9(11)-unsaturated neuroactive steroids and methods of use thereof

Abstract

Provided herein is a compound of Formula (I) or a pharmaceutically acceptable salt thereof, wherein n, R 19 , R 5 , R 3 , R 6a , R 6b , R 2a , R 2b , R 4a , R 4b , R 7a , R 7b , R 11 , R 12a , R 12b , R 16 , R 21a , R 21b , and R 21c are as defined herein. Also provided herein are pharmaceutical compositions comprising a compound of Formula (I), and methods of using the compounds, e.g., in the treatment of CNS-related disorders.

Description

[0001] Cross-references to related applications

[0002] This application claims the benefit of U.S. Provisional Patent Application No. 62 / 748,016, filed October 19, 2018, the entire contents of which are incorporated herein by reference. Background Technology

[0003] Brain excitability is defined as the level of arousal in an animal (a continuum ranging from coma to seizures) and is regulated by various neurotransmitters. Generally, neurotransmitters are responsible for regulating the conduction of ions across the neuronal membrane. At rest, the neuronal membrane has a potential (or membrane voltage) of approximately -70 mV, with the intracellular portion being negative relative to the extracellular portion. Potential (voltage) is the amount of ion (K+) transported across the semipermeable membrane of the neuron. + Na + Cl - This is a result of the balance of (organic anions). Neurotransmitters are stored in presynaptic vesicles and released under the influence of neuronal action potentials. When released into the synaptic cleft, the potential changes from -70mV to -50mV. This action is mediated by postsynaptic nicotinic receptors, which are stimulated by acetylcholine to increase the response to Na+. + Membrane permeability of ions. A decreased membrane potential stimulates neuronal excitability in the form of postsynaptic action potentials.

[0004] In the case of the GABA receptor complex (GRC), the effect on brain excitability is mediated by gamma-aminobutyric acid (GABA), a neurotransmitter. GABA has a profound impact on overall brain excitability because up to 40% of neurons in the brain utilize GABA as a neurotransmitter. GABA modulates the excitability of individual neurons by regulating the conduction of chloride ions across the neuronal membrane. GABA interacts with its recognition site on the GRC to promote the flow of chloride ions down the electrochemical gradient of the GRC into the cell. This increase in intracellular anion levels leads to hyperpolarization of the transmembrane potential, making neurons less susceptible to excitatory input, i.e., reducing neuronal excitability. In other words, the higher the chloride ion concentration in neurons, the lower the brain's excitability and arousal level.

[0005] The literature provides ample evidence that GRCs are responsible for mediating anxiety, seizures, and sedation. Therefore, GABA and drugs that act like GABA or promote its effects (e.g., therapeutically available barbiturates and benzodiazepines (BZs), such as...) ) by interacting with specific regulatory sites on the GRC. Accumulating evidence now indicates that the GRC contains a unique site for neuroactive steroids in addition to the benzodiazepine and barbiturate binding sites. See, e.g., Lan, N.C. et al., Neurochem. Res. (1991) 16:347-356.

[0006] Neuroactive steroids can occur endogenously. The most potent endogenous neuroactive steroids are 3a-hydroxy-5-reducpregnane-20-one and 3a-21-dihydroxy-5-reducpregnane-20-one, which are metabolites of the hormonal steroids progesterone and deoxycorticosterone, respectively. The ability of these steroid metabolites to alter brain excitability was recognized in 1986 (Majewska, M.D. et al., Science 232:1004-1007 (1986); Harrison, N.L. et al., J Pharmacol. Exp. Ther. 241:346-353 (1987)).

[0007] There is a need for novel and improved neuroactive steroids for use 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. SUMMARY

[0008] Provided herein are neuroactive steroids designed, for example, for use as GABA modulators. In some embodiments, it is envisioned that such compounds can be used as therapeutic agents for the treatment of CNS-related disorders.

[0009] 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, a compound of the application is provided in an effective amount in a pharmaceutical composition. In certain embodiments, a compound of the application is provided in a therapeutically effective amount. In certain embodiments, a compound of the application is provided in a prophylactically effective amount.

[0010] In one aspect, provided herein is a compound of Formula (I):

[0011]

[0012] or a pharmaceutically acceptable salt thereof;

[0013] In some embodiments, the compound of Formula (I) is a compound of Formula (I-a):

[0014]

[0015] or a pharmaceutically acceptable salt thereof;

[0016] In some embodiments, the compound of Formula (I) is a compound of Formula (I-b1) or (1-b2):

[0017]

[0018] or a pharmaceutically acceptable salt thereof.

[0019] In some embodiments, the compound of Formula (I) is a compound of Formula (I-c1):

[0020]

[0021] or a pharmaceutically acceptable salt thereof.

[0022] In some embodiments, the compound of Formula (I) is a compound of Formula (I-c2):

[0023]

[0024] or a pharmaceutically acceptable salt thereof.

[0025] In some embodiments, the compound of Formula (I) is a compound of Formula (I-d):

[0026]

[0027] or a pharmaceutically acceptable salt thereof.

[0028] In some embodiments, the compound of Formula (I) is a compound of Formula (I-e):

[0029]

[0030] or a pharmaceutically acceptable salt thereof.

[0031] In some embodiments, the compound of Formula (I) is a compound of Formula (I-f):

[0032]

[0033] or a pharmaceutically acceptable salt thereof.

[0034] In some embodiments, the compound of Formula (I) is a compound of Formula (I-g):

[0035]

[0036] or a pharmaceutically acceptable salt thereof.

[0037] In some embodiments, the compound of Formula (I) is a compound of Formula (I-h):

[0038]

[0039] or a pharmaceutically acceptable salt thereof;

[0040] In some embodiments, the compound of Formula (I) is a compound of Formula (I-i):

[0041]

[0042] or a pharmaceutically acceptable salt thereof.

[0043] In some embodiments, the compound of Formula (I) is a compound of Formula (I-j1):

[0044]

[0045] or a pharmaceutically acceptable salt thereof,

[0046] In some embodiments, the compound of Formula (I) is a compound of Formula (I-j2):

[0047]

[0048] or a pharmaceutically acceptable salt thereof,

[0049] In some embodiments, the compound of Formula (I) is a compound of Formula (I-k1):

[0050]

[0051] or a pharmaceutically acceptable salt thereof,

[0052] In some embodiments, the compound of Formula (I) is a compound of Formula (I-k2):

[0053]

[0054] or a pharmaceutically acceptable salt thereof,

[0055] In some embodiments, the compound of Formula (I) is a compound of Formula (I-l1) or (I-l2):

[0056]

[0057] or a pharmaceutically acceptable salt thereof,

[0058] In some embodiments, the compound of Formula (I) is a compound of Formula (I-l2):

[0059]

[0060] or a pharmaceutically acceptable salt thereof,

[0061] In some embodiments, the compound of Formula (I) is a compound of Formula (I-m1):

[0062]

[0063] In some embodiments, the compound of Formula (I) is a compound of Formula (I-m2):

[0064]

[0065] or a pharmaceutically acceptable salt thereof,

[0066] In some embodiments, the compound of Formula (I) is a compound of Formula (I-n1):

[0067]

[0068] or a pharmaceutically acceptable salt thereof;

[0069] In some embodiments, the compound of Formula (I) is a compound of Formula (I-n2):

[0070]

[0071] or a pharmaceutically acceptable salt thereof,

[0072] In some embodiments, the compound of Formula (I) is a compound of Formula (I) of Formula (I-o):

[0073]

[0074] or a pharmaceutically acceptable salt thereof.

[0075] In some embodiments, the compound of Formula (I) is a compound of Formula (I) of Formula (I-p)

[0076]

[0077] or a pharmaceutically acceptable salt thereof.

[0078] In some embodiments, the compound of Formula (I) is a compound of Formula (I) of Formula (I-q)

[0079]

[0080] In some embodiments, the compound of Formula (I) is a compound of Formula (I) of Formula (I-r)

[0081]

[0082] or a pharmaceutically acceptable salt thereof.

[0083] In some embodiments, the compound of Formula (I) has Formula (Is)

[0084]

[0085] or a pharmaceutically acceptable salt thereof.

[0086] In some embodiments, the compound of Formula (I) has Formula (I-t)

[0087]

[0088] or a pharmaceutically acceptable salt thereof.

[0089] In some embodiments, the compound of Formula (I) has Formula (I-u)

[0090]

[0091] or a pharmaceutically acceptable salt thereof.

[0092] In one aspect, provided herein is a pharmaceutically acceptable salt of a compound described herein (e.g., a compound of Formula (I)).

[0093] 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, e.g., by continuous intravenous infusion.

[0094] The compounds of the application, as described herein, are in certain embodiments useful as GABA modulators, e.g., to positively or negatively affect GABA A receptors. As modulators of excitability of the central nervous system (CNS), such compounds are expected to have CNS activity, as mediated by their ability to modulate GABA A receptors.

[0095] In one aspect, described herein is a method for treating a CNS-related disorder in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof.

[0096] In some embodiments, the CNS-related disorder is a sleep disorder, a mood disorder, a schizophrenia spectrum disorder, a convulsive disorder, a memory and / or cognition disorder, a movement disorder, a personality disorder, an autism spectrum disorder, pain, a traumatic brain injury, a vascular disease, a substance abuse disorder and / or withdrawal syndrome, tinnitus, or a status epilepticus.

[0097] 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.

[0098] In some embodiments, the compound is selected from the group consisting of the compounds identified in Table 1 herein. DETAILED DESCRIPTION

[0099] As generally described herein, the present application provides neuroactive steroids designed, for example, for use as GABA modulators. In certain embodiments, it is envisioned that such compounds can be used as therapeutic agents for treating CNS-related disorders (e.g., disorders as described herein, e.g., depression, such as postpartum depression or major depressive disorder).

[0100] DEFINITIONS

[0101] CHEMICAL DEFINITIONS

[0102] The definitions of certain functional groups and chemical terms used herein are more fully described below. The chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75thEd., inside cover, and specific functional groups are generally defined as described therein. Additionally, general principles of organic chemistry, as well as specific functional moieties and reactivity, are described in Thomas Sorrell, Organic Chemistry, University Science Books, Sausalito, 1999; Smith and March, March's Advanced Organic Chemistry, 5thEd., 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, 3rdEd., Cambridge University Press, Cambridge, 1987.

[0103] Isomers, such as stereoisomers, can be separated from mixtures by methods known to those skilled in the art, including chiral high pressure liquid chromatography (HPLC) and formation and crystallization of chiral salts; or preferred isomers can be prepared by asymmetric synthesis. See, e.g., 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 (E. L. Eliel, ed., Univ. of Notre Dame Press, Notre Dame, IN 1972). The present application additionally encompasses the compounds described herein in individual isomer form substantially free of other isomers, and alternatively, as mixtures of various isomers.

[0104] As used herein, a pure enantiomeric compound is substantially free of other enantiomers or stereoisomers of the compound (i.e., an enantiomeric excess). In other words, the “S” form of a compound is substantially free of the “R” form of the compound, and thus is in enantiomeric excess of the “R” form. The term “enantiomerically pure” or “pure enantiomer” means that the compound contains more than 75% by weight, more than 80% by weight, more than 85% by weight, more than 90% by weight, more than 91% by weight, more than 92% by weight, more than 93% by weight, more than 94% by weight, more than 95% by weight, more than 96% by weight, more than 97% by weight, more than 98% by weight, more than 98.5% by weight, more than 99% by weight, more than 99.2% by weight, more than 99.5% by weight, more than 99.6% by weight, more than 99.7% by weight, more than 99.8% by weight, or 99.9% by weight of the enantiomer. In certain embodiments, the weight is based on the total weight of all enantiomers or stereoisomers of the compound.

[0105] In the compositions provided herein, enantiomerically pure compounds can be present with other active or inactive ingredients. For example, a pharmaceutical composition comprising enantiomerically pure R compounds can comprise, for example, about 90% excipient and about 10% enantiomerically pure R compounds. In certain embodiments, the enantiomerically pure R compounds in such compositions can comprise, for example, at least about 95% by weight R compounds and at most about 5% by weight S compounds, based on the total weight of the compounds. For example, a pharmaceutical composition comprising enantiomerically pure S compounds can comprise, for example, about 90% excipient and about 10% enantiomerically pure S compounds. In certain embodiments, the enantiomerically pure S compounds in such compositions can comprise, for example, at least about 95% by weight S compounds and at most about 5% by weight R compounds, based on the total weight of the compounds. In certain embodiments, the active ingredients can be formulated with little or no excipient or carrier.

[0106] The article "a" and "an" are used herein to refer to one or more than one (i.e., to at least one) of the grammatical object of the article. By way of example, "an analog" means one analog or more than one analog.

[0107] When a range of values is recited, it is intended to encompass each value and sub-range within the range. For example, "C 1-6 "Alkyl" is intended to encompass 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 groups.

[0108] The following terms are intended to have the meanings provided below and are used in accordance with the description and intended scope of the present application.

[0109] "Alkyl" refers to a straight or branched chain saturated hydrocarbon group ("C 1–20 alkyl") having from one to twenty carbon atoms. In some embodiments, the alkyl group has from one to twelve carbon atoms ("C 1–12 alkyl"). In some embodiments, the alkyl group has from one to ten carbon atoms ("C 1-10 alkyl"). In some embodiments, the alkyl group has from one to nine carbon atoms ("C 1-9 alkyl"). In some embodiments, the alkyl group has from one to eight carbon atoms ("C1-8 alkyl”). In some embodiments, the alkyl group has 1 to 7 carbon atoms (“C 1-7 alkyl”). In some embodiments, the alkyl group has 1 to 6 carbon atoms (“C 1–6 alkyl”, also referred to herein as “lower alkyl”). In some embodiments, the alkyl group has 1 to 5 carbon atoms (“C 1-5 alkyl”). In some embodiments, the alkyl group has 1 to 4 carbon atoms (“C 1-4 alkyl”). In some embodiments, the alkyl group has 1 to 3 carbon atoms (“C 1-3 alkyl”). In some embodiments, the alkyl group has 1 to 2 carbon atoms (“C 1-2 alkyl”). In some embodiments, the alkyl group has 1 carbon atom (“C1alkyl”). In some embodiments, the alkyl group has 2 to 6 carbon atoms (“C 2-6 alkyl”). C 1-6 Examples of alkyl groups include methyl (C1), ethyl (C2), n-propyl (C3), i-propyl (C3), n-butyl (C4), t-butyl (C4), sec-butyl (C4), i-butyl (C4), n-pentyl (C5), 3-pentyl (C5), amyl (C5), neopentyl (C5), 3-methyl-2-butyl (C5), t-amyl (C5), and n-hexyl (C6). Other examples of alkyl groups include n-heptyl (C7), n-octyl (C8), and the like. Unless otherwise indicated, alkyl groups are independently, at each occurrence, 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, the alkyl group is an unsubstituted C 1-10 alkyl (e.g., -CH3). In certain embodiments, the alkyl group is a substituted C 1-10 alkyl. Common alkyl abbreviations include Me (-CH3), Et (-CH2CH3), iPr (-CH(CH3)2), nPr (-CH2CH2CH3), n-Bu (-CH2CH2CH2CH3), or i-Bu (-CH2CH(CH3)2).

[0110] "Alkylene" refers to an alkyl group that has two hydrogen atoms removed to provide a divalent group, and it can be substituted or unsubstituted. Unsubstituted alkylenes include, but are not limited to, methylene (-CH2-), ethylene (-CH2CH2-), propylene (-CH2CH2CH2-), butylene (-CH2CH2CH2CH2-), pentylene (-CH2CH2CH2CH2CH2-), and hexylene (-CH2CH2CH2CH2CH2CH2-). Exemplary substituted alkylene groups (e.g., substituted with one or more alkyl (methyl) groups) include, but are not limited to, substituted methylene (-CH(CH3)-, (-C(CH3)2-), substituted ethylene (-CH(CH3)CH2-, -CH2CH(CH3)-, -C(CH3)2CH2-, -CH2C(CH3)2-), substituted propylene (-CH(CH3)CH2CH2-, -CH2CH(CH3)CH2-, -CH2CH2CH(CH3)-, -C(CH3)2CH2CH2-, -CH2C(CH3)2CH2-, -CH2CH2C(CH3)2-), etc. When a range or number of carbons is provided for a particular alkylene group, it should be understood that the range or number refers to the range or number of carbons in a straight-chain divalent carbon chain. Alkylene groups may be substituted with one or more substituents as described herein or may not be substituted.

[0111] "Alkenyl" refers to a straight-chain or branched hydrocarbon group ("C") 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). 2-20 Alkenyl group (“Alkenyl”). In some embodiments, the alkenyl group does not contain any triple bonds. In some embodiments, the alkenyl group has 2 to 10 carbon atoms (“C”). 2-10 Alkenyl group (“Alkenyl”). In some embodiments, the alkenyl group has 2 to 9 carbon atoms (“C”). 2-9 Alkenyl group (“Alkenyl”). In some embodiments, the alkenyl group has 2 to 8 carbon atoms (“C”). 2-8 Alkenyl group (“Alkenyl”). In some embodiments, the alkenyl group has 2 to 7 carbon atoms (“C”). 2-7 Alkenyl group (“Alkenyl”). In some embodiments, the alkenyl group has 2 to 6 carbon atoms (“C”). 2-6 Alkenyl group (“Alkenyl”). In some embodiments, the alkenyl group has 2 to 5 carbon atoms (“C”). 2-5 Alkenyl group (“Alkenyl”). In some embodiments, the alkenyl group has 2 to 4 carbon atoms (“C”). 2-4 Alkenyl group (“Alkenyl”). In some embodiments, the alkenyl group has 2 to 3 carbon atoms (“C”). 2-3Alkenyl (“C2-alkenyl”). In some embodiments, the alkenyl group has two carbon atoms (“C2-alkenyl”). One or more carbon-carbon double bonds may be located internally (e.g., 2-butenyl) or terminally (e.g., 1-butenyl). C 2-4 Examples of alkenyl groups include vinyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), etc. 2-6 Examples of alkenyl groups include the aforementioned C... 2-4 Alkenyl groups include pentenyl (C5), pentadienyl (C5), hexenyl (C6), etc. Other examples of alkenyl groups include heptenyl (C7), octenyl (C8), octetrinyl (C8), etc. Unless otherwise stated, the alkenyl group is independently and optionally substituted each time it appears, i.e., unsubstituted (“unsubstituted alkenyl”) or substituted by one or more substituents (e.g., 1 to 5 substituents, 1 to 3 substituents, or 1 substituent) (“substituted alkenyl”). In some embodiments, the alkenyl group is an unsubstituted C5 group. 2-10 Alkenyl. In some embodiments, the alkenyl group is a substituted C. 2-10 Alkenyl group.

[0112] "Alkyne" refers to a straight-chain or branched hydrocarbon group ("C") 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). 2-20 The alkynyl group (“Alynyl”) is present in some embodiments. In some embodiments, the alkynyl group has 2 to 10 carbon atoms (“C”). 2-10 The alkynyl group (“C”) is present in some embodiments. In some embodiments, the alkynyl group has 2 to 9 carbon atoms (“C”). 2-9 The alkynyl group (“acetylenic”) has 2 to 8 carbon atoms in some embodiments. 2-8 The alkynyl group (“C”) has 2 to 7 carbon atoms in some embodiments. 2-7 The alkynyl group (“C”) has 2 to 6 carbon atoms in some embodiments. 2-6 The alkynyl group (“H”) has 2 to 5 carbon atoms in some embodiments. 2-5 The alkynyl group (“C”) is present in some embodiments. In some embodiments, the alkynyl group has 2 to 4 carbon atoms (“C”). 2-4 The alkynyl group (“C”) is present in some embodiments. In some embodiments, the alkynyl group has 2 to 3 carbon atoms (“C”). 2-3 The alkynyl group (“C2-alkynyl”) is present in some embodiments. One or more carbon-carbon triple bonds may be located internally (e.g., 2-butynyl) or terminally (e.g., 1-butynyl). 2-4Examples of alkynyl groups include, but are not limited to, ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), and 2-butynyl (C4). 2-6 Examples of alkenyl groups include the aforementioned C... 2-4 The alkynyl group includes pentynyl (C5), hexynyl (C6), etc. Other examples of the alkynyl group include heptynyl (C7), octyynyl (C8), etc. Unless otherwise stated, the alkynyl group is independently and optionally substituted each time it appears, i.e., unsubstituted (“unsubstituted alkynyl”) or substituted by one or more substituents (e.g., 1 to 5 substituents, 1 to 3 substituents, or 1 substituent) (“substituted alkynyl”). In some embodiments, the alkynyl group is an unsubstituted C5 group. 2-10 Alkyne group. In some embodiments, the alkynyl group is a substituted C- group. 2-10 Alkyne group.

[0113] As used herein, the term "heteroalkyl" refers to an alkyl group as defined herein that further comprises 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 one or more heteroatoms are inserted between carbon atoms and the parent molecule, i.e., between connection points. In some embodiments, a heteroalkyl group refers to a saturated group having 1 to 10 carbon atoms and 1, 2, 3, or 4 heteroatoms ("heteroalkyl group"). 1-10 Alkyl group (“heteroalkyl”). In some embodiments, the heteroalkyl group is a saturated group having 1 to 9 carbon atoms and 1, 2, 3 or 4 heteroatoms (“heteroalkyl”). 1-9 Alkyl group (“heteroalkyl”). In some embodiments, the heteroalkyl group is a saturated group having 1 to 8 carbon atoms and 1, 2, 3 or 4 heteroatoms (“heteroalkyl”). 1-8 Alkyl group (“heteroalkyl”). In some embodiments, the heteroalkyl group is a saturated group having 1 to 7 carbon atoms and 1, 2, 3 or 4 heteroatoms (“heteroalkyl”). 1-7 Alkyl group (“heteroalkyl”). In some embodiments, a heteroalkyl group is a group having 1 to 6 carbon atoms and 1, 2 or 3 heteroatoms (“heteroalkyl”). 1-6 Alkyl group (“heteroalkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 5 carbon atoms and 1 or 2 heteroatoms (“heteroalkyl”). 1-5 Alkyl group (“heteroalkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 4 carbon atoms and 1 or 2 heteroatoms (“heteroalkyl”). 1-4 Alkyl group (“heteroalkyl”). In some embodiments, the heteroalkyl group is a saturated group having 1 to 3 carbon atoms and 1 heteroatom (“heteroalkyl”). 1-3 Alkyl group (“heteroalkyl”). In some embodiments, the heteroalkyl group is a saturated group having 1 to 2 carbon atoms and 1 heteroatom (“heteroalkyl”). 1-2Alkyl group (“heteroalkyl”). In some embodiments, a heteroalkyl group is a saturated group having one carbon atom and one heteroatom (“heteroC1 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having two to six carbon atoms and one or two heteroatoms (“heteroC1 alkyl”). 2-6 Alkyl group”. Unless otherwise stated, each heteroalkyl group is independently unsubstituted (“unsubstituted heteroalkyl”) or substituted with one or more substituents (“substituted heteroalkyl”) each time it appears. In some embodiments, the heteroalkyl group is an unsubstituted heteroalkyl group. 1-10 Alkyl group. In some embodiments, the heteroalkyl group is a substituted heteroC. 1-10 alkyl.

[0114] "Aryl" refers to a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14π electrons shared in a cyclic array) group having 6 to 14 ring carbon atoms and zero heteroatoms ("C") provided in the aromatic ring system. 6-14 Aryl group (“C6 aryl”). In some embodiments, the aryl group has six ring carbon atoms (“C6 aryl”; for example, phenyl). In some embodiments, the aryl group has ten ring carbon atoms (“C6 aryl”). 10 Aryl; for example, naphthyl, such as 1-naphthyl and 2-naphthyl). In some embodiments, the aryl group has fourteen ring carbon atoms (“C14”). 14 "Aryl" (e.g., anthracene). "Aryl" also includes ring systems in which an aryl ring, as defined above, is fused with one or more carbocyclic or heterocyclic groups, wherein the linking group or linking point is on the aryl ring, and in such cases, the number of carbon atoms continues to indicate the number of carbon atoms in the aryl ring system. Typical aryl groups include, but are not limited to, groups derived from: anthracene, acenaphthene, phenanthrene, anthracene, azulene, benzene, etc. , benzo[a]benzene, fluoranthene, fluorene, hexaphenyl, hexalene, hexalene, asymmetric indole, symmetric indole, dihydroindene, indene, naphthalene, octaphenyl, octaphenyl, aldrin, oleophane, pentadiene, pentaphenyl, dinaphthalene, phenaene, phenanthrene, dinaphthalene, heptamethrin, pyrene, pyridine, rubigin, triphenylene, and trinaphthalene. Specific aryl groups include phenyl, naphthyl, indene, and tetrahydronaphthalene. Unless otherwise specified, the aryl group is independently and optionally substituted each time it appears, i.e., unsubstituted (“unsubstituted aryl”) or substituted by one or more substituents (“substituted aryl”). In some embodiments, the aryl group is an unsubstituted C 6-14 Aryl. In some embodiments, the aryl group is a substituted C. 6-14 Aryl.

[0115] In some embodiments, the aryl group is substituted with one or more of the following groups: halogen, C1-C8 alkyl, C1-C8 haloalkyl, cyano, hydroxyl, C1-C8 alkoxy, and amino.

[0116] Representative examples of substituted aryl groups include the following

[0117]

[0118] Where R 56 and R 57 One of them can be hydrogen, and R 56 and R 57 At least one of them is independently selected from C1-C8 alkyl, C1-C8 haloalkyl, 4-10 membered heterocyclic, alkanoyl, C1-C8 alkoxy, heteroaryloxy, alkylamino, arylamino, heteroarylamino, NR 58 COR 59 NR 58 SOR 59 NR 58 SO2R 59 COO alkyl, COO aryl, CONR 58 R 59 CONR 58 OR 59 NR 58 R 59 SO2NR 58 R 59 S-alkyl, SO-alkyl, SO2alkyl, S-aryl, SO-aryl, SO2aryl; or R 56 and R 57 Five to eight atoms can be bonded to form a cyclic ring (saturated or unsaturated), which optionally contains one or more heteroatoms selected from the group consisting of N, O, or S. R 60 and R 61 Independently, it is hydrogen, C1-C8 alkyl, C1-C4 haloalkyl, C3-C 10 Cycloalkyl, 4-10 membered heterocyclic, C6-C 10 Aryl, substituted C6-C 10 Aryl, 5-10 heteroaryl or substituted 5-10 heteroaryl.

[0119] "Fused aryl" refers to an aryl group whose two ring carbons are the same as the second aryl or heteroaryl ring, or the same as the carbocyclic or heterocyclic ring.

[0120] "Heteroaryl" refers to a 5-10 member monocyclic or bicyclic 4n+2 aromatic ring system (e.g., having 6 or 10π electrons shared in a cyclic array), wherein the aromatic ring system provides a cyclic carbon atom and 1-4 cyclic heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-10 member heteroaryl"). In heteroaryls containing one or more nitrogen atoms, the linkage can be a carbon or nitrogen atom, where the valence allows. A heteroaryl bicyclic system may include one or more heteroatoms in one or both rings. "Heteroaryl" includes a cyclic system in which a heteroaryl ring as defined above is fused with one or more carbocyclic or heterocyclic groups, wherein the linkage is located on the heteroaryl ring, and in such cases, the number of ring members continues to indicate the number of ring members in the heteroaryl cyclic system. "Heteroaryl" also includes ring systems fused with one or more aryl groups as defined above, wherein the linking point is located on the aryl or heteroaryl ring, and in such cases, the number of ring members indicates the number of ring members in the fused (aryl / heteroaryl) ring system. A bicyclic heteroaryl group (e.g., indolyl, quinolinyl, carbazolyl, etc.) whose ring does not contain a heteroatom can have the linking point on either ring, i.e., a ring with a heteroatom (e.g., 2-indolyl) or a ring without a heteroatom (e.g., 5-indolyl).

[0121] In some embodiments, the heteroaryl group is a 5-10 membered aromatic ring system, wherein the aromatic ring system provides a cyclic carbon atom and 1 to 4 cyclic heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-10 membered heteroaryl”). In some embodiments, the heteroaryl group is a 5-8 membered aromatic ring system, wherein the aromatic ring system provides a cyclic carbon atom and 1 to 4 cyclic heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-8 membered heteroaryl”). In some embodiments, the heteroaryl group is a 5-6 membered aromatic ring system, wherein the aromatic ring system provides a cyclic carbon atom and 1 to 4 cyclic heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-6 membered heteroaryl”). In some embodiments, the 5-6 membered heteroaryl group has 1 to 3 cyclic heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heteroaryl group has 1 to 2 cyclic heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heteroaryl group has one cyclic heteroatom selected from nitrogen, oxygen, and sulfur. Unless otherwise specified, the heteroaryl group is optionally substituted independently each time it appears, i.e., unsubstituted (“unsubstituted heteroaryl”) or substituted by one or more substituents (“substituted heteroaryl”). In some embodiments, the heteroaryl group is an unsubstituted 5-14 membered heteroaryl group. In some embodiments, the heteroaryl group is a substituted 5-14 membered heteroaryl group.

[0122] Exemplary 5-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyrroleyl, 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, pyridinyl, pyrimidinyl, and pyrazinyl. Exemplary 6-membered heteroaryl groups containing three or four heteroatoms include, but are not limited to, triazinyl and tetraazinyl, 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, indazole, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl, benzoimidazolyl, benzoxazolyl, benzoisoxazolyl, benzoxadiazolyl, benzothiazolyl, benzoisothiazolyl, benzothiadiazolyl, indolazinyl, and purinyl. Exemplary 6,6-bicyclic heteroaryl groups include, but are not limited to, naphthidyl, pteridyl, quinolinyl, isoquinolinyl, cenolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl.

[0123] Representative examples of heteroaryl groups include the following:

[0124]

[0125] Each Z is selected from carbonyl, N, NR 65 O and S; and R 65 Independently, it is hydrogen, C1-C8 alkyl, C3-C 10 Cycloalkyl, 4-10 membered heterocyclic, C6-C 10 Aryl and 5-10 heteroaryl compounds.

[0126] "Carbocyclic group" or "carbocyclic" refers to a non-aromatic ring system having 3 to 10 ring carbon atoms ("C"). 3-10 A group consisting of a carbocyclic group (“C”) and a non-aromatic hydrocarbon group with zero heteroatoms. In some embodiments, the carbocyclic group has 3 to 8 cyclic carbon atoms (“C”). 3-8 Carbocyclic group (“CCR”). In some embodiments, the carbocyclic group has 3 to 6 cyclic carbon atoms (“C”). 3-6 Carbocyclic group (“CCR”). In some embodiments, the carbocyclic group has 3 to 6 cyclic carbon atoms (“C”). 3-6 (Carbocyclic group). In some embodiments, the carbocyclic group has 5 to 10 cyclic carbon atoms (“C”). 5-10 (Carbocyclic group). Example C 3-6Carbocyclic groups include, but are not limited to, cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), and cyclohexadienyl (C6). Example C 3-8 Carbocyclic groups include, but are not limited to, the aforementioned C 3-6 Carbocyclic groups, including cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cyclohepttrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptyl (C7), bicyclo[2.2.2]octyl (C8), etc. Example C 3-10 Carbocyclic groups include, but are not limited to, the aforementioned C 3-8 Carbocyclic groups and cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C9) 10 ), cyclodecenyl (C 10 ), octahydro-1H-indenyl (C9), decahydronaphthyl (C9) 10 ), spiro[4.5]decyl(C 10 As illustrated in the foregoing examples, in some embodiments, the carbocyclic group is monocyclic (“monocyclic carbocyclic”) or contains a fused, bridged, or spirocyclic system, such as a bicyclic system (“bicyclic carbocyclic”), and may be saturated or partially unsaturated. “Carbocyclic” also includes ring systems where the carbocyclic ring as defined above is fused with one or more aryl or heteroaryl groups, wherein the connection point is on the carbocyclic ring, and in such cases, the number of carbon atoms continues to indicate the number of carbon atoms in the carbocyclic system. Unless otherwise specified, the carbocyclic group is optionally substituted independently each time it appears, i.e., unsubstituted (“unsubstituted carbocyclic”) or substituted by one or more substituents (“substituted carbocyclic”). In some embodiments, the carbocyclic group is an unsubstituted C 3-10 Carbocyclic group. In some embodiments, the carbocyclic group is a substituted C 3-10 Carbon cyclic group.

[0127] In some implementations, "carbocyclic group" is a monocyclic saturated carbocyclic group ("C") having 3 to 10 ring carbon atoms. 3-10 cycloalkyl group (“Cycloalkyl”). In some embodiments, the cycloalkyl group has 3 to 8 cyclic carbon atoms (“C”). 3-8 cycloalkyl group (“Cycloalkyl”). In some embodiments, the cycloalkyl group has 3 to 6 cyclic carbon atoms (“C”). 3-6 cycloalkyl group (“Cycloalkyl”). In some embodiments, the cycloalkyl group has 5 to 6 cyclic carbon atoms (“C”). 5-6 cycloalkyl group (“Cycloalkyl”). In some embodiments, the cycloalkyl group has 5 to 10 cyclic carbon atoms (“C”). 5-10 cycloalkyl). C 5-6 Examples of cycloalkyl groups include cyclopentyl (C5) and cyclohexyl (C5). 3-6Examples of cycloalkyl groups include the aforementioned C 5-6 Cycloalkyl groups, as well as cyclopropyl (C3) and cyclobutyl (C4). C 3–8 Examples of cycloalkyl groups include the aforementioned C 3–6 Cycloalkyl groups, including cycloheptyl (C7) and cyclooctyl (C8). Unless otherwise stated, each cycloalkyl group is independently unsubstituted (“unsubstituted cycloalkyl”) or substituted with one or more substituents (“substituted cycloalkyl”). In some embodiments, the cycloalkyl group is an unsubstituted C7 group. 3-10 Cycloalkyl. In some embodiments, the cycloalkyl group is a substituted C-shaped group. 3-10 Cycloalkyl.

[0128] A "heterocyclic group" or "heterocycle" refers to a group comprising a 3- to 10-membered nonaromatic ring system having a ring carbon atom and one to four ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon ("3- to 10-membered heterocyclic groups"). In heterocyclic groups containing one or more nitrogen atoms, the linking point can be a carbon or nitrogen atom, where the valence allows. Heterocyclic groups can be monocyclic ("monocyclic heterocyclic groups") or fused, bridged, or spirocyclic systems, such as bicyclic systems ("bicyclic heterocyclic groups"), and can be saturated or partially unsaturated. A heterocyclic bicyclic system may include one or more heteroatoms in one or both rings. "Heterocyclic group" also includes ring systems fused with one or more carbocyclic groups as defined above, wherein the connection point is located on the carbocyclic or heterocyclic ring; or ring systems fused with one or more aryl or heteroaryl groups as defined above, wherein the connection point is located on the heterocyclic ring. In such cases, the number of ring members continues to indicate the number of ring members in the heterocyclic ring system. Unless otherwise specified, the heterocyclic group is optionally substituted independently each time it appears, i.e., unsubstituted ("unsubstituted heterocyclic group") or substituted by one or more substituents ("substituted heterocyclic group"). In some embodiments, the heterocyclic group is an unsubstituted 3-10 membered heterocyclic group. In some embodiments, the heterocyclic group is a substituted 3-10 membered heterocyclic group.

[0129] In some embodiments, the heterocyclic group is a 5-10 membered non-aromatic ring system having a cyclic carbon atom and 1-4 cyclic heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon (“5-10 membered heterocyclic group”). In some embodiments, the heterocyclic group is a 5-8 membered non-aromatic ring system having a cyclic carbon atom and 1-4 cyclic heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-8 membered heterocyclic group”). In some embodiments, the heterocyclic group is a 5-6 membered non-aromatic ring system having a cyclic carbon atom and 1-4 cyclic heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-6 membered heterocyclic group”). In some embodiments, the 5-6 membered heterocyclic group has 1-3 cyclic heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heterocyclic group has 1-2 cyclic heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heterocyclic group has one cyclic heteroatom selected from nitrogen, oxygen, and sulfur.

[0130] Exemplary 3-membered heterocyclic groups containing one heteroatom include, but are not limited to, azirdinyl, oxiranyl, and thiorenyl. Exemplary 4-membered heterocyclic groups containing one heteroatom include, but are not limited to, azetidinyl, oxetanyl, and thietanyl. Exemplary 5-membered heterocyclic groups containing one heteroatom include, but are not limited to, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolidinyl, and pyrrolidin-2,5-dione. Exemplary 5-membered heterocyclic groups containing two heteroatoms include, but are not limited to, dioxolanyl, oxasulfuranyl, disulfuranyl, and oxazolidin-2-one. Exemplary 5-membered heterocyclic groups containing three heteroatoms include, but are not limited to, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclic groups containing one heteroatom include, but are not limited to, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thioalkyl. Exemplary 6-membered heterocyclic groups containing two heteroatoms include, but are not limited to, piperazinyl, morpholinyl, dithiaalkyl, and dioxaneyl. Exemplary 6-membered heterocyclic groups containing two heteroatoms include, but are not limited to, triazinanyl. Exemplary 7-membered heterocyclic groups containing one heteroatom include, but are not limited to, azepanyl, oxepanyl, and thiepanyl. Exemplary 8-membered heterocyclic groups containing one heteroatom include, but are not limited to, azocanyl, oxecanyl, and thiocanyl. Exemplary 5-membered heterocyclic groups fused with a C6 aryl ring (also referred to herein as 5,6-bicyclic heterocycles) include, but are not limited to, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, benzoxazolinone, etc. Exemplary 6-membered heterocyclic groups fused with aromatic rings (also referred to herein as 6,6-bicyclic heterocycles) include, but are not limited to, tetrahydroquinolinyl, tetrahydroisoquinolinyl, etc.

[0131] "Nitrogen-containing heterocyclic group" means a 4- to 7-membered non-aromatic cyclic 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), azacyclic butane, pyrrolidone, imidazoline, imidazolidinone, 2-pyrazoline, pyrazolidine, piperazine, and N-alkylpiperazine, such as N-methylpiperazine. Specific examples include azacyclic butane, piperidinone, and piperazinone.

[0132] When used to describe a compound or a group present on a compound, "hetero" means that one or more carbon atoms in the compound or group have been replaced by nitrogen, oxygen, or sulfur heteroatoms. "Hetero" can be applied to any of the aforementioned hydrocarbon groups, such as alkyl groups (e.g., heteroalkyl, cycloalkyl), heterocyclic groups (e.g., heteroaryl), aryl groups (e.g., heteroaryl), cycloalkenyl groups (e.g., cycloheterenyl), etc., having 1 to 5, and more specifically 1 to 3, heteroatoms.

[0133] "Acyl" refers to the group -C(O)R 20 , where R 20 As defined herein, it is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclic, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. "Alkyl" is where R... 20 Acyl groups are groups other than hydrogen. Representative acyl groups include, but are not limited to, formyl (-CHO), acetyl (-C(=O)CH3), cyclohexylcarbonyl, cyclohexylmethylcarbonyl, benzoyl (-C(=O)Ph), benzylcarbonyl (-C(=O)CH2Ph), -C(O)-C1-C8 alkyl, and -C(O)-(CH2). t (C6-C 10 Aryl), -C(O)-(CH2) t (5-10 heteroaryl groups), -C(O)-(CH2) t (C3-C 10 Cycloalkyl) and -C(O)-(CH2) t (4-10-membered heterocyclic group), where t is an integer from 0 to 4. In some implementations, R 21 It is a C1-C8 alkyl group substituted with a halogen or hydroxyl group; or a C3-C... 10 Cycloalkyl, 4-10 membered heterocyclic, C6-C 10 Aryl, arylalkyl, 5-10 heteroaryl or heteroarylalkyl, each of which is substituted by: an unsubstituted C1-C4 alkyl, a halogroup, an unsubstituted C1-C4 alkoxy, an unsubstituted C1-C4 haloalkyl, an unsubstituted C1-C4 hydroxyalkyl, or an unsubstituted C1-C4 haloalkoxy or hydroxyl.

[0134] "Alkoxy group" refers to the group -OR 29 , where R 29It is a substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclic, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. Specific alkoxy groups are methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexyloxy, and 1,2-dimethylbutoxy. Specific alkoxy groups are lower alkoxy groups, i.e., having 1 to 6 carbon atoms. Other specific alkoxy groups have 1 to 4 carbon atoms.

[0135] In some implementations, R 29 It is a group having one or more substituents, for example, one to five substituents, and more specifically, one to three substituents, particularly one substituent, said substituent being selected from the group consisting of: amino, substituted amino, C6-C 10 Aryl, aryloxy, carboxyl, cyano, C3-C 10 Cycloalkyl, 4-10 membered heterocyclic groups, halogens, 5-10 membered heteroaryl groups, hydroxyl groups, nitro groups, thioalkoxy groups, thioaryloxy groups, thiols, alkyl-S(O)-, aryl-S(O)-, alkyl-S(O)2-, and aryl-S(O)2-. Exemplary "substituted alkoxy groups" include, but are not limited to, -O-(CH2). t (C6-C 10 Aryl), -O-(CH2) t (5-10 heteroaryl groups), -O-(CH2) t (C3-C 10 cycloalkyl) and -O-(CH2) t (4-10 membered heterocyclic groups), where t is an integer from 0 to 4, and any aryl, heteroaryl, cycloalkyl, or heterocyclic group present may be substituted with: an unsubstituted C1-C4 alkyl, a halogroup, an unsubstituted C1-C4 alkoxy, an unsubstituted C1-C4 haloalkyl, an unsubstituted C1-C4 hydroxyalkyl, or an unsubstituted C1-C4 haloalkoxy or hydroxyl. Specific exemplary “substituted alkoxy” are -OCF3, -OCH2CF3, -OCH2Ph, -OCH2-cyclopropyl, -OCH2CH2OH, and -OCH2CH2NMe2.

[0136] "Amino" refers to the group -NH2.

[0137] "Oxide group" refers to -C(=O)-.

[0138] "Substituted amino group" refers to the formula -N(R 38 The amino group of )2, wherein R 38It is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclic, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or amino protecting group, wherein R 38 At least one of them is not hydrogen. In some implementations, each R 38 Independently selected from hydrogen, C1-C8 alkyl, C3-C8 alkenyl, C3-C8 alkynyl, C6-C 10 Aryl, 5-10 membered heteroaryl, 4-10 membered heterocyclic or C3-C 10 Cycloalkyl, or C1-C8 alkyl substituted with a halogen or hydroxyl group, or C3-C8 alkenyl substituted with a halogen or hydroxyl group, C3-C8 alkynyl substituted with a halogen or hydroxyl group, or -(CH2). t (C6-C 10 Aryl), -(CH2) t (5-10 heteroaryl groups), -(CH2) t (C3-C 10 (cycloalkyl) or -(CH2) t (4-10 membered heterocyclic groups), where t is an integer from 0 to 8, each of the groups being substituted by: an unsubstituted C1-C4 alkyl, a halogroup, an unsubstituted C1-C4 alkoxy, an unsubstituted C1-C4 haloalkyl, an unsubstituted C1-C4 hydroxyalkyl, or an unsubstituted C1-C4 haloalkoxy or hydroxyl; or two R groups. 38 Groups combine to form alkylene groups.

[0139] 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 grade heteroaryl), -NR 39 -(CH2) t (C3-C 10 cycloalkyl) and -NR 39 -(CH2) t (4-10-membered heterocyclic base), where t is an integer from 0 to 4, for example 1 or 2, for each R 39Independently representing H or C1-C8 alkyl; and any alkyl group present may itself be substituted with a halogen, a substituted or unsubstituted amino group, or a hydroxyl group; and any aryl, heteroaryl, cycloalkyl, or heterocyclic group present may itself be substituted with: an unsubstituted C1-C4 alkyl, a halogen, an unsubstituted C1-C4 alkoxy, an unsubstituted C1-C4 haloalkyl, an unsubstituted C1-C4 hydroxyalkyl, or an unsubstituted C1-C4 haloalkoxy or hydroxyl group. 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 encompasses both monosubstituted and disubstituted amino groups.

[0140] "Carboxyl group" refers to the group -C(O)OH.

[0141] "Cyano" refers to the group -CN.

[0142] "Halogen" or "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br), and iodine (I). In some embodiments, the halogen is fluorine or chlorine.

[0143] "Halogenated alkyl" refers to an alkyl group in which one or more halogens are substituted. Typical halogenated alkyl groups include, but are not limited to, trifluoromethyl, difluoromethyl, fluoromethyl, chloromethyl, dichloromethyl, dibromoethyl, tribromomethyl, tetrafluoroethyl, etc.

[0144] "Hydroxy group" refers to the -OH group.

[0145] "Nitro" refers to the group -NO2.

[0146] "Thionyl group" refers to the group =S.

[0147] Alkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, and heteroaryl groups as defined herein are optionally substituted (e.g., “substituted” or “unsubstituted” alkyl, “substituted” or “unsubstituted” alkenyl, “substituted” or “unsubstituted” alkynyl, “substituted” or “unsubstituted” carbocyclic, “substituted” or “unsubstituted” heterocyclic, “substituted” or “unsubstituted” aryl, or “substituted” or “unsubstituted” heteroaryl). Generally, regardless of whether the preceding term “optionally” is used, the term “substituted” means that at least one hydrogen atom present on a group (e.g., a carbon or nitrogen atom) is replaced by a permissible substituent, such as a substituent that, upon substitution, produces a stable compound, such as a compound that cannot spontaneously undergo transformation, for example, by rearrangement, cyclization, elimination, or other reactions. Unless otherwise specified, a “substituted” group has substituents at one or more substituted 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 "substitution" is intended to include substitution by any permissible substituent of an organic compound, or any substituent described herein that results in the formation of a stable compound. This invention covers any and all such combinations to obtain a stable compound. For the purposes of this invention, a heteroatom (such as nitrogen) may have a hydrogen substituent and / or any suitable substituent described herein that satisfies the heteroatom valence and results in the formation of a stable moiety.

[0148] Exemplary carbon atom substituents include, but are not limited to, halogens, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, and -OR. aa -ON(R) bb )2、-N(R bb )2、-N(R bb )3 + X - -N(OR) cc )R bb -SH, -SR aa -SSR cc -C(=O)R aa -CO2H, -CHO, -C(OR) cc )2、-CO2R aa -OC(=O)R aa -OCO2R aa -C(=O)N(R) bb )2、-OC(=O)N(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)R aa 、-P(=O)2R aa 、-OP(=O)2R aa 、-P(=O)(R aa )2、-OP(=O)(R aa )2、-OP(=O)(OR cc )2、-P(=O)2N(R bb )2、-OP(=O)2N(R bb )2、-P(=O)(NR bb )2、-OP(=O)(NR bb )2、-NR bb P(=O)(OR cc )2、-NR bb P(=O)(NRbb )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 group, C 3-10 Carbocyclic groups, 3-14 membered heterocyclic groups, C 6-14 Aryl and 5-14 membered heteroaryl groups, wherein each alkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, and heteroaryl group is independently bounded by 0, 1, 2, 3, 4, or 5 R groups. dd Group substitution; or two homohydrogen atoms on a carbon atom being replaced by =O, =S, =NN(R) groups. 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 Displacement;

[0149] R aa Each time it appears, it is independently selected from C. 1-10 Alkyl, C 1-10 Haloalkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 3-10 Carbocyclic groups, 3-14 membered heterocyclic groups, C 6-14 aryl and 5-14 membered heteroaryl rings, or two R aa Groups are joined to form a 3-14 membered heterocyclic group or a 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, and heteroaryl group is independently bounded by 0, 1, 2, 3, 4, or 5 R groups. dd Group substitution;

[0150] R bb Each time it appears, it is independently selected from hydrogen, -OH, -OR. aa -N(R) cc )2、-CN、-C(=O)R aa -C(=O)N(R) cc )2、-CO2R aa -SO2Raa -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 group, C 3-10 Carbocyclic groups, 3-14 membered heterocyclic groups, C 6-14 aryl and 5-14 heteroaryl, or two R bb The linkages form 3-14 membered heterocyclic or 5-14 membered heteroaryl rings, wherein each alkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, and heteroaryl group is independently bounded by 0, 1, 2, 3, 4, or 5 R groups. dd Group substitution;

[0151] R cc Each time it appears, it is independently selected from hydrogen, C 1-10 Alkyl, C 1-10 Haloalkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 3-10 Carbocyclic groups, 3-14 membered heterocyclic groups, C 6-14 aryl and 5-14 membered heteroaryl rings, or two R cc Groups are joined to form a 3-14 membered heterocyclic group or a 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, and heteroaryl group is independently bounded by 0, 1, 2, 3, 4, or 5 R groups. dd Group substitution;

[0152] R dd Each occurrence is independently selected from halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OR ee -ON(R) ff )2、-N(R ff )2、-N(R ff)3 + X - 、 -N(OR ee )R ff 、 -SH、 -SR ee 、 -SSR ee 、 -C(=O)R ee 、 -CO2H、 -CO2R ee 、 -OC(=O)R ee 、 -OCO2R ee 、 -C(=O)N(R ff )2、 -OC(=O)N(R ff )2、 -NR ff C(=O)R ee 、 -NR ff CO2R ee 、 -NR ff C(=O)N(R ff )2、 -C(=NR ff )OR ee 、 -OC(=NR ff )R ee 、 -OC(=NR ff )OR ee 、 -C(=NR ff )N(R ff )2、 -OC(=NR ff )N(R ff )2、 -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, C2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Carbocyclic groups, 3-10 membered heterocyclic groups, C 6-10 Aryl, 5-10-membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, and heteroaryl group is independently bounded by 0, 1, 2, 3, 4, or 5 R groups. gg Group substitution, or two homologous Rs dd Substituents can combine to form =O or =S;

[0153] R ee Each time it appears, it is independently selected from C. 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 carbonyl group, C 6-10 Aryl, 3-10 membered heterocyclic and 3-10 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl and heteroaryl group is independently bounded by 0, 1, 2, 3, 4 or 5 R groups. gg Group substitution;

[0154] R ff Each time it appears, it is independently selected from hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 Carbocyclic groups, 3-10 membered heterocyclic groups, C 6-10 aryl and 5-10 heteroaryl, or two R ff Groups are joined to form a 3-14 membered heterocyclic group or a 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, and heteroaryl group is independently bounded by 0, 1, 2, 3, 4, or 5 R groups. gg Group substitution; and

[0155] R gg Each occurrence is independently a halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, or -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 groups, -NH(OH), -SH, -SC 1-6 Alkyl, -SS(C 1-6 Alkyl), -C(=O)(C 1-6 Alkyl group, -CO2H, -CO2(C 1-6 Alkyl), -OC (=O)(C 1-6 Alkyl), -OCO2(C 1-6 Alkyl groups, -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 groups, -NHC(=O)NH2, -C(=NH)O(C 1-6 Alkyl), -OC (=NH)(C 1-6 Alkyl group), -OC (=NH)OC 1-6 Alkyl group, -C(=NH)N(C 1-6 Alkyl)2、-C(=NH)NH(C 1-6 Alkyl groups, -C(=NH)NH2, -OC(=NH)N(C 1-6 Alkyl)2、-OC(NH)NH(C 1-6 Alkyl groups, -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 groups, -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 1-6Alkyl), C(=S)NH2, -C(=O)S(C 1-6 Alkyl), -C(=S)SC 1-6 Alkyl, -SC (=S)SC 1-6 Alkyl group, -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 group, C 3-10 carbonyl group, C 6-10 aryl, 3-10 heterocyclic, 5-10 heteroaryl; or two homocyclic Rs gg Substituents can combine to form =O or =S; where X - It is a relative ion.

[0156] A "relative ion" or "anionic relative ion" is a negatively charged group that associates with a quaternary amino group of a cationic group to maintain electron neutrality. Exemplary relative ions include halide ions (e.g., F). - Cl - ,Br - I - NO3 - ClO4 - OH - H2PO4 - HSO4 - Sulfonate ions (e.g., methanesulfonate, trifluoromethanesulfonate, p-toluenesulfonate, benzenesulfonate, 10-camphorsulfonate, naphthalene-2-sulfonate, naphthalene-1-sulfonate-5-sulfonate, ethane-1-sulfonate-2-sulfonate, etc.) and carboxylate ions (e.g., acetate, propionate, benzoate, glycerate, lactate, tartrate, glycolate, etc.).

[0157] These and other exemplary substituents are described in more detail in the detailed embodiments and claims. This invention is not intended to be limited in any way by the above list of exemplary substituents.

[0158] Other definitions

[0159] As used herein, the term “modulation” refers to the inhibition or enhancement of GABA receptor function. A “modulator” (e.g., a modulatory compound) can be, for example, an agonist, partial agonist, antagonist, or partial antagonist of the GABA receptor.

[0160] "Pharmaceutical acceptable" means approved or permitted by a federal or state government regulatory agency or the corresponding agency in a country other than the United States, or listed in the United States Pharmacopeia or other generally recognized pharmacopoeias for use in animals, and more specifically for use in humans.

[0161] "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. Specifically, such salts are non-toxic and can be inorganic or organic acid addition salts and base addition salts. Specifically, such salts include: (1) acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc.; or acid addition salts formed with organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentylpropionic 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-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-Naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo[2.2.2]-oct-2-en-1-carboxylic acid, glucoheponic acid, 3-phenylpropionic acid, trimethylacetic acid, tert-butylacetic acid, lauryl sulfate, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, mucoconic acid, etc.; or (2) when the acidic proton present in the parent compound is replaced by a metal ion (e.g., alkali metal ion, alkaline earth metal ion or aluminum ion); or when coordinated with an organic base (e.g. ethanolamine, diethanolamine, triethanolamine, N-methylglucosamine, etc.). Salts also include (by example only) sodium salts, potassium salts, calcium salts, magnesium salts, ammonium salts, tetraalkylammonium salts, etc.; and when the compound contains a basic functional group, it further includes salts of non-toxic organic or inorganic acids, such as hydrochloride, hydrobromide, tartrate, methanesulfonate, acetate, maleate, oxalate, etc. The term "pharmaceutically acceptable cation" refers to an acceptable cationic relative ion with an acidic functional group. Examples of such cations include sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium cations, etc. See, for example, Berge et al., J. Pharm. Sci. (1977) 66(1):1–79.

[0162] The term "prodrug" is intended to cover compounds that are converted into the therapeutically active agents of the present invention under physiological conditions. A common method for manufacturing a prodrug involves hydrolysis under physiological conditions to expose selected portions of the desired molecule. In other embodiments, the prodrug is converted via the enzymatic activity of a subject.

[0163] In some embodiments, the compound of formula (I) is a prodrug, wherein the prodrug includes a cleavable portion at a C3 hydroxyl group, as depicted in the formula. Exemplary prodrugs containing hydroxyl groups include, for example, esters.

[0164] "Solventrolyte" refers to a compound form that typically associates with a solvent or water (also called "hydrate") via a solvent decomposition reaction. This physical association includes hydrogen bonding. Common solvents include water, ethanol, acetic acid, etc. The compounds of this invention can be prepared, for example, in crystalline form and are soluble or hydrated. Suitable solvates include pharmaceutically acceptable solvates, such as hydrates, and also include both stoichiometric and non-stoichiometric solvates. In some instances, the solvate will be separable, for example when one or more solvent molecules are incorporated into the lattice of a crystalline solid. "Solventrolyte" encompasses both solution phases and separable solvates. Representative solvates include hydrates, ethanolates, and methanolates.

[0165] "Stereoisomers": It should also be understood that compounds with the same molecular formula but differing in properties, atomic bonding order, or atomic spatial arrangement are called "isomers." Isomers differing in atomic spatial arrangement are called "stereoisomers." Stereoisomers that are not mirror images of each other are called "diastereomers," and isomers that are non-overlapping mirror images of each other are called "enantiomers." When a compound has an asymmetry center, for example, when it is bonded to four different groups, a pair of enantiomers may exist. Enantiomers can be characterized by the absolute configuration of their asymmetry center and described according to the Cahn and Prelog R and S sequencing rules, or by the way the molecule rotates around a polarized plane and is designated 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."

[0166] "Tautomers" are compounds that are interchangeable forms of a particular compound's structure and exhibit variations in the shifts of hydrogen atoms and electrons. Thus, the two structures can be balanced through the movement of π electrons and atoms (usually H). For example, enols and ketones are tautomers because they can rapidly interconvert by treatment with acids or bases. Another example of tautomerism is the acid and nitro forms of phenylnitromethane, also formed by acid or base treatment. Tautomerism can be associated with achieving optimal chemical reactivity and biological activity of the target compound.

[0167] The term "subject" encompasses, but is not limited to, humans (i.e., males or females of any age, such as child subjects (e.g., infants, children, adolescents) or adult subjects (e.g., young adults, middle-aged adults, or older adults)) and / or non-human animals, such as mammals like primates (e.g., cynomolgus monkeys, rhesus monkeys), cattle, pigs, horses, sheep, goats, rodents, cats, and / or dogs. In some embodiments, the subject is a human. In some embodiments, the subject is a non-human animal. The terms "human," "patient," and "subject" are used interchangeably herein.

[0168] In some embodiments, the substituent present on the oxygen atom is an oxygen protecting group (also called 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, where R aa R bb and R cc As defined herein, oxygen protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, TW Greene, and PGM Wuts, 3rd Edition, John Wiley & Sons, 1999, which are incorporated herein by reference.

[0169] Exemplary oxygen protecting groups include, but are not limited to, methyl, methoxymethyl (MOM), 2-methoxyethoxymethyl (MEM), benzyl (Bn), triisopropylsilyl (TIPS), tert-butyldimethylsilyl (TBDMS), tert-butylmethoxyphenylsilyl (TBMPS), methanesulfonate (methanesulfonate), and toluenesulfonate (Ts).

[0170] In some embodiments, the substituent present on the sulfur atom is a sulfur protecting group (also called 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, where R aa R bb and R cc As defined herein, sulfur protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, TW Greene, and PGM Wuts, 3rd Edition, John Wiley & Sons, 1999, which are incorporated herein by reference.

[0171] In some embodiments, the substituent present on the nitrogen atom is an amino protecting group (also referred to herein 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(R) cc )2、-S(=O)2R aa -C(=NR) cc )R aa -C(=NR) cc OR aa -C(=NR) cc )N(R cc )2、-SO2N(R cc )2、-SO2R cc -SO2OR cc -SOR aa -C(=S)N(R) cc )2、-C(=O)SR cc -C(=S)SR cc C 1-10 Alkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 3-10 Carbocyclic groups, 3-14 membered heterocyclic groups, C 6-14 Aryl and 5-14 membered heteroaryl groups, wherein each alkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, and heteroaryl group is independently bounded by 0, 1, 2, 3, 4, or 5 R groups. dd Group substitution, and wherein R aa R bb R cc和 R dd As defined herein, amino protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, TW Greene, and PGM Wuts, 3rd Edition, John Wiley & Sons, 1999, which are incorporated herein by reference.

[0172] 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; urethane groups (e.g., -C(=O)OR aa ), including but not limited to fluorenyl methyl carbamate (Fmoc), tert-butyl carbamate (BOC), and benzyl carbamate (Cbz); sulfonamide groups (e.g., -S(=O)2R) aa ), including but not limited to p-toluenesulfonamide (Ts), methanesulfonamide (Ms) and N-[2-(trimethylsilyl)ethoxy]methylamine (SEM).

[0173] Disease, symptom, and illness are used interchangeably in this article.

[0174] As used herein, and unless otherwise specified, the terms “treat,” “treating,” and “treatment” encompass actions that reduce the severity of a specified disease, condition, or illness, or delay or slow the progression of such disease, condition, or illness when the subject has contracted it (“therapeutic treatment”), and also encompass actions that occur before the subject begins to contract the specified disease, condition, or illness (“preventive treatment”).

[0175] Generally, an "effective amount" of a compound refers to an amount sufficient to induce a desired biological response for, for example, treatment of CNS-related conditions, such that the amount is sufficient to induce anesthesia or sedation. As those skilled in the art will understand, the effective amount of the compound of the present invention can vary depending on factors such as the desired biological endpoint, the pharmacokinetics of the compound, the disease being treated, the mode of administration, and the age, weight, health, and condition of the subject. Effective amounts cover both therapeutic and prophylactic treatments.

[0176] As used herein, and unless otherwise specified, a “therapeuticly effective amount” of a compound is an amount sufficient to provide a therapeutic benefit in treating a disease, condition, or disorder, or to delay or minimize one or more symptoms associated with the disease, condition, or disorder. A therapeutically effective amount of a compound means the amount of a therapeutic agent, alone or in combination with other therapies, that provides a therapeutic benefit in treating a disease, condition, or disorder. The term “therapeuticly effective amount” may also encompass amounts that improve overall therapy, reduce or prevent symptoms or causes of a disease or disorder, or enhance the therapeutic efficacy of another therapeutic agent.

[0177] As used herein, and unless otherwise specified, a “preventively effective amount” of a compound is an amount sufficient to prevent a disease, condition, or disorder, or one or more symptoms associated with a disease, condition, or disorder, or to prevent its recurrence. A preventively effective amount of a compound means the amount of a therapeutic agent, alone or in combination with other agents, that provides therapeutic benefit in preventing a disease, condition, or disorder. The term “preventively effective amount” may also encompass amounts that improve overall prevention or enhance the preventive efficacy of another preventive agent.

[0178] compound

[0179] One aspect of the invention provides substituted unsaturated steroids and related organic compounds. These substituted unsaturated steroids and related organic compounds are intended for use in the methods, compositions, and kits described herein.

[0180] In some embodiments, this document provides a compound of formula (I):

[0181]

[0182] Or its pharmaceutically acceptable salt;

[0183] in:

[0184] When the valence allows, it represents a single or double bond;

[0185] R 2a R 2b R 4a R 4b R 6a R 6b R 7a R 7b R 12a and R 12b Each of these elements independently is hydrogen, halogen, cyano, nitro, hydroxyl, alkoxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclic, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -OR A1 -SR A1 -N(R) A1 )2、-NHC(=O)R A1 -NHC(=O)OR A1 -S(=O)R A2 -SO2R A2 or -S(=O)2OR A1 , where R A1 Each time it appears independently, it is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclic, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, oxygen-protecting group when attached to an oxygen atom, sulfur-protecting group when attached to a sulfur atom, nitrogen-protecting group when attached to a nitrogen atom, or two R groups. A1 Groups combine to form heterocyclic or heteroaryl rings; and R A2 It is a substituted or unsubstituted alkyl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted alkynyl, a substituted or unsubstituted carbocyclic, a substituted or unsubstituted heterocyclic, a substituted or unsubstituted aryl, or a substituted or unsubstituted heteroaryl.

[0186] R 11 and R 16 Each of them is independently hydrogen, halogen, cyano, nitro, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclic, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl;

[0187] R 3It is a substituted or unsubstituted alkyl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted alkynyl, a substituted or unsubstituted carbocyclic, a substituted or unsubstituted heterocyclic, a substituted or unsubstituted aryl, or a substituted or unsubstituted heteroaryl.

[0188] when When both are single bonds, R 5 It is hydrogen or methyl; and when When one of them is a double bond, R 5 and R 4a Or R 4b One of them does not exist; or R 5 and R 6a Or R 6b One of them does not exist;

[0189] R 19 It is hydrogen or a substituted or unsubstituted alkyl group;

[0190] R 21a R 21b and R 21c Each of these elements is independently hydrogen, a -substituted or unsubstituted alkyl group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group, a substituted or unsubstituted carbocyclic group, a substituted or unsubstituted heterocyclic group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted heteroaryl group; and

[0191] n is 0, 1, 2, or 3;

[0192] The prerequisite is that the following compounds and their salts are specifically excluded:

[0193]

[0194] Group R 2a R 2b R 4a R 4b R 6a R 6b R 7a R 7b R 12a and R 12b

[0195] In some implementation schemes, R 2a R 2b R 4a R 4b R 6a R 6b R 7a R 7b R 12a and R 12bEach of these is independently hydrogen, halogen, cyano, nitro, hydroxyl, alkoxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclic, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0196] In some implementation schemes, R 2a R 2b R 4a R 4b R 6a R 6b R 7a R 7b R 12a and R 12b Each of them is independently hydrogen, hydroxyl, alkoxy, cyano, C1-C6 substituted or unsubstituted alkyl.

[0197] In some implementation schemes, R 2a R 2b R 4a R 4b R 6a R 6b R 7a R 7b R 12a and R 12b Each of them is hydrogen independently.

[0198] In some implementation schemes, R 2a R 2b R 4a R 4b R 6a R 6b R 7a R 7b R 12a and R 12b They're all hydrogen.

[0199] Group R 11 and R 16

[0200] In some implementation schemes, R 11 and R 16 Each of them is independently hydrogen, halogen, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl.

[0201] In some implementation schemes, R 11 and R 16 Each of them is independently hydrogen, halogen, cyano, substituted or unsubstituted alkyl.

[0202] In some implementation schemes, R 11 and R 16 Each of them is hydrogen independently.

[0203] In some implementation schemes, R 11 and R 16 Both are hydrogen.

[0204] Group R 3

[0205] In some implementation schemes, R 3 It is a substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, or substituted or unsubstituted aryl.

[0206] In some implementation schemes, R 3 It is a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkenyl group, or a substituted or unsubstituted alkynyl group.

[0207] In some implementation schemes, R 3 It is a group of the following formula:

[0208]

[0209] Where R 3a Each time it appears, it is independently hydrogen, substituted or unsubstituted C1-C6 alkyl, methoxymethyl, methoxyethyl, or ethoxymethyl, -OR F1 , where R F1 It is a substituted or unsubstituted alkyl group, or -CH2X, or -CHX2, where X is a halide group; and R 3b and R 3c Each time it appears, it is independently hydrogen, a halogen, or a substituted or unsubstituted alkyl, a substituted or unsubstituted carbocyclic, or a substituted or unsubstituted heterocyclic.

[0210] In some implementation schemes, R 3 It is an unsubstituted alkyl group.

[0211] In some implementation schemes, R 3 It is an unsubstituted C1-C4 alkyl group.

[0212] In some implementation schemes, R 3 It is a methyl group.

[0213] Group R 5

[0214] In some implementation schemes, R 5 It is hydrogen.

[0215] In some implementation schemes, R 5 It is a methyl group.

[0216] In some embodiments, the compound of formula (I) is the compound of formula (Ia):

[0217]

[0218] In some embodiments, the compound of formula (I) is a compound of formula (I-b1) or (1-b2):

[0219]

[0220] In some embodiments, the compound of formula (I) is the compound of formula (I-c1):

[0221]

[0222] In some embodiments, the compound of formula (I) is the compound of formula (I-c2):

[0223]

[0224] In some embodiments, the compound of formula (I) is the compound of formula (Id):

[0225]

[0226] In some embodiments, the compound of formula (I) is the compound of formula (Ie):

[0227]

[0228] Group R 19

[0229] In some implementation schemes, R 19 It is a hydrogen or C1-C6 substituted or unsubstituted alkyl group.

[0230] In some implementation schemes, R 19 It is hydrogen or an unsubstituted C1-C6 alkyl group.

[0231] In some implementation schemes, R 19 It is hydrogen or an unsubstituted C1-C4 alkyl group.

[0232] In some implementation schemes, R 19 It is either hydrogen or methyl.

[0233] In some implementation schemes, R 19 It is hydrogen.

[0234] In some implementation schemes, R 19 It is a methyl group.

[0235] In some embodiments, the compound of formula (I) is the compound of formula (If):

[0236]

[0237] In some embodiments, the compound of formula (I) is the compound of formula (Ig):

[0238]

[0239] Group R 21

[0240] In some implementation schemes, R 21a and R 21b Each of these is independently hydrogen, a substituted or unsubstituted alkyl group, or a substituted or unsubstituted aryl group; and R 21c It is hydrogen, a substituted or unsubstituted heteroaryl group, a substituted or unsubstituted 5-membered heteroaryl group, a substituted or unsubstituted 5-membered heteroaryl group with one heteroatom, a substituted or unsubstituted 5-membered heteroaryl group with two heteroatoms, a substituted or unsubstituted 5-membered heteroaryl group with three heteroatoms, and a substituted or unsubstituted 5-membered heteroaryl group with four heteroatoms; and

[0241] n is 0, 1, 2, or 3.

[0242] In some implementation schemes, R 21a and R 21b Each of them is independently hydrogen, substituted or unsubstituted alkyl; and R 21c Independently hydrogen, a substituted or unsubstituted heteroaryl group selected from the group consisting of: substituted or unsubstituted imidazolyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, quinolone, isoquinolone, dihydroquinolone, and dihydroisoquinolone; and

[0243] n is 0, 1, 2, or 3.

[0244] In some implementation schemes, R 21a and R 21b Each of them is independently hydrogen and; and R 21c It is hydrogen, and a substituted or unsubstituted heteroaryl group selected from the group consisting of: substituted or unsubstituted imidazolyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, oxadiazolyl, thiadiazolyl, or tetrazolyl; and

[0245] n is 0, 1, 2, or 3.

[0246] In some implementation schemes, R 21a and R 21b It is hydrogen; and R 21cIt is hydrogen, a substituted or unsubstituted heteroaryl group selected from the group consisting of: substituted or unsubstituted pyrazolyl, 1,2,3-triazolyl or tetrazolyl; and

[0247] n is 0, 1, 2, or 3.

[0248] In some implementation schemes, R 21a and R 21b It is hydrogen; and R 21c yes:

[0249] Or hydrogen;

[0250] Where R D Each time it appears, it is independently hydrogen, -CN, or methyl; and

[0251] n is 1

[0252] e is 1 or 2.

[0253] In some implementation schemes, R 21a and R 21b It is hydrogen; and R 21c yes:

[0254]

[0255] Where R D Each time it appears, it is independently hydrogen, -CN, or methyl; and

[0256] n is 1

[0257] e is 1 or 2.

[0258] In some implementations, n is 0. In some implementations, n is 1. In other implementations, n is 2.

[0259] In some embodiments, the compound of formula (I) is the compound of formula (Ih):

[0260]

[0261] Or its pharmaceutically acceptable salt;

[0262] in:

[0263] Where R 21a R 21b and R 21c Each time it appears, it is independently hydrogen, a -substituted or unsubstituted alkyl group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group, a substituted or unsubstituted carbocyclic group, a substituted or unsubstituted heterocyclic group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted heteroaryl group; and

[0264] n is 0, 1, 2, or 3.

[0265] In some embodiments, the compound of formula (I) is the compound of formula (Ii):

[0266]

[0267] or its pharmaceutically acceptable salt

[0268] Where: R 21c It is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl.

[0269] In some embodiments, the compound of formula (I) is:

[0270]

[0271] Or its pharmaceutically acceptable salt.

[0272] In some implementation schemes, R 21c yes:

[0273]

[0274] Where R D Each time it appears, it is independently hydrogen, halogen, -NO2, -CN, or -OR. GA -N(R) GA )2、-C(=O)R GA -C(=O)OR GA -OC(=O)R GA -OC(=O)OR GA -C(=O)N(R) GA )2、-N(R GA )C(=O)R GA -OC(=O)N(R) GA )2、-N(R GA )C(=O)OR GA -S(=O)2R GA -S(=O)2OR GA -OS(=O)2R GA -S(=O)2N(R) GA )2 or -N(R GA )S(=O)2R GA ; substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 Alkyne group, substituted or unsubstituted C 3-4A carbocyclic group, a substituted or unsubstituted 3- to 4-membered heterocyclic group, or optionally two R groups. GA Together with intercalated atoms, they form substituted or unsubstituted 3- or 4-membered carbon rings or heterocycles;

[0275] Where R GA Each time it appears, it is independently hydrogen, substituted, or unsubstituted C. 1-6 Alkyl, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 Alkyne group, substituted or unsubstituted C 3-6 Carbocyclic group, substituted or unsubstituted 3- to 6-membered heterocyclic group, substituted or unsubstituted aryl group, substituted or unsubstituted heteroaryl group, oxygen protecting group when attached to oxygen, nitrogen protecting group when attached to nitrogen, or two R groups. GA The group and the intercalated atom together form a substituted or unsubstituted carbocyclic or heterocyclic ring; and

[0276] e is 1, 2, 3, 4 or 5.

[0277] In some implementation schemes, R 21c yes:

[0278]

[0279] Where R D Each time it appears, it is independently hydrogen, halogen, -NO2, -CN, or -OR. GA -N(R) GA )2、-C(=O)R GA -C(=O)OR GA -OC(=O)R GA -OC(=O)OR GA -C(=O)N(R) GA )2、-N(R GA )C(=O)R GA -OC(=O)N(R) GA )2、-N(R GA )C(=O)OR GA -S(=O)2R GA -S(=O)2OR GA -OS(=O)2R GA -S(=O)2N(R) GA )2 or -N(R GA )S(=O)2R GA ; substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 Alkyne group, substituted or unsubstituted C 3-4A carbocyclic group, a substituted or unsubstituted 3- to 4-membered heterocyclic group, or optionally two R groups. GA Together with intercalated atoms, they form substituted or unsubstituted 3- or 4-membered carbon rings or heterocycles;

[0280] Where R GA Each time it appears, it is independently hydrogen, substituted, or unsubstituted C. 1-6 Alkyl, substituted or unsubstituted C 2-6 alkenyl, substituted or unsubstituted C 2-6 Alkyne group, substituted or unsubstituted C 3-6 Carbocyclic group, substituted or unsubstituted 3- to 6-membered heterocyclic group, substituted or unsubstituted aryl group, substituted or unsubstituted heteroaryl group, oxygen protecting group when attached to oxygen, nitrogen protecting group when attached to nitrogen, or two R groups. GA The group and the intercalated atom together form a substituted or unsubstituted carbocyclic or heterocyclic ring; and

[0281] e can be 1, 2, 3, or 4.

[0282] In some embodiments, the compound of formula (I) is the compound of formula (I-j1):

[0283]

[0284] Or its pharmaceutically acceptable salt.

[0285] Each R E It is independently hydrogen, halogen, alkyl, hydroxyl or cyano.

[0286] e can be 0, 1, 2, or 3.

[0287] In some embodiments, the compound of formula (I) is the compound of formula (I-j2):

[0288]

[0289] Or its pharmaceutically acceptable salt.

[0290] Each R E It is independently hydrogen, halogen, alkyl, hydroxyl or cyano.

[0291] e can be 0, 1, 2, or 3.

[0292] In some embodiments, the compound of formula (I) is a compound of formula (I-j2) or a pharmaceutically acceptable salt thereof, wherein R E Independently, it is either hydrogen or cyano.

[0293] e can be 0, 1, 2, or 3.

[0294] In some embodiments, the compound of formula (I) is the compound of formula (I-k1):

[0295] Or its pharmaceutically acceptable salt.

[0296] Each R E It is independently hydrogen, halogen, alkyl, hydroxyl or cyano.

[0297] e represents 0, 1, or 2.

[0298] In some embodiments, the compound of formula (I) is the compound of formula (I-k2):

[0299]

[0300] Or its pharmaceutically acceptable salt.

[0301] Each R E It is independently hydrogen, halogen, alkyl, hydroxyl or cyano.

[0302] e represents 0, 1, or 2.

[0303] In some embodiments, the compound of formula (I) is a compound of formula (I-11) or (I-12):

[0304]

[0305] Or its pharmaceutically acceptable salt.

[0306] Each R E It can be hydrogen, halogen, alkyl, hydroxyl, or cyano.

[0307] In some embodiments, the compound of formula (I) is a compound of formula (I-I2):

[0308]

[0309] Or a pharmaceutically acceptable salt thereof, wherein each R E It can be hydrogen, halogen, alkyl, hydroxyl, or cyano.

[0310] In some embodiments, the compound of formula (I) is the compound of formula (I-m1):

[0311]

[0312] Or its pharmaceutically acceptable salt.

[0313] Each R E It can be hydrogen, halogen, alkyl, hydroxyl, or cyano.

[0314] In some embodiments, the compound of formula (I) is the compound of formula (I-m2):

[0315]

[0316] Or its pharmaceutically acceptable salt.

[0317] Each R E It can be hydrogen, halogen, alkyl, hydroxyl, or cyano.

[0318] In some embodiments, the compound of formula (I) is the compound of formula (I-n1):

[0319]

[0320] Or its pharmaceutically acceptable salt.

[0321] Each R E It is independently hydrogen, halogen, alkyl, hydroxyl or cyano.

[0322] e represents 0, 1, or 2.

[0323] In some embodiments, the compound of formula (I) is the compound of formula (I-n2):

[0324]

[0325] Or its pharmaceutically acceptable salt.

[0326] Each R E It is independently hydrogen, halogen, alkyl, hydroxyl or cyano.

[0327] e represents 0, 1, or 2.

[0328] In some embodiments, the compound of formula (I) is a compound of formula (Io):

[0329]

[0330] Or its pharmaceutically acceptable salt.

[0331] In some embodiments, the compound of formula (I) is a compound of formula (Ip).

[0332]

[0333] Or its pharmaceutically acceptable salt.

[0334] In some embodiments, the compound of formula (I) is a compound of formula (Iq).

[0335]

[0336] In some embodiments, the compound of formula (I) is a compound of formula (Ir).

[0337]

[0338] Or its pharmaceutically acceptable salt.

[0339] Where m is 0, 1, 2 or 3;

[0340] p is 0, 1, or 3;

[0341] Each R32 is independently a halogen, alkyl, hydroxyl, or cyano group.

[0342] In some embodiments, the compound of formula (I) has formula (Is).

[0343]

[0344] Or its pharmaceutically acceptable salt.

[0345] Where u is 0, 1, or 2; each X is independently -C(RN)-, -C(RN)2-, -O-, -S-, -N-, or N(RN)-, where RN is independently hydrogen, substituted or unsubstituted C1-6 alkyl, C(=O)RGA, -C(=O)ORGA, -C(=O)N(RGA)2, -S(=O)2RGA, or -S(=O)2N(RGA)2; and

[0346] Each time an RGA appears, it is independently hydrogen, a substituted or unsubstituted C1-6 alkyl, a substituted or unsubstituted C2-6 alkenyl, a substituted or unsubstituted C2-6 ynyl, a substituted or unsubstituted C3-6 carbocyclic, a substituted or unsubstituted 3- to 6-membered heterocyclic, a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, an oxygen-protecting group when attached to oxygen, a nitrogen-protecting group when attached to nitrogen, or two RGA groups together with intercalation atoms to form a substituted or unsubstituted heterocyclic or heteroaryl ring.

[0347] In some embodiments, the compound of formula (I) has the formula (It).

[0348]

[0349] Or its pharmaceutically acceptable salt.

[0350] Each R35 is independently a halogen, alkyl, hydroxyl, or cyano group; and r is 0, 1, 2, or 3.

[0351] In some embodiments, the compound of formula (I) has the formula (Iu).

[0352]

[0353] Or its pharmaceutically acceptable salt.

[0354] Where s is 0, 1, or 2; each X is independently -C(RN)-, -C(RN)2-, -O-, -S-, -N-, or N(RN)-, where RN is independently hydrogen, substituted or unsubstituted C1-6 alkyl, C(=O)RGA, -C(=O)ORGA, -C(=O)N(RGA)2, -S(=O)2RGA, or -S(=O)2N(RGA)2; and

[0355] Each time an RGA appears, it is independently hydrogen, a substituted or unsubstituted C1-6 alkyl, a substituted or unsubstituted C2-6 alkenyl, a substituted or unsubstituted C2-6 ynyl, a substituted or unsubstituted C3-6 carbocyclic, a substituted or unsubstituted 3- to 6-membered heterocyclic, a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, an oxygen-protecting group when attached to oxygen, a nitrogen-protecting group when attached to nitrogen, or two RGA groups together with intercalation atoms to form a substituted or unsubstituted heterocyclic or heteroaryl ring.

[0356] In some embodiments, the pharmaceutical composition comprises the compound described herein or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0357] In some embodiments, a method of treating a subject with a CNS-related condition includes administering to the subject an effective amount of the compound described herein or a pharmaceutically acceptable salt thereof. In some embodiments, the CNS-related condition is a sleep disorder, mood disorder, schizophrenia spectrum disorder, seizure disorder, memory and / or cognitive impairment, motor disorder, personality disorder, autism spectrum disorder, pain, traumatic brain injury, vascular disease, substance abuse disorder and / or withdrawal syndrome, tinnitus, or status epilepticus. In some embodiments, the CNS-related condition is depression. In some embodiments, the CNS-related condition is postpartum depression. In some embodiments, the CNS-related condition is major depressive disorder. In some embodiments, major depressive disorder is moderate major depressive disorder. In some embodiments, major depressive disorder is severe major depressive disorder.

[0358] In some implementations, the compounds are selected from the group consisting of compounds identified in Table 1 below:

[0359] Table 1

[0360]

[0361]

[0362]

[0363]

[0364] In one respect, this article provides pharmaceutically acceptable salts of the compounds described herein (e.g., compounds of formula (I)).

[0365] In one aspect, this document provides 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 some embodiments, the compound of the present invention is provided in an effective amount in the pharmaceutical composition. In some embodiments, the compound of the present invention is provided in a therapeutically effective amount. In some embodiments, the compound of the present invention is provided in a preventatively effective amount.

[0366] The compounds of the present invention described herein are used as GAB in some embodiments. A Modifiers, such as those that affect GABA in a positive or negative way. A Receptors. Acting as regulators of excitability in the central nervous system (CNS), such as through their regulation of GABA. A Mediated by the receptor's ability, such compounds are expected to have CNS activity.

[0367] Therefore, in another aspect, a method is provided for treating CNS-related disorders in a subject in need, the method comprising administering an effective amount of the compound of the present invention to the subject. In some embodiments, CNS-related disorders are sleep disorders, mood disorders, schizophrenia spectrum disorders, seizure disorders, memory and / or cognitive impairments, motor disorders, personality disorders, autism spectrum disorders, pain, traumatic brain injury, vascular disease, substance abuse disorders and / or withdrawal syndromes, tinnitus, or status epilepticus. In some embodiments, CNS-related disorders are depression. In some embodiments, CNS-related disorders are postpartum depression.

[0368] In some embodiments, the CNS-related condition 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. In some embodiments, the compound is administered orally, subcutaneously, intravenously, or intramuscularly. In some embodiments, the compound is administered orally. In some embodiments, the compound is administered for a prolonged period. In some embodiments, the compound is administered continuously, for example, by continuous intravenous infusion.

[0369] Exemplary compounds of the present invention can be synthesized from the following known starting materials using methods known to those skilled in the art or certain references. In one aspect, pharmaceutically acceptable salts of the compounds described herein (e.g., compounds of formula (I)) are provided.

[0370] Alternative implementation plan

[0371] 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 N, etc. In other embodiments, specific isotopes (e.g., 3 H, 13 C 14 C 18 O or 15 N) can represent 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 specific position in the compound.

[0372] Pharmaceutical Composition

[0373] In one aspect, this document provides 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 some embodiments, the compound of the present invention is provided in an effective amount in the pharmaceutical composition. In some embodiments, the compound of the present invention is provided in a therapeutically effective amount. In some embodiments, the compound of the present invention is provided in a preventatively effective amount.

[0374] In some embodiments, the pharmaceutical composition comprises an effective amount of the active ingredient. In some embodiments, the pharmaceutical composition comprises a therapeutically effective amount of the active ingredient. In some embodiments, the pharmaceutical composition comprises a preventatively effective amount of the active ingredient.

[0375] The pharmaceutical compositions described herein can be administered via 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.

[0376] Generally, the compounds described in this article are administered in effective amounts. The actual amount of active agent administered will be determined by the physician based on relevant circumstances, including the disease to be treated, the chosen route of administration, the specific compound administered, the individual patient's age, weight, and response, as well as the severity of the patient's symptoms.

[0377] When used for the prevention of CNS symptoms, the compound described herein should generally be administered to subjects at the dosage levels described above, under the supervision of a physician, to those at risk of developing the aforementioned condition. Subjects at risk of developing a specific condition generally include those with a family history of the condition, or those identified through genetic testing or screening as particularly susceptible to the condition.

[0378] The pharmaceutical compositions provided herein can also be administered long-term (“long-term administration”). Long-term administration means administering the compound or a pharmaceutical composition thereof for an extended period of time, such as 3 months, 6 months, 1 year, 2 years, 3 years, 5 years, or indefinitely, such as until the death of the subject. In some embodiments, long-term administration is intended to provide a constant level of the compound in the blood, for example, within a therapeutic window over an extended period of time.

[0379] The pharmaceutical compositions of the present invention can be further delivered using a variety of administration methods. For example, in some embodiments, the pharmaceutical composition may be given in a bolus form, for instance, to increase the concentration of the compound in the blood to an effective level. The placement of a single dose depends on the systemic level of the desired active ingredient throughout the body; for example, an intramuscular or subcutaneous single dose allows for a slow release of the active ingredient, while delivering a bolus directly into the vein (e.g., via IV infusion) allows for a much faster delivery, which rapidly increases the concentration of the active ingredient in the blood to an effective level. In other embodiments, the pharmaceutical composition may be administered via continuous infusion (e.g., via IV infusion) to maintain a stable concentration of the active ingredient in the subject. Furthermore, in other embodiments, the pharmaceutical composition may be administered initially as a single dose, followed by continuous infusion.

[0380] Compositions intended for oral administration may be in the form of bulk liquid solutions, suspensions, or bulk powders. However, compositions are more commonly presented in unit dosage forms to facilitate precise dosing. The term "unit dosage form" refers to a physically discontinuous unit suitable for administration to human subjects and other mammals in unit doses, each unit containing a predetermined amount of active substance calculated to produce the desired therapeutic effect, combined with suitable pharmaceutical excipients. Typical unit dosage forms include ampoules or syringes pre-filled with the predicted amount of liquid composition, or pills, tablets, capsules, etc. (in the case of solid compositions). In such compositions, the compound is typically a minor component (about 0.1% by weight to about 50% by weight, or preferably about 1% by weight to about 40% by weight), with the remainder being various mediators or excipients and processing aids that contribute to the formation of the desired form of administration.

[0381] Oral administration of one to five, particularly two to four, and typically three, oral doses per day is a representative therapy. Using these administration modalities, each dose provides about 0.01 to about 20 mg / kg of the compound provided herein, wherein preferred doses each provide about 0.1 to about 10 mg / kg, and particularly about 1 to about 5 mg / kg.

[0382] The transdermal dose is generally selected to provide blood levels similar to or lower than those achieved using an injectable dose, and the amount is generally in the range of about 0.01% to about 20% by weight, preferably about 0.1% to about 20% by weight, more preferably about 0.1% to about 10% by weight, and more preferably about 0.5% to about 15% by weight.

[0383] Injectable dose levels range from about 0.1 mg / kg / hour to at least 20 mg / kg / hour, lasting from about 1 to about 120 hours, and especially 24 to 96 hours. Preloaded pellets of about 0.1 mg / kg to about 10 mg / kg or more may also be administered to achieve adequate steady-state levels. For human patients weighing 40 to 80 kg, the maximum total dose is expected not to exceed about 5 g / day.

[0384] Liquid forms suitable for oral administration may include suitable aqueous or non-aqueous media and buffers, suspending and dispersing agents, colorants, flavoring agents, etc. Solid forms may include, for example, any of the following components or compounds with similar properties: binders, such as microcrystalline cellulose, tragacanth gum, or gelatin; excipients, such as starch or lactose; disintegrants, such as alginate, sodium hydroxyacetate (Primogel), or corn starch; lubricants, such as magnesium stearate; slip agents, such as colloidal silica; sweeteners, such as sucrose or saccharin; or flavoring agents, such as peppermint, methyl salicylate, or orange flavorings.

[0385] Injectable compositions are typically based on injectable sterile saline or phosphate-buffered saline or other injectable excipients known in the art. As previously mentioned, the active compound in such compositions is usually a minor component, often ranging from about 0.05% to 10% by weight, with the remainder being injectable excipients, etc.

[0386] Transdermal compositions are typically formulated as topical ointments or creams containing one or more active ingredients. When formulated as an ointment, the active ingredient is usually combined with a paraffin or water-miscible ointment base. Alternatively, the active ingredient may be formulated as a cream using, for example, an oil-in-water cream base. These transdermal formulations are well known in the art and generally include additional ingredients to enhance the dermal penetration stability of the active ingredient or formulation. All such known transdermal formulations and ingredients are included within the scope provided herein.

[0387] The compounds described herein can also be administered via transdermal devices. Therefore, transdermal administration can be achieved using reservoir-type, porous membrane-type, or solid matrix patches.

[0388] The components described above for use in oral, injectable, or topical compositions are representative only. Other substances 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.

[0389] The compounds of this invention can also be administered in a sustained-release form or from a sustained-release drug delivery system. Descriptions of representative sustained-release substances can be found at Remington's Pharmaceutical Sciences.

[0390] This invention also relates to pharmaceutically acceptable acid addition salts of the compounds of this invention. The acids that can be used to prepare pharmaceutically acceptable salts are those that form non-toxic acid addition salts, i.e., acids containing a pharmaceutically acceptable anion, such as hydrochlorides, hydroiodides, hydrobromates, nitrates, sulfates, hydrogen sulfates, phosphates, acetates, lactates, citrates, tartrates, succinates, maleates, fumarates, benzoates, p-toluenesulfonates, etc.

[0391] In another aspect, the present invention provides a pharmaceutical composition comprising the compounds of the present invention and pharmaceutically acceptable excipients, such as those suitable for injection, such as compositions for intravenous (IV) administration.

[0392] Pharmaceutically acceptable excipients include any and all diluents or other liquid media, dispersants or suspending agents, surfactants, isotonic agents, preservatives, lubricants, etc., suitable for the desired specific dosage form, such as injections. General considerations in the formulation and / or manufacture of pharmaceutical compositions can be found, for example, in Remington's Pharmaceutical Sciences, 16th edition, EW Martin (Mack Publishing Co., Easton, Pa., 1980) and Remington: The Science and Practice of Pharmacy, 21st edition (Lippincott Williams & Wilkins, 2005).

[0393] For example, injectable formulations (such as sterile injectable aqueous suspensions) can be formulated using suitable dispersants or wetting agents and suspending agents according to known techniques. Exemplary excipients that may be used include, but are not limited to, water, sterile saline or phosphate-buffered saline or Ringer's solution.

[0394] In some embodiments, the pharmaceutical composition further comprises a cyclodextrin derivative. The most common cyclodextrins are α-cyclodextrin, β-cyclodextrin, and γ-cyclodextrin, respectively, composed of 6, 7, and 8 α-1,4-linked glucose units, optionally containing one or more substituents at the linked sugar moieties, including but not limited to substituted or unsubstituted methylation, hydroxyalkylation, acylation, and sulfonyl alkyl ether substitution. In some embodiments, the cyclodextrin is a sulfonyl alkyl ether β-cyclodextrin, such as sulfobutyl ether β-cyclodextrin, also known as... See, for example, US 5,376,645. In some embodiments, the composition comprises hexapropyl-β-cyclodextrin. In more specific embodiments, the composition comprises hexapropyl-β-cyclodextrin (10%-50% in water).

[0395] Injectable compositions can be sterilized, for example, by filtering through a bacterial trapping filter or by incorporating a sterilizing agent in the form of a sterile solid composition that can be dissolved or dispersed in sterile water or other sterile injectable media before use.

[0396] Generally, the compounds described in this article are administered in effective amounts. The actual amount of active agent administered will be determined by the physician based on relevant circumstances, including the disease to be treated, the chosen route of administration, the actual compound administered, the individual patient's age, weight, response, and the severity of the patient's symptoms.

[0397] The compositions are presented in unit dosage forms to facilitate precise drug delivery. The term "unit dosage form" refers to a physically discontinuous unit suitable for administration to human subjects and other mammals in unit doses, each unit containing a predetermined amount of active substance calculated to produce the desired therapeutic effect, combined with suitable pharmaceutical excipients. Typical unit dosage forms include pre-filled liquid compositions, ampoules of predicted quantities, or syringes. In such compositions, the compound is typically a minor component (about 0.1% by weight to about 50% by weight, or preferably about 1% by weight to about 40% by weight), with the remainder being various media or carriers and processing aids that facilitate the formation of the desired form of administration.

[0398] The compounds provided herein can be administered as the sole active agent, or in combination with other active agents. In one aspect, the invention provides combinations of the compounds of the invention with another pharmacologically active agent. Combination administration can be performed by any technique known to those skilled in the art, including, for example, administration alone, sequentially, simultaneously, and alternately.

[0399] Although the descriptions of pharmaceutical compositions provided herein primarily pertain to those suitable for human administration, those skilled in the art should understand that such compositions are generally suitable for administration to all types of animals. It should be fully understood that modifications to pharmaceutical compositions suitable for human administration are necessary to make them suitable for administration to a variety of animals, and that such modifications can generally be designed and / or performed by a veterinary pharmacologist using only routine experiments. General considerations in the formulation and / or manufacture of pharmaceutical compositions can be found, for example, in Remington: The Science and Practice of Pharmacy, 21st edition, Lippincott Williams & Wilkins, 2005.

[0400] On one hand, a cassette is provided containing a composition (e.g., a solid composition) comprising a compound of formula (I).

[0401] Use and treatment methods

[0402] On one hand, it is envisioned that the compounds described herein, such as compounds of formula (I), can be used as therapeutic agents for treating CNS-related conditions (e.g., sleep disorders, mood disorders such as depression, schizophrenia spectrum disorders, seizure disorders, epilepsy, memory and / or cognitive impairments, motor disorders, personality disorders, autism spectrum disorders, pain, traumatic brain injury, vascular disease, substance abuse disorders and / or withdrawal syndromes or tinnitus) in subjects in need (e.g., subjects with Rett syndrome, Fragile X syndrome or Angelman syndrome). Exemplary CNS disorders associated with GABA regulation include, but are not limited to, sleep disorders [e.g., insomnia], mood disorders [e.g., depression, mild depression (e.g., mild depressive disorder), 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 (e.g., obsessive-compulsive disorder (OCD))], schizophrenia spectrum disorders [e.g., schizophrenia, schizophrenic affective disorder], seizure disorders [e.g., epilepsy (e.g., status epilepticus (SE)), seizures], memory and / or cognitive disorders [e.g., attention deficit disorder (e.g., attention deficit hyperactivity disorder (ADHD))], dementia (e.g., Alzheimer's type dementia, Lewis body type dementia, vascular dementia)], and movement disorders [e.g., Huntington's disease, Parkinson's disease]. Diseases, personality disorders [e.g., antisocial personality disorder, obsessive-compulsive personality disorder], autism spectrum disorders (ASD) [e.g., autism, monogenic autism, such as synaptic disorders, e.g., Rett syndrome, Fragile X syndrome, Angelman syndrome], pain [e.g., neuralgia, injury-related pain syndrome, acute pain, chronic pain], traumatic brain injury (TBI), vascular diseases [e.g., stroke, ischemia, vascular malformations], substance abuse disorders and / or withdrawal syndromes [e.g., opiate, cocaine and / or alcohol addiction], and tinnitus.

[0403] In some embodiments, CNS-related disorders are sleep disorders, mood disorders, schizophrenia spectrum disorders, seizure disorders, memory and / or cognitive impairments, motor disorders, personality disorders, autism spectrum disorders, pain, traumatic brain injury, vascular disease, substance abuse disorders and / or withdrawal syndromes, tinnitus, or status epilepticus. In some embodiments, CNS-related disorders are depression. In some embodiments, CNS-related disorders are postpartum depression. In some embodiments, CNS-related disorders are major depressive disorder. In some embodiments, major depressive disorder is moderate major depressive disorder. In some embodiments, major depressive disorder is severe major depressive disorder.

[0404] In one aspect, a method is provided to alleviate or prevent epileptic seizures in a subject, the method comprising administering an effective amount of the compound of the present invention to a subject requiring such treatment. In some embodiments, the method alleviates or prevents the occurrence of epilepsy.

[0405] In another aspect, combinations of the compounds of the present invention with another pharmacologically active agent are provided. The compounds provided herein may be administered as the sole active agent, or may be administered in combination with other agents. Combination administration can be performed by any technique known to those skilled in the art, including, for example, administration alone, sequentially, simultaneously, and alternately.

[0406] In another aspect, a method is provided for treating or preventing brain excitability in a subject who is susceptible to or suffers from a disorder related to brain excitability, the method comprising administering to the subject an effective amount of the compound of the present invention.

[0407] On the other hand, a method for treating or preventing stress or anxiety in a subject is provided, the method comprising administering an effective amount of the compound or a combination thereof of the present invention to the subject who requires such treatment.

[0408] On the other hand, a method for relieving or preventing insomnia in a subject is provided, the method comprising administering an effective amount of the compound or a combination thereof of the present invention to a subject who requires such treatment.

[0409] On the other hand, a method is provided for inducing sleep and substantially maintaining REM sleep levels found in normal sleep, wherein substantial rebound insomnia is not induced, the method comprising administering an effective amount of the compound of the present invention.

[0410] On the other hand, a method is provided for alleviating or preventing premenstrual syndrome (PMS) or postpartum depression (PND) in a subject, the method comprising administering an effective amount of the compound of the present invention to a subject who requires such treatment.

[0411] In another aspect, a method for treating or preventing a mood disorder in a subject is provided, the method comprising administering an effective amount of the compound of the present invention to a subject who requires such treatment. In some embodiments, the mood disorder is depression.

[0412] On the other hand, a method is provided for enhancing cognition or treating memory impairment by administering a therapeutically effective amount of the compound of the invention to a subject. In some embodiments, the condition is Alzheimer's disease. In some embodiments, the condition is Rett syndrome.

[0413] In another aspect, a method for treating attention deficit disorder is provided by administering a therapeutically effective amount of the compound of the present invention to a subject. In other embodiments, the attention deficit disorder is ADHD.

[0414] In some implementations, the compound is administered to the subject over a prolonged period. In some implementations, the compound is administered to the subject orally, subcutaneously, intravenously, or intramuscularly.

[0415] Neuroendocrine disorders and dysfunction

[0416] This article provides methods for treating neuroendocrine disorders and dysfunctions. As used herein, “neuroendocrine disorder” or “neuroendocrine dysfunction” refers to a variety of disorders caused by imbalances in the production of hormones directly related to the brain. Neuroendocrine disorders involve the interaction between the nervous and endocrine systems. Because the hypothalamus and pituitary gland are two brain regions that regulate hormone production, damage to the hypothalamus or pituitary gland, such as from 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 condition or disorder (e.g., the women’s health condition or disorder described herein). In some embodiments, the neuroendocrine disorder or dysfunction associated with a women’s health condition or disorder is polycystic ovary syndrome (PCOS).

[0417] Symptoms of neuroendocrine disorders include, but are not limited to, behavioral, mood and sleep-related symptoms, reproductive function-related symptoms and somatic symptoms; including but not limited to fatigue, poor memory, anxiety, depression, weight gain or loss, mood instability, poor concentration, difficulty paying attention, loss of libido, infertility, amenorrhea, muscle loss, increased abdominal body fat, low blood pressure, decreased heart rate, hair loss, anemia, constipation, poor cold tolerance and dry skin.

[0418] Neurodegenerative diseases and conditions

[0419] The methods described in this article can be used to treat neurodegenerative diseases and conditions. The term "neurodegenerative disease" includes diseases and conditions associated with the progressive loss of neuronal structure or function or neuronal death.Neurodegenerative diseases and conditions, including but not limited to Alzheimer's disease (including symptoms associated with mild, moderate, or severe cognitive impairment); amyotrophic lateral sclerosis (ALS); hypoxic and ischemic injuries; ataxia and seizures (including those used to treat and prevent seizures caused by schizophrenia or by medications used to treat schizophrenia); benign amnesia; cerebral edema; cerebellar ataxia, including McLeod neuroacanthocytosis. MLS; closed head injury; coma; contusion injuries (e.g., spinal cord injury and head injury); dementia, including multi-infarct dementia and Alzheimer's disease; confusion; Down syndrome; drug-induced or drug-induced Parkinson's disease (e.g., tadalafil-induced acute akathisia, acute dystonia, Parkinson's disease or tardive dyskinesia, tadalafil-induced malignant syndrome or drug-induced postural tremor); epilepsy; Fragile X syndrome; Gilles de la Tourette's syndrome; head trauma; hearing impairment and loss; Huntington's disease; Lennox syndrome. Levodopa-induced motor difficulties; intellectual disability; motor disorders, including akinesia and akinesia (rigid) syndromes (including basal ganglia calcification, corticobasal ganglia degeneration, multiple systemic atrophy, Parkinson's disease-ALS dementia complex, Parkinson's disease, post-encephalitis Parkinson's disease, and progressive supranuclear palsy); muscle spasms and conditions associated with muscle spasms or weakness, including chorea (such as benign hereditary chorea, drug-induced chorea, hemiparesis, Huntington's disease, neuroacanthocytosis, Sydenham's chorea). Chorea and symptomatic chorea), motor difficulties (including tics, such as complex tics, simple tics, and symptomatic tics), myoclonus (including generalized myoclonus and focal hysteria), tremor (such as resting tremor, postural tremor, and intention tremor), and dystonia (including axial dystonia, dystonic finger spasticity, hemiplegic dystonia, sudden onset dystonia, and focal dystonia, such as blepharospasm, oromandibular dystonia, and spasmodic phonation). Difficulty and torticollis); neuronal damage, including eye damage, retinopathy, or macular degeneration; neurotoxic damage following stroke, thromboembolic stroke, hemorrhagic stroke, cerebral ischemia, cerebral vasospasm, hypoglycemia, amnesia, hypoxia, hypoxia, perinatal asphyxia, and cardiac arrest; Parkinson's disease; seizures; status epilepticus; stroke; tinnitus; tubular sclerosis and viral infection-induced neurodegeneration (e.g., from 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, hypoxia, neurotoxic damage following perinatal asphyxia and cardiac arrest. Treatment or prevention of neurodegenerative diseases also includes treating or preventing the neuronal function loss specific to neurodegenerative conditions.

[0420] Mood Disorders

[0421] This document also provides methods for treating mood disorders such as clinical depression, postpartum depression, perinatal depression, atypical depression, melancholic depression, psychotic major depressive disorder, catatonic depression, seasonal affective disorder, mild depression, dual depression, depressive personality disorder, recurrent transient depression, mild depressive disorder, bipolar disorder or manic-depressive disorder, depression caused by a chronic medical condition, treatment-resistant depression, treatment-resistant depression, suicidal ideation, or suicidal behavior. In some embodiments, the methods described herein provide a therapeutic effect on a subject suffering from depression (e.g., moderate or severe depression). In some embodiments, the mood disorder is associated with the diseases or conditions described herein (e.g., neuroendocrine disorders and conditions, neurodegenerative diseases and conditions (e.g., epilepsy), movement disorders, tremors (e.g., Parkinson's disease), women's health conditions or disorders).

[0422] Clinical depression, also known as major depressive disorder (MDD), severe depression, unipolar depression, unipolar mental disorder, and recurrent depression, is a mental disorder characterized by a generalized and persistent low mood, accompanied by low self-esteem and loss of interest or pleasure in normal recreational activities. Some people with clinical depression experience difficulty falling asleep, weight loss, and generally feel anxious and irritable. Clinical depression affects an individual's feelings, thoughts, and behaviors, and can cause a range of emotional and physical problems. Individuals with clinical depression may experience difficulty with daily activities and may feel that life is not worth living.

[0423] Perinatal depression refers to depression during pregnancy. Symptoms include irritability, crying, restlessness, difficulty falling asleep, extreme fatigue (emotional and / or physical), changes in appetite, difficulty concentrating, increased anxiety and / or worry, a sense of disconnection from the baby and / or fetus, and loss of interest in previously enjoyable activities.

[0424] Postpartum depression (PND), also known as postpartum depression (PPD), is a clinical type of depression that affects women after childbirth. Symptoms may include sadness, fatigue, changes in sleep and eating habits, decreased libido, crying episodes, anxiety, and irritability. In some implementations, PND is treatment-resistant depression (e.g., treatment-resistant depression as described herein). In some implementations, PND is treatment-resistant depression (e.g., treatment-resistant depression as described herein).

[0425] In some implementations, subjects with perinatal depression (PND) also experience depression or depressive symptoms during pregnancy. This depression is referred to herein as perinatal depression. In one implementation, subjects experiencing perinatal depression have an increased risk of developing PND.

[0426] Atypical depression (AD) is characterized by mood responsiveness (e.g., paradoxical anhedonia) and positivity, significant weight gain, or increased appetite. Patients with AD may also experience excessive sleepiness or somnolence (hypersomnia), a feeling of heaviness in the limbs, and significant social impairment due to hypersensitivity to perceived interpersonal rejection.

[0427] Melancholic depression is characterized by loss of pleasure in most or all activities (anhedonia), inability to respond to pleasurable stimuli, more pronounced depressive mood than sadness or loss, excessive weight loss, or excessive guilt.

[0428] Major psychotic depression (PMD) or psychotic depression refers to major depressive episodes, specifically those with a melancholic nature in which the individual experiences psychotic symptoms such as delusions and hallucinations.

[0429] Catatonic depression is a severe form of depression involving motor and behavioral disturbances as well as other symptoms. Individuals may become silent and apathetic, unable to move, or exhibit aimless or bizarre movements.

[0430] Seasonal affective disorder (SAD) is a type of seasonal depression in which an individual experiences depressive episodes that occur seasonally during the fall or winter.

[0431] Mild depression refers to a disorder associated with unipolar depression in which the same physical and cognitive problems are evident. It is not very severe and tends to last longer (e.g., at least 2 years).

[0432] Dual depression refers to a period of extremely depressed mood (mild depression) lasting at least 2 years, interspersed with periods of severe depression.

[0433] Depressive personality disorder (DPD) refers to a personality disorder characterized by depression.

[0434] Recurrent transient depression (RBD) is a condition in which an individual experiences depression approximately once a month, with each episode lasting two weeks or less and usually less than two to three days.

[0435] Mild depressive disorder or mild depression is defined as depression in which at least two symptoms are present for two weeks.

[0436] Bipolar disorder, or manic-depressive disorder, causes extreme mood swings, including elevated mood (mania or hypomania) and depressed mood (depression). During mania, individuals may feel or exhibit abnormal happiness, energy, or irritability. They often make hasty decisions with little regard for consequences. Sleep needs are typically reduced. During depression, they may cry out, lack eye contact with others, and adopt a negative outlook on life. Suicide risk is higher in patients with these conditions, exceeding 6% over 20 years, while self-harm rates are 30%-40%. Other mental health problems such as anxiety disorders and substance use disorders are often associated with bipolar disorder.

[0437] Depression caused by chronic medical conditions refers to depression caused by chronic medical conditions such as cancer, chronic pain, chemotherapy, or chronic stress.

[0438] Treatment-resistant depression refers to a condition in which an individual has received treatment for depression, but whose symptoms have not improved. For example, antidepressants or psychotherapy (psychotherapy) have not reduced the depressive symptoms of a subject with treatment-resistant depression. In some cases, an individual with treatment-resistant depression experiences symptom improvement, only to relapse. Treatment-resistant depression occurs in patients with depression who are resistant to standard pharmacological treatments, including tricyclic antidepressants, MAOIs, SSRIs, and dual and triple reuptake inhibitors and / or anxiolytics, as well as non-pharmacological treatments (e.g., psychotherapy, electroconvulsive therapy, vagus nerve stimulation, and / or transcranial magnetic stimulation).

[0439] Postoperative depression refers to depressive moods that occur after a surgical procedure (e.g., facing the outcome of death). For example, an individual may experience persistent feelings of sadness or emptiness, loss of pleasure or interest in normally enjoyed hobbies and activities, or persistent feelings of worthlessness or despair.

[0440] Mood disorders associated with women’s health conditions or illnesses are mood disorders (e.g., depression) that are associated with (e.g., caused by) women’s health conditions or illnesses (e.g., as described herein).

[0441] Suicidal tendencies, suicidal ideation, and suicidal behavior refer to an individual's tendency to commit suicide. Suicidal ideation involves thoughts about suicide or an abnormal focus on suicide. The range of suicidal ideation varies greatly, from fleeting thoughts to deep ideas, detailed plans, role-playing, and attempted suicide. Symptoms include discussing suicide, acquiring methods to commit suicide, social withdrawal, obsessive thinking about death, feeling trapped or hopeless about something, increased alcohol or drug use, engaging in risky or self-destructive activities, and saying goodbye to people as if they will never see them again.

[0442] Symptoms of depression include persistent anxiety or sadness, feelings of helplessness, hopelessness, pessimism, worthlessness, lethargy, restlessness, difficulty falling asleep, insomnia, irritability, fatigue, aggression, lack of interest in recreational activities or hobbies, poor concentration, lack of energy, low self-esteem, lack of positive thoughts or plans, excessive sleep, overeating, loss of appetite, insomnia, self-harm, suicidal thoughts, and suicide attempts. The presence, severity, frequency, and duration of symptoms can vary depending on the individual. Symptoms of depression and their relief can be determined by a physician or psychologist (e.g., through a mental status examination).

[0443] In some implementations, the method includes using known depression scales, such as the Hamilton Depression Rating Scale (HAM-D), the Clinical Global Impression-Improvement Scale (CGI), and the Montgomery-Asperger Depression Rating Scale. Subjects are monitored using the Depression Rating Scale (MADRS). In some implementations, treatment effectiveness can be determined by a decrease in the subject's total Hamilton Depression Rating Scale (HAM-D) score. The decrease in the total HAM-D score occurs within 4, 3, 2, or 1 day; or within 96, 84, 72, 60, 48, 24, 20, 16, 12, 10, 8 hours, or less. Treatment effectiveness can be assessed throughout the entire designated treatment period. For example, therapeutic effect can be determined by the reduction in the total HAM-D score compared to baseline after administration of a compound described herein, such as a compound of formula (I) (e.g., 12, 24, or 48 hours after administration; or 24, 48, 72, or 96 hours or longer; 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 a lifetime).

[0444] In some embodiments, the subject has a mild depressive disorder, such as mild major depressive disorder. In some embodiments, the subject has a moderate depressive disorder, such as moderate major depressive disorder. In some embodiments, the subject has a severe depressive disorder, such as severe major depressive disorder. In some embodiments, the subject has an extremely severe depressive disorder, such as extremely severe major depressive disorder. In some embodiments, the subject's baseline HAM-D total score (i.e., prior to treatment with the compound described herein, such as compound (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 between 14 and 18 (inclusive). In some embodiments, the subject's baseline HAM-D total score is between 19 and 22 (inclusive). In some embodiments, the subject's HAM-D total score prior to treatment with the compound described herein, such as compound (I) is greater than or equal to 23. In some embodiments, the baseline score is at least 10, 15, or 20. In some embodiments, after treatment with a compound described herein, such as compound (I), the subject's total HAM-D score is approximately 0 to 10 (e.g., less than 10; 0 to 10; 0 to 6; 0 to 4; 0 to 3; 0 to 2 or 1.8). In some embodiments, after treatment with a compound described herein, such as compound (I), the total HAM-D score is less than 10, 7, 5 or 3. In some embodiments, after treatment with a compound described herein (e.g., compound (I), the total HAM-D score decreases from a baseline score of approximately 20 to 30 (e.g., 22 to 28, 23 to 27, 24 to 27, 25 to 27, 26 to 27) to a total HAM-D score of approximately 0 to 10 (e.g., less than 10; 0 to 10, 0 to 6, 0 to 4, 0 to 3, 0 to 2 or 1.8). In some embodiments, the reduction in baseline HAM-D total score to HAM-D total score after treatment with a compound described herein, such as a compound of formula (I), is at least 1, 2, 3, 4, 5, 7, 10, 25, 40, 50, or 100 times. In some embodiments, the percentage reduction in baseline HAM-D total score to HAM-D total score after treatment with a compound described herein, such as a compound of formula (I), is at least 50% (e.g., 60%, 70%, 80%, or 90%). In some embodiments, the therapeutic effect is measured as a reduction in HAM-D total score after treatment with a compound described herein, such as a compound of formula (I), relative to baseline HAM-D total score (e.g., 12 hours, 24 hours, 48 ​​hours; or 24 hours, 48 ​​hours, 72 hours, 96 hours or longer; or 1 day, 2 days, 14 days or longer).

[0445] In some embodiments, the method of treating a depressive disorder (e.g., major depressive disorder) provides therapeutic effect within 14 days, 10 days, 4 days, 3 days, 2 days, or 1 day, or 24 hours, 20 hours, 16 hours, 12 hours, 10 hours, or 8 hours or less (e.g., as measured by a reduction in the Hamilton Depression Rating Scale (HAM-D)). In some embodiments, the method of treating a depressive disorder (e.g., major depressive disorder) provides therapeutic effect within the first or second day of treatment with a compound described herein, such as a compound of formula (I) (e.g., as measured by a statistically significant reduction in the total HAM-D score). In some embodiments, the method of treating a depressive disorder (e.g., major depressive disorder) provides therapeutic effect within 14 days of the start of treatment with a compound described herein, such as a compound of formula (I) (e.g., as measured by a statistically significant reduction in the total HAM-D score). In some embodiments, the method of treating a depressive disorder (e.g., major depressive disorder) provides a therapeutic effect (e.g., as determined by a statistically significant reduction in the total HAM-D score) within 21 days of initiation of treatment with a compound described herein, such as compound (I). In some embodiments, the method of treating a depressive disorder (e.g., major depressive disorder) provides a therapeutic effect (e.g., as determined by a statistically significant reduction in the total HAM-D score) within 28 days of initiation of treatment with a compound described herein, such as compound (I). In some embodiments, the therapeutic effect is a reduction in the total HAM-D score from baseline following treatment with a compound described herein, such as compound (I) (e.g., treatment with a compound described herein, such as compound (I), once daily for 14 days). In some embodiments, the subject's total HAM-D score was at least 24 prior to treatment with a compound described herein, such as compound (I). In some embodiments, the subject's total HAM-D score was at least 18 prior to treatment with a compound described herein, such as compound (I). In some embodiments, the subject's total HAM-D score is between 14 and 18 (inclusive) prior to treatment with a compound described herein, such as compound (I). In some embodiments, the subject's total HAM-D score decreases by at least 10 relative to baseline after treatment with a compound described herein, such as compound (I). In some embodiments, the subject's total HAM-D score decreases by at least 15 (e.g., at least 17) relative to baseline after treatment with a compound described herein, such as compound (I). In some embodiments, the total HAM-D score associated with treatment with a compound described herein, such as compound (I), is no more than a value in the range of 6 to 8.In some implementations, the total HAM-D score associated with treatment of a subject with the compounds described herein, such as those of formula (I), does not exceed 7.

[0446] In some embodiments, the method provides a therapeutic effect within 14 days, 10 days, 4 days, 3 days, 2 days, or 1 day, or 24 hours, 20 hours, 16 hours, 12 hours, 10 hours, or 8 hours or less (e.g., as measured by a decrease in the Clinical Global Impression Improvement Scale (CGI)). In some embodiments, the CNS condition is a depressive disorder, such as major depressive disorder. In some embodiments, the method for treating a depressive disorder (e.g., major depressive disorder) provides a therapeutic effect on the second day of the treatment period. In some embodiments, the therapeutic effect is a decrease in the CGI score from baseline at the end of the treatment period (e.g., 14 days after administration).

[0447] In some embodiments, the method provides therapeutic effect over a period of 14 days, 10 days, 4 days, 3 days, 2 days, or 1 day, or 24 hours, 20 hours, 16 hours, 12 hours, 10 hours, or 8 hours or less (e.g., as measured by a decrease in the Montgomery-Asperger's Depression Rating Scale (MADRS)). In some embodiments, the CNS condition is a depressive disorder, such as major depressive disorder. In some embodiments, the method for treating a depressive disorder (e.g., major depressive disorder) provides therapeutic effect on the second day of the treatment period. In some embodiments, the therapeutic effect is a decrease in the MADRS score from baseline at the end of the treatment period (e.g., 14 days after administration).

[0448] The therapeutic effect of major depressive disorder can be measured by a decrease in the Montgomery-Asperger's Depression Rating Scale (MADRS) score demonstrated by the subject. For example, MADRS scores may decrease within 4 days, 3 days, 2 days, or 1 day; or within 96 hours, 84 hours, 72 hours, 60 hours, 48 ​​hours, 24 hours, 20 hours, 16 hours, 12 hours, 10 hours, 8 hours, or less. The Montgomery-Asperger's Depression Rating Scale (MADRS) is a ten-item diagnostic questionnaire (about facial sadness, reported sadness, anxiety, decreased sleep, decreased appetite, difficulty concentrating, fatigue, feelings of weakness, pessimistic thoughts, and suicidal ideation) used by psychiatrists to measure the severity of depressive episodes in patients with mood disorders.

[0449] In some embodiments, the method provides a therapeutic effect over a period of 4 days, 3 days, 2 days, 1 day; 24 hours, 20 hours, 16 hours, 12 hours, 10 hours, 8 hours, or less (e.g., as measured by a reduction in the Edinburgh Postnatal Depression Scale (EPDS)). In some embodiments, the therapeutic effect is an improvement as measured by the EPDS.

[0450] In some implementations, the method provides therapeutic effects over a period of 4 days, 3 days, 2 days, 1 day; 24 hours, 20 hours, 16 hours, 12 hours, 10 hours, 8 hours or less (e.g., as measured by a reduction in the Generalized Anxiety Disorder 7-Item Scale (GAD-7)).

[0451] Anxiety disorder

[0452] This article provides methods for treating anxiety disorders (e.g., generalized anxiety disorder, panic disorder, obsessive-compulsive disorder, phobias, post-traumatic stress disorder). Anxiety disorders are a broad term encompassing several different forms of abnormal and pathological fear and anxiety. Current diagnostic criteria for mental illness identify various anxiety disorders.

[0453] Generalized anxiety disorder (GAD) is a common chronic condition characterized by persistent anxiety and an inability to focus on any single goal or situation. Individuals with GAD experience nonspecific, persistent fear and worry, and become excessively concerned about daily events. GAD is the most common anxiety disorder affecting older adults.

[0454] In panic disorder, an individual experiences brief episodes of intense fear and anxiety, typically characterized by trembling, shaking, confusion, dizziness, nausea, and difficulty breathing. These panic attacks are defined by the APA as sudden onset of fear or discomfort that peaks within ten minutes, can last for several hours, and can be triggered by stress, fear, or even movement; however, the specific cause remains unclear. In addition to recurrent, unexpected panic attacks, a diagnosis of panic disorder requires that the attacks have chronic consequences: worry about the potential impact of the attack, persistent fear of future attacks, or significant behavioral changes associated with the attack. Therefore, individuals with panic disorder experience symptoms even outside of specific panic attacks. Typically, panic sufferers notice normal changes in their heart rate, leading them to believe that there is something wrong with their heart or that they are about to experience another panic attack. In some cases, heightened perception of bodily functions (hypervigilance) occurs during a panic attack, where any perceived physiological changes are interpreted as potentially life-threatening illness (i.e., extreme hypochondria).

[0455] Obsessive-compulsive disorder (OCD) is a type of anxiety disorder characterized by repetitive distress (troubling, persistent, and intrusive thoughts or images) and compulsions (intense urges to perform specific actions or rituals). OCD thought patterns can be likened to superstition, linking beliefs to causal relationships that do not actually exist. Often, this process is completely illogical; for example, a compulsive walking in a certain pattern may be used to relieve distress over impending harm. And in many cases, the compulsions are entirely unexplained, merely a stress-triggered urge to complete a ritual. In rare cases, individuals with OCD may experience only distress without overt compulsive behaviors; very few experience only compulsive behaviors.

[0456] The single largest category of anxiety disorders is phobias, which include all situations in which fear and anxiety are triggered by specific stimuli or circumstances. Patients typically anticipate terrifying consequences from encountering the object they fear, which can range from animals to bodily fluid locations.

[0457] Post-traumatic stress disorder, or PTSD, is an anxiety disorder caused by a traumatic experience. PTSD can be triggered by extreme situations such as fighting, rape, hostage situations, or even serious accidents. It can also be caused by prolonged (chronic) exposure to severe stressors, such as a soldier who has endured individual combat but is unable to cope with continuous fighting. Common symptoms include instantaneous re-experiencing, avoidance behavior, and depression.

[0458] Women's health conditions

[0459] This article provides methods for treating women’s health-related disorders or conditions. Women’s health-related disorders or conditions include, but are not limited to, gynecological health conditions and conditions (e.g., premenstrual syndrome (PMS), premenstrual anxiety disorder (PMDD)), pregnancy problems (e.g., miscarriage, abortion), infertility and related conditions (e.g., polycystic ovary syndrome (PCOS)), other conditions and disorders, and problems related to women’s overall health and wellness (e.g., amenorrhea).

[0460] Women’s gynecological health and conditions include menstruation and irregular menstruation; urinary tract health, including urinary incontinence and pelvic floor disorders; and conditions such as bacterial vaginosis, vaginitis, uterine fibroids, and vulvar pain.

[0461] Premenstrual syndrome (PMS) refers to the physical and emotional symptoms that occur one to two weeks before a woman's menstrual period. Symptoms can vary but may include bleeding, mood swings, breast tenderness, food cravings, fatigue, irritability, acne, and depression.

[0462] Premenstrual anxiety disorder (PMDD) is a severe form of PMS. PMDD symptoms are similar to PMS but more severe and can interfere with work, social activities, and relationships. PMDD symptoms include mood swings, depressed mood or feelings of hopelessness, marked anger, increased interpersonal conflict, tension and anxiety, irritability, decreased interest in common activities, difficulty concentrating, fatigue, changes in appetite, feelings of being out of control or overwhelmed, sleep problems, and physical problems (e.g., bloating, breast tenderness, swelling, headaches, joint or muscle pain).

[0463] Pregnancy problems include preconception and prenatal care, pregnancy loss (miscarriage and stillbirth), premature birth and premature birth, infant death syndrome (SIDS), breastfeeding and birth defects.

[0464] Miscarriage refers to a pregnancy that terminates spontaneously within 20 weeks before conception.

[0465] Abortion is the intentional termination of pregnancy, which can be performed during the first 28 weeks of pregnancy.

[0466] Infertility and related conditions include uterine fibroids, polycystic ovary syndrome, endometriosis, and primary ovarian insufficiency.

[0467] Polycystic ovary syndrome (PCOS) is an endocrine disorder affecting women of reproductive age. PCOS is a group of symptoms caused by elevated levels of androgens in a woman's body. Most women with PCOS develop numerous small follicles on their ovaries. Symptoms of PCOS include irregular or absent menstruation, heavy menstrual bleeding, excessive body and facial hair, acne, pelvic pain, difficulty conceiving, and spots on rough, dark, and smooth skin. PCOS can be associated with conditions including type 2 diabetes, obesity, obstructive sleep apnea, heart disease, mood disorders, and endometrial cancer.

[0468] Other conditions and illnesses that affect women only include Turner syndrome, Rett syndrome, and ovarian and cervical cancer.

[0469] Women’s overall health and wellness issues include violence against women, women with disabilities and their unique challenges, osteoporosis and bone health, and menopause.

[0470] Amenorrhea refers to the period 12 months after a woman's last menstrual period, marking the end of her menstrual cycle. It typically occurs in women in their 40s or 50s. Physical symptoms of amenorrhea (such as hot flashes) and emotional symptoms can disrupt sleep, reduce energy, or trigger anxiety, feelings of sadness, or loss. Amenorrhea includes natural amenorrhea and surgical amenorrhea, which is a type of amenorrhea induced by events such as surgery (e.g., hysterectomy, oophorectomy; cancer). Amenorrhea can also be induced when the ovaries are severely damaged due to factors such as radiation, chemotherapy, or other drug treatments.

[0471] Epilepsy

[0472] A compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable composition thereof, may be used in the methods described herein, for example, for the treatment of the conditions described herein, such as epilepsy, status epilepticus, or seizures.

[0473] Epilepsy is a brain disorder characterized by recurrent seizures over time. Types of epilepsy include, but are not limited to, generalized epilepsy, such as childhood absence epilepsy, juvenile myoclonic epilepsy, arousal-onset grand mal epilepsy, West syndrome, and Lennox-Gastaut syndrome; and partial epilepsy, such as temporal lobe epilepsy, frontal lobe epilepsy, and benign focal epilepsy in children.

[0474] Epilepsy

[0475] The compounds and methods described herein can be used to treat or prevent epilepsy. Epilepsy is a progressive process by which the normal brain produces epileptic seizures (a chronic disorder in which seizures occur). Epilepsy is caused by neuronal damage resulting from initial lesions (e.g., status epilepticus).

[0476] Status epilepticus (SE)

[0477] Status epilepticus (SE) can include, for example, convulsive status epilepticus, such as early status epilepticus, established status epilepticus, refractory status epilepticus, and ultra-refractory status epilepticus; nonconvulsive status epilepticus, such as generalized status epilepticus and complex partial status epilepticus; generalized periodic epileptiform discharges; and periodic unilateral epileptiform discharges. Convulsive status epilepticus is characterized by the presence of convulsive status epileptic seizures and can include early status epilepticus, established status epilepticus, refractory status epilepticus, and ultra-refractory status epilepticus. Early status epilepticus is treated with first-line therapy. Established status epilepticus is characterized by status epileptic seizures that persist despite first-line therapy and second-line therapy. Refractory status epilepticus is characterized by status epileptic seizures that persist despite first-line and second-line therapy and is usually treated with general anesthetics. Ultra-refractory status epilepticus is characterized by status epileptic seizures that persist despite treatment with first-line, second-line, and general anesthetics for 24 hours or longer.

[0478] Nonconvulsive status epilepticus can include, for example, focal nonconvulsive status epilepticus, such as complex partial nonconvulsive status epilepticus, simple partial nonconvulsive status epilepticus, and subtle nonconvulsive status epilepticus; and generalized nonconvulsive status epilepticus, such as late-onset absence nonconvulsive status epilepticus, atypical absence nonconvulsive status epilepticus, or typical absence nonconvulsive status epilepticus.

[0479] The compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable combination thereof, may also be administered as a prophylactic agent to a subject with a CNS condition (e.g., traumatic brain injury; status epilepticus, such as convulsive status epilepticus, such as early status epilepticus, established status epilepticus, refractory status epilepticus, ultra-refractory status epilepticus; nonconvulsive status epilepticus, such as generalized status epilepticus, complex partial status epilepticus; generalized periodic epileptiform discharges; and periodic unilateral epileptiform discharges) prior to a seizure.

[0480] Seizures

[0481] An epileptic seizure is a physiological change or behavioral response that occurs following an event of abnormal electrical activity in the brain. The term "epileptic seizure" is often used interchangeably with "convulsion." A convulsion is a rapid and uncontrollable shaking of the body. During a convulsion, the body's muscles repeatedly contract and relax.

[0482] Based on the type of behavior and brain activity, epileptic seizures are divided into two broad categories: generalized and partial (also known as focal or localized). Classifying the type of epileptic seizure helps doctors diagnose whether a patient has epilepsy.

[0483] Generalized seizures are produced by electrical impulses throughout the entire brain, while partial seizures (at least initially) are produced by electrical impulses in a relatively small part of the brain. The part of the brain that produces a seizure is sometimes called a lesion.

[0484] There are six types of generalized seizures. The most common, severe, and therefore best known is the generalized tonic-clonic seizure, also called a grand mal seizure. In this type of seizure, the patient loses consciousness and usually collapses. After loss of consciousness, there is a generalized rigidity of the body (called the “tonic” phase of the seizure) for 30 to 60 seconds, followed by violent convulsions (the “clonic” phase) for 30 to 60 seconds, after which the patient enters a deep sleep (the “postictal” or post-ictal phase). Injuries and accidents such as tongue biting and urinary incontinence may occur during a grand mal seizure.

[0485] Absence seizures cause brief loss of consciousness (lasting only a few seconds) and are almost asymptomatic. Patients (most commonly children) typically stop their activity and stare blankly. These seizures begin and end suddenly and can occur several times a day. Patients are usually unaware of their seizures, but they may be aware of the "passage of time."

[0486] Myoclonic seizures consist of occasional muscle twitches, usually on both sides of the body. Patients sometimes describe these muscle twitches as brief electric shocks. In severe cases, these seizures may cause objects to fall or be unintentionally thrown.

[0487] Clonic seizures are repetitive, rhythmic muscle spasms that involve both sides of the body.

[0488] A characteristic feature of tonic-clonic seizures is muscle stiffness.

[0489] Atonic seizures consist of a sudden and generalized loss of muscle tone, particularly in the arms and legs, and often result in falls.

[0490] The epileptic seizures described in this article may include: epileptic seizures; acute repetitive seizures; dense seizures; continuous seizures; uninterrupted seizures; long-term seizures; recurrent seizures; status epilepticus, such as refractory convulsive status epilepticus and nonconvulsive status epilepticus; refractory seizures; myoclonic seizures; tonic seizures; tonic-clonic seizures; simple partial seizures; complex partial seizures; secondary generalized seizures; atypical absence seizures; absence seizures; atonic seizures; benign seizures. Rolandic seizures; febrile seizures; mood seizures; focal seizures; gelastic seizures; generalized seizures; infantile spasms; Jacksonian seizures; massive bilateral myoclonic seizures; multifocal seizures; neonatal paroxysmal seizures; nocturnal seizures; occipital lobe seizures; post-traumatic seizures; subtle seizures; Sylvanseizures; visual reflex seizures; or withdrawal seizures. In some implementations, the seizures are generalized seizures associated with Dravet syndrome, Leigh-Gastaut syndrome, tuberous sclerosis complex, Rett syndrome, or PCDH19 in female infants with epilepsy.

[0491] Movement disorders

[0492] This article also describes methods for treating movement disorders. As used herein, “movement disorder” refers to a variety of diseases and conditions associated with hyperkinetic movement disorders and abnormalities related to muscle control. Exemplary movement disorders include, but are not limited to, Parkinson’s disease and Parkinson’s syndrome (specifically defined by bradykinesia), dystonia, chorea and Huntington’s disease, ataxia, tremor (e.g., essential tremor), myoclonus and startle reflex, tics and Tourette syndrome, restless legs syndrome, stiff-person syndrome, and gait disorders.

[0493] Tremor

[0494] The methods described herein can be used to treat tremors, for example, compounds of formula (I) can be used to treat cerebellar tremor or intention tremor, dystonia tremor, essential tremor, orthostatic tremor, Parkinson's tremor, physiological tremor, psychogenic tremor or red nucleus tremor. Tremors can be categorized as follows: hereditary, degenerative, and idiopathic conditions, such as Wilson's disease, Parkinson's disease, and spontaneous tremor; metabolic disorders (e.g., thyroid-parathyroid disease, liver disease, and hypoglycemia); peripheral neuropathy (associated with Charcot-Marie-Tooth disease, Roussy-Levy disease, diabetes, and complex regional pain syndrome); toxins (nicotine, mercury, lead, CO, manganese, arsenic, toluene); drug-induced tremors (narcolepsy, tricyclic antidepressants, lithium, cocaine, alcohol, adrenaline, bronchodilators, theophylline, caffeine, steroids, valproate, amiodarone, thyroid hormones, vincristine); and psychogenic disorders. Clinical tremor can be classified into physiological tremor, enhanced physiological tremor, essential tremor syndrome (including classic essential tremor, primary orthostatic tremor, and task-specific and position-specific tremor), dystonia tremor, Parkinsonian tremor, cerebellar tremor, Hodgkin's tremor (i.e., red nucleus tremor), palatal tremor, neuropathic tremor, toxin or drug-induced tremor, and psychogenic tremor.

[0495] Tremor is an involuntary, sometimes rhythmic, muscular contraction and relaxation that may involve oscillations or twitches in one or more body parts (e.g., hands, arms, eyes, face, head, vocal cord folds, trunk, legs).

[0496] Cerebellar tremor, or intention tremor, is a slow, widespread tremor of the extremities that occurs after purposeful movement. Cerebellar tremor is caused by cerebellar lesions or damage resulting from causes such as tumors, stroke, or diseases (e.g., multiple sclerosis, a hereditary degenerative disease).

[0497] Dystonic tremor occurs in individuals affected by dystonia (a movement disorder in which persistent involuntary muscle contractions cause twisting and repetitive movements and / or pain and abnormal posture or position). Dystonic tremor can affect any muscle in the body. Dystonic tremor occurs irregularly and is often relieved by complete rest.

[0498] Essential tremor, or benign essential tremor, is the most common type of tremor. Essential tremor can be mild and in some cases non-progressive, and it can progress slowly, starting on one side of the body but affecting both sides within 3 years. The hands are most commonly affected, but the head, voice, tongue, legs, and trunk can also be involved. The frequency of tremor may decrease with age, but its severity may increase. Elevated emotions, stress, fever, exhaustion, or hypoglycemia can trigger tremors and / or increase their severity. Symptoms generally develop over time, are visible after an attack, and persist.

[0499] Orthostatic tremor is characterized by rapid (e.g., above 12 Hz) rhythmic muscle contractions that occur quickly in the legs and trunk after standing. Cramps may be felt in the thighs and legs, and the patient may tremble uncontrollably when asked to stand in one place. Orthostatic tremor can also occur in patients with essential tremor.

[0500] Parkinson's tremor is caused by damage to the brain structures that control movement. It is often a precursor to Parkinson's disease and typically manifests as a "pill-rolling" motion in the hands, but can also affect the jaw, lips, legs, and trunk. Onset of Parkinson's tremor usually begins after age 60. The movement begins in one limb or one side of the body and can progress to include the other side.

[0501] Physiological tremor can occur in normal individuals and is not clinically significant. It can be seen in all voluntary muscle groups. Physiological tremor can be caused by certain medications, alcohol withdrawal, or medical conditions including overactive thyroid and hypoglycemia. The tremor typically has a frequency of about 10 Hz.

[0502] Psychogenic tremor, or hysterical tremor, can occur at rest or during postural or dynamic movement. Patients with psychogenic tremor may also have conversion disorder or another mental illness.

[0503] Red nucleus tremor is characterized by coarse and slow tremors that can be present at rest, while in a posture, and even when consciously engaged. This tremor is associated with disorders affecting the red nucleus in the midbrain, and is a classic example of aberrant stroke.

[0504] Parkinson's disease affects the nerve cells in the brain that produce dopamine. Symptoms include muscle rigidity, tremor, and changes in speech and gait. Parkinson's disease is characterized by tremor, bradykinesia, rigidity, and postural instability. While Parkinson's syndrome shares the symptoms found in Parkinson's disease, it is a complex syndrome rather than a progressive neurodegenerative disease.

[0505] Dystonia is a movement disorder characterized by persistent or intermittent muscle contractions that cause abnormal (often repetitive) movements or postures. Dystonic movements can be patterned, twisting, and may be tremor-like. Dystonia often begins or worsens with voluntary actions and is associated with spillover muscle activation.

[0506] Chorea is a neurological disorder characterized by twitching, involuntary movements that typically affect the shoulders, hips, and face. Huntington's disease is a genetic disorder that causes progressive weakening of nerve cells in the brain. Symptoms include uncontrolled movements, clumsiness, and balance problems. Huntington's disease can impair walking, speaking, and swallowing.

[0507] Ataxia is the loss of complete control over limb movement and can affect the fingers, hands, arms, legs, body, speech, and eye movements.

[0508] Myoclonus and startle are responses to sudden and unexpected stimuli, which can be auditory, tactile, visual, or vestibular.

[0509] Tics are involuntary movements, usually with a sudden onset, brief, repetitive, but non-rhythmic, often mimicking normal behavior and typically occurring against a background of normal activity. Tics can be classified as motor tics or vocal tics; motor tics are related to movement, while vocal tics are related to sound. Tics can be simple or complex. For example, simple motor tics involve only a few muscles limited to a specific part of the body. Tourette syndrome is a hereditary neuropsychiatric disorder that occurs in children and is characterized by multiple motor tics and at least one vocal tic.

[0510] Restless legs syndrome is a neurosensory-motor disorder characterized by an uncontrollable urge to move the legs at rest.

[0511] Stiff-person syndrome is a progressive movement disorder characterized by involuntary painful spasms and muscle rigidity, typically involving the lower back and legs. It usually produces a stiff-legged gait with increased lumbar hyperbola. Characteristic abnormalities are typically observed on EMG recordings of continuous motor unit activity involving the paravertebral muscles. Variants include "stiff limb syndrome," which produces focal stiffness that typically affects the distal leg and foot.

[0512] Gait disorders are abnormalities in walking patterns or styles caused by neuromuscular, arthritis, or other bodily changes. Gait is classified according to the system responsible for abnormal movement and includes hemiplegic gait, bilateral paraplegic gait, neuropathic gait, myopathic gait, Parkinsonian gait, choreiform gait, ataxia gait, and sensory gait.

[0513] Anesthesia / Sedation

[0514] Anesthesia is a pharmacologically induced and reversible state of amnesia, analgesia, loss of responsiveness, loss of musculoskeletal reflexes, reduced stress response, or all of these simultaneously. These effects can be achieved by a single drug alone providing the correct combination of effects, or by combinations of drugs (e.g., hypnotics, sedatives, anesthetics, analgesics) to achieve very specific combined results. Anesthesia allows patients to undergo surgery and other procedures without the pain and suffering they would otherwise experience.

[0515] Sedation is achieved by administering pharmacological agents to reduce irritability or agitation, often to facilitate medical or diagnostic procedures.

[0516] Sedation and analgesia encompass the continuum of states of consciousness ranging from mild sedation (sedatives) to general anesthesia.

[0517] Minimal sedation, also known as sedation, is a drug-induced state in which the patient responds normally to verbal commands. Cognitive function and coordination may be impaired. Ventilation and cardiovascular function are usually unaffected.

[0518] Moderate sedation / analgesia (awake sedation) is drug-induced inhibition of consciousness during which the patient purposefully responds to verbal commands, alone or with light and tactile stimulation. No intervention is usually required to maintain airway patency. Spontaneous ventilation is usually sufficient. Cardiovascular function is usually maintained.

[0519] Deep sedation / analgesia involves drug-induced inhibition of consciousness, during which the patient cannot be easily awakened but will respond purposefully to repeated or painful stimuli (reflexive withdrawal of non-painful stimuli). Independent ventilation may be impaired, and the patient may require assistance to maintain airway patency. Spontaneous ventilation may be insufficient. Cardiovascular function is usually maintained.

[0520] General anesthesia is a drug-induced loss of consciousness during which the patient cannot be awakened, even by painful stimuli. The ability to maintain independent ventilation is usually impaired, and assistance is often required to maintain airway patency. Positive pressure ventilation may be necessary due to reduced spontaneous ventilation or drug-induced neuromuscular inhibition. Cardiovascular function may be impaired.

[0521] Sedation in the intensive care unit (ICU) allows for the suppression of a patient's environmental awareness and reduces their response to external stimuli. It can be effective in caring for critically ill patients and covers a wider range of symptoms that vary with individual changes throughout the patient's life and the course of their illness. In critical care, deep sedation has been used to promote endotracheal tube tolerance and ventilator synchronization, often using neuromuscular blocking agents.

[0522] In some implementations, sedation is induced and maintained in the ICU for a longer period of time (e.g., long-term sedation, sustained sedation) (e.g., 1 day, 2 days, 3 days, 5 days, 1 week, 2 weeks, 3 weeks, 1 month, 2 months). Long-term sedatives can have a long duration of action. Sedatives in the ICU can have a shorter elimination half-life.

[0523] Procedural sedation and analgesia, also known as conscious sedation, is a technique that involves administering sedatives or dissociative agents, with or without analgesics, to induce a procedure that allows the subject to undergo an intolerable process while maintaining cardiopulmonary function.

[0524] Example

[0525] To provide a more complete understanding of the invention described herein, the following embodiments are illustrated. The synthetic and biological embodiments described in this application are provided to illustrate the compounds, pharmaceutical compositions, and methods provided herein, and should not be construed as limiting their scope in any way.

[0526] Materials and methods

[0527] The compounds described herein can be prepared from readily available starting materials using the following general methods and procedures. It should be understood that, given typical or preferred process conditions (i.e., reaction temperature, time, molar ratio of reactants, solvent, pressure, etc.), other process conditions may be used unless otherwise specified. Optimal reaction conditions may vary depending on the specific reactants or solvents used, but such conditions can be determined by those skilled in the art through conventional optimization procedures.

[0528] Furthermore, as will be apparent to those skilled in the art, conventional protecting groups may be required to prevent certain functional groups from undergoing unwanted reactions. The selection of protecting groups suitable for specific functional groups and the appropriate conditions for protection and deprotection is well known in the art. For example, many protecting groups and their introduction and removal are described in TW Greene and PGM Uts, *Protecting Groups in Organic Synthesis*, 2nd edition, Wiley, New York, 1991, and the references cited therein.

[0529] The compounds described herein can be isolated and purified using known standard procedures. Such procedures include (but are not limited to) recrystallization, column chromatography, HPLC, or supercritical fluid chromatography (SFC). Details regarding the preparation of the representative oxidized sterols listed herein are presented below. The compounds described herein can be prepared by those skilled in the art of organic synthesis from known or commercially available starting materials and reagents. Exemplary chiral columns that can be used to separate / purify the enantiomers / diasteromers described herein include, but are not limited to, those used for the purpose of separation / purification. AD-10, OB OB-H, OD, OD-H, OF OG, OJ and OK.

[0530] This article reports 1 ¹H-NMR (e.g., for the region between about 0.5 and about 4 ppm δ (ppm)) should be understood as an exemplary interpretation of the NMR spectrum of the compound (e.g., exemplary peak integration). Exemplary general method for preparative HPLC: Column: Waters RBridge preparative 10 μm C18, 19*250 mm. Mobile phase: Acetonitrile, water (NH₄HCO₃) (30 L water, 24 g NH₄HCO₃, 30 mL NH₃·H₂O). Flow rate: 25 mL / min.

[0531] Exemplary general method for preparative HPLC: Column: Waters RBridge preparative HPLC C18, 19*250mm. Mobile phase: acetonitrile, water (NH4HCO3) (30L water, 24g NH4HCO3, 30mL NH3.H2O). Flow rate: 25mL / min.

[0532] Exemplary general method for analytical HPLC: Mobile phase: A: water (10 mM NH4HCO3), B: acetonitrile; Gradient: 5%-95% B over 1.6 or 2 min; Flow rate: 1.8 or 2 mL / min; Column: XBridge C18, 4.6*50 mm, operating at 45°C. .

[0533] Exemplary general method for preparative HPLC (Column: Waters Xbridge 150*25 5u; Conditions: Water (10mM NH4HCO3)-ACN; Start B: 60; End B: 80; Gradient time (min): 7; 100% B hold time (min): 2)

[0534] Exemplary general method for preparative HPLC (Column: Waters Xbridge 150*25 5u; Conditions: Water (10mM NH4HCO3)-ACN; Start B: 55; End B: 75; Gradient time (min): 7; 100% B hold time (min): 2)

[0535] Exemplary general method for preparative HPLC (instrument: AE; column: Xtimate) Conditions: Water (0.225% FA) - ACN; Start B: 58; End B: 78; Gradient time (min): 7; 100% B hold time (min): 3; Flow rate (mL / min): 25; Injection: 7)

[0536] Example general method of SFC: Column: AD CSP (250mm*30mm, 10μm), gradient: 45% B, A = NH3H2O, B = MeOH, flow rate: 60mL / min. For example, AD_3_EtOH_DEA_5_40_25ML would indicate: "Column: Chiralpak AD-3 150x4.6 mm ID, 3µm mobile phase: A: CO2, B: ethanol (0.05% DEA), gradient: B from 5% to 40% over 5 min and held at 40% for 2.5 min, followed by B at 5% for 2.5 min, flow rate: 2.5mL / min, column temperature: 35℃".

[0537] LC-ELSD / MS: Mobile phase: 1.5 mL / 4 L TFA / water (solvent A) and 0.75 mL / 4 L TFA / acetonitrile (solvent B), eluted at 1.2 mL / min for 0.9 min using an elution gradient of 30%-90% (solvent B) and maintained at 90% for 0.6 min; Column: Ultimate C18 2.1*30 mm. Wavelength: UV 220nm; Column temperature: 50℃; MS ionization: ESI; Detector: PDA & ELSD.

[0538] abbreviation:

[0539] PE: petroleum ether; EtOAc: ethyl acetate; THF: tetrahydrofuran; DCM: dichloromethane; MTBE: methyl tert-butyl ether; 9-BBN: 9-boronbicyclo[3.3.1]nonane; BHT: 2,6-di-tert-butyl-4-methylphenol; DMP: Dess-Martin periodoalkane; LDA: lithium diisopropylamino; MAD: methylaluminum bis(2,6-di-tert-butyl-4-methylphenyl oxide); NBS: N-bromosuccinimide.

[0540] Example 1: Synthesis of 1-((3R,5S,8S,10S,13S,14S,17S)-3-hydroxy-3,10,13-trimethyl-2,3,4,5,6,7,8,10,12,13,14,15,16,17-tetradecanohydro-1H-cyclopentan[a]phenanthrene-17-yl)ethyl-1-one (A5)

[0541]

[0542] Synthetic A2

[0543]

[0544] A suspension of LiCl (1.23 g, 29.1 mmol, anhydrous) in THF (200 mL, anhydrous) was stirred for 30 min at 10 °C under N2, followed by the addition of FeCl3 (2.46 g, 15.2 mmol, anhydrous). The mixture was cooled to -30 °C and MeMgBr (18.5 mL, 3 M in THF) was added dropwise. After stirring at -30 °C for 30 min, A1 (4 g, 13.9 mmol, CAS No. 15375-19-6) was added. After stirring at -15 °C for 2 h, citric acid (500 mL, 10% aqueous solution) was added and the mixture was extracted with EtOAc (2 x 300 mL). The combined organic solutions were washed with brine (2 x 300 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel chromatography (PE / EtOAc = 0% to 10%) to give A2 (3.27 g) as a solid.

[0545] 1 H NMR (400MHz, CDCl3)δ H 5.39(d,J=5.6Hz,1H),2.53-2.38(m,1H),2.29-1.92(m,6H),1.75-1.59(m,3H),1.55-1.47(m,3H),1. 44-1.30(m,4H),1.28-1.18(m,4H),1.14-1.02(m,1H),0.91(s,3H),0.82(s,3H); LC-ELSD / MS: Purity 99%, C 20 H 29 O1[M-H2O+H] + The calculated MS ESI value is 285.2, and the experimental value is also 285.2.

[0546] Synthetic A3

[0547]

[0548] t-BuOK (3.53 g, 31.5 mmol) was added to a suspension of EtPPh3Br (11.6 g, 31.5 mmol) in THF (200 mL) at 15 °C under N2. After stirring at 50 °C for 1 h, A2 (3.2 g, 10.5 mmol) was added fractionally at below 40 °C. After stirring at 30 °C for 3 h, the reaction mixture was quenched at 0 °C with a saturated aqueous NH4Cl solution (20 mL) and extracted with EtOAc (2 x 100 mL). The combined organic solutions were concentrated under vacuum to give an oil, which was purified by grinding with MeOH / H2O (1:1, 140 mL) to give A3 (3.5 g) as a solid. The solid (3.5 g) was purified by rapid column chromatography (0 to 2% EtOAc / PE) to give A2 (2.97 g) as a solid.

[0549] 1 H NMR (400MHz, CDCl3)δ H 5.35(d,J=5.8Hz,1H),5.24-5.11(m,1H),2.49-2.18(m,4H),2.14-2.05(m,1H),1.99-1.90(m,1H),1.79-1.66(m,2H),1.66-1. 64(m,3H),1.63-1.56(m,3H),1.53-1.49(m,1H),1.46-1.24(m,7H),1.22(s,3H),1.12-0.95(m,1H),0.89(s,3H),0.81(s,3H).

[0550] Synthetic A4

[0551]

[0552] 9-BBN dimer (4.17 g, 17.1 mmol) was added to a solution of A3 (2.7 g, 8.58 mmol) in THF (30 mL). The mixture was stirred at 40 °C for 12 h and then cooled to 15 °C. Ethanol (20 mL) was added, the reactants were cooled to 0 °C, and NaOH aqueous solution (17.1 mL, 5.0 M, 85.8 mmol) and hydrogen peroxide (8.58 mL, 10 M, 85.8 mmol) were added dropwise. After stirring at 78 °C for 1 h, the mixture was cooled to 15 °C and water (200 mL) was added. The resulting solid was filtered, dissolved in DCM (300 mL), washed with saturated Na2S2O3 aqueous solution, filtered, and evaporated to give A4 (2.8 g impure) as a solid.

[0553] 1 H NMR (400MHz, CDCl3)δH 5.30(d,J=5.6Hz,1H),3.78-3.62(m,1H),2.14-1.79(m,6H),1.70-1.58(m,3H),1.54-1.47 (m,2H),1.45-1.25(m,8H),1.24-1.13(m,7H),1.07-0.94(m,1H),0.88(s,3H),0.59(s,3H)

[0554] Synthetic A5

[0555]

[0556] Silica gel (4 g) and PCC (3.59 g, 16.8 mmol) were added to a solution of A4 (2.8 g, 8.42 mmol) in DCM (30 mL) at 20 °C. After stirring at 20 °C for 3 h, the resulting mixture was filtered, and the filtrate was concentrated under vacuum. The residue was purified by rapid chromatography with elution using petroleum ether / ethyl acetate = 5 / 1 to give A5 (1.82 g) as a solid.

[0557] 1 H NMR (400MHz, CDCl3)δ H 5.44-5.29(m,1H),2.59(t,J=9.4Hz,1H),2.34-2.15(m,3H),2.13(s,3H),2.08-1.96(m,1H),1.94-1.78(m,2H),1.75-1.61(m, 3H),1.55-1.45(m,2H),1.43-1.24(m,6H),1.23-1.20(m,4H),1.09-0.94(m,1H),0.88(s,3H),0.54(s,3H); LC-ELSD / MS purity 99%, C 22 H 33 O1[M-H2O+H] + The calculated MS ESI value is 313.3, and the experimental value is also 313.3. de% > 99% (via 1H NMR).

[0558] Examples 2 and 3 synthesize 1-(2-((3R,5S,8S,10S,13S,14S,17S)-3-hydroxy-3,10,13-trimethyl-2,3,4,5,6,7,8,10,12,13,14,15,16,17-tetradecanoic acid-1H-cyclopentan[a]phenanthrene-17-yl)-2-oxoethyl)-1H-pyrazole-4-carboxynitrile ( A7) and 1-(2-((3R,5S,8S,10S,13S,14S,17R)-3-hydroxy-3,10,13-trimethyl-2,3,4,5,6,7,8,10,12,13,14,15,16,17-tetradecanoic acid-1H-cyclopentan[a]phenanthrene-17-yl)-2-oxoethyl)-1H-pyrazole-4-carboxynitrile (A8)

[0559]

[0560] Synthetic A6

[0561]

[0562] HBr (97.7 mg, 0.48 mmol, 40% / water) and Br2 (405 mg, 2.54 mmol) were added to a solution of A5 (800 mg, 2.42 mmol) in MeOH (20 mL) at 20 °C. After stirring at 20 °C for 12 h, the mixture was quenched with a saturated NaHCO3 aqueous solution (10 mL), treated with water (20 mL), and extracted with EtOAc (2 x 30 mL). The combined organic solutions were washed with brine (30 mL), dried over anhydrous Na2SO4, filtered, and concentrated to obtain solid A6 (950 mg, crude material) which was used directly in the next step.

[0563] Synthesize A7 and A8

[0564]

[0565] To a solution of A6 (300 mg, crude material) in acetone (5 mL), 1H-pyrazole-4-carboxynitrile (68.2 mg, 0.7327 mmol) and K₂CO₃ (302 mg, 2.19 mmol) were added. After stirring at 25 °C for 12 h, water (20 mL) was added, and the mixture was extracted with EtOAc (2 x 30 mL). The combined organic solutions were separated, dried over Na₂SO₄, filtered, and concentrated. The residue was purified by preparative HPLC to give A7 (65 mg) and A8 (5 mg) as solids. A7 (65 mg) was ground with n-hexane (10 mL) at 20 °C to give A7 (46 mg) as a solid.

[0566] A7: 1H NMR (400MHz, CDCl3)δ H 7.86(s,1H),7.81(s,1H),5.42-5.30(m,1H),5.12-4.79(m,2H),2.67(t,J=9.3Hz,1H),2.35-2.18(m,3H),2.12-1.99(m,1H),1.98-1.83( m,2H),1.83-1.59(m,4H),1.51-1.25(m,7H),1.22(s,3H),1.18(s,1H),1.08-0.97(m,1H),0.89(s,3H),0.60(s,3H); LC-ELSD / MS purity 99%; C 26 H36N3O2[M+H] + The calculated MS ESI value was 422.3, and the experimental value was also 422.3. de% > 99% (via 1H NMR).

[0567] A8: 1 H NMR (400MHz, CDCl3)δ H 7.86(s,1H),7.82(s,1H),5.35(s,1H),5.15-4.79(m,2H),2.83(d,J=8.4Hz,1H),2.10-1.85(m,7H),1.69-1.62(m,2H) ,1.54-1.26(m,9H),1.21(s,2H),1.23-1.18(m,1H),1.15-1.03(m,1H),0.88(s,3H),0.87(s,3H); LC-ELSD / MS purity 99%;; C 26 H 34 N3O1[M-H2O+H] + The calculated MS ESI value is 404.2, and the experimental value is also 404.2. de% > 99% (via 1H NMR).

[0568] Examples 4 and 5: Synthesis of 1-((3R,5S,8S,10S,13S,14S,17S)-3-hydroxy-3,10,13-trimethyl-2,3,4,5,6,7,8,10,12,13,14,15,16,17-tetradecanohydro-1H-cyclopentan[a]phenanthrene-17-yl)-2-(5-methyl-2H-tetrazol-2-yl)ethyl-1-one (A9) and 1-((3R,5S,8S,10S,13S,14S,17S)-3-hydroxy-3,10,13-trimethyl-2,3,4,5,6,7,8,10,12,13,14,15,16,17-tetradecanohydro-1H-cyclopentan[a]phenanthrene-17-yl)-2-(5-methyl-1H-tetrazol-1-yl)ethyl-1-one (A10)

[0569]

[0570] 5-Methyl-1H-1,2,3,4-tetraazole (54.2 mg, 0.65 mmol) and K₂CO₃ (222 mg, 1.61 mmol) were added to a solution of A₆ (220 mg, crude) in THF (5 mL). After stirring at 25 °C for 12 h, the mixture was diluted with water (40 mL) and extracted with EtOAc (2 x 50 mL). The organic layer was dried over Na₂SO₄, filtered, and concentrated. The residue was purified by rapid column chromatography (10 to 60% EtOAc / PE) to give A₁₉ (20 mg) and A₁₀ (22 mg) as solids.

[0571] A9: 1 H NMR (400MHz, CDCl3)δ H 5.36(s,3H),2.70(t,J=9.3Hz,1H),2.56(s,3H),2.35-2.20(m,3H),2.13-2.01(m,1H),1.96-1.58(m, 6H),1.54-1.27(m,8H),1.22(s,3H),1.11-0.97(m,1H),0.89(s,3H),0.65(s,3H); LC-ELSD / MS purity 99%, C 24 H 37 N4O2[M+H] + The calculated MSESI value is 413.3, and the experimental value is also 413.3.

[0572] A10: 1¹H NMR (400MHz, CDCl₃) δ 5.43–5.35 (m, 1H), 5.25–4.90 (m, 2H), 2.73 (t, J = 9.2 Hz, 1H), 2.48 (s, 3H), 2.37–2.23 (m, 3H), 2.11–2.01 (m, 1H), 1.96–1.62 (m, 6H), 1.49–1.26 (m, 9H), 1.23 (s, 3H), 0.89 (s, 3H), 0.62 (s, 3H); LC-ELSD / MS purity 99%, C 24 H 37 N4O2[M+H] + The calculated MS ESI value is 413.3, and the experimental value is also 413.3.

[0573] Examples 6 and 7: Synthesis of 1-((3R,5S,8S,10S,13S,14S,17S)-3-hydroxy-3,10,13-trimethyl-2,3,4,5,6,7,8,10,12,13,14,15,16,17-tetradecanohydro-1H-cyclopentan[a]phenanthrene-17-yl)-2-(1H-1,2,3-triazol-1-yl)ethyl-1-one ( A11) and 1-((3R,5S,8S,10S,13S,14S,17S)-3-hydroxy-3,10,13-trimethyl-2,3,4,5,6,7,8,10,12,13,14,15,16,17-tetradecanohydro-1H-cyclopentan[a]phenanthrene-17-yl)-2-(2H-1,2,3-triazol-2-yl)ethyl-1-one (A12)

[0574]

[0575] To a solution of A6 (350 mg, crude material) in THF (5 mL), 1H-1,2,3-triazole (70.4 mg, 1.02 mmol) and K₂CO₃ (353 mg, 2.56 mmol) were added. After stirring at 25 °C for 12 h, water (40 mL) was added, and the mixture was extracted with EtOAc (2 x 50 mL). The combined organic solutions were dried over Na₂SO₄, filtered, and concentrated. The residue was purified by preparative HPLC to give A11 (34 mg) and A12 (27 mg) as solids. Based on the triazole proton... 1 H NMR specifies the isomer at the location.

[0576] A11: 1 H NMR (400MHz, CDCl3)δ H7.76(d,J=0.8Hz,1H),7.65(d,J=0.8Hz,1H),5.40-5.36(m,1H),5.32-5 .11(m,2H),2.72(t,J=9.3Hz,1H),2.36-2.21(m,J=2.5Hz,3H),2.08-2.0 0(m,1H),1.97-1.85(m,2H),1.84-1.60(m,4H),1.53-1.27(m,8H),1.22( s,3H),1.08-0.98(m,1H),0.89(s,3H),0.61(s,3H); LC-ELSD / MS purity 99%, C 24 H 36 N3O2[M+H] + The calculated MSESI value is 398.3, and the experimental value is also 398.3. de% > 99 (via LC-ELSD / MS)

[0577] A12: 1 H NMR (400MHz, CDCl3)δ H 7.68(s,2H),5.40-5.34(m,1H),5.25(d,J=2.8Hz,2H),2.65(t,J=9.3Hz,1H),2.38-2.19(m,3H),2.12-1.98(m,1H),2.12-1.98(m,1H), 1.96-1.82(m,2H),1.81-1.62(m,3H),1.53-1.26(m,8H),1.22(s,3H),1.09-0.96(m,1H),0.89(s,3H),0.65(s,3H); LC-ELSD / MS purity 99%, C 24 H 36 N3O2[M+H] + The calculated MS ESI value is 398.3, and the experimental value is also 398.3. de% > 99% (via LC-ELSD / MS).

[0578] Example 8: Synthesis of 1-((3R,5R,8S,10S,13S,14S,17S)-3-hydroxy-3,10,13-trimethyl-2,3,4,5,6,7,8,10,12,13,14,15,16,17-tetradecanohydro-1H-cyclopentan[a]phenanthrene-17-yl)ethyl-1-one (A17)

[0579]

[0580] Synthetic A14

[0581]

[0582] AlMe3 (2M in toluene, 9.05mL, 18.1mmol) was added dropwise to a solution of BHT (8g, 36.3mmol) in toluene (17.4mL) under nitrogen at 0°C. After stirring at 25°C for 1 h, a solution of Al3 (3.5g, 12.2mmol, CAS No. 1093397-63-7) in DCM (26.3mL) was added dropwise to the above solution in MAD form at -70°C. After stirring at -70°C under N2 for 1 h, MeMgBr (10.1mL, 30.5mmol, 3M in diethyl ether) was added dropwise. After stirring at -70°C for another 2 h, the reaction mixture was poured into a saturated aqueous solution of citric acid (200mL) at below 10°C and extracted with EtOAc (2 x 50mL). The combined organic solutions were dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by rapid column chromatography (0 to 30% EtOAc / PE) to give A14 (2 g, 54.3%) as an oil.

[0583] 1 H NMR (400MHz, CDCl3)δ H 5.44(d,J=5.6Hz,1H),2.52-2.40(m,1H),2.25-2.09(m,3H),2.08-1.93(m,4H),1.79-1.58(m,3H),1.55-1.49(m,2H), 1.48-1.42(m,1H),1.41-1.27(m,3H),1.26(s,3H),1.25-1.18(m,2H),1.10(s,3H),0.82(s,3H); LC-ELSD / MS purity 99.5%, C 20 H 29 O1[M-H2O+H] + The calculated MS ESI value is 285.2, and the experimental value is also 285.2.

[0584] Synthetic A15

[0585]

[0586] t-BuOK (3.7 g, 33.0 mmol) was added to a mixture of EtPPh3Br (12.2 g, 33.0 mmol) in THF (50 mL) at 20 °C under N2. After stirring at 50 °C for 30 min, A14 (3.35 g, 11 mmol) was added fractionally at below 40 °C. After stirring at 40 °C for 3 h, the reaction mixture was quenched with saturated NH4Cl aqueous solution (20 mL) and extracted with EtOAc (2 x 10 mL). The combined organic solutions were concentrated. The residue was purified by rapid column chromatography (0 to 20% EtOAc / PE) to give A15 (1.8 g, 52.1%) as an oil.

[0587] 1 H NMR (400MHz, CDCl3)δ H 5.41-5.39(m,1H),5.25-5.15(m,1H),2.45-2.35(m,3H),2.30-2.15(m,1H),2.0 5-1.95(m,5H),1.75-1.50(m,10H),1.45-1.15(m,7H),1.08(s,3H),0.79(s,3H).

[0588] Synthetic A16

[0589]

[0590] 9-BBN dimer (2.78 g, 11.4 mmol) was added to a solution of A15 (1.8 g, 5.72 mmol) in THF (10 mL). After stirring at 30 °C for 2 h, ethanol (10 mL) was added dropwise at 15 °C, followed by the dropwise addition of NaOH aqueous solution (11.4 mL, 5.0 M, 57.2 mmol) at 0 °C, and then the dropwise addition of hydrogen peroxide (5.72 mL, 10 M, 57.2 mmol). After stirring at 50 °C for 1 h, the mixture was cooled to 15 °C, water (100 mL) was added, and the resulting solid was filtered. The solid was dissolved in THF (80 mL), washed with saturated Na2S2O3 aqueous solution, filtered, and concentrated under vacuum. The residue was purified by rapid column chromatography (0 to 25% EtOAc / PE) to give A16 (1.25 g, 65.7%) as a solid.

[0591] 1 H NMR (400MHz, CDCl3)δ H5.35-5.30(m,1H),3.75-3.65(m,1H),2.05-1.85(m,6H),1.80-1.50(m ,6H),1.45-1.35(m,3H),1.35-1.15(m,13H),1.07(s,3H),0.57(s,3H).

[0592] Synthetic A17

[0593]

[0594] DMP (254 mg, 0.6 mmol) was added to a solution of A16 (100 mg, 0.3 mmol) in DCM (5 mL) at 25 °C. After stirring at 25 °C for 0.5 h, the mixture was quenched with saturated NaHCO3 (80 mL) and saturated Na2S2O3 (80 mL) and extracted with DCM (2 x 80 mL). The organic solution was dried over Na2SO4, filtered, and concentrated. The residue was purified by rapid column chromatography (5 to 30% EtOAc / PE) to give A17 (60 mg, 60.4%) as a solid.

[0595] 1 H NMR (400MHz, CDCl3)δ H 5.40(br d,J=5.6Hz,1H),2.59(t,J=9.2Hz,1H),2.37-2.30(m,1H),2.24-2.14(m,2H),2.13(s,3H),2.05-1.92(m,3H),1.86-1.76(m,1 H),1.75-1.59(m,4H),1.56-1.49(m,1H),1.47-1.34(m,3H),1.33-1.15(m,8H),1.07(s,3H),0.52(s,3H); LC-ELSD / MS purity 99%, C 22 H 33 O1[M-H2O+H] + The calculated MS ESI value is 313.2, and the experimental value is also 313.2.

[0596] Example 9: Synthesis of 1-(2-((3R,5R,8S,10S,13S,14S,17S)-3-hydroxy-3,10,13-trimethyl-2,3,4,5,6,7,8,10,12,13,14,15,16,17-tetradecanoic acid-1H-cyclopentan[a]phenanthrene-17-yl)-2-oxoethyl)-1H-pyrazole-4-carboxynitrile (A19)

[0597]

[0598] Synthetic A18

[0599]

[0600] HBr (12.2 mg, 0.06 mmol, 40% / water) and Br2 (48.3 mg, 0.3 mmol) were added to a solution of A17 (100 mg, 0.3 mmol) in MeOH (2 mL) at 25 °C. After stirring at 25 °C for 4 h, the mixture was quenched with a saturated NaHCO3 aqueous solution (10 mL), treated with water (20 mL), and extracted with EtOAc (2 x 30 mL). The combined organic solutions were washed with brine (30 mL), dried over anhydrous Na2SO4, filtered, and concentrated to obtain solid A18 (130 mg) which was used directly in the next step.

[0601] 1 H NMR (400MHz, CDCl3)δ H 5.39(br d,J=5.6Hz,1H),3.97-3.87(m,2H),2.89(t,J=9.2Hz,1H),2.38-2.30(m,1H),2.27-2.15(m,2H),2. 03-1.95(m,3H),1.88-1.58(m,5H),1.52-1.39(m,4H),1.33-1.18(m,8H),1.07(s,3H),0.55(s,3H).

[0602] Synthetic A19

[0603]

[0604] To a solution of A18 (130 mg, crude matter) in acetone (2 mL), 1H-pyrazole-4-carboxynitrile (35.4 mg, 0.38 mmol) and K₂CO₃ (131 mg, 0.95 mmol) were added. After stirring at 25 °C for 12 h, water (20 mL) was added to the mixture and it was extracted with EtOAc (2 x 30 mL). The combined organic solutions were dried over Na₂SO₄, filtered, and concentrated. The residue was purified by rapid column chromatography (10 to 50% EtOAc / PE) to give A19 (40 mg, 30%) as a solid.

[0605] 1 H NMR (400MHz, CDCl3)δ H7.86(s,1H),7.81(s,1H),5.41(br d,J=5.6Hz,1H),5.06-4.87(m,2H),2.68(t,J=9.2Hz,1H),2.42-2.19(m,3H),2.07-1.94(m,3H),1.93-1.75(m ,2H),1.74-1.59(m,3H),1.52-1.41(m,3H),1.37-1.16(m,9H),1.08(s,3H),0.58(s,3H); LC-ELSD / MS purity 99%, C 26 H 35 N3O2[M+1] + The calculated MS ESI value is 421.3, and the experimental value is 422.3.

[0606] Examples 10 and 11: Synthesis of 1-((3R,5R,8S,10S,13S,14S,17S)-3-hydroxy-3,10,13-trimethyl-2,3,4,5,6,7,8,10,12,13,14,15,16,17-tetradecanohydro-1H-cyclopentan[a]phenanthrene-17-yl)-2-(5-methyl-2H-tetrazole-2-yl)ethyl-1-one (A20) and 1-((3R,5R,8S,10S,13S,14S,17S)-3-hydroxy-3,10,13-trimethyl-2,3,4,5,6,7,8,10,12,13,14,15,16,17-tetradecanohydro-1H-cyclopentan[a]phenanthrene-17-yl)-2-(5-methyl-1H-tetrazol-1-yl)ethyl-1-one (A21).

[0607]

[0608] 5-Methyl-1H-1,2,3,4-tetraazole (61.6 mg, 0.73 mmol) and K₂CO₃ (252 mg, 1.83 mmol) were added to a solution of A18 (250 mg, crude) in THF (2 mL). After stirring at 25 °C for 12 h, the reaction mixture was diluted with water (40 mL) and extracted with EtOAc (2 x 50 mL). The combined organic solutions were separated, dried over Na₂SO₄, filtered, and concentrated. The residue was purified by rapid column chromatography (10 to 80% EtOAc / PE) to give A20 (50 mg, 19.9%) and A21 (44 mg, 17.5%) as solids. A20 (50 mg, 0.12 mmol) was lyophilized with CH₃CN (2 mL) and H₂O (25 mL) to give A20 (45 mg, 90.1%) as solids. 1 H NMR specifies the isomer at the location.

[0609] A20: 1 H NMR (400MHz, CDCl3)δ H 5.45-5.39 (m, 1H), 5.36 (s, 2H), 2.70 (t, J = 9.2 Hz, 1H), 2.57 (s, 3H), 2.40-2.19 (m, 3H), 2.06-1.96 (m, 3H), 1.92-1.60 (m, 5H), 1.52-1.42 (m, 3H), 1.38-1.15 (m, 9H), 1.08 (s, 3H), 0.63 (s, 3H); LC-ELSD / MS purity 99%, C 24 H 35 N4O1[M-H2O+H] + The calculated MS ESI value is 395.2, and the experimental value is also 395.2. de% > 99% (via LC-ELSD / MS).

[0610] A21: 1 H NMR (400MHz, CDCl3)δ H 5.43(br d,J=5.2Hz,1H),5.22-5.00(m,2H),2.73(t,J=9.2Hz,1H),2.56-2.38(m,4H),2.34-2.20(m,2H),2.08-1.95(m,3H),1.9 3-1.60(m,5H),1.50-1.39(m,2H),1.38-1.19(m,9H),1.09(s,3H),0.91-0.81(m,1H),0.60(s,3H); LC-ELSD / MS purity 99%, C 24 H 35 N4O1[M-H2O+H] + The calculated MS ESI value is 395.2, and the experimental value is also 395.2. de% > 99% (via LC-ELSD / MS).

[0611] Examples 12 and 13: Synthesis of 1-((3R,5R,8S,10S,13S,14S,17S)-3-hydroxy-3,10,13-trimethyl-2,3,4,5,6,7,8,10,12,13,14,15,16,17-tetradecanohydro-1H-cyclopentan[a]phenanthrene-17-yl)-2-(2H-1,2,3-triazol-2-yl)ethyl-1-one (A23) and 1-((3R,5R,8S,10S,13S,14S,17S)-3-hydroxy-3,10,13-trimethyl-2,3,4,5,6,7,8,10,12,13,14,15,16,17-tetradecanohydro-1H-cyclopentan[a]phenanthrene-17-yl)-2-(1H-1,2,3-triazol-1-yl)ethyl-1-one (A22)

[0612]

[0613] To a solution of A18 (250 mg, crude material) in THF (2 mL), 1H-1,2,3-triazole (50.6 mg, 0.73 mmol) and K₂CO₃ (252 mg, 1.83 mmol) were added. After stirring at 25 °C for 12 h, the mixture was diluted with water (40 mL) and extracted with EtOAc (2 x 50 mL). The combined organic solutions were separated, dried over Na₂SO₄, filtered, and concentrated. The residue was purified by rapid column chromatography (10 to 80% EtOAc / PE) to give A23 (22 mg, 9.09%) and A22 (33 mg, 14%) as solids. Based on triazole... 1 H NMR specifies the isomer at the location.

[0614] A23: 1 H NMR (400MHz, CDCl3)δ H 7.69 (s, 2H), 5.46–5.37 (m, 1H), 5.25 (s, 2H), 2.65 (t, J = 9.2 Hz, 1H), 2.33–2.17 (m, 3H), 2.06–1.95 (m, 3H), 1.90–1.58 (m, 5H), 1.50–1.40 (m, 3H), 1.35–1.17 (s, 9H), 1.08 (s, 3H), 0.63 (s, 3H); LC-ELSD / MS purity 99%, C 24 H 35 N3O2[M+1] + The calculated MS ESI value is 397.3, and the experimental value is 398.3. de% > 99% (via LC-ELSD / MS)

[0615] A22: 1 H NMR (400MHz, CDCl3)δH 7.76(s,1H),7.65(s,1H),5.42(br d,J=5.6Hz,1H),5.32-5.12(m,2H),2.72(t,J=9.2Hz,1H),2.45-2.20(m,3H),2.07-1.95(m,3H),1. 91-1.60(m,5H),1.52-1.41(m,2H),1.37-1.17(m,9H),1.08(s,3H),0.92-0.81(m,1H),0.59(s,3H).

[0616] LC-ELSD / MS purity 99%, C 24 H 35 N3O2[M+1] + The calculated MS ESI value is 397.3, and the experimental value is 398.3. de% > 99% (via LC-ELSD / MS)

[0617] Example 14: Synthesis of 1-((3R,5S,8S,10S,13S,14S,17S)-3-(ethoxymethyl)-3-hydroxy-10,13-dimethyl-2,3,4,5,6,7,8,10,12,13,14,15,16,17-tetradecanohydro-1H-cyclopentan[a]phenanthrene-17-yl)ethyl-1-one

[0618]

[0619] Synthesize 14.1

[0620] t-BuOK (813 mg, 7.3 mmol) was added to a stirred solution of trimethylsulfonium iodide (1.59 g, 7.3 mmol) in DMSO (10 mL). After heating at 60 °C for 1 h under N2, 14.0 g (1.6 g, 5.6 mmol) of (5α)-androst-9(11)-en-3,17-dione was added. After stirring at 25 °C for 16 h, the reaction mixture was diluted with water (50 mL) and extracted with EtOAc (2 x 50 mL). The combined organic phases were washed with water (2 x 50 mL) and brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum to give 14.1 g (2.0 g) as a solid.

[0621] 1 H NMR (400MHz, CDCl3)δ H5.40(d,J=5.6Hz,1H),2.63(s,2H),2.52-2.41(m,1H),2.20-1.98(m,6H),1.89(t,J=13.2H z,1H),1.77-1.29(m,10H),1.16-1.02(m,1H),0.99(s,3H),0.98-0.92(m,1H),0.83(s,3H).

[0622] Synthesize 14.2

[0623] Na (1.52 g, 66.5 mmol) was added to anhydrous ethanol (50 mL) in ten fractions. The mixture was stirred at 25 °C for 2 h. EtOH (5 mL) containing 1.1 g (2.0 g, 6.7 mmol) was added to freshly prepared EtOH (66.5 mmol) containing EtOH (50 mL) at 25 °C. After stirring at 65 °C for 16 h, the reaction mixture was cooled to 0 °C and quenched with water (200 mL). The aqueous phase was extracted with EtOAc (3 x 100 mL). The combined organic phases were washed with brine (2 x 100 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated. The residue was purified by rapid column chromatography (0 to 30% EtOAc / PE) to give 14.2 g (1.0 g, 43.4%) as a solid.

[0624] 1 H NMR (400MHz, CDCl3)δ H 5.46-5.39(m,1H),3.55(q,J=6.8Hz,2H),3.25(s,2H),2.53-2.43(m,1H),2.30-1.99(m,6H),1.88-1.65(m,4H),1.88- 1.65(m,4H),1.60-1.49(m,4H),1.42-1.28(m,1H),1.23(t,J=7.2Hz,3H),1.17-1.03(m,1H),0.93(s,3H),0.84(s,3H).

[0625] Synthesize 14.3

[0626] t-BuOK (1.15 g, 10.3 mmol) was added to a suspension of EtPPh3Br (3.82 g, 10.3 mmol) in THF (10 mL) at 25 °C under N2. After stirring at 40 °C for 30 min, 14.2 (1.2 g, 3.5 mmol) was added fractionally at 40 °C. After stirring at 40 °C for 3 h, the reaction mixture was quenched at 25 °C with a saturated aqueous solution of NH4Cl (30 mL). The aqueous layer was extracted with EtOAc (2 x 50 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by rapid column chromatography (0 to 20% EtOAc / PE) to give 14.3 (900 mg, 72.5%) as a solid.

[0627] 1 H NMR (400MHz, CDCl3)δ H 5.40-5.32(m,1H),5.23-5.11(m,1H),3.53(q,J=7.2Hz,2H),3.23(s,2H),2.47-2.18(m,4H),2.14-2.05(m,1H),1.97-1.89(m,1H),1.78- 1.69(m,3H),1.68-1.60(m,5H),1.58-1.48(m,2H),1.44-1.23(m,6H),1.20(t,J=6.9Hz,3H),1.10-0.99(m,1H),0.89(s,3H),0.81(s,3H)

[0628] Synthesized 14.4

[0629] 9-BBN dimer (1.82 g, 7.5 mmol) was added to a solution of 14.3 (900 mg, 2.5 mmol) in anhydrous THF (10 mL) at 25 °C under N2. After stirring at 50 °C for 2 hours, the mixture was cooled and diluted with EtOH (10 mL) at 0 °C. NaOH (1 g / 5.0 mL water, 5 M, 25.0 mmol) was then added very slowly, followed by H2O2 (2.5 mL, 25.0 mmol, 10 M) until the internal temperature no longer increased and remained below 30 °C. After stirring at 50 °C for 1 hour, the mixture was poured into saturated Na2S2O3 (50 mL), stirred for 30 min, and then extracted with EtOAc (2 x 50 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under vacuum to give 14.4 (2.7 g) as a solid. The residue (300 mg) was purified by rapid column chromatography (0 to 30% EtOAc / PE) to give 14.4 (32 mg, 10.7%) as a solid.

[0630] 1 H NMR (400MHz, CDCl3)δ H 5.31 (d, J = 6.0 Hz, 1H), 3.76-3.64 (m, 1H), 3.53 (q, J = 6.8 Hz, 2H), 3.22 (s, 2H), 2.12-1.59 (m, 10H), 1.53-1.47 (m, 2H), 1.45-1.16 (m, 14H), 1.13-1.12 (m, 1H), 1.07-0.93 (m, 1H), 0.88 (s, 3H), 0.60 (s, 3H). LCMS purity ≥ 99%, C 24 H 40 O3Na[M+Na] + The calculated MS ESI value is 399.3, and the experimental value is also 399.3.

[0631] Synthesis 14

[0632] NaCNBH3 (402 mg, 6.4 mmol) was added to a solution of 14.4 (300 mg, 0.8 mmol) and (1R)-1-phenylethyl-1-amine (581 mg, 4.8 mmol) in DCE (5 mL) at 25 °C. After stirring at 50 °C for 16 h, the reaction mixture was quenched with water (50 mL) and then extracted with DCM (2 x 50 mL). The combined organic phases were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by rapid column chromatography (0 to 30% EtOAc / PE) to give 14 (200 mg, 52.0%) as a solid.

[0633] 1 H NMR (400MHz, CDCl3)δ H 7.39-7.28(m,4H),7.25-7.18(m,1H),5.35(d,J=5.6Hz,1H),3.90(q,J=6.4 Hz,1H),3.53(q,J=6.8Hz,2H),3.23(s,2H),2.78-2.68(m,1H),2.43-2.35( m,1H),2.08-1.96(m,3H),1.92-1.62(m,8H),1.41-1.25(m,10H),1.20(t,J =7.2Hz,4H),1.16-1.09(m,1H),1.05-0.95(m,1H),0.90(s,6H),0.73(s,3H)

[0634] LC-ELSD / MS purity 98.1%, C 32 H50 NO2[M+H] + The calculated MS ESI value is 480.4, and the experimental value is also 480.4.

[0635] Example 15: Synthesis of 1-((3R,5R,8S,10S,13S,14S,17S)-3-(ethoxymethyl)-3-hydroxy-10,13-dimethyl-2,3,4,5,6,7,8,10,12,13,14,15,16,17-tetradecanohydro-1H-cyclopentan[a]phenanthrene-17-yl)ethyl-1-one

[0636]

[0637] Synthesize 15.1

[0638] At 0 °C, NaH (831 mg, 20.8 mmol, 60% / mineral oil) was added to a stirred solution of trimethylsulfonium iodide (4.24 g, 20.8 mmol) in DMSO (25 mL) and THF (12 mL). After stirring under N2 for 1.0 h, a solution of (5β)-androst-9(11)-ene-3,17-dione, 15.0 g (5 g, 17.4 mmol), in DMSO (15 mL) was added to the mixture at 0 °C. After stirring at 25 °C for 2 h, the reactants were diluted with water (300 mL) and extracted with EtOAc (2 x 200 mL). The combined organic phases were washed with water (2 x 100 mL) and brine (100 mL), dried over anhydrous Na2SO4, filtered, and concentrated to give 15.1 g (5 g, 95.7%) as an oil.

[0639] 1 H NMR (400MHz, CDCl3)δ H 5.62-5.43(m,1H),2.66-2.34(m,3H),2.25-2.04(m,6H),2.01-1.85(m,2H),1.81-1.7 1(m,1H),1.66-1.50(m,3H),1.45-1.25(m,2H),1.23-0.97(m,5H),0.87-0.78(m,4H).

[0640] Synthesize 15.2 and 15.2a

[0641] Na (1.9 g, 83 mmol) was added fractionally to anhydrous EtOH (50 mL) at 25 °C under N2. After stirring at 75 °C for 1 h, anhydrous ethanol (50 mL) containing 6.1 (5 g, 16.6 mmol) was added to the sodium ethoxylate solution at 75 °C. After stirring at 75 °C for 16 h, the reaction mixture was quenched with water (200 mL). The reaction mixture was concentrated to remove most of the solvent. The mixture was then extracted with EtOAc (2 x 150 mL). The combined organic phases were washed with brine (150 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by rapid column chromatography (0 to 25% EtOAc / PE) to give 15.2a (2.3 g, 39.9%) and 15.2 (1.8 g, 31.3%) as oils.

[0642] 15.2: 1 H NMR (400MHz, CDCl3)δ H 5.44(d,J=6.0Hz,1H),3.53(q,J=6.8Hz,2H),3.47-3.40(m,2H),2.50-2.39(m,1H),2.22-2.05(m,4H), 2.03-1.93(m,3H),1.83-1.53(m,6H),1.42-1.28(m,3H),1.25-1.14(m,5H),1.09(s,3H),0.80(s,3H).

[0643] 15.2a: 1 H NMR (400MHz, CDCl3)δ H 5.41 (d, J = 5.2 Hz, 1H), 3.51 (q, J = 6.8 Hz, 2H), 3.20 (s, 2H), 2.51–2.38 (m, 1H), 2.24–1.91 (m, 8H), 1.84–1.56 (m, 4H), 1.53–1.42 (m, 3H), 1.27–1.16 (m, 7H), 1.12 (s, 3H), 0.81 (s, 3H). LC-ELSD / MS purity 99%, C 22 H 33 O2[M+H-H2O] + The calculated MSESI value is 329.2, and the experimental value is also 329.2.

[0644] Synthesize 15.3

[0645] t-BuOK (1.64 g, 14.7 mmol) was added to a suspension of EtPPh3Br (5.45 g, 14.7 mmol) in THF (45 mL) under N2. After stirring at 50 °C for 30 min, THF (5 mL) containing 15.2 (1.7 g, 4.9 mmol) was added. After stirring at 40 °C for 2 h, the reaction mixture was quenched with 10% NH4Cl aqueous solution (200 mL). The aqueous layer was collected and extracted with EtOAc (2 x 150 mL). The combined organic phases were concentrated. The residue was purified by rapid column chromatography (0 to 10% EtOAc / PE) to give 15.3 (1.1 g, 62.8%) as an oil.

[0646] 1 H NMR (400MHz, CDCl3)δ H 3 5.45-5.37(m,1H),5.22-5.14(m,1H),3.53(q,J=7.2Hz,2H),3.47-3.40(m,2H),2.41-2.18(m,4H),2 .03-1.94(m,3H),1.75-1.58(m,8H),1.51-1.27(m,5H),1.24-1.17(m,5H),1.07(s,3H),0.79(s,3H).

[0647] Synthesize 15.4

[0648] 9-BBN dimer (1.48 g, 6.12 mmol) was added to a solution of 15.3 (1.1 g, 3.06 mmol) in THF (20 mL). After stirring at 45 °C for 2 h, the resulting mixture was treated with ethanol (2 mL) at 15 °C and then with an aqueous solution of NaOH (6 mL, 5.0 M, 30 mmol) at 0 °C. Hydrogen peroxide (3 mL, 10 M, 30 mmol) was added dropwise at 0 °C. After stirring at 78 °C for 1 h, the mixture was cooled to 15 °C and quenched with a saturated aqueous solution of Na₂S₂O₃ (200 mL). The aqueous phase was collected and extracted with EtOAc (2 x 150 mL). The combined organic phases were washed with brine (150 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated. The residue was purified by rapid column chromatography (0 to 40% EtOAc / PE) to give 15.4 (1 g, 86.9%) as an oil.

[0649] 1 H NMR (400MHz, CDCl3)δ H5.36(br s,1H),3.75-3.66(m,1H),3.53(q,J=6.8Hz,2H),3.47-3.40(m,2H),2.02-1.87(m,5H ),1.84-1.60(m,7H),1.54-1.29(m,7H),1.25-1.12(m,9H),1.06(s,3H),0.57(s,3H).

[0650] Synthesize 15

[0651] DMP (2.24 g, 5.3 mmol) was added fractionally to a solution of 15.4 (1 g, 2.65 mmol) in DCM (10 mL). After stirring at 25 °C for 20 min, the mixture was quenched with saturated NaHCO3 aqueous solution (150 mL). The aqueous phase was collected and extracted with DCM (2 x 150 mL). The combined organic phases were washed with saturated Na2S2O3 aqueous solution (2 x 200 mL) and brine (200 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by rapid column chromatography (0 to 25% EtOAc / PE) to give 15 (720 mg, 72.5%) as a solid.

[0652] 1 H NMR (400MHz, CDCl3)δ H 5.41(br d,J=6.0Hz,1H),3.54(q,J=6.8Hz,2H),3.47-3.40(m,2H),2.60(t,J=9.2Hz,1H),2.38-2.30(m,1H),2.24-2.16(m,2H) ,2.13(s,3H),2.04-1.92(m,3H),1.85-1.63(m,5H),1.60-1.58(m,1H),1.51-1.16(m,11H),1.06(s,3H),0.52(s,3H).

[0653] LC-ELSD / MS purity 99%, C 24 H 37 O2[M+H-H2O] + The calculated MS ESI value is 357.3, and the experimental value is also 357.3.

[0654] Example 16: Synthesis of 1-((3R,5R,8S,10S,13S,14S,17S)-3-hydroxy-3-(methoxymethyl)-10,13-dimethyl-2,3,4,5,6,7,8,10,12,13,14,15,16,17-tetradecanohydro-1H-cyclopentan[a]phenanthrene-17-yl)ethyl-1-one

[0655]

[0656] Synthesize 16.1 and 16.1a

[0657] Na (2.5 g, 109 mmol) was added to anhydrous methanol (25 mL) in five fractions. After stirring at 25 °C for 2 h, THF (25 mL) containing 15.1 (3.3 g, 10.9 mmol) was added. After stirring at 60 °C for 5 h, the reaction mixture was cooled to 0 °C and quenched by adding H₂O (100 mL). This solution was purified together with another batch (2.6 g 15.1). The aqueous phase was extracted with EtOAc (3 x 100 mL). The combined organic phases were washed with brine (2 x 100 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated. The residue was purified by rapid column chromatography (0 to 40% EtOAc / PE) to give 16.1a (2.0 g, 31.7%) and 16.1 (2.0 g, 31.7%) as solids. The stereochemistry of C3 in these two compounds is determined by the chemical shift of the methylene group at the C3 side chain: the equatorial orientation is located in a region higher than the axial orientation.

[0658] 16.1a: 1 H NMR (400MHz, CDCl3)δ H 5.38 (d, J = 5.6 Hz, 1H), 3.34 (s, 3H), 3.15 (s, 2H), 2.59–2.24 (m, 2H), 2.23–2.03 (m, 6H), 1.98–1.67 (m, 5H), 1.67–1.34 (m, 6H), 1.33–1.28 (m, 1H), 1.10 (s, 4H), 0.78 (s, 3H). 100% de (based on H-NMR).

[0659] 16.1: 1 H NMR (400MHz, CDCl3)δ H 5.45 (d, J = 5.6 Hz, 1H), 3.45–3.35 (m, 5H), 2.45 (dd, J = 18.8, 8.0 Hz, 1H), 2.20–1.96 (m, 7H), 1.66–1.50 (m, 8H), 1.39–1.18 (m, 4H), 1.09 (s, 3H), 0.80 (s, 3H). LC-ELSD / MS purity 99%, 100% de (based on H-NMR). C 21 H 31 O2[M+H-H2O] + The calculated MS ESI value is 315.2, and the experimental value is also 315.2.

[0660] Synthesize 16.2

[0661] t-BuOK (3.83 g, 34.2 mmol) was added to a mixture of EtPPh3Br (12.6 g, 34.2 mmol) and THF (50 mL) at 15 °C under N2. After stirring at 50 °C for 30 min, 16.1 (1.9 g, 5.71 mmol) was added fractionally at below 40 °C. After stirring at 40 °C for 1 h, the reaction mixture was quenched at 15 °C with 10% NH4Cl aqueous solution (100 mL). The aqueous layer was collected and extracted with EtOAc (200 mL). The combined organic phases were concentrated under vacuum. The residue was purified by grinding with MeOH / H2O (1:1, 300 mL) under reflux to give 16.2 (8 g), which was further purified by silica gel column chromatography (PE / EtOAc = 1 / 10 to 1 / 5) to give 16.2 (1.5 g, 77%) as a solid.

[0662] 1 H NMR (400MHz, CDCl3)δ H 5.40(d,J=2.0Hz,1H),5.25-5.15(m,1H),3.52-3.21(m,5H),2.64-2.19(m,5H),2.03(s, 5H),1.78-1.51(m,8H),1.46-1.30(m,3H),1.22-1.12(m,2H),1.07(s,3H),0.78(s,3H).

[0663] Synthesize 16.3

[0664] 9-BBN dimer (3.17 g, 13.0 mmol) was added to a solution of 16.2 (1.5 g, 4.35 mmol) in 10 mL of THF at 15 °C. After stirring at 40 °C for 1 h, the resulting mixture was diluted with ethanol (18 mL, 130 mmol) at 15 °C, diluted with aqueous NaOH solution (26 mL, 5 M, 130 mmol) at -10 °C, and finally diluted dropwise with H2O2 (13 mL, 10 M, 130 mmol). After the addition, the mixture was stirred at 80 °C for one hour. The aqueous layer was collected and extracted with EtOAc (100 mL). The combined organic phases were washed with brine (2 x 100 mL), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum to give 16.3 (2.8 g) as a solid.

[0665] 1 H NMR (400MHz, CDCl3)δ H5.34(s,1H),3.73-3.62(m,1H),3.43-3.33(m,5H),1.86-1.83(m,4H),1.68-1.61(m,8 H),1.52-1.47(m,6H),1.39-1.27(m,4H),1.20-1.10(m,3H),1.05(s,3H),0.56(s,3H).

[0666] Synthesize 16

[0667] Dessmartin (6.52 g, 15.4 mmol) was added to a solution of 16.3 (2.8 g, 7.72 mmol) in DCM (20 mL) at 25 °C. After holding at 25 °C for 10 min, the mixture was quenched at 25 °C with a saturated NaHCO3 / Na2S2O3 aqueous solution (1:1, 400 mL). The organic phase was separated and washed with a saturated NaHCO3 / Na2S2O3 aqueous solution (1:1, 400 mL) and brine (200 mL), dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by rapid column chromatography (5 to 15% EtOAc / PE) to give 16 (800 mg, 28.7%) as a solid.

[0668] 1 H NMR (400MHz, CDCl3)δ H 5.41(d,J=5.6Hz,1H),3.45-3.33(m,5H),2.59(t,J=9.29Hz,1H),2.36-2.17(m,3H),2.12( s,3H),2.00-1.92(m,3H),1.86-1.57(m,7H),1.50-1.17(m,8H),1.06(s,3H),0.52(s,3H). LC-ELSD / MS purity 99%, C 23 H 35 O2[M+H-H2O] + The calculated MS ESI value is 343.3, and the experimental value is also 343.3.

[0669] Example 17: Synthesis of 1-(2-((3R,5R,8S,10S,13S,14S,17S)-3-hydroxy-3-(methoxymethyl)-10,13-dimethyl-2,3,4,5,6,7,8,10,12,13,14,15,16,17-tetradecanoic acid-1H-cyclopentan[a]phenanthrene-17-yl)-2-oxoethyl)-1H-pyrazole-4-carboxynitrile

[0670]

[0671] Synthesize 17.1

[0672] At 25°C, HBr (0.02 mL, 0.55 mmol, 40% / water) and Br2 (106 mg, 0.66 mmol) were added to a solution of 16 (200 mg, 0.55 mmol) in MeOH (2 mL). After stirring at 25°C for 2 h, the mixture was quenched with a saturated aqueous solution of NaHCO3 (10 mL), diluted with water (20 mL), and extracted with EtOAc (2 x 30 mL). The combined organic phases were washed with brine (30 mL), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum to give 17.1 (260 mg, crude substance) as a solid, which was directly used in the next step.

[0673] Synthesis 17

[0674] To a solution of 17.1 (260 mg, 0.5916 mmol) in acetone (5 mL), 1H-pyrazole-4-carboxynitrile (66 mg, 0.7099 mmol) and K₂CO₃ (163 mg, 1.18 mmol) were added. After stirring at 25 °C for 16 h, water (20 mL) was added to the mixture and extracted with EtOAc (2 x 30 mL). The combined organic layers were separated, dried over anhydrous Na₂SO₄, filtered, and concentrated. The residue was purified by rapid column chromatography (20 to 50% EtOAc / PE) to give 17 (61 mg, 22.8%) as a solid.

[0675] 1 H NMR (400MHz, DMSO-d6)δ H 7.86(s,1H),7.81(s,1H),5.45-5.40(m,1H),5.12-4.80(m,2H),3.44-3.38(m,5H),2.68(t,J=8.88Hz,1H ),2.44-2.12(m,3H),2.06-1.92(m,3H),1.88-1.58(m,5H),1.49-1.13(m,9H),1.07(s,3H),0.58(s,3H). LC-ELSD / MS purity 99%, C 27 H 36 N3O2[M+H-H2O] + The calculated MS ESI value is 434.3, and the experimental value is also 434.3.

[0676] Example 18: Biological Data

[0677] TBPS-bound steroid inhibition

[0678] The use of rat cerebral cortex membranes in the presence of 5 mM GABA has been described. 35 [S]-tert-butylbicyclic thiophosphate (TBPS) binding determination (Gee et al., J. Pharmacol. Exp. Ther. 1987, 241, 346-353; Hawkinson et al., Mol. Pharmacol. 1994, 46, 977-985; Lewin, AH et al., Mol. Pharmacol. 1989, 35, 189-194).

[0679] In summary, after decapitation of Sprague-Dawley rats (200-250g) under carbon dioxide anesthesia, the cortex was rapidly removed. The cortex was homogenized in 10 volumes of ice-cold 0.32M sucrose using a glass / Teflon homogenizer and centrifuged at 1500xg for 10 min at 4°C. The resulting supernatant was centrifuged at 10,000xg for 20 min at 4°C to obtain P2 clumps. The P2 clumps were resuspended in 200 mM NaCl / 50 mM Na-K phosphate pH 7.4 buffer and centrifuged at 10,000xg for 10 min at 4°C. This washing procedure was repeated twice, and the clumps were resuspended in 10 volumes of buffer. In the presence of 5 mM GABA, aliquots (100 mL) of the membrane suspension were mixed with 3 nM [ 35 5 mL aliquots of TBPS and test drug (final 0.5%) dissolved in dimethyl sulfoxide (DMSO) were incubated together. The incubation was brought to a final volume of 1.0 mL with buffer. Nonspecific binding was measured in the presence of 2 mM unlabeled TBPS in the range of 15% to 25%. After incubation at room temperature for 90 min, the assay was terminated by filtration through a glass fiber filter (Schleicher and Schuell No. 32) using a cell collector (Brandel) and rinsing three times with ice-cold buffer. Filter-bound radioactivity was measured by liquid scintillation spectroscopy. Nonlinear curve fitting was performed on all data for each drug at each concentration average using Prism (GraphPad). If the sum of squares was significantly lower by the F-test, the data were fitted to a partial rather than complete inhibition model. Similarly, if the sum of squares was significantly lower by the F-test, the data were fitted to a two-component rather than a one-component inhibition model. With the same model used for all data, 50% inhibition (IC50) of a specific binding was measured for each individual experiment. 50 ) and maximum inhibition level (I max The concentrations of the test compounds were determined, and then the mean ± SEM values ​​for each individual experiment were calculated. Pichia pastoris was used as a positive control in these studies, and it has been shown to robustly inhibit TBPS binding.

[0680] Screening or screening various compounds to determine their in vitro [functions / properties] 35 The potential of S-TBPS binding modifiers. These determinations can be made according to or may be made according to the above.

[0681] In Table 2 below, A represents TBPS. B indicates TBPS IC 50 (uM) is to C represents TBPS for to D represents TBPS for to And E means .

[0682] Table 2.

[0683]

[0684]

[0685]

[0686]

[0687] Equivalent schemes and scope

[0688] Unless otherwise specified or obvious from the context, in the claims, articles such as “a,” “an,” and “the” may indicate one or more. Unless otherwise specified or obvious from the context, the phrase “or” includes the claim or description among one or more members being satisfied if one, more than one, or all of the members are present, employed, or otherwise involved in a given product or process. The invention includes embodiments in which a given product or process contains, employs, or otherwise involves exactly one member of the group. The invention also includes embodiments in which a given product or process contains, employs, or otherwise involves more than one or all of the members of the group.

[0689] Furthermore, this invention covers all variations, combinations, and permutations in which one or more limitations, elements, clauses, and descriptive terms from one or more of the listed claims are incorporated into another claim. For example, any claim dependent on another claim may be modified to include one or more limitations visible in any other claim dependent on the same basic claim. Where elements are presented in list form, such as in a Markush group format, each subgroup of said elements is also disclosed, and any one or more elements may be removed from that group. It should be understood that, in general, when an invention or aspect of the invention is referred to as comprising specific elements and / or features, certain embodiments of the invention or aspect of the invention consist of or are substantially composed of such elements and / or features. For simplicity, those embodiments are not specifically described herein in the same terms. It should also be noted that the terms “comprising” and “containing” are intended to be open-ended and allow for the inclusion of additional elements or steps. When a scope is given, end values ​​are included. Furthermore, unless otherwise specified or apparent from the context and from the understanding of one of ordinary skill in the art, in different embodiments of the invention, values ​​expressed as ranges may be assumed to be any specific value or subrange within the range, accurate to one-tenth of the lower limit of the range, unless the context otherwise explicitly specifies.

[0690] This application references various published patents, patent applications, journal articles, and other publications, all of which are incorporated herein by reference. In the event of any conflict between any incorporated reference and this specification, this specification shall prevail. Furthermore, any particular embodiment of the invention that pertains to the prior art may be expressly excluded from any one or more of the claims. Because such embodiments are considered known to those skilled in the art, they may be excluded, even if such exclusion is not expressly stated herein. Any particular embodiment of the invention may be excluded from any claim for any reason, whether or not related to the existence of prior art.

[0691] Those skilled in the art will recognize or be able to determine many equivalent embodiments of the specific implementations described herein using only conventional experimentation. The scope of the embodiments of the invention described herein is not intended to be limited to the above description, but rather as set forth in the appended claims. Those skilled in the art will understand that various changes and modifications can be made to this specification without departing from the spirit or scope of the invention as defined in the claims.

Claims

1. A compound of formula (Ip): Or its pharmaceutically acceptable salt; in: R 21c yes Each R D Independently hydrogen, methyl, or cyano, and e is 1.

2. The compound or pharmaceutically acceptable salt of claim 1, wherein the compound of (Ip) is a compound having the formula (I-j1): Or its pharmaceutically acceptable salt. Where R E It is cyano; and e is 1.

3. The compound or pharmaceutically acceptable salt of claim 1, wherein the compound of formula (Ip) is a compound having formula (I-m1): Or its pharmaceutically acceptable salt. Where R E It is a methyl group.

4. The compound or pharmaceutically acceptable salt of claim 1, wherein the compound of formula (Ip) is a compound having formula (I-n1): Or its pharmaceutically acceptable salt. Where R E It is hydrogen; and e is 1.

5. A compound, said compound being selected from the group consisting of: Or its pharmaceutically acceptable salt.

6. A pharmaceutical composition comprising a compound or pharmaceutically acceptable salt as described in any one of claims 1-5, and a pharmaceutically acceptable carrier.

7. Use of the compound or pharmaceutically acceptable salt of any one of claims 1-5 in the preparation of a medicament for treating CNS-related conditions in a subject of need.

8. The use as described in claim 7, wherein the CNS-related disorder is insomnia, depression, mood disorder, seizure disorder, memory disorder, attention disorder, anxiety disorder, bipolar disorder, schizophrenia, depression, schizophrenic disorder, anxiety disorder, personality disorder, psychosis, obsessive-compulsive disorder, post-traumatic stress disorder, autism spectrum disorder, mild depression, social anxiety disorder, obsessive-compulsive disorder, pain, sleep disorder, or dementia.

9. The use as claimed in claim 7, wherein the CNS-related condition is depression.

10. The use according to claim 9, wherein the depression is postpartum depression.

11. The use according to claim 9, wherein the depression is major depressive disorder.

12. The use according to claim 11, wherein the major depressive disorder is a moderate major depressive disorder.

13. The use as claimed in claim 11, wherein the major depressive disorder is a severe major depressive disorder.

14. The use according to claim 7, wherein the CNS-related condition is epileptic seizures.

15. The use as claimed in claim 7, wherein the CNS-related condition is tremor.

16. The use of claim 15, wherein the tremor is idiopathic tremor.

17. The use according to claim 7, wherein the drug is administered orally.

18. The use according to claim 7, wherein the drug is administered over a long period of time.

19. Use of any compound or pharmaceutically acceptable salt of any one of claims 1-5 in the preparation of a medicament for inducing sedation and / or anesthesia in a subject in need.

Images