3,3-disubstituted 19-norpregnane compound and use of the same

Abstract

To provide a 3,3-disubstituted 19-nor-steroid compound.SOLUTION: Provided are 3,3-disubstituted 19-nor-steroid compounds according to formulas (I) and (III). The compounds of the present invention are contemplated to be useful for the prevention and treatment of various CNS-associated symptoms, e.g. treatment of sleep disorder, mood disorder, insomnia, anxiety, depression, traumatic brain injury (TBI), stress and epilepsy.SELECTED DRAWING: None

Description

[Technical field]

[0001] Related Applications This application claims priority under U.S.C. §119(e) to U.S. Provisional Patent Application No. 61 / 547,291, filed October 14, 2011, and U.S. Provisional Patent Application No. 61 / 698,204, filed September 7, 2012, each of which is incorporated herein by reference. [Background technology]

[0002] 2. Background of the Invention Brain excitability is defined as the level of alertness of an animal, which is a continuum ranging from coma to convulsions, and is controlled by various neurotransmitters. In general, neurotransmitters are involved in controlling the conductance of ions across the neuronal membrane. At rest, the neuronal membrane has an electrical potential (or membrane voltage) of approximately -70 mV, with the inside of the cell being negative with respect to the outside of the cell. The electrical potential (voltage) is determined by the flow of ions (K + , Na + , Cl - Neurotransmitters are stored in presynaptic vesicles and are released under the influence of a neuronal action potential. When released into the synaptic cleft, excitatory chemical transmitters such as acetylcholine cause membrane depolarization (a change in potential from -70 mV to -50 mV). This action is mediated by Na + It is mediated by postsynaptic nicotinic receptors stimulated by acetylcholine, which increases the membrane permeability to ions. The reduced membrane potential stimulates neuronal excitability in the form of postsynaptic action potentials.

[0003] In the case of the GABA receptor complex (GRC), its effect on brain excitability is mediated by the neurotransmitter GABA. Because up to 40% of neurons in the brain utilize GABA as a neurotransmitter, GABA exerts a profound influence on overall brain excitability. GABA controls the excitability of individual neurons by controlling the conductance of chloride ions across the neuronal membrane. By interacting with recognition sites on the GRC, GABA promotes the flow of chloride ions into the cell down the electrochemical gradient of the GRC. An intracellular increase in the level of this anion causes hyperpolarization of the transmembrane potential, making the neuron less sensitive to excitatory inputs (i.e., the neuron is less excitable). In other words, the higher the concentration of chloride ions in the neuron, the lower the brain's excitability (level of arousal).

[0004] GRC has been well documented to mediate anxiety, seizure activity and sedation. Thus, GABA and drugs that act like GABA or enhance the action of GABA (e.g., therapeutically useful barbiturates and benzodiazepines (BZ), e.g., Valium®) exert their therapeutically useful effects by interacting with specific regulatory sites on GRC. Accumulating evidence now suggests that GRC contains a separate site for neuroactive steroids in addition to benzodiazepine and barbiturate binding sites (Non-Patent Document 1).

[0005] Neuroactive steroids can occur endogenously. The most potent endogenous neuroactive steroids are 3α-hydroxy-5-reduced pregnan-20-one and 3α-21-dihydroxy-5-reduced pregnan-20-one (metabolites of the hormonal steroids progesterone and deoxycorticosterone, respectively). The ability of these steroid metabolites to change brain excitability was recognized in 1986 (Non-Patent Document 2; Non-Patent Document 3).

[0006] It has been demonstrated that the ovarian hormone progesterone and its metabolites have a profound effect on brain excitability (Non-Patent Document 4; Non-Patent Document 5; Non-Patent Document 6; Non-Patent Document 7). The levels of progesterone and its metabolites vary depending on the stage of the menstrual cycle. It has been well established that the levels of progesterone and its metabolites fall before the onset of menstruation. It has also been well established that certain physical symptoms recur every month before the onset of menstruation. These symptoms associated with premenstrual syndrome (PMS) include stress, anxiety, and migraines (Non-Patent Document 8). Subjects with PMS experience recurrent symptoms every month that appear before menstruation and disappear after menstruation.

[0007] In a similar manner, the reduction in progesterone also correlates temporally with an increase in seizure frequency in female epilepsy patients (i.e., menstrual epilepsy) (Non-Patent Document 9). A more direct correlation was observed with a reduction in progesterone metabolites (Non-Patent Document 10). Furthermore, in subjects with primary generalized petit mal seizure epilepsy, the temporal occurrence of seizures correlated with the occurrence of symptoms of premenstrual syndrome (Non-Patent Document 11). The steroid deoxycorticosterone was found to be effective in treating subjects with epileptic seizures correlated with the menstrual cycle (Non-Patent Document 12).

[0008] Also associated with low progesterone levels is postpartum depression (PND). Immediately after birth, progesterone levels fall dramatically, leading to the onset of PND. Symptoms of PND range from mild depression to psychosis requiring hospitalization. PND is also accompanied by severe anxiety and irritability. Depression associated with PND is not amenable to treatment with conventional antidepressants, and women experiencing PND show a high incidence of PMS (Non-Patent Document 8).

[0009] Taken together, these findings imply a crucial role for progesterone and deoxycorticosterone, and more specifically their metabolites, in the homeostatic control of brain excitability, which manifests as increased seizure activity or symptoms associated with catamenial epilepsy, PMS and PND. The correlation between low levels of progesterone and symptoms associated with PMS, PND and catamenial epilepsy (Non-Patent Document 11; Non-Patent Document 8) has prompted the use of progesterone in their treatment (Non-Patent Document 13 and Non-Patent Document 8). However, progesterone is not always effective in the treatment of the above-mentioned syndromes. For example, there is no dose-response relationship for progesterone in the treatment of PMS (Non-Patent Document 14; Non-Patent Document 15).

[0010] There is a need for new and improved neurostimulatory steroids that act as regulators of brain excitability and as agents for the prevention and treatment of CNS-related diseases. The compounds, compositions and methods described herein are directed to this end. [Prior art documents] [Non-patent literature]

[0011] [Non-Patent Document 1] Lan, N.C. et al., Neurochem. Res. 16:347-356 (1991) [Non-Patent Document 2] Majewska, MD et al., Science 232:1004-1007(1986) [Non-Patent Document 3] Harrison, N.L. et al., J Pharmacol. Exp. Ther. 241:346-353 (1987) [Non-Patent Document 4] Backstrom, T. et al., Acta Obstet. Gynecol. Scand. Suppl. 130:19-24 (1985) [Non-Patent Document 5] Pfaff, DW and McEwen, BS, Science 219:808-814(1983) [Non-Patent Document 6] Gyermek et al., J Med Chem. 11:117 (1968) [Non-Patent Document 7] Lambert, J. et al., Trends Pharmacol. Sci. 8:224-227 (1987) [Non-Patent Document 8] Dalton, K., Premenstrual Syndrome and Progesterone Therapy, 2nd edition, Chicago Yearbook, Chicago (1984) [Non-Patent Document 9] Laidlaw, J., Lancet, 1235-1237 (1956) [Non-Patent Document 10] Rosciszewska et al., J. Neurol. Neurosurg. Psych. 49:47-51 (1986) [Non-Patent Document 11] Backstrom, T. et al., J. Psychosom. Obstet. Gynaecol. 2:8-20 (1983) [Non-Patent Document 12] Aird, R.B. and Gordan, G., J. Amer. Med. Soc. 145:715-719 (1951) [Non-Patent Document 13] Mattson et al., “Medroxyprogesterone therapy of catamenial epilepsy,” Advances in Epileptology: XVth Epilepsy International Symposium, Raven Press, New York (1984), pp. 279-282. [Non-Patent Document 14] Maddocks et al., Obstet. Gynecol. 154:573-581 (1986) [Non-Patent Document 15] Dennerstein et al., Brit.Med J 290:16-17 (1986) Summary of the Invention [Means for solving the problem]

[0012] Summary of the Invention The present invention is based in part on the desire to provide novel 19-nor compounds with superior potency, pharmacokinetic (PK) properties, oral bioavailability, formulatability, stability, safety, clearance and / or metabolism. One important feature of the compounds as described herein is the disubstitution at the C3 position. The inventors anticipate that the disubstitution at C-3 will eliminate the possibility for oxidation to a ketone, prevent further metabolism, and reduce the possibility for a second elimination pathway such as glucuronidation. The inventors further anticipate that the overall effect of the C3 disubstitution should be to improve overall PK parameters and reduce potential toxicity and side effects, which may allow for oral and / or chronic administration in certain embodiments. Another important feature of the compounds as described herein is the presence of a hydrogen rather than a methyl group at the C10 position ("19-nor"). The inventors anticipate that the 19-nor compounds will have improved physical properties, such as improved solubility, compared to their C10-methyl counterparts. The inventors futher predict that, for example, solubility will be enhanced when the AB ring system is in the cis configuration.

[0013] Thus, in one embodiment, a compound according to formula (I) or (III):

[0014] [ka] or a pharma- ceutically acceptable salt, solvate, hydrate, prodrug, stereoisomer, tautomer, isotopic variant, or N-oxide thereof, or combinations thereof; 2 , R 4 , R 6a , R 6b , R 11a , R11b is as defined 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) 2 R A2 , -OS(=O) 2 OR A1 , -SS(=O) 2 R A2 , -SS(=O) 2 OR A1 , -S(=O)R A2 , -SO 2 R A2 or -S(=O) 2 OR A1 where R A1each occurrence is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, 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 groups linked together form a substituted or unsubstituted heterocyclic or heteroaryl ring; R A2 is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 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; R 3’ is hydrogen, -C(=O)R C1 , -C(=O)OR C1 , -C(=O)SR C1 , -C(=O)N(R C1 ) 2 , -S(=O) 2 R C2 , -S(=O) 2 OR C1 , -P(=O) 2 R C2 , -P(=O) 2 OR C1 , -P(=O)(OR C1 ) 2 , -P(=O)(R C2 ) 2 or -P(=O)(R C2 )(OR C1 ), where R C1is 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 linked together form a substituted or unsubstituted heterocyclic ring; R C2 is a 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 is unsubstituted heteroaryl; During the ceremony,

[0015] [ka] independently represent a single bond or a double bond, and when a double bond is present in ring B, R 6a or R 6b When one of the groups is absent and a single bond is present in ring B, the hydrogen at C5 is in the alpha or beta position.

[0016] In another aspect, a pharmaceutical composition is provided that comprises a compound of formula (I) or (III) and a pharma- ceutically acceptable carrier.In certain embodiments, the compound of the present invention is provided in an effective amount in the pharmaceutical composition.In certain embodiments, the compound of the present invention is provided in a therapeutically effective amount.In certain embodiments, the compound of the present invention is provided in a prophylactically effective amount.

[0017] Compounds as described herein may, in certain embodiments, be used to treat, for example, GABA A These compounds act as GABA modulators, which affect the GABA receptor in a positive or negative manner. AThey are predicted to have central nervous system (CNS) activity as regulators of CNS excitability as mediated by their ability to modulate receptors.

[0018] Thus, in another aspect, a method for treating a CNS-related condition 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 certain embodiments, the CNS-related condition is insomnia, depression, mood disorder, convulsive disorder, memory disorder, attention disorder, anxiety disorder, bipolar disorder, schizophrenia, depression, bipolar disorder, schizoaffective disorder, mood disorder, anxiety disorder, personality disorder, psychosis, compulsive disorders, post-traumatic stress disorder, autism spectrum disorder, dysthymia, social anxiety disorder, obsessive compulsive disorder, pain, sleep disorder, memory disorder, dementia, Alzheimer's disease, seizure disorder, traumatic brain injury, stroke, addiction disorder, autism, Huntington's disease, Parkinson's disease, Rett syndrome, withdrawal syndrome, or tinnitus.

[0019] Other objects and advantages will become apparent to those skilled in the art from a consideration of the following detailed description, examples and claims. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0020] definition chemical definition Definitions of certain functional groups and chemical terms are detailed below. Chemical elements are identified according to the Periodic Table of the Elements (CAS version, Handbook of Chemistry and Physics, 75th Ed., inside cover), and certain functional groups are generally defined as set forth therein. Additionally, general rules of organic chemistry, as well as certain functional moieties and reactivities, are described in detail in Thomas Sorrell, Organic Chemistry, University Science Books, Sausalito, 1999; Smith and March, March's Advanced Organic Chemistry, 5th Edition, John Wiley & Sons, Inc., New York, 2001; Larock, Comprehensive Organic Transformations, VCH Publishers, Inc., New York, 1989; and Carruthers, Som eModern Methods of Organic Synthesis, 3rd Edition, Cambridge University Press, Cambridge, 1987.

[0021] The compounds described herein may contain one or more asymmetric centers and therefore may exist as various isomers, e.g., enantiomers and / or diastereomers. For example, the compounds described herein may be in the form of 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 isolated 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, for example, Jacques et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen et al., Tetrahedron 33:2725 (1977); Eliel, Stereochemistry of Carbon and Wilen, Tables of Resolving Agents and Optical Resolutions p. 268 (EL Eliel, 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 and alternatively as mixtures of various isomers.

[0022] As used herein, a pure enantiomer is substantially free of the other enantiomer or stereoisomer of the compound (i.e., in enantiomeric excess). In other words, the "S" form of the compound is substantially free of the "R" form of the compound and is therefore in enantiomeric excess of the "R" form. The term "enantiomerically pure" or "pure enantiomer" refers to a compound that contains more than 75%, more than 80%, more than 85%, more than 90%, more than 91%, more than 92%, more than 93%, more than 94%, more than 95%, more than 96%, more than 97%, more than 98%, more than 98.5%, more than 99%, more than 99.2%, more than 99.5%, more than 99.6%, more than 99.7%, more than 99.8%, or more than 99.9% by weight of its enantiomer. In certain embodiments, the weights are based on the total weight of all enantiomers or stereoisomers of the compound.

[0023] As used herein, and unless otherwise indicated, the term "enantiomerically pure R-compounds" refers to at least about 80% by weight of R-compounds and at most about 20% by weight of S-compounds, at least about 90% by weight of R-compounds and at most about 10% by weight of S-compounds, at least about 95% by weight of R-compounds and at most about 5% by weight of S-compounds, at least about 99% by weight of R-compounds and at most about 1% by weight of S-compounds, at least about 99.9% by weight of R-compounds, or at most about 0.1% by weight of S-compounds. In certain embodiments, the weights are based on the total weight of the compounds.

[0024] As used herein, and unless otherwise indicated, the term "enantiomerically pure S-compound" or "S-compound" refers to at least about 80% by weight S-compound and at most about 20% by weight R-compound, at least about 90% by weight S-compound and at most about 10% by weight R-compound, at least about 95% by weight S-compound and at most about 5% by weight R-compound, at least about 99% by weight S-compound and at most about 1% by weight R-compound, or at least about 99.9% by weight S-compound and at most about 0.1% by weight R-compound. In certain embodiments, the weight is based on the total weight of the compound.

[0025] In the compositions provided herein, the enantiomerically pure compound may be present with other active or inactive ingredients. For example, a pharmaceutical composition comprising an enantiomerically pure R-compound may comprise, for example, about 90% of excipients and about 10% of the enantiomerically pure R-compound. In certain embodiments, the enantiomerically pure R-compound in such a composition may comprise, for example, about 95% by weight of the R-compound and about 5% by weight of the S-compound, based on the total weight of the compound. For example, a pharmaceutical composition comprising an enantiomerically pure S-compound may comprise, for example, about 90% of excipients and about 10% of the enantiomerically pure S-compound. In certain embodiments, the enantiomerically pure S-compound in such a composition may comprise, for example, about 95% by weight of the S-compound and about 5% by weight of the R-compound, based on the total weight of the compound. In certain embodiments, the active ingredient may be formulated with little or no excipients or carriers.

[0026] The articles "a" and "an" may be used herein to refer to one or to more than one (i.e., to at least one) of the grammatical object of the article. By way of example, "an analogue" means one analogue or more than one analogue.

[0027] The following terms are intended to have the meanings indicated therewith below and are helpful in understanding the description and intended scope of the present invention.

[0028] When a range of values ​​is listed, it is intended to encompass each value and subrange within that range. For example, "C 1-6 Alkyl" is C 1 , C 2 , C 3 , C 4 , C 5 , C 6 , C 1-6 , C 1-5 , C 1-4 , C 1-3 , C 1-2 , C 2-6 , C 2-5 , C 2-4 , C 2-3 , C 3-6 , C 3-5 , C 3-4 , C 4-6 , C 4-5 and C 5-6 Alkyl is intended to be included.

[0029] "Alkyl" means the radical of a linear or branched saturated hydrocarbon group having 1 to 20 carbon atoms ("C 1-20 In some embodiments, an alkyl group has 1 to 12 carbon atoms ("C 1-12 In some embodiments, an alkyl group has 1 to 10 carbon atoms ("C 1-10 In some embodiments, an alkyl group has 1 to 9 carbon atoms ("C 1-9 In some embodiments, an alkyl group has 1 to 8 carbon atoms ("C 1-8 In some embodiments, an alkyl group has 1 to 7 carbon atoms ("C 1-7 In some embodiments, an alkyl group has 1 to 6 carbon atoms (also referred to herein as "lower alkyl"). 1-6In some embodiments, an alkyl group has 1 to 5 carbon atoms ("C 1-5 In some embodiments, an alkyl group has 1 to 4 carbon atoms ("C 1-4 In some embodiments, an alkyl group has 1 to 3 carbon atoms ("C 1-3 In some embodiments, an alkyl group has 1 to 2 carbon atoms ("C 1-2 In some embodiments, the alkyl group has one carbon atom ("C 1 In some embodiments, an alkyl group has 2 to 6 carbon atoms ("C 2-6 "Alkyl"). C 1-6 Examples of alkyl groups include methyl (C 1 ), ethyl (C 2 ), n-propyl (C 3 ), isopropyl (C 3 ), n-Butyl (C 4 ), tert-Butyl (C 4 ), sec-Butyl (C 4 ), iso-butyl (C 4 ), n-pentyl (C 5 ), 3-pentanyl (C 5 ), Amyl (C 5 ), neopentyl (C 5 ), 3-methyl-2-butanyl (C 5 ), tertiary amyl (C 5 ) and n-hexyl (C 6 Further examples of alkyl groups include n-heptyl (C 7 ), n-octyl (C 8 Unless otherwise specified, each occurrence of an alkyl group is independently optionally substituted. In certain embodiments, an alkyl group is an unsubstituted C alkyl group, i.e., it is not substituted ("unsubstituted alkyl") or it is substituted with one or more substituents; for example, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent ("substituted alkyl"). 1-10 Alkyl (e.g., -CH 3In certain embodiments, the alkyl group is a substituted C 1-10 "Alkylene" refers to a substituted or unsubstituted alkyl group, as defined above, where two hydrogens have been removed to provide a divalent radical. Exemplary divalent alkylene groups include methylene (-CH 2 -), ethylene (-CH 2 CH 2 -), propylene isomers (e.g., -CH 2 CH 2 CH 2 - and -CH(CH 3 )CH 2 -), but are not limited to these.

[0030] "Alkenyl" means a radical of a straight-chain or branched hydrocarbon group containing 2 to 20 carbon atoms, one or more carbon-carbon double bonds but no triple bonds ("C 2-20 In some embodiments, an alkenyl group has 2 to 10 carbon atoms ("C 2-10 In some embodiments, the alkenyl group has 2 to 9 carbon atoms ("C 2-9 In some embodiments, the alkenyl group has 2 to 8 carbon atoms ("C 2-8 In some embodiments, the alkenyl group has 2 to 7 carbon atoms ("C 2-7 In some embodiments, the alkenyl group has 2 to 6 carbon atoms ("C 2-6 In some embodiments, the alkenyl group has 2 to 5 carbon atoms ("C 2-5 In some embodiments, the alkenyl group has 2 to 4 carbon atoms ("C 2-4 In some embodiments, the alkenyl group has 2 to 3 carbon atoms ("C 2-3 In some embodiments, the alkenyl group has two carbon atoms ("C 2The one or more carbon-carbon double bonds can be internal (e.g., 2-butenyl) or terminal (e.g., 1-butenyl). 2-4 Examples of alkenyl groups include ethenyl (C 2 ), 1-propenyl (C 3 ), 2-propenyl (C 3 ), 1-butenyl (C 4 ), 2-butenyl (C 4 ), butadienyl (C 4 ) etc. 2-6 Examples of alkenyl groups include the above-mentioned C 2-4 Alkenyl groups, as well as pentenyl (C 5 ), pentadienyl (C 5 ), hexenyl (C 6 Further examples of alkenyl include heptenyl (C 7 ), octenyl (C 8 ), octatrienyl (C 8 Unless otherwise specified, each occurrence of an alkenyl group is independently optionally substituted, i.e., unsubstituted ("unsubstituted alkenyl") or substituted with one or more substituents, e.g., 1-5 substituents, 1-3 substituents, or 1 substituent ("substituted alkenyl"). In certain embodiments, an alkenyl group is an unsubstituted C 2-10 In certain embodiments, the alkenyl group is a substituted C 2-10 It is alkenyl.

[0031] "Alkenylene" refers to a substituted or unsubstituted alkenyl group, as defined above, where two hydrogens have been removed to provide a divalent radical. Exemplary divalent alkenylene groups include ethenylene (-CH=CH-), propenylene (e.g., -CH=CHCH 2 - and -C(CH 3 )=CH- and -CH=C(CH 3 )-) and the like, but are not limited to these.

[0032] "Alkynyl" means a radical of a linear or branched hydrocarbon group 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, an alkynyl group has 2 to 10 carbon atoms ("C 2-10 In some embodiments, the alkynyl group has 2 to 9 carbon atoms ("C 2-9 In some embodiments, the alkynyl group has 2 to 8 carbon atoms ("C 2-8 In some embodiments, the alkynyl group has 2 to 7 carbon atoms. ("C 2-7 In some embodiments, the alkynyl group has 2 to 6 carbon atoms ("C 2-6 In some embodiments, the alkynyl group has 2 to 5 carbon atoms ("C 2-5 In some embodiments, the alkynyl group has 2 to 4 carbon atoms ("C 2-4 In some embodiments, the alkynyl group has 2 to 3 carbon atoms ("C 2-3 In some embodiments, the alkynyl group has two carbon atoms ("C 2 The one or more carbon-carbon triple bonds can be internal (e.g., 2-butynyl) or terminal (e.g., 1-butynyl). 2-4 Examples of alkynyl groups include ethynyl (C 2 ), 1-propynyl (C 3 ), 2-propynyl (C 3 ), 1-butynyl (C 4 ), 2-butynyl (C 4 ) but are not limited to these. 2-6 Examples of alkenyl groups include the above-mentioned C 2-4 Alkynyl groups, as well as pentynyl (C 5 ), Hexynyl (C 6 Further examples of alkynyl include heptynyl (C7 ), Octynyl (C 8 Unless otherwise specified, each occurrence of an alkynyl group is independently optionally substituted, i.e., unsubstituted ("unsubstituted alkynyl") or substituted with one or more substituents; for example, 1-5 substituents, 1-3 substituents, or 1 substituent ("substituted alkynyl"). In certain embodiments, an alkynyl group is an unsubstituted C 2-10 In certain embodiments, the alkynyl group is a substituted C 2-10 It is alkynyl.

[0033] "Alkynylene" refers to a substituted or unsubstituted alkynyl group, as defined above, where two hydrogens have been removed to provide a divalent radical. Exemplary divalent alkynylene groups include, but are not limited to, ethynylene, propynylene, and the like.

[0034] "Aryl" refers to a radical of a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10 or 14 pi electrons shared in a cyclic arrangement) having 6 to 14 ring carbon atoms and 0 heteroatoms provided in the aromatic ring system ("C 6-14 In some embodiments, an aryl group has six ring carbon atoms ("C 6 aryl"; e.g., phenyl). In some embodiments, an aryl group has 10 ring carbon atoms ("C 10 Aryl"; for example, naphthyl, such as 1-naphthyl and 2-naphthyl). In some embodiments, an aryl group has 14 ring carbon atoms ("C 14"Aryl"; e.g., anthracyl). "Aryl" also includes ring systems in which an aryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups, where the attachment 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. Exemplary aryl groups include, but are not limited to, groups derived from aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, coronene, fluoranthene, fluorene, hexacene, hexaphene, hexalene, as-indacene, s-indacene, indane, indene, naphthalene, octacene, octaphene, octalene, ovalene, penta-2,4-diene, pentacene, pentalene, pentaphene, perylene, phenalene, phenanthrene, picene, pleiadene, pyrene, pyranthrene, rubicene, triphenylene and trinaphthalene. In particular, aryl groups include phenyl, naphthyl, indenyl and tetrahydronaphthyl. Unless otherwise specified, each occurrence of the aryl group is independently optionally substituted, i.e., unsubstituted ("unsubstituted aryl") or substituted with one or more substituents ("substituted aryl"). In certain embodiments, the aryl group is an unsubstituted C 6-14 In certain embodiments, the aryl group is a substituted C 6-14 In certain embodiments, the aryl group is halo, C 1 -C 8 Alkyl, C 1 -C 8 Haloalkyl, cyano, hydroxy, C 1 -C 8 It is substituted with one or more groups selected from alkoxy and amino.

[0035] Representative examples of substituted aryl include:

[0036] [ka] In these formulas, R 56 and R57 can be hydrogen, and R 56 and R 57 At least one of each independently represents C 1 -C 8 Alkyl, C 1 -C 8 Haloalkyl, 4-10 membered heterocyclyl, alkanoyl, C 1 -C 8 Alkoxy, heteroaryloxy, alkylamino, arylamino, heteroarylamino, -NR 58 COR 59 , -NR 58 SOR 59 , -NR 58 SO 2 R 59 , -COO alkyl, -COO aryl, -CONR 58 R 59 , -CONR 58 OR 59 , -NR 58 R 59 , -SO 2 NR 58 R 59 , -S-alkyl, -SO alkyl, -SO 2 Alkyl, -S aryl, -SO aryl, -SO 2 aryl; or R 56 and R 57 may be linked to form a cyclic ring (saturated or unsaturated) of 5 to 8 atoms, optionally including one or more heteroatoms selected from the group N, O, or S. 60 and R 61 are independently hydrogen, C 1 -C 8 Alkyl, C 1 -C 4 Haloalkyl, C 3 -C 10 Cycloalkyl, 4-10 membered heterocyclyl, C 6 -C 10 Aryl, Substituted C 6 -C 10 It is aryl, 5- to 10-membered heteroaryl or substituted 5- to 10-membered heteroaryl.

[0037] "Fused aryl" refers to an aryl having two ring carbons in common with a second aryl ring or an aliphatic ring.

[0038] "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.

[0039] "Heteroaryl" refers to a radical 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) in which ring carbon atoms and 1-4 ring heteroatoms are provided in the aromatic ring system, where 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, as permitted by valence. Heteroaryl bicyclic ring systems may contain one or more heteroatoms in one or both rings. "Heteroaryl" includes ring systems in which a heteroaryl ring as defined above is fused with one or more carbocyclyl or heterocyclyl groups, where the point of attachment is on the heteroaryl ring, and in such cases the number of ring members continues to refer to the number of ring members in the heteroaryl ring system. "Heteroaryl" also includes ring systems in which a heteroaryl ring as defined above is fused with one or more aryl groups, where the point of attachment can be on either the aryl ring or the 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. In bicyclic heteroaryl groups in which one ring does not contain a heteroatom (e.g., indolyl, quinolinyl, carbazolyl, etc.), the point of attachment can be on either ring, i.e., on the ring with a heteroatom (e.g., 2-indolyl) or on the ring without a heteroatom (e.g., 5-indolyl).

[0040] In some embodiments, the heteroaryl group is a 5-10 membered aromatic ring system provided with ring carbon atoms and 1-4 ring heteroatoms, where each heteroatom is are independently selected from nitrogen, oxygen, and sulfur ("5-10 membered heteroaryl"). In some embodiments, the heteroaryl group is a 5-8 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-8 membered heteroaryl"). In some embodiments, the heteroaryl group is a 5-6 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, where 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 one ring heteroatom selected from nitrogen, oxygen, and sulfur. Unless otherwise specified, each occurrence of a heteroaryl group is independently optionally substituted, i.e., unsubstituted ("unsubstituted heteroaryl") or substituted ("substituted heteroaryl") with one or more substituents. In certain embodiments, a heteroaryl group is an unsubstituted 5-14 membered heteroaryl. In certain embodiments, a heteroaryl group is a substituted 5-14 membered heteroaryl.

[0041] Exemplary 5-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyrrolyl, furanyl, and thiophenyl. Exemplary 5-membered heteroaryl groups containing two heteroatoms include, but are not limited to, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered heteroaryl groups containing three heteroatoms include, but are not limited to, triazolyl, oxadiazolyl, and thiadiazolyl.

[0042] Exemplary 5-membered heteroaryl groups containing 4 heteroatoms include, but are not limited to, tetrazolyl. Exemplary 6-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyridinyl. Exemplary 6-membered heteroaryl groups containing two heteroatoms include, but are not limited to, pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6-membered heteroaryl groups containing three or four heteroatoms include, but are not limited to, triazinyl and tetrazinyl, respectively. Exemplary 7-membered heteroaryl groups containing one heteroatom include, but are not limited to, azepinyl, oxepinyl, and thiepinyl. Exemplary 5,6-bicyclic heteroaryl groups include, but are not limited to, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzthiazolyl, benzisothiazolyl, benzthiadiazolyl, indolizinyl, and purinyl. Exemplary 6,6-bicyclic heteroaryl groups include, but are not limited to, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl.

[0043] Representative examples of heteroaryls include the following:

[0044] [ka] where each Y is carbonyl, N, NR 65 , O and S; R 65 are independently hydrogen, C 1 -C 8 Alkyl, C 3 -C 10 Cycloalkyl, 4-10 membered heterocyclyl, C 6 -C 10 aryl and 5-10 membered heteroaryl.

[0045] Representative examples of aryls having heteroatom-containing substitution include the following:

[0046] [ka] where each W is C(R 66 ) 2 , N.R. 66 , O and S; each Y is selected from carbonyl, NR 66 , O and S; R 66 are independently hydrogen, C 1 -C 8 Alkyl, C 3 -C 10 Cycloalkyl, 4-10 membered heterocyclyl, C 6 -C 10 aryl and 5-10 membered heteroaryl.

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

[0048] "Carbocyclyl" or "carbocyclic" means a ring system having 3 to 10 ring carbon atoms ("C 3-10 In some embodiments, a carbocyclyl group has 3 to 8 ring carbon atoms ("C 3-8 In some embodiments, a carbocyclyl group has 3 to 7 ring carbon atoms ("C 3-7 In some embodiments, a carbocyclyl group has 3 to 6 ring carbon atoms ("C 3-6 In some embodiments, a carbocyclyl group has 5 to 10 ring carbon atoms ("C 5-10 Carbocyclyl). Exemplary C 3-6 The carbocyclyl group is cyclopropyl (C3 ), cyclopropenyl (C 3 ), cyclobutyl (C 4 ), cyclobutenyl (C 4 ), cyclopentyl (C 5 ), cyclopentenyl (C 5 ), cyclohexyl (C 6 ), cyclohexenyl (C 6 ), cyclohexadienyl (C 6 ) and the like. Exemplary C 3-8 The carbocyclyl group is the above-mentioned C 3-6 Carbocyclyl groups, as well as cycloheptyl (C 7 ), cycloheptenyl (C 7 ), cycloheptadienyl (C 7 ), cycloheptatrienyl (C 7 ), cyclooctyl (C 8 ), cyclooctenyl (C 8 ), bicyclo[2.2.1]heptanyl (C 7 ), bicyclo[2.2.2]octanyl (C 8 ) and the like. Exemplary C 3-10 The carbocyclyl group is the above-mentioned C 3-8 Carbosi The acrylic group and cyclononyl (C 9 ), cyclononenyl (C 9 ), cyclodecyl (C 10 ), cyclodecenyl (C 10 ), octahydro-1H-indenyl (C 9 ), decahydronaphthalenyl (C 10 ), spiro[4.5]decanyl (C 10), and the like. As the foregoing examples are illustrated, in certain embodiments, a carbocyclyl group is monocyclic ("monocyclic carbocyclyl") or includes fused, bridged, or spiro ring systems (e.g., bicyclic systems ("bicyclic carbocyclyl")), and may be saturated or partially unsaturated. "Carbocyclyl" also includes ring systems in which a carbocyclyl ring, as defined above, is fused with one or more aryl or heteroaryl groups, where the point of attachment is on the carbocyclyl ring, and in such cases the number of carbons continues to refer to the number of carbons in the carbocyclyl ring system. Unless otherwise specified, each occurrence of a carbocyclyl group is independently optionally substituted, i.e., unsubstituted ("unsubstituted carbocyclyl") or substituted with one or more substituents ("substituted carbocyclyl"). In certain embodiments, a carbocyclyl group is an unsubstituted C 3-10 In certain embodiments, the carbocyclyl group is a substituted C 3-10 It is a carbocyclyl.

[0049] In some embodiments, "carbocyclyl" refers to a monocyclic saturated carbocyclyl group having 3 to 10 ring carbon atoms ("C 3-10 In some embodiments, a cycloalkyl group has 3 to 8 ring carbon atoms ("C 3-8 In some embodiments, a cycloalkyl group has 3 to 6 ring carbon atoms ("C 3-6 In some embodiments, a cycloalkyl group has 5 to 6 ring carbon atoms ("C 5-6 In some embodiments, a cycloalkyl group has 5 to 10 ring carbon atoms ("C 5-10 "Cycloalkyl"). C 5-6 Examples of cycloalkyl groups include cyclopentyl (C 5 ) and cyclohexyl (C 5 ) are listed. C 3-6 Examples of cycloalkyl groups include the above-mentioned C 5-6Cycloalkyl groups, as well as cyclopropyl (C 3 ) and cyclobutyl (C 4 ) are listed. C 3-8 Examples of cycloalkyl groups include the above-mentioned C 3-6 Cycloalkyl groups, as well as cycloheptyl (C 7 ) and cyclooctyl (C 8 Unless otherwise specified, each occurrence of a cycloalkyl group is independently unsubstituted ("unsubstituted cycloalkyl") or substituted ("substituted cycloalkyl") with one or more substituents. In certain embodiments, a cycloalkyl group is an unsubstituted C 3-10 In certain embodiments, the cycloalkyl group is a substituted C 3-10 It is cycloalkyl.

[0050] "Heterocyclyl" or "heterocyclic" refers to the radical of a 3- to 10-membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, where each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon ("3- to 10-membered heterocyclyl"). In heterocyclyl groups containing one or more nitrogen atoms, the point of attachment may be at a carbon or nitrogen atom, when valence permits. Heterocyclyl groups may be monocyclic ring systems ("monocyclic heterocyclyl") or fused, bridged, or spiro ring systems, such as bicyclic systems ("bicyclic heterocyclyl"), and may be saturated or partially unsaturated. Heterocyclyl bicyclic ring systems may contain one or more heteroatoms in one or both rings. "Heterocyclyl" also includes ring systems in which a heterocyclyl ring as defined above is fused with one or more carbocyclyl groups, where the point of attachment is on the carbocyclyl or heterocyclyl ring, or on a ring system in which a heterocyclyl ring as defined above is fused with one or more aryl or heteroaryl groups, where the point of attachment is on the heterocyclyl ring, in such cases the number of ring members continues to refer to the number of ring members in the heterocyclyl ring system. Unless otherwise specified, each occurrence of heterocyclyl is independently optionally substituted, i.e., unsubstituted ("unsubstituted heterocyclyl") or substituted with one or more substituents ("substituted heterocyclyl"). Certain In embodiments, the heterocyclyl group is unsubstituted 3-10 membered heterocyclyl.In certain embodiments, the heterocyclyl group is substituted 3-10 membered heterocyclyl.

[0051] In some embodiments, a heterocyclyl group is a 5-10 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, where each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon ("5-10 membered heterocyclyl"). In some embodiments, a heterocyclyl group is a 5-8 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-8 membered heterocyclyl"). In some embodiments, a heterocyclyl group is a 5-6 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-6 membered heterocyclyl"). In some embodiments, a 5-6 membered heterocyclyl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5- to 6-membered heterocyclyl has 1 to 2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5- to 6-membered heterocyclyl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur.

[0052] Exemplary 3-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azirdinyl, oxiranyl, thiorenyl, etc. Exemplary 4-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azetidinyl, oxetanyl, and thietanyl.

[0053] Exemplary 5-membered heterocyclyl groups containing one heteroatom include, but are not limited to, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2,5-dione. Exemplary 5-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, dioxolanyl, oxasulfuranyl, disulfuranyl, and oxazolidin-2-one. Exemplary 5-membered heterocyclyl groups containing three heteroatoms include, but are not limited to, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclyl groups containing one heteroatom include, but are not limited to, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary 6-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, piperazinyl, morpholinyl, dithianyl, and dioxanyl. Exemplary 6-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, triazinanyl. Exemplary 7-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azepanyl, oxepanyl, and thiepanyl. Exemplary 8-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azocanyl, oxecanyl, and thiocanyl. 6 Exemplary 5-membered heterocyclyl groups (also referred to herein as 5,6-bicyclic heterocyclic rings) fused to an aryl ring include, but are not limited to, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, benzoxazolinonyl, etc. Exemplary 6-membered heterocyclyl groups (also referred to herein as 6,6-bicyclic heterocyclic rings) fused to an aryl ring include, but are not limited to, tetrahydroquinolinyl, tetrahydroisoquinolinyl, etc.

[0054] Particular examples of heterocyclyl groups are shown in the following illustrative examples:

[0055] [ka] where each W is CR 67 , C(R 67 ) 2 , N.R. 67 , O and S; each Y is selected from NR 67 , O and S; R 67 are independently hydrogen, C 1 -C 8 Alkyl, C 3 -C 10 Cycloalkyl, 4-10 membered heterocyclyl, C 6 -C 10 These heterocyclyl rings are acyl, acylamino, acyloxy, alkoxy, alkoxycarbonyl, alkoxycarbonylamino, amino, substituted amino, aminocarbonyl (carbamoyl or amido), aminocarbonylamino, aminosulfonyl, sulfonylamino, aryl, aryloxy, azido, carboxyl, cyano, cycloalkyl, halogen, hydroxy, keto, nitro, thiol, -S-alkyl, -S-aryl, -S(O)-alkyl, -S(O)-aryl, -S(O) 2 -Alkyl and -S(O) 2 -aryl. The substituents include carbonyl or thiocarbonyl, which provide, for example, lactam and urea derivatives.

[0056] "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 are replaced by a nitrogen, oxygen, or sulfur heteroatom. Hetero can apply to any of the hydrocarbyl groups described above having 1 to 5, especially 1 to 3, heteroatoms (e.g., alkyl, e.g., heteroalkyl, cycloalkyl, e.g., heterocyclyl, aryl, e.g., heteroaryl, cycloalkenyl, e.g., cycloheteroalkenyl, etc.).

[0057] "Acyl" means -C(O)R 20 This refers to the radical, 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. "Alkanoyl" refers to any group represented by R 20 is an acyl group, which is a group other than hydrogen. Representative acyl groups are formyl (-CHO), acetyl (-C(=O)CH 3 ), cyclohexylcarbonyl, cyclohexylmethylcarbonyl, benzoyl (-C(=O)Ph), benzylcarbonyl (-C(=O)CH 2 Ph), --C(O)-C 1 -C 8 Alkyl, -C(O)-(CH 2 ) t (C 6 -C 10 aryl), -C(O)-(CH 2 ) t (5-10 membered heteroaryl), -C(O)-(CH 2 ) t (C 3 -C 10 Cycloalkyl) and -C(O)-(CH 2 ) t (4-10 membered heterocyclyl) (t is an integer from 0 to 4). 21 is a halo or hydroxy substituted C 1 -C 8 Alkyl; or C 3 -C 10 Cycloalkyl, 4-10 membered heterocyclyl, C 6 -C 10 Aryl, arylalkyl, 5-10 membered heteroaryl or heteroarylalkyl, each of which is an unsubstituted C 1 -C 4 Alkyl, halo, unsubstituted C 1 -C 4 Alkoxy, unsubstituted C 1 -C4 Haloalkyl, unsubstituted C 1 -C 4 Hydroxyalkyl or unsubstituted C 1 -C 4 substituted with haloalkoxy or hydroxy.

[0058] "Acylamino" means -NR 22 C(O)R 23 This refers to the radical, where R 22 and each occurrence of R23 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" groups include, but are not limited to, formylamino, acetylamino, cyclohexylcarbonylamino, cyclohexylmethyl-carbonylamino, benzoylamino, and benzylcarbonylamino. Certain exemplary "acylamino" groups are -NR 24 C(O)-C 1 -C 8 Alkyl, -NR 24 C(O)-(CH 2 ) t (C 6 -C 10 Aryl), -NR 24 C(O)-(CH 2 ) t (5-10 membered heteroaryl), -NR 24 C(O)-(CH 2 ) t (C 3 -C 10 Cycloalkyl) and -NR 24 C(O)-(CH 2 ) t (4-10 membered heterocyclyl), where t is an integer from 0 to 4, and each R 24 are independently H or C 1 -C 8In certain embodiments, R 25 is H, halo or hydroxy substituted C 1 -C 8 Alkyl;C 3 -C 10 Cycloalkyl, 4-10 membered heterocyclyl, C 6 -C 10 aryl, arylalkyl, 5-10 membered heteroaryl or heteroarylalkyl, each of which is an unsubstituted C 1 -C 4 Alkyl, halo, unsubstituted C 1 -C 4 Alkoxy, unsubstituted C 1 -C 4 Haloalkyl, unsubstituted C 1 -C 4 Hydroxyalkyl or unsubstituted C 1 -C 4 substituted with haloalkoxy or hydroxy; R 26 is H, halo or hydroxy substituted C 1 -C 8 Alkyl;C 3 -C 10 Cycloalkyl, 4-10 membered heterocyclyl, C 6 -C 10 aryl, arylalkyl, 5-10 membered heteroaryl or heteroarylalkyl, each of which is an unsubstituted C 1 -C 4 Alkyl, halo, unsubstituted C 1 -C 4 Alkoxy, unsubstituted C 1 -C 4 Haloalkyl, unsubstituted C 1 -C 4 Hydroxyalkyl or unsubstituted C 1 -C 4 substituted with haloalkoxy or hydroxyl; except that R 25 and R 26 At least one of is other than H.

[0059] "Acyloxy" means -OC(O)R 27 This refers to the radical, where R27 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 certain embodiments, R 28 is a halo or hydroxy substituted C 1 -C 8 Alkyl;C 3 -C 10 Cycloalkyl, 4-10 membered heterocyclyl, C 6 -C 10 aryl, arylalkyl, 5-10 membered heteroaryl or heteroarylalkyl, each of which is an unsubstituted C 1 -C 4 Alkyl, halo, unsubstituted C 1 -C 4 Alkoxy, unsubstituted C 1 -C 4 Haloalkyl, unsubstituted C 1 -C 4 Hydroxyalkyl or unsubstituted C 1 -C 4 Substituted with haloalkoxy or hydroxy.

[0060] "Alkoxy" means -OR 29 The R 29is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl. Particular alkoxy groups are methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy and 1,2-dimethylbutoxy. Particular alkoxy groups are lower alkoxy, i.e. having 1 to 6 carbon atoms. Further particular alkoxy groups have 1 to 4 carbon atoms.

[0061] In certain embodiments, R 29 is amino, substituted amino, C 6 -C 10 Aryl, aryloxy, carboxyl, cyano, C 3 -C 10 Cycloalkyl, 4-10 membered heterocyclyl, halogen, 5-10 membered heteroaryl, hydroxyl, nitro, thioalkoxy, thioaryloxy, thiol, alkyl-S(O)-, aryl-S(O)-, alkyl-S(O) 2 - and aryl-S(O) 2 -, for example, 1 to 5 substituents, particularly 1 to 3 substituents, and particularly 1 substituent selected from the group consisting of. Exemplary "substituted alkoxy" groups include -O-(CH 2 ) t (C 6 -C 10 Aryl), -O-(CH 2 ) t (5-10 membered heteroaryl), -O-(CH 2 ) t (C 3 -C 10 Cycloalkyl) and -O-(CH 2 ) t (4-10 membered heterocyclyl), where t is an integer from 0 to 4, and any aryl, heteroaryl, cycloalkyl or heterocyclyl group present may itself be an unsubstituted C1 -C 4 Alkyl, halo, unsubstituted C 1 -C 4 Alkoxy, unsubstituted C 1 -C 4 Haloalkyl, unsubstituted C 1 -C 4 Hydroxyalkyl or unsubstituted C 1 -C 4 A particularly exemplary "substituted alkoxy" group is -OCF 3 , -OCH 2 CF 3 , -OCH 2 Ph, -OCH 2 -Cyclopropyl, -OCH 2 CH 2 OH and -OCH 2 CH 2 NMe 2 It is.

[0062] "Amino" means -NH 2 It refers to radicals.

[0063] "Substituted amino" refers to a group of the formula -N(R 38 ) 2 where R 38 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or an amino protecting group, where R 38 At least one of R is not hydrogen. 38 are independently hydrogen, C 1 -C 8 Alkyl, C 3 -C 8 Alkenyl, C 3 -C 8 Alkynyl, C 6 -C 10 Aryl, 5-10 membered heteroaryl, 4-10 membered heterocyclyl or C 3 -C 10Cycloalkyl; or halo or hydroxy substituted C 1 -C 8 Alkyl; halo or hydroxy substituted C 3 -C 8 Alkenyl; C substituted with halo or hydroxy 3 -C 8 Alkynyl, or -(CH 2 ) t (C 6 -C 10 Aryl), -(CH 2 ) t (5-10 membered heteroaryl), -(CH 2 ) t (C 3 -C 10 Cycloalkyl) or -(CH 2 ) t (4-10 membered heterocyclyl), where t is an integer from 0 to 8, each of which is selected from unsubstituted C 1 -C 4 Alkyl, halo, unsubstituted C 1 -C 4 Alkoxy, unsubstituted C 1 -C 4 Haloalkyl, unsubstituted C 1 -C 4 Hydroxyalkyl or unsubstituted C 1 -C 4 or both R are substituted by haloalkoxy or hydroxy; 38 The groups are linked to form an alkylene group.

[0064] An exemplary "substituted amino" group is -NR 39 -C 1 -C 8 Alkyl, -NR 39 -(CH 2 ) t (C 6 -C 10 Aryl), -NR 39 -(CH 2 ) t (5-10 membered heteroaryl), -NR 39 -(CH 2 ) t (C3 -C 10 Cycloalkyl) and -NR 39 -(CH 2 ) t (4-10 membered heterocyclyl), where t is an integer from 0 to 4, e.g., 1 or 2, and each R 39 are independently H or C 1 -C 8 any alkyl group present may itself be substituted by halo, substituted or unsubstituted amino, or hydroxy; any aryl, heteroaryl, cycloalkyl, or heterocyclyl group present may itself be substituted by an unsubstituted C 1 -C 4 Alkyl, halo, unsubstituted C 1 -C 4 Alkoxy, unsubstituted C 1 -C 4 Haloalkyl, unsubstituted C 1 -C 4 Hydroxyalkyl or unsubstituted C 1 -C 4 It may be substituted by haloalkoxy or hydroxy. For the avoidance of doubt, the term "substituted amino" includes alkylamino, substituted alkylamino, alkylarylamino, substituted alkylarylamino, arylamino, substituted arylamino, dialkylamino and substituted dialkylamino groups, as defined below. Amino includes both mono- and di-substituted amino groups.

[0065] "Azide" means -N 3 It refers to radicals.

[0066] "Carbamoyl" or "amide" means -C(O)NH 2 It refers to radicals.

[0067] "Substituted carbamoyl" or "substituted amide" refers to a -C(O)N(R 62 ) 2 refers to radicals, where each R 62are 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, where R 62 At least one of R is not hydrogen. 62 , H, C 1 -C 8 Alkyl, C 3 -C 10 Cycloalkyl, 4-10 membered heterocyclyl, C 6 -C 10 Aryl, aralkyl, 5-10 membered heteroaryl and heteroaralkyl; or C substituted with halo or hydroxy. 1 -C 8 Alkyl; or C 3 -C 10 Cycloalkyl, 4-10 membered heterocyclyl, C 6 -C 10 aryl, aralkyl, 5- to 10-membered heteroaryl or heteroaralkyl, each of which is selected from unsubstituted C 1 -C 4 Alkyl, halo, unsubstituted C 1 -C 4 Alkoxy, unsubstituted C 1 -C 4 Haloalkyl, unsubstituted C 1 -C 4 Hydroxyalkyl or unsubstituted C 1 -C 4 substituted by haloalkoxy or hydroxy; provided that at least one R 62 is other than H. Exemplary "substituted carbamoyl" groups include -C(O)NR 64 -C 1 -C 8 Alkyl, -C(O)NR 64 -(CH 2 ) t (C 6 -C 10 Aryl), -C(O)N 64 -(CH 2 ) t(5-10 membered heteroaryl), -C(O)NR 64 -(CH 2 ) t (C 3 -C 10 cycloalkyl) and -C(O)NR 64 -(CH 2 ) t (4-10 membered heterocyclyl), where t is an integer from 0 to 4, and each R 64 are independently H or C 1 -C 8 alkyl, and any aryl, heteroaryl, cycloalkyl or heterocyclyl group present is itself an unsubstituted C 1 -C 4 Alkyl, halo, unsubstituted C 1 -C 4 Alkoxy, unsubstituted C 1 -C 4 Haloalkyl, unsubstituted C 1 -C 4 Hydroxyalkyl or unsubstituted C 1 -C 4 It may be substituted by haloalkoxy or hydroxy.

[0068] "Carboxy" refers to the -C(O)OH radical.

[0069] "Cyano" refers to the -CN radical.

[0070] "Halo" or "halogen" refers to fluoro (F), chloro (Cl), bromo (Br) and iodo (I). In certain embodiments, a halo group is fluoro or chloro.

[0071] "Hydroxy" refers to the -OH radical.

[0072] "Nitro" means -NO 2 It refers to radicals.

[0073] "Cycloalkylalkyl" refers to an alkyl radical in which the alkyl group is substituted with a cycloalkyl group. Exemplary cycloalkylalkyl groups include, but are not limited to, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cycloheptylmethyl, cyclooctylmethyl, cyclopropylethyl, cyclobutylethyl, cyclopentylethyl, cyclohexylethyl, cycloheptylethyl, and cyclooctylethyl.

[0074] "Heterocyclylalkyl" refers to an alkyl radical in which the alkyl group is substituted with a heterocyclyl group. Exemplary heterocyclylalkyl groups include, but are not limited to, pyrrolidinylmethyl, piperidinylmethyl, piperazinylmethyl, morpholinylmethyl, pyrrolidinylethyl, piperidinylethyl, piperazinylethyl, morpholinylethyl, and the like.

[0075] "Cycloalkenyl" refers to substituted or unsubstituted carbocyclyl groups having from 3 to 10 carbon atoms and having a single cyclic ring or multiple condensed rings (including fused and bridged ring systems) and having at least one, and especially one to two, sites of olefinic unsaturation. Such cycloalkenyl groups include, by way of example, single ring structures such as cyclohexenyl, cyclopentenyl, cyclopropenyl, and the like.

[0076] "Fused cycloalkenyl" refers to a cycloalkenyl having two ring carbon atoms in common with a second aliphatic or aromatic ring and having olefinic unsaturation positioned so as to impart aromaticity to the cycloalkenyl ring.

[0077] "Ethenyl" refers to a substituted or unsubstituted -(CH=CH)-.

[0078] "Ethylene" means a substituted or unsubstituted -(CH 2 -CH 2 )-This refers to

[0079] "Ethynyl" refers to --(C≡C)--.

[0080] A "nitrogen-containing heterocyclyl" group refers to a 4- to 7-membered non-aromatic ring group containing at least one nitrogen atom, including, but not limited to, morpholine, piperidine (e.g., 2-piperidinyl, 3-piperidinyl, and 4-piperidinyl), pyrrolidine (e.g., 2-pyrrolidinyl and 3-pyrrolidinyl), azetidine, pyrrolidone, imidazoline, imidazolidinone, 2-pyrazoline, pyrazolidine, piperazine, and N-alkylpiperazines (e.g., N-methylpiperazine). Particular examples include azetidine, piperidone, and piperazone.

[0081] "Thioketo" refers to the =S group.

[0082] As defined herein, alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl groups are optionally substituted (e.g., a "substituted" or "unsubstituted" alkyl, a "substituted" or "unsubstituted" alkenyl, a "substituted" or "unsubstituted" alkynyl, a "substituted" or "unsubstituted" carbocyclyl, a "substituted" or "unsubstituted" heterocyclyl, a "substituted" or "unsubstituted" aryl, or a "substituted" or "unsubstituted" heteroaryl group). 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 an acceptable substituent, e.g., a substituent that, when substituted, gives rise to a stable compound, e.g., a compound that does not spontaneously undergo transformation (e.g., by rearrangement, cyclization, elimination, or other reaction). Unless otherwise indicated, a "substituted" group has a substituent at one or more substitutable positions of the group, and when more than one position in any given structure is substituted, the substituents are the same or different at each position. The term "substituted" is intended to include substitution with all permissible substituents of organic compounds, any of the substituents described herein that form a stable compound. The present invention contemplates any and all such combinations to arrive at a stable compound. For purposes of 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 heteroatom and thus form a stable moiety.

[0083] Exemplary carbon atom substituents include halogen, -CN, -NO 2 , -N 3 , -SO 2 H, -SO 3 H, -OH, -OR aa , -ON(R bb ) 2 , -N(R bb ) 2 , -N(R bb ) 3 + X - , -N(ORcc )R bb 、-SH、-SR aa 、-SSR cc 、-C(=O)R aa 、-CO 2 H、-CHO、-C(OR cc ) 2 、-CO 2 R aa 、-OC(=O)R aa 、-OCO 2 R aa 、-C(=O)N(R bb ) 2 、-OC(=O)N(R bb ) 2 、-NR bb C(=O)R aa 、-NR bb CO 2 R 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 SO 2 R aa 、-NR bb SO 2 R aa 、-SO 2 N(R bb ) 2 、-SO 2 R aa 、-SO 2 OR aa 、-OSO 2 R aa 、-S(=O)Raa 、-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) 2 R aa 、-OP(=O) 2 R aa 、-P(=O)(R aa ) 2 、-OP(=O)(R aa ) 2 、-OP(=O)(OR cc ) 2 、-P(=O) 2 N(R bb ) 2 、-OP(=O) 2 N(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 1-10Alkyl, C 1-10 Perhaloalkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Carbocyclyl, 3-14 membered heterocyclyl, C 6-14 aryl and 5-14 membered heteroaryl, where each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently has 0, 1, 2, 3, 4, or 5 R dd or the two geminal hydrogens on the carbon atom are ═O, ═S, ═NN(R bb ) 2 , =NNR bb C(=O)R aa , =NNR bb C(=O)OR aa , =NNR bb S(=O) 2 R aa , =NR bb OR =NOR cc Replaced by groups; R aa Each occurrence of is independently 1-10 Alkyl, C 1-10 Perhaloalkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Carbocyclyl, 3-14 membered heterocyclyl, C 6-14 aryl and 5- to 14-membered heteroaryl, or two R aa groups linked together form a 3- to 14-membered heterocyclyl or a 5- to 14-membered heteroaryl ring, where each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently represents 0, 1, 2, 3, 4, or 5 R dd substituted with a group; R bb Each occurrence of is independently hydrogen, -OH, -OR aa , -N(R cc ) 2 , -CN, -C(=O)R aa , -C(=O)N(R cc ) 2 , -CO2 R aa , -SO 2 R aa , -C(=NR cc ) OR aa , -C(=NR cc )N(R cc ) 2 , -SO 2 N(R cc ) 2 , -SO 2 R cc , -SO 2 OR cc , -SOR aa , -C(=S)N(R cc ) 2 , -C(=O)SR cc , -C(=S)SR cc , -P(=O) 2 R aa , -P(=O)(R aa ) 2 , -P(=O) 2 N(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 Carbocyclyl, 3-14 membered heterocyclyl, C 6-14 aryl and 5- to 14-membered heteroaryl, or two R bb groups linked together form a 3- to 14-membered heterocyclyl or a 5- to 14-membered heteroaryl ring, where each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently represents 0, 1, 2, 3, 4, or 5 R dd substituted with a group; R cc Each occurrence of is independently hydrogen, C 1-10 Alkyl, C 1-10 Perhaloalkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Carbocyclyl, 3-14 C6-14 aryl and 5- to 14-membered heteroaryl, or two R cc groups linked together form a 3- to 14-membered heterocyclyl or a 5- to 14-membered heteroaryl ring, where each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently represents 0, 1, 2, 3, 4, or 5 R dd substituted with a group; R dd Each occurrence of is independently a halogen, -CN, -NO 2 , -N 3 , -SO 2 H, -SO 3 H, -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 , -CO 2 H, -CO 2 R ee , -OC(=O)R ee , -OCO 2 R ee , -C(=O)N(R ff ) 2 , -OC(=O)N(R ff ) 2 , -NR ff C(=O)R ee , -NR ff CO 2 R 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(Rff ) 2 , -OC(=NR ff )N(R ff ) 2 , -NR ff C(=NR ff )N(R ff ) 2 , -NR ff SO 2 R ee , -SO 2 N(R ff ) 2 , -SO 2 R ee , -SO 2 OR ee , -OSO 2 R 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) 2 R 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 Carbocyclyl, 3-10 membered heterocyclyl, C 6-10 aryl, and 5- to 10-membered heteroaryl, where each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently selected from 0, 1, 2, 3, 4, or 5 R gg substituted with a group or two geminal R dd the substituents may be linked to form =O or =S; R eeEach occurrence of is independently 1-6 Alkyl, C 1-6 Perhaloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocyclyl, C 6-10 aryl, 3- to 10-membered heterocyclyl, and 3- to 10-membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently selected from 0, 1, 2, 3, 4, or 5 R gg substituted with a group; R ff Each occurrence of is independently hydrogen, C 1-6 Alkyl, C 1-6 Perhaloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocyclyl, 3-10 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl, or two R ff groups linked together form a 3- to 14-membered heterocyclyl or a 5- to 14-membered heteroaryl ring, where each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently represents 0, 1, 2, 3, 4, or 5 R gg substituted with a group; R gg Each occurrence of is independently a halogen, -CN, -NO 2 , -N 3 , -SO 2 H, -SO 3 H, -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 - , -NH 2 (C 1-6 Alkyl)+ X - , -NH 3 + 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), -CO 2 H, -CO 2 (C 1-6 alkyl), -OC(=O)(C 1-6 Alkyl), -OCO 2 (C 1-6 alkyl), -C(=O)NH 2 , -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), -NHCO 2 (C 1-6 alkyl), -NHC(=O)N(C 1-6 Alkyl) 2 , -NHC(=O)NH(C 1-6 alkyl), -NHC(=O)NH 2 , -C(=NH)O(C 1-6 alkyl), -OC(=NH)(C 1-6 alkyl), -OC(=NH)OC 1-6 Alkyl, -C(=NH)N(C 1-6 Alkyl) 2 , -C(=NH)NH(C 1-6 Alkyl ), -C(=NH)NH 2 , -OC(=NH)N(C 1-6 Alkyl) 2 , -OC(NH)NH(C 1-6 alkyl), -OC(NH)NH 2 , -NHC(NH)N(C 1-6 Alkyl) 2 , -NHC(=NH)NH2 , -NHSO 2 (C 1-6 Alkyl), -SO 2 N(C 1-6 Alkyl) 2 , -SO 2 NH(C 1-6 Alkyl), -SO 2 NH 2 , -SO 2 C 1-6 Alkyl, -SO 2 O.C. 1-6 Alkyl, -OSO 2 C 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)NH 2 , -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 Carbocyclyl, C 6-10 aryl, 3- to 10-membered heterocyclyl, 5- to 10-membered heteroaryl; or two geminal R gg The substituents may be linked to form =O or =S; where X - is the counter ion.

[0084] A "counterion" or "anionic counterion" is a negatively charged group that associates with a cationic quaternary amino group to maintain electrical neutrality. Exemplary counterions include halide ions (e.g., F - , Cl - , Br - , I - ), NO 3 - , ClO 4 - , O.H. - , H 2 PO 4 - , HSO 4 - , sulfonate ions (e.g., methanesulfonate, trifluoromethanesulfonate, p-toluenesulfonate, benzenesulfonate, 10-camphorsulfonate, naphthalene-2-sulfonate, naphthalene-1-sulfonic acid-5-sulfonate, ethane-1-sulfonic acid-2-sulfonate, etc.) and carboxylate ions (e.g., acetate, ethanoate, propanoate, benzoate, glycerate, lactate, tartrate, glycolate, etc.).

[0085] Nitrogen atoms may be substituted or unsubstituted, as permitted by valence, and may include primary, secondary, tertiary, and quaternary nitrogen atoms. Exemplary nitrogen atom substitutents include hydrogen, -OH, -OR. aa , -N(R cc ) 2 , -CN, -C(=O)R aa , -C(=O)N(R cc ) 2 , -CO 2 R aa , -SO 2 R aa , -C(=NR bb )R aa , -C(=NR cc ) OR aa , -C(=NR cc )N(R cc ) 2 , -SO 2 N(R cc ) 2, -SO 2 R cc , -SO 2 OR cc , -SOR aa , -C(=S)N(R cc ) 2 , -C(=O)SR cc , -C(=S)SR cc , -P(=O) 2 R aa , -P(=O)(R aa ) 2 , -P(=O) 2 N(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 Carbocyclyl, 3-14 membered heterocyclyl, C 6-14 aryl and 5-14 membered heteroaryl; or two R cc The groups are linked to form a 3- to 14-membered heterocyclyl or 5- to 14-membered heteroaryl ring, where each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently represents 0, 1, 2, 3, 4, or 5 R dd is substituted with a R aa , R bb , R cc and R dd is as defined above.

[0086] In certain 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 -OH, -OR aa , -N(R cc ) 2 , -C(=O)R aa , -C(=O)N(R cc ) 2 , -CO 2 R aa , -SO 2 Raa , -C(=NR cc )R aa , -C(=NR cc ) OR aa , -C(=NR cc )N(R cc ) 2 , -SO 2 N(R cc ) 2 , -SO 2 R cc , -SO 2 OR 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 Carbocyclyl, 3-14 membered heterocyclyl, C 6-14 aryl and 5-14 membered heteroaryl groups, where each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aralkyl, aryl, and heteroaryl independently has 0, 1, 2, 3, 4, or 5 R dd is substituted with a R aa , R bb , R cc and R dd is as defined herein. Nitrogen protecting groups are well known in the art and include those described in Protecting Groups in Organic Synthesis, TW Greene and PG M Huts, 3 rd edition, John Wiley & Sons, 1999, which is incorporated herein by reference.

[0087] For example, an amide group (e.g., -C(=O)R aaNitrogen protecting groups such as acetamide, chloroacetamide, trichloroacetamide, trifluoroacetamide, phenylacetamide, 3-phenylpropanamide, picolinamide, 3-pyridylcarboxamide, N-benzoylphenylalanyl derivatives, benzamide, p-phenylbenzamide, o-nitrophenylacetamide, o-nitrophenoxyacetamide, acetoacetamide, (N'-dithiobenzyloxyacylamino)acetamide, 3-(p-hydroxyphenyl)propanamide, 3-(o-nitrophenyl)propanamide, 2-methyl-2-(o-nitrophenoxy)propanamide, 2-methyl-2-(o-phenylazophenoxy)propanamide, 4-chlorobutanamide, 3-methyl-3-nitrobutanamide, o-nitrocinnamide, N-acetylmethionine derivatives, o-nitrobenzamide, and o-(benzoyloxymethyl)benzamide.

[0088] Carbamate groups (e.g., -C(=O)OR aaNitrogen protecting groups such as methyl carbamate, ethyl carbamate (carbamante), 9-fluorenylmethyl carbamate (Fmoc), 9-(2-sulfo)fluorenylmethyl carbamate, 9-(2,7-dibromo)fluoroenylmethyl carbamate, 2,7-di-t-butyl-[9-(10,10-dioxo-10,10,10,10-tetrahydrothioxanthy]methyl carbamate (DBD-Tmoc), 4-methoxyphenacyl carbamate (Phenoc), 2,2,2-trichloroethyl carbamate (Troc), ), 2-trimethylsilylethyl carbamate (Teoc), 2-phenylethyl carbamate (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-t-butylphenyl)-1-methylethyl carbamate (t -Bumeoc), 2-(2'- and 4'-pyridyl)ethyl carbamate (Pyoc), 2-(N,N-dicyclohexylcarboxamido)ethyl carbamate, t-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, alkyldithiocarbamate, Carbamate, benzyl carbamate (Cbz), p-methoxybenzyl carbamate (Moz), p-nitrobenzyl carbamate, 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-dithianyl)]methyl carbamate, (Dmoc), 4-methylthiophenylcarbamate (Mtpc), 2,4-dimethylthiophenylcarbamate (Bmpc), 2-phosphonioethylcarbamate (Peoc), 2-triphenylphosphonioisopropylcarbamate (Ppoc), 1,1-dimethyl-2-cyanoethylcarbamate, m-chloro-p-acyloxybenzylcarbamate, p-(dihydroxyboryl)benzylcarbamate, 5-benzisoxazolylmethylcarbamate, 2-(trifluoromethyl)-6-chromonylmethylcarbamate (Tcr oc), m-nitrophenyl carbamate, 3,5-dimethoxybenzyl carbamate, o-nitrobenzyl carbamate, 3,4-dimethoxy-6-nitrobenzyl carbamate, phenyl (o-nitrophenyl) methyl carbamate, t-amyl carbamate, S-benzyl thiocarbamate, p-cyanobenzyl carbamate, cyclobutyl carbamate, cyclohexyl carbamate, cyclopentyl carbamate, cyclopropyl methyl carbamate, p-decyloxybenzyl carbamate, 2,2-dimethoxyacyl vinyl carbamate Carbamate, o-(N,N-dimethylcarboxamido)benzyl carbamate, 1,1-dimethyl-3-(N,N-dimethylcarboxamido)propyl carbamate, 1,1-dimethylpropynyl carbamate, di(2-pyridyl)methyl carbamate, 2-furanylmethyl carbamate, 2-iodoethyl carbamate, isobornyl carbamate, isobutyl carbamate, isonicotinyl carbamate, p-(p'-methoxyphenylazo)benzyl carbamate, 1-methylcyclobutyl carbamate, 1- Methylcyclohexyl carbamate, 1-methyl-1-cyclopropylmethyl carbamate, 1-methyl-1-(3,5-dimethoxyphenyl)ethyl carbamate, 1-methyl-1-(p-phenylazophenyl)ethyl carbamate, 1-methyl-1-phenylethyl carbamate, 1-methyl-1-(4-pyridyl)ethyl carbamate, phenyl carbamate, p-(phenylazo)benzyl carbamate, 2,4,6-tri-t-butylphenyl carbamate, 4-(trimethylammonium)benzyl carbamate and 2,4,Examples include, but are not limited to, 6-trimethylbenzyl carbamate.

[0089] Sulfonamide groups (e.g., -S(=O) 2 R aa ) and nitrogen protecting groups such as 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 phenacylsulfonamide.

[0090] Other nitrogen protecting groups include 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-dithiasuccinimide (Dts), N-2,3-diphenylmaleimide, N-2,5-dimethylpyrrole, N-1,1,4,4-tetramethyldisilylazacyclopentane adduct (STABASE), 5-substituted 1,3-dimethyl-1,3,5-triazacyclohexane-2-ones, 5-substituted 1,3-dibenzyl-1,3,5-triazacyclohexane-2-ones, 1-substituted 3,5-dinitro-4-pyridones, N-methylamines, N-allylamines, N-[2-(trimethylsilyl) N-(1-isopropyl-4-nitro-2-oxo-3-pyrrolin-3-yl)amine, quaternary ammonium salts, N-benzylamine, N-di(4-methoxyphenyl)methylamine, N-5-dibenzosuberylamine, N-triphenylmethylamine (Tr), N-[(4-methoxyphenyl)diphenylmethyl]amine (MMTr), N-9-phenylfluorenylamine (PhF), N-2,7-dichloro-9-fluorophenyl N-phenylmethyleneamine, N-ferrocenylmethylamino (Fcm), N-2-picolylamino N'-oxide, N-1,1-dimethylthiomethyleneamine, N-benzylideneamine, Np-methoxybenzylideneamine, N-diphenylmethyleneamine, N-[(2-pyridyl)mesityl]methyleneamine, N-(N',N'-dimethylaminomethylene)amine, N,N'-isopropylidenediamine, Np-nitrobenzylideneamine, N-salicylideneamine, N-5-chlorosalicylideneamine, N These include, but are not limited to, -(5-chloro-2-hydroxyphenyl)phenylmethyleneamine, N-cyclohexylideneamine, N-(5,5-dimethyl-3-oxo-1-cyclohexenyl)amine, N-borane derivatives, N-diphenylborinic acid derivatives, N-[phenyl(pentaacylchromium- or tungsten)acyl]amine, N-copper chelates, N-zinc chelates, N-nitroamines, N-nitrosamines, amine N-oxides, diphenylphosphinamide (Dpp), dimethylthiophosphinamide (Mpt), diphenylthiophosphinamide (Ppt), dialkyl phosphoramidates, dibenzyl phosphoramidates, diphenyl phosphoramidates, benzenesulfenamides, o-nitrobenzenesulfenamide (Nps), 2,4-dinitrobenzenesulfenamide, pentachlorobenzenesulfenamide, 2-nitro-4-methoxybenzenesulfenamide, triphenylmethylsulfenamide, and 3-nitropyridine sulfenamide (Npys).

[0091] In certain embodiments, the substituent present on the oxygen atom is an oxygen protecting group (also referred to as a hydroxyl protecting group). Oxygen protecting groups include -R aa , -N(R bb ) 2 , -C(=O)SR aa , -C(=O)R aa , -CO 2 R 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 , -SO 2 R aa , -Si(R aa ) 3 , -P(R cc ) 2 , -P(R cc ) 3 , -P(=O) 2 R aa , -P(=O)(R aa ) 2 , -P(=O)(OR cc ) 2 , -P(=O) 2 N(R bb ) 2 and -P(=O)(NR bb ) 2 (where R aa , R bb and R cc (wherein is defined herein). Oxygen protecting groups are well known in the art and include those described in Protecting Groups in Organic Synthesis, TW Greene and PG M Huts, 3 rd edition, John Wiley & Sons, 1999, which is incorporated herein by reference.

[0092] Exemplary oxygen protecting groups include methyl, methoxylmethyl (MOM), methylthiomethyl (MTM), t-butylthiomethyl, (phenyldimethylsilyl)methoxymethyl (SMOM), benzyloxymethyl (BOM), p-methoxybenzyloxymethyl (PMBM), (4-methoxyphenoxy)methyl (p-AOM), guaiacolmethyl (GUM), t-butoxymethyl, 4-pentenyloxymethyl (POM), siloxymethyl, 2-methoxyethoxymethyl (MEM), 2,2,2-trichloroethoxymethyl, biphenyl, phenylmethyl ... S(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-dioxan-2-yl, tetrahydrofuran nyl, tetrahydrothiofuranyl, 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-( phenylselenyl)ethyl, t-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-oxide, diphenylmethyl chil, p,p'-dinitrobenzhydryl, 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-benzodisulfuran-2-yl, benzisothiazolyl S,S-dioxide, trimethylsilyl (TMS), triethylsilyl (TES), triisopropylsilyl (TIPS), dimethylisopropylsilyl (IPDMS), diethylisopropylsilyl (DEIPS), dimethylthexylsilyl, t-butyldimethylsilyl (TBDMS), t-butyldiphenylsilyl (TBDPS), tribenzylsilyl, tri-p-xylylsilyl, triphenylsilyl, diphenylmethylsilyl (DPMS), t-butylmethoxyphenylsilyl (TBMPS), formate, benzoylformate, acetate, chloroacetate, dichloroacetate, trichloroacetate, trifluoroacetate, methoxyacetate, triphenylmethoxyacetate, phenoxyacetate, p-chlorophenoxyacetate, 3-phenylpropionate, 4-oxopentanoate (levulinate), 4,4-(ethylenediaminetetraacetate), dithio) pentanoate (levulinoyl dithioacetal), pivaloate, adamantoate, crotonate, 4-methoxycrotonate, benzoate, p-phenylbenzoate, 2,4,6-trimethylbenzoate (mesitoate), 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-(triphenylphosphonio)ethyl carbonate (Peoc), alkyl isobutyl carbonate, alkyl vinyl carbonate, alkyl aryl 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-napththyl carbonate, methyl dithiocarbonate, 2-iodobenzoate, 4-azidobutyrate, 4-nitro-4-methylpentanoate, o-(dibromomethyl)benzoate, 2-formylbenzenesulfonate, 2-(methylthiomethoxy)ethyl, 4-(methylthiomethoxy) butyrate, 2-(methylthiomethoxymethyl)benzoate, 2,6-dichloro-4-methylphenoxyacetate, 2,6-dichloro-4-(1,1,3,3-tetramethylbutyl)phenoxyacetate, 2,4-bis(1,1-dimethylpropyl)phenoxyacetate, chlorodiphenylacetate, isobutyrate, monosuccinoate, (E)-2-methyl-2-butenoate, o-(methoxyacyl)benzoate, α-naphthoate, nitrate, alkyl N,N,N',N'-tetramethyl, These include, but are not limited to, alkyl phosphorodiamidates, alkyl N-phenylcarbamates, borates, dimethylphosphinothioyls, alkyl 2,4-dinitrophenylsulfenates, sulfates, methanesulfonates (mesylates), benzylsulfonates, and tosylates (Ts).

[0093] In certain embodiments, the substituent present on the sulfur atom is a sulfur protecting group (also referred to as a thiol protecting group). Sulfur protecting groups include -R aa , -N(R bb ) 2 , -C(=O)SR aa , -C(=O)R aa , -CO 2 R 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)Raa , -SO 2 R aa , -Si(R aa ) 3 , -P(R cc ) 2 , -P(R cc ) 3 , -P(=O) 2 R aa , -P(=O)(R aa ) 2 , -P(=O)(OR cc ) 2 , -P(=O) 2 N(R bb ) 2 and -P(=O)(NR bb ) 2 (where R aa , R bb and R cc (wherein is as defined herein). Sulfur protecting groups are well known in the art and include those described in Protecting Groups in Organic Synthesis, TW Greene and PG M Huts, 3 rd edition, John Wiley & Sons, 1999, which is incorporated herein by reference.

[0094] "Compounds of the invention" and equivalent expressions are meant to include compounds as described herein, in particular compounds according to any formula listed and / or described herein, including prodrugs, pharma- ceutically acceptable salts and solvates, e.g., hydrates, if the context so permits. Similarly, references to intermediates, whether or not they are themselves claimed, are meant to include their salts and solvates, if the context so permits. These and other exemplary substituents are described in detail in the detailed description, examples and claims. It is not intended that the present invention be limited in any way by the exemplary enumeration of the above substituents.

[0095] Other definitions "Pharmaceutically acceptable" means approved or approvable by a regulatory agency of the Federal or State government or a corresponding agency in a country other than the United States, or listed in the United States Pharmacopeia or other generally recognized pharmacopoeias, for use in animals, and more particularly in humans.

[0096] "Pharmaceutically acceptable salts" refers to salts of the compounds of the present invention that are pharma- ceutically acceptable and possess the desired pharmacological activity of the parent compound. In particular, such salts are non-toxic and may be inorganic or organic acid addition salts and inorganic or organic base addition salts. In particular, such salts include: (1) salts formed with inorganic acids (e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc.); or salts formed with organic acids (e.g., 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, benzoic ... (2) acid addition salts formed with acids such as benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo[2.2.2]-oct-2-ene-1-carboxylic acid, glucoheptonic acid, 3-phenylpropionic acid, trimethylacetic acid, tert-butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, and the like; or (3) acid addition salts formed with an acidic proton present in the parent compound, such as an alkali metal ion, or are coordinated with organic bases (e.g., ethanolamine, diethanolamine, triethanolamine, N-methylglucamine, etc.). Additionally, salts include, by way of example only, salts of sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, etc.; and salts of non-toxic organic or inorganic acids (e.g., hydrochloride, hydrobromide, tartrate, maleate, acetate, maleate, oxalate, etc.) when the compound contains a basic functional group.

[0097] The term "pharmaceutical 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.

[0098] "Solvate" refers to a form of a compound associated with a solvent or water (also called "hydrate"), usually by solvolysis. This physical association includes hydrogen bonding. Conventional solvents include water, ethanol, acetic acid, and the like. The compounds of the present invention may be prepared, for example, in crystalline form, and may be solvated or hydrated. Suitable solvates include pharma- ceutically acceptable solvates (e.g., hydrates), and further include both stoichiometric and non-stoichiometric solvates. In certain cases, for example, when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid, the solvate may be isolated. "Solvate" encompasses both solution-phase and isolatable solvates. Representative solvates include hydrates, ethanolates, and methanolates.

[0099] "Subjects" to which administration is contemplated include, but are not limited to, humans (i.e., male or female of any age group, e.g., pediatric subjects (e.g., infants, children, adolescents) or adult subjects (e.g., young adults, middle-aged adults, or elderly adults)) and / or non-human animals, e.g., mammals (e.g., primates (e.g., cynomolgus monkeys, rhesus monkeys), cows, pigs, horses, sheep, goats, rodents, cats, and / or dogs). In certain embodiments, the subject is a human. In certain embodiments, the subject is a non-human animal. The terms "human," "patient," and "subject" are used interchangeably herein.

[0100] "Condition," "disease," and "disorder" are used interchangeably herein.

[0101] "Effective amount" means an amount of a compound that, when administered to a subject for treating or preventing 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 being treated. "Therapeutically effective amount" refers to an amount effective for therapeutic treatment. "Prophylactically effective amount" refers to an amount effective for prophylactic treatment.

[0102] "Prevent" or "prevention" or "prophylactic treatment" refers to a reduction in the risk of acquiring or developing a disease or disorder (i.e., not developing at least one clinical symptom of the disease in a subject who has not been exposed to a disease-causing agent or in a pre-disease subject who is susceptible to the disease). The term "protection" relates to "prophylaxis" and refers to a measure or procedure whose purpose is to prevent, rather than treat or cure, a disease.

[0103] "Treat" or "treatment" or "therapeutic treatment" with respect to any disease or disorder In another embodiment, "treat" or "treatment" refers to ameliorating a disease or disorder (i.e., halting the disease or reducing at least one sign, degree or severity of its clinical symptoms). In another embodiment, "treat" or "treatment" refers to ameliorating at least one physical parameter (which may not be discernible by the subject). In yet another embodiment, "treat" or "treatment" refers to modulating a disease or disorder physically (e.g., stabilization of discernible symptoms), physiologically (e.g., stabilization of physical parameters), or both. In a further embodiment, "treat" or "treatment" relates to slowing the progression of a disease.

[0104] As used herein, the term "isotopic variant" refers to a compound that contains unnatural proportions of isotopes at one or more of the atoms that constitute the 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( 15 In compounds containing such isotopic substitutions, the following atoms (if present) may be replaced with, for example, any hydrogen: 2 H / D or any carbon 13 C or any nitrogen 15 It will be understood that the presence and location of atoms may vary, such as may be N, and that the presence and location of such atoms may be determined within the skill of the art. Similarly, the present invention may include the preparation of isotopic variants using radioactive isotopes, for example, when the resulting compounds may be used for drug and / or substrate tissue distribution studies. The radioactive isotope tritium, i.e. 3 H, and carbon-14, i.e. 14 C are particularly useful for this purpose in light of their ease of incorporation and the means for their detection. In addition, positron-emitting isotopes (e.g., 11 C. 18 F, 15 O and 13Compounds can be prepared that are substituted with 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 112, 120, 133, 140, 141, 152, 163, 170, 171, 182, 193, 194, 195, 196, 197, 198, 199, 200, 211, 220, 232

[0105] "Stereoisomers": It should also be understood that compounds that have the same molecular formula but differ in the nature or sequence of bonds 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 one another are referred to as "diastereomers" and stereoisomers that are non-superimposable mirror images of one another are referred to as "enantiomers". When a compound has an asymmetric center, for example, when it is bonded to four different groups, pairs of enantiomers can exist. Enantiomers can be characterized by the absolute configuration of their asymmetric center and described by the R- and S-sequencing rules of Cahn and Prelog or by the way in which the molecule rotates the plane of polarized light and is designated as dextrorotatory or levorotatory (i.e., (+) or (-)-isomers, respectively). Chiral compounds can exist as individual enantiomers or mixtures thereof. A mixture containing equal ratios of enantiomers is referred to as a "racemic mixture".

[0106] "Tautomers" refer to compounds that are interchangeable forms of a particular compound structure, differing in the displacement of hydrogen atoms and electrons. Thus, two structures can be in equilibrium through the movement of π electrons and atoms (usually H). For example, enols and ketones are tautomers because they quickly interconvert upon treatment with acid or base. Another example of tautomerism is the aci and nitro forms of phenylnitromethane, which are similarly formed upon treatment with acid or base. Tautomers can be relevant to obtaining optimal chemical reactivity and biological activity of a compound of interest.

[0107] A "pharmacologically acceptable metabolically cleavable group" refers to a group that is cleaved in vivo to yield a parent molecule of the structural formula depicted herein. Examples of such groups are -COR, -COOR, -CONRR and -CH 2 Included are OR radicals, where R is independently selected at each occurrence from alkyl, trialkylsilyl, carbocyclic aryl, or carbocyclic aryl substituted with one or more of alkyl, halogen, hydroxy, or alkoxy. Specific examples of representative metabolically cleavable groups include acetyl, methoxycarbonyl, benzoyl, methoxymethyl, and trimethylsilyl groups.

[0108] "Prodrug" refers to a compound (including derivatives of the compounds of the present invention) that has a cleavable group and becomes a pharmacologic active compound of the present invention in vivo by solvolysis or under physiological conditions. Such examples include, but are not limited to, choline ester derivatives, N-alkylmorpholine esters, and the like. Other derivatives of the compounds of the present invention are active in both their acid form and acid derivative form, but the acid-sensitive form often offers advantages of solubility, tissue compatibility, or delayed release in mammalian organisms (see Bundgard, H., Design of Prodrugs, pp.7-9, 21-24, Elsevier, Amsterdam 1985). Prodrugs include acid derivatives well known to those skilled in the art (e.g., esters prepared by reacting the parent acid with a suitable alcohol, or amides prepared by reacting the parent acid compound with a substituted or unsubstituted amine or acid anhydride or mixed anhydride). Simple aliphatic or aromatic esters, amides, and anhydrides obtained from pendant acid groups on the compounds of the present invention are particular prodrugs. In some cases, it is desirable to prepare double ester type prodrugs (e.g., (acyloxy)alkyl esters or ((alkoxycarbonyl)oxy)alkyl esters). In particular, the C 1 ~C 8 Alkyl, C2 -C 8 Alkenyl, C 2 -C 8 Alkynyl, Aryl, C 7 -C 12 Substituted Aryl and C 7 -C 12 Aryl alkyl esters.

[0109] "Compounds of the invention" and equivalent expressions are meant to include compounds as described herein, in particular compounds according to any formula listed and / or described herein, and the expressions include prodrugs, pharma- ceutically acceptable salts and solvates, e.g., hydrates, where the context so permits. Similarly, reference to intermediates, whether or not they are themselves claimed, is meant to include their salts and solvates, where the context so permits.

[0110] Detailed Description of Certain Embodiments of the Invention As described herein, the present invention is based in part on a desire to provide novel 19-nor compounds with superior potency, pharmacokinetic (PK) properties, oral bioavailability, formulation suitability, stability, safety, clearance and / or metabolism. One important feature of the compounds as described herein is the disubstitution at the C3 position. The inventors anticipate that the disubstitution at C-3 will eliminate the possibility of oxidation to a ketone, prevent further metabolism, and reduce the possibility of a second elimination pathway such as glucuronidation. The inventors further anticipate that the overall effect of the C3 disubstitution should be to improve overall PK parameters and reduce potential toxicity and side effects, which may allow for oral and / or chronic administration in certain embodiments. Another important feature of the compounds as described herein is the presence of a hydrogen rather than a methyl group at the C10 position ("19-nor"). The inventors anticipate that the 19-nor compounds will have improved physical properties, such as improved solubility, compared to their C10-methyl counterparts. The inventors further expect that, for example, solubility will be enhanced when the AB ring system is in the cis configuration.

[0111] Thus, in one embodiment, the 3,3-disubstituted 19-norpregnane derivative of formula (I) compound:

[0112] [ka] or a pharma- ceutically acceptable salt, solvate, hydrate, prodrug, stereoisomer, tautomer, isotopic variant, or N-oxide thereof, or a combination thereof; During the ceremony: 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 , -SRA1 , -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) 2 R A2 , -OS(=O) 2 OR A1 , -SS(=O) 2 R A2 , -SS(=O) 2 OR A1 , -S(=O)R A2 , -SO 2 R A2 or -S(=O) 2 OR A1 where R A1 each occurrence is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, an oxygen protecting group (when attached to an oxygen atom), a sulfur protecting group (when attached to a sulfur atom), a nitrogen protecting group (when attached to a nitrogen atom), or two R A1 groups linked together form a substituted or unsubstituted heterocyclic or heteroaryl ring; R A2 is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 2 is hydrogen, halo, 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 , -NH 2 , -N(R B1 ) 2 or -NR B1 C(=O)R B1 where R B1 each occurrence is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl, 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 are linked 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 carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 3’ is hydrogen, -C(=O)R C1 , -C(=O)OR C1 , -C(=O)SR C1 , -C(=O)N(R C1 ) 2 , -S(=O) 2 R C2 , -S(=O) 2 OR C1 , -P(=O) 2 R C2 , -P(=O) 2 OR C1 , -P(=O)(OR C1 ) 2 , -P(=O)(R C2 ) 2or -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 linked together form a substituted or unsubstituted heterocyclic ring; R C2 is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 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 Each of R is independently hydrogen, halo, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl, or R 6a and R 6b are linked to form an oxo (=O) group; R 11a and R 11b each independently represents hydrogen, halo, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, -OH, -OR D1 , -OC(=O)R D1 , -NH 2 , -N(R D1 ) 2 or -NR D1 C(=O)R D1 where R D1each occurrence is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl 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 groups linked together form a substituted or unsubstituted heterocyclic ring; or R 11a and R 11b are linked to form an oxo (=O) group; During the ceremony,

[0113] [ka] represents a single bond or a double bond, and when a double bond is present in ring B, R 6a or R 6b is absent and a single bond is present in ring B, then the hydrogen at C5 is in the alpha or beta position; However, the following compounds and pharma- ceutically acceptable salts thereof are specifically excluded:

[0114] [ka]

[0115] [ka]

[0116] [ka] In another embodiment, a 3,3-disubstituted 19-norpregnane compound of formula (III):

[0117] [ka] or a pharma- ceutically acceptable salt, solvate, hydrate, prodrug, stereoisomer, tautomer, isotopic variant, or N-oxide thereof, or a combination thereof; 1 , R 2 , R 3 , R 3’ , R 4 , R 6a , R 6b , R 11a and R 11b is as defined herein.

[0118] In certain embodiments, the compound is a pharma- ceutically acceptable salt, such as a sodium salt, a potassium salt, an ammonium salt, or a calcium salt. In certain embodiments, the compound is a sodium salt. In certain embodiments, the compound is an acid addition salt, such as a hydrochloride, a hydrobromide, a benzoate, a mesylate, or a besylate.

[0119] It is contemplated that the compounds of Formulae (I) and (III) act, in certain embodiments, as GABA modulators.

[0120] R 1 base As broadly 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) 2 R A2 , -OS(=O) 2 OR A1 , -SS(=O) 2 R A2 , -SS(=O) 2 OR A1 , -S(=O)R A2 , -SO 2 R A2 or -S(=O) 2 OR A1 where R A1 each occurrence is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, an oxygen protecting group (when attached to an oxygen atom), a sulfur protecting group (when attached to a sulfur atom), a nitrogen protecting group (when attached to a nitrogen atom), or two R A1 groups linked together form a substituted or unsubstituted heterocyclic or heteroaryl ring; R A2 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.

[0121] In certain embodiments, R 1 is hydrogen.

[0122] In certain embodiments, R 1 is halogen, for example, fluoro, bromo, chloro, or iodo. In certain embodiments, R 1 is bromo.

[0123] In certain embodiments, R 1 is a substituted or unsubstituted alkyl, e.g., substituted or unsubstituted C 1-6 Alkyl, C 2-6 Alkyl, C 3-6 Alkyl, C 4-6 Alkyl, C 5-6 Alkyl, C 1 Alkyl, C 2 Alkyl, C 3 Alkyl, C 4 Alkyl, C 5 Alkyl or C 6 In certain embodiments, R 1 is a substituted alkyl (e.g., haloalkyl, alkyoxyalkyl).

[0124] In certain embodiments, R 1 is a substituted or unsubstituted alkenyl, 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 C 2 Alkenyl, substituted or unsubstituted C 3 Alkenyl, substituted or unsubstituted C 4 Alkenyl, substituted or unsubstituted C 5 Alkenyl or substituted or unsubstituted C 6 It is alkenyl.

[0125] In certain embodiments, R 1 is a substituted or unsubstituted alkynyl, 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 C 2 Alkynyl, substituted or unsubstituted C 3Alkynyl, substituted or unsubstituted C 4 Alkynyl, substituted or unsubstituted C 5 Alkynyl or substituted or unsubstituted C 6 It is alkynyl.

[0126] In certain embodiments, R 1 is a substituted or unsubstituted carbocyclyl, for example a substituted or unsubstituted C 3-6 It is cycloalkyl.

[0127] In certain embodiments, R 1 is 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 heterocyclyl, such as pyrolidinyl. In certain embodiments, R 1 is a substituted or unsubstituted 6-membered heterocyclyl, for example, substituted or unsubstituted morpholinyl, substituted or unsubstituted piperidinyl, or substituted or unsubstituted piperizinyl.

[0128] In certain embodiments, R 1 is substituted or unsubstituted aryl, for example, substituted or unsubstituted phenyl or substituted or unsubstituted naphthyl.

[0129] In certain embodiments, R 1 is substituted or unsubstituted heteroaryl. In certain embodiments, R 1 is a substituted or unsubstituted 5-membered heteroaryl. In certain embodiments, R 1 is a substituted or unsubstituted 5-membered heteroaryl having one heteroatom. In certain embodiments, R 1is a substituted or unsubstituted 5-membered heteroaryl having 2 heteroatoms. In certain embodiments, R 1 is a substituted or unsubstituted 5-membered heteroaryl having 3 heteroatoms. 1 is a substituted or unsubstituted 5-membered heteroaryl having 4 heteroatoms. In certain embodiments, R 1 is an alkyl, alkenyl, alkynyl, halo, haloalkyl, haloalkenyl, haloalkynyl, hydroxyl, alkoxy, alkoxyalkyl, amino, acyl, acylamino, oxo, cyano, aryl, heteroaryl, -SO-alkyl, -SO 2 -Alkyl, -SO-Aryl , -SO 2 -aryl, -SO-heteroaryl, -SO 2 -heteroaryl. However, in certain embodiments, R 1 is unsubstituted heteroaryl.

[0130] In certain 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, oxadiazolyl, thiadiazolyl, tetrazolyl, quinolonyl, isoquinolonyl, dihydroquinolonyl, and dihydroisoquinolonyl. 1 is imidazolyl. In certain embodiments, R 1 is pyrazolyl. In certain embodiments, R 1 is 1,2,3-triazolyl. In certain embodiments, R 1 is 1,2,4-triazolyl. In certain embodiments, R 1 is tetrazolyl.

[0131] In certain embodiments, R 1is imidazolyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, oxadiazolyl, thiadiazolyl or tetrazolyl; each is unsubstituted or -SMe, -SOMe, -SO 2 Me, -CH 3 , F, Cl, -CN, -CH 2 F, -CHF 2 and -CF 3 In certain embodiments, R 1 is imidazol-1-yl, 1,2,3-triazol-1-yl or 1,2,3-triazol-2-yl, each of which is unsubstituted or is -SMe, -SOMe, -SO 2 Me, -CH 3 , F, Cl, -CN, -CH 2 F, -CHF 2 and -CF 3 and wherein the aryl group is substituted with one or two substituents selected from the group consisting of:

[0132] In certain 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.

[0133] In certain embodiments, R 1 is quinolinyl, isoquinolinyl or purinyl; each is unsubstituted or -SMe, -SOMe, -SO 2 Me, -CH 3 , F, Cl, -CN, -CH 2 F, -CHF 2 and -CF 3 and wherein the aryl group is substituted with one or two substituents selected from the group consisting of:

[0134] In certain embodiments, R 1 is quinolonyl or isoquinolonyl; each is unsubstituted or -SMe, -SOMe, -SO2 Me, -CH 3 , F, Cl, -CN, -CH 2 F, -CHF 2 and -CF 3 and wherein the aryl group is substituted with one or two substituents selected from the group consisting of:

[0135] In certain embodiments, R 1 is dihydroquinolonyl or dihydroisoquinolonyl; each is unsubstituted or -SMe, -SOMe, -SO 2 Me, -CH 3 , F, Cl, -CN, -CH 2 F, -CHF 2 and -CF 3 and wherein the aryl group is substituted with one or two substituents selected from the group consisting of:

[0136] In certain embodiments, R 1 -OR A1 For example, R 1 is -OH or -O-(heteroaryl).

[0137] In certain embodiments, R 1 -SR A1 For example, R 1 is -SH or -S-(heteroaryl).

[0138] In certain embodiments, R 1 is -OC(=O)R A1 For example, -OC(=O)CH 2 -CH 2 -CO 2 It's H.

[0139] In certain embodiments, R 1 is -OC(=O)OR A1 It is.

[0140] In certain embodiments, R 1 is -OC(=O)SR A1 It is.

[0141] In certain embodiments, R 1 is -OC(=O)N(R A1 ) 2 It is.

[0142] In certain embodiments, R 1 is -SC(=O)R A2 It is.

[0143] In certain embodiments, R 1 -SC(=O)OR A1 It is.

[0144] In certain embodiments, R 1 is -SC(=O)SR A1 It is.

[0145] In certain embodiments, R 1 is -SC(=O)N(R A1 ) 2 It is.

[0146] In certain embodiments, R 1 -OS(=O) 2 R A2 It is.

[0147] In certain embodiments, R 1 -OS(=O) 2 OR A1 , e.g., -O-SO 3 It's H.

[0148] In certain embodiments, R 1 -SS(=O) 2 R A2 It is.

[0149] In certain embodiments, R 1 -SS(=O) 2 OR A1 , e.g., -S-SO 3 It's H.

[0150] In certain embodiments, R 1 is -S(=O)R A2 It is.

[0151] In certain embodiments, R 1 -SO 2 R A2 It is.

[0152] In certain embodiments, R 1 is -S(=O) 2 OR A1 , e.g., -SO 3 It's H.

[0153] In certain embodiments, R 1 is -N(R A1 ) 2 , -NHC(=O)R A1 , -NHC(=O)OR A1 , -NHC(=O)SR A1 , -NHC(=O)N(R A1 ) 2 In certain embodiments, R 1 is -N(R A1 ) 2 In certain embodiments, R 1 is -NHC(=O)R A1 In certain embodiments, R 1 is -NHC(=O)OR A1 In certain embodiments, R 1 is -NHC(=O)SR A1 In certain embodiments, R 1 is -NHC(=O)N(R A1 ) 2 It is.

[0154] In certain embodiments, R 1 -OH, -O-CO-CH 2 -CH 2 -CO 2 H, -O-SO 3 H, -SH, -S-SO 3is selected from H, heteroaryl, -O-(heteroaryl) and -S-(heteroaryl), where heteroaryl is imidazolyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, quinolinyl, isoquinolinyl or purinyl; each heteroaryl is unsubstituted or selected from oxo, -CH 3 , F, Cl, -CN, -SMe, -SOMe, -SO 2 Me and -CF 3 In certain embodiments, R 1 is -O-quinolinyl, -O-isoquinolinyl, -O-purinyl, -S-quinolinyl, -S-isoquinolinyl or -S-purinyl; each is unsubstituted or is -CH 3 , F, C l, -CN, -SMe, -SOMe, -SO 2 Me, -CH 2 F, -CHF 2 and -CF 3 and wherein the aryl group is substituted with one or two substituents selected from the group consisting of:

[0155] In certain embodiments, R 1 -OH, -O-CH 2 -CH 2 -CO 2 H, -SO 3 H, -OSO 3 H, -SSO 3 H, pyrazol-1-yl, imidazol-1-yl, 1,2,4-triazol-1-yl or 1,2,3-triazol-1-yl. 1 is -OH. In certain embodiments, R 1 is -O-CH 2 -CH 2 -CO 2 H. In certain embodiments, R 1 -SO 3 H. In certain embodiments, R 1 -OSO 3H. In certain embodiments, R 1 -SSO 3 H. In certain embodiments, R 1 is pyrazol-1-yl. In certain embodiments, R 1 is imidazol-1-yl. In certain embodiments, R 1 is 1,2,4-triazol-1-yl. In certain embodiments, R 1 is 1,2,3-triazol-1-yl.

[0156] In certain embodiments, R 1 is a substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted heterocyclyl, substituted or unsubstituted thioalkoxy (-S-alkyl), -OH, -O-CO-(CH 2 ) t -CO 2 H, -SO 3 H, -O-SO 3 H, -SH, -S-SO 3 H or substituted or unsubstituted -Y- (heteroaryl); where Y is a bond, -O-, -S-, C 1 -C 4 Alkylene, C 2 -C 4 Alkenylene or C 2 -C 4 alkynylene; and the subscript t is an integer between 2 and 5, inclusive.

[0157] In certain embodiments, R 1 is Br, -OH, -OMe, substituted or unsubstituted heterocyclyl, -O-CO-CH 2 -CH 2 -CO 2 H, -SO 3 H, -O-SO 3 H, -S-SO 3 H, OP(=O)(OH) 2 , pyrazolyl, imidazolyl or triazolyl; R 2 , R3’ , R 4 , R 11a and R 11b each of the dotted bonds is a single bond; 3 Et, -CF 3 , ethynyl, 4-hydroxypropynyl or (4-acyl)-phenylethynyl.

[0158] In any of the above embodiments, at least one R A1 is unsubstituted heteroaryl or is halogen, -CN, -NO 2 , -N 3 , -SO 2 H, -SO 3 H, -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 , -CO 2 H, -CHO, -C(OR cc ) 2 , -CO 2 R aa , -OC(=O)R aa , -OCO 2 R aa , -C(=O)N(R bb ) 2 , -OC(=O)N(R bb ) 2 , -NR bb C(=O)R aa , -NR bb CO 2 R 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 SO 2 R aa 、-NR bb SO 2 R aa 、-SO 2 N(R bb ) 2 、-SO 2 R aa 、-SO 2 OR aa 、-OSO 2 R 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) 2 R aa 、-OP(=O) 2 R aa 、-P(=O)(R aa ) 2 、-OP(=O)(R aa ) 2 、-OP(=O)(OR cc ) 2 、-P(=O) 2 N(R bb) 2 , -OP(=O) 2 N(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 Carbocyclyl, 3-14 membered heterocyclyl, C 6-14 heteroaryl substituted with one or more substituents selected from the group consisting of aryl and 5-14 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently comprises 0, 1, 2, 3, 4, or 5 R dd or the two geminal hydrogens on the carbon atom are ═O, ═S, ═NN(R bb ) 2 , =NNR bb C(=O)R aa , =NNR bb C(=O)OR aa , =NNR bb S(=O) 2 R aa , =NR bb OR =NOR ccReplaced by group; R aa , R bb , R cc , R dd , R ee and R ff is as described herein.

[0159] In any of the above embodiments, at least one R A1 is unsubstituted heteroaryl or is selected from the group consisting of alkyl, alkenyl, alkynyl, halo, haloalkyl, haloalkenyl, haloalkynyl, hydroxyl, alkoxy, alkoxyalkyl, amino, acyl, acylamino, oxo, cyano, aryl, heteroaryl, -SO-alkyl, -SO 2 -Alkyl, -SO-Aryl, -SO 2 -aryl, -SO-heteroaryl and -SO 2 -heteroaryl substituted with one or more substituents selected from the group consisting of:

[0160] In any of the above embodiments, at least one R A1 is a heteroaryl selected from the group consisting of unsubstituted pyrrolyl, imidazolyl, pyrazolyl, oxazoyl, thiazolyl, isoxazoyl, 1,2,3-triazolyl, 1,2,4-triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxylinyl, naphthyridinyl, indolyl, indazolyl, benzimidazolyl, pyrrolopyridinyl, pyrrolopyrimidinyl, pyridopyrimidinyl, and purinyl.

[0161] In any of the above embodiments, at least one R A1is a heteroaryl selected from the group consisting of pyrrolyl, imidazolyl, pyrazolyl, oxazoyl, thiazolyl, isoxazoyl, 1,2,3-triazolyl, 1,2,4-triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxylinyl, naphthyridinyl, indolyl, indazolyl, benzimidazolyl, pyrrolopyridinyl, pyrrolopyrimidinyl, pyridopyrimidinyl, and purinyl, each of which is selected from the group consisting of alkyl, haloalkyl, alkenyl, alkynyl, oxo, hydroxy, halo, alkoxy, -S-alkyl, aryl, heteroaryl, -SO-alkyl, -SO 2 -Alkyl, -SO-Aryl, -SO 2 -aryl, -SO-heteroaryl, -SO 2 -Substituted with one or more substituents selected from the group consisting of heteroaryl, amino, cyano and acyl.

[0162] R 2 base As broadly defined above, R 2 is hydrogen, halo, 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 , -NH 2 , -N(R B1 ) 2 or -NR B1 C(=O)R B1 where R B1 each occurrence is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl, an oxygen protecting group (when attached to an oxygen atom), a nitrogen protecting group (when attached to a nitrogen atom), or two R B1The groups are linked to form a substituted or unsubstituted heterocyclic ring. do.

[0163] In certain embodiments, R 2 is hydrogen.

[0164] In certain embodiments, R 2 is halo, e.g., -F, -Br, -I, or -Cl. In certain embodiments, R 2 is -F. In certain embodiments, R 2 is -Cl. In certain embodiments, R 2 is -Br.

[0165] In certain embodiments, R 2 is a substituted or unsubstituted alkyl, e.g., 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 An exemplary R is an alkyl group. 2 C 1-6 The alkyl group may be substituted or unsubstituted methyl (C 1 ), substituted or unsubstituted ethyl (C 2 ), substituted or unsubstituted n-propyl (C 3 ), substituted or unsubstituted isopropyl (C 3 ), substituted or unsubstituted n-butyl (C 4 ), substituted or unsubstituted tert-butyl (C 4 ), substituted or unsubstituted sec-butyl (C 4 ), substituted or unsubstituted iso-butyl (C 4 ), substituted or unsubstituted n-pentyl (C 5 ), substituted or unsubstituted 3-pentanyl (C 5 ), substituted or unsubstituted amyl (C 5 ), substituted or unsubstituted neopentyl (C 5), substituted or unsubstituted 3-methyl-2-butanyl (C 5 ), substituted or unsubstituted tertiary amyl (C 5 ) or substituted or unsubstituted n-hexyl (C 6 Exemplary substituted alkyl groups include, but are not limited to, alkyl substituted with halogen groups ("haloalkyl") and alkyl substituted with alkoxy groups ("alkoxyalkyl"). Exemplary haloalkyl groups include, but are not limited to, -CF 3 , -CH 2 F, -CHF 2 , difluoroethyl, 2,2,2-trifluoro-1,1-dimethyl-ethyl, -CH 2 Cl and -CHCl 2 Exemplary alkoxyalkyl groups include, but are not limited to, -CH 2 OCH 3 and -CH 2 OCH 2 CH 3 These include, but are not limited to:

[0166] In certain embodiments, R 2 is a substituted or unsubstituted alkenyl, 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 substituted with a halogen group ("haloalkenyl") and alkenyl substituted with an alkoxy group ("alkoxyalkenyl").

[0167] In certain embodiments, R 2 is a substituted or unsubstituted alkynyl, for example, a substituted or unsubstituted C 2-6 Alkynyl, substituted or unsubstituted C 2-3 Alkynyl, substituted or unsubstituted C 3-4Alkynyl, substituted or unsubstituted C 4-5 Alkynyl or substituted or unsubstituted C 5-6 Exemplary substituted alkynyl groups include, but are not limited to, alkynyl substituted with a halogen group ("haloalkynyl") and alkynyl substituted with an alkoxy group ("alkoxyalkynyl").

[0168] In certain embodiments, R 2 is a substituted or unsubstituted carbocyclyl, for example a substituted or unsubstituted C 3-6 Carbocyclyl, substituted or unsubstituted C 3-4 Carbocyclyl, substituted or unsubstituted C 4-5 Carbocyclyl or substituted or unsubstituted C 5-6 It is a carbocyclyl.

[0169] In certain embodiments, R 2 is a substituted or unsubstituted heterocyclyl, for example a substituted or unsubstituted C 3-6 Heterocyclyl, substituted or unsubstituted C 3-4 Heterocyclyl, substituted or unsubstituted C 4-5 Heterocyclyl or substituted or unsubstituted C 5-6 Haeta For example, in certain embodiments, R 2 is a substituted or unsubstituted piperidinyl, substituted or unsubstituted piperazinyl, or substituted or unsubstituted morpholinyl ring. 2 is a substituted or unsubstituted morpholinyl ring.

[0170] In certain embodiments, R 2 is substituted or unsubstituted aryl, for example, substituted or unsubstituted phenyl.

[0171] In certain embodiments, R 2 is a substituted or unsubstituted heteroaryl, for example, an optionally substituted 5-6 membered heteroaryl.

[0172] In certain embodiments, R 2 -OH, -OR B1 or -OC(=O)R B1 In certain embodiments, R B1 is a substituted or unsubstituted alkyl, e.g., 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 An exemplary R is an alkyl group. B1 C 1-6 The alkyl group may be substituted or unsubstituted methyl (C 1 ), substituted or unsubstituted ethyl (C 2 ), substituted or unsubstituted n-propyl (C 3 ), substituted or unsubstituted isopropyl (C 3 ), substituted or unsubstituted n-butyl (C 4 ), substituted or unsubstituted tert-butyl (C 4 ), substituted or unsubstituted sec-butyl (C 4 ), substituted or unsubstituted iso-butyl (C 4 ), substituted or unsubstituted n-pentyl (C 5 ), substituted or unsubstituted 3-pentanyl (C 5 ), substituted or unsubstituted amyl (C 5 ), substituted or unsubstituted neopentyl (C 5 ), substituted or unsubstituted 3-methyl-2-butanyl (C 5 ), substituted or unsubstituted tertiary amyl (C 5 ) or substituted or unsubstituted n-hexyl (C 6 ), but are not limited to these.

[0173] In certain embodiments, R 2 is -NH 2 , -N(R B1 ) 2 or -NR B1 C(=O)RB1 In certain embodiments, R B1 is hydrogen or substituted or unsubstituted alkyl, e.g., 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 An exemplary R is an alkyl group. B1 C 1-6 The alkyl group may be substituted or unsubstituted methyl (C 1 ), ethyl (C 2 ), n-propyl (C 3 ), isopropyl (C 3 ), n-Butyl (C 4 ), tert-Butyl (C 4 ), sec-Butyl (C 4 ), iso-butyl (C 4 ), n-pentyl (C 5 ), 3-pentanyl (C 5 ), Amyl (C 5 ), neopentyl (C 5 ), 3-methyl-2-butanyl (C 5 ), tertiary amyl (C 5 ) or n-hexyl (C 6 ), but are not limited to these.

[0174] In certain embodiments, R 2 is halo, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, -OR B1 or -OC(=O)R B1 In certain embodiments, R 2 is hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl, alkoxyalkyl, -OH, -OR B1 , -OC(=O)R B1 , -NH 2 , -N(R B1 ) 2 or -NRB1 C(=O)R B1 It is.

[0175] In certain embodiments, R 2 is a substituted alkyl (e.g., haloalkyl, alkoxyalkyl).

[0176] In certain embodiments, R 2 is -F, -Cl, methyl, ethyl, n-propyl, methoxy, ethoxy, propoxy, butoxy, ethynyl, hydroxybutynyl, methoxy cyclopropynyl, chloroethynyl or cyclopropynyl.

[0177] In certain embodiments, R 2 is a non-hydrogen group at the alpha position. In certain embodiments, R 2 is a non-hydrogen group at the beta position.

[0178] R 3 base As broadly defined above, 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.

[0179] In certain embodiments, R 3 is a substituted or unsubstituted alkyl, e.g., 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 An exemplary R is an alkyl group. 3 C 1-6 The alkyl group may be substituted or unsubstituted methyl (C 1 ), ethyl (C 2), n-propyl (C 3 ), isopropyl (C 3 ), n-Butyl (C 4 ), tert-Butyl (C 4 ), sec-Butyl (C 4 ), iso-butyl (C 4 ), n-pentyl (C 5 ), 3-pentanyl (C 5 ), Amyl (C 5 ), neopentyl (C 5 ), 3-methyl-2-butanyl (C 5 ), tertiary amyl (C 5 ), n-hexyl (C 6 ), C substituted with 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more fluoro groups 1-6 Alkyl (e.g., -CF 3 , -CH 2 F, -CHF 2 , 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 (e.g., -CH 2 Cl, -CHCl 2 ) and alkoxy-substituted C 1-6 Alkyl (e.g., -CH 2 OCH 3 and -CH 2 OCH 2 CH 3 In certain embodiments, R 3 is a substituted alkyl, e.g., R 3 is haloalkyl, alkoxyalkyl, or aminoalkyl. In certain embodiments, R 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. 3ais Me, Et, n-Pr, n-Bu, or i-Bu. 3 is methoxymethyl, ethoxymethyl, propoxymethyl, methoxyethyl, or ethoxyethyl. In certain embodiments, R 3 is trifluoromethoxymethyl. In certain embodiments, R 3 is fluoromethyl, chloromethyl, difluoromethyl, trifluoromethyl, difluoroethyl, trifluoroethyl, or 2,2,2-trifluoro-1,1-dimethyl-ethyl. 3 is trifluoromethyl.

[0180] In certain embodiments, R 3 is a substituted or unsubstituted alkenyl, 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. In certain embodiments, R 3 is an ethenyl (C ) unsubstituted or substituted with one or more substituents selected from the group consisting of alkyl, halo, haloalkyl, alkoxyalkyl, or hydroxyl; 2 ), propenyl (C 3 ) or butenyl (C 4 In certain embodiments, R 3 is ethenyl, propenyl, or butenyl, unsubstituted or substituted with alkyl, halo, haloalkyl, alkoxyalkyl, or hydroxy. In certain embodiments, R 3 is ethenyl.

[0181] In certain embodiments, R 3 is a substituted or unsubstituted alkynyl, for example, a substituted or unsubstituted C 2-6 Alkynyl, substituted or unsubstituted C 2-3Alkynyl, substituted or unsubstituted C 3-4 Alkynyl, substituted or unsubstituted C 4-5 Alkynyl or substituted or unsubstituted C 5-6 alkynyl. Exemplary substituted or unsubstituted R 3 Alkynyl groups are unsubstituted or substituted with alkyl, halo, haloalkyl (e.g., CF 3 ), alkoxyalkyl, cycloalkyl (e.g., cyclopropyl or cyclobutyl), or hydroxyl-substituted ethynyl, propynyl, or butynyl. In certain embodiments, R 3 is selected from the group consisting of trifluoroethynyl, cyclopropylethynyl, cyclobutylethynyl, and propynyl, fluoropropynyl, and chloroethynyl. 3 is ethynyl (C ) unsubstituted or substituted with one or more substituents selected from the group consisting of substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted carbocyclyl and substituted or unsubstituted heterocyclyl. 2 ), Propynyl (C 3 ) or butynyl (C 4 In certain embodiments, R 3 is an ethynyl (C 2 ), Propynyl (C 3 ) or butynyl (C 4 In certain embodiments, the phenyl substitutent is further substituted with one or more substituents selected from the group consisting of halo, alkyl, trifluoroalkyl, alkoxy, acyl, amino, or amido. 3 is an ethynyl (C ) substituted with substituted or unsubstituted pyrrolyl, imidazolyl, pyrazolyl, oxazoyl, thiazolyl, isoxazoyl, 1,2,3-triazolyl, 1,2,4-triazolyl, oxadiazolyl, thiadiazolyl or tetrazolyl; 2 ), Propynyl (C 3 ) or butynyl (C 4).

[0182] In certain embodiments, R 3 is ethynyl, propynyl, or butynyl, unsubstituted or substituted with alkyl, halo, haloalkyl, alkoxyalkyl, or hydroxyl. In certain embodiments, R 3a is ethynyl or propynyl substituted with substituted or unsubstituted aryl. In certain embodiments, R 3 is ethynyl or propynyl, unsubstituted or substituted with phenyl, which is substituted with halo, alkyl, alkoxy, haloalkyl, trihaloalkyl, or acyl. In certain embodiments, R 3 is ethynyl or propynyl substituted with substituted or unsubstituted carbocyclyl. In certain embodiments, R 3 is ethynyl or propynyl, substituted with substituted or unsubstituted cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In certain embodiments, R 3 is ethynyl or propynyl substituted with substituted or unsubstituted heteroaryl. In certain embodiments, R 3 is ethynyl or propynyl substituted with substituted or unsubstituted pyridinyl or pyrimidinyl. In certain embodiments, R 3 is ethynyl or propynyl substituted with substituted or unsubstituted pyrrolyl, imidazolyl, pyrazolyl, oxazoyl, thiazolyl, isoxazoyl, 1,2,3-triazolyl, 1,2,4-triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl. In certain embodiments, R 3 is ethynyl or propynyl substituted with substituted or unsubstituted heterocyclyl. In certain embodiments, R 3a is ethynyl or propynyl, substituted with substituted or unsubstituted pyrrolidinyl, piperidinyl, piperazinyl, or mopholinyl. In certain embodiments, R 3is propynyl or butynyl substituted with hydroxyl or alkoxy. In certain embodiments, R 3 is propynyl or butynyl substituted with methoxy or ethoxy. In certain embodiments, R 3 is ethynyl or propynyl substituted with Cl. In certain embodiments, R 3 is ethynyl or propynyl substituted with trifluoromethyl.

[0183] In certain embodiments, R 3 is a substituted or unsubstituted carbocyclyl, for example Substituted or unsubstituted C 3-6 Carbocyclyl, substituted or unsubstituted C 3-4 Carbocyclyl, substituted or unsubstituted C 4-5 Carbocyclyl or substituted or unsubstituted C 5-6 It is a carbocyclyl.

[0184] In certain embodiments, R 3 is a substituted or unsubstituted heterocyclyl, for example, a substituted or unsubstituted 3- to 6-membered heterocyclyl, a substituted or unsubstituted 3- to 4-membered heterocyclyl, a substituted or unsubstituted 4- to 5-membered heterocyclyl, or a substituted or unsubstituted 5- to 6-membered heterocyclyl.

[0185] In certain embodiments, R 3 is substituted or unsubstituted aryl. In certain embodiments, R 3 is substituted or unsubstituted phenyl.

[0186] In certain embodiments, R 3 is a substituted or unsubstituted heteroaryl, for example, an optionally substituted 5-6 membered heteroaryl.

[0187] R as substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl and substituted or unsubstituted alkynyl groups 3 Further embodiments of the invention are shown below:

[0188] [ka] In the formula, R 3a Each occurrence of is hydrogen, halo, or -OR F1 where R F1 is substituted or unsubstituted alkyl; R 3b and R 3c Each occurrence of is independently hydrogen, halo, or substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclyl, or substituted or unsubstituted heterocyclyl.

[0189] In certain embodiments, at least one R 3a is hydrogen. In certain embodiments, at least two R 3c is hydrogen. In certain embodiments, each R 3a is hydrogen. In certain embodiments, at least one R 3a is halogen (e.g., fluoro, chloro, bromo, iodo). In certain embodiments, at least two R 3a is halogen (e.g., fluoro, chloro, bromo, iodo). In certain embodiments, each R 3a is a halogen (e.g., -CF 3 In certain embodiments, at least one R 3a -OR F1 (e.g., OMe or OEt). In certain embodiments, at least two R 3a -OR F1 (e.g., OMe or OEt). In certain embodiments, at least one R 3a is hydrogen, F, -OMe, or -OEt. 3a is a non-hydrogen group (e.g., -F, -OMe, or OEt); the rest are H as provided in the formula below:

[0190] [ka] In certain embodiments, R 3b is hydrogen. In certain embodiments, R 3b is halogen (e.g., fluoro, chloro, bromo, iodo). In certain embodiments, R 3b is an alkyl group, e.g., -CH 3 , -CF 3 , -CH 2 CH 2 Cl. In certain embodiments, R 3b is substituted or unsubstituted carbocyclyl, e.g., cyclopropyl or cyclobutyl. In certain embodiments, R 3b is hydrogen, -F, -Br, -Cl, -I, -CH 3 , -CF 3 , cyclopropyl or cyclobutyl. 3b is substituted or unsubstituted cyclopropyl. In certain embodiments, R 3b is hydrogen, -F, -Br, -Cl, -I, -CH 3 , -CF 3 , -CH 2 CH 2 Cl, cyclopropyl or cyclobutyl. In certain embodiments, R 3b is Me or Cl. In certain embodiments, R 3b is a substituted or unsubstituted heterocyclyl.

[0191] In certain embodiments, at least one R 3c is hydrogen. In certain embodiments, each R 3c is hydrogen. In certain embodiments, at least one R 3c is halogen (e.g., fluoro, chloro, bromo, iodo). In certain embodiments, each R 3c is halogen (e.g., fluoro, chloro, bromo, iodo). In certain embodiments, R 3c Each of is alkyl, for example, R2c Each of R is Me. 3c is alkyl; the other is hydrogen, e.g., R 3c is Me; the other is hydrogen. In certain embodiments, R 3c One of R is a substituted or unsubstituted carbocyclyl, such as cyclopropyl or cyclobutyl, and the other is hydrogen. In certain embodiments, at least one R 3c is hydrogen, -F, -Br, -Cl, -I, -CH 3 , -CF 3 , cyclopropyl or cyclobutyl. 3c Each occurrence of is H. In certain embodiments, R 3c Each occurrence of R is halogen (e.g., fluoro, chloro, bromo, iodo). 3c Each occurrence of is alkyl, e.g., -CH 3 , -CF 3 , -CH 2 CH 2 Cl. In certain embodiments, R 3c Each occurrence of is a substituted or unsubstituted carbocyclyl, e.g., cyclopropyl or cyclobutyl. In certain embodiments, R 3c is substituted or unsubstituted cyclopropyl. In certain embodiments, R 3c Each occurrence of is hydrogen, -F, -Br, -Cl, -I, -CH 3 , -CF 3 , -CH 2 CH 2 Cl, cyclopropyl or cyclobutyl. In certain embodiments, R 3c is Me or Cl. In certain embodiments, R 3c is a substituted or unsubstituted heterocyclyl.

[0192] R 3’ base As broadly defined above, R 3’ is H, -C(=O)R C1, -C(=O)OR C1 , -C(=O)SR C1 , -C(=O)N(R C1 ) 2 , -S(=O) 2 R C2 , -S(=O) 2 OR C1 , -P(=O) 2 R C2 , -P(=O) 2 OR 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 linked together form a substituted or unsubstituted heterocyclic ring; R C2 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.

[0193] In certain embodiments, R 3’ is H (hydrogen).

[0194] In certain embodiments, R 3’ is -C(=O)R C1 , -C(=O)OR C1 , -C(=O)SR C1 , -C(=O)N(R C1 ) 2 , -S(=O) 2 R C1, -S( =O) 2 OR C1 , -P(=O) 2 R C1 , -P(=O) 2 OR C1 , -P(=O)(OR C1 ) 2 , -P(=O)(R C1 ) 2 or -P(=O)(R C1 )(OR C1 ).

[0195] In certain embodiments, R C1 At least one occurrence 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). C1 At least one occurrence of is hydrogen.

[0196] In certain embodiments, R C1 At least one occurrence of is substituted or unsubstituted alkyl, e.g., 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 An exemplary R is an alkyl group. C1 C 1-6 The alkyl group may be substituted or unsubstituted methyl (C 1 ), ethyl (C 2 ), n-propyl (C 3 ), isopropyl (C 3 ), n-Butyl (C 4 ), tert-Butyl (C 4 ), sec-Butyl (C 4 ), iso-butyl (C 4 ), n-pentyl (C 5 ), 3-pentanyl (C 5 ), Amyl (C5 ), neopentyl (C 5 ), 3-methyl-2-butanyl (C 5 ), tertiary amyl (C 5 ), n-hexyl (C 6 ), C substituted with 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more fluoro groups 1-6 Alkyl (e.g., -CF 3 , -CH 2 F, -CHF 2 , 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 (e.g., -CH 2 Cl, -CHCl 2 ), and alkoxy-substituted C 1-6 Alkyl (e.g., -CH 2 OCH 3 and -CH 2 OCH 2 CH 3 ), but are not limited to these.

[0197] In certain embodiments, R C1 At least one occurrence of is substituted or unsubstituted alkenyl, e.g., 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 It is alkenyl.

[0198] In certain embodiments, R C1 At least one occurrence of is substituted or unsubstituted alkynyl, e.g., 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 5-6It is alkynyl.

[0199] In certain embodiments, R C1 At least one occurrence of is substituted or unsubstituted carbocyclyl, e.g., substituted or unsubstituted C 3-6 Carbocyclyl, substituted or unsubstituted C 3-4 Carbocyclyl, substituted or unsubstituted C 4-5 Carbocyclyl or substituted or unsubstituted C 5-6 It is a carbocyclyl.

[0200] In certain embodiments, R C1 At least one occurrence of is substituted or unsubstituted heterocyclyl, for example, substituted or unsubstituted 3- to 6-membered heterocyclyl, substituted or unsubstituted 3- to 4-membered heterocyclyl, substituted or unsubstituted 4- to 5-membered heterocyclyl, or substituted or unsubstituted 5- to 6-membered heterocyclyl.

[0201] In certain embodiments, R C1 At least one occurrence of is substituted or unsubstituted aryl, for example, substituted or unsubstituted phenyl.

[0202] In certain embodiments, R C1 At least one occurrence of Heteroaryl, for example, optionally substituted 5-6 membered heteroaryl.

[0203] In certain embodiments, two R C1 The groups are linked 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.

[0204] In certain embodiments, R 3’ is -C(=O)R C1 , -C(=O)OR C1 , -C(=O)N(R C1 ) 2 or -C(=O)N(ORC1 )(R C1 ), where R C1 is as defined herein.

[0205] In certain embodiments, R 3’ is -C(=O)R C1 For example, where R C1 is, for example, a substituted or unsubstituted methyl (C 1 ), ethyl (C 2 ), n-propyl (C 3 ), isopropyl (C 3 ), n-Butyl (C 4 ), tert-Butyl (C 4 ), sec-Butyl (C 4 ), iso-butyl (C 4 ), n-pentyl (C 5 ), 3-pentanyl (C 5 ), Amyl (C 5 ), neopentyl (C 5 ), 3-methyl-2-butanyl (C 5 ), tertiary amyl (C 5 ) or n-hexyl (C 6 In certain embodiments, R 3’ is -C(=O)CH 3 In certain embodiments, R 3’ is -C(=O)(CH 2 ) m CO 2 H, where m is an integer between 2 and 5, inclusive. In certain embodiments, m is 2. In certain embodiments, m is 3. In certain embodiments, m is 4. In certain embodiments, m is 5. In certain embodiments, R 3’ is -C(=O)CH 2 CH 2 C(=O)OH.

[0206] In certain embodiments, R 3’ is -C(=O)OR C1 For example, where R C1is, for example, a substituted or unsubstituted methyl (C 1 ), ethyl (C 2 ), n-propyl (C 3 ), isopropyl (C 3 ), n-Butyl (C 4 ), tert-Butyl (C 4 ), sec-Butyl (C 4 ), iso-butyl (C 4 ), n-pentyl (C 5 ), 3-pentanyl (C 5 ), Amyl (C 5 ), neopentyl (C 5 ), 3-methyl-2-butanyl (C 5 ), tertiary amyl (C 5 ) or n-hexyl (C 6 ).

[0207] In certain embodiments, R 3’ is -C(=O)SR C1 For example, where R C1 is, for example, a substituted or unsubstituted methyl (C 1 ), ethyl (C 2 ), n-propyl (C 3 ), isopropyl (C 3 ), n-Butyl (C 4 ), tert-Butyl (C 4 ), sec-Butyl (C 4 ), iso-butyl (C 4 ), n-pentyl (C 5 ), 3-pentanyl (C 5 ), Amyl (C 5 ), neopentyl (C 5 ), 3-methyl-2-butanyl (C 5 ), tertiary amyl (C 5 ) or n-hexyl (C 6 ).

[0208] In certain embodiments, R 3’ is -C(=O)N(R C1 ) 2 For example, -C(=O)NH 2 or -C(=O)NHRC1 where R C1 is, for example, a substituted or unsubstituted methyl (C 1 ), ethyl (C 2 ), n-propyl (C 3 ), isopropyl (C 3 ), n-Butyl (C 4 ), tert-Butyl (C 4 ), sec-Butyl (C 4 ), iso-butyl (C 4 ), n-pentyl (C 5 ), 3-pentanyl (C 5 ), Amyl (C 5 ), neopentyl (C 5 ), 3-methyl-2-butanyl (C 5 ), tertiary amyl (C 5 ) or n-hexyl (C 6 ) or R 3’ is -C(=O)N(R C1 ) 2 where the two R C1 The groups are linked 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.

[0209] In certain embodiments, R 3’ is -S(=O) 2 R C1 or -S(=O) 2 OR C1 where R C1 is, for example, hydrogen or a substituted or unsubstituted methyl Lu (C 1 ), ethyl (C 2 ), n-propyl (C 3 ), isopropyl (C 3 ), n-Butyl (C 4 ), tert-Butyl (C 4 ), sec-Butyl (C 4 ), iso-butyl (C 4 ), n-pentyl (C 5 ), 3-pentanyl (C 5 ), Amyl (C5 ), neopentyl (C 5 ), 3-methyl-2-butanyl (C 5 ), tertiary amyl (C 5 ) or n-hexyl (C 6 ) or substituted or unsubstituted phenyl. In certain embodiments, R 3’ is -S(=O) 2 R C1 In certain embodiments, R 3’ is -S(=O) 2 OR C1 , e.g., -SO 3 It's H.

[0210] In certain embodiments, R 3’ is -P(=O) 2 R C1 , -P(=O) 2 OR C1 , -P(=O)(OR C1 ) 2 , -P(=O)(R C1 ) 2 or -P(=O)(R C1 )(OR C1 ), where each R C1 are, for example, independently hydrogen, substituted or unsubstituted methyl (C 1 ), ethyl (C 2 ), n-propyl (C 3 ), isopropyl (C 3 ), n-Butyl (C 4 ), tert-Butyl (C 4 ), sec-Butyl (C 4 ), iso-butyl (C 4 ), n-pentyl (C 5 ), 3-pentanyl (C 5 ), Amyl (C 5 ), neopentyl (C 5 ), 3-methyl-2-butanyl (C 5 ), tertiary amyl (C 5 ) or n-hexyl (C 6 ) or substituted or unsubstituted phenyl. In certain embodiments, R 3’ is -P(=O)2 R C1 In certain embodiments, R 3’ is -P(=O) 2 OR C1 In certain embodiments, R 3’ -P(=O)(OR C1 ) 2 In certain embodiments, R 3’ is -P(=O)(R C1 ) 2 In certain embodiments, R 3’ is -P(=O)(R C1 )(OR C1 ).

[0211] R 4 , R 6a , R 6b , R 11a and R 11b base As broadly 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.

[0212] In certain embodiments, R 4 is H, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl.

[0213] In certain embodiments, R 4 -H, -CH 3 Or ethynyl.

[0214] In certain embodiments, R 4 is H.

[0215] As broadly defined above, R 6a and R 6bEach of R is independently hydrogen, halo (e.g., fluoro), substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl, or R 6a and R 6b are linked together to form an oxo (=O) group,

[0216] [ka] represents a single bond or a double bond, and when a double bond is present in ring B, R 6a or R 6b When one of the groups is absent and a single bond is present in ring B, the hydrogen at C5 is in the alpha or beta position.

[0217] As broadly defined above,

[0218] [ka] independently represent a single bond or a double bond, and when a double bond is present in ring B, R 6a or R 6b When one of the two is absent and a single bond is present in ring B, the hydrogen at C5 is in the alpha or beta position.

[0219] [ka] represents a single bond and the hydrogen at position 5 is in the 5α-configuration. In certain embodiments, the dashed line between C5 and C6

[0220] [ka] represents a single bond and the hydrogen at position 5 is in a 5β-configuration. In certain embodiments, the dashed line between C5 and C6

[0221] [ka] represents a double bond.

[0222] [ka] In certain embodiments, R 6a and R 6b are both hydrogen.

[0223] [ka] represents a single bond, and R 6a and R 6b In certain embodiments, one of R 6a is alpha(down) and R 6b is beta (up). In certain embodiments, R 6b is alpha(lower) and R 6a is beta(up).

[0224] [ka] In certain embodiments, R 6a is hydrogen and R 6b is halo, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl. 6a is hydrogen and R 6b is halo (e.g., fluoro). In certain embodiments, R 6a is hydrogen and R 6b is a substituted or unsubstituted alkyl, e.g., 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 5-6alkyl, for example, methyl, ethyl, propyl, or isopropyl. In certain embodiments, R 6a is hydrogen and R 6b is substituted or unsubstituted alkenyl. In certain embodiments, R 6a is hydrogen and R 6b is replaced or unsubstituted alkynyl.

[0225] [ka] In certain embodiments, R 6b is hydrogen and R 6a is halo, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl. 6b is hydrogen and R 6a is halo (e.g., fluoro). In certain embodiments, R 6b is hydrogen and R 6a is a substituted or unsubstituted alkyl, e.g., 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, for example, methyl, ethyl, propyl, or isopropyl. In certain embodiments, R 6b is hydrogen and R 6a is substituted or unsubstituted alkenyl. In certain embodiments, R 6b is hydrogen and R 6a is a substituted or unsubstituted alkynyl.

[0226] or,

[0227] [ka] In certain embodiments, R 6a and R 6b are linked to form an oxo (=O) group.

[0228] [ka] In certain embodiments, R represents a double bond. 6a is hydrogen.

[0229] [ka] In certain embodiments, R represents a double bond. 6a is halo, for example fluoro.

[0230] [ka] In certain embodiments, R represents a double bond. 6a is a substituted or unsubstituted alkyl, e.g., 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 is, for example, methyl, ethyl, propyl or isopropyl.

[0231] [ka] In certain embodiments, R represents a double bond. 6a is a substituted or unsubstituted alkenyl.

[0232] [ka] In certain embodiments, R represents a double bond. 6a is a substituted or unsubstituted alkynyl.

[0233] As broadly defined above, R 11a and R 11b each independently represents hydrogen, halo, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, -OH, -OR D1 , -OC(=O)R D1 , -NH 2 , -N(R D1 ) 2 or -NR D1 C(=O)R D1 where R D1 each occurrence is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, an oxygen protecting group (when attached to an oxygen atom), a nitrogen protecting group (when attached to a nitrogen atom), or two R D1 groups are linked to form a substituted or unsubstituted heterocyclic ring; or R 11a and R 11b are linked to form an oxo (=O) group.

[0234] In certain embodiments, R 11a is alpha(lower) and R 11b is beta (up). In certain embodiments, R 11b is alpha(lower) and R 11a is beta(up).

[0235] In certain embodiments, R 11a and R 11b At least one of R is hydrogen. 11a and R 11b Each of is H.

[0236] In certain embodiments, R 11a and R 11bAt least one of R is halo, e.g., -F, -Br, -I, or -Cl. 11a is a halo, R 11b is hydrogen. In certain embodiments, R 11b is a halo, R 11a is hydrogen.

[0237] In certain embodiments, R 11a and R 11b At least one of is a substituted or unsubstituted alkyl, e.g., 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 An exemplary R is an alkyl group. 11a C 1-6 The alkyl group may be substituted or unsubstituted methyl (C 1 ), substituted or unsubstituted ethyl (C 2 ), substituted or unsubstituted n-propyl (C 3 ), substituted or unsubstituted iso-propyl (C 3 ), substituted or unsubstituted n-butyl (C 4 ), substituted or unsubstituted tert-butyl (C 4 ), substituted or unsubstituted sec-butyl (C 4 ), substituted or unsubstituted iso-butyl (C 4 ), substituted or unsubstituted n-pentyl (C 5 ), substituted or unsubstituted 3-pentanyl (C 5 ), substituted or unsubstituted amyl (C 5 ), substituted or unsubstituted neopentyl (C 5 ), substituted or unsubstituted 3-methyl-2-butanyl (C 5 ), substituted or unsubstituted tertiary amyl (C 5 ) or substituted or unsubstituted n-hexyl (C 6Exemplary substituted alkyl groups include, but are not limited to, alkyl substituted with halogen groups ("haloalkyl") and alkyl substituted with alkoxy groups ("alkoxyalkyl"). Exemplary haloalkyl groups include, but are not limited to, -CF 3 , -CH 2 F, -CHF 2 , difluoroethyl, 2,2,2-trifluoro-1,1-dimethyl-ethyl, -CH 2 Cl and -CHCl 2 Exemplary alkoxyalkyl groups include, but are not limited to, -CH 2 OCH 3 and -CH 2 OCH 2 CH 3 In certain embodiments, R 11a and R 11b At least one of is a substituted alkyl (e.g., haloalkyl, alkoxyalkyl). In terms of form, R 11a is alkyl, R 11b is hydrogen. In certain embodiments, R 11b is alkyl, R 11a is hydrogen.

[0238] In certain embodiments, R 11a and R 11b At least one of is a substituted or unsubstituted alkenyl, 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 substituted with a halogen group ("haloalkenyl") and alkenyl substituted with an alkoxy group ("alkoxyalkenyl"). In certain embodiments, R 11ais alkenyl, R 11b is hydrogen. In certain embodiments, R 11b is alkenyl, R 11a is hydrogen.

[0239] In certain embodiments, R 11a and R 11b At least one of is substituted or unsubstituted alkynyl, e.g., 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 Exemplary substituted alkynyl groups include, but are not limited to, alkynyl substituted with a halogen group ("haloalkynyl") and alkynyl substituted with an alkoxy group ("alkoxyalkynyl"). In certain embodiments, R 11a is alkynyl, and R 11b is hydrogen. In certain embodiments, R 11b is alkynyl, and R 11a is hydrogen.

[0240] In certain embodiments, R 11a and R 11b At least one of is a substituted or unsubstituted carbocyclyl, e.g., a substituted or unsubstituted C 3-6 Carbocyclyl, substituted or unsubstituted C 3-4 Carbocyclyl, substituted or unsubstituted C 4-5 Carbocyclyl or substituted or unsubstituted C 5-6 In certain embodiments, R 11a is carbocyclyl, R 11b is hydrogen. In certain embodiments, R 11b is carbocyclyl, R 11a is hydrogen.

[0241] In certain embodiments, R11a and R 11b At least one of is substituted or unsubstituted heterocyclyl, e.g., substituted or unsubstituted C 3-6 Heterocyclyl, substituted or unsubstituted C 3-4 Heterocyclyl, substituted or unsubstituted C 4-5 Heterocyclyl or substituted or unsubstituted C 5-6 For example, in certain 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 At least one of R is a substituted or unsubstituted morpholinyl ring. 11a is heterocyclyl, and R 11b is hydrogen. In certain embodiments, R 11b is heterocyclyl, and R 11a is hydrogen.

[0242] In certain embodiments, R 11a and R 11b At least one of R is substituted or unsubstituted aryl, e.g., substituted or unsubstituted phenyl. In certain embodiments, R 11a is aryl, and R 11b is hydrogen. In certain embodiments, R 11b is aryl, and R 11a is hydrogen.

[0243] In certain embodiments, R 11a and R 11b At least one of R is substituted or unsubstituted heteroaryl, e.g., optionally substituted 5- to 6-membered heteroaryl. 11a is heteroaryl, and R 11b is hydrogen. In certain embodiments, R 11b is heteroaryl, and R11a is hydrogen.

[0244] In certain embodiments, R 11a and R 11b At least one of the following is -OH, -OR D1 or -OC(=O)R D1 In certain embodiments, R D1 is a substituted or unsubstituted alkyl, e.g., 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 An exemplary R is an alkyl group. D1 C 1-6 The alkyl group may be substituted or unsubstituted methyl (C 1 ), substituted or unsubstituted ethyl (C 2 ), substituted or unsubstituted n-propyl (C 3 ), substituted or unsubstituted isopropyl (C 3 ), substituted or unsubstituted n-butyl (C 4 ), substituted or unsubstituted tert-butyl (C 4 ), substituted or unsubstituted sec-butyl (C 4 ), substituted or unsubstituted iso-butyl (C 4 ), substituted or unsubstituted n-pentyl (C 5 ), substituted or unsubstituted 3-pentanyl (C 5 ), substituted or unsubstituted amyl (C 5 ), substituted or unsubstituted neopentyl (C 5 ), substituted or unsubstituted 3-methyl-2-butanyl (C 5 ), substituted or unsubstituted tertiary amyl (C 5 ) or substituted or unsubstituted n-hexyl (C 6 In certain embodiments, R 11a and R 11bAt least one of R is -OH. 11a -OH, -OR D1 or -OC(=O)R D1 and R 11b is hydrogen. In certain embodiments, R 11b -OH, -OR D1 or -OC(=O)R D1 and R 11a is hydrogen.

[0245] In certain embodiments, R 11a and R 11b At least one of the following is -NH 2 , -N(R D1 ) 2 or -NR D1 C(=O)R D1 In certain embodiments, R D1 is hydrogen or substituted or unsubstituted alkyl, e.g., 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 An exemplary R is an alkyl group. D1 C 1-6 The alkyl group may be substituted or unsubstituted methyl (C 1 ), substituted or unsubstituted ethyl (C 2 ), substituted or unsubstituted n-propyl (C 3 ), substituted or unsubstituted isopropyl (C 3 ), substituted or unsubstituted n-butyl (C 4 ), substituted or unsubstituted tert-butyl (C 4 ), substituted or unsubstituted sec-butyl (C 4 ), substituted or unsubstituted iso-butyl (C 4 ), substituted or unsubstituted n-pentyl (C 5 ), substituted or unsubstituted 3-pentanyl (C 5 ), substituted or unsubstituted amyl (C5 ), substituted or unsubstituted neopentyl (C 5 ), substituted or unsubstituted 3-methyl-2-butanyl (C 5 ), substituted or unsubstituted tertiary amyl (C 5 ) or substituted or unsubstituted n-hexyl (C 6 In certain embodiments, R 11a and R 11b At least one of -N(R D1 ) 2 , e.g., -NH 2 , -N(CH 3 ) 2 In certain embodiments, R 11a is -NH 2 , -N(R D1 ) 2 or -NR D1 C(=O)R D1 and R 11b is hydrogen. In certain embodiments, R 11b is -NH 2 , -N(R D1 ) 2 or -NR D1 C(=O)R D1 and R 11a is hydrogen.

[0246] In certain embodiments, R 11a and R 11b are linked to form an oxo (=O) group.

[0247] Further embodiments of formulas (I) and (III) Various combinations of the above embodiments are further contemplated herein. For example, in certain embodiments, the compound of formula (I) is a compound of formula (I-a1), (I-a2) or (I-a3):

[0248] [ka] or a pharma- ceutically 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) 2 R A2 , substituted or unsubstituted heterocyclyl, or substituted or unsubstituted heteroaryl. In certain embodiments, R 1 is hydrogen, bromine or -OH. In certain embodiments, R 2 is hydrogen, substituted or unsubstituted heterocyclyl, -OH, -OR B1 , -OC(=O)R B1 , -NH 2 , -N(R B1 ) 2 or -NR B1 C(=O)R B1 In certain embodiments, R 3 is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl. In certain embodiments, R 3 ’ is hydrogen. In certain embodiments, R 4 is hydrogen. In certain embodiments, R 6a and R 6b and R are hydrogen. 6a and R 6b is a non-hydrogen group. 6a is a non-hydrogen alpha group. In certain embodiments, R 6a is a non-hydrogen beta group. In certain embodiments, R 6a is halo, e.g., fluoro, or alkyl. In certain embodiments, R 6a is halo, e.g., fluoro, or alkyl; R 6b is hydrogen. In certain embodiments, R6a and R 6b are both halo, e.g., fluoro. In certain embodiments, R 6a and R 6b are both alkyl, e.g., methyl. In certain embodiments, R 6a and R 6b are linked to form an oxo group. 11a and R 11b and R are hydrogen. 11a and R 11b is a non-hydrogen group. 11a and R 11b are linked to form an oxo group.

[0249] In certain embodiments, the compound of formula (III) is a compound of formula (III-a1), (III-a2) or (III-a3):

[0250] [ka] or a pharma- ceutically 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) 2 R A2 , substituted or unsubstituted heterocyclyl, or substituted or unsubstituted heteroaryl. In certain embodiments, R 1 is hydrogen, bromine or -OH. In certain embodiments, R 2 is hydrogen, substituted or unsubstituted heterocyclyl, -OH, -OR B1 , -OC(=O)R B1 , -NH 2 , -N(R B1 ) 2 or -NRB1 C(=O)R B1 In certain embodiments, R 3 is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl. In certain embodiments, R 3’ is hydrogen. In certain embodiments, R 4 is hydrogen. In certain embodiments, R 6a and R 6b and R are hydrogen. 6a and R 6b is a non-hydrogen group. 6a is a non-hydrogen alpha group. In certain embodiments, R 6a is a non-hydrogen beta group. In certain embodiments, R 6a is halo, e.g., fluoro, or alkyl. In certain embodiments, R 6a is halo, e.g., fluoro, or alkyl; R 6b is hydrogen. In certain embodiments, R 6a and R 6b are both halo, e.g., fluoro. In certain embodiments, R 6a and R 6b are both alkyl, e.g., methyl. In certain embodiments, R 6a and R 6b are linked to form an oxo group. 11a and R 11b and R are hydrogen. 11a and R 11b is a non-hydrogen group. 11a and R 11b are linked to form an oxo group.

[0251] R 2 and R 4In certain embodiments, where is hydrogen, the compound of formula (I) may be a compound of formula (I-b1), (I-b2) or (I-b3):

[0252] [ka] or a pharma- ceutically 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) 2 R A2 , substituted or unsubstituted heterocyclyl, or substituted or unsubstituted heteroaryl. In certain embodiments, R 1 is hydrogen, bromine or -OH. In certain embodiments, R 3 is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl. In certain embodiments, R 3’ is hydrogen. In certain embodiments, R 6a and R 6b and R are hydrogen. 6a and R 6b is a non-hydrogen group. 6a is a non-hydrogen alpha group. In certain embodiments, R 6a is a non-hydrogen beta group. In certain embodiments, R 6a is halo, e.g., fluoro, or alkyl. In certain embodiments, R 6a is halo, e.g., fluoro, or alkyl; R 6b is hydrogen. In certain embodiments, R 6a and R 6b are both halo, e.g., fluoro. In certain embodiments, R 6a and R6b are both alkyl, e.g., methyl. In certain embodiments, R 6a and R 6b are linked to form an oxo group. 11a and R 11b and R are hydrogen. 11a and R 11b is a non-hydrogen group. 11a and R 11b are linked to form an oxo group.

[0253] R 2 and R 4 In certain embodiments, where is hydrogen, the compound of formula (III) may be a compound of formula (III-b1), (III-b2) or (III-b3):

[0254] [ka] or a pharma- ceutically 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) 2 R A2 , substituted or unsubstituted heterocyclyl, or substituted or unsubstituted heteroaryl. In certain embodiments, R 1 is hydrogen, bromine or -OH. In certain embodiments, R 3 is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl. In certain embodiments, R 3’ is hydrogen. In certain embodiments, R 6a and R 6b and R are hydrogen.6a and R 6b is a non-hydrogen group. 6a is a non-hydrogen alpha group. In certain embodiments, R 6a is a non-hydrogen beta group. In certain embodiments, R 6a is halo, e.g., fluoro, or alkyl. In certain embodiments, R 6a is halo, e.g., fluoro, or alkyl; R 6b is hydrogen. In certain embodiments, R 6a and R 6b are both halo, e.g., fluoro. In certain embodiments, R 6a and R 6b are both alkyl, e.g., methyl. In certain embodiments, R 6a and R 6b are linked to form an oxo group. 11a and R 11b and R are hydrogen. 11a and R 11b is a non-hydrogen group. 11a and R 11b are linked to form an oxo group.

[0255] R 2 , R 4 , R 11a and R 11b In certain embodiments, where is hydrogen, the compound of Formula (I) may be a compound of formula (I-c1), (I-c2) or (I-c3):

[0256] [ka] or a pharma- ceutically acceptable salt, solvate, hydrate, prodrug, stereoisomer, tautomer, isotopic variant, or N-oxide thereof, or a combination thereof. 1is hydrogen, halogen (e.g., bromine), -OR A1 (e.g., -OH), -N(R A1 ) 2 , -SS(=O) 2 R A2 , substituted or unsubstituted heterocyclyl, or substituted or unsubstituted heteroaryl. In certain embodiments, R 1 is hydrogen, bromine or -OH. In certain embodiments, R 3 is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl. In certain embodiments, R 3’ is hydrogen. In certain embodiments, R 6a and R 6b and R are hydrogen. 6a and R 6b is a non-hydrogen group. 6a is a non-hydrogen alpha group. In certain embodiments, R 6a is a non-hydrogen beta group. In certain embodiments, R 6a is halo, e.g., fluoro, or alkyl. In certain embodiments, R 6a is halo, e.g., fluoro, or alkyl; R 6b is hydrogen. In certain embodiments, R 6a and R 6b are both halo, e.g., fluoro. In certain embodiments, R 6a and R 6b are both alkyl, e.g., methyl. In certain embodiments, R 6a and R 6b are linked to form an oxo group.

[0257] R 2 , R 4 , R 11a and R 11b In certain embodiments, where is hydrogen, the compound of formula (III) may be a compound of formula (III-c1), (III-c2) or (III-c3):

[0258] [ka] or a pharma- ceutically 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) 2 R A2 , substituted or unsubstituted heterocyclyl, or substituted or unsubstituted heteroaryl. In certain embodiments, R 1 is hydrogen, bromine or -OH. In certain embodiments, R 3 is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl. In certain embodiments, R 3’ is hydrogen. In certain embodiments, R 6a and R 6b and R are hydrogen. 6a and R 6b is a non-hydrogen group. 6a is a non-hydrogen alpha group. In certain embodiments, R 6a is a non-hydrogen beta group. In certain embodiments, R 6a is halo, e.g., fluoro, or alkyl. In certain embodiments, R 6a is halo, e.g., fluoro, or alkyl; R 6b is hydrogen. In certain embodiments, R 6a and R 6b are both halo, e.g., fluoro. In certain embodiments, R 6a and R 6b are both alkyl, e.g., methyl. In certain embodiments, R 6a and R6b are linked to form an oxo group.

[0259] R 2 , R 4 , R 11a , R 11b , R 6a , R 6b In certain embodiments, where is hydrogen, the compound of formula (I) may be a compound of formula (I-d1), (I-d2) or (I-d3):

[0260] [ka] or a pharma- ceutically 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) 2 R A2 , substituted or unsubstituted heterocyclyl, or substituted or unsubstituted heteroaryl. In certain embodiments, R 1 is hydrogen, bromine or -OH. In certain embodiments, R 3 is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl. In certain embodiments, R 3’ is hydrogen.

[0261] R 2 , R 4 , R 11a , R 11b , R 6a , R 6b In certain embodiments, where is hydrogen, the compound of formula (III) may be a compound of formula (III-d1), (III-d2) or (III-d3):

[0262] [ka]

[0263] [ka] or a pharma- ceutically 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) 2 R A2 , substituted or unsubstituted heterocyclyl, or substituted or unsubstituted heteroaryl. In certain embodiments, R 1 is hydrogen, bromine or -OH. In certain embodiments, R 3 is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl. In certain embodiments, R 3’ is hydrogen.

[0264] In certain further embodiments of Formulas (I) and (III), R 1 is 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(RA1 ) 2 , -OS(=O) 2 R A2 , -OS(=O) 2 OR A1 , -SS(=O) 2 R A2 , -SS(=O) 2 OR A1 , -S(=O)R A2 , -SO 2 R A2 or -S(=O) 2 OR A1 ;R 2 is hydrogen, substituted or unsubstituted heterocyclyl, -OH, -OR B1 , -OC(=O)R B1 , -NH 2 , -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 carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 3’ is hydrogen; R 4 is hydrogen; R 6a and R 6b Each of R is independently hydrogen, halo, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl, or R 6a and R 6b are linked together to form an oxo (=O) group; R 11a and R 11b each independently represents hydrogen, -OH, -OR D1 , -OC(=O)R D1 , -NH 2 , -N(R D1 ) 2 Or -NR D1 C(=O)R D1 or R 11a and R 11b are linked to form an oxo (=O) group.

[0265] Further embodiments of formula (I) are discussed further herein. For example, in certain embodiments, the compound of formula (I) has the following formula:

[0266] [ka]

[0267] [ka]

[0268] [ka] or a pharma- ceutically acceptable salt, solvate, hydrate, prodrug, stereoisomer, tautomer, isotopic variant, or N-oxide thereof, or a combination thereof.

[0269] In certain embodiments, the compound of formula (I) has the following formula:

[0270] [ka] or a pharma- ceutically acceptable salt, solvate, hydrate, prodrug, stereoisomer, tautomer or isotopic variant thereof, or a combination thereof.

[0271] In certain embodiments, the compound of formula (I) has the following formula:

[0272] [ka] or a pharma- ceutically acceptable salt, solvate, hydrate, prodrug, stereoisomer, tautomer or isotopic variant thereof, or a combination thereof.

[0273] In certain embodiments, the compound of formula (I) has the following formula:

[0274] [ka] wherein m is 0, 1, or 2; 1c independently, -CH 3 , F, Cl, -CN, -OMe, -SMe, -SOMe, -SO 2 Me, -CH 2 F, -CHF 2 Or -CF 3 or a pharma- ceutically acceptable salt, solvate, hydrate, prodrug, stereoisomer, tautomer, isotopic variant, or N-oxide thereof, or a combination thereof.

[0275] In certain embodiments, the compound of formula (I) has the following formula:

[0276] [ka] wherein m is 0, 1, or 2; 1c are independently -CH 3 , F, Cl, -CN, -OMe, -SMe, -SOMe, -SO 2 Me, -CH 2 F, -CHF 2 Or -CF 3 or a pharma- ceutically acceptable salt, solvate, hydrate, prodrug, stereoisomer, tautomer, isotopic variant, or N-oxide thereof, or a combination thereof.

[0277] In certain embodiments, the compound of formula (I) has the following formula:

[0278] [ka] wherein m is 0, 1, or 2; 1c are independently -CH 3 , Cl, F, -CN, -OMe, -SMe, -SOMe, -SO 2 Me, -CH 2 F, -CHF 2 Or -CF 3 or a pharma- ceutically acceptable salt, solvate, hydrate, prodrug, stereoisomer, tautomer, isotopic variant, or N-oxide thereof, or a combination thereof. In certain embodiments, m is 0. In certain embodiments, m is 1. In certain embodiments, m is 2. In certain embodiments, m is 1 and each R 1c -CH 3 , Cl, or -CN. In certain embodiments, m is 2 and each R 1c -CH 3 , Cl or -CN.

[0279] In certain embodiments, the compound of formula (I) has the following formula:

[0280] [ka] Any one of the following (wherein R 1c -H, -CH 3 , Cl, F, -CN, OMe, -SMe, -SOMe, -SO 2 Me, -CH 2 F, -CHF 2 Or -CF 3 or a pharma- ceutically acceptable salt, solvate, hydrate, prodrug, stereoisomer, tautomer, isotopic variant, or N-oxide thereof, or a combination thereof.

[0281] In certain embodiments, the compound of formula (I) has the following formula:

[0282] [ka] (wherein X is -O- or -S-; R 1c are independently H, -CH 3 , F, Cl, -CN, OMe, -SMe, -SOMe, -SO 2 Me, -CH 2 F, -CHF 2 Or -CF 3 or a pharma- ceutically acceptable salt, solvate, hydrate, prodrug, stereoisomer, tautomer, isotopic variant, or N-oxide thereof, or a combination thereof.

[0283] In certain embodiments, the compound of formula (I) has the following formula:

[0284] [ka] or a pharma- ceutically acceptable salt, solvate, hydrate, prodrug, stereoisomer, tautomer or isotopic variant thereof, or a combination thereof.

[0285] In certain embodiments, the compound of formula (I) has the following formula:

[0286] [ka] or a pharma- ceutically acceptable salt, solvate, hydrate, prodrug, stereoisomer, tautomer or isotopic variant thereof, or a combination thereof.

[0287] In certain embodiments, the compound of formula (I) has the following formula:

[0288] [ka] wherein m is 0, 1, or 2; 1c are independently -CH3 , F, Cl, -CN, -OMe, -SMe, -SOMe, -SO 2 Me, -CH 2 F, -CHF 2 Or -CF 3 or a pharma- ceutically acceptable salt, solvate, hydrate, prodrug, stereoisomer, tautomer, isotopic variant, or N-oxide thereof, or a combination thereof. In certain embodiments, m is 0. In certain embodiments, m is 1. In certain embodiments, m is 2. In certain embodiments, m is 2 and each R 1c -CH 3 , Cl or -CN.

[0289] In certain embodiments, the compound of formula (I) has the following formula:

[0290] [ka] wherein m is 0, 1, or 2; 1c is, independently, - CH 3 , F, Cl, -CN, -OMe, -SMe, -SOMe, -SO 2 Me, -CH 2 F, -CHF 2 Or -CF 3 or a pharma- ceutically acceptable salt, solvate, hydrate, prodrug, stereoisomer, tautomer, isotopic variant, or N-oxide thereof, or a combination thereof.

[0291] In certain embodiments, the compound of formula (I) has the following formula:

[0292] [ka] wherein m is 0, 1, or 2; 1c are independently -CH 3, F, Cl, -CN, -OMe, -SMe, -SOMe, -SO 2 Me, -CH 2 F, -CHF 2 Or -CF 3 or a pharma- ceutically acceptable salt, solvate, hydrate, prodrug, stereoisomer, tautomer, isotopic variant, or N-oxide thereof, or a combination thereof.

[0293] In certain embodiments, the compound of formula (I) has the following formula:

[0294] [ka] Any one of the following (wherein R 1c -H, -CH 3 , Cl, -CN, -OMe, -SMe, -F, -SOMe, -SO 2 Me, -CH 2 F, -CHF 2 Or -CF 3 or a pharma- ceutically acceptable salt, solvate, hydrate, prodrug, stereoisomer, tautomer, isotopic variant, or N-oxide thereof, or a combination thereof.

[0295] In certain embodiments, the compound of formula (I) has the following formula:

[0296] [ka] (wherein X is -O- or -S-; R 1c is, independently, H, -CH 3 , F, Cl, -CN, -OMe, -SMe, -SOMe, -SO 2 Me, -CH 2 F, -CHF 2 Or -CF 3or a pharma- ceutically acceptable salt, solvate, hydrate, prodrug, stereoisomer, tautomer, isotopic variant, or N-oxide thereof, or a combination thereof. 1c are independently H, -CH 3 , F, Cl, -CN, -OMe, -SMe, -SOMe, -SO 2 Me, -CH 2 F, -CHF 2 Or -CF 3 In certain embodiments, R 1c -CH 3 , -CH 2 F, -CHF 2 Or -CF 3 In certain embodiments, R 1c is F, Cl or CN. In certain embodiments, R 1c is OMe. In certain embodiments, R 1c -SMe, -SOMe or -SO 2 In certain embodiments, X is -Me. In certain embodiments, X is -O-. In certain embodiments, X is -S-.

[0297] In certain embodiments, the compound of formula (I) has the following formula:

[0298] [ka] Any one of the following (wherein R 1 , R 2 and R 3 is as described herein); or a pharma- ceutically acceptable salt, solvate, hydrate, prodrug, stereoisomer, tautomer, isotopic variant, or N-oxide thereof, or combinations thereof.

[0299] In certain embodiments, the compound of formula (I) is selected from any one of the following compounds, or a pharma- ceutically acceptable salt, solvate, prodrug, stereoisomer, tautomer, isotopic variant, N-oxide, or combination thereof:

[0300] [ka]

[0301] [ka]

[0302] [ka]

[0303] [ka]

[0304] [ka] In certain embodiments, the compound of formula (I) is selected from any one of the following compounds, or a pharma- ceutically acceptable salt, solvate, prodrug, stereoisomer, tautomer, isotopic variant, N-oxide, or combination thereof:

[0305] [ka]

[0306] [ka]

[0307] [ka]

[0308] [ka]

[0309] [ka]

[0310] [ka] In certain embodiments, the compound of formula (I) is selected from any one of the following compounds, or a pharma- ceutically acceptable salt, solvate, prodrug, stereoisomer, tautomer, isotopic variant, N-oxide, or combination thereof:

[0311] [ka]

[0312] [ka]

[0313] [ka]

[0314] [ka]

[0315] [ka] In certain embodiments, the compound of formula (III) is selected from any one of the following compounds, or a pharma- ceutically acceptable salt, solvate, prodrug, stereoisomer, tautomer, isotopic variant, N-oxide, or combination thereof:

[0316] [ka]

[0317] [ka]

[0318] [ka]

[0319] [ka]

[0320] [ka] In certain embodiments, the compound of formula (III) is selected from any one of the following compounds, or a pharma- ceutically acceptable salt, solvate, prodrug, stereoisomer, tautomer, isotopic variant, N-oxide, or combination thereof:

[0321] [ka]

[0322] [ka]

[0323] [ka]

[0324] [ka]

[0325] [ka]

[0326] [ka] In certain embodiments, the compound of formula (III) is selected from any one of the following compounds, or a pharma- ceutically acceptable salt, solvate, prodrug, stereoisomer, tautomer, isotopic variant, N-oxide, or combination thereof:

[0327] [ka]

[0328] [ka]

[0329] [ka]

[0330] [ka]

[0331] [ka] Pharmaceutical Compositions In another aspect, the present invention provides a pharmaceutical composition comprising the compound of the present invention and a pharma- ceutically acceptable carrier.In certain embodiments, the pharmaceutical composition comprises an effective amount of the compound.In certain embodiments, the pharmaceutical composition comprises a therapeutically effective amount of the compound.In certain embodiments, the pharmaceutical composition comprises a prophylactically effective amount of the compound.

[0332] When used as pharmaceuticals, 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 contain at least one active compound.

[0333] In one embodiment, with respect to the pharmaceutical composition, the carrier is a parenteral carrier, an oral carrier, or a topical carrier.

[0334] The present invention also relates to a compound of the present invention or a pharmaceutical composition thereof for use as a medicine or medicament.

[0335] Generally, the compounds provided herein are administered in a therapeutically effective amount.The amount of the compound actually administered is typically determined by the physician in light of the relevant circumstances, including the condition being treated, the route of administration selected, the actual compound being administered, the age, weight and response of the individual patient, the severity of the patient's symptoms, etc.

[0336] The pharmaceutical compositions provided herein can be administered by various routes, including oral, rectal, transdermal, subcutaneous, intravenous, intramuscular and intranasal. Depending on the intended delivery route, the compounds provided herein are preferably formulated as injectable or oral compositions, or as ointments, lotions or patches (all for transdermal administration).

[0337] The pharmaceutical compositions provided herein may also be administered chronically ("chronic administration"). Chronic administration refers to administration of a compound or pharmaceutical composition thereof for an extended period of time, e.g., 3 months, 6 months, 1 year, 2 years, 3 years, 5 years, etc., or may continue indefinitely, e.g., for the remainder of the subject's life. In certain embodiments, chronic administration is intended to provide a constant level of the compound in the blood, e.g., within the therapeutic window, for an extended period of time.

[0338] Compositions for oral administration may take the form of bulk liquid solutions or suspensions or bulk powders. More commonly, however, compositions are provided in unit dosage forms to facilitate accurate dosing. The term "unit dosage form" refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined amount of active material calculated to produce the desired therapeutic effect together with suitable pharmaceutical excipients. Typical unit dosage forms include pre-measured, pre-filled ampoules or syringes of liquid compositions, or In the case of solid compositions, pills, tablets, capsules, etc. are mentioned. In such compositions, the compound is usually a minor component (about 0.1 to about 50% by weight, or preferably about 1 to about 40% by weight), with the remainder being various vehicles or carriers and processing aids that help to form the desired dosage form.

[0339] Liquid forms suitable for oral administration include buffers, suspensions and dispensing preparations. The formulation may contain a suitable aqueous or non-aqueous vehicle containing additives, colorants, flavoring agents, and the like. Solid forms may contain, for example, any of the following ingredients or compounds of a similar nature: binders (e.g., microcrystalline cellulose, gum tragacanth, or gelatin); excipients (e.g., starch or lactose); disintegrating agents (e.g., alginic acid, Primogel, or corn starch); lubricants (e.g., magnesium stearate); glidants (e.g., colloidal silicon dioxide); sweetening agents (e.g., sucrose or saccharin); or flavoring agents (e.g., peppermint, methyl salicylate, or orange flavoring).

[0340] Injectable compositions are typically based on injectable sterile saline or phosphate buffered saline or other injectable carriers known in the art. Conventionally, the active compound in such compositions is typically a minor component, often about 0.05-10% by weight, with the remainder being the injectable carrier and the like.

[0341] Transdermal compositions are typically formulated as topical ointments or creams containing the active ingredient in an amount generally ranging from about 0.01 to about 20% by weight, preferably from about 0.1 to about 20% by weight, preferably from about 0.1 to about 10% by weight, more preferably from about 0.5 to about 15% by weight. When formulated as an ointment, the active ingredient is typically mixed with a paraffinic ointment base or a water-miscible ointment base. Alternatively, the active ingredient may be formulated as a cream, for example, with an oil-in-water cream base. Such transdermal formulations are well known in the art and generally include additional ingredients that enhance the skin penetration or stability of the active ingredient or formulation. All such known transdermal formulations and ingredients are included within the scope provided herein.

[0342] The compounds provided herein can also be administered by a transdermal device.Thus, transdermal administration can be accomplished using a patch either of the reservoir or porous membrane type or of a solid matrix variety.

[0343] The components described above for orally administrable, injectable, or topically administrable compositions are merely representative. Other materials, as well as processing techniques, etc., are set forth in Part 8 of Remington's Pharmaceutical Sciences, 17th edition, 1985, Mack Publishing Company, Easton, Pennsylvania, which is incorporated herein by reference.

[0344] The components described above for orally administrable, injectable, or topically administrable compositions are merely representative. Other materials and processing techniques, etc. are shown in Part 8 of Remington's The Science and Practice of Pharmacy, 21st edition, 2005, Publisher: Lippincott Williams & Wilkins (herein incorporated by reference).

[0345] The compounds of the invention can also be administered in sustained release forms or from sustained release drug delivery systems. A description of representative sustained release materials can be found in Remington's Pharmaceutical Sciences.

[0346] The present invention also relates to pharma- ceutically acceptable formulations of the compounds of the invention. In one embodiment, the formulation comprises water. In another embodiment, the formulation comprises a cyclodextrin derivative. The most common cyclodextrins are α-, β-, and γ-cyclodextrins, consisting of 6, 7, and 8 α-1,4-linked glucose units, respectively, optionally containing one or more substituents on the linked sugar moiety, including, but not limited to, methylation, hydroxyalkylation, acylation, and sulfoalkyl ether substitution. In certain embodiments, the cyclodextrin is a sulfoalkyl ether β-cyclodextrin, e.g., sulfobutyl ether β-cyclodextrin, also known as Captisol®. See, e.g., U.S. Patent No. 5,376,645. In certain embodiments, the formulation comprises hexapropyl-β-cyclodextrin (e.g., 10-50% in water).

[0347] The present invention also relates to pharmaceutically acceptable acid addition salts of the compounds of the present invention.The acids that can be used to prepare pharmaceutically acceptable salts are those that form non-toxic acid addition salts, i.e., salts containing pharmacologically acceptable anions (e.g., hydrochloride, hydroiodide, hydrobromide, nitrate, sulfate, bisulfate, phosphate, acetate, lactate, citrate, tartrate, succinate, maleate, fumarate, benzoate, para-toluenesulfonate, etc.).

[0348] The following formulation examples illustrate representative pharmaceutical compositions that may be prepared according to the present invention, but the present invention is not limited to the following pharmaceutical compositions.

[0349] Exemplary Formulation 1 - Tablets: A compound of the invention may be blended as a dry powder with a dry gelatin binder in approximately a 1:2 weight ratio. A trace amount of magnesium stearate is added as a lubricant. The mixture is formed into 240-270 mg tablets (80-90 mg of active compound per tablet) in a tablet press. Exemplary Formulation 2 - Capsules: A compound of the invention can be mixed as a dry powder with a starch diluent in approximately a 1:1 weight ratio. The mixture is filled into 250 mg capsules (125 mg of active compound per capsule).

[0350] Exemplary Formulation 3-Liquid: A compound of the invention (125 mg) can be combined with sucrose (1.75 g) and xanthan gum (4 mg), the resulting mixture is blended and passed through a No. 10 mesh US sieve, then mixed with a previously prepared aqueous solution of microcrystalline cellulose and sodium carboxymethylcellulose (11:89, 50 mg). Sodium benzoate (10 mg), flavor, and color are diluted with water and added with stirring. Sufficient water can then be added to bring the total volume to 5 mL.

[0351] Exemplary Formulation 4 - Tablets: A compound of the invention may be blended as a dry powder with a dry gelatin binder in approximately a 1:2 weight ratio. A trace amount of magnesium stearate is added as a lubricant. The mixture is formed into 450-900 mg tablets (150-300 mg of active compound) in a tablet press.

[0352] Exemplary Formulation 5 - Injection: A compound of the invention may be dissolved or suspended in sterile, buffered saline injectable aqueous medium to a concentration of approximately 5 mg / mL.

[0353] Exemplary Formulation 6 - Tablets: A compound of the invention may be blended as a dry powder with a dry gelatin binder in approximately a 1:2 weight ratio. A trace amount of magnesium stearate is added as a lubricant. The mixture is formed into 90-150 mg tablets (30-50 mg of active compound per tablet) in a tablet press.

[0354] Exemplary Formulation 7 - Tablets: A compound of the invention may be blended as a dry powder with a dry gelatin binder in approximately a 1:2 weight ratio. A trace amount of magnesium stearate is added as a lubricant. The mixture is formed into 30-90 mg tablets (10-30 mg of active compound per tablet) in a tablet press.

[0355] Exemplary Formulation 8 - Tablets: A compound of the invention may be blended as a dry powder with a dry gelatin binder in approximately a 1:2 weight ratio. A trace amount of magnesium stearate is added as a lubricant. The mixture is formed into 0.3-30 mg tablets (0.1-10 mg of active compound per tablet) in a tablet press.

[0356] Exemplary Formulation 9 - Tablets: A compound of the invention may be blended as a dry powder with a dry gelatin binder in approximately a 1:2 weight ratio. A trace amount of magnesium stearate is added as a lubricant. The mixture is formed into 150-240 mg tablets (50-80 mg of active compound per tablet) in a tablet press.

[0357] Exemplary Formulation 10 - Tablets: A compound of the invention may be blended as a dry powder with a dry gelatin binder in approximately a 1:2 weight ratio. A trace amount of magnesium stearate is added as a lubricant. The mixture is formed into 270-450 mg tablets (90-150 mg of active compound per tablet) in a tablet press.

[0358] Injectable dose levels range from about 0.1 mg / kg / hour to at least 10 mg / kg / hour, all over a period of about 1 to about 120 hours, particularly 24 to 96 hours. A preloading bolus of about 0.1 mg / kg to about 10 mg / kg or more may also be administered to achieve adequate steady state levels. The maximum total dose is not expected to exceed about 2 g / day for a 40-80 kg human patient.

[0359] For the prevention and / or treatment of long-term conditions, the regimen for treatment usually extends over months or years, so oral administration is preferred for patient convenience and tolerance. For oral administration, oral administration 1-5 times per day, particularly 2-4 times, typically 3 times per day is a typical regimen. When using these dosing patterns, each dose provides about 0.01 to about 20 mg / kg of the compound provided herein, with preferred doses providing about 0.1 to about 10 mg / kg, particularly about 1 to about 5 mg / kg, respectively.

[0360] Transdermal doses are generally selected to provide blood levels similar to or lower than those achieved using an injection dose.

[0361] When used to prevent the development of CNS disorder, the compounds provided herein can typically be administered to subjects at risk of developing the condition at dosage levels described above, with the advice and under the supervision of a physician.Subjects at risk of developing a particular condition generally include subjects with a family history of the condition, or subjects identified by genetic testing or screening as being particularly susceptible to developing the condition.

[0362] Methods of Use and Treatment Previous studies (see, e.g., Gee et al., European Journal of Pharmacology, 136:419-423 (1987)) have demonstrated that certain 3α-hydroxylated steroids are regulators of GRC, contrary to what others have reported (e.g., Majewska et al., Science 232:1004-1007 (1986); Harrison et al., J Pharmacol. Exp. Ther. 241:34 6-353 (1987)). Majewska et al. and Harrison et al. taught that 3α-hydroxylated-5-reduced steroids are only capable of a much lower level of efficacy. In vitro and in vivo experimental data demonstrated that the high potency of these steroids makes them therapeutically useful in modulating brain excitability via GRC (see, e.g., Gee et al., European Journal of Pharmacology, 136:419-423 (1987); Wieland et al., Psychopharmacology 118(1):65-71 (1995)).

[0363] Various synthetic steroids have also been prepared as neuroactive steroids, see, for example, U.S. Patent No. 5,232,917 (disclosing neuroactive steroid compounds useful in treating stress, anxiety, insomnia, seizure disorders and mood disorders (e.g., depression) in a therapeutically beneficial manner that are amenable to agents effective against GRC). Furthermore, 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), and therapeutically beneficial effects on stress, anxiety, sleep, mood, and seizure disorders have previously been elicited (e.g., Gee, KW and 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, KG and 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 See Pharmacology, 136:419-423 (1987). These compounds are desirable for their duration, potency and oral activity (as well as other forms of administration).

[0364] Thus, the compounds and pharmaceutical compositions provided herein find use as therapeutics for the prevention and / or treatment of CNS conditions in mammals, including humans and non-human mammals.Thus, as stated above, the present invention includes and extends within its scope the recited treatment methods, as well as the compounds for such methods, and the use of such compounds to prepare medicaments useful for such methods.

[0365] In one embodiment, the compounds of the invention are used, for example, for the treatment of a CNS condition in a mammal (e.g., insomnia, depression, mood disorders, seizure disorders, memory disorders, attention disorders, anxiety disorders (e.g., stress), bipolar disorder (e.g., Type I and / or Type 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 (mild depression), social It is contemplated as a therapeutic agent for treating anxiety disorder, obsessive-compulsive disorder (OCD), pain (e.g., painful syndrome or disorder, such as acute pain, chronic pain, neuropathic pain), sleep disorder, memory disorder, dementia, Alzheimer's disease, seizure disorder (e.g., epilepsy), traumatic brain injury, stroke, addictive disorder (e.g., addiction to opiates, cocaine and / or alcohol), autism, Huntington's disease, Parkinson's disease, Rett syndrome, withdrawal syndrome or tinnitus).In certain embodiments, the compounds of the present invention are useful in treating depression, anxiety, mood disorder, sleep disorder, memory disorder, traumatic brain injury, stroke, epilepsy and schizophrenia.

[0366] In another aspect, a method of treating a mammal susceptible to or afflicted with a condition associated with brain excitability is provided, the method comprising administering an effective amount of one or more of the pharmaceutical compositions described herein.

[0367] In yet another aspect there is provided the use of a compound of the invention as a pharmaceutical, for example, in the treatment or prophylaxis of, among other, the aforementioned conditions and diseases.

[0368] In still yet another aspect, there is provided a method for the manufacture of a medicament for the treatment or prevention of one of the aforementioned conditions and diseases.

[0369] In still yet another aspect, the present invention provides a method for preventing, treating, ameliorating or managing a disease or condition, which method comprises administering to a subject in need of such prevention, treatment, amelioration or management a prophylactically or therapeutically effective amount of a compound of the present invention or a pharmaceutical composition thereof.

[0370] In yet another aspect, the present invention provides the use of a compound of the present invention for 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 disorder, memory disorder and mood disorder.

[0371] In yet another aspect, the present invention provides a method of treating a mammal, e.g., a human, for treating a disease associated with brain excitability, the method comprising treating said mammal with an effective amount of a compound of the present invention or a composition thereof.

[0372] In yet another aspect, the present invention provides a combination of the compound of the present invention with another pharmacologically active substance.As broadly understood herein, the compound provided herein can be administered as the only active substance, or can be administered in combination with other substances.The administration in combination can be carried out by any method that is clear to those skilled in the art, including, for example, separate administration, sequential administration, simultaneous administration and alternating administration.

[0373] In yet another aspect, the present invention provides the use of the compound of the present invention or a composition thereof for the manufacture of a medicament for treating a CNS-related disease or condition in a subject.In certain embodiments, the disease or condition is selected from sleep disorder, mood disorder, insomnia, anxiety, depression, TBI, stress and epilepsy.

[0374] In yet another aspect, the present invention provides a GABA A A method is provided for in vitro modulating a receptor-chloride ionophore complex in a subject by binding to a neurosteroid site on said complex, comprising administering to said subject an amount of a compound of the invention effective to modulate said complex.

[0375] In yet another aspect, the present invention provides a GABA A A method of modulating a receptor-chloride ionophore complex in a subject by binding to a neurosteroid site on the complex is provided, the method comprising administering to the subject an amount of a compound of the invention effective to modulate the complex.

[0376] In yet another aspect, the present invention provides a method of treating or preventing stress or anxiety in a subject, the method comprising administering to a subject in need of such treatment an effective amount of a compound of the present invention or a composition thereof.

[0377] In yet another aspect, the present invention provides a method for reducing or preventing seizure activity in a subject. The present invention provides a method for treating a subject in need of such treatment, which method comprises administering to a subject in need of such treatment an effective amount of a compound of the present invention or a composition thereof.

[0378] In yet another aspect, the present invention provides a method of alleviating or preventing insomnia in a subject, the method comprising administering to a subject in need of such treatment an effective amount of a compound of the present invention or a composition thereof.

[0379] In yet another aspect, the present invention provides a method of inducing sleep and substantially maintaining the level of REM sleep seen 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.

[0380] In yet another aspect, the present invention provides a method of alleviating or preventing PMS or PND in a subject, the method comprising administering to a subject in need of such treatment an effective amount of a compound of the present invention or a composition thereof.

[0381] In yet another aspect, the present invention provides a method of treating or preventing a mood disorder in a subject, the method comprising administering to a subject in need of such treatment an effective amount of a compound of the present invention or a composition thereof.

[0382] In certain embodiments, the mood disorder is depression.

[0383] In yet another aspect, the present invention provides a method for inducing anesthesia in a subject, comprising administering to the subject an effective amount of a compound of the present invention.In certain embodiments, the subject is a human.In certain embodiments, the compound is a pharmaceutically acceptable 3-ester or 3-diester of an acid selected from the group consisting of acetic acid, propionic acid, maleic acid, fumaric acid, ascorbic acid, pimelic acid, succinic acid, glutaric acid, bismethylenesalicylic acid, methanesulfonic acid, ethane-di-sulfonic 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.

[0384] In yet another aspect, the present invention provides a method for enhancing cognition or treating memory impairment by administering to a subject a therapeutically effective amount of a compound of the present invention. In certain embodiments, the disorder is Alzheimer's disease. In certain embodiments, the disorder is Rett syndrome.

[0385] 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 certain embodiments, the attention disorder is ADHD.

[0386] In certain embodiments, the compound is administered chronically to the subject. In certain embodiments, the compound is administered orally to the subject. EXAMPLES

[0387] Example In order that the invention described herein may be more fully understood, the following examples are set forth. The synthetic and biological examples described herein are provided to illustrate, but in no way limit the scope of, the compounds, pharmaceutical compositions and methods provided herein. This document should not be construed as defining the scope of the

[0388] material and method The compounds provided herein can be prepared from readily available starting materials using the following general methods and procedures. See, for example, the synthetic schemes below. Although typical or preferred process conditions (i.e., reaction temperature, time, molar ratio of reactants, solvent, pressure, etc.) are given, it will be understood that other process conditions can also be used unless otherwise stated. Optimum reaction conditions may vary with the particular reactants or solvents used, but such conditions can be determined by one skilled in the art by routine optimization procedures.

[0389] Moreover, as may be clear to those skilled in the art, conventional protecting groups may be necessary to prevent certain functional groups from undergoing undesired reactions.The selection of suitable protecting groups for certain functional groups and the conditions suitable for protection and deprotection are well known in the art.For example, numerous protecting groups and their introduction and removal are described in TW Greene and PG M Huts, Protecting Groups in Organic Synthesis, Second Edition, Wiley, New York, 1991 and the references cited therein.

[0390] The compounds provided herein can be isolated and purified by known standard procedures. Such procedures include (but are not limited to) recrystallization, column chromatography or HPLC. The following schemes are presented in detail for the preparation of representative substituted biaryl amides listed herein. The compounds provided herein can be prepared from known or commercially available starting materials and reagents by those skilled in the art of organic synthesis.

[0391] The enantiomerically pure compounds provided herein can be prepared according to any method known to those skilled in the art. For example, they can be prepared by chiral or asymmetric synthesis from suitable optically pure precursors, or can be obtained from the racemates by any conventional method, for example, chromatographic resolution using chiral columns, TLC, or preparation of diastereoisomers, their separation, and regeneration of the desired enantiomer. See, e.g., Enantiomers, Racemates and Resolutions, J. Jacques, A. Collet, and S.H. Wilen, (Wiley-Interscience, New York, 1981); S.H. Wilen, A. Collet, and J. Jacques, Tetrahedron, 2725 (1977); E.L. Eliel, Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); and S.H. Wilen Tables of Resolving Agents and Optical Resolutions 268 (E.L. Eliel ed., 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, Mihaly Nogradi (1995 VCH Publishers, Inc., NY, NY).

[0392] In certain embodiments, enantiomerically pure compounds of formula (I) may 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 Ad. sorption,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 Resolution via Diastereomeric Salt Formation, the contents of which are incorporated herein by reference in their entireties.

[0393] Enantiomerically pure compounds may also be recovered from the crystallized diastereomers or mother liquors, depending on the solubility characteristics of the particular acid resolving agent used and the particular acid enantiomer used. The identity and optical purity of the particular compound so recovered may be measured by polarimetry or other analytical methods known in the art. The diasteroisomers may then be separated, for example, by chromatography or fractional crystallization, and the desired enantiomer may be regenerated by treatment with an appropriate base or acid. The other enantiomer may be obtained from the racemate in a similar manner or may be worked up from the initial separation liquid.

[0394] In certain embodiments, enantiomerically pure compounds can be separated from racemates by chiral chromatography.Various chiral columns and eluents are available for use in separating enantiomers, and suitable separation conditions can be empirically determined by methods known to those skilled in the art.Exemplary chiral columns available for use in separating enantiomers provided herein include, but are not limited to, CHIRALCEL® OB, CHIRALCEL® OB-H, CHIRALCEL® OD, CHIRALCEL® OD-H, CHIRALCEL® OF, CHIRALCEL® OG, CHIRALCEL® OJ and CHIRALCEL® OK.

[0395] Synthesis procedure The compounds of the present invention can be prepared according to the methods reported in the art (Upasani et al., J.Med.Chem.1997,40:73-84; and Hogenkamp et al., J.Med.Chem.1997,40:61-72) using suitable reagents, starting materials and purification methods known to those skilled in the art. Some representative methods are shown below. In any of the schemes shown below, the compound can be 5α-isomer or 5β-isomer.

[0396] Scheme 1. Exemplary Synthesis of 3β-Methyl-3α-hydroxy-19-nor-pregnan-20-one

[0397] [ka] Scheme 2. Exemplary Synthesis of 3β-Fluoromethyl-3α-hydroxy-19-nor-pregnan-20-one

[0398] [ka] Scheme 3. Exemplary Synthesis of 3β-Difluoromethyl-3α-hydroxy-19-nor-pregnan-20-one

[0399] [ka] Here, the base can be KOt-Bu.

[0400] Scheme 4. Exemplary Synthesis of 3β-ethenyl-3α-hydroxy-19-nor-pregnan-20-one

[0401] [ka] Scheme 5. Exemplary Synthesis of 3β-Chloroethynyl-3α-hydroxy-19-nor-pregnan-20-one

[0402] [ka] Scheme 6. Exemplary Synthesis of 3β-Cyclopropylethynyl-3α-hydroxy-19-nor-pregnan-20-one

[0403] [ka] Scheme 7. Exemplary Synthesis of 3β-Propyn-1-yl-3α-hydroxy-19-nor-pregnan-20-one

[0404] [ka] Scheme 8. Exemplary Synthesis of 3β-Methoxymethyl-3α-hydroxy-19-nor-pregnan-20-one

[0405] [ka] Scheme 9. Exemplary Synthesis of 3β-Trifluoroethynyl-3α-hydroxy-19-nor-pregnan-20-one

[0406] [ka] Scheme 10. Exemplary syntheses of 21-hydroxy and 21-hemisuccinate 19-norpregnanes

[0407] [ka] Scheme 11. Exemplary Synthesis of 19-norpregnane 21-thiosulfates

[0408] [ka] Scheme 12. Exemplary Synthesis of 21-Heteroaryl-19-norpregnanes

[0409] [ka] wherein Cy is an N-containing heteroaryl.

[0410] Scheme 13. Exemplary Synthesis of 21-Heteroaryloxy / Thiooxy 19-norpregnanes

[0411] [ka] wherein Cy is heteroaryl; and X is -O- or -S-.

[0412] Example 1. Synthesis of Compounds 8a / b, 9a / b and 10a / b

[0413] [ka] 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 using a hydrogen balloon. After stirring at room temperature for 24 h, 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%).1 H NMR (400 MHz, CDCl 3 ), δ(ppm), 2.61-2.54(m, 1H), 0.98(S, 3H).

[0414] Synthesis of compound 3. To a solution of compound 2 (274 mg. 1 mmol) in methanol (4 mL) was added iodine (0.1 mmol). After stirring at 60° C. for 12 h, TLC showed no SM and the solvent was removed in vacuo. The crude product was dissolved in dichloromethane (20 mL) and saturated NaHCO 3 (15 mL), washed with brine, and then with Na 2 SO 4 Dry and filter, The residue was purified by chromatography on basic alumina (petroleum ether / ethyl acetate=9:1) to give compound 3 (280 mg, 0.87 mmol, 87%). 1 H NMR (400 MHz, CDCl 3 ), δ(ppm), 3.19(S, 3H), 3.13(S, 3H), 3.18-3.13(m, 1H), 0.83(S, 3H).

[0415] Synthesis of compound 4. To a suspension of t-BuOK (300 mg, 2.68 mmol) in THF (30 mL) at 0° C., ethyltriphenylphosphonium bromide (995 mg, 2.69 mmol) was added slowly. After stirring at 60° C. for 3 h, compound 3 (86 mg, 0.268 mmol) was added and the mixture was stirred at 60° C. for another 2 h. The reaction mixture was poured into saturated ammonium chloride and extracted with EtOAc (2×50 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated to give crude compound 4 (274 mg). The crude product was used in the next step without further purification.

[0416] 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 h, 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 give compound 5 (60 mg, 0.21 mmol, 78% for two steps). 1 H NMR (400 MHz, CDCl3), δ(ppm), 5.13-5.08(m, 3H), 0.73(m, 3H).

[0417] Synthesis of Compounds 6a and 6b. To a solution of MeMgBr (5 mmol, 1 M in THF) in THF (20 mL) at 0° C., a solution of compound 5 (858 mg, 3 mmol) in dry THF (5 mL) was added by syringe pump over 30 min. After stirring at 0° C. for 5 h, 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 layers were 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, CDCl 3 ), 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 (400 MHz, CDCl 3 ), δ(ppm), 5.14-5.09(m, 1H), 1.21(s, 3H), 0.88(s, 3H).

[0418] Synthesis of Compound 7a. To a solution of Compound 6a (200 mg, 0.66 mmol) in dry THF (5 mL) was added borane-tetrahydrofuran complex (2 mL of a 1.0 M solution in THF). After stirring at room temperature for 1 h, the reaction mixture was cooled in an ice bath and then washed with 10% aqueous NaOH (1 mL), followed by H 2 O 2 The mixture was stirred at room temperature for 1 h and then extracted with EtOAc (3×10 mL). The combined organic layers were washed with 10% Na 2 S 2 O 3 Wash with aqueous solution (10 mL), brine (10 mL), and MgSO 4 The crude product was used in the next step without further purification.

[0419] Synthesis of compound 7b. Compound 6b (150 mg, 0.50 mmHg) in dry THF (5 mL) was dissolved in 100 mL of ethyl acetate. To a solution of 1.0 ml of 1.5% NaOH (1 mL) was added borane-tetrahydrofuran complex (1.34 mL of a 1.0 M solution in THF). After stirring at room temperature for 1 h, the reaction mixture was cooled in an ice bath and then diluted with 10% aqueous NaOH (1 mL), followed by H 2 O 2 The mixture was stirred at room temperature for 1 h and then extracted with EtOAc (3×10 mL). The combined organic layers were washed with 10% Na 2 S 2 O 3 Wash with aqueous solution (10 mL), brine (10 mL), and MgSO 4 The crude product was used in the next step without further purification.

[0420] Synthesis of compound 8a. 10 mL of H 2 O-saturated dichloromethane (dichloromethane in a few milliliters of H 2To a solution of crude compound 7a (260 mg) dissolved in 100 mL of ethyl acetate (which had been shaken with 200 mL of ethyl acetate and then separated from the aqueous layer) was added Dess-Martin periodinate (449 mg, 1.06 mmol). After stirring at room temperature for 24 h, the reaction mixture was extracted with dichloromethane (3×10 mL). The combined organic layers were washed with 10% Na 2 S 2 O 3 Wash with aqueous solution (10 mL), brine (10 mL), and MgSO 4 The mixture was dried at 40° C., filtered and concentrated, and the residue was purified by chromatography on silica gel (petroleum ether / ethyl acetate=4:1 to 2:1) to give the title compound 8a (85 mg, 0.27 mmol, 40% in two steps) as a white solid. 1 H NMR (400 MHz, CDCl 3 ), δ(ppm), 2.57-2.53(m, 1H), 2.12(S, 3H), 1.20(S, 3H), 0.62(S, 3H).

[0421] Synthesis of compound 8b. 10 mL of H 2 O-saturated dichloromethane (dichloromethane in a few milliliters of H 2 To a solution of crude compound 7b (200 mg) dissolved in 100 mL of ethyl acetate (which had been shaken with 200 O and then separated from the aqueous layer) was added Dess-Martin periodinate (400 mg, 0.94 mmol). After stirring at room temperature for 24 h, the reaction mixture was extracted with dichloromethane (3×10 mL). The combined organic layers were washed with 10% Na 2 S 2 O 3 Wash with aqueous solution (10 mL), brine (10 mL), and MgSO 4 The mixture was dried at 40° C., filtered and concentrated, and the residue was purified by chromatography on silica gel (petroleum ether / ethyl acetate=4:1 to 2:1) to give the title compound 8b (90 mg, 0.28 mmol, 57% in two steps) as a white solid. 1 H NMR (400 MHz, CDCl 3), δ(ppm), 2.55-2.51(m, 1H), 2.11(S, 3H), 1.32(S, 3H), 0.61(S, 3H).

[0422] Synthesis of compound 9a. To a solution of compound 8a (70 mg, 0.22 mmol) in MeOH (5 mL), 2 drops of HBr (48%) were added followed by bromine (100 mg, 0.63 mmol). After stirring at room temperature for 1 h, the reaction mixture was poured into ice water and then extracted with ethyl acetate (15 mL x 3). The combined organic layers were washed with brine (20 mL) and concentrated with MgSO 4 The crude product was used in the next step without further purification.

[0423] Synthesis of compound 9b. To a solution of compound 8b (80 mg, 0.25 mmol) in MeOH (5 mL), 2 drops of HBr (48%) were added followed by bromine (100 mg, 0.63 mmol). After stirring at room temperature for 1 h, the reaction mixture was poured into ice water and then extracted with ethyl acetate (15 mL x 3). The combined organic layers were washed with brine (20 mL) and concentrated with MgSO 4 The crude product was used in the next step without further purification.

[0424] Synthesis of compound 10a. A solution of crude compound 9a (90 mg) in acetone (10 mL) was purified by CF 3 COOH (0.5 mL) and Et 3 N (0.7 mL). After heating at reflux for 30 min, CF 3 COONa salt (540 mg, 3.97 mmol) was added and the mixture was Reflux overnight. The reaction was cooled to room temperature and the solvent was removed in vacuo. The residue was extracted with ethyl acetate (10 mL x 3). The combined organic layers were washed with brine (15 mL) and MgSO 4The mixture was dried at 40° C., filtered and concentrated, and the residue was purified by chromatography on silica gel (petroleum ether / ethyl acetate=3:1) to give compound 10a (25 mg, 0.075 mmol, 34% for two steps). 1 H NMR (400 MHz, CDCl 3 ), δ(ppm), 4.24-4.12(m, 2H), 2.48-2.44(m, 1H), 1.07(S, 3H), 0.64(S, 3H).

[0425] Synthesis of compound 10b. A solution of crude compound 9b (95 mg) in acetone (10 mL) was purified by CF 3 COOH (0.5 mL) and Et 3 N (0.7 mL). After heating at reflux for 30 min, CF 3 COONa salt (540 mg, 3.97 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 x 3). The combined organic layers were washed with brine (15 mL) and MgSO 4 The mixture was dried at 40° C., filtered and concentrated. The residue was purified by chromatography on silica gel (petroleum ether / ethyl acetate=3:1) to give compound 10b (34 mg, 0.10 mmol, 41% for two steps). 1 H NMR (400 MHz, CDCl 3 ), δ(ppm), 4.25-4.12(m, 2H), 2.48-2.44(m, 1H), 1.32(S, 3H ), 0.64(S, 3H).

[0426] Example 2. Synthesis of compounds 14a / b, 15a / b and 16a / b

[0427] [ka] Synthesis of Compounds 11a and 11b. 2Compound 5 (800 mg, 2.79 mmol) and PhSO in THF (25 mL) and HMPA (0.5 mL) at −78 °C 2 CF 2 To a solution of H (540 mg, 2.79 mmol) was added LHMDS (4 mL, 1 M in THF) dropwise. After stirring at -78 °C for 2 h, the reaction mixture was diluted with saturated NH 4 Quench with aqueous Cl (10 mL), warm to room temperature, and then add Et 2 The mixture was extracted with 20 mL x 3 O. 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 11a and 11b (700 mg). The mixture was further purified by chiral-HPLC to give compound 11a (200 mg, t = 4.31 min). 1 H NMR (400 MHz, CDCl 3 ), 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 (260mg,t=5.66min) 1 H NMR (400 MHz, CDCl 3 ), 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) were obtained. Chiral-HPLC separation conditions: Co-solvent: MeOH (0.1%HNEt 2 ), Column: OZ-H(4.6 * 250mm 5μm), column temperature: 38.9, CO 2 Flow rate: 2.10, cosolvent flow rate: 0.9, cosolvent %: 30, PDA start wavelength: 214 nm, PDA start wavelength: 359 nm, peak 1: 11a RT = 4.31 min, peak 2: 11b RT = 5.66 min Synthesis of compound 12a. 2Compound 11a (100 mg, 0.209 mmol) and anhydrous Na in anhydrous methanol (5 mL) at -20°C 2 HPO 4 To a solution of (100 mg), 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 dissolved in Et 2 The combined organic layers were washed with brine (20 mL) and MgSO. 4 The mixture was dried at 40° C., 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 (400 MHz, CDCl3), δ(ppm), 5.60-5.45(t, 1H, J= 60 Hz), 5.17-5.15(m, 1H), 0.88(m, 3H).

[0428] Synthesis of compound 12b. 2 Compound 11b (100 mg, 0.209 mmol) and anhydrous Na in anhydrous methanol (5 mL) at -20 °C 2 HPO 4 To a solution of (100 mg), 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 dissolved in Et 2 The combined organic layers were washed with brine (20 mL) and MgSO. 4 The mixture was dried at 40° C., 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 (400 MHz, CDCl 3 ), δ(ppm), 6.02-5.88(t, 1H, J=49.2 Hz), 5.17-5.15(m, 1H), 0.88(s, 3H).

[0429] Synthesis of Compound 13a. To a solution of Compound 12a (150 mg, 0.443 mmol) in dry THF (5 mL) was added borane-tetrahydrofuran complex (1.34 mL of a 1.0 M solution in THF). After stirring at room temperature for 1 h, the reaction mixture was cooled in an ice bath and then washed with 10% aqueous NaOH (1 mL), followed by H 2 O 2 The mixture was stirred at room temperature for 1 h and then extracted with EtOAc (3×10 mL). The combined organic layers were washed with 10% Na 2 S 2 O 3 Wash with aqueous solution (10 mL), brine (10 mL), and MgSO 4 The crude product was used in the next step without further purification.

[0430] Synthesis of Compound 13b. To a solution of Compound 12b (150 mg, 0.443 mmol) in dry THF (5 mL) was added borane-tetrahydrofuran complex (1.34 mL of a 1.0 M solution in THF). After stirring at room temperature for 1 h, the reaction mixture was cooled in an ice bath and then washed with 10% aqueous NaOH (1 mL), followed by H 2 O 2 The mixture was stirred at room temperature for 1 h and then extracted with EtOAc (3×10 mL). The combined organic layers were washed with 10% Na 2 S 2 O 3 Wash with aqueous solution (10 mL), brine (10 mL), and MgSO 4 The crude product was used in the next step without further purification.

[0431] Synthesis of compound 14a. 10 mL of H 2 O-saturated dichloromethane (a few milliliters of dichloromethane) Litre of H 2To a solution of crude compound 13a (200 mg) dissolved in 100 mL of ethyl acetate (which had been shaken with 200 O and then separated from the aqueous layer) was added Dess-Martin periodinate (449 mg, 1.06 mmol). After stirring at room temperature for 24 h, the reaction mixture was extracted with dichloromethane (3×10 mL). The combined organic layers were washed with 10% Na 2 S 2 O 3 Wash with aqueous solution (10 mL), brine (10 mL), and MgSO 4 The mixture was dried at 40° C., filtered and concentrated, and the residue was purified by chromatography on silica gel (petroleum ether / ethyl acetate=5:1) to give compound 14a (85 mg, 0.24 mmol, 54%) as a white solid. 1 H NMR (400 MHz, CDCl 3 ), δ(ppm), 5.60-5.71(t, 1H, J=56.8 Hz), 2.57-2.51(m, 1H), 0.62(S, 3H).

[0432] Synthesis of compound 14b. 10 mL of H 2 O-saturated dichloromethane (dichloromethane in a few milliliters of H 2 To a solution of crude compound 13b (210 mg) dissolved in 100 mL of ethyl acetate (which had been shaken with 200 mL of ethyl acetate and then separated from the aqueous layer) was added Dess-Martin periodinate (380 mg, 0.896 mmol). After stirring at room temperature for 24 h, the reaction mixture was extracted with dichloromethane (3×10 mL). The combined organic layers were washed with 10% Na 2 S 2 O 3 Wash with aqueous solution (10 mL), brine (10 mL), and MgSO 4 The mixture was dried at 40° C., filtered and concentrated. The residue was purified by chromatography on silica gel (petroleum ether / ethyl acetate=5:1) to give compound 14b (90 mg, 0.254 mmol, 57%) as a white solid. 1 H NMR (400 MHz, CDCl 3), δ(ppm), 6.01-5.73(t, 1H, J = 56.4 Hz), 2.55-2.54(m, 1H), 2.12(S, 3H), 0.62(S, 3H).

[0433] 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 h, the reaction mixture was poured into ice water and then extracted with ethyl acetate (15 mL x 3). The combined organic layers were washed with brine (20 mL) and concentrated with MgSO 4 The crude product was used in the next step without further purification.

[0434] 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 h, the reaction mixture was poured into ice water and then extracted with ethyl acetate (15 mL x 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.

[0435] Synthesis of compound 16a. A solution of crude compound 15a (90 mg) in acetone (10 mL) was purified by CF 3 COOH (0.5 mL) and Et 3 N (0.7 mL). After heating at reflux for 30 min, CF 3 COONa 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 x 3). The combined organic layers were washed with brine (15 mL) and MgSO 4The mixture was dried at 40° C., filtered and concentrated, and the residue was purified by chromatography on silica gel (petroleum ether / ethyl acetate=3:1) to give compound 16a (25 mg, 0.067 mmol, 34% for two steps). 1 H NMR (400 MHz, CDCl 3 ), δ(ppm), 5.60-5.31(t, 1H, J= 56.8 Hz), 4.22-4.18(m, 2H), 0.64(S, 3H).

[0436] Synthesis of compound 16b. A solution of crude compound 15b (95 mg) in acetone (10 mL) was purified by CF 3 COOH (0.5 mL) and Et 3 The mixture was treated with N (0.7 mL) for 30 min. After heating to reflux, CF 3 COONa 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 x 3). The combined organic layers were washed with brine (15 mL) and MgSO 4 The mixture was dried at 40° C., filtered and concentrated, and the residue was purified by chromatography on silica gel (pertroleum:ether / ethyl acetate=3:1) to give compound 16b (38 mg, 0.102 mmol, 46% for two steps). 1 H NMR(400 MHz, CDCl3), δ(ppm), 6.00-5.74(t, 1H, J=51.2 Hz), 4.42-4.18(m, 2H), 0.64(S, 3H).

[0437] Example 3. Synthesis of Compounds 9, 9a / b / c and 11a / b

[0438] [ka] Synthesis of compound 5. To a solution of 4 (5 g, 15 mmol) in dry THF (20 mL) was added borane-tetrahydrofuran complex (30 mL of a 1.0 M solution in THF). After stirring at room temperature for 1 h, the reaction mixture was cooled in an ice bath and added with 10% aqueous NaOH (56 mL) followed by H 2 O 2 The reaction mixture was stirred at room temperature for 1 h and then extracted with EtOAc (3×100 mL). The combined organic layers were washed with 10% Na 2 S 2 O 3 Wash with aqueous solution (100 mL), brine (100 mL), and MgSO 4 The crude product 5 was obtained by drying at 40° C., filtering and concentrating. (3.2 g, 9.0 mmol). The crude product was used in the next step without further purification.

[0439] Synthesis of compound 6. To a solution of compound 5 (3.2 g, 9 mmol) in THF (40 mL), hydrogen chloride (3 mL, 3 M aqueous solution) was added. After stirring at room temperature for 12 h, 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 (400 MHz, 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).

[0440] 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 h, a suspension of compound 6 (2.2 g, 7.2 mmol) in DMSO (20 mL) was added dropwise. After stirring at room temperature for an additional 2.5 h, the reaction mixture was poured into ice-cold water and extracted with ether (100 mL x 3). The combined organic layers were washed with brine (100 mL x 3), dried (MgSO 4 ), filtered and concentrated to give compound 7 (1.6 g, 70%) as a white solid. 1 H NMR (400 MHz, 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).

[0441] Synthesis of compound 8. 60 mL of H 2 Saturated dichloromethane (CH 2 Cl 2 to a few milliliters of H 2 To a solution of compound 7 (1.6 g, 5.0 mmol) in 100 mL of 1H2O (which had been separated from the aqueous layer) was added Dess-Martin periodinane (4.2 g, 10 mmol). After stirring at room temperature for 24 h, the reaction mixture was extracted with dichloromethane (3 x 100 mL). The combined organic layers were washed with 10% Na 2 S 2 O 3 Wash with aqueous solution (100 mL), brine (100 mL), and MgSO 4 The mixture was dried at 40° C., filtered and concentrated, and the residue was purified by chromatography on silica gel (petroleum ether / ethyl acetate=20:1 to 10:1) to give compound 8 (1.2 g, 75%) as a white solid. 1 H NMR(400 MHz, CDCl3), δ(ppm), 2.50-2.58(m, 2H), 2.56-2.61(m, 2H), 2.19(s, 3H), 0.65(s, 3H). Synthesis of compound 9. To a solution of compound 8 (1.2 g, 3.8 mmol) in dry methanol (250 mL) was added Na (262 mg, 11.4 mmol). After heating at reflux for 16 h, the solvent was removed in vacuo and the residue was dissolved in dichloromethane (100 mL) and then diluted with H 2 HO (3 × 50 mL) and brine (100 mL), and then washed with MgSO 4 The mixture was dried at 70° C., filtered and concentrated. The residue was purified by silica gel chromatography (petroleum ether / ethyl acetate=10:1 to 5:1) to give 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(400 MHz, 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).

[0442] Synthesis of compound 10a. Compound 9a (50 mg, 0.14 mmol) in MeOH (5 mL) was dissolved in 10 mL of 10 ... To a solution of l) were added 2 drops of HBr (48%) followed by 6 drops of bromine. After stirring at room temperature for 1 h, the reaction mixture was poured into ice water and then extracted with ethyl acetate (15 mL x 3). The combined organic layers were washed with brine (50 mL) and diluted with MgSO 4 The crude product was used in the next step without further purification. Synthesis of compound 11a. A solution of compound 10a (46 mg, 0.11 mmol) in acetone (10 mL) was dissolved in CF 3 COOH (0.5 mL) and Et 3 N (0.7 mL). After heating at reflux for 30 min, CF 3 COONa (300 mg, 2.2 mmol) was added in portions over 10 h. The reaction mixture was cooled to room temperature and the solvent was removed in vacuo. The residue was extracted with ethyl acetate (10 mL x 3). The combined organic layers were washed with brine (30 mL) and MgSO 4 The mixture was dried at 77° C., filtered and concentrated. The residue was purified by chromatography on silica gel (petroleum ether / ethyl acetate=10:1 to 3:1) to give compound 11a (10 mg, 25%). 1 H NMR (400 MHz, 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).

[0443] Synthesis of compound 10b. To a solution of compound 9b (50 mg, 0.14 mmol) in MeOH (5 mL), 2 drops of HBr (48%) were added followed by 6 drops of bromine. After stirring at room temperature for 1 h, the reaction mixture was poured into ice water and then extracted with ethyl acetate (15 mL x 3). The combined organic layers were washed with brine (50 mL) and concentrated with MgSO 4 The crude product was used in the next step without further purification.

[0444] Synthesis of compound 11b. A solution of compound 10b (46 mg, 0.11 mmol) in acetone (10 mL) was dissolved in CF 3 COOH (0.5 mL) and Et 3 N (0.7 mL). After heating at reflux for 30 min, CF 3COONa (300 mg, 2.2 mmol) was added in portions over 10 h. The reaction mixture was cooled to room temperature and the solvent was removed in vacuo. The residue was extracted with ethyl acetate (10 mL x 3). The combined organic layers were washed with brine (30 mL) and MgSO 4 The mixture was dried at 77° C., filtered and concentrated. The residue was purified by chromatography on silica gel (petroleum ether / ethyl acetate=10:1 to 3:1) to give compound 11b (10 mg, 25%). 1 H NMR(400 MHz, 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).

[0445] Example 3. Synthesis of 6-difluoro analogues

[0446] [ka] (a) Ethane-1,2-diol, cat. TsOH, toluene, refluxed overnight; (b) Ac 2 (c) BH 3 , THF, NaOH / H 2 O 2 , 0 °C then room temperature; (d) Dess-Martin periodinane, CH 2 Cl 2 (e) DAST (neat), 40° C., 4 days; (f) potassium carbonate, MeOH, overnight at room temperature; (g) MeMgBr, THF, 0° C.; (h) 3M HCl, acetone; (i) (ethyl)-triphenylphosphonium bromide, t-BuOK, THF, 65° C.

[0447] Example 4. Synthesis of 5,6-alkenyl-6-monofluoro analogs

[0448] [ka]

[0449] [ka] (a) Ethane-1,2-diol, cat. TsOH, toluene, refluxed overnight; (b) Ac 2 (c) BH 3 , THF, NaOH / H 2 O 2 , 0 °C then room temperature; (d) Dess-Martin periodinane, CH 2 Cl 2 (e) DAST (neat), cat. H2SO4, fuming; (f) Potassium carbonate, MeOH, overnight at room temperature; (g) MeMgBr, THF, 0°C; (h) 3M HCl, acetone; (i) (ethyl)-triphenylphosphonium bromide, t-BuOK, THF, 65°C.

[0450] Example 5. Synthesis of 6β-Me Analogues

[0451] [ka]

[0452] [ka] (a) Ethane-1,2-diol, cat. TsOH, toluene, refluxed overnight; (b) Ac 2 (c) BH 3 , THF, NaOH / H 2 O 2 , 0 °C then room temperature; (d) Dess-Martin periodinane, CH 2 Cl 2 (e) methyltriphenylphosphonium bromide, potassium tert-butoxide, THF, room temperature; (f) TCDI, DMAP, CH2Cl2, 40°C; (g) Ph3SnH, AlBN, toluene, 110°C; (h) potassium carbonate, MeOH, room temperature overnight; (i) MeMgBr, THF, 0°C

[0453] [ka] (a) 3M HCl, acetone; (b) (ethyl)-triphenylphosphonium bromide, t-BuOK, THF, 65°C; (c) BH 3 , THF, NaOH / H 2 O 2 , 0 °C then room temperature; (d) Dess-Martin periodinane, CH 2 Cl 2 , room temperature overnight.

[0454] Example 6

[0455] [ka]

[0456] [ka] Synthesis of compounds 39 and 40. A small piece of lithium (7.63 g, 1.1 mol) was added to 2.7 L of concentrated ammonia in a three-neck 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 min until the reaction mixture turned pale yellow. Ammonium chloride (70 g) was added and the excess ammonia was allowed to evaporate by standing. The residue was extracted with 0.5 N HCl (500 mL) and dichloromethane (500 mL x 2). The combined organic layers were washed with saturated NaHCO 3 Wash with solution of Na 2 SO 4The mixture was dried over 500 ml, 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 a suspension of pyridinium chlorochromate (PCC) (32.8 g, 152 mmol) in 450 mL of dichloromethane. After stirring at room temperature for 2 h, the dark brown reaction mixture was added with 2N NaOH solution (500 mL) and stirred for an additional 10 min. The resulting solution was extracted with dichloromethane and the combined organic layers were washed with 2N HCl, brine and Na 2 SO 4 The mixture was dried at 77° C., filtered and concentrated. The residue was purified by chromatography on silica gel (petroleum ether / ethyl acetate=20:1 to 10:1) to give the title compound 40 (16.8 g, 80%) as a white solid. 1 H NMR (400 MHz, CDCl 3 ), δ(ppm), 3.65(t, 1H, J= 8 Hz, 1H), 0.77(s, 3H).40 1 H NMR (400 MHz, CDCl 3 ), δ(ppm), 0.88(s, 3H).

[0457] 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 h, the solvent was removed in vacuo. The crude product was dissolved in dichloromethane (200 mL) and saturated NaHCO 3 (150 mL), washed with brine, and then with Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated, and 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%). 1 H NMR (400 MHz, CDCl 3 ), δ(ppm), 3.18(s, 3H), 3.12(s, 3H), 0.85(s, 3H).

[0458] Synthesis of compound 42. To a suspension of t-BuOK (7.36 g, 65.7 mmol) in THF (100 mL) at 0° C., ethyltriphenylphosphonium bromide (26 g, 70 mmol) was added slowly. After stirring at 60° C. for 3 h, compound 41 (7 g, 21.9 mmol) was added and the mixture was stirred at 60° C. for another 2 h. After cooling to room temperature, the reaction mixture was poured into saturated ammonium chloride and extracted with EtOAc (2×500 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated to give crude compound 42 (7.36 g, 100%). The crude product was used in the next step without further purification.

[0459] 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 h, 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 give compound 43 (4.8 g, 16.7 mmol, 76% for two steps). 1 H NMR (400 MHz, CDCl 3 ), δ(ppm), 5.12-5.10(m, 1H), 1.64-1.63(m, 3H), 0.77(s, 3H).

[0460] Synthesis of Compounds 44a and 44b. To a solution of MeMgBr (28 mmol, 1 M in THF) in THF (50 mL) at 0° C., a solution of compound 43 (4.8 g, 16.8 mmol) in dry THF (10 mL) was added by syringe pump over 30 min. After stirring at 0° C. for 5 h, 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 layers were 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). 1 H NMR (400 MHz, CDCl 3 ), 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 (400 MHz, CDCl 3 ), δ(ppm), 5.12-5.10(m, 1H), 1.12(s, 3H), 0.88(s, 3H).

[0461] Synthesis of compound 45a. To a solution of compound 44a (2 g, 6.62 mmol) in dry THF (50 mL) was added borane-tetrahydrofuran complex (20 mL; 1.0 M solution in THF). After stirring at room temperature for 1 h, the reaction mixture was cooled in an ice bath and then washed with 10% aqueous NaOH (10 mL) followed by H 2 O 2 The mixture was slowly quenched with a 30% aqueous solution of (12 mL). After stirring at room temperature for 1 h, the mixture was extracted with EtOAc (3×100 mL). The combined organic layers were washed with 10% Na 2 S 2 O 3 Aqueous solution (100mL) , washed with brine (100 mL) and MgSO 4The crude product was used in the next step without further purification.

[0462] Synthesis of compound 46a. 60 mL of aqueous dichloromethane (dichloromethane dissolved in a few milliliters of H 2 To a solution of crude compound 45a (2 g, 6.62 mmol) in 1H2O (which had been separated from the aqueous layer) was added Dess-Martin periodinate (5.5 g, 13 mmol). After stirring at room temperature for 24 h, the reaction mixture was extracted with dichloromethane (3 x 100 mL). The combined organic layers were washed with 10% Na 2 S 2 O 3 Wash with aqueous solution (100 mL), brine (100 mL), and MgSO 4 The mixture was dried at 40° C., filtered and concentrated, and the residue was purified by chromatography on silica gel (petroleum ether / ethyl acetate=10:1 to 5:1) to give compound 46a (1 g, 3.14 mmol, 47% in two steps) as a white solid. 1 H NMR (400 MHz, CDCl 3 ), δ(ppm), 2.56-2.51(m, 1H), 2.11(s, 3H), 1.20(s, 3H), 0.62(s, 3H).

[0463] Synthesis of compound 47a. To a solution of compound 46a (600 mg, 1.89 mmol) in MeOH (20 mL) was added 5 drops of HBr (48%) followed by bromine (302 mg, 1.89 mmol). After stirring at room temperature for 1 h, the reaction mixture was poured into ice water and then extracted with ethyl acetate (100 mL x 3). The combined organic layers were washed with brine (200 mL) and diluted with MgSO 4 The crude product was used in the next step without further purification.

[0464] Synthesis of compound 48a. A solution of compound 47a (600 mg, 1.5 mmol) in 10 mL of acetone was purified by CF 3 COOH (6.8 mL) and Et 3 N (9.5 mL). After refluxing for 30 min, CF 3 COONa salt (4.49 g, 33 mmol) was added in portions over 10 h. The reaction mixture was cooled to room temperature and the solvent was removed in vaccuo. The residue was extracted with ethyl acetate and MgSO 4 The mixture was dried at 47° C., filtered and concentrated, and purified by chromatography on silica gel (petroleum ether / ethyl acetate=10:1 to 3:1) to give 48a (300 mg, yield: 50% for two steps). 1 H NMR (400 MHz, CDCl 3 ), 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).

[0465] Synthesis of compound 45b. To a solution of compound 44b (500 mg, 1.66 mmol) in dry THF (13 mL) was added borane-tetrahydrofuran complex (5 mL; 1.0 M solution in THF). After stirring at room temperature for 1 h, the reaction mixture was cooled in an ice bath and then washed with 10% aqueous NaOH (2.5 mL) followed by H 2 O 2 The mixture was slowly quenched with a 30% aqueous solution of (3 mL). The mixture was warmed to room temperature and stirred for 1 h, then extracted with EtOAc (3×25 mL). The combined organic layers were washed with 10% Na 2 S 2 O 3 Wash with aqueous solution (25 mL), brine (25 mL), and MgSO 4 The crude product was used in the next step without further purification.

[0466] Synthesis of compound 46b. 15 mL of wet dichloromethane (dichloromethane in a few milliliters of H 2To a solution of crude compound 45b (500 mg, 1.66 mmol) in 1H2O (which had been separated from the aqueous layer) was added Dess-Martin periodinate (1.38 g, 3.3 mmol). After stirring at room temperature for 24 h, the reaction mixture was extracted with dichloromethane (3 x 25 mL). The combined organic layers were washed with 10% NaCl and diluted with 10% NaCl. 2 S 2 O 3 Wash with aqueous solution (25 mL), brine (25 mL), and MgSO 4 Dry and filter, The residue was purified by chromatography on silica gel (petroleum ether / ethyl acetate=10:1 to 5:1) to give the title compound 46b (250 mg, 0.79 mmol, 47% for two steps) as a white solid. 1 H NMR (400 MHz, CDCl 3 ), δ(ppm), 2.54-2.50(m, 1H), 2.11(s, 3H), 1.23(s, 3H), 0.62(s, 3H).

[0467] Synthesis of compound 47b. To a solution of compound 46b (250 mg, 0.79 mmol) in MeOH (5 mL) was added 2 drops of HBr (48%) followed by bromine (126 mg, 0.79 mmol). After stirring at room temperature for 1 h, the reaction mixture was poured into ice water and then extracted with ethyl acetate (10 mL x 3). The combined organic layers were washed with brine (20 mL) and concentrated with MgSO 4 The crude product was used in the next step without further purification.

[0468] Synthesis of compound 48b. A solution of compound 47b (60 mg, 0.15 mmol) in acetone (10 mL) was purified by CF 3 COOH (0.7 mL) and Et 3 N (0.9 mL). After refluxing for 30 min, CF 3COONa salt (449 mg, 3.3 mmol) was added in portions over 10 h. The reaction mixture was cooled to room temperature and the solvent was removed in vacuo. The residue was extracted with ethyl acetate and MgSO 4 The mixture was dried at 47° C., filtered and concentrated, and the residue was purified by chromatography on silica gel (petroleum ether / ethyl acetate=10:1 to 3:1) to give 48b (20 mg, yield: 33% for two steps). 1 H NMR (400 MHz, CDCl 3 ), 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).

[0469] Example 7

[0470] [ka]

[0471] [ka] Synthesis of compounds 49a and 49b. 2 Compound 43 (800 mg, 2.79 mmol) and PhSO in THF (25 mL) and HMPA (0.5 mL) at −78 °C under 2 CF 2 To a solution of H (540 mg, 2.79 mmol) was added LHMDS (4 mL, 1 M in THF) dropwise. After stirring at -78 °C for 2 h, the reaction mixture was diluted with saturated NH 4 Quench with aqueous Cl (10 mL), warm to room temperature, and then add Et 2The mixture was extracted with 20 mL x 3 O. 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 give compounds 49a (250 mg, t = 3.29 min) and 49b (230 mg, t = 3.89 min). Chiral-HPLC conditions: Elutant = MeOH (0.1% DEA); Column = AS-H (4.6 * 250mm, 5μm).

[0472] Synthesis of compound 50a. 2 Compound 49a (250 mg, 0.524 mmol) and anhydrous Na in anhydrous methanol (5 mL) at -20 °C 2 HPO 4 To a solution of (150 mg) was added Na / Hg amalgam (800 mg). After stirring at -20°C to 0°C for 1 hour, the methanol solution was decanted and the solid residue was dissolved in Et 2 The combined organic phase was removed in vacuo and 20 ml of brine was added, followed by Et 2 The combined ether phase was extracted with MgSO 4 The mixture was dried at 40° C., 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 (400 MHz, CDCl 3 ), δ(ppm), 5.60-5.30(t, 1H, J= 63.6 Hz), 5.14-5.09(m, 1H), 0.88(m, 3H).

[0473] Synthesis of compound 50b. 2 Compound 49b (230 mg, 0.489 mmol) and anhydrous Na in anhydrous methanol (5 mL) at -20 °C 2 HPO 4To a solution of (150 mg) 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 dissolved in Et 2 The combined organic phase was removed in vacuo and 20 ml of brine was added, followed by Et 2 The combined ether phase was extracted with MgSO 4 The mixture was dried at 40° C., 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 (400 MHz, CD 3 COCD 3 ), δ(ppm), 6.02-5.88(t, 1H, J= 59.6 Hz), 5.13-5.08(m, 1H), 0.92(s, 3H).

[0474] Synthesis of compound 51a. To a solution of compound 50a (130 mg, 0.384 mmol) in dry THF (5 mL) was added borane-tetrahydrofuran complex (1.3 mL; 1.0 M solution in THF). After stirring at room temperature for 1 h, the reaction mixture was cooled in an ice bath and then washed with 10% aqueous NaOH (1 mL) followed by H 2 O 2 The mixture was stirred at room temperature for 1 h and then slowly quenched with a 30% aqueous solution of Et The mixture was extracted with OAc (3×10 mL). The combined organic layers were washed with 10% Na 2 S 2 O 3 Wash with aqueous solution (10 mL), brine (10 mL), and MgSO 4 The crude product was used in the next step without further purification.

[0475] Synthesis of compound 51b. To a solution of compound 50b (120 mg, 0.355 mmol) in dry THF (5 mL) was added borane-tetrahydrofuran complex (1.20 mL; 1.0 M solution in THF). After stirring at room temperature for 1 h, the reaction mixture was cooled in an ice bath and then washed with 10% aqueous NaOH (1 mL) followed by H 2 O 2 The mixture was stirred at room temperature for 1 h and then extracted with EtOAc (3×10 mL). The combined organic layers were washed with 10% Na 2 S 2 O 3 Wash with aqueous solution (10 mL), brine (10 mL), and MgSO 4 The crude product was used in the next step without further purification.

[0476] Synthesis of compound 52a. 10 mL of aqueous dichloromethane (dichloromethane in a few milliliters of H 2 To a solution of compound 51a (200 mg, crude) in 1H2O (which had been separated from the aqueous layer) was added Dess-Martin periodinate (400 mg, 0.94 mmol). After stirring at room temperature for 24 h, the reaction mixture was extracted with dichloromethane (3×10 mL). The combined organic layers were washed with 10% Na 2 S 2 O 3 Wash with aqueous solution (10 mL), brine (10 mL), and MgSO 4 The mixture was dried at 40° C., filtered and concentrated. The residue was purified by chromatography on silica gel (petroleum ether / ethyl acetate=1:5) to give compound 52a (75 mg, 55.1% for two steps) as a white solid. 1 H NMR (400 MHz, CDCl3), δ(ppm), 5.58-5.32(t, 1H, J= 52.0 Hz), 2.53-2.51(m, 1H), 2.14(s, 3H), 0.62(s, 3H).

[0477] Synthesis of compound 52b. 10 mL of wet dichloromethane (dichloromethane in a few milliliters of H 2 To a solution of compound 51b (180 mg, crude) in 1H2O (which had been separated from the aqueous layer) was added Dess-Martin periodinate (380 mg, 0.896 mmol). After stirring at room temperature for 24 h, the reaction mixture was extracted with dichloromethane (3 x 10 mL). The combined organic layers were washed with 10% Na 2 S 2 O 3 Wash with aqueous solution (10 mL), brine (10 mL), and MgSO 4 The mixture was dried at 40° C., filtered and concentrated. The residue was purified by chromatography on silica gel (petroleum ether / ethyl acetate=1:5) to give compound 52b (70 mg, 55.7% for two steps) as a white solid. 1 H NMR (400 MHz, CDCl3), δ(ppm), 5.90-5.61(t, 1H, J = 60 Hz), 2.48-2.43(m, 1H), 2.10(s, 3H), 0.55(s, 3H).

[0478] 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 h, the reaction mixture was poured into ice water and then extracted with ethyl acetate (15 mL x 3). The combined organic layers were washed with brine (20 mL) and concentrated with MgSO 4 The crude product was used in the next step without further purification.

[0479] Synthesis of compound 53b. To a solution of compound 52b (50 mg, 0.14 mmol) in MeOH (5 mL), 2 drops of HBr (48%) were added followed by bromine (100 mg, 0.62 mmol). After stirring at room temperature for 1 h, the reaction mixture was poured into ice water and then extracted with ethyl acetate (15 mL x 3). The combined organic layers were washed with brine (20 mL). Purified with MgSO 4 The crude product was used in the next step without further purification.

[0480] Synthesis of compound 54a. A solution of compound 53a (84 mg, crude) in acetone (6 mL) was purified by CF 3 COOH (0.3 mL) and Et 3 N (0.5 mL). After heating at reflux for 30 min, CF 3 COONa 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 vacuo. The residue was extracted with ethyl acetate (10 mL x 3). The combined organic layers were washed with brine (15 mL) and MgSO 4 The mixture was dried at 40° C., filtered and concentrated. The residue was purified by chromatography on silica gel (petroleum ether / ethyl acetate=3:1) to give compound 54a (15 mg, 36% for two steps). 1 H NMR (500 MHz, CDCl3), δ(ppm), 5.56-5.33(t, 1H, J=56.5 Hz), 4.22-4.13(m, 2H), 3.25-3.23(m, 1H), 0.64(s, 3H).

[0481] Synthesis of compound 54b. A solution of compound 53b (72 mg, crude) in acetone (5 mL) was purified by CF 3 COOH (0.3 mL) and Et 3 N (0.45 mL). After heating at reflux for 30 min, CF 3 COONa 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 x 3). The combined organic layers were washed with brine (10 mL) and MgSO 4 The mixture was dried at 40° C., filtered and concentrated. The residue was purified by chromatography on silica gel (petroleum ether / ethyl acetate=3:1) to give compound 54b (10 mg, 19.2% for two steps). 1H NMR (400 MHz, CDCl3), δ(ppm), 5.96-5.68(t, 1H, J= 56 Hz), 4.24-4.10(m, 2H), 3.2(s,1H), 0.64(s, 3H).

[0482] Example 8

[0483] [ka] Synthesis of compounds 55a and 55b. 2 Compound 5 (1.2 g, 4.2 mmol) and PhSO in THF (25 mL) and HMPA (0.5 mL) at −78 °C under 2 CF 2 To a solution of H (730 mg, 4.2 mmol) was added LHMDS (5.5 mL, 1 M in THF) dropwise. After stirring at -78 °C for 2 h, the reaction mixture was diluted with saturated NH 4 The mixture was warmed to room temperature and quenched with Et 2 The mixture was extracted with 20 mL x 3 O. 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 give compound 55a1 (220 mg, t = 3.62 min). 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(200mg,t=3.94 min) 1H 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(235mg,t=4.95min) 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(220mg,t=6.92min) 1 H 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=46Hz), 5.07-4.98(m, 1H), 0.88(s,3H). Chiral-HPLC conditions: eluent=MeOH(0.1%DEA); column=IC(4.6 * 250mm, 5μm).

[0484] Synthesis of compound 56a. 2 Compound 55a1 (200 mg, 0.434 mmol) and anhydrous Na in anhydrous methanol (15 mL) at -20°C 2 HPO 4 To a solution of (100 mg), Na / Hg amalgam (400 mg) was added. After stirring at -20°C to 0°C for 1 h, the methanol solution was decanted and the solid residue was dissolved in Et 2 The combined organic phase was removed in vacuo and 20 mL of brine was added, followed by Et 2 The combined ether phase was extracted with MgSO 4 The mixture was dried at 40° C., 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 (500 MHz, CDCl3), δ(ppm), 5.12-5.11(m, 1H), 4.2-4.15(d, 2H, J=48 Hz), 0.62(s, 3H).

[0485] Synthesis of compound 56b. 2 Compound 55b2 (200 mg, 0.434 mmol) and anhydrous Na in anhydrous methanol (5 mL) at -20 °C 2 HPO 4 To a solution of (100 mg), 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 dissolved in Et 2 The combined organic phase was removed in vacuo and 20 mL of brine was added, followed by Et 2 The combined ether phase was extracted with MgSO 4 The mixture was dried at 40° C., 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 (500 MHz, CDCl3), δ(ppm), 5.14-4.10(m, 1H), 4.50-4.35(m, 2H), 0.79(s, 3H).

[0486] Synthesis of compound 57a. To a solution of compound 56a (90 mg, 0.281 mmol) in dry THF (5 mL) was added borane-tetrahydrofuran complex (1 mL; 1.0 M solution in THF). After stirring at room temperature for 1 h, the reaction mixture was cooled in an ice bath and then washed with 10% aqueous NaOH (1 mL) followed by H 2 O 2 The mixture was stirred at room temperature for 1 h and then extracted with EtOAc (3×10 mL). The combined organic layers were washed with 10% Na 2 S 2 O 3 Wash with aqueous solution (10 mL), brine (10 mL), and MgSO 4The crude product was used in the next step without further purification.

[0487] Synthesis of compound 57b. To a solution of compound 56b (95 mg, 0.297 mmol) in dry THF (5 mL) was added borane-tetrahydrofuran complex (1.1 mL; 1.0 M solution in THF). After stirring at room temperature for 1 h, the reaction mixture was cooled in an ice bath and then washed with 10% aqueous NaOH (1 mL) followed by H 2 O 2 The mixture was stirred at room temperature for 1 h and then extracted with EtOAc (3×10 mL). The combined organic layers were washed with 10% Na 2 S 2 O 3 Wash with aqueous solution (10 mL), brine (10 mL), and MgSO 4 The crude product was used in the next step without further purification.

[0488] Synthesis of compound 58a. 10 mL of wet dichloromethane (dichloromethane in a few milliliters of H 2 To a solution of compound 57a (130 mg crude) in 1H2O (which had been separated from the aqueous layer) was added Dess-Martin periodinate (300 mg, 707 mmol). After stirring at room temperature for 24 h, the reaction mixture was extracted with dichloromethane (3 x 10 mL). The combined organic layers were washed with 10% Na 2 S 2 O 3 Wash with aqueous solution (10 mL), brine (10 mL), and MgSO 4 The mixture was dried at 40° C., filtered and concentrated, and the residue was purified by chromatography on silica gel (petroleum ether / ethyl acetate=1:5) to give compound 58a (60 mg, 64% for two steps) as a white solid. 1H NMR (500 MHz, CDCl3), δ(ppm), 4.23-4.11(d, 2H, J= 60 Hz), 2.55-2.51(m, 1H), 2.09(s, 3H), 0.62(s, 3H).

[0489] Synthesis of compound 58b. 10 mL of wet dichloromethane (dichloromethane in a few milliliters of H 2 To a solution of compound 57b (135 mg crude) in 1H2O (which had been separated from the aqueous layer) was added Dess-Martin periodinate (380 mg, 0.896 mmol). After stirring at room temperature for 24 h, the reaction mixture was extracted with dichloromethane (3 x 10 mL). The combined organic layers were washed with 10% Na 2 S 2 O 3 Wash with aqueous solution (10 mL), brine (10 mL), and MgSO 4 The mixture was dried at 40° C., filtered and concentrated. The residue was purified by chromatography on silica gel (petroleum ether / ethyl acetate=1:5) to give compound 58b (68 mg, 69%) as a white solid. 1 H NMR (500 MHz, CDCl3), δ(ppm), 4.50-4.34(m, 2H), 2.56-2.52(m, 1H), 2.15(s, 3H), 0.61(s, 3H).

[0490] 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 h, the reaction mixture was poured into ice water and then extracted with ethyl acetate (15 mL x 3). The combined organic layers were washed with brine (20 mL) and concentrated with MgSO 4 The crude product was used in the next step without further purification.

[0491] Synthesis of compound 60a. A solution of compound 59a (60 mg crude) in acetone (5 mL) was purified by CF 3COOH (0.1 mL) and Et 3 N (0.17 mL). After heating at reflux for 30 min, CF 3 COONa salt (180 mg, 1.3 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 x 3). The combined organic layers were washed with brine (15 mL) and MgSO 4 The mixture was dried at 40° C., filtered and concentrated. The residue was purified by chromatography on silica gel (petroleum ether / ethyl acetate=3:1) to give compound 60a (15 mg, 36% for two steps). 1 H NMR(500 MHz, CDCl3), δ(ppm), 4.21-4.11(m, 4H), 3.39-3.36(m, 1H), 2.84(s, 1H), 0.65(s, 3H).

[0492] Example 9

[0493] [ka]

[0494] [ka] Synthesis of compound 61. To a solution of compound 42 (5 g, 15 mmol) in dry THF (20 mL) was added borane-tetrahydrofuran complex (30 mL; 1.0 M solution in THF). After stirring at room temperature for 1 h, the reaction mixture was cooled in an ice bath and then washed with 10% aqueous NaOH (56 mL) followed by H 2 O 2 The mixture was slowly quenched with a 30% aqueous solution of (67 mL). After stirring at room temperature for 1 h, the mixture was extracted with EtOAc (3×100 mL). The combined organic layers were washed with 10% Na 2 S 2 O 3 Wash with aqueous solution (100 mL), brine (100 mL), and MgSO 4The crude product was used in the next step without further purification.

[0495] 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 h, 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 give compound 62 (2.2 g, 7 mmol, 81% for two steps). m / z (ES+APCI) + :[M+H] + 305.

[0496] Synthesis of compound 63. Dissolve trimethylsulfonium iodide (8.1) in 100 mL of DMSO. To a stirred solution of Compound 62 (60%; 1.26 g, 31.5 mmol) (60%; 1.26 g, 36.9 mmol) was added NaH (60%; 1.26 g, 31.5 mmol). After stirring at room temperature for 1 h, a suspension of Compound 62 (2.2 g, 7.2 mmol) in DMSO (20 mL) was added dropwise. The mixture was stirred for an additional 2.5 h, then poured into ice-cold water and extracted with ether (100 mL x 3). The combined ether layers were then washed with brine (100 mL x 3) and MgSO 4 Drying at 40° C., filtration and concentration gave crude product 63 (2.2 g), which was used in the next step without further purification.

[0497] Synthesis of compound 64. 60 mL of aqueous dichloromethane (dichloromethane dissolved in several milliliters of H 2 To a solution of crude compound 63 (1.6 g, 5 mmol) in 1H2O (which had been separated from the aqueous layer) was added Dess-Martin periodinate (4.2 g, 10 mmol). After stirring at room temperature for 24 h, the reaction mixture was extracted with dichloromethane (3 x 100 mL). The combined organic layers were washed with 10% Na 2 S2 O 3 Wash with aqueous solution (100 mL), brine (100 mL), and MgSO 4 The mixture was dried at 40° C., filtered and concentrated, and the residue was purified by chromatography on silica gel (petroleum ether / ethyl acetate=20:1 to 10:1) to give compound 64 (1.2 g, 3.8 mmol, 75% for two steps) as a white solid. 1 H NMR (400 MHz, CDCl 3 ), δ(ppm), 2.63-2.58(m, 3H), 2.11(s, 3H), 0.63(s, 3H).

[0498] 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 h, the solvent was evaporated and the residue was dissolved in dichloromethane. The mixture was diluted with H 2 HO (3 × 50 mL), brine (100 mL), and MgSO 4 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 white solids. 65a, 1H NMR (400 MHz, CDCl 3 ), 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(400 MHz, CDCl 3 ), δ(ppm), 3.40(s, 3H), 3.37(s, 2H), 2.54-2.50(m, 1H), 2.11(s, 3H), 0.62(s, 3H).

[0499] Synthesis of compound 66a. To a solution of compound 65a (50 mg, 0.14 mmol) in MeOH (10 mL) was added 2 drops of HBr (48%) followed by bromine (23 mg, 0.14 mmol). After stirring at room temperature for 1 h, the reaction mixture was poured into ice water and then extracted with ethyl acetate (10 mL x 3). The combined organic layers were washed with brine (20 mL) and concentrated with MgSO 4 The crude product was used in the next step without further purification.

[0500] Synthesis of compound 67a. A solution of compound 66a (46 mg, 0.11 mmol) in 10 mL of acetone was purified by CF 3 COOH (0.5 mL) and Et 3 N (0.7 mL). After refluxing for 30 min, CF 3 COONa salt (300 mg, 2.2 mmol) was added in portions over 10 h. The reaction mixture was cooled to room temperature and the solvent was removed in vacuo. The residue was extracted with ethyl acetate and MgSO 4 The mixture was dried at 77° C., filtered and concentrated. The mixture was purified by chromatography on silica gel (petroleum ether / ethyl acetate=10:1 to 3:1) to give 67a (10 mg, yield: 25% for two steps). NMR (400 MHz, CDCl 3 ), 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).

[0501] Example 10

[0502] [ka] Synthesis of compound 68a. To a solution of compound 15a (200 mg, 0.63 mmol) in acetic anhydride (10 mL), pyridine (50 mg, 0.63 mmol) was added. The reaction mixture was stirred at 80 °C for 10 h. The reaction mixture was poured into ice-cold water and extracted with ethyl acetate (20 mL x 3). The combined ether layer was then washed with brine (10 mL x 3) and diluted with MgSO 4 Drying at 40° C., filtration and concentration gave crude product 68a (160 mg, 80%) which was used in the next step without further purification. 1 HNMR (400 MHz, CDCl 3 ), δ(ppm), 2.55-2.50(t, J = 9.2 Hz, 1H), 2.38-2.34(m, 1H), 2.11(s, 3H), 2.00(s, 3H), 1.45(s, 3H), 0.62(s, 3H).

[0503] Example 11

[0504] [ka] Synthesis of compound 71

[0505] [ka] K in THF (5 mL) 2 CO 3 To a suspension of 16a (25 mg, 0.18 mmol) was added morpholine (16 mg, 0.18 mmol) and compound 16a (36 mg, 0.09 mmol). After stirring at room temperature for 15 h, the reaction mixture was diluted with 5 mL of H 2 The reaction mixture was poured into 200 mL of ethyl acetate and extracted with EtOAc (2×10 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated. The reaction mixture was subjected to reverse phase prep-HPLC. The title compound was obtained as a white solid (12 mg, 33%) by purification using 1H NMR (500 MHz, CDCl 3), 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).

[0506] Synthesis of compound 72

[0507] [ka] K in THF (5 mL) 2 CO 3 (25 mg, 0.18 mmol) was added to a suspension of 16a (36 mg, 0.09 mmol). After stirring at room temperature for 15 h, the reaction mixture was diluted with 5 mL of H 2 The mixture was poured into 200 mL and extracted with EtOAc (2×10 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated. The reaction mixture was purified by reverse-phase prep-HPLC to give the title compound as a white solid (12 mg, 33%). 1H NMR (500 MHz, CDCl 3 ), δ(ppm), 3.12-3.04(m, 2H), 2.57-2.53(t, J = 9 Hz, 1H), 2.59-2.50(m, 5H), 2.19-2.12(m, 1H), 1.20(s, 3H), 0.63(s, 3H).

[0508] Synthesis of compound 73

[0509] [ka] K in THF (5 mL) 2 CO 3 To a suspension of 16a (25 mg, 0.18 mmol) was added pyrrolidine (13 mg, 0.18 mmol) and compound 16a (36 mg, 0.09 mmol). After stirring at room temperature for 15 h, the reaction mixture was diluted with 5 mL of H 2The mixture was poured into 200 mL and extracted with EtOAc (2×10 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated. The reaction mixture was purified by reverse-phase prep-HPLC to give the title compound as a white solid (15 mg, 42%). 1H NMR (400 MHz, CDCl 3 ), 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).

[0510] Synthesis of compound 74

[0511] [ka] K in THF (5 mL) 2 CO 3 To a suspension of 16a (14 mg, 0.10 mmol), 1H-imidazole (7 mg, 0.10 mmol) and compound 16a (20 mg, 0.05 mmol) were added. After stirring at room temperature for 15 h, the reaction mixture was diluted with 5 mL of H 2 The mixture was poured into 200 mL and extracted with EtOAc (2×10 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated. The reaction mixture was purified by reverse-phase prep-HPLC to give the title compound as a white solid (7 mg, 35%). 1H NMR (500 MHz, CDCl 3 ), 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 = 8.5 Hz, 1H), 2.21-2.13(m, 1H), 1.21(s, 3H), 0.68(s, 3H).

[0512] Example 12

[0513] [ka]

[0514] [ka] Synthesis of compounds 75a and 75b. 2 Compound 43 (1.3 g, 4.5 mmol) and PhSO in THF (25 mL) and HMPA (0.5 mL) at −78 °C under 2 CH 2 To a solution of F (790 mg, 4.5 mmol), LHMDS (5.5 mL, 1 M in THF) was added dropwise. After stirring at -78 °C for 2 h, the reaction mixture was diluted with saturated NH 4 Quench with aqueous Cl (10 mL), warm to room temperature, and then add Et 2 The mixture was extracted with 20 mL x 3 O. 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 give compound 75a1 (220 mg, t = 3.41 min). 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(200mg,t=3.66min); 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(235mg,t=4.9min) 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(220mg,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 * 250mm, 5μm).

[0515] Synthesis of compound 76a. 2 Compound 75a1 (200 mg, 0.434 mmol) and anhydrous Na in anhydrous methanol (15 mL) at -20°C 2 HPO 4 To a solution of (100 mg), Na / Hg amalgam (400 mg) was added. After stirring at -20°C to 0°C for 1 h, the methanol solution was decanted and the solid residue was dissolved in Et 2 The combined organic phase was washed with Et2O (5 x 3 mL). The solvent was removed in vacuo and 20 ml of brine was added, followed by Et2O. The combined ether phase was dried over MgSO4 and the ether was removed to give the crude product, which was further purified by silica gel chromatography (PE / EA=10 / 1) to give compound 76a (99 mg, 69%). 1 H NMR (500 MHz, CDCl3), δ(ppm), 5.12-5.10(m, 1H,), 4.21-24.11(d, 2H, J= 47.5 Hz), 0.88(s, 3H).

[0516] Synthesis of compound 77a. To a solution of compound 76a (95 mg, 0.296 mmol) in dry THF (5 mL) was added borane-tetrahydrofuran complex (1 mL of a 1.0 M solution in THF). After stirring at room temperature for 1 h, the reaction mixture was cooled in an ice bath and then washed with 10% aqueous NaOH (1 mL) followed by H2 O 2 The mixture was stirred at room temperature for 1 h and then extracted with EtOAc (3×10 mL). The combined organic layers were washed with 10% Na 2 S 2 O 3 Wash with aqueous solution (10 mL), brine (10 mL), and MgSO 4 The crude product was used in the next step without further purification.

[0517] Synthesis of compound 78a. 10 mL of aqueous dichloromethane (dichloromethane dissolved in several milliliters of H 2 To a solution of compound 77a (120 mg crude) dissolved in 100 ml of ethyl acetate (which had been shaken with 200 mL of 1000 mL of ethyl acetate and then separated from the aqueous layer) was added Dess-Martin periodinate (300 mg, 707 mmol). After stirring at room temperature for 24 h, the reaction mixture was extracted with dichloromethane (3×10 mL). The combined organic layers were washed with 10% Na 2 S 2 O 3 Wash with aqueous solution (10 mL), brine (10 mL), and MgSO 4 The mixture was dried at 40° C., filtered and concentrated, and the residue was purified by chromatography on silica gel (petroleum ether / ethyl acetate=1:5) to give compound 78a (70 mg, 70% for two steps) as a white solid. 1 H NMR (500 MHz, CDCl3), δ(ppm), 4.21-4.11(d, 2H, J= 48 Hz), 2.19(s, 3H), 0.62(s, 3H).

[0518] Assay Method Compounds provided herein may be evaluated using a variety of in vitro and in vivo assays; examples of such assays are described below.

[0519] Steroid inhibition of TBPS binding A TBPS binding assay using rat brain cortical membranes in the presence of 5 μM GABA has been reported (Gee et al., J. Pharmacol. Exp. Ther. 1987, 241, 346-353; Hawkinson et al., Mol. Pharmacol. 1994, 46, 977-985).

[0520] Briefly, after decapitation of carbon dioxide-anesthetized Sprague-Dawley rats (200-250 g), the cortices are rapidly removed. The cortices are homogenized in 10 volumes of ice-cold 0.32 M sucrose using a glass / Teflon homogenizer and centrifuged at 1500 x g for 10 min at 4 °C. The resulting supernatant is centrifuged at 10,000 x g for 20 min at 4 °C to obtain a P2 pellet. The P2 pellet is resuspended in 200 mM NaCl / 50 mM Na-K phosphate pH 7.4 buffer and centrifuged at 10,000 x g for 10 min at 4 °C. This washing procedure is repeated twice and the pellet is resuspended in 10 volumes of buffer. Aliquots (100 μL) of the membrane suspension are diluted with 2 nM [ 35 S]-TBPS, and a 5 μL aliquot of the test drug dissolved in dimethyl sulfoxide (DMSO) in the presence of 5 μM GABA (0.5% final). This incubation resulted in a 1.0 mL solution of the test drug containing buffer. The final volume is generated. Nonspecific binding is measured in the presence of 2 μM unlabeled TBPS and ranges from 15 to 25%. After 90 min incubation at room temperature, the assay is terminated by filtration onto glass fiber filters (Schleicher and Schuell No. 32) using a cell harvester (Brandel) and rinsed three times with ice-cold buffer. Filter-bound radioactivity is measured by liquid scintillation spectrometry. Nonlinear curve fitting of the entire data for each drug averaged over each concentration is performed using Prism (GraphPad). If the sum of squares is significantly lower by F-test, the data are fitted to a partial inhibition model instead of a complete inhibition model. Similarly, if the sum of squares is significantly lower by F-test, the data are fitted to a two-component inhibition model instead of a one-component inhibition model. The concentration of test compound that produces 50% inhibition of specific binding (IC 50 ) and the maximum degree of inhibition (I max ) is determined for each individual experiment using the same model used for the entire data, and then the mean value ± SEM for that individual experiment is calculated.

[0521] Various compounds were tested in vitro 35 S]-TBPS binding. These assays are or can be performed according to the procedures discussed above.

[0522] In vivo pharmacology Male NSA mice weighing 15-20 g are obtained from Harlan Sprague-Dawley (San Diego, CA). Upon arrival, they are housed (4 per cage) in standard polycarbonate cages in a room with a 12-h (07.00-19.00 light) light / dark cycle and constant temperature (23.0±2.5°C) with sterile bedding material. Food (Teklad LM 485) and water are available ad libitum. Mice are allowed to acclimate for a minimum of 4 days prior to the experiment.

[0523] Pentylenetetrazol-induced seizures Seizures are induced by administration of 85 mg / kg sc pentylenetetrazole (30 min observation period). The doses used were: CD 97 The time interval is predetermined to be 100 s. A clonic seizure is defined as a forelimb clonus of ≧3 seconds duration. Data are treated quantally.

[0524] Maximal electroshock-induced seizures Seizures are induced by application of electrical current (50 mA, 60 pulses / sec, 0.8 msec pulse width, 1 sec duration, DC) using a Ugo Basile ECT device (Model 7801). Mice are restrained by grasping the loose skin on the dorsum and two saline-coated corneal electrodes are lightly held against the cornea. Current is applied and mice are observed for up to 30 s for the occurrence of a tonic hindlimb extensor response. A tonic seizure is defined as hindlimb extension greater than 90 degrees out of the plane of the body. Outcomes are treated in a quantal manner.

[0525] Wire suspension The wire suspension test used a custom-made apparatus consisting of a metal wire (2 mm diameter) suspended horizontally above a padded surface (25 cm). Mice were held by the base of the tail and placed with the forepaws in contact with the wire, then released. To be scored as a pass, the animal must contact both hind paws to the wire within 5 seconds. Results were treated quantally.

[0526] Drug Metabolism and Pharmacokinetics: The HERG Assay HEK293 cells stably expressing the HERG potassium channel are used for electrophysiological studies. For stable transfection of this channel in HEK cells, Methods for this can be found elsewhere (Zhou et al., Biophys. J. 74:230-41, 1998). On the day before the experiment, the cells are harvested from the culture flasks and plated onto glass coverslips in standard Minimum Essential Medium (MEM) containing 10% fetal calf serum (FCS). The plated cells are incubated at 4°C for 24 hours in 95% O. 2 / 5%CO 2Store the cells in a 37 °C incubator maintained at a constant temperature of 37 °C. Examine the cells 15 to 28 hours after harvesting.

[0527] HERG currents were examined in whole-cell mode using standard patch clamp techniques. During the experiment, cells were maintained in a 10-well plate with the following composition (in mM): NaCl, 130; KCl, 4; CaCl, 100; 2 ,2;MgCl 2 Perfuse the rat with a standard external solution of pH 7.4 (1 mM; glucose, 10; HEPES, 5; NaOH). 2Whole-cell recordings are performed using patch pipettes with a resistance of 1-3 MOhm when filled with a standard internal solution of pH 7.2 with KOH, 1.0; HEPES, 10; EGTA, 5.0. Only those cells with an access resistance less than 15 MOhm and a seal resistance of >1 GOhm are accepted for further experiments. Series resistance compensation was applied up to 80%. No leak subtraction was performed. However, the acceptable access resistance depended on the size of the recorded current and the level of series resistance compensation that could be safely used. After the whole-cell configuration was achieved and sufficient time (>5 min) had elapsed for cell dialysis with the pipette solution, a standard voltage protocol was applied to the cell to induce membrane currents. The voltage protocol was as follows: The membrane was depolarized from a holding potential of -80 mV to +40 mV for 1000 ms. This was followed by a descending voltage ramp (rate 0.5 mV msec-1) back to the holding potential. This voltage protocol is applied to the cells continuously throughout the experiment, every 4 seconds (0.25 Hz). The amplitude of the peak current evoked during this ramp is measured at approximately -40 mV. Once a stable evoked current response is obtained in the external solution, vehicle (0.5% DMSO in standard external solution) is applied for 10-20 minutes by peristaltic pump. Once the amplitude of the evoked current response is minimal in the vehicle control condition, test compound at 0.3, 1, 3 or 10 mM is applied for 10 minutes. The 10 minutes included the time for the feeding solution to pass through the tubing from the solution reservoir to the recording chamber via the pump. The exposure time of the cells to the compound solution was more than 5 minutes after the drug concentration in the chamber well reached the attempting concentration. This was followed by a 10-20 minute washout period to assess reversibility. Finally, the cells were exposed to a high dose of the specific IKr blocker dofetilide (5 mM) to assess the insensitive endogenous current.

[0528] All experiments are performed at room temperature (23±1° C.). Evoked membrane currents are recorded online on a computer, filtered at 500-1 KHz (Bessel-3 dB), and sampled at 1-2 KHz using a patch clamp amplifier and specific data analysis software. Peak current amplitudes occurring at approximately −40 mV are measured offline on a computer.

[0529] The arithmetic mean of the 10 values ​​of amplitude is calculated under vehicle control conditions and in the presence of drug. The percent reduction of IN in each experiment is 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 drug and IC is the average current value under control conditions. Separate experiments are performed for each drug concentration or time-matched control, and the arithmetic mean in each experiment is defined as the result of the study.

[0530] Recombinant α 1 β 2 Gamma 2 GABA A Patch clamp electrophysiology of receptors Using cellular electrophysiology, we investigated the effect of GABA receptor agonist (GABA receptor agonist) on Ltk cells. A The in vitro potency and efficacy of receptor modulators are measured. Each compound was tested using EPC-10 Submaximal agonist doses (GABA EC10=0.5 μM) are tested for their ability to affect GABA-mediated currents in whole-cell patch clamp experiments using a HEKA Electronics Amplifier and PatchMaster software. These experiments measure potency, efficacy (Emax), direct gating properties and acute desensitization. Test substances are added at 0.1, 1.0 and 10 μM.

[0531] Drug metabolism and pharmacokinetics: Half-life in human liver microsomes (HLM) Test compounds (1 μM) were incubated in 96-deep well plates in 100 mM potassium phosphate buffer (pH 7.4) at 37° C. with 3.3 mM MgCl 2 and 0.78 mg / mL HLM (HL101). The reaction mixture is divided into two groups, non-P450 and P450. Only NADPH is added to the reaction mixture of the P450 group. Sample aliquots of the P450 group are collected at 0, 10, 30 and 60 min, where 0 min indicates the time when NADPH is added to the reaction mixture of the P450 group. Sample aliquots of the non-P450 group are collected at -10 and 65 min. The collected aliquots are extracted with an acetonitrile solution containing an internal standard. The precipitated proteins are spun down in a centrifuge (2000 rpm, 15 min). The compound concentration in the supernatant is measured by an LC / MS / MS system. The half-life value is obtained by plotting the natural logarithm of the peak area ratio of the compound / internal standard against time. The slope of the best fit line through the points gives the metabolic rate (k). This is converted to a half-life value using the equation: Half-life = ln2 / k.

[0532] [Table 1-1]

[0533] [Table 1-2] Other embodiments In the claims, articles (e.g., "a," "an," and "the") can mean one or more than one, unless indicated to the contrary or otherwise clear from the context. Unless indicated to the contrary or otherwise clear from the context, a claim or description including "or" between one or more members of a group is deemed to satisfy that one, more than one, or all group members are present in, used in, or otherwise relevant to a given product or process. The invention includes embodiments in which exactly one member of the group is present in, used in, or otherwise relevant to a given product or process. The invention includes embodiments in which more than one or all group members are present in, used in, or otherwise relevant to a given product or process.

[0534] Moreover, the invention includes all variations, combinations, and permutations in which one or more limitations, elements, clauses, and descriptive terms from one or more of the recited claims are introduced into another claim. For example, any claim that is dependent on another claim may be modified to include one or more limitations found in any other claim that is dependent on the same base claim. . When elements are presented as a list, for example in the form of a Markush group, each subgroup of the elements is also disclosed and any element may be removed from the group. In general, when the invention or aspects of the invention are referred to as comprising certain elements and / or features, it is to be understood that certain embodiments of the invention or aspects of the invention consist or consist essentially of such elements and / or features. For the sake of simplicity, those embodiments have not been expressly set forth herein in these exact words. It is also noted that the terms "comprising" and "containing" are intended to be open and allow for the inclusion of additional elements or steps. When ranges are given, the endpoints are included. Furthermore, unless otherwise indicated or otherwise clear from the context and the understanding of one of ordinary skill in the art, values ​​expressed as ranges may assume any particular value or subrange within the range set forth in the various embodiments of the invention to the tenth of the unit of the lower limit of that range, unless the context clearly dictates otherwise.

[0535] This application refers to various issued patents, published patent applications, journal articles, and other publications, all of which are incorporated herein by reference. In the event of a conflict between any incorporated reference and this specification, this specification shall control. Furthermore, any particular embodiment of the present invention that falls within the scope of the prior art may be expressly excluded from any one or more of the claims. Since such embodiments are deemed known to those skilled in the art, they may be excluded even if the exclusion is not expressly set forth herein. Any particular embodiment of the present invention may be excluded from any claim for any reason, whether or not related to the existence of prior art.

[0536] Those skilled in the art will recognize or be able to ascertain, using no more than routine experimentation, many equivalents to the specific embodiments described herein. The scope of the embodiments described herein is not intended to be limited to the above description, but is as set forth in the appended claims. Those skilled in the art will recognize that various changes and modifications to this description can be made without departing from the spirit or scope of the invention as defined in the following claims.

[0537] According to a preferred embodiment of the present invention, for example, the following is provided: (Section 1) Compounds of formula (I): [ka] or a pharma- ceutically acceptable salt thereof; During the ceremony: 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)2 R A2 , -OS(=O) 2 OR A1 , -SS(=O) 2 R A2 , -SS(=O) 2 OR A1 , -S(=O)R A2 , -SO 2 R A2 or -S(=O) 2 OR A1 where R A1 each occurrence is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, an oxygen protecting group (when attached to an oxygen atom), a sulfur protecting group (when attached to a sulfur atom), a nitrogen protecting group (when attached to a nitrogen atom), or two R A1 groups linked together form a substituted or unsubstituted heterocyclic or heteroaryl ring; R A2 is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 2 is hydrogen, halo, 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 , -NH 2 , -N(R B1 ) 2 or -NR B1 C(=O)R B1 where R B1each occurrence is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl, 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 are linked 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 carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 3’ is hydrogen, -C(=O)R C1 , -C(=O)OR C1 , -C(=O)SR C1 , -C(=O)N(R C1 ) 2 , -S(=O) 2 R C2 , -S(=O) 2 OR C1 , -P(=O) 2 R C2 , -P(=O) 2 OR 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 linked together form a substituted or unsubstituted heterocyclic ring; RC2 is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 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 Each of R is independently hydrogen, halo, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl, or R 6a and R 6b are linked to form an oxo (=O) group; R 11a and R 11b each independently represents hydrogen, halo, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, -OH, -OR D1 , -OC(=O)R D1 , -NH 2 , -N(R D1 ) 2 or -NR D1 C(=O)R D1 where R D1 each occurrence is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl 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 groups are linked to form a substituted or unsubstituted heterocyclic ring; or R 11a and R 11b are linked to form an oxo (=O) group; During the ceremony, [ka] represents a single bond or a double bond, and when a double bond is present in ring B, R 6a or R 6b is absent and a single bond is present in ring B, then the hydrogen at C5 is in the alpha or beta position; However, the following compounds and their salts: [ka] [ka] [ka] is specifically excluded, compounds of formula (I) or pharma- ceutically acceptable salts thereof. (Section 2) Compounds of formula (III): [ka] or a pharma- ceutically acceptable salt thereof; During the ceremony: 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) 2 R A2 , -OS(=O) 2 OR A1 , -SS(=O) 2 R A2 , -SS(=O) 2 OR A1 , -S(=O)R A2 , -SO 2 R A2 or -S(=O) 2 OR A1 where R A1 each occurrence is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, an oxygen protecting group (when attached to an oxygen atom), a sulfur protecting group (when attached to a sulfur atom), a nitrogen protecting group (when attached to a nitrogen atom), or two R A1 groups linked together form a substituted or unsubstituted heterocyclic or heteroaryl ring; R A2 is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 2 is hydrogen, halo, 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 , -NH 2 , -N(R B1) 2 or -NR B1 C(=O)R B1 where R B1 each occurrence is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl, 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 are linked 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 carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 3’ is hydrogen, -C(=O)R C1 , -C(=O)OR C1 , -C(=O)SR C1 , -C(=O)N(R C1 ) 2 , -S(=O) 2 R C2 , -S(=O) 2 OR C1 , -P(=O) 2 R C2 , -P(=O) 2 OR C1 , -P(=O)(OR C1 ) 2 , -P(=O)(R C2 ) 2 or -P(=O)(R C2 )(OR C1 ), where R C1 Water a substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted...

Claims

[Claim 1] Excellent efficacy.

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