in toluene (5 mL) was added trimethylaluminum (1.03 mL, 2 M toluene solution) at 25 °C. After stirring at 65 °C for 16 h, the mixture was poured into water (30 mL) and extracted with EtOAc (2 × 20 mL). The combined organic solution was washed with brine (30 mL), dried over NaSO, filtered, and concentrated. The residue was purified by HPLC separation (column: YMC-Actus Triart C18 100*30 mm*5 μm, gradient: 65-95% B, conditioning solvent: (water (0.05% HCl)-ACN), flow rate: 25 mL / min) to give A14 (25 mg, 9%) and A16 (30 mg) as solids.

[0409] A16 (30 mg) was purified by HPLC separation (column: YMC-Actus Triart C18 100*30 mm*5 um, gradient: 70-100% B, conditioning solvent: (water (0.05% HCl)-ACN), flow rate: 25 mL / min) to give A16 (16 mg, 53.5%) as a solid. A14: 1 HNMR (400MHz,CDCl3) δ 4.19-4.13 (m,1H), 3.57(s, 1H), 2.74-2.71 (m, 1H), 2.39 (s, 2H), 1.94-1.79(m, 6H), 1.76-1.57(m, LC-ELSD / MS Purity 99%, MS ESI C 26 H 44 NO2[M+H] + Calculated value 402, measured value 402. A15: 1 HNMR (400MHz, CDCl3) δ 4.23-4.18 (m,1H), 3.64-3.60(m, 1H), 2.62-2.57 (m, 1H), 2.40-2.27 (m,2H), 1.94-1.71 (m, 8H), 1.69-1.59 LC-ELSD / MS purity 99%, MS ESI C 26 H 44 NO2[M+H] + Calculated value 402, measured value 402.

[0410] Example 8: Synthesis of N-(((3R,5R,8R,9R,10S,13S,14S,17S)-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)methyl)-2-phenylacetamide (A16) [ka] To a suspension of 2-phenylacetic acid (800 mg, 5.88 mmol) and HATU (2.79 g, 7.35 mmol) in DCM (10 mL) was added EtN (2.47 g, 24.5 mmol) under nitrogen at 25 °C. After stirring for 30 min at 25 °C, a solution of A5 (1.5 g, 4.90 mmol) was added. After stirring for 18 h at 25 °C, the mixture was quenched with water (10 mL) and extracted with DCM (2 × 10 mL). The combined organic solution was washed with brine (2 × 5 mL), dried over NaSO, filtered, and concentrated in vacuo to give A16 (1.41 g). The product (150 mg, 0.354 mmol) was purified by HPLC (Column: YMC-Actus Triart C18 100*30 mm*5 um; Conditioning solvent: water (0.05% HCl)-ACN; Start B: 70; End B: 95; Gradient time (min): 8; 100% B retention time (min): 1; Flow rate (ml / min): 25; Injections: 6) to give A16 (36 mg, 24.1%) as a solid. 1 H NMR (400 MHz,CDCl3) δ 7.38-7.30 (m,3H), 7.29-7.23 (m, 2H), 5.20 (s, 1H), 3.56 (s,2H), 3.28-3.22 (m, 1H), 3.21-3.12(m, 1H), 1.87-1.77 (m, 3H), 1.76-1.59 (m, 2H),1.56-1.47(m, 1H), 1.46-1.31 (m,9H), 1.30-1.18 (m, 7H), 1.06-0.94 (m, 6H), 0.58(m, 3H);LC-ELSD / MS purity 99%, MS ESIC 28 H 42 NO2[M+H] + Calculated value 424, measured value 424.

[0411] Examples 9 and 10: Synthesis of (R)-1-(((3R,5R,8R,9R,10S,13S,14S,17S)-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene)-17-yl)methyl)-4-phenylpyrrolidin-2-one (A18) and (S)-1-(((3R,5R,8R,9R,10S,13S,14S,17S)-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)methyl)-4-phenylpyrrolidin-2-one (A19) [ka] Synthesis of A17 To a solution of A5 (400 mg, 1.30 mmol) in toluene (10 mL) was added benzenepropanoic acid, β-formyl, methyl ester (499 mg, 2.60 mmol). After stirring at 115 °C for 3 h, the reaction was cooled to 25 °C, and MeOH (20 mL) and sodium borane hydride (123 mg, 3.25 mmol) were added. After stirring at 25 °C for 1 h, the mixture was poured into ice-water (50 mL) and extracted with EtOAc (2 × 30 mL). The combined organic solution was washed with brine (50 mL), dried over NaSO, filtered, and concentrated in vacuo. The residue was purified by Combiflash (0–20% EtOAc in PE) to give A17 (190 mg, 33%) as a solid. 1 H NMR (400 MHz,CDCl3) δ 7.55-7.41 (m,5H), 6.44-6.42 (m, 1H), 4.38-4.29 (m, 2H), 3.72-3.62(m, 1H), 3.41-3.31 (m, 1H),1.88-1.61 (m, 9H), 1.49-1.35 (m, 8H), 1.28 (s, 3H), 1.24(s, 3H), 1.19-0.99 (m,8H).

[0412] Synthesis of A18 and A19 To a solution of A17 (190 mg, 0.4244 mmol) in MeOH (20 mL), dry Pd / C (50 mg) was added and the mixture was hydrogenated under H (15 psi) at 20 °C. After stirring for 16 h, the reaction mixture was filtered through a Celite pad and concentrated to give an oil (100 mg, 53%). The oil was purified by SFC (column: YMC CHIRAL Amylose-C (250 mm * 30 mm, 10 μm, conditioning solvent: 0.1% NH3HO ETOH, start B: 55%, end B: 55%) to give A18 (peak 1, 21 mg, 18%) and A19 (peak 2, 20 mg, 17%), both as solids. A18: 1 H NMR (400MHz, CDCl3) δ 7.41-7.29(m,3H), 7.25-7.20 (m, 2H), 3.76-3.73 (m, 1H),3.52-3.48 (m, 1H), 3.45-3.41 (m,1H),3.40-3.36 (m, 1H), 3.28-3.22 (m, 1H), 2.84-2.75(m, 1H), 2.61-2.52 (m, 1H),1.91-1.59 (m, 10H), 1.51-1.29 (m, 10H), 1.26 (s, 3H),1.25-0.99(m, 5H), 0.72 (s,3H);LC-ELSD / MS 99% purity, MS C 30 H 44 NO2[M+H] + The calculated value is 450, and the measured value is 450. A19: 1 H NMR (400MHz, CDCl3) δ 7.41-7.29(m,3H), 7.25-7.20 (m, 2H), 3.76-3.73 (m, 1H),3.52-3.48 (m, 1H), 3.45-3.36 (m,2H),3.28-3.22 (m, 1H), 2.84-2.75 (m, 1H), 2.61-2.52(m, 1H), 1.91-1.59 (m, 10H),1.51-1.29(m, 10H), 1.26 (s, 3H), 1.25-0.99 (m, 5H),0.72 (s, 3H);LC-ELSD / MS purity 99%, MSC 30 H 44 NO2[M+H]+ The calculated value is 450, and the measured value is 450.

[0413] Examples 11 and 12: Synthesis of (S)-1-(((3R,5R,8R,9R,10S,13S,14S,17S)-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene)-17-yl)methyl)-3-phenylpyrrolidin-2-one (A20) and (R)-1-(((3R,5R,8R,9R,10S,13S,14S,17S)-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)methyl)-3-phenylpyrrolidin-2-one (A21) [ka] To a cold (-78 °C) solution of lithium diisopropylamide, prepared by adding n-butyl-lithium in hexanes (4.6 mL, 2.5 M, 11.5 mmol) to diisopropylamine (2 mL, 0.72 g / mL, 14.2 mmol) in THF (5 mL) at -78 °C, was added A16 (500 mg, 1.18 mmol) in THF (5 mL). After stirring at -78 °C for 1 h, 1-bromo-2-chloroethane (507 mg, 3.54 mmol) was added to the reaction mixture. The reaction was warmed to 20 °C and stirred for 16 h. After quenching with water (50 mL), the reaction was extracted with EtOAc (2 x 50 mL). The combined organic solution was washed with brine (100 mL), dried over NaSO, filtered, concentrated, and purified by Combiflash (0-30% EtOAc in PE) to give the desired product, which was further purified by SFC (column: YMC CHIRAL Amylose-C (250 mm * 30 mm, 10 μm, conditioning solvent: 0.1% NHHO ETOH, start B: 50%, end B: 50%) to give A20 (peak 1, 18 mg, 3%) and A21 (peak 2, 54 mg, 10%), both as solids. A20: 1H NMR (400MHz, CDCl3) δ 7.35-7.28(m,2H), 7.24-7.19 (m, 3H), 3.69-3.61 (m, 1H),3.49-3.35 (m, 3H), 3.33-3.22 (m,1H),2.55-2.45 (m, 2H), 2.17-2.09 (m,1H), 1.92-1.61(m, 11H), 1.51-1.31 (m,7H),1.27 (s, 3H), 1.21-0.99 (m,6H), 0.73 (s, 3H).LC-ELSD / MS purity 99%, MS ESI C 30 H 44 NO2[M+H] + The calculated value is 450, and the measured value is 450. A21: 1 H NMR (400MHz, CDCl3) δ 7.35-7.28(m,3H), 7.24-7.19 (m, 2H), 3.69-3.61 (m, 1H),3.49-3.41 (m, 2H), 3.40-3.35 (m,1H),3.33-3.22 (m, 1H), 2.55-2.45 (m, 2H), 2.17-2.09(m,1H), 1.92-1.61 (m, 11H),1.51-1.31 (m,7H), 1.27 (s, 3H), 1.21-0.99 (m,6H),0.71(s, 3H);LC-ELSD / MS purity 99%, MSESI C 30 H 44 NO2[M+H] + The calculated value is 450, and the measured value is 450.

[0414] Examples 13 and 14: Synthesis of (R)-1-(((3R,5R,8R,9R,10S,13S,14S,17S)-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene)-17-yl)methyl)-6-phenylpiperidin-2-one (A22) and (S)-1-(((3R,5R,8R,9R,10S,13S,14S,17S)-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)methyl)-6-phenylpiperidin-2-one (A23) [ka] To a stirred solution of A5 (300 mg, 0.9819 mmol) in methanol (40 mL) was added methyl 5-oxo-5-phenylpentanoate (241 mg, 1.17 mmol) and NaCNBH (154 mg, 2.45 mmol). The mixture was brought to pH 6 with HOAc (1 mL). After stirring at 70 °C for 48 h, the reaction mixture was extracted with ethyl acetate (2 × 80 mL). The combined organic solutions were washed with brine (100 mL), dried over NaSO, filtered, and concentrated in vacuo to give a residue that was triturated in MeCN (20 mL) at 20 °C to give a solid (410 mg). This material was first purified by flash column chromatography (ethyl acetate in petroleum ether, 75%) to give a solid (140 mg, 34%), and then purified by SFC (column: AD (250 mm * 30 mm, 5 μm), gradient: 35-35% B (A = 0.1% NH3 / HO, B = EtOH), flow rate: 80 mL / min) to give A22 (peak 1, 50 mg, 36%) and A23 (peak 2, 40 mg, 29%) as solids. A22: 1 HNMR (400MHz, CDCl3) δ 7.34 (d, J = 4.0 Hz,4H), 7.30-7.27 (m, 1H), 5.32 (s, 1H), 4.70 (s,1H), 3.40-3.26 (m, 1H), 3.21-3.05(m,1H), 2.29 (d, J = 3.6 Hz, 1H), 2.24-2.15 (m,2H), 1.88-1.58 (m, 9H), 1.53-1.28(m,11H), 1.26 (s, 4H), 1.18-0.93 (m, 6H), 0.65(s,3H);LC-ELSD / MS purity 96.6%,MS ESIC 31 H 46 NO2[M+H] + Calculated value: 464, Found value: 464. Analytical SFC 100% de. (Conditions: Column: ChiralPak AD-3 150 x 4.6 mm ID, 3 μm; Gradient: 40% ethanol in CO2 (0.05% DEA); Flow rate: 2.5 mL / min; Column temperature: 40 °C). A23: 1 HNMR (400MHz, CDCl3) δ 7.34 (d, J = 4.4 Hz,4H), 7.30-7.27 (m, 1H), 5.37-5.29 (m,1H), 4.74-4.66(m, 1H), 3.40-3.27 (m, 1H),3.18-3.10 (m, 1H), 2.30 (s, 1H), 2.24-2.14 (m, 2H), 1.90-1.58(m, 9H), 1.53-1.28(m, 11H), 1.26 (s, 4H), 1.19-0.96 (m, 6H),0.65 (s, 3H);LC-ELSD / MS purity 98.5%, MS ESIC 31 H 46 NO2[M+H] + Calculated value for 464. Analytical SFC 100% de. (Conditions: Column: ChiralPak AD-3 150 x 4.6 mm ID, 3 μm; Gradient: 40% ethanol (0.05% DEA) in CO2; Flow rate: 2.5 mL / min; Column temperature: 40 °C).

[0415] Example 15: Synthesis of N-(((3R,5R,8R,9R,10S,13S,14S,17S)-3-(ethoxymethyl)-3-hydroxy-13-methylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)methyl)benzamide (A32) [ka] Synthesis of A25 To a stirred solution of iodotrimethyl-4-sulfane (77.9 g, 382 mmol) and NaH (60%, 15.2 g, 382 mmol) in DMSO (900 mL) was added a solution of estrane-3,17-dione (100 g, 364 mmol) in DMSO (300 mL). After stirring at 15 °C for 16 h, the reaction was treated with water (1000 mL) and extracted with EtOAc (2 × 1000 mL). The combined organic solutions were washed with water (2 × 1000 mL), brine (1000 mL), dried over anhydrous NaSO, filtered, and concentrated in vacuo. Trituration of the residue from MeOH (1000 mL) at 65 °C afforded the filter cake A25a (20 g, 19%) as a solid. The filtrate was concentrated to afford A25 (80 g) as an oil. Trituration of A25 (80.0 g) from MeOH (300 mL) at 65° C. gave a filter cake (15 g, mixture) as a solid, and the filtrate was concentrated to give A25 (65 g) as an oil. 1 H NMR (400 MHz,CDCl3) δ 2.65-2.55 (m, 2H), 2.48-2.40(m, 1H), 2.28-1.50(m, 11H), 1.50-1.00 (m, 10H),0.95-0.90 (m, 1H), 0.88 (s, 3H).

[0416] Synthesis of A26 To freshly prepared sodium ethoxide in ethanol (50 mL) (Na (8 g, 347 mmol) was added in five portions to a solution of ethanol (50 mL) under N at 40 °C and stirred for 2 h at 40 °C), A25 (8 g, 27.7 mmol) was added at 40 °C. After stirring at 60 °C for 16 h, the mixture was cooled, poured into water (150 mL), and extracted with EtOAc (2 × 300 mL). The combined organic solution was washed with brine (150 mL), dried over anhydrous NaSO, filtered, and concentrated. The residue was purified by flash column (0–10% EtOAc in PE) to give A26 (4.9 g, 52.9%, delivered 140 mg) as an oil. 1H NMR (400 MHz,CDCl3) δ 3.53 (q, J = 6.8 Hz, 2H),3.43 (q, J = 9.2 Hz, 2H), 2.70 (s, 1H), 2.48-2.38(m, 1H), 2.14-1.61 (m,9H), 1.54-1.03(m, 16H), 0.86 (s, 3H);LC-ELSD / MS purity 99%,MS ESIC 19 H 27 O [M-ETOH-HO+H] + Calculated value 271, measured value 271.

[0417] Synthesis of A27 To a mixture of MePPhBr (9.78 g, 27.4 mmol) in THF (20 mL) was added t-BuOK (3.06 g, 27.4 mmol) under N at 15 °C. After stirring at 60 °C for 30 min, A27 (4.6 g, 13.7 mmol) in THF (30 mL) was added portionwise below 60 °C. After stirring at 60 °C for 16 h, the reaction mixture was quenched with HO (100 mL) at 15 °C and extracted with EtOAc (2 × 200 mL). The combined organic solution was washed with brine (100 mL), dried over anhydrous NaSO, filtered, and concentrated. The residue was purified by flash column chromatography (0–10% EtOAc in PE) to give A27 (3.7 g, 81.3%) as an oil. 1 H NMR (400 MHz,CDCl3) δ 4.66-4.59 (m, 2H), 3.54(q, J = 6.8 Hz, 2H),3.44 (q, J = 9.2 Hz, 2H), 2.69(s, 1H), 2.54-2.43 (m, 1H),2.30-2.18 (m, 1H), 1.77 (s, 7H), 1.52-1.07 (m, 17H),0.78 (s, 3H).

[0418] Synthesis of A28 To a solution of A27 (3.7 g, 11.1 mmol) in THF (40 mL) was added 9-BBN dimer (5.41 g, 22.2 mmol) under N2. After stirring at 60 °C for 1 h, the mixture was cooled to 15 °C, and ethanol (6.38 mL, 111 mmol) and NaOH (22.2 mL, 5 M, 111 mmol) were added. HO2 (11.1 mL, 10 M, 111 mmol) was added dropwise at 25 °C, followed by saturated aqueous Na2SO3 (10 mL). After stirring at 15 °C for an additional 1 h, the mixture was poured into water (20 mL) and extracted with EtOAc (2 × 30 mL). The combined organic solution was washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by flash column (0-35% EtOAc in PE) to give A28 (2.8 g, 71.9%) as a solid. 1 H NMR (400 MHz,CDCl3) δ 3.76-3.67 (m, 1H), 3.57-3.50(m, 3H), 3.46-3.38(m, 2H), 2.72-2.67 (m, 1H),1.88-1.72 (m, 5H), 1.68-1.57(m,5H), 1.49-1.35 (m, 6H), 1.30-1.01 (m, 12H), 0.65(s, 3H);LC-ELSD / MS purity 99%,MS ESIC 22 H 36 O2 [M-H2O] + Calculated value 333, measured value 333.

[0419] Synthesis of A29 To a solution of A28 (2.7 g, 7.70 mmol) in DCM (30 mL) at 15° C. was added 1-methyl-1H-imidazole (1.26 g, 15.4 mmol), TEA (1.55 g, 15.4 mmol), and TsCl (2.93 g, 15.4 mmol). After stirring at 15° C. for 2 h, the mixture was washed with water (2×80 mL), brine (80 mL), dried over NaSO, filtered, and concentrated in vacuo to give A29 (4.7 g) as an oil. 1H NMR (400 MHz,CDCl3) δ 7.79 (d, J = 8.0 Hz, 2H),7.35 (d, J = 8.0 Hz, 2H), 4.10-4.03 (m, 1H), 3.97-3.90(m, 1H), 3.71 (s, 1H), 3.57-3.49(m, 2H), 3.46-3.38 (m, 2H), 2.46(s, 3H), 1.84-1.70(m, 6H), 1.65-1.55 (m, 4H),1.49-1.33 (m, 6H), 1.23-0.96 (m, 11H),0.57 (s, 3H).

[0420] Synthesis of A30 To a solution of A29 (4.7 g, 9.31 mmol) in DMSO (100 mL) was added NaN (1.81 g, 27.9 mmol). After stirring at 70 °C for 16 h, the mixture was cooled and saturated aqueous NaHCO was added until the pH exceeded 8. The mixture was extracted with EtOAc (2 × 100 mL), and the combined organic solutions were washed with brine (100 mL), dried over anhydrous NaSO, filtered, and concentrated in vacuo to give A30 (2.5 g, 72%) as a solid. 1 H NMR (400 MHz,CDCl3) δ 3.53 (q, J = 7.2 Hz, 2H),3.46-3.38 (m, 2H), 3.29-3.15 (m, 2H), 2.70 (s,1H), 1.76 (m, 9H), 1.50-1.32(m,7H), 1.20 (m, 11H), 0.62 (s, 3H).

[0421] Synthesis of A31 A solution of A30 (2.5 g, 6.65 mmol) in THF (25 mL) with Pd / C (0.2 g, >50% water) was hydrogenated under 15 psi of hydrogen. After 3 h, the mixture was filtered through a pad of Celite and the filtrate was concentrated in vacuo to give A31 (1.85 g) as a solid. 1H NMR (400 MHz,CDCl3) δ 3.53 (q, J = 6.8 Hz, 2H),3.46-3.38 (m, 2H), 2.87-2.50 (m, 7H), 1.98-1.56(m, 9H), 1.38 (m, 7H), 1.20(t,J= 7.2 Hz, 9H), 0.60 (s, 3H);LC-ELSD / MS purity 99%,MS ESIC 22 H 40 NO2[M+H] + The calculated value is 350, and the measured value is 350.

[0422] Synthesis of A32 To a solution of A31 (300 mg, 0.858 mmol) in anhydrous DCM (5 mL) was added TEA (260 mg, 2.57 mmol) and BzCl (240 mg, 1.71 mmol) under N at 25 °C. After stirring for 16 h, the mixture was poured into water (20 mL) and extracted with EtOAc (2 × 30 mL). The combined organic solution was washed with brine (30 mL), dried over anhydrous NaSO, filtered, and concentrated. The residue was purified by HPLC (column: YMC-Actus Triart C18 100 × 30 mm, 5 μm; conditioning solvent: water (0.05% HCl)-ACN; gradient: 80% to 96% B in 7.5 min; flow rate: 25 mL / min; injection: 8) to give A32 (140 mg, 35.9%) as a solid. 1 H NMR (400 MHz,CDCl3) δ 7.77-7.70 (m, 2H), 7.52-7.40(m, 3H), 6.06-5.91(m, 1H), 3.53(d, J = 6.8Hz, 3H), 3.42 (d, J = 10.8 Hz, 3H),1.95-1.74 (m, 5H), 1.69-1.55 (m, 8H), 1.45-1.34(m, 6H), 1.27-1.04 (m, 10H), 0.72(s,3H);LC-ELSD / MS purity 99%,MS ESI C 29 H 44 NO3[M+H] + The calculated value is 454, and the measured value is 454.

[0423] Example 16: Synthesis of N-(((3R,5R,8R,9R,10S,13S,14S,17S)-3-hydroxy-3-(methoxymethyl)-13-methylhexadecahydro-1H-cyclopenta[a]phenanthren-17)-yl)methyl)benzamide (A39) [ka] Synthesis of A33 To anhydrous methanol (100 mL) was added Na (6.34 g, 276 mmol) in five portions. The mixture was stirred at 25 °C for 2 h. A25 (8.00 g, 27.7 mmol) in THF (50 mL) was added to the reaction mixture and stirred at 60 °C for 5 h. After the reaction mixture was cooled to 0 °C, the reaction mixture was quenched by adding HO (100 mL) and extracted with EtOAc (3 × 100 mL). The combined organic solution was washed with saturated brine (2 × 100 mL), dried over anhydrous NaSO, filtered, and concentrated. The residue was purified by flash column (0–30% EtOAc in PE) to give A333 (5.352 g, 60%) as a solid. 1 H NMR (400 MHz,CDCl3) δ 3.45-3.35 (m,5H), 2.63-2.58 (m, 1H), 2.49-2.40 (m, 1H), 2.13-2.03(m, 1H), 1.96-1.56 (m, 8H),1.56-1.00 (m, 13H), 0.86 (s, 3H);LC-ELSD / MS purity 99%,MSESI C 20 H 31 O2 [M-H2O+H] + Calculated value 303, measured value 303

[0424] Synthesis of A34 To a mixture of MePPhBr (11.5 g, 32.4 mmol) in THF (80 mL) was added t-BuOK (3.62 g, 32.4 mmol) under N at 15 °C. After stirring at 60 °C for 30 min, A33 (5.20 g, 16.2 mmol) in THF (20 mL) was added portionwise. After stirring at 60 °C for 16 h, the reaction mixture was quenched with HO (50 mL) at 15 °C and extracted with EtOAc (3 × 50 mL). The combined organic solutions were washed with saturated brine (2 × 50 mL), dried over anhydrous NaSO, filtered, and concentrated. The residue was triturated with CHOH:HO = 1 / 1 (100 mL) at 15 °C to give A34 (4.50 g, 87%) as an oil. 1 H NMR (400 MHz,CDCl3) δ 4.65-4.58 (m,2H), 3.45-3.35 (m, 5H), 2.58 (s, 1H), 2.50-2.43(m, 1H), 2.25-2.13 (m, 1H), 1.88-1.56(m, 8H), 1.56-1.05 (m, 13H), 0.77 (s, 3H).

[0425] Synthesis of A35 To a solution of A34 (5.00 g, 15.6 mmol) in THF (50 mL) was added 9-BBN dimer (7.61 g, 31.2 mmol) under N2. After stirring at 60 °C for 1 h under N2, the mixture was cooled to 15 °C, and ethanol (8.97 mL, 156 mmol) and NaOH (31.2 mL, 5 M, 156 mmol) were added. HO2 (15.6 mL, 10 M, 156 mmol) was added dropwise at 15 °C. After stirring at 60 °C for 1 h, EtOAc (30 mL) and Na2SO3 (30 mL) were added at 15 °C. After stirring for 1 h, the mixture was extracted with EtOAc (3 × 50 mL). The combined organic solution was 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 A35 (4.50 g) as a solid. 1H NMR (400 MHz,CDCl3) δ 3.75-3.62 (m,1H), 3.57-3.52 (m, 1H), 3.45-3.35 (m, 5H), 2.58(brs, 1H), 1.85-1.50 (m, 11H), 1.50-1.00(m, 14H), 0.65 (s, 3H);LC-ELSD / MS purity 99%,MSESIC 21 H 35 O2 [M-H2O+H] + Calculated value 319, measured value 319.

[0426] Synthesis of A36 To a solution of A35 (4.40 g, 13.0 mmol) in DCM (50 mL) at 15 °C, 1-methyl-1H-imidazole (2.13 g, 26.0 mmol), TEA (2.63 g, 26.0 mmol), and TsCl (4.95 g, 26.0 mmol) were added. After stirring at 15 °C for 2 h, the mixture was washed with water (2 × 100 mL), brine (100 mL), dried over NaSO, filtered, and concentrated in vacuo, which was purified by column chromatography (0–20% EtOAc in PE) to give A36 (5.00 g, 78%) as a solid. 1 H NMR (400 MHz,CDCl3) δ 7.80-7.77 (m,2H), 7.37-7.30 (m, 2H), 4.10-4.05 (m, 1H), 3.98-3.92(m, 1H), 3.42-3.35 (m, 5H),2.56 (s, 1H), 2.46 (s, 3H), 1.83-1.50 (m, 10H), 1.50-0.92(m, 14H), 0.56 (s, 3H).

[0427] Synthesis of A37 To a solution of A36 (5.00 g, 10.1 mmol) in DMSO (100 mL) was added NaN (1.96 g, 30.3 mmol). After stirring at 70 °C for 16 h, the mixture was cooled and 10% aqueous NaHCO (200 mL) was added until the pH exceeded 8. The mixture was extracted with EtOAc (2 × 100 mL), and the combined organic solutions were washed with brine 1 (300 mL), dried over anhydrous NaSO, filtered, and concentrated in vacuo to give A37 (3.50 g, 96%) as an oil. 1 H NMR (400 MHz,CDCl3) δ 3.45-3.35 (m,5H), 3.28-3.13 (m, 2H), 2.60-2.53 (m, 2H), 1.98-1.50(m, 12H), 1.50-0.95 (m, 11H),0.63 (s, 3H)

[0428] Synthesis of A38 A solution of A37 (1 g, 2.76 mmol) in THF (10 mL) with Pd / C (0.2 g, >50% water) was hydrogenated at 15 psi. After 3 h, the mixture was filtered through a pad of Celite and the filtrate was concentrated in vacuo to give A38 (1.08 g) as a solid. 1 H NMR (400 MHz,CDCl3) δ 8.25 (s, 3 H),3.44-3.34 (m, 5 H), 3.07 (s, 1 H), 2.87-2.61 (m,2 H), 2.07 (s, 1 H), 1.65-1.85(m, 7 H), 1.32-1.51 (m, 7 H), 0.98-1.29 (m, 8 H),0.64(s, 3 H).

[0429] Synthesis of A39 To a solution of A38 (300 mg, 0.894 mmol) in DCM (5 mL) were added EtN (271 mg, 2.68 mmol) and BzCl (250 mg, 1.78 mmol). After stirring at 20 °C for 16 h, the mixture was quenched with HO (5 mL) and extracted with DCM (2 × 2 mL). The combined organic solution was filtered, concentrated (0.53 g), and purified by preparative HPLC (column: YMC-Actus Triart C18 100*30 mm*5 um; conditioning solvent: water (0.05% HCl)-ACN; start B: 75; end B: 93; gradient time (min): 7; 100% B retention time (min): 1; flow rate (ml / min): 25; injection time: 7) to give A39 (221 mg, 56%) as a solid. 1 H NMR (400 MHz,CDCl3) δ 7.77-7.70 (m,2 H), 7.54-7.38 (m,3H), 6.04-5.95 (m, 1H), 3.60-3.51(m, 1H), 3.31-3.45 (m, 6H),2.60 (s, 1H), 1.73-1.95 (m, 5H), 1.6 -1.72 (m, 4H), 0.98-1.51(m, 15H), 0.72 (s,3H); LC-ELSD / MS purity 99%, MS ESI C 28 H 42 NO2[M+H] + Calculated value 440, measured value 440

[0430] Examples 17 and 18: Synthesis of N-((S)-1-((3R,5R,8R,9R,10S,13S,14S,17S)-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethyl)benzenesulfonamide (B4) and N-((R)-1-((3R,5R,8R,9R,10S,13S,14S,17S)-3-hydroxy-3,13-)dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethyl)benzenesulfonamide (B5) [ka] Synthesis of B2 To a solution of KOH (2.61 g, 46.7 mmol) in EtOH (50 mL) was added 19-norpregnan-20-one, 3-hydroxy-3-methyl-,(3α,5β)-(B1) (5 g, 15.6 mmol) and hydroxylamine.HCl (2.16 g, 31.2 mmol) at 15 °C. After stirring for 16 h at 15 °C, the reaction was diluted with water (100 mL) and extracted with EtOAc (3 × 50 mL). The combined organic solutions were washed with brine (50 mL), dried over anhydrous NaSO, filtered, and concentrated in vacuo to give B2 (51 g) as an oil.

[0431] Synthesis of B3 To a solution of B2 (4 g, 11.9 mmol) in THF (200 mL) was added LiAlH4 (4.52 g, 119 mmol) at 0 °C. After stirring at 70 °C for 16 h, the reaction was cooled to 0 °C, and HO (10 mL) followed by NaOH (10%, 10 mL) was added. After stirring at 15 °C for 0.5 h, the mixture was filtered, and the residue was washed with anhydrous THF (2 × 200 mL). The combined organic solution was concentrated in vacuo to give B3 (4.2 g) as an oil.

[0432] Synthesis of B4 and B5 To a solution of B3 (1 g, 3.12 mmol), TEA (630 mg, 6.24 mmol), and 2,6-dimethylpyridine (667 mg, 6.24 mmol) in DCM (10 mL) was added benzenesulfonyl chloride (577 mg, 3.27 mmol) at 0° C. After stirring at room temperature for 16 h, the mixture was poured into water (20 mL) and extracted with ethyl acetate (2×20 mL). The combined organic solution was washed with brine (10 mL), dried over Na2SO4, filtered, concentrated in vacuo, and purified by HPLC (column: YMC-Actus Triart C18 100*30 mm*5 μm, gradient: 75-96% B (water (0.05% HCl)-ACN), flow rate: 25 mL / min), followed by SFC (column: YMC CHIRAL Amylose-C (250 mm*30 mm, 10 μm, gradient: 40-40% B (0.1% NH3HO IPA), flow rate: 70 mL / min)) to give B4 (100 mg) and B5 (113 mg, 13%) as solids. Trituration of B4 (100 mg, 0.2175 mmol) from HO (10 mL) at 65 °C gave B4 (78 mg, 78%) as a solid. B4: 1 H NMR (400MHz, CDCl3) δ H 7.90-7.80(m,2H), 7.65-7.40 (m, 3H), 4.20-4.10 (m, 1H),3.35-3.30 (m, 1H), 1.85-1.65 (m,5H),1.65-1.50 (m, 2H), 1.50-1.25 (m, 7H), 1.25-0.85(m, 9H), 0.61 (s, 3H);LC-ELSD / MS purity 99%,MS ESI C 27 H 41 NO3SNa[M+Na] + Calculated value: 482, measured value: 482. B5: 1 H NMR δ H7.90-7.80 (m, 2H), 7.65-7.40(m, 3H), 4.20-4.10(m, 1H), 3.35-3.30 (m, 1H), 2.15-1.95(m, 1H), 1.80-1.70 (m,3H), 1.70-1.50 (m, 2H), 1.50-1.20 (m, 15H), 1.20-0.75(m, 10H),0.61 (s, 3H); LC-ELSD / MS purity 99%, MS ESI C 27 H 41 NO3SNa[M+Na] + Calculated value: 482, measured value: 482.

[0433] Examples 19 and 20: Synthesis of N-((S)-1-((3R,5R,8R,9R,10S,13S,14S,17S)-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethyl)-N-methylbenzamide (B7) and N-((1R)-1-((3R,5R,9R,10S,13S,14S,17S)-3-hydroxy-3,13)-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethyl)-N-methylbenzamide (B8) [ka] B6 synthesis A solution of B1 (500 mg, 1.6 mmol) in MeNH2 (7.8 mL, 2 M EtOH solution, 15.6 mmol) was stirred at 25 °C for 10 h. Then, NaBH4 (295 mg, 7.8 mmol) was added to the reaction mixture at 25 °C. After the mixture was stirred at 25 °C for 0.5 h, HO (20 mL) was added to the reaction mixture, which was then extracted with EtOAc (3 × 20 mL). The combined organic solution was washed with saturated brine (2 × 20 mL), dried over anhydrous Na2SO4, filtered, and concentrated to give B6 (700 mg) as a solid.

[0434] Synthesis of B7 and B8 To a solution of B6 (700 mg, 2.1 mmol) in pyridine (10 mL) was added benzoyl chloride (321 mg, 2.3 mmol). After stirring at 20° C. for 4 h, the reaction mixture was poured into water (20 mL) and extracted with EtOAc (2×20 mL). The combined organic solution was washed with brine (2 × 20 mL), dried over anhydrous NaSO, filtered, concentrated, and purified by HPLC (column: YMC-Actus Triart C18 100 × 30 mm × 5 μm, gradient: 70–99% B (water (0.05% HCl)-ACN), flow rate: 25 mL / min) and SFC (column: DAICEL CHIRALPAK AS (250 mm × 30 mm, 10 μm, gradient: 30–30% B (0.1% NH3HO ETOH), flow rate: 65 mL / min) to give B7 (223 mg, 24%) and B8 (78 mg, 9%) as solids. 1 H NMR (400 MHz, CDCl3) δ H 7.40-7.27 (m,5H), 4.98-4.80 (m, 0.4H), 3.75-3.60 (m, 0.6H),2.93 (s, 1.5H), 2.74 (s, 1.5H), 1.95-1.65(m, 7H), 1.65-1.26 (m, 18H), 1.26-0.85(m, 6H), 0.83 (s, 1.5H), 0.29 (s, 1.5H); LC-ELSD / MS purity 99%, MS ESI C 29 H 44 NO2[M+H] + Calculated value 438, measured value 438. 1 H NMR δ H 7.55-7.27 (m, 5H), 4.98-4.80(m, 0.5H), 3.75-3.60 (m, 0.5 H), 2.93 (s, 1.3H), 2.74(s, 1.8H), 1.95-1.65 (m, 9H),1.65-1.26 (m, 15H), 1.26-0.95 (m, 7H), 0.95-0.82(m,2H), 0.81 (s, 1.8H), 0.26 (s,1.2H);LC-ELSD / MS purity 99%,MS ESI C 29 H 44NO2[M+H] + Calculated value 438, measured value 438.

[0435] Examples 21 and 22: Synthesis of N-((S)-1-((3R,5R,8R,9R,10S,13S,14S,17S)-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethyl)-N-methylbenzenesulfonamide (B9) and N-((R)-1-((3R,5R,8R,9R,10S,13S,14S,17S)-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethyl)-N-methylbenzenesulfonamide (B10) [ka] To a solution of B6 (700 mg, 2.2 mmol), TEA (442 mg, 4.4 mmol), and 2,6-dimethylpyridine (468 mg, 4.4 mmol) in DCM (10 mL) was added benzenesulfonyl chloride (404 mg, 2.3 mmol) at 0° C. After stirring at 25° C. for 12 h, the mixture was poured into water (100 mL) and extracted with ethyl acetate (2×50 mL). The combined organic solution was washed with brine (100 mL), dried over NaSO, filtered, concentrated in vacuo, and purified by HPLC (column: YMC-Actus Triart C18 100 x 30 mm x 5 μm, gradient: 70-99% B (water (0.05% HCl)-ACN), flow rate: 25 mL / min) and SFC (column: DAICEL CHIRALPAK AS (250 mm x 30 mm, 10 μm, gradient: 30-30% B (0.1% NH3HO ETOH), flow rate: 65 mL / min)) to give B10 (195 mg, 32.7%) and B9 (72 mg, 12.0%) as solids. B9: 1 H NMR (400MHz, CDCl3) δ H7.74 (d,J = 7.2 Hz, 2H), 7.50-7.39 (m, 3H), 3.89 (dd,J =6.8, 10.8 Hz, 1H), 2.60 (s, 3H),1.79-1.67 (m, 4H), 1.61-1.48 (m, 4H), 1.46 (s,7H),1.29-1.18 (m, 7H), 1.06-0.95(m, 5H), 0.74 (d, J = 6.4 Hz, 3H), 0.67 (s, 3H);LC-ELSD / MS purity 99%,MS ESI C 28 H 44 NO3S[M+H] + Calculated value: 474, measured value: 474. B10: 1 H NMR (400MHz, CDCl3) δ H 7.77-7.73 (m, 2H),7.52-7.41 (m, 3H), 4.01-3.92(m, 1H), 2.57 (s, 3H), 2.11-2.07(m, 1H), 1.82-1.71(m, 3H), 1.59-1.51 (m, 4H), 1.43-1.29(m, 7H), 1.26-1.13 (m,7H), 1.04-0.97 (m, 5H),0.82 (s, 3H), 0.54 (d, J = 6.4 Hz,3H);LC-ELSD / MS purity 99%,MSESI C 28 H 44 NO3S [M+H] + Calculated value: 474, measured value: 474.

[0436] Examples 23 and 24: Synthesis of N-((S)-1-((3R,5R,8R,9R,10S,13S,14S,17S)-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethyl)benzamide (B11) and N-((R)-1-((3R,5R,8R,9R,10S,13S,14S,17S)-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethyl)benzamide (B12) [ka] To a solution of B3 (875 mg, 2.7 mmol) in DCM (10 mL) was added benzoyl chloride (574 mg, 4.1 mmol) and TEA (690 mg, 6.8 mmol). After stirring at 15 °C for 16 h, the reaction mixture was poured into water (40 mL) and extracted with EtOAc (2 × 40 mL). The combined organic solution was washed with water (2 × 40 mL), dried over anhydrous NaSO, filtered, and concentrated. The residue was purified by flash column chromatography (0–30% EtOAc in PE) to give a mixture of diastereomers (800 mg, 69.5%). The diastereomers were purified by SFC (Column: Chiralpak AD-3 150iA 4.6 mm ID, 3 μm, Mobile Solution: A:CO₂, B:ethanol (0.05% DEA), Gradient: 5% to 40% B for 5 min, hold at 40% for 2.5 min, then 5% B for 2.5 min, Flow Rate: 2.5 mL / min, Column Temperature: 35°C, ABPR: 1500 psi) to give B12 (232 mg, 29.1%) and B11 (279 mg, 35%) as solids. B12: 1 H NMR (400MHz, CDCl3) δ H 7.77 - 7.72 (m,2H), 7.54-7.34 (d, J=7.5 Hz,3H), 5.89 (d, J=9.3 Hz, 1H), 4.20 (d,J=5.5 Hz, 1H),1.95-1.75 (d, J=9.0 Hz, 5H),1.68 - 1.58 (m, 3H), 1.48 - 1.33 (m,8H), 1.25 (s, 6H), 1.23 - 1.20 (m, 1H), 1.17(d, J=6.3 Hz, 3H),1.14 - 0.95 (m,5H), 0.74 (s, 3H);LC-ELSD / MS purity 99%, MS ESI C 28 H 42 NO2[M+H] + Calculated value 424, measured value 424. B11: 1 H NMR (400MHz, CDCl3) δ H7.76 - 7.70 (m,2H), 7.43 (d, J=7.5 Hz, 3H),5.88 (d, J=9.0 Hz, 1H), 4.22 (d, J=6.3Hz, 1H), 1.98-1.75 (s, 5H), 1.68 - 1.59 (m,3H), 1.54 - 1.33 (m, 8H), 1.31 - 1.02(m, 15H), 0.77 (s, 3H);LC-ELSD / MS purity 99%,MSESI C 28 H 42 NO2[M+H] + Calculated value 424, measured value 424.

[0437] Examples 25 and 26: Synthesis of (3R,5R,8R,9R,10S,13S,14S,17S)-3,13-dimethyl-17-((R)-1-(phenylamino)ethyl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-ol (B14) and (3R,5R,8R,9R,10S,13S,14S,17S)-3,13-dimethyl-17-((S)-1-(phenylamino)ethyl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-ol (B15) [ka] B13 synthesis To a solution of B1 (700 mg, 2.2 mmol) and aniline (1.01 g, 10.9 mmol) in toluene (10 mL) was added molecular sieves 4A (2.8 g) followed by TsOH (113 mg, 0.6 mmol) at 15° C. After stirring the suspension at 120° C. for 3 h, the mixture was concentrated in vacuo to give B13 (4 g), which was used in the next step without purification.

[0438] Synthesis of B14 and B15 To a solution of B13 and molecular sieves (4.0 g) in THF (40 mL) at 20 °C, NaBH (382 mg, 10.1 mmol) was added dropwise, followed by MeOH (10 mL). After stirring at 20 °C for 1 h, the mixture was filtered, and the filtrate was quenched with saturated aqueous NH Cl (50 mL). The mixture was extracted with DCM (2 × 50 mL). The combined organic solution was washed with brine (100 mL), dried over Na2SO4, filtered, concentrated, and purified by flash column (0–30% EtOAc in PE) to give a mixture of diastereomers (400 mg), which was separated by SFC (Column: Chiralcel OJ-3 150iA 4.6 mm ID, 3 μm, Mobile Solution: A: CO2, B: Ethanol (0.05% DEA), Gradient: 5%–40% B for 5 min, hold at 40% for 2.5 min, then 5% B for 2.5 min, Flow Rate: 2.5 mL / min, Column Temperature: 35 °C, ABPR: 1500 psi) to give B14 (80 mg, 20%) and B15 (30 mg, 7.51%) as solids. B14: 1 H NMR (400MHz, CDCl3) δ H 7.15 (br d, J=1.0Hz, 2H), 6.62 (s, 1H), 6.53(d, J=7.8 Hz, 2H), 3.39 (br dd, J=6.0,9.8 Hz, 1H), 2.13- 2.04 (m, 1H), 1.80 (s,4H), 1.68 - 1.63 (m, 4H), 1.26 (s, 15H),1.08 (d, J=6.0 Hz, 7H),1.01 - 0.93 (m, 2H),0.66 (s, 3H);LC-ELSD / MS purity 99%,MS ESIC 27 H 42 NO[M+H] + Calculated value 396, measured value 396. B15: 1 H NMR (400MHz, CDCl3) δ H7.14 (s, 2H), 6.63 (s, 1H), 6.55 (br d, J=8.0Hz, 2H), 3.37 (br s, 1H), 1.95 (brs, 2H), 1.80(br s, 3H), 1.69 - 1.60 (m, 3H), 1.41(br s, 8H), 1.27(s, 7H), 1.18(br d, J=5.8 Hz, 9H), 0.74 (s, 4H);LC-ELSD / MS purity 99%,MSESI C 27 H 42 NO[M+H] + Calculated value 396, measured value 396.

[0439] Examples 27 and 28: Synthesis of (3R,5R,8R,9R,10S,13S,14S,17S)-17-((R)-1-(benzylamino)ethyl)-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-3-ol (B16) and (3R,5R,8R,9R,10S,13S,14S,17S)-17-((S)-1-(benzylamino)ethyl)-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-3-ol (B17) [ka] To a solution of B1 (8.00 g, 25.1 mmol) in MeOH (100 mL) was added 1-phenylmethanamine (16.0 g, 150 mmol), the pH of the solution was adjusted to pH 6 with acetic acid (10 mL), and THF (100 mL) was added at 25 °C under N . After stirring at 25 °C for 10 min, NaBH CN (1.48 g, 25.1 mmol) was added. After stirring at 65 °C for 1 h, the reaction mixture was cooled, diluted with water (200 mL), and extracted with EtOAc (3 × 200 mL). The combined organic solution was washed with saturated brine (2 × 200 mL), dried over anhydrous Na SO , filtered, and concentrated. The residue was purified by flash column chromatography (0–10% DCM in CH OH) to give B16 (5.00 g) and B17 (5.00 g) as solids. B16: 1H NMR (400MHz, CDCl3) δ = 7.34 -7.21 (m, 5H), 3.93 - 3.57 (m, 2H), 2.70-2.58 (m,1H), 2.06-1.98 (m, 1H), 1.95-1.56(m, 8H), 1.70 - 1.18 (m, 15H), 1.18 - 0.95 (m,8H),0.62 (s, 3H) B17: 1 H NMR (400 MHz, CDCl3) δ = 7.34 -7.27 (m,5H), 3.93 - 3.57 (m, 2H), 2.63-2.52 (m, 1H), 1.95-1.75 (m, 5H), 1.70 -1.30 (m, 11H),1.28 - 0.95 (m, 16H), 0.65 (s, 3H)

[0440] Example 29: Synthesis of N-((R)-1-((3R,5R,8R,9R,10S,13S,14S,17S)-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethyl)nicotinamide (B19) [ka] Synthesis of B18 To a solution of B16 (5.00 g, 12.2 mmol) in EtOH (50 mL) was added Pd—C (dry, 500 mg) under N. The suspension was degassed under vacuum and purged with H three times. The mixture was stirred under H (15 psi) at 25 °C for 16 h to give a suspension. The reaction mixture was filtered through a pad of Celite and washed with THF (3 × 10 mL). The filtrate was concentrated to give B18 (3 g) as a solid. 1 H NMR (400 MHz,CDCl3)δ = 2.90-2.80(m, 1H), 2.00-1.56 (m, 12H), 1.56-1.12 (m, 18H), 1.00-0.98 (m, 3H),0.73 (s, 3H).

[0441] Synthesis of B19 To a solution of B18 (200 mg, 0.625 mmol) in DMF (3 mL) was added HATU (475 mg, 1.25 mmol) and DIPEA (403 mg, 3.12 mmol). After stirring at 25° C. for 15 min, pyridine-3-carboxylic acid (153 mg, 1.25 mmol) was added. After stirring at 25° C. for 16 h, the reaction mixture was diluted with EtOAc (10 mL), washed with water (10 mL), 3% aqueous LiCl (10 mL), water (10 mL), and brine (10 mL), dried over sodium sulfate, filtered, and concentrated. The residue was purified by HPLC (Agela DuraShell 150mm_25mm_5um column; conditioning solvent: water (0.04% NH3H2O ​​+ 10mM NH4HCO3)-ACN, start B: 48, end B: 78, gradient time (min) 8.5; 100% B hold time (min) 2, flow rate (ml / min) 30; injection 10) to give B19 (48 mg, 18%) as a solid. 1 H NMR (400 MHz,CDCl3) δ = 8.94 (d, J=1.8Hz, 1H), 8.75-8.70 (m, 1H), 8.11 (td, J=2.0,7.8 Hz, 1H), 7.40 (dd, J=5.0, 8.3 Hz,1H),5.90 (br d, LC-ELSD / MS purity 99%, MS ESI C 27 H 41 N2O2[M+H] + Calculated value: 425, measured value: 425.

[0442] Example 30: Synthesis of N-((S)-1-((3R,5R,8R,9R,10S,13S,14S,17S)-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethyl)nicotinamide (B21) [ka] Synthesis of B20 To a solution of B17 (2.00 g, 4.88 mmol) in EtOH (20 mL) was added Pd—C (dry, 200 mg) under N. The suspension was degassed under vacuum and purged with H three times. The mixture was stirred under H (15 psi) at 25 °C for 16 h to give a suspension. The reaction mixture was filtered through a pad of Celite and washed with THF (3 × 10 mL). The filtrate was concentrated to give B20 (1.7 g) as a solid. 1 H NMR (400 MHz,CDCl3) δ = 2.83-2.72(m, 1H), 2.00-1.75 (m,7H), 1.56-1.25 (m, 18H), 1.25-0.95(m, 8H), 0.65 (s, 3H).

[0443] Synthesis of B21 To a solution of pyridine-3-carboxylic acid (153 mg, 1.25 mmol) in DMF (5 mL) was added HATU (356 mg, 0.937 mmol) and DIPEA (403 mg, 3.12 mmol). After stirring at 25° C. for 15 min, B20 (200 mg, 0.625 mmol) was added. After stirring at 25° C. for 16 h, the reaction mixture was diluted with EtOAc (10 mL), washed with water (10 mL), 3% aqueous LiCl (10 mL), water (10 mL), and brine (10 mL), dried over sodium sulfate, filtered, and concentrated. The residue was purified by preparative HPLC (column BostonPrime C18 150*30mm 5um; conditioning solvent: water (0.05v / v% ammonia hydroxide)-ACN, start B: 60; end B: 90, gradient time (min) 8, 100% B retention time (min) 0.1, flow rate (ml / min) 25; injection 8) to give B21 (101mg, 38%) as a solid. 1H NMR (400 MHz,CDCl3) δ = 8.91 (d, J=1.5Hz, 1H), 8.71 (dd, J=1.6, 4.9 Hz, 1H), 8.08(d, J=7.8 Hz, 1H), 7.43 - 7.34 (m, 1H),5.91 (br d, J=8.8 Hz, 1H), 4.33 - 4.20 (m,1H), 2.00-1.75 (m, 5H), 1.70 - 1.56 (m,12H),1.56-1.00 (m, 14H), 0.77 (s, 3H);LC-ELSD / MS purity 99%,MS ESI C 27 H 41 N2O2[M+H] + Calculated value: 425, measured value: 425.

[0444] Examples 31 and 32: Synthesis of 5-cyano-N-((R)-1-((3R,5R,8R,9R,10S,13S,14S,17S)-3-hydroxy-3-(methoxymethyl)-13-methylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethyl)picolinamide (B25) and 5-cyano-N-((S)-1-((3R,5R,8R,9R,10S,13S,14S,17S)-3-hydroxy-3-(methoxymethyl)-13-methylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethyl)picolinamide (B26) [ka] Synthesis of B23 To a solution of B22 (1 g, 2.86 mmol) and 1-phenylmethanamine (1.83 g, 17.1 mmol) in MeOH (15 mL) at 25 °C, adjusted to pH 6 (using acetic acid and anhydrous THF), was added NaBHCN (215 mg, 3.43 mmol) after 30 min. After stirring at 80 °C for 16 h, the solution was diluted with aqueous NaHCO (20 mL) and extracted with EtOAc (2 × 30 mL). The combined organic solution was washed with brine, dried over sodium sulfate, concentrated, and purified by column chromatography on silica gel (50–80% EtOAc in PE) to give the desired product (1.09 g) as a solid. 1 H NMR (400 MHz,CDCl3) δ 7.36-7.28 (m, 4H), 7.25-7.20(m, 1H), 3.90-3.86(m, 1H), 3.63-3.59 (m, 1H),3.42-3.35 (m, 5H), 2.66-2.53(m, 1H), 2.04-1.69 (m, 6H), 1.66-1.52 (m, 7H), 1.47-1.30(m, 8H), 1.28-0.96 (m, 8H),0.64-0.62 (m, 3H).

[0445] Synthesis of B24 To a solution of B23 (1.09 g, 2.47 mmol) in EtOH (10 mL) was added Pd / C (dry, 100 mg). The mixture was stirred under H (15 psi) at 25 °C for 16 h. The reaction mixture was filtered through a Celite pad and washed with MeOH (3 × 10 mL). The filtrate was concentrated to give B24 (700 mg) as a solid. The product was purified by flash column (2% MeOH in CHCl) to give B24 (500 mg, 71%) as an oil. 1 H NMR (400 MHz,CDCl3) δ 3.42-3.36 (m, 5H), 2.88-2.77(m, 1H), 2.01-1.71(m, 6H), 1.70-1.49 (m, 8H),1.48-1.16 (m, 8H), 1.14-0.97(m,8H), 0.72-0.65 (m, 3H).

[0446] Synthesis of 25 and 26 [ka] To a solution of 5-cyanopicolinic acid (500 mg, 3.37 mmol) in DCM (30 mL) and DMF (1 mL) was added oxalyl chloride (431 mg, 3.37 mmol) dropwise at 0 °C. After stirring at 10 °C for 18 h, DIPEA (147 mg, 1.14 mmol) and B24 (100 mg, 0.286 mmol) were added. After stirring at 25 °C for 48 h, saturated aqueous NH4Cl (50 mL) was added to the mixture, which was then extracted with ethyl acetate (3 × 30 mL). The combined organic solution was washed with aqueous LiCl (3 × 50 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The product was purified by flash column chromatography (20% EtOAc in PE) to give a mixture of diastereomers (180 mg) as an oil. The diastereomers were separated by SFC {column: DAICEL CHIRALPAK AD (250 mm * 30 mm, 10 μm), conditioning solvent: 0.1% NH3H2O ​​ETOH, starting B: 40%, ending B: 40%} and lyophilized to give B25 (20 mg, peak 1) and B26 (22 mg, peak 2) as solids. B25: 1 H NMR (400MHz, CDCl3) δ 8.83 (d, J = 1.2Hz,1H), 8.34-8.32 (m,1H), 8.14-8.11 (m, 1H), 7.83(d, J = 9.2Hz, 1H), 4.15-4.09 (m,1H), 3.41-3.34 (m, 5H), 2.60 (s, 1H), 1.89-1.68(m, 5H), 1.67-1.49 (m, 8H), 1.47-1.29(m, 8H), 1.25-0.85 (m, 6H), 0.68 (s, 3H).LC-ELSD / MS purity 99%, MS ESI C 29 H 42 N3O3[M+H] + Calculated value 480, measured value 480. SFC 100% de. B26: 1H NMR (400MHz, CDCl3) δ 8.82-8.80 (m, 1H),8.33-8.31 (m, 1H), 8.13-8.11 (m, 1H),7.83 (d, J= 9.2Hz, 1H), 4.22-4.13 (m, 1H),3.42-3.36 (m, 5H), 2.61 (s, 1H), 1.85 (m, 5H), 1.96-1.68(m, 8H), 1.67-1.53 ​​(m,5H),1.51-1.32 (m, 3H), 1.28-1.01 (m, 6H), 0.75 (s, 3H).LC-ELSD / MS purity 99%, MS ESIC 29 H 42 N3O3[M+H] + Calculated value 480, measured value 480. SFC 100% de.

[0447] Example 33: Synthesis of 4-(((R)-1-((3R,5R,8R,9R,10S,13S,14S,17S)-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethyl)amino)benzonitrile (C1) [ka] To a solution of 4-bromobenzonitrile (127 mg, 0.703 mmol) in toluene (5 mL), (acetyloxy)paradioacetate (10.5 mg, 0.047 mmol), CsCO (305 mg, 0.938 mmol), and BANAP (29.2 mg, 0.047 mmol) were added under N. After stirring at 25 °C for 20 min, B18 (150 mg, 0.469 mmol) was added to the mixture. After stirring at 110 °C for 6 h under N, the reaction was cooled to 25 °C and stirred overnight. The reaction mixture was filtered and concentrated. The residue was purified by HPLC (Column Xtimate C18 150*25mm*5um; conditioning solvent: water (0.225% FA)-ACN, start B84; end B100, gradient time (min) 7; 100% B retention time (min) 2, flow rate (ml / min) 25; injection 5) to give C1 (80 mg, 41%) as a solid. 1H NMR (400 MHz,CDCl3) δ = 7.39 (d, J=8.8 Hz, 2H),6.47 (d, J=8.8 Hz,2H), 3.95 (br d, J=8.9 Hz, 1H),3.51-3.31 (m, 1H), 1.93-1.75(m, 5H), 1.70-1.53 ​​(m, 2H), 1.49-1.23(m, 15H), 1.15-0.95(m, 9H), 0.62 (s, 3H); LCMS purity 99%, MS ESI C 28 H 41 NO[M+H] + Calculated value 421, measured value 421.

[0448] Examples 34 to 37: 1-((S)-2-((3R,5R,8R,9R,10S,13S,14S,17R)-3-hydroxy-3-(methoxymethyl)-13-methylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)propyl)-1H-pyrazole-5-carbonitrile (C5) (Example 34), 1-((S)-2-((3R,5R,8R,9R,10S,13S,14S,17R)-3-hydroxy-3-(methoxymethyl)-13-methylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)propyl)-1H-pyrazole-3-carbonitrile (C6) (Example 3 5), 1-((R)-2-((3R,5R,8R,9R,10S,13S,14S,17R)-3-hydroxy-3-(methoxymethyl)-13-methylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)propyl)-1H-pyrazole-3-carbonitrile (C7) (Example 36), and 1-((R)-2-((3R,5R,8R,9R,10S,13S,14S,17R)-3-hydroxy-3-(methoxymethyl)-13-methylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)propyl)-1H-pyrazole-5-carbonitrile (C8) (Example 37) [ka] Synthesis of C2 To a solution of MePPhBr (12.2 g, 34.0 mmol) in THF (20 mL) was added t-BuOK (2.88 g, 25.8 mmol) at 15 °C. After stirring at 15 °C for 1 h, B22 (3 g, 8.60 mmol) in THF (20 mL) was added. After stirring at 45 °C for 3 h, the mixture was treated with saturated NHCl (50 mL) and extracted with EtOAc (2 × 30 mL). The combined organic solution was washed with brine (100 mL), dried over anhydrous NaSO, filtered, and concentrated. The residue was purified by flash column chromatography (0–40% EtOAc in PE) to give C2 (4.5 g, crude) as an oil. 1 H NMR (400MHz,CDCl3) δ 4.83 (s, 1H),4.45 (s, 1H), 3.47-3.31(m, 5H), 2.61 (s, 1H), 2.05-2.02(m, 1H), 1.91-1.77 (m,4H), 1.74 (s,3H), 1.68-1.52 (m, 5H), 1.49-1.31 (m, 7H), 1.28-1.04(m, 7H), 0.59-0.50(m, 3H).

[0449] Synthesis of C3 To a solution of C2 (4.5 g, 12.9 mmol) in THF (30 mL) was added BH3.Me2S (11.6 mL, 116 mL). After stirring at 15 °C for 1 h, aqueous NaOH (6.16 g, 154 mmol) was added at 0 °C, followed by hydrogen peroxide (15.4 mL, 10 M aqueous solution, 154 mmol). After stirring at 78 °C for 3 h, the residue was poured into water (35 mL) and extracted with EtOAc (3 × 30 mL). The combined organic solution was washed with brine (2 × 20 mL), dried over anhydrous Na2SO4, filtered, and concentrated. Trituration of the residue from CH3OH (20 mL) and water (200 mL) gave C3 (4.5 g) as an oil, which was purified by flash column chromatography (0–30% EtOAc in PE) to give C3 (1.7 g, 38%) as a solid. 1H NMR (400MHz,CDCl3) δ 3.77-3.69 (m,0.6H), 3.62 (dd, J=3.3,10.5 Hz, 0.4H), 3.40-3.36(m, 6H), 1.94 (d, 12.5 Hz, 1H),1.87-1.71 (m, 6H), 1.67-1.52 (m, 4H), 1.49-1.29(m,7H), 1.22-0.99 (m, 10H), 0.94(d, J=6.8 Hz, 2H), 0.66 (s, 3H).

[0450] C4 synthesis To a solution of C3 (1.3 g, 3.56 mmol) in CHCl (15 mL) at 0 °C, PPh3 (1.11 g, 4.27 mmol) and NBS (755 mg, 4.27 mmol) were added. After stirring at 20 °C for 3 h, the reaction mixture was poured into water (20 mL) and extracted with EtOAc (3 × 30 mL). The combined organic solution was washed with brine (2 × 20 mL), dried over anhydrous NaSO, filtered, and concentrated. The residue was purified by flash column chromatography (0–15% EtOAc in PE) to give C4 (1.0 g, 59%) as an oil. 1 H NMR (400MHz,CDCl3) δ 3.63 (dd, J=3.2,9.6 Hz, 0.6H), 3.53-3.47 (m, 0.4H), 3.43-3.33(m, 6H), 1.97-1.87 (m, 1H), 1.86-1.78(m,3H), 1.64-1.51 (m, 4H), 1.64-1.51 (m, 4H),1.48-1.32 (m, 6H), 1.29-1.19 (m,3H), 1.13-0.95 (m, 8H), 0.67 (s, 3H).

[0451] Synthesis of C5, C6, C7, and C8 To a solution of C4 (450 mg, 1.05 mmol) in DMF (10 mL) were added CsCO (682 mg, 2.1 mmol) and 1H-pyrazole-3-carbonitrile (195 mg, 2.1 mmol). After stirring at 85 °C for 12 h, the reaction mixture was diluted with EtOAc (50 mL), washed with water (20 mL), aqueous LiCl (50 mL, 3%), and brine (50 mL), dried over anhydrous NaSO, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography (8% EtOAc in PE) to give C5 and C8 (130 mg) and C6 and C7 (300 mg) as oils.

[0452] A mixture of C5 and C8 (130 mg) was purified by SFC (column: DAICEL CHIRALCEL OJ-H (250 mm x 30 mm, 5 μm), conditioning solvent: 0.1% NH3H2O ​​ETOH, starting B: 20%, ending B: 20%), then concentrated and lyophilized to obtain C5 (12 mg, peak 1) and C8 (26 mg, peak 2), both as solids.

[0453] The mixture of C6 and C7 was purified by SFC (column: DAICEL CHIRALCEL OD-H (250 mm x 30 mm, 5 μm), conditioning solvent: 0.1% NH3H2O ​​ETOH, starting B: 30%, ending B: 30%), then concentrated and lyophilized to obtain C6 (83 mg, peak 1) and C7 (97 mg, peak 2), both as solids. C5: 1 H NMR (400MHz, CDCl3) δ 7.57 (d, J = 2 Hz, 1H),6.76 (d, J = 2 Hz, 1H), 4.39-4.35 (m, 1H),3.94-3.88 (m, 1H), 3.42-3.36 (m, 5H),2.59 (s, 1H), 2.15-1.64 (m, 6H), 1.60-1.52(m,8H), 1.49-1.31 (m, 5H), 1.27-0.98(m, 6H), 0.81 (d, J = 6.4 Hz, 3H), 0.71 (s, 3H).LC-ELSD / MS purity 99%, MS ESI C 27 H 41N3O2Na[M+Na] + Calculated value for it is 462, measured value is 462. SFC 98.79% de. C6: 1 H NMR (400 MHz, CDCl3) δ 7.39 (d, J = 2.8 Hz, 1H), 6.65 (d, J = 2.4 Hz, 1H), 4.29 - 4.25 (m, 1H), 3.75 - 3.69 (m, 1H), 3.42 - 3.33 (m, 5H), 2.60 (s, 1H), 2.05 - 1.71 (m, 6H), 1.65 - 1.55 (m, 6H), 1.48 - 1.27 (m, 6H), 1.09 (m, 7H), 1.21 - 0.98 (d, J = 6.4 Hz, 3H), 0.70 (s, 3H). LC - ELSD / MS purity 99%, MS ESI C 27 H 41 N3O2Na[M+Na] + Calculated value for it is 462, measured value is 462. SFC 100% de. C7: 1 H NMR (400 MHz, CDCl3) δ 7.39 (d, J = 2.8 Hz, 1H), 6.65 (d, J = 2.4 Hz, 1H), 4.53 - 4.48 (m, 1H), 3.70 - 3.64 (m, 1H), 3.42 - 3.36 (m, 5H), 2.61 (s, 1H), 2.16 - 2.05 (m, 1H), 1.89 - 1.71 (m, 5H), 1.66 - 1.52 (m, 7H), 1.49 - 1.31 (m, 6H), 1.27 - 1.01 (m, 6H), 0.79 (s, 3H), 0.67 (d, J = 6.4 Hz, 3H). LC - ELSD / MS purity 99%, MS ESI C 27 H 41 N3O2Na[M+Na] + Calculated value for it is 462, measured value is 462. SFC 100% de. C8: 1H NMR (400MHz, CDCl3) δ 7.56 (d, J = 2 Hz, 1H),6.77 (d, J = 2 Hz, 1H), 4.61-4.57 (m, 1H),3.93-3.87 (m, 1H), 3.43-3.36 (m, 5H),2.59 (s, 1H), 2.23-2.14 (m, 1H), 1.93-1.71(m,5H), 1.67-1.52 (m, 8H), 1.49-1.31(m, 5H), 1.28-1.01 (m, 6H), 0.82 (s, 3H), 0.68(d, J = 6.4 Hz, 3H).LC-ELSD / MS purity 99%, MSESIC 27 H 42 N3O2[M+H] + Calculated value 440, measured value 440. SFC 97%.

[0454] Examples 38 and 39: Synthesis of (3R,5R,8R,9R,10S,13S,14S,17S)-3,13-dimethyl-17-((R)-1-(methyl(phenyl)amino)ethyl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-ol (C9) and (3R,5R,8R,9R,10S,13S,14S,17S)-3,13-dimethyl-17-((S)-1-(methyl(phenyl)amino)ethyl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-ol (C10) [ka] B14 / B15 (740 mg, 1.87 mmol) and (HCHO) at 25°C n To a solution of (561 mg, 18.7 mmol) in DCE (20 mL) was added NaBH(OAc)3 (470 mg, 7.48 mmol). After stirring at 25 °C for 16 h, additional (HCHO) n(561 mg, 18.7 mmol) and NaCNBH3 (620 mg) were added. After stirring overnight, the reaction was poured into water (30 mL) and extracted with EtOAc (3 × 30 mL). The combined organic solution was washed with saturated brine (2 × 20 mL), dried over anhydrous Na2SO4, filtered, and concentrated to give a mixture of C9 and C10 (800 mg) as an oil, which was further purified by preparative HPLC (Column: Xbridge 150*30 mm*10 um; Conditioning solvent: water (10 mM NH4HCO3)-ACN, 95% to 100% in 7 min; 100% B retention time: 1 min; Flow rate: 25 ml / min) to give a mixture of C9 and C10 (260 mg, 0.6346 mmol) as an oil. Purification by SFC (column: DAICEL CHIRALPAK AD-H (250 mm * 30 mm, 5 μm), conditioning solvent: 0.1% NH3H2O ​​ETOH, start B: 40%, end B: 40%, flow rate (ml / min): 50, injection: 70) gave C9 (76 mg, peak 1) and C10 (62 mg, peak 2) as solids. C9: 1 HNMR (400 MHz,CDCl3) δ 7.26-7.20 (m, 2H), 6.79-6.77(m, 2H), 6.75-6.65 (m, 1H), 3.85-3.77 (m, 1H),2.65 (s, 3H), 1.81-1.77(m, 6H),1.75-1.49 (m, 7H), 1.48-1.31 (m, 6H), 1.30-1.24 (m,3H), 1.23-1.09 (m, 4H),1.08-0.96(m, 5H), 0.64 (s, 3H).LC-ELSD / MS Purity 99%, MS ESI C 28 H 44 NO[M+H] + Calculated value 410, measured value 410. SFC 100% de. C10: 1HNMR(400 MHz,CACl3) δ 7.22-7.18 (m, 2H), 6.75-6.72(m, 2H), 6.65-6.61(m, 1H), 3.85 -3.79 (m, 1H),2.69 (s, 3H), 2.00-1.77 (m, 5H),1.75-1.60 (m, 4H),1.59-1.50 (m, 7H), 1.49-1.24 (m,8H), 1.23-1.06 (m, 7H), 0.77(s, 3H).LC-ELSD / MS purity 99%,MS ESI C 28 H 44 NO[M+H] + Calculated value 410, measured value 410. SFC 100% de.

[0455] Example 40: Synthesis of 2-((R)-1-((3R,5R,8R,9R,10S,13S,14S,17S)-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl)ethyl)-1-oxoisoindoline-5-carbonitrile (D3) [ka] Synthesis of D2 To a mixture of 5-cyanophthalide (1 g, 6.28 mmol) in thionyl chloride (20 mL) was added BF3·Et2O (100 mg, 0.8849 mmol), followed by benzyltriethylammonium chloride (858 mg, 3.77 mmol). After stirring at 90 °C for 72 h, the reaction mixture was cooled and concentrated in vacuo. The resulting residue was dissolved in dry CHCl2 (100 mL), cooled in an EtOH ice bath for 5 min, and dry MeOH (50 mL) was added dropwise. After adjusting the pH to 8 with DIPEA, the mixture was concentrated, diluted with EtOAc (300 mL), and filtered. The filtrate was concentrated and purified by silica gel chromatography (3% ethyl acetate in PE) to give D2 (1.30 g, 99%) as a solid. 1 H NMR (400 MHz, CDCl3) δ H8.06 (d, J = 8.0 Hz,1H), 7.90 (d, J = 1.0 Hz, 1H),7.69 (dd, J = 1.6, 8.0 Hz, 1H),5.03 (s, 2H), 3.97(s, 3H).

[0456] Synthesis of D3 A mixture of D2 (392 mg, 1.87 mmol), B18 (300 mg, 0.9388 mmol), and K2CO3 (387 mg, 2.81 mmol) in EtOH (15 mL) was stirred at 25 °C for 1 h. After stirring at 95 °C for 72 h, the reaction mixture was diluted with DCM (100 mL), washed with water (100 mL), brine (100 mL), dried over Na2SO4, filtered, and concentrated in vacuo to give a solid, which was purified by preparative HPLC (Column: Xtimate C18 150*25 mm*5 um, Conditioning solvent: water (0.225% FA)-ACN, Start B: 82%, End B: 95%, Gradient time (min): 7, Retention time of 100% B (min): 1, Flow rate (ml / min) 25) to give D3 (110 mg) as a solid. Trituration of the solid in hexanes (20 mL) gave a solid (87 mg, 20%). 1 H NMR (400 MHz, CDCl3) δ H 7.94 (d, J = 8.8 Hz,1H), 7.78-7.73 (m, 2H), 4.58-4.47(m, 1H), 4.44-4.34 (m, 2H),1.90-1.59 (m, 6H),1.50-1.27 (m, 9H), 1.25-1.20 (m, 8H),1.19-0.84 (m, 8H), 0.80(s, 3H);LC-ELSD / MS purity 99%,MS ESI C 30 H 41 N2O2[M+H] + Calculated value 461, measured value 461.

[0457] Example 41: Synthesis of 6-(((R)-1-((3R,5R,8R,9R,10S,13S,14S,17S)-3-hydroxy-3-(methoxymethyl)-13-methylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethyl)amino)nicotinonitrile (E3) [ka] Synthesis of E1 To a solution of B22 (5.00 g, 14.3 mmol) and (1R)-1-phenylethan-1-amine (10.3 g, 85.8 mmol) in DCE (50 mL) was added NaCNBH (7.06 g, 114 mmol) at 25 °C. After stirring at 50 °C for 16 h, the reaction was quenched with water (50 mL) and extracted with DCM (2 × 50 mL). The combined organic solution was washed with brine (100 mL), dried over NaSO, filtered, and concentrated. The residue was purified by flash column (0–20% EtOAc in PE) to give ST-320-046-009_2 (4.5 g, 69%) as a solid. 1 H NMR (400MHz, CDCl3) δ H 7.38-7.27(m, 4H), 7.24-7.16(m, 1H), 3.89 (q, J=6.3Hz, 1H),3.48-3.28 (m, 5H), 2.80-2.66(m, 1H), 2.56 (s, 1H), 2.23 (br d, J=11.8 Hz,1H), 1.93-1.55 (m, 9H), 1.40-1.21(m, 13H), 1.17-1.01(m, 5H), 0.89 (d, J=6.0 Hz,3H), 0.78 (s, 3H).de%99+(1H by NMR), SFC100%de.

[0458] Synthesis of E2 To a solution of E1 (4.50 g, 9.91 mmol) in EtOH (50 mL) was added Pd-C (dry, 450 mg) under N2. The suspension was degassed under vacuum and purged with H2 three times. After stirring at 50 °C under H2 (50 psi) for 16 h, the reaction mixture was filtered through a Celite pad and washed with THF (3 x 50 mL). The combined filtrates were concentrated to give E2 (3.0 g, 87%) as a solid. The stereochemistry of C20 was C21-Me. 1 Assignment was based on 1 HNMR. 1 H NMR (400MHz, CDCl3) δ H 3.51-3.31(m, 5H), 2.93-2.72(m, 1H), 2.01-1.91 (m,1H), 1.87-1.62 (m, 7H), 1.51-1.03 (m,19H), 1.00 (d,J=6.0 Hz, 3H), 0.72 (s, 3H).

[0459] Synthesis of E3 To a solution of 6-chloropyridine-3-carbonitrile (118 mg, 0.858 mmol) in toluene (2 mL), Pd(OAc) (9.63 mg, 0.043 mmol), CsCO (279 mg, 0.858 mmol), and BINAP (26.7 mg, 0.043 mmol) were added under N. After stirring at 25 °C for 20 min, E (150 mg, 0.429 mmol) was added. After stirring at 110 °C for 32 h, the reaction mixture was filtered and concentrated. The residue was purified by flash column chromatography (0–50% EtOAc in PE) to give a solid. The solid was purified by HPLC (Column: Xtimate C18 150*25mm*5um; Conditioning solvent: water (0.225% FA)-ACN, Start B 80, End B 100, Gradient time (min) 7; 100% B Retention time (min) 1, Flow rate (ml / min) 25) to give E3 (24 mg, 15% mmol) as a solid. 1H NMR (400MHz, CDCl3)δ H8.34 (d, J=2.0Hz, 1H), 7.53 (br d, J=7.3 Hz, 1H), 6.29 (d, J=8.8 Hz,1H), 4.80 (br s, 1H), 3.44-3.22(m,5H), 2.63 (br s, 1H), 1.92-1.63 (m, 7H), 1.56-1.27(m, 10H), 1.26-0.89 (m, 11H),0.62(s,3H).LC-ELSD / MS purity 99%, MS ESI C 28 H 42 N3O2[M+H] + The calculated value is 452, and the measured value is 452.

[0460] Example 42: Synthesis of N-((R)-1-((3R,5R,8R,9R,10S,13S,14S,17S)-3-(ethoxymethyl)-3-hydroxy-13-methylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethyl)-2-fluorobenzamide (F9) [ka] Synthesis of F2 To a stirred solution of trimethylsulfonium iodide (70 g, 343 mmol) in DMSO (200 mL) and THF (100 mL) was added NaH (14 g, 583 mmol) over 2 h at 0 °C under N. A solution of estrane-3,17-dione, (5β)- (50 g, 182 mmol) in DMSO (200 mL) and THF (100 mL) was added to the mixture at 0 °C. After stirring at 25 °C for 16 h, the reaction mixture was poured into HO (500 mL) and extracted with EtOAc (2 × 700 mL). The combined organic solution was washed with water (2 × 300 mL), brine (300 mL), dried over anhydrous NaSO, filtered, and concentrated. The residue was purified by silica gel chromatography (PE / EtOAc = 0 to 9 / 1 to 4 / 1) to give F2 (37 g) as an oil, which was triturated with MeOH (200 mL) at 25 °C to give F2 (27 g, 52%) as a solid. 1 H NMR (400 MHz, CDCl3) δ H2.63-2.55 (m, 3H), 2.48-2.40 (m, 1H), 2.27-2.19 (m,1H), 2.12-1.76 (m, 7H), 1.71-1.64(m, 2H), 1.53 (m,8H), 1.18-1.09 (m, 2H), 1.04-0.98(m, 1H), 0.89-0.87 (m, 3H).

[0461] Synthesis of F3 To anhydrous EtOH (200 mL) was added NaH (22.4 g, 933 mmol) portionwise at 25 °C. After stirring at 25 °C for 1 h, F2 (27 g, 93.6 mmol) in absolute ethanol (100 mL) was added to the freshly prepared sodium ethoxide solution. After stirring at 75 °C for 16 h, the reaction mixture was cooled, quenched with aqueous NH4Cl (200 mL), and extracted with EtOAc (2 × 300 mL). The combined organic solutions were washed with brine (200 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by silica gel chromatography (PE / EtOAc = 0-9 / 1 to 4 / 1) to give F3 (12.2 g, 39%) and F3a (10.4 g, 33%) as an oil. F3: 1 H NMR (400MHz, CDCl3) δ H 3.53 (q, J = 6.8 Hz, 2H), 3.42 (q, J = 9.2 Hz,2H), 2.72 (s, 1H), 2.43 (dd, J =8.2, 19.2 Hz, 1H), 2.13-2.05 (m, 1H), 1.97-1.89(m, 1H), 1.86-1.74 (m, 5H), 1.66-1.57(m, 4H), 1.53 (s, 1H), 1.52-1.50 (m, 1H), 1.46-1.27(m, 7H), 1.20 (t, J = 6.8 Hz,4H), 1.12-1.04 (m, 1H), 0.86 (s, 3H).

[0462] Synthesis of F4 To a mixture of EtPPhBr (39.7 g, 107 mmol) in THF (150 mL) was added t-BuOK (12.0 g, 107 mmol) under N at 25 °C. After stirring at 25 °C for 30 min, F3 (12 g, 35.8 mmol) in THF (50 mL) was added. After stirring at 75 °C for 16 h, the reaction mixture was diluted with water (200 mL) and extracted with EtOAc (2 × 300 mL). The combined organic solution was washed with brine (200 mL), dried over anhydrous NaSO, filtered, and concentrated. The residue was purified by flash column chromatography (0–10% EtOAc in PE) to give F4 (10.4 g, 84%) as an oil. 1 H NMR (400 MHz, CDCl3) δ H 5.15-5.07 (m, 1H), 3.53 (q, J = 6.8 Hz, 2H), 3.43(q, J = 9.2 Hz, 2H), 2.68 (s,1H), 2.40-2.30 (m, 1H), 2.28-2.13 (m, 2H), 1.87-1.69(m, 4H), 1.67-1.58 (m, 8H),1.55-1.35 (m, 7H), 1.28-1.23(m,2H), 1.20 (t, J = 7.2Hz, 4H), 1.17-1.06 (m,3H),0.87 (s, 1H).

[0463] Synthesis of F5 To a solution of F4 (10.4 g, 30.0 mmol) in THF (200 mL) was added 9-BBN dimer (14.6 g, 60.0 mmol) under N2. After stirring at 60 °C for 1 h under N2, the mixture was cooled to 25 °C, and ethanol (30 mL, 30.0 mmol) and NaOH (60.0 mL, 5 M, 300 mmol) were added. Once clear, HO2 (30.0 mL, 10 M, 300 mmol) was added dropwise at 25 °C, followed by saturated aqueous Na2SO3 (100 mL). After stirring at 25 °C for an additional 1 h, the mixture was poured into water (150 mL) and extracted with EtOAc (2 × 200 mL). The combined organic solution was washed with brine (150 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was triturated from MeOH / H2O (100 mL / 100 mL) at 25°C to give F5 (11.6 g) as a solid. 1 H NMR (400 MHz, CDCl3) δ H 3.52 (q, J = 6.8 Hz,2H), 3.42 (q, J = 9.2 Hz, 2H),1.92-1.74 (m, 7H), 1.66-1.55(m, 8H), 1.45-1.34 (m,7H), 1.25 (t, J = 6.8 Hz, 3H), 1.23-1.19 (m, 6H), 1.16-1.08(m, 4H), 0.65 (s, 1H).

[0464] Synthesis of F6 To a solution of F5 (11.6 g, 31.8 mmol) in DCM (150 mL) was added silica gel (17 g) and PCC (17.0 g, 79.5 mmol) at 25 °C. After stirring at 25 °C for 1 h, the mixture was filtered through a Celite pad, washed with DCM (2 × 100 mL), filtered, and concentrated. The residue was purified by flash column (0–25% EtOAc in PE) to give F6 (8.5 g, 74%) as an oil. 1 H NMR (400 MHz, CDCl3) δ H3.55-3.49 (m, 2H), 3.46-3.37 (m, 2H), 2.79-2.68 (m,1H), 2.53 (t, J = 8.8 Hz, 1H),2.16-2.11 (m, 1H), 2.10 (s, 3H), 2.02-1.96 (m, 1H),1.85-1.56 (m, 9H), 1.49-1.35(m, 7H), 1.27-1.18 (m, 7H),1.15-1.01 (m, 3H), 0.60 (s,1H).

[0465] Synthesis of F7 To a solution of F6 (12.8 g, 35.3 mmol) and (1R)-1-phenylethan-1-amine (25.5 g, 211 mmol) in DCE (100 mL) at 25 °C was added NaCNBH (17.7 g, 282 mmol). After stirring at 50 °C for 16 h, the reaction was diluted with water (300 mL) and extracted with DCM (2 × 250 mL). The combined organic solution was washed with brine (200 mL), dried over NaSO, filtered, and concentrated. The residue was triturated from MeOH / HO (200 mL / 200 mL) and purified by flash column (0–10% EtOAc in PE) to give F7 (8.8 g, 73%) as a colorless oil. 1 H NMR (400 MHz,CDCl3) δ 7.36-7.27 (m, 4H), 7.24-7.18(m, 1H), 3.93-3.85(m, 1H), 3.57-3.49 (m, 2H),3.48-3.37 (m, 2H), 2.69 (s, 2H),2.26-2.18 (m, 1H), 1.89-1.70(m, 4H), 1.69-1.55 (m,5H), 1.45-1.31 (m, 6H), 1.28(d,J = 6.4 Hz, 3H), 1.26-1.19 (m, 7H), 1.14-1.01 (m,5H), 0.89 (d, J = 6.0 Hz,3H), 0.78 (s,3H).de%99+( 1 H NMR). SFC 100% de.

[0466] Synthesis of F8 To a solution of F7 (8.7 g, 18.6 mmol) in EtOH (100 mL) was added Pd-C (dry, 900 mg) and one drop of NH3H2O. After stirring under H2 (50 psi) at 50 °C for 72 h, the reaction mixture was filtered through a Celite pad and washed with EtOH (3 × 150 mL). The filtrate was concentrated to give F8 (6.7 g, 99%) as an oil. The stereochemistry of C20 was C21-Me. 1 Assignment was based on 1 HNMR. 1 H NMR (400 MHz, CDCl3) δ H 3.56-3.49 (m, 2H), 3.46-3.37 (m, 2H), 2.88-2.79 (m,1H), 2.00-1.92 (m, 1H), 1.85-1.69(m, 5H), 1.67-1.54 (m, 8H), 1.49-1.28 (m, 8H),1.20 (t, J = 7.2 Hz, 4H), 1.13-1.04(m, 4H), 1.01(d, J = 6.0 Hz, 3H), 0.72 (s, 3H).

[0467] Synthesis of F9 To a solution of 2-fluorobenzoic acid (77.0 mg, 0.550 mmol) in pyridine (3 mL) at 25 °C was added EDCI (105 mg, 0.550 mmol). After stirring at 25 °C for 30 min, F8 (100 mg, 0.275 mmol) was added. After stirring at 50 °C for 16 h, the mixture was diluted with water (20 mL) and extracted with EtOAc (2 × 30 mL). The combined organic solution was washed with brine (20 mL), dried over anhydrous NaSO, filtered, and concentrated. The residue was purified by HPLC (Column: Xtimate C18 150 × 25 mm; 5 μm; Conditioning Solvent: water (0.225% FA)-ACN; Gradient: 70% to 90% B over 7 min, hold at 100% for 1 min; Flow rate: 25 mL / min) to give F9 (47 mg, 35%) as a solid. 1 H NMR (400 MHz, CDCl3)δ H8.16-8.10 (m, 1H), 7.49-7.42 (m, 1H), 7.29-7.26 (m, 1H), 7.14-7.07(m, 1H), 6.68-6.57(m, 1H), 4.28-4.13 (m, 1H), 3.55-3.49 (m, 2H), 3.45-3.36 (m, 2H),2.70 (s, 1H),1.89-1.60 (m, 7H), 1.54-1.23 (m, 10H), 1.22-1.17 (m, 7H), 1.16-0.88(m, 6H), 0.73(s, 3H). 19 FNMR (376 MHz, CDCl3) δ F -113.67.LC-ELSD / MS purity 99%, MS ESI C 30 H 45 FNO3[M+H] + The calculated value is 486, and the measured value is 486.

[0468] Example 43: Synthesis of 2-((R)-1-((3R,5R,8R,9R,10S,13S,14S,17S)-3-(ethoxymethyl)-3-hydroxy-13-methylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethyl)-1-oxoisoindoline-5-carbonitrile (F10) [ka] A mixture of D2 (184 mg, 0.88 mmol), F8 (160 mg, 0.44 mmol), and K2CO3 (182 mg, 1.32 mmol) in EtOH (15 mL) was stirred at 25 °C for 1 h. After stirring at 95 °C for 16 h, the reaction mixture was diluted with DCM (100 mL), washed with water (100 mL), brine (100 mL), dried over Na2SO4, filtered, and concentrated in vacuo to give a solid. The residue was purified by preparative HPLC (conditioning solvent: water (0.225% FA)-ACN, start B: 80, end B: 100, gradient time (min): 7, 100% B, retention time (min): 0, flow rate (ml / min): 25) to give F10 (11 mg, 5%) as a solid. 1 H NMR (400 MHz, CDCl3) δ H7.94 (d, 1H), 7.81-7.68(m, 2H), 4.60-4.45 (m, 1H),4.39 (d, J=2.0 Hz, 2H), 3.61-3.46(m, 2H), 3.44-3.29(m, 2H), 2.71 (s, 1H), 1.88-1.55(m, 7H), 1.53-1.36 (m, 7H),1.34-1.25 (m, 3H), 1.24-1.14 (m, 9H), 1.14-0.82 (m, 4H),0.80 (s, 3H).LC-ELSD / MS purity 99%, MS ESI C 32 H 45 N2O3[M+H] + Calculated value 505, measured value 505.

[0469] Example 44: Synthesis of 2-((R)-1-((3R,5R,8R,9R,10S,13S,14S,17S)-3-hydroxy-3-(methoxymethyl)-13-methylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethyl)-1-oxoisoindoline-5-carbonitrile (F11) [ka] A mixture of D2 (345 mg, 1.65 mmol), E2 (300 mg, 0.825 mmol), and K2CO3 (340 mg, 2.47 mmol) in EtOH (15 mL) was stirred for 1 h at 25 °C. After stirring for 72 h at 95 °C, the reaction mixture was diluted with DCM (100 mL), washed with water (100 mL), brine (100 mL), dried over Na2SO4, filtered, and concentrated in vacuo to give F11 (500 mg) as a solid, which was purified by preparative HPLC (conditioning solvent: water (0.225% FA)-ACN, start B: 69, end B: 99, gradient time (min): 7, 100% B retention time (min): 1, flow rate (ml / min): 25) to give F11 (95 mg, 19%) as a solid. 1 H NMR (400 MHz, CDCl3) δ H7.93 (m, 1H), 7.81-7.71(m, 2H), 4.63-4.33 (m, 3H),3.45-3.26 (m, 5H), 2.59 (s,1H), 1.90-1.65 (m, 6H), 1.57-1.35(m, 7H), 1.34-1.27 (m,2H), 1.24-1.09 (m, 8H),1.08-0.84 (m, 4H), 0.79 (s, 3H).LC-ELSD / MS purity 99%,MS ESI C 31 H 43 N2O3[M+H] + Calculated value: 491, measured value: 491.

[0470] Example 45: Synthesis of 2-((R)-1-((3R,5R,8R,9R,10S,13S,14S,17S)-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-6-carbonitrile (F13) [ka] Synthesis of F12 To a solution of B18 (300 mg, 0.938 mmol) and benzoic acid, 4-cyano-2-(2-oxoethyl)-, methyl ester (379 mg, 1.87 mmol) in DCE (6 mL) and CHOH (6 mL) was added NaCNBH (176 mg, 2.81 mmol) and acetic acid (168 mg, 2.81 mmol) under N at 25 °C. After stirring at room temperature for 16 h, the mixture was poured into water (20 mL) and extracted with DCM (3 × 20 mL). The combined organic solution was washed with brine (2 × 20 mL), dried over anhydrous NaSO, filtered, and concentrated to give F12 (300 mg) as an oil, which was used directly in the next step.

[0471] Synthesis of F13 A solution of F12 (300 mg, 0.592 mmol) in toluene (20 mL) was stirred at 110° C. for 16 hours. The reaction mixture was concentrated and purified by HPLC (Column: Xtimate C18 150*25 mm*5 um, Conditioning solvent: water (0.225% FA)-ACN, Start B 80, End B 100, Gradient time (min) 7, 100% B Retention time (min) 2; Flow rate (ml / min) 25) to give F13 (72 mg, 26%) as a solid. 1H NMR (400MHz, CDCl3)δ H 8.19 (d, J=8.1Hz, 1H), 7.62 (d, J=8.0 Hz, 1H), 7.48 (s, 1H), 4.93(br s, 1H), 3.72-3.31 (m, 2H),3.19-3.01(m, 1H), 2.91 (br d, LC-ELSD / MS purity 99%, MSESIC 31 H 43 N2O2[M+H] + Calculated value: 475, measured value: 475.

[0472] Example 46: Synthesis of 2-((R)-1-((3R,5R,8R,9R,10S,13S,14S,17S)-3-(ethoxymethyl)-3-hydroxy-13-methylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)ethyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-6-carbonitrile (15) [ka] Synthesis of F14 To a solution of F8 (100 mg, 1.23 mmol) and benzoic acid, 4-cyano-2-(2-oxoethyl)-, methyl ester (250 mg, 1.23 mmol) in CH3OH / DCE (2 mL / 2 mL) was added acetic acid (88.2 mg, 1.47 mmol) and NaBH3CN (92.3 mg, 1.47 mmol) in one portion under N2 at 25 °C. After stirring at room temperature for 16 h, the reaction was combined with another batch prepared from 100 mg of F8 and poured into aqueous NaHCO3 (20 mL). The aqueous solution was extracted with DCM (2 × 50 mL). The combined organic solution was washed with brine (2 × 30 mL), dried over anhydrous Na2SO4, filtered, and concentrated to give F14 (600 mg) as an oil. LC-ELSD / MS purity 82%, MSESIC 30 H 51 N2O4[M+H] + Calculated value 551, measured value 551.

[0473] Synthesis of F15 A solution of F14 (580 mg, 1.05 mmol) in toluene (20 mL) was refluxed for 16 h. The reaction mixture was concentrated and purified by HPLC (Xtimate C18 column 150*25 mm*5 μm, conditioning solvent: water (0.225% FA)-ACN, start B 90, end B 100, gradient time (min) 7, 100% B retention time (min) 0; flow rate (ml / min) 30) to give F15 (42 mg, 8%) as a solid. 1 H NMR (400 MHz, CDCl3) δ H 8.19 (d, J = 7.6 Hz,1H), 7.62 (d, J = 7.6 Hz, 1H),7.48 (s, 1H), 5.00-4.90 (m,1H), 3.59-3.30 (m, 6H), 3.17-3.02 (m, 1H), 2.98-2.91(m, 1H), 0.76-0.70(m, 1H),1.83-1.70 (m, 4H), 1.68-1.54 (m, 8H), 1.43-1.24 (m, 7H),1.25-1.15 (m, 4H),1.15-1.07(m, 6H), 1.15-0.90 (m, 1H), 0.79 (s, 3H).LC-ELSD / MS purity 99%, MSESI C33 H 47 N2O3[M+H] + Calculated value 519, measured value 519.

[0474] Examples 47 and 48: Synthesis of (3R,5R,8R,9R,10S,13R,14S,17R)-3-(methoxymethyl)-13-methyl-17-(2-(5-methyl-2H-tetrazol-2-yl)ethyl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-ol (G5) and (3R,5R,8R,9R,10S,13R,14S,17R)-3-(methoxymethyl)-13-methyl-17-(2-(5-methyl-1H-tetrazol-1-yl)ethyl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-ol (G6) [ka] Synthesis of G1 To a stirred solution of sodium hydride (1.23 g, 30.8 mmol, 60% in oil) in THF (75 mL) was added ethyl 2-(diethoxyphosphanyl)acetate (7.32 g, 32.7 mmol) at 40 °C. After stirring under N for 30 min, A33 (3.0 g, 9.4 mmol) was added. After stirring at 65 °C for 4 h, the mixture was cooled and concentrated under reduced pressure at 40 °C. The mixture was poured into ice-water (100 mL) and extracted with EtOAc (3 × 100 mL). The combined organic solution was washed with saturated brine (2 × 100 mL), dried over anhydrous NaSO, filtered, and concentrated. The residue was purified by flash column (0–20% EtOAc in PE) to give G1 (2.9 g, 79%) as an oil. 1 H NMR (400 MHz, CDCl3) δ H 5.51 (t, J = 2.4 Hz,1H), 4.19-4.05 (m, 2H), 3.43-3.29(m, 5H), 2.85-2.78 (m, 2H),2.60 (s, 1H), 1.98-1.75 (m, 7H), 1.68-1.00 (m, 15H), 0.88-0.84(m, 2H), 0.83-0.78(m, 3H)

[0475] Synthesis of G2 To a solution of G1 (2.9 g, 7.42 mmol) in EtOH (50 mL) under N was added Pd—C (wet, 10%, 3 g). The suspension was degassed under vacuum and purged with H three times. The mixture was stirred under H (15 psi) at 25° C. for 12 h to give a suspension. The reaction mixture was filtered through a Celite pad and washed with EtOH (3×50 mL). The filtrate was concentrated to give G2 (2.7 g), which was used directly in the next step. LC-ELSD / MS purity 99%, MS ESI C 24 H 39 O3 [M-H2O+H] + Calculated value 375, measured value 375.

[0476] Synthesis of G3 To a solution of G2 (2.7 g, 6.9 mmol) in THF (50 mL) was added lithium aluminum hydride (390 mg, 10.3 mmol) in one portion at 20 °C under N. After stirring at 20 °C for 12 h, HO (2 mL) was added, followed by 1 M HCl until the pH reached 5. The aqueous solution was extracted with EtOAc (3 × 10 mL). The combined organic solution was washed with saturated brine (2 × 20 mL), dried over anhydrous NaSO, filtered, and concentrated. The residue was purified by flash column chromatography (0–50% EtOAc in PE) to give G3 (2.2 g, 92%) as a solid. 1 H NMR (400 MHz, CDCl3) δ H 3.73-3.57 (m, 2H), 3.43-3.35 (m, 5H), 2.59 (s, 1H),1.90- 1.71 (m, 7H), 1.52-1.19(m, 13H), 1.18-0.97(m, 7H), 0.59 (s, 3H).

[0477] Synthesis of G4 To a solution of G3 (2.2 g, 6.3 mmol) in CHCl (20 mL) at 0 °C, PPh (1.9 g, 7.5 mmol) and NBS (1.3 g, 7.5 mmol) were added. After stirring at room temperature for 4 h, the reaction mixture was diluted with water (100 mL) and extracted with EtOAc (3 × 30 mL). The combined organic solution was washed with saturated brine (2 × 20 mL), dried over anhydrous NaSO, filtered, and concentrated. The residue was purified by flash column chromatography (0–15% EtOAc in PE) to give G4 (1.1 g, 30%) as an oil. 1 H NMR (400 MHz, CDCl3) δ H 3.51-3.26 (m, 7H), 2.58 (s, 1H), 2.01-1.53 ​​(m, 12H),1.49-0.94 (m, 14H), 0.59 (s,3H).

[0478] Synthesis of G5 and G6 To a solution of G4 (250 mg, 0.6 mmol) in DMF (5 mL) were added CsCO (390 mg, 1.2 mmol) and 5-methyl-2H-1,2,3,4-tetrazole (100 mg, 1.2 mmol). After stirring at 85 °C for 12 h, the reaction mixture was diluted with water (100 mL) and extracted with EtOAc (3 × 20 mL). The combined organic solution was washed with brine (2 × 50 mL), dried over NaSO, filtered, concentrated, and purified by flash column chromatography (0–30% EtOAc in DCM) to give G5 (90 mg, 45%) as a solid and G6 (40 mg, 20%) as a solid. G5: 1 H NMR (400MHz, CDCl3) δ H 4.61-4.44 (m, 2H), 3.44-3.36 (m, 5H), 2.56 (s, 1H), 2.53 (s, 3H), 2.16-2.07 (m, 1H), 1.90-1.61 (m, 9H), 1.50-0.97 (m, 16H), 0.61 (s, 3H). The structure was confirmed by HMBC. LC-ELSD / MS purity 99%, MSESI C 24 H 39 NO[M-HO+H] +The calculated value is 399, and the measured value is 399. G6: 1 H NMR (400MHz, CDCl3) δ H 4.22 (t, J = 8.0 Hz, 2H), 3.45-3.34 (m, 5H), 2.64-2.55 (m, 4H), 2.06-1.96 (m, 1H), 1.87-1.62 (m, 9H), 1.51-1.01 (m, 16H), 0.60 (s, 3H). The structure was confirmed by HMBC. LC-ELSD / MS purity 99%, MSESI C 24 H 39 NO[M-HO+H] + The calculated value is 399, and the measured value is 399.

[0479] Examples 49 and 50: Synthesis of (3R,5R,8R,9R,10S,13R,14S,17R)-17-(2-(2H-1,2,3-triazol-2-yl)ethyl)-3-(methoxymethyl)-13-methylhexadecahydro-1H-cyclopenta[a]phenanthren-3-ol (G7) and (3R,5R,8R,9R,10S,13R,14S,17R)-17-(2-(1H-1,2,3-triazol-1-yl)ethyl)-3-(methoxymethyl)-13-methylhexadecahydro-1H-cyclopenta[a]phenanthren-3-ol (G8) [ka] To a solution of G4 (200 mg, 0.48 mmol) in DMF (5 mL) were added CsCO (315 mg, 0.97 mmol) and 2H-1,2,3-triazole (66.8 mg, 0.97 mmol). After stirring at 85 °C for 12 h, the mixture was diluted with water (100 mL) and extracted with EtOAc (3 × 20 mL). The combined organic solution was washed with brine (2 × 50 mL), dried over anhydrous NaSO, filtered, concentrated, and purified by flash column chromatography (0–30% EtOAc in DCM) to give G7 (82 mg, 41%) as a solid and G8 (40 mg, 32%, Rf = 0.20, PE / EtOAc = 3 / 1) as a solid. G7: 1H NMR (400MHz, CDCl3) δ H 7.58 (s, 2H), 4.52-4.35(m, 2H), 3.42-3.35 (m,5H), 2.58 (s, 1H), 2.16-2.05 (m,1H), 1.85-1.68 (m, 6H), 1.59-0.98 (m, 19H), 0.60(s, 3H).LC-ELSD / MS purity 99%, MS ESIC 24 H 40 N3O2[M+H] + Calculated value 402, measured value 402. G8: 1 H NMR (400MHz, CDCl3) δ H 7.70 (s, 1H), 7.53(s, 1H), 4.46-4.27 (m, 2H),3.45-3.29 (m, 5H), 2.57 (s, 1H),2.09-2.00 (m, 1H), 1.88-1.80 (m, 2H), 1.69-1.59(m, 8H), 1.42-1.01 (m, 15H), 0.60(s, 3H).LC-ELSD / MS purity 99%, MS ESI C 24 H 40 N3O2[M+H] + Calculated value 402, measured value 402.

[0480] Examples 51 and 52: Synthesis of 1-((R)-2-((3R,5R,8R,9R,10S,13S,14S,17R)-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)propyl)-1H-pyrazole-4-carbonitrile (H7) and 1-((S)-2-((3R,5R,8R,9R,10S,13S,14S,17R)-3-hydroxy-3,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)propyl)-1H-pyrazole-4-carbonitrile (H8) [ka] Synthesis of H1 To a mixture of MePPhBr (16.6 g, 46.7 mmol) in THF (150 mL) was added t-BuOK (5.24 g, 46.7 mmol) under N at 25 °C. After stirring at 50 °C for 30 min, B1 (5 g, 15.6 mmol) was added. After stirring at 50 °C for 2 h, the reaction mixture was quenched with 10% aqueous NHCl (300 mL) at 25 °C and extracted with EtOAc (2 × 200 mL). The combined organic solution was concentrated and triturated with MeOH / HO (1:1, 300 mL) to give H1 (4.8 g, 97.3%) as a solid. 1 H NMR (400 MHz, CDCl3) δ H 4.84 (s, 1H), 4.70 (s,1H), 2.03 (t, J=9.2 Hz, 1H),1.90-1.78(m, 4H), 1.75 (s,3H), 1.72-1.59 (m, 5H), 1.50-1.24 (m, 12H), 1.23-0.98(m, 6H),0.57 (s, 3H).

[0481] Synthesis of H2 To a solution of H1 (4.8 g, 15.1 mmol) in THF (100 mL) was added 9-BBN dimer (7.3 g, 30.2 mmol). After stirring at 45 °C for 16 h, ethanol (10 mL) was added at 15 °C, followed by aqueous NaOH (30.1 mL, 5.0 M, 151 mmol) at 0 °C. Hydrogen peroxide (15 mL, 10 M, 151 mmol) was then added dropwise at 0 °C. After stirring at 78 °C for 1 h, the mixture was cooled to 15 °C and water (150 mL) was added. After stirring at 25 °C for 20 min, the solid was filtered, washed with water (2 × 10 mL), and dried under vacuum to give H2 (4.3 g).

[0482] NOTE: The ratio of 21-α-Me to 21-β-Me based on H-NMR is 4:1. 1 H NMR (400 MHz, CDCl3) δ H3.77-3.59 (m, 1H), 3.48-3.30 (m, 1H), 1.96 (td, J=3.2,12.4 Hz, 1H), 1.89-1.76 (m, 4H), 1.58-1.34(m, 8H), 1.33-1.14 (m, 12H), 1.09-0.93(m, 8H), 0.68 (s, 3H).

[0483] Synthesis of H3 To a solution of H2 (2 g, 5.97 mmol) in DCM (20 mL) was added DMP (5.04 g, 11.9 mmol) in portions. After stirring at 25 °C for 30 min, the mixture was quenched with saturated aqueous NaHCO3 (200 mL). The aqueous solution was extracted with DCM (2 × 150 mL). The combined organic solutions were washed with saturated aqueous Na2S2O3 (200 mL), brine (200 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by flash column chromatography (0–20% EtOAc in PE) to give H3 (1 g, 50.5%) as an oil.

[0484] NOTE: The ratio of 21-α-Me to 21-β-Me based on H-NMR is 4:1. 1 H NMR (400 MHz, CDCl3) δ H 9.56 (d, J=3.2 Hz, 0.8H),9.52 (d, J=3.2 Hz, 0.2H),2.59-2.17 (m, 2H), 2.04 (s,1H), 1.94-1.80 (m, 5H), 1.68-1.60 (m, 4H), 1.50-1.27(m, 12H),1.14-1.03 (m, 8H),0.71-0.66 (m, 3H).

[0485] Synthesis of H4 To a solution of H3 (1 g, 3 mmol) in THF (20 mL) was added TsOH (1.03 g, 6 mmol). After stirring at 25 °C for 16 h, the mixture was added to HO (100 mL) and extracted with EtOAc (2 × 100 mL). The combined organic solutions were washed with saturated NaHCO3 (200 mL), brine (200 mL), dried over anhydrous Na2SO4, filtered, and concentrated to give H4 (1 g), which was used as is.

[0486] Note: The ratio of 21-α-Me to 21-β-Me based on H-NMR is 2:3. 1 H NMR (400 MHz, CDCl3)δ H 9.56 (d, J=3.2 Hz, 0.4H), 9.52 (d, J=4.8 Hz, 0.6H),2.59-2.18 (m, 2H),1.94-1.80(m, 5H), 1.68-1.61 (m, 5H), 1.46-1.24 (m, 12H), 1.12-1.02 (m, 8H),0.71-0.66(m,3H).

[0487] Synthesis of H5 To a solution of H4 (1 g) in MeOH (10 mL) was added NaBH4 (226 mg, 6 mmol). After stirring at 25 °C for 16 h, the reaction mixture was quenched with saturated NH4Cl (150 mL) and extracted with EtOAc (3 × 100 mL). The combined organic solutions were washed with brine (200 mL), dried over anhydrous Na2SO4, filtered, and concentrated to give H5 (1 g) as a solid, which was used as is. 1 H NMR (400 MHz, CDCl3) δ H 3.79-3.58 (m, 1H), 3.49-3.33 (m, 1H), 1.96-1.78 (m,5H), 1.55-1.35 (m, 9H), 1.33-1.17(m, 11H), 1.09-0.92 (m, 8H), 0.68 (s, 3H).

[0488] Synthesis of H6 To a solution of H5 (1 g, 2.98 mmol) in DCM (10 mL) at 0 °C, PPh3 (936 mg, 3.57 mmol) and NBS (635 mg, 3.57 mmol) were added. After stirring at 25 °C for 1 h, the reaction mixture was poured into water (50 mL) and extracted with DCM (3 × 50 mL). The combined organic solution was washed with saturated brine (100 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by flash column (0–10% EtOAc in PE) to give H6 (640 mg, 54.2%) as an oil. 1 H NMR (400 MHz, CDCl3) δ H 3.63 (dd, J=2.8, 9.6Hz, 0.6H), 3.50 (dd, J=2.8, 9.6Hz, 0.4H), 3.41-3.29 (m, 1H),1.95-1.75 (m, 5H),1.69-1.60 (m, 4H), 1.45-1.23 (m,14H), 1.11-0.96 (m, 9H), 0.69-0.67(m, 1H).

[0489] Synthesis of H7 and H8 To a solution of H6 (640 mg, 1.61 mmol) in acetone (10 mL) were added CsCO (1.58 g, 4.83 mmol) and 1H-pyrazole-4-carbonitrile (224 mg, 2.41 mmol). After stirring at 55 °C for 12 h, the reaction mixture was added to water (100 mL) and extracted with EtOAc (2 × 80 mL). The combined organic solution was dried over NaSO, filtered, concentrated, and purified by flash column (0–25% EtOAc in PE) to give a mixture of H7 and H8 (500 mg) as an oil. The diastereomers (350 mg, 0.85 mmol) were separated by SFC (column: DAICEL CHIRALPAKIC AS-H (250 mm * 30 mm, 5 μm); conditioning solvent: 0.1% NH3H2O ​​ETOH; start B: 30%; end B: 30%; flow rate (ml / min): 65) to give H7 (156 mg, 44.6%) and H8 (120 mg, 34.3%), both as solids. H7: 1 H NMR (400MHz, CDCl3) δ H7.80 (s, 1H), 7.75(s, 1H), 4.49 (dd, J=4.4,13.6 Hz, 1H),3.66 (dd, J=10.8, 13.2Hz, 1H), 2.17-2.04 (m, 1H), 1.91-1.73 (m, 5H),1.70-1.60 (m, 3H), 1.50-1.25 (m,13H), 1.22-1.00 (m, 7H), 0.79 (s, 3H), 0.68 (d,J=6.4 Hz, 3H). LC-ELSD / MS purity 99%, analytical SFC: 100% de, MS ESI C 26 H 39 N3O[M+H] + Calculated value for 410.3, measured value 410.3. H8: 1 H NMR (400MHz, CDCl3) δ H 7.79 (s, 1H), 7.75 (s, 1H), 4.25 (dd, J=4.0,13.2Hz, 1H),3.72 (dd, J=9.6, 13.6Hz, 1H), 2.07-1.77 (m, 6H), 1.70-1.60 (m, 3H), 1.50-1.25(m, 13H), 1.21-1.00 (m,7H), 0.81 (d, J=6.4 Hz, 3H), 0.71 (s, 3H). LC-ELSD / MS purity 99%, analytical SFC: 97.08% de, MS ESI C 26 H 39 N3O[M+H] + Calculated value for 410.3, measured value 410.3.

[0490] Examples 53 to 56: (3R,5S,8R,9R,10S,13S,14S,17R)-3-(methoxymethyl)-13-methyl-17-((R)-1-(5-methyl-2H)-tetrazol-2-yl)propan-2-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-ol (H20), (3R,5S,8R,9R,10S,13S,14S,17R)-3-(methoxymethyl)-13-methyl-17-((S)-1-(5-methyl-2H-tetrazol-2-yl)propan-2-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-ol (H2 Synthesis of 1), (3R,5S,8R,9R,10S,13S,14S,17R)-3-(methoxymethyl)-13-methyl-17-((R)-1-(5-methyl-1H-tetrazol-1-yl)propan-2-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-ol (H22), and (3R,5S,8R,9R,10S,13S,14S,17R)-3-(methoxymethyl)-13-methyl-17-((S)-1-(5-methyl-1H-tetrazol-1-yl)propan-2-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-ol (H23) [ka] Synthesis of H10 To a solution of trimethylsulfoxonium iodide (4.2 g, 19.1 mmol) in DMSO (50 mL) was added t-BuOK (2.14 g, 19.1 mmol). After stirring at 60 °C for 1 h under N, (5α)-estrane-3,17-dione (5 g, 18.2 mmol, CAS: 5696-58-2) was added. After stirring at 25 °C for 2 h, the reaction was diluted with water (200 mL) and extracted with EtOAc (2 × 200 mL). The combined organic solution was washed with brine (300 mL), dried over anhydrous NaSO, filtered, and concentrated in vacuo to give H10 (5 g, 95.4%) as a solid. 1 H NMR (400 MHz, CDCl3) δ H2.67-2.61 (m, 2H), 2.44 (dd, J=8.4, 19.2 Hz, 1H),2.13-2.03 (m, 1H), 2.00-1.74 (m,6H), 1.70-1.61(m, 2H), 1.55-1.40 (m, 2H), 1.38-0.99(m, 9H), 0.92-0.71 (m, 5H).

[0491] Synthesis of H11 To anhydrous MeOH (100 mL) was added Na (1.19 g, 51.9 mmol) portionwise at 25 °C. After 30 min, H10 (5 g, 17.3 mmol) was added. After stirring at 60 °C for 16 h, the r...

Claims

1. Compound of formula (I-l): 【Chemical 242】 or a pharmaceutically acceptable salt thereof, wherein: R １ａ , R １ｂ , R ２ａ , R ２ｂ , R ４ａ , R ４ｂ , R ６ａ , R ６ｂ , R ７ａ , R ７ｂ , R １１ａ , R １１ｂ , R １２ａ , and R １２ｂ each is hydrogen; R ３ａ is methyl; R １８ is methyl or ethyl; R １９ is hydrogen, methyl, or ethyl; R Ｙ is methyl or cyano; Each R Ｄ is hydrogen; q is 0, 1, 2, 3, 4, or 5; and R ５５ａ and R ５５ｂ together with the intervening atom, 【Chemical 243】 where p is 1; and R ａ is -CN, The compound or a pharmaceutically acceptable salt thereof.

2. R １９ 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein is methyl or hydrogen.

3. R １９ 3. The compound of claim 2, or a pharmaceutically acceptable salt thereof, wherein is methyl.

4. R １９ 3. The compound of claim 2, or a pharmaceutically acceptable salt thereof, wherein is hydrogen.

5. R Ｙ 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein is methyl.

6. R ５５ａ and R ５５ｂ together with the intervening atom, 【Chemical 244】 6. The compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, which forms:

7. The compound of formula (I-l) is a compound of formula (I-m) or a compound of formula (In) 【Chemistry 245】 or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1, wherein:

8. The compound of formula (I-l) is a compound of formula (I-m) 【Chemical formula 246】 or a pharmaceutically acceptable salt thereof.

8. The compound of claim 7, wherein:

9. R １９ 9. The compound of claim 8, or a pharmaceutically acceptable salt thereof, wherein is methyl or hydrogen.

10. R １９ 10. The compound of claim 9, or a pharmaceutically acceptable salt thereof, wherein is methyl.

11. R １９ 10. The compound of claim 9, or a pharmaceutically acceptable salt thereof, wherein is hydrogen.

12. R Ｙ The compound according to any one of claims 9 to 11, or a pharmaceutically acceptable salt thereof, wherein is methyl.

13. R ５５ａ and R ５５ｂ together with the intervening atom, 【Chemical 247】 13. The compound of claim 12, wherein the compound forms: or a pharmaceutically acceptable salt thereof.

14. The compound of formula (I-I) is a compound of formula (I-Il) 【Chemical 248】 or a pharmaceutically acceptable salt thereof, wherein R １５ａ , R １５ｂ , R １６ａ , and R １６ｂ 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein each of is hydrogen.

15. The compound of formula (I-Il) is a compound of formula (I-Im) or a compound of formula (I-In) 【Chemical 249】 or a pharmaceutically acceptable salt thereof.

15. The compound of claim 14, wherein:

16. The compound of formula (I-Il) is a compound of formula (I-Im) 【Chemistry 250】 or a pharmaceutically acceptable salt thereof.

16. The compound of claim 15, wherein:

17. R ５５ａ and R ５５ｂ together with the intervening atom, 【Chemistry 251】 17. The compound according to any one of claims 14 to 16, or a pharmaceutically acceptable salt thereof, which forms:

18. below: 【Chemical Formula 252】 or a pharmaceutically acceptable salt thereof.

19. Compound of formula (I-l): 【Chemistry 253】 And, Here, R １ａ , R １ｂ , R ２ａ , R ２ｂ , R ４ａ , R ４ｂ , R ６ａ , R ６ｂ , R ７ａ , R ７ｂ , R １１ａ , R １１ｂ , R １２ａ , and R １２ｂ each is hydrogen; R ３ａ is methyl; R １８ is methyl or ethyl; R １９ is hydrogen, methyl, or ethyl; R Ｙ is methyl or cyano; Each R Ｄ is hydrogen; q is 0, 1, 2, 3, 4, or 5; and R ５５ａ and R ５５ｂ together with the intervening atom, 【Chemical 254】 where p is 1; and R ａ is -CN, compound.

20. R １９ 20. The compound of claim 19, wherein is methyl or hydrogen.

21. R １９ 21. The compound of claim 20, wherein is methyl.

22. R １９ 21. The compound of claim 20, wherein is hydrogen.

23. R Ｙ 20. The compound of claim 19, wherein is methyl.

24. R ５５ａ and R ５５ｂ together with the intervening atom, 【Chemistry 255】 The compound according to any one of claims 19 to 23, which forms

25. The compound of formula (I-l) is a compound of formula (I-m) or a compound of formula (In) 【256】 20. The compound of claim 19, wherein:

26. The compound of formula (I-l) is a compound of formula (I-m) 【Chemistry 257】 26. The compound of claim 25, wherein:

27. R １９ 27. The compound of claim 26, wherein is methyl or hydrogen.

28. R １９ 28. The compound of claim 27, wherein is methyl.

29. R １９ 28. The compound of claim 27, wherein is hydrogen.

30. R Ｙ 27. The compound of any one of claims 26, wherein is methyl.

31. R ５５ａ and R ５５ｂ together with the intervening atom, 【Chemical 258】 The compound according to any one of claims 25 to 30, which forms

32. The compound of formula (I-I) is a compound of formula (I-Il) 【Chemical 259】 where R １５ａ , R １５ｂ , R １６ａ , and R １６ｂ 20. The compound of claim 19, wherein each of is hydrogen.

33. The compound of formula (I-Il) is a compound of formula (I-Im) or a compound of formula (I-In) 【Chemistry 260】 33. The compound of claim 32, wherein:

34. The compound of formula (I-Il) is a compound of formula (I-Im) 【Chemical 261】 34. The compound of claim 33, wherein:

35. R ５５ａ and R ５５ｂ together with the intervening atom, 【Chemical 262】 36. The compound of claim 34 or claim 35, wherein the compound forms:

36. below: 【Chemical 263】 A compound selected from:

37. structure 【Chemical 264】 37. The compound of claim 36, having the formula:

38. structure 【Chemical 265】 37. The compound of claim 36, having the formula:

39. structure 【Chemical 266】 37. The compound of claim 36, having the formula:

40. structure 【Chemical 267】 37. The compound of claim 36, having the formula:

41. structure 【Chemical 268】 37. The compound of claim 36, having the formula:

42. structure 【Chemical 269】 37. The compound of claim 36, having the formula:

43. structure 【Chemistry 270】 37. The compound of claim 36, having the formula:

44. structure 【Chemical 271】 37. The compound of claim 36, having the formula:

45. structure 【Chemical 272】 37. The compound of claim 36, having the formula:

46. structure 【Chemical 273】 37. The compound of claim 36, having the formula:

47. A pharmaceutical composition comprising the compound according to any one of claims 1 to 18 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

48. A pharmaceutical composition comprising a compound according to any one of claims 19 to 46 and a pharmaceutically acceptable excipient.

49. Use of a compound according to any one of claims 1 to 18 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 47 or claim 48, in the manufacture of a medicament for treating a CNS-related disorder.

50. 50. The use of claim 49, wherein the CNS-related disorder is a sleep disorder, a mood disorder, a schizophrenia spectrum disorder, a seizure disorder, 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, tinnitus, or status epilepticus.

51. 50. The use of claim 49, wherein the CNS-related disorder is depression.

52. 52. The use of claim 51, wherein the depression is postpartum depression.

53. 52. The use of claim 51, wherein the depression is major depressive disorder.

54. 54. The use of claim 53, wherein the major depressive disorder is moderate major depressive disorder.

55. 54. The use of claim 53, wherein the major depressive disorder is severe major depressive disorder.

56. 50. The use of claim 49, wherein the CNS-related disorder is seizures.

57. 50. The use of claim 49, wherein the CNS-related disorder is tremor.

58. 58. The use of claim 57, wherein the tremor is essential tremor.

59. The use according to any one of claims 49 to 58, wherein the compound or pharmaceutical composition is adapted to be orally administrable.

60. The use according to any one of claims 49 to 59, wherein the compound or pharmaceutical composition is suitable for long-term administration.

61. A composition comprising a compound according to any one of claims 1 to 18 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 47 or claim 48, for use in the treatment of a CNS-related disorder.

62. 62. The composition or pharmaceutical composition of claim 61, wherein the CNS-related disorder is a sleep disorder, a mood disorder, a schizophrenia spectrum disorder, a seizure disorder, 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, tinnitus, or status epilepticus.

63. 62. The composition or pharmaceutical composition of claim 61, wherein the CNS-related disorder is depression.

64. 64. The composition or pharmaceutical composition of claim 63, wherein the depression is postpartum depression.

65. 64. The composition or pharmaceutical composition of claim 63, wherein the depression is major depressive disorder.

66. 66. The composition or pharmaceutical composition of claim 65, wherein the major depressive disorder is moderate major depressive disorder.

67. 66. The composition or pharmaceutical composition of claim 65, wherein the major depressive disorder is severe major depressive disorder.

68. 62. The composition or pharmaceutical composition of claim 61, wherein the CNS-related disorder is seizures.

69. 62. The composition or pharmaceutical composition of claim 61, wherein the CNS-related disorder is tremor.

70. 70. The composition or pharmaceutical composition of claim 69, wherein the tremor is essential tremor.

71. A composition or pharmaceutical composition according to any one of claims 61 to 70, wherein said composition or pharmaceutical composition is adapted to be orally administrable.

72. 72. The composition or pharmaceutical composition according to any one of claims 61 to 71, wherein said composition or pharmaceutical composition is suitable for long-term administration.

73. The compounds or methods described herein.

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