3, 3-disubstituted 19-norpregnane compounds, compositions, and uses thereof

Abstract

Provided herein are 3, 3-disubstituted 19-norsteroids according to formulae (I) and (III) wherein R1, R2, R3, R3 ', R4, R6a, R6a, R11a and R11b are as defined herein. Compounds of the invention are contemplated to be useful for the prevention and treatment of a variety of CNS-related conditions, such as the treatment of sleep disorders, mood disorders, insomnia, anxiety, depression, traumatic brain injury (TBI), stress and epilepsy. # imgabs0 #

Description

[0001] This application is a divisional application of a patent application with Chinese application number 202110494113.1, invention name “3,3-disubstituted 19-norpregnane compounds, compositions, and uses thereof” and application date October 12, 2012.

[0002] Related Applications

[0003] This application claims priority under 35 U.S.C. §119(e) to U.S. Provisional Patent Application USSN 61 / 547,291 filed on October 14, 2011 and U.S. Provisional Patent Application USSN 61 / 698,204 filed on September 7, 2012, each of which is incorporated herein by reference. Background Art

[0004] Brain excitability is defined as the animal's level of arousal (ranging on a continuum from coma to convulsions) and is regulated by various neurotransmitters. In general, neurotransmitters are responsible for regulating the conductivity of ions across the neuronal membrane. At rest, the neuronal membrane has an electrical potential (or membrane voltage) of approximately -70 mV, with the interior of the cell being negative relative to the exterior of the cell. The electrical potential (voltage) is the function of the ions (K) across the semipermeable membrane of the neuron. + 、Na + , Cl - , organic anions). Neurotransmitters are stored in presynaptic vesicles and released under the influence of the neuronal action potential. When released into the synaptic cleft, excitatory chemical transmitters such as acetylcholine will cause membrane depolarization (change in potential from -70mV to -50mV). This effect is mediated by postsynaptic nicotinic receptors, which are stimulated by acetylcholine to increase Na + Membrane permeability of ions. The reduced membrane potential stimulates neuronal excitability in the form of postsynaptic action potential.

[0005] In the case of the GABA receptor complex (GRC), the effect on brain excitability is mediated by the GABA neurotransmitter. GABA has a profound effect on total brain excitability because up to 40% of neurons in the brain utilize GABA as a neurotransmitter. GABA regulates the excitability of individual neurons by regulating the conduction of chloride ions across neuronal membranes. GABA interacts with its recognition site on the GRC to promote the influx of chloride ions into cells along the electrochemical gradient of the GRC. The intracellular increase in the level of this anion leads to hyperpolarization of the transmembrane potential, making neurons less sensitive to excitatory input (i.e., reduced neuronal excitability). In other words, the higher the chloride ion concentration in the neuron, the lower the brain excitability (arousal level).

[0006] It is well documented that the GRC is responsible for the mediation of anxiety, seizure behavior, and sedation. Therefore, GABA and drugs that act like GABA or enhance the effects of GABA (e.g., therapeutically useful barbiturates and benzodiazepines) are important. (BZ) For example ) produce their therapeutically useful effects by interacting with specific regulatory sites on the GRC. Accumulating evidence now suggests that, in addition to benzodiazepines In addition to the barbiturate binding site, the GRC also contains a different site for neuroactive steroids (steroids) (Lan, NC et al., Neurochem. Res. 16: 347-356 (1991)).

[0007] Neuroactive steroids can occur endogenously. The most potent endogenous neuroactive steroids are 3a-hydroxy-5-reduced pregnane-20-one and 3α-21-dihydroxy-5-reduced pregnane-20-one, which are metabolites of the hormonal steroids progesterone and deoxycorticosterone, respectively. The ability of these steroid metabolites to alter brain excitability was recognized in 1986 (Majewska, MD et al., Science 232: 1004-1007 (1986); Harrison, NL et al., J Pharmacol. Exp. Ther. 241: 346-353 (1987)).

[0008] The ovarian hormone progesterone and its metabolites have been shown to have a profound effect on brain excitability (Backstrom, T. et al., Acta Obstet. Gynecol. Scand. Suppl. 130: 19-24 (1985); Pfaff, DW and McEwen, BS, Science 219: 808-814 (1983); Gyermek et al., J Med Chem. 11: 117 (1968); Lambert, J. et al., Trends Pharmacol. Sci. 8: 224-227 (1987)). The levels of progesterone and its metabolites vary with the phases of the menstrual cycle. There are many documents that show that the levels of progesterone and its metabolites decrease before the onset of menstruation. The monthly recurrence of some physical symptoms before the onset of menstruation has also been documented by many documents. These symptoms, which have become associated with premenstrual syndrome (PMS), include stress (tension), anxiety, and migraines (Dalton, K., Premenstrual Syndrome and Progesterone Therapy, 2nd edition, Chicago Yearbook, Chicago (1984)). Subjects with PMS have a monthly recurrence of symptoms that are present before the menstrual period and absent after the menstrual period.

[0009] In a similar manner, a decrease in progesterone has also been temporally associated with an increase in the frequency of seizures in female epileptic patients, namely catamenial epilepsy (Laidlaw, J., Lancet, 1235-1237 (1956)). A more direct association has been observed for a decrease in progesterone metabolites (Rosciszewska et al., J. Neurol. Neurosurg. Psych. 49:47-51 (1986)). In addition, for subjects with primary generalized petit mal epilepsy, the temporal incidence of seizures has been associated with the incidence of symptoms of premenstrual syndrome (Backstrom, T. et al., J. Psychosom. Obstet. Gynaecol. 2:8-20 (1983)). The steroid deoxycorticosterone has been found to be effective in treating subjects with epileptic seizures related to their menstrual cycle (Aird, RB and Gordan, G., J. Amer. Med. Soc. 145:715-719 (1951)).

[0010] The syndrome also associated with low progesterone levels is postpartum depression (PND). Progesterone levels decrease sharply immediately after childbirth, leading to the onset of PND. The symptoms of PND range from mild depression to psychosis requiring hospitalization. PND is also associated with severe anxiety and irritability. The depression associated with PND is not affected by the treatment of classical antidepressants, and women experiencing PND show an increased incidence of PMS (Dalton, K., Premenstrual Syndrome and Progesterone Therapy, 2nd edition, Chicago Yearbook, Chicago (1984)).

[0011] Collectively, these observations implicate a critical role for progesterone and deoxycorticosterone, and more particularly their metabolites, in the homeostatic regulation of brain excitability, which manifests as an increase in seizure behaviors or symptoms associated with catamenial epilepsy, PMS, and PND. The correlation between decreased progesterone levels and symptoms associated with PMS, PND, and catamenial epilepsy (Backstrom, T. et al., J Psychosom. Obstet. Gynaecol. 2:8-20 (1983)); Dalton, K., Premenstrual Syndrome and Progesterone Therapy, 2nd edition, Chicago Yearbook, Chicago (1984)) has prompted the use of progesterone in their treatment (Mattson et al., "Medroxyprogesterone therapy of catamenial epilepsy," Advances in Epileptology: XVth Epilepsy International Symposium, Raven Press, New York (1984), pp. 279-282 and Dalton, K., Premenstrual Syndrome and Progesterone Therapy, 2nd edition, Chicago Yearbook, Chicago (1984)). However, progesterone is not consistently effective in the treatment of the above syndromes. For example, a dose-response relationship does not exist for progesterone in the treatment of PMS (Maddocks et al., Obstet. Gynecol. 154:573-581 (1986); Dennerstein et al., Brit. Med J 290:16-17 (1986)).

[0012] There is a need for new and improved neuroactive steroids that act as modulators of brain excitability, as well as agents for the prevention and treatment of CNS-related diseases. The compounds, compositions and methods described herein are directed to this goal. Summary of the invention

[0013] The present invention is based in part on the desire to provide novel 19-nor compounds with good efficacy, pharmacokinetic (PK) properties, oral bioavailability, formulatability, stability, safety, clearance and / or metabolism. A key feature of the compounds as described herein is the di-substitution at the C3 position. The inventors envision that the di-substitution at C-3 eliminates the possibility of oxidation to ketones, prevents further metabolism, and reduces the possibility of secondary elimination pathways such as glucuronidation. The inventors further envision that the overall effect of C3 di-substitution should be to improve overall PK parameters and reduce potential toxicity and side effects, which may allow oral and / or long-term (chronically) administration in some embodiments. Another key feature of the compounds as described herein is the presence of hydrogen ("19-nor") instead of methyl at the C10 position. The inventors envision that 19-nor compounds have improved physical properties, such as improved solubility, compared to their C10-methyl counterparts. The present inventors foresee a further increase in solubility, for example when the AB ring system is in the cis configuration.

[0014] Thus, in one aspect, provided herein are compounds according to formula (I) or (III):

[0015]

[0016] or a pharmaceutically acceptable salt, solvate, hydrate, prodrug, stereoisomer, tautomer, isotopic variant, or N-oxide thereof, or a combination thereof; wherein R 2 , R 4 , R 6a , R 6b , R 11a , R 11b As defined herein,

[0017] R 1 is hydrogen, halogen, 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, substituted or unsubstituted heteroaryl, -OR A1 、-SR A1 、-N(R A1 )2, -OC(=O)RA1 、-OC(=O)OR A1 、-OC(=O)SR A1 、-OC(=O)N(R A1 )2, -SC(=O)R A2 、-SC(=O)OR A1 、-SC(=O)SR A1 、-SC(=O)N(R A1 )2, -NHC(=O)R A1 、-NHC(=O)OR A1 、-NHC(=O)SR A1 、-NHC(=O)N(R A1 )2, -OS(=O)2R A2 、-OS(=O)2OR A1 、-SS(=O)2R A2 、-SS(=O)2OR A1 、-S(=O)R A2 、-SO2R A2 , or -S(=O)2OR A1 , where R A1 Each instance of R is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, an oxygen protecting group when attached to an oxygen atom, a sulfur protecting group when attached to a sulfur atom, a nitrogen protecting group when attached to a nitrogen atom, or two R A1 The groups are combined to form a substituted or unsubstituted heterocyclic or heteroaryl ring; and R A2 is 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, or substituted or unsubstituted heteroaryl group;

[0018] R 3 is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; and

[0019] R 3’ is hydrogen, -C(=O)R C1 、-C(=O)OR C1 、-C(=O)SR C1 、-C(=O)N(R C1 )2, -S(=O)2R C2 、-S(=O)2ORC1 、-P(=O)2R C2 、-P(=O)2OR C1 、-P(=O)(OR C1 )2. -P(=O)(R C2 )2, or -P(=O)(R C2 )(OR C1 ), where R C1 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, an oxygen protecting group when attached to an oxygen atom, a sulfur protecting group when attached to a sulfur atom, a nitrogen protecting group when attached to a nitrogen atom, or two R C1 groups are combined to form a substituted or unsubstituted heterocyclic ring; and R C2 is 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, or substituted or unsubstituted heteroaryl group;

[0020] in independently represent a single bond or a double bond, provided that if the double bond is present in ring B, then R 6a or R 6b One of them is absent, and provided that if a single bond is present in ring B, the hydrogen at C5 is in the alpha or beta position.

[0021] In another aspect, a pharmaceutical composition is provided, comprising a compound of formula (I) or (III) and a pharmaceutically acceptable carrier. In some embodiments, the compound of the present invention is provided in the pharmaceutical composition in an effective amount. In some embodiments, the compound of the present invention is provided in a therapeutically effective amount. In some embodiments, the compound of the present invention is provided in a preventive effective amount.

[0022] The compounds described herein act in some embodiments as GABA modulators, for example affecting GABA in a positive or negative manner. A Receptors. As a regulator of the excitability of the central nervous system (CNS), when it regulates GABA A Such compounds are expected to have CNS-activity when mediated through the ability of the agonist to a CNS receptor.

[0023] Thus, in another aspect, a method for treating a CNS-related disorder in a subject in need thereof is provided, comprising administering to the subject an effective amount of a compound of formula (I) or (III). In some embodiments, the CNS-related disorder is insomnia, depression, mood disorders, convulsive disorders, memory disorders, attention disorders, anxiety disorders, bipolar disorders, schizophrenia, depression, bipolar disorders, schizoaffective disorders, mood disorders, anxiety disorders, personality disorders, psychosis, obsessive-compulsive disorders, post-traumatic stress disorder, autism spectrum disorder, dysthymia, social anxiety disorder, obsessive-compulsive disorder, pain, sleep disorders, memory disorders, dementia, Alzheimer's disease, episodic disorders, traumatic brain injury, stroke, addictive disorders, autism, Huntington's disease, Parkinson's disease, Rett syndrome, withdrawal syndrome, or tinnitus.

[0024] Other objects and advantages will become apparent to those skilled in the art from consideration of the ensuing detailed description, examples, and claims.

[0025] definition

[0026] Chemical Definition

[0027] Definitions of specific functional groups and chemical terms are described in more detail below. Chemical elements are identified according to the CAS version of the Periodic Table of the Elements on the inside front cover of the Handbook of Chemistry and Physics 75th edition, and specific functional groups are generally defined as described therein. In addition, general principles of organic chemistry, as well as 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, 5 th Edition, John Wiley & Sons, Inc., New York, 2001; Larock, Comprehensive Organic Transformations, VCH Publishers, Inc., New York, 1989; and Carruthers, Some Modern Methods of Organic Synthesis, 3 rd Edition, Cambridge University Press, Cambridge, 1987.

[0028] The compounds described herein may include one or more asymmetric centers and may therefore exist in a variety of isomeric forms such as enantiomers and / or diastereomers. For example, the compounds described herein may be individual enantiomers, diastereomers or geometric isomers, or may be in the form of a mixture of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomers. Isomers may be separated from the mixture 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 may be prepared by asymmetric synthesis. See, e.g., Jacques et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen et al., Tetrahedron 33:2725 (1977); Eliel, Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); and Wilen, Tables of Resolving Agents and Optical Resolutions p. 268 (ELEliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN 1972). The present invention further includes the compounds described herein as individual isomers substantially free of other isomers, or as mixtures of multiple isomers.

[0029] As used herein, a pure enantiomer compound is substantially free of the other enantiomers or stereoisomers of the compound (i.e., is in enantiomeric excess). In other words, the "S" form of a compound is substantially free of the "R" form of the compound, and is therefore in enantiomeric excess of the "R" form. The term "enantiomerically pure" or "pure enantiomer" means that the compound includes more than 75% by weight, more than 80% by weight, more than 85% by weight, more than 90% by weight, more than 91% by weight, more than 92% by weight, more than 93% by weight, more than 94% by weight, more than 95% by weight, more than 96% by weight, more than 97% by weight, more than 98% by weight, more than 98.5% by weight, more than 99% by weight, more than 99.2% by weight, more than 99.5% by weight, more than 99.6% by weight, more than 99.7% by weight, more than 99.8% by weight, or more than 99.9% by weight of the enantiomer. In some embodiments, the weight is based on the total weight of all enantiomers or stereoisomers of the compound.

[0030] As used herein and unless otherwise indicated, the term "enantiomerically pure R-compound" refers to at least about 80% by weight of the R-compound and up to about 20% by weight of the S-compound, at least about 90% by weight of the R-compound and up to about 10% by weight of the S-compound, at least about 95% by weight of the R-compound and up to about 5% by weight of the S-compound, at least about 99% by weight of the R-compound and up to about 1% by weight of the S-compound, at least about 99.9% by weight of the R-compound, or up to about 0.1% by weight of the S-compound. In some embodiments, the weight is based on the total weight of the compound.

[0031] As used herein and unless otherwise indicated, the term "enantiomerically pure S-compound" or "S-compound" refers to at least about 80% by weight of the S-compound and up to about 20% by weight of the R-compound, at least about 90% by weight of the S-compound and up to about 10% by weight of the R-compound, at least about 95% by weight of the S-compound and up to about 5% by weight of the R-compound, at least about 99% by weight of the S-compound and up to about 1% by weight of the R-compound, or at least about 99.9% by weight of the S-compound and up to about 0.1% by weight of the R-compound. In some embodiments, the weight is based on the total weight of the compound.

[0032] In the compositions provided herein, enantiomerically pure compounds may be present with other active or inactive ingredients. For example, a pharmaceutical composition including an enantiomerically pure R-compound may include, for example, about 90% of an excipient and about 10% of an enantiomerically pure R-compound. In some embodiments, the enantiomerically pure R-compound in such a composition may, for example, include at least about 95% by weight of the R-compound and up to about 5% by weight of the S-compound of the total weight of the compound. For example, a pharmaceutical composition including an enantiomerically pure S-compound may include, for example, about 90% of an excipient and about 10% of the enantiomerically pure S-compound. In some embodiments, the enantiomerically pure S-compound in such a composition may, for example, include at least about 95% by weight of the S-compound and up to about 5% by weight of the R-compound of the total weight of the compound. In some embodiments, the active ingredient may be formulated with very little excipient or carrier or without excipient or carrier.

[0033] The articles "a" and "an" may be used herein to refer to one or more than one (i.e., at least one) of the grammatical object of the article. As an example, "analog" means one analog or more than one analog.

[0034] The following terms are intended to have the meanings provided therewith below and are useful in understanding the specification and intended scope of the present invention.

[0035] When a range of values ​​is listed, it is intended to include every value and sub-range within the range. For example, "C 1–6 "Alkyl" is intended to include C1, C2, C3, C4, C5, C6, C 1–6 , C 1–5 , C 1–4 , C 1–3 , C 1–2 , C 2–6 , C 2–5 , C 2–4 , C 2–3 , C 3–6 , C 3–5 , C 3–4 , C 4–6 , C 4–5 and C 5–6 alkyl.

[0036] "Alkyl" refers to a straight chain or branched saturated hydrocarbon group having 1 to 20 carbon atoms. 1–20 In some embodiments, the alkyl group has 1-12 carbon atoms (“C 1–12 In some embodiments, the alkyl group has 1-10 carbon atoms (“C 1–10 In some embodiments, the alkyl group has 1-9 carbon atoms (“C 1–9 In some embodiments, the alkyl group has 1-8 carbon atoms. 1–8 In some embodiments, the alkyl group has 1-7 carbon atoms (C 1–7 In some embodiments, the alkyl group has 1-6 carbon atoms (“C 1–6 In some embodiments, the alkyl group has 1-5 carbon atoms (“C 1–5 In some embodiments, the alkyl group has 1-4 carbon atoms (“C 1–4 In some embodiments, the alkyl group has 1-3 carbon atoms (“C 1–3 In some embodiments, the alkyl group has 1-2 carbon atoms (“C 1–2 In some embodiments, the alkyl group has 1 carbon atom ("C1 alkyl"). In some embodiments, the alkyl group has 2-6 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). Additional examples of alkyl groups include n-heptyl (C7), n-octyl (C8), and the like. Unless otherwise specified, each instance of alkyl is independently optionally substituted, i.e., unsubstituted ("unsubstituted alkyl") or substituted with one or more substituents, such as 1-5 substituents, 1-3 substituents, or 1 substituent ("substituted alkyl"). In some embodiments, alkyl is unsubstituted C 1–10 In some embodiments, the alkyl group is a substituted C 1–10 alkyl.

[0037] "Alkylene" refers to a substituted or unsubstituted alkyl group as defined above, wherein two hydrogens are removed to provide a divalent group. Exemplary divalent alkylene groups include, but are not limited to, methylene (-CH2-), ethylene (-CH2CH2-), propylene isomers (e.g., -CH2CH2CH2- and -CH(CH3)CH2-), and the like.

[0038] "Alkenyl" refers to a straight-chain or branched hydrocarbon group having 2 to 20 carbon atoms, one or more carbon-carbon double bonds, and no triple bonds ("C 2–20 In some embodiments, the alkenyl group has 2-10 carbon atoms. 2–10 In some embodiments, the alkenyl group has 2-9 carbon atoms (C 2–9 In some embodiments, the alkenyl group has 2-8 carbon atoms (“C 2–8 In some embodiments, the alkenyl group has 2-7 carbon atoms (“C 2–7 In some embodiments, the alkenyl group has 2-6 carbon atoms (“C 2–6 In some embodiments, the alkenyl group has 2-5 carbon atoms (“C 2–5 In some embodiments, the alkenyl group has 2-4 carbon atoms (“C 2–4 In some embodiments, the alkenyl group has 2-3 carbon atoms (“C 2–3 In some embodiments, an alkenyl group has 2 carbon atoms ("C2 alkenyl"). The one or more carbon-carbon double bonds may be internal (such as in 2-butenyl) or terminal (such as in 1-butenyl). C 2–4Examples 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 above-mentioned C 2–4 In some embodiments, alkenyl is an unsubstituted C 1-4- substituted 1-6- substituted ... 2–10 In some embodiments, alkenyl is substituted C 2–10 Alkenyl.

[0039] "Alkenylene" refers to a substituted or unsubstituted alkenyl as defined above, wherein two hydrogens are removed to provide a divalent group. Exemplary divalent alkenylene groups include, but are not limited to, vinylene (-CH=CH-), propenylene (e.g., -CH=CHCH2- and -C(CH3)=CH- and -CH=C(CH3)-), and the like.

[0040] "Alkynyl" refers to a straight chain or branched hydrocarbon radical having 2 to 20 carbon atoms, one or more carbon-carbon triple bonds and optionally one or more double bonds ("C 2–20 In some embodiments, the alkynyl group has 2-10 carbon atoms ("C 2–10 In some embodiments, the alkynyl group has 2-9 carbon atoms (“C 2–9 In some embodiments, the alkynyl group has 2-8 carbon atoms ("C 2–8 In some embodiments, the alkynyl group has 2-7 carbon atoms (“C 2–7 In some embodiments, the alkynyl group has 2-6 carbon atoms ("C 2–6 In some embodiments, the alkynyl group has 2-5 carbon atoms (“C 2–5 In some embodiments, the alkynyl group has 2-4 carbon atoms (“C 2–4 In some embodiments, the alkynyl group has 2-3 carbon atoms ("C 2–3 In some embodiments, an alkynyl group has 2 carbon atoms (a "C2 alkynyl"). The one or more carbon-carbon triple bonds can be internal (such as in 2-butynyl) or terminal (such as in 1-butynyl). 2-4Examples 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 above-mentioned C 2-4 Alkynyl and pentynyl (C5), hexynyl (C6), etc. Additional examples of alkynyl include heptynyl (C7), octynyl (C8), etc. Unless otherwise specified, each instance of alkynyl is independently optionally substituted, i.e., unsubstituted (“unsubstituted alkynyl”) or substituted with one or more substituents, such as 1-5 substituents, 1-3 substituents, or 1 substituent (“substituted alkynyl”). In some embodiments, alkynyl is unsubstituted C 2-10 In some embodiments, the alkynyl group is a substituted C 2-10 Alkynyl.

[0041] "Alkyne" refers to a substituted or unsubstituted alkynyl group as defined above, wherein two hydrogens are removed to provide a divalent group. Exemplary divalent alkynyl groups include, but are not limited to, ethynylene, propynylene, and the like.

[0042] "Aryl" refers to a group having a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 π electrons shared in a cyclic arrangement) with 6-14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system ("C 6-14 In some embodiments, an aryl group has six ring carbon atoms (a "C6 aryl"; e.g., phenyl). In some embodiments, an aryl group has ten ring carbon atoms (a "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 carbocyclic or heterocyclic groups, wherein the radical or point of attachment is on the aryl ring, and in such cases, the number of carbon atoms continues to refer to the number of carbon atoms in the aryl ring system. Typical aryl groups include, but are not limited to, radicals derived from benzoacenaphthene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, Coronene, fluoranthene, fluorene, hexacene, hexylene, hexalene, unsymmetrical indacene, symmetrical indacene, indane, indene, naphthalene, octacene, octalene, octalene, ovalene, penta-2,4-diene, pentacene, pentalene, pentaphene, perylene, phenalene, phenanthracene, pyrrolidine, pyranthracene, rubrocene, triphenylene and ternaphthyl. In particular, aryl includes phenyl, naphthyl, indenyl and tetrahydronaphthyl. Unless otherwise specified, each instance of aryl is independently optionally substituted, i.e., unsubstituted ("unsubstituted aryl") or substituted ("substituted aryl") with one or more substituents. In some embodiments, aryl is unsubstituted C 6-14 In some embodiments, the aryl group is a substituted C 6-14 Aryl. In some embodiments, the aryl group is substituted with one or more groups selected from the group consisting of halogen, C1-C8 alkyl, C1-C8 haloalkyl, cyano, hydroxy, C1-C8 alkoxy, and amino.

[0043] Representative examples of substituted aryl groups include the following:

[0044]

[0045] In these formulas, R 56 and R 57 One of them may be hydrogen, and R 56 and R 57 At least one of each 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 S02R 59 、-COOalkyl、-COOaryl、-CONR 58 R 59 、-CONR 58 OR 59 、-NR 58 R 59 、-SO2NR 58 R 59 , -S-alkyl, -SOalkyl, -SO2alkyl, -Saryl, -SOaryl, -SO2aryl; or R 56 and R 57 May be combined to form a cyclic ring (saturated or unsaturated) of 5 to 8 atoms, the cyclic ring optionally containing one or more heteroatoms selected from the group consisting of N, O or S. R 60 and R 61 are independently hydrogen, C1-C8 alkyl, C1-C4 haloalkyl, C3-C10 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.

[0046] "Fused aryl" refers to an aryl group having two of its ring carbons in common with a second aryl ring or with an aliphatic ring.

[0047] "Aralkyl" is a subset of alkyl and aryl as defined herein, and refers to an optionally substituted alkyl group substituted by an optionally substituted aryl group.

[0048] "Heteroaryl" refers to a group of a 5-10 membered monocyclic or bicyclic 4n+2 aromatic ring system (e.g., having 6 or 10 π electrons shared in a cyclic arrangement) having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, 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 may be a carbon or nitrogen atom when 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 numerical value of the ring members continues to represent 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 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 the heteroatom (e.g., 5-indolyl).

[0049] In some embodiments, heteroaryl is a 5-10 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, 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 1-4 ring heteroatoms provided in the aromatic ring system, 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 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen and sulfur ("5-6 membered heteroaryl"). In some embodiments, the 5-6 membered heteroaryl has 1-3 ring heteroatoms selected from nitrogen, oxygen and sulfur. In some embodiments, the 5-6 membered heteroaryl has 1-2 ring heteroatoms selected from nitrogen, oxygen and sulfur. In some embodiments, the 5-6 membered heteroaryl has 1 ring heteroatom selected from nitrogen, oxygen and sulfur. Unless otherwise specified, each instance of heteroaryl is independently optionally substituted, i.e., unsubstituted ("unsubstituted heteroaryl") or substituted ("substituted heteroaryl") with one or more substituents. In some embodiments, heteroaryl is an unsubstituted 5-14 membered heteroaryl. In some embodiments, heteroaryl is a substituted 5-14 membered heteroaryl.

[0050] 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, Azolyl, iso Exemplary 5-membered heteroaryl groups containing three heteroatoms include, but are not limited to, triazolyl, oxadiazolyl and thiadiazolyl.

[0051] 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, aza- Oxalic acid thia Exemplary 5,6-bicyclic heteroaryl groups include, but are not limited to, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl, benzimidazolyl, benzo Azolyl, benzyl Azolyl, benzo oxadiazolyl, benzothiazolyl, benzisothiazolyl, benzothiadiazolyl, indolizinyl and purinyl. Exemplary 6,6-bicyclic heteroaryl groups include, but are not limited to, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl and quinazolinyl.

[0052] Representative examples of heteroaryl groups include the following:

[0053]

[0054] Wherein each Y 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.

[0055] Representative examples of aryl groups having substitutions containing heteroatoms include the following:

[0056]

[0057] Wherein each W is selected from C(R 66 )2. NR 66 , O and S; and each Y is selected from carbonyl, NR 66 , O and S; and R 66 are independently hydrogen, C1-C8 alkyl, C3-C 10 Cycloalkyl, 4-10 membered heterocyclic group, C6-C 10 Aryl and 5-10 membered heteroaryl.

[0058] "Heteroaralkyl" is a subset of alkyl and heteroaryl as defined herein, and refers to an optionally substituted alkyl substituted by an optionally substituted heteroaryl.

[0059] "Carbocyclyl" or "carbocyclic" refers to a non-aromatic cyclic hydrocarbon radical having 3-10 ring carbon atoms and zero heteroatoms in the non-aromatic ring system ("Carbocyclyl" or "carbocyclic"). 3-10 In some embodiments, a carbocyclyl group has 3-8 ring carbon atoms ("C 3-8 In some embodiments, a carbocyclyl group has 3-7 ring carbon atoms (“C 3-7 In some embodiments, a carbocyclyl group has 3-6 ring carbon atoms ("C 3-6 In some embodiments, a carbocyclyl group has 5-10 ring carbon atoms ("C 5-10 Carbocyclyl”). Exemplary C 3-6Carbocyclic groups include, but are not limited to, cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), and the like. Exemplary C 3-8 The carbocyclic group includes but is not limited to the above 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 The carbocyclic group includes but is not limited to the above 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 ) and the like. As described in the foregoing examples, in some embodiments, the carbocyclyl is monocyclic ("monocyclic carbocyclyl") or comprises a fused ring system, a bridged ring system or a spirocyclic system such as a bicyclic system ("bicyclic carbocyclyl") and may be saturated or may be partially unsaturated. "Carbocyclyl" also includes a ring system in which the carbocyclyl ring as defined above is fused to one or more aryl or heteroaryl groups, wherein the point of attachment is on the carbocyclyl ring, and in such a case, the numerical value of carbon continues to represent the number of carbons in the carbocyclyl system. Unless otherwise specified, each case of the carbocyclyl is independently optionally substituted, that is, unsubstituted ("unsubstituted carbocyclyl") or substituted by one or more substituents ("substituted carbocyclyl"). In some embodiments, the carbocyclyl is unsubstituted C 3–10 In some embodiments, the carbocyclyl group is a substituted C 3–10 Carbocyclic group.

[0060] In some embodiments, "carbocyclyl" is a monocyclic, saturated carbocyclyl having 3-10 ring carbon atoms. 3–10 In some embodiments, the cycloalkyl group has 3-8 ring carbon atoms "(C 3–8 In some embodiments, the cycloalkyl group has 3-6 ring carbon atoms ("C 3–6 In some embodiments, the cycloalkyl group has 5-6 ring carbon atoms ("C 5–6 In some embodiments, the cycloalkyl group has 5-10 ring carbon atoms ("C 5–10 (cycloalkyl) 5–6 Examples of cycloalkyl groups include cyclopentyl (C5) and cyclohexyl (C5). 3–6Examples of the cycloalkyl group include the above-mentioned C 5–6 Cycloalkyl as well as cyclopropyl (C3) and cyclobutyl (C4). 3–8 Examples of the cycloalkyl group include the above-mentioned C 3–6 Cycloalkyl and cycloheptyl (C7) and cyclooctyl (C8). Unless otherwise specified, each instance of cycloalkyl is independently unsubstituted (“unsubstituted cycloalkyl”) or substituted (“substituted cycloalkyl”) with one or more substituents. In some embodiments, cycloalkyl is unsubstituted C 3–10 In some embodiments, the cycloalkyl group is a substituted C 3–10 Cycloalkyl.

[0061] "Heterocyclyl" or "heterocyclic" refers to a radical of a 3-10 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 ("3-10 membered heterocyclyl"). In heterocyclyl groups containing one or more nitrogen atoms, the point of attachment may be a carbon or nitrogen atom when valence permits. A heterocyclyl group may be a monocyclic ("monocyclic heterocyclyl") or a fused, bridged or spirocyclic ring system such as a bicyclic ring system ("bicyclic heterocyclyl"), and may be saturated or may be 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 the carbocyclyl or heterocyclyl ring, or a ring system in which a heterocyclyl ring as defined above is fused to one or more aryl or heteroaryl groups, wherein the point of attachment is on the heterocyclyl ring, and in such a case, the numerical value of the ring members continues to represent the number of ring members in the heterocyclyl ring system. Unless otherwise specified, each case of heterocyclyl is independently optionally substituted, i.e., unsubstituted ("unsubstituted heterocyclyl") or substituted by one or more substituents ("substituted heterocyclyl"). In some embodiments, heterocyclyl is an unsubstituted 3-10 membered heterocyclyl. In some embodiments, heterocyclyl is a substituted 3-10 membered heterocyclyl.

[0062] In some embodiments, the heterocyclyl 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, the heterocyclyl 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, the heterocyclyl 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, the 5-6 membered heterocyclyl has 1-3 ring heteroatoms selected from nitrogen, oxygen and sulfur. In some embodiments, the 5-6 membered heterocyclyl has 1-2 ring heteroatoms selected from nitrogen, oxygen and sulfur. In some embodiments, the 5-6 membered heterocyclyl has one ring heteroatom selected from nitrogen, oxygen, and sulfur.

[0063] Exemplary 3-membered heterocyclic groups containing one heteroatom include, but are not limited to, aziridinyl, oxirane, and thiorenyl. Exemplary 4-membered heterocyclic groups containing one heteroatom include, but are not limited to, azetidinyl, oxetane, and thietanyl.

[0064] Exemplary 5-membered heterocyclic groups containing one heteroatom include, but are not limited to, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, dihydrothienyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2,5-dione. Exemplary 5-membered heterocyclic groups containing two heteroatoms include, but are not limited to, dioxolanyl, oxasulfuranyl, disulfuranyl, and Exemplary 5-membered heterocyclic groups containing three heteroatoms include, but are not limited to, triazolinyl, Diazolinyl 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, dithiohexyl, dioxane. Exemplary 6-membered heterocyclic groups containing two heteroatoms include, but are not limited to, hexahydrotriazine (triazinanyl). Exemplary 7-membered heterocyclic groups containing one heteroatom include, but are not limited to, azepine, oxane and thianyl. Exemplary 8-membered heterocyclic groups containing one heteroatom include, but are not limited to, azepine, oxane and thianyl. Exemplary 5-membered heterocyclyl groups fused to a C6 aryl ring (also referred to herein as 5,6-bicyclic heterocycles) include, without limitation, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, benzo Exemplary 6-membered heterocyclic groups fused to an aryl ring (also referred to herein as 6,6-bicyclic heterocyclic rings) include, without limitation, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and the like.

[0065] Specific examples of the heterocyclic group are shown in the following illustrative examples:

[0066]

[0067] Where each W is selected from CR 67 , C(R 67 )2. NR 67 , O and S; and each Y is selected from NR 67 , O and S; and R 67 are independently hydrogen, C1-C8 alkyl, C3-C 10 Cycloalkyl, 4-10 membered heterocyclic group, C6-C 10 The heterocyclic rings may be optionally substituted by one or more substituents selected from the group consisting of acyl, acylamino, acyloxy, alkoxy, alkoxycarbonyl, alkoxycarbonylamino, amino, substituted amino, aminocarbonyl (carbamoyl or acylamino), aminocarbonylamino, aminosulfonyl, sulfonamido, aryl, aryloxy, azido, carboxyl, cyano, cycloalkyl, halogen, hydroxyl, keto, nitro, thiol, -S-alkyl, -S-aryl, -S(O)-alkyl, -S(O)-aryl, -S(O)2-alkyl and -S(O)2-aryl. Substituent groups include carbonyl or thiocarbonyl, which provide, for example, lactam and urea derivatives.

[0068] "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 by nitrogen, oxygen, or sulfur heteroatoms. Hetero can be applied to any of the hydrocarbon groups described above, such as: alkyl, such as heteroalkyl; cycloalkyl, such as heterocyclyl; aryl, such as heteroaryl; cycloalkenyl, such as cycloheteroalkenyl, etc., which have 1-5 and particularly 1-3 heteroatoms.

[0069] "Acyl" refers to the group -C(O)R 20 , where R 20 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl as defined herein. 20is 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 some embodiments, R 21 is a C1-C8 alkyl group substituted by halogen or hydroxy; or a C3-C 10 Cycloalkyl, 4-10 membered heterocyclic group, C6-C 10 Aryl, aralkyl, 5-10 membered heteroaryl or heteroaralkyl, each of which is substituted with unsubstituted C1-C4 alkyl, halogen, unsubstituted C1-C4 alkoxy, unsubstituted C1-C4 haloalkyl, unsubstituted C1-C4 hydroxyalkyl, or unsubstituted C1-C4 haloalkoxy or hydroxy.

[0070] "Acylamino" refers to the group -NR 22 C(O)R 23 , where R 22 and R 23 Each instance of is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl as defined herein, or R 22 is an amino protecting group. Exemplary "acylamino" include, but are not limited to, formylamino, acetylamino, cyclohexylcarbonylamino, cyclohexylmethyl-carbonylamino, benzylamino and benzylcarbonylamino. Specific exemplary "acylamino" is -NR 24 C(O)-C1-C8 alkyl, –NR 24 C(O)-(CH2) t( C6-C 10 Aryl), –NR 24 C(O)-(CH2) t( 5-10 membered heteroaryl), –NR 24 C(O)-(CH2) t( C3-C 10 Cycloalkyl) and –NR 24 C(O)-(CH2)t (4-10 membered heterocyclic group), wherein t is an integer from 0 to 4, and each R 24 R independently represents H or C1-C8 alkyl. 25 is H, C1-C8 alkyl substituted by halogen or hydroxyl; C3-C 10 Cycloalkyl, 4-10 membered heterocyclic group, C6-C 10 aryl, aralkyl, 5-10 membered heteroaryl or heteroaralkyl, each of which is substituted with unsubstituted C1-C4 alkyl, halogen, unsubstituted C1-C4 alkoxy, unsubstituted C1-C4 haloalkyl, unsubstituted C1-C4 hydroxyalkyl, or unsubstituted C1-C4 haloalkoxy or hydroxy; and R 26 is H, C1-C8 alkyl substituted by halogen or hydroxyl; C3-C 10 Cycloalkyl, 4-10 membered heterocyclic group, C6-C 10 aryl, aralkyl, 5-10 membered heteroaryl or heteroaralkyl, each of which is substituted with unsubstituted C1-C4 alkyl, halogen, unsubstituted C1-C4 alkoxy, unsubstituted C1-C4 haloalkyl, unsubstituted C1-C4 hydroxyalkyl, or unsubstituted C1-C4 haloalkoxy or hydroxy; provided that R 25 and R 26 At least one of is different from H.

[0071] "Acyloxy" refers to the group -OC(O)R 27 , where R 27 R is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl as defined herein. Representative examples include, but are not limited to, formyl, acetyl, cyclohexylcarbonyl, cyclohexylmethylcarbonyl, benzoyl, and benzylcarbonyl. In some embodiments, R 28 is a C1-C8 alkyl group substituted by halogen or hydroxyl; 10 Cycloalkyl, 4-10 membered heterocyclic group, C6-C 10 Aryl, aralkyl, 5-10 membered heteroaryl or heteroaralkyl, each of which is substituted with unsubstituted C1-C4 alkyl, halogen, unsubstituted C1-C4 alkoxy, unsubstituted C1-C4 haloalkyl, unsubstituted C1-C4 hydroxyalkyl, or unsubstituted C1-C4 haloalkoxy or hydroxy.

[0072] "Alkoxy" refers to the group -OR 29 , where R 29is a substituted or unsubstituted alkyl, a substituted or unsubstituted alkenyl, a substituted or unsubstituted alkynyl, 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. Specific alkoxy groups are 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., having 1-6 carbon atoms. Further specific alkoxy groups have 1-4 carbon atoms.

[0073] In some embodiments, R 29 is a group having one or more substituents, for example 1 to 5 substituents, and particularly 1 to 3 substituents, particularly 1 substituent 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 of 0-4, and any aryl, heteroaryl, cycloalkyl or heterocyclyl present may itself be substituted by unsubstituted C1-C4 alkyl, halogen, unsubstituted C1-C4 alkoxy, unsubstituted C1-C4 haloalkyl, unsubstituted C1-C4 hydroxyalkyl, or unsubstituted C1-C4 haloalkoxy or hydroxy. Specific exemplary 'substituted alkoxy' is -OCF3, -OCH2CF3, -OCH2Ph, -OCH2-cyclopropyl, -OCH2CH2OH and -OCH2CH2NMe2.

[0074] "Amino" refers to the group -NH2.

[0075] "Substituted amino" refers to a group of the formula -N(R 38 )2 amino group, wherein R 38 is 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 an amino protecting group, wherein R 38At least one of is not hydrogen. In some embodiments, each R 38 independently selected from: hydrogen, C1-C8 alkyl, C3-C8 alkenyl, C3-C8 alkynyl, C6-C 10 Aryl, 5-10 membered heteroaryl, 4-10 membered heterocyclic group, or C3-C 10 Cycloalkyl; or C1-C8 alkyl substituted by halogen or hydroxy; 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 by unsubstituted C1-C4 alkyl, halogen, unsubstituted C1-C4 alkoxy, unsubstituted C1-C4 haloalkyl, unsubstituted C1-C4 hydroxyalkyl, or unsubstituted C1-C4 haloalkoxy or hydroxy; or two R 38 The groups combine to form an alkylene group.

[0076] Exemplary "substituted amino" is -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 heterocyclic group), wherein t is an integer from 0 to 4, such as 1 or 2, and each R 39Independently represents H or C1-C8 alkyl; and any alkyl present can itself be substituted by halogen, substituted or unsubstituted amino, or hydroxyl; and any aryl, heteroaryl, cycloalkyl, or heterocyclic radical present can itself be substituted by unsubstituted C1-C4 alkyl, halogen, unsubstituted C1-C4 alkoxy, unsubstituted C1-C4 haloalkyl, unsubstituted C1-C4 hydroxyalkyl, or unsubstituted C1-C4 haloalkoxy or hydroxyl. 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 includes both monosubstituted amino and disubstituted amino.

[0077] "Azide" refers to the group -N3.

[0078] "Carbamoyl" or "amido" refers to the group -C(O)NH2.

[0079] "Substituted carbamoyl" or "substituted amido" refers to the group -C(O)N(R 62 )2, where each R 62 are independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or an amino protecting group, wherein R 62 In some embodiments, at least one of R is not hydrogen. 62 Selected from H, C1-C8 alkyl, C3-C 10 Cycloalkyl, 4-10 membered heterocyclic group, C6-C 10 Aryl, aralkyl, 5-10 membered heteroaryl, and heteroaralkyl; or C1-C8 alkyl substituted by halogen or hydroxy; or C3-C 10 Cycloalkyl, 4-10 membered heterocyclic group, C6-C 10 aryl, aralkyl, 5-10 membered heteroaryl, or heteroaralkyl, each of which is substituted with unsubstituted C1-C4 alkyl, halogen, unsubstituted C1-C4 alkoxy, unsubstituted C1-C4 haloalkyl, unsubstituted C1-C4 hydroxyalkyl, or unsubstituted C1-C4 haloalkoxy or hydroxy; provided that at least one R 62 Different from H. Exemplary "substituted carbamoyl" include, but are not limited to, -C(O)NR 64 -C1-C8 alkyl, –C(O)NR 64 -(CH2) t (C6-C 10 Aryl), –C(O)N 64 -(CH2) t(5-10 membered heteroaryl), –C(O)NR 64 -(CH2) t (C3-C 10 Cycloalkyl) and –C(O)NR 64 -(CH2) t (4-10 membered heterocyclic group), wherein t is an integer from 0 to 4, each R 64 independently represents H or C1-C8 alkyl, and any aryl, heteroaryl, cycloalkyl or heterocyclyl present may itself be substituted by unsubstituted C1-C4 alkyl, halogen, unsubstituted C1-C4 alkoxy, unsubstituted C1-C4 haloalkyl, unsubstituted C1-C4 hydroxyalkyl, or unsubstituted C1-C4 haloalkoxy or hydroxy.

[0080] "Carboxy" refers to the group -C(O)OH.

[0081] "Cyano" refers to the radical -CN.

[0082] "Halo" or "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br), and iodine (I). In some embodiments, the halo group is fluorine or chlorine.

[0083] "Hydroxy" refers to the radical -OH.

[0084] "Nitro" refers to the radical -NO2.

[0085] "Cycloalkylalkyl" refers to an alkyl group in which the alkyl group is substituted with a cycloalkyl group. Typical cycloalkylalkyl groups include, but are not limited to, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cycloheptylmethyl, cyclooctylmethyl, cyclopropylethyl, cyclobutylethyl, cyclopentylethyl, cyclohexylethyl, cycloheptylethyl, and cyclooctylethyl, etc.

[0086] "Heterocyclylalkyl" refers to an alkyl group in which the alkyl group is substituted with a heterocyclyl group. Typical heterocyclylalkyl groups include, but are not limited to, pyrrolidinylmethyl, piperidinylmethyl, piperazinylmethyl, morpholinylmethyl, pyrrolidinylethyl, piperidinylethyl, piperazinylethyl, morpholinylethyl, and the like.

[0087] "Cycloalkenyl" refers to a substituted or unsubstituted carbocyclic group having 3-10 carbon atoms and having a single cyclic ring or multiple fused rings (including fused ring systems and bridged ring systems) and having at least one and particularly 1-2 olefinic unsaturated sites. Such cycloalkenyl groups include, for example, monocyclic structures such as cyclohexenyl, cyclopentenyl, cyclopropenyl, etc.

[0088] "Fused cycloalkenyl" refers to a cycloalkenyl having two of its ring carbon atoms in common with a second aliphatic or aromatic ring and having its olefinic unsaturation positioned so as to impart aromaticity to the cycloalkenyl ring.

[0089] "Vinyl" refers to a substituted or unsubstituted -(CH=CH)- group.

[0090] "Ethylene" refers to substituted or unsubstituted -(CH2-CH2)-.

[0091] "Ethynyl" refers to -(C≡C)-.

[0092] "Nitrogen-containing heterocyclic group" means a 4-7 membered non-aromatic cyclic group containing at least one nitrogen atom, for example, without limitation, 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.

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

[0094] Alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl groups as defined herein are optionally substituted (e.g., "substituted" or "unsubstituted" alkyl, "substituted" or "unsubstituted" alkenyl, "substituted" or "unsubstituted" alkynyl, "substituted" or "unsubstituted" 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, when substituted, results in a stable compound, such as a compound that does not spontaneously undergo a transformation (e.g., by rearrangement, cyclization, elimination or other reaction). Unless otherwise stated, 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 at each position is the same or different. The term "substituted" is intended to include substitutions with all permissible substituents of an organic compound (resulting in any substituent described herein that forms a stable compound). The present invention is designed (expected) to obtain any and all such combinations of stable compounds. For the present invention, heteroatoms such as nitrogen may have hydrogen substituents and / or any suitable substituents as described herein that satisfy the valence of the heteroatoms and result in the formation of a stable part.

[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)SRaa , –SC(=O)SR aa 、–OC(=O)SR aa , –SC(=O)OR aa , –SC(=O)R aa 、–P(=O)2R aa 、–OP(=O)2R aa , –P(=O)(R aa )2. –OP(=O)(R aa )2. –OP(=O)(OR cc )2, –P(=O)2N(R bb )2, –OP(=O)2N(R bb )2, –P(=O)(NR bb )2. –OP(=O)(NR bb )2. –NR bb P(=O)(OR cc )2. –NR bb P(=O)(NR bb )2. –P(R cc )2. –P(R cc )3. –OP(R cc )2. –OP(R cc )3. –B(R aa )2. –B(OR cc 2. –BR aa (OR cc ), C 1–10 Alkyl, C 1–10 Perhaloalkyl, 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 the two geminal hydrogen atoms on the 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 Each case is independently selected from C1–10 Alkyl, C 1–10 Perhaloalkyl, 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 aa The groups are combined 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 substituted by 0, 1, 2, 3, 4, or 5 R dd Group substitution;

[0097] R bb Each instance of is independently selected from hydrogen, -OH, -OR aa , –N(R cc )2, –CN, –C(=O)R aa , –C(=O)N(R cc 2. –CO2R aa , –SO2R aa , –C(=NR cc )OR aa , –C(=NR cc )N(R cc )2, –SO2N(R cc 2. –SO2R cc , –SO2OR cc , –SOR aa , –C(=S)N(R cc )2, –C(=O)SR cc , –C(=S)SR cc 、–P(=O)2R aa , –P(=O)(R aa )2, –P(=O)2N(R cc )2, –P(=O)(NR cc 2. C 1–10 Alkyl, C 1–10 Perhaloalkyl, 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 The groups are combined 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 substituted by 0, 1, 2, 3, 4, or 5 R dd Group substitution;

[0098] R ccEach instance of is independently selected from hydrogen, C 1–10 Alkyl, C 1–10 Perhaloalkyl, 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 cc The groups are combined 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 substituted by 0, 1, 2, 3, 4, or 5 R dd Group substitution;

[0099] R dd Each instance of is independently selected from halogen, –CN, –NO2, –N3, –SO2H, –SO3H, –OH, –OR ee ,–ON(R ff )2. –N(R ff )2. –N(R ff )3 + X – 、–N(OR ee )R ff , –SH, –SR ee , –SSR ee , –C(=O)R ee , –CO2H, –CO2R ee 、–OC(=O)R ee , –OCO2R ee , –C(=O)N(R ff )2. –OC(=O)N(R ff )2. –NR ff C(=O)R ee ,–NR ff CO2R ee ,–NR ff C(=O)N(R ff )2, –C(=NR ff )OR ee 、–OC(=NR ff )R ee 、–OC(=NR ff )OR ee , –C(=NR ff )N(R ff )2. –OC(=NR ff )N(R ff )2. –NR ff C(=NR ff )N(R ff )2. –NRff S02R 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 Perhaloalkyl, C 2–6 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 substituted by 0, 1, 2, 3, 4, or 5 R gg Group substitution, or two geminal R dd Substituents may combine to form =O or =S;

[0100] R ee Each case is independently selected from C 1–6 Alkyl, C 1–6 Perhaloalkyl, 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 Each instance of is independently selected from hydrogen, C 1-6 Alkyl, C 1-6 Perhaloalkyl, 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 Rff The groups are combined 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 substituted by 0, 1, 2, 3, 4, or 5 R gg Group substitution; and

[0102] R gg Each case is independently 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(C1-6 alkyl), -C(=NH)NH2, -OC(=NH)N(C 1-6 Alkyl)2, -OC(NH)NH(C 1-6 alkyl), -OC(NH)NH2, -NHC(NH)N(C 1-6 Alkyl)2, -NHC(=NH)NH2, -NHSO2(C 1-6 Alkyl), -SO2N(C 1-6 Alkyl)2, -SO2NH(C 1-6 Alkyl), -SO2NH2, -SO2C 1-6 Alkyl, -SO2OC 1-6 Alkyl, -OSO2C 1-6 Alkyl, -SOC 1-6 Alkyl, -Si(C 1-6 Alkyl)3, -OSi(C 1-6 alkyl)3-C(=S)N(C 1-6 alkyl)2, C(=S)NH(C 1-6 alkyl), C(=S)NH2, -C(=O)S(C 1-6 Alkyl), -C(=S)SC 1-6 Alkyl, -SC(=S)SC 1-6 Alkyl, -P(=O)2(C 1-6 alkyl), -P(=O)(C 1-6 Alkyl)2, -OP(=O)(C 1-6 Alkyl)2, -OP(=O)(OC 1-6 Alkyl)2, C 1-6 Alkyl, C 1-6 Perhaloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocyclic group, C 6-10 aryl, 3-10 membered heterocyclyl, 5-10 membered heteroaryl; or two geminal R gg Substituents may combine to form =O or =S; where X - For the counter ion.

[0103] "Counter ions" or "anionic counter ions" are negatively charged groups that associate with cationic quaternary amino groups to maintain electrical neutrality. Exemplary counter ions include halide ions (e.g., F - , Cl - Br - ,I - )、NO3 - 、ClO4 - OH - 、H2PO4 - 、HSO4- , sulfonate ions (e.g., methanesulfonate, trifluoromethanesulfonate, p-toluenesulfonate, benzenesulfonate, 10-camphorsulfonate, naphthalene-2-sulfonate, naphthalene-1-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] The nitrogen atoms may be substituted or unsubstituted where valence permits, and include primary, secondary, tertiary, and quaternary nitrogen atoms. Exemplary nitrogen atom substituents include, but are not limited to, hydrogen, -OH, -OR aa , –N(R cc )2, –CN, –C(=O)R aa , –C(=O)N(R cc 2. –CO2R aa , –SO2R aa , –C(=NR bb )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 、–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 Perhaloalkyl, 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 attached to the nitrogen atom cc The groups are combined 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 substituted by 0, 1, 2, 3, 4, or 5 R dd substituted with a group, and wherein R aa , R bb , R cc and R ddAs defined above.

[0105] In some embodiments, the substituent present on the nitrogen atom is a nitrogen protecting group (also referred to as an amino protecting group). Nitrogen protecting groups include, but are not limited to, -OH, -OR aa , –N(R cc )2. –C(=O)R aa , –C(=O)N(R cc 2. –CO2R aa , –SO2R 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 (e.g., aralkyl, heteroaralkyl), 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, aralkyl, aryl and heteroaryl is independently substituted by 0, 1, 2, 3, 4, or 5 R dd substituted with a group, and wherein R aa , R bb , R cc and R dd As defined herein. Nitrogen protecting groups are well known in the art and are included in Protecting Groups in Organic Synthesis, TW Greene and PGM Wuts, 3 rd Those described in detail in , John Wiley & Sons, edition, 1999, which is incorporated herein by reference.

[0106] For example, a nitrogen protecting group such as an amide group (eg, -C(=O)R aa) include, but are not limited to, formamide, acetamide, chloroacetamide, trichloroacetamide, trifluoroacetamide, phenylacetamide, 3-phenylpropionamide, picolinamide, 3-pyridylformamide, N-benzoylphenylalanyl derivatives, benzamide, p-phenylbenzamide, o-nitrophenylacetamide, o-nitrophenoxyacetamide, acetoacetamide, (N'-dithiobenzyloxyamido)acetamide, 3-(p-hydroxyphenyl)propionamide, 3-(o-nitrophenyl)propionamide, 2-methyl-2-(o-nitrophenoxy)propionamide, 2-methyl-2-(o-phenylazophenoxy)propionamide, 4-chlorobutanamide, 3-methyl-3-nitrobutanamide, o-nitrocinnamamide, N-acetylmethionine derivatives, o-nitrobenzamide, and o-(benzoyloxymethyl)benzamide.

[0107] Nitrogen protecting groups such as carbamate groups (e.g., -C(=O)OR aa) include, but are not limited to, methyl carbamate, ethyl carbamate, 9-fluorenylmethyl carbamate (Fmoc), 9-(2-sulfo)fluorenylmethyl carbamate, 9-(2,7-dibromo)fluorenylmethyl carbamate, 2,7-di-tert-butyl-[9-(10,10-dioxo-10,10,10,10-tetrahydrothioxanthenyl)]methyl carbamate (DBD-Tmoc), 4-methoxybenzoylmethyl carbamate (Phenoc), 2,2,2-trichloroethyl carbamate (Troc), 2-trimethylsilylethyl carbamate (Teoc), 2-phenylethyl ester (hZ), 1-(1-adamantyl)-1-methylethyl carbamate (Adpoc), 1,1-dimethyl-2-haloethyl carbamate, 1,1-dimethyl-2,2-dibromoethyl carbamate (DB-t-BOC), 1,1-dimethyl-2,2,2-trichloroethyl carbamate (TCBOC), 1-methyl-1-(4-biphenylyl)ethyl carbamate (Bpoc), 1-(3,5-di-tert-butylphenyl)-1-methylethyl carbamate (t-Bumeoc), 2-(2'- and 4'-pyridyl)ethyl carbamate ( Pyoc), 2-(N,N-dicyclohexylcarbamyl)ethyl carbamate, tert-butyl carbamate (BOC), 1-adamantyl carbamate (Adoc), vinyl carbamate (Voc), allyl carbamate (Alloc), 1-isopropyl allyl carbamate (Ipaoc), cinnamyl carbamate (Coc), 4-nitrocinnamyl carbamate (Noc), 8-quinolyl carbamate, N-hydroxypiperidinyl carbamate, alkyl dithiocarbamate, benzyl carbamate (Cbz), p-methoxybenzyl carbamate (Moz), amino p-Nitrobenzyl formate, p-bromobenzyl carbamate, p-chlorobenzyl carbamate, 2,4-dichlorobenzyl carbamate, 4-methylsulfinylbenzyl carbamate (Msz), 9-anthrylmethyl carbamate, diphenylmethyl carbamate, 2-methylthioethyl carbamate, 2-methylsulfonylethyl carbamate, 2-(p-toluenesulfonyl)ethyl carbamate, [2-(1,3-dithiohexyl)]methyl carbamate (Dmoc), 4-methylthiophenyl carbamate (Mtpc), 2,4-dimethylthiophenyl carbamate (Bmpc), 2-phosphorus carbamate Ethyl ester (Peoc), 2-triphenylphosphine carbamate isopropyl carbamate (Ppoc), 1,1-dimethyl-2-cyanoethyl carbamate, m-chloro-p-acyloxybenzyl carbamate, p-(dihydroxyboryl)benzyl carbamate, 5-benzisohexyl carbamate oxazolidinyl methyl ester, 2-(trifluoromethyl)-6-chromonyl methyl carbamate (Tcroc), m-nitrophenyl carbamate, 3,5-dimethoxybenzyl carbamate, o-nitrobenzyl carbamate, 3,4-dimethoxy-6-nitrobenzyl carbamate, phenyl (o-nitrophenyl) methyl carbamate, tert-amyl carbamate, S-benzyl thiocarbamate, p-cyanobenzyl carbamate, cyclobutyl carbamate, cyclohexyl carbamate, cyclopentyl carbamate, cyclopropyl methyl carbamate, p-decyloxybenzyl carbamate, 2,2-dimethoxyacylvinyl carbamate, o-(N,N-dimethylformamido)benzyl carbamate, 1,1-dimethyl-3-(N,N-dimethylformamido)propyl carbamate, 1,1-dimethylpropynyl carbamate, di(2 1-(4-pyridyl)ethyl carbamate, phenyl carbamate, p-(phenylazo)benzyl carbamate, 2,4,6-tri-tert-butylphenyl carbamate, 4-(trimethylammonium)benzyl carbamate and 2,4,6-trimethylbenzyl carbamate.

[0108] Nitrogen protecting groups such as sulfonamide groups (e.g., -S(=O)2R aa ) include, but are not limited to, p-toluenesulfonamide (Ts), benzenesulfonamide, 2,3,6,-trimethyl-4-methoxybenzenesulfonamide (Mtr), 2,4,6-trimethoxybenzenesulfonamide (Mtb), 2,6-dimethyl-4-methoxybenzenesulfonamide (Pme), 2,3,5,6-tetramethyl-4-methoxybenzenesulfonamide (Mte), 4-methoxybenzenesulfonamide (Mbs), 2,4,6-trimethylbenzenesulfonamide (Mts), 2,6-dimethoxy-4-methylbenzenesulfonamide (iMds), 2,2,5,7,8-pentamethylchroman-6-sulfonamide (Pmc), methanesulfonamide (Ms), β-trimethylsilylethanesulfonamide (SES), 9-anthracenesulfonamide, 4-(4′,8′-dimethoxynaphthylmethyl)benzenesulfonamide (DNMBS), benzylsulfonamide, trifluoromethylsulfonamide and phenacylmethylsulfonamide.

[0109] Other nitrogen protecting groups include, but are not limited to, phenothiazinyl-(10)-acyl derivatives, N'-p-toluenesulfonylaminoacyl derivatives, N'-phenylaminothioacyl derivatives, N-benzoylphenylalanyl derivatives, N-acetylmethionine derivatives, 4,5-diphenyl-3- oxazolin-2-one, N-phthalimide, N-dithiosuccinimide (Dts), N-2,3-diphenylmaleimide, N-2,5-dimethylpyrrole, N-1,1,4,4-tetramethyldisilaziridine adduct (STABASE), 5-substituted 1,3-dimethyl-1,3,5-triazacyclohexane-2-one, 5-substituted 1,3-dibenzyl-1,3,5-triazacyclohexane-2-one, 1-substituted 3,5-dinitro-4-pyridone, N-methylamine, N-allylamine, N-[2-(trimethylsilyl)ethoxy]methylamine (SEM), N-3-acetoxypropylamine, N -(1-isopropyl-4-nitro-2-oxo-3-pyrrolin-3-yl)amine, quaternary ammonium salts, N-benzylamine, N-di(4-methoxyphenyl)methylamine, N-5-dibenzocycloheptylamine, N-triphenylmethylamine (Tr), N-[(4-methoxyphenyl)diphenylmethyl]amine (MMTr), N-9-phenylfluorenylamine (PhF), N-2,7-dichloro-9-fluorenylmethyleneamine, N-ferrocenylmethylamino (Fcm), N-2-pyridylmethylamino N'-oxide, N-1,1-dimethylthiomethyleneamine, N-benzylideneamine, N-p-methoxybenzylideneamine, N-diphenylmethyleneamine, N-[(2-pyridyl) [yl] methyleneamine, N-(N',N'-dimethylaminomethylene)amine, N,N'-isopropylidene diamine, N-p-nitrobenzylideneamine, N-salicylideneamine, N-5-chlorosalicylideneamine, N-(5-chloro-2-hydroxyphenyl)phenylmethyleneamine, N-cyclohexyleneamine, N-(5,5-dimethyl-3-oxo-1-cyclohexenyl)amine, N-borane derivatives, N-diphenylboronic acid (borinic acid) derivatives, N-[phenyl(pentacylchromium- or tungsten)acyl]amine, N-copper chelates, N-zinc chelates, N-nitroamines, N-nitrosoamines, amine N-oxides, diphenylphosphoramide (Dpp), dimethylthiophosphoramide (Mpt), diphenylthiophosphoramide (Ppt), dialkylphosphoramidates, dibenzylphosphoramidate, diphenylphosphoramidate, benzenesulfenamide, o-nitrobenzenesulfenamide (Nps), 2,4-dinitrobenzenesulfenamide, pentachlorobenzenesulfenamide, 2-nitro-4-methoxybenzenesulfenamide, triphenylmethylsulfenamide, and 3-nitropyridinesulfenamide (Npys).

[0110] In some 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 are included in Protecting Groups in Organic Synthesis, TW Greene and PGM Wuts, 3 rd Those described in detail in , John Wiley & Sons, edition, 1999, which is incorporated herein by reference.

[0111] Exemplary oxygen protecting groups include, but are not limited to, methyl, methoxymethyl (MOM), methylthiomethyl (MTM), tert-butylthiomethyl, (phenyldimethylsilyl)methoxymethyl (SMOM), benzyloxymethyl (BOM), p-methoxybenzyloxymethyl (PMBM), (4-methoxyphenoxy)methyl (p-AOM), guaiacolmethyl (GUM), tert-butoxymethyl, 4-pentenyloxymethyl (POM), silyloxymethyl, 2-methoxyethoxymethyl (ME M), 2,2,2-trichloroethoxymethyl, bis(2-chloroethoxy)methyl, 2-(trimethylsilyl)ethoxymethyl (SEMOR), tetrahydropyranyl (THP), 3-bromotetrahydropyranyl, tetrahydrothiopyranyl, 1-methoxycyclohexyl, 4-methoxytetrahydropyranyl (MTHP), 4-methoxytetrahydrothiopyranyl, 4-methoxytetrahydrothiopyranyl S,S-dioxide, 1-[(2-chloro-4-methyl)phenyl]-4-methoxypiperidin-4-yl (CTMP), 1,4-dihydro- alkyl-2-yl, tetrahydrofuranyl, tetrahydrothienyl, 2,3,3a,4,5,6,7,7a-octahydro-7,8,8-trimethyl-4,7-methanobenzofuran-2-yl, 1-ethoxyethyl, 1-(2-chloroethoxy)ethyl, 1-methyl-1-methoxyethyl, 1-methyl-1-benzyloxyethyl, 1-methyl-1-benzyloxy-2-fluoroethyl, 2,2,2-trichloroethyl, 2-trimethylsilylethyl, 2-(phenylseleno)ethyl, tert-butyl, allyl, p-chlorophenyl, p-methoxyphenyl, 2,4-dinitrophenyl, benzyl (Bn), p-methoxybenzyl, 3,4-dimethoxybenzyl, o-nitrobenzyl, p-nitrobenzyl, p-halobenzyl, 2,6- dichlorobenzyl, p-cyanobenzyl, p-phenylbenzyl, 2-picolyl, 4-picolyl, 3-methyl-2-picolyl N-oxido, diphenylmethyl, p,p'-dinitrodiphenylmethyl, 5-dibenzosuberyl, triphenylmethyl, α-naphthyldiphenylmethyl, p-methoxyphenyldiphenylmethyl, di(p-methoxyphenyl)phenylmethyl, tri(p-methoxyphenyl)methyl, 4-(4'-bromophenacyloxyphenyl)diphenylmethyl, 4,4',4"-tris(4,5-dichlorophthalimidophenyl)methyl, 4,4',4"-tris(levulinoyloxyphenyl)methyl, 4,4',4"-tris(benzoyloxyphenyl)methyl, 3-(Imidazol-1-yl)bis(4′,4″-dimethoxyphenyl)methyl, 1,1-bis(4-methoxyphenyl)-1′-pyrenylmethyl, 9-anthryl, 9-(9-phenyl)xanthenyl, 9-(9-phenyl-10-oxo)anthryl, 1,3-benzodithiolan-2-yl, benzisothiazolyl S,S-dioxy bridge, trimethylsilyl (TMS), triethylsilyl (TES), triisopropylsilyl (TIPS), dimethylisopropylsilyl (IPDMS), diethylisopropylsilyl (DEIPS), dimethylhexyl (ethyl, thexyl) silyl, tert-butyldimethylsilyl (TBDMS), tert-butyldiphenylsilyl (TBDPS) , tribenzylsilyl, tri-p-xylylsilyl, triphenylsilyl, diphenylmethylsilyl (DPMS), tert-butylmethoxyphenylsilyl (TBMPS), formates, benzoylformates, acetates, chloroacetates, dichloroacetates, trichloroacetates, trifluoroacetates, methoxyacetates, triphenylmethoxyacetates, phenoxyacetates, p-chlorophenoxyacetates, 3-phenylpropionate, 4-oxopentanoate (levulinic acid ester), 4,4-(ethylenedithio)pentanoate (levulinic acid dithioacetal), pivalate, adamantanoate (adamantoate), crotonate, 4-methoxycrotonate, benzoate, p-phenylbenzoate, 2,4,6-Trimethylbenzoate (, esters), alkyl methyl carbonate, 9-fluorenylmethyl carbonate (Fmoc), alkyl ethyl carbonate, alkyl 2,2,2-trichloroethyl carbonate (Troc), 2-(trimethylsilyl)ethyl carbonate (TMSEC), 2-(phenylsulfonyl)ethyl carbonate (Psec), 2-(triphenylphosphinoyl)carbonate alkyl)ethyl carbonate (Peoc), alkyl isobutyl carbonate, alkyl vinyl carbonate, alkyl allyl carbonate, alkyl p-nitrophenyl carbonate, alkyl benzyl carbonate, alkyl p-methoxybenzyl carbonate, alkyl 3,4-dimethoxybenzyl carbonate, alkyl o-nitrobenzyl carbonate, alkyl p-nitrobenzyl carbonate, alkyl S-benzyl thiocarbonate, 4-ethoxy-1-naphthyl carbonate, methyl dithiocarbonate, 2-iodobenzoate, 4-azidobutyrate, 4-nitro-4-methylvalerate, o-(dibromomethyl)benzoate, 2-formylbenzenesulfonate, 2-(methylthiomethoxy)ethyl, 4-(methylthiomethoxy)butyrate, 2-(methylthio esters, esters of 2,4-bis(1,1-dimethylpropyl)phenoxyacetate, chlorodiphenylacetate, isobutyrate, monosuccinate, (E)-2-methyl-2-butenoate, o-(methoxyacyl)benzoate, α-naphthoate, nitrate, alkyl N,N,N',N'-tetramethylphosphorodiamidate, alkyl N-phenylcarbamate, borate, dimethylphosphinothioate, alkyl 2,4-dinitrophenylsulfenate, sulfate, methanesulfonate (mesylate), benzylsulfonate and toluenesulfonate (Ts).

[0112] In some 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 cc As defined herein. Sulfur protecting groups are well known in the art and are included in Protecting Groups in Organic Synthesis, TW Greene and PGM Wuts, 3 rd Those described in detail in , John Wiley & Sons, edition, 1999, which is incorporated herein by reference.

[0113] "Compounds of the invention" and equivalent expressions are intended to include compounds as described herein, particularly compounds according to any formula listed and / or described herein, including prodrugs, pharmaceutically acceptable salts and solvates such as hydrates, when the context so permits. Similarly, references to intermediates, whether or not they themselves are claimed, are intended to include their salts and solvates, when the context so permits.

[0114] These and other exemplary substituents are described in greater detail in the Detailed Description, Examples, and Claims.It is not intended that the present invention be limited in any way by the above exemplary list of substituents.

[0115] Other definitions

[0116] "Pharmaceutically acceptable" means approved or approvable by a regulatory agency of the Federal or a state government or equivalent 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.

[0117] "Pharmaceutically acceptable salt" refers to a salt of a compound of the present invention that is pharmaceutically acceptable and has the desired pharmacological activity of the parent compound. Specifically, such salts are non-toxic and may be organic or inorganic acid addition salts and base addition salts. In particular, such salts include: (1) acid addition salts, which are formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc.; or 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 The present invention also includes salts of (i) 4-(2-hydroxy-4-(2-hydroxy-2-oxo-1-yl)-1 ...

[0118] The term "pharmaceutically acceptable cation" refers to an acceptable cationic counterion of an acidic functional group. Such cations are exemplified by sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium cations, and the like. See, e.g., Berge, et al., J. Pharm. Sci. (1977) 66 (1): 1–79.

[0119] "Solvate" refers to a form of a compound that is associated with a solvent or water (also referred to as a "hydrate"), typically by solvolysis. This physical association includes hydrogen bonding. Conventional solvents include water, ethanol, acetic acid, and the like. The compounds of the invention can be prepared, for example, in a crystalline form and can be solvated or hydrated. Suitable solvates include pharmaceutically acceptable solvates such as hydrates, and also include both stoichiometric solvates and non-stoichiometric solvates. In some cases, the solvate is capable of separation, for example when one or more solvent molecules are introduced into the crystal lattice of the crystalline solid. "Solvate" includes both solution phase and separable solvates. Representative solvates include hydrates, ethanolates, and methanolates.

[0120] "Subjects" intended for administration include, but are not limited to, humans (i.e., males or females of any age group, e.g., pediatric subjects (e.g., infants, children, adolescents) or adult subjects (e.g., young adults, middle-aged adults, or older adults)) and / or non-human animals, e.g., mammals such as primates (e.g., cynomolgus monkeys, rhesus monkeys), cattle, pigs, horses, sheep, goats, rodents, cats, and / or dogs. In some embodiments, the subject is a human. In some embodiments, the subject is a non-human animal. The terms "human," "patient," and "subject" are used interchangeably herein.

[0121] "Condition," "disease," and "disorder" are used interchangeably herein.

[0122] "Effective amount" means the amount of a compound that, when administered to a subject for the treatment or prevention of a disease, is sufficient to effect such treatment or prevention. "Effective amount" may vary depending on the compound, the disease and its severity, and the age, weight, etc., of the subject to be treated. "Therapeutically effective amount" refers to an effective amount for therapeutic treatment. "Prophylactically effective amount" refers to an effective amount for preventive treatment.

[0123] "Prevention" or "prophylactic treatment" refers to the reduction of the risk of acquiring or developing a disease or condition (i.e., preventing the development of at least one clinical symptom of a disease in a subject susceptible to the disease, or not exposed to the pathogen prior to the onset of the disease). The term "prophylaxis" is related to "prevention" and refers to measures or procedures whose purpose is to prevent, rather than treat or cure, a disease.

[0124] "Treatment" or "therapeutic treatment" of any disease or condition refers to ameliorating the disease or condition (i.e., preventing (inhibiting) the disease or reducing the manifestation, extent, or severity of at least one of its clinical symptoms). In another embodiment, "treatment" refers to improving at least one physical parameter, which may not be discernible by the subject. In yet another embodiment, "treatment" refers to modulating the disease or condition physically (e.g., stabilization of discernible symptoms), physiologically (e.g., stabilization of a physical parameter), or both. In additional embodiments, "treatment" involves slowing the progression of a disease.

[0125] As used herein, the term "isotopic variant" refers to a compound that contains an unnatural proportion of isotopes at one or more of the atoms that constitute such a compound. For example, an "isotopic variant" of a compound may contain one or more non-radioactive isotopes, such as deuterium ( 2 H or D), carbon-13 ( 13 C), nitrogen-15 ( 15It will be appreciated that in compounds in which such isotopic substitutions are made, the following atoms, when present, may be altered so that, for example, any hydrogen may be 2 H / D, any carbon can be 13 C, or any nitrogen can be 15 N, and the presence and arrangement of such atoms can be determined within the skill of the art. Likewise, in cases where, for example, the resulting compound is useful for drug and / or substrate tissue distribution studies, the invention may include the use of radioactive isotopes to prepare isotopic variants. 3 H and carbon-14 14 They are particularly useful for this purpose due to the ease of introduction of C and the ready availability of detection means. In addition, it is possible to prepare 11 C. 18 F. 15 O and 13 N-substituted compounds, and they will be useful in positron emission tomography (PET) studies for examining substrate receptor occupancy. All isotopic variations (radioactive or non-radioactive) of the compounds provided herein are intended to be included within the scope of the present invention.

[0126] "Stereoisomers": It will also be understood that compounds having the same molecular formula but differing in the nature or order of bonding of their atoms or the arrangement of their atoms in space are referred to as "isomers". Isomers that differ in the arrangement of their atoms in space are referred to as "stereoisomers". Stereoisomers that are not mirror images of each other are referred to as "diastereomers", and those that are non-superimposable mirror images of each other are referred to as "enantiomers". When a compound has an asymmetric center, for example, it is bonded to four different groups, a pair of enantiomers is possible. Enantiomers can be characterized by the absolute configuration of their asymmetric center and are described by the R- and S-ordering rules of Cahn and Prelog, or by the manner in which the molecule rotates the plane of polarized light, and are referred to as right-handed or left-handed (i.e., (+) or (-)-isomers, respectively). Chiral compounds can exist as individual enantiomers or mixtures thereof. A mixture containing equal proportions of enantiomers is referred to as a "racemic mixture".

[0127] "Tautomers" refer to compounds that are interchangeable forms of a particular compound structure and vary in the displacement of hydrogen atoms and electrons. Thus, the two structures may be in equilibrium through the movement of π electrons and atoms (usually H). For example, enols and ketones are tautomers because they rapidly interconvert upon treatment with an acid or base. Another example of tautomerism is the acid and nitro forms of phenylnitromethane, which are likewise formed upon treatment with an acid or base. Tautomeric forms may be relevant to achieving optimal chemical reactivity and biological activity of the compound of interest.

[0128] "Pharmaceutically acceptable metabolically cleavable group" refers to a group that is cleaved in vivo to produce the parent molecule of the structural formula shown herein. Examples of metabolically cleavable groups include -COR, -COOR, -CONRR and -CH2OR groups, wherein R at each occurrence is independently selected from alkyl, trialkylsilyl, carbocyclic aryl, or carbocyclic aryl substituted with one or more of alkyl, halogen, hydroxyl or alkoxy. Specific examples of representative metabolically cleavable groups include acetyl, methoxycarbonyl, benzoyl, methoxymethyl and trimethylsilyl.

[0129] "Prodrug" refers to a compound having a cleavable group and becoming a pharmaceutically active compound of the present invention by solvent decomposition or under physiological conditions in vivo, including derivatives of the compounds of the present invention. Such examples include, but are not limited to, choline ester derivatives, etc., N-alkyl morpholine esters, etc. Other derivatives of the compounds of the present invention are active in both their acid and acid derivative forms, but often provide delayed release in mammalian organisms, tissue compatibility or solubility advantages in acid-sensitive forms (see Bundgard, H., Design of Prodrugs, pp.7-9, 21-24, Elsevier, Amsterdam 1985). Prodrugs include acid derivatives known to practitioners in the art, such as esters prepared by reaction of the parent acid with a suitable alcohol, or amides, or anhydrides, or mixed anhydrides prepared by reaction of the parent acid compound with a substituted or unsubstituted amine. Simple aliphatic or aromatic esters, amides and anhydrides produced by acid groups pendant on the compounds of the present invention are specific prodrugs. In some cases, it is desirable to prepare a double ester type prodrug such as an (acyloxy)alkyl ester or a ((alkoxycarbonyl)oxy)alkyl ester. Specifically, the C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, aryl, C7-C8 12 Substituted aryl and C7-C 12 Arylalkyl esters.

[0130] "Compounds of the invention" and equivalent expressions are intended to include compounds as described herein, particularly compounds according to any formula listed and / or described herein, including prodrugs, pharmaceutically acceptable salts and solvates such as hydrates, when the context so permits. Similarly, references to intermediates, whether or not they themselves are claimed, are intended to include their salts and solvates, when the context so permits. DETAILED DESCRIPTION

[0131] As described herein, the present invention is based in part on the desire to provide novel 19-nor compounds with good efficacy, pharmacokinetic (PK) properties, oral bioavailability, formulability, stability, safety, clearance and / or metabolism. A key feature of the compounds as described herein is the disubstitution at the C3 position. The inventors foresee that the disubstitution at C-3 eliminates the possibility of oxidation to ketones, prevents further metabolism, and reduces the possibility of secondary elimination pathways such as glucuronidation. The inventors further foresee that the overall effect of C3 disubstitution should be to improve overall PK parameters and reduce potential toxicity and side effects, which may allow oral and / or long-term administration in some embodiments. Another key feature of the compounds as described herein is the presence of hydrogen ("19-nor") instead of methyl at the C10 position. The inventors foresee that 19-nor compounds have improved physical properties, such as improved solubility, compared to their C10-methyl counterparts. The inventors foresee further increases in solubility, for example, when the AB ring system is in a cis configuration.

[0132] Thus, in one aspect, there is provided a 3,3-disubstituted 19-norpregnane compound of formula (I):

[0133]

[0134] or a pharmaceutically acceptable salt, solvate, hydrate, prodrug, stereoisomer, tautomer, isotopic variant, or N-oxide thereof, or a combination thereof;

[0135] in:

[0136] R 1 is hydrogen, halogen, 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, substituted or unsubstituted heteroaryl, -OR A1 、-SR A1 、-N(R A1 )2, -OC(=O)R A1 、-OC(=O)OR A1 、-OC(=O)SR A1 、-OC(=O)N(R A1 )2, -SC(=O)R A2 、-SC(=O)OR A1 、-SC(=O)SR A1 、-SC(=O)N(R A1 )2, -NHC(=O)R A1 、-NHC(=O)OR A1 、-NHC(=O)SR A1、-NHC(=O)N(R A1 )2, -OS(=O)2R A2 、-OS(=O)2OR A1 、-SS(=O)2R A2 、-SS(=O)2OR A1 、-S(=O)R A2 、-SO2R A2 , or –S(=O)2OR A1 , where R A1 Each instance of R is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, an oxygen protecting group when attached to an oxygen atom, a sulfur protecting group when attached to a sulfur atom, a nitrogen protecting group when attached to a nitrogen atom, or two R A1 The groups are combined to form a substituted or unsubstituted heterocyclic or heteroaryl ring; and R A2 is 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, or substituted or unsubstituted heteroaryl group;

[0137] R 2 is hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, –OH, –OR B1 、–OC(=O)R B1 、–NH2、–N(R B1 )2, or –NR B1 C(=O)R B1 , where R B1 Each instance of R is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, an oxygen protecting group when attached to an oxygen atom, a nitrogen protecting group when attached to a nitrogen atom, or two R B1 The groups combine to form a substituted or unsubstituted heterocyclic ring;

[0138] R 3 is 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, or substituted or unsubstituted heteroaryl group;

[0139] R3’ is hydrogen, –C(=O)R C1 、–C(=O)OR C1 、–C(=O)SR C1 , –C(=O)N(R C1 )2.

[0140] –S(=O)2R C2 、–S(=O)2OR C1 、–P(=O)2R C2 、–P(=O)2OR C1 、–P(=O)(OR C1 )2. –P(=O)(R C2 )2, or –P(=O)(R C2 )(OR C1 ), where R C1 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, an oxygen protecting group when attached to an oxygen atom, a sulfur protecting group when attached to a sulfur atom, a nitrogen protecting group when attached to a nitrogen atom, or two R C1 groups are combined to form a substituted or unsubstituted heterocyclic ring; and R C2 is 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, or substituted or unsubstituted heteroaryl group;

[0141] R 4 is selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl;

[0142] R 6a and R 6b are each independently hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl, or R 6a and R 6b Combine to form an oxo (=O) group;

[0143] R 11a and R 11b are each independently hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, -OH, -OR D1 、-OC(=O)R D1 、-NH2、-N(R D1)2, or -NR D1 C(=O)R D1 , where R D1 Each instance of R is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, an oxygen protecting group when attached to an oxygen atom, a nitrogen protecting group when attached to a nitrogen atom, or two R D1 The groups are combined to form a substituted or unsubstituted heterocyclic ring; or R 11a and R 11b Combine to form an oxo (=O) group;

[0144] in represents a single bond or a double bond, provided that if the double bond is present in ring B, then R 6a or R 6b one of is absent, and provided that if a single bond is present in ring B, the hydrogen at C5 is in the α or β position;

[0145] Provided that the following compounds, and pharmaceutically acceptable salts thereof, are specifically excluded:

[0146]

[0147]

[0148]

[0149] In another aspect, a 3,3-disubstituted 19-norpregnane compound of formula (III) is provided:

[0150] or a pharmaceutically acceptable salt, solvate, hydrate, prodrug, stereoisomer, tautomer, isotopic variant, or N-oxide thereof, or a combination thereof; wherein R 1 , R 2 , R 3 , R 3’ , R 4 , R 6a , R 6b , R 11a , and R 11b As defined in this article.

[0151] In some embodiments, the compound is a pharmaceutically acceptable salt, such as a sodium, potassium, ammonium or calcium salt. In some embodiments, the compound is a sodium salt. In some embodiments, the compound is an acid addition salt, such as a hydrochloride, a hydrobromide, a benzoate, a methanesulfonate, or a benzenesulfonate.

[0152] Compounds of Formula (I) and (III) are contemplated to act as GABA modulators in some embodiments.

[0153] Group R 1

[0154] As generally described herein, R 1 is hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, –OR A1 ,–SR A1 , –N(R A1 )2. –OC(=O)R A1 、–OC(=O)OR A1 、–OC(=O)SR A1 、–OC(=O)N(R A1 )2. –SC(=O)R A2 , –SC(=O)OR A1 , –SC(=O)SR A1 , –SC(=O)N(R A1 )2. –NHC(=O)R A1 、–NHC(=O)OR A1 , –NHC(=O)SR A1 、–NHC(=O)N(R A1 )2, –OS(=O)2R A2 、–OS(=O)2OR A1 、–S–S(=O)2R A2 、–S–S(=O)2OR A1 , –S(=O)R A2 , –SO2R A2 , or –S(=O)2OR A1 , where R A1 Each instance of R is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, an oxygen protecting group when attached to an oxygen atom, a sulfur protecting group when attached to a sulfur atom, a nitrogen protecting group when attached to a nitrogen atom, or two R A1 The groups are combined to form a substituted or unsubstituted heterocyclic or heteroaryl ring; and R A2 is a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group, a substituted or unsubstituted carbocyclic group, a substituted or unsubstituted heterocyclic group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted heteroaryl group.

[0155] In some embodiments, R 1 For hydrogen.

[0156] In some embodiments, R 1 is halogen, for example, fluorine, bromine, chlorine or iodine. 1 For bromine.

[0157] In some embodiments, R 1 is a substituted or unsubstituted alkyl group, for example, a substituted or unsubstituted C 1-6 Alkyl, C 2-6 Alkyl, C 3-6 Alkyl, C 4-6 Alkyl, C 5-6 In some embodiments, R 1 is a substituted alkyl group (eg, a haloalkyl group, an alkoxyalkyl group).

[0158] In some embodiments, R 1 is a substituted or unsubstituted alkenyl group, for example, a substituted or unsubstituted C 2-6 Alkenyl, substituted or unsubstituted C 3-6 Alkenyl, substituted or unsubstituted C 4-6 Alkenyl, substituted or unsubstituted C 5-6 alkenyl, substituted or unsubstituted C2 alkenyl, substituted or unsubstituted C3 alkenyl, substituted or unsubstituted C4 alkenyl, substituted or unsubstituted C5 alkenyl, or substituted or unsubstituted C6 alkenyl.

[0159] In some embodiments, R 1 is a substituted or unsubstituted alkynyl group, for example, a substituted or unsubstituted C 2-6 Alkynyl, substituted or unsubstituted C 3-6 Alkynyl, substituted or unsubstituted C 4-6 Alkynyl, substituted or unsubstituted C 5-6 alkynyl, substituted or unsubstituted C2 alkynyl, substituted or unsubstituted C3 alkynyl, substituted or unsubstituted C4 alkynyl, substituted or unsubstituted C5 alkynyl, or substituted or unsubstituted C6 alkynyl.

[0160] In some embodiments, R 1 is a substituted or unsubstituted carbocyclic group, for example, a substituted or unsubstituted C 3-6 Cycloalkyl.

[0161] In some embodiments, R 1is a substituted or unsubstituted heterocyclyl, for example, a substituted or unsubstituted 3- to 6-membered heterocyclyl, for example, a substituted or unsubstituted 3-membered heterocyclyl, a substituted or unsubstituted 4-membered heterocyclyl, a substituted or unsubstituted 5-membered heterocyclyl, or a substituted or unsubstituted 6-membered heterocyclyl. 1 is a substituted or unsubstituted 5-membered heterocyclic group, for example, pyrrolidinyl. 1 is a substituted or unsubstituted 6-membered heterocyclic group, for example, a substituted or unsubstituted morpholinyl group, a substituted or unsubstituted piperidinyl group, or a substituted or unsubstituted piperazinyl group.

[0162] In some embodiments, R 1 is a substituted or unsubstituted aryl group, for example, a substituted or unsubstituted phenyl group or a substituted or unsubstituted naphthyl group.

[0163] In some embodiments, R 1 is a substituted or unsubstituted heteroaryl. 1 is a substituted or unsubstituted 5-membered heteroaryl. 1 is a substituted or unsubstituted 5-membered heteroaryl group having 1 heteroatom. 1 is a substituted or unsubstituted 5-membered heteroaryl group having 2 heteroatoms. 1 is a substituted or unsubstituted 5-membered heteroaryl group having 3 heteroatoms. 1 is a substituted or unsubstituted 5-membered heteroaryl group having 4 heteroatoms. 1 is a heteroaryl substituted with one or more substituents selected from the group consisting of alkyl, alkenyl, alkynyl, halogen, haloalkyl, haloalkenyl, haloalkynyl, hydroxy, alkoxy, alkoxyalkyl, amino, acyl, acylamino, oxo, cyano, aryl, heteroaryl, -SO-alkyl, -SO2-alkyl, -SO-aryl, -SO2-aryl, -SO-heteroaryl, -SO2-heteroaryl. However, in some embodiments, R 1 is an unsubstituted heteroaryl group.

[0164] In some embodiments, R 1 is a substituted or unsubstituted heteroaryl selected from the group consisting of substituted or unsubstituted imidazolyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, In some embodiments, R 1 In some embodiments, R 1 In some embodiments, R 1is 1,2,3-triazolyl. 1 is 1,2,4-triazolyl. 1 It is a tetrazolyl group.

[0165] In some embodiments, R 1 is imidazolyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, oxadiazolyl, thiadiazolyl, or tetrazolyl; each is unsubstituted or substituted by one or two substituents selected from the group consisting of: -SMe, -SOMe, -SO2Me, -CH3, F, Cl, -CN, -CH2F, -CHF2, and -CF3. In some embodiments, R 1 It is imidazol-1-yl, 1,2,3-triazol-1-yl, or 1,2,3-triazol-2-yl, each of which is unsubstituted or substituted by one or two substituents selected from the following: -SMe, -SOMe, -SO2Me, -CH3, F, Cl, -CN, -CH2F, -CHF2, and -CF3.

[0166] In some embodiments, R 1 is imidazolyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, oxadiazolyl, thiadiazolyl, or tetrazolyl; each is unsubstituted or substituted with oxo.

[0167] In some embodiments, R 1 is quinolyl, isoquinolyl, or purinyl; each is unsubstituted or substituted by one or two substituents selected from the following: -SMe, -SOMe, -SO2Me, -CH3, F, Cl, -CN, -CH2F, -CHF2, and -CF3.

[0168] In some embodiments, R 1 is quinolone or isoquinolone; each is unsubstituted or substituted by one or two substituents selected from the following: -SMe, -SOMe, -SO2Me, -CH3, F, Cl, -CN, -CH2F, -CHF2, and -CF3.

[0169] In some embodiments, R 1 is a dihydroquinolone group or a dihydroisoquinolone group; each is unsubstituted or substituted by one or two substituents selected from the following: -SMe, -SOMe, -SO2Me, -CH3, F, Cl, -CN, -CH2F, -CHF2, and -CF3.

[0170] In some embodiments, R 1 For-OR A1 , for example, R1 is -OH or -O-(heteroaryl).

[0171] In some embodiments, R 1 For-SR A1 , for example, R 1 is -SH or -S-(heteroaryl).

[0172] In some embodiments, R 1 -OC(=O)R A1 , for example, -OC(=O)CH2-CH2-CO2H.

[0173] In some embodiments, R 1 -OC(=O)OR A1 .

[0174] In some embodiments, R 1 =OC(=O)SR A1 .

[0175] In some embodiments, R 1 -OC(=O)N(R A1 )2.

[0176] In some embodiments, R 1 -SC(=O)R A2 .

[0177] In some embodiments, R 1 -SC(=O)OR A1 .

[0178] In some embodiments, R 1 =SC(=O)SR A1 .

[0179] In some embodiments, R 1 -SC(=O)N(R A1 )2.

[0180] In some embodiments, R 1 -OS(=O)2R A2 .

[0181] In some embodiments, R 1 -OS(=O)2OR A1 , for example, -O-SO3H.

[0182] In some embodiments, R 1 is -SS(=O)2R A2 .

[0183] In some embodiments, R 1 -SS(=O)2OR A1 , for example, -S-SO3H.

[0184] In some embodiments, R 1 -S(=O)R A2 .

[0185] In some embodiments, R 1 SO2R A2 .

[0186] In some embodiments, R 1 -S(=O)2OR A1 , for example, -SO3H.

[0187] In some embodiments, R 1 -N(R A1 )2, -NHC(=O)R A1 、-NHC(=O)OR A1 、-NHC(=O)SR A1 、-NHC(=O)N(R A1 )2. In some embodiments, R 1 -N(R A1 )2. In some embodiments, R 1 -NHC(=O)R A1 In some embodiments, R 1 -NHC(=O)OR A1 In some embodiments, R 1 -NHC(=O)SR A1 In some embodiments, R 1 -NHC(=O)N(R A1 )2.

[0188] In some embodiments, R 1 is selected from -OH, -O-CO-CH2-CH2-CO2H, -O-SO3H, -SH, -S-SO3H, heteroaryl, -O-(heteroaryl), and -S-(heteroaryl), wherein heteroaryl is imidazolyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, quinolyl, isoquinolyl or purinyl; and each heteroaryl is unsubstituted or substituted with one or two substituents selected from the group consisting of oxo, -CH3, F, Cl, -CN, -SMe, -SOMe, -SO2Me, and -CF3. In some embodiments, R 1is -O-quinolyl, -O-isoquinolyl, -O-purinyl, -S-quinolyl, -S-isoquinolyl, or -S-purinyl; each is unsubstituted or substituted by one or two substituents selected from the following: -CH3, F, Cl, -CN, -SMe, -SOMe, -SO2Me, -CH2F, -CHF2, and -CF3.

[0189] In some embodiments, R 1 is -OH, -O-CH2-CH2-CO2H, -SO3H, -OSO3H, -SSO3H, pyrazol-1-yl, imidazole-1-yl, 1,2,4-triazole-1-yl, or 1,2,3-triazole-1-yl. In some embodiments, R 1 In some embodiments, R 1 is -O-CH2-CH2-CO2H. In some embodiments, R 1 In some embodiments, R 1 is -OSO3H. In some embodiments, R 1 In some embodiments, R 1 In some embodiments, R 1 is imidazol-1-yl. In some embodiments, R 1 is 1,2,4-triazol-1-yl. In some embodiments, R 1 It is 1,2,3-triazol-1-yl.

[0190] In some embodiments, R 1 is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted heterocyclic, substituted or unsubstituted thioalkoxy (-S-alkyl), -OH, -O-CO-(CH2) t -CO2H, -SO3H, -O-SO3H, -SH, -S-SO3H, or substituted or unsubstituted -Y-(heteroaryl); wherein Y is a bond, -O-, -S-, C1-C4 alkylene, C2-C4 alkenylene, or C2-C4 alkynylene; and subscript t is an integer from 2 to 5, inclusive.

[0191] In some embodiments, R 1 is Br, -OH, -OMe, substituted or unsubstituted heterocyclic, -O-CO-CH2-CH2-CO2H, -SO3H, -O-SO3H, -S-SO3H, OP(=O)(OH)2, pyrazolyl, imidazolyl, or triazolyl; each R 2 , R 3’ , R 4 , R11a and R 11b is H; and the dotted-line bond is a single bond; then R 3 It is not Et, -CF3, ethynyl, 4-hydroxypropynyl, or (4-acyl)-phenylethynyl.

[0192] In any of the above embodiments, at least one R A1 is unsubstituted or substituted with one or more substituents selected from the group consisting of 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 S02R aa ,–NR bb S02Raa 、–SO2N(R bb 2. –SO2R aa , –SO2OR aa 、–OSO2R aa , –S(=O)R aa 、–OS(=O)R aa , –Si(R aa )3. –OSi(R aa )3–C(=S)N(R bb )2, –C(=O)SR aa , –C(=S)SR aa , –SC(=S)SR aa , –SC(=O)SR aa 、–OC(=O)SR aa , –SC(=O)OR aa , –SC(=O)R aa 、–P(=O)2R aa 、–OP(=O)2R aa , –P(=O)(R aa )2. –OP(=O)(R aa )2. –OP(=O)(OR cc )2, –P(=O)2N(R bb )2, –OP(=O)2N(R bb )2, –P(=O)(NR bb )2. –OP(=O)(NR bb )2. –NR bb P(=O)(OR cc )2. –NR bb P(=O)(NR bb )2. –P(R cc )2. –P(R cc )3. –OP(R cc )2. –OP(R cc )3. –B(R aa )2. –B(OR cc 2. –BR aa (OR cc ), C 1–10 Alkyl, C 1–10 Perhaloalkyl, 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 Rdd or the two geminal hydrogen atoms on the 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; and R aa , R bb , R cc , R dd , R ee and R ff As described herein.

[0193] In any of the above embodiments, at least one R A1 The heteroaryl group is unsubstituted or substituted by one or more substituents selected from the group consisting of alkyl, alkenyl, alkynyl, halogen, haloalkyl, haloalkenyl, haloalkynyl, hydroxy, alkoxy, alkoxyalkyl, amino, acyl, acylamino, oxo, cyano, aryl, heteroaryl, -SO-alkyl, -SO2-alkyl, -SO-aryl, -SO2-aryl, -SO-heteroaryl, and -SO2-heteroaryl.

[0194] In any of the above embodiments, at least one R A1 is a heteroaryl group selected from the group consisting of unsubstituted pyrrolyl, imidazolyl, pyrazolyl, Azolyl, thiazolyl, iso Azolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, quinolyl, isoquinolyl, quinazolinyl, quinoxilinyl, naphthyridinyl, indolyl, indazolyl, benzimidazolyl, pyrrolopyridinyl, pyrrolopyrimidinyl, pyridopyrimidinyl, and purinyl.

[0195] In any of the above embodiments, at least one R A1 is a heteroaryl group selected from the group consisting of pyrrolyl, imidazolyl, pyrazolyl, Azolyl, thiazolyl, iso Azolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, The oxadiazolyl, thiadiazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, quinolyl, isoquinolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, indolyl, indazolyl, benzimidazolyl, pyrrolopyridinyl, pyrrolopyrimidinyl, pyridopyrimidinyl, and purinyl groups are each substituted with one or more substituents selected from the group consisting of alkyl, haloalkyl, alkenyl, alkynyl, oxo, hydroxy, halogen, alkoxy, -S-alkyl, aryl, heteroaryl, -SO-alkyl, -SO2-alkyl, -SO-aryl, -SO2-aryl, -SO-heteroaryl, -SO2-heteroaryl, amino, cyano, and acyl groups.

[0196] Group R 2

[0197] As generally defined above, R 2 is hydrogen, halogen, 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, -OH, -OR B1 、-OC(=O)R B1 、-NH2、-N(R B1 )2, or -NR B1 C(=O)R B1 , where R B1 Each instance of R is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, an oxygen protecting group when attached to an oxygen atom, a nitrogen protecting group when attached to a nitrogen atom, or two R B1 The groups combine to form a substituted or unsubstituted heterocyclic ring.

[0198] In some embodiments, R 2 For hydrogen.

[0199] In some embodiments, R 2 is a halogen, for example, -F, -Br, -I, or -Cl. In some embodiments, R 2 In some embodiments, R 2 In some embodiments, R 2 It is -Br.

[0200] In some embodiments, R 2 is a substituted or unsubstituted alkyl group, for example, a substituted or unsubstituted C 1–6 Alkyl, substituted or unsubstituted C 1–2 Alkyl, substituted or unsubstituted C 2–3 Alkyl, substituted or unsubstituted C3–4 Alkyl, substituted or unsubstituted C 4–5 Alkyl, or substituted or unsubstituted C 5–6 Alkyl. Exemplary R 2 C 1–6 Alkyl groups include, but are not limited to, substituted or unsubstituted methyl (C1), substituted or unsubstituted ethyl (C2), substituted or unsubstituted n-propyl (C3), substituted or unsubstituted isopropyl (C3), substituted or unsubstituted n-butyl (C4), substituted or unsubstituted tert-butyl (C4), substituted or unsubstituted sec-butyl (C4), substituted or unsubstituted isobutyl (C4), substituted or unsubstituted n-pentyl (C5), substituted or unsubstituted 3-pentyl (C5), substituted or unsubstituted pentyl (C5), substituted or unsubstituted neopentyl (C5), substituted or unsubstituted 3-methyl-2-butyl (C5), substituted or unsubstituted tert-pentyl (C5), or substituted or unsubstituted n-hexyl (C6). Exemplary substituted alkyl groups include, but are not limited to, alkyl groups substituted by halogen groups ("haloalkyl") and alkyl groups substituted by alkoxy groups ("alkoxyalkyl"). Exemplary haloalkyl groups include, but are not limited to, -CF3, -CH2F, -CHF2, difluoroethyl, 2,2,2-trifluoro-1,1-dimethyl-ethyl, -CH2Cl, and -CHCl2. Exemplary alkoxyalkyl groups include, but are not limited to, -CH2OCH3 and -CH2OCH2CH3.

[0201] In some embodiments, R 2 is a substituted or unsubstituted alkenyl group, for example, a substituted or unsubstituted C 2–6 Alkenyl, substituted or unsubstituted C 2–3 Alkenyl, substituted or unsubstituted C 3–4 Alkenyl, substituted or unsubstituted C 4–5 Alkenyl, or substituted or unsubstituted C 5–6 Alkenyl. Exemplary substituted alkenyl groups include, but are not limited to, alkenyl groups substituted with halogen groups ("haloalkenyl") and alkenyl groups substituted with alkoxy groups ("alkoxyalkenyl").

[0202] In some embodiments, R 2 is a substituted or unsubstituted alkynyl group, for example, a substituted or unsubstituted C 2–6 Alkynyl, substituted or unsubstituted C 2–3 Alkynyl, substituted or unsubstituted C 3–4 Alkynyl, substituted or unsubstituted C 4–5 Alkynyl, or substituted or unsubstituted C 5–6 Alkynyl. Exemplary substituted alkynyl groups include, but are not limited to, alkynyl groups substituted with a halo group (a "haloalkynyl") and alkynyl groups substituted with an alkoxy group (an "alkoxyalkynyl").

[0203] In some embodiments, R 2 is a substituted or unsubstituted carbocyclic group, for example, a substituted or unsubstituted C 3–6 Carbocyclic, substituted or unsubstituted C 3–4 Carbocyclic, substituted or unsubstituted C 4–5 Carbocyclic group, or substituted or unsubstituted C 5–6 Carbocyclic group.

[0204] In some embodiments, R 2 is a substituted or unsubstituted heterocyclic group, for example, a substituted or unsubstituted C 3–6 Heterocyclic, substituted or unsubstituted C 3–4 Heterocyclic, substituted or unsubstituted C 4–5 Heterocyclic group, or substituted or unsubstituted C 5–6 For example, in some embodiments, R 2 is a substituted or unsubstituted piperidinyl, a substituted or unsubstituted piperazinyl, or a substituted or unsubstituted morpholinyl ring. 2 is a substituted or unsubstituted morpholinyl ring.

[0205] In some embodiments, R 2 is a substituted or unsubstituted aryl group, for example, a substituted or unsubstituted phenyl group.

[0206] In some embodiments, R 2 is a substituted or unsubstituted heteroaryl group, for example, an optionally substituted 5-6-membered heteroaryl group.

[0207] In some embodiments, R 2 For –OH, –OR B1 , or –OC(=O)R B1 In some embodiments, R B1 is a substituted or unsubstituted alkyl group, for example, a substituted or unsubstituted C 1–6 Alkyl, substituted or unsubstituted C 1–2 Alkyl, substituted or unsubstituted C 2–3 Alkyl, substituted or unsubstituted C 3–4 Alkyl, substituted or unsubstituted C 4–5 Alkyl, or substituted or unsubstituted C 5–6 Alkyl. Exemplary R B1 C 1–6Alkyl groups include, but are not limited to, substituted or unsubstituted methyl (C1), substituted or unsubstituted ethyl (C2), substituted or unsubstituted n-propyl (C3), substituted or unsubstituted isopropyl (C3), substituted or unsubstituted n-butyl (C4), substituted or unsubstituted tert-butyl (C4), substituted or unsubstituted sec-butyl (C4), substituted or unsubstituted isobutyl (C4), substituted or unsubstituted n-pentyl (C5), substituted or unsubstituted 3-pentyl (C5), substituted or unsubstituted pentyl (C5), substituted or unsubstituted neopentyl (C5), substituted or unsubstituted 3-methyl-2-butyl (C5), substituted or unsubstituted tert-pentyl (C5), or substituted or unsubstituted n-hexyl (C6).

[0208] In some embodiments, R 2 for –NH2, –N(R B1 )2, or –NR B1 C(=O)R B1 In some embodiments, R B1 is hydrogen or substituted or unsubstituted alkyl, for example, substituted or unsubstituted C 1–6 Alkyl, substituted or unsubstituted C 1–2 Alkyl, substituted or unsubstituted C 2–3 Alkyl, substituted or unsubstituted C 3–4 Alkyl, substituted or unsubstituted C 4–5 Alkyl, or substituted or unsubstituted C 5–6 Alkyl. Exemplary R B1 C 1–6 Alkyl groups include, but are not limited to, substituted or unsubstituted 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), or n-hexyl (C6).

[0209] In some embodiments, R 2 is halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, –OR B1 , or -OC(=O)R B1 In some embodiments, R 2 is hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, alkoxyalkyl, –OH, –OR B1 、–OC(=O)R B1 、–NH2、–N(R B1 )2, or –NR B1 C(=O)R B1 .

[0210] In some embodiments, R 2 is a substituted alkyl group (eg, a haloalkyl group, an alkoxyalkyl group).

[0211] In some embodiments, R 2 is -F, -Cl, methyl, ethyl, n-propyl, methoxy, ethoxy, propoxy, butoxy, ethynyl, hydroxybutynyl, methoxypropynyl, chloroethynyl, or cyclopropynyl.

[0212] In some embodiments, R 2 is a non-hydrogen group at the α position. 2 is a non-hydrogen group at the β position.

[0213] Group R 3

[0214] As generally defined above, R 3 is a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group, a substituted or unsubstituted carbocyclic group, a substituted or unsubstituted heterocyclic group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted heteroaryl group.

[0215] In some embodiments, R 3 is a substituted or unsubstituted alkyl group, for example, a substituted or unsubstituted C 1–6 Alkyl, substituted or unsubstituted C 1–2 Alkyl, substituted or unsubstituted C 2–3 Alkyl, substituted or unsubstituted C 3–4 Alkyl, substituted or unsubstituted C 4–5 Alkyl, or substituted or unsubstituted C 5–6 Alkyl. Exemplary R 3 C 1–6 Alkyl includes, but is not limited to, substituted or unsubstituted 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), n-hexyl (C6), C6 substituted with 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more fluorine groups. 1–6 Alkyl (e.g., -CF3, -CH2F, -CHF2, difluoroethyl, and 2,2,2-trifluoro-1,1-dimethyl-ethyl), C substituted with 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more chloro groups 1–6 Alkyl groups (e.g., –CH2Cl, –CHCl2), and C1–6 In some embodiments, R 3 is a substituted alkyl group, for example, R 3 is a haloalkyl group, an alkoxyalkyl group, or an aminoalkyl group. 3 is Me, Et, n-Pr, n-Bu, i-Bu, fluoromethyl, chloromethyl, difluoromethyl, trifluoromethyl, trifluoroethyl, difluoroethyl, 2,2,2-trifluoro-1,1-dimethyl-ethyl, methoxymethyl, methoxyethyl, or ethoxymethyl. 3a is Me, Et, n-Pr, n-Bu, or i-Bu. In some embodiments, R 3 is methoxymethyl, ethoxymethyl, propoxymethyl, methoxyethyl, or ethoxyethyl. 3 In some embodiments, R 3 In some embodiments, R 3 It is trifluoromethyl.

[0216] In some embodiments, R 3 is a substituted or unsubstituted alkenyl group, for example, a substituted or unsubstituted C 2-6 Alkenyl, substituted or unsubstituted C 2-3 Alkenyl, substituted or unsubstituted C 3-4 Alkenyl, substituted or unsubstituted C 4-5 Alkenyl, or substituted or unsubstituted C 5-6 In some embodiments, R 3 is unsubstituted or substituted with one or more substituents selected from alkyl, halogen, haloalkyl, alkoxyalkyl, or hydroxyl vinyl (C2), propenyl (C3), or butenyl (C4). 3 is unsubstituted or substituted with alkyl, halogen, haloalkyl, alkoxyalkyl, or hydroxyl vinyl, propenyl, or butenyl. 3 For vinyl.

[0217] In some embodiments, R 3 is a substituted or unsubstituted alkynyl group, for example, a substituted or unsubstituted C 2-6 Alkynyl, substituted or unsubstituted C 2-3 Alkynyl, substituted or unsubstituted C 3-4 Alkynyl, substituted or unsubstituted C 4-5 Alkynyl, or substituted or unsubstituted C 5-6Alkynyl. Exemplary substituted or unsubstituted R 3 Alkynyl includes, but is not limited to, ethynyl, propynyl, or butynyl, which are unsubstituted or substituted with alkyl, halogen, haloalkyl (e.g., CF3), alkoxyalkyl, cycloalkyl (e.g., cyclopropyl or cyclobutyl), or hydroxy. 3 is selected from trifluoroethynyl, cyclopropylethynyl, cyclobutylethynyl, and propynyl, fluoropropynyl, and chloroethynyl. 3 is unsubstituted or substituted ethynyl (C2), propynyl (C3), or butynyl (C4) selected from one or more substituents: substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted carbocyclyl, and substituted or unsubstituted heterocyclyl. In some embodiments, R 3 is substituted phenyl substituted ethynyl (C2), propynyl (C3), or butynyl (C4). In some embodiments, the phenyl substituent is further substituted by one or more substituents selected from the following: halogen, alkyl, trifluoroalkyl, alkoxy, acyl, amino or acylamino. In some embodiments, R 3 is substituted or unsubstituted pyrrolyl, imidazolyl, pyrazolyl, Azolyl, thiazolyl, iso Azolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, ethynyl (C2), propynyl (C3), or butynyl (C4) substituted with oxadiazolyl, thiadiazolyl, or tetrazolyl.

[0218] In some embodiments, R 3 is unsubstituted or substituted with alkyl, halogen, haloalkyl, alkoxyalkyl, or hydroxyl substituted ethynyl, propynyl, or butynyl. 3a is ethynyl or propynyl substituted with substituted or unsubstituted aryl. 3 is ethynyl or propynyl substituted with phenyl, the phenyl being unsubstituted or substituted with halogen, alkyl, alkoxy, haloalkyl, trihaloalkyl, or acyl. 3 is ethynyl or propynyl substituted by a substituted or unsubstituted carbocyclic group. 3 is ethynyl or propynyl substituted by substituted or unsubstituted cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. 3 is ethynyl or propynyl substituted with substituted or unsubstituted heteroaryl. 3 is substituted or unsubstituted pyridyl, or pyrimidinyl substituted ethynyl or propynyl. 3is substituted or unsubstituted pyrrolyl, imidazolyl, pyrazolyl, Azolyl, thiazolyl, iso Azolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl substituted ethynyl or propynyl. 3 is ethynyl or propynyl substituted by a substituted or unsubstituted heterocyclic group. 3a is ethynyl or propynyl substituted by substituted or unsubstituted pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl. 3 is a propynyl or butynyl substituted by a hydroxyl or alkoxy group. 3 is a propynyl or butynyl substituted by a methoxy or ethoxy group. 3 is ethynyl or propynyl substituted by Cl. 3 It is ethynyl or propynyl substituted by trifluoromethyl.

[0219] In some embodiments, R 3 is a substituted or unsubstituted carbocyclic group, for example, a substituted or unsubstituted C 3-6 Carbocyclic, substituted or unsubstituted C 3-4 Carbocyclic, substituted or unsubstituted C 4-5 Carbocyclic group, or substituted or unsubstituted C 5-6 Carbocyclic group.

[0220] In some embodiments, R 3 It is a substituted or unsubstituted heterocyclic group, for example, a substituted or unsubstituted 3-6 membered heterocyclic group, a substituted or unsubstituted 3-4 membered heterocyclic group, a substituted or unsubstituted 4-5 membered heterocyclic group, or a substituted or unsubstituted 5-6 membered heterocyclic group.

[0221] In some embodiments, R 3 is a substituted or unsubstituted aryl group. 3 is substituted or unsubstituted phenyl.

[0222] In some embodiments, R 3 is a substituted or unsubstituted heteroaryl group, for example, an optionally substituted 5-6-membered heteroaryl group.

[0223] R as substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl 3 Further embodiments are described below:

[0224]

[0225] Where R 3a Each case of is hydrogen, halogen, or -OR F1 , where R F1 is a substituted or unsubstituted alkyl group; and R 3b and R 3c Each instance of is independently hydrogen, halogen, or substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclyl, or substituted or unsubstituted heterocyclyl.

[0226] In some embodiments, at least one R 3a In some embodiments, at least two R 3c In some embodiments, each R 3a In some embodiments, at least one R 3a is a halogen (e.g., fluorine, chlorine, bromine, iodine). 3a is halogen (e.g., fluorine, chlorine, bromine, iodine). 3a is halogen (e.g., fluorine to provide a group -CF3). In some embodiments, at least one R 3a For-OR F1 (e.g., OMe or OEt). In some embodiments, at least two R 3a For-OR F1 (eg, OMe or OEt). In some embodiments, at least one R 3a is hydrogen, F, -OMe, or -OEt. In some embodiments, R 3a One of them is a non-hydrogen group (e.g., -F, -OMe, or OEt); and the remaining are H, such as provided in the following formula:

[0227]

[0228] In some embodiments, R 3b In some embodiments, R 3b is halogen (eg, fluorine, chlorine, bromine, iodine). 3b is an alkyl group, for example, -CH3, -CF3, -CH2CH2Cl. 3b is a substituted or unsubstituted carbocyclic group, for example, a cyclopropyl group or a cyclobutyl group. 3b is hydrogen, -F, -Br, -Cl, -I, -CH3, -CF3, cyclopropyl, or cyclobutyl. 3b is a substituted or unsubstituted cyclopropyl. 3bIn some embodiments, R 3b is Me or Cl. In some embodiments, R 3b is a substituted or unsubstituted heterocyclic group.

[0229] In some embodiments, at least one R 3c In some embodiments, each R 3c In some embodiments, at least one R 3c is halogen (e.g., fluorine, chlorine, bromine, iodine). 3c is halogen (eg, fluorine, chlorine, bromine, iodine). 3c Each is an alkyl group, for example, R 2c Each is Me. In some embodiments, R 3c one is alkyl; and the other is hydrogen, for example, R 3c One is Me; and the other is hydrogen. In some embodiments, R 3c One of R is a substituted or unsubstituted carbocyclyl, for example, cyclopropyl or cyclobutyl, and the other is hydrogen. 3c is hydrogen, -F, -Br, -Cl, -I, -CH3, -CF3, cyclopropyl, or cyclobutyl. 3c Each case of is H. In some embodiments, R 3c Each instance of is halogen (e.g., fluorine, chlorine, bromine, iodine). In some embodiments, R 3c Each case of is alkyl, for example, -CH3, -CF3, -CH2CH2Cl. In some embodiments, R 3c Each instance of is a substituted or unsubstituted carbocyclyl, for example, cyclopropyl or cyclobutyl. 3c is a substituted or unsubstituted cyclopropyl. 3c Each instance of is hydrogen, -F, -Br, -Cl, -I, -CH3, -CF3, -CH2CH2Cl, cyclopropyl, or cyclobutyl. In some embodiments, R 3c is Me or Cl. In some embodiments, R 3c is a substituted or unsubstituted heterocyclic group.

[0230] Group R 3’

[0231] As generally defined above, R 3’ H, –C(=O)R C1 、–C(=O)OR C1、–C(=O)SR C1 , –C(=O)N(R C1 )2, –S(=O)2R C2 、–S(=O)2OR C1 、–P(=O)2R C2 、–P(=O)2OR C1 、–P(=O)(OR C1 )2. –P(=O)(R C2 )2, or –P(=O)(R C2 )(OR C1 ), where R C1 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, an oxygen protecting group when attached to an oxygen atom, a sulfur protecting group when attached to a sulfur atom, a nitrogen protecting group when attached to a nitrogen atom, or two R C1 groups are combined to form a substituted or unsubstituted heterocyclic ring; and R C2 is a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group, a substituted or unsubstituted carbocyclic group, a substituted or unsubstituted heterocyclic group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted heteroaryl group.

[0232] In some embodiments, R 3’ It is H (hydrogen).

[0233] In some embodiments, R 3’ = –C(=O)R C1 、–C(=O)OR C1 、–C(=O)SR C1 , –C(=O)N(R C1 )2, –S(=O)2R C1 、–S(=O)2OR C1 、–P(=O)2R C1 、–P(=O)2OR C1 、–P(=O)(OR C1 )2. –P(=O)(R C1 )2, or –P(=O)(R C1 )(OR C1 ).

[0234] In some embodiments, R C1 At least one instance of R is hydrogen or a protecting group, i.e., an oxygen protecting group when attached to an oxygen atom, a sulfur protecting group when attached to a sulfur atom, or a nitrogen protecting group when attached to a nitrogen atom. C1At least one instance of is hydrogen.

[0235] In some embodiments, R C1 At least one instance of which is a substituted or unsubstituted alkyl group, for example, a substituted or unsubstituted C 1–6 Alkyl, substituted or unsubstituted C 1–2 Alkyl, substituted or unsubstituted C 2–3 Alkyl, substituted or unsubstituted C 3–4 Alkyl, substituted or unsubstituted C 4–5 Alkyl, or substituted or unsubstituted C 5–6 Alkyl. Exemplary R C1 C 1–6 Alkyl includes, but is not limited to, substituted or unsubstituted 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), n-hexyl (C6), C6 substituted with 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more fluorine groups. 1–6 Alkyl (e.g., -CF3, -CH2F, -CHF2, difluoroethyl, and 2,2,2-trifluoro-1,1-dimethyl-ethyl), C substituted with 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more chloro groups 1–6 Alkyl groups (e.g., –CH2Cl, –CHCl2), and C 1–6 Alkyl groups (e.g., –CH2OCH3 and –CH2OCH2CH3).

[0236] In some embodiments, R C1 At least one instance of which is a substituted or unsubstituted alkenyl group, for example, a substituted or unsubstituted C 2–6 Alkenyl, substituted or unsubstituted C 2–3 Alkenyl, substituted or unsubstituted C 3–4 Alkenyl, substituted or unsubstituted C 4–5 Alkenyl, or substituted or unsubstituted C 5–6 Alkenyl.

[0237] In some embodiments, R C1 At least one instance of which is a substituted or unsubstituted alkynyl group, for example, a substituted or unsubstituted C 2–6 Alkynyl, substituted or unsubstituted C 2–3 Alkynyl, substituted or unsubstituted C 3–4 Alkynyl, substituted or unsubstituted C 4–5 Alkynyl, or substituted or unsubstituted C 5–6 Alkynyl.

[0238] In some embodiments, R C1 At least one instance of which is a substituted or unsubstituted carbocyclic group, for example, a substituted or unsubstituted C 3–6 Carbocyclic, substituted or unsubstituted C 3–4 Carbocyclic, substituted or unsubstituted C 4–5 Carbocyclic group, or substituted or unsubstituted C 5–6 Carbocyclic group.

[0239] In some embodiments, R C1 At least one instance of is a substituted or unsubstituted heterocyclyl, for example, a substituted or unsubstituted 3-6 membered heterocyclyl, a substituted or unsubstituted 3-4 membered heterocyclyl, a substituted or unsubstituted 4-5 membered heterocyclyl, or a substituted or unsubstituted 5-6 membered heterocyclyl.

[0240] In some embodiments, R C1 At least one instance of is a substituted or unsubstituted aryl group, for example, a substituted or unsubstituted phenyl group.

[0241] In some embodiments, R C1 At least one instance of is substituted or unsubstituted heteroaryl, for example, optionally substituted 5-6 membered heteroaryl.

[0242] In some embodiments, two R C1 Combine to form a substituted or unsubstituted heterocyclic ring, for example, a substituted or unsubstituted piperidinyl, substituted or unsubstituted piperazinyl, or substituted or unsubstituted morpholinyl ring.

[0243] In some embodiments, R 3’ = –C(=O)R C1 、–C(=O)OR C1 , –C(=O)N(R C1 )2 or –C(=O)N(OR C1 )(R C1 ), where R C1 As defined herein.

[0244] In some embodiments, R 3’ = –C(=O)R C1 , for example, where R C1 For example, substituted or unsubstituted 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), or n-hexyl (C6). In some embodiments, R3’ is -C(=O)CH3. In some embodiments, R 3’ -C(=O)(CH2) m CO2H, wherein m is an integer from 2 to 5, inclusive. In some embodiments, m is 2. In some embodiments, m is 3. In some embodiments, m is 4. In some embodiments, m is 5. In some embodiments, R 3’ It is –C(=O)CH2CH2C(=O)OH.

[0245] In some embodiments, R 3’ –C(=O)OR C1 , for example, where R C1 For example, substituted or unsubstituted 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), or n-hexyl (C6).

[0246] In some embodiments, R 3’ = –C(=O)SR C1 , for example, where R C1 For example, substituted or unsubstituted 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), or n-hexyl (C6).

[0247] In some embodiments, R 3’ =C(=O)N(R C1 )2, for example, -C(=O)NH2 or -C(=O)NHR C1 , where R C1 is, for example, substituted or unsubstituted 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), or n-hexyl (C6), or R 3’ =C(=O)N(R C1 )2, where two R C1Combine to form a substituted or unsubstituted heterocyclic ring, for example, a substituted or unsubstituted piperidinyl, substituted or unsubstituted piperazinyl, or substituted or unsubstituted morpholinyl ring.

[0248] In some embodiments, R 3’ is –S(=O)2R C1 or –S(=O)2OR C1 , where R C1 is, for example, hydrogen, or substituted or unsubstituted 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), or n-hexyl (C6), or substituted or unsubstituted phenyl. In some embodiments, R 3’ is –S(=O)2R C1 In some embodiments, R 3’ –S(=O)2OR C1 , for example, -SO3H.

[0249] In some embodiments, R 3’ = –P(=O)2R C1 、–P(=O)2OR C1 、–P(=O)(OR C1 )2. –P(=O)(R C1 )2, or –P(=O)(R C1 )(OR C1 ), where each R C1 R is independently, for example, hydrogen, substituted or unsubstituted 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), or n-hexyl (C6), or substituted or unsubstituted phenyl. In some embodiments, R 3’ = –P(=O)2R C1 In some embodiments, R 3’ = –P(=O)2OR C1 In some embodiments, R 3’ =P(=O)(OR C1 )2. In some embodiments, R 3’ =P(=O)(R C1 )2. In some embodiments, R 3’ =P(=O)(RC1 )(OR C1 ).

[0250] Group R 4 , R 6a , R 6b , R 11a and R 11b

[0251] As generally defined above, R 4 is H, 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.

[0252] In some embodiments, R 4 is H, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl.

[0253] In some embodiments, R 4 It is H, -CH3, or ethynyl.

[0254] In some embodiments, R 4 For H.

[0255] As generally defined above, R 6a and R 6b are each independently hydrogen, halogen (eg, fluorine), substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl, or R 6a and R 6b to form an oxo (=O) group, and represents a single bond or a double bond, provided that if the double bond is present in ring B, then R 6a or R 6b One of them is absent, and provided that if a single bond is present in ring B, the hydrogen at C5 is in the alpha or beta position.

[0256] As generally defined above, where independently represent a single bond or a double bond, provided that if the double bond is present in ring B, then R 6a or R 6b One of is absent, and provided that if a single bond is present in ring B, the hydrogen at C5 is in the alpha or beta position. In some embodiments, the dash between C5 and C6 represents a single bond, and the hydrogen at the 5-position is in the 5a-configuration. In some embodiments, the dash between C5 and C6 represents a single bond, and the hydrogen at the 5-position is in the 5β-configuration. In some embodiments, the dash between C5 and C6 Represents a double bond.

[0257] In it In some embodiments where R represents a single bond, 6a and R 6b Both are hydrogen.

[0258] In it represents a single bond and R 6a and R 6b In some embodiments where one of the groups is a non-hydrogen group, R 6a is α (downward) and R 6b is β (upward). In some embodiments, R 6b is α (downward) and R 6a is β (upward).

[0259] In it In some embodiments where R represents a single bond, 6a is hydrogen, and R 6b is halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl. 6a is hydrogen, and R 6b is halogen (eg, fluorine). In some embodiments, R 6a is hydrogen, and R 6b is a substituted or unsubstituted alkyl group, for example, a substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 1-2 Alkyl, substituted or unsubstituted C 2-3 Alkyl, substituted or unsubstituted C 3-4 Alkyl, substituted or unsubstituted C 4-5 Alkyl, or substituted or unsubstituted C 5-6 In some embodiments, R 6a is hydrogen, and R 6b is a substituted or unsubstituted alkenyl. 6a is hydrogen, and R 6b is a substituted or unsubstituted alkynyl group.

[0260] In it In some embodiments where R represents a single bond, 6b is hydrogen, and R 6a is halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl. 6b is hydrogen, and R 6a is halogen (eg, fluorine). In some embodiments, R 6b is hydrogen, and R 6ais a substituted or unsubstituted alkyl group, for example, a substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 1-2 Alkyl, substituted or unsubstituted C 2-3 Alkyl, substituted or unsubstituted C 3-4 Alkyl, substituted or unsubstituted C 4-5 Alkyl, or substituted or unsubstituted C 5-6 In some embodiments, R 6b is hydrogen, and R 6a is a substituted or unsubstituted alkenyl. 6b is hydrogen, and R 6a is a substituted or unsubstituted alkynyl group.

[0261] or, in which In some embodiments where R represents a single bond, 6a and R 6b Combine to form an oxo (=O) group.

[0262] In it In some embodiments where R represents a double bond, 6a For hydrogen. In some embodiments where R represents a double bond, 6a is a halogen, for example, fluorine. In some embodiments where R represents a double bond, 6a is a substituted or unsubstituted alkyl group, for example, a substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 1-2 Alkyl, substituted or unsubstituted C 2-3 Alkyl, substituted or unsubstituted C 3-4 Alkyl, substituted or unsubstituted C 4-5 Alkyl, or substituted or unsubstituted C 5-6 Alkyl, such as methyl, ethyl, propyl, or isopropyl. In some embodiments where R represents a double bond, 6a is a substituted or unsubstituted alkenyl group. In some embodiments where R represents a double bond, 6a is a substituted or unsubstituted alkynyl group.

[0263] As generally defined above, R 11a and R 11b are each independently hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, -OH, -OR D1 、-OC(=O)R D1 、-NH2、-N(R D1)2, or -NR D1 C(=O)R D1 , where R D1 Each instance of R is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, an oxygen protecting group when attached to an oxygen atom, a nitrogen protecting group when attached to a nitrogen atom, or two R D1 The groups are combined to form a substituted or unsubstituted heterocyclic ring; or R 11a and R 11b Combine to form an oxo (=O) group.

[0264] In some embodiments, R 11a is α (downward) and R 11b is β (upward). In some embodiments, R 11b is α (downward) and R 11a is β (upward).

[0265] In some embodiments, R 11a and R 11b In some embodiments, at least one of R 11a and R 11b Each is H.

[0266] In some embodiments, R 11a and R 11b At least one of R is halogen, for example, -F, -Br, -I, or -Cl. 11a is halogen and R 11b In some embodiments, R 11b is halogen and R 11a For hydrogen.

[0267] In some embodiments, R 11a and R 11b At least one of which is a substituted or unsubstituted alkyl group, for example, a substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 1-2 Alkyl, substituted or unsubstituted C 2–3 Alkyl, substituted or unsubstituted C 3–4 Alkyl, substituted or unsubstituted C 4–5 Alkyl, or substituted or unsubstituted C 5–6 Alkyl. Exemplary R 11a C 1–6Alkyl groups include, but are not limited to, substituted or unsubstituted methyl (C1), substituted or unsubstituted ethyl (C2), substituted or unsubstituted n-propyl (C3), substituted or unsubstituted isopropyl (C3), substituted or unsubstituted n-butyl (C4), substituted or unsubstituted tert-butyl (C4), substituted or unsubstituted sec-butyl (C4), substituted or unsubstituted isobutyl (C4), substituted or unsubstituted n-pentyl (C5), substituted or unsubstituted 3-pentyl (C5), substituted or unsubstituted pentyl (C5), substituted or unsubstituted neopentyl (C5), substituted or unsubstituted 3-methyl-2-butyl (C5), substituted or unsubstituted tert-pentyl (C5), or substituted or unsubstituted n-hexyl (C6). Exemplary substituted alkyl groups include, but are not limited to, alkyl groups substituted by halogen groups ("haloalkyl") and alkyl groups substituted by alkoxy groups ("alkoxyalkyl"). Exemplary haloalkyl groups include, but are not limited to, -CF3, -CH2F, -CHF 2、 difluoroethyl, 2,2,2-trifluoro-1,1-dimethyl-ethyl, -CH2Cl, and -CHCl2. Exemplary alkoxyalkyl groups include, but are not limited to, -CH2OCH3 and -CH2OCH2CH3. In some embodiments, R 11a and R 11b At least one of R is a substituted alkyl group (eg, a haloalkyl group, an alkoxyalkyl group). 11a is an alkyl group and R 11b In some embodiments, R 11b is an alkyl group and R 11a For hydrogen.

[0268] In some embodiments, R 11a and R 11b At least one of which is a substituted or unsubstituted alkenyl group, for example, a substituted or unsubstituted C 2–6 Alkenyl, substituted or unsubstituted C 2–3 Alkenyl, substituted or unsubstituted C 3–4 Alkenyl, substituted or unsubstituted C 4–5 Alkenyl, or substituted or unsubstituted C 5–6 Exemplary substituted alkenyl groups include, but are not limited to, alkenyl groups substituted with halogen groups (“haloalkenyl”) and alkenyl groups substituted with alkoxy groups (“alkoxyalkenyl”). 11a is alkenyl and R 11b In some embodiments, R 11b is alkenyl and R 11a For hydrogen.

[0269] In some embodiments, R 11a and R 11bAt least one of which is a substituted or unsubstituted alkynyl group, for example, a substituted or unsubstituted C 2–6 Alkynyl, substituted or unsubstituted C 2–3 Alkynyl, substituted or unsubstituted C 3–4 Alkynyl, substituted or unsubstituted C 4–5 Alkynyl, or substituted or unsubstituted C 5–6 Alkynyl. Exemplary substituted alkynyl groups include, but are not limited to, alkynyl groups substituted with halogen groups (“haloalkynyl”) and alkynyl groups substituted with alkoxy groups (“alkoxyalkynyl”). 11a is an alkynyl group and R 11b In some embodiments, R 11b is an alkynyl group and R 11a For hydrogen.

[0270] In some embodiments, R 11a and R 11b At least one of which is a substituted or unsubstituted carbocyclic group, for example, a substituted or unsubstituted C 3–6 Carbocyclic, substituted or unsubstituted C 3–4 Carbocyclic, substituted or unsubstituted C 4–5 Carbocyclic group, or substituted or unsubstituted C 5–6 In some embodiments, R 11a is a carbocyclic group and R 11b In some embodiments, R 11b is a carbocyclic group and R 11a For hydrogen.

[0271] In some embodiments, R 11a and R 11b At least one of which is a substituted or unsubstituted heterocyclic group, for example, a substituted or unsubstituted C 3–6 Heterocyclic, substituted or unsubstituted C 3–4 Heterocyclic, substituted or unsubstituted C 4–5 Heterocyclic group, or substituted or unsubstituted C 5–6 For example, in some embodiments, R 11a and R 11b At least one of R is a substituted or unsubstituted piperidinyl, substituted or unsubstituted piperazinyl, or substituted or unsubstituted morpholinyl ring. 11a and R 11b In some embodiments, at least one of R is a substituted or unsubstituted morpholinyl ring. 11a is a heterocyclic group and R 11b In some embodiments, R 11b is a heterocyclic group and R 11a For hydrogen.

[0272] In some embodiments, R 11a and R 11b At least one of R is a substituted or unsubstituted aryl group, for example, a substituted or unsubstituted phenyl group. 11a is an aromatic group and R 11b In some embodiments, R 11b is an aromatic group and R 11a For hydrogen.

[0273] In some embodiments, R 11a and R 11b At least one of R is a substituted or unsubstituted heteroaryl, for example, an optionally substituted 5-6 membered heteroaryl. 11a is a heteroaryl group and R 11b In some embodiments, R 11b is a heteroaryl group and R 11a For hydrogen.

[0274] In some embodiments, R 11a and R 11b At least one of -OH, -OR D1 , or –OC(=O)R D1 In some embodiments, R D1 is a substituted or unsubstituted alkyl group, for example, a substituted or unsubstituted C 1–6 Alkyl, substituted or unsubstituted C 1–2 Alkyl, substituted or unsubstituted C 2–3 Alkyl, substituted or unsubstituted C 3–4 Alkyl, substituted or unsubstituted C 4–5 Alkyl, or substituted or unsubstituted C 5–6 Alkyl. Exemplary R D1 C 1–6 Alkyl includes, but is not limited to, substituted or unsubstituted methyl (C1), substituted or unsubstituted ethyl (C2), substituted or unsubstituted n-propyl (C3), substituted or unsubstituted isopropyl (C3), substituted or unsubstituted n-butyl (C4), substituted or unsubstituted tert-butyl (C4), substituted or unsubstituted sec-butyl (C4), substituted or unsubstituted isobutyl (C4), substituted or unsubstituted n-pentyl (C5), substituted or unsubstituted 3-pentyl (C5), substituted or unsubstituted pentyl (C5), substituted or unsubstituted neopentyl (C5), substituted or unsubstituted 3-methyl-2-butyl (C5), substituted or unsubstituted tert-pentyl (C5), or substituted or unsubstituted n-hexyl (C6). In some embodiments, R 11a and R 11b At least one of R is -OH. 11a For –OH, –ORD1 , or –OC(=O)R D1 And R 11b In some embodiments, R 11b For –OH, –OR D1 , or –OC(=O)R D1 And R 11a For hydrogen.

[0275] In some embodiments, R 11a and R 11b At least one of -NH2, -N(R D1 )2, or –NR D1 C(=O)R D1 In some embodiments, R D1 is hydrogen or substituted or unsubstituted alkyl, for example, substituted or unsubstituted C 1–6 Alkyl, substituted or unsubstituted C 1–2 Alkyl, substituted or unsubstituted C 2-3 Alkyl, substituted or unsubstituted C 3-4 Alkyl, substituted or unsubstituted C 4-5 Alkyl, or substituted or unsubstituted C 5-6 Alkyl. Exemplary R D1 C 1-6 Alkyl includes, but is not limited to, substituted or unsubstituted methyl (C1), substituted or unsubstituted ethyl (C2), substituted or unsubstituted n-propyl (C3), substituted or unsubstituted isopropyl (C3), substituted or unsubstituted n-butyl (C4), substituted or unsubstituted tert-butyl (C4), substituted or unsubstituted sec-butyl (C4), substituted or unsubstituted isobutyl (C4), substituted or unsubstituted n-pentyl (C5), substituted or unsubstituted 3-pentyl (C5), substituted or unsubstituted pentyl (C5), substituted or unsubstituted neopentyl (C5), substituted or unsubstituted 3-methyl-2-butyl (C5), substituted or unsubstituted tert-pentyl (C5), or substituted or unsubstituted n-hexyl (C6). In some embodiments, R 11a and R 11b At least one of -N(R D1 )2, for example, -NH2, -N(CH3)2. In some embodiments, R 11a -NH2, -N(R D1 )2, or -NR D1 C(=O)R D1 And R 11b In some embodiments, R 11b -NH2, -N(R D1 )2, or -NR D1 C(=O)R D1 And R11a For hydrogen.

[0276] In some embodiments, R 11a and R 11b Combine to form an oxo (=O) group.

[0277] Other embodiments of formula (I) and (III)

[0278] Various combinations of the above embodiments are further contemplated herein. For example, in some embodiments, the compound of formula (I) is of formula (I-a1), (I-a2) or (I-a3):

[0279]

[0280] or a pharmaceutically acceptable salt, solvate, hydrate, prodrug, stereoisomer, tautomer, isotopic variant, or N-oxide thereof, or a combination thereof. 1 is hydrogen, halogen (e.g., bromine), -OR A1 (e.g., -OH), -N(R A1 )2, -SS(=O)2R A2 , substituted or unsubstituted heterocyclyl, or substituted or unsubstituted heteroaryl. In some embodiments, R 1 is hydrogen, bromine, or -OH. In some embodiments, R 2 is hydrogen, substituted or unsubstituted heterocyclic group, -OH, -OR B1 、-OC(=O)R B1 、-NH2、-N(R B1 )2, or -NR B1 C(=O)R B1 In some embodiments, R 3 is a substituted or unsubstituted alkyl, a substituted or unsubstituted alkenyl, or a substituted or unsubstituted alkynyl. 3’ In some embodiments, R 4 In some embodiments, R 6a and R 6b Both are hydrogen. In some embodiments, R 6a and R 6b One of them is a non-hydrogen group. In some embodiments, R 6a is a non-hydrogen alpha group. 6a is a non-hydrogen β group. 6a is halogen such as fluorine, or alkyl. 6a is halogen such as fluorine, or alkyl, and R 6bIn some embodiments, R 6a and R 6b Both are halogen, for example, fluorine. In some embodiments, R 6a and R 6b Both are alkyl, for example, methyl. In some embodiments, R 6a and R 6b Combine to form an oxo group. In some embodiments, R 11a and R 11b Both are hydrogen. In some embodiments, R 11a and R 11b One of them is a non-hydrogen group. In some embodiments, R 11a and R 11b Combine to form an oxo group.

[0281] In some embodiments, the compound of formula (III) is formula (III-a1), (III-a2) or (III-a3):

[0282]

[0283] or a pharmaceutically acceptable salt, solvate, hydrate, prodrug, stereoisomer, tautomer, isotopic variant, or N-oxide thereof, or a combination thereof. 1 is hydrogen, halogen (e.g., bromine), -OR A1 (e.g., -OH), -N(R A1 )2, -SS(=O)2R A2 , substituted or unsubstituted heterocyclyl, or substituted or unsubstituted heteroaryl. In some embodiments, R 1 is hydrogen, bromine, or -OH. In some embodiments, R 2 is hydrogen, substituted or unsubstituted heterocyclic group, -OH, -OR B1 、-OC(=O)R B1 、-NH2、-N(R B1 )2, or -NR B1 C(=O)R B1 In some embodiments, R 3 is a substituted or unsubstituted alkyl, a substituted or unsubstituted alkenyl, or a substituted or unsubstituted alkynyl. 3’ In some embodiments, R 4 In some embodiments, R 6a and R 6b Both are hydrogen. In some embodiments, R 6a and R 6b One of them is a non-hydrogen group. In some embodiments, R6a is a non-hydrogen alpha group. 6a is a non-hydrogen β group. 6a is halogen such as fluorine, or alkyl. 6a is halogen such as fluorine, or alkyl, and R 6b In some embodiments, R 6a and R 6b Both are halogen, for example, fluorine. In some embodiments, R 6a and R 6b Both are alkyl, for example, methyl. In some embodiments, R 6a and R 6b Combine to form an oxo group. In some embodiments, R 11a and R 11b Both are hydrogen. In some embodiments, R 11a and R 11b One of them is a non-hydrogen group. In some embodiments, R 11a and R 11b Combine to form an oxo group.

[0284] In which R 2 and R 4 In some embodiments where R is hydrogen, the compound of formula (I) is of formula (I-b1), (I-b2) or (I-b3):

[0285]

[0286] or a pharmaceutically acceptable salt, solvate, hydrate, prodrug, stereoisomer, tautomer, isotopic variant, or N-oxide thereof, or a combination thereof. 1 is hydrogen, halogen (e.g., bromine), -OR A1 (e.g., -OH), -N(R A1 )2, -SS(=O)2R A2 , substituted or unsubstituted heterocyclyl, or substituted or unsubstituted heteroaryl. In some embodiments, R 1 is hydrogen, bromine, or -OH. In some embodiments, R 3 is a substituted or unsubstituted alkyl, a substituted or unsubstituted alkenyl, or a substituted or unsubstituted alkynyl. 3’ In some embodiments, R 6a and R 6b Both are hydrogen. In some embodiments, R 6a and R 6b One of them is a non-hydrogen group. In some embodiments, R 6ais a non-hydrogen alpha group. 6a is a non-hydrogen β group. 6a is halogen such as fluorine, or alkyl. 6a is halogen such as fluorine, or alkyl, and R 6b In some embodiments, R 6a and R 6b Both are halogen, for example, fluorine. In some embodiments, R 6a and R 6b Both are alkyl, for example, methyl. In some embodiments, R 6a and R 6b Combine to form an oxo group. In some embodiments, R 11a and R 11b Both are hydrogen. In some embodiments, R 11a and R 11b One of them is a non-hydrogen group. In some embodiments, R 11a and R 11b Combine to form an oxo group.

[0287] In which R 2 and R 4 In some embodiments where R is hydrogen, the compound of formula (III) is of formula (III-b1), (III-b2) or (III-b3):

[0288]

[0289] or a pharmaceutically acceptable salt, solvate, hydrate, prodrug, stereoisomer, tautomer, isotopic variant, or N-oxide thereof, or a combination thereof. 1 is hydrogen, halogen (e.g., bromine), -OR A1 (e.g., -OH), -N(R A1 )2, -SS(=O)2R A2 , substituted or unsubstituted heterocyclyl, or substituted or unsubstituted heteroaryl. In some embodiments, R 1 is hydrogen, bromine, or -OH. In some embodiments, R 3 is a substituted or unsubstituted alkyl, a substituted or unsubstituted alkenyl, or a substituted or unsubstituted alkynyl. 3’ In some embodiments, R 6a and R 6b Both are hydrogen. In some embodiments, R 6a and R 6b One of them is a non-hydrogen group. In some embodiments, R 6ais a non-hydrogen alpha group. 6a is a non-hydrogen β group. 6a is halogen such as fluorine, or alkyl. 6a is halogen such as fluorine, or alkyl, and R 6b In some embodiments, R 6a and R 6b Both are halogen, for example, fluorine. In some embodiments, R 6a and R 6b Both are alkyl, for example, methyl. In some embodiments, R 6a and R 6b Combine to form an oxo group. In some embodiments, R 11a and R 11b Both are hydrogen. In some embodiments, R 11a and R 11b One of them is a non-hydrogen group. In some embodiments, R 11a and R 11b Combine to form an oxo group.

[0290] In which R 2 , R 4 , R 11a and R 11b In some embodiments where R is hydrogen, the compound of formula (I) is of formula (I-c1), (I-c2) or (I-c3):

[0291]

[0292] or a pharmaceutically acceptable salt, solvate, hydrate, prodrug, stereoisomer, tautomer, isotopic variant, or N-oxide thereof, or a combination thereof. 1 is hydrogen, halogen (e.g., bromine), -OR A1 (e.g., -OH), -N(R A1 )2, -SS(=O)2R A2 , substituted or unsubstituted heterocyclyl, or substituted or unsubstituted heteroaryl. In some embodiments, R 1 is hydrogen, bromine, or -OH. In some embodiments, R 3 is a substituted or unsubstituted alkyl, a substituted or unsubstituted alkenyl, or a substituted or unsubstituted alkynyl. 3’ In some embodiments, R 6a and R 6b Both are hydrogen. In some embodiments, R 6a and R 6bOne of them is a non-hydrogen group. In some embodiments, R 6a is a non-hydrogen alpha group. 6a is a non-hydrogen β group. 6a is halogen such as fluorine, or alkyl. 6a is halogen such as fluorine, or alkyl, and R 6b In some embodiments, R 6a and R 6b Both are halogen, for example, fluorine. In some embodiments, R 6a and R 6b Both are alkyl, for example, methyl. In some embodiments, R 6a and R 6b Combine to form an oxo group.

[0293] In which R 2 , R 4 , R 11a and R 11b In some embodiments where R is hydrogen, the compound of formula (III) is of formula (III-c1), (III-c2) or (III-c3):

[0294]

[0295] or a pharmaceutically acceptable salt, solvate, hydrate, prodrug, stereoisomer, tautomer, isotopic variant, or N-oxide thereof, or a combination thereof. 1 is hydrogen, halogen (e.g., bromine), -OR A1 (e.g., -OH), -N(R A1 )2, -SS(=O)2R A2 , substituted or unsubstituted heterocyclyl, or substituted or unsubstituted heteroaryl. In some embodiments, R 1 is hydrogen, bromine, or -OH. In some embodiments, R 3 is a substituted or unsubstituted alkyl, a substituted or unsubstituted alkenyl, or a substituted or unsubstituted alkynyl. 3’ In some embodiments, R 6a and R 6b Both are hydrogen. In some embodiments, R 6a and R 6b One of them is a non-hydrogen group. In some embodiments, R 6a is a non-hydrogen alpha group. 6a is a non-hydrogen β group. 6a is halogen such as fluorine, or alkyl.6a is halogen such as fluorine, or alkyl, and R 6b In some embodiments, R 6a and R 6b Both are halogen, for example, fluorine. In some embodiments, R 6a and R 6b Both are alkyl, for example, methyl. In some embodiments, R 6a and R 6b Combine to form an oxo group.

[0296] In which R 2 , R 4 , R 11a , R 11b , R 6a , R 6b In some embodiments where R is hydrogen, the compound of formula (I) is of formula (I-d1), (I-d2) or (I-d3):

[0297]

[0298] or a pharmaceutically acceptable salt, solvate, hydrate, prodrug, stereoisomer, tautomer, isotopic variant, or N-oxide thereof, or a combination thereof. 1 is hydrogen, halogen (e.g., bromine), -OR A1 (e.g., -OH), -N(R A1 )2, -SS(=O)2R A2 , substituted or unsubstituted heterocyclyl, or substituted or unsubstituted heteroaryl. In some embodiments, R 1 is hydrogen, bromine, or -OH. In some embodiments, R 3 is a substituted or unsubstituted alkyl, a substituted or unsubstituted alkenyl, or a substituted or unsubstituted alkynyl. 3’ For hydrogen.

[0299] In which R 2 , R 4 , R 11a , R 11b , R 6a , R 6b In some embodiments where R is hydrogen, the compound of formula (III) is of formula (III-d1), (III-d2) or (III-d3):

[0300]

[0301]

[0302] or a pharmaceutically acceptable salt, solvate, hydrate, prodrug, stereoisomer, tautomer, isotopic variant, or N-oxide thereof, or a combination thereof. 1 is hydrogen, halogen (e.g., bromine), -OR A1 (e.g., -OH), -N(R A1 )2, -SS(=O)2R A2 , substituted or unsubstituted heterocyclyl, or substituted or unsubstituted heteroaryl. In some embodiments, R 1 is hydrogen, bromine, or -OH. In some embodiments, R 3 is a substituted or unsubstituted alkyl, a substituted or unsubstituted alkenyl, or a substituted or unsubstituted alkynyl. 3’ For hydrogen.

[0303] In some further embodiments of formula (I) and (III), R 1 For hydrogen, halogen, -OR A1 、-SR A1 、-N(R A1 )2, -OC(=O)R A1 、-OC(=O)OR A1 、-OC(=O)SR A1 、-OC(=O)N(R A1 )2, -SC(=O)R A2 、-SC(=O)OR A1 、-SC(=O)SR A1 、-SC(=O)N(R A1 )2, -NHC(=O)R A1 、-NHC(=O)OR A1 、-NHC(=O)SR A1 、-NHC(=O)N(R A1 )2, -OS(=O)2R A2 、-OS(=O)2OR A1 、-SS(=O)2R A2 、-SS(=O)2OR A1 、-S(=O)R A2 、-SO2R A2 , or -S(=O)2OR A1 ; R 2 is hydrogen, substituted or unsubstituted heterocyclic group, -OH, -OR B1 、-OC(=O)R B1 、-NH2、-N(R B1 )2, or -NR B1 C(=O)R B1; R 3 is 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, or substituted or unsubstituted heteroaryl group; R 3’ is hydrogen; R 4 is hydrogen; R 6a and R 6b are each independently hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl, or R 6a and R 6b Combined to form an oxo (=O) group; and R 11a and R 11b are independently hydrogen, -OH, -OR D1 、-OC(=O)R D1 、-NH2、-N(R D1 )2, or -NR D1 C(=O)R D1 , or R 11a and R 11b Combine to form an oxo (=O) group.

[0304] Additional embodiments of formula (I) are further contemplated herein. For example, in some embodiments, the compound of formula (I) is selected from any one of the following formulae:

[0305]

[0306]

[0307] or a pharmaceutically acceptable salt, solvate, hydrate, prodrug, stereoisomer, tautomer, isotopic variant, or N-oxide thereof, or a combination thereof.

[0308] In some embodiments, the compound of formula (I) is selected from any one of the following formulae:

[0309]

[0310] or a pharmaceutically acceptable salt, solvate, hydrate, prodrug, stereoisomer, tautomer, or isotopic variant thereof, or a combination thereof.

[0311] In some embodiments, the compound of formula (I) is selected from any one of the following formulae:

[0312]

[0313] or a pharmaceutically acceptable salt, solvate, hydrate, prodrug, stereoisomer, tautomer, or isotopic variant thereof, or a combination thereof.

[0314] In some embodiments, the compound of formula (I) is selected from any one of the following formulae:

[0315]

[0316] or a pharmaceutically acceptable salt, solvate, hydrate, prodrug, stereoisomer, tautomer, isotopic variant, or N-oxide thereof, or a combination thereof, wherein m is 0, 1 or 2; and each R 1c are independently -CH3, F, Cl, -CN, -OMe, -SMe, -SOMe, -SO2Me, -CH2F, -CHF2, or -CF3.

[0317] In some embodiments, the compound of formula (I) is selected from any one of the following formulae:

[0318]

[0319]

[0320] or a pharmaceutically acceptable salt, solvate, hydrate, prodrug, stereoisomer, tautomer, isotopic variant, or N-oxide thereof, or a combination thereof, wherein m is 0, 1 or 2; and each R 1c are independently -CH3, F, Cl, -CN, -OMe, -SMe, -SOMe, -SO2Me, -CH2F, -CHF2, or -CF3.

[0321] In some embodiments, the compound of formula (I) is selected from any one of the following formulae:

[0322]

[0323]

[0324] or a pharmaceutically acceptable salt, solvate, hydrate, prodrug, stereoisomer, tautomer, isotopic variant, or N-oxide thereof, or a combination thereof, wherein m is 0, 1 or 2; and each R 1c In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 1, and each R 1c is -CH3, Cl or -CN. In some embodiments, m is 2, and each R 1c It is -CH3, Cl or -CN.

[0325] In some embodiments, the compound of formula (I) is selected from any one of the following formulae:

[0326]

[0327] or a pharmaceutically acceptable salt, solvate, hydrate, prodrug, stereoisomer, tautomer, isotopic variant, or N-oxide thereof, or a combination thereof, wherein R 1c is H, -CH3, Cl, F, -CN, OMe, -SMe, -SOMe, -SO2Me, -CH2F, -CHF2, or -CF3.

[0328] In some embodiments, the compound of formula (I) is selected from any one of the following formulae:

[0329]

[0330] or a pharmaceutically acceptable salt, solvate, hydrate, prodrug, stereoisomer, tautomer, isotopic variant, or N-oxide thereof, or a combination thereof, wherein X is -O- or -S-; and R 1c are independently H, -CH3, F, Cl, -CN, OMe, -SMe, -SOMe, -SO2Me, -CH2F, -CHF2, or -CF3.

[0331] In some embodiments, the compound of formula (I) is selected from any one of the following formulae:

[0332]

[0333] or a pharmaceutically acceptable salt, solvate, hydrate, prodrug, stereoisomer, tautomer, or isotopic variant thereof, or a combination thereof.

[0334] In some embodiments, the compound of formula (I) is selected from any one of the following formulae:

[0335]

[0336] or a pharmaceutically acceptable salt, solvate, hydrate, prodrug, stereoisomer, tautomer, or isotopic variant thereof, or a combination thereof.

[0337] In some embodiments, the compound of formula (I) is selected from any one of the following formulae:

[0338]

[0339] or a pharmaceutically acceptable salt, solvate, hydrate, prodrug, stereoisomer, tautomer, isotopic variant, or N-oxide thereof, or a combination thereof, wherein m is 0, 1 or 2; and each R1c In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 2, and each R 1c It is -CH3, Cl or -CN.

[0340] In some embodiments, the compound of formula (I) is selected from any one of the following formulae:

[0341]

[0342] or a pharmaceutically acceptable salt, solvate, hydrate, prodrug, stereoisomer, tautomer, isotopic variant, or N-oxide thereof, or a combination thereof, wherein m is 0, 1 or 2; and each R 1c are independently -CH3, F, Cl, -CN, -OMe, -SMe, -SOMe, -SO2Me, -CH2F, -CHF2, or -CF3.

[0343] In some embodiments, the compound of formula (I) is selected from any one of the following formulae:

[0344]

[0345] or a pharmaceutically acceptable salt, solvate, hydrate, prodrug, stereoisomer, tautomer, isotopic variant, or N-oxide thereof, or a combination thereof, wherein m is 0, 1 or 2; and each R 1c are independently -CH3, F, Cl, -CN, -OMe, -SMe, -SOMe, -SO2Me, -CH2F, -CHF2, or -CF3.

[0346] In some embodiments, the compound of formula (I) is selected from any one of the following formulae:

[0347]

[0348]

[0349] or a pharmaceutically acceptable salt, solvate, hydrate, prodrug, stereoisomer, tautomer, isotopic variant, or N-oxide thereof, or a combination thereof, wherein R 1c It is H, -CH3, Cl, -CN, -OMe, -SMe, -F, -SOMe, -SO2Me, -CH2F, -CHF2, or -CF3.

[0350] In some embodiments, the compound of formula (I) is selected from any one of the following formulae:

[0351]

[0352] or a pharmaceutically acceptable salt, solvate, hydrate, prodrug, stereoisomer, tautomer, isotopic variant, or N-oxide thereof, or a combination thereof, wherein X is -O- or -S-; and R 1c R is independently H, -CH3, F, Cl, -CN, -OMe, -SMe, -SOMe, -SO2Me, -CH2F, -CHF2, or -CF3. 1c R is independently H, -CH3, F, Cl, -CN, -OMe, -SMe, -SOMe, -SO2Me, -CH2F, -CHF2, or -CF3. 1c is -CH3, -CH2F, -CHF2, or -CF3. In some embodiments, R 1c is F, Cl, or CN. In some embodiments, R 1c In some embodiments, R 1c In some embodiments, X is -S-.

[0353] In some embodiments, the compound of formula (I) is selected from any one of the following formulae:

[0354]

[0355] or a pharmaceutically acceptable salt, solvate, hydrate, prodrug, stereoisomer, tautomer, isotopic variant, or N-oxide thereof, or a combination thereof, wherein R 1 , R 2 and R 3 As described herein.

[0356] In some embodiments, the compound of formula (I) is selected from any one of the following compounds, or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, tautomer, isotopic variant, N-oxide, or a combination thereof:

[0357]

[0358]

[0359]

[0360]

[0361]

[0362] In some embodiments, the compound of formula (I) is selected from any one of the following compounds, or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, tautomer, isotopic variant, N-oxide, or a combination thereof:

[0363]

[0364]

[0365]

[0366]

[0367]

[0368] In some embodiments, the compound of formula (I) is selected from any one of the following compounds, or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, tautomer, isotopic variant, N-oxide, or a combination thereof:

[0369]

[0370]

[0371]

[0372]

[0373]

[0374] In some embodiments, the compound of formula (III) is selected from any one of the following compounds, or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, tautomer, isotopic variant, N-oxide, or a combination thereof:

[0375]

[0376]

[0377]

[0378]

[0379]

[0380] In some embodiments, the compound of formula (III) is selected from any one of the following compounds, or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, tautomer, isotopic variant, N-oxide, or a combination thereof:

[0381]

[0382]

[0383]

[0384]

[0385]

[0386] In some embodiments, the compound of formula (III) is selected from any one of the following compounds, or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, tautomer, isotopic variant, N-oxide, or a combination thereof:

[0387]

[0388]

[0389]

[0390]

[0391]

[0392] Pharmaceutical composition

[0393] In another aspect, the present invention provides a pharmaceutical composition comprising a compound of the present invention and a pharmaceutically acceptable carrier. In some embodiments, the pharmaceutical composition comprises an effective amount of the compound. In some embodiments, the pharmaceutical composition comprises a therapeutically effective amount of the compound. In some embodiments, the pharmaceutical composition comprises a preventive effective amount of the compound.

[0394] When used as a medicine, the compounds provided herein are typically administered in the form of a pharmaceutical composition. Such compositions can be prepared in a manner well known in the pharmaceutical art and include at least one active compound.

[0395] In one embodiment, with respect to the pharmaceutical composition, the carrier is a parenteral carrier, an oral carrier, or a topical (external) carrier.

[0396] The present invention also relates to the compounds of the present invention or pharmaceutical compositions thereof for use as a medicine or medicament.

[0397] Typically, the compounds provided herein are administered in a therapeutically effective amount. The amount of the compound actually administered will typically be determined by a physician based on 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, the severity of the patient's symptoms, etc.

[0398] The pharmaceutical compositions provided herein can be administered by a variety of routes, including oral, rectal, transdermal, subcutaneous, intravenous, intramuscular and intranasal. Depending on the intended route of delivery, the compounds provided herein are preferably formulated as injectable or oral compositions or as ointments, as lotions, or as patches (all for transdermal administration).

[0399] The pharmaceutical compositions provided herein can also be administered chronically ("chronic administration"). Chronic administration refers to administration of a compound or pharmaceutical composition thereof over a long-term period of time, such as 3 months, 6 months, 1 year, 2 years, 3 years, 5 years, etc., or may continue indefinitely, such as for the rest of the subject's life. In some embodiments, chronic administration is intended to provide a constant level of the compound in the blood during the long-term period of time, for example, within a therapeutic window.

[0400] Compositions for oral administration can take the form of bulk liquid solutions or suspensions, or bulk powders. However, more generally, the compositions are provided in unit dosage form to facilitate accurate dosing. The term "unit dosage form" refers to a physically discrete unit suitable as a unit dose for human subjects and other mammals, each unit containing a predetermined amount of active substance calculated to produce a 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, or pills, tablets, capsules, etc. in the case of solid compositions. In such compositions, the compound is generally a relatively small component (about 0.1-about 50% by weight or preferably about 1-about 40% by weight), and the remainder is various vehicles or carriers and processing aids useful for forming a desired dosage form.

[0401] Liquid forms suitable for oral administration may include a suitable aqueous or non-aqueous vehicle and buffers, suspending and dispersing agents, colorants, flavoring agents, etc. Solid forms may include, for example, any of the following ingredients or compounds of a similar nature: binders such as microcrystalline cellulose, tragacanth, or gelatin; excipients such as starch or lactose, disintegrants such as alginic acid, Primogel, or corn starch; lubricants such as magnesium stearate; glidants such as colloidal silicon dioxide; sweeteners such as sucrose or saccharin; or flavoring agents such as mint, methyl salicylate, or orange flavoring.

[0402] Injectable compositions are typically based on injectable sterile saline or phosphate buffered saline or other injectable carriers known in the art. As previously mentioned, the active compound in such compositions is typically a minor component, often about 0.05-10% by weight, and the remainder is an injectable carrier, etc.

[0403] Transdermal compositions are typically formulated as topical ointments or creams, comprising active ingredients, typically in an amount of about 0.01-about 20% by weight, preferably about 0.1-about 20% by weight, preferably about 0.1-about 10% by weight, and more preferably about 0.5-about 15% by weight. When formulated as an ointment, the active ingredient is typically combined with paraffin or a water-miscible ointment base. Alternatively, the active ingredient can be formulated with an emulsion with, for example, an oil-in-water cream base. Such transdermal preparations are well known in the art and typically include additional ingredients for skin penetration that enhance the stability of the active ingredient or preparation. All such known transdermal preparations and ingredients are included in the scope provided herein.

[0404] The compounds provided herein may also be administered by transdermal means. Thus, transdermal administration may be achieved using patches of either the reservoir or porous membrane type, or of the solid matrix variety.

[0405] The above components 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.

[0406] The above components for orally administrable, injectable or topically administrable compositions are merely representative. Other materials and processing techniques are described in Part 8 of Remington's The Science and Practice of Pharmacy, 21st edition, 2005, Publisher: Lippincott Williams & Wilkins, which is incorporated herein by reference.

[0407] The compounds of the invention may also be administered in sustained release form or from a sustained release administration system. A description of representative sustained release materials can be found in Remington's Pharmaceutical Sciences.

[0408] The present invention also relates to pharmaceutically acceptable formulations of the compounds of the present invention. In one embodiment, the formulation includes water. In another embodiment, the formulation includes a cyclodextrin derivative. The most common cyclodextrins are α-, β- and γ-cyclodextrins composed of 6, 7 and 8 α-l,4-linked glucose units, respectively, which optionally include one or more substituents on the linked sugar portion, including, but not limited to, methylated, hydroxyalkylated, acylated and sulfoalkyl ether substitutions. In some embodiments, the cyclodextrin is a sulfoalkyl ether β-cyclodextrin, for example, sulfobutyl ether β-cyclodextrin, also known as See, e.g., US 5,376,645. In some embodiments, the formulation includes hexapropyl-β-cyclodextrin (e.g., 10-50% in water).

[0409] 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 hydrochloride, hydroiodide, hydrobromide, nitrate, sulfate, bisulfate, phosphate, acetate, lactate, citrate, tartrate, succinate, maleate, fumarate, benzoate, p-toluenesulfonate, etc.

[0410] The following formulation examples illustrate representative pharmaceutical compositions that can be prepared according to the present invention. However, the present invention is not limited to the following pharmaceutical compositions.

[0411] Exemplary Formulation 1 - Tablets: The compound of the invention may be mixed as a dry powder with a dry gelatin binder in a weight ratio of about 1:2. A smaller amount of magnesium stearate is added as a lubricant. The mixture is formed into 240-270 mg tablets (80-90 mg active compound per tablet) in a tablet press.

[0412] Exemplary Formulation 2 - Capsules: A compound of the invention may be mixed as a dry powder with a starch diluent in a weight ratio of about 1 : 1. The mixture is filled into 250 mg capsules (125 mg active compound per capsule).

[0413] Exemplary Formulation 3 - Liquid: A compound of the invention (125 mg) may be mixed with sucrose (1.75 g) and xanthan gum (4 mg), and the resulting mixture may be blended, passed through a No. 10 mesh U.S. sieve, and then mixed with a pre-made solution of microcrystalline cellulose and sodium carboxymethyl cellulose (11:89, 50 mg) in water. Sodium benzoate (10 mg), flavoring, and coloring agents are diluted with water and added with stirring. Sufficient water may then be added to produce a total volume of 5 mL.

[0414] Exemplary Formulation 4 - Tablets: The compound of the invention may be mixed as a dry powder with a dry gelatin binder in a weight ratio of about 1:2. A smaller amount of magnesium stearate is added as a lubricant. The mixture is formed into 450-900 mg tablets (150-300 mg active compound) in a tablet press.

[0415] Exemplary Formulation 5 - Injectable: The compound of the invention may be dissolved or suspended in a buffered sterile saline injectable aqueous medium to a concentration of about 5 mg / mL.

[0416] Exemplary Formulation 6 - Tablets: The compound of the invention may be mixed as a dry powder with a dry gelatin binder in a weight ratio of about 1:2. A smaller amount of magnesium stearate is added as a lubricant. The mixture is formed into 90-150 mg tablets (30-50 mg active compound per tablet) in a tablet press.

[0417] Exemplary Formulation 7 - Tablets: The compound of the invention may be mixed as a dry powder with a dry gelatin binder in a weight ratio of about 1:2. A smaller amount of magnesium stearate is added as a lubricant. The mixture is formed into 30-90 mg tablets (10-30 mg active compound per tablet) in a tablet press.

[0418] Exemplary Formulation 8 - Tablets: The compound of the invention may be mixed as a dry powder with a dry gelatin binder in a weight ratio of about 1:2. A smaller amount of magnesium stearate is added as a lubricant. The mixture is formed into 0.3-30 mg tablets (0.1-10 mg active compound per tablet) in a tablet press.

[0419] Exemplary Formulation 9 - Tablets: The compound of the invention may be mixed as a dry powder with a dry gelatin binder in a weight ratio of about 1:2. A smaller amount of magnesium stearate is added as a lubricant. The mixture is formed into 150-240 mg tablets (50-80 mg active compound per tablet) in a tablet press.

[0420] Exemplary Formulation 10 - Tablets: The compound of the invention may be mixed as a dry powder with a dry gelatin binder in a weight ratio of about 1:2. A smaller amount of magnesium stearate is added as a lubricant. The mixture is formed into 270-450 mg tablets (90-150 mg active compound per tablet) in a tablet press.

[0421] Injection dosage levels range from about 0.1 mg / kg / hour to at least 10 mg / kg / hour, all for about 1 to about 120 hours and especially 24 to 96 hours. A preloading bolus of about 0.1 mg / kg to about 10 mg / kg or more may also be administered to achieve an appropriate steady-state level. For a 40-80 kg human patient, it is not expected that the maximum total dose will exceed about 2 g / day.

[0422] For the prevention and / or treatment of long-term conditions, treatment regimens are usually carried out for many months or years, so for the convenience and tolerability of the patient, oral dosage administration is preferred. For oral dosage administration, one to five times a day and especially two to four times and typically three oral doses are representative regimens. Using these dosage administration modes, each dose provides about 0.01-about 20 mg / kg of the compound provided herein, wherein the preferred dose each provides about 0.1-about 10 mg / kg and especially about 1-about 5 mg / kg.

[0423] Transdermal doses are generally selected to provide blood levels (blood concentrations) similar to or lower than that achieved with injected doses.

[0424] When used to prevent the onset of CNS-disorders, the compounds provided herein are administered to subjects at risk of developing the disorder, typically under the advice and supervision of a physician, at the dosage levels described above. Subjects at risk of developing a particular disorder typically include those with a family history of the disorder, or those who have been identified by genetic testing or screening as being particularly susceptible to the development of the disorder.

[0425] Treatment and use

[0426] Early studies (see, e.g., Gee et al., European Journal of Pharmacology, 136: 419-423 (1987)) demonstrated that some 3a-hydroxylated steroids were orders of magnitude more potent as GRC modulators than other reported substances (see, e.g., Majewska et al., Science 232: 1004-1007 (1986); Harrison et al., J Pharmacol. Exp. Ther. 241: 346-353 (1987)). Majewska et al. and Harrison et al. teach that 3a-hydroxylated-5-reduced steroids are only able to achieve much lower levels of efficacy. In vitro and in vivo experimental data have now demonstrated that the high potency of these steroids allows them to be therapeutically useful in the modulation of brain excitability via the GRC (see, e.g., Gee et al., European Journal of Pharmacology, 136:419-423 (1987); Wieland et al., Psychopharmacology 118(1):65-71 (1995)).

[0427] A variety of synthetic steroids have also been prepared as neuroactive steroids. See, for example, U.S. Pat. No. 5,232,917, which discloses neuroactive steroid compounds useful in treating stress, anxiety, insomnia, episodic disorders, and mood disorders that are acted upon by GRC-active agents, such as depression, in a therapeutically beneficial manner. Moreover, these steroids have previously been shown to interact at a unique site on the GRC that is distinct from other known interaction sites (e.g., barbiturates, benzodiazepines, and GABA), where other known interaction sites have previously been shown to have therapeutic benefits for stress, anxiety, sleep, mood disorders, and seizure disorders (see, e.g., Gee, KWand Yamamura, HI, "Benzodiazepines and Barbiturates: Drugs for the Treatment of Anxiety, Insomnia and Seizure Disorders," Central Nervous System Disorders, Horvell, ed., Marcel-Dekker, New York (1985), pp. 123-147; Lloyd, KGand Morselli, PL, "Psychopharmacology of GABAergic Drugs," Psychopharmacology: The Third Generation of Progress, HY Meltzer, ed., Raven Press, NY (1987), pp. 183-195; and Gee et al., European Journal of Pharmacology, 136:419-423 (1987). These compounds are desirable because of their duration, potency, and oral activity (as well as other forms of administration).

[0428] Thus, the compounds and pharmaceutical compositions provided herein find use as therapies for preventing and / or treating CNS disorders in mammals, including humans and non-human mammals. Thus, and as previously stated, the present invention includes and extends within its scope to the described methods of treatment, as well as compounds for use in such methods, and the use of such compounds in the preparation of medicaments useful for such methods.

[0429] In one aspect, the compounds of the invention are designed as therapeutic agents, e.g., for the treatment of a CNS disorder in a mammal, e.g., for the treatment of insomnia, depression, mood disorders, convulsive disorders, memory disorders, attention disorders, anxiety disorders (e.g., stress), bipolar disorder (e.g., I and / or II), schizophrenia, depression, bipolar disorder, schizoaffective disorder, mood disorders, anxiety disorders, personality disorders, psychosis, obsessive-compulsive disorder, post-traumatic stress disorder (PTSD), autism spectrum disorder (ASD), dysthymia (minor depression), social anxiety disorder, obsessive-compulsive disorder (OCD), pain (e.g., a pain syndrome or disorder, e.g., acute pain, chronic pain, neuropathic pain), sleep disorders, memory disorders, dementia, Alzheimer's disease, seizure disorders (e.g., epilepsy), traumatic brain injury, stroke, addictive disorders (e.g., addiction to alcohol), autism, Huntington's disease, Parkinson's disease, Rett syndrome, withdrawal syndrome, or tinnitus. In some embodiments, the compounds of the invention are useful in the treatment of depression, anxiety, mood disorders, sleep disorders, memory disorders, traumatic brain injury, stroke, epilepsy, and schizophrenia.

[0430] In another aspect, a method of treating a mammal susceptible to or afflicted with a disorder related to brain excitability is provided, the method comprising administering an effective amount of one or more of the pharmaceutical compositions described herein.

[0431] In a further aspect, there is provided a compound of the invention for use as a medicament, such as, inter alia, in the treatment or prevention of the above mentioned conditions and diseases.

[0432] In yet another aspect, a method for producing a medicament for treating or preventing one of the above-mentioned conditions and diseases is provided.

[0433] In still another aspect, the present invention provides a method for preventing, treating, ameliorating or controlling a disease or condition, comprising administering to a subject in need of such prevention, treatment, improvement or control a preventively or therapeutically effective amount of a compound of the present invention or a pharmaceutical composition thereof.

[0434] In yet another aspect, the present invention provides the use of a compound of the present invention in the manufacture of a medicament for treating a disease or condition associated with brain excitability. In one embodiment, the disease or condition is selected from depression, anxiety, schizophrenia, sleep disorders, memory disorders, and mood disorders.

[0435] In yet another aspect, the invention provides a method of treating a mammal, such as a human, for treating a disease associated with brain excitability, comprising treating the mammal with an effective amount of a compound of the invention or a composition thereof.

[0436] In another aspect, the present invention provides a combination of a compound of the present invention and an additional pharmacologically active agent. As generally understood herein, the compounds provided herein can be administered as the sole active agent or they can be administered in combination with other agents. Combination administration can be performed by any technique that is clear to those skilled in the art, including, for example, single, sequential, simultaneous, and alternating administration.

[0437] In another aspect, the present invention provides a compound of the present invention or a composition thereof for use in the manufacture of a medicament for treating a CNS-related disease or condition in a subject. In some embodiments, the disease or condition is selected from sleep disorders, mood disorders, insomnia, anxiety, depression, TBI, stress and epilepsy.

[0438] In yet another aspect, the present invention provides a method for binding to GABA A A method for in vitro modulation of a neurosteroid site on a receptor-chloride ionophore complex in a subject comprises administering to the subject an amount of a compound of the invention effective for modulation of the complex.

[0439] In yet another aspect, the present invention provides a method for binding to GABA A A method for modulating a neurosteroid site on a receptor-chloride ionophore complex in a subject comprises administering an amount of a compound of the invention effective for modulating the complex.

[0440] In yet another aspect, the present invention provides a method of treating or preventing stress or anxiety in a subject, comprising administering to a subject in need of such treatment an effective amount of a compound of the present invention, or a composition thereof.

[0441] In yet another aspect, the present invention provides a method of reducing or preventing seizure behavior in a subject, comprising administering to a subject in need of such treatment an effective amount of a compound of the present invention, or a composition thereof.

[0442] In yet another aspect, the present invention provides a method of alleviating or preventing insomnia in a subject, comprising administering to a subject in need of such treatment an effective amount of a compound of the present invention, or a composition thereof.

[0443] In yet another aspect, the present invention provides a method of inducing sleep and maintaining substantially REM sleep levels 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, or a composition thereof.

[0444] In yet another aspect, the present invention provides a method of alleviating or preventing PMS or PND in a subject, comprising administering to a subject in need of such treatment an effective amount of a compound of the present invention, or a composition thereof.

[0445] In yet another aspect, the present invention provides a method of treating or preventing a mood disorder in a subject, comprising administering to a subject in need of such treatment an effective amount of a compound of the present invention, or a composition thereof.

[0446] In some embodiments, the mood disorder is depression.

[0447] In yet another aspect, the present invention provides a method of inducing anesthesia in a subject, comprising administering to the subject an effective amount of a compound of the present invention. In some embodiments, the subject is a human. In some embodiments, the compound is a pharmaceutically acceptable 3-ester or 3-diester selected from the following acids: acetic acid, propionic acid, maleic acid, fumaric acid, ascorbic acid, pimelic acid, succinic acid, glutaric acid, dimethylene salicylic acid, methanesulfonic acid, ethanedisulfonic acid, oxalic acid, tartaric acid, salicylic acid, citric acid, gluconic acid, itaconic acid, glycolic acid, γ-aminobenzoic acid, aspartic acid, glutamic acid, γ-amino-butyric acid, α-(2-hydroxyethylamino)-propionic acid, glycine and other α-amino acids, phosphoric acid, sulfuric acid, glucuronic acid and 1-methyl-1,4-dihydronicotinic acid.

[0448] In another aspect, the present invention provides a method of cognitive enhancement or treating memory disorders by administering to a subject a therapeutically effective amount of a compound of the present invention. In some embodiments, the disorder is Alzheimer's disease. In some embodiments, the disorder is Rett syndrome.

[0449] In yet another aspect, the present invention provides a method of treating an attention disorder by administering to a subject a therapeutically effective amount of a compound of the present invention. In some embodiments, the attention disorder is ADHD.

[0450] In some embodiments, the compound is chronically administered to the subject. In some embodiments, the compound is orally administered to the subject.

[0451] Example

[0452] In order that the invention described herein may be more fully understood, the following examples are set forth.The synthetic and biological examples described in this application are provided to illustrate the compounds, pharmaceutical compositions and methods provided herein, and are not to be construed in any way as limiting their scope.

[0453] Materials and methods

[0454] The compounds provided herein can be prepared from readily available raw materials using the following overall methods and procedures. See, for example, the following synthesis scheme. It will be understood that where typical or preferred process conditions (i.e., reaction temperature, time, molar ratio of reactants, solvent, pressure, etc.) are given, other process conditions may also be used unless otherwise stated. Optimum 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.

[0455] In addition, as will be clear to those skilled in the art, conventional blocking groups may be necessary to prevent some functional groups from experiencing undesirable reactions. Suitable blocking groups for specific functional groups and selection for suitable conditions for protection and deprotection are well known in the art. For example, many blocking 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.

[0456] The compounds provided herein can be separated and purified by known standard procedures. Such procedures include, but are not limited to, recrystallization, column chromatography or HPLC. The following scheme is proposed with details about the preparation of representative substituted diarylamides listed herein. The compounds provided herein can be prepared by those skilled in the art of organic synthesis from known or commercially available raw materials and reagents.

[0457] The enantiomerically pure compounds provided herein can be prepared according to any technique known to those skilled in the art. For example, they can be prepared from suitable optically pure precursors by chiral or asymmetric synthesis, or from racemates by any conventional technique, for example, by chromatographic separation using chiral columns, TLC, or by the preparation of diastereomers, their separation and the regeneration of the desired enantiomer. See, for example, J. Jacques, A. Collet and SH Wilen, Enantiomers, Racemates and Resolutions (Wiley-Interscience, New York, 1981); SH Wilen, A. Collet, and J. Jacques, Tetrahedron, 2725 (1977); EL Eliel, Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); and SH Wilen Tables of Resolving Agents and Optical Resolutions 268 (ELElieled., Univ. of Notre Dame Press, Notre Dame, IN, 1972, Stereochemistry of Organic Compounds, Ernest L. Eliel, Samuel H. Wilen and Lewis N. Manda (1994 John Wiley & Sons, Inc.), and Stereoselective Synthesis A Practical Approach, Mihály Nógrádi (1995 VCH Publishers, Inc., NY, NY).

[0458] In some embodiments, the enantiomerically pure compound of formula (I) can be obtained by reaction of the racemate with a suitable optically active acid or base. Suitable acids or bases include those described in Bighley et al., 1995, Salt Forms of Drugs and Adsorption, Encyclopedia of Pharmaceutical Technology, vol. 13, Swarbrick & Boylan, eds., Marcel Dekker, New York; ten Hoeve & H. Wynberg, 1985, Journal of Organic Chemistry 50: 4508-4514; Dale & Mosher, 1973, J. Am. Chem. Soc. 95: 512; and CRC Handbook of Optical Rsolution via Diastereomeric Salt Formation, the contents of which are hereby incorporated by reference in their entirety.

[0459] The enantiomer-pure compound can also be collected from the diastereomer of crystallization or from the mother liquor, depending on the solubility properties of the specific acid resolving agent adopted and the specific acid enantiomer used. The identity (identification, identity) and optical purity of the specific compound collected in this way can be determined by polarimetry or other analytical methods known in the art. The diastereomer can then be separated, for example, by chromatography or fractional crystallization, and the desired enantiomer can be regenerated by treating with a suitable base or acid. Other enantiomers can be obtained in a similar manner from the racemate or set up (work up) by the mother liquor of the first separation.

[0460] In some embodiments, enantiomerically pure compounds can be separated from racemic compounds by chiral chromatography. A variety of chiral columns and eluents for use in the separation of enantiomers are available and suitable conditions for separation can be determined empirically by methods known to those skilled in the art. Exemplary chiral columns that can be used for the separation of enantiomers provided herein include, but are not limited to, OB, OB-H, OD, OD-H, OF OG, OJ and OK.

[0461] Synthesis Procedure

[0462] The compounds of the present invention can be prepared according to methods described in the art (Upasani et al., J. Med. Chem. 1997, 40: 73-84; and Hogenkamp et al., J. Med. Chem. 1997, 40: 61-72) and using appropriate reagents, starting materials, and purification methods known to those skilled in the art. Some representative methods are described below. In any of the schemes depicted below, the compound can be a 5a- or 5β-isomer.

[0463] Scheme 1. Exemplary Synthesis of 3β-Methyl-3a-Hydroxy-19-nor-Pregnane-20-One

[0464]

[0465] Scheme 2. Exemplary Synthesis of 3β-Fluoromethyl-3a-Hydroxy-19-nor-Pregnane-20-One

[0466]

[0467] Scheme 3. Exemplary Synthesis of 3β-Dichloromethyl-3a-hydroxy-19-nor-pregnane-20-one

[0468]

[0469] The base may be KOt-Bu.

[0470] Scheme 4. Exemplary Synthesis of 3β-vinyl-3a-hydroxy-19-nor-pregnane-20-one

[0471]

[0472] Scheme 5. Exemplary Synthesis of 3β-Chloroethynyl-3a-hydroxy-19-nor-pregnane-20-one

[0473]

[0474] Scheme 6. Exemplary Synthesis of 3β-Cyclopropylethynyl-3a-hydroxy-19-nor-pregnane-20-one

[0475]

[0476] Scheme 7. Exemplary Synthesis of 3β-Propyn-1-yl-3a-hydroxy-19-nor-pregnane-20-one

[0477]

[0478] Scheme 8. Exemplary Synthesis of 3β-Methoxymethyl-3a-hydroxy-19-nor-pregnane-20-one

[0479]

[0480] Scheme 9. Exemplary Synthesis of 3β-Trifluoroethynyl-3a-hydroxy-19-nor-pregnane-20-one

[0481]

[0482] Scheme 10. Exemplary Synthesis of 21-Hydroxy and 21-Hemisuccinate 19-Norpregnane

[0483]

[0484] Scheme 11. Exemplary Synthesis of 19-Norpregnane 21-Thiosulfate

[0485]

[0486] Scheme 12. Exemplary Synthesis of 21-Heteroaryl-19-norpregnane

[0487]

[0488] Wherein Cy is a N-containing heteroaryl group.

[0489] Scheme 13. Exemplary Synthesis of 21-Heteroaryloxy / Thiooxy 19-Norpregnane

[0490]

[0491] wherein Cy is heteroaryl; and X is -O- or -S-.

[0492] Example 1. Synthesis of compounds 8a / b, 9a / b and 10a / b

[0493]

[0494]

[0495] Synthesis of Compound 2. Compound 1 (500 mg, 1.84 mmol) and 10% Pd / C (20 mg) in tetrahydrofuran (5 mL) and concentrated hydrobromic acid (0.02 mL) were hydrogenated with a hydrogen balloon (cylinder). After stirring at room temperature for 24 hours, the mixture was filtered through a celite pad and the filtrate was concentrated in vacuo. Recrystallization from acetone gave Compound 2 (367 mg, 1.34 mmol, 73%). 1H NMR (400MHz, CDCl3), δ (ppm), 2.61-2.54 (m, 1H), 0.98 (S, 3H).

[0496] Synthesis of compound 3. Iodine (0.1mmol) was added to a solution of compound 2 (274mg, 1mmol) in methanol (4mL). After stirring at 60°C for 12 hours, TLC showed no raw material and the solvent was removed in vacuo. The crude product was dissolved in dichloromethane (20mL) and washed with saturated NaHCO (15mL), brine, dried over Na SO, filtered, and concentrated. The residue was purified by chromatography on basic alumina (petroleum ether / ethyl acetate=9:1) to give compound 3 (280mg, 0.87mmol, 87%). 1 H NMR (400MHz, CDCl3), δ (ppm), 3.19 (S, 3H), 3.13 (S, 3H), 3.18-3.13 (m, 1H), 0.83 (S, 3H).

[0497] Synthesis of Compound 4. To a suspension of t-BuOK (300 mg, 2.68 mmol) in THF (30 mL) at 0°C was slowly added ethyltriphenylphosphine bromide. The product was stirred for 3 hours at 60 ° C. The reaction mixture was poured into saturated ammonium chloride and extracted with EtOAc (2 × 50 mL). The combined organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated to provide crude compound 4 (274 mg). The crude product was used in the next step without further purification.

[0498] Synthesis of compound 5. A solution of crude compound 4 (274 mg) in THF (4 mL) was acidified to pH = 3 by 1N HCl aqueous solution. After stirring at room temperature for 12 hours, the reaction mixture was extracted with ethyl acetate (15 mL × 3). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography (petroleum ether / ethyl acetate = 10: 1 to 5: 1) to provide compound 5 (60 mg, 0.21 mmol, 78% for two steps). 1 H NMR (400MHz, CDCl3), δ (ppm), 5.13-5.08 (m, 3H), 0.73 (m, 3H).

[0499] Synthesis of compounds 6a and 6b. A solution of compound 5 (858 mg, 3 mmol) in dry THF (5 mL) was added to a solution of MeMgBr (5 mmol, 1 M in THF) in THF (20 mL) at 0 ° C via a syringe pump during 30 minutes. After stirring for 5 hours at 0 ° C, the reaction mixture was warmed and stirred at room temperature overnight. The reaction mixture was quenched with ice-cold water and extracted with ethyl acetate (15 mL × 3). The combined organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated. The white residue was purified by flash column chromatography (petroleum ether / ethyl acetate = 20: 1 to 10: 1) to give compound 6a (450 mg, 1.49 mmol, 50%; Rf = 0.35, PE: EtOAc = 10: 1). 1 H NMR (400 MHz, CDCl3), δ (ppm), 5.14-5.08 (m, 1H), 1.26 (s, 3H), 0.87 (s, 3H) and compound 6b (150 mg, 0.50 mmol, 17%; Rf = 0.30, PE: EtOAc = 10: 1). 1 H NMR (400MHz, CDCl3), δ (ppm), 5.14-5.09 (m, 1H), 1.21 (s, 3H), 0.88 (s, 3H).

[0500] Synthesis of compound 7a. Borane-tetrahydrofuran complex (2 mL of 1.0 M solution in THF) was added to a solution of compound 6a (200 mg, 0.66 mmol) in dry THF (5 mL). After stirring at room temperature for 1 hour, the reaction mixture was cooled in an ice bath and then slowly quenched with a 10% NaOH aqueous solution (1 mL) followed by a 30% H2O2 aqueous solution (1.2 mL). The mixture was stirred at room temperature for 1 hour and then extracted with EtOAc (3 × 10 mL). The combined organic layers were washed with 10% Na2S2O3 aqueous solution (10 mL), brine (10 mL), dried over MgSO4, filtered, and concentrated to provide crude compound 7a (260 mg). The crude product was used in the next step without further purification.

[0501] Synthesis of compound 7b. Borane-tetrahydrofuran complex (1.34 mL of 1.0 M solution in THF) was added to a solution of compound 6b (150 mg, 0.50 mmol) in dry THF (5 mL). After stirring at room temperature for 1 hour, the reaction mixture was cooled in an ice bath and then slowly quenched with 10% NaOH aqueous solution (1 mL) followed by 30% H2O2 aqueous solution (1.2 mL). The mixture was stirred at room temperature for 1 hour and then extracted with EtOAc (3×10 mL). The combined organic layers were washed with 10% Na2S2O3 aqueous solution (10 mL), brine (10 mL), dried over MgSO4, filtered, and concentrated to provide crude compound 7b (200 mg). The crude product was used in the next step without further purification.

[0502] Synthesis of compound 8a. To a solution of crude compound 7a (260 mg) dissolved in 10 mL of H2O-saturated dichloromethane (dichloromethane had been oscillated with a few milliliters of H2O and then separated from the aqueous layer) was added Dess-Martin periodinate (449 mg, 1.06 mmol). After stirring at room temperature for 24 hours, the reaction mixture was extracted with dichloromethane (3×10 mL). The combined organic layers were washed with 10% Na2S2O3 aqueous solution (10 mL), brine (10 mL), dried over MgSO4, filtered, and concentrated. The residue was purified by chromatography on silica gel (petroleum ether / ethyl acetate=4:1 to 2:1) to provide the title compound 8a (85 mg, 0.27 mmol, 40% for two steps) as a white solid. 1 H NMR (400MHz, CDCl3), δ (ppm), 2.57-2.53 (m, 1H), 2.12 (S, 3H), 1.20 (S, 3H), 0.62 (S, 3H).

[0503] Synthesis of compound 8b. To a solution of crude compound 7b (200 mg) dissolved in 10 mL of H2O saturated dichloromethane (dichloromethane had been oscillated with a few milliliters of H2O and then separated from the aqueous layer) was added Dess-Martin periodinane (400 mg, 0.94 mmol). After stirring at room temperature for 24 hours, the reaction mixture was extracted with dichloromethane (3×10 mL). The combined organic layers were washed with 10% Na2S2O3 aqueous solution (10 mL), brine (10 mL), dried over MgSO4, filtered, and concentrated. The residue was purified by chromatography on silica gel (petroleum ether / ethyl acetate=4:1 to 2:1) to provide the title compound 8b (90 mg, 0.28 mmol, 57% for two steps) as a white solid. 1H NMR (400MHz, CDCl3), δ (ppm), 2.55-2.51 (m, 1H), 2.11 (S, 3H), 1.32 (S, 3H), 0.61 (S, 3H).

[0504] Synthesis of compound 9a. Add 2 drops of HBr (48%) to a solution of compound 8a (70 mg, 0.22 mmol) in MeOH (5 mL), followed by bromine (100 mg, 0.63 mmol). After stirring at room temperature for 1 hour, the reaction mixture was poured into ice water and then extracted with ethyl acetate (15 mL × 3). The combined organic layer was washed with brine (20 mL), dried over MgSO, filtered, and concentrated to give crude compound 9a (90 mg). The crude product was used in the next step without further purification.

[0505] Synthesis of compound 9b. Add 2 drops of HBr (48%) to a solution of compound 8b (80 mg, 0.25 mmol) in MeOH (5 mL), followed by bromine (100 mg, 0.63 mmol). After stirring at room temperature for 1 hour, the reaction mixture was poured into ice water and then extracted with ethyl acetate (15 mL × 3). The combined organic layer was washed with brine (20 mL), dried over MgSO, filtered, and concentrated to give crude compound 9b (95 mg). The crude product was used in the next step without further purification.

[0506] The synthesis of compound 10a. Use CFCOOH (0.5mL) and EtN (0.7mL) to process the solution of crude compound 9a (90mg) in acetone (10mL). After heating under reflux for 30 minutes, add CFCOONa salt (540mg, 3.97mmol) and reflux the mixture overnight. Make the reaction cool to room temperature and remove the solvent in a vacuum. The residue is extracted with ethyl acetate (10mL×3). The combined organic layer is washed with brine (15mL), passed through MgSO4, dried, filtered, and concentrated. The residue is purified by chromatography on silica gel (petroleum ether / ethyl acetate=3:1) to provide compound 10a (25mg, 0.075mmol, 34% for two steps). 1 H NMR (400MHz, CDCl3), δ (ppm), 4.24-4.12 (m, 2H), 2.48-2.44 (m, 1H), 1.07 (S, 3H), 0.64 (S, 3H).

[0507] Synthesis of compound 10b. Use CFCOOH (0.5mL) and EtN (0.7mL) to process the solution of crude compound 9b (95mg) in acetone (10mL). After heating under reflux for 30 minutes, add CFCOONa salt (540mg, 3.97mmol) and reflux the mixture overnight. Make the reaction cool to room temperature and remove the solvent in a vacuum. The residue is extracted with ethyl acetate (10mL×3). The combined organic layer is washed with brine (15mL), passed through MgSO4, dried, filtered, and concentrated. The residue is purified by chromatography on silica gel (petroleum ether / ethyl acetate=3:1) to provide compound 10b (34mg, 0.10mmol, 41% for two steps). 1 H NMR (400MHz, CDCl3), δ (ppm), 4.25-4.12 (m, 2H), 2.48-2.44 (m, 1H), 1.32 (S, 3H), 0.64 (S, 3H).

[0508] Example 2. Synthesis of compounds 14a / b, 15a / b and 16a / b

[0509]

[0510]

[0511] Synthesis of compounds 11a and 11b. To a solution of compound 5 (800 mg, 2.79 mmol) and PhSOCFH (540 mg, 2.79 mmol) in THF (25 mL) and HMPA (0.5 mL) at -78 °C under N2, LHMDS (4 mL, 1 M in THF) was added dropwise. After stirring for 2 hours at -78 °C, the reaction mixture was quenched with saturated NH4Cl aqueous solution (10 mL) and allowed to warm to room temperature, then extracted with Et2O (20 mL × 3). The combined organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to give a mixture of compounds 11a and 11b (700 mg). The mixture was further purified by chiral-HPLC to provide compound 11a (200 mg, t = 4.31 minutes). 1 H NMR (400 MHz, CDCl3), δ (ppm), 7.99-7.97 (d, 2H, J = 7.6 Hz), 7.77-7.75 (m, 1H), 7.64-7.60 (m, 2H), 5.14-5.08 (m, 1H), 0.88 (s, 3H); Compound 11b (260 mg, t = 5.66 min). 1H NMR (400 MHz, CDCl3), δ (ppm), 8.00-7.98 (d, 2H, J = 7.6 Hz), 7.77-7.75 (m, 1H), 7.64-7.60 (m, 2H), 5.14-5.09 (m, 1H), 0.88 (s, 3H). Chiral-HPLC separation conditions: co-solvent: MeOH (0.1% HNEt2), column: OZ-H (4.6*250mm5μm), column temperature: 38.9, CO2 flow rate: 2.10, co-solvent flow rate: 0.9, co-solvent%: 30, PDA starting wavelength: 214 nm, PDA starting wavelength: 359 nm, peak 1: 11a RT = 4.31 minutes, peak 2: 11b RT = 5.66 minutes.

[0512] Synthesis of compound 12a. To a solution of compound 11a (100 mg, 0.209 mmol) and anhydrous NaHPO (100 mg) in anhydrous methanol (5 mL) at -20 ° C under N2, Na / Hg amalgam (500 mg) was added. After stirring at -20 ° C to 0 ° C for 1 hour, the methanol solution was decanted and the solid residue was washed with Et2O (5 × 3 mL). The combined organic layer was washed with brine (20 mL), passed through MgSO4, dried, filtered, and concentrated. The residue was purified by silica gel chromatography (petroleum ether / ethyl acetate=10 / 1) to give compound 12a (30 mg, 0.089 mmol, 42%). 1 H NMR (400MHz, CDCl3), δ (ppm), 5.60-5.45 (t, 1H, J=60Hz), 5.17-5.15 (m, 1H), 0.88 (m, 3H).

[0513] Synthesis of compound 12b. To a solution of compound 11b (100 mg, 0.209 mmol) and anhydrous NaHPO (100 mg) in anhydrous methanol (5 mL) at -20 ° C under N2, Na / Hg amalgam (500 mg) was added. After stirring at -20 ° C to 0 ° C for 1 hour, the methanol solution was decanted and the solid residue was washed with Et2O (5 × 3 mL). The combined organic layer was washed with brine (20 mL), dried over MgSO4, filtered, and concentrated. The residue was purified by silica gel chromatography (petroleum ether / ethyl acetate=10 / 1) to give compound 12b (36 mg, 0.106 mmol, 51%). 1 H NMR (400MHz, CDCl3), δ (ppm), 6.02-5.88 (t, 1H, J = 49.2Hz), 5.17-5.15 (m, 1H), 0.88 (s, 3H).

[0514] Synthesis of compound 13a. Borane-tetrahydrofuran complex (1.34 mL of 1.0 M solution in THF) was added to a solution of compound 12a (150 mg, 0.443 mmol) in dry THF (5 mL). After stirring at room temperature for 1 hour, the reaction mixture was cooled in an ice bath and then slowly quenched with 10% NaOH aqueous solution (1 mL) followed by 30% H2O2 aqueous solution (1.2 mL). The mixture was stirred at room temperature for 1 hour and then extracted with EtOAc (3×10 mL). The combined organic layers were washed with 10% Na2S2O3 aqueous solution (10 mL), brine (10 mL), dried over MgSO4, filtered, and concentrated to provide crude compound 13a (200 mg). The crude product was used in the next step without further purification.

[0515] Synthesis of compound 13b. Borane-tetrahydrofuran complex (1.34 mL of 1.0 M solution in THF) was added to a solution of compound 12b (150 mg, 0.443 mmol) in dry THF (5 mL). After stirring at room temperature for 1 hour, the reaction mixture was cooled in an ice bath and then slowly quenched with 10% NaOH aqueous solution (1 mL) followed by 30% H2O2 aqueous solution (1.2 mL). The mixture was stirred at room temperature for 1 hour and then extracted with EtOAc (3×10 mL). The combined organic layers were extracted with 10% Na2S2O3 aqueous solution (10 mL), brine (10 mL), dried over MgSO4, filtered, and concentrated to provide crude compound 13b (210 mg). The crude product was used in the next step without further purification.

[0516] Synthesis of compound 14a. To the crude compound 13a (200 mg) dissolved in 10 mL of H2O saturated dichloromethane (dichloromethane has been oscillated with a few milliliters of H2O, then separated from the aqueous layer) solution, Dess-Martin periodinane (449 mg, 1.06 mmol) was added. After stirring at room temperature for 24 hours, the reaction mixture was extracted with dichloromethane (3 × 10 mL). The combined organic layer was washed with 10% Na2S2O3 aqueous solution (10 mL), brine (10 mL), dried by MgSO4, filtered, and concentrated. The residue was purified by chromatography on silica gel (petroleum ether / ethyl acetate=5:1) to provide compound 14a (85 mg, 0.24 mmol, 54%) as a white solid. 1 H NMR (400MHz, CDCl3), δ (ppm), 5.60-5.71 (t, 1H, J=56.8Hz), 2.57-2.51 (m, 1H), 0.62 (S, 3H).

[0517] Synthesis of compound 14b. To the crude compound 13b (210 mg) dissolved in 10 mL of H2O-saturated dichloromethane (dichloromethane has been oscillated with a few milliliters of H2O, then separated from the aqueous layer) solution, Dess-Martin periodinane (380 mg, 0.896 mmol) was added. After stirring at room temperature for 24 hours, the reaction mixture was extracted with dichloromethane (3×10 mL). The combined organic layer was washed with 10% Na2S2O3 aqueous solution (10 mL), brine (10 mL), dried by MgSO4, filtered, and concentrated. The residue was purified by chromatography on silica gel (petroleum ether / ethyl acetate=5:1) to provide compound 14b (90 mg, 0.254 mmol, 57%) as a white solid. 1 H NMR (400MHz, CDCl3), δ (ppm), 6.01-5.73 (t, 1H, J = 56.4Hz), 2.55-2.54 (m, 1H), 2.12 (S, 3H), 0.62 (S, 3H).

[0518] Synthesis of compound 15a. To a solution of compound 14a (70 mg, 0.197 mmol) in MeOH (5 mL) was added 2 drops of HBr (48%), followed by bromine (100 mg, 0.63 mmol). After stirring at room temperature for 1 hour, the reaction mixture was poured into ice water, then extracted with ethyl acetate (15 mL×3), the combined organic layers were washed with brine (20 mL), dried over MgSO4, filtered, and concentrated to give crude compound 15a (90 mg). The crude product was used in the next step without further purification.

[0519] Synthesis of compound 15b. To a solution of compound 14b (80 mg, 0.226 mmol) in MeOH (5 mL) was added 2 drops of HBr (48%), followed by bromine (100 mg, 0.63 mmol). After stirring at room temperature for 1 hour, the reaction mixture was poured into ice water, then extracted with ethyl acetate (15 mL×3), the combined organic layers were washed with brine (20 mL), dried over MgSO4, filtered, and concentrated to give crude compound 15b (95 mg). The crude product was used in the next step without further purification.

[0520] The synthesis of compound 16a. A solution of crude compound 15a (90 mg) in acetone (10 mL) was treated with CFCOOH (0.5 mL) and EtN (0.7 mL). After heating at reflux for 30 minutes, CFCOONa salt (540 mg, 3.9 mmol) was added and the mixture was refluxed overnight. The reaction was cooled to room temperature and the solvent was removed in vacuo. The residue was extracted with ethyl acetate (10 mL × 3). The combined organic layer was washed with brine (15 mL), dried by MgSO, filtered, and concentrated. The residue was purified by chromatography on silica gel (petroleum ether / ethyl acetate=3:1) to provide compound 16a (25 mg, 0.067 mmol, 34% for two steps). 1 H NMR (400MHz, CDCl3), δ (ppm), 5.60-5.31 (t, 1H, J = 56.8Hz), 4.22-4.18 (m, 2H), 0.64 (S, 3H).

[0521] Synthesis of compound 16b. A solution of crude compound 15b (95 mg) in acetone (10 mL) was treated with CFCOOH (0.5 mL) and EtN (0.7 mL). After heating at reflux for 30 minutes, CFCOONa salt (540 mg, 3.9 mmol) was added and the mixture was refluxed overnight. The reaction was cooled to room temperature and the solvent was removed in vacuo. The residue was extracted with ethyl acetate (10 mL × 3). The combined organic layer was washed with brine (15 mL), dried by MgSO, filtered, and concentrated. The residue was purified by chromatography on silica gel (petroleum ether / ethyl acetate=3:1) to provide compound 16b (38 mg, 0.102 mmol, 46% for two steps). 1 H NMR (400MHz, CDCl3), δ (ppm), 6.00-5.74 (t, 1H, J = 51.2Hz), 4.42-4.18 (m, 2H), 0.64 (S, 3H).

[0522] Example 3. Synthesis of Compounds 9, 9a / b / c and 11a / b

[0523]

[0524] Synthesis of compound 5. Borane-tetrahydrofuran complex (30 mL of 1.0 M solution in THF) was added to a solution of 4 (5 g, 15 mmol) in dry THF (20 mL). After stirring at room temperature for 1 hour, the reaction mixture was cooled in an ice bath and slowly quenched with 10% NaOH aqueous solution (56 mL) followed by 30% H2O2 aqueous solution (67 mL). The reaction mixture was stirred at room temperature for 1 hour and then extracted with EtOAc (3×100 mL). The combined organic layers were washed with 10% Na2S2O3 aqueous solution (100 mL), brine (100 mL), dried over MgSO4, filtered, and concentrated to provide a crude product 5 (3.2 g, 9.0 mmol). The crude product was used in the next step without further purification.

[0525] Synthesis of compound 6. To a solution of compound 5 (3.2 g, 9 mmol) in THF (40 mL) was added hydrogen chloride (3 mL, 3 M aqueous solution). After stirring at room temperature for 12 hours, the solvent was removed under reduced pressure, and the residue was purified by silica gel chromatography (petroleum ether / ethyl acetate=10:1 to 5:1) to give compound 6 (2.2 g, 81%) as a white solid. 1 H NMR (400MHz, CDCl3), δ (ppm), 3.82-3.93 (m, 1H), 2.58-2.62 (m, 1H), 2.19-2.23 (m, 4H), 0.72 (s, 3H).

[0526] Synthesis of compound 7. To a solution of trimethylsufoxonium iodide (8.1 g, 36.9 mmol) in DMSO (100 mL) was added NaH (60%; 1.26 g, 31.5 mmol). After stirring at room temperature for 1 hour, a suspension of compound 6 (2.2 g, 7.2 mmol) in DMSO (20 mL) was added dropwise. After stirring at room temperature for another 2.5 hours, the reaction mixture was poured into ice-cold water and extracted with ether (100 mL×3). The combined organic layers were washed with brine (100 mL×3), dried over MgSO4, filtered, and concentrated to give compound 7 (1.6 g, 70%) as a white solid. 1 H NMR (400MHz, CDCl3), δ (ppm), 3.69-3.71 (m, 1H), 2.56-2.61 (m, 2H), 2.21-2.28 (m, 1H), 0.68 (s, 3H).

[0527] The synthesis of compound 8. Add Dess-Martin oxidation agent (4.2g, 10mmol) to the solution of compound 7 (1.6g, 5.0mmol) in 60mL of H2O-saturated dichloromethane (CH2Cl2 has been oscillated with several milliliters of H2O, then separated from the aqueous layer). After stirring at room temperature for 24 hours, the reaction mixture was extracted with dichloromethane (3×100mL). The organic layer combined was washed with 10% Na2S2O3 aqueous solution (100mL), brine (100mL), passed through MgSO4 drying, filtered, and concentrated. The residue was purified by chromatography on silica gel (petroleum ether / ethyl acetate=20:1 to 10:1) to provide compound 8 (1.2g, 75%) as a white solid. 1 H NMR (400MHz, CDCl3), δ (ppm), 2.50-2.58 (m, 2H), 2.56-2.61 (m, 2H), 2.19 (s, 3H), 0.65 (s, 3H).

[0528] Synthesis of compound 9. Na (262 mg, 11.4 mmol) was added to a solution of compound 8 (1.2 g, 3.8 mmol) in dry methanol (250 mL). After heating under reflux for 16 hours, the solvent was removed in a vacuum and the residue was dissolved in dichloromethane (100 mL), then washed with H2O (3 × 50 mL) and brine (100 mL), dried over MgSO4, filtered, and concentrated. The residue was purified by silica gel chromatography (petroleum ether / ethyl acetate = 10: 1 to 5: 1) to provide compounds 9a (300 mg, 25%), 9b (100 mg, 8%) and 9c (20 mg, 2%) as white solids. Compound 9a: 1 H NMR (400 MHz, CDCl3), δ (ppm), 3.38-3.43 (m, 5H), 2.52-2.56 (m, 1H), 2.16 (s, 3H), 0.60 (s, 3H). Compound 9b: 1 H NMR (400 MHz, CDCl3), δ (ppm), 3.39 (s, 3H), 3.20 (s, 2H), 2.48-2.54 (m, 1H), 2.70 (s, 3H), 0.61 (s, 3H). Compound 9c: 1 H NMR (400MHz, CDCl3), δ (ppm), 3.39 (s, 3H), 3.18 (s, 2H), 2.81-2.83 (d, 1H), 2.65 (s, 3H), 0.61 (s, 3H).

[0529] Synthesis of compound 10a. To a solution of compound 9a (50 mg, 0.14 mmol) in MeOH (5 mL) was added 2 drops of HBr (48%), followed by bromine (6 drops). After stirring at room temperature for 1 hour, the reaction mixture was poured into ice water and then extracted with ethyl acetate (15 mL × 3). The combined organic layers were washed with brine (50 mL), dried over MgSO4, filtered, and concentrated to give compound 10a (46 mg. 0.11 mmol). The crude product was used in the next step without further purification.

[0530] The synthesis of compound 11a. A solution of compound 10a (46 mg, 0.11 mmol) in acetone (10 mL) was treated with CF3COOH (0.5 mL) and Et3N (0.7 mL). After heating at reflux for 30 minutes, CF3COONa (300 mg, 2.2 mmol) was added in batches during 10 hours. The reaction mixture was cooled to room temperature and the solvent was removed in vacuo. The residue was extracted with ethyl acetate (10 mL × 3). The combined organic layer was washed with brine (30 mL), dried by MgSO4, filtered, and concentrated. The residue was purified by chromatography on silica gel (petroleum ether / ethyl acetate=10:1 to 3:1) to provide compound 11a (10 mg, 25%). Compound 11a: 1 H NMR (400MHz, CDCl3), δ (ppm), 4.17-4.98 (m, 2H), 3.39-3.40 (m, 5H), 2.44-2.52 (m, 1H), 2.18-2.24 (m, 1H), 0.63 (s, 3H).

[0531] Synthesis of compound 10b. To a solution of compound 9b (50 mg, 0.14 mmol) in MeOH (5 mL) were added 2 drops of HBr (48%, followed by bromine (6 drops). After stirring at room temperature for 1 hour, the reaction mixture was poured into ice water and then extracted with ethyl acetate (15 mL×3). The combined organic layers were washed with brine (50 mL), dried over MgSO 4 , filtered, and concentrated to give compound 10b (46 mg, 0.11 mmol). The crude product was used in the next step without further purification.

[0532] Synthesis of compound 11b. A solution of compound 10b (46 mg, 0.11 mmol) in acetone (10 mL) was treated with CF3COOH (0.5 mL) and Et3N (0.7 mL). After heating at reflux for 30 minutes, CF3COONa (300 mg, 2.2 mmol) was added in batches during 10 hours. The reaction mixture was cooled to room temperature and the solvent was removed in vacuo. The residue was extracted with ethyl acetate (10 mL × 3). The combined organic layer was washed with brine (30 mL), dried by MgSO4, filtered, and concentrated. The residue was purified by chromatography on silica gel (petroleum ether / ethyl acetate=10:1 to 3:1) to provide compound 11b (10 mg, 25%). Compound 11b: 1 H NMR (400MHz, CDCl3), δ (ppm), 4.16-4.19 (m, 2H), 3.39 (s, 3H), 3.32 (s, 1H), 3.20 (s, 2H), 2.23-2.45 (m, 1H), 2.00-2.12 (m, 2H), 0.64 (s, 3H).

[0533] Example 3.6-Synthesis of dichloro analogs

[0534]

[0535] (a) Ethane-1,2-diol, catalyst TsOH, toluene, reflux overnight; (b) Ac2O, pyridine, room temperature overnight; (c) BH3, THF, NaOH / H2O2, 0°C then room temperature; (d) Dess-Martin periodinane, CH2Cl2, room temperature overnight; (e) DAST (neat), 40°C, 4 days; (f) K2CO3, MeOH, room temperature overnight; (g) MeMgBr, THF, 0°C; (h) 3M HCl, acetone; (i) (Ethyl)-triphenylphosphine bromide t-BuOK, THF, 65 °C.

[0536] Example 4. Synthesis of 5,6-alkenyl-6-monofluoro analogs

[0537]

[0538]

[0539] (a) Ethane-1,2-diol, catalyst TsOH, toluene, reflux overnight; (b) Ac2O, pyridine, room temperature overnight; (c) BH3, THF, NaOH / H2O2, 0°C then room temperature; (d) Dess-Martin periodinane, CH2Cl2, room temperature overnight; (e) DAST (neat), catalyst fuming H2SO4; (f) K2CO3, MeOH, room temperature overnight; (g) MeMgBr, THF, 0°C; (h) 3M HCl, acetone; (i) (Ethyl)-triphenylphosphine bromide t-BuOK, THF, 65 °C.

[0540] Example 5.6 Synthesis of β-Me Analogs

[0541]

[0542] (a) Ethane-1,2-diol, catalyst TsOH, toluene, reflux overnight; (b) Ac2O, pyridine, room temperature overnight; (c) BH3, THF, NaOH / H2O2, 0℃ then room temperature; (d) Dess-Martin periodinane, CH2Cl2, room temperature overnight; (e) Methyltriphenylphosphine bromide Potassium tert-butoxide, THF, room temperature; (f) TCDI, DMAP, CH2Cl2, 40°C; (g) Ph3SnH, AIBN, toluene, 110°C; (h) potassium carbonate, MeOH, room temperature overnight; (i) MeMgBr, THF, 0°C.

[0543]

[0544] (a) 3M HCl, acetone; (b) (Ethyl)-triphenylphosphine bromide t-BuOK, THF, 65°C; (c) BH3, THF, NaOH / H2O2, 0°C then room temperature; (d) Dess-Martin periodinane, CH2Cl2, room temperature overnight

[0545] Example 6.

[0546]

[0547]

[0548] Synthesis of compounds 39 and 40. A small piece of lithium (7.63 g, 1.1 mol) was added to 2.7 L of condensed ammonia in a three-necked flask at -70°C. Once all the lithium was dissolved, the blue solution was warmed to -50°C. A solution of 19-norandrost-4-ene-3,17-dione 1 (1.30 g, 110 mmol) and tert-BuOH (8.14 g, 110 mmol) in 800 mL of anhydrous tetrahydrofuran was added dropwise and stirred for 90 minutes until the reaction mixture turned light yellow. Ammonium chloride (70 g) was added and the excess ammonia was evaporated. The residue was extracted with 0.5N HCl (500 mL) and dichloromethane (500 mL×2). The combined organic layers were washed with saturated NaHCO3 solution, dried over Na2SO4, filtered and concentrated to give a mixture of 39 and 40 (21 g, 70%), which was used directly in the next step without further purification. A solution of 39 and 40 (21 g, 76 mmol) in 50 mL of anhydrous dichloromethane was added to pyridinium chlorochromate. A suspension of (PCC) (32.8 g, 152 mmol) in 450 mL of dichloromethane. After stirring at room temperature for 2 hours, 2N NaOH solution (500 mL) was added to the dark brown reaction mixture and stirred for another 10 minutes. The resulting solution was extracted with dichloromethane, and the combined organic layers were washed with 2N HCl, brine, dried over Na2SO4, filtered and concentrated. The residue was purified by chromatography on silica gel (petroleum ether / ethyl acetate = 20: 1 to 10: 1) to provide the title compound 40 (16.8 g, 80%) as a white solid. 39 1 H NMR (400MHz, CDCl3), δ (ppm), 3.65 (t, 1H, J=8Hz, 1H), 0.77 (s, 3H). 40's 1 H NMR (400MHz, CDCl3), δ (ppm), 0.88 (s, 3H).

[0549] Synthesis of compound 41. To a solution of compound 40 (16.8 g. 61.3 mmol) in methanol (250 mL) was added iodine (1.54 g, 6.1 mmol). After stirring at 60 ° C for 12 hours, the solvent was removed in vacuo. The crude product was dissolved in dichloromethane (200 mL) and washed with saturated NaHCO (150 mL), brine, dried over Na SO, filtered and concentrated. The residue was purified by chromatography on basic alumina (petroleum ether / ethyl acetate=100:1) to give compound 41 (14 g, 43.8 mmol, 71%). 1H NMR (400MHz, CDCl3), δ (ppm), 3.18 (s, 3H), 3.12 (s, 3H), 0.85 (s, 3H).

[0550] Synthesis of compound 42. To a suspension of t-BuOK (7.36 g, 65.7 mmol) in THF (100 mL) at 0°C was slowly added ethyltriphenylphosphine bromide. The product was stirred for 3 hours at 60 ° C, and the mixture was stirred for another 2 hours at 60 ° C. After cooling to room temperature, the reaction mixture was poured into saturated ammonium chloride and extracted with EtOAc (2 × 500mL). The combined organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated to provide crude compound 42 (7.36g, 100%). The crude product was used in the next step without further purification.

[0551] Synthesis of compound 43. A solution of crude compound 42 (7.36 g, 21.9 mmol) in THF (50 mL) was acidified to pH = 3 by 1N HCl aqueous solution. After stirring at room temperature for 12 hours, the reaction mixture was extracted with ethyl acetate (250 mL × 3). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by column chromatography (petroleum ether / ethyl acetate = 30: 1 to 20: 1) to provide compound 43 (4.8 g, 16.7 mmol, 76% for two steps). 1 H NMR (400MHz, CDCl3), δ (ppm), 5.12-5.10 (m, 1H), 1.64-1.63 (m, 3H), 0.77 (s, 3H).

[0552] Synthesis of compounds 44a and 44b. A solution of compound 43 (4.8 g, 16.8 mmol) in dry THF (10 mL) was added to a solution of MeMgBr (28 mmol, 1 M in THF) in THF (50 mL) at 0 ° C via a syringe pump during 30 minutes. After stirring for 5 hours at 0 ° C, the reaction mixture was warmed and stirred at room temperature overnight. The reaction mixture was quenched with ice-cold water and extracted with ethyl acetate (150 mL × 3). The combined organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated. The white residue was purified by flash column chromatography (petroleum ether / ethyl acetate = 20: 1 to 10: 1) to give compound 44a (2.5 g, 8.28 mmol, 49%; Rf = 0.35, PE: EtOAc = 10: 1). 1H NMR (400 MHz, CDCl3), δ (ppm), 5.05-5.03 (m, 1H), 1.21 (s, 3H), 0.90 (s, 3H) and compound 44b (800 mg, 2.64 mmol, 16%; Rf = 0.30, PE:EtOAc = 10:1). 1 H NMR (400MHz, CDCl3), δ (ppm), 5.12-5.10 (m, 1H), 1.12 (s, 3H), 0.88 (s, 3H).

[0553] Synthesis of compound 45a. Borane-tetrahydrofuran complex (20 mL; 1.0 M solution in THF) was added to a solution of compound 44a (2 g, 6.62 mmol) in dry THF (50 mL). After stirring at room temperature for 1 hour, the reaction mixture was cooled in an ice bath and then slowly quenched with 10% NaOH aqueous solution (10 mL) followed by 30% H2O2 aqueous solution (12 mL). After stirring at room temperature for 1 hour, the mixture was extracted with EtOAc (3×100 mL). The combined organic layers were washed with 10% Na2S2O3 aqueous solution (100 mL), brine (100 mL), dried over MgSO4, filtered and concentrated to provide crude compound 45a (2 g, 100%). The crude product was used in the next step without further purification.

[0554] Synthesis of compound 46a. Add Dess-Martin periodinane (5.5 g, 13 mmol) to a solution of crude compound 45a (2 g, 6.62 mmol) in 60 mL of wet dichloromethane (dichloromethane has been oscillated with a few milliliters of H2O and then separated from the aqueous layer). After stirring at room temperature for 24 hours, the reaction mixture was extracted with dichloromethane (3×100 mL). The combined organic layers were extracted with 10% Na2S2O3 aqueous solution (100 mL), brine (100 mL), dried over MgSO4, filtered and concentrated. The residue was purified by chromatography on silica gel (petroleum ether / ethyl acetate=10:1 to 5:1) to provide compound 46a (1 g, 3.14 mmol, 47% for two steps) as a white solid. 1 H NMR (400MHz, CDCl3), δ (ppm), 2.56-2.51 (m, 1H), 2.11 (s, 3H), 1.20 (s, 3H), 0.62 (s, 3H).

[0555] Synthesis of compound 47a. Add 5 drops of HBr (48%) to a solution of compound 46a (600 mg, 1.89 mmol) in MeOH (20 mL), then add bromine (302 mg, 1.89 mmol). After stirring at room temperature for 1 hour, the reaction mixture was poured into ice water, then extracted with ethyl acetate (100 mL × 3). The combined organic layer was washed with salt water (200 mL), dried by MgSO4, filtered and concentrated to give crude compound 47a (600 mg). The crude product was used in the next step without further purification.

[0556] The synthesis of compound 48a. A solution of compound 47a (600 mg, 1.5 mmol) in acetone 10 mL was treated with CFCOOH (6.8 mL) and EtN (9.5 mL). After refluxing for 30 minutes, CFCOONa salt (4.49 g, 33 mmol) was added in batches during 10 hours. The reaction mixture was cooled to room temperature and the solvent was removed in a vacuum. The residue was extracted with ethyl acetate, dried by MgSO, filtered and concentrated. The mixture was purified by chromatography on silica gel (petroleum ether / ethyl acetate=10:1 to 3:1) to provide 48a (300 mg, yield: 50% for two steps). 1 H NMR (400MHz, CDCl3), δ (ppm), 4.23-4.13 (m, 2H), 2.48-2.44 (m, 1H), 2.24-2.17 (m, 1H), 1.20 (s, 3H), 0.64 (s, 3H).

[0557] Synthesis of compound 45b. Borane-tetrahydrofuran complex (5 mL; 1.0 M solution in THF) was added to a solution of compound 44b (500 mg, 1.66 mmol) in dry THF (13 mL). After stirring at room temperature for 1 hour, the reaction mixture was cooled in an ice bath and then slowly quenched with 10% NaOH aqueous solution (2.5 mL) followed by 30% H2O2 aqueous solution (3 mL). The mixture was warmed to room temperature and stirred for 1 hour, then extracted with EtOAc (3×25 mL). The combined organic layers were washed with 10% Na2S2O3 aqueous solution (25 mL), brine (25 mL), dried over MgSO4, filtered and concentrated to provide crude compound 45b (500 mg). The crude product was used in the next step without further purification.

[0558] Synthesis of compound 46b. To a solution of crude compound 45b (500 mg, 1.66 mmol) in 15 mL of wet dichloromethane (dichloromethane had been oscillated with a few milliliters of H2O and then separated from the aqueous layer) was added Dess-Martin periodinane (1.38 g, 3.3 mmol). After stirring at room temperature for 24 hours, the reaction mixture was extracted with dichloromethane (3×25 mL). The combined organic layers were washed with 10% Na2S2O3 aqueous solution (25 mL), brine (25 mL), dried over MgSO4, filtered and concentrated. The residue was purified by chromatography on silica gel (petroleum ether / ethyl acetate=10:1 to 5:1) to provide the title compound 46b (250 mg, 0.79 mmol, 47% for two steps) as a white solid. 1 H NMR (400MHz, CDCl3), δ (ppm), 2.54-2.50 (m, 1H), 2.11 (s, 3H), 1.23 (s, 3H), 0.62 (s, 3H).

[0559] Synthesis of compound 47b. Add 2 drops of HBr (48%) to a solution of compound 46b (250 mg, 0.79 mmol) in MeOH (5 mL), followed by bromine (126 mg, 0.79 mmol). After stirring at room temperature for 1 hour, the reaction mixture was poured into ice water and then extracted with ethyl acetate (10 mL × 3). The combined organic layer was washed with brine (20 mL), dried over MgSO, filtered and concentrated to give crude compound 47b (250 mg). The crude product was used in the next step without further purification.

[0560] Synthesis of compound 48b. A solution of compound 47b (60 mg, 0.15 mmol) in acetone (10 mL) was treated with CFCOOH (0.7 mL) and EtN (0.9 mL). After refluxing for 30 minutes, CFCOONa salt (449 mg, 3.3 mmol) was added in batches during 10 hours. The reaction mixture was cooled to room temperature and the solvent was removed in a vacuum. The residue was extracted with ethyl acetate, dried by MgSO, filtered and concentrated. The residue was purified by chromatography on silica gel (petroleum ether / ethyl acetate=10:1 to 3:1) to provide 48b (20 mg, yield: 33% for two steps). 1 H NMR (400MHz, CDCl3), δ (ppm), 4.24-4.12 (m, 2H), 2.48-2.43 (m, 1H), 2.24-2.16 (m, 1H), 1.23 (s, 3H), 0.64 (s, 3H).

[0561] Example 7.

[0562]

[0563]

[0564] Synthesis of compounds 49a and 49b. To a solution of compound 43 (800 mg, 2.79 mmol) and PhSOCFH (540 mg, 2.79 mmol) in THF (25 mL) and HMPA (0.5 mL) at -78 °C under N2, LHMDS (4 mL, 1 M in THF) was added dropwise. After stirring for 2 hours at -78 °C, the reaction mixture was quenched with saturated NH4Cl aqueous solution (10 mL) and allowed to warm to room temperature, then extracted with Et2O (20 mL × 3). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to give a mixture of compounds 49a and 49b (650 mg). The mixture was further purified by chiral-HPLC to provide compounds 49a (250 mg, t = 3.29 minutes) and 49b (230 mg, t = 3.89 minutes). Chiral-HPLC conditions: Eluent = MeOH (0.1% DEA); Column = AS-H (4.6*250 mm, 5 um).

[0565] Synthesis of compound 50a. To a solution of compound 49a (250 mg, 0.524 mmol) and anhydrous NaHPO (150 mg) in anhydrous methanol (5 mL) at -20 ° C under N2, Na / Hg amalgam (800 mg) was added. After stirring at -20 ° C to 0 ° C for 1 hour, the methanol solution was decanted and the solid residue was washed with Et2O (5×3 mL). The combined organic phase was removed under vacuum, and 20 mL of saline was added, followed by extraction with Et2O. The combined ether phases were dried with MgSO4, filtered and concentrated. The crude product was purified by silica gel chromatography (PE / EA=10 / 1) to give compound 49a (130 mg, 73%). 1 H NMR (400MHz, CDCl3), δ (ppm), 5.60-5.30 (t, 1H, J = 63.6Hz), 5.14-5.09 (m, 1H), 0.88 (m, 3H).

[0566] Synthesis of compound 50b. To a solution of compound 49b (230 mg, 0.489 mmol) and anhydrous NaHPO (150 mg) in anhydrous methanol (5 mL) at -20°C under N2 was added Na / Hg amalgam (700 mg). After stirring at -20°C to 0°C for 1 hour, the methanol solution was decanted and the solid residue was washed with Et2O (5×3 mL). The combined organic phase was removed under vacuum, and 20 mL of brine was added, followed by extraction with Et2O. The combined ether phases were dried with MgSO4, filtered and concentrated. The crude product was purified by silica gel chromatography (PE / EA=10 / 1) to give compound 50b (120 mg, 73%). 1 H NMR (400MHz, CD3COCD3), δ (ppm), 6.02-5.88 (t, 1H, J=59.6Hz), 5.13-5.08 (m, 1H), 0.92 (s, 3H).

[0567] Synthesis of compound 51a. Borane-tetrahydrofuran complex (1.3 mL; 1.0 M solution in THF) was added to a solution of compound 50a (130 mg, 0.384 mmol) in dry THF (5 mL). After stirring at room temperature for 1 hour, the reaction mixture was cooled in an ice bath and then slowly quenched with 10% NaOH aqueous solution (1 mL) followed by 30% H2O2 aqueous solution (1.2 mL). The mixture was stirred at room temperature for 1 hour and then extracted with EtOAc (3×10 mL). The combined organic layers were washed with 10% Na2S2O3 aqueous solution (10 mL), brine (10 mL), dried over MgSO4, filtered and concentrated to provide compound 51a (200 mg, crude). The crude product was used in the next step without further purification.

[0568] Synthesis of compound 51b. Borane-tetrahydrofuran complex (1.20 mL; 1.0 M solution in THF) was added to a solution of compound 50b (120 mg, 0.355 mmol) in dry THF (5 mL). After stirring at room temperature for 1 hour, the reaction mixture was cooled in an ice bath and then slowly quenched with 10% NaOH aqueous solution (1 mL) followed by 30% H2O2 aqueous solution (1.2 mL). The mixture was stirred at room temperature for 1 hour and then extracted with EtOAc (3×10 mL). The combined organic layers were washed with 10% Na2S2O3 aqueous solution (10 mL), brine (10 mL), dried over MgSO4, filtered and concentrated to provide compound 51b (180 mg, crude). The crude product was used in the next step without further purification.

[0569] Synthesis of compound 52a. To a solution of compound 51a (200 mg, crude) in 10 mL of wet dichloromethane (dichloromethane had been oscillated with a few milliliters of H2O and then separated from the aqueous layer) was added Dess-Martin periodinane (400 mg, 0.94 mmol). After stirring at room temperature for 24 hours, the reaction mixture was extracted with dichloromethane (3×10 mL). The combined organic layers were washed with 10% Na2S2O3 aqueous solution (10 mL), brine (10 mL), dried over MgSO4, filtered and concentrated. The residue was purified by chromatography on silica gel (petroleum ether / ethyl acetate=1:5) to provide compound 52a (75 mg, 55.1% for two steps) as a white solid. 1 H NMR (400MHz, CDCl3), δ (ppm), 5.58-5.32 (t, 1H, J=52.0Hz), 2.53-2.51 (m, 1H), 2.14 (s, 3H), 0.62 (s, 3H).

[0570] Synthesis of compound 52b. To a solution of compound 51b (180 mg, crude) in 10 mL of wet dichloromethane (dichloromethane had been oscillated with a few milliliters of H2O and then separated from the aqueous layer) was added Dess-Martin periodinane (380 mg, 0.896 mmol). After stirring at room temperature for 24 hours, the reaction mixture was extracted with dichloromethane (3×10 mL). The combined organic layers were washed with 10% Na2S2O3 aqueous solution (10 mL), brine (10 mL), dried over MgSO4, filtered and concentrated. The residue was purified by chromatography on silica gel (petroleum ether / ethyl acetate=1:5) to provide compound 52b (70 mg, 55.7% for two steps) as a white solid. 1 H NMR (400MHz, CDCl3), δ (ppm), 5.90-5.61 (t, 1H, J = 60Hz), 2.48-2.43 (m, 1H), 2.10 (s, 3H), 0.55 (s, 3H).

[0571] Synthesis of compound 53a. To a solution of compound 52a (40 mg, 0.113 mmol) in MeOH (5 mL) was added 2 drops of HBr (48%), followed by bromine (100 mg, 0.62 mmol). After stirring at room temperature for 1 hour, the reaction mixture was poured into ice water and then extracted with ethyl acetate (15 mL × 3). The combined organic layer was washed with brine (20 mL), dried over MgSO, filtered and concentrated to give compound 53a (84 mg, crude). The crude product was used in the next step without further purification.

[0572] Synthesis of compound 53b. To a solution of compound 52b (50 mg, 0.14 mmol) in MeOH (5 mL) was added 2 drops of HBr (48%), followed by bromine (100 mg, 0.62 mmol). After stirring at room temperature for 1 hour, the reaction mixture was poured into ice water and then extracted with ethyl acetate (15 mL×3). The combined organic layers were washed with brine (20 mL), dried over MgSO4, filtered and concentrated to give compound 53b (72 mg, crude). The crude product was used in the next step without further purification.

[0573] The synthesis of compound 54a. A solution of compound 53a (84 mg, crude) in acetone (6 mL) was treated with CFCOOH (0.3 mL) and EtN (0.5 mL). After heating at reflux for 30 minutes, CFCOONa salt (432 mg, 3.12 mmol) was added and the mixture was refluxed overnight. The reaction was cooled to room temperature and the solvent was removed in a vacuum. The residue was extracted with ethyl acetate (10 mL × 3). The combined organic layer was washed with brine (15 mL), dried by MgSO, filtered and concentrated. The residue was purified by chromatography on silica gel (petroleum ether / ethyl acetate=3:1) to provide compound 54a (15 mg, 36% for two steps). 1 HNMR (500MHz, CDCl3), δ (ppm), 5.56-5.33 (t, 1H, J = 56.5Hz), 4.22-4.13 (m, 2H), 3.25-3.23 (m, 1H), 0.64 (s, 3H).

[0574] Synthesis of compound 54b. A solution of compound 53b (72 mg, crude) in acetone (5 mL) was treated with CFCOOH (0.3 mL) and EtN (0.45 mL). After heating at reflux for 30 minutes, CFCOONa salt (270 mg, 1.95 mmol) was added and the mixture was refluxed overnight. The reaction was cooled to room temperature and the solvent was removed in vacuo. The residue was extracted with ethyl acetate (10 mL × 3). The combined organic layer was washed with brine (10 mL), dried by MgSO, filtered and concentrated. The residue was purified by chromatography on silica gel (petroleum ether / ethyl acetate=3:1) to provide compound 54b (10 mg, 19.2% for two steps). 1 H NMR (400MHz, CDCl3), δ (ppm), 5.96-5.68 (t, 1H, J=56Hz), 4.24-4.10 (m, 2H), 3.2 (s, 1H), 0.64 (s, 3H).

[0575] Example 8.

[0576]

[0577] Synthesis of compounds 55a and 55b. To a solution of compound 5 (1.2 g, 4.2 mmol) and PhSOCFH (730 mg, 4.2 mmol) in THF (25 mL) and HMPA (0.5 mL) at -78 °C under N2, LHMDS (5.5 mL, 1 M in THF) was added dropwise. After stirring for 2 hours at -78 °C, the reaction mixture was quenched with saturated NH4Cl aqueous solution (10 mL). The mixture was warmed to room temperature and extracted with Et2O (20 mL × 3). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to give a mixture of compounds 55a and 55b (1.4 g). The mixture was further purified by chiral-HPLC to provide compound 55a1 (220 mg, t = 3.62 minutes). 1 H NMR (500 MHz, CDCl3), δ (ppm), 7.99-7.97 (d, 2H, J = 7.6 Hz), 7.76-7.72 (m, 1H), 7.62-7.60 (m, 2H), 5.17-5.13 (m, 1H), 4.88-4.78 (d, 1H, J = 46 Hz), 0.88 (s, 3H); 55a2 (200 mg, t = 3.94 min). 1 H NMR (500 MHz, CDCl3), δ (ppm), 7.97-7.95 (d, 2H, J = 7.6 Hz), 7.77-7.76 (m, 1H), 7.66-7.62 (m, 2H), 5.11-5.10 (m, 1H), 4.88-4.78 (d, 1H, J = 46 Hz), 0.88 (s, 3H); 55b1 (235 mg, t = 4.95 min). 1 H NMR (500 MHz, CDCl3), δ (ppm), 7.98-7.96 (d, 2H, J=7.5 Hz), 7.72-7.76 (m, 1H), 7.62-7.59 (m, 2H), 5.37-5.27 (d, 1H, J=46 Hz), 5.07-5.05 (m, 1H), 0.88 (s, 3H); 55b2 (220 mg, t=6.92 min). 1H NMR (500 MHz, CDCl3), δ (ppm), 7.98-7.96 (d, 2H, J = 7.5 Hz), 7.76-7.72 (m, 1H), 7.62-7.59 (m, 2H), 5.37-5.27 (d, 1H, J = 46 Hz), 5.07-4.98 (m, 1H), 0.88 (s, 3H). Chiral-HPLC conditions: eluent = MeOH (0.1% DEA); column = IC (4.6*250 mm, 5 um).

[0578] Synthesis of compound 56a. To a solution of compound 55a1 (200 mg, 0.434 mmol) and anhydrous NaHPO (100 mg) in anhydrous methanol (15 mL) at -20 ° C under N2, Na / Hg amalgam (400 mg) was added. After stirring at -20 ° C to 0 ° C for 1 hour, the methanol solution was decanted and the solid residue was washed with Et2O (5×3 mL). The combined organic phase was removed under vacuum, and 20 mL of saline was added, followed by extraction with Et2O. The combined ether phase was dried with MgSO4, filtered and concentrated. The crude product was purified by silica gel chromatography (PE / EA=10 / 1) to give compound 56a (90 mg, 65%). 1 H NMR (500MHz, CDCl3), δ (ppm), 5.12-5.11 (m, 1H), 4.2-4.15 (d, 2H, J=48Hz), 0.62 (s, 3H).

[0579] Synthesis of compound 56b. To a solution of compound 55b2 (200 mg, 0.434 mmol) and anhydrous NaHPO (100 mg) in anhydrous methanol (5 mL) at -20 ° C under N was added Na / Hg amalgam (500 mg). After stirring at -20 ° C to 0 ° C for 1 hour, the methanol solution was decanted and the solid residue was washed with EtO (5×3 mL). The combined organic phase was removed under vacuum, and 20 mL of saline was added, followed by extraction with EtO. The combined ether phases were dried with MgSO4, filtered and concentrated. The crude product was purified by silica gel chromatography (PE / EA=10 / 1) to give compound 56b (95 mg, 68%). 1 H NMR (500MHz, CDCl3), δ (ppm), 5.14-4.10 (m, 1H), 4.50-4.35 (m, 2H), 0.79 (s, 3H).

[0580] Synthesis of compound 57a. Borane-tetrahydrofuran complex (1 mL; 1.0 M solution in THF) was added to a solution of compound 56a (90 mg, 0.281 mmol) in dry THF (5 mL). After stirring at room temperature for 1 hour, the reaction mixture was cooled in an ice bath and then slowly quenched with 10% NaOH aqueous solution (1 mL) followed by 30% H2O2 aqueous solution (1.2 mL). The mixture was stirred at room temperature for 1 hour and then extracted with EtOAc (3×10 mL). The combined organic layers were washed with 10% Na2S2O3 aqueous solution (10 mL), brine (10 mL), dried over MgSO4, filtered and concentrated to provide compound 57a (130 mg, crude). The crude product was used in the next step without further purification.

[0581] Synthesis of compound 57b. Borane-tetrahydrofuran complex (1.1 mL; 1.0 M solution in THF) was added to a solution of compound 56b (95 mg, 0.297 mmol) in dry THF (5 mL). After stirring at room temperature for 1 hour, the reaction mixture was cooled in an ice bath and then slowly quenched with 10% NaOH aqueous solution (1 mL) followed by 30% H2O2 aqueous solution (1.2 mL). The mixture was stirred at room temperature for 1 hour and then extracted with EtOAc (3×10 mL). The combined organic layers were washed with 10% Na2S2O3 aqueous solution (10 mL), brine (10 mL), dried over MgSO4, filtered and concentrated to provide compound 57b (135 mg crude). The crude product was used in the next step without further purification.

[0582] Synthesis of compound 58a. A solution of compound 57a (130 mg crude) in 10 mL of wet dichloromethane (dichloromethane has been oscillated with a few milliliters of H2O and then separated from the aqueous layer) was added with Dess-Martin periodinane (300 mg, 707 mmol). After stirring at room temperature for 24 hours, the reaction mixture was extracted with dichloromethane (3×10 mL). The combined organic layers were washed with 10% Na2S2O3 aqueous solution (10 mL), brine (10 mL), dried over MgSO4, filtered and concentrated. The residue was purified by chromatography on silica gel (petroleum ether / ethyl acetate=1:5) to provide compound 58a (60 mg, 64% for two steps) as a white solid. 1 H NMR (500MHz, CDCl3), δ (ppm), 4.23-4.11 (d, 2H, J = 60Hz), 2.55-2.51 (m, 1H), 2.09 (s, 3H), 0.62 (s, 3H).

[0583] Synthesis of compound 58b. Add Dess-Martin periodinane (380 mg, 0.896 mmol) to a solution of compound 57b (135 mg crude) in 10 mL wet dichloromethane (dichloromethane has been oscillated with a few milliliters of H2O and then separated from the aqueous layer). After stirring at room temperature for 24 hours, the reaction mixture was extracted with dichloromethane (3×10 mL). The combined organic layers were washed with 10% Na2S2O3 aqueous solution (10 mL), brine (10 mL), dried over MgSO4, filtered and concentrated. The residue was purified by chromatography on silica gel (petroleum ether / ethyl acetate=1:5) to provide compound 58b (68 mg, 69%) as a white solid. 1 H NMR (500MHz, CDCl3), δ (ppm), 4.50-4.34 (m, 2H), 2.56-2.52 (m, 1H), 2.15 (s, 3H), 0.61 (s, 3H).

[0584] Synthesis of compound 59a. To a solution of compound 58a (40 mg, 0.119 mmol) in MeOH (5 mL) was added 2 drops of HBr (48%), followed by bromine (100 mg, 0.62 mmol). After stirring at room temperature for 1 hour, the reaction mixture was poured into ice water and then extracted with ethyl acetate (15 mL × 3). The combined organic layer was washed with brine (20 mL), dried over MgSO4, filtered and concentrated to give compound 59a (60 mg, crude). The crude product was used in the next step without further purification.

[0585] The synthesis of compound 60a. Use CFCOOH (0.1mL) and EtN (0.17mL) to process the solution of compound 59a (60mg rough) in acetone (5mL). After heating under reflux for 30 minutes, add CFCOONa salt (180mg, 1.3mmol) and reflux the mixture overnight. Make the reaction cool to room temperature and remove the solvent in a vacuum. The residue is extracted with ethyl acetate (10mL×3). The combined organic layer is washed with brine (15mL), passed through MgSO4, dried, filtered and concentrated. The residue is purified by chromatography on silica gel (petroleum ether / ethyl acetate=3:1) to provide compound 60a (15mg, 36% for two steps). 1 HNMR (500MHz, CDCl3), δ (ppm), 4.21-4.11 (m, 4H), 3.39-3.36 (m, 1H), 2.84 (s, 1H), 0.65 (s, 3H).

[0586] Example 9.

[0587]

[0588] Synthesis of compound 61. Borane-tetrahydrofuran complex (30 mL; 1.0 M solution in THF) was added to a solution of compound 42 (5 g, 15 mmol) in dry THF (20 mL). After stirring at room temperature for 1 hour, the reaction mixture was cooled in an ice bath and then slowly quenched with 10% NaOH aqueous solution (56 mL) followed by 30% H2O2 aqueous solution (67 mL). After stirring at room temperature for 1 hour, the mixture was extracted with EtOAc (3×100 mL). The combined organic layers were washed with 10% Na2S2O3 aqueous solution (100 mL), brine (100 mL), dried over MgSO4, filtered and concentrated to provide crude compound 61 (5 g). The crude product was used in the next step without further purification.

[0589] Synthesis of compound 62. A solution of crude compound 61 (3.2 g, 9 mmol) in THF (50 mL) was acidified to pH = 3 by 1N HCl aqueous solution. After stirring at room temperature for 12 hours, the reaction mixture was extracted with ethyl acetate (150 mL×3). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by column chromatography (petroleum ether / ethyl acetate=30:1 to 20:1) to provide compound 62 (2.2 g, 7 mmol, 81% for two steps). m / z (ES+APCI) + :[M+H] + 305.

[0590] Synthesis of compound 63. To a stirred solution of trimethylsulfonium iodide (8.1 g, 36.9 mmol) in 100 mL DMSO was added NaH (60%; 1.26 g, 31.5 mmol). After stirring at room temperature for 1 hour, a suspension of compound 62 (2.2 g, 7.2 mmol) in DMSO (20 mL) was added dropwise. The mixture was stirred for another 2.5 hours, then poured into ice-cold water and extracted with ether (100 mL × 3). The combined ether layers were washed with brine (100 mL × 3), dried by MgSO4, filtered, and concentrated to give a crude product 63 (2.2 g). The crude product was used in the next step without further purification.

[0591] Synthesis of compound 64. Add Dess-Martin periodinane (4.2 g, 10 mmol) to a solution of crude compound 63 (1.6 g, 5 mmol) in 60 mL of wet dichloromethane (dichloromethane has been oscillated with a few milliliters of H2O and then separated from the aqueous layer). After stirring at room temperature for 24 hours, the reaction mixture was extracted with dichloromethane (3×100 mL). The combined organic layers were washed with 10% Na2S2O3 aqueous solution (100 mL), brine (100 mL), dried over MgSO4, filtered and concentrated. The residue was purified by chromatography on silica gel (petroleum ether / ethyl acetate=20:1 to 10:1) to provide compound 64 (1.2 g, 3.8 mmol, 75% for two steps) as a white solid. 1 H NMR (400MHz, CDCl3), δ (ppm), 2.63-2.58 (m, 3H), 2.11 (s, 3H), 0.63 (s, 3H).

[0592] Synthesis of compound 65. To a solution of compound 64 (1.2 g, 3.8 mmol) in dry methanol (250 mL) was added Na (262 mg, 11.4 mmol). After refluxing for 16 hours, the solvent was evaporated and the residue was dissolved in dichloromethane. The mixture was washed with H2O (3 × 50 mL), brine (100 mL), dried over MgSO4, filtered, and concentrated. The crude product was purified by silica gel chromatography (petroleum ether / ethyl acetate = 10: 1 to 5: 1) to give compound 65a (300 mg, 25%) and compound 65b (100 mg, 8%) as a white solid. 65a, 1H NMR (400 MHz, CDCl3), δ (ppm), 3.38 (s, 3H), 3.18 (s, 2H), 2.56-2.51 (m, 1H), 2.11 (s, 3H), 0.61 (s, 3H). 65b, 1H NMR (400MHz, CDCl3), δ (ppm), 3.40 (s, 3H), 3.37 (s, 2H), 2.54-2.50 (m, 1H), 2.11 (s, 3H), 0.62 (s, 3H).

[0593] Synthesis of compound 66a. Add 2 drops of HBr (48%) to a solution of compound 65a (50 mg, 0.14 mmol) in MeOH (10 mL), followed by bromine (23 mg, 0.14 mmol). After stirring at room temperature for 1 hour, the reaction mixture was poured into ice water and then extracted with ethyl acetate (10 mL × 3). The combined organic layer was washed with brine (20 mL), dried over MgSO, filtered and concentrated to give crude compound 66a (46 mg, 92%). The crude product was used in the next step without further purification.

[0594] Synthesis of compound 67a. A solution of compound 66a (46 mg, 0.11 mmol) in acetone 10 mL was treated with CFCOOH (0.5 mL) and EtN (0.7 mL). After refluxing for 30 minutes, CFCOONa salt (300 mg, 2.2 mmol) was added in batches during 10 hours. The reaction mixture was cooled to room temperature and the solvent was removed in a vacuum. The residue was extracted with ethyl acetate, dried by MgSO, filtered and concentrated. The mixture was purified by chromatography on silica gel (petroleum ether / ethyl acetate=10:1 to 3:1) to provide 67a (10 mg, yield: 25% for two steps). 67a,1H NMR (400MHz, CDCl3), δ (ppm), 4.20-4.16 (m, 2H), 3.39 (s, 3H), 3.25 (m, 1H), 3.18 (s, 2H), 2.48-2.45 (m, 1H), 2.23-2.17 (m, 1H), 0.64 (s, 3H).

[0595] Example 10.

[0596]

[0597] Synthesis of compound 68a. Pyridine (50 mg, 0.63 mmol) was added to a solution of compound 15a (200 mg, 0.63 mmol) in acetic anhydride (10 mL). The reaction mixture was stirred at 80 ° C for 10 hours. The reaction mixture was poured into ice-cold water and extracted with ethyl acetate (20 mL × 3). The combined ether layer was then washed with brine (10 mL × 3), dried over MgSO4, filtered and concentrated to give a crude product 68a (160 mg, 80%). The crude product was used in the next step without further purification. 1 H NMR (400MHz, CDCl3), δ (ppm), 2.55-2.50 (t, J = 9.2Hz, 1H), 2.38-2.34 (m, 1H), 2.11 (s, 3H), 2.00 (s, 3H), 1.45 (s, 3H), 0.62 (s, 3H).

[0598] Example 11.

[0599]

[0600] Synthesis of compound 71

[0601]

[0602] To KCO (25mg, 0.18mmol) suspension in THF (5mL) add morpholine (16mg, 0.18mmol) and compound 16a (36mg, 0.09mmol). After stirring at room temperature for 15 hours, the reaction mixture is poured into 5mLH2O and extracted with EtOAc (2×10mL). The combined organic layer is washed with brine, dried over sodium sulfate, filtered and concentrated. The reaction mixture is purified by reverse phase preparative HPLC (prep-HPLC) to provide the title compound (12mg, 33%) as a white solid. 1 H NMR (500MHz, CDCl3), δ (ppm), 3.77-3.75 (m, 4H), 3.19-3.18 (m, 2H), 2.59-2.50 (m, 5H), 2.19-2.12 (m, 1H), 1.20 (s, 3H), 0.63 (s, 3H).

[0603] Synthesis of compound 72

[0604]

[0605] To KCO (25mg, 0.18mmol) suspension in THF (5mL) piperidine (16mg, 0.18mmol) and compound 16a (36mg, 0.09mmol) are added. After stirring at room temperature for 15 hours, the reaction mixture is poured into 5mL HO and extracted with EtOAc (2×10mL). The combined organic layer is washed with brine, dried over sodium sulfate, filtered and concentrated. The reaction mixture is purified by reverse phase preparative HPLC to provide the title compound (12mg, 33%) as a white solid. 1 H NMR (500MHz, CDCl3), δ (ppm), 3.12-3.04 (m, 2H), 2.57-2.53 (t, J=9Hz, 1H), 2.59-2.50 (m, 5H), 2.19-2.12 (m, 1H), 1.20 (s, 3H), 0.63 (s, 3H).

[0606] Synthesis of compound 73

[0607]

[0608] To KCO (25mg, 0.18mmol) suspension in THF (5mL) add pyrrolidine (13mg, 0.18mmol) and compound 16a (36mg, 0.09mmol).After stirring at room temperature for 15 hours, the reaction mixture is poured into 5mL H2O and extracted with EtOAc (2×10mL).The combined organic layer is washed with brine, dried over sodium sulfate, filtered and concentrated.The reaction mixture is purified by reverse phase preparative HPLC to provide the title compound (15mg, 42%) as a white solid. 1 H NMR (400MHz, CDCl3), δ (ppm), 3.43-3.31 (m, 2H), 2.61-2.53 (m, 5H), 2.21-2.13 (m, 1H), 1.20 (s, 3H), 0.63 (s, 3H).

[0609] Synthesis of compound 74

[0610]

[0611] To KCO (14mg, 0.10mmol) suspension in THF (5mL) add 1H-imidazole (7mg, 0.10mmol) and compound 16a (20mg, 0.05mmol).After stirring at room temperature for 15 hours, the reaction mixture is poured into 5mL H2O and extracted with EtOAc (2×10mL).The combined organic layer is washed with brine, dried over sodium sulfate, filtered and concentrated.The reaction mixture is purified by reverse phase preparative HPLC to provide the title compound (7mg, 35%) as a white solid. 1 H NMR (500MHz, CDCl3), δ (ppm), 7.49 (s, 1H), 7.12 (s, 1H), 6.86 (s, 1H), 4.75-4.66 ( m, 2H), 2.60-2.56 (t, J=8.5Hz, 1H), 2.21-2.13 (m, 1H), 1.21 (s, 3H), 0.68 (s, 3H).

[0612] Example 12.

[0613]

[0614] Synthesis of compounds 75a and 75b. To a solution of compound 43 (1.3 g, 4.5 mmol) and PhSOCHF (790 mg, 4.5 mmol) in THF (25 mL) and HMPA (0.5 mL) at -78 °C under N was added dropwise LHMDS (5.5 mL, 1 M in THF). After stirring for 2 hours at -78 °C, the reaction mixture was quenched with saturated NHCl aqueous solution (10 mL) and allowed to warm to room temperature, then extracted with EtO (20 mL × 3). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate=10 / 1) to give a mixture of compounds 75a and 75b (1.53 g). The mixture was further purified by chiral-HPLC to provide compound 75a1 (220 mg, t=3.41 minutes). 1 H NMR (500 MHz, CDCl3), δ (ppm), 7.99-7.97 (m, 2H), 7.75-7.74 (m, 1H), 7.62-7.55 (m, 2H), 5.13-5.09 (m, 1H), 4.86-4.78 (d, 1H, J = 42 Hz), 0.88 (s, 3H); 75a2 (200 mg, t = 3.66 min); 1 H NMR (500 MHz, CDCl3), δ (ppm), 7.96-7.95 (m, 1H), 7.71-7.69 (m, 1H), 7.62-7.58 (m, 2H), 5.13-5.09 (m, 1H), 4.87-4.77 (d, 1H, J=46.5 Hz), 0.88 (s, 3H); 75b1 (235 mg, t=4.9 min). 1 H NMR (500 MHz, CDCl3), δ (ppm), 7.99-7.97 (m, 1H), 7.72-7.70 (m, 1H), 7.62-7.59 (m, 2H), 5.29-5.20 (d, 1H, J=43 Hz), 4.88-4.78 (m, 1H), 0.88 (s, 3H); 75b2 (220 mg, t=5.2 min). 1 H NMR (500 MHz, CDCl3), δ (ppm), 7.99-7.97 (m, 2H), 7.72 (m, 1H), 7.62-7.59 (m, 2H), 5.30-5.20 (d, 1H, J=46.5 Hz), 5.09-5.08 (m, 1H), 0.88 (s, 3H). Chiral HPLC conditions: eluent = MeOH (0.1% DEA); column = IC (4.6*250 mm, 5 um).

[0615] Synthesis of compound 76a. To a solution of compound 75a1 (200 mg, 0.434 mmol) and anhydrous NaHPO (100 mg) in anhydrous methanol (15 mL) at -20 ° C under N was added Na / Hg amalgam (400 mg). After stirring at -20 ° C to 0 ° C for 1 hour, the methanol solution was decanted and the solid residue was washed with EtO (5×3 mL). The solvent of the combined organic phase was removed under vacuum, and 20 mL of saline was added, followed by extraction with EtO. The combined ether phases were dried with MgSO4, and ether was removed to give a crude product, which was further purified by silica gel chromatography (PE / EA=10 / 1) to give compound 76a (99 mg, 69%). 1 H NMR (500MHz, CDCl3), δ (ppm), 5.12-5.10 (m, 1H), 4.21-24.11 (d, 2H, J=47.5Hz), 0.88 (s, 3H).

[0616] Synthesis of compound 77a. Borane-tetrahydrofuran complex (1 mL of 1.0 M solution in THF) was added to a solution of compound 76a (95 mg, 0.296 mmol) in dry THF (5 mL). After stirring at room temperature for 1 hour, the reaction mixture was cooled in an ice bath and then slowly quenched with 10% NaOH aqueous solution (1 mL) followed by 30% H2O2 aqueous solution (1.2 mL). The mixture was stirred at room temperature for 1 hour and then extracted with EtOAc (3×10 mL). The combined organic layers were washed with 10% Na2S2O3 aqueous solution (10 mL), brine (10 mL), dried over MgSO4, filtered and concentrated to provide compound 77a (120 mg, crude). The crude product was used in the next step without further purification.

[0617] Synthesis of compound 78a. Add Dess-Martin periodinane (300mg, 707mmol) to a solution of compound 77a (120mg crude) dissolved in 10mL wet dichloromethane (dichloromethane has been oscillated with a few milliliters of H2O, then separated from the aqueous layer). After stirring at room temperature for 24 hours, the reaction mixture was extracted with dichloromethane (3×10mL). The combined organic layers were washed with 10% Na2S2O3 aqueous solution (10mL), brine (10mL), dried over MgSO4, filtered and concentrated. The residue was purified by chromatography on silica gel (petroleum ether / ethyl acetate=1:5) to provide compound 78a (70mg, 70% for two steps) as a white solid. 1H NMR (500MHz, CDCl3), δ (ppm), 4.21-4.11 (d, 2H, J = 48Hz), 2.19 (s, 3H), 0.62 (s, 3H).

[0618] Determination method

[0619] A variety of in vitro and in vivo assays can be used to evaluate the compounds provided herein; examples of which are described below.

[0620] Steroid inhibition of TBPS binding

[0621] TBPS binding assays using rat brain cortical membranes in the presence of 5 μM GABA have been described (Gee et al, J. Pharmacol. Exp. Ther. 1987, 241, 346-353; Hawkinson et al, Mol. Pharmacol. 1994, 46, 977-985).

[0622] Briefly, the cortex was quickly removed after decapitation of Sprague-Dawley rats (200-250 g) anesthetized with carbon dioxide. The cortex was homogenized in 10 volumes of ice-cold 0.32 M sucrose using a glass / Teflon homogenizer and centrifuged at 1500 x g for 10 minutes at 4°C. The resulting supernatant was centrifuged at 10,000 x g for 20 minutes at 4°C to obtain P2 pellets. The P2 aggregates were resuspended in 200 mM NaCl / 50 mM phosphate Na-K pH 7.4 buffer and centrifuged at 10,000 x g for 10 minutes at 4°C. The ishing procedure was repeated twice and the aggregates were resuspended in 10 volumes of buffer. An aliquot (100 μL) of the membrane suspension was treated with a 5 μL aliquot (final 0.5%) of the test drug dissolved in dimethyl sulfoxide (DMSO) and 2 nM [ 35S]-TBPS was incubated in the presence of 5 μM GABA. The incubation was brought to a final volume of 1.0 mL with buffer. Nonspecific binding was measured in the presence of 2 μM unlabeled TBPS and ranged from 15% to 25%. After 90 minutes of incubation at room temperature, the assay was terminated by filtering through a glass fiber filter (Schleicher and Schuell No.32) using a cell collector (Brandel), and rinsed three times with ice-cold buffer. The filter-bound radioactivity was measured by liquid scintillation spectrometry. Prism (GraphPad) was used to perform nonlinear curve fitting of the total data of each drug averaged for each concentration. If the sum of squares was significantly lower by the F test, the data were suitable for a partial inhibition model, rather than a complete inhibition model. Similarly, if the sum of squares was significantly lower by the F test, the data were suitable for a two-component inhibition model, rather than a one-component inhibition model. The same model used for the total data was used to determine the 50% inhibition (IC) of specific binding for a single experiment. 50 ) and the maximum inhibition level (I max ) of the test compound, and then the average of the individual experiments was calculated + SEM.s.

[0623] A variety of compounds have been or can be screened to determine whether they are [ 35 [S]-TBPS binding in vitro potential modulators. These assays are or can be performed according to the procedures discussed above.

[0624] In vivo pharmacology

[0625] Male NSA mice weighing 15-20 g were obtained from Harlan Sprague-Dawley (San Diego, CA). Upon arrival, they were housed in standard polycarbonate cages (4 per cage) containing sterilized bedding material in a constant temperature (23.0°C ± 2.5°C) room with a 12-hour (07.00-19.00 light on) light / dark cycle. Food (Teklad LM 485) and water were freely available. Mice were acclimated for a minimum of 4 days prior to the experiment.

[0626] Pentylenetetrazol-induced seizures

[0627] Seizures were induced by subcutaneous administration of 85 mg / kg pentylenetetrazol (30 min observation period). The dose used was predetermined as CD 97 Clonic seizures were defined as forelimb clonus of ≥ 3 seconds duration. Data were processed quantally.

[0628] Maximum electroconvulsive seizure

[0629] Seizures were induced by applying current (50 mA, 60 pulses / second, 0.8 millisecond pulse width, 1 second duration, DC) using an Ugo Basile ECT device (Model 7801). The mice were restrained by clamping the loose skin on the back of the mice and holding the saline-coated corneal electrodes gently against both corneas. The current was applied and the mice were observed for a period of up to 30 seconds for the occurrence of tonic hindlimb extensor responses. A tonic seizure was defined as an extension of the hindlimbs exceeding 90 degrees from the plane of the body. The results were processed in a counting manner.

[0630] Hanging Wire

[0631] The hanging wire test uses a custom-made apparatus consisting of a metal wire (2 mm in diameter) suspended horizontally above the padded surface (cushion surface, padded surface) (25 cm). The mice are fixed by the base of the tail, their front paws are placed in contact with the wire, and then released. The animals are required to contact the wire with both hind paws within 5 seconds to be scored as a pass. The results are processed statistically.

[0632] Drug metabolism and pharmacokinetics: HERG assay

[0633] HEK 293 cells stably expressing HERG potassium channels are used for electrophysiological studies. The method for stable transfection of this channel in HEK cells can be found elsewhere (Zhou et al., Biophys. J. 74: 230-41, 1998). Before the experiment that day, cells were harvested from culture flasks and inoculated into standard Minimum Essential Medium (MEM) culture medium with 10% fetal calf serum (FCS) on glass slides. The inoculated cells were stored in an incubator at 37° C. in an atmosphere maintained at 95% O2 / 5% CO2. Cells were studied at 15-28 hours after harvest.

[0634] HERG currents were studied in whole-cell mode using standard patch clamp techniques. During experiments, cells were superfused with a standard external solution of the following composition (mM): NaCl, 130; KCl, 4; CaCl2, 2; MgCl2, 1; Glucose, 10; HEPES, 5; pH 7.4 with NaOH. Whole-cell recordings were performed using patch pipettes and patch clamp amplifiers that had a resistance of 1-3 MΩ when filled with a standard internal solution of the following composition (mM): KCl, 130; MgATP, 5; MgCl2, 1.0; HEPES, 10; EGTA 5, pH 7.2 with KOH. For further experiments, only those cells with an access resistance below 15 MΩ and a seal resistance > 1 GΩ were accepted. Series resistance compensation was applied up to a maximum value of 80%. No leak subtraction was performed. However, the acceptable access resistance depends on the magnitude of the current recorded and the level of series resistance compensation that can be safely used. After achieving whole cell configuration and sufficient time (>5 minutes) for cell dialysis using pipette solution, a standard voltage protocol was applied to the cells to induce membrane currents. The voltage protocol was as follows. The membrane was depolarized from a holding potential of -80 mV to +40 mV over 1000 ms. This was followed by a descending voltage ramp (rate 0.5 mV msec) back to the holding potential. -1 ). The voltage scheme was applied to the cells continuously every 4 seconds (0.25Hz) throughout the experiment. The amplitude of the peak current drawn near -40mV during the ramp was measured. Once a stable evoked current response was obtained in the external solution, a vehicle (0.5% DMSO in a standard external solution) was applied by a peristaltic pump for 10-20 minutes. Under the condition of minimal change in the amplitude of the evoked current response in the vehicle control condition, 0.3, 1, 3 or 10mM of the test compound was applied for 10 minutes. The 10-minute period includes the time for the supply solution to pass from the solution reservoir to the recording chamber via a pump. After the drug concentration in the chamber reached the attempting concentration well, the cells were exposed to the compound solution for more than 5 minutes. There was a subsequent washing time of 10-20 minutes to obtain reversibility. Finally, the cells were exposed to a high dose of dofetilide (5mM) (specific IKr blocker) to evaluate insensitive endogenous currents.

[0635] All experiments were performed at room temperature (23 ± 1 ° C). Evoked membrane currents were recorded online on a computer, filtered at 500-1 KHz (Bessel-3dB) and sampled at 1-2 KHz using a patch clamp amplifier and specific data analysis software. The peak current amplitude occurring near -40 mV was measured offline on a computer.

[0636] The arithmetic mean of ten amplitude values ​​was calculated under vehicle control conditions and in the presence of drugs. The percentage decrease of IN in each experiment was obtained by normalizing the current value using the following formula: IN = (1-ID / IC) × 100, where ID is the average current value in the presence of drugs and IC is the average current value under control conditions. A separate experiment was performed for each drug concentration or time-matched control, and the arithmetic mean in each experiment was defined as the result of the study.

[0637] Recombinant α1β2γ2GABA A Patch clamp electrophysiology of receptors

[0638] Using cell electrophysiology to measure GABA in Ltk cells A In vitro potency and efficacy of receptor modulators. Each compound was tested for its ability to affect GABA-mediated currents at a submaximal (submaximal) agonist dose (GABAEC10 = 0.5 μM) using the EPC-10, HEKA Electronics Amplifier and PatchMaster software with whole-cell patch clamp techniques. These experiments measure potency, efficacy (Emax), direct gating properties and acute desensitization. Test articles were added at 0.1, 1.0 and 10 μM.

[0639] Drug metabolism and pharmacokinetics: half-life in human liver microsomes (HLM)

[0640] Test compounds (1 μM) were incubated at 37°C with 0.78 mg / mL HLM (HL101) and 3.3 mM MgCl2 in 100 mM potassium phosphate buffer (pH 7.4) on 96 deep well plates. The reaction mixture was divided into two groups, non-P450 and P450 groups. Only NADPH was added to the reaction mixture of the P450 group. Aliquots of samples of the P450 group were collected at 0, 10, 30 and 60 minute time points, wherein the 0 minute time point represents the time when NADPH was added to the reaction mixture of the P450 group. Aliquots of samples of the non-P450 group were collected at -10 and 65 minute time points. The collected aliquots were extracted with an acetonitrile solution containing an internal standard. The precipitated protein was spun down in a centrifuge (2000 rpm, 15 minutes). The compound concentration in the supernatant was measured by an LC / MS / MS system. The half-life value is obtained by plotting the natural logarithm of the peak area ratio of compound / internal standard versus time. The slope of the best fit line through the points provides the metabolic rate (k). This is converted to a half-life value using the following equation: Half-life = ln 2 / k.

[0641]

[0642]

[0643]

[0644] In summary, the present invention mainly relates to the following aspects:

[0645] 1. Compounds of formula (I):

[0646]

[0647] or a pharmaceutically acceptable salt thereof;

[0648] in:

[0649] R 1 is hydrogen, halogen, 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, substituted or unsubstituted heteroaryl, -OR A1 、-SR A1 、-N(R A1 )2, -OC(=O)R A1 、-OC(=O)OR A1 、-OC(=O)SR A1 、-OC(=O)N(R A1 )2, -SC(=O)R A2 、-SC(=O)OR A1、-SC(=O)SR A1 、-SC(=O)N(R A1 )2, -NHC(=O)R A1 、-NHC(=O)OR A1 、-NHC(=O)SR A1 、-NHC(=O)N(R A1 )2, -OS(=O)2R A2 、-OS(=O)2OR A1 、-SS(=O)2R A2 、-SS(=O)2OR A1 、-S(=O)R A2 、-SO2R A2 , or -S(=O)2OR A1 , where R A1 Each instance of R is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, an oxygen protecting group when attached to an oxygen atom, a sulfur protecting group when attached to a sulfur atom, a nitrogen protecting group when attached to a nitrogen atom, or two R A1 The groups are combined to form a substituted or unsubstituted heterocyclic or heteroaryl ring; and R A2 is 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, or substituted or unsubstituted heteroaryl group;

[0650] R 2 is hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, –OH, –OR B1 、–OC(=O)R B1 、–NH2、–N(R B1 )2, or –NR B1 C(=O)R B1 , where R B1 Each instance of R is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, an oxygen protecting group when attached to an oxygen atom, a nitrogen protecting group when attached to a nitrogen atom, or two R B1 The groups combine to form a substituted or unsubstituted heterocyclic ring;

[0651] R3 is 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, or substituted or unsubstituted heteroaryl group;

[0652] R 3’ is hydrogen, –C(=O)R C1 、–C(=O)OR C1 、–C(=O)SR C1 , –C(=O)N(R C1 )2.

[0653] –S(=O)2R C2 、–S(=O)2OR C1 、–P(=O)2R C2 、–P(=O)2OR C1 、–P(=O)(OR C1 )2. –P(=O)(R C2 )2, or –P(=O)(R C2 )(OR C1 ), where R C1 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, an oxygen protecting group when attached to an oxygen atom, a sulfur protecting group when attached to a sulfur atom, a nitrogen protecting group when attached to a nitrogen atom, or two R C1 groups are combined to form a substituted or unsubstituted heterocyclic ring; and R C2 is 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, or substituted or unsubstituted heteroaryl group;

[0654] R 4 is selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl;

[0655] R 6a and R 6b are each independently hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl, or R 6a and R 6b Combine to form an oxo (=O) group;

[0656] R 11a and R11b are each independently hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, -OH, -OR D1 、-OC(=O)R D1 、-NH2、-N(R D1 )2, or -NR D1 C(=O)R D1 , where R D1 Each instance of R is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, an oxygen protecting group when attached to an oxygen atom, a nitrogen protecting group when attached to a nitrogen atom, or two R D1 The groups are combined to form a substituted or unsubstituted heterocyclic ring; or R 11a and R 11b Combine to form an oxo (=O) group;

[0657] in represents a single bond or a double bond, provided that if the double bond is present in ring B, then R 6a or R 6b one of is absent, and provided that if a single bond is present in ring B, the hydrogen at C5 is in the α or β position;

[0658] Provided that the following compounds, and their salts, are specifically excluded:

[0659]

[0660]

[0661]

[0662] 2. Compounds of formula (III):

[0663]

[0664] or a pharmaceutically acceptable salt thereof;

[0665] in:

[0666] R 1 is hydrogen, halogen, 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, substituted or unsubstituted heteroaryl, -OR A1 、-SR A1 、-N(R A1 )2, -OC(=O)R A1、-OC(=O)OR A1 、-OC(=O)SR A1 、-OC(=O)N(R A1 )2, -SC(=O)R A2 , –SC(=O)OR A1 , –SC(=O)SR A1 , –SC(=O)N(R A1 )2. –NHC(=O)R A1 、–NHC(=O)OR A1 , –NHC(=O)SR A1 、–NHC(=O)N(R A1 )2, –OS(=O)2R A2 、–OS(=O)2OR A1 、–S–S(=O)2R A2 、–S–S(=O)2OR A1 , –S(=O)R A2 , –SO2R A2 , or –S(=O)2OR A1 , where R A1 Each instance of R is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, an oxygen protecting group when attached to an oxygen atom, a sulfur protecting group when attached to a sulfur atom, a nitrogen protecting group when attached to a nitrogen atom, or two R A1 The groups are combined to form a substituted or unsubstituted heterocyclic or heteroaryl ring; and R A2 is 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, or substituted or unsubstituted heteroaryl group;

[0667] R 2 is hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, –OH, –OR B1 、–OC(=O)R B1 、–NH2、–N(R B1 )2, or –NR B1 C(=O)R B1 , where R B1Each instance of R is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, an oxygen protecting group when attached to an oxygen atom, a nitrogen protecting group when attached to a nitrogen atom, or two R B1 The groups combine to form a substituted or unsubstituted heterocyclic ring;

[0668] R 3 is 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, or substituted or unsubstituted heteroaryl group;

[0669] R 3’ is hydrogen, –C(=O)R C1 、–C(=O)OR C1 、–C(=O)SR C1 , –C(=O)N(R C1 )2.

[0670] –S(=O)2R C2 、–S(=O)2OR C1 、–P(=O)2R C2 、–P(=O)2OR C1 、–P(=O)(OR C1 )2. –P(=O)(R C2 )2, or –P(=O)(R C2 )(OR C1 ), where R C1 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, an oxygen protecting group when attached to an oxygen atom, a sulfur protecting group when attached to a sulfur atom, a nitrogen protecting group when attached to a nitrogen atom, or two R C1 groups are combined to form a substituted or unsubstituted heterocyclic ring; and R C2 is 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, or substituted or unsubstituted heteroaryl group;

[0671] R 4 is selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl;

[0672] R 6a and R 6b are each independently hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl, or R 6a and R 6b Combine to form an oxo (=O) group;

[0673] R 11a and R 11b are each independently hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, -OH, -OR D1 、-OC(=O)R D1 、-NH2、-N(R D1 )2, or -NR D1 C(=O)R D1 , where R D1 Each instance of R is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, an oxygen protecting group when attached to an oxygen atom, a nitrogen protecting group when attached to a nitrogen atom, or two R D1 The groups are combined to form a substituted or unsubstituted heterocyclic ring; or R 11a and R 11b Combine to form an oxo (=O) group;

[0674] in represents a single bond or a double bond, provided that if the double bond is present in ring B, then R 6a or R 6b One of them is absent, and provided that if a single bond is present in ring B, the hydrogen at C5 is in the alpha or beta position.

[0675] 3. The compound of item 1 or 2, wherein R 1 For hydrogen, halogen, -OR A1 、-SR A1 、-N(R A1 )2, -OC(=O)R A1 、-OC(=O)OR A1 、-OC(=O)SR A1 、-OC(=O)N(R A1 )2, -SC(=O)R A2 、-SC(=O)OR A1 、-SC(=O)SR A1 、-SC(=O)N(R A1 )2, -NHC(=O)R A1 、-NHC(=O)ORA1 、-NHC(=O)SR A1 、-NHC(=O)N(R A1 )2, -OS(=O)2R A2 、-OS(=O)2OR A1 、-SS(=O)2R A2 、-SS(=O)2OR A1 、-S(=O)R A2 、-SO2R A2 , or -S(=O)2OR A1 .

[0676] 4. The compound of item 1 or 2, wherein R 1 For hydrogen, halogen, -OR A1 、-N(R A1 )2, -SS(=O)2R A2 , a substituted or unsubstituted heterocyclic group, or a substituted or unsubstituted heteroaryl group.

[0677] 5. The compound of item 1 or 2, wherein R 2 is hydrogen, substituted or unsubstituted heterocyclic group, -OH, -OR B1 、-OC(=O)R B1 、-NH2、-N(R B1 )2, or -NR B1 C(=O)R B1 .

[0678] 6. The compound of item 1 or 2, wherein R 3 is a substituted or unsubstituted alkyl, a substituted or unsubstituted alkenyl, or a substituted or unsubstituted alkynyl.

[0679] 7. The compound of item 1 or 2, wherein R 3 A group of the formula:

[0680]

[0681] Where R 3a Each case of is hydrogen, halogen, or -OR F1 , where R F1 is a substituted or unsubstituted alkyl group; and R 3b and R 3c Each instance of is independently hydrogen, halogen, or substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclyl, or substituted or unsubstituted heterocyclyl.

[0682] 8. The compound of item 1 or 2, wherein R 3’ For hydrogen.

[0683] 9. The compound of item 1 or 2, wherein R4 For hydrogen.

[0684] 10. The compound of item 1 or 2, wherein R 6a and R 6b are each independently hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl, or R 6a and R 6b Combine to form an oxo (=O) group.

[0685] 11. The compound of item 1 or 2, wherein R 6a and R 6b Both are hydrogen.

[0686] 12. The compound of item 1 or 2, wherein R 6a and R 6b One of them is a non-hydrogen group.

[0687] 13. The compound of item 1 or 2, wherein R 6a It is a non-hydrogen α group.

[0688] 14. The compound of item 1 or 2, wherein R 6a It is a non-hydrogen β group.

[0689] 15. The compound of item 1 or 2, wherein R 6a is halogen or alkyl and R 6b For hydrogen.

[0690] 16. The compound of item 1 or 2, wherein R 6a and R 6b Both are halogens.

[0691] 17. The compound of item 1 or 2, wherein R 6a and R 6b Both are alkyl groups.

[0692] 18. The compound of item 1 or 2, wherein R 6a and R 6b Combine to form an oxo group.

[0693] 19. The compound of item 1 or 2, wherein R 11a and R 11b are independently hydrogen, -OH, -OR D1 、-OC(=O)R D1 、-NH2、-N(R D1 )2, or -NR D1 C(=O)R D1 , or R 11a and R 11b Combine to form an oxo (=O) group.

[0694] 20. The compound of item 1 or 2, wherein R 11a and R 11b Both are hydrogen.

[0695] 21. The compound of item 1 or 2, wherein R 11a and R 11b One of them is a non-hydrogen group.

[0696] 22. The compound of item 1 or 2, wherein R 11a and R 11b Combine to form an oxo group.

[0697] 23. The compound of item 1, wherein the compound of formula (I) is formula (I-a1), (I-a2) or (I-a3):

[0698]

[0699]

[0700] or a pharmaceutically acceptable salt thereof.

[0701] 24. The compound of item 2, wherein the compound of formula (III) is formula (III-a1), (III-a2) or (III-a3):

[0702]

[0703] or a pharmaceutically acceptable salt thereof.

[0704] 25. The compound of item 1, wherein the compound is selected from:

[0705]

[0706]

[0707]

[0708]

[0709]

[0710]

[0711]

[0712]

[0713]

[0714]

[0715]

[0716]

[0717] and pharmaceutically acceptable salts thereof.

[0718] 26. The compound of item 2, wherein the compound is selected from:

[0719]

[0720]

[0721]

[0722]

[0723]

[0724]

[0725]

[0726]

[0727]

[0728]

[0729]

[0730]

[0731] and pharmaceutically acceptable salts thereof.

[0732] 27. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound according to any one of items 1 to 26 or a pharmaceutically acceptable salt thereof.

[0733] 28. A method for treating a CNS-related disorder in a subject in need thereof, comprising administering to the subject an effective amount of a compound of any one of items 1-21, or a pharmaceutically acceptable salt thereof.

[0734] 29. The method of claim 28, wherein the disease or condition comprises insomnia, depression, mood disorders, convulsive disorders, memory disorders, attention disorders, anxiety disorders, bipolar disorder, schizophrenia, depression, bipolar disorder, schizoaffective disorder, mood disorders, anxiety disorders, personality disorders, psychosis, obsessive-compulsive disorder, post-traumatic stress disorder, autism spectrum disorder, dysthymia, social anxiety disorder, obsessive-compulsive disorder, pain, sleep disorders, memory disorders, dementia, Alzheimer's disease, seizure disorders, traumatic brain injury, stroke, addictive disorders, autism, Huntington's disease, Parkinson's disease, Rett syndrome, withdrawal syndrome, or tinnitus.

[0735] 30. The method of claim 28, wherein the compound is administered orally.

[0736] 31. The method of claim 28, wherein the compound is administered chronically.

[0737] Other Implementations

[0738] In the claims, articles such as "a," "an," and "the" may mean one or more than one, unless stated to the contrary or otherwise obvious from the context. Claims or specifications including "or" between one or more members of the group are considered satisfied if one, more than one, or all of the group members are present, used in, or otherwise related to a given product or method, unless stated to the contrary or otherwise obvious from the context. The invention includes embodiments in which exactly one member of the group is present, used in, or otherwise related to a given product or method. The invention includes embodiments in which more than one or all of the group members are present, used in, or otherwise related to a given product or method.

[0739] Moreover, the present invention includes all variations, combinations and arrangements in which one or more limitations, elements, clauses and descriptive terms from one or more of the listed claims are introduced into other claims. For example, any claim that is subordinate to another claim may be changed to include one or more limitations found in any other claim that is subordinate to the same basic claim. When an element is presented as a list, for example, in the form of a Markush group, each subgroup of the element is also disclosed, and any element can be removed from the group. It should be understood that, in general, when the present invention or aspects of the present invention are referred to as including specific elements and / or features, some 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 the sake of simplicity, those embodiments are not specifically described in these words herein. It is also noted that the terms "include" and "comprising" are intended to be open and allow the inclusion of additional elements or steps. When a range is given, the endpoints are included. Moreover, unless otherwise stated or otherwise apparent from the context and the understanding of those skilled in the art, the numerical value expressed as a range can be taken as one-tenth of the unit of the lower limit of the range in the stated range in different embodiments of the present invention or sub-range, unless the context clearly stipulates otherwise.

[0740] The present application refers to patents, published patent applications, journal articles and other publications of multiple authorizations, all of which are incorporated herein by reference. If there is a conflict between any reference introduced and this specification, this specification shall prevail. In addition, any specific embodiment of the present invention falling into the prior art can be explicitly excluded from any one or more of the claims. Because such an embodiment is considered to be known to those skilled in the art, even if it is not explicitly stated in this article to exclude, they can also be excluded. Any specific embodiment of the present invention can be excluded from any claim for any reason (whether or not relevant to the existence of the prior art).

[0741] Those skilled in the art will recognize or be able to determine many equivalents to the specific embodiments described herein using only routine experimentation. The scope of the present embodiments described herein is not intended to be limited to the above description, but as set forth in the appended claims. It will be appreciated by those of ordinary skill in the art that various changes and modifications to this specification may be made without departing from the spirit and scope of the invention as defined in the appended claims.

Claims

1. Compounds of formula (I): or a pharmaceutically acceptable salt thereof; in: R 1 is hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, –OR A1 ,–SR A1 , –N(R A1 )2. –OC(=O)R A1 、–OC(=O)OR A1 、–OC(=O)SR A1 、–OC(=O)N(R A1 )2. –SC(=O)R A2 , –SC(=O)OR A1 , –SC(=O)SR A1 , –SC(=O)N(R A1 )2. –NHC(=O)R A1 、–NHC(=O)OR A1 , –NHC(=O)SR A1 、–NHC(=O)N(R A1 )2, –OS(=O)2R A2 、–OS(=O)2OR A1 、–S–S(=O)2R A2 、–S–S(=O)2OR A1 , –S(=O)R A2 , –SO2R A2 , or –S(=O)2OR A1 , where R A1 Each instance of R is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, an oxygen protecting group when attached to an oxygen atom, a sulfur protecting group when attached to a sulfur atom, a nitrogen protecting group when attached to a nitrogen atom, or two R A1 The groups are combined to form a substituted or unsubstituted heterocyclic or heteroaryl ring; and R A2 is 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, or substituted or unsubstituted heteroaryl group; R 2 is hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, –OH, –OR B1 、–OC(=O)R B1 、–NH2、–N(R B1 )2, or –NR B1 C(=O)R B1 , where R B1 Each instance of R is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, an oxygen protecting group when attached to an oxygen atom, a nitrogen protecting group when attached to a nitrogen atom, or two R B1 The groups combine to form a substituted or unsubstituted heterocyclic ring; R 3 is 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, or substituted or unsubstituted heteroaryl group; R 3’ is hydrogen, -C(=O)R C1 , -C(=O)OR C1 , -C(=O)SR C1 , -C(=O)N(R C1 )2, -S(=O)2R C2 、-S(=O)2OR C1 、-P(=O)2R C2 、-P(=O)2OR C1 、-P(=O)(OR C1 )2. -P(=O)(R C2 )2, or -P(=O)(R C2 )(OR C1 ), where R C1 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, an oxygen protecting group when attached to an oxygen atom, a sulfur protecting group when attached to a sulfur atom, a nitrogen protecting group when attached to a nitrogen atom, or two R C1 groups are combined to form a substituted or unsubstituted heterocyclic ring; and R C2 is 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, or substituted or unsubstituted heteroaryl group; R 4 is selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl; R 6a and R 6b are each independently hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl, or R 6a and R 6b Combine to form an oxo (=O) group; R 11a and R 11b are each independently hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, -OH, -OR D1 、-OC(=O)R D1 、-NH2、-N(R D1 )2, or -NR D1 C(=O)R D1 , where R D1 Each instance of R is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, an oxygen protecting group when attached to an oxygen atom, a nitrogen protecting group when attached to a nitrogen atom, or two R D1 The groups are combined to form a substituted or unsubstituted heterocyclic ring; or R 11a and R 11b Combine to form an oxo (=O) group; in represents a single bond or a double bond, provided that if the double bond is present in ring B, then R 6a or R 6b one of is absent, and provided that if a single bond is present in ring B, the hydrogen at C5 is in the α or β position; Provided that the following compounds, and their salts, are specifically excluded:

2. Compounds of formula (III): or a pharmaceutically acceptable salt thereof; in: R 1 is hydrogen, halogen, 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, substituted or unsubstituted heteroaryl, -OR A1 、-SR A1 、-N(R A1 )2, -OC(=O)R A1 、-OC(=O)OR A1 、-OC(=O)SR A1 、-OC(=O)N(R A1 )2, -SC(=O)R A2 , –SC(=O)OR A1 , –SC(=O)SR A1 , –SC(=O)N(R A1 )2. –NHC(=O)R A1 、–NHC(=O)OR A1 , –NHC(=O)SR A1 、–NHC(=O)N(R A1 )2, –OS(=O)2R A2 、–OS(=O)2OR A1 、–S–S(=O)2R A2 、–S–S(=O)2OR A1 , –S(=O)R A2 , –SO2R A2 , or –S(=O)2OR A1 , where R A1 Each instance of R is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, an oxygen protecting group when attached to an oxygen atom, a sulfur protecting group when attached to a sulfur atom, a nitrogen protecting group when attached to a nitrogen atom, or two R A1 The groups are combined to form a substituted or unsubstituted heterocyclic or heteroaryl ring; and R A2 is 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, or substituted or unsubstituted heteroaryl group; R 2 is hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, –OH, –OR B1 、–OC(=O)R B1 、–NH2、–N(R B1 )2, or –NR B1 C(=O)R B1 , where R B1 Each instance of R is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, an oxygen protecting group when attached to an oxygen atom, a nitrogen protecting group when attached to a nitrogen atom, or two R B1 The groups combine to form a substituted or unsubstituted heterocyclic ring; R 3 is 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, or substituted or unsubstituted heteroaryl group; R 3’ is hydrogen, –C(=O)R C1 、–C(=O)OR C1 、–C(=O)SR C1 、–C(=O)N(R C1 )2、 –S(=O)2R C2 、–S(=O)2OR C1 、–P(=O)2R C2 、–P(=O)2OR C1 、–P(=O)(OR C1 )2. –P(=O)(R C2 )2, or –P(=O)(R C2 )(OR C1 ), where R C1 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, an oxygen protecting group when attached to an oxygen atom, a sulfur protecting group when attached to a sulfur atom, a nitrogen protecting group when attached to a nitrogen atom, or two R C1 groups are combined to form a substituted or unsubstituted heterocyclic ring; and R C2 is 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, or substituted or unsubstituted heteroaryl group; R 4 is selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl; R 6a and R 6b are each independently hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl, or R 6a and R 6b Combine to form an oxo (=O) group; R 11a and R 11b are each independently hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, -OH, -OR D1 、-OC(=O)R D1 、-NH2、-N(R D1 )2, or -NR D1 C(=O)R D1 , where R D1 Each instance of R is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, an oxygen protecting group when attached to an oxygen atom, a nitrogen protecting group when attached to a nitrogen atom, or two R D1 The groups are combined to form a substituted or unsubstituted heterocyclic ring; or R 11a and R 11b Combine to form an oxo (=O) group; in represents a single bond or a double bond, provided that if the double bond is present in ring B, then R 6a or R 6b One of them is absent, and provided that if a single bond is present in ring B, the hydrogen at C5 is in the alpha or beta position.

3. The compound of claim 1 or 2, wherein R 1 For hydrogen, halogen, -OR A1 、-SR A1 、-N(R A1 )2, -OC(=O)R A1 、-OC(=O)OR A1 、-OC(=O)SR A1 、-OC(=O)N(R A1 )2, -SC(=O)R A2 、-SC(=O)OR A1 、-SC(=O)SR A1 、-SC(=O)N(R A1 )2, -NHC(=O)R A1 、-NHC(=O)OR A1 、-NHC(=O)SR A1 、-NHC(=O)N(R A1 )2, -OS(=O)2R A2 、-OS(=O)2OR A1 、-SS(=O)2R A2 、-SS(=O)2OR A1 、-S(=O)R A2 、-SO2R A2 , or -S(=O)2OR A1 .

4. The compound of claim 1 or 2, wherein R 1 For hydrogen, halogen, -OR A1 、-N(R A1 )2, -SS(=O)2R A2 , a substituted or unsubstituted heterocyclic group, or a substituted or unsubstituted heteroaryl group.

5. The compound of claim 1 or 2, wherein R 2 is hydrogen, substituted or unsubstituted heterocyclic group, -OH, -OR B1 、-OC(=O)R B1 、-NH2、-N(R B1 )2, or -NR B1 C(=O)R B1 .

6. The compound of claim 1 or 2, wherein R 3 is a substituted or unsubstituted alkyl, a substituted or unsubstituted alkenyl, or a substituted or unsubstituted alkynyl.

7. The compound of claim 1 or 2, wherein R 3 A group of the formula: Where R 3a Each case of is hydrogen, halogen, or –OR F1 , where R F1 is a substituted or unsubstituted alkyl group; and R 3b and R 3c Each instance of is independently hydrogen, halogen, or substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclyl, or substituted or unsubstituted heterocyclyl.

8. The compound of claim 1 or 2, wherein R 3’ For hydrogen.

9. The compound of claim 1 or 2, wherein R 4 For hydrogen.

10. The compound of claim 1 or 2, wherein R 6a and R 6b are each independently hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl, or R 6a and R 6b Combine to form an oxo (=O) group.

Images