Neuroactive steroids substituted at position 10 with a cyclic group for the treatment of CNS disorders

Abstract

The present invention provides a compound of formula (I) #imgabs0# or a pharmaceutically acceptable salt thereof, wherein n, R 19 、R 5 、R 3a 、R 6a 、R 6b 、R 1 、R 2a 、R 2b 、R 4a 、R 4b 、R 7a 、R 7b 、R 11a 、R 11b 、R 12a 、R 12b 、R 17b 、R 15a 、R 15b 、R 16a and R 16b As defined herein. Also provided herein are pharmaceutical compositions comprising compounds of formula (I), and methods of using the compounds, for example, in the treatment of CNS-related disorders.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims priority to USSN 62 / 745,109, filed October 12, 2018, the contents of which are incorporated herein by reference in their entirety. Background Art

[0003] Brain excitability is defined as the animal's level of arousal (ranging from coma to convulsions) and is regulated by various neurotransmitters. In general, 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 interior of the cell being negative relative to the exterior of the cell. The potential (voltage) is the sum of the ions (K) across the semipermeable membrane of the neuron. + 、Na + 、Cl - The neurotransmitter is 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 effect is mediated by postsynaptic nicotinic receptors, which are stimulated by acetylcholine to increase the sensitivity to Na. + Membrane permeability to ions. The reduced 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 effect on overall brain excitability because up to 40% of neurons in the brain use GABA as a neurotransmitter. GABA regulates 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. An increase in the level of this anion within the cell leads to a hyperpolarization of the transmembrane potential, making the neuron less susceptible to excitatory inputs, i.e., reducing neuronal excitability. In other words, the higher the chloride ion concentration in the neuron, the lower the brain excitability and arousal level.

[0005] It is well documented that the GRC is responsible for mediating anxiety, seizures, and sedation. Thus, GABA and drugs that act like or enhance the actions of GABA (e.g., therapeutically available barbiturates and benzodiazepines (BZ), such as ) produces its therapeutically useful effects by interacting with specific regulatory sites on the GRC. Accumulating evidence now indicates that, in addition to the benzodiazepine and barbiturate binding sites, the GRC contains a unique site for neuroactive steroids. See, e.g., Lan, NC et al., Neurochem. Res. (1991) 16:347-356.

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

[0007] There is a need for new and improved neuroactive steroids that are useful as modulators of brain excitability and as agents for the prevention and treatment of CNS-related diseases. The compounds, compositions, and methods described herein are directed to this end. Summary of the Invention

[0008] Provided herein are compounds designed, for example, to act as GABA modulators. In some embodiments, it is contemplated that such compounds may be used as therapeutic agents for treating CNS-related disorders.

[0009] In one aspect, provided herein is a compound of formula (I):

[0010]

[0011] or a pharmaceutically acceptable salt thereof.

[0012] In some embodiments, the compound of formula (I) is a compound of formula (Ia):

[0013]

[0014] or a pharmaceutically acceptable salt thereof.

[0015] In some embodiments, the compound of formula (I) is a compound of formula (Ib):

[0016]

[0017] or a pharmaceutically acceptable salt thereof.

[0018] In some embodiments, the compound of formula (I) is a compound of formula (Ic):

[0019]

[0020] or a pharmaceutically acceptable salt thereof.

[0021] In some embodiments, the compound of formula (I) is a compound of formula (Id):

[0022]

[0023] or a pharmaceutically acceptable salt thereof.

[0024] In some embodiments, the compound of formula (I) is a compound of formula (Ie):

[0025]

[0026] or a pharmaceutically acceptable salt thereof.

[0027] In some embodiments, the compound of formula (I) is a compound of formula (If):

[0028]

[0029] or a pharmaceutically acceptable salt thereof.

[0030] In some embodiments, the compound of formula (I) is a compound of formula (Ig):

[0031]

[0032] or a pharmaceutically acceptable salt thereof.

[0033] In some embodiments, the compound of formula (I) is a compound of formula (Ih):

[0034]

[0035] or a pharmaceutically acceptable salt thereof.

[0036] In one aspect, provided herein is a pharmaceutical composition comprising a compound as described herein (e.g., a compound of Formula (I)) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. In certain embodiments, the compound of the present invention is provided in an effective amount in the pharmaceutical composition. In certain embodiments, the compound of the present invention is provided in a therapeutically effective amount. In certain embodiments, the compound of the present invention is provided in a prophylactic effective amount.

[0037] In one aspect, provided herein are pharmaceutically acceptable salts of the compounds described herein (eg, compounds of Formula (I)).

[0038] In certain embodiments, the compound is administered orally, subcutaneously, intravenously, or intramuscularly. In certain embodiments, the compound is administered orally. In certain embodiments, the compound is administered chronically. In certain embodiments, the compound is administered continuously, for example, by continuous intravenous infusion.

[0039] As described herein, the compounds of the present invention are useful in certain embodiments as GABA modulators, for example, influencing GABA in a positive or negative manner. A Receptors. Acts as a regulator of central nervous system (CNS) excitability, such as through its regulation of GABA A Such compounds are expected to have CNS activity mediated by the ability of the cytochrome P68 receptor to activate CNS function.

[0040] In one aspect, described herein is a method for treating a CNS-related disorder in a subject in need thereof, comprising administering to the subject an effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof.

[0041] 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 cognitive disorder, a movement disorder, a personality disorder, an autism spectrum disorder, pain, traumatic brain injury, a vascular disease, a substance abuse disorder and / or withdrawal syndrome, tinnitus, or status epilepticus.

[0042] 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.

[0043] In some embodiments, the compound is selected from the group consisting of the compounds identified in Table 1 herein. DETAILED DESCRIPTION

[0044] As generally described herein, the present invention provides GABA A In certain embodiments, it is contemplated that such compounds may be useful as therapeutic agents for treating CNS-related disorders (e.g., disorders as described herein, such as depression, such as postpartum depression or major depressive disorder).

[0045] definition

[0046] Chemical definition

[0047] The definitions of specific functional groups and chemical terms are described in more detail below. Chemical elements are identified according to the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75th edition, inside cover, and specific functional groups are generally defined as described therein. In addition, the general principles of organic chemistry and specific functional moieties and reactivities are described in the following: Thomas Sorrell, Organic Chemistry, University Science Books, Sausalito, 1999; Smith and March, March's Advanced Organic Chemistry, 5th edition, John Wiley & Sons, Inc., New York, 2001; Larock, Comprehensive Organic Transformations, VCH Publishers, Inc., New York, 1989; and Carruthers, Some Modern Methods of Organic Synthesis, 3rd edition, Cambridge University Press, Cambridge, 1987.

[0048] 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 the formation and crystallization of chiral salts; or preferred isomers can be prepared by asymmetric synthesis. See, for example, Jacques et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen et al., Tetrahedron 33: 2725 (1977); Eliel, Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); and Wilen, Tables of Resolving Agents and Optical Resolutions, page 268 (E.L. Eliel, ed., Univ. of Notre Dame Press, Notre Dame, IN 1972). The present invention further encompasses the compounds described herein in the form of individual isomers that are substantially free of other isomers and alternatively in the form of mixtures of various isomers.

[0049] “Stereoisomers”: It will also be understood that compounds that have the same molecular formula but differ in the properties or the order in which their atoms are bonded or the arrangement of their atoms in space are termed “isomers”. Isomers that differ in the arrangement of their atoms in space are termed “stereoisomers”. Stereoisomers that are not mirror images of one another are termed “diastereomers” and isomers that are non-superimposable mirror images of one another are termed “enantiomers”. When a compound has an asymmetric 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 asymmetric center and described according to the R and S sequencing rules of Cahn and Prelog, or by the manner in which the molecule rotates about the plane of polarization and designated as right- or left-handed (i.e., (+) or (-) isomers, respectively). Chiral compounds can exist as individual enantiomers or as mixtures thereof. A mixture containing equal proportions of enantiomers is termed a “racemic mixture”.

[0050] As used herein, a pure enantiomer compound is substantially free of the other enantiomers or stereoisomers of the compound (i.e., enantiomeric excess). In other words, the "S" form of the compound is substantially free of the "R" form of the compound, and is therefore in enantiomeric excess of the "R" form. The terms "enantiomerically pure" or "pure enantiomer" mean that the compound contains more than 75%, more than 80%, more than 85%, more than 90%, more than 91%, more than 92%, more than 93%, more than 94%, more than 95%, more than 96%, more than 97%, more than 98%, more than 98.5%, more than 99%, more than 99.2%, more than 99.5%, more than 99.6%, more than 99.7%, more than 99.8%, or 99.9% by weight of the enantiomer. In certain embodiments, weights are based on the total weight of all enantiomers or stereoisomers of the compound.

[0051] In the compositions provided herein, enantiomerically pure compounds may be present with other active or inactive ingredients. For example, a pharmaceutical composition comprising an enantiomerically pure R position / center / carbon compound may comprise, for example, about 90% excipient and about 10% enantiomerically pure R compound. In certain embodiments, the enantiomerically pure R compound in such a composition may, for example, comprise at least about 95% by weight of the R compound and up to about 5% by weight of the S compound, based on the total weight of the compound. For example, a pharmaceutical composition comprising an enantiomerically pure S compound may comprise, for example, about 90% excipient and about 10% enantiomerically pure S compound. In certain embodiments, the enantiomerically pure S compound in such a composition may, for example, comprise at least about 95% by weight of the S compound and up to about 5% by weight of the R compound, based on the total weight of the compound. In certain embodiments, the active ingredient may be formulated in the absence of substantially any excipient or carrier.

[0052] As used herein, the term "diastereomeric purity" refers to the amount of a compound having the depicted absolute stereochemistry, expressed as a percentage of the total amount of the depicted compound and its diastereomers. The term "diastereomerically pure" means that the compound contains more than 75%, more than 80%, more than 85%, more than 90%, more than 91%, more than 92%, more than 93%, more than 94%, more than 95%, more than 96%, more than 97%, more than 98%, more than 98.5%, more than 99%, more than 99.2%, more than 99.5%, more than 99.6%, more than 99.7%, more than 99.8%, or more than 99.9% by weight of a diastereomer. Methods for determining diastereomeric purity and enantiomeric purity are known in the art. Diastereomeric purity may be determined by any analytical method capable of quantitatively distinguishing between a compound and its diastereomers, such as high performance liquid chromatography (HPLC).

[0053] The article "a" can be used herein to refer to one or more than one (ie, to at least one) of the grammatical object of the article. For example, "an analogue" means one analogue or more than one analogue.

[0054] When a range of values is listed, 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 、C2-3 、C 3-6 、C 3-5 、C 3-4 、C 4-6 、C 4-5 and C 5-6 alkyl.

[0055] The following terms are intended to have the meanings provided below and are applicable to understanding the description and intended scope of the present invention.

[0056] "Alkyl" refers to a straight or branched chain saturated hydrocarbon group ("C 1-20 In some embodiments, an alkyl group has 1 to 12 carbon atoms ("C 1-12 In some embodiments, an alkyl group has 1 to 10 carbon atoms ("C 1-10 In some embodiments, an alkyl group has 1 to 9 carbon atoms ("C 1-9 In some embodiments, an alkyl group has 1 to 8 carbon atoms ("C 1-8 In some embodiments, an alkyl group has 1 to 7 carbon atoms ("C 1-7 In some embodiments, an alkyl group has 1 to 6 carbon atoms ("C 1-6 In some embodiments, an alkyl group has 1 to 5 carbon atoms ("C 1-5 In some embodiments, an alkyl group has 1 to 4 carbon atoms ("C 1-4 In some embodiments, an alkyl group has 1 to 3 carbon atoms ("C 1-3 In some embodiments, an alkyl group has 1 to 2 carbon atoms ("C 1-2 In some embodiments, an alkyl group has 1 carbon atom ("C1 alkyl"). In some embodiments, an alkyl group has 2 to 6 carbon atoms ("C 2-6 C 1-6Examples of alkyl groups include methyl (C1), ethyl (C2), n-propyl (C3), isopropyl (C3), n-butyl (C4), tert-butyl (C4), sec-butyl (C4), isobutyl (C4), n-pentyl (C5), 3-pentyl (C5), pentyl (C5), neopentyl (C5), 3-methyl-2-butyl (C5), tert-pentyl (C5), and n-hexyl (C6). Other examples of alkyl groups include n-heptyl (C7), n-octyl (C8), and the like. Unless otherwise specified, alkyl groups are independently optionally substituted at each occurrence, i.e., unsubstituted ("unsubstituted alkyl") or substituted ("substituted alkyl") with one or more substituents (e.g., 1 to 5 substituents, 1 to 3 substituents, or 1 substituent). In certain embodiments, alkyl groups are unsubstituted C 1-10 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).

[0057] "Alkylene" refers to an alkyl group with two hydrogens removed to provide a divalent group and can be substituted or unsubstituted. Unsubstituted alkylene includes, but is not limited to, methylene (-CH2-), ethylene (-CH2CH2-), propylene (-CH2CH2CH2-), butylene (-CH2CH2CH2CH2-), pentylene (-CH2CH2CH2CH2CH2-), hexylene (-CH2CH2CH2CH2CH2CH2-) and the like. Exemplary substituted alkylene groups (e.g., substituted with one or more alkyl(methyl) groups) include, but are not limited to, substituted methylene (—CH(CH)—, (—C(CH)—), substituted ethylene (—CH(CH)CH—, —CHCH(CH)—, —C(CH)CH—, —CHC(CH)—), substituted propylene (—CH(CH)CHCH—, —CHCH(CH)CH—, —CHCHCH(CH)—, —C(CH)CHCH—, —CHC(CH)—, —CHCHC(CH)—), and the like. When a range or number of carbons is provided for a particular alkylene group, it is understood that the range or number refers to the range or number of carbons in a linear carbon divalent chain. Alkylene groups may be substituted or unsubstituted with one or more substituents as described herein.

[0058] "Alkenyl" refers to a straight or branched chain 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 In certain embodiments, an alkenyl group does not contain any triple bonds. In some embodiments, an alkenyl group has 2 to 10 carbon atoms ("C 2-10 In some embodiments, an alkenyl group has 2 to 9 carbon atoms ("C 2-9 In some embodiments, an alkenyl group has 2 to 8 carbon atoms ("C 2-8 In some embodiments, an alkenyl group has 2 to 7 carbon atoms ("C 2-7 In some embodiments, an alkenyl group has 2 to 6 carbon atoms ("C 2-6 In some embodiments, an alkenyl group has 2 to 5 carbon atoms ("C 2-5 In some embodiments, an alkenyl group has 2 to 4 carbon atoms ("C 2-4 In some embodiments, an alkenyl group has 2 to 3 carbon atoms ("C 2-3 In some embodiments, an alkenyl group has 2 carbon atoms ("C2 alkenyl"). One or more carbon-carbon double bonds can be internal (eg, 2-butenyl) or terminal (eg, 1-butenyl). C 2-4 Examples of alkenyl groups include ethenyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), and the like. 2-6 Examples of the alkenyl group include the aforementioned C 2-4 In some embodiments, alkenyl is an unsubstituted C 1-4, C 1-6, C 1-8, C 1-17, C 1-19, C 2-30, C 3-41, C 3-6, C 3-7, C 3-8, C 3-9, C 4-10, C 5-11, C 5-12, C 6-13, C 7-14, C 8-15, C 1-16, C 1-17, C 1-18, C 1-19, C 2-20, C 2-30, C 2-31, C 2-32, C 2-33, C 2-34, C 2-35, C 2-36, C 2-37, C 2-38, C 2-39, C 3-40, C 3-41, C 3-42, C 3-43, C 3-44, C 3-45, C 3-46, C 3-47, C 3-48, C 3-49, C 4-50, C 4-51, C 4-52, C 4-53, C 4-54, C 4-55, C 4-56, C 4-57, C 4-58, C 4-59, C 4-60, C 4-70, C 4-71, C 4-72, C 4-73, C 4-74, C 4-75, C 4-76, C 4-77, C 4-78, C 4-79, C 4-80, C 4-81, C 4-82, C 4-83, C 4-84, C 4-85, C 4-86, C 4-87, C 4-88, C 4 2-10 In certain embodiments, alkenyl is a substituted C 2-10 Alkenyl.

[0059] "Alkynyl" refers to a straight or branched chain 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). 2-20In certain embodiments, an alkynyl group does not contain any double bonds. In some embodiments, an alkynyl group has 2 to 10 carbon atoms ("C 2-10 In some embodiments, an alkynyl group has 2 to 9 carbon atoms ("C 2-9 In some embodiments, an alkynyl group has 2 to 8 carbon atoms ("C 2-8 In some embodiments, an alkynyl group has 2 to 7 carbon atoms ("C 2-7 In some embodiments, an alkynyl group has 2 to 6 carbon atoms ("C 2-6 In some embodiments, an alkynyl group has 2 to 5 carbon atoms ("C 2-5 In some embodiments, an alkynyl group has 2 to 4 carbon atoms ("C 2-4 In some embodiments, an alkynyl group has 2 to 3 carbon atoms ("C 2-3 In some embodiments, an alkynyl group has two carbon atoms (a "C2 alkynyl"). One or more carbon-carbon triple bonds can be internal (e.g., 2-butynyl) or terminal (e.g., 1-butynyl). C 2-4 Examples of alkynyl groups include, but are not limited to, ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), and the like. 2-6 Examples of the alkenyl group include the aforementioned C 2-4 Alkynyl and pentynyl (C5), hexynyl (C6), etc. Other examples of alkynyl include heptynyl (C7), octynyl (C8), etc. Unless otherwise specified, alkynyl is independently optionally substituted at each occurrence, i.e., unsubstituted (an "unsubstituted alkynyl") or substituted with one or more substituents (e.g., 1 to 5 substituents, 1 to 3 substituents, or 1 substituent) (a "substituted alkynyl"). In certain embodiments, alkynyl is an unsubstituted C 2-10 In certain embodiments, the alkynyl group is a substituted C 2-10 Alkynyl.

[0060] 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 within the parent carbon chain and / or one or more heteroatoms are inserted between a carbon atom and the parent molecule, i.e., between the points of attachment. In certain embodiments, heteroalkyl refers to a saturated group ("heteroalkyl") having 1 to 10 carbon atoms and 1, 2, 3, or 4 heteroatoms. 1-10 In some embodiments, a heteroalkyl group is a saturated group having 1 to 9 carbon atoms and 1, 2, 3, or 4 heteroatoms (“heteroC 1-9In some embodiments, a heteroalkyl group is a saturated group having 1 to 8 carbon atoms and 1, 2, 3, or 4 heteroatoms (“heteroC 1-8 In some embodiments, a heteroalkyl group is a saturated group having 1 to 7 carbon atoms and 1, 2, 3, or 4 heteroatoms (“heteroC 1-7 In some embodiments, a heteroalkyl group is a group having 1 to 6 carbon atoms and 1, 2, or 3 heteroatoms (“heteroC 1-6 In some embodiments, a heteroalkyl group is a saturated group having 1 to 5 carbon atoms and 1 or 2 heteroatoms (“heteroC 1-5 In some embodiments, a heteroalkyl group is a saturated group having 1 to 4 carbon atoms and 1 or 2 heteroatoms (“heteroC 1-4 In some embodiments, a heteroalkyl group is a saturated group having 1 to 3 carbon atoms and 1 heteroatom (“heteroC 1-3 In some embodiments, a heteroalkyl group is a saturated group having 1 to 2 carbon atoms and 1 heteroatom (“heteroC 1-2 In some embodiments, a heteroalkyl group is a saturated group having 1 carbon atom and 1 heteroatom ("heteroC1 alkyl"). In some embodiments, a heteroalkyl group is a saturated group having 2 to 6 carbon atoms and 1 or 2 heteroatoms ("heteroC1 2-6 Unless otherwise specified, each occurrence of heteroalkyl is independently unsubstituted (an “unsubstituted heteroalkyl”) or substituted (a “substituted heteroalkyl”) with one or more substituents. In certain embodiments, heteroalkyl is an unsubstituted heteroC 1-10 In certain embodiments, heteroalkyl is substituted heteroC 1-10 alkyl.

[0061] "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 the cyclic array) radical having 6 to 14 ring carbon atoms and zero heteroatoms ("C 6-14 In some embodiments, an aryl group has six ring carbon atoms ("C6 aryl"; e.g., phenyl). In some embodiments, an aryl group has ten ring carbon atoms ("C 10 In some embodiments, an aryl group has fourteen ring carbon atoms ("C 14"Aryl" also includes ring systems in which an aryl ring as defined above is fused to one or more carbocyclyl or heterocyclyl groups, wherein the radical or point of attachment 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 aceanthrene, acenaphthylene, acephenanthren, anthracene, azulene, benzene, Coronene, fluoranthene, fluorene, hexacene, hexalene, hexalene, unsymmetrical indacene, symmetrical indacene, indane, indene, naphthalene, octaacene, octabenzene, aldrin, ovalene, penta-2,4-diene, pentacene, pentalene, pentacene, perylene, phenalene, phenanthrene, dinaphthobenzene, septaphene, pyrene, pyranthracene, rubrocene, triphenylene and trinaphthalene. Specific aryl groups include phenyl, naphthyl, indenyl and tetrahydronaphthyl. Unless otherwise specified, aryl is independently optionally substituted at each occurrence, i.e., unsubstituted ("unsubstituted aryl") or substituted ("substituted aryl") with one or more substituents. In certain embodiments, aryl is unsubstituted C 6-14 In certain embodiments, aryl is substituted C 6-14 Aryl.

[0062] In certain embodiments, the aryl group is substituted with one or more groups selected from the group consisting of halo, C1-C8 alkyl, C1-C8 haloalkyl, cyano, hydroxy, C1-C8 alkoxy, and amino.

[0063] Representative examples of substituted aryl groups include the following

[0064]

[0065] where R 56 and R 57 One of them may 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 heterocyclyl, 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, SO 2 alkyl, S aryl, SO aryl, SO 2 aryl; or R 56 and R 57 From 5 to 8 atoms may be joined to form a cyclic ring (saturated or unsaturated), which optionally contains one or more heteroatoms selected from the group consisting of N, O and S. 60 and R 61 are independently hydrogen, C1-C8 alkyl, C1-C4 haloalkyl, C3-C 10 Cycloalkyl, 4-10 membered heterocyclic group, C6-C 10 Aryl, substituted C6-C 10 aryl, 5-10 membered heteroaryl or substituted 5-10 membered heteroaryl.

[0066] "Fused aryl" refers to an aryl group wherein two of its ring carbons are the same as a second aryl or heteroaryl ring or as a carbocyclyl or heterocyclyl ring.

[0067] "Heteroaryl" refers to a 5-10 membered monocyclic or bicyclic 4n+2 aromatic ring system (e.g., having 6 or 10π electrons shared in a cyclic array) radical provided with ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-10 membered heteroaryl"). In heteroaryl groups containing one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, where valence permits. Heteroaryl bicyclic ring systems may include one or more heteroatoms in one or both rings. "Heteroaryl" includes ring systems in which a heteroaryl ring as defined above is fused to one or more carbocyclyl or heterocyclyl groups, wherein the point of attachment is on the heteroaryl ring, and in such cases, the number of ring members continues to indicate the number of ring members in the heteroaryl ring system. "Heteroaryl" also includes ring systems in which a heteroaryl ring as defined above is fused to one or more aryl groups, wherein the point of attachment is on either the aryl or heteroaryl ring, and in such cases, the number of ring members refers to the number of ring members in the fused (aryl / heteroaryl) ring system. For bicyclic heteroaryls in which one ring does not contain heteroatoms (e.g., indolyl, quinolinyl, carbazolyl, etc.), the point of attachment can be on either ring, i.e., the ring with the heteroatom (e.g., 2-indolyl) or the ring without heteroatoms (e.g., 5-indolyl).

[0068] In some embodiments, heteroaryl is a 5-10 membered aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-10 membered heteroaryl”). In some embodiments, heteroaryl is a 5-8 membered aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-8 membered heteroaryl”). In some embodiments, heteroaryl is a 5-6 membered aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-6 membered heteroaryl”). In some embodiments, 5-6 membered heteroaryl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, 5-6 membered heteroaryl has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heteroaryl group has one ring heteroatom selected from nitrogen, oxygen, and sulfur. Unless otherwise specified, each occurrence of a heteroaryl group is independently optionally substituted, i.e., unsubstituted (an "unsubstituted heteroaryl") or substituted (a "substituted heteroaryl") with one or more substituents. In certain embodiments, a heteroaryl group is an unsubstituted 5-14 membered heteroaryl group. In certain embodiments, a heteroaryl group is a substituted 5-14 membered heteroaryl group.

[0069] Exemplary 5-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyrrolyl, furanyl, and thienyl. Exemplary 5-membered heteroaryl groups containing two heteroatoms include, but are not limited to, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered heteroaryl groups containing three heteroatoms include, but are not limited to, triazolyl, oxadiazolyl, and thiadiazolyl. Exemplary 5-membered heteroaryl groups containing four heteroatoms include, but are not limited to, tetrazolyl. Exemplary 6-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyridinyl. Exemplary 6-membered heteroaryl groups containing two heteroatoms include, but are not limited to, pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6-membered heteroaryl groups containing three or four heteroatoms include, but are not limited to, triazinyl and tetrazinyl, respectively. Exemplary 7-membered heteroaryl groups containing one heteroatom include, but are not limited to, azepinyl, oxepinyl, and thiepinyl. Exemplary 5,6-bicyclic heteroaryls include, but are not limited to, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothienyl, isobenzothienyl, benzofuranyl, benzisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzothiazolyl, benzisothiazolyl, benzothiadiazolyl, indolizinyl and purinyl. Exemplary 6,6-bicyclic heteroaryls include, but are not limited to, naphthyridinyl, pteridinyl, quinolyl, isoquinolyl, cinnolinyl, quinoxalinyl, phthalazinyl and quinazolinyl.

[0070] Examples of representative heteroaryl groups include the following:

[0071]

[0072] wherein each Z is selected from carbonyl, N, NR 65 , O and S; and R 65 are independently hydrogen, C1-C8 alkyl, C3-C 10 Cycloalkyl, 4-10 membered heterocyclic group, C6-C 10 aryl and 5-10 membered heteroaryl.

[0073] "Carbocyclyl" or "carbocycle" refers to a non-aromatic ring system having 3 to 10 ring carbon atoms ("C 3-10 In some embodiments, the carbocyclyl group has 3 to 8 ring carbon atoms ("C 3-8 In some embodiments, a carbocyclyl group has 3 to 6 ring carbon atoms ("C 3-6 In some embodiments, a carbocyclyl group has 3 to 6 ring carbon atoms ("C 3-6 In some embodiments, a carbocyclyl group has 5 to 10 ring carbon atoms ("C 5-10 Carbocyclyl”). Exemplary C 3-6 Carbocyclic groups include, but are not limited to, cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), and the like. 3-8 Carbocyclic groups include but are not limited to the aforementioned C 3-6 Carbocyclic groups and cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo [2.2.1] heptyl (C7), bicyclo [2.2.2] octyl (C8), etc. Exemplary C 3-10 Carbocyclic groups include but are not limited to the aforementioned C 3-8 Carbocyclic groups and cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C 10 ), cyclodecenyl (C 10 ), octahydro-1H-indenyl (C9), decahydronaphthyl (C 10 ), spiro[4.5]decyl (C 10) etc. As described in the foregoing examples, in certain embodiments, carbocyclyl is a monocycle ("monocyclic carbocyclyl") or contains a fused, bridged or spirocyclic system, such as a bicyclic system ("bicyclic carbocyclyl"), and can be saturated or can be partially unsaturated. "Carbocyclyl" also includes the ring system of the carbocyclyl ring as defined above and one or more aryl or heteroaryl fused, wherein the connection point is on the carbocyclyl 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, carbocyclyl is optionally substituted independently at each occurrence, i.e., unsubstituted ("unsubstituted carbocyclyl") or substituted ("substituted carbocyclyl") by one or more substituents. In certain embodiments, carbocyclyl is unsubstituted C 3-10 In certain embodiments, a carbocyclyl group is a substituted C 3-10 Carbocyclic group.

[0074] In some embodiments, a "carbocyclyl" is a monocyclic saturated carbocyclyl ("C 3-10 In some embodiments, a cycloalkyl group has 3 to 8 ring carbon atoms ("C 3-8 In some embodiments, a cycloalkyl group has 3 to 6 ring carbon atoms ("C 3-6 In some embodiments, a cycloalkyl group has 5 to 6 ring carbon atoms ("C 5-6 In some embodiments, a cycloalkyl group has 5 to 10 ring carbon atoms ("C 5-10 Cycloalkyl”). C 5-6 Examples of cycloalkyl groups include cyclopentyl (C5) and cyclohexyl (C5). 3-6 Examples of the cycloalkyl group include the aforementioned C 5-6 Cycloalkyl as well as cyclopropyl (C3) and cyclobutyl (C4). 3-8 Examples of the cycloalkyl group include the aforementioned C 3-6 Cycloalkyl and cycloheptyl (C7) and cyclooctyl (C8). Unless otherwise specified, cycloalkyl is independently unsubstituted ("unsubstituted cycloalkyl") or substituted ("substituted cycloalkyl") at each occurrence with one or more substituents. In certain embodiments, cycloalkyl is unsubstituted C 3-10 In certain embodiments, the cycloalkyl group is a substituted C 3-10 Cycloalkyl.

[0075] "Heterocyclyl" or "heterocycle" refers to a radical of a 3-10 membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus and silicon ("3-10 membered heterocyclyl"). In heterocyclyl groups containing one or more nitrogen atoms, the point of attachment may be a carbon or nitrogen atom, where valence permits. A heterocyclyl group may be a monocyclic ring ("monocyclic heterocyclyl") or a fused, bridged or spirocyclic ring system, such as a bicyclic ring system ("bicyclic heterocyclyl"), and may be saturated or partially unsaturated. Heterocyclyl bicyclic ring systems may include one or more heteroatoms in one or both rings. "Heterocyclyl" also includes a ring system in which a heterocyclyl ring as defined above is fused to one or more carbocyclyls, wherein the point of attachment is on a carbocyclyl or heterocyclyl ring, or a ring system in which a heterocyclyl as defined above is fused to one or more aryl or heteroaryl groups, wherein the point of attachment is on a heterocyclyl ring, and in such cases, the number of ring members continues to indicate the number of ring members in the heterocyclyl ring system. Unless otherwise specified, heterocyclyl is independently optionally substituted at each occurrence, i.e., unsubstituted ("unsubstituted heterocyclyl") or substituted ("substituted heterocyclyl") by one or more substituents. In certain embodiments, heterocyclyl is an unsubstituted 3-10 membered heterocyclyl. In certain embodiments, heterocyclyl is a substituted 3-10 membered heterocyclyl.

[0076] In some embodiments, a heterocyclyl group is a 5-10 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon (“5-10 membered heterocyclyl”). In some embodiments, a heterocyclyl group is a 5-8 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-8 membered heterocyclyl”). In some embodiments, a heterocyclyl group is a 5-6 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-6 membered heterocyclyl”). In some embodiments, a 5-6 membered heterocyclyl group has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, a 5-6 membered heterocyclyl group has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, a 5-6 membered heterocyclyl group has one ring heteroatom selected from nitrogen, oxygen, and sulfur.

[0077] 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, dihydropyrrolyl, and pyrrolyl-2,5-diketone. 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 thianyl. Exemplary 6-membered heterocyclic groups containing two heteroatoms include, but are not limited to, piperazinyl, morpholinyl, dithianyl, and dioxanyl. 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 to a C6 aryl ring (also referred to herein as 5,6-bicyclic heterocycles) include, but are not limited to, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, benzoxazolinone, and the like. Exemplary 6-membered heterocyclic groups fused to an aromatic ring (also referred to herein as 6,6-bicyclic heterocycles) include, but are not limited to, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and the like.

[0078] "Nitrogen-containing heterocyclic group" means a 4-7 membered non-aromatic ring group containing at least one nitrogen atom, such as, but not limited to, morpholine, piperidine (e.g., 2-piperidinyl, 3-piperidinyl and 4-piperidinyl), pyrrolidine (e.g., 2-pyrrolidinyl and 3-pyrrolidinyl), azetidine, pyrrolidone, imidazoline, imidazolidinone, 2-pyrazoline, pyrazolidine, piperazine and N-alkylpiperazines such as N-methylpiperazine. Specific examples include azetidine, piperidone and piperazinone.

[0079] "Hetero" when used to describe a compound or a group present on a compound means that one or more carbon atoms in the compound or group have been replaced with nitrogen, oxygen, or sulfur heteroatoms. Hetero can be applied to any of the above-mentioned hydrocarbon groups, such as alkyl groups (e.g., heteroalkyl, cycloalkyl) having 1 to 5, and specifically 1 to 3, heteroatoms, such as heterocyclyl, aryl groups (e.g., heteroaryl), cycloalkenyl groups (e.g., cycloheteroalkenyl), and the like.

[0080] "Acyl" refers to the group -C(O)R 20 , where R 20 As defined herein, "alkanoyl" is a radical wherein R 20 is an acyl group 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, -C(O)-(CH2) t (C6-C 10 Aryl), -C(O)-(CH2) t (5-10 membered heteroaryl), -C(O)-(CH2) t (C3-C 10 Cycloalkyl) and -C(O)-(CH2) t (4-10 membered heterocyclyl), wherein t is an integer from 0 to 4. In certain embodiments, R 21 is a C1-C8 alkyl group substituted by a halogen or hydroxyl group; or a C3-C 10 Cycloalkyl, 4-10 membered heterocyclic group, C6-C 10 Aryl, arylalkyl, 5-10 membered heteroaryl or heteroarylalkyl, each of which is substituted with unsubstituted C1-C4 alkyl, halo, unsubstituted C1-C4 alkoxy, unsubstituted C1-C4 haloalkyl, unsubstituted C1-C4 hydroxyalkyl, or unsubstituted C1-C4 haloalkoxy or hydroxy.

[0081] "Alkoxy" refers to the group -OR 29 , where R 29is a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group, a substituted or unsubstituted carbocyclyl group, a substituted or unsubstituted heterocyclyl group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted heteroaryl group. Specific alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, and 1,2-dimethylbutoxy. Specific alkoxy groups are lower alkoxy groups, i.e., groups having 1 to 6 carbon atoms. Other specific alkoxy groups have 1 to 4 carbon atoms.

[0082] In certain embodiments, R 29 is a group having 1 or more substituents, for example 1 to 5 substituents, and specifically 1 to 3 substituents, specifically 1 substituent, the 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 heterocyclyl, halogen, 5-10 membered heteroaryl, hydroxy, nitro, thioalkoxy, thioaryloxy, thiol, alkyl-S(O)-, aryl-S(O)-, alkyl-S(O)2- and aryl-S(O)2-. Exemplary "substituted alkoxy" include, but are not limited to -O-(CH2) t (C6-C 10 Aryl), -O-(CH2) t (5-10 membered heteroaryl), -O-(CH2) t (C3-C 10 Cycloalkyl) and -O-(CH2) t (4-10 membered heterocyclyl), wherein t is an integer from 0 to 4, and any aryl, heteroaryl, cycloalkyl, or heterocyclyl present may itself be substituted with unsubstituted C1-C4 alkyl, halo, unsubstituted C1-C4 alkoxy, unsubstituted C1-C4 haloalkyl, unsubstituted C1-C4 hydroxyalkyl, or unsubstituted C1-C4 haloalkoxy or hydroxy. Specific exemplary "substituted alkoxy" are -OCF3, -OCH2CF3, -OCH2Ph, -OCH2-cyclopropyl, -OCH2CH2OH, and -OCH2CH2NMe2.

[0083] "Amino" refers to the group -NH2.

[0084] "Oxo" refers to -C(=O)-.

[0085] "Substituted amino" refers to a group of the formula -N(R 38 )2 amino group, wherein R 38is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclic group, substituted or unsubstituted heterocyclic group, substituted or unsubstituted aryl group, substituted or unsubstituted heteroaryl group or amino protecting group, wherein R 38 In certain embodiments, at least one of 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 group or C3-C 10 Cycloalkyl, or C1-C8 alkyl substituted by halogen or hydroxy, or C3-C8 alkenyl substituted by halogen or hydroxy, C3-C8 alkynyl substituted by halogen or hydroxy, or -(CH2) t (C6-C 10 Aryl), -(CH2) t (5-10 membered heteroaryl), -(CH2) t (C3-C 10 Cycloalkyl) or -(CH2) t (4-10 membered heterocyclyl), wherein t is an integer from 0 to 8, each of which is substituted with unsubstituted C1-C4 alkyl, halo, unsubstituted C1-C4 alkoxy, unsubstituted C1-C4 haloalkyl, unsubstituted C1-C4 hydroxyalkyl, or unsubstituted C1-C4 haloalkoxy or hydroxy; or two R 38 The groups are joined to form an alkylene group.

[0086] Exemplary "substituted amino" include, but are not limited to, -NR 39 -C1-C8 alkyl, -NR 39 -(CH2) t (C6-C 10 Aryl), -NR 39 -(CH2) t (5-10 membered heteroaryl), -NR 39 -(CH2) t (C3-C 10 Cycloalkyl) and -NR 39 -(CH2) t (4-10 membered heterocyclyl), wherein t is an integer from 0 to 4, such as 1 or 2, and each R 39and any aryl, heteroaryl, cycloalkyl or heterocyclyl groups present may themselves be substituted with unsubstituted C1-C4 alkyl, halo, unsubstituted C1-C4 alkoxy, unsubstituted C1-C4 haloalkyl, unsubstituted C1-C4 hydroxyalkyl, or unsubstituted C1-C4 haloalkoxy or hydroxy. For the avoidance of doubt, the term "substituted amino" includes the groups alkylamino, substituted alkylamino, alkylarylamino, substituted alkylarylamino, arylamino, substituted arylamino, dialkylamino and substituted dialkylamino, as defined below. Substituted amino encompasses both monosubstituted and disubstituted amino groups.

[0087] "Carboxy" refers to the group -C(O)OH.

[0088] "Cyano" refers to the radical -CN.

[0089] "Halo" or "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br), and iodine (I). In certain embodiments, halo is fluorine or chlorine.

[0090] "Haloalkyl" refers to an alkyl group substituted with one or more halogens. Typical haloalkyl groups include, but are not limited to, trifluoromethyl, difluoromethyl, fluoromethyl, chloromethyl, dichloromethyl, dibromoethyl, tribromomethyl, tetrafluoroethyl, and the like.

[0091] "Hydroxy" refers to the radical -OH.

[0092] "Nitro" refers to the radical -NO2.

[0093] "Thioketo" refers to the group =S.

[0094] As defined herein, alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl groups are optionally substituted (e.g., "substituted" or "unsubstituted" alkyl, "substituted" or "unsubstituted" alkenyl, "substituted" or "unsubstituted" alkynyl, "substituted" or "unsubstituted" carbocyclyl, "substituted" or "unsubstituted" heterocyclyl, "substituted" or "unsubstituted" aryl, or "substituted" or "unsubstituted" heteroaryl). In general, the term "substituted", whether preceded by the term "optionally" or not, means that at least one hydrogen present on a group (e.g., a carbon or nitrogen atom) is replaced with a permissible substituent, such as a substituent that, upon substitution, results in a stable compound, such as a compound that cannot undergo a transformation spontaneously, such as by rearrangement, cyclization, elimination, or other reaction. Unless otherwise indicated, a "substituted" group has a substituent at one or more substitutable positions of the group, and when more than one position in any given structure is substituted, the substituent may be the same or different at each position. The term "substituted" is intended to include substitution with all permissible substituents of organic compounds, any substituent described herein that results in the formation of stable compounds. The present invention contemplates any and all such combinations to yield stable compounds. For purposes of this invention, heteroatoms (such as nitrogen) may have hydrogen substituents and / or any suitable substituents as described herein that satisfy the valences of the heteroatoms and result in the formation of a stable moiety.

[0095] Exemplary carbon atom substituents include, but are not limited to, halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OR aa 、-ON(R bb )2、-N(R bb )2、-N(R bb )3 + X - 、-N(OR cc )R bb 、-SH、-SR aa 、-SSR cc 、-C(=O)R aa 、-CO2H、-CHO、-C(OR cc )2, -CO2R aa 、-OC(=O)R aa 、-OCO2R aa 、-C(=O)N(R bb )2、-OC(=O)N(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 Halogenated alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Carbocyclic group, 3-14 membered heterocyclic group, C 6-14 Aryl and 5-14 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl is independently substituted by 0, 1, 2, 3, 4 or 5 R dd or two geminal hydrogen atoms on a carbon atom are replaced by groups =O, =S, =NN(R bb )2, =NNR bb C(=O)R aa 、=NNR bb C(=O)OR aa 、=NNR bb S(=O)2R aa 、=NR bb or = NOR cc replacement;

[0096] R aa In each occurrence, independently selected from C 1-10 Alkyl, C 1-10 Halogenated alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Carbocyclic group, 3-14 membered heterocyclic group, C 6-14 Aryl and 5-14 membered heteroaryl rings, or two R aa The groups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl group is independently replaced by 0, 1, 2, 3, 4 or 5 R dd group substitution;

[0097] R bb is independently selected at each occurrence 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 Halogenated alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Carbocyclic group, 3-14 membered heterocyclic group, C 6-14 Aryl and 5-14 membered heteroaryl, or two R bb to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl group is independently replaced by 0, 1, 2, 3, 4 or 5 R dd group substitution;

[0098] R cc independently selected at each occurrence from hydrogen, C 1-10 Alkyl, C 1-10 Halogenated alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Carbocyclic group, 3-14 membered heterocyclic group, C 6-14 Aryl and 5-14 membered heteroaryl rings, or two R cc The groups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl group is independently replaced by 0, 1, 2, 3, 4 or 5 R dd group substitution;

[0099] R dd is independently selected at each occurrence 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, C 3-10 Carbocyclic group, 3-10 membered heterocyclic group, C 6-10 Aryl, 5-10 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl is independently replaced by 0, 1, 2, 3, 4 or 5 R gg Group substitution, or two geminal R dd Substituents may be joined to form =O or =S;

[0100] R ee In each occurrence, independently selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocyclic group, C 6-10 Aryl, 3-10 membered heterocyclyl and 3-10 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl is independently substituted by 0, 1, 2, 3, 4 or 5 R gg group substitution;

[0101] R ff independently selected at each occurrence from hydrogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocyclic group, 3-10 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, or two R ff The groups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl group is independently replaced by 0, 1, 2, 3, 4 or 5 R gg group substitution; and

[0102] R gg is independently at each occurrence halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OC 1-6 Alkyl, -ON(C 1-6 Alkyl)2, -N(C 1-6 Alkyl)2, -N(C 1-6 Alkyl)3 + X - 、-NH(C 1-6 Alkyl)2 + X - 、-NH2(C 1-6 alkyl) + X - 、-NH3+ X - 、-N(OC 1-6 Alkyl)(C 1-6 Alkyl), -N(OH)(C 1-6 Alkyl), -NH(OH), -SH, -SC 1-6 Alkyl, -SS(C 1-6 alkyl), -C(=O)(C 1-6 alkyl), -CO2H, -CO2(C 1-6 alkyl), -OC(=O)(C 1-6 Alkyl), -OCO2(C 1-6 alkyl), -C(=O)NH2, -C(=O)N(C 1-6 alkyl)2, -OC(=O)NH(C 1-6 alkyl), -NHC(=O)(C 1-6 Alkyl), -N(C 1-6 alkyl)C(=O)(C 1-6 Alkyl), -NHCO2(C 1-6 alkyl), -NHC(=O)N(C 1-6 Alkyl)2, -NHC(=O)NH(C 1-6 alkyl), -NHC(=O)NH2, -C(=NH)O(C 1-6 alkyl), -OC(=NH)(C 1-6 alkyl), -OC(=NH)OC 1-6 Alkyl, -C(=NH)N(C 1-6 Alkyl)2, -C(=NH)NH(C 1-6 alkyl), -C(=NH)NH2, -OC(=NH)N(C 1-6 Alkyl)2, -OC(NH)NH(C 1-6 alkyl), -OC(NH)NH2, -NHC(NH)N(C 1-6 Alkyl)2, -NHC(=NH)NH2, -NHSO2(C 1-6 Alkyl), -SO2N(C 1-6 Alkyl)2, -SO2NH(C 1-6 alkyl), -SO2NH2, -SO2C 1-6 Alkyl, -SO2OC 1-6 Alkyl, -OSO2C 1-6 Alkyl, -SOC 1-6 Alkyl, -Si(C 1-6 alkyl)3, -OSi(C 1-6 alkyl)3-C(=S)N(C 1-6 alkyl)2、C(=S)NH(C 1-6alkyl), C(=S)NH2, -C(=O)S(C 1-6 alkyl), -C(=S)SC 1-6 Alkyl, -SC(=S)SC 1-6 Alkyl, -P(=O)2(C 1-6 alkyl), -P(=O)(C 1-6 alkyl)2, -OP(=O)(C 1-6 alkyl)2, -OP(=O)(OC 1-6 Alkyl)2, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocyclic group, C 6-10 Aryl, 3-10 membered heterocyclic group, 5-10 membered heteroaryl; or two geminal R gg Substituents may be joined to form =O or =S; where X - is the relative ion.

[0103] A "counterion" or "anionic counterion" is a negatively charged group that associates with a cationic quaternary amino group to maintain electronic neutrality. Exemplary counterions include halides (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-sulfonic acid-5-sulfonate, ethane-1-sulfonic acid-2-sulfonate, etc.) and carboxylate ions (e.g., acetate, acetate, propionate, benzoate, glycerate, lactate, tartrate, glycolate, etc.).

[0104] These and other exemplary substituents are described in more detail in the detailed description and claims.The present invention is not intended to be limited in any manner by the above list of exemplary substituents.

[0105] He defines

[0106] As used herein, the term "modulate" refers to inhibiting or enhancing GABA A receptor function. A "modulator" (eg, a modulator compound) can be, for example, GABA A Agonist, partial agonist, antagonist or partial antagonist of a receptor.

[0107] "Pharmaceutically acceptable" means approved or approvable by a regulatory agency of the Federal or a state government, or corresponding agencies in countries outside the United States, or listed in the U.S. Pharmacopeia or other generally recognized pharmacopeia for use in animals, and more particularly in humans.

[0108] "Pharmaceutically acceptable salts" refer to salts of the compounds of the present invention that are pharmaceutically acceptable and possess the desired pharmacological activity of the parent compound. Specifically, such salts are non-toxic and may 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, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo[2.2.2]-oct-2-ene-1-carboxylic acid, glucoheptonic acid, 3-phenylpropionic acid, trimethylacetic acid, tert-butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, etc.; or (2) salts formed when an acidic proton present in the parent compound is replaced by a metal ion (e.g., an alkali metal ion, an alkaline earth metal ion, or an aluminum ion); or when coordinated with an organic base (e.g., ethanolamine, diethanolamine, triethanolamine, N-methylglucamine, etc.). Salts also include, by way of example only, sodium salts, potassium salts, calcium salts, magnesium salts, ammonium salts, tetraalkylammonium salts, etc.; and when the compound contains a basic functional group, further salts of non-toxic organic or inorganic acids such as hydrochlorides, hydrobromides, tartrates, methanesulfonates, acetates, maleates, oxalates, etc. are also included. The term "pharmaceutically acceptable cation" refers to an acceptable cationic counterion of an acidic functional group. Examples of such cations are sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium cations, and the like. See, for example, Berge, et al., J. Pharm. Sci. (1977) 66(1): 1-79.

[0109] The term "prodrug" is intended to encompass compounds without therapeutic activity that are converted to therapeutically active agents of the present invention under physiological conditions. One approach for making a prodrug is to design a selected portion that hydrolyzes or cleaves at the target site of action in the body under physiological conditions to reveal the desired molecule and subsequently produce its therapeutic effect. In certain embodiments, the prodrug is converted via an enzymatic activity of the subject. In an alternative embodiment, the present invention provides a prodrug of a compound of formula (I), wherein the prodrug includes a cleavable portion at the C3 hydroxyl group, as depicted in formula (I).

[0110] In some embodiments, the compound of formula (I) is a prodrug, wherein the prodrug includes a cleavable moiety at the C3 hydroxyl group, as depicted in formula (I). Exemplary hydroxyl-containing prodrugs include, for example, esters.

[0111] "Tautomers" refer to compounds that are interchangeable forms of a particular compound structure and that vary in the displacement of hydrogen atoms and electrons. Thus, the two structures can maintain equilibrium via the movement of π electrons and atoms (usually H). For example, enols and ketones are tautomers because they can be rapidly interconverted by treatment with acid or base. Another example of tautomerism is the acid and nitro forms of phenylnitromethane, which are also formed by treatment with acid or base. Tautomeric forms can be relevant to achieving optimal chemical reactivity and biological activity of a target compound.

[0112] "Subjects" encompassed for administration include, but are not limited to, humans (i.e., male or female, of any age, such as pediatric subjects (e.g., infants, children, adolescents) or adult subjects (e.g., young adults, middle-aged adults, or elderly adults)) and / or non-human animals, such as mammals, such as primates (e.g., cynomolgus monkeys, rhesus monkeys), cattle, pigs, horses, sheep, goats, rodents, cats, and / or dogs. In certain embodiments, the subject is a human. In certain embodiments, the subject is a non-human animal.

[0113] In certain embodiments, the substituent present on the oxygen atom is an oxygen protecting group (also known as a hydroxy 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 ed., John Wiley & Sons, 1999, incorporated herein by reference.

[0114] 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 (mesylate), and tosylate (Ts).

[0115] In certain embodiments, the substituent present on the sulfur atom is a sulfur protecting group (also known as a thiol protecting group). Sulfur protecting groups include but are not limited to -R aa 、-N(R bb )2, -C(=O)SR aa 、-C(=O)R aa 、-CO2R aa 、-C(=O)N(R bb )2、-C(=NR bb )R aa 、-C(=NR bb )OR aa 、-C(=NR bb )N(R bb )2、-S(=O)R aa 、-SO2R aa 、-Si(R aa )3、-P(R cc )2、-P(R cc )3, -P(=O)2R aa 、-P(=O)(R aa )2、-P(=O)(OR cc )2、-P(=O)2N(R bb )2 and -P(=O)(NR bb )2, where R aa 、R bb and R ccAs 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 ed., John Wiley & Sons, 1999, incorporated herein by reference.

[0116] In certain 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, C 3-10 Carbocyclic group, 3-14 membered heterocyclic group, C 6-14 Aryl and 5-14 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl is independently replaced by 0, 1, 2, 3, 4 or 5 R dd group substituted, and wherein R aa 、R bb 、R cc and 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 ed., John Wiley & Sons, 1999, incorporated herein by reference.

[0117] Exemplary amino protecting groups include, but are not limited to, amide groups (e.g., -C(=O)R aa ), including but not limited to formamide and acetamide; carbamate groups (e.g., -C(=O)OR aa ), including but not limited to 9-fluorenylmethyl carbamate (Fmoc), tert-butyl carbamate (BOC), and benzyl carbamate (Cbz); sulfonamide groups (e.g., -S(=O)2R aa ), which include but are not limited to toluenesulfonamide (Ts), methanesulfonamide (Ms) and N-[2-(trimethylsilyl)ethoxy]methylamine (SEM).

[0118] Disease, disorder, and condition are used interchangeably herein.

[0119] As used herein, and unless otherwise specified, the terms "treat," "treating," and "treatment" encompass an effect that reduces the severity of, or delays or slows the progression of, a specified disease, disorder, or condition in a subject suffering from the disease, disorder, or condition. In an alternative embodiment, the present invention encompasses administering a compound of the invention as a preventive measure before a subject begins to develop the specified disease, disorder, or condition.

[0120] Generally speaking, an "effective amount" of a compound refers to an amount sufficient to induce anesthesia or sedation due to a desired biological response, such as to treat a CNS-related disorder. As will be appreciated by one of ordinary skill in the art, an effective amount of a compound of the invention may 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. An effective amount encompasses both therapeutic and prophylactic treatments.

[0121] As used herein, and unless otherwise specified, a "therapeutically 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 an amount of a therapeutic agent, alone or in combination with other therapies, that provides a therapeutic benefit in treating the disease, condition, or disorder. The term "therapeutically effective amount" can encompass an amount that improves overall therapy, reduces or avoids symptoms or causes of a disease or disorder, or enhances the therapeutic efficacy of another therapeutic agent.

[0122] As used herein, and unless otherwise specified, a "prophylactically effective amount" of a compound is an amount sufficient to prevent a disease, condition, or illness, or one or more symptoms associated with a disease, condition, or illness, or to prevent its recurrence. A prophylactically effective amount of a compound means an amount of a therapeutic agent, alone or in combination with other agents, that provides a therapeutic benefit in preventing the disease, condition, or illness. The term "prophylactically effective amount" can encompass an amount that improves overall prevention or enhances the prophylactic efficacy of another prophylactic agent.

[0123] Compound

[0124] It should be understood that the formulae described herein may refer to specific carbon atoms, such as C17, C3, C19, etc. These references to carbon atoms are based on the position of the carbon atoms according to the steroid nomenclature known and used in the industry, as shown below:

[0125]

[0126] For example, C17 refers to the carbon at position 17, and C3 refers to the carbon at position 3.

[0127] In one aspect, there is provided a compound of formula (I)

[0128]

[0129] or a pharmaceutically acceptable salt thereof;

[0130] in:

[0131] indicates a single bond or a double bond, provided that if a double bond exists, then R 6a or R 6b One of them does not exist;

[0132] R 1 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -OR A1 、-N(R A1 )2、-SR A1 、-C(=O)R A1 、-C(=O)OR A1 、-C(=O)SR A1 、-C(=O)N(R A1 )2, -OC(=O)R A1 、-OC(=O)OR A1 、-OC(=O)N(R A1 )2, -OC(=O)SR A1 、-OS(=O)2R A1、-OS(=O)2OR A1 、-OS(=O)2N(R A1 )2、-N(R A1 )C(=O)R A1 、-N(R A1 )C(=NR A1 )R A1 、-N(R A1 )C(=O)OR A1 、-N(R A1 )C(=O)N(R A1 )2、-N(R A1 )C(=NR A1 )N(R A1 )2、-N(R A1 )S(=O)2R A1 、-N(R A1 )S(=O)2OR A1 、-N(R A1 )S(=O)2N(R A1 )2、-SC(=O)R A1 、-SC(=O)OR A1 、-SC(=O)SR A1 、-SC(=O)N(R A1 )2、-S(=O)2R A1 、-S(=O)2OR A1 or -S(=O)2N(R A1 )2, where R A1 is independently selected at each occurrence from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, or substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, an oxygen protecting group when attached to oxygen, a nitrogen protecting group when attached to nitrogen, a sulfur protecting group when attached to sulfur, or two R A1 The group and the intervening atoms together form a substituted or unsubstituted heterocyclic ring;

[0133] R 2a 、R 2b 、R 4a 、R 4b 、R 7a 、R 7b 、R 11a 、R 11b 、R 12a 、R 12b or R 17bEach of the above is independently hydrogen, halogen, -CN, -NO2, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -OR A1 、-N(R A1 )2、-SR A1 、-C(=O)R A1 、-C(=O)OR A1 、-C(=O)SR A1 、-C(=O)N(R A1 )2, -OC(=O)R A1 、-OC(=O)OR A1 、-OC(=O)N(R A1 )2, -OC(=O)SR A1 、-OS(=O)2R A1 、-OS(=O)2OR A1 、-OS(=O)2N(R A1 )2、-N(R A1 )C(=O)R A1 、-N(R A1 )C(=NR A1 )R A1 、-N(R A1 )C(=O)OR A1 、-N(R A1 )C(=O)N(R A1 )2、-N(R A1 )C(=NR A1 )N(R A1 )2、-N(R A1 )S(=O)2R A1 、-N(R A1 )S(=O)2OR A1 、-N(R A1 )S(=O)2N(R A1 )2、-SC(=O)R A1 、-SC(=O)OR A1 、-SC(=O)SR A1 、-SC(=O)N(R A1 )2、-S(=O)2R A1 、-S(=O)2OR A1 or -S(=O)2N(R A1 )2, where R A1is independently selected at each occurrence from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, or substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, an oxygen protecting group when attached to oxygen, a nitrogen protecting group when attached to nitrogen, a sulfur protecting group when attached to sulfur, or two R A1 The group and the intervening atoms together form a substituted or unsubstituted heterocyclic ring;

[0134] R 3a is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

[0135] R 5 is hydrogen or methyl; when When it is a double bond, R 5 does not exist;

[0136] R 6a and R 6b Each of which is hydrogen, halogen, -CN, -NO2, -OH, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl; or R 6a and R 6b conjugated to form an oxo group (=O);

[0137] R 15a 、R 15b 、R 16a and R 16b Each of them is independently hydrogen, halogen, -CN, 1NO2, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -OR C3 、-N(R C3 )2、-SR C3 、-C(=O)R C3 、-C(=O)OR C3 、-C(=O)SR C3 、-C(=O)N(R C3 )2, -OC(=O)R C3 、-OC(=O)OR C3 、-OC(=O)N(R C3 )2, -OC(=O)SR C3 、-OS(=O)2R C3 、-OS(=O)2OR C3 、-OS(=O)2N(RC3 )2、-N(R C3 )C(=O)R C3 、-N(R C3 )C(=NR C3 )R C3 、-N(R C3 )C(=O)OR C3 、-N(R C3 )C(=O)N(R C3 )2、-N(R C3 )C(=NR C3 )N(R C3 )2、-N(R C3 )S(=O)2R C3 、-N(R C3 )S(=O)2OR C3 、-N(R C3 )S(=O)2N(R C3 )2、-SC(=O)R C3 、-SC(=O)OR C3 、-SC(=O)SR C3 、-SC(=O)N(R C3 )2、-S(=O)2R C3 、-S(=O)2OR C3 or -S(=O)2N(R C3 )2, where R C3 is independently selected at each occurrence from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted carbocyclyl, or substituted or unsubstituted heterocyclyl, an oxygen protecting group when attached to oxygen, a nitrogen protecting group when attached to nitrogen, a sulfur protecting group when attached to sulfur, or two R C3 The group and the intervening atoms together form a substituted or unsubstituted heterocyclic ring;

[0138] R 19 is a substituted or unsubstituted C3-C6 carbocyclic group, or a substituted or unsubstituted aryl group; and

[0139] n is 0, 1, or 2.

[0140] Group R 1

[0141] In some embodiments, R 1 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0142] In some embodiments, R 1 is hydrogen, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0143] In some embodiments, R 1 is substituted carbocyclyl, substituted heterocyclyl, substituted aryl, or substituted heteroaryl, each of which is further substituted with substituted carbocyclyl, substituted heterocyclyl, substituted aryl, or substituted heteroaryl.

[0144] In some embodiments, R 1 In some embodiments, R 1 is a substituted or unsubstituted alkyl group. 1 In some embodiments, R 1 yes In some embodiments, R 1 yes

[0145] In some embodiments, R 1 Selected from the group consisting of:

[0146]

[0147] in:

[0148] R a is independently at each occurrence hydrogen, halogen, -NO2, -CN, -OR D4 、-N(R D4 )2, -C(=O)R D4 、-C(=O)OR D4 、-C(=O)N(R D4 )2, -OC(=O)R D4 、-OC(=O)OR D4 、-N(R D4 )C(=O)R D4 、-OC(=O)N(R D4 )2、-N(R D4 )C(=O)OR D4 、-S(=O)2R D4 、-S(=O)2OR D4 、-OS(=O)2R D4 、-S(=O)2N(R D4 )2 or -N(R D4 )S(=O)2R D4 , substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 2-6Alkenyl, substituted or unsubstituted C 2-6 Alkynyl, substituted or unsubstituted C 3-6 Carbocyclic group, substituted or unsubstituted 3 to 6 membered heterocyclic group, substituted or unsubstituted C 5-10 aryl, substituted or unsubstituted 5- to 10-membered heteroaryl;

[0149] R D4 is independently hydrogen, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 2-6 Alkenyl, substituted or unsubstituted C 2-6 Alkynyl, substituted or unsubstituted C 3-6 Carbocyclic group, substituted or unsubstituted 3 to 6 membered heterocyclic group, substituted or unsubstituted C 5-10 aryl, substituted or unsubstituted 5- to 10-membered heteroaryl, an oxygen protecting group when attached to oxygen, a nitrogen protecting group when attached to nitrogen, or two R D4 The group and the intervening atoms together form a substituted or unsubstituted heterocyclic ring; and

[0150] p is an integer selected from 0 to 11.

[0151] In some embodiments, R 1 Selected from the group consisting of:

[0152]

[0153] in:

[0154] R a is independently at each occurrence hydrogen, halogen, -NO2, -CN, -OR D4 、-N(R D4 )2, -C(=O)R D4 、-C(=O)OR D4 、-C(=O)N(R D4 )2, -OC(=O)R D4 、-OC(=O)OR D4 、-N(R D4 )C(=O)R D4 、-OC(=O)N(R D4 )2、-N(R D4 )C(=O)OR D4 、-S(=O)2R D4 、-S(=O)2OR D4 、-OS(=O)2R D4 、-S(=O)2N(R D4 )2 or -N(R D4 )S(=O)2R D4 , substituted or unsubstituted C1-6 Alkyl, substituted or unsubstituted C 2-6 Alkenyl, substituted or unsubstituted C 2-6 Alkynyl, substituted or unsubstituted C 3-6 Carbocyclic group, substituted or unsubstituted 3 to 6 membered heterocyclic group, substituted or unsubstituted C 5-10 aryl, substituted or unsubstituted 5- to 10-membered heteroaryl;

[0155] R D4 is independently hydrogen, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 2-6 Alkenyl, substituted or unsubstituted C 2-6 Alkynyl, substituted or unsubstituted C 3-6 Carbocyclic group, substituted or unsubstituted 3 to 6 membered heterocyclic group, substituted or unsubstituted C 5-10 aryl, substituted or unsubstituted 5- to 10-membered heteroaryl, an oxygen protecting group when attached to oxygen, a nitrogen protecting group when attached to nitrogen, or two R D4 The group and the intervening atoms together form a substituted or unsubstituted heterocyclic ring; and

[0156] p is an integer selected from 0 to 11.

[0157] Group R 2a and R 2b

[0158] In some embodiments, R 2a and R 2b are each independently hydrogen, halogen, -CN, -NO2, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, -OR E5 、-OC(=O)R E5 、-OS(=O)2OR E5 、-N(R E5 )2 or -N(R E5 )C(=O)R E5 、-N(R E5 )S(=O)2R E5 、-N(R E5 )S(=O)2OR E5 ; where R E5 is independently at each occurrence hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, or two R E5 The group and the intervening atoms together form a substituted or unsubstituted heterocyclic ring.

[0159] In some embodiments, R2a and R 2b are independently hydrogen, halogen, -CN, -NO2, -OR F6 、-OC(=O)R F6 、-N(R F6 )2 or -N(R F6 )C(=O)R F6 ; where R F6 is independently at each occurrence hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, or two R F6 The group and the intervening atoms together form a substituted or unsubstituted heterocyclic ring.

[0160] In some embodiments, R 2a and R 2b are independently hydrogen, -OH or substituted or unsubstituted C 1-6 alkyl.

[0161] In some embodiments, R 2a and R 2b Each of which is independently hydrogen, -OH, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy or C 1-6 Alkoxyhalide.

[0162] In some embodiments, R 2a and R 2b is independently -CH3, -CH2CH3, -OH, -OCH3 or -CH(CH3)2.

[0163] In some embodiments, R 2a and R 2b All are hydrogen.

[0164] In some embodiments, R 2a and R 2b Joining to form an oxo group (=O).

[0165] Group R 3a

[0166] In some embodiments, R 3a is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl.

[0167] In some embodiments, R 3a is 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.

[0168] In some embodiments, R 3a is substituted or unsubstituted C 1-6 alkyl.

[0169] In some embodiments, R 3 is a substituted alkyl. In some embodiments, R 3a is an unsubstituted alkyl group.

[0170] In some embodiments, R 3a In some embodiments, R 3a It's hydrogen.

[0171] In some embodiments, R 3a yes

[0172] In some embodiments, R 3a yes

[0173] Group R 4a and R 4b

[0174] In some embodiments, R 4a and R 4b are each independently hydrogen, halogen, -CN, -NO2, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, -OR E5 、-OC(=O)R E5 、-OS(=O)2OR E5 、-N(R E5 )2 or -N(R E5 )C(=O)R E5 、-N(R E5 )S(=O)2R E5 、-N(R E5 )S(=O)2OR E5 ; where R E5 is independently at each occurrence hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, or two R E5 The group and the intervening atoms together form a substituted or unsubstituted heterocyclic ring.

[0175] In some embodiments, R 4a and R 4b are independently hydrogen, halogen, -CN, -NO2, -OR F6 、-OC(=O)R F6 、-N(R F6)2 or -N(R F6 )C(=O)R F6 ; where R F6 is independently at each occurrence hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, or two R F6 The group and the intervening atoms together form a substituted or unsubstituted heterocyclic ring.

[0176] In some embodiments, R 4a and R 4b are independently hydrogen, -OH or substituted or unsubstituted C 1-6 alkyl.

[0177] In some embodiments, R 4a and R 4b Each of which is independently hydrogen, -OH, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy or C 1-6 Alkoxyhalide.

[0178] In some embodiments, R 4a and R 4b is independently -CH3, -CH2CH3, -OH, -OCH3 or -CH(CH3)2.

[0179] In some embodiments, R 4a and R 4b All are hydrogen.

[0180] In some embodiments, R 4a and R 4b Joining to form an oxo group (=O).

[0181] Group R 5

[0182] In some embodiments, R 5 is relative to R 19 In some embodiments, R 5 is relative to R 19 In some embodiments, R 5 is relative to R 19 In some embodiments, R 5 is relative to R 19 A methyl group in the trans position.

[0183] Group R 6a and R 6b

[0184] In some embodiments, R 6a and R 6b and R and R are independently hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl.

[0185] In some embodiments, R 6a and R 6b is independently hydrogen or substituted alkyl.

[0186] In some embodiments, R 6a and R 6b is independently hydrogen or unsubstituted alkyl.

[0187] In some embodiments, R 6a and R 6b All are hydrogen.

[0188] In some embodiments, R 6a is a halo or alkyl group and R 6b It's hydrogen.

[0189] In some embodiments, R 6a and R 6b All are halogen groups.

[0190] In some embodiments, R 6a and R 6b All are alkyl groups.

[0191] Group R 7a and R 7b

[0192] In some embodiments, R 7a and R 7b are each independently hydrogen, halogen, -CN, -NO2, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, -OR E5 、-OC(=O)R E5 、-OS(=O)2OR E5 、-N(R E5 )2 or -N(R E5 )C(=O)R E5 、-N(R E5 )S(=O)2R E5 、-N(R E5 )S(=O)2OR E5 ; where R E5 is independently at each occurrence hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, or two RE5 The group and the intervening atoms together form a substituted or unsubstituted heterocyclic ring.

[0193] In some embodiments, R 7a and R 7b are independently hydrogen, halogen, -CN, -NO2, -OR F6 、-OC(=O)R F6 、-N(R F6 )2 or -N(R F6 )C(=O)R F6 ; where R F6 is independently at each occurrence hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, or two R F6 The group and the intervening atoms together form a substituted or unsubstituted heterocyclic ring.

[0194] In some embodiments, R 7a and R 7b are independently hydrogen, -OH or substituted or unsubstituted C 1-6 alkyl.

[0195] In some embodiments, R 7a and R 7b Each of which is independently hydrogen, -OH, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy or C 1-6 Alkoxyhalide.

[0196] In some embodiments, R 7a and R 7b is independently -CH3, -CH2CH3, -OH, -OCH3 or -CH(CH3)2.

[0197] In some embodiments, R 7a and R 7b All are hydrogen.

[0198] In some embodiments, R 7a and R 7b Joining to form an oxo group (=O).

[0199] Group R 11a and R 11b

[0200] In some embodiments, R 11a and R 11bare each independently hydrogen, halogen, -CN, -NO2, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, -OR E5 、-OC(=O)R E5 、-OS(=O)2OR E5 、-N(R E5 )2 or -N(R E5 )C(=O)R E5 、-N(R E5 )S(=O)2R E5 、-N(R E5 )S(=O)2OR E5 ; where R E5 is independently at each occurrence hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, or two R E5 The group and the intervening atoms together form a substituted or unsubstituted heterocyclic ring.

[0201] In some embodiments, R 11a and R 11b are independently hydrogen, halogen, -CN, -NO2, -OR F6 、-OC(=O)R F6 、-N(R F6 )2 or -N(R F6 )C(=O)R F6 ; where R F6 is independently at each occurrence hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, or two R F6 The group and the intervening atoms together form a substituted or unsubstituted heterocyclic ring.

[0202] In some embodiments, R 11a and R 11b are independently hydrogen, -OH or substituted or unsubstituted C 1-6 alkyl.

[0203] In some embodiments, R 11a and R 11b Each of which is independently hydrogen, -OH, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy or C 1-6 Alkoxyhalide.

[0204] In some embodiments, R 11a and R11b is independently -CH3, -CH2CH3, -OH, -OCH3 or -CH(CH3)2.

[0205] In some embodiments, R 11a and R 11b All are hydrogen.

[0206] In some embodiments, R 11a and R 11b Joining to form an oxo group (=O).

[0207] Group R 12a and R 12b

[0208] In some embodiments, R 12a and R 12b are each independently hydrogen, halogen, -CN, -NO2, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, -OR E5 、-OC(=O)R E5 、-OS(=O)2OR E5 、-N(R E5 )2 or -N(R E5 )C(=O)R E5 、-N(R E5 )S(=O)2R E5 、-N(R E5 )S(=O)2OR E5 ; where R E5 is independently at each occurrence hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, or two R E5 The group and the intervening atoms together form a substituted or unsubstituted heterocyclic ring.

[0209] In some embodiments, R 12a and R 12b are independently hydrogen, halogen, -CN, -NO2, -OR F6 、-OC(=O)R F6 、-N(R F6 )2 or -N(R F6 )C(=O)R F6 ; where R F6 is independently at each occurrence hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, or two R F6The group and the intervening atoms together form a substituted or unsubstituted heterocyclic ring.

[0210] In some embodiments, R 12a and R 12b are independently hydrogen, -OH or substituted or unsubstituted C 1-6 alkyl.

[0211] In some embodiments, R 12a and R 12b Each of which is independently hydrogen, -OH, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy or C 1-6 Alkoxyhalide.

[0212] In some embodiments, R 12a and R 12b is independently -CH3, -CH2CH3, -OH, -OCH3 or -CH(CH3)2.

[0213] In some embodiments, R 12a and R 12b All are hydrogen.

[0214] In some embodiments, R 12a and R 12b Joining to form an oxo group (=O).

[0215] Group R 17b

[0216] In some embodiments, R 17b is fluoro, hydroxy, methyl or hydrogen; wherein the hydrogen may be optionally replaced by deuterium. In some embodiments, R 17b It's hydrogen.

[0217] Group R 19

[0218] In some respects, R 19 is substituted or unsubstituted C 3-6 Carbocyclic group, or substituted or unsubstituted C 6-10 In some embodiments, R 19 is substituted or unsubstituted C 3-6 In some embodiments, R 19 It is cyclopropyl.

[0219] In some embodiments, R 19 is substituted or unsubstituted C 3-6 Carbocyclic group.

[0220] In some embodiments, R 19is substituted or unsubstituted C 6-10 Aryl.

[0221] In some embodiments, R 19 Selected from the group consisting of:

[0222]

[0223] in:

[0224] R b is independently at each occurrence hydrogen, halogen, -NO2, -CN, -OR G7 、-N(R G7 )2, -C(=O)R G7 、-C(=O)OR G7 、-C(=O)N(R G7 )2, -OC(=O)R G7 、-OC(=O)OR G7 、-N(R G7 )C(=O)R G7 、-OC(=O)N(R G7 )2、-N(R G7 )C(=O)OR G7 、-S(=O)2R G7 、-S(=O)2OR G7 、-OS(=O)2R G7 、-S(=O)2N(R G7 )2 or -N(R G7 )S(=O)2R G7 , substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 2-6 Alkenyl, substituted or unsubstituted C 2-6 Alkynyl, substituted or unsubstituted C 3-6 Carbocyclic group, substituted or unsubstituted 3 to 6 membered heterocyclic group, substituted or unsubstituted C 5-10 aryl, substituted or unsubstituted 5- to 10-membered heteroaryl;

[0225] R G7 is independently hydrogen, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 2-6 Alkenyl, substituted or unsubstituted C 2-6 Alkynyl, substituted or unsubstituted C 3-6 Carbocyclic group, substituted or unsubstituted 3 to 6 membered heterocyclic group, substituted or unsubstituted C 5-10 aryl, substituted or unsubstituted 5- to 10-membered heteroaryl, an oxygen protecting group when attached to oxygen, a nitrogen protecting group when attached to nitrogen, or two R G7The group and the intervening atoms together form a substituted or unsubstituted heterocyclic ring; and

[0226] q is an integer selected from 0 to 11.

[0227] Group R 15a and R 15b

[0228] In some embodiments, R 15a and R 15b Each of them is independently hydrogen, halogen, -CN, -NO2, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -OR C3 、-N(R C3 )2、-SR C3 、-C(=O)R C3 、-C(=O)OR C3 、-C(=O)SR C3 、-C(=O)N(R C3 )2, -OC(=O)R C3 、-OC(=O)OR C3 、-OC(=O)N(R C3 )2, -OC(=O)SR C3 、-OS(=O)2R C3 、-OS(=O)2OR C3 、-OS(=O)2N(R C3 )2、-N(R C3 )C(=O)R C3 、-N(R C3 )C(=NR C3 )R C3 、-N(R C3 )C(=O)OR C3 、-N(R C3 )C(=O)N(R C3 )2、-N(R C3 )C(=NR C3 )N(R C3 )2、-N(R C3 )S(=O)2R C3 、-N(R C3 )S(=O)2OR C3 、-N(R C3 )S(=O)2N(R C3 )2、-SC(=O)R C3 、-SC(=O)OR C3 、-SC(=O)SRC3 、-SC(=O)N(R C3 )2、-S(=O)2R C3 、-S(=O)2OR C3 or -S(=O)2N(R C3 )2, where R C3 is independently selected at each occurrence from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted carbocyclyl, or substituted or unsubstituted heterocyclyl, an oxygen protecting group when attached to oxygen, a nitrogen protecting group when attached to nitrogen, a sulfur protecting group when attached to sulfur, or two R C3 The group and the intervening atoms together form a substituted or unsubstituted heterocyclic ring.

[0229] In some embodiments, R 15a and R 15b All are hydrogen.

[0230] Group R 16a and R 16b

[0231] In some embodiments, R 16a and R 16b Each of them is independently hydrogen, halogen, -CN, -NO2, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -OR C3 、-N(R C3 )2、-SR C3 、-C(=O)R C3 、-C(=O)OR C3 、-C(=O)SR C3 、-C(=O)N(R C3 )2, -OC(=O)R C3 、-OC(=O)OR C3 、-OC(=O)N(R C3 )2, -OC(=O)SR C3 、-OS(=O)2R C3 、-OS(=O)2OR C3 、-OS(=O)2N(R C3 )2、-N(R C3 )C(=O)R C3 、-N(R C3 )C(=NR C3 )R C3 、-N(R C3 )C(=O)ORC3 、-N(R C3 )C(=O)N(R C3 )2、-N(R C3 )C(=NR C3 )N(R C3 )2、-N(R C3 )S(=O)2R C3 、-N(R C3 )S(=O)2OR C3 、-N(R C3 )S(=O)2N(R C3 )2、-SC(=O)R C3 、-SC(=O)OR C3 、-SC(=O)SR C3 、-SC(=O)N(R C3 )2、-S(=O)2R C3 、-S(=O)2OR C3 or -S(=O)2N(R C3 )2, where R C3 is independently selected at each occurrence from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted carbocyclyl, or substituted or unsubstituted heterocyclyl, an oxygen protecting group when attached to oxygen, a nitrogen protecting group when attached to nitrogen, a sulfur protecting group when attached to sulfur, or two R C3 The group and the intervening atoms together form a substituted or unsubstituted heterocyclic ring.

[0232] In some embodiments, R 16a and R 16b All are hydrogen.

[0233] n

[0234] In some embodiments, n is 0. In some embodiments, n is 1. In some other embodiments, n is 2.

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

[0236]

[0237] or a pharmaceutically acceptable salt thereof.

[0238] In some embodiments, the compound of formula (I) is a compound of formula (Ib):

[0239]

[0240] or a pharmaceutically acceptable salt thereof.

[0241] In some embodiments, the compound of formula (I) is a compound of formula (Ic):

[0242]

[0243] or a pharmaceutically acceptable salt thereof.

[0244] In some embodiments, the compound of formula (I) is a compound of formula (Id):

[0245]

[0246] or a pharmaceutically acceptable salt thereof; wherein: R a is independently at each occurrence halogen, cyano, hydroxy or substituted or unsubstituted alkyl; and p is 0, 1, 2 or 3.

[0247] In some embodiments, the compound of formula (I) is a compound of formula (Ie):

[0248]

[0249] or a pharmaceutically acceptable salt thereof; wherein:

[0250] Each X is independently -C(R N )-、-C(R N )2-、-O-、-S-、-N- or N(R N )-, wherein RN is independently hydrogen, substituted or unsubstituted C 1-6 Alkyl, C(=O)R GA 、-C(=O)OR GA 、-C(=O)N(R GA )2、-S(=O)2R GA or -S(=O)2N(R GA )2; R GA is independently hydrogen, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 2-6 Alkenyl, substituted or unsubstituted C 2-6 Alkynyl, substituted or unsubstituted C 3-6 a carbocyclyl, a substituted or unsubstituted 3- to 6-membered heterocyclyl, 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 R GA The groups, together with the intervening atoms, form a substituted or unsubstituted heterocyclyl or heteroaryl ring.

[0251] In some embodiments, the compound of formula (I) is a compound of formula (If):

[0252]

[0253] or a pharmaceutically acceptable salt thereof; wherein:

[0254] Each X is independently -C(R N )-、-C(R N )2-、-O-、-S-、-N- or N(R N )-, wherein RN is independently hydrogen, substituted or unsubstituted C 1-6 Alkyl, C(=O)R GA 、-C(=O)OR GA 、-C(=O)N(R GA )2、-S(=O)2R GA or -S(=O)2N(R GA )2; R GA is independently hydrogen, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 2-6 Alkenyl, substituted or unsubstituted C 2-6 Alkynyl, substituted or unsubstituted C 3-6 a carbocyclyl, a substituted or unsubstituted 3- to 6-membered heterocyclyl, 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 R GA The groups, together with the intervening atoms, form a substituted or unsubstituted heterocyclyl or heteroaryl ring.

[0255] In some embodiments, the compound of formula (I) is a compound of formula (Ig):

[0256]

[0257] or a pharmaceutically acceptable salt thereof; wherein:

[0258] R a is independently at each occurrence halogen, alkyl, hydroxy, or cyano; and

[0259] p is an integer selected from 0 to 11.

[0260] In some embodiments, the compound of formula (I) is a compound of formula (Ih):

[0261]

[0262] or a pharmaceutically acceptable salt thereof; wherein:

[0263] Each X is independently -C(R N )-、-C(R N )2-、-O-、-S-、-N- or N(RN )-, wherein RN is independently hydrogen, substituted or unsubstituted C 1-6 Alkyl, C(=O)R GA 、-C(=O)OR GA 、-C(=O)N(R GA )2、-S(=O)2R GA or -S(=O)2N(R GA )2; R CA is independently hydrogen, substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 2-6 Alkenyl, substituted or unsubstituted C 2-6 Alkynyl, substituted or unsubstituted C 3-6 a carbocyclyl, a substituted or unsubstituted 3- to 6-membered heterocyclyl, 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 R GA The groups, together with the intervening atoms, form a substituted or unsubstituted heterocyclyl or heteroaryl ring.

[0264] In one aspect, provided herein is a pharmaceutical composition comprising a compound as described herein (e.g., a compound of Formula (I)) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. In certain embodiments, the compound of the present invention is provided in an effective amount in the pharmaceutical composition. In certain embodiments, the compound of the present invention is provided in a therapeutically effective amount. In certain embodiments, the compound of the present invention is provided in a prophylactic effective amount.

[0265] In one aspect, provided herein are pharmaceutically acceptable salts of the compounds described herein (eg, compounds of Formula (I)).

[0266] In certain embodiments, the compound is administered orally, subcutaneously, intravenously, or intramuscularly. In certain embodiments, the compound is administered orally. In certain embodiments, the compound is administered chronically. In certain embodiments, the compound is administered continuously, for example, by continuous intravenous infusion.

[0267] As described herein, the compounds of the present invention are useful in certain embodiments as GABA modulators, for example, influencing GABA in a positive or negative manner. A Receptors. Acts as a regulator of central nervous system (CNS) excitability, such as through its regulation of GABA A Such compounds are expected to have CNS activity mediated by the ability of the cytochrome P68 receptor to activate CNS function.

[0268] In one aspect, described herein is a method for treating a CNS-related disorder in a subject in need thereof, comprising administering to the subject an effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof.

[0269] 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 cognitive disorder, a movement disorder, a personality disorder, an autism spectrum disorder, pain, traumatic brain injury, a vascular disease, a substance abuse disorder and / or withdrawal syndrome, tinnitus, or status epilepticus.

[0270] 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.

[0271] In some embodiments, the compound is selected from the group consisting of the compounds identified in Table 1 below:

[0272] Table 1.

[0273]

[0274]

[0275] 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, provided herein are pharmaceutically acceptable salts of the compounds described herein (eg, compounds of formula (I)).

[0276] Alternative implementation plans

[0277] 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 e.g. 13 C or 14 C; oxygen can be e.g. 18 O; nitrogen can be e.g. 15 N, etc. In other embodiments, specific isotopes (e.g., 3 H. 13 C. 14 C. 18 O or 15N) 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 particular position in the compound.

[0278] Pharmaceutical composition

[0279] In one aspect, provided herein is a pharmaceutical composition comprising a compound as described herein (e.g., a compound of Formula (I)) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. In certain embodiments, the compound of the present invention is provided in an effective amount in the pharmaceutical composition. In certain embodiments, the compound of the present invention is provided in a therapeutically effective amount. In certain embodiments, the compound of the present invention is provided in a prophylactic effective amount.

[0280] In certain embodiments, the pharmaceutical composition comprises an effective amount of the active ingredient. In certain embodiments, the pharmaceutical composition comprises a therapeutically effective amount of the active ingredient. In certain embodiments, the pharmaceutical composition comprises a prophylactically effective amount of the active ingredient.

[0281] The pharmaceutical compositions provided herein can be administered by a variety of routes, including, but not limited to, oral (enteral), parenteral (by injection), rectal, transdermal, intradermal, intrathecal, subcutaneous (SC), intravenous (IV), intramuscular (IM), and intranasal.

[0282] Generally speaking, the compounds provided herein are administered in an effective amount. The amount of active agent actually administered will be determined by the physician based on the relevant circumstances, including the condition to be treated, the route of administration selected, the actual compound administered, the age, weight and response of the individual patient, and the severity of the patient's symptoms.

[0283] When used to prevent the onset of CNS disorders, the compounds provided herein should generally be administered at the dosage levels described above to subjects at risk of developing the disorder, according to the advice of a physician and under the supervision of a physician. Subjects at risk of developing a particular disorder generally include those with a family history of the disorder, or those who have been identified as being particularly susceptible to the disorder by genetic testing or screening.

[0284] The pharmaceutical compositions provided herein can also be administered long-term ("chronic administration"). Long-term administration refers to administration of a compound or pharmaceutical composition thereof over an extended period of time, e.g., 3 months, 6 months, 1 year, 2 years, 3 years, 5 years, etc., or can continue indefinitely, e.g., until the end of the subject's life. In certain embodiments, long-term administration is intended to provide a constant level of the compound in the blood, e.g., within a therapeutic window over an extended period of time.

[0285] The pharmaceutical composition of the present invention can be further delivered using a variety of administration methods. For example, in certain embodiments, the pharmaceutical composition can be given in a bolus, such as 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 active ingredient required in the whole body, such as intramuscular or subcutaneous single doses allow the active ingredient to be slowly released, and the bolus is directly delivered to the vein (for example, via IV drip) to allow much faster delivery, which quickly increases the concentration of the active ingredient in the blood to an effective level. In other embodiments, the pharmaceutical composition can be administered by continuous infusion (for example, by IV drip) so that a stable active ingredient concentration is maintained in the subject. In addition, in other embodiments, the pharmaceutical composition can first be administered with a single dose, followed by continuous infusion.

[0286] Compositions for oral administration can take the form of bulk liquid solutions or suspensions or bulk powders. However, compositions are more commonly presented in unit dosage forms to facilitate accurate administration. The term "unit dosage form" refers to physically discontinuous units suitable for use in human subjects and other mammals in unit dosage form, each unit containing a predetermined amount of active substance calculated to produce the desired therapeutic effect, in combination with suitable pharmaceutical excipients. Typical unit dosage forms include pre-filled pre-measured ampoules or syringes of liquid compositions, or pills, tablets, capsules, etc. (in terms 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), and the remainder is various vehicles or excipients and processing aids that contribute to the formation of the desired form of administration.

[0287] Under oral administration, one to five and especially two to four and usually three oral doses per day are representative therapies. Using these modes of administration, each dose provides about 0.01 to about 20 mg / kg of a compound provided herein, wherein preferred doses each provide about 0.1 to about 10 mg / kg, and especially about 1 to about 5 mg / kg.

[0288] Transdermal doses are generally selected to provide blood levels similar to or lower than those achieved using injectable doses, generally in amounts ranging from about 0.01% to about 20% by weight, preferably from about 0.1% to about 20% by weight, preferably from about 0.1% to about 10% by weight, and more preferably from about 0.5% to about 15% by weight.

[0289] Injection dose levels range from about 0.1 mg / kg / hour to at least 20 mg / kg / hour, all for about 1 to about 120 hours and particularly 24 to 96 hours. A preload bolus of about 0.1 mg / kg to about 10 mg / kg or more may also be administered to achieve adequate steady-state levels. For a 40 to 80 kg human patient, the maximum total dose is not expected to exceed about 5 grams / day.

[0290] Liquid forms suitable for oral administration may include a suitable aqueous or non-aqueous vehicle with buffers, suspending and dispersing agents, colorants, flavorings, etc. Solid forms may include, for example, any of the following ingredients or compounds of similar properties: binders such as microcrystalline cellulose, tragacanth, or gelatin; excipients such as starch or lactose; disintegrants such as alginic acid, sodium starch glycolate (Primogel), or corn starch; lubricants such as magnesium stearate; glidants such as colloidal silicon dioxide; sweeteners such as sucrose or saccharin; or flavorings such as peppermint, methyl salicylate, or orange flavor.

[0291] Injectable compositions are generally 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 generally a minor component, usually about 0.05% to 10% by weight, with the remainder being injectable excipients and the like.

[0292] Transdermal compositions are typically formulated as topical ointments or creams containing one or more active ingredients. When formulated as an ointment, the active ingredient will typically be combined with a paraffin or water-miscible ointment base. Alternatively, the active ingredient can be formulated into a cream using, for example, an oil-in-water cream base. Such transdermal formulations are well known in the art and typically 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.

[0293] The compounds provided herein can also be administered via transdermal devices. Thus, transdermal administration can be achieved using reservoir-type or porous membrane-type or solid matrix-type patches.

[0294] The components described above for orally administrable, injectable or topically administrable compositions are representative only. Other materials and processing techniques are described in Part 8 of Remington's Pharmaceutical Sciences, 17th edition, 1985, Mack Publishing Company, Easton, Pennsylvania, which is incorporated herein by reference.

[0295] The compounds of the present invention may also be administered in sustained release form or from a sustained release drug delivery system. Descriptions of representative sustained release materials can be found in Remington's Pharmaceutical Sciences.

[0296] The present invention also relates to pharmaceutically acceptable acid addition salts of the compounds of the present invention. Acids that can be used to prepare pharmaceutically acceptable salts are acids that form non-toxic acid addition salts, i.e., salts containing pharmacologically acceptable anions, such as hydrochlorides, hydroiodides, hydrobromides, nitrates, sulfates, bisulfates, phosphates, acetates, lactates, citrates, tartrates, succinates, maleates, fumarates, benzoates, p-toluenesulfonates, and the like.

[0297] In another aspect, the present invention provides a pharmaceutical composition comprising a compound of the present invention and a pharmaceutically acceptable excipient, eg, a composition suitable for injection, such as for intravenous (IV) administration.

[0298] Pharmaceutically acceptable excipients include any and all diluents or other liquid vehicles suitable for the particular dosage form desired, such as injectable solutions, dispersion or suspension aids, surfactants, isotonicity agents, preservatives, lubricants, etc. General considerations in the formulation and / or manufacture of pharmaceutical compositions and medicaments 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).

[0299] For example, injectable preparations (such as sterile injectable aqueous suspensions) can be formulated using suitable dispersing or wetting agents and suspending agents according to known techniques. Exemplary excipients that can be used include, but are not limited to, water, sterile saline or phosphate-buffered saline or Ringer's solution.

[0300] In certain embodiments, the pharmaceutical composition further comprises a cyclodextrin derivative. The most common cyclodextrins are α-cyclodextrin, β-cyclodextrin, and γ-cyclodextrin, which are composed of 6, 7, and 8 α-1,4-linked glucose units, respectively, optionally containing one or more substituents on the linked sugar moiety, including but not limited to substituted or unsubstituted methylation, hydroxyalkylation, acylation, and sulfoalkyl ether substitution. In certain embodiments, the cyclodextrin is a sulfoalkyl ether β-cyclodextrin, such as sulfobutyl ether β-cyclodextrin, also known as See, for example, US Pat. No. 5,376,645. In certain embodiments, the composition comprises hexapropyl-β-cyclodextrin. In more specific embodiments, the composition comprises hexapropyl-β-cyclodextrin (10%-50% in water).

[0301] The injectable compositions can be sterilized, for example, by filtration through a bacteria-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions that can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.

[0302] Generally speaking, the compounds provided herein are administered in an effective amount. The amount of active agent actually administered will be determined by the physician based on the relevant circumstances, including the condition to be treated, the route of administration selected, the actual compound administered, the age, weight, response of the individual patient, and the severity of the patient's symptoms.

[0303] The composition is presented in unit dosage form to facilitate accurate administration. The term "unit dosage form" refers to a physically discrete unit suitable for use in unit dosage form for human subjects and other mammals, each unit containing a predetermined amount of active substance calculated to produce the desired therapeutic effect, in combination with a suitable pharmaceutical excipient. Typical unit dosage forms include pre-filled, pre-measured ampoules or syringes of liquid compositions. In such compositions, the compound is usually a minor component (about 0.1% to about 50% by weight, or preferably about 1% to about 40% by weight), with the remainder being various vehicles or carriers and processing aids that help form the desired administration form.

[0304] The compounds provided herein can be administered as the sole active agent, or they can be administered in combination with other active agents. In one aspect, the present invention provides a combination of a compound of the present invention and another pharmacologically active agent. Administration of the combination can be performed by any technique apparent to those skilled in the art, including, for example, separate, sequential, simultaneous, and alternating administration.

[0305] Although the descriptions of pharmaceutical compositions provided herein primarily relate to pharmaceutical compositions suitable for administration to humans, it will be understood by those skilled in the art that such compositions are generally suitable for administration to all types of animals. It is well understood that pharmaceutical compositions suitable for administration to humans may be modified to render the compositions suitable for administration to various animals, and such modifications can be designed and / or performed by a veterinary pharmacologist using only ordinary experimentation. 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.

[0306] In one aspect, a kit is provided comprising a composition (eg, a solid composition) comprising a compound of Formula (I).

[0307] Use and treatment methods

[0308] In one aspect, it is contemplated that the compounds described herein, e.g., compounds of Formula (I), can be used as therapeutic agents for treating a CNS-related disorder (e.g., sleep disorders, mood disorders such as depression, schizophrenia spectrum disorders, convulsive disorders, epileptogenesis, memory and / or cognitive disorders, movement disorders, personality disorders, autism spectrum disorders, pain, traumatic brain injury, vascular disease, substance abuse disorders and / or withdrawal syndromes, or tinnitus) in a subject in need thereof (e.g., a subject with Rett syndrome, Fragile X syndrome, or Angelman syndrome). Exemplary CNS disorders associated with GABA modulation include, but are not limited to, sleep disorders [e.g., insomnia], mood disorders [e.g., depression (e.g., major depressive disorder (MDD)), hypoactive depression (e.g., minor depression), bipolar disorder (e.g., type I and / or type II), anxiety disorders (e.g., generalized anxiety disorder (GAD), social anxiety disorder), stress, post-traumatic stress disorder (PTSD), obsessive-compulsive disorder (e.g., obsessive-compulsive disorder (OCD))], schizophrenia spectrum disorders [e.g., schizophrenia, schizoaffective disorder], convulsive disorders [e.g., epilepsy (e.g., status epilepticus (SE)), seizures], memory and / or cognitive disorders [e.g., attention disorders (e.g., attention deficit hyperactivity disorder (ADHD)), dementia (e.g., Alzheimer's type dementia, Lewis body type dementia, vascular dementia], movement disorders [e.g., Huntington's disease ( disease), Parkinson's disease], personality disorders [e.g., antisocial personality disorder, obsessive-compulsive personality disorder], autism spectrum disorders (ASD) [e.g., autism, monogenic autism, such as synaptopathy, e.g., Rett syndrome, fragile X syndrome, Angelman syndrome], pain [e.g., neuropathic pain, injury-related pain syndrome, acute pain, chronic pain], traumatic brain injury (TBI), vascular disease [e.g., stroke, ischemia, vascular malformations], substance abuse disorders and / or withdrawal syndromes [e.g., opiate, cocaine, and / or alcohol addiction], and tinnitus.

[0309] In certain embodiments, CNS related conditions are sleep disorders, mood disorders, schizophrenia spectrum disorders, convulsive disorders, memory and / or cognitive disorders, movement disorders, personality disorders, autism spectrum disorders, pain, traumatic brain injury, vascular disease, substance abuse disorders and / or withdrawal syndrome, tinnitus or status epilepticus. In certain embodiments, CNS related conditions are depression. In certain embodiments, CNS related conditions are postpartum depression. In certain embodiments, CNS related conditions are major depressive disorder. In certain embodiments, major depressive disorder is moderate major depressive disorder. In certain embodiments, major depressive disorder is severe major depressive disorder.

[0310] In one aspect, a method of ameliorating or preventing an epileptic seizure in a subject is provided, the method comprising administering to a subject in need of such treatment an effective amount of a compound of the invention. In some embodiments, the method ameliorates or prevents epileptogenesis.

[0311] In another aspect, a combination of a compound of the invention and another pharmacologically active agent is provided. The compounds provided herein can be administered as the sole active agent, or they can be administered in combination with other agents. Administration of the combination can be performed by any technique apparent to those skilled in the art, including, for example, separate, sequential, simultaneous, and alternating administration.

[0312] In another aspect, provided is a method of treating or preventing brain excitability in a subject susceptible to or suffering from a disorder associated with brain excitability, the method comprising administering to the subject an effective amount of a compound of the present invention.

[0313] In another aspect, provided is a method of treating or preventing stress or anxiety in a subject, the method comprising administering to a subject in need of such treatment an effective amount of a compound of the present invention or a composition thereof.

[0314] In another aspect, provided is a method of alleviating or preventing insomnia in a subject, the method comprising administering to a subject in need of such treatment an effective amount of a compound of the present invention or a composition thereof.

[0315] In another aspect, there is provided a method of inducing sleep and maintaining substantially the levels of REM sleep found in normal sleep, wherein substantial rebound insomnia is not induced, the method comprising administering an effective amount of a compound of the present invention.

[0316] In another aspect, provided is a method of alleviating or preventing premenstrual syndrome (PMS) or postpartum depression (PND) in a subject, the method comprising administering to the subject in need of such treatment an effective amount of a compound of the present invention.

[0317] In another aspect, a method of treating or preventing a mood disorder in a subject is provided, the method comprising administering to a subject in need of such treatment an effective amount of a compound of the invention. In certain embodiments, the mood disorder is depression.

[0318] In another aspect, a method of enhancing cognition or treating a memory disorder by administering to a subject a therapeutically effective amount of a compound of the invention is provided. In certain embodiments, the disorder is Alzheimer's disease. In certain embodiments, the disorder is Rett syndrome.

[0319] In another aspect, a method of treating an attention disorder by administering to a subject a therapeutically effective amount of a compound of the invention is provided. In other embodiments, the attention disorder is ADHD.

[0320] In certain embodiments, the compound is administered to the subject chronically. In certain embodiments, the compound is administered to the subject orally, subcutaneously, intravenously, or intramuscularly.

[0321] Neuroendocrine disorders and dysfunctions

[0322] Provided herein are methods that can be used to treat neuroendocrine disorders and dysfunctions. As used herein, "neuroendocrine disorders" or "neuroendocrine dysfunction" refer to a variety of conditions caused by an imbalance in hormone production in the body directly related to the brain. Neuroendocrine disorders relate to the interaction between the nervous system and the endocrine system. Because the hypothalamus and pituitary gland are two brain regions that regulate hormone production, damage to the hypothalamus or pituitary gland, such as caused by traumatic brain injury, can affect hormone production and other neuroendocrine functions of the brain. In some embodiments, the neuroendocrine disorder or dysfunction is associated with a women's health disorder or illness (e.g., a women's health disorder or illness described herein). In some embodiments, the neuroendocrine disorder or dysfunction associated with a women's health disorder or illness is polycystic ovary syndrome.

[0323] Symptoms of neuroendocrine disorders include, but are not limited to, behavioral, mood and sleep-related symptoms, symptoms related to reproductive function, and somatic symptoms; including, but not limited to, fatigue, poor memory, anxiety, depression, weight gain or loss, mood swings, difficulty concentrating, attention difficulties, loss of libido, infertility, amenorrhea, loss of muscle mass, increased abdominal body fat, low blood pressure, slowed heart rate, hair loss, anemia, constipation, cold intolerance, and dry skin.

[0324] Neurodegenerative diseases and conditions

[0325] The methods described herein can be used to treat neurodegenerative diseases and disorders.The term "neurodegenerative disease" includes diseases and disorders associated with progressive loss of neuronal structure or function, or neuronal death.Neurodegenerative diseases and conditions include, but are not limited to, Alzheimer's disease (including symptoms associated with mild, moderate, or severe cognitive impairment); amyotrophic lateral sclerosis (ALS); anoxic and ischemic injury; ataxia and convulsions (including for the treatment and prevention of seizures caused by schizoaffective disorder or by drugs used to treat schizophrenia); benign amnesia; cerebral edema; cerebellar ataxia, including McLeod neuroacanthocytosis syndrome (McLeod neuroacanthocytosis syndrome); syndrome (MLS); closed head injury; coma; contusive injury (e.g., spinal cord injury and head injury); dementia, including multi-infarct dementia and Alzheimer's disease; confusion; Down syndrome; drug-induced or pharmacotherapy-induced Parkinsonism (e.g., neuroleptic-induced acute akathisia, acute dystonia, parkinsonism, or tardive dyskinesia, neuroleptic 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 syndrome); levodopa-induced dyskinesia; mental retardation; movement disorders, including akinesia and akinetic (rigid) syndromes (including basal ganglia calcification, corticobasal degeneration, multiple system atrophy, Parkinson's disease-ALS dementia complex, Parkinson's disease, postencephalitic parkinsonism, and progressive supranuclear palsy); muscle spasticity and conditions associated with muscle spasticity or weakness, including chorea (e.g., benign hereditary chorea, drug-induced chorea, hemishama, Huntington's disease, neuroacanthocytosis, Sydenham's chorea); chorea and symptomatic chorea), dyskinesias (including tics such as complex tics, simple tics and symptomatic tics), myoclonus (including generalized myoclonus and focal myoclonus), tremor (such as rest tremor, postural tremor and intention tremor) and dystonias (including axial dystonia, dystonic digital spasm, hemiplegic dystonia, paroxysmal dystonia and focal dystonias such as blepharospasm, oromandibular dystonia and spasmodic dystonia). neuronal damage, including eye damage, retinal disease or macular degeneration of the eye; neurotoxic injury following cerebral stroke, thromboembolic stroke, hemorrhagic stroke, cerebral ischemia, cerebral vasospasm, hypoglycemia, amnesia, hypoxia, anoxia, perinatal asphyxia and cardiac arrest; Parkinson's disease; epileptic seizures; status epilepticus; stroke; tinnitus; tubular sclerosis and viral infection-induced neurodegeneration (e.g., caused by acquired immune deficiency syndrome (AIDS) and encephalopathy).Neurodegenerative diseases also include, but are not limited to, cerebral stroke, thromboembolic stroke, hemorrhagic stroke, cerebral ischemia, cerebral vasospasm, hypoglycemia, amnesia, hypoxia, anoxia, perinatal asphyxia, and neurotoxic injury following cardiac arrest. Methods for treating or preventing neurodegenerative diseases also include treating or preventing the loss of neuronal function characteristic of neurodegenerative disorders.

[0326] Mood disorders

[0327] Also provided herein are methods for treating mood disorders, such as clinical depression, postpartum depression or postpartum depression, perinatal depression, atypical depression, melancholic depression, psychotic major depressive disorder, catatonic depression, seasonal affective disorder, minor depression, double depression, depressive personality disorder, recurrent brief depression, minor depressive disorder, bipolar disorder or manic-depressive disorder, depression caused by a chronic medical condition, treatment-resistant depression, refractory depression, suicidal tendencies, suicidal ideation, or suicidal behavior. In some embodiments, the methods described herein provide a therapeutic effect for a subject suffering from depression (e.g., moderate or severe depression). In some embodiments, the mood disorder is associated with a disease or condition described herein (e.g., neuroendocrine diseases and conditions, neurodegenerative diseases and conditions (e.g., epilepsy), movement disorders, tremor (e.g., Parkinson's disease), women's health conditions or disorders).

[0328] Clinical depression is also known as major depressive disorder, major depressive disorder (MDD), major depressive disorder, unipolar depression, unipolar disorder and recurrent depression and refers to a mental disorder characterized by a general and persistent low mood, accompanied by low self-esteem and loss of interest or pleasure in normal recreational activities. Some people with clinical depression have difficulty sleeping, lose weight and generally feel anxious and easily irritated. Clinical depression affects the individual's feelings, thoughts and behavior and can cause many emotional and physical problems. Individuals with clinical depression may have difficulty carrying out daily activities and feel that life is not worth living.

[0329] Perinatal depression refers to depression during pregnancy. Symptoms include irritability, crying spells, feeling restless, difficulty sleeping, extreme tiredness (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 a loss of interest in previously pleasurable activities.

[0330] Postpartum depression (PND) is also known as postpartum depression (PPD) and refers to a type of clinical depression that affects women after childbirth. Symptoms can include sadness, fatigue, changes in sleeping and eating habits, decreased libido, crying spells, anxiety, and irritability. In some embodiments, PND is treatment-resistant depression (e.g., as described herein). In some embodiments, PND is refractory depression (e.g., as described herein).

[0331] In some embodiments, the subject with PND also experiences depression or depressive symptoms during pregnancy. This depression is referred to herein as perinatal depression. In one embodiment, subjects experiencing perinatal depression have an increased risk of experiencing PND.

[0332] Atypical depression (AD) is characterized by increased emotional reactivity (e.g., abnormal anhedonia) and motivation, significant weight gain, or increased appetite. Patients with AD may also experience excessive sleep or sleepiness (hypersomnia), a feeling of heaviness in the limbs, and significant social impairment due to hypersensitivity to perceived interpersonal rejection.

[0333] Melancholic depression is characterized by loss of pleasure in most or all activities (anhedonia), inability to respond to pleasurable stimuli, moodiness that is more pronounced than sadness or loss, excessive weight loss, or excessive guilt.

[0334] Psychotic major depressive disorder (PMD) or psychotic depression refers to a major depressive episode, particularly of a melancholic nature, in which the individual experiences psychotic symptoms such as delusions and hallucinations.

[0335] Catatonic depression refers to severe depression that involves disturbances in motor behavior and other symptoms. Individuals may become silent and apathetic, unable to move or exhibit purposeless or bizarre movements.

[0336] Seasonal affective disorder (SAD) refers to a type of seasonal depression in which an individual has a seasonal pattern of depressive episodes that arrives in the fall or winter.

[0337] Hypochondriasis refers to a condition related to unipolar depression in which the same physical and cognitive problems are evident. It is less severe and tends to last longer (e.g., at least 2 years).

[0338] Double depression is a period of extremely depressed mood (hypotension) lasting at least 2 years, interspersed with periods of major depression.

[0339] Depressive personality disorder (DPD) refers to a personality disorder with depressive features.

[0340] Recurrent brief depressive disorder (RBD) is a disorder in which an individual experiences depressive episodes approximately once a month, with each episode lasting 2 weeks or less and usually less than 2-3 days.

[0341] Minor depressive disorder or minor depression is depression in which at least two symptoms are present for 2 weeks.

[0342] Bipolar disorder, or manic-depressive disorder, causes extreme mood swings, including highs (mania or hypomania) and lows (depression). During mania, a person may feel or appear unusually happy, energetic, or irritable. They often make ill-considered decisions with little regard for the consequences. The need for sleep is often reduced. During depression, a person may cry, lack eye contact with others, and have a negative attitude towards life. The risk of suicide is higher in people with the condition, exceeding 6% over a 20-year period, while the rate of self-harm is 30%-40%. Other mental health problems, such as anxiety disorders and substance use disorders, are often associated with bipolar disorder.

[0343] Depression caused by chronic medical conditions refers to depression caused by chronic medical conditions such as cancer or chronic pain, chemotherapy, or chronic stress.

[0344] Treatment-resistant depression refers to a condition in which an individual has been treated for depression but the symptoms have not improved. For example, antidepressants or psychological counseling (psychotherapy) have not alleviated the depressive symptoms of a subject with treatment-resistant depression. In some cases, the symptoms of a subject with treatment-resistant depression improve but then return. Refractory depression occurs in patients with depression who are resistant to standard pharmacological treatments including tricyclic antidepressants, MAOIs, SSRIs, and double and triple uptake inhibitors and / or anxiolytics, as well as non-pharmacological treatments (e.g., psychotherapy, electroconvulsive therapy, vagus nerve stimulation, and / or transcranial magnetic stimulation).

[0345] Postoperative depression refers to depressed mood that develops after a surgical procedure (e.g., having to face the consequences of death). For example, individuals may experience persistent feelings of sadness or emptiness, a loss of pleasure or interest in hobbies and activities they normally enjoy, or a persistent feeling of worthlessness or hopelessness.

[0346] A mood disorder associated with a women's health disorder or condition refers to a mood disorder (eg, depression) that is associated with (eg, caused by) a women's health disorder or condition (eg, as described herein).

[0347] Suicidal tendencies, suicidal ideation, and suicidal behavior refer to a person's tendency to commit suicide. Suicidal ideation involves thoughts or an unusual preoccupation with suicide. Suicidal ideation can range from fleeting thoughts to in-depth thoughts, detailed planning, role-playing, and attempted suicide. Symptoms include discussing suicide, acquiring methods to carry out suicide, withdrawing from social contact, preoccupied thoughts about death, feeling trapped or hopeless about a situation, increased alcohol or drug use, engaging in risky or self-destructive behaviors, and saying goodbye to people as if they will never see them again.

[0348] The symptoms of depression include persistent anxiety or sadness, feeling helpless, hopeless, pessimistic, worthless, listless, restless, difficulty falling asleep, insomnia, irritability, fatigue, motor aggression, lack of interest in recreational activities or hobbies, lack of concentration, lack of energy, poor self-esteem, no positive thoughts or plans, excessive sleeping, excessive eating, loss of appetite, insomnia, self-harm, suicidal thoughts and attempted suicide. The presence, severity, frequency and duration of symptoms can vary depending on the situation. The symptoms of depression and their alleviation can be determined by a physician or psychologist (e.g., through a mental status examination).

[0349] In some embodiments, the method comprises using a known depression rating scale, such as the Hamilton Depression (HAM-D) scale, the Clinical Global Impression-Improvement Scale (CGI), and the Montgomery-Asberg Depression Rating Scale (MTRS). The subjects are monitored using the Hamilton Depression Rating Scale (MADRS). In some embodiments, therapeutic effect can be determined by a decrease in the Hamilton Depression Rating Scale (HAM-D) total score exhibited by the subject. A decrease in the HAM-D total score occurs 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 therapeutic effect can be assessed over a specified treatment period. For example, a therapeutic effect can be determined by a decrease in HAM-D total score compared to baseline after administration of a compound described herein, e.g., a compound of Formula (I) (e.g., 12 hours, 24 hours, or 48 hours; or 24 hours, 48 hours, 72 hours, 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 lifetime after administration).

[0350] In some embodiments, the subject suffers from mild depressive disorder, such as mild major depressive disorder. In some embodiments, the subject suffers from moderate depressive disorder, such as moderate major depressive disorder. In some embodiments, the subject suffers from severe depressive disorder, such as severe major depressive disorder. In some embodiments, the subject suffers from extremely severe depressive disorder, such as extremely severe major depressive disorder. In some embodiments, the baseline HAM-D total score of the subject (that is, before using a compound as described herein, such as a compound of formula (I)) is at least 24. In some embodiments, the baseline HAM-D total score of the subject is at least 18. In some embodiments, the baseline HAM-D total score of the subject is between 14 and 18 (including the end value). In some embodiments, the baseline HAM-D total score of the subject is between 19 and 22 (including the end value). In some embodiments, the HAM-D total score of the subject before using a compound as described herein, such as a compound of formula (I) is greater than or equal to 23. In some embodiments, the baseline score is at least 10 points, 15 points or 20 points. In some embodiments, after treatment with a compound described herein, e.g., a compound of Formula (I), the subject's HAM-D total score is about 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, e.g., a compound of Formula (I), the HAM-D total score is less than 10, 7, 5, or 3. In some embodiments, after treatment with a compound described herein, e.g., a compound of Formula (I), the HAM-D total score decreases from a baseline score of about 20 to 30 (e.g., 22 to 28, 23 to 27, 24 to 27, 25 to 27, 26 to 27) to a HAM-D total score of about 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 from baseline HAM-D total score to HAM-D total score after treatment with a compound as described herein, e.g., 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 of reduction from baseline HAM-D total score to HAM-D total score after treatment with a compound as described herein, e.g., 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 as described herein, e.g., a compound of formula (I), which is at least 10, 15, or 20 points relative to baseline HAM-D total score (e.g., 12 hours, 24 hours, 48 hours after administration; or 24 hours, 48 hours, 72 hours, 96 hours, or longer; or 1 day, 2 days, 14 days, or longer).

[0351] In some embodiments, the methods for treating a depressive disorder (e.g., major depressive disorder) provide a therapeutic effect (e.g., as measured by a decrease in the Hamilton Depression Scale (HAM-D)) 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. In some embodiments, the methods for treating a depressive disorder (e.g., major depressive disorder) provide a therapeutic effect (e.g., as measured by a decrease in the Hamilton Depression Scale (HAM-D)) within the first or second day of treatment with a compound as described herein, e.g., a compound of Formula (I). In some embodiments, the methods for treating a depressive disorder (e.g., major depressive disorder) provide a therapeutic effect (e.g., as measured by a statistically significant decrease in the HAM-D total score) within less than or equal to 14 days of initiation of treatment with a compound as described herein, e.g., a compound of Formula (I). In some embodiments, the method for treating a depressive disorder (e.g., a major depressive disorder) provides a therapeutic effect (e.g., as measured by a statistically significant reduction in a HAM-D total score) within 21 days of starting treatment with a compound as described herein, e.g., a compound of formula (I). In some embodiments, the method for treating a depressive disorder (e.g., a major depressive disorder) provides a therapeutic effect (e.g., as measured by a statistically significant reduction in a HAM-D total score) within 28 days of starting treatment with a compound as described herein, e.g., a compound of formula (I). In some embodiments, the therapeutic effect is a decrease in the HAM-D total score from baseline after treatment with a compound as described herein, e.g., a compound of formula (I) (e.g., treatment with a compound as described herein, e.g., a compound of formula (I) once a day for 14 days). In some embodiments, the HAM-D total score of the subject before treatment with a compound as described herein, e.g., a compound of formula (I) is at least 24. In some embodiments, the HAM-D total score of the subject before treatment with a compound as described herein, e.g., a compound of formula (I) is at least 18. In some embodiments, the subject's HAM-D total score prior to treatment with a compound described herein, e.g., a compound of Formula (I) is between 14 and 18 (inclusive). In some embodiments, the HAM-D total score is reduced by at least 10 after treatment of the subject with a compound described herein, e.g., a compound of Formula (I) relative to the baseline HAM-D total score. In some embodiments, the HAM-D total score is reduced by at least 15 (e.g., at least 17) after treatment of the subject with a compound described herein, e.g., a compound of Formula (I) relative to the baseline HAM-D total score. In some embodiments, the HAM-D total score associated with treatment of the subject with a compound described herein, e.g., a compound of Formula (I) does not exceed a value within the range of 6 to 8.In some embodiments, the HAM-D total score associated with treating a subject with a compound described herein, eg, a compound of Formula (I), is no greater than 7.

[0352] In some embodiments, the method provides a therapeutic effect (e.g., as measured by a decrease in the Clinical Global Impression Improvement scale (CGI)) 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. In some embodiments, the CNS disorder 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 within 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).

[0353] In some embodiments, the method provides a therapeutic effect (e.g., as measured by a reduction in the Montgomery-Asberg Depression Rating Scale (MADRS)) in 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. In some embodiments, the CNS disorder is a depressive disorder, such as a major depressive disorder. In some embodiments, the method for treating a depressive disorder (e.g., a major depressive disorder) provides a therapeutic effect within the second day of the treatment period. In some embodiments, the therapeutic effect is that the MADRS score decreases from baseline at the end of the treatment period (e.g., 14 days after administration).

[0354] The therapeutic effect of major depressive disorder can be measured by the reduction of the Montgomery-Asberg Depression Rating Scale (MADRS) score shown by the experimenter.For example, MADRS scoring can be in 4 days, 3 days, 2 days or 1 day; Or reduce in 96 hours, 84 hours, 72 hours, 60 hours, 48 hours, 24 hours, 20 hours, 16 hours, 12 hours, 10 hours, 8 hours or less.Montgomery-Asberg Depression Rating Scale (MADRS) is a 10-item diagnostic questionnaire (about looking sad, reporting sadness, inner tension, sleep reduction, appetite reduction, difficulty in concentrating, fatigue, powerless feeling, pessimistic thoughts and suicidal thoughts), which psychiatrists use to measure the severity of the depressive episodes of patients with mood disorders.

[0355] In some embodiments, the method provides a therapeutic effect (e.g., as measured by a decrease in the Edinburgh Postnatal Depression Scale (EPDS)) within 4 days, 3 days, 2 days, 1 day; 24 hours, 20 hours, 16 hours, 12 hours, 10 hours, 8 hours, or less. In some embodiments, the therapeutic effect is an improvement as measured by the EPDS.

[0356] In some embodiments, the method provides a therapeutic effect (e.g., as measured by a decrease in the Generalized Anxiety Disorder 7-Item Scale (GAD-7)) in 4 days, 3 days, 2 days, 1 day; 24 hours, 20 hours, 16 hours, 12 hours, 10 hours, 8 hours, or less.

[0357] anxiety disorders

[0358] Provided herein are methods for treating anxiety disorders (e.g., generalized anxiety disorder, panic disorder, obsessive-compulsive disorder, phobias, post-traumatic stress disorder). Anxiety disorders are an umbrella term covering several different forms of abnormal and pathological fear and anxiety. Current psychiatric diagnostic criteria identify various anxiety disorders.

[0359] Generalized anxiety disorder is a common, chronic condition characterized by persistent anxiety and an inability to focus on any one goal or situation. Individuals with generalized anxiety disorder experience nonspecific, persistent fears and worries and become excessively concerned about everyday events. Generalized anxiety disorder is the most common anxiety disorder affecting older adults.

[0360] In panic disorder, an individual suffers from brief episodes of intense fear and apprehension, typically characterized by trembling, shaking, confusion, dizziness, nausea, and difficulty breathing. These panic attacks are defined by the APA as fear or discomfort that appears suddenly and reaches its peak in less than ten minutes, can last for several hours, and can be triggered by stress, fear, or even movement; however, the specific cause is still unclear. In addition to recurrent, unexpected panic attacks, a diagnosis of panic disorder also 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 attacks. Therefore, individuals with panic disorder experience symptoms even outside of specific panic attacks. Often, panic patients notice normal changes in their heartbeat, making them think that something is wrong with their heart or that they are about to suffer another panic attack. In some cases, a heightened sense of bodily functions (hypervigilance) occurs during a panic attack, with any perceived physiological changes interpreted as potentially life-threatening illness (i.e., extreme hypochondriasis).

[0361] Obsessive-compulsive disorder (OCD) is a type of anxiety disorder characterized by repetitive obsessions (distressing, persistent, and intrusive thoughts or images) and compulsions (strong urges to perform specific actions or rituals). OCD thought patterns can be compared to superstitions, to the extent that they link beliefs to causal relationships that do not actually exist. Often, this process is completely illogical; for example, the compulsion to walk in a certain pattern may serve to alleviate obsessions about impending harm. And in many cases, the compulsions are completely unexplained, simply a stress-triggered urge to complete a ritual. In rare cases, people with OCD experience only obsessions without overt compulsions; rarely, only compulsions.

[0362] The single largest category of anxiety disorders is phobias, which include all conditions in which fear and anxiety are triggered by a specific stimulus or situation. Sufferers typically anticipate a terrifying consequence from encountering the object of their fear, which can be anything from an animal to a body fluid.

[0363] Post-traumatic stress disorder, or PTSD, is an anxiety disorder resulting from a traumatic experience. Post-traumatic stress can be caused by extreme situations, such as combat, rape, hostage situations, or even serious accidents. It can also be caused by long-term (chronic) exposure to severe stressors, such as soldiers who have experienced individual combat but cannot cope with continuous combat. Common symptoms include flashbacks, avoidance behaviors, and depression.

[0364] Women's health conditions

[0365] Provided herein are methods for treating conditions or illnesses related to women's health, including, but not limited to, gynecological health and illnesses (e.g., premenstrual syndrome (PMS), premenstrual dysphoric disorder (PMDD)), pregnancy problems (e.g., miscarriage, abortion), infertility and related conditions (e.g., polycystic ovary syndrome (PCOS)), other conditions and illnesses, and women's overall health and wellness-related issues (e.g., menopause).

[0366] Gynecological health and conditions affecting women include menstruation and menstrual irregularities; urinary tract health, including urinary incontinence and pelvic floor disorders; and conditions such as bacterial vaginosis, vaginitis, uterine fibroids, and vulvodynia.

[0367] Premenstrual syndrome (PMS) refers to the physical and emotional symptoms that occur one to two weeks before a woman's period. Symptoms vary but can include bleeding, mood swings, breast tenderness, food cravings, fatigue, irritability, acne, and depression.

[0368] Premenstrual dysphoric disorder (PMDD) is a severe form of PMS. The symptoms of PMDD are similar to those of PMS but are more severe and can interfere with work, social activities, and relationships. Symptoms of PMDD include mood swings, depressed mood or feelings of hopelessness, overt anger, increased conflict in relationships, tension and anxiety, irritability, decreased interest in usual activities, difficulty concentrating, fatigue, changes in appetite, feelings of being out of control or overwhelmed, sleep problems, and physical complaints (for example, bloating, breast tenderness, swelling, headaches, and joint or muscle pain).

[0369] Pregnancy issues include preconception and antenatal care, pregnancy loss (miscarriage and stillbirth), preterm labor and premature birth, sudden infant death syndrome (SIDS), breastfeeding, and birth defects.

[0370] A miscarriage is a pregnancy that ends on its own during the first 20 weeks of gestation.

[0371] Abortion is the intentional termination of pregnancy and can be performed during the first 28 weeks of pregnancy.

[0372] Infertility and related conditions include uterine fibroids, polycystic ovary syndrome, endometriosis, and primary ovarian insufficiency.

[0373] Polycystic ovary syndrome (PCOS) refers to an endocrine disorder that affects women of reproductive age. PCOS is a group of symptoms caused by elevated levels of male hormones in a woman's body. Most women with PCOS develop numerous small cysts on their ovaries. Symptoms of PCOS include irregular or absent menstrual periods, heavy menstrual bleeding, excess body and facial hair, acne, pelvic pain, difficulty conceiving, and blotchy, rough, darkened, and often pliable skin. PCOS can be associated with conditions including type 2 diabetes, obesity, obstructive sleep apnea, heart disease, mood disorders, and endometrial cancer.

[0374] Other conditions and disorders that affect only females include Turner syndrome, Rett syndrome, and ovarian and cervical cancer.

[0375] Issues related to women's overall health and wellness include violence against women, women with disabilities and their unique challenges, osteoporosis and bone health, and menopause.

[0376] Menopause refers to the 12 months after a woman's last menstrual period and marks the end of the menstrual cycle. Menopause usually occurs in women in their 40s or 50s. The physical symptoms (such as hot flashes) and emotional symptoms of menopause can disrupt sleep, reduce energy or trigger anxiety or feelings of sadness or loss. Menopause includes natural menopause and surgical menopause, which is a type of menopause induced by events such as surgery (e.g., hysterectomy, oophorectomy; cancer). Menopause can occur when the ovaries are severely damaged by, for example, radiation, chemotherapy or other drug treatments.

[0377] epilepsy

[0378] The compounds of formula (I) or pharmaceutically acceptable salts, or pharmaceutically acceptable compositions thereof, can be used in the methods described herein, for example, for treating a condition described herein, such as epilepsy, status epilepticus, or epileptic seizures.

[0379] Epilepsy is a brain disorder characterized by repetitive seizures over time. Types of epilepsy may include, but are not limited to, generalized epilepsy, such as childhood absence epilepsy, juvenile myoclonic epilepsy, grand mal epilepsy on awakening, West syndrome, and Lennox-Gastaut syndrome; and partial epilepsy, such as temporal lobe epilepsy, frontal lobe epilepsy, and benign focal epilepsy in children.

[0380] Epilepsy

[0381] The compounds and methods described herein can be used to treat or prevent epilepsy. Epilepsy is a gradual process in which the normal brain produces epilepsy (a chronic condition in which seizures occur). Epilepsy is caused by neuronal damage that is facilitated by an initial injury (e.g., status epilepticus).

[0382] Status epilepticus (SE)

[0383] Status epilepticus (SE) may include, for example, convulsive status epilepticus, such as early status epilepticus, established status epilepticus, refractory status epilepticus, and super-refractory status epilepticus; non-convulsive status epilepticus, such as generalized status epilepticus, complex partial status epilepticus; generalized periodic epileptiform discharges; and periodic lateralized epileptic discharges. Convulsive status epilepticus is characterized by the presence of convulsive status epilepticus attacks and may include early status epilepticus, established status epilepticus, refractory status epilepticus, and super-refractory status epilepticus. Early status epilepticus is treated with first-line therapy. Established status epilepticus is characterized by status epilepticus attacks that persist despite treatment with first-line therapy and the administration of second-line therapy. Refractory status epilepticus is characterized by status epilepticus attacks that persist despite treatment with first-line therapy and second-line therapy and typically the administration of general anesthetics. Super-refractory status epilepticus is characterized by status epilepticus attacks that persist despite treatment with first-line therapy, second-line therapy, and general anesthetics for 24 hours or longer.

[0384] Non-convulsive status epilepticus may include, for example, focal non-convulsive status epilepticus, such as complex partial non-convulsive status epilepticus, simple partial non-convulsive status epilepticus, subtle non-convulsive status epilepticus; generalized non-convulsive status epilepticus, such as late-onset absence non-convulsive status epilepticus, atypical absence non-convulsive status epilepticus, or typical absence non-convulsive status epilepticus.

[0385] A compound of formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable composition thereof, can also be administered as a prophylactic agent to subjects with CNS disorders (e.g., traumatic brain injury; status epilepticus, such as convulsive status epilepticus, such as early status epilepticus, established status epilepticus, refractory status epilepticus, super-refractory status epilepticus; non-convulsive status epilepticus, such as generalized status epilepticus, complex partial status epilepticus; generalized periodic epileptiform discharges; and periodic lateralized epileptiform discharges) prior to the onset of an epileptic seizure.

[0386] epileptic seizures

[0387] A seizure is a physiological finding or change in behavior that occurs after an episode of abnormal electrical activity in the brain. The term "seizure" is often used interchangeably with "convulsion." A convulsion is a rapid, uncontrolled shaking of a person's body. During a convulsion, a person's muscles repeatedly contract and relax.

[0388] Based on the type of behavior and brain activity, epileptic seizures are divided into two broad categories: generalized and partial (also called localized or focal). Categorizing seizure types helps doctors diagnose whether a patient has epilepsy.

[0389] Generalized seizures are caused by electrical impulses throughout the brain, while partial seizures are caused (at least initially) by electrical impulses in a relatively small part of the brain. The part of the brain where the seizure occurs is sometimes called the focus.

[0390] There are six types of generalized epileptic seizures. The most common and severe, and therefore the best known, is a generalized convulsion, also known as a grand mal seizure. In this type of seizure, the patient loses consciousness and usually collapses. Loss of consciousness is followed by generalized stiffness (known as the "tonic" phase of the seizure) for 30 to 60 seconds, followed by violent jerking (the "clonic" phase) for 30 to 60 seconds, after which the patient enters a deep sleep (the "postictal" or post-ictal phase). During a grand mal seizure, injuries and accidents may occur, such as tongue biting and urinary incontinence.

[0391] Absence seizures cause a brief loss of consciousness (only a few seconds) and are almost asymptomatic. The patient (most often a child) typically stops moving and becomes stunned. These seizures start and end suddenly and may occur several times a day. The patient is usually unaware that they are having a seizure, but they may be aware that "time is slipping away."

[0392] Myoclonic seizures consist of sporadic muscle twitches, usually on both sides of the body. People sometimes describe the muscle twitches as brief electric shocks. When severe, these seizures may cause the person to drop or throw objects unintentionally.

[0393] Clonic seizures are repetitive rhythmic muscle twitches that involve both sides of the body at the same time.

[0394] Tonic seizures are characterized by muscle stiffness.

[0395] Atonic seizures consist of a sudden and generalized loss of muscle tone, particularly in the arms and legs, often resulting in a fall.

[0396] The seizures described herein may include epileptic seizures; acute repetitive seizures; clustered seizures; continuous seizures; uninterrupted seizures; prolonged seizures; recurrent seizures; status epilepticus, such as refractory convulsive status epilepticus, nonconvulsive status epilepticus; refractory seizures; myoclonic seizures; tonic seizures; tonic-clonic seizures; simple partial seizures; complex partial seizures; secondarily generalized seizures; atypical absence seizures; absence seizures; atonic seizures; benign In some embodiments, the seizure is a generalized seizure associated with Dravet syndrome, Leigh-Chiari syndrome, tuberous sclerosis complex, Rett syndrome, or PCDH19 epilepsy.

[0397] Movement disorders

[0398] Also described herein are methods for treating movement disorders. As used herein, "movement disorders" refers to a variety of diseases and conditions associated with hyperkinetic movement disorders and related abnormalities in 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, tics and Tourette syndrome, restless legs syndrome, stiff-person syndrome, and gait disorders.

[0399] Tremor

[0400] The methods described herein can be used to treat tremor, for example, compounds of formula (I) can be used to treat cerebellar or intention tremor, dystonic tremor, essential tremor, orthostatic tremor, Parkinson's tremor, physiologic tremor, psychogenic tremor, or rubrospinal tremor. Tremor includes: hereditary, degenerative, and idiopathic conditions, such as Wilson's disease, Parkinson's disease, and essential tremor, respectively; metabolic diseases (e.g., thyroid-parathyroid disease, liver disease, and hypoglycemia); peripheral neuropathy (associated with Charcot-Marie-Tooth, Roussy-Levy, diabetes, complex regional pain syndrome); toxins (nicotine, mercury, lead, CO, manganese, arsenic, toluene); drug-induced (narcolepsy, tricyclics, lithium, cocaine, alcohol, epinephrine, bronchodilators, theophylline, caffeine, steroids, valproate, amiodarone, thyroid hormones, vincristine); and psychogenic disorders. Clinical tremor can be categorized as physiologic tremor, augmented physiologic tremor, essential tremor syndrome (including classic essential tremor, primary orthostatic tremor, and task-specific and position-specific tremors), dystonic tremor, parkinsonian tremor, cerebellar tremor, Hodgkin's tremor (ie, rubrospinal tremor), palatal tremor, neuropathic tremor, toxin- or drug-induced tremor, and psychogenic tremor.

[0401] Tremors are involuntary, sometimes rhythmic, muscle contractions and relaxations that may involve oscillations or twitching of one or more body parts (eg, hands, arms, eyes, face, head, vocal folds, trunk, legs).

[0402] Cerebellar tremor, or intention tremor, is a slow, widespread tremor of the extremities that occurs after a purposeful movement. Cerebellar tremor is caused by lesions or damage to the cerebellum due to, for example, tumors, stroke, or disease (e.g., multiple sclerosis, a hereditary degenerative disorder).

[0403] Dystonic tremors occur in individuals affected by dystonia (a movement disorder in which sustained, involuntary muscle contractions cause twisting and repetitive movements and / or pain and abnormal postures or positions). Dystonic tremors can affect any muscle in the body. Dystonic tremors occur irregularly and are often relieved by complete rest.

[0404] Essential tremor, or benign essential tremor, is the most common type of tremor. Essential tremor can be mild and in some cases non-progressive, or 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 affected. The frequency of tremors may decrease with age, but their severity may increase. High emotions, stress, fever, exhaustion, or low blood sugar can trigger tremors and / or increase their severity. Symptoms generally develop over time and are noticeable and persistent after an episode.

[0405] Orthostatic tremor is characterized by rapid (e.g., greater than 12 Hz) rhythmic muscle contractions in the legs and trunk that occur soon after standing. The thighs and legs may feel cramped, and the patient may shake uncontrollably when asked to stand in one place. Orthostatic tremor can occur in patients with essential tremor.

[0406] Parkinsonian tremors are caused by damage to structures in the brain that control movement. Parkinsonian tremors are often a precursor to Parkinson's disease and typically manifest as "pill-rolling" movements of the hands, but can also affect the jaw, lips, legs, and trunk. Onset of Parkinsonian tremors usually begins after age 60. The movements begin in one limb or side of the body and can progress to include the other side.

[0407] Physiological tremors may occur in normal individuals and have no clinical significance. They are seen in all voluntary muscle groups. Physiological tremors can be caused by certain medications, alcohol withdrawal, or medical conditions including an overactive thyroid and hypoglycemia. Tremors typically have a frequency of about 10 Hz.

[0408] Psychogenic or hysterical tremor can occur at rest or during postural or dynamic movements. Patients with psychogenic tremor may have conversion disorder or another psychiatric disorder.

[0409] Rubrostral tremor is characterized by a coarse, slow tremor that can be present at rest, during posture, and during deliberate effort. The tremor is associated with disorders affecting the red nucleus in the midbrain, typically with abnormal stroke.

[0410] Parkinson's disease affects the dopamine-producing nerve cells in the brain. Symptoms include muscle stiffness, tremors, and changes in speech and gait. Parkinson's disease is characterized by tremors, bradykinesia, rigidity, and postural instability. Parkinson's disease shares symptoms found in Parkinson's disease, but it is a syndrome rather than a progressive neurodegenerative disease.

[0411] Dystonia is a movement disorder characterized by sustained or intermittent muscle contractions that cause abnormal (often repetitive) movements or postures. Dystonic movements can be patterned, with twisting movements, and may be tremor-like. Dystonia is often initiated or exacerbated by voluntary movements and is associated with overflow muscle activation.

[0412] Chorea is a neurological disorder characterized by jerky, involuntary muscle movements that typically affect the shoulders, hips, and face. Huntington's disease is a genetic disorder that causes nerve cells in the brain to gradually weaken. Symptoms include uncontrolled movements, clumsiness, and balance problems. Huntington's disease can also affect walking, speaking, and swallowing.

[0413] Ataxia is a loss of complete control over limb movements and can affect the fingers, hands, arms, legs, body, speech, and eye movements.

[0414] Myoclonus and startle are responses to sudden and unexpected stimuli, which may be auditory, tactile, visual, or vestibular.

[0415] Tics are involuntary movements that usually have a sudden onset, are brief, repetitive, but non-rhythmic, often mimicking normal behavior and often occurring in the context of normal activity. Tics can be classified as motor tics, which are associated with movement, or vocal tics, which are associated with sound. Tics can be simple or complex in character. For example, simple motor tics involve only a few muscles confined to a specific part of the body. Tourette syndrome is an inherited neuropsychiatric disorder that occurs in children and is characterized by multiple motor tics and at least one vocal tic.

[0416] Restless legs syndrome is a neurological sensorimotor disorder characterized by an irresistible urge to move the legs while at rest.

[0417] Stiff-person syndrome is a progressive movement disorder characterized by involuntary painful spasms and muscle stiffness, typically involving the lower back and legs. A stiff-legged gait with aggravated lumbar hyperprotrusion is typically produced. Characteristic abnormalities on EMG recordings with continuous motor unit activity of the paraxial muscles of the spine are typically observed. Variants include "stiff limb syndrome," which produces focal stiffness that typically affects the distal legs and feet.

[0418] Gait disorders are abnormalities in the pattern or style of walking that result from neuromuscular, arthritic, or other physical changes. Gaits are classified based on the system responsible for the abnormal movement and include hemiparetic gait, bilateral paretic gait, neuropathic gait, myopathic gait, parkinsonian gait, choreiform gait, ataxia gait, and sensory gait.

[0419] Anesthesia / sedation

[0420] Anesthesia is a pharmacologically induced and reversible state of amnesia, analgesia, loss of responsiveness, loss of skeletal muscle reflexes, reduced stress responses, or all of these simultaneously. These effects can be achieved by a single drug that alone provides the right combination of effects, or occasionally by a combination of drugs (e.g., hypnotics, sedatives, anesthetics, analgesics) to achieve a very specific combination of results. Anesthesia allows patients to undergo surgery and other procedures without the pain and suffering they would otherwise experience.

[0421] Sedation is the reduction of irritability or agitation by the administration of pharmacological agents, usually to facilitate medical or diagnostic procedures.

[0422] Sedation and analgesia encompass a continuum of states of consciousness ranging from minimal sedation (sedatives) to general anesthesia.

[0423] Minimal sedation is also known as tranquilizer. It is a drug-induced state during which patients respond normally to verbal commands. Cognitive function and coordination may be impaired. Ventilation and cardiovascular function are usually unaffected.

[0424] Moderate sedation / analgesia (conscious sedation) is a drug-induced suppression of consciousness during which the patient responds purposefully to verbal commands, alone or with light tactile stimulation. Interventions to maintain airway patency are usually not required. Spontaneous ventilation is usually adequate. Cardiovascular function is usually maintained.

[0425] Deep sedation / analgesia is a drug-induced depression of consciousness during which the patient cannot be easily aroused but responds purposefully to repeated or painful stimuli (reflex withdrawal of non-painful stimuli). Independent ventilatory function may be impaired and the patient may require assistance to maintain a patent airway. Spontaneous ventilation may be inadequate. Cardiovascular function is usually preserved.

[0426] General anesthesia is a drug-induced loss of consciousness during which the patient cannot be aroused, even with 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 required due to low spontaneous ventilation or drug-induced neuromuscular suppression. Cardiovascular function may be impaired.

[0427] Sedation in the intensive care unit (ICU) allows the patient to suppress their environmental awareness and reduce their response to external stimuli. It can be effective in the care of critically ill patients and covers a wide range of symptom control that will vary with the individual patient and their disease course. In critical care, deep sedation has been used to facilitate endotracheal tube tolerance and ventilator synchronization, usually using neuromuscular blocking agents.

[0428] In some embodiments, sedation is induced and maintained (e.g., long-term sedation, sustained sedation) in the ICU for a longer period of time (e.g., 1 day, 2 days, 3 days, 5 days, 1 week, 2 weeks, 3 weeks, 1 month, 2 months). Long-term sedatives can have a long duration of action. Sedatives can have a shorter elimination half-life in the ICU.

[0429] Procedural sedation and analgesia, also known as conscious sedation, is the administration of sedatives or dissociative agents with or without analgesics to induce techniques that allow the subject to undergo a difficult procedure while maintaining cardiopulmonary function.

[0430] Example

[0431] In order to more fully understand the invention described herein, the following examples are set forth.The synthetic and biological examples described in this application are provided to illustrate the compounds, pharmaceutical compositions and methods provided herein and should not be construed as limiting the scope thereof in any way.

[0432] Materials and methods

[0433] The compounds provided herein can be prepared using the following general methods and procedures from readily available starting materials. It should be understood that, when given typical or preferred process conditions (i.e., reaction temperature, time, molar ratio of reactants, solvent, pressure, etc.), other process conditions may also be used unless otherwise indicated. Optimal reaction conditions may vary with the specific reactants or solvents used, but such conditions may be determined by conventional optimization procedures by those skilled in the art.

[0434] In addition, as will be apparent to those skilled in the art, conventional protecting groups may be needed to prevent certain functional groups from experiencing unwanted reactions. The selection of protecting groups suitable for specific functional groups and the conditions for protecting and deprotecting is well known in the art. For example, many protecting groups and their introduction and removal are described in TW Greene and PGM Wuts, Protecting Groups in Organic Synthesis, second edition, Wiley, New York, 1991 and the references cited therein.

[0435] The compounds provided herein can be separated and purified by known standard procedures. Such procedures include, but are not limited to, recrystallization, column chromatography, HPLC, or supercritical fluid chromatography (SFC). The following schemes are presented for the details of preparing the representative oxysterols listed herein. The compounds provided herein can be prepared by one 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 / diastereomers provided herein include, but are not limited to AD-10, OB, OB-H, OD, OD-H, OF OG, OJ and OK.

[0436] This article reports 1 H-NMR (e.g., for the region between δ (ppm) from about 0.5 to about 4 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.

[0437] Exemplary general method for analytical HPLC: Mobile phase: A: water (10 mM NH4HCO3), B: acetonitrile Gradient: 5%-95% B in 1.6 or 2 min; Flow rate: 1.8 or 2 mL / min; Column: XBridge C18, 4.6*50 mm, 3.5 μm at 45°C.

[0438] Exemplary general method for preparative HPLC: column Waters Xbridge 150*25, 5u conditions water (10 mM NH4HCO3)-ACN, start B 85, end B 100, gradient time (min) 6.5, 100% B hold time (min) 1, flow rate (ml / min) 25, injection 4).

[0439] Exemplary general method for SFC: Column: DAICEL CHIRALPAK AD (250 mm*50 mm, 10 μm; Condition: 0.1% NH 3 H 2 O ETOH; Start B: 25%, End B: 25%; Flow rate (ml / min): 200)

[0440] Exemplary general method for LCMS / LC: ELSD: 30-90 AB_2 min. Lcm. (Mobile phase: 1.5 mL / 4 L TFA / water (solvent A) and 0.75 mL / 4 L TFA / acetonitrile (solvent B), using an elution gradient of 30%-90% (solvent B) over 0.9 min at a flow rate of 1.2 mL / min and holding at 90% for 0.6 min; Column: Xtimate C18 2.1*30 mm, 3 μm; Wavelength: UV 220 nm; Column temperature: 50° C.; MS ionization: ESI; Detector: PDA & ELSD)

[0441] Abbreviations: PE: petroleum ether; EtOAc: ethyl acetate; THF: tetrahydrofuran; PCC: pyridinium chlorochromate; TLC: thin layer chromatography; PCC: pyridinium chlorochromate; t-BuOK: potassium tert-butoxide; 9-BBN: 9-borabicyclo[3.3.1]nonane; Pd(t-Bu3P)2: bis(tri-tert-butylphosphine)palladium(0); AcCl: acetyl chloride; i-PrMgCl: isopropylmagnesium chloride; TBSCl: tert-butyl(chloro)dimethylsilane; (i-PrO)4Ti: tetraisopropylsilane Titanium propoxide; BHT: 2,6-di-tert-butyl-4-methylphenoxide; Me: methyl; i-Pr: isopropyl; t-Bu: tert-butyl; Ph: phenyl; Et: ethyl; Bz: benzoyl; BzCl: benzoyl chloride; CsF: cesium fluoride; DCC: dicyclohexylcarbodiimide; DCM: dichloromethane; DMF: N,N-dimethylformamide; DMAP: 4-dimethylaminopyridine; DMSO: dimethyl sulfoxide; DMP: Dess-Martin periodinane; EtMgBr: ethylmagnesium bromide; EtOAc: ethyl acetate; TEA: triethylamine; AlaOH: alanine; Boc: tert-butoxycarbonyl. Py: pyridine; TBAF: tetra-n-butylammonium fluoride; THF: tetrahydrofuran; TBS: tert-butyldimethylsilyl; TMS: trimethylsilyl; TMSCF3: (trifluoromethyl)trimethylsilane; Ts: p-toluenesulfonyl; Bu: butyl; Ti(OiPr)4: tetraisopropoxytitanium; LAH: lithium aluminum hydride; LDA: lithium diisopropylamide; LiOH.H2O: lithium hydroxide hydrate; MAD: bis(2,6-di- tert-Butyl-4-methylphenoxide) methylaluminum; MeCN: acetonitrile; NBS: N-bromosuccinimide; Na2SO4: sodium sulfate; Na2S2O3: sodium thiosulfate; MeCN: acetonitrile; MeOH: methanol; Boc: tert-butoxycarbonyl; MTBE: methyl tert-butyl ether; K-selectride: potassium tri(sec-butyl)borohydride; 9-BBN dimer: 9-borabicyclo(3.3.1)nonane (dimer).

[0442] Example 1: Synthesis of 14(3R,5R,8S,9S,10R,13S,14S,17S)-10-cyclopropyl-3-hydroxy-3,13-dimethylhexahydro-1H-cyclopenta[a]phenanthrene-17-yl)ethan-1-one (A9)

[0443]

[0444] Synthesis A2

[0445]

[0446] At 15 DEG C, to MePPh Br (145g, 408mmol) suspension in THF (300mL) add t-BuOK (45.7g, 408mmol).After stirring at 45 DEG C for 0.5 hour, at 45 DEG C, add A1 (CAS#5696-44-6) (80g, 204mmol) solution in THF (200mL) and at 45 DEG C, stir reaction mixture 1h.Dilute the mixture with PE (300mL), filter subsequently.Concentrate filtrate, obtain oily matter (200g).After stirring product 16 hours with PE (1L), filter solid and concentrate filtrate, obtain product A2 as oily matter, use it directly in next step. 1 H NMR (400 MHz, CDCl3) δ H 6.30 (dd, J=11.2, 17.6Hz, 1H), 5.15-4.96 (m, 2H), 3.94-3.81 (m, 8H), 2.02-1.73 (m, 7H), 1.58-1.35 (m, 13H), 1.22-1.14 (m, 2H), 0.81 (s, 3H).

[0447] Synthesis A3

[0448]

[0449] To a solution of EtZn (30.5 mL, 1 M in hexane) in DCM (50 mL) was added CFCOOH (3.47 g, 30.4 mmol) (5 mL in DCM) dropwise under N2 atmosphere over a 1 h period, followed by the addition of CHI (8.16 g, 30.5 mmol) (5 mL in DCM) dropwise at 0 ° C over a 15 min period. After the addition, A2 (4 g, 10.2 mmol) (5 mL in DCM) was added to the reaction mixture and stirred at 0 ° C for 3 hours, then at 25 ° C for 16 hours. The reaction was quenched by adding saturated NH4Cl aqueous solution (80 mL) and the aqueous phase was extracted with DCM (3x60 mL). The combined organic phases were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated to give A3 (4.5 g) as an oil. (Based on H-NMR, approximately 40% starting material remained.)

[0450] Synthesis of A4 and A5

[0451]

[0452] To a solution of A3 (4.5 g) in THF (25 mL), hydrochloric acid (12 mL, 2 M aqueous solution) was added and the reaction mixture was stirred at 25 ° C for 16 hours. Saturated NaHCO was added to the reaction mixture (50 mL) to a pH of approximately 8, and extracted with EtOAc (2x80 mL). The combined organic phases were washed with brine (50 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated. The residue was purified by flash column (0 to 10% EtOAc / PE) to obtain A5 (1.1 g). Purified by SFC (column: DAICEL CHIRALPAK AD (250 mm * 50 mm, 10 μm; condition: 0.1% NH 3 H 2 O ETOH; start B: 25%, end B: 25%; flow rate (ml / min): 200) to obtain A4 (550 mg, 29.1%) and A5 (420 mg) as an oil.

[0453] A4: 1 H NMR (400 MHz, CDCl3) δ H 2.73-2.61 (m, 1H), 2.47 (dd, J=8.8, 19.2Hz, 1H), 2.35-2.22 (m, 1H), 2.17-1.85 (m, 8H), 1.77-1.61 (m, 4H), 1.56-1.50 (m, 1H), 1 .47-1.39 (m, 1H), 1.36-1.22 (m, 5H), 0.92 (s, 3H), 0.90-0.84 (m, 1H), 0.54-0.40 (m, 2H), 0.34-0.25 (m, 1H), 0.12-0.04 (m, 1H).

[0454] Synthetic A6

[0455]

[0456] To a solution of BHT (2.22 g, 10.08 mmol) in toluene (6 mL) was added dropwise AlMe 3 (2.6 mL, 2 M in toluene) at 0 ° C under nitrogen. The mixture was stirred at 25 ° C for 1 h. The reaction mixture was used directly as a MAD solution for the next step without monitoring and further purification. A solution of A4 (530 mg, 1.68 mmol) in DCM (5 mL) was added dropwise to a MAD (5.04 mmol) solution at -70 ° C. After stirring at -70 ° C for 1 h under N 2 , MeMgBr (1.7 mL, 5.1 mmol, 3 M in ether) was added dropwise at -70 ° C. The resulting solution was stirred for another 3 hours at -70 ° C. The reaction mixture was poured into a saturated aqueous solution of citric acid (100 mL) below 10 ° C and extracted with EtOAc (2x80 mL). The combined organic layer was dried over Na 2 SO 4 , filtered and concentrated. The residue was purified by flash column (0 to 20% EtOAc / PE) to give A6 (480 mg, 86.4%) as a solid.

[0457] 1 H NMR (400 MHz, CDCl3) δ H 2.44 (dd, J=8.2, 19.2Hz, 1H), 2.14-1.88 (m, 4H), 1.87-1.76 (m, 2H), 1.64-1.60 (m, 1H), 1.58-1.49 (m, 5H), 1.48-1 .33(m, 4H), 1.31-1.21(m, 6H), 1.19(s, 3H), 0.88(s, 3H), 0.56-0.33(m, 3H), 0.30-0.20(m, 1H), 0.10-0.00(m, 1H).

[0458] LCMS Rt = 0.980 min / 2 min chromatography, 30-90AB_2 min. Lcm. (mobile phase: 1.5 mL / 4 L TFA / water (solvent A) and 0.75 mL / 4 L TFA / acetonitrile (solvent B), elution gradient 30%-90% (solvent B) over 0.9 min at a flow rate of 1.2 mL / min and hold at 90% for 0.6 min; column: Xtimate C18 2.1*30 mm, 3 μm; wavelength: UV 220 nm; column temperature: 50°C; MS ionization: ESI; detector: PDA & ELSD), LC-ELSD purity 99%; C 22 H 33 O[M-H2O+H] + MS ESI calcd. 313.2, found 313.2.

[0459] Synthetic A7

[0460]

[0461] To a suspension of EtPPhBr (1.52 g, 4.11 mmol) in THF (10 mL) was added t-BuOK (461 mg, 4.11 mmol) at 25 ° C under N2. The resulting mixture was stirred at 50 ° C for 30 min. A6 (455 mg, 1.37 mmol) was added below 40 ° C. The reaction mixture was stirred at 40 ° C for 3 hours to obtain a suspension. The reaction mixture was quenched with saturated NH4Cl aqueous solution (150 mL) at 25 ° C. The aqueous layer was extracted with EtOAc (2x80 mL). The combined organic phase was concentrated. The residue was purified by flash column (0 to 10% EtOAc / PE) to obtain A7 (320 mg, 68.2%) as an oil. 1 H NMR (400 MHz, CDCl3) δ H 5.16-5.07(m, 1H), 2.42-2.31(m, 1H), 2.29-2.13(m, 2H), 2.07-1.89(m, 2H), 1.68-1.61(m, 5H), 1.54-1.4 0 (m, 6H), 1.38-1.14 (m, 12H), 0.93-0.79 (m, 4H), 0.53-0.33 (m, 3H), 0.29-0.16 (m, 1H), 0.09-0.04 (m, 1H).

[0462] Synthetic A8

[0463]

[0464] To a solution of A7 (300 mg, 0.88 mmol) in THF (10 mL) was added 9-BBN dimer (427 mg, 1.75 mmol) and stirred at 45 ° C for 14 hours. Ethanol (2 mL) was added to the resulting mixture at 15 ° C, followed by a NaOH aqueous solution (1.75 mL, 5.0 M, 8.75 mmol) at 0 ° C. Hydrogen peroxide (1 mL, 10 M, 10 mmol) was added dropwise at 0 ° C. The reaction mixture was stirred at 78 ° C for 1 hour. The mixture was cooled to 15 ° C. The mixture was added to water (10 mL). Saturated Na2S2O3 saturated aqueous solution (20 mL) was added, and the excess H2O2 was destroyed (not turned blue) by potassium iodide starch paper inspection, and the aqueous phase was extracted with EtOAc (3x40 mL). The combined organic phase was washed with brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by flash column (10 to 35% EtOAc / PE) to give Isomer 1 (150 mg) and Isomer 2 (80 mg) as solids.

[0465] Isomer 1: 1 H NMR (400 MHz, CDCl3) δ H 3.76-3.63(m, 1H), 2.02-1.82(m, 4H), 1.71-1.60(m, 3H), 1.53-1.32(m, 9H), 1.31- 1.09 (m, 15H), 0.67 (s, 3H), 0.52-0.33 (m, 3H), 0.280.19 (m, 1H), 0.08-0.03 (m, 1H).

[0466] Isomer 2: 1 H NMR (400 MHz, CDCl3) δ H 3.79-3.66(m, 1H), 2.07-1.81(m, 5H), 1.71-1.59(m, 4H), 1.50-1.33(m, 6H), 1.32-1 .10 (m, 16H), 0.77 (s, 3H), 0.51-0.33 (m, 3H), 0.27-0.19 (m, 1H), 0.07-0.02 (m, 1H).

[0467] Synthetic A9

[0468]

[0469] To a solution of A8 (80 mg, 0.22 mmol) in DCM (2 mL) was added DMP (188 mg, 0.44 mmol), the reaction mixture was stirred at 25 ° C for 6 hours. The reaction mixture was quenched with saturated NaHCO (80 mL) and saturated NaS O (30 mL) and extracted with DCM (2x50 mL). The organic layer was dried over NaSO, filtered, and concentrated. The residue was purified by flash column (10% to 30% EtOAc / PE) to give A9 as a solid. 1 H NMR (400 MHz, CDCl3) δ H 2.54 (t, J = 8.8 Hz, 1H), 2.28-2.14 (m, 1H), 2.11 (s, 3H), 2.06-1.90 (m, 3H), 1.72-1.57 (m, 5H), 1.53-1.35 (m, 6H), 1.33-1.11 (m, 11H), 0.62 (s, 3H), 0.53-0.35 (m, 3H), 0.28-0.20 (m, 1H), 0.07-0.01 (m, 1H); LC-ELSD purity 99%; C 24 H 37 O[M-H2O+H] +MS ESI calcd. 341.3, found 341.3.

[0470] Example 2: Synthesis of 1-(2-((3R,5R,8S,9S,10R,13S,14S,17S)-10-cyclopropyl-3-hydroxy-3,13-dimethylhexahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-oxoethyl)-1H-pyrazole-4-carbonitrile (A11)

[0471]

[0472] Synthetic A10

[0473]

[0474] To a solution of A9 (60 mg, 0.17 mmol) in MeOH (2 ml) was added HBr (6.75 mg, 0.03 mmol, 40% in water) and Br (32 mg, 0.2 mmol) at 25 ° C. The mixture was stirred at 25 ° C for 2 hours. The mixture was quenched with saturated NaHCO aqueous solution (10 mL), treated with water (30 mL), and extracted with EtOAc (2 x 50 mL). The combined organic phases were washed with brine (30 mL), dried over anhydrous Na SO , filtered, and concentrated to give A10 (65 mg) as an oil, which was used directly in the next step.

[0475] Synthetic A11

[0476]

[0477] To a solution of A10 (65 mg, 0.15 mmol) in acetone (2 mL) was added KCO (61.5 mg, 0.45 mmol) and 1H-pyrazole-4-carbonitrile (20.7 mg, 0.22 mmol), the reaction mixture was stirred at 25 ° C for 14 hours. Water (20 mL) was added to the mixture and extracted with EtOAc (2x30 mL). The organic layer was separated, dried over NaSO, filtered and concentrated. The residue was purified by flash column (20% to 50% EtOAc / PE) to obtain A11 (15 mg, 22.4%) as a solid. 1 H NMR (400 MHz, CDCl3) δ H7.85 (s, 1H), 7.81 (s, 1H), 5.06-4.85 (m, 2H), 2.61 (t, J=8.8Hz, 1H), 2.27-2.15 (m, 1H), 2.09-1.89 (m, 3H), 1.81-1.63 (m, 4H), 1.54-1.3 7 (m, 5H), 1.32-1.18 (m, 12H), 0.92-0.78 (m, 1H), 0.68 (s, 3H), 0.54-0.35 (m, 3H), 0.29-0.21 (m, 1H), 0.07-0.01 (m, 1H); LC-ELSD purity 99%; C 28 H 39 N3O2Na[M+Na] + MS ESI calcd. 472.3, found 472.3.

[0478] Example 4: Synthesis of 1-((3R, 5R, 8S, 9S, 10R, 13S, 14S, 17S)-10.cyclopropyl-3-(ethoxymethyl)-3-hydroxy-13-methylhexahydro-1H-cyclopenta[a]phenanthren-17-yl)ethan-1-one, 4.12

[0479]

[0480] Synthesis 4.2

[0481] Under N2, Pd-C (wet, 10%, 5g) is added to a solution of 4.1 (50g, 165mmol) in THF (500mL). The suspension is degassed under vacuum and purged three times with H2. At 25°C under H2 (15psi), the mixture is stirred for 16 hours to obtain a suspension. The reaction mixture is filtered through a celite pad and washed with THF (3x200mL). The filtrate is concentrated to obtain 4.2 (40g) in a solid state. The solid is blended with 5 other batches (5*50g 4.1) in acetone (150mL), and stirred for 1h at 25°C. The mixture is filtered to obtain 4.2 (180g) in a solid state.

[0482] 1 H NMR (400 MHz, CDCl3) δ H 3.94 (dd, J=4.8, 10.8Hz, 1H), 3.67 (dd, J=5.6, 10.8Hz, 1H), 2.64 (t, J=14.4Hz, 1H), 2.45 (dd , J=8.8, 19.6Hz, 1H), 2.39-2.23(m, 3H), 2.12-1.80(m, 8H), 1.69-1.19(m, 10H), 0.86(s, 3H)

[0483] Synthesis 4.3

[0484] To a solution of 4.2 (180 g, 591 mmol) in toluene (1500 mL) was added pyridinium hydrochloride (13.5 g, 118 mmol) and ethane-1,2-diol (183 g, 2955 mmol). The mixture was stirred at 140 ° C for 48 hours. The mixture was cooled to 25 ° C. Water (1000 mL) was then added to the mixture, followed by extraction with EtOAc (3x1000 mL). The combined organic phases were washed with brine (2x1000 mL), dried over anhydrous Na2SO4, filtered and concentrated to give 4.3 (180 g, 460 mmol) as an oil.

[0485] 1 H NMR (400 MHz, CDCl3) δ H 3.95-3.79(m, 10H), 2.05-1.92(m, 3H), 1.78-1.64(m, 5H), 1.56-1.36(m, 10H), 1.30-1.03(m, 5H), 0.82(s, 3H)

[0486] Synthesis 4.4

[0487] To a solution of 4.3 (100 g, 254 mmol) in DCM (1000 mL) was added silica gel (82 g, 381 mmol) in portions at 25° C. The mixture was stirred at 25° C. for 1 h. The mixture was filtered and the filter cake was washed with DCM (3 x 200 mL). The combined filtrates were concentrated to give 4.4 (100 g, 254 mmol) as an oil.

[0488] 1 H NMR (400 MHz, CDCl3) δ H 9.57(s, 1H), 3.96-3.84(m, 8H), 2.26-2.07(m, 2H), 1.84-1.46(m, 20H), 0.91(s, 3H)

[0489] Synthesis 4.5

[0490] At 25 DEG C, PPh is added to the solution of t-BuOK (86.1g, 768mmol) in THF (500mL) MeBr (274g, 768mmol).After stirring 0.5h at 50 DEG C, a solution of 4.4 (100g, 256mmol) in THF (300mL) is added to the reaction mixture at 50 DEG C. After stirring for 12 hours at 50 DEG C, the mixture is poured into water (1000mL) and extracted with EtOAc (2x500mL). The organic phase merged is washed with saturated brine (2x500mL), through anhydrous Na sO dried, filtered and concentrated under vacuum (100g). Solid is ground from MTBE (500mL) at 25 DEG C to obtain 4.5 (90g) as an oil. The oil was triturated again from MTBE (500 mL) at 25 °C to give 4.5 (80 g) as an oil, which was purified by flash column (0 to 10% EtOAc / PE) to give 4.5 (30 g, 38%) as a solid.

[0491] 1 H NMR (400 MHz, CDCl3) δ H 6.30 (dd, J=11.2, 17.6Hz, 1H), 5.13-5.01 (m, 2H), 3.94-3.83 (m, 8H), 2.01-1.76 (m, 6H), 1.54-1.36 (m, 12H), 1.27-1.15 (m, 4H), 0.81 (s, 3H)

[0492] Synthesis 4.6

[0493] At 0 DEG C under N2 atmosphere through 1h time period to Et2Zn (46.2mL, 1M in hexane) in DCM (250mL) solution dropwise add CF3COOH (4.38g, 38.5mmol), then dropwise add CH2I2 (12.3g, 46.2mmol) through 15min time period, then finally add DCM (50mL) solution containing 4.5 (6g, 15.4mmol).Reactant mixture is stirred at 0 DEG C for 1h, then at 25 DEG C, stir for 12 hours.By adding saturated NH4Cl aqueous solution (150mL) come quenching reactant.With DCM (3x100mL) aqueous phase extracted.By merged organic phase salt water (150mL) washing, through anhydrous Na2SO4 drying, filter and concentrate, obtain 4.7 (6.0g, 14.9mmol) as oil, it is used as it is.

[0494] Synthesis 4.7

[0495] To a solution of 4.6 (6.0 g, 14.9 mmol) in THF (50 mL) was added hydrogen chloride (14.9 mL, 29.8 mmol, 2 M). After stirring at 25 ° C for 16 h, the reaction mixture was adjusted to pH = 8 with saturated NaHCO (150 mL) and extracted with EtOAc (3x50 mL). The combined organic phases were washed with brine (2x100 mL), dried over anhydrous Na SO, filtered and concentrated, and then purified by flash column (0 to 30% EtOAc / PE) to give 4.7 (1.8 g, 52%) as a solid.

[0496] 1 H NMR (400 MHz, CDCl3) δ H 2.72-2.62(m, 1H), 2.52-2.22(m, 3H), 2.16-2.06(m, 4H), 2.01-1.67(m, 7H), 1.60- 1.29(m, 8H), 0.92(s, 3H), 0.55-0.36(m, 2H), 0.34-0.25(m, 1H), 0.12-0.02(m, 1H)

[0497] Synthesis 4.8

[0498] To a stirred solution of trimethylsulfonium iodide (2.42 g, 11.9 mmol) in DMSO (10 mL) and THF (5 mL) was added NaH (475 mg, 11.9 mmol, 60% in oil) at 0 ° C under N2 for 1.0 h. A solution of 4.7 (2.5 g, 7.9 mmol) in DMSO (5 mL) was added to the mixture at 0 ° C. After stirring for 6 h at 25 ° C, the reactant was diluted with water (50 mL) and extracted with EtOAc (3x20 mL). The combined organic phases were washed with water (2x50 mL), brine (2x50 mL), dried over anhydrous Na2SO4, filtered and concentrated under vacuum to give 4.8 (2.5 g, 7.6 mmol) as an oil, which was used as is.

[0499] Synthesis of 4.9a and 4.9b

[0500] To anhydrous EtOH (10 mL) was added Na (874 mg, 38.0 mmol) in three portions at 25 ° C. After stirring at 75 ° C for 1 h, anhydrous EtOH (20 mL) containing 4.8 (2.5 g, 7.6 mmol) was added to the sodium ethoxide solution at 75 ° C. After stirring at 75 ° C for 4 h, the reactant was diluted with water (50 mL) and then concentrated to remove most of the solvent. The mixture was extracted with EtOAc (2x30 mL). The combined organic phases were washed with saturated brine (2x50 mL), dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by flash column (0 to 30% EtOAc / PE) to give 4.9a (950 mg, de%>99 (via 1 H NMR, R f =0.3, PE / EtOAc=3 / 1) and 4.9b (750 mg, de%>99 (via 1 H NMR), R f =0.55, PE / EtOAc=3 / 1), both of which were oily.

[0501] 4.9a (50 mg) was further purified by preparative HPLC (column: Waters Xbridge Prep OBD C18 150*30 5μ, gradient: 50%-80% B (water (10 mM NH4HCO3)-ACN, flow rate: 25 mL / min) to give 4.9a (10 mg, 20%) as a solid.

[0502] 4.9b (50 mg) was further purified by preparative HPLC (column: Waters Xbridge Prep OBD C18 150*30 5μ, gradient: 60%-90% B (water (10 mM NH4HCO3)-ACN, flow rate: 25 mL / min) to give 4.9b (12 mg, 24%) as a solid.

[0503] 4.9a: 1 H NMR (400 MHz, CDCl3) δ H 3.52 (q, J=7.2Hz, 2H), 3.34 (dd, J=8.8, 24.0Hz, 2H), 2.68 (s, 1H), 2.44 (dd, J=8.4, 19.2Hz, 1H), 2.14-1.59 (m, 9H) , 1.55-1.24 (m, 12H), 1.20 (t, J=6.8Hz, 3H), 0.88 (s, 3H), 0.47-0.36 (m, 3H), 0.29-0.21 (m, 1H), 0.06--0.03 (m, 1H)

[0504] LC-ELSD / MS purity 99%, C 24 H 37 O2[M-H2O+H] + MS ESI calcd. 357.2, calcd. 357.2.

[0505] 4.9b: 1 H NMR (400 MHz, CDCl3) δ H 3.52 (q, J=7.2Hz, 2H), 3.22 (dd, J=8.8, 12.8Hz, 2H), 2.45 (dd, J=8.4, 19.2Hz, 1H), 2.13- 1.61 (m, 9H), 1.56-1.08 (m, 16H), 0.95-0.85 (m, 4H), 0.47-0.34 (m, 2H), 0.29-0.17 (m, 2H)

[0506] LC-ELSD / MS purity 99%, C 24 H 37 O2[M-H2O+H] + MS ESI calcd. 357.3, calcd. 357.3.

[0507] Synthesis 4.10

[0508] To a solution of t-BuOK (1.33 g, 11.9 mmol) in THF (20 mL) was added ethyl triphenylphosphonium bromide (4.41 g, 11.9 mmol) at 25 ° C. After stirring for 0.5 h at 40 ° C, a solution of 4.9a (900 mg, 2.4 mmol) in THF (10 mL) was added to the reactant at 40 ° C. After stirring for 16 hours at 40 ° C, the mixture was poured into water (50 mL) and extracted with EtOAc (2x20 mL). The combined organic phases were washed with saturated brine (2x50 mL), dried over anhydrous Na SO dried, filtered and concentrated under vacuum to give residue, which was purified by flash column (0 to 30% EtOAc / PE) to give 4.10 (300 mg, 32%) as an oil.

[0509] 1 H NMR (400 MHz, CDCl3) δ H5.14-5.09 (m, 1H), 3.51 (q, J=7.2Hz, 2H), 3.34 (dd, J=9.6, 15.2Hz, 2H), 2.40-2.16 (m, 4H), 2.01-1.82 (m, 3H), 1.68-1.45(m, 16H), 1.30-1.10(m, 6H), 0.88(s, 3H), 0.45-0.30(m, 3H), 0.28-0.17(m, 1H), 0.02--0.08(m, 1H)

[0510] Synthesis 4.11

[0511] To a solution of 4.10 (800 mg, 2.1 mmol) in THF (10 mL) was added 9-BBN dimer (2.01 g, 8.24 mmol) at 25 ° C. The mixture was then stirred at 40 ° C for 16 hours to obtain a solution. After cooling to 0 ° C, the mixture was diluted very slowly with ethanol (1.89 g, 41.2 mmol) and then NaOH (8.24 mL, 41.2 mmol, 5 M). After the addition was complete, H2O2 (4 mL, 39.7 mmol, 30%) was slowly added, and the internal temperature was maintained below 25 ° C. After stirring at 75 ° C for 1 hour, saturated Na2S2O3 aqueous solution (50 mL) was added, and the mixture was stirred at 0 ° C for another hour. The reactants were checked with potassium iodide starch paper to confirm that the excess H2O2 was destroyed. The mixture was cooled and poured into water (50 mL). The mixture was extracted with EtOAc (3x20 mL) and washed with saturated brine (2x50 mL), dried over anhydrous Na2SO4, filtered and concentrated under vacuum. The residue (800 mg) was purified by flash column (0 to 30% EtOAc / PE) to give 4.11 (400 mg, 50%) as an oil.

[0512] 1 H NMR (400 MHz, CDCl3) δ H 3.72-3.65 (m, 1H), 3.51 (q, J=6.8Hz, 2H), 3.34 (dd, J=9.6, 24.0Hz, 2H), 2.00-1.83 (m, 7H), 1.69-1. 32(m, 15H), 1.28-1.11(m, 9H), 0.66(s, 3H), 0.44-0.30(m, 3H), 0.27-0.17(m, 1H), 0.02-0.09(m, 1H)

[0513] Synthesis 4.12

[0514] To the solution of 4.11 (200mg, 0.5mmol) in DCM (10mL) was added DMP (419mg, 0.9884mmol) in batches. After stirring for 0.5h at 25°C, the mixture was quenched with NaHCO (50mL) and extracted with EtOAc (3x10mL). The organic layer was washed with NaS O (2x50mL) and salt solution (2x50mL), dried over anhydrous NaSO, filtered and concentrated under vacuum. Residue (190mg) was purified by flash column (0 to 50% EtOAc / PE) to obtain 4.12 (180mg, 95%) as a solid.

[0515] 1 H NMR (400 MHz, CDCl3) δ H 3.52 (q, J=6.8Hz, 2H), 3.34 (dd, J=8.8, 23.2Hz, 2H), 2.70 (s, 1H), 2.55 (t, J=8.8Hz, 1H), 2.11 (m, 4H), 2.03-1.86 (m, 3H), 1.74-1.59 (m, 5H), 1.54-1.36(m, 7H), 1.29-1.13(m, 9H), 0.62(s, 3H), 0.47-0.31(m, 3H), 0.28-0.18(m, 1H), 0.04--0.07(m, 1H); LC-ELSD / MS purity 98%, C 26 H 41 O2[M-H2O+H] + MS ESI calcd. 385.3, found 385.3.

[0516] Example 5: Synthesis of 1-(2-((3R,5R,8S,9S,10R,13S,14S,17S)-10-cyclopropyl-3-(ethoxymethyl)-3-hydroxy-13-methylhexahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-oxoethyl)-1H-pyrazole-4-carbonitrile, 5.2

[0517]

[0518] To a solution of 4.12 (60 mg, 0.15 mmol) in MeOH (10 ml) was added HBr (6.5 mg, 0.03 mmol, 40% in water) and Br (26.1 mg, 0.16 mmol) at 25° C. After stirring for 2 h at 25° C., the mixture was quenched with saturated NaHCO (30 mL) and water (30 mL), then extracted with EtOAc (3×20 mL). The combined organic phases were washed with brine (2×50 mL), dried over anhydrous NaSO, filtered, and concentrated in vacuo to afford 5.1 (70 mg, 0.15 mmol) as an oil, which was used directly in the next step without further purification.

[0519] Synthesis 5.2

[0520] To a solution of 5.1 (70 mg, 0.15 mmol) in acetone (5 mL) was added 1H-pyrazole-4-carbonitrile (20.2 mg, 0.22 mmol), followed by K CO (40.1 mg, 0.29 mmol). After stirring at 50 ° C for 2 h, the mixture was quenched with water (30 mL) and then extracted with EtOAc (3x10 mL). The combined organic phases were washed with brine (2x30 mL), dried over anhydrous Na SO , filtered and concentrated to give a residue. The residue was purified by preparative HPLC (column: Waters Xbridge 150*25 5 μ, gradient: 60%-90% B (water (10 mM NH HCO )-ACN, flow rate: 25 mL / min) to give 5.2 (17 mg, 24%) as a solid.

[0521] 1 H NMR (400 MHz, CDCl3) δ H 7.85 (s, 1H), 7.80 (s, 1H), 4.95 (dd, J=18.0, 51.2Hz, 2H), 3.52 (q, J=6.8Hz , 2H), 3.34 (dd, J=9.2, 22.4Hz, 2H), 2.72 (s, 1H), 2.61 (t, J=8.4Hz, 1H), 2. 26-1.74(m, 6H), 1.65-1.42(m, 9H), 1.37-1.17(m, 10H), 0.67(s, 3H), 0.47 -0.32(m, 3H), 0.29-0.19(m, 1H), 0.05--0.04(m, 1H); LC-ELSD / MS purity 97%, C 30 H 42 N3O2[M-H2O+H] + The MSESI calculated value is 476.3, and the experimental value is 476.3.

[0522] Example 6: Synthesis of 1-(2-((3R, 5R, 8S, 9S, 10R, 13S, 14S, 17S)-10-cyclopropyl-3-(ethoxymethyl)-3-hydroxy-13-methylhexahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-oxoethyl)-1H-pyrazole-3-carbonitrile, 6

[0523]

[0524] To a solution of 5.1 (110 mg, 0.23 mmol) in acetone (10 mL) was added 1H-pyrazole-5-carbonitrile (31.8 mg, 0.34 mmol) and K CO (63.1 mg, 0.46 mmol). After stirring at 50 ° C for 2 h, saturated water (50 mL) was added to the mixture, followed by extraction with EtOAc (3x10 mL). The combined organic phases were washed with brine (2x30 mL), dried over anhydrous Na SO, filtered and concentrated to give a residue. The residue was purified by preparative HPLC (column: Xtimate C18 150*25 mm*5 μm, gradient: 65%-95% B (water (10 mM NH HCO)-ACN, flow rate: 30 mL / min) to give 6 (28 mg, 25%) as a solid.

[0525] 1 H NMR (400 MHz, CDCl3) δ H 7.48 (d, J=2.4Hz, 1H), 6.73 (d, J=2.4Hz, 1H), 4.97 (dd, J=18.0, 53.2Hz, 2H), 3.52 (q, J =7.2Hz, 2H), 3.35 (dd, J=9.2, 22.4Hz, 2H), 2.72 (s, 1H), 2.61 (t, J=8.8Hz, 1H), 2.25-1. 88 (m, 4H), 1.79-1.59 (m, 6H), 1.52-1.18 (m, 15H), 0.68 (s, 3H), 0.48-0.34 (m, 3H), 0.31-0.20 (m, 1H), 0.06-0.07 (m, 1H); the structure was confirmed by HMBC (H1 showed a clear signal with C4); LC-ELSD / MS purity 99%, C 30 H 42 N3O2[M-H2O+H] + MS ESI calcd. 476.3, found 476.3.

[0526] Example 7: Synthesis of 1-((3R,5R,8S,9S,10R,13S,14S,17S)-10-cyclopropyl-3-hydroxy-3-(methoxymethyl)-13-methylhexahydro-1H-cyclopenta[a]phenanthren-17-yl)ethan-1-one, 7.4

[0527]

[0528] Synthesis of 7.1a and 7.1b

[0529] Na (979 mg, 42.6 mmol) was added to anhydrous MeoH (10 mL) in three portions at 25 ° C. The reaction mixture was stirred at 65 ° C for 1 h. Anhydrous MeOH (20 mL) containing 4.8 (2.8 g, 8.5 mmol) was added to a sodium methoxide solution at 65 ° C. After stirring at 65 ° C for 4 h, the reaction mixture was diluted with water (50 mL) and then concentrated to remove most of the solvent. The mixture was extracted with EtOAc (2x20 mL). The combined organic phases were washed with saturated brine (2x50 mL), dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by flash column (0 to 10% EtOAc / PE) to give 7.1a (900 mg, Rf=0.2, PE / EtOAc=3 / 1, de%>99 (via 1 H NMR)) and 7.1b (900 mg, Rf = 0.35, PE / EtOAc = 3 / 1), de% > 99 (via 1 H NMR)).

[0530] 7.1a (100 mg) was purified by preparative HPLC (column: Waters Xbridge Prep OBD C18 150*30 5 μm, gradient: 58%-88% B (water (10 mM NH4HCO3)-ACN, flow rate: 25 mL / min) to give 7.1a (24 mg, 24%) as a solid.

[0531] 7.1b (100 mg) was purified by preparative HPLC (column: Waters Xbridge Prep OBD C18 150*30 5 μm, gradient: 58%-88% B (water (10 mM NH4HCO3)-ACN, flow rate: 25 mL / min) to give 7.1b (25 mg, 25%) as a solid.

[0532] 7.1a: 1 H NMR (400 MHz, CDCl3) δ H3.38 (s, 3H), 3.32 (dd, J = 8.8, 23.2 Hz, 2H), 2.57 (s, 1H), 2.44 (dd, J = 8.8, 19.2 Hz, 1H), 2.15-1.57 (m, 9H), 1.54-1.16 (m, 12H), 0.88 (s, 3H), 0.49-0.34 (m, 3H), 0.31-0.21 (m, 1H), 0.07-0.03 (m, 1H); LC-ELSD / MS purity 98%, C 23 H 35 O2[M-H2O+H] + MS ESI calcd. 343.3, found 343.3.

[0533] 7.1b: 1 H NMR (400 MHz, CDCl3) δ H 3.38 (s, 3H), 3.19 (d, J = 2.4 Hz, 2H), 2.45 (dd, J = 8.4, 19.2 Hz, 1H), 2.13-1.60 (m, 9H), 1.55-1.10 (m, 13H), 0.89 (m, 4H), 0.48-0.32 (m, 2H), 0.29-0.16 (m, 2H); LC-ELSD / MS purity 98%, C 23 H 35 O2[M-H2O+H] + MS ESI calcd. 343.3, found 343.3.

[0534] Synthesis 7.2

[0535] At 25 ℃, ethyl triphenyl phosphonium bromide (4.08g, 11.0mmol) is added to a solution of t-BuOK (1.23g, 11.0mmol) in THF (20mL). After stirring for 0.5h at 40 ℃, a solution of 7.1a (800mg, 2.2mmol) in THF (10mL) is added to the reactant at 40 ℃. After stirring for 16h at 40 ℃, the mixture is poured into water (50mL) and extracted with EtOAc (2x20mL). The organic phases merged are washed with saturated brine (2x50mL), dried over anhydrous Na SO dried, filtered and concentrated under vacuum to obtain residue, which is purified by flash column (0 to 20% EtOAc / PE) to obtain 7.2 (500mg, 1.3mmol) as an oil.

[0536] Synthesis 7.3

[0537] To a solution of 7.2 (500 mg, 1.3 mmol) in THF (10 mL) was added 9-BBN dimer (1.30 g, 5.4 mmol) at 25 ° C. The mixture was stirred at 40 ° C for 16 hours to obtain a solution. After cooling to 0 ° C, the mixture was diluted very slowly with ethanol (1.23 g, 26.8 mmol) and NaOH (5.36 mL, 26.8 mmol, 5 M). After the addition was complete, H2O2 (2.7 mL, 26.8 mmol, 30%) was slowly added and the internal temperature was maintained below 25 ° C. The resulting solution was stirred at 75 ° C for 1 hour. Saturated Na2S2O3 aqueous solution (50 mL) was added and the mixture was stirred at 0 ° C for another hour. The reactants were checked with potassium iodide starch paper to confirm that the excess H2O2 was destroyed. The mixture was cooled and poured into water (50 mL). The mixture is extracted with EtOAc (3x20mL), and washed with saturated brine (2x50mL), through anhydrous NaSODrying is filtered and concentrated under vacuum.Residue (500mg) is passed through flash column (0 to 30% EtOAc / PE) purification to obtain 7.3 (250mg, 50%) as an oil.80mg 7.3 passes through preparation HPLC (post HT high load C18 250*25mm*5 μm, condition water (10mM NHHCO)-ACN, start B 75, end B 95) purification to obtain 7.3 (23mg) as a solid.

[0538] 1 H NMR (400 MHz, CDCl3) δ H 4.25-4.15(m, 1H), 3.40-3.27(m, 5H), 2.07-1.77(m, 5H), 1.70-1.00(m, 23H ), 0.67(m, 3H), 0.45-0.30(m, 3H), 0.30-0.20(m, 1H), 0.05-(-0.05)(m, 1H).

[0539] LC-ELSD / MS purity 98%, C 25 H 41 O[M-H2O+H] + MS ESI calcd. 373.3, found 373.3.

[0540] Synthesis 7.4

[0541] To the solution of 7.3 (150mg, 0.4mmol) in DCM (10mL) DMP (325mg, 0.8mmol) is added dropwise. After stirring 0.5h at 25°C, the mixture is quenched with saturated NaHCO solution (50mL), and extracted with EtOAc (3x10mL). The organic layer merged is washed with Na s o (2x50mL), salt water (2x50mL), through Na s o dried, filtered and concentrated under vacuum. Residue (140mg) is purified by flash column (0 to 50% EtOAc / PE) to obtain 7.4 (120mg, 86%) as a solid.

[0542] 1 H NMR (400 MHz, CDCl3) δ H 1.70 -1.63(m, 4H), 1.51-1.37(m, 7H), 1.28-1.16(m, 6H), 0.62(s, 3H), 0.46-0.32(m, 3H), 0.28-0.19(m, 1H), 0.04--0.06(m, 1H)

[0543] LC-ELSD / MS purity 98%, C 25 H 39 O2[M-H2O+H] + MS ESI calcd. 371.3, calcd. 371.3.

[0544] Example 8: Synthesis of 1-(2-((3R,5R,8S,9S,10R,13S,14S,17S)-10-cyclopropyl-3-hydroxy-3-(methoxymethyl)-13-methylhexahydro-1H-cyclopenta[a]phenanthren-17-yl)-2-oxoethyl)-1H-pyrazole-4-carbonitrile (8.2b)

[0545]

[0546] Synthesis 8.1

[0547] To a solution of 7.4 (100 mg, 0.3 mmol) in MeOH (10 mL) was added HBr (10.4 mg, 0.05 mmol, 40% in water) and Br (45.2 mg, 0.3 mmol) at 25° C. After stirring for 2 h at 25° C., the mixture was quenched with saturated NaHCO solution (30 mL) and water (30 mL), followed by extraction with EtOAc (3×20 mL). The combined organic phases were washed with brine (2×50 mL), dried over anhydrous NaSO, filtered, and concentrated in vacuo to afford 8.1 (120 mg, 0.3 mmol) as an oil, which was used directly in the next step without further purification.

[0548] Synthesis 8.2b

[0549] To a solution of 8.1 (120 mg, 0.3 mmol) in acetone (10 mL) was added 1H-pyrazole-4-carbonitrile (35.8 mg, 0.4 mmol), followed by K CO (70.9 mg, 0.5 mmol). After stirring at 50 ° C for 12 h, the mixture was quenched with water (30 mL) and then extracted with EtOAc (3x10 mL). The combined organic phases were washed with brine (2x30 mL), dried over anhydrous Na SO , filtered and concentrated to give a residue. The residue was purified by preparative HPLC (column: Waters Xbridge 150*255 μ, gradient: 60%-90% B (water (10 mM NH HCO )-ACN, flow rate: 25 mL / min) to give 8.2b (35 mg, 28%) as a solid.

[0550] 8.2b: 1 H NMR (400 MHz, CDCl3) δ H 7.85 (s, 1H), 7.81 (s, 1H), 4.96 (dd, J=18.0, 51.6Hz, 2H), 3.39 (s, 3H), 3.32 (dd, J=8.8, 22.0Hz, 2H), 2.68-2.56 (m, 2H), 2.26 -2.16 (m, 1H), 2.08-1.65 (m, 8H), 1.53-1.16 (m, 13H), 0.68 (s, 3H), 0.47-0.34 (m, 3H), 0.28-0.19 (m, 1H), 0.05--0.03 (m, 1H). The structure was confirmed by 2D NMR (H18 showed a clear signal with H20, H18 showed a weak signal with H17); LC-ELSD / MS based on H-NMR had a purity of 99%, 100% deoxygenase; C 29 H 42 N3O3[for M] +MS ESI calcd. 480.3, found 480.3.

[0551] Example 9:

[0552] Steroid inhibition of TBPS binding

[0553] The use of rat cerebral cortical membranes in the presence of 5 mM GABA has been described [ 35 S]-tert-butyl bicyclic phosphorothioate (TBPS) binding assay (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).

[0554] Briefly, after decapitation of Sprague-Dawley rats (200-250 g) anesthetized with carbon dioxide, the cortex was quickly removed. The cortex was homogenized using a glass / Teflon homogenizer in 10 volumes of ice-cold 0.32 M sucrose and centrifuged at 1500 x g for 10 min at 4 ° C. The resulting supernatant was centrifuged at 10,000 x g for 20 min at 4 ° C to obtain a P2 pellet. The P2 pellet was resuspended in 200 mM NaCl / 50 mM Na-K phosphate pH 7.4 buffer and centrifuged at 10,000 x g for 10 min at 4 ° C. This washing procedure was repeated twice and the pellet was resuspended in 10 volumes of buffer. An aliquot (100 mL) of the membrane suspension was mixed with 3 nM [ 35[S] -TBPS and 5mL aliquots of the test drug (final 0.5%) dissolved in dimethyl sulfoxide (DMSO) were incubated together. The incubation was brought to a final volume of 1.0mL with buffer. Nonspecific binding was determined in the presence of 2mM unlabeled TBPS and a range of 15% to 25%. After incubation for 90min at room temperature, the assay was terminated by filtering through a glass fiber filter (Schleicher and Schuell No. 32) using a cell harvester (Brandel) and rinsing three times with ice-cold buffer. Filter binding radioactivity was measured by liquid scintillation spectrometry. Prism (GraphPad) was used to perform nonlinear curve fitting of the entire data of each drug averaged for each concentration. If the sum of squares was significantly lower by the F-test, the data were fitted to a partial rather than a 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 component inhibition model. In the case of the same model for all data, 50% inhibition (IC) of specific binding was generated for individual experimental determinations. 50 ) and the maximum inhibition level (I max ) concentration of the test compound, and the mean ± SEM of individual experiments was calculated. Picrotoxin was used as a positive control in these studies, which has been shown to robustly inhibit TBPS binding.

[0555] Various compounds may be screened to determine their performance as in vitro [ 35 [S]-TBPS binding modulator potential. These assays are or can be performed as described above.

[0556] In the following Table 2, A represents TBPS IC 50 (μM)<0.1μM, B represents TBPS IC 50 (μM) is 0.1μM to <1.0μM, C represents TBPS IC 50 (μM) is 1 μM to <10.0 μM, and D means ≥10 μM.

[0557] Table 2.

[0558]

[0559]

[0560] Equivalent schemes and scope

[0561] Unless indicated to the contrary or obvious from the context, in the claims, articles such as "a," "an," and "the" may mean one or more than one. Unless indicated to the contrary or obvious from the context, a claim or description including "or" between one or more group members is satisfied if one, more than one, or all of the group members are present, employed, or otherwise involved in a given product or process. The invention includes embodiments in which exactly one member of the group is present, employed, or otherwise involved in a given product or process. The invention also includes embodiments in which more than one or all of the group members are present, employed, or otherwise involved in a given product or process.

[0562] In addition, the present invention encompasses all variations, combinations and arrangements in which one or more limitations, elements, clauses and descriptive terms from one or more listed claims are introduced into another claim. For example, any claim attached to another claim can be modified to include one or more limitations visible in any other claim attached to the same basic claim. In the case of presenting elements in a list form, for example, in a Markush group format, each subgroup of the elements is also disclosed, and any one or more elements can be removed from the group. It should be understood that, generally speaking, when the present invention or aspects of the present invention are referred to as including specific elements and / or features, certain embodiments of the present invention or aspects of the present invention are composed of such elements and / or features or are substantially composed of such elements and / or features. For simplicity, those embodiments are not specifically described in the same words herein. It should also be noted that the terms "comprising" and "containing" are intended to be open and allow the inclusion of additional elements or steps. When a range is given, end values are included. Furthermore, unless otherwise indicated or apparent from the context and understanding of one of ordinary skill in the art, in various embodiments of the present invention, values expressed as ranges can be assumed to be any specific value or sub-range within the stated range, to the tenth of the unit of the lower limit of the range, unless the context clearly dictates otherwise.

[0563] This application mentions various issued patents, published patent applications, journal articles and other publications, all of which are incorporated herein by reference. If there is a conflict between any incorporated reference and this specification, this specification shall prevail. In addition, any specific embodiment of the present invention that belongs to the prior art may be explicitly excluded from any one or more of the claims. Because such embodiments are considered to be known to those of ordinary skill in the art, they may be excluded, even if the exclusion is not explicitly set forth herein. Any specific embodiment of the present invention may be excluded from any claim for any reason, whether or not related to the existence of the prior art.

[0564] Those skilled in the art will recognize or be able to ascertain, using only routine experimentation, many equivalents to the specific embodiments described herein. The scope of the embodiments of the present invention described herein is not intended to be limited to the foregoing description, but is set forth in the appended claims. Those skilled in the art will appreciate that various changes and modifications may 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 (Ia): or a pharmaceutically acceptable salt thereof; in: represents a single bond; R 1 is hydrogen or a 5-6 membered heteroaryl containing 1-4 nitrogen atoms, wherein the 5-6 membered heteroaryl is optionally replaced by -CN or C 1-3 Alkyl substitution; R 12a and R 12b Each of is hydrogen; R 3a Is optional C 1-6 Alkoxy-substituted C 1-6 alkyl; R 5 is hydrogen or methyl; R 6a and R 6b Each of is hydrogen; R 16a and R 16b Each of is hydrogen; R 19 is an unsubstituted C3-C6 carbocyclyl; and n is 0 or 1.

2. The compound or pharmaceutically acceptable salt of claim 1, wherein R 1 is hydrogen or a 5-6 membered heteroaryl group containing 2-4 nitrogen atoms, wherein the 5-6 membered heteroaryl group is optionally substituted by -CN or methyl.

3. The compound or pharmaceutically acceptable salt of claim 1, wherein R 1 It's hydrogen.

4. The compound or pharmaceutically acceptable salt of claim 1, wherein R 1 Selected from the group consisting of: in: Each R a are independently hydrogen, –CN or unsubstituted C 1-3 alkyl; and p is an integer selected from 0 or 1.

5. The compound or pharmaceutically acceptable salt of claim 4, wherein R 1 Selected from the group consisting of:

6. The compound or pharmaceutically acceptable salt of claim 1, wherein R 3a is unsubstituted C 1-6 alkyl.

7. The compound or pharmaceutically acceptable salt of claim 1, wherein R 3a It is methyl, methoxymethyl or ethoxymethyl.

8. The compound or pharmaceutically acceptable salt of claim 1, wherein R 5 is relative to R 19 A hydrogen or a methyl group in the cis position.

9. The compound or pharmaceutically acceptable salt of claim 1, wherein R 5 is relative to R 19 A hydrogen or methyl group in the trans position.

10. The compound or pharmaceutically acceptable salt of claim 1, wherein R 19 Selected from the group consisting of: in: Each R b is hydrogen; and q is an integer selected from 0 to 9 as allowed by valence.

11. The compound or pharmaceutically acceptable salt of claim 1, wherein n is 0.

12. The compound or pharmaceutically acceptable salt of claim 1, wherein n is 1.

13. The compound or pharmaceutically acceptable salt of claim 1, wherein the compound of formula (Ia) is a compound of formula (Ib): or a pharmaceutically acceptable salt thereof.

14. The compound or pharmaceutically acceptable salt of claim 1, wherein the compound of formula (Ia) is a compound of formula (Ic): or a pharmaceutically acceptable salt thereof.

15. The compound or pharmaceutically acceptable salt of claim 1, wherein the compound of formula (Ia) is a compound of formula (Id): or a pharmaceutically acceptable salt thereof; in: Each R a is cyano or methyl; and p is 0 or 1.

16. The compound or pharmaceutically acceptable salt of claim 1, wherein the compound of formula (Ia) is a compound of formula (Ih): or a pharmaceutically acceptable salt thereof; in: Each X is independently -C(R N )-、-C(R N )2-, -N- or -N(R N )-, where each R N are independently hydrogen, unsubstituted C 1-3 Alkyl or -CN, provided there is only one R N Not hydrogen.

17. A compound or a pharmaceutically acceptable salt thereof, wherein the compound is selected from 18. The compound of claim 17, wherein the compound is 19. The compound of claim 17, wherein the compound is 20. The compound of claim 17, wherein the compound is 21. The compound of claim 17, wherein the compound is 22. A pharmaceutical composition comprising the compound according to any one of claims 1 to 21 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

23. Use of the compound according to any one of claims 1 to 21 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating CNS-related disorders.

24. The use of claim 23, wherein the CNS-related disorder is a sleep disorder, a mood disorder, a schizophrenia spectrum disorder, a convulsive disorder, a memory and / or cognitive disorder, a movement disorder, a personality disorder, an autism spectrum disorder, pain, a traumatic brain injury, a vascular disease, a substance abuse disorder and / or withdrawal syndrome, tinnitus, or status epilepticus.

25. The use according to claim 23, wherein the CNS-related disorder is depression.

26. The use according to claim 25, wherein the depression is postpartum depression.

27. The use according to claim 26, wherein the depression is major depressive disorder.

28. The use according to claim 26, wherein the CNS-related disorder is epileptic seizure.

29. The use according to claim 26, wherein the CNS-related disorder is tremor.

30. Use of a compound or pharmaceutically acceptable salt according to any one of claims 1 to 21 in the preparation of a medicament for inducing sedation and / or anesthesia.

31. Use of the pharmaceutical composition according to claim 22 in the preparation of a medicament for treating CNS-related disorders.

32. The method of claim 31, wherein the CNS-related disorder is a sleep disorder, a mood disorder, a schizophrenia spectrum disorder, a convulsive disorder, a memory and / or cognitive disorder, a movement disorder, a personality disorder, an autism spectrum disorder, pain, a traumatic brain injury, a vascular disease, a substance abuse disorder and / or withdrawal syndrome, tinnitus, or status epilepticus.

33. The use according to claim 31, wherein the CNS-related disorder is depression.

34. The use of claim 33, wherein the depression is postpartum depression.

35. The use of claim 33, wherein the depression is major depressive disorder.

36. The use of claim 35, wherein the major depressive disorder is moderate major depressive disorder.

37. The use of claim 35, wherein the major depressive disorder is severe major depressive disorder.

38. The use according to claim 31, wherein the CNS-related disorder is epileptic seizure.

39. The use according to claim 31, wherein the CNS-related disorder is tremor.

40. The use according to claim 39, wherein the tremor is essential tremor.

41. The method of claim 31, wherein the medicament is for oral administration.

42. The use of claim 31, wherein the medicament is for long-term administration.

43. Use of the pharmaceutical composition of claim 22 in the preparation of a medicament for inducing sedation and / or anesthesia.

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