Neuroactive steroids, compositions, and uses thereof

Abstract

Novel and improved neurostimulant steroids that modify brain excitability are provided for the prevention and treatment of CNS-related pathologies. [Solution] Formula (I) TIFF2023040180000222.tif4576 and pharmaceutically acceptable salts thereof, as well as pharmaceutical compositions thereof. The compounds of the present invention are believed to be useful in the prevention and treatment of a variety of CNS-related pathologies in mammals.

Description

[Technical Field]

[0001] Related Applications This application claims priority under 35 U.S.C. §119(e) to U.S. Provisional Patent Application No. 61 / 532,427, filed September 8, 2011. [Background technology]

[0002] Brain excitability is defined as the level of arousal (a continuum ranging from coma to convulsions) of an animal and is regulated by various neurotransmitters. In general, neurotransmitters are responsible for regulating the conductance of ions across the neuronal membrane. At rest, the neuronal membrane possesses a potential (i.e., membrane voltage) of approximately -70 mV, with the interior of the cell negative relative to the exterior. This potential (voltage) is determined by the flow of ions (K) across the neuronal semipermeable membrane. + , Na + , Cl - Neurotransmitters are stored in presynaptic vesicles and are released as a result of neuronal action potentials. Upon release into the synaptic cleft, excitatory chemical transmitters such as acetylcholine will cause membrane depolarization (a change in potential from -70 mV to -50 mV). This effect is stimulated by acetylcholine and Na + It is mediated by postsynaptic nicotinic receptors that increase membrane permeability to ions. The reduced membrane potential stimulates neuronal excitability in the form of postsynaptic action potentials.

[0003] NMDA receptors are highly expressed in the CNS and are involved in excitatory synaptic transmission and synaptic plasticity, as well as excitotoxicity. These receptors transduce Ca upon binding of the neurotransmitter glutamate. 2+NMDA receptors are ligand-gated ion channels that are essential for excitatory neurotransmission and neuronal CNS function. NMDA receptors are heteromeric complexes composed of NR1, NR2, and / or NR3 subunits and possess distinct recognition sites for exogenous and endogenous ligands. These recognition sites include binding sites for glycine and glutamate agonists and modulators. These modulators may be useful therapeutic agents with potential clinical use as cognitive enhancers and in the treatment of psychiatric disorders in which glutamatergic transmission is reduced or impaired (see, e.g., Horak et al., J. of Neuroscience, 2004, 24(46), 10318-10325).

[0004] Neuroactive steroids such as pregnenolone sulfate (PS) bind to several types of neurotransmitter receptors, e.g., GABA A It has been shown to exert direct modulatory effects on receptors, glycine receptors, AMPA-kainate receptors, and NMDA receptors. NMDA receptors are positively modified by PS; however, the degree of modulation varies considerably.

[0005] In addition to PS, several other 3β-hydroxysteroids have been shown to potentiate NMDA receptors (e.g., Paul et al., J. Pharm. and Exp. Ther. 1994, 271, 677-682). Recently, a 3β-hydroxy-ergost-5-ene steroid derivative (1) was reported as a positive modulator of NMDA (NR1a / NR2A). Compound (1) (also called Org-1) inhibits the GABA AIt has been found that NMDA selectively modulates NMDA compared to NMDA (see, for example, Non-Patent Document 3 (Madau et al., Program No. 613.2 / B87.2009 Neuroscience Meeting Planner. Chicago, IL: Society for Neuroscience, 2009); Non-Patent Document 4 (Connick et al., Program No. 613.1 / B86.2009 Neuroscience Meeting Planner. Chicago, IL: Society for Neuroscience, 2009)). [ka] [Prior art documents] [Non-patent literature]

[0006] [Non-Patent Document 1] Horak et al., J.of Neuroscience, 2004, 24(46), 10318-10325 [Non-patent document 2] Paul et al., J. Pharm. and Exp. Ther. 1994, 271, 677-682 [Non-patent document 3] Madau et al., Program No.613.2 / B87.2009 Neuroscience Meeting Planner. Chicago, IL: Society for Neuroscience, 2009 [Non-patent document 4] Connick et al., Program No. 613.1 / B86.2009 Neuroscience Meeting Planner. Chicago, IL: Society for Neuroscience, 2009 Summary of the Invention [Problem to be solved by the invention]

[0007] There is a need for new and improved neurostimulatory steroids that modify brain excitability for the prevention and treatment of CNS-related pathologies. The compounds, compositions and methods described herein are directed toward this end. [Means for solving the problem]

[0008] The novel 3-alpha and 3beta-hydroxysteroids described herein are potential NMDA receptor modulators and are therefore useful for the prevention and / or treatment of a wide range of CNS-related conditions, including, but not limited to, schizophrenia, depression, bipolar disorder (e.g., I and / or II), schizoaffective disorder, mood disorders, anxiety disorders, personality disorders, psychosis, compulsive disorders, post-traumatic stress disorder (PTSD), autism spectrum disorder (ASD), dysthymia (mild depression), social anxiety disorder, obsessive-compulsive disorder (OCD), pain (e.g., painful syndromes or disorders), sleep disorders, memory disorders, dementia, Alzheimer's disease, seizure disorders (e.g., epilepsy), traumatic brain injury, stroke, addictive disorders (e.g., opiate, cocaine, and / or alcohol addiction), autism, Huntington's disease, insomnia, Parkinson's disease, withdrawal syndromes, or tinnitus. These compounds are expected to exhibit improved in vivo efficacy, pharmacokinetic (PK) properties, oral bioavailability, formulatability, stability and / or safety.

[0009] In one embodiment, a compound according to formula (I): [ka] (In the formula, Z is a group represented by formula (i), (ii), (iii), (iv) or (v): [ka] is the basis of; L 1 , L 2 , L 3 , X 1 , X 2, Y, R Z4 , R Z5 , R Z6 ,n,R 1 , R 2 , R 3a , R 3b , R 4a , R 4b , R 6a , R 6b , R 7a , R 7b , R 11a , R 11b , R 14 , R 17 , R 19 , R 20 , R 23a , R 23b , and R 24 is as defined herein; and the group -XR at the C3 position 3b is either alpha or beta) or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, tautomer, isotopic variant or N-oxide thereof, or a combination thereof.

[0010] For example, in certain embodiments, the compound of formula (I) is of formula (Iw): [ka] (In the formula, Z is a group represented by formula (i), (ii), (iii), (iv) or (v): [ka] is the basis of L 1 and L 2 is selected from the group consisting of a bond, substituted or unsubstituted C1-C6 alkylene, substituted or unsubstituted C2-C6 alkenylene, substituted or unsubstituted C2-C6 alkynylene, substituted or unsubstituted heteroC1-C6 alkylene, substituted or unsubstituted heteroC2-C6 alkenylene, and substituted or unsubstituted heteroC2-C6 alkynylene; L 3is a substituted or unsubstituted C1-C6 alkylene, a substituted or unsubstituted C2-C6 alkenylene, a substituted or unsubstituted C2-C6 alkynylene, a substituted or unsubstituted hetero C1-C6 alkylene, a substituted or unsubstituted hetero C2-C6 alkenylene, or a substituted or unsubstituted hetero C2-C6 alkynylene; X 1 and X 2 each instance of is independently -O-, -S-, or -NH-; R 1 is hydrogen or substituted or unsubstituted alkyl; R 3b is hydrogen; R 3a is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl; R 2 , R 11a , and R 11b Each instance of is independently hydrogen or -OR B1 (In this formula, R B1 is hydrogen or substituted or unsubstituted alkyl), or R 11a and R 11b together form an oxo (=O) group; R 6a and R 6b each is independently hydrogen, halo, or substituted or unsubstituted alkyl; and [ka] represents a single bond or a double bond, provided that if a double bond is present, R 6a or R 6b is absent, and if a single bond is present, the hydrogen at C5 is in the alpha or beta position; R 19 and R 20 Each instance of is independently hydrogen or —CH; and R 23a and R 23bEach instance of is independently hydrogen, halogen, or substituted or unsubstituted alkyl, or R 23a and R 23b taken together to form a substituted or unsubstituted C3-C6 cycloalkyl; R 24 is hydrogen or substituted or unsubstituted alkyl; Y is -O-, -S-, or -NR Z5 - and; R Z4 are independently 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 Z5 , -SR Z5 , or N(R Z5 )2; R Z5 Each instance of is independently hydrogen or substituted or unsubstituted alkyl; and R Z6 Each instance of is independently hydrogen or substituted or unsubstituted alkyl, or two R Z6 The bases together form C 3-6 forming a carbocyclic ring; and The subscript n is either 0 or 1. or a pharmaceutically acceptable salt thereof, However, the following compounds: [ka] subject to the specific exclusion of

[0011] In certain embodiments, Z has the formula: [ka] It is based on.

[0012] In certain embodiments, L 3 is the expression: [ka] wherein p is 1, 2, or 3; and R Z7 and R Z8 Each instance of is independently hydrogen, halo, substituted or unsubstituted C 1-6 Alkyl, or -OR Z5 is) It is based on.

[0013] In certain embodiments, L 3 is the expression: [ka] wherein w is 0 or 1 and p is 1, 2, or 3, or w is 1 and p is 0, 1, 2, or 3; and R Z7 and R Z8 Each instance of is independently hydrogen, halo, substituted or unsubstituted C 1-6 Alkyl, or -OR Z5 (which is the base).

[0014] In certain embodiments, L 3 is the expression: [ka] It is based on.

[0015] In certain embodiments, L 3 is the expression: [ka] It is based on.

[0016] In certain embodiments, L 3 is the expression: [ka] It is based on.

[0017] In certain embodiments, Z is of the formula [ka] It is of the type.

[0018] In certain embodiments, the group [ka] is the expression: [ka] [ka] It is of the type.

[0019] In certain embodiments, Z is of the formula [ka] It is of the type.

[0020] In certain embodiments, Y in formula (I) is —O—, and L 3 is an alkylene or heteroalkylene group.

[0021] In certain embodiments, the group [ka] is the expression: [ka] It is of the type.

[0022] In certain embodiments, Z is of the formula [ka] It is of the type.

[0023] In certain embodiments, Y is —O— and L 3 is alkylene or heteroalkylene.

[0024] In certain embodiments, the group [ka] is the expression: [ka] It is of the type.

[0025] In certain embodiments, the group -X 1 R 3b is in beta position, and R 3a is in the alpha position. 1 R 3b is —OH. In certain embodiments, R 3a is hydrogen. In certain embodiments, R 3a is substituted or unsubstituted alkyl. In certain embodiments, R 6b is halogen or substituted or unsubstituted alkyl. In certain embodiments, R 2 is hydrogen or -OR B1 In certain embodiments, R 11b is hydrogen or -OR B1 and R 11a is hydrogen. In certain embodiments, R 11a and R 11b taken together form an oxo group. In certain embodiments, [ka] represents a single bond, and the hydrogen at C5 is in the alpha position. [ka] represents a double bond. In certain embodiments, R 19 is -CH3.

[0026] In another aspect, a pharmaceutical composition is provided comprising a compound of the present invention and a pharmaceutically acceptable carrier. In certain embodiments, the compound of the present invention is provided in an effective amount. 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.

[0027] In certain embodiments, the compounds of the present invention are provided as negative allosteric modulators (NAMs) of the NMDA receptor and are therefore useful for the prevention and / or treatment of a wide range of CNS conditions, including, but not limited to, schizophrenia, depression, bipolar disorder (I and II), schizoaffective disorder, mood disorders, anxiety disorders, personality disorders, psychosis, stereotypic disorders, post-traumatic stress disorder (PTSD), autism spectrum disorder (ASD), dysthymia (mild depression), social anxiety disorder, obsessive-compulsive disorder (OCD), all pain syndromes and disorders, sleep disorders, memory disorders and dementia (including Alzheimer's disease, epilepsy and any seizure disorder), traumatic brain injury (TBI), stroke, addictive disorders (including opiates and cocaine and alcohol), autism, Huntington's disease, insomnia, Parkinson's disease, withdrawal syndrome or tinnitus. For example, in one embodiment, a method for modulating NMDA receptors is provided, comprising administering to a subject in need thereof an effective amount of a compound of the present invention. In another embodiment, a method for modifying CNS activity is provided, comprising administering to a subject in need thereof an effective amount of a compound of the present invention. In yet another embodiment, a method for modifying brain excitability is provided, comprising administering to a subject in need thereof an effective amount of a compound of the present invention. The present invention provides a method comprising administering a compound of formula (I) to a subject.

[0028] Other objects and advantages will become apparent to those skilled in the art from consideration of the detailed description, examples, and claims. DETAILED DESCRIPTION OF THE INVENTION

[0029] definition chemical definition The definitions of specific functional groups and chemical terms are explained in more detail below.Chemical elements are identified according to the Periodic Table of the Elements, CAS edition, Handbook of Chemistry and Physics, 75th edition, inside cover, and specific functional groups are generally defined as described therein.In addition, the general principles of organic chemistry, as well as specific functional moieties and reactivity, are described in Thomas Sorrell, Organic Chemistry, University Science Books, Sausalito, 1999; Smith and March, March's Advanced Organic Chemistry, 5th edition, John Wiley & Sons, Inc., New York, 2001; Larock, Comprehensive Organic Transformations, VCH Publishers, Inc., New York, 1989; and Carruthers, Some Modern Methods of Organic Synthesis, 3rd edition, Cambridge University Press, Cambridge, 1987.

[0030] The compounds described herein may contain one or more asymmetric centers and therefore may exist in various isomeric forms, 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 exist in the form of mixtures of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomers. Isomers can be isolated from mixtures by methods known to those skilled in the art, including chiral high-pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or preferred isomers can be prepared by asymmetric synthesis. See, for example, Jacques et al., Enantiomers, Racemates, and Resolutions (Wiley Interscience, New York, 1981); Wilen et al., Tetrahedron 33:2725 (1977); Eliel, Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); and Wilen, Tables of Resolving See Agents and Optical Resolutions p. 268 (E.L. Eliel, ed., Univ. of Notre Dame Press, Notre Dame, IN 1972). The present invention further encompasses the compounds described herein as individual isomers substantially free of other isomers, and alternatively, as mixtures of various isomers.

[0031] When a range of values ​​is listed, it is intended to encompass each value and subrange within the range. For example, "C 1-6 "Alkyl" refers to C1, C2, C3, C4, C5, C6, C 1-6 , C 1-5 , C 1-4 , C 1-3 , C 1-2 , C 2-6 , C 2-5 , C 2-4 , C 2-3 , C 3-6 , C 3-5 , C3-4 , C 4-6 , C 4-5 , and C 5-6 Alkyl is intended to be included.

[0032] The following terms are intended to have the meanings presented below and are useful in describing and understanding the intended scope of the present invention: Compounds, medicaments containing such compounds In describing the present invention, which may include compositions and methods of using such compounds and compositions, the following terms, when present, have the following meanings unless otherwise indicated. As described herein, it should also be understood that any of the moieties defined hereinafter below may be substituted with various substituents, and that each definition is intended to include such substituted moieties within its scope as set forth below. Unless otherwise stated, the term "substituted" shall be defined as set forth below. It should further be understood that the terms "group" and "radical" can be considered interchangeable when used herein. The articles "a" and "an" can be used herein to refer to one or to more than one (i.e., at least one) of the grammatical object of the article. By way of example, "an analogue" means one analogue or more than one analogue.

[0033] "Alkyl" means a straight-chain or branched saturated hydrocarbon group having from 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 1-8In some embodiments, an alkyl group has 1 to 7 carbon atoms ("C 1-7 In some embodiments, an alkyl group has 1 to 6 carbon atoms ("C 1-6 In some embodiments, an alkyl group has 1 to 5 carbon atoms ("C 1-5 In some embodiments, an alkyl group has 1 to 4 carbon atoms ("C 1-4 In some embodiments, an alkyl group has 1 to 3 carbon atoms ("C 1-3 In some embodiments, an alkyl group has 1 to 2 carbon atoms ("C 1-2 In some embodiments, the alkyl group has 1 carbon atom ("C alkyl"). In some embodiments, the alkyl group has 2 to 6 carbon atoms ("C 2-6 alkyl). C 1-6 Examples of alkyl groups include methyl (C1), ethyl (C2), n-propyl (C3), isopropyl (C3), n-butyl (C4), tert-butyl (C4), sec-butyl (C4), iso-butyl (C4), n-pentyl (C5), 3-pentanyl (C5), amyl (C5), neopentyl (C5), 3-methyl-2-butanyl (C5), tertiary amyl (C5), and n-hexyl (C6). Additional examples of alkyl groups include n-heptyl (C7), n-octyl (C8), and the like. Unless otherwise specified, each instance of an alkyl group is independently optionally substituted, i.e., unsubstituted ("unsubstituted alkyl") or substituted with one or more substituents, for example, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent ("substituted alkyl"). In certain embodiments, an alkyl group is an unsubstituted C 1-10 In certain embodiments, the alkyl group is a substituted C 1-10Common alkyl abbreviations include Me(-CH), Et(-CHCH), iPr(-CH(CH)), nPr(-CHCHCH), n-Bu(-CHCHCHCHCH), or i-Bu(-CHCH(CH)).

[0034] As used herein, "alkylene," "alkenylene," and "alkynylene" refer to the divalent radical of an alkyl, alkenyl, and alkynyl group, respectively. When a range or number of carbons is given for a particular "alkylene," "alkenylene," and "alkynylene" group, it is understood that the range or number refers to the range or number of carbons in a divalent linear carbon chain. "Alkylene," "alkenylene," and "alkynylene" groups can be substituted or unsubstituted with one or more substituents as described herein.

[0035] "Alkylene" refers to an alkyl group, which may be substituted or unsubstituted, from which two hydrogens have been removed to produce a divalent radical. Unsubstituted alkylene groups include, but are not limited to, methylene (-CH-), ethylene (-CHCH-), propylene (-CHCHCH-), butylene (-CHCHCHCHCH-), pentylene (-CHCHCHCHCHCH-), hexylene (-CHCHCHCHCHCHCH-), and the like. Exemplary substituted alkylene groups, e.g., substituted with one or more alkyl (methyl) groups, include, but are not limited to, substituted methylene (-CH(CH)-, (-C(CH)-), substituted ethylene (-CH(CH)CH-, -CHCH(CH)-, -C(CH)CH-, -CHC(CH)-), substituted propylene (-CH(CH)CHCH-, -CHCH(CH)CH-, -CHCHCH(CH)-, -C(CH)CHCHCH-, -CHC(CH)CH-, -CHCHC(CH)-), and the like.

[0036] "Alkenyl" refers to a straight-chain or branched hydrocarbon group having from 2 to 20 carbon atoms, one or more carbon-carbon double bonds (e.g., 1, 2, 3, or 4 double bonds), and no triple bonds ("C 2-20 In some embodiments, an alkenyl group has 2 to 10 carbon atoms ("C 2-10 In some embodiments, an alkenyl group has 2 to 9 carbon atoms ("C 2-9 In some embodiments, an alkenyl group has 2 to 8 carbon atoms ("C 2-8 In some embodiments, an alkenyl group has 2 to 7 carbon atoms ("C 2-7 In some embodiments, an alkenyl group has 2 to 6 carbon atoms ("C 2-6 In some embodiments, an alkenyl group has 2 to 5 carbon atoms ("C 2-5 In some embodiments, an alkenyl group has 2 to 4 carbon atoms ("C 2-4 In some embodiments, an alkenyl group has 2 to 3 carbon atoms ("C 2-3 In some embodiments, the alkenyl group has two carbon atoms ("C2 alkenyl"). The one or more carbon-carbon double bonds can be internal (e.g., as in 2-butenyl) or terminal (e.g., as in 1-butenyl). C 2-4 Examples of alkenyl groups include ethenyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), and the like. 2-6 Examples of alkenyl groups include the above-mentioned C 2-4Alkenyl groups, of course, also include pentenyl (C5), pentadienyl (C5), hexenyl (C6), and the like. Additional examples of alkenyl include heptenyl (C7), octenyl (C8), octatrienyl (C8), and the like. Unless otherwise specified, each instance of an alkenyl group is independently optionally substituted, i.e., unsubstituted ("unsubstituted alkenyl") or substituted with one or more substituents, for example, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent ("substituted alkenyl"). In certain embodiments, an alkenyl group is an unsubstituted C 2-10 In certain embodiments, the alkenyl group is a substituted C 2-10 It is alkenyl.

[0037] "Alkenylene" refers to an alkenyl group, which may be substituted or unsubstituted, from which two hydrogens have been removed to produce a divalent radical. Exemplary unsubstituted divalent alkenylene groups include, but are not limited to, ethenylene (-CH=CH-) and propenylene (e.g., -CH=CHCH2-, -CH2-CH=CH-). Exemplary substituted alkenylene groups, for example, those substituted with one or more alkyl (methyl) groups, include substituted ethylene (-C (CH3)=CH-, -CH=C(CH3)-), substituted propylene (e.g., -C(CH3)=CHCH2-, -CH=C(CH3)CH2-, -CH=CHCH(CH3)-, -CH=CHC(CH3)2-, -CH(CH3)-CH=CH-, -C(CH3)2-CH=CH-, -CH2-C(CH3)CH-, -CH2-CH=C(CH3)-), and the like.

[0038] "Alkynyl" refers to a straight-chain or branched hydrocarbon group having from 2 to 20 carbon atoms, one or more carbon-carbon triple bonds (e.g., 1, 2, 3, or 4 triple bonds), and optionally one or more double bonds (e.g., 1, 2, 3, or 4 double bonds) ("C 2-20Alkynyl groups having one or more triple bonds and one or more double bonds are also referred to as "ene-yene" groups. In some embodiments, alkynyl groups have from 2 to 10 carbon atoms ("C 2-10 In some embodiments, an alkynyl group has 2 to 9 carbon atoms ("C 2-9 In some embodiments, an alkynyl group has 2 to 8 carbon atoms ("C 2-8 In some embodiments, an alkynyl group has 2 to 7 carbon atoms ("C 2-7 In some embodiments, an alkynyl group has 2 to 6 carbon atoms ("C 2-6 In some embodiments, an alkynyl group has 2 to 5 carbon atoms ("C 2-5 In some embodiments, an alkynyl group has 2 to 4 carbon atoms ("C 2-4 In some embodiments, an alkynyl group has 2 to 3 carbon atoms ("C 2-3 In some embodiments, the alkynyl group has two carbon atoms ("C2 alkynyl"). The one or more carbon-carbon triple bonds can be internal (e.g., as in 2-butynyl) or terminal (e.g., as in 1-butynyl). C 2-4 Examples of alkynyl groups include, but are not limited to, ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), and the like. 2-6 Examples of alkenyl groups include the above-mentioned C 2-4Alkynyl groups, of course, include pentynyl (C5), hexynyl (C6), and the like. Additional examples of alkynyl include heptynyl (C7), octynyl (C8), and the like. Unless otherwise specified, each instance of an alkynyl group is independently optionally substituted, i.e., unsubstituted ("unsubstituted alkynyl") or substituted with one or more substituents, for example, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent ("substituted alkynyl"). In certain embodiments, an alkynyl group is an unsubstituted C 2-10 In certain embodiments, the alkynyl group is a substituted C 2-10 It is alkynyl.

[0039] "Alkynylene" refers to an alkynyl group, which may be substituted or unsubstituted, from which two hydrogens have been removed to form a divalent radical. Exemplary divalent alkynylene groups include, but are not limited to, substituted or unsubstituted ethynylene, substituted or unsubstituted propynylene, and the like.

[0040] The term "heteroalkyl," as used herein, refers to an alkyl group, as defined herein, further comprising one or more (e.g., 1, 2, 3, or 4) heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus) in the parent chain, wherein the one or more heteroatoms are inserted between adjacent carbon atoms in the parent carbon chain and / or between a carbon atom and the parent molecule, i.e., between the points of attachment. In certain embodiments, a heteroalkyl group is a saturated group having from 1 to 10 carbon atoms and 1, 2, 3, or 4 heteroatoms ("heteroC 1-10 In some embodiments, a heteroalkyl group refers to a saturated group having 1 to 9 carbon atoms and 1, 2, 3, or 4 heteroatoms ("heteroC 1-9 In some embodiments, heteroalkyl groups have 1 to 8 carbon atoms and 1, 2, 3 or a saturated group having four heteroatoms ("hetero C"); 1-8 In some embodiments, a heteroalkyl group is a saturated group having 1 to 7 carbon atoms and 1, 2, 3, or 4 heteroatoms ("heteroC 1-7 In some embodiments, a heteroalkyl group is a saturated group having 1 to 6 carbon atoms and 1, 2, or 3 heteroatoms ("heteroC 1-6 In some embodiments, a heteroalkyl group is a saturated group having 1 to 5 carbon atoms and 1 or 2 heteroatoms ("heteroC 1-5 In some embodiments, a heteroalkyl group is a saturated group having 1 to 4 carbon atoms and 1 or 2 heteroatoms ("heteroC 1-4 In some embodiments, a heteroalkyl group is a saturated group having 1 to 3 carbon atoms and 1 heteroatom ("heteroC 1-3 In some embodiments, a heteroalkyl group is a saturated group having 1 to 2 carbon atoms and 1 heteroatom ("heteroC 1-2 In some embodiments, the heteroalkyl group is a saturated group having 1 carbon atom and 1 heteroatom ("heteroC alkyl"). In some embodiments, the heteroaryl group is a saturated group having 2 to 6 carbon atoms and 1 or 2 heteroatoms ("heteroC 2-6 Unless otherwise specified, each instance of a heteroalkyl group is independently unsubstituted (an "unsubstituted heteroalkyl") or substituted (a "substituted heteroalkyl") with one or more substituents. In certain embodiments, a heteroalkyl group is an unsubstituted heteroC 1-10 In certain embodiments, the heteroalkyl group is a substituted heteroC 1-10 It is alkyl.

[0041] The term "heteroalkenyl," as used herein, refers to an alkenyl group, as defined herein, further comprising one or more (e.g., 1, 2, 3, or 4) heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus), wherein said one or more heteroatoms are inserted between adjacent carbon atoms in the parent carbon chain and / or between a carbon atom and the parent molecule, i.e., between the points of attachment. In certain embodiments, a heteroalkenyl group refers to a group having 2 to 10 carbon atoms, at least one double bond, and 1, 2, 3, or 4 heteroatoms ("heteroalkenyl groups"). 3-10 In some embodiments, heteroalkenyl groups have 2 to 9 carbon atoms, at least one double bond, and 1, 2, 3, or 4 heteroatoms ("heteroC 2-9 In some embodiments, heteroalkenyl groups have 2 to 8 carbon atoms, at least one double bond, and 1, 2, 3, or 4 heteroatoms ("heteroC 2-8 In some embodiments, heteroalkenyl groups have 2 to 7 carbon atoms, at least one double bond, and 1, 2, 3, or 4 heteroatoms ("heteroC 2-7 In some embodiments, heteroalkenyl groups have 2 to 6 carbon atoms, at least one double bond, and 1, 2, or 3 heteroatoms ("heteroC 2-6 In some embodiments, heteroalkenyl groups have 2 to 5 carbon atoms, at least one double bond, and 1 or 2 heteroatoms ("heteroC 2-5 In some embodiments, heteroalkenyl groups have 2 to 4 carbon atoms, at least one double bond, and 1 or 2 heteroatoms ("heteroC 2-4 In some embodiments, heteroalkenyl groups have 2 to 3 carbon atoms, at least one double bond, and one heteroatom ("heteroC 2-3In some embodiments, heteroalkenyl groups have 2 to 6 carbon atoms, at least one double bond, and 1 or 2 heteroatoms ("heteroC 2-6 Unless otherwise specified, each instance of a heteroalkenyl group is independently unsubstituted (an "unsubstituted heteroalkenyl") or substituted (a "substituted heteroalkenyl") with one or more substituents. In certain embodiments, a heteroalkenyl group is an unsubstituted heteroC 2-10 In certain embodiments, the heteroalkenyl group is a substituted heteroC 2-10 It is alkenyl.

[0042] The term "heteroalkynyl," as used herein, refers to an alkynyl group, as defined herein, further comprising one or more (e.g., 1, 2, 3, or 4) heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus), wherein the one or more heteroatoms are inserted between adjacent carbon atoms in the parent carbon chain and / or between a carbon atom and the parent molecule, i.e., between the points of attachment. In certain embodiments, a heteroalkynyl group refers to a group having 2 to 10 carbon atoms, at least one triple bond, and 1, 2, 3, or 4 heteroatoms ("heteroalkynyl groups"). 2-10 In some embodiments, a heteroalkynyl group has 2 to 9 carbon atoms, at least one triple bond, and 1, 2, 3, or 4 heteroatoms ("heteroC 2-9 In some embodiments, heteroalkynyl groups have 2 to 8 carbon atoms, at least one triple bond, and 1, 2, 3, or 4 heteroatoms ("heteroC 2-8 In some embodiments, heteroalkynyl groups have 2 to 7 carbon atoms, at least one triple bond, and 1, 2, 3, or 4 heteroatoms ("heteroC 2-7In some embodiments, heteroalkynyl groups have 2 to 6 carbon atoms, at least one triple bond, and 1, 2, or 3 heteroatoms ("heteroC 2-6 In some embodiments, heteroalkynyl groups have 2 to 5 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms ("heteroC 2-5 In some embodiments, heteroalkynyl groups have 2 to 4 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms ("heteroC 2-4 In some embodiments, heteroalkynyl groups have 2 to 3 carbon atoms, at least one triple bond, and one heteroatom ("heteroC 2-3 In some embodiments, heteroalkynyl groups have 2 to 6 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms ("heteroC 2-6 Unless otherwise specified, each instance of a heteroalkynyl group is independently unsubstituted (an "unsubstituted heteroalkynyl") or substituted (a "substituted heteroalkynyl") with one or more substituents. In certain embodiments, a heteroalkynyl group is an unsubstituted heteroC 2-10 In certain embodiments, the heteroalkynyl group is a substituted heteroC 2-10 It is alkynyl.

[0043] As used herein, "alkylene," "alkenylene," "alkynylene," "heteroalkylene," "heteroalkenylene," and "heteroalkynylene" refer to the divalent radical of an alkyl, alkenyl, alkynyl group, heteroalkyl, heteroalkenyl, and heteroalkynyl group, respectively. When a range or number of carbons is given for a particular "alkylene," "alkenylene," "alkynylene," "heteroalkylene," "heteroalkenylene," or "heteroalkynylene" group, it is understood that the range or number refers to the range or number of carbons in a divalent linear carbon chain. "Alkylene," "alkenylene," "alkynylene," "heteroalkylene," "heteroalkenylene," and "heteroalkynylene" groups can be substituted or unsubstituted with one or more substituents as described herein.

[0044] "Aryl" refers to a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system having 6 to 14 ring carbon atoms and zero heteroatoms present within the aromatic ring system (e.g., having 6, 10, or 14 shared π atoms in a cyclic arrangement) ("C 6~14 In some embodiments, an aryl group has 6 ring carbon atoms ("C aryl", e.g., phenyl). In some embodiments, an aryl group has 10 ring carbon atoms ("C 10 aryl," e.g., 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 radical or point of attachment is on the aryl ring; in such cases, the number of carbon atoms still refers to the number of carbon atoms in the aryl ring system. Typical aryl groups include, but are not limited to, groups derived from aceanthrylene, acenaphthylene, acephenanthrphene, 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 instance of an aryl group is independently optionally substituted, i.e., unsubstituted ("unsubstituted aryl") or substituted with one or more substituents ("substituted aryl"). In certain embodiments, an aryl group is an unsubstituted C 6-14 In certain embodiments, the aryl group is a substituted C 6-14 It is aryl.

[0045] In certain embodiments, the aryl group is substituted with one or more groups selected from halo, C1-C8 alkyl, C1-C8 haloalkyl, cyano, hydroxy, C1-C8 alkoxy, and amino.

[0046] Representative examples of substituted aryl include: [ka] In these formulas, R 56 and R 57 may be hydrogen, and R 56 and R 57At least one of the groups independently represents C1-C8 alkyl, C1-C8 haloalkyl, 4- to 10-membered heterocyclyl, alkanoyl, C1-C8 alkoxy, heteroaryloxy, alkylamino, arylamino, heteroarylamino, NR 58 COR 59 , N.R. 58 SOR 59 NR 58 SO2R 59 , COO alkyl, COO aryl, CONR 58 R 59 ,CONR 58 OR 59 , N.R. 58 R 59 , SO2NR 58 R 59 , S-alkyl, SO alkyl, SO alkyl, S aryl, SO aryl, SO aryl; or R 56 and R 57 may together form a cyclic ring (saturated or unsaturated) of 5 to 8 atoms, which may optionally contain one or more heteroatoms selected from N, O or S. R 60 and R 61 are independently hydrogen, C1-C8 alkyl, C1-C4 haloalkyl, C3-C 10 Cycloalkyl, 4-10 membered heterocyclyl, C6-C 10 Aryl, substituted C6-C 10 It is aryl, 5- to 10-membered heteroaryl, or substituted 5- to 10-membered heteroaryl.

[0047] Other representative aryls with fused heterocyclyl groups include: [ka] (In these formulas, W is C(R 66 )2, NR 66 , O, and S; and each Y is selected from carbonyl, NR 66 , O and S; and R 66 are independently hydrogen, C1-C8 alkyl, C3-C10 Cycloalkyl, 4-10 membered heterocyclyl, C6-C 10 aryl, and 5- to 10-membered heteroaryl).

[0048] "Fused aryl" refers to an aryl having two of its ring carbons in common with a second aryl or heteroaryl or with a carbocyclyl or heterocyclyl ring.

[0049] "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.

[0050] "Heteroaryl" refers to a radical of a 5- to 10-membered monocyclic or bicyclic 4n+2 aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms (e.g., having 6 or 10 shared pi electrons in a cyclic arrangement) within the aromatic ring system, each heteroatom independently selected from nitrogen, oxygen, and sulfur ("5- to 10-membered heteroaryl"). In heteroaryl groups containing one or more nitrogen atoms, the point of attachment may be to a carbon atom or to a nitrogen atom, if valence permits. 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 to one or more carbocyclyl or heterocyclyl groups, the point of attachment being on the heteroaryl ring; in such cases, the number of ring members still refers 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 to one or more aryl groups, and the point of attachment is on either the aryl ring or the heteroaryl ring; 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, and the like), the point of attachment can be on either ring, i.e., on the ring containing the heteroatom (e.g., 2-indolyl) or on the ring that does not contain a heteroatom (e.g., 5-indolyl).

[0051] In some embodiments, heteroaryl groups are 5- to 10-membered aromatic ring systems having ring carbon atoms and 1-4 ring heteroatoms, each independently selected from nitrogen, oxygen, and sulfur ("5- to 10-membered heteroaryl"). In some embodiments, heteroaryl groups are 5- to 8-membered aromatic ring systems having ring carbon atoms and 1-4 ring heteroatoms, each independently selected from nitrogen, oxygen, and sulfur ("5- to 8-membered heteroaryl"). In some embodiments, heteroaryl groups are 5- to 6-membered aromatic ring systems having ring carbon atoms and 1-4 ring heteroatoms, each independently selected from nitrogen, oxygen, and sulfur ("5- to 6-membered heteroaryl"). In some embodiments, the 5- to 6-membered heteroaryl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5- to 6-membered heteroaryl has 1 to 2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5- to 6-membered heteroaryl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur. Unless otherwise specified, each instance of a heteroaryl group is independently optionally substituted, i.e., unsubstituted ("unsubstituted heteroaryl") or substituted with one or more substituents ("substituted heteroaryl"). In certain embodiments, the heteroaryl group is an unsubstituted 5- to 14-membered heteroaryl. In certain embodiments, the heteroaryl group is a substituted 5- to 14-membered heteroaryl.

[0052] Exemplary 5-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyrrolyl, furanyl, and thiophenyl. Exemplary 5-membered heteroaryl groups containing two heteroatoms include, but are not limited to, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered heteroaryl groups containing three heteroatoms include, but are not limited to, triazolyl, oxadiazolyl, and thiadiazolyl. Exemplary 5-membered heteroaryl groups containing four heteroatoms include, but are not limited to, tetrazolyl. Exemplary 6-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6-membered heteroaryl groups containing three or four heteroatoms include, but are not limited to, triazinyl and tetrazinyl, respectively. Exemplary 7-membered heteroaryl groups containing one heteroatom include, but are not limited to, azepinyl, oxepinyl, and thiepinyl. Exemplary 5,6-bicyclic heteroaryl groups include, but are not limited to, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzothiazolyl, benzisothiazolyl, benzothiadiazolyl, indolizinyl, and purinyl. Exemplary 6,6-bicyclic heteroaryl groups include, but are not limited to, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnonyl, quinoxalinyl, phthalazinyl, and quinazolinyl.

[0053] Representative examples of heteroaryls include: [ka] (In these formulas, each Y is a carbonyl, N, NR 65, O and S; and R 65 are independently hydrogen, C1-C8 alkyl, C3-C 10 Cycloalkyl, 4-10 membered heterocyclyl, C6-C 10 aryl, and 5- to 10-membered heteroaryl).

[0054] "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.

[0055] "Carbocyclyl" or "carbocyclic" means a non-aromatic cyclic hydrocarbon group having 3 to 10 ring carbon atoms ("C 3-10 carbocyclyl) having zero carbon atoms in the non-aromatic ring system In some embodiments, a carbocyclyl group has 3 to 8 ring carbon atoms ("C 3-8 In some embodiments, a carbocyclyl group has 3 to 6 ring carbon atoms ("C 3-6 In some embodiments, a carbocyclyl group has 3 to 6 ring carbon atoms ("C 3-6 In some embodiments, a carbocyclyl group has 5 to 10 ring carbon atoms ("C 5-10 carbocyclyl). Exemplary C 3-6 Carbocyclyl groups include, but are not limited to, cyclopropyl (C), cyclopropenyl (C), cyclobutyl (C), cyclobutenyl (C), cyclopentyl (C), cyclopentenyl (C), cyclohexyl (C), cyclohexenyl (C), cyclohexadienyl (C), and the like. Exemplary C 3-8 The carbocyclyl group includes, but is not limited to, the above-mentioned C 3-6Carbocyclyl groups include, of course, cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (C8), and the like. Exemplary C 3-10 The carbocyclyl group includes, but is not limited to, the above-mentioned C 3-8 In addition to carbocyclyl groups, cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C 10 ), cyclodecenyl (C 10 ), octahydro-1H-indenyl (C9), decahydronaphthalenyl (C 10 ), spiro[4.5]decanyl (C 10 ) and the like. As the above examples illustrate, in certain embodiments, a carbocyclyl group is monocyclic ("monocyclic carbocyclyl") or contains a fused, bridged, or spiro ring system, e.g., a bicyclic system ("bicyclic carbocyclyl"), and may be saturated or partially saturated. "Carbocyclyl" also includes ring systems in which a carbocyclyl ring, as defined above, is fused to one or more aryl or heteroaryl groups, the point of attachment being on the carbocyclyl ring; in such cases, the number of carbons still refers to the number of carbons in the carbocyclyl ring system. Unless otherwise specified, each instance 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.

[0056] 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" has 3 to 8 ring carbon atoms ("C3-8 In some embodiments, a "cycloalkyl group" has 3 to 6 ring carbon atoms ("C 3-6 In some embodiments, a "cycloalkyl group" has 5 to 6 ring carbon atoms ("C 5-6 In some embodiments, a "cycloalkyl group" has 5 to 10 ring carbon atoms ("C 5-10 Cycloalkyl). C 5-6 Examples of cycloalkyl groups include cyclopentyl (C5) and cyclohexyl (C5). 3-6 Examples of cycloalkyl groups include the above-mentioned C 5-6 Cycloalkyl groups include, of course, cyclopropyl (C3) and cyclobutyl (C4). 3-8 Examples of cycloalkyl groups include the above-mentioned C 3-6 Cycloalkyl groups also include cycloheptyl (C7) and cyclooctyl (C8). Unless otherwise specified, each instance 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.

[0057] "Heterocyclyl" or "heterocyclic" means a heterocyclic ring system having ring carbon atoms and one to four ring heteroatoms. where each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon ("3-10-membered heterocyclyl"). In heterocyclyl groups containing one or more nitrogen atoms, the point of attachment may be to a carbon atom or to the nitrogen atom, if valence permits. Heterocyclyl groups may be monocyclic ("monocyclic heterocyclyl") or may be fused, bridged, or spiro ring systems, e.g., 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 to one or more carbocyclyl groups, with the point of attachment being on either the carbocyclyl ring or the heterocyclyl ring, or in which a heterocyclyl ring, as defined above, is fused to one or more aryl or heteroaryl groups, with the point of attachment being on the heterocyclyl ring; in such cases, the number of ring members still refers to the number of ring members in the heterocyclyl ring system. Unless otherwise specified, each instance of heterocyclyl is independently optionally substituted, i.e., unsubstituted ("unsubstituted heterocyclyl") or substituted with one or more substituents ("substituted heterocyclyl"). In certain embodiments, the heterocyclyl group is an unsubstituted 3- to 10-membered heterocyclyl. In certain embodiments, the heterocyclyl group is a substituted 3- to 10-membered heterocyclyl.

[0058] In some embodiments, a heterocyclyl group is a 5- to 10-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, each heteroatom independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon ("5- to 10-membered heterocyclyl"). In some embodiments, a heterocyclyl group is a 5- to 8-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, each heteroatom independently selected from nitrogen, oxygen, and sulfur ("5- to 8-membered heterocyclyl"). In some embodiments, a heterocyclyl group is a 5- to 6-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, each heteroatom independently selected from nitrogen, oxygen, and sulfur ("5- to 6-membered heterocyclyl"). In some embodiments, the 5- to 6-membered heterocyclyl has 1 to 3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5- to 6-membered heterocyclyl has 1 to 2 ring heteroatoms selected from nitrogen, oxygen, and sulfur, In some embodiments, the 5- to 6-membered heterocyclyl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur.

[0059] Exemplary 3-membered heterocyclyl groups containing one heteroatom include, but are not limited to, aziridinyl, oxiranyl, and thiorenyl. Exemplary 4-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azetidinyl, oxetanyl, and thietanyl. Exemplary 5-membered heterocyclyl groups containing one heteroatom include, but are not limited to, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2,5-dione. Exemplary 5-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, dioxolanyl, oxasulfuranyl, disulfuranyl, and oxazolidin-2-one. Exemplary 5-membered heterocyclyl groups containing three heteroatoms include, but are not limited to, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclyl groups containing one heteroatom include, but are not limited to, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary 6-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, piperazinyl, morpholinyl, dithianyl, and dioxanyl. Exemplary 6-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, triazinanyl. Exemplary 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, triazinanyl. Exemplary 7-membered heterocyclyl groups include, but are not limited to, azepanyl, oxepanyl, and thiepanyl. Exemplary 8-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azocanyl, oxecanyl, and thiocanyl. Exemplary 5-membered heterocyclyl groups (also referred to herein as 5,6-bicyclic heterocyclic rings) fused to a C6 aryl ring include, but are not limited to, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, benzoxazolinonyl, and the like. 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, and the like.

[0060] Particular examples of heterocyclyl groups are shown in the following illustrative examples: [ka] (In these formulas, each W is CR 67 , C(R 67 )2, NR 67 , O, and S; and each Y is NR 67 , O and S; and R 67 are independently hydrogen, C1-C8 alkyl, C3-C 10 Cycloalkyl, 4-10 membered heterocyclyl, C6-C 10and aryl and 5- to 10-membered heteroaryl. These heterocyclyl rings may be optionally substituted with one or more groups selected from the group consisting of 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. Substituents include, for example, carbonyl or thiocarbonyl, giving rise to lactam and urea derivatives.

[0061] "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 be applied to any of the hydrocarbyl groups described above, such as alkyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkenyl, cycloheteroalkenyl, and the like having 1 to 5, and particularly 1 to 3, heteroatoms.

[0062] "Acyl" is the radical -C(O)R 20 In this case, R 20 is hydrogen or 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 unsubstituted heptyl, as defined herein. "Alkanoyl" is R 20is a group other than hydrogen. Representative acyl groups include formyl (-CHO), acetyl (-C(=O)CH3), cyclohexylcarbonyl, cyclohexylmethylcarbonyl, benzoyl (-C(=O)Ph), benzylcarbonyl (-C(=O)CH2Ph), -C(O)-C1-C8 alkyl, and -C(O)-(CH2). t (C6-C 10 aryl), -C(O)-(CH2) t (5-10 membered heteroaryl), -C(O)-(CH2) t (C3-C 10 cycloalkyl), and -C(O)-(CH2) t (4-10 membered heterocyclyl), where t is an integer from 0 to 4. In certain embodiments, R 21 is C1-C8 alkyl substituted with halo or hydroxy; C3-C each substituted with unsubstituted C1-C4 alkyl, halo, unsubstituted C1-C4 alkoxy, unsubstituted C1-C4 haloalkyl, unsubstituted C1-C4 hydroxyalkyl or unsubstituted C1-C4 haloalkoxy or hydroxy; 10 Cycloalkyl, 4-10 membered heterocyclyl, C6-C 10 It is an aryl, arylalkyl, 5- to 10-membered heteroaryl or heteroarylalkyl.

[0063] "Acylamino" is the radical -NR 22 C(O)R 23 In this case, R 22 and each instance 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 22is an amino-protecting group. Exemplary "acylamino" groups include, but are not limited to, formylamino, acetylamino, cyclohexylcarbonylamino, cyclohexylmethyl-carbonylamino, benzoylamino, and benzylcarbonylamino. Particular exemplary "acylamino" groups are -NR 24 C(O)-C1-C8 alkyl, -NR 24 C(O)-(CH2) t (C6-C 10 alkyl), -NR 24 C(O)-(CH2) t (5-10 membered heteroaryl), -NR 24 C(O)-(CH2) t (C3-C 10 cycloalkyl), and NR 24 C(O)-(CH2) t (4- to 10-membered heterocyclyl), where t is an integer from 0 to 4, and each R 24 independently represent hydrogen or C1-C8 alkyl. In certain embodiments, R 25 is H; is C1-C8 alkyl substituted with halo or hydroxy; is C3-C4 alkyl, each substituted with unsubstituted C1-C4 alkyl, halo, unsubstituted C1-C4 alkoxy, unsubstituted C1-C4 haloalkyl, unsubstituted C1-C4 hydroxyalkyl or unsubstituted C1-C4 haloalkoxy or hydroxy; 10 Cycloalkyl, 4-10 membered heterocyclyl, C6-C 10 aryl, arylalkyl, 5- to 10-membered heteroaryl or heteroarylalkyl; and R 26 is H; is C1-C8 alkyl substituted with halo or hydroxy; is C3-C4 alkyl, each substituted with unsubstituted C1-C4 alkyl, halo, unsubstituted C1-C4 alkoxy, unsubstituted C1-C4 haloalkyl, unsubstituted C1-C4 hydroxyalkyl or unsubstituted C1-C4 haloalkoxy or hydroxy; 10 Cycloalkyl, 4-10 membered heterocyclyl, C6-C 10aryl, arylalkyl, 5- to 10-membered heteroaryl, or heteroarylalkyl, provided that R 25 and R 26 is provided that at least one of is other than hydrogen.

[0064] "Acyloxy" is the radical -OC(O)R 27 In this case, R 27 is hydrogen or 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 C1-C8 alkyl substituted with halo or hydroxy; unsubstituted C1-C4 alkyl each substituted with alkyl, halo, unsubstituted C1-C4 alkoxy, unsubstituted C1-C4 haloalkyl, unsubstituted C1-C4 hydroxyalkyl or unsubstituted C1-C4 haloalkoxy or hydroxy; 10 Cycloalkyl, 4-10 membered heterocyclyl, C6-C 10 It is an aryl, arylalkyl, 5- to 10-membered heteroaryl or heteroarylalkyl.

[0065] "Alkoxy" refers to the group -OR 29 In this case, 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., those having between 1 and 6 carbon atoms. Further particular alkoxy groups have between 1 and 4 carbon atoms.

[0066] In certain embodiments, R 29 is amino, substituted amino, C6-C 10 Aryl, aryloxy, carboxyl, cyano, C3-C 10 Groups having one or more substituents, for example 1 to 5 substituents, and particularly 1 to 3 substituents, and particularly 1 substituent, selected from the group consisting of cycloalkyl, 4- to 10-membered heterocyclyl, halogen, 5- to 10-membered heteroaryl, hydroxyl, nitro, thioalkoxy, thioaryloxy, thiol, alkyl-S(O)-, aryl-S(O)-, alkyl-S(O)2-, and aryl-S(O)2-. Exemplary "substituted alkoxy" groups include -O-(CH2) t (C6-C 10 aryl), -O-(CH2) t (5-10 membered heteroaryl), -O-(CH2) t (C3-C 10 cycloalkyl), and -O-(CH2) t(4-10 membered heterocyclyl), where t is an integer from 0 to 4, and any aryl, heteroaryl, cycloalkyl, or heterocyclyl groups present may themselves be unsubstituted or substituted with unsubstituted C-C alkyl, halo, unsubstituted C-C alkoxy, unsubstituted C-C haloalkyl, unsubstituted C-C hydroxyalkyl, or unsubstituted C-C haloalkoxy or hydroxy. Particular exemplary "substituted alkoxy" groups are -OCF, -OCHCF, -OCHPh, -OCH-cyclopropyl, -OCHCHOH, and -OCHCHNMe.

[0067] "Amino" refers to the radical -NH2.

[0068] "Substituted amino" refers to a group of the formula -N(R 38 )2, in which 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 or substituted or unsubstituted heteroaryl, or an amino protecting group; R 38 At least one of R is not hydrogen. 38 is hydrogen, C1-C8 alkyl, C3-C8 alkenyl, C3-C8 alkynyl, C6-C 10 Aryl, 5- to 10-membered heteroaryl, 4- to 10-membered heterocyclyl, or C3-C 10 cycloalkyl; or C1-C8 alkyl substituted with halo or hydroxy; C3-C8 alkenyl substituted with halo or hydroxy; C3-C8 alkynyl substituted with halo or hydroxy, or -(CH2) t (C6-C 10 aryl), -(CH2) t (5-10 membered heteroaryl), -(CH2) t (C3-C 10 cycloalkyl) or -(CH2) t(4-10 membered heterocyclyl) (where t is an integer from 0 to 8), each of which is independently selected from unsubstituted C1-C4 alkyl, halo, unsubstituted C1-C4 alkoxy, unsubstituted C1-C4 haloal. substituted with alkyl, unsubstituted C1-C4 hydroxyalkyl or unsubstituted C1-C4 haloalkoxy or hydroxy; or both R 38 The groups taken together form an alkylene group.

[0069] Exemplary "substituted amino" groups include -NR 39 -C1-C8 alkyl, -NR 39 -(CH2) t (C6-C 10 aryl), -NR 39 -(CH2) t (5-10 membered heteroaryl), -NR 39 -(CH2) t (C3-C 10 cycloalkyl) and -NR 39 -(CH2) t (4- to 10-membered heterocyclyl), where t is an integer from 0 to 4, e.g., 1 or 2, and each R 39 independently represent H or C1-C8 alkyl; and any alkyl groups may themselves be substituted with halo, substituted or unsubstituted amino, or hydroxy; and any aryl, heteroaryl, cycloalkyl, or heterocyclyl groups may themselves be substituted with unsubstituted C1-C4 alkyl, halo, unsubstituted C1-C4 alkoxy, unsubstituted C1-C4 haloalkyl, unsubstituted C1-C4 hydroxyalkyl, or unsubstituted C1-C4 haloalkoxy or hydroxy. For the avoidance of doubt, the term "substituted amino" includes the groups alkylamino, substituted alkylamino, alkylarylamino, substituted alkylarylamino, arylamino, substituted arylamino, dialkylamino, and substituted dialkylamino, as defined below. Substituted amino includes both mono- and di-substituted amino groups.

[0070] "Azide" refers to the radical -N3.

[0071] "Carbamoyl" or "amido" refers to the radical -C(O)NH2.

[0072] A "substituted carbamoyl" or "substituted amide" is a radical -C(O)N(R 62 )2, and in this case, each R 62 are independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl, or an amino protecting group; R 62 At least one of R is not hydrogen. 62 is H, C1-C8 alkyl, C3-C 10 Cycloalkyl, 4-10 membered heterocyclyl, C6-C 10 Aryl, aralkyl, 5-10 membered heteroaryl and heteroaralkyl; or C1-C8 alkyl substituted with halo or hydroxy; or C3-C4 alkyl, each substituted with unsubstituted C1-C4 alkyl, halo, unsubstituted C1-C4 alkoxy, unsubstituted C1-C4 haloalkyl, unsubstituted C1-C4 hydroxyalkyl or unsubstituted C1-C4 haloalkoxy or hydroxy. 10 Cycloalkyl, 4-10 membered heterocyclyl, C6-C 10 aryl, aralkyl, 5- to 10-membered heteroaryl, or heteroaralkyl; provided that at least one of R 62 is subject to the condition that it is not H.

[0073] Exemplary "substituted carbamoyl" groups include -C(O)NR 64 -C1-C8 alkyl, -C(O)NR 64 -(CH2) t (C6-C 10 aryl), -C(O)NR 64 -(CH2) t (5-10 membered heteroaryl), -C(O)NR 64-(CH2) t (C3-C 10 cycloalkyl), and -C(O)N 64 -(CH2) t (4- to 10-membered heterocyclyl), where t is an integer from 0 to 4, and each R 64 independently represent H or C1-C8 alkyl, and any aryl, heteroaryl, cycloalkyl or heterocyclyl group present may themselves be substituted by unsubstituted C1-C4 alkyl, halo, unsubstituted C1-C4 alkoxy, unsubstituted C1-C4 haloalkyl, unsubstituted C1-C4 hydroxyalkyl or unsubstituted C1-C4 haloalkoxy or hydroxy.

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

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

[0076] "Halo" or "halogen" refers to fluoro (F), chloro (Cl), bromo (Br), and iodo (I). In certain embodiments, a halo group is either fluoro or chloro.

[0077] "Hydroxy" refers to the -OH radical.

[0078] "Nitro" refers to the radical -NO2.

[0079] "Cycloalkylalkyl" refers to an alkyl radical in which the alkyl group is substituted with a cycloalkyl group. Typical cycloalkylalkyl groups include, but are not limited to, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cycloheptylmethyl, cyclooctylmethyl, cyclopropylethyl, cyclobutylethyl, cyclopentylethyl, cyclohexylethyl, cycloheptylethyl, and cyclooctylethyl, and the like.

[0080] "Heterocyclylalkyl" refers to an alkyl radical in which the alkyl group is substituted with a heterocyclyl group. Typical heterocyclylalkyl groups include, but are not limited to, pyrrolidinylmethyl, piperidinylmethyl, piperazinylmethyl, morpholinylmethyl, pyrrolidinylethyl, piperidinylethyl, piperazinylethyl, morpholinylethyl, and the like.

[0081] "Cycloalkenyl" refers to a substituted or unsubstituted carbocyclyl group 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.

[0082] "Fused cycloalkenyl" refers to a cycloalkenyl that shares two of its ring carbon atoms with a second aliphatic or aromatic ring and has its olefinic unsaturation positioned so as to confer aromaticity to the cycloalkenyl ring.

[0083] "Ethenyl" refers to a substituted or unsubstituted --(C.dbd.C)--.

[0084] "Ethylene" refers to a substituted or unsubstituted --(CC)--.

[0085] "Ethynyl" refers to -(C≡C)-.

[0086] A "nitrogen-containing heterocyclyl" group refers to a 4- to 7-membered non-aromatic cyclic group containing at least one nitrogen atom, such as, but not limited to, morpholine, piperidine (e.g., 2-piperidinyl, 3-piperidinyl, and 4-piperidinyl), pyrrolidine (e.g., 2-pyrrolidinyl and 3-pyrrolidinyl), azetidine, pyrrolidone, imidazoline, imidazolidinone, 2-pyrazoline, pyrazolidine, piperazine, and N-alkylpiperazines such as N-methylpiperazine. Specific examples include azetidine, piperidone, and piperazone.

[0087] "Thioketo" refers to the group ═S.

[0088] 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," means that at least one hydrogen atom present on the group (e.g., a carbon or nitrogen atom) is replaced with a permissible substituent, e.g., a substituent that results in a stable compound, e.g., a compound that does not spontaneously undergo transformation by rearrangement, cyclization, elimination, or other reaction, etc. Unless otherwise specified, a "substituted" group has a substituent at one or more substitutable positions of the group, and when one or more positions in any given structure are substituted, the substituents can be 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 result in the formation of 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 can have hydrogen substituents and / or any suitable substituent described herein that satisfies the valence of the heteroatom and results in the formation of a stable moiety.

[0089] Exemplary carbon atom substituents include halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OR aa , -ON(R bb )2, -N(R bb )2, -N(R bb )3 + X - , -N(OR cc )R bb , -SH, -SR aa , -SSR cc、-C(=O)R aa 、-CO2H、-CHO、-C(OR cc )2、-CO2R aa 、-OC(O)R aa 、-OCO2R aa 、-C(=O)N(R bb )2、-OC(=O)N(R bb )2、-NR bb C(=O)R aa 、-NR bb CO2R aa 、-NR bb C(=O)N(R bb )2、-C(=NR bb )R aa 、-C(=NR bb )OR aa 、-OC(=NR bb )R aa 、-OC(=NR bb )OR aa 、-C(=NR bb )N(R bb )2、-OC(=NR bb )N(R bb )2、-NR bb C(=NR bb )N(R bb )2、-C(=O)NR bb SO2R aa 、-NR bb SO2R aa 、-SO2N(R bb )2、-SO2R aa 、-SO2OR aa 、-OSO2R aa 、-S(=O)R aa 、-OS(=O)R aa 、-Si(R aa )3、-Si(R aa )3-C(=S)N(R bb )2、-C(=O)SR aa 、-C(=S)SR aa 、-SC(=S)SR aa 、-SC(=O)SR aa 、-OC(=O)SR aa 、-SC(=O)OR aa 、-SC(=O)R aa 、-P(=O)2R aa, -OP(=O)2R aa , -P(=O)(R aa )2, -OP(=O)(R aa )2, -OP(=O)(OR cc )2, -P(=O)2N(R bb )2, -OP(=O)2N(R bb )2, -P(=O)(NR bb )2, -OP(=O)(NR bb )2, -NR bb P(=O)(NR 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- to 14-membered heterocyclyl, C 6-14 aryl, and 5- to 14-membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl independently has 0, 1, 2, 3, 4, or 5 R dd is substituted with a group; or Two geminal hydrogens on a carbon atom are bonded to the groups =O, =S, =NN(R bb )2, =NNR bb C(=O)R aa , =NNR bb C(=O)OR aa , =NNR bb S(=O)2R aa , =NR bb or =NOR cc has been replaced by; R aa Each instance of 1-10 Alkyl, C 1-10Perhaloalkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C3-C 10 Carbocyclyl, 3- to 14-membered heterocyclyl, C 6-14 aryl and 5- to 14-membered heteroaryl, or two R aa The groups taken together form a 3- to 14-membered heterocyclyl or 5- to 14-membered heteroaryl ring, where each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl may be selected from 0, 1, 2, 3, 4, or 5 R dd independently substituted with groups; R bb Each instance of is independently hydrogen, -OH, -OR aa , -N(R cc )2, -CN, -C(=O)R aa , -C(=O)N(R cc )2, -CO2R aa , -SO2R aa , -C(=NR cc ) OR aa , -C(=NR cc )N(R cc )2, -SO2N(R cc )2, -SO2R cc , -SO2OR cc , -SOR aa , -C(=S)N(R cc )2, -C(=O)SR cc , -C(=S)SR cc , -P(=O)2R aa , -P(=O)(R aa )2, -P(=O)2N(R cc )2, -P(=O)(NR cc )2, C 1-10 Alkyl, C 1-10 Perhaloalkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Carbocyclyl, 3- to 14-membered heterocyclyl, C 6~14 aryl, and 5- to 14-membered heteroaryl, or two R bbThe groups taken together form a 3- to 14-membered heterocyclyl or 5- to 14-membered heteroaryl ring, where each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl may be selected from 0, 1, 2, 3, 4, or 5 R dd independently substituted with groups; R cc Each instance of 1-10 Alkyl, C 1-10 Perhaloalkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Carbocyclyl, 3- to 14-membered heterocyclyl, C 6~14 aryl, and 5- to 14-membered heteroaryl, or two R cc The groups taken together form a 3- to 14-membered heterocyclyl or 5- to 14-membered heteroaryl ring, where each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl may be selected from 0, 1, 2, 3, 4, or 5 R dd independently substituted with groups; R dd Each instance of is independently a halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OR ee , -ON(R ff )2, -N(R ff )2, -N(R ff )3 + X - , -N(OR ee )R ff , -SH, -SR ee , -SSR ee , -C(=O)R ee , -CO2H, -CO2R ee , -OC(=O)R ee , -OCO2R ee , -C(=O)N(R ff )2, -OC(=O)N(R ff )2, -NR ff C(=O)R ee , -NR ff CO2R ee , -NR ff C(=O)N(R ff)2, -C(=NR ff ) OR ee , -OC(=NR ff )R ee , -OC(=NR ff ) OR ee , -C(=NR ff )N(R ff )2, -OC(=NR ff )N(R ff )2, -NR ff C(=NR ff )N(R ff )2, -NR ff SO2R ee , -SO2N(R ff )2, -SO2R ee , -SO2OR ee , -OSO2R ee , -S(=O)R ee , -Si(R ee )3, -OSi(R ee )3, -C(=S)N(R ff )2, -C(=O)SR ee , -C(=S)SR ee , -SC(=S)SR ee , -P(=O)2R ee , -P(=O)(R ee )2, -OP(=O)(R ee )2, -OP(=O)(OR ee )2, C 1-6 Alkyl, C 1-6 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, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is selected from 0, 1, 2, 3, 4, or 5 R gg groups, or two geminal R dd The substituents may be taken together to form =O or =S; R ee Each instance of 1-6 Alkyl, C 1-6Perhaloalkyl, 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 selected from 0, 1, 2, 3, 4, or 5 R gg independently substituted with the law of nature; R ff Each instance of 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 3- to 10-membered heteroaryl, or two R ff The groups taken together form a 3- to 14-membered heterocyclyl or 5- to 14-membered heteroaryl ring, where each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl may be selected from 0, 1, 2, 3, 4, or 5 R gg independently substituted with groups; R gg Each instance of is independently a halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OC 1-6 Alkyl, -ON(C 1-6 alkyl)2, -N(C 1-6 alkyl)2, -N(C 1-6 alkyl)3 + X - , -NH(C 1-6 alkyl)2 + X - , -NH2(C 1-6 alkyl) + X - , -NH3 + X - , -N(OC 1-6 Alkyl)(C 1-6 alkyl), -N(OH)(C 1-6alkyl), -NH(OH), -SH, -SC 1-6 Alkyl, -SS(C 1-6 alkyl), -C(=O)(C 1-6 alkyl), -CO2H, -CO2(C 1-6 alkyl), -OC(=O)(C 1-6 alkyl), -OCO2(C 1-6 alkyl), -C(=O)NH2, -C(=O)N(C 1-6 alkyl)2, -OC(=O)NH(C 1-6 alkyl), -NHC(=O)(C 1-6 alkyl), -N(C 1-6 alkyl)C(=O)(C 1-6 alkyl), -NHCO2(C 1-6 alkyl), -NHC(=O)N(C 1-6 alkyl)2, -NHC(=O)NH(C 1-6 alkyl), -NHC(=O)NH2, -C(=NH)O(C 1-6 alkyl), -OC(=NH)(C 1-6 alkyl), -OC(=NH)OC 1-6 Alkyl, -C(=NH)N(C 1-6 alkyl)2, -C(=NH)NH(C 1-6 alkyl), -C(=NH)NH2, -OC(=NH)N(C 1-6 alkyl)2, -OC(NH)NH(C 1-6 alkyl), -OC(NH)NH2, -NHC(NH)N(C 1-6 alkyl)2, -NHC(=NH)NH2, -NHSO2(C 1-6 alkyl), -SO2N(C 1-6 alkyl)2, -SO2NH(C 1-6 alkyl), -SO2NH2, -SO2C 1-6 Alkyl, -SO2OC 1-6 Alkyl, -OSO2C 1-6 Alkyl, -SOC 1-6 Alkyl, -Si(C 1-6 alkyl)3, -OSi(C 1-6 alkyl)3-C(=S)N(C 1-6 alkyl)2, C(=S)NH(C 1-6alkyl), C(=S)NH2, -C(=O)S(C 1-6 alkyl), -C(=S)SC 1-6 Alkyl, -SC(=S)SC 1-6 Alkyl, -P(=O)2(C 1-6 alkyl), -P(=O)(C 1-6 alkyl)2, -OP(=O)(C 1-6 alkyl)2, -OP(=O)(OC 1-6 Alkyl)2, C 1-6 Alkyl, C 1-6 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 taken together to form =O or =S; in this case, X - is the counter ion.

[0090] A "counterion" or "anionic counterion" is a negatively charged group associated with a cationic quaternary amino group to maintain electronic neutrality. Exemplary counterions include halide ions (e.g., F - , Cl - , Br - , I - ), NO3 - , ClO4 - , O.H. - , H2PO4 - , HSO4 - , sulfonates (e.g., methanesulfonate, trifluoromethanesulfonate, p-toluenesulfonate, benzenesulfonate, 10-camphorsulfonate, naphthalene-2-sulfonate, naphthalene-1-sulfonic acid-5-sulfonate, ethane-1-sulfonic acid-2-sulfonate, and the like), and carboxylates (e.g., acetate, ethanoate, propanoate, benzoate, glycerate, lactate, tartrate, glycolate, and the like).

[0091] Nitrogen atoms may be substituted or unsubstituted, where valence allows, and include primary, secondary, tertiary, and quaternary nitrogen atoms. Exemplary nitrogen atom substituents include hydrogen, -OH, -OR aa , -N(R cc )2, -CN, -C(=O)R aa , -C(=O)N(R cc )2, -CO2R aa , -SO2R aa , -C(=NR bb )R aa , -C(=NR cc ) OR aa , -C(=NR cc )N(R cc )2, -SO2N(R cc )2, -SO2R cc , -SO2OR cc , -SOR aa , -C(=S)N(R cc )2, -C(=O)SR cc , -C(=S)SR cc , -P(=O)2R aa , -P(=O)(R aa )2, -P(=O)2N(R cc )2, -P(=O)(NR cc )2, C 1-10 Alkyl, C 1-10 Perhaloalkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Carbocyclyl, 3- to 14-membered heterocyclyl, C 6~14 aryl, and 5- to 14-membered heteroaryl, or two R attached to a nitrogen atom cc The groups taken together form a 3- to 14-membered heterocyclyl or 5- to 14-membered heteroaryl ring, where each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is selected from the group consisting of 0, 1, 2, 3, 4, or 5 R dd groups, and R aa , R bb , R cc and Rdd is as defined above.

[0092] In certain embodiments, the substituent present on the nitrogen atom is an amino protecting group (also referred to herein as a nitrogen protecting group). Amino protecting groups include -OH, -OR aa , -N(R cc )2, -C(=O)R aa , -C(=O)N(R cc )2, -CO2R aa , -SO2R aa , -C(=NR cc )R aa , -C(=NR cc ) OR aa , -C(=NR cc )N(R cc )2, -SO2N(R cc )2, -SO2R cc , -SO2OR cc , -SOR aa , -C(=S)N(R cc )2, -C(=O)SR cc , -C(=S)SR cc , C 1-10 Alkyl (e.g., aralkyl, heteroaralkyl), C 2-10 Alkenyl, C 2-10 Alkynyl, C 3-10 Carbocyclyl, 3- to 14-membered heterocyclyl, C 6~14 aryl, and 5- to 14-membered heteroaryl groups, where each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aralkyl, aryl, and heteroaryl may be selected from the group consisting of 0, 1, 2, 3, 4, or 5 R dd groups, and R aa , R bb , R cc and R ddis as defined above. Amino protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T.W. Greene and P.G.M. Butts, 3rd Edition, John Wiley & Sons, 1999, which reference is incorporated herein by reference.

[0093] For example, an amide group (e.g., —C(═O)R aa ), include, but are not limited to, formamide, 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.

[0094] Carbamate groups (e.g., -C(=O)OR aa ) and the like, the amino protecting group includes methyl carbamate, ethyl carbamate, 9-fluoro fluorenylmethyl carbamate (Fmoc), 9-(2-sulfo)fluorenylmethyl carbamate, 9-(2,7-dibromo)fluorenylmethyl carbamate, 2,7-di-t-butyl-[9-(10,10-dioxo-10,10,10,10-tetrahydrothioxanthyl)]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-diphenyl)ethyl carbamate ( ... Cyclohexylcarboxamido)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, benzyl carbamate (Cb z), 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-chromonyl Methyl carbamate (Tcroc), m-nitrophenyl carbamate, 3,5-dimethoxybenzyl carbamate, o-nitrobenzyl carbamate, 3,4-dimethoxy-6-nitrobenzyl carbamate, phenyl (o-nitrophenyl) methyl carbamate, t-amyl carbamate, S-benzylthiocarbamate, p-cyanobenzyl carbamate, cyclobutyl carbamate, cyclohexyl carbamate, cyclopentyl carbamate, cyclopropylmethyl carbamate, p-decyloxybenzyl carbamate, 2,2-dimethoxybenzyl Cetiacil vinyl 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-trimethylbenzylcarbamate.

[0095] Sulfonamide groups (e.g., -S(=O)R aa ), amino 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), These include, but are not limited to, 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.

[0096] Other amino 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, and N-1,1,4,4-tetramethyldisilylazacylate. 1-substituted 3,5-dinitro-4-pyridone, N-methylamine, N-allylamine, N-[2-(trimethylsilyl)ethoxy]methylamine (SEM), N-3-acetoxypropylamine, N-(1-isopropyl-4-nitro-2-oxo-3-pyrroline-3-yl)-2-pyridone, N ... 3-yl)amine, quaternary ammonium salts, N-benzylamine, N-di(4-methoxyphenyl)methylamine, N-5-dibenzoylperylamine, N-triphenylmethylamine (Tr), N-[(4-methoxyphenyl)diphenylmethyl]amine (MMTr), N-9-phenylfluorenylamine (PhF), N-2,7-dichloro-9-fluorenylmethyleneamine, N-ferrocenylmethylamine (Fcm), N-2-picolylamino N'-oxide, N-1,1-dimethyl N-Benzylideneamine, Np-Methoxybenzylideneamine, N-Diphenylmethyleneamine, N-[(2-pyridyl)mesityl]methyleneamine, N-(N',N'-Dimethylaminomethylene)amine, N,N'-Isopropylidenediamine, Np-Nitrobezylideneamine, N-Salicylideneamine, N-5-Chlorosalicylideneamine, N-(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 chelate, N-zinc chelate, N-nitroamine, N-nitrosamine, amine N-oxide, diphenylphosphinamide (Dpp), dimethylthiophosphinamide (Mpt), diphenylthiophosphinamide (Ppt), dialkyl phosphoramidate, dibenzyl phosphoramidate, diphenyl phosphoramidate, benzenesulfenamide, o-nitrobenzenesulfenamide (Nps), 2,4-dinitrobenzenesulfenamide, pentachlorobenzenesulfenamide, 2-nitro-4-methoxybenzenesulfenamide, triphenylmethylsulfenamide, and 3-nitropyridine sulfenamide (Npys).

[0097] In certain embodiments, the substituent present on the oxygen atom is an oxygen protecting group (hydroxyl The oxygen protecting group is -R aa , -N(R bb )2, -C(=O)SR aa , -C(=O)R aa , -CO2R aa , -C(=O)N(R bb )2, -C(=NR bb )R aa , -C(=NR bb ) OR aa , -C(=NR bb )N(R bb )2, -S(=O)R aa , -SO2R aa , -Si(R aa ) 3、 -P(R cc )2, -P(R cc )3, -P(=O)2R aa , -P(=O)(R aa )2, -P(=O)(OR cc )2, -P(=O)2N(R bb )2, and -P(=O)(NR bb) 2, in which R aa , R bb and R cc is as defined herein. Oxygen protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T.W. Greene and P.G.M. Butts, 3rd Edition, John Wiley & Sons, 1999, which reference is incorporated herein by reference.

[0098] Exemplary oxygen protecting groups include methyl, methoxymethyl (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, and 2-methoxyethoxymethyl (MEM). , 2,2,2-trichloroethoxymethyl, bis(2-chloroethoxy)methyl, 2-(trimethylsilyl)ethoxymethyl (SEMOR), tetrahydropyranyl (THP), 3-bromotetrahydropyranyl, tetrahydrothiopyranyl, 1-methoxycyclohexyl, 4-methoxytetrahydropyranyl (MTHP), 4-methoxytetrahydrothiopyranyl, 4-methoxytetrahydrothiopyranyl S,S-dioxide, 1-[(2-chloro-4-methyl)phenyl]-4- Methoxypiperidin-4-yl (CTMP), 1,4-dioxan-2-yl, tetrahydrofuranyl, 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, 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-an Tolyl, 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, benzylsilyl, benzoyl formate, acetate, chloroacetate, dichloroacetate, trichloroacetate, trifluoroacetate, methoxyacetate, triphenylmethoxyacetate, phenoxyacetate, p-chlorophenoxyacetate, 3-phenylpropionate, 4-oxopentanoate (levulinate), 4,4-(ethylenedithio)pentanoate (levulinoyl dithioacetal), pivaloate, adamantoate, crotonate, 4-methoxycrotonate, benzoate, p-phenylbenzyl benzoate, 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 allyl carbonate, alkyl p-nitrophenyl carbonate, alkyl benzyl carbonate, alkyl p-methoxybenzyl carbonate, alkyl 3,4-dimethoxybenzyl carbonate, alkyl o-nitrobenzyl carbonate, alkyl p-nitrobenzyl carbonate, alkyl S-benzyl thiocarbonate, 4-ethoxy-1-naphthyl carbonate, methyl dithiocarbonate, 2-iodobenzoate, 4-azidobutyrate, 4-nitro-4-methylpentanoate, o-(dibromomethyl)benzoate, 2-formylbenzenesulfonate sulfonate, 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',These include, but are not limited to, N'-tetramethylphosphorodiamidate, alkyl N-phenylcarbamate, borate, dimethylphosphinothioyl, alkyl 2,4-dinitrophenylsulfenate, sulfate, methanesulfonate (mesylate), benzylsulfonate, and tosylate (Ts).

[0099] In certain embodiments, the substituent present on the sulfur atom is a sulfur protecting group (also called a thiol protecting group). Sulfur protecting groups include -R aa , -N(R bb )2, -C(=O)SR aa , -C(=O)R aa , -CO2R aa , -C(=O)N(R bb )2, -C(=NR bb )R aa , -C(=NR bb ) OR aa , -C(=NR bb )N(R bb )2, -S(=O)R aa , -SO2R aa , -Si(R aa ) 3、 -P(R cc )2, -P(R cc )3, -P(=O)2R aa , -P(=O)(R aa )2, -P(=O)(OR cc )2, -P(=O)2N(R bb )2, and -P(=O)(NR bb ) 2, in which R aa , R bb and R cc is as defined herein. Sulfur protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T.W. Greene and P.G.M. Butts, 3rd Edition, John Wiley & Sons, 1999, which reference is incorporated herein by reference.

[0100] "Compounds of the invention" and equivalent expressions are intended to encompass compounds as described above, particularly compounds according to any formula listed and / or described herein, and the expression includes prodrugs, pharmaceutically acceptable salts, and solvates, e.g., hydrates, where the context so permits. Similarly, reference to intermediates, whether or not they themselves are claimed, is intended to include their salts and solvates, where the context so permits.

[0101] These and other exemplary substituents are described in more detail in the detailed description, examples, and claims. The present invention is not intended to be limited in any way by the above exemplary list of substituents.

[0102] 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 pharmacopeia for use in animals, and more particularly in humans.

[0103] "Pharmaceutically acceptable salts" refers to salts of compounds of the present invention that are pharmaceutically acceptable and that possess the desired pharmacological activity of the parent compound. In particular, such salts are non-toxic and can be inorganic or organic acid addition salts and base addition salts. Specifically, such salts include: (1) acid addition salts formed with inorganic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or organic acids, such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4-methylbiphenylsulfonic acid, 4-methylbenzyl ... Acid addition salts formed with cyclo[2.2.2]-oct-2-ene-1-carboxylic acid, glucoheptanic 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 (2) salts formed when an acidic proton present in the parent compound is replaced by a metal ion, such as an alkali metal ion, alkaline earth ion, or aluminum ion; or salts formed when coordinated with organic bases, such as ethanolamine, diethanolamine, triethanolamine, N-methylglucamine, and the like. Salts further include, by way of example only, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, and the like; and salts of non-toxic organic or inorganic acids when the compound contains a basic functional group, such as hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate, oxalate, and the like. The term "pharmaceutically acceptable cation" refers to an acceptable cationic counterion of an acidic functional group.Such cations are exemplified by sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium cations, and the like (see, eg, Berge et al., J. Pharm. Sci. 66(1):1-79 (January 1977)).

[0104] "Pharmaceutically acceptable vehicle" refers to a diluent, adjuvant, excipient, or carrier with which a compound of the invention is administered.

[0105] A "pharmaceutically acceptable metabolically cleavable group" refers to a group that is cleaved in vivo to yield a parent compound of the structural formula shown herein. Examples of metabolically cleavable groups include -COR, -COOR, -CONRR, and -CHOR radicals, where R, in each occurrence, is independently selected from alkyl, trialkylsilyl, carbocyclic aryl, or carbocyclic aryl substituted with one or more alkyl, halogen, hydroxy, or alkoxy. Specific examples of representative metabolically cleavable groups include acetyl, methoxycarbonyl, benzoyl, methoxymethyl, and trimethylsilyl groups.

[0106] "Prodrug" refers to a compound (including derivatives of the compounds of the present invention) that has a cleavable group and that is pharmaceutically active in vivo by solvolysis or under physiological conditions. Examples include, but are not limited to, choline ester derivatives and the like, N-alkylmorpholine esters and the like. Other derivatives of the compounds of the present invention are active in both their acid and acid derivative forms, but often offer the advantage of solubility, tissue compatibility, or delayed release in mammalian organisms in the acid-sensitive form (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, such as esters prepared by reacting the parent acid with a suitable alcohol, or amides prepared by reacting the parent acid with a substituted or unsubstituted amine, acid anhydride, or mixed anhydride. Simple aliphatic or aromatic esters, amides, and anhydrides derived from pendant acidic groups on the compounds of the present invention are particular prodrugs. In some cases, it may be desirable to prepare double ester type prodrugs, e.g., (acyloxy)alkyl esters or ((alkoxycarbonyl)oxy)alkyl esters. Specifically, the C1 to C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, aryl, C7-C8 12 Substituted Aryl and C7-C 12 Aryl alkyl esters.

[0107] "Solvate" refers to a form of a compound associated with a solvent or with water (also called a "hydrate"), usually by solvolysis. This physical association involves hydrogen bonding. Conventional solvents include water, ethanol, acetic acid, and the like. The compounds of the present invention can be prepared, for example, in crystalline form, and can be solvated or hydrated. Suitable solvates include pharmaceutically acceptable solvates, such as hydrates, and further include both stoichiometric and non-stoichiometric solvates. In certain cases, solvates will be isolable, for example, when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid. "Solvate" encompasses both solution-phase and isolable solvates. Representative solvates include hydrates, ethanolates, and methanolates.

[0108] "Subjects" to which administration is contemplated include, but are not limited to, humans (i.e., male or female of any age group, e.g., a pediatric subject (e.g., infant, child, adolescent) or an adult subject (e.g., young adult, middle-aged adult, or geriatric)) and / or non-human animals, e.g., mammals, such as primates (e.g., cynomolgus monkeys, rhesus monkeys), cows, pigs, 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.

[0109] "Effective amount" means the amount of a compound that, when administered to a subject to treat or prevent a disease, is sufficient to effect such treatment or prevention. The "effective amount" may vary depending on the compound, the disease and its severity, and the age, weight, etc., of the subject to be treated. A "therapeutically effective amount" refers to an amount effective for therapeutic treatment. A "prophylactically effective amount" refers to an amount effective for prophylactic treatment.

[0110] "Preventing" or "prevention" or "prophylactic treatment" refers to reducing the risk of acquiring or developing a disease or disorder (i.e., preventing at least one clinical symptom of the disease from developing in a subject who has not yet been exposed to a pathogen or who has a predisposition to the disease prior to the onset of the disease).

[0111] The term "prophylaxis" is related to "prevention" and refers to a measure or procedure whose purpose is to prevent, rather than treat or cure, a disease. Non-limiting examples of prophylactic measures include administering a vaccine; administering low molecular weight heparin to hospitalized patients who are at risk of blood clots, for example due to immobility; and administering an antimalarial drug such as chloroquine prior to visiting a geographic area where malaria is endemic or where there is an increased risk of exposure to malaria.

[0112] "Treating" any disease or disorder or "treatment" or "therapeutic treatment" of any disease or disorder refers, in one embodiment, to ameliorating the disease or disorder (i.e., preventing the disease or reducing the manifestation, extent, or severity of at least one of its clinical symptoms). In another embodiment, "treating" or "treatment" refers to improving at least one physical parameter, which may not be discernible by the subject. In yet another embodiment, "treating" or "treatment" refers to either or both physical modification of the disease or disorder (e.g., stabilization of discernible symptoms), physiological modification (e.g., stabilization of physiological parameters). In a further embodiment, "treating" or "treatment" relates to slowing the progression of the disease.

[0113] As used herein, the term "isotopic variant" refers to a compound that contains an unnatural proportion of isotopes with respect to one or more of the atoms that constitute such 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( 15In such isotopically substituted compounds, the following atoms, if present, are: 2 Any carbon that can be H / D 13 C or any nitrogen 15 It will be understood that the presence and location of such atoms may vary, such as may be N, and that the presence and location of such atoms is within the skill of the art. Similarly, the present invention may include the preparation of isotopic variations with radioactive isotopes, where the resulting compounds may be used, for example, in 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 given their ease of incorporation and ready means of detection. Additionally, positron emitting isotopes, e.g. 11 C. 18 F, 15 O and 13 N-substituted compounds can be prepared and would be useful for examining substrate receptor occupancy in positron emission tomography (PET) studies. All isotopic variations of the compounds provided herein, radioactive or not, are intended to be encompassed within the scope of the present invention.

[0114] It should also be understood that compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or in the arrangement of their atoms in space are termed "isomers." Isomers that differ in the arrangement of their atoms in space are termed "stereoisomers."

[0115] Stereoisomers that are not mirror images of one another are called "diastereomers," and those that are non-superimposable mirror images of each other are called "enantiomers." When a compound has an asymmetric center, for example, when it is bonded to four different groups, a pair of enantiomers is possible. Enantiomers can be characterized by the absolute configuration of their asymmetric center and are described by the R- and S-sequencing rules of Cahn and Prelog, or by the way the molecule rotates the plane of polarized light, designated as dextrorotatory or levorotatory (i.e., as (+)- or (-)-isomers, respectively). Chiral compounds can exist as individual enantiomers or as mixtures thereof. A mixture containing equal proportions of enantiomers is called a "racemic mixture."

[0116] "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 due to the shifting of π electrons and atoms (usually H). For example, enols and ketones are tautomers because they are rapidly interconverted by treatment with either acid or base. Another example of tautomerism is the aci- and nitro-forms of phenylnitromethane, which are also formed by treatment with acid or base. Tautomeric forms can be significant in achieving optical chemical reactivity and biological activity of compounds of interest.

[0117] As used herein, an enantiomerically pure compound is substantially free of other enantiomers or stereoisomers 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 terms "enantiomerically pure" or "pure enantiomer" indicate that a compound contains more than 75% by weight, more than 80% by weight, more than 85% by weight, more than 90% by weight, more than 91% by weight, more than 92% by weight, more than 93% by weight, more than 94% by weight, more than 95% by weight, more than 96% by weight, more than 97% by weight, more than 98% by weight, more than 98.5% by weight, more than 99% by weight, more than 99.2% by weight, more than 99.5% by weight, more than 99.6% by weight, more than 99.7% by weight, more than 99.8% by weight, or more than 99.9% by weight of an enantiomer. In certain embodiments, the weight is based on the total weight of all enantiomers or stereoisomers of the compound.

[0118] As used herein, 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 and at most about 0.1% by weight of S-compounds. In certain embodiments, the weights are based on the total weight of the compounds.

[0119] As used herein, unless otherwise indicated, the term "enantiomerically pure S-compound" or "S-compound" refers to at least about 80% by weight of S-compound and at most about 20% by weight of R-compound, at least about 90% by weight of S-compound and at most about 10% by weight of R-compound, at least about 95% by weight of S-compound and at most about 5% by weight of R-compound, at least about 99% by weight of S-compound and at most about 1% by weight of R-compound, at least about 99.9% by weight of S-compound and at most about 0.1% by weight of R-compound. In certain embodiments, the weights are based on the total weight of the compound.

[0120] In the compositions provided herein, an enantiomerically pure compound or its pharmaceutically acceptable salt, solvate, hydrate, or prodrug may be present together with other active or inactive ingredients.For example, a pharmaceutical composition containing an enantiomerically pure R-compound may contain, for example, about 90% excipients and about 10% enantiomerically pure R-compound.In some embodiments, the enantiomerically pure R-compound in such a composition may contain, for example, a minimum of about 95% by weight of the R-compound and a maximum of 5% by weight of the S-compound, based on the total weight of the compound.For example, a pharmaceutical composition containing an enantiomerically pure S-compound may contain, for example, about 90% excipients and about 10% enantiomerically pure S-compound.In some embodiments, the enantiomerically pure S-compound in such a composition may contain, for example, a minimum of about 95% by weight of the R-compound and a maximum of 5% by weight of the R-compound, based on the total weight of the compound. In certain embodiments, the active ingredients can be formulated with little or no excipients or carriers.

[0121] The compounds of the present invention may possess one or more asymmetric centers; therefore, such compounds can be produced as individual (R)- or (S)-stereoisomers or as mixtures thereof.

[0122] Unless otherwise indicated, the description or naming of a particular compound in the specification and claims is intended to include both individual enantiomers and mixtures thereof, racemic or not. Methods for the determination of stereochemistry and the separation of stereoisomers are well-known in the art.

[0123] Those of ordinary skill in the art of organic synthesis will understand that the maximum number of heteroatoms in a stable, chemically feasible heterocyclic ring, whether the ring is aromatic or non-aromatic, is determined by the ring size, the degree of unsaturation, and the valence of the heteroatoms. Generally, a heterocyclic ring can have from 1 to 4 heteroatoms, so long as the heteroaromatic ring is chemically feasible and stable.

[0124] Detailed Description of Certain Embodiments of the Invention In certain embodiments, provided herein are 3-alpha and 3beta-hydroxysteroid compounds useful as NMDA receptor modulators and therefore for the prevention and / or treatment of a wide range of CNS conditions, including, among others, schizophrenia, depression, bipolar disorder (e.g., I and / or II), schizoaffective disorder, mood disorders, anxiety disorders, personality disorders, psychosis, stereotypic disorders, post-traumatic stress disorder (PTSD), autism spectrum disorder (ASD), dysthymia (mild depression), social anxiety disorder, obsessive-compulsive disorder (OCD), pain (e.g., painful syndromes and disorders), sleep disorders, memory disorders, dementia, Alzheimer's disease, seizure disorders (e.g., epilepsy), traumatic brain injury, stroke, addictive disorders (e.g., opiate, cocaine, and / or alcohol addiction), autism, Huntington's disease, insomnia, Parkinson's disease, withdrawal syndrome, or tinnitus. These compounds are expected to exhibit improved in vivo efficacy, pharmacokinetic (PK) properties, oral bioavailability, formulability, stability and / or safety.

[0125] compound In one embodiment, a compound according to formula (I): [ka] (In the formula, Z is a group represented by formula (i), (ii), (iii), (iv) or (v): [ka] is the basis of L 1 and L 2 is selected from the group consisting of a bond, substituted or unsubstituted C1-C6 alkylene, substituted or unsubstituted C2-C6 alkenylene, substituted or unsubstituted C2-C6 alkynylene, substituted or unsubstituted heteroC1-C6 alkylene, substituted or unsubstituted heteroC2-C6 alkenylene, and substituted or unsubstituted heteroC2-C6 alkynylene; L 3 is a substituted or unsubstituted C1-C6 alkylene, a substituted or unsubstituted C2-C6 alkenylene, a substituted or unsubstituted C2-C6 alkynylene, a substituted or unsubstituted hetero C1-C6 alkylene, a substituted or unsubstituted hetero C2-C6 alkenylene, or a substituted or unsubstituted hetero C2-C6 alkynylene; X 1 and X 2 Each instance of is independently -O-, -S-, or -N(R X )-, and in this case R X each instance of is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroalkyl, or an amino protecting group; R 1 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, halo, -N3, -NO2, -SCN, -CN, -OR A1 , -SR A1 , -N(R A1 )2, -N=NR A1 , -N=C(R A1 )2, -N(ORA1 )(R A1 ), -C(=O)R A1 , -C(=O)OR A1 , -C(=O)SR A1 , -C(=O)N(R A1 )2, -C(=O)N(OR A1 )(R A1 ), -OC(=O)R A1 , -OC(=O)OR A1 , -OC(=O)SR A1 , -OC(=O)N(R A1 )2, -NR A1 C(=O)R A1 , -NR A1 C(=O)OR A1 , -NR A1 C(=O)SR A1 , -NR A1 C(=O)N(R A1 )2, -SC(=O)R A2 , -SC(=O)OR A1 , -SC(=O)SR A1 , -SC(=O)N(R A1 )2, -OS(=O)2R A2 , -OS(=O)2OR A1 , -SS(=O)2R A2 , -SS(=O)2OR A1 , -S(=O)R A2 , -SO2R A2 , -NR A1 SO2R A2 , or -SO2N(R A1 )2, in which case R A1 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, or a nitrogen protecting group when attached to a nitrogen atom, or two R A1 groups taken together form a substituted or unsubstituted heterocyclic ring; and R A2is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, or R A1 Groups and R A2 the groups taken together form a substituted or unsubstituted heterocyclic ring; R 2 , R 4a , R 4b , R 7a , R 7b , R 11a and R 11b Each instance of and hydrogen, -OH, 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, -N3, -NO2, -SCN, -CN, -OR B1 , -SR B1 , -N(R B1 )2, -N=NR B1 , -N=C(R B1 )2, -N(OR B1 )(R B1 ), -C(=O)R B1 , -C(=O)OR B1 , -C(=O)SR B1 , -C(=O)N(R b1 )2, -C(=O)N(OR B1 )(R B1 ), -OC(=O)R B1 , -OC(=O)OR B1 , -OC(=O)SR B1 , -OC(=O)N(R B1 )2, -NR B1 C(=O)R B1 , -NR B1 C(=O)OR B1 , -NR B1 C(=O)SR B1 , -NR B1 C(=O)N(R B1 )2, -SC(=O)R B2 , -SC(=O)ORB1 , -SC(=O)SR B1 , -SC(=O)N(R B1 )2, -OS(=O)2R B2 , -OS(=O)2OR B1 , -SS(=O)2R B2 , -SS(=O)2OR B1 , -S(=O)R B2 , -SO2R B2 , -NR B1 SO2R B2 , or -SO2N(R B1 )2(in this case, R B1 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, or a nitrogen protecting group when attached to a nitrogen atom, or two R B1 groups taken together form a substituted or unsubstituted heterocyclic ring; and R B2 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, or R B1 Groups and R B2 groups taken together form a substituted or unsubstituted heterocyclic ring); or optionally, R 4a and R 4b , and / or R 7a and R 7b , and / or R 11a and R 11b taken together form an oxo (=O) group; R 3a is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 3b is hydrogen, -C(=O)R C1 , -C(=O)OR C1 , -C(=O)SR C1 , -C(=O)N(R C1 )2, -S(=O)2R C2 , -S(=O)2OR C1 , -P(=O)2R C2 , -P(=O)2OR C1 , -P(=O)(OR C1 )2, -P(=O)(R C2 )2, or -P(=O)(R C2 )(OR C1 ), in this case, 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, or a nitrogen protecting group when attached to a nitrogen atom, or two R C1 groups taken together form a substituted or unsubstituted heterocyclic ring; and R C2 is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 6a and R 6b each is independently hydrogen, halo, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl; and [ka] represents a single bond or a double bond, provided that when a double bond is present in ring B, R 6a or R 6b is absent, and if a single bond is present in ring B, the hydrogen at C5 is in the alpha or beta position; R 14 is hydrogen or substituted or unsubstituted alkyl; R 17 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, or -OR D1 In this case, R D1 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 oxygen protecting group; R 18 , R 19 and R 20 Each instance of is independently hydrogen or substituted or unsubstituted alkyl; and R 23a and R 23b Each instance of is independently hydrogen, halogen, or substituted or unsubstituted alkyl, or R 23a and R 23b taken together to form a substituted or unsubstituted C3-C6 cycloalkyl; R 24 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, -C(=O)R E1 , -C(=O)OR E1 , -C(=O)SR E1 , -C(=O)N(R E1 )2, -S(=O)2R E2 , -S(=O)2OR E1 , -P(=O)2R E2 , -P(=O)2OR E1 , -P(=O)(OR E1 )2, -P(=O)(R E2 )2, or -P(=O)(RE2 )(OR E1 ), in this case, R E1 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, or a nitrogen protecting group when attached to a nitrogen atom, or two R E1 groups taken together form a substituted or unsubstituted heterocyclic ring; and R E2 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; Y is -O-, -S-, or -NR Z5 - and; R Z4 are independently 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 Z5 , -SR Z5 , or N(R Z5 )2; R Z5 Each instance of is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, 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 Z5 groups taken together form a substituted or unsubstituted heterocyclic ring; and R Z6 Each instance of is independently hydrogen or substituted or unsubstituted alkyl, or two RZ6 The bases together form C 3-6 forming a carbocyclic ring; and The subscript n is 0, 1, 2, or 3. or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, tautomer, isotopic variant or N-oxide thereof, or a combination thereof.

[0126] In certain embodiments, R 3a is H, n is 1, and R 19 When Me, R 1 is other than H, alkyl, alkenyl, or alkynyl. 3a is H and R 3b is -COMe and R 19 When is Me and n is 0, R 1 is OH. In certain embodiments, R 3a is H, n is 0, and R 20 But when it is alkyl , R 1 is other than OH. In certain embodiments, R 19 When Me, R 1 is other than H, alkyl, alkenyl, or alkynyl. 1 is H, and R 19 is other than Me. In certain embodiments, each R 1 and R 3a is H, and R 19 is other than Me.

[0127] In certain embodiments, R 3a When H, R 1 is other than H, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl. 3a When H, R 1is a substituted or unsubstituted carbocyclyl, a substituted or unsubstituted heterocyclyl, a substituted or unsubstituted aryl, a substituted or unsubstituted heteroaryl, halo, -N3, -NO2, -SCN, -CN, -OR A1 , -SR A1 , -N(R A1 )2, -N=NR A1 , -N=C(R A1 )2, -N(OR A1 )(R A1 ), -C(=O)R A1 , -C(=O)OR A1 , -C(=O)SR A1 , -C(=O)N(R A1 )2, -C(=O)N(OR A1 )(R A1 ), -OC(=O)R A1 , -OC(=O)OR A1 , -OC(=O)SR A1 , -OC(=O)N(R A1 )2, -NR A1 C(=O)R A1 , -NR A1 C(=O)OR A1 , -NR A1 C(=O)SR A1 , -NR A1 C(=O)N(R A1 )2, -SC(=O)R A2 , -SC(=O)OR A1 , -SC(=O)SR A1 , -SC(=O)N(R A1 )2, -OS(=O)2R A2 , -OS(=O)2OR A1 , -SS(=O)2R A2 , -SS(=O)2OR A1 , -S(=O)R A2 , -SO2R A2 , -NR A1 SO2R A2 , or -SO2N(R A1 )2.

[0128] In certain further embodiments, the following compound: [ka] and pharmaceutically acceptable salts, solvates, prodrugs, stereoisomers, tautomers, isotopic variants or N-oxides thereof, or combinations thereof, are specifically excluded.

[0129] R 3a Various embodiments of As generally defined above, R 3a R is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. 3a It is generally understood that R may be in the alpha (lower) position or the beta (upper) position. In certain embodiments, R 3a is alpha. In certain embodiments, R 3a is beta.

[0130] In certain embodiments, R 3a is hydrogen.

[0131] In certain embodiments, R 3a is a substituted or unsubstituted alkyl, for example, a substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 1-2 Alkyl, substituted or unsubstituted C 2-3 Alkyl, substituted or unsubstituted C 3-4 Alkyl, substituted or unsubstituted C 4-5 Alkyl, or substituted or unsubstituted C 5-6 An exemplary R is alkyl. 3a C 1-6 a Alkyl groups include substituted or unsubstituted methyl (C1), ethyl (C2), n-propyl (C3), isopropyl (C3), n-butyl (C4), tert-butyl (C4), sec-butyl (C4), iso-butyl (C4), n-pentyl (C5), 3-pentanyl (C5), amyl (C5), neopentyl (C5), 3-methyl-2-butanyl (C5), tertiary amyl (C5), n-hexyl (C6); C alkyl groups substituted with 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more fluoro groups (e.g., -CF3, -CH2F, CHF2, difluoroethyl, and 2,2,2-trifluoro-1,1-dimethyl-ethyl). 1-6 alkyl; C substituted with 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more chloro groups (e.g., -CH2Cl, -CHCl2) 1-6 C substituted with alkyl; and alkoxy groups (e.g., -CH2OCH3 and -CH2OCH2CH3) 1-6 In certain embodiments, R 3a is a substituted alkyl, for example, R 3a is haloalkyl, alkoxyalkyl, or aminoalkyl. In certain embodiments, R 3a is Me, Et, n-Pr, n-Bu, i-Bu, fluoromethyl, chloromethyl, difluoromethyl, trifluoromethyl, trifluoroethyl, difluoroethyl, 2,2,2-trifluoro-1,1-dimethyl-ethyl, methoxymethyl, methoxyethyl, or ethoxymethyl. 3a is Me, Et, n-Pr, n-Bu, or i-Bu. In certain embodiments, R 3a is methoxymethyl, ethoxymethyl, propoxymethyl, methoxyethyl, or ethoxyethyl. In certain embodiments, R 3a is trifluoromethoxymethyl. In certain embodiments, R 3ais fluoromethyl, chloromethyl, difluoromethyl, trifluoromethyl, difluoroethyl, trifluoroethyl, or 2,2,2-trifluoro-1,1-dimethyl-ethyl. 3a is trifluoromethyl.

[0132] In certain embodiments, R 3a 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 3a is ethenyl (C2), propenyl (C3), or butenyl (C4), unsubstituted or substituted with one or more substituents selected from alkyl, halo, haloalkyl, alkoxyalkyl, or hydroxyl. In certain embodiments, R 3a is ethenyl, propenyl, or butenyl, unsubstituted or substituted with alkyl, halo, haloalkyl, alkoxyalkyl, or hydroxyl. In certain embodiments, R 3a is ethenyl.

[0133] In certain embodiments, R 3a 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 3-4 Alkynyl, substituted or unsubstituted C 4-5 Alkynyl, or substituted or unsubstituted C 5-6 alkynyl. Exemplary substituted or unsubstituted R 3aAlkynyl groups include, but are not limited to, ethynyl, propynyl, or butynyl, unsubstituted or substituted with alkyl, halo, haloalkyl (e.g., CF), alkoxyalkyl, cycloalkyl (e.g., cyclopropyl or cyclobutyl), or hydroxyl. In certain embodiments, R 3a is selected from the group consisting of trifluoroethynyl, cyclopropylethynyl, cyclobutylethynyl, and propynyl, fluoropropynyl, and chloroethynyl. 3a is ethynyl (C2), propynyl (C3), or butynyl (C4), unsubstituted or substituted with substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted carbocyclyl, and substituted or unsubstituted heterocyclyl. In certain embodiments, R 3a is substituted with substituted phenyl, ethynyl (C2), propynyl In certain embodiments, the phenyl substituent is further substituted with one or more substituents selected from the group consisting of halo, alkyl, trifluoroalkyl, alkoxy, acyl, amino, or amido. 3a is ethynyl (C2), propynyl (C3) or butynyl (C4) substituted with substituted or unsubstituted pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, isoxazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, oxadiazolyl, thiadiazolyl or tetrazolyl.

[0134] In certain embodiments, R 3a 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 3ais ethynyl or propynyl substituted with unsubstituted phenyl or phenyl substituted with halo, alkyl, alkoxy, haloalkyl, trihaloalkyl, or acyl. 3a is ethynyl or propynyl substituted with a substituted or unsubstituted carbocyclyl. 3a is ethynyl or propynyl, substituted with substituted or unsubstituted cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. 3a is ethynyl or propynyl substituted with substituted or unsubstituted heteroaryl. In certain embodiments, R 3a is ethynyl or propynyl, substituted with substituted or unsubstituted pyridinyl or pyrimidinyl. 3a is ethynyl or propynyl substituted with substituted or unsubstituted pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, isoxazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl. 3a 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 morpholinyl. In certain embodiments, R 3a is propynyl or butynyl substituted with hydroxyl or alkoxy. In certain embodiments, R 3a is propynyl or butynyl substituted with methoxy or ethoxy. In certain embodiments, R 3a is ethynyl or propynyl substituted with Cl. In certain embodiments, R 3a is ethynyl or propynyl substituted with trifluoromethyl.

[0135] In certain embodiments, R3a 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.

[0136] In certain embodiments, R 3a 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.

[0137] In certain embodiments, R 3a is substituted or unsubstituted aryl. In certain embodiments, R 3a is substituted or unsubstituted phenyl.

[0138] In certain embodiments, R 3a is a substituted or unsubstituted heteroaryl, for example, an optionally substituted 5- to 6-membered heteroaryl.

[0139] R is a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkenyl group, and a substituted or unsubstituted alkynyl group. 3a Further embodiments are illustrated below: [ka] (In these formulas, R 3c Each instance of is hydrogen, halo, or -OR F1 (In this case, R F1 is substituted or unsubstituted alkyl; and R 3d Each instance of is hydrogen, halo, or substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclyl, or substituted or unsubstituted heterocyclyl).

[0140] In certain embodiments, at least one R 3c is hydrogen. In certain embodiments, at least two 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, at least two R 3c is halogen (e.g., fluoro, chloro, bromo, iodo). In certain embodiments, each R 3c is halogen (e.g., fluoro, to give the group -CF). In certain embodiments, at least one R 3c -OR F1 (e.g., OMe or OEt). In certain embodiments, at least two R 3c -OR F1 (e.g., OMe or OEt). In certain embodiments, at least one R 3c is hydrogen, F, -OMe, or -OEt. In certain embodiments, R 3c one of is F, -OMe, or -OEt; the rest are H.

[0141] In certain embodiments, at least one R 3d is hydrogen. In certain embodiments, each R 2c is hydrogen. In certain embodiments, at least one R 3d is halogen (e.g., fluoro, chloro, bromo, iodo). In certain embodiments, each R 3d is halogen (e.g., fluoro, chloro, bromo, iodo). In certain embodiments, R 3d Each of is alkyl, e.g., R 2c Each of R is Me. 3d is alkyl and the other is hydrogen, e.g., R 3d One of R is Me and the other is hydrogen. 3dIn certain embodiments, one of R is substituted or unsubstituted carbocyclyl, e.g., cyclopropyl or cyclobutyl, and the other is hydrogen. 3d is hydrogen, -F, -Br, -Cl, -I, -CH, -CF, cyclopropyl, or cyclobutyl. 3d Each instance of is H. In certain embodiments, R 3d Each instance of R is halogen (e.g., fluoro, chloro, bromo, iodo). 3d Each instance of R is alkyl, e.g., —CH, —CF, —CHCHCl. 3d Each instance of is a substituted or unsubstituted carbocyclyl, for example, cyclopropyl or cyclobutyl. In certain embodiments, R 3d is substituted or unsubstituted cyclopropyl. In certain embodiments, R 3d Each instance of R is hydrogen, -F, -Br, -Cl, -I, -CH, -CF, -CHCHCl, cyclopropyl, or cyclobutyl. 3d is Me or Cl. In certain embodiments, R 3d is a substituted or unsubstituted heterocyclyl.

[0142] -X 1 -R 3b Various embodiments of Group-X 1 -R 3b As defined above, X 1 are independently -O-, -S- or -N(R X )-, in this case, R X Each instance of R is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroalkyl, or an amino protecting group; and R 3b is hydrogen, -C(=O)RC1 , -C(=O)OR C1 , -C(=O)SR C1 , -C(=O)N(R C1 )2, -S(=O)2R C1 , -S(=O)2OR C1 , -P(=O)2R C1 , -P(=O)2OR C1 , -P(=O)(OR C1 )2, -P(=O)(R C1 )2, or -P(=O)(R C1 )(OR C1 ), in this case, 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, or a nitrogen protecting group when attached to a nitrogen atom, or two R C1 The groups taken together form a substituted or unsubstituted heterocyclic ring. 1 -R 3b It is generally understood that the -X group may be in the alpha (lower) or beta (upper) position. 1 -R 3b is alpha. In certain embodiments, the group -X 1 -R 3b is beta.

[0143] In certain embodiments, X 1 is —O—. In certain embodiments, X 1 is -S-. In certain embodiments, X 1 is -N(R X In certain embodiments, R X is alkyl. In certain embodiments, R X is Me, Et, or i-Pr. In certain embodiments, R X is H, i.e., in this case, X 1is -NH-.

[0144] In certain embodiments, R 3b is hydrogen. For example, in certain embodiments, the group -X 1 R 3b is -OH. In certain embodiments, the group -X 1 R 3b is -SH. In certain embodiments, the group -X 1 R 3b is -NH2 or -NHR X is.

[0145] In certain embodiments, R 3b is -C(=O)R C1 , -C(=O)OR C1 , -C(=O)SR C1 , -C(=O)N(R C1 )2, -S(=O)2R C1 , -S(=O)2OR C1 , -P(=O)2R C1 , -P(=O)2OR C1 , -P(=O)(OR C1 )2, -P(=O)(R C1 )2, or -P(=O)(R C1 )(OR C1 )

[0146] In certain embodiments, R C1 At least one instance of R is hydrogen or a protecting group, i.e., an oxygen protecting group when attached to an oxygen atom, a sulfur protecting group when attached to a sulfur atom, or a nitrogen protecting group when attached to a nitrogen atom. C1 At least one instance of is hydrogen.

[0147] In certain embodiments, R C1 At least one example 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 C3-4 Alkyl, substituted or unsubstituted C 4-5 Alkyl, or substituted or unsubstituted C 5-6 An exemplary R is alkyl. C1 C 1-6 Alkyl groups include substituted or unsubstituted methyl (C1), ethyl (C2), n-propyl (C3), isopropyl (C3), n-butyl (C4), tert-butyl (C4), sec-butyl (C4), iso-butyl (C4), n-pentyl (C5), 3-pentanyl (C5), amyl (C5), neopentyl (C5), 3-methyl-2-butanyl (C5), tertiary amyl (C5), n-hexyl (C6); 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more fluoro groups (e.g., -CF3, - C substituted with CH2F, CHF2, difluoroethyl, and 2,2,2-trifluoro-1,1-dimethyl-ethyl) 1-6 alkyl; C substituted with 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more chloro groups (e.g., -CH2Cl, -CHCl2) 1-6 C substituted with alkyl; and alkoxy groups (e.g., -CH2OCH3 and -CH2OCH2CH3) 1-6 Examples include, but are not limited to, alkyl.

[0148] In certain embodiments, R C1 At least one example 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.

[0149] In certain embodiments, R C1 At least one example 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 C3-4 Alkynyl, substituted or unsubstituted C 4-5 Alkynyl, or substituted or unsubstituted C 5-6 It is alkynyl.

[0150] In certain embodiments, R C1 At least one example 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 It is a carbocyclyl.

[0151] In certain embodiments, R C1 At least one example of 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.

[0152] In certain embodiments, R C1 At least one instance of is substituted or unsubstituted aryl, for example, substituted or unsubstituted phenyl.

[0153] In certain embodiments, R C1 At least one instance of is a substituted or unsubstituted heteroaryl, for example, an optionally substituted 5- to 6-membered heteroaryl.

[0154] In certain instances, two R C1 The groups taken together form a substituted or unsubstituted heterocyclic ring, for example, a substituted or unsubstituted piperidinyl, substituted or unsubstituted piperazinyl, or substituted or unsubstituted morpholinyl ring.

[0155] In certain instances, R 3b is -C(=O)R C1 , -C(=O)OR C1 , -C(=O)N(RC1 )2, or -C(=O)N(OR C1 )(R C1 ) and in this case R C1 is as defined herein.

[0156] In certain embodiments, R 3b is -C(=O)R C1 For example, R C1 is, for example, substituted or unsubstituted methyl (C1), ethyl (C2), n-propyl (C3), isopropyl (C3), n-butyl (C4), tert-butyl (C4), sec-butyl (C4), iso-butyl (C4), n-pentyl (C5), 3-pentanyl (C5), amyl (C5), neopentyl (C5), 3-methyl-2-butanyl (C5), tertiary amyl (C5), or n-hexyl (C6). C1 In certain embodiments, R 3b is —C(═O)CH. In certain embodiments, R 3b is -C(=O)(CH2) m COH, 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 3b is -C(=O)CHCHC(=O)OH.

[0157] In certain embodiments, R 3b is -C(=O)OR C1 For example, R C1 is, for example, substituted or unsubstituted methyl (C1), ethyl (C2), n-propyl (C3), isopropyl (C3), n-butyl (C4), tert-butyl (C4), sec-butyl (C4), iso-butyl (C4), n-pentyl (C5), 3-pentanyl (C5), amyl (C5), neopentyl (C5), 3-methyl-2-butanyl (C5), tertiary amyl (C5) or n-hexyl (C6), -C(=O)ORC1 is.

[0158] In certain embodiments, R 3b is -C(=O)SR C1 For example, R C1 is, for example, substituted or unsubstituted methyl (C1), ethyl (C2), n-propyl (C3), isopropyl (C3), n-butyl (C4), tert-butyl (C4), sec-butyl (C4), iso-butyl (C4), n-pentyl (C5), 3-pentanyl (C5), amyl (C5), neopentyl (C5), 3-methyl-2-butanyl (C5), tertiary amyl (C5), or n-hexyl (C6). C1 is.

[0159] In certain embodiments, R 3b is R C1 is, for example, substituted or unsubstituted methyl (C1), ethyl (C2), n-propyl (C3), isopropyl (C3), n-butyl (C4), tert-butyl (C4), sec-butyl (C4), iso-butyl (C4), n-pentyl (C5), 3-pentanyl (C5), amyl (C5), neopentyl (C5), 3-methyl-2-butanyl (C5), tertiary amyl (C5), or n-hexyl (C6). C1 )2, for example, -C(=O)NH2 or -C(=O)NHR C1 or R 1 is two R C1 -C(=O)N(R C1 )2.

[0160] In certain embodiments, R 3b is -S(=O)2R C1 or -S(=O)2OR C1 In this case, R C1is, for example, hydrogen, substituted or unsubstituted methyl (C1), ethyl (C2), n-propyl (C3), isopropyl (C3), n-butyl (C4), tert-butyl (C4), sec-butyl (C4), iso-butyl (C4), n-pentyl (C5), 3-pentanyl (C5), amyl (C5), neopentyl (C5), 3-methyl-2-butanyl (C5), tertiary amyl (C5) or n-hexyl (C6), or substituted or unsubstituted phenyl. In certain embodiments, R 3b is -S(=O)2R C1 In certain embodiments, R 3b is -S(=O)2OR C1 , for example, -SO3H.

[0161] In certain embodiments, R 3b is -P(=O)2R C1 , -P(=O)2OR C1 , -P(=O)(OR C1 )2, -P(=O)(R C1 )2, or -P(=O)(R C1 )(OR C1 ) where each R C1 are, for example, independently hydrogen, substituted or unsubstituted methyl (C1), ethyl (C2), n-propyl (C3), isopropyl (C3), n-butyl (C4), tert-butyl (C4), sec-butyl (C4), iso-butyl (C4), n-pentyl (C5), 3-pentanyl (C5), amyl (C5), neopentyl (C5), 3-methyl-2-butanyl (C5), tertiary amyl (C5), or n-hexyl (C6), or substituted or unsubstituted phenyl. In certain embodiments, R 3b is -P(=O)2R C1 In certain embodiments, R 3b is -P(=O)2OR C1 In certain embodiments, R 3b is -P(=O)(OR C1 )2. In certain embodiments, R 3b is -P(=O)(R C1 )2 In certain embodiments, R 3b is -P(=O)(R C1 )(OR C1 )

[0162] Various embodiments in which Z is a group of formula (i) or (ii) In certain embodiments, Z is a group represented by formula (i): [ka] It is based on.

[0163] In certain embodiments, Z is of formula (ii): [ka] It is based on.

[0164] As generally defined above, L 1 and L 2 is a bond (i.e., in other words, absent), or is a substituted or unsubstituted C1-C6 alkylene, substituted or unsubstituted C2-C6 alkenylene, substituted or unsubstituted C2-C6 alkynylene, substituted or unsubstituted heteroC1-C6 alkylene, substituted or unsubstituted heteroC2-C6 alkenylene, or substituted or unsubstituted heteroC2-C6 alkynylene.

[0165] In certain embodiments, L 1 or L 2 is a bond.

[0166] In certain embodiments, L 1 or L 2 is a substituted or unsubstituted C1-C6 alkylene. In certain embodiments, L 1 or L 2 is a substituted or unsubstituted C1-C4 alkylene. In certain embodiments, L 1 or L 2 is a substituted or unsubstituted C1-C3 alkylene. In certain embodiments, L 1 or L 2is a substituted or unsubstituted C1-C2 alkylene. In certain embodiments, L 1 or L 2 is a substituted or unsubstituted C alkylene. In certain embodiments, L 1 or L 2 is a substituted or unsubstituted C alkylene. In certain embodiments, L 1 or L 2 is a substituted or unsubstituted C alkylene. In certain embodiments, L 1 or L 2 is a substituted or unsubstituted C4 alkylene. In certain embodiments, L 1 or L 2 is a substituted or unsubstituted C5 alkylene. In certain embodiments, L 1 or L 2 is a substituted or unsubstituted C alkylene. In certain embodiments, L 1 or L 2 is an alkylene group, as described above, substituted with one or more substituents selected from the group consisting of substituted or unsubstituted alkyl and halo. 1 or L 2 is -CH2-, -CHMe-, -CMe2-, -CH2-CH2-, -CF2-CH2-, -CH2-CMe2-, -CH2-CH2-CH2-, or -CH2-CH2-CMe2-.

[0167] In certain embodiments, L 1 or L 2 is substituted or unsubstituted C-C alkenylene. In certain embodiments, L 1 or L 2 is substituted or unsubstituted C2-C5 alkenylene. In certain embodiments, L 1 or L 2 is substituted or unsubstituted C2-C4 alkenylene. In certain embodiments, L 1 or L 2 is a substitution or non- In certain embodiments, L is a substituted C2-C3 alkenylene. 1or L 2 is substituted or unsubstituted C2 alkenylene. In certain embodiments, L 1 or L 2 is substituted or unsubstituted C alkenylene. In certain embodiments, L 1 or L 2 is substituted or unsubstituted C4 alkenylene. In certain embodiments, L 1 or L 2 is substituted or unsubstituted C5 alkenylene. In certain embodiments, L 1 or L 2 is substituted or unsubstituted C6 alkenylene. In certain embodiments, L 1 or L 2 is an alkenylene group, as described above, substituted with one or more substituents selected from the group consisting of substituted or unsubstituted alkyl and halo.

[0168] In certain embodiments, L 1 or L 2 is substituted or unsubstituted C2-C6 alkynylene. In certain embodiments, L 1 or L 2 is substituted or unsubstituted C2-C5 alkynylene. In certain embodiments, L 1 or L 2 is substituted or unsubstituted C2-C4 alkynylene. In certain embodiments, L 1 or L 2 is substituted or unsubstituted C2-C3 alkynylene. In certain embodiments, L 1 or L 2 is substituted or unsubstituted C alkynylene. In certain embodiments, L 1 or L 2 is substituted or unsubstituted C alkynylene. In certain embodiments, L 1 or L 2 is substituted or unsubstituted C4 alkynylene. In certain embodiments, L 1 or L 2 is substituted or unsubstituted C5 alkynylene. In certain embodiments, L1 or L 2 is substituted or unsubstituted C alkynylene. In certain embodiments, L 1 or L 2 is an alkynylene group, as described above, substituted with one or more substituents selected from the group consisting of substituted or unsubstituted alkyl and halo.

[0169] Additionally, in certain embodiments, L 1 or L 2 is a substituted or unsubstituted heterocyclic C 1-6 Alkylene, e.g., substituted or unsubstituted hetero C 1-2 Alkylene, substituted or unsubstituted hetero C 2-3 Alkylene, substituted or unsubstituted hetero C 3-4 Alkylene, substituted or unsubstituted hetero C 4-5 Alkylene, or substituted or unsubstituted hetero C 5-6 In certain embodiments, L 1 or L 2 is a substituted or unsubstituted heterocyclic C 2-6 Alkenylene, for example, substituted or unsubstituted hetero C 2-3 Alkenylene, substituted or unsubstituted hetero C 3-4 Alkenylene, substituted or unsubstituted hetero C 4-5 Alkenylene, or substituted or unsubstituted hetero C 5-6 In certain embodiments, L is alkenylene. 1 or L 2 is a substituted or unsubstituted heterocyclic C 2-6 Alkynylene, for example, substituted or unsubstituted hetero C 2-3 Alkynylene, substituted or unsubstituted hetero C 3-4 Alkynylene, substituted or unsubstituted hetero C 4-5 Alkynylene, or substituted or unsubstituted hetero C 5-6 In any of the above examples, in certain embodiments, L 1 or L 2 is unsubstituted, or halo (e.g., fluoro) or substituted or unsubstituted C 1-6It is heteroalkylene, heteroalkenylene or heteroalkynylene substituted with alkyl.

[0170] As generally defined above, R 1 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, halo, -N3, -NO2, -SCN, -CN, -OR A1 , -SR A1 , -N(R A1 )2, -N=NR A1 , -N=C(R A1 )2, -N(OR A1 )(R A1 ), -C(=O)R A1 , -C(=O)OR A1 , -C(=O)SR A1 , -C(=O)N(R A1 )2, -C(=O)N(OR A1 )(R A1 ), -OC(=O)R A1 , -OC(=O)OR A1 , -OC(=O)SR A1 , -OC(=O)N(R A1 )2, -NR A1 C(=O)R A1 , -NR A1 C(=O)OR A1 , -NR A1 C(=O)SR A1 , -NR A1 C(=O)N(R A1 )2, -SC(=O)R A2 , -SC(=O)OR A1 , -SC(=O)SR A1 , -SC(=O)N(R A1 )2, -OS(=O)2R A2 , -OS(=O)2OR A1 , -SS(=O)2R A2 , -SS(=O)2O R A1 , -S(=O)R A2 , -SO2R A2 , -NRA1 SO2R A2 , or -SO2N(R A1 )2, in which case R A1 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, or a nitrogen protecting group when attached to a nitrogen atom, or two R A1 groups taken together form a substituted or unsubstituted heterocyclic ring; and 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, or R A1 Groups and R A2 The groups taken together form a substituted or unsubstituted heterocyclic ring.

[0171] In certain embodiments, R 1 is hydrogen.

[0172] In certain embodiments, R 1 is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl. In certain embodiments, R 1 is substituted or unsubstituted alkyl, e.g., Me, Et, or i-Pr. In certain embodiments, R 1 is substituted or unsubstituted alkenyl, for example, substituted or unsubstituted ethenyl or substituted or unsubstituted propenyl. 1 is a substituted or unsubstituted alkynyl.

[0173] In certain embodiments, R 1 is selected from substituted or unsubstituted carbocyclyl or substituted or unsubstituted heterocyclyl.

[0174] In certain embodiments, R 1 is substituted or unsubstituted aryl, for example phenyl.

[0175] In certain embodiments, R 1 is a substituted or unsubstituted heteroaryl, for example, a substituted or unsubstituted heteroaryl selected from pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, isoxazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, quinolinyl, isoquinolinyl, quinazonyl, quinoxalinyl, naphthyridinyl, indolyl, indazolyl, benzimidazolyl, pyrrolopyridinyl, pyrrolopyrimidinyl, pyridopyrimidinyl, or purinyl. In certain embodiments, the heteroaryl group is substituted with one or more groups selected from substituted or unsubstituted alkyl, haloalkyl, alkenyl, substituted or unsubstituted alkynyl, oxo, hydroxy, halo, alkoxy, -S-alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted -SO-alkyl, substituted or unsubstituted -SO2-alkyl, substituted or unsubstituted -SO2-aryl, substituted or unsubstituted -SO2-aryl, substituted or unsubstituted -SO2-heteroaryl, substituted or unsubstituted -SO2-heteroaryl, amino, cyano, and acyl. 1 is imidazolyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, oxadiazolyl, thiadiazolyl, or tetrazolyl, each of which is unsubstituted or substituted with one or two groups independently selected from oxo, Me, F, Cl, —CN, and —CF. In certain embodiments, R 1 is quinolinyl, isoquinolinyl, or purinyl, each of which is unsubstituted or substituted with one or two groups independently selected from oxo, Me, F, Cl, —CN, and —CF 3 .

[0176] In certain embodiments, R 1 -OR A1 In certain embodiments, R 1 is -O-quinolinyl, -O-isoquinolinyl, -O-purinyl, each of which is unsubstituted or substituted with 1 or 2 groups independently selected from Me, F, Cl, -CN, and -CF. In certain embodiments, R 1 is -OH or -O-CO-CH2-CH2-CO2H.

[0177] In certain embodiments, R 1 -SR A1 In certain embodiments, R 1 is -S-quinolinyl, -S-isoquinolinyl, or -S-purinyl, each of which is unsubstituted or substituted with 1 or 2 groups independently selected from Me, F, Cl, -CN, and -CF. In certain embodiments, R 1 is -SH.

[0178] In certain embodiments, R 1 is -OS(=O)2R A2 In certain embodiments, R 1 is -OS(=O)2OR A1 , for example, —O—SO3H. In certain embodiments, R 1 is -SS(=O)2R A2 In certain embodiments, R 1 is -SS(=O)2OR A1 , for example, -S-SO3H.

[0179] As generally defined above, R 20 are independently hydrogen or substituted or unsubstituted alkyl. In certain embodiments, R 20 is hydrogen. In certain embodiments, R 20 is substituted or unsubstituted alkyl (e.g., —CH 3 ).

[0180] As generally defined above, R 23a and R 23b Each instance of is independently hydrogen, halogen, or substituted or unsubstituted alkyl, or R 23a and R 23b taken together form a substituted or unsubstituted C3-C6 cycloalkyl. In certain embodiments, R 23a and R 23b Each instance of R is hydrogen. 23a and R 23b is halogen, for example fluoro, and R 23a and R 23b The other of R is hydrogen, halogen, or substituted or unsubstituted alkyl. 23a and R 23b Each instance of is halogen, e.g., fluoro. In certain embodiments, R 23a and R 23b Each instance of is independently substituted or unsubstituted alkyl. In certain embodiments, R 23a and R 23b Each of R is Me. 23a and R 23b One of R is H. In certain embodiments, R 23a and R 23b is H; and the other is substituted or unsubstituted alkyl. In certain embodiments, R 23a and R 23b is H; and the other is Me or Et. In certain embodiments, R 23a and R 23b taken together form a substituted or unsubstituted C3-C6 cycloalkyl. In certain embodiments, R 23a and R 23b taken together to form a substituted or unsubstituted cyclopropyl.

[0181] In certain embodiments, the group [ka] is the expression: [ka] It is of the type.

[0182] As generally defined above, X 2 are independently -O-, -S-, or -N(R X )-, in this case, R X Each instance of is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroalkyl, or an amino protecting group.

[0183] In certain embodiments, X 2 is —O—. In certain embodiments, X 2 is -S-. In certain embodiments, X 2 is -N(R X In certain embodiments, R X is alkyl. In certain embodiments, R X is Me, Et, or i-Pr. In certain embodiments, R X is hydrogen.

[0184] In certain embodiments, X 1 is -O-, and X 2 is —O—. In certain embodiments, X 1 is -O-, and X 2 is -S-. In certain embodiments, X 1 is -O-, and X 2 is -N(R X In certain embodiments, X 1 is -S-, and X 2 is —O—. In certain embodiments, X 1 is -S-, and X 2 is -S-. In certain embodiments, X1 is -S-, and X 2 is -N(R X In certain embodiments, X 1 is -N(R X )- and X 2 is —O—. In certain embodiments, X 1 is -N(R X )- and X 2 is -S-. In certain embodiments, X 1 is -N(R X )- and X 2 is -N(R X )-.

[0185] As generally defined above, R 24 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, substituted or unsubstituted heteroaryl, -C(=O)R E1 , -C(=O)OR E1 , -C(=O)SR E1 , -C(=O)N(R E1 )2, -S(=O)2R E2 , -S(=O)2OR E1 , -P(=O)2R E2 , -P(=O)2OR E1 , -P(=O)(OR E1 )2, -P(=O)(R E2 )2, or -P(=O)(R E2 )(OR E1 )

[0186] In certain embodiments, R 24 is hydrogen.

[0187] In certain embodiments, R 24 is substituted or unsubstituted alkyl. In certain embodiments, R 24is unsubstituted alkyl or alkyl substituted with one or more substituents selected from the group consisting of halo and hydroxyl. In certain embodiments, R 24 is substituted or unsubstituted alkenyl. In certain embodiments, R 24 is substituted or unsubstituted alkynyl. In certain embodiments, R 24 is placed In certain embodiments, R is substituted or unsubstituted carbocyclyl. 24 is substituted or unsubstituted heterocyclyl. In certain embodiments, R 24 is substituted or unsubstituted aryl. In certain embodiments, R 24 is a substituted or unsubstituted heteroaryl.

[0188] In certain embodiments, R 24 is -C(=O)R E1 For example, R 24 is -C(=O)(CH2) p COH, where p is an integer between 2 and 5, inclusive. In certain embodiments, p is 2. In certain embodiments, p is 3. In certain embodiments, p is 4. In certain embodiments, p is 5. In certain embodiments, R 24 is -C(=O)OR E1 In certain embodiments, R 24 is -C(=O)SR E1 In certain embodiments, R 24 is -C(=O)N(R E1 )2. In certain embodiments, R 24 is -S(=O)2R E2 In certain embodiments, R 24 is -S(=O)2OR E1 , for example, —SO3H. In certain embodiments, R 24 is -P(=O)2R E2 In certain embodiments, R 24 is -P(=O)2OR E1In certain embodiments, R 24 is -P(=O)(OR E1 )2. In certain embodiments, R 24 is -P(=O)(R E2 )2. In certain embodiments, R 24 is -P(=O)(R E2 )(OR E1 )

[0189] As generally defined above, the subscript n is 0, 1, 2, or 3. In certain embodiments, n is 0. In certain embodiments, n is 1. In certain embodiments, n is 2. In certain embodiments, n is 3.

[0190] Various embodiments in which Z is a group of formula (iii), (iv) or (v) In certain embodiments, Z is a group of formula (iii), (iv), or (v): [ka] is.

[0191] In certain embodiments, L 3 is a substituted or unsubstituted C 1-6 Alkylene, for example, substituted or unsubstituted C 1-2 Alkylene, substituted or unsubstituted C 2-3 Alkylene, substituted or unsubstituted C 3-4 Alkylene, substituted or unsubstituted C 4-5 Alkylene, or substituted or unsubstituted C 5-6 In certain embodiments, L 3 is a substituted or unsubstituted C 2-6 Alkenylene, for example, substituted or unsubstituted C 2-3 Alkenylene, substituted or unsubstituted C 3-4 Alkenylene, substituted or unsubstituted C 4-5 Alkenylene, or substituted or unsubstituted C 5-6 In certain embodiments, L is alkenylene.3 is a substituted or unsubstituted C 2-6 Alkynylene, for example, substituted or unsubstituted C 2-3 Alkynylene, substituted or unsubstituted C 3-4 Alkynylene, substituted or unsubstituted C 4-5 Alkynylene, or substituted or unsubstituted C 5-6 In any of the above examples, in certain embodiments, L 3 is unsubstituted, or halo (e.g., fluoro), substituted or unsubstituted C 1-6 Alkyl and / or -OR Z5 and n is 0 or 1. The group is alkylene, alkenylene, or alkynylene, substituted with

[0192] Additionally, in certain embodiments, L 3 is a substituted or unsubstituted heterocyclic C 1-6 Alkylene, e.g., substituted or unsubstituted hetero C 1-2 Alkylene, substituted or unsubstituted hetero C 2-3 Alkylene, substituted or unsubstituted hetero C 3-4 Alkylene, substituted or unsubstituted hetero C 4-5 Alkylene, or substituted or unsubstituted hetero C 5-6 In certain embodiments, L 3 is a substituted or unsubstituted heterocyclic C 2-6 Alkenylene, For example, substituted or unsubstituted hetero C 2-3 Alkenylene, substituted or unsubstituted hetero C 3-4 Alkenylene, substituted or unsubstituted hetero C 4-5 Alkenylene, or substituted or unsubstituted hetero C 5-6 In certain embodiments, L is alkenylene. 3 is a substituted or unsubstituted heterocyclic C 2-6 Alkynylene, for example, substituted or unsubstituted hetero C 2-3 Alkynylene, substituted or unsubstituted hetero C 3-4 Alkynylene, substituted or unsubstituted hetero C 4-5 Alkynylene, or substituted or unsubstituted hetero C 5-6In any of the above examples, in certain embodiments, L 3 is unsubstituted, or halo (e.g., fluoro) or substituted or unsubstituted C 1-6 Alkyl and / or -OR Z5 Heteroalkylene, heteroalkenylene or heteroalkynylene substituted with

[0193] In either the above or below examples, in certain embodiments, at least one R Z5 is hydrogen.

[0194] In any of the above or below examples, in certain embodiments, R Z5 At least one example 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 alkyl. Z5 C 1-6 Alkyl groups include substituted or unsubstituted methyl (C1), ethyl (C2), n-propyl (C3), isopropyl (C3), n-butyl (C4), tert-butyl (C4), sec-butyl (C4), iso-butyl (C4), n-pentyl (C5), 3-pentanyl (C5), amyl (C5), neopentyl (C5), 3-methyl-2-butanyl (C5), tertiary amyl (C5), n-hexyl (C6); C6 substituted with 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more fluoro groups (e.g., -CF3, -CH2F, CHF2, difluoroethyl, and 2,2,2-trifluoro-1,1-dimethyl-ethyl). 1-6 alkyl; C substituted with 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more chloro groups (e.g., -CH2Cl, -CHCl2) 1-6C substituted with alkyl; and alkoxy groups (e.g., -CH2OCH3 and -CH2OCH2CH3) 1-6 Examples include, but are not limited to, alkyl.

[0195] In any of the above or below examples, in certain embodiments, R Z5 At least one example 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.

[0196] In any of the above or below examples, in certain embodiments, R Z5 At least one example 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 It is alkynyl.

[0197] In any of the above or below examples, in certain embodiments, R Z5 At least one example 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 It is a carbocyclyl.

[0198] In any of the above or below examples, in certain embodiments, R Z5 At least one example of is a substituted or unsubstituted heterocyclyl, e.g., a substituted or unsubstituted 3-6 substituted or unsubstituted 3- or 4-membered heterocyclyl, substituted or unsubstituted 4- or 5-membered heterocyclyl, or substituted or unsubstituted 5- or 6-membered heterocyclyl.

[0199] In any of the above or below examples, in certain embodiments, R Z5 At least one instance of is substituted or unsubstituted aryl, for example, substituted or unsubstituted phenyl.

[0200] In any of the above or below examples, in certain embodiments, R Z5 At least one instance of is a substituted or unsubstituted heteroaryl, for example, an optionally substituted 5-6 membered heteroaryl.

[0201] In any of the above or below examples, in certain embodiments, R Z5 is a protecting group, for example, 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.

[0202] In certain embodiments, two R Z5 When attached to a nitrogen atom, those two R Z5 The groups taken together form a substituted or unsubstituted heterocyclic ring, for example, a substituted or unsubstituted piperidinyl, substituted or unsubstituted piperazinyl, or substituted or unsubstituted morpholinyl ring.

[0203] Further, in any of the above or below examples, in certain embodiments, R Z6 Each instance of is independently hydrogen, substituted or unsubstituted alkyl, or two R Z6 The bases come together, C 3-6 Forms a carbocyclic ring.

[0204] In certain embodiments, R Z6 At least one instance of is hydrogen.

[0205] In certain embodiments, R Z6 At least one example 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 alkyl. Z4 C 1-6 Alkyl groups include substituted or unsubstituted methyl (C1), ethyl (C2), n-propyl (C3), isopropyl (C3), n-butyl (C4), tert-butyl (C4), sec-butyl (C4), iso-butyl (C4), n-pentyl (C5), 3-pentanyl (C5), amyl (C5), neopentyl (C5), 3-methyl-2-butanyl (C5), tertiary amyl (C5), n-hexyl (C6); C6 substituted with 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more fluoro groups (e.g., -CF3, -CH2F, CHF2, difluoroethyl, and 2,2,2-trifluoro-1,1-dimethyl-ethyl). 1-6 alkyl; C substituted with 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more chloro groups (e.g., -CH2Cl, -CHCl2) 1-6 C substituted with alkyl; and alkoxy groups (e.g., -CH2OCH3 and -CH2OCH2CH3) 1-6 Examples include, but are not limited to, alkyl.

[0206] In certain embodiments, two R Z6 The bases come together, C 3-6 It forms a carbocyclic ring, for example, a substituted or unsubstituted cyclopropyl, substituted or unsubstituted cyclobutyl, substituted or unsubstituted cyclopentyl, or substituted or unsubstituted cyclohexyl ring.

[0207] In certain embodiments, R Z4 is a substituted or unsubstituted alkyl, for example, a substituted or unsubstituted C1-6 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 alkyl. Z4 C 1-6 Alkyl groups include substituted or unsubstituted methyl (C1), ethyl (C2), n-propyl (C3), isopropyl (C3), n-butyl (C4), tert-butyl (C4), sec-butyl (C4), iso-butyl (C4), n-pentyl (C5), 3-pentanyl (C5), amyl (C5), neopentyl (C5), 3-methyl-2-butanyl (C5), tertiary amyl (C5), n-hexyl (C6); C6 substituted with 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more fluoro groups (e.g., -CF3, -CH2F, CHF2, difluoroethyl, and 2,2,2-trifluoro-1,1-dimethyl-ethyl). 1-6 alkyl; C substituted with 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more chloro groups (e.g., -CH2Cl, -CHCl2) 1-6 C substituted with alkyl; and alkoxy groups (e.g., -CH2OCH3 and -CH2OCH2CH3) 1-6 Examples include, but are not limited to, alkyl.

[0208] In certain embodiments, R Z4 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

[0209] In certain embodiments, R Z4is 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 3-4 Alkynyl, substituted or unsubstituted C 4-5 Alkynyl, or substituted or unsubstituted C 5-6 Alkynyl

[0210] In certain embodiments, R Z4 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.

[0211] In certain embodiments, R Z4 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.

[0212] In certain embodiments, R Z4 is substituted or unsubstituted aryl, for example, substituted or unsubstituted phenyl.

[0213] In certain embodiments, R Z4 is a substituted or unsubstituted heteroaryl, for example, an optionally substituted 5-6 membered heteroaryl.

[0214] In certain embodiments, R Z4 -OR Z5 In this case, R Z5 is as defined herein, for example, R Z5is hydrogen, methyl (C1), ethyl (C2), n-propyl (C3), isopropyl (C3), n-butyl (C4), tert-butyl (C4), sec-butyl (C4), iso-butyl (C4), n-pentyl (C5), 3-pentanyl (C5), amyl (C5), neopentyl (C5), 3-methyl-2-butanyl (C5), tertiary amyl (C5), or n-hexyl (C6).

[0215] In certain embodiments, R Z4 -SR Z5 In this case, R Z5 is as defined herein, for example, R Z5 is hydrogen, methyl (C1), ethyl (C2), n-propyl (C3), isopropyl (C3), n-butyl (C4), tert-butyl (C4), sec-butyl (C4), isobutyl (C4), n-pentyl (C5) , 3-pentanyl (C5), amyl (C5), neopentyl (C5), 3-methyl-2-butanyl (C5), tertiary amyl (C5), or n-hexyl (C6).

[0216] In certain embodiments, R Z4 is R Z5 is as defined herein, for example, R Z5 is hydrogen, methyl (C1), ethyl (C2), n-propyl (C3), isopropyl (C3), n-butyl (C4), tert-butyl (C4), sec-butyl (C4), iso-butyl (C4), n-pentyl (C5), 3-pentanyl (C5), amyl (C5), neopentyl (C5), 3-methyl-2-butanyl (C5), tertiary amyl (C5), or n-hexyl (C6). Z5 )2, for example, R Z4 is -NH2 or -NHR Z5 or two R Z5 -N(R ) groups taken together form a substituted or unsubstituted heterocyclic ring, for example, a substituted or unsubstituted piperidinyl, a substituted or unsubstituted piperazinyl, or a substituted or unsubstituted morpholinyl ring; Z5)2.

[0217] specific L 3 Alkylene groups are contemplated herein. For example, in certain embodiments, L 3 is the expression: [ka] wherein p is 1, 2, or 3; and R Z7 and R Z8 Each instance of is independently hydrogen, halo, substituted or unsubstituted C 1-6 Alkyl, or -OR Z5 is) In certain embodiments, p is 1. In certain embodiments, p is 2. In certain embodiments, p is 3.

[0218] specific L 3 Alkenylene groups are also contemplated herein. For example, in certain embodiments, L 3 is the expression: [ka] wherein q is 0, 1, or 2; and R Z7 and R Z8 Each instance of is independently hydrogen, halo, substituted or unsubstituted C 1-6 Alkyl, or -OR Z5 is) In certain embodiments, q is an alkenylene group of the formula: In certain embodiments, q is 0. In certain embodiments, q is 1. In certain embodiments, q is 2.

[0219] specific L 3 Heteroalkylene groups are also contemplated herein, for example, in certain embodiments, L 3 is the expression: [ka] wherein w is 0 or 1 and p is 1, 2, or 3, or w is 1 and p is 0, 1, 2, or 3; and R Z7 and R Z8 Each instance of is independently hydrogen, halo, substituted or unsubstituted C 1-6 Alkyl, or -OR Z5 is) is a heteroalkylene group of the formula:

[0220] In certain embodiments, p is 0. In certain embodiments, p is 1. In certain embodiments, p is 2. In certain embodiments, p is 3. In certain embodiments, w is 0. In certain embodiments, w is 1. In certain embodiments, w is 0 and p is 1. In certain embodiments, w is 0 and p is 2. In certain embodiments, w is 0 and p is 3. In certain embodiments, w is 1 and p is 1. In certain embodiments, w is 1 and p is 2. In certain embodiments, w is 1 and p is 3.

[0221] For example, in certain embodiments, when w is 0, the formula: [ka] (where p and R Z8 is as defined herein) L 3 A heteroalkylene group is obtained.

[0222] In certain embodiments, when w is 1, the formula: [ka] (where p and R 27 and R Z8 is as defined herein) L 3 A heteroalkylene group is obtained.

[0223] In certain embodiments, R Z7 At least one instance of is hydrogen. In any of the above instances, in certain embodiments, R Z7 At least one instance of is halo, e.g., fluoro. In any of the above instances, in certain embodiments, R Z7 At least one instance of 1-6 Alkyl, e.g., 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 alkyl. Z7 C 1-6 Alkyl groups include substituted or unsubstituted methyl (C1), ethyl (C2), n-propyl (C3), isopropyl (C3), n-butyl (C4), tert-butyl (C4), sec-butyl (C4), iso-butyl (C4), n-pentyl (C5), 3-pentanyl (C5), amyl (C5), neopentyl (C5), 3-methyl-2-butanyl (C5), tertiary amyl (C5), n-hexyl (C6); C6 substituted with 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more fluoro groups (e.g., -CF3, -CH2F, CHF2, difluoroethyl, and 2,2,2-trifluoro-1,1-dimethyl-ethyl). 1-6 alkyl; C substituted with 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more chloro groups (e.g., -CH2Cl, -CHCl2) 1-6 C substituted with alkyl; and alkoxy groups (e.g., -CH2OCH3 and -CH2OCH2CH3) 1-6 In any of the above examples, in certain embodiments, R Z7 At least one example of is -CH, -CF, -CHCH(Et), or -CH(CH)(iPr). In any of the above examples, in certain embodiments, R Z7At least one instance of -OR Z5 , for example -OH.

[0224] In certain embodiments, R Z8 At least one example of is hydrogen. In either case, in certain embodiments, R Z8 At least one instance of is halo, e.g., fluoro. In any of the above instances, in certain embodiments, R Z8 At least one instance of 1-6 Alkyl, e.g., 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 alkyl. Z8 C 1-6 Alkyl groups include substituted or unsubstituted methyl (C1), ethyl (C2), n-propyl (C3), isopropyl (C3), n-butyl (C4), tert-butyl (C4), sec-butyl (C4), iso-butyl (C4), n-pentyl (C5), 3-pentanyl (C5), amyl (C5), neopentyl (C5), 3-methyl-2-butanyl (C5), tertiary amyl (C5), n-hexyl (C6); C6 substituted with 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more fluoro groups (e.g., -CF3, -CH2F, CHF2, difluoroethyl, and 2,2,2-trifluoro-1,1-dimethyl-ethyl). 1-6 alkyl; C substituted with 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more chloro groups (e.g., -CH2Cl, -CHCl2) 1-6 C substituted with alkyl; and alkoxy groups (e.g., -CH2OCH3 and -CH2OCH2CH3) 1-6 In any of the above examples, in certain embodiments, R Z8At least one example of is -CH, -CF, -CHCH(Et), or -CH(CH)(iPr). In any of the above examples, in certain embodiments, R Z8 At least one instance of -OR Z5 , for example -OH.

[0225] Exemplary L 3 Examples of the alkylene group include: [ka] These include, but are not limited to:

[0226] Exemplary L 3 Examples of the alkenylene group include: [ka] These include, but are not limited to:

[0227] Exemplary L 3 Examples of the heteroalkylene group include: [ka] These include, but are not limited to:

[0228] In certain embodiments, the group [ka] (In the formula, L 3 is an alkylene or heteroalkylene group is the expression: [ka] [ka] It is of the type.

[0229] In certain embodiments, the group [ka] wherein Y is —O— and L 3 is an alkylene or heteroalkylene group is the expression: [ka] It is of the type.

[0230] In certain embodiments, the group [ka] wherein Y is —NH— and L 3 is an alkylene or heteroalkylene group is the expression: [ka] It is of the type.

[0231] In certain embodiments, the group [ka] wherein Y is —O— and L 3 is an alkylene or heteroalkylene group is the expression: [ka] It is of the type.

[0232] In certain embodiments, the group [ka] wherein Y is —NH— and L 3 is an alkylene or heteroalkylene group is the expression: [ka] It is of the type.

[0233] R 2 , R 11a and R 11b Various embodiments of As generally defined above, R 2 , R 11a and R 11b Each instance of is independently selected from H, —OH, 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, —N, —NO, —SCN, —CN, —OR B1 , -SR B1 , -N(R B1 )2, -N=NR B1 , -N=C(R B1 )2, -N(OR B1 )(R B1 ), -C(=O)R B1 , -C(=O)OR B1 , -C(=O)SR B1 , -C(=O)N(R b1 )2, -C(=O)N(OR B1 )(R B1 ), -OC(=O)R B1 , -OC(=O)OR B1 , -OC(=O)SR B1 , -OC(=O)N(R B1 )2, -NR B1 C(=O)R B1 , -NR B1 C(=O)OR B1 , -NR B1 C(=O)SR B1 , -NR B1 C(=O)N(R B1 )2, -SC(=O)R B2 , -SC(=O)OR B1 , -SC(=O)SR B1 , -SC(=O)N(R B1 )2, -OS(=O)2R B2 , -OS(=O)2OR B1 , -SS(=O)2R B2 , -SS(=O)2OR B1 , -S(=O)RB2 , -SO2R B2 , -NR B1 SO2R B2 , or -SO2N(R B1 )2 and / or R 11a and R 11b together form an oxo (=O) group.

[0234] In certain embodiments, R 2 is H. In certain embodiments, R 2 is substituted or unsubstituted alkyl. In certain embodiments, R 2 is substituted or unsubstituted alkenyl. In certain embodiments, R 2 is substituted or unsubstituted alkynyl. In certain embodiments, R 2 -OR B1 In certain embodiments, R 2 -SR B1 In certain embodiments, R 2 is -N(R B1 )2. In certain embodiments, R 2 is H, halo, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, -OR B1 , -SR B1 , or -N(R B1 )2. In certain embodiments, R 2 are F, Cl, Me, Et, n-Pr, methoxy, ethoxy, propoxy, butoxy, ethynyl, hydroxybutynyl, meth In certain embodiments, R is cyclopropynyl, chloroethynyl, or cyclopropynyl. 2 is CF, amino, or dimethylamino. In certain embodiments, R 2 is a non-hydrogen group at the alpha position. In certain embodiments, R 2 is a non-hydrogen group in the beta position.

[0235] In certain embodiments, R 11a and R 11bEach instance of R is hydrogen. 11a and R 11b One of R is hydrogen. 11a and R 11b is hydrogen, and the other is -OR B1 , -SR B1 , or -N(R B1 )2. In certain embodiments, R 11a and R 11b is hydrogen, and the other is -OH, -OMe, amino, or dialkylamino. 11b is a non-hydrogen group, and R 11a is hydrogen. In certain embodiments, R 11a is a non-hydrogen group, and R 11b is hydrogen.

[0236] In certain embodiments, R 11a and R 11b together form an oxo group.

[0237] R 4a , R 4b , R 6 , R 7a , R 7b , R 14 , R 17 , R 18 and R 19 Various embodiments of As generally defined above, R 4a , R 4b , R 7a , and R 7b Each instance of is independently selected from hydrogen, —OH, 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, —N, —NO, —SCN, —CN, —OR B1 , -SR B1 , -N(R B1 )2, -N=NR B1 , -N=C(RB1 )2, -N(OR B1 )(R B1 ), -C(=O)R B1 , -C(=O)OR B1 , -C(=O)SR B1 , -C(=O)N(R b1 )2, -C(=O)N(OR B1 )(R B1 ), -OC(=O)R B1 , -OC(=O)OR B1 , -OC(=O)SR B1 , -OC(=O)N(R B1 )2, -NR B1 C(=O)R B1 , -NR B1 C(=O)OR B1 , -NR B1 C(=O)SR B1 , -NR B1 C(=O)N(R B1 )2, -SC(=O)R B2 , -SC(=O)OR B1 , -SC(=O)SR B1 , -SC(=O)N(R B1 )2, -OS(=O)2R B2 , -OS(=O)2OR B1 , -SS(=O)2R B2 , -SS(=O)2OR B1 , -S(=O)R B2 , -SO2R B2 , -NR B1 SO2R B2 , or -SO2N(R B1 )2(in this case, R B1 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, or a nitrogen protecting group when attached to a nitrogen atom, or two R B1 groups taken together form a substituted or unsubstituted heterocyclic ring; and R B2is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, or R B1 Groups and R B2 groups taken together form a substituted or unsubstituted heterocyclic ring); or optionally, R 4a and R 4b , and / or R 7a and R 7b taken together form an oxo (=O) group.

[0238] In certain embodiments, R 4a and R 4b Each instance of R is hydrogen. 4a and R 4b One of R is hydrogen. 4a and R 4b One of the groups is hydrogen, and the other is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl. In the embodiment, R 4a and R 4b is hydrogen and the other is Me, Et, ethenyl, ethynyl, propenyl, or propynyl. 4a and R 4b Each of R is independently substituted or unsubstituted alkyl. 4a and R 4b Each of is Me.

[0239] In certain embodiments, R 7a and R 7b Each instance of is hydrogen.

[0240] As generally defined above, R 6a and R 6beach is independently hydrogen, halo, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl; and [ka] represents a single bond or a double bond, provided that when a double bond is present in ring B, R 6a or R 6b is absent, and if a single bond is present in ring B, the hydrogen at C5 is in the alpha or beta position.

[0241] In certain embodiments, [ka] represents a single bond, R 6a and R 6b Each instance of R is hydrogen. 6a and R 6b Each instance of is halo, for example fluoro.

[0242] In certain embodiments, [ka] represents a single bond, 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, for example, a substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 1-2 Alkyl, substituted or unsubstituted C 2-3 Alkyl, substituted or unsubstituted C 3-4 Alkyl, substituted or unsubstituted C4-5 Alkyl, or substituted or unsubstituted C 5-6 alkyl, 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 a substituted or unsubstituted alkynyl.

[0243] In certain embodiments, [ka] represents a single bond, 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, for example, a substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 1-2 Alkyl, substituted or unsubstituted C 2-3 Alkyl, substituted or unsubstituted C 3-4 Alkyl, substituted or unsubstituted C 4-5 Alkyl, or substituted or unsubstituted C 5-6 alkyl, 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 replaced or unsubstituted alkynyl.

[0244] In certain embodiments, [ka] represents a double bond, R 6a is hydrogen. In certain embodiments, [ka] represents a double bond, R 6a is halo, e.g., fluoro. In certain embodiments, [ka] represents a double bond, R 6a is a substituted or unsubstituted alkyl, for example, a substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 1-2 Alkyl, substituted or unsubstituted C 2-3 Alkyl, substituted or unsubstituted C 3-4 Alkyl, substituted or unsubstituted C 4-5 Alkyl, or substituted or unsubstituted C 5-6 alkyl, for example, methyl, ethyl, propyl, or isopropyl. [ka] represents a double bond, R 6a is substituted or unsubstituted alkenyl. In certain embodiments, [ka] represents a double bond, R 6a is a substituted or unsubstituted alkynyl.

[0245] As generally defined above, R 17 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, or -OR D1In certain embodiments, R 17 is hydrogen. In certain embodiments, R 17 is halo. In certain embodiments, R 17 is substituted or unsubstituted alkyl. In certain embodiments, R 17 is substituted or unsubstituted alkenyl. In certain embodiments, R 17 is substituted or unsubstituted alkynyl. In certain embodiments, R 17 is substituted or unsubstituted carbocyclyl. In certain embodiments, R 17 is substituted or unsubstituted heterocyclyl. In certain embodiments, R 17 is substituted or unsubstituted aryl. In certain embodiments, R 17 is substituted or unsubstituted heteroaryl. In certain embodiments, R 17 -OR D1 (e.g., —OH).

[0246] As generally defined above, R 14 is H or substituted or unsubstituted alkyl. In certain embodiments, R 14 is H. In certain embodiments, R 14 is substituted or unsubstituted alkyl (e.g., —CH 3 ).

[0247] As generally defined above, R 18 are independently hydrogen or substituted or unsubstituted alkyl. In certain embodiments, R 18 is hydrogen. In certain embodiments, R 18 is substituted or unsubstituted alkyl (e.g., —CH 3 ).

[0248] As generally defined above, R 19 are independently hydrogen or substituted or unsubstituted alkyl. In certain embodiments, R 19 is hydrogen. In certain embodiments, R 19 is substituted or unsubstituted alkyl (e.g., —CH 3 ).

[0249] In certain embodiments, R 14 is hydrogen and R 18 is -CH3, and R 19 is -CH3.

[0250] In certain embodiments, R 14 is hydrogen and R 18 is -CH3, and R 19 is hydrogen.

[0251] Further embodiments of formula (I) Various combinations of the above embodiments are further contemplated herein. For example, in certain embodiments, the compound of formula (I) is of formula (Iw): [ka] or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, tautomer, isotopic variant or N-oxide thereof, or a combination thereof. 3b is hydrogen. In certain embodiments, the group -X at the C3 position 1 R 3b is beta. In certain embodiments, R 3a is hydrogen or substituted or unsubstituted alkyl. In certain embodiments, R 2 is hydrogen or -OR B1 In certain embodiments, R 11a is hydrogen, and R 11b is hydrogen or -OR B1 In certain embodiments, [ka] represents a single bond, and R 5 is alpha (lower), and R 6a is hydrogen. In certain embodiments, [ka] represents a double bond. In certain embodiments, R 6a and R 6b are both hydrogen. In certain embodiments, R 6a is halo, e.g., fluoro, or alkyl. In certain embodiments, R 6b is halo, e.g., fluoro, or alkyl, and R 6a is hydrogen. In certain embodiments, R 6a and R 6b and R are both halo, e.g., fluoro. 19 is methyl.

[0252] In certain embodiments, the compound of formula (I) is of formula (Ix): [ka] or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, tautomer, isotopic variant or N-oxide thereof, or a combination thereof. In certain embodiments, the -OH group at the C3 position is beta. In certain embodiments, R 3a is hydrogen or substituted or unsubstituted alkyl. In certain embodiments, R 2 is hydrogen or -OR B1 In certain embodiments, R 11a is hydrogen, and BiR 11b is hydrogen or -OR B1 In certain embodiments, [ka] is a single bond, and R 5 is alpha (lower), and R 6a is hydrogen. In certain embodiments, [ka] represents a double bond. In certain embodiments, R 6a and R 6bare both hydrogen. In certain embodiments, R 6a is halo, e.g., fluoro, or alkyl. In certain embodiments, R 6b is halo, e.g., fluoro, or alkyl, and R 6a is hydrogen. In certain embodiments, R 6a and R 6b and R are both halo, e.g., fluoro. 19 is methyl.

[0253] In certain embodiments, the compound of formula (I) is of formula (Iy): [ka] or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, tautomer, isotopic variant or N-oxide thereof, or a combination thereof. In certain embodiments, the -OH group at the C3 position is beta. In certain embodiments, R 3a is hydrogen or substituted or unsubstituted alkyl. In certain embodiments, R 2 is hydrogen or -OR B1 In certain embodiments, R 11a is hydrogen, and R 11b is hydrogen or -OR B1 In certain embodiments, [ka] is a single bond, and R 5 is alpha (lower), and R 6a is hydrogen. In certain embodiments, [ka] represents a double bond. In certain embodiments, R 6a and R 6b are both hydrogen. In certain embodiments, R 6ais halo, e.g., fluoro, or alkyl. In certain embodiments, R 6b is halo, e.g., fluoro, or alkyl, and R 6a is hydrogen. In certain embodiments, R 6a and R 6b are both halo, e.g., fluoro.

[0254] In certain embodiments, the compound of formula (I) is of formula (Iz): [ka] or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof , isotopic variants or N-oxides, or combinations thereof. In certain embodiments, the group -OH at the C3 position is beta. In certain embodiments, R 3a is hydrogen or substituted or unsubstituted alkyl. In certain embodiments, R 2 is hydrogen or -OR B1 In certain embodiments, R 11a is hydrogen, and R 11b is hydrogen or -OR B1 In certain embodiments, [ka] is a single bond, and R 5 is alpha (lower), and R 6a is hydrogen. In certain embodiments, [ka] represents a double bond. In certain embodiments, R 6a and R 6b are both hydrogen. In certain embodiments, R 6a is halo, e.g., fluoro, or alkyl. In certain embodiments, R 6b is halo, e.g., fluoro, or alkyl, and R 6ais hydrogen. In certain embodiments, R 6a and R 6b are both halo, e.g., fluoro.

[0255] In certain embodiments, the compound of Formula (I) is of formula (I-a1), (I-a2) or (I-a3): [ka] or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, tautomer, isotopic variant or N-oxide thereof, or a combination thereof. 3b is hydrogen. In certain embodiments, the group -OR at the C3 position 3b is beta. In certain embodiments, R 3a is hydrogen or substituted or unsubstituted alkyl. In certain embodiments, R 2 is hydrogen or -OR B1 In certain embodiments, R 11a is hydrogen, and R 11b is hydrogen or -OR B1 In certain embodiments, R 6a and R 6b are both hydrogen. In certain embodiments, R 6a is halo, e.g., fluoro, or alkyl. In certain embodiments, R 6b is halo, e.g., fluoro, or alkyl, and R 6a is hydrogen. In certain embodiments, R 6a and R 6b are both halo, e.g., fluoro.

[0256] In certain embodiments, the compound of Formula (I) is of formula (I-b1), (I-b2) or (I-b3): [ka] or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, tautomer, isotopic variant or N-oxide thereof, or a combination thereof. 3b is hydrogen. In certain embodiments, R 3a is hydrogen or substituted or unsubstituted alkyl. In certain embodiments, R 2 is hydrogen or -OR B1 In certain embodiments, R 11a is hydrogen, and R 11b is hydrogen or -OR B1 In certain embodiments, R 6a and R 6b are both hydrogen. In certain embodiments, R 6a is halo, e.g., fluoro, or alkyl. In certain embodiments, R 6b is halo, e.g., fluoro, or alkyl, and R 6a is hydrogen. In certain embodiments, R 6a and R 6b are both halo, e.g., fluoro.

[0257] In certain embodiments, the compound of Formula (I) is of formula (I-c1), (I-c2) or (I-c3): [ka] or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, tautomer, isotopic variant or N-oxide thereof, or a combination thereof. 3b is hydrogen. In certain embodiments, R 3a is hydrogen or substituted or unsubstituted alkyl. In certain embodiments, R 2 is hydrogen or -OR B1 In certain embodiments, R 11a is hydrogen, and R 11b is hydrogen -OR B1In certain embodiments, R 6a and R 6b are both hydrogen. In certain embodiments, R 6a is halo, e.g., fluoro, or alkyl. In certain embodiments, R 6b is halo, e.g., fluoro, or alkyl, and R 6a is hydrogen. In certain embodiments, R 6a and R 6b are both halo, e.g., fluoro.

[0258] In certain embodiments, the compound is of formula (Id): [ka] or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, tautomer, isotopic variant or N-oxide thereof, or a combination thereof. 3b is hydrogen. In certain embodiments, the group -X at the C3 position 1 R 3b is beta. In certain embodiments, R 3a is hydrogen or substituted or unsubstituted alkyl. In certain embodiments, R 2 is hydrogen or -OR B1 In certain embodiments, R 11a is hydrogen, and R 11b is hydrogen or -OR B1 In certain embodiments, [ka] represents a single bond, and R 5 is alpha (lower), and R 6a is hydrogen. In certain embodiments, [ka] represents a double bond. In certain embodiments, R 6a and R 6bare both hydrogen. In certain embodiments, R 6a is halo, e.g., fluoro, or alkyl. In certain embodiments, R 6b is halo, e.g., fluoro, or alkyl, and R 6a is hydrogen. In certain embodiments, R 6a and R 6b and R are both halo, e.g., fluoro. 19 is methyl. In certain embodiments, each R Z6 is independently hydrogen or methyl.

[0259] In certain embodiments, the compound is of formula (Ie): [ka] or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, tautomer, isotopic variant or N-oxide thereof, or a combination thereof. In R 3a is hydrogen or substituted or unsubstituted alkyl. In certain embodiments, R 2 is hydrogen or -OR B1 In certain embodiments, R 11a is hydrogen, and R 11b is hydrogen or -OR B1 In certain embodiments, [ka] represents a single bond, and R 5 is alpha (lower), and R 6a is hydrogen. In certain embodiments, [ka] represents a double bond. In certain embodiments, R 6a and R 6b are both hydrogen. In certain embodiments, R 6ais halo, e.g., fluoro, or alkyl. In certain embodiments, R 6b is halo, e.g., fluoro, or alkyl, and R 6a is hydrogen. In certain embodiments, R 6a and R 6b and R are both halo, e.g., fluoro. 19 is methyl. In certain embodiments, each R Z6 is independently hydrogen or methyl.

[0260] In certain embodiments, the compound of formula (I) is of formula (If): [ka] or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, tautomer, isotopic variant or N-oxide thereof, or a combination thereof. 3b is hydrogen. In certain embodiments, the group -X at the C3 position 1 R 3b is beta. In certain embodiments, R 3a is hydrogen or substituted or unsubstituted alkyl. In certain embodiments, R 2 is hydrogen or -OR B1 In certain embodiments, R 11a is hydrogen, and R 11b is hydrogen or -OR B1 In certain embodiments, [ka] represents a single bond, and R 5 is alpha (lower), and R 6a is hydrogen. In certain embodiments, [ka] represents a double bond. In certain embodiments, R 6a and R 6bare both hydrogen. In certain embodiments, R 6a is halo, e.g., fluoro, or alkyl. In certain embodiments, R 6b is halo, e.g., fluoro, or alkyl, and R 6a is hydrogen. In certain embodiments, R 6a and R 6b and R are both halo, e.g., fluoro. 19 is methyl. In certain embodiments, each R Z6 is hydrogen or methyl. In certain embodiments, R Z5 is hydrogen or methyl.

[0261] In certain embodiments, the compound is of formula (Ig): [ka] or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, tautomer, isotopic variant or N-oxide thereof, or a combination thereof. 3a is hydrogen or substituted or unsubstituted alkyl. In certain embodiments, R 2 is hydrogen or -OR B1 In certain embodiments, R 11a is hydrogen, and R 11b is hydrogen or -OR B1 In certain embodiments, [ka] represents a single bond, and R 5 is alpha (lower), and R 6a is hydrogen. In certain embodiments, [ka] represents a double bond. In certain embodiments, R 6a and R 6bare both hydrogen. In certain embodiments, R 6a is halo, e.g., fluoro, or alkyl. In certain embodiments, R 6b is halo, e.g., fluoro, or alkyl, and R 6a is hydrogen. In certain embodiments, R 6a and R 6b and R are both halo, e.g., fluoro. 19 is methyl. In certain embodiments, each R Z6 is independently hydrogen or methyl. In certain embodiments, R Z5 is hydrogen or methyl.

[0262] In certain embodiments, the compound is of formula (Ih): [ka] or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, tautomer, isotopic variant or N-oxide thereof, or a combination thereof. 3b is hydrogen. In certain embodiments, the group -X at the C3 position 1 R 3b is beta. In certain embodiments, R 3a is hydrogen or substituted or unsubstituted alkyl. In certain embodiments, R 2 is hydrogen or -OR B1 In certain embodiments, R 11a is hydrogen, and R 11b is hydrogen or -OR B1 In certain embodiments, [ka] represents a single bond, and R 5 is alpha (lower), and R 6a is hydrogen. In certain embodiments, [ka] represents a double bond. In certain embodiments, R 6a and R 6b are both hydrogen. In certain embodiments, R 6a is halo, e.g., fluoro, or alkyl. In certain embodiments, R 6b is halo, e.g., fluoro, or alkyl, and R 6a is hydrogen. In certain embodiments, R 6a and R 6b and R are both halo, e.g., fluoro. 19 is methyl. In certain embodiments, R Z6 is isopropyl.

[0263] In certain embodiments, the compound is of formula (Ii): [ka] or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, tautomer, isotopic variant or N-oxide thereof, or a combination thereof. 3a is hydrogen or substituted or unsubstituted alkyl. In certain embodiments, R 2 is hydrogen or -OR B1 In certain embodiments, R 11a is hydrogen, and R 11b is hydrogen or -OR B1 In certain embodiments, [ka] represents a single bond, and R 5 is alpha (lower), and R 6a is hydrogen. In certain embodiments, [ka] represents a double bond. In certain embodiments, R 6a and R6b are both hydrogen. In certain embodiments, R 6a is halo, e.g., fluoro, or alkyl. In certain embodiments, R 6b is halo, e.g., fluoro, or alkyl, and R 6a is hydrogen. In certain embodiments, R 6a and R 6b and R are both halo, e.g., fluoro. 19 is methyl. In certain embodiments, R Z6 is isopropyl.

[0264] Further embodiments of formula (I) include compounds of the formula: [ka] [ka] [ka] [ka] [ka]

[0265] In certain embodiments, the compound is the following compound: [ka] [ka] [ka] [ka] [ka] [ka] [ka] or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, tautomer, isotopic variant or N-oxide thereof, or a combination thereof.

[0266] In certain embodiments, the compound is the following compound: [ka] [ka] [ka] [ka] or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, tautomer, isotopic variant or N-oxide thereof, or a combination thereof.

[0267] In certain embodiments, the compound is the following compound: [ka] [ka] or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, tautomer, isotopic variant or N-oxide thereof, or a combination thereof.

[0268] In certain embodiments, the compound is the following compound: [ka] [ka] [ka] or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, tautomer, isotopic variant or N-oxide thereof, or a combination thereof.

[0269] In certain embodiments, the compound is the following compound: [ka] [ka] or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, tautomer, isotopic variant or N-oxide thereof, or a combination thereof.

[0270] In certain embodiments, the compound is the following compound: [ka] or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, tautomer, isotopic variant or N-oxide thereof, or a combination thereof.

[0271] In certain embodiments, the compound is the following compound: [ka] or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, tautomer, isotopic variant or N-oxide thereof, or a combination thereof.

[0272] In certain embodiments, the compounds of the invention are pharmaceutically acceptable salts.

[0273] Pharmaceutical Composition In another aspect, the present invention provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier and an effective amount of a compound of formula (I).

[0274] When used as pharmaceuticals, the compounds provided herein are typically administered in the form of pharmaceutical compositions. Such compositions can be prepared by techniques well known in the pharmaceutical arts and comprise at least one active compound.

[0275] In one embodiment of the pharmaceutical composition, the carrier is a parenteral carrier, an oral carrier, or a topical carrier.

[0276] The present invention also relates to a compound of the present invention or a pharmaceutical composition thereof for use as a medicine or pharmaceutical product.

[0277] Generally, the compounds provided herein are administered in a therapeutically effective amount. The actual amount of the compound administered will typically be determined by a physician taking into account the applicable circumstances, including the condition to be treated, the selected route of administration, the actual compound administered, the age, weight, and response of the individual patient, the severity of the patient's symptoms, and the like.

[0278] 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 either injectable compositions or oral compositions, or as ointments, lotions or patches (all for transdermal administration).

[0279] Compositions for oral administration may take the form of bulk liquid solutions or suspensions, or bulk powders. More commonly, however, the compositions are provided in unit dosage forms to facilitate accurate dosing. The term "unit dosage form" refers to a unit dosage for human subjects and other mammals. It refers to suitable physically discrete units, each containing a predetermined amount of active ingredient calculated to produce a desired therapeutic effect, together with suitable pharmaceutical excipients. Typical unit dosage forms include pre-filled, pre-measured ampoules or syringes for liquid compositions, or pills, tablets, capsules, or the like for solid compositions. In such compositions, the compound is usually a minor component (about 0.1 to about 50% by weight, or preferably about 1 to about 40% by weight), with the remainder being various vehicles or carriers and processing aids that help form the desired dosage form.

[0280] Liquid forms suitable for oral administration will include a suitable aqueous or nonaqueous vehicle with buffers, suspending and dispersing agents, colorants, flavorings, and the like. Solid forms may include, for example, any of the following ingredients, or compounds of a similar nature: binders such as microcrystalline cellulose, gum tragacanth, or gelatin; excipients such as starch or lactose; disintegrating agents such as alginic acid, Primogel, or corn starch; lubricants such as magnesium stearate; glidants such as colloidal silicon dioxide; sweeteners such as sucrose or saccharin; or flavoring agents such as peppermint, methyl salicylate, or orange flavoring.

[0281] Injectable compositions are typically based on injectable sterile saline or phosphate-buffered saline or other injectable carriers known in the art. As before, the active compound in such compositions is typically a minor component, often about 0.05 to 10% by weight, with the remainder being injectable carriers and the like.

[0282] Transdermal compositions are typically formulated as topical ointments or creams containing the active ingredient(s) in an amount 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 combined with a paraffinic or water-miscible ointment base. Alternatively, the active ingredient can be formulated into a cream, for example, using an oil-in-water cream base. Such transdermal formulations are well known in the art and generally include additional ingredients to improve skin penetration of the active ingredient or the stability of the formulation. All such known transdermal formulations and ingredients are included within the scope provided herein.

[0283] The compounds provided herein can also be administered by a transdermal device. Accordingly, transdermal delivery can be accomplished using a patch either of the reservoir or porous membrane type or of a solid matrix variety.

[0284] The above ingredients for orally administrable, injectable, or topically administrable compositions are merely representative. Other materials and processing techniques and the like are set forth in Part 8 of Remington's Pharmaceutical Sciences (17th ed., 1985, Mack Publishing Company, Easton, Pennsylvania), which reference is incorporated herein by reference.

[0285] The above ingredients for orally administrable, injectable, or topically administrable compositions are merely representative. Other materials and processing techniques and the like are set forth in Part 8 of Remington's The Science and Practice of Pharmacy (21st ed., 2005, Publisher: Lippincott Williams & Wilkins), which reference is incorporated herein by reference.

[0286] 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.

[0287] The present invention also relates to pharmaceutically acceptable formulations of the compounds of the present invention. In one embodiment, the formulation contains water. In another embodiment, the formulation contains a cyclodextrin derivative. The most common cyclodextrins are α-, β-, and γ-cyclodextrins, which consist of 6, 7, and 8 α-1,4-linked glucose units, respectively, optionally containing one or more substituents on the linked sugar chain, including, but not limited to, methylated, hydroxyalkylated, acylated, and sulfoalkyl ether substituted. 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. Pat. No. 5,376,645. In certain embodiments, the formulation contains hexapropyl-β-cyclodextrin. In more particular embodiments, the formulation contains hexapropyl-β-cyclodextrin (10-50% in water).

[0288] 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 said pharmaceutically acceptable salts are those capable of forming non-toxic acid addition salts, i.e., salts containing pharmacologically acceptable anions, such as hydrochloride, hydroiodide, hydrobromide, nitrate, sulfate, bisulfate, phosphate, acetate, lactate, citrate, tartrate, succinate, maleate, fumarate, benzoate, para-toluenesulfonate, and the like.

[0289] The following formulation examples illustrate representative pharmaceutical compositions that can be prepared in accordance with the present invention, but the present invention is not limited to the following pharmaceutical compositions.

[0290] Exemplary Formulation 1—Tablets: A compound of the invention can be mixed as a dry powder with a dry gelatin binder in an approximate 1:2 weight ratio. A small 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.

[0291] Exemplary Formulation 2—Capsules: A compound of the invention can be mixed as a dry powder with a starch diluent in an approximately 1:1 weight ratio. The mixture is filled into 250 mg capsules (125 mg of active compound per capsule).

[0292] Exemplary Formulation 3 - Liquid: A compound of the invention (125 mg) can be mixed with sucrose (1.75 g) and xanthan gum (4 mg), and the resulting mixture can be blended and passed through a No. 10 mesh US sieve, then mixed with a pre-prepared solution of microcrystalline cellulose and sodium carboxymethylcellulose (11:89, 50 mg) in water. Sodium benzoate (10 mg), flavoring agent, and coloring agent can be diluted with water and added with stirring. Sufficient water can then be added to produce a total volume of 5 mL.

[0293] Exemplary Formulation 4—Tablets: A compound of the invention can be mixed as a dry powder with a dry gelatin binder in an approximate 1:2 weight ratio. A small amount of magnesium stearate can be added as a lubricant. The mixture is formed into 450-900 mg tablets (150-300 mg of active compound) in a tablet press.

[0294] Exemplary Formulation 5—Injection: A compound of the invention is dissolved in a buffered sterile saline injectable aqueous medium in an amount of approximately 100 mg / ml. It can be dissolved or suspended to a concentration of 5 mg / mL.

[0295] Exemplary Formulation 6—Tablets: A compound of the invention can be mixed as a dry powder with a dry gelatin binder in an approximate 1:2 weight ratio. A small amount of magnesium stearate can be added as a lubricant. The mixture can be formed into 90-150 mg tablets (30-50 mg of active compound per tablet) in a tablet press.

[0296] Exemplary Formulation 7—Tablets: A compound of the invention can be mixed as a dry powder with a dry gelatin binder in an approximate 1:2 weight ratio. A small 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.

[0297] Exemplary Formulation 8—Tablets: A compound of the invention can be mixed as a dry powder with a dry gelatin binder in approximately a 1:2 weight ratio. A small 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.

[0298] Exemplary Formulation 9—Tablets: A compound of the invention can be mixed as a dry powder with a dry gelatin binder in an approximate 1:2 weight ratio. A small 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.

[0299] Exemplary Formulation 10—Tablets: A compound of the invention can be mixed as a dry powder with a dry gelatin binder in approximately a 1:2 weight ratio. A small 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.

[0300] Injection dose levels range from about 0.1 mg / kg / hour to at least 10 mg / kg / hour (all for about 1 to about 120 hours, and especially for 24 to 96 hours). A pretreatment 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 for a 40 to 80 kg human patient is expected not to exceed about 2 g / day.

[0301] For the prevention and / or treatment of long-term conditions, treatment regimens usually last for months or years, so oral administration is preferred for patient convenience and tolerance. For oral administration, 1 to 5, particularly 2 to 4, and typically 3 oral doses per day is a typical regimen. Using these dosage 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, and particularly about 1 to about 5 mg / kg, respectively.

[0302] Transdermal doses are generally selected to produce blood levels similar to or lower than those achieved with injection doses.

[0303] When used to prevent the onset of CNS disorder, provided herein is compound at the dosage level described above, will be administered to the patient at risk of developing this condition, typically under the advice and supervision of a doctor.The subject at risk of developing certain condition generally includes the subject with family history of this condition, or the subject identified by genetic test or screening as being particularly susceptible to developing this condition.

[0304] Treatment and Use Previous studies (see, e.g., Gee et al., European Journal of Pharmacology, 136:419-423 (1987)) have demonstrated that certain 3α-hydroxylated steroids are orders of magnitude more potent as modulators of GRC than others (see, e.g., Majewska et al., Science 232:1004-1007 (1986); Harrison et al., J Pharmacol. Exp. Ther. 241:346-353 (1987)). Majewska et al. and Harrison et al. teach that 3α-hydroxylated-5-reduced steroids are capable of much lower levels of efficacy. In vitro and in vivo experimental data now demonstrate that the high potency of these steroids makes them therapeutically useful for modulating brain excitability through GRC (see, e.g., Gee et al., European Journal of Pharmacology, 136:419-423 (1987); Wieland et al., Psychopharmacology 118(1):65-71 (1995)).

[0305] Various synthetic steroids have also been prepared as neurostimulant steroids. See, for example, U.S. Pat. No. 5,232,917, which discloses neurostimulant steroid compounds useful for treating stress, anxiety, insomnia, seizure disorders, and mood disorders that are amenable to treatment with GRC activators, such as suppression, in a therapeutically useful manner. Furthermore, these steroids interact with other known sites of interaction (e.g., barbiturates, benzodiazepines, and GABA) from which therapeutically beneficial effects for stress, anxiety, sleep, mood disorders, and seizure disorders have previously been elicited (see, e.g., Gee, KW, and Yamamura, HI, "Benzodiazepines and Barbiturates: Drugs for "The Treatment of Anxiety, Insomnia and Seizure Disorders" in Central Nervous System Disorders, edited by Horvell, Marcel-Dekker, New GABAergic drugs have previously been demonstrated to interact at unique sites on the GRC that are distinct from those of other drugs (see, for example, Lloyd, KG and Morselli, PL, "Psychopharmacology of GABAergic Drugs," in Psychopharmacology: The Third Generation of Progress, edited by H.Y. Meltzer, Raven Press, NY (1987), pp. 123-147; Lloyd, KG and Morselli, PL, "Psychopharmacology of GABAergic Drugs," in Psychopharmacology: The Third Generation of Progress, edited by H.Y. Meltzer, Raven Press, NY (1987), pp. 183-195; and Gee et al., European Journal of Pharmacology, 136:419-423 (1987)). These compounds are desirable for their duration, potency, and oral activity (as well as other forms of administration).

[0306] Therefore, the compounds and pharmaceutical compositions provided herein are used as therapeutic agents for the prevention and / or treatment of CNS pathologies in mammals, including humans and non-human mammals.Therefore, as stated above, the present invention encompasses within its scope the listed treatment methods as well as the compounds for such methods and the use of such compounds for the preparation of medicaments useful for such methods, and extends to such methods as well as such compounds and such uses.It is believed that the novel 3α- and 3β-hydroxysteroids of the present invention can act as negative allosteric modulators of NMDA receptors, and therefore may be useful for the prevention and / or treatment of a wide range of CNS pathologies.

[0307] In one embodiment, the compounds of the invention are used as therapeutic agents, e.g., for the treatment of CNS conditions in a mammal, such as, for example, schizophrenia, depression, bipolar disorder (e.g., I and / or II), schizoaffective disorder, mood disorders, anxiety disorders, personality disorders, psychosis, stereotypic disorders, post-traumatic stress disorder (PTSD), autism spectrum disorder (ASD), dysthymia (mild depression), social anxiety disorder, obsessive-compulsive disorder (OCD), pain (e.g., painful syndromes and disorders), sleep disorders, memory disorders, dementia, Alzheimer's disease, seizure disorders (e.g., epilepsy), traumatic brain injury, and the like. In certain embodiments, the compounds of the present invention are useful for treating depression, anxiety, mood disorders, sleep disorders, memory disorders, traumatic brain injury, stroke, epilepsy, and schizophrenia.

[0308] In another aspect, there is provided a method of treating a mammal susceptible to or suffering from a condition associated with brain excitability, comprising administering an effective amount of one or more of the pharmaceutical compositions described herein.

[0309] In yet another aspect, there is provided the use of a compound of the invention as a pharmaceutical, for example in the treatment or prevention of, among other conditions and diseases mentioned above.

[0310] In still yet another aspect, there is provided a method for the manufacture of a medicament for treating or preventing one of the above-mentioned conditions and diseases.

[0311] In still yet another aspect, the present invention provides a method for preventing, treating, ameliorating or managing a disease or condition, comprising 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.

[0312] 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 disorders, memory disorders, and mood disorders.

[0313] 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, comprising treating the mammal with an effective amount of a compound of the present invention or a composition thereof.

[0314] In yet another aspect, the present invention provides a combination of a compound of the present invention with another pharmacologically active agent.

[0315] The compounds provided herein can be administered as the sole active agent or can be administered in combination with other agents. The administration in combination can proceed by any technique apparent to one skilled in the art, including, for example, separate, sequential, simultaneous, and alternating administration. [Example]

[0316] 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 offered to illustrate the compounds, pharmaceutical compositions, and methods provided herein, and are not to be construed as in any way limiting the scope thereof.

[0317] material and method The compounds provided herein can be prepared from readily available starting materials using the following general methods and procedures. Where typical or preferred process conditions (i.e., reaction temperature, time, molar ratio of reactants, solvent, pressure, etc.) are given, it 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.

[0318] In addition, as will be apparent to those skilled in the art, conventional protecting groups may be required to prevent certain functional groups from undergoing undesired reactions.The selection of suitable protecting groups for specific functional groups, as well as the selection of suitable protection and deprotection conditions, are well known in the art.For example, a large number of protecting groups and their introduction and removal are described in TW Greene and PG M Buts, Protecting Groups in Organic Synthesis, 2nd Edition, Wiley, New York, 1991 and the references cited therein.

[0319] 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 provided with details on the preparation of representative substituted biaryl amides listed herein. Those skilled in the art of organic synthesis can prepare the compounds provided herein from known or commercially available starting materials and reagents.

[0320] The enantiomerically pure compounds provided herein can be prepared according to any technique known to those skilled in the art. For example, they can be prepared by chiral or asymmetric synthesis from suitable optically pure precursors, or they can be obtained by any conventional technique, for example, by chromatographic resolution using a chiral column, TLC, or by preparing diastereoisomers, separating them, and regenerating the desired enantiomer. For example, see "Enantiomers, Racemates and Resolutions" by 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., University 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., New York, NY).

[0321] In certain embodiments, the enantiomerically pure compound of the present invention can be obtained by reacting racemate with suitable optically active acid or base.Suitable acid or base includes those described in Bighley et al., 1995, Salt Forms of Drugs and Adsorption, in Encyclopedia of Pharmaceutical Technology, 13th Edition, edited by Swarbrick and Boylan, Marcel Dekker, New York; ten Hoeve and H. Wynberg, 1985, Journal of Organic Chemistry 50:4508-4514; Dale and 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 entirety.

[0322] Depending on the particular acidic resolving agent utilized and the solubility characteristics of the particular acid enantiomer used, enantiomerically pure compounds may be recovered from either the crystallized diastereomer or the mother liquor. The identity and optical purity of the particular compound so recovered may be determined by polarimetry or other analytical methods known in the art. The diastereoisomers may then be separated, for example, by chromatography or fractional crystallization, and the desired enantiomer regenerated by treatment with an appropriate base or acid. The other enantiomer may similarly be obtained from the racemate or worked up from the initial separation. In certain embodiments, enantiomerically pure compounds can be separated from racemates by chiral chromatography. A variety of chiral columns and eluents are available for use in separating enantiomers, and suitable separation conditions can be determined empirically by methods known to those skilled in the art. Exemplary 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.

[0323] Synthesis procedure General processes for preparing compounds of the invention are provided as further embodiments of the invention and are illustrated in generalized Schemes 1-13 and Examples 1-36. For Schemes 1-13, where not defined, R' is alkyl and R 23 is R 23a or R 23b and X 1 , L 1 , R 1 , R 3a , R 3b , R 23a and R23b is as described herein. Scheme 1. Synthesis of 3α-substituted-3β-hydroxysteroids [ka] Scheme 2. Synthesis of 3α-substituted-3β-hydroxysteroids [ka] Scheme 3. Synthesis of 3β-amino- and 3β-alkylamino steroids [ka] Scheme 4. Synthesis of steroid sulfates [ka] Scheme 5. Synthesis of steroid 3β-esters and amides [ka] Scheme 6. Synthesis of 3-oxosteroids [ka] Scheme 7. Synthesis of 21-heteroaryl-3β-hydroxysteroids [ka] Scheme 8. Synthesis of 3α-substituted-3β-hydroxysteroids [ka] Scheme 9. Synthesis of 3α-substituted-3β-hydroxysteroids [ka] Scheme 10. Synthesis of 3α-substituted-3β-hydroxysteroids [ka] Scheme 11. Synthesis of 3α-substituted-3β-hydroxysteroids [ka] Scheme 12. Synthesis of 3α-substituted-3β-hydroxysteroids [ka] Scheme 13. Synthesis of 3α-substituted-3β-hydroxysteroids [ka]

[0324] Example 1. Preparation of Compound ST-200-A-001 [ka]

[0325] Preparation of compound 2: To a solution of ketone 1 (50.0 g, 0.17 mol, 1.0 equiv.) and ethylene glycol (62 mL) in toluene (600 mL) was added p-toluenesulfonic acid (1.4 g, 7.28 mmol). The reaction mixture was heated at reflux overnight using a Dean-Stark trap. LCMS showed complete consumption of the starting material. The mixture was cooled to room temperature, diluted with ethyl acetate (500 mL), and washed with saturated aqueous sodium bicarbonate (300 mL × 2) and brine (300 mL × 2). The organic phase was dried over sodium sulfate and concentrated in vacuo to give crude product 2 (64.0 g, 100%), which was used directly in the next step without further purification. 1H NMR: (400 MHz, CDCl3) δ 5.35 (d, J=5.6 Hz, 1H), 3.97-3.82 (m, 4H), 3.59-3.47 (m, 1H), 2.34-2.21(m, 2H), 2.06-1.94 (m, 2H), 1.90-1.74 (m, 3H), 1.73-1.64 (m, 1H), 1.63-1.33 (m, 10H), 1.32-1.19 (m, 1H), 1.14-1.03 (m, 1H), 1.01 (s, 3H), 0.99-0.93 (m, 1H), 0.86 (s, 3H).

[0326] Preparation of compound 3: To a solution of compound 2 (32 g, 96 mmol, 1.0 equiv.) in dry CHCl (1200 mL) was added Dess-Martin (81 mg, 192 mmol, 2.0 equiv.) portionwise at 0 °C. The reaction mixture was then stirred at room temperature for 3 h. TLC (PE:EA = 3:1) showed complete consumption of the starting material. The mixture was quenched with saturated aqueous NaHCO / NaSO (1:3) (1 L). The organic phase was washed with brine (500 mL), dried over NaSO, and the solvent was evaporated to give crude product 3 (33.0 g, 100%), which was used directly in the next step without further purification. 1 H NMR: (400 MHz, CDCl3) δ 5.34 (d, J=5.2 Hz, 1H), 3.77-4.00 (m, 4H), 3.19-3.39 (m, 1H), 2.83 (dd, J=16.44, 2.13 Hz, 1H), 2.38-2.59 (m, 1H), 2.21-2.37 (m, 1H), 1.95-2.09 (m, 3H), 1.54-1.73 (m, 4H), 1.74-1.90 (m, 2H), 1.37-1.51 (m, 3H), 1.21-1.34 (m, 2H), 1.19 (s, 3H), 0.98-1.12 (m, 1H), 0.83-0.93 (m, 3H).

[0327] Preparation of MAD: To a solution of compound 5 (96 g, 436 mmol, 1.0 equiv.) in toluene (300 mL) at room temperature was added a solution of AlMe3 (109 mL, 218 mmol, 0.5 equiv., 2 M in hexanes), at which time methane gas was immediately evolved. The resulting mixture was stirred at room temperature for 1 h and used in the next step as a solution of MAD in toluene without further purification.

[0328] Preparation of compound 4: A solution of MAD (218 mmol, 2.3 equiv., freshly prepared) in toluene (300 mL) was added dropwise to a solution of compound 4 (33 g, 96 mmol, 1.0 equiv.) in toluene (100 mL) at −78° C. under nitrogen for 1 h. The reaction mixture was then stirred for 30 min, and a solution of MeMgBr (205 mL, 288 mmol, 3.0 equiv., 1.4 M in toluene) was added dropwise at −78° C. The reaction mixture was warmed to −40° C. and stirred at this temperature for 3 h. TLC (PE:EA=3:1) showed that the starting material was completely consumed. The mixture was poured into saturated aqueous NH4Cl (200 mL) and extracted with EA (150 mL × 2). The combined organic phases were dried over Na2SO4, and the solvent was evaporated to give the crude product. The crude product was purified by silica gel chromatography eluting with PE:EA (15:1) to give the product (7.64 g, 22%) as a white powder. 1 H NMR: (400 MHz, CDCl3) δ 5.30 (d, J=5.2 Hz, 1H), 3.75-4.04 (m, 4H), 2.42 (d, J=13.6 Hz, 1H), 1.88-2.12 (m, 3H), 1.73-1.86 (m, 2H), 1.64-1.72 (m, 2H), 1.52-1.63 (m, 4H), 1.35-1.51 (m, 4H), 1.19-1.32 (m, 1H), 1.12-1.18 (m, 1H), 1.10 (s, 3H), 0.99-1.03 (m, 3H), 0.92-0.98 (m, 1H), 0.86 (s, 3H).

[0329] Compound INT A: To a solution of compound 4 (6.0 g, 17.3 mmol, 1.0 equiv.) in THF (200 mL) was added aqueous HCl (35 mL, 1 M) and toluene (35 mL). The reaction mixture was stirred at room temperature overnight. TLC (PE:EA = 3:1) showed the reaction was complete. The reaction mixture was then diluted with EA (200 mL), washed with saturated aqueous NaHCO3 (200 mL), dried over Na2SO4, and evaporated under reduced pressure to give the product (5.2 g, 99.2%). 1 H NMR: (400 MHz, CDCl3) δ 5.27 (d, J=6.8 Hz, 1H), 2.45-2.35 (m, 2H), 2.09-1.84 (m, 4 H), 1.82-1.57 (m, 6H), 1.50-1.35 (m, 4H), 1.26-1.08 (m, 4H), 1.05 (s, 3H), 0.95 (s, 3H), 0.86 (s, 3H).

[0330] Compound A_001_1: To a solution of PPh3CH3Br (28.3 g, 79.35 mmol) in THF (50 mL) was added a solution of t-BuOK (8.96 g, 79.35 mmol) in THF (20 mL) at room temperature. After stirring for 1 h, INT A (4.0 g, 13.22 mmol) dissolved in THF (10 mL) was added dropwise. The reaction mixture was refluxed for 3 h. The reaction mixture was cooled to room temperature, quenched with saturated NH4Cl, and extracted with EA. The combined organic layers were washed with brine, dried, and concentrated to give the crude product, which was purified by flash column chromatography (PE / EA=15 / 1) to give compound A_001_1 (3.2 g, Y=80%) as a white solid. 1H NMR: (400 MHz, CDCl3) δ 5.32 (d, J=5.2 Hz, 1H), 4.65-4.64 (m, 2H), 2.50-2.42 (m, 2H), 2.27-2.22 (m, 1H), 2.07-1.97 (m, 1H), 1.87-1.68 (m, 4H), 1.68-1.49 (m, 7H), 1.40-1.15 (m, 4H), 1.12 (s, 3H), 1.05 (s, 3H), 1.04-0.96 (m, 1H), 0.80 (s, 3H).

[0331] Preparation of compound A_001_2: To a solution of compound A_001_1 (300 mg, 1.0 mmol, 1.0 equiv) and methyl propionate (250 mg, 3.0 mmol, 3.0 equiv) in CHCl (5 mL) was added EtAlCl (4 mL, 4.0 mmol, 1 M in toluene) dropwise with stirring at 25 °C, and the reaction mixture was then stirred overnight. TLC (PE / EA = 3 / 1) showed that the starting material was completely consumed. The solution was washed with saturated aqueous NaHCO (5 mL), dried over NaSO, and concentrated under reduced pressure to give the crude product, which was purified by silica gel chromatography eluting with PE:EA (15:1) to give the desired product (200 mg, 52%) as a white powder. 1 H NMR: (400 MHz, CDCl3) δ 7.03-6.97 (m, 1H), 5.86 (dd, J1=1.2Hz, 5.35 (d, J=1.2Hz, 1H), 5.32 (d, J=5.2Hz, 1H), 3.72 (s, 3H), 2.87 (d, J=6.8 Hz, 2H), 2.42 (d, J=13.2 Hz, 1H), 2.13-1.95 (m, 3H), 2.00-1.40 (m, 11H), 1.40-1.20 (m, 4H), 1.11 (s, 3H), 1.06 (s, 3H), 0.90-0.82 (m, 3H), 0.78 (s, 3H).

[0332] Preparation of A_001_3: To a solution of compound A_001_2 (192 mg, 0.5 mmol, 1.0 equiv) in EA (5 mL) was added Pd / C (5%, 40 mg) under N2. The suspension was degassed under vacuum and purged with H2 several times. The mixture was then stirred under a H2 balloon at 30 °C for 1 h. TLC (PE:EA = 3:1) showed the reaction was complete. The suspension was filtered through a pad of Celite, and the pad was washed with EA (5 mL × 2). The combined filtrates were concentrated to dryness to give the product (185 mg, 95%) as a white powder. 1 H NMR: (400 MHz, CDCl3) δ 5.31 (d, J=4.4Hz, 1H), 3.67 (s, 3H), 2.42 (d, J=13.2 Hz, 1H), 2.35-2.28 (m, 2H), 2.02-1.92 (m, 2H), 1.90-1.60 (m, 6H), 1.55-1.30 (m, 6H), 1.30-1.13 (m, 5H), 1.12 (s, 3H), 1.02(s, 3H), 1.00-0.75 (m, 4H), 0.58 (s, 3H).

[0333] Preparation of compound ST-200-A-001: A solution of compound A_001_3 (150 mg, 0.386 mmol, 1.0 equiv.) in THF (5 mL) was treated with MeLi at −78 °C under nitrogen. (2 mL, 3.200 mmol, 8.3 equiv, 1.6 M in THF) was added dropwise. After the addition, the reaction mixture was warmed to -40 °C and stirred for 1 h. TLC (PE:EA = 3:1) showed the reaction was complete. The reaction mixture was quenched with saturated aqueous NH4Cl (10 mL) and extracted with EA (10 mL × 2). The combined organic layers were concentrated under reduced pressure to give the crude product, which was purified by silica gel chromatography eluting with PE:EA (10:1) to give the product (91 mg, 60%) as a white powder. 1H NMR: (400 MHz, CDCl3) δ 5.31 (d, J=5.6Hz, 1H), 2.43 (d, J=13.2 Hz, 1H), 2.05-1.95 (m, 2H), 1.90-1.60 (m, 6H), 1.21 (s, 6H), 1.12 (s, 3H), 1.11-1.04 (m, 1H), 1.03 (s, 3H), 1.01-0.92 (m, 2H), 0.58 (s, 3H).

[0334] Example 2. Preparation of compound ST-200-A-003 [ka]

[0335] Preparation of Compound A_003_1: To a solution of PPh3PEtBr (12.25 g, 33.00 mmol, 10.0 equiv.) in THF (15 mL) was added dropwise a solution of t-BuOK (3.70 g, 33.00 mmol, 10.0 equiv.) in dry THF (10 mL) at 0 °C under N2. The mixture was stirred at room temperature for 1.5 h. Then, a solution of INT A (1.00 g, 3.31 mmol, 1.0 equiv.) in THF (10 mL) was added dropwise, and the resulting mixture was stirred at 70 °C for 4 h. TLC (PE:EA = 3:1) showed that the starting material was completely consumed. The reaction was quenched with saturated aqueous NH4Cl (50 mL) and extracted with EA (30 mL × 2). The combined organic phase was dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (eluent: PE:EA=12:1) to give the product (900 mg, 90.9%) as a white solid. 1 H NMR: (400 MHz, CDCl3) δ 5.32 (d, J=5.2Hz, 1H), 5.15-5.12 (m, 1H), 2.44-2.30 (m, 3H), 2.29-2.21 (m, 1H), 2.05-1.97 (m, 2H), 1.81-1.45 (m, 14H), 1.30-1.15 (m, 3H), 1.12 (s, 3H), 1.02 (s, 3H), 0.95-1.01 (m, 1H), 0.90 (s, 3H).

[0336] Preparation of compound A_003_2: To a solution of compound A_003_1 (1.00 g, 3.20 mmol, 1.0 equiv.) and methyl propionate (0.67 g, 8.00 mmol, 2.5 equiv.) in dry DCM (15 mL) was added dropwise a solution of EtAlCl (12.8 mL, 12.8 mmol, 4.0 equiv., 1 M in toluene) with stirring at 0 °C. The reaction was then warmed to room temperature and stirred overnight. TLC (PE:EA = 5:1) showed complete consumption of the starting material. The mixture was quenched with saturated aqueous NaHCO (30 mL) and extracted with DCM (30 mL × 2). The combined organic phase was dried over NaSO and concentrated in vacuo. The residue was purified by chromatography on silica gel (eluent: PE:EA=10:1) to give the product (1.00 g, 78.7%) as a white powder. 1 H NMR: (400 MHz, CDCl3) δ 6.97-6.91 (m, 1 H) 5.82 (d, J=16 Hz, 1 H), 5.42-5.41 (m, 1H), 5.32 (d, J=5.2Hz, 1H), 3.73 (s, 3 H), 3.04-3.00 (m, 1H), 2.43 (d, J=12.8 Hz, 1H), 2.11-1.97 (m, 3H), 1.88-1.50 (m, 12H), 1.40-1.20 (m, 3H), 1.21-1.26 (m, 1H), 1.18 (d, J=6.78 Hz, 3H), 1.12 (s, 3H), 1.04 (s, 3H), 0.82 (s, 3H).

[0337] Preparation of A_003_3: To a solution of compound A_003_2 (160 mg, 0.40 mmol) in EA (15 mL) was added Pd / C (30 mg, 5%). The reaction was stirred under 15 psi of H2 at room temperature for 2 h. TLC (PE / EA = 3 / 1) showed that the starting material was completely consumed. The reaction mixture was then filtered, and the filtrate was evaporated under reduced pressure to give the product (150 mg, 92.8%). 1 H NMR: (400 MHz, CDCl3) δ 5.32 (d, J=5.2Hz, 1H), 3.67 (s, 3 H), 2.48-1.96 (m, 7H), 1.90-1.62 (m, 5H), 1.60 -1.55 (m, 7H), 1.11 (s, 3H), 1.03-0.99 (m, 3H), 0.95-0.93 (m, 2H), 0.70-0.66 (m, 2H).

[0338] Preparation of compound ST-200-A-003: To a solution of compound A_003_2 (100 mg, 0.25 mmol, 1.0 equiv.) in dry THF (1 mL) was added MeLi (1.56 mL, 2.50 mmol, 1.6 M in THF) dropwise at −78° C., and the mixture was stirred at this temperature for 30 min. TLC (PE:EA=3:1) showed the reaction was complete. The reaction mixture was quenched with saturated aqueous NH4Cl (5 mL) and extracted with EA (5 mL × 2). The combined organic layers were concentrated under reduced pressure to give the crude product, which was purified by silica gel chromatography eluting with PE:EA (10:1) to give the product (45 mg, 45%) as a white powder. 1 H NMR: (400 MHz, CDCl3) δ 5.30 (d, J=5.2Hz, 1H), 2.42 (d, J=12 Hz, 1 H), 2.02-1.98 (m, 3 H), 1.92-1.66 (m, 3 H), 1.61-1.56 (m, 2 H), 1.55-1.54 (m, 2H), 1.53-1.23 (m, 11 H), 1.20 (s, 6H), 1.10 (s, 3 H), 1.05 (s, 3H), 1.02 (s, 3 H), 0.95-0.90 (m, 3 H), 0.68 (s, 3 H).

[0339] Example 3. Preparation of compound ST-200-A-007 [ka]

[0340] Preparation of compound INT E: To a solution of 9-BBN (0.5 M in THF, 133 mL, 66.6 mmol, 10.0 equiv) under ice bath was added dropwise a solution of A_001_1 (2.0 g, 6.66 mmol, 1.0 equiv) in THF (10 mL). The reaction mixture was heated to 60 °C and stirred for 20 h. The mixture was cooled to 0 °C, and 10% aqueous NaOH (20 mL) was added, followed by 30% aqueous HO (30%, 10 mL). The mixture was stirred for 2 h at 0 °C and then extracted with EA (30 mL × 3). The combined organic layers were washed with brine (30 mL), dried over NaSO, and concentrated in vacuo to give the crude product, which was purified by flash column chromatography eluting with PE / EA (10 / 1) to give INT E (1.0 g, 47%) as a white solid. 1 H NMR: (400 MHz, CDCl3) δ 5.30 (d, J=5.2Hz, 1H), 3.75-3.71 (dd, J1=10.4Hz, J2=6.8Hz, 1H), 3.58-3.53 (dd, J1=10.4Hz, J2=7.6Hz, 1H), 2.43-2.41 (d, J=10.4Hz, 1H), 2.02-1.96 (m, 2H), 1.91 -1.75 (m, 3H), 1.72-1.44 (m, 10H), 1.33-1.20 (m, 5H), 1.18 (s, 3H), 1.06 (s, 3H), 1.04-0.99 (m, 1H), 0.67 (s, 3H).

[0341] Preparation of compound INT B: To a solution of INT E (100 mg, 0.314 mmol, 1.0 equiv) in DCM (10 mL) under ice bath, Dess-Martin reagent (265 mg, 0.628 mmol, 2.0 equiv) was added. The reaction mixture was warmed to room temperature and stirred for 2 h. The mixture was poured into a solution of NaSO (4.5 g) and NaHCO (1.5 g) in water (20 mL) and extracted with EA (20 mL × 3). The combined organic layers were washed with brine (20 mL), dried over NaSO, and concentrated in vacuo to give the crude product (100 mg, 100%), which was used directly in the next step without further purification.

[0342] Preparation of compound A_007_1: Dissolve INT B (100 mg, 0.316 mmol, 1.0 equiv.) and Ph3P = CHCOOCH3 (634 mg, 1.0 equiv.) in toluene (10 mL). The mixture of (89 mmol, 6.0 equiv.) was stirred for 3 h at 80° C. and then concentrated in vacuo. The residue was purified by flash column chromatography eluting with PE / EA (12 / 1) to give product A_007_1 (65 mg, 55.2%) as a white solid. 1 H NMR: (400 MHz, CDCl3) δ 6.99-6.93 (dd, J1=16 Hz, J2=8.4Hz, 1H), 5.82-5.77 (dd, J1=15.6 Hz, J2=1.2Hz, 1H), 5.30 (d, J=5.2Hz, 1H), 3.73 (s, 3H), 2.42 (d, J=12.4Hz, 1H), 2.14-2.11 (m, 1H), 2.05-1.99 (m, 2H), 1.98-1.41 (m, 15H), 1.29-1.24 (m, 2H), 1.12-1.14 (m, 1H), 1.12 (s, 3H), 1.06 (s, 3H), 1.02-0.95 (m, 1H), 0.66 (s, 3H).

[0343] Preparation of compound A_007_2: A mixture of compound A_007_001 (65 mg, 0.174 mmol, 1.0 equiv) and Pd / C (5%, 20 mg) in EA (5 mL) was stirred for 2 h at room temperature under H2 (1 atm). The mixture was filtered, and the filtrate was concentrated in vacuo to give product A_007_2 (65 mg, 100%), which was used directly in the next step without further purification.

[0344] Preparation of compound ST-200-A-007: To a solution of A_007_2 (65 mg, 0.17 mmol, 1.0 equiv.) in THF (2 mL) at −78 °C, CH3Li (1.6 M in THF, 1 mL, 1.7 mmol, 10.0 equiv.) was added dropwise under nitrogen. The reaction mixture was warmed to room temperature and stirred for 1 h. The mixture was quenched with saturated aqueous NH4Cl (10 mL) and then extracted with EA (5 mL × 2). The combined organic layers were washed with brine (5 mL), dried over Na2SO4, and concentrated in vacuo to give the crude product, which was purified by flash column chromatography (eluent: PE / EA = 8 / 1) to give ST-200-A-007 (27 mg, 41%) as a white solid. 1 H NMR: (400 MHz, CDCl3) δ 5.30 (d, J=5.2Hz, 1H), 2.42 (d, J=15.2 Hz, 1H), 2.02-1.96 (m, 2H), 1.86 -1.38 (m, 14H), 1.25-1.14 (m, 4H), 1.21 (s, 6H), 1.11 (s, 3H), 1.09-1.05 (m, 2H) 1.02 (s, 3H), 1.01-0.94 (m, 3H), 0.61 (s, 3H).

[0345] Example 4. Preparation of compound ST-200-A-011 [ka]

[0346] Preparation of compound INT D: INT in MeOH (30 mL) and THF (15 mL) To a solution of A (2.00 g, 6.58 mmol, 1.0 equiv) was added CeCl3·7H2O (2.45 g, 6.58 mmol, 1.0 equiv). The reaction mixture was stirred at room temperature for 10 min. Then, NaBH4 (0.50 g, 13.16 mmol, 2.0 equiv) was slowly added, and the resulting mixture was stirred at room temperature for 30 min. TLC (PE / EA = 3 / 1) showed the reaction was complete. The reaction mixture was quenched by the addition of saturated aqueous NH4Cl (50 mL) and extracted with EA (50 mL × 2). The combined organic layers were dried over Na2SO4 and evaporated to dryness to give the desired product (1.84 g, 91%) as a white solid. 1 H NMR: (400 MHz, CDCl3) δ 5.30 (d, J=5.2 Hz, 1H), 3.65 (t, J=8.6 Hz, 1H), 2.43 (d, J=13.2 Hz, 1H), 2.09-1.97 (m, 3H), 1.97-1.68 (m, 3H), 1.64-1.38 (m, 5H), 1.31-1.20 (m, 2H), 1.19-1.16 (m, 1H), 1.11 (s, 3H), 1.11-1.04 (m, 1H), 1.03 (s, 3H), 1.01-0.93 (m, 2H), 0.88-0.84 (m, 1H), 0.76 (s, 3H).

[0347] Preparation of compound A_011_1: To a solution of INT D (500 mg, 1.63 mmol, 1.0 equiv) in DCM (10 mL), methyl propionate (325 mg, 3.30 mmol, 2.0 equiv) and NMM (287 mg, 3.30 mmol, 2.0 equiv) were added sequentially. The reaction mixture was stirred at room temperature for 2 days. TLC (PE / EA = 3 / 1) showed the reaction was complete. The reaction mixture was washed with saturated aqueous NaHCO3 (20 mL) and brine (20 mL), dried over Na2SO4, and evaporated to dryness to give the crude product. The residue was purified by silica gel chromatography eluting with PE:EA (15:1) to give the desired product (274 mg, 43%) as a white solid. 1H NMR: (400 MHz, CDCl3) δ 7.54 (d, J=12.8 Hz, 1H), 5. 29 (d, J=5.2 Hz, 1H), 5.24 (d, J=12.8 Hz, 1H), 3.88 (t, J=8.2 Hz, 1H), 3.68 (s, 3H), 2.42 (d, J=13.2 Hz, 1H), 2.19-2.09 (m, 1H), 2.00-1.89 (m, 2H), 1.88-1.84 (m, 1H), 1.80-1.70 (m, 2H), 1.62-1.50 (m, 5H), 1.49-1.41 (m, 2H), 1.39-1.29 (m, 1H), 1.19-1.10 (m, 2H), 1.11 (s, 3H), 1.02 (s, 3H), 1.00-0.91 (m, 2H), 0.79 (s, 3H).

[0348] Preparation of compound A_011_2: To a solution of compound A_011_1 (50 mg, 0.128 mmol) in EA (5 mL) under argon was added 5% Pd / C (50%, 25 mg). The suspension was degassed under vacuum and purged with H2 several times. The mixture was stirred under a H2 balloon at room temperature for 4 h. TLC (PE / EA = 3 / 1) showed that the starting material was completely consumed. The suspension was then filtered through a pad of Celite and washed with EA (5 mL × 3). The combined filtrates were concentrated to dryness to give the product (48 mg, 96%) as a white solid, which was used directly in the next step without further purification. 1 H NMR: (400 MHz, CDCl3) δ 5.30 (d, J=5.2 Hz, 1H), 3.77-3.69 (m, 2H), 3.66 (s, 3H), 3.32 (t, J=8.4 Hz, 1H), 2.56 (t, J=6.4 Hz, 2H), 2.42 (d, J=12.4 Hz, 1H), 2.00-1.89 (m, 4H), 1.81-1.67 (m, 2H), 1.57-1.44 (m, 6H), 1.43-1.32 (m, 1H), 1.30-1.13 (m, 4H), 1.11 (s, 3H), 1.02 (s, 3H), 0.99-0.91 (m, 2H), 0.74 (s, 3H).

[0349] Preparation of compound ST-200-A-011: To a solution of compound A_011_2 (60 mg, 0.16 mmol, 1.0 equiv) in anhydrous THF (5 mL) was added MeLi (1 mL, 1.60 mmol, 10.0 equiv, 1.6 M in EtO) dropwise at −78 °C under N. The reaction mixture was stirred at −78 °C for 30 min and then warmed to room temperature for another 30 min. TLC (PE / EA = 3 / 1) showed complete consumption of the starting material. The reaction mixture was quenched with saturated aqueous NHCl (5 mL). The resulting solution was extracted with EA (5 mL × 3). The combined organic layers were washed with brine (10 mL), dried over NaSO, and concentrated in vacuo. The residue was purified by silica gel chromatography eluting with PE:EA (10:1) to give the target product (25 mg, 42%) as a white solid. 1 H NMR: (400 MHz, CDCl3) δ 5.29 (d, J=4.8Hz, 1H), 3.80-3.62 (m, 2H), 3.27 (t, J=8.4 Hz, 1H), 2.39 (d, J=13.2 Hz, 1H), 2.05-1.86 (m, 4H), 1.76-1.64 (m, 3H), 1.59-1.37 (m, 8H), 1.27-1.20 (m, 1H), 1.19 (s, 6H), 1.12-1.08 (m, 2H), 1.07 (s, 3H), 0.99 (s, 3H), 0.98-0.89 (m, 2H), 0.72 (s, 3H).

[0350] Example 5. Preparation of compound ST-200-A-013 [ka]

[0351] To a solution of INT E (150 mg, 0.471 mmol, 1.0 equiv.) in DMSO (1 mL) was added KOH (53 mg, 0.942 mmol, 2.0 equiv.) and 2,2-dimethyloxirane (340 mg, 4.717 mmol, 10.0 equiv.). The reaction mixture was stirred at 50 °C for 16 h. TLC (PE / EA = 3 / 1) showed that the starting material was completely consumed. The mixture was cooled to room temperature, diluted with ethyl acetate (20 mL), and washed with saturated aqueous NH4Cl (10 mL × 2) and water (10 mL × 2). The organic phase was dried over sodium sulfate and concentrated under vacuum to give the crude product, which was purified by column chromatography followed by preparative HPLC to give the pure product ST- 200-A-013 (14 mg, 8%) was obtained. 1 H NMR (400MHz, CDCl3) δ 5.30 (d, J=5.2Hz, 1H), 3.57-3.48 (m, 1H), 3.38-3.35 (m, 1H), 3.20 (s, 2H), 2.42-2.40 (m, 1H), 2.03-1.85 (m, 3H), 1.76 (m, 4H), 1.55-1.43 (m, 4H), 1.25 (s, 3H), 1.28-1.25 (m, 6H), 1.17-1.13 (m, 2H), 1.11 (s, 3H), 1.06-0.96 (m, 5H), 0.92-0.79 (m, 2H), 0.65 (s, 3H).

[0352] Example 6. Preparation of compound ST-200-A-017 [ka]

[0353] To a solution of compound INT D (150 mg, 0.49 mmol, 1.0 equiv) and 2,2-dimethyloxirane (1.5 g, 20.8 mol, 42.0 equiv) in DMSO (3 mL) was added KOH (56 mg, 1.0 mmol, 2.0 equiv), and the reaction mixture was then stirred at 60° C. for 5 hours. TLC (PE:EA=3:1) showed the reaction was complete. The solution was cooled to room temperature, diluted with water (10 mL), and extracted with EA (5 mL×2). The combined organic layer was concentrated under reduced pressure to give the crude product, which was purified by pre-HPLC to give the product (6.6 mg, 3.5%) as a white powder. 1 H NMR: (400 MHz, CDCl3) δ 5.30 (d, J=5.2Hz, 1H), 3.33 (t, J=8.0Hz, 1H), 3.29-3.22 (m, 2H), 2.40-2.50 (m, 2H), 2.05-1.85 (m, 4H), 1.82-1.65 (m, 2H), 1.60-1.35 (m, 9H), 1.34- 1.22 (m, 1H), 1.20-1.15 (m, 6H), 1.14-1.11 (m, 1H), 1.12 (s, 3H), 1.05 (s, 3H), 0.90-1.00 (m, 2H), 0.79 (s, 3H).

[0354] Example 7. Preparation of compound ST-200-A-021 [ka]

[0355] To a solution of compound A_001_3 (150 mg, 0.39 mmol, 1.0 equiv) in THF / HO (4 mL, 1 / 1) was added LiOH (90 mg, 2.20 mmol, 5.6 equiv). The reaction was stirred at room temperature overnight. TLC (PE / EA = 3 / 1) showed that compound A_001_3 was completely consumed. The mixture was diluted with water (3 mL), washed with MTBE (5 mL × 2), and then acidified to pH = 4 with 1 M aqueous HCl. The precipitate was collected by filtration and dried under vacuum to give the product (54 mg, 37.3%). 1 H NMR: (400 MHz, CDCl3) δ 5.30 (d, J=5.2 Hz, 2H), 2.43-2.37 (m, 1H), 2.37-2.33 (m, 2H), 2.05-1.93 (m, 2H), 1.90-1.79 (m, 2H), 1.78-1.61 (m, 6H), 1.61-1.50 (m, 6H), 1.50-1.37 (m, 3H), 1.34-1.13 (m, 4H), 1.12 (s, 3H), 1.02 (s, 3H), 0.93-1.01 (m, 3H), 0.61 (s, 3H).

[0356] Example 8. Preparation of compounds ST-200-A-022 and ST-200-A-023 [ka]

[0357] Preparation of compound 7: To a solution of ketone 6 (16.7 g, 52.71 mmol, 1.0 equiv.) and ethylene glycol (20 mL) in toluene (450 mL) was added p-toluenesulfonic acid (418 mg, 2.20 mmol). The reaction mixture was heated at reflux overnight with a Dean-Stark trap. LCMS indicated complete consumption of the starting material. The mixture was cooled to room temperature, diluted with ethyl acetate (400 mL), and washed with saturated aqueous sodium bicarbonate (200 mL × 2) and brine (200 mL × 2). The organic phase was dried over sodium sulfate and concentrated in vacuo to give crude product 7 (19.0 g, 100%), which was used directly in the next step without further purification. 1 H NMR: (400 MHz, CDCl3) δ 5.34 (d, J=5.2 Hz, 2H), 4.00-3.85 (m, 4H), 3.53-3.51 (m, 1H), 2.28-2.22(m, 2H), 2.12-2.00 (m, 1H), 1.99-1.95 (m, 1H), 1.86-1.73 (m, 5H), 1.71-1.44 (m, 8H), 1.29 (s, 3H), 1.08 (s, 3H), 1.07 (s, 3H), 1.06-0.92 (m, 1H), 0.77 (s, 3H).

[0358] Preparation of compound 8: To a solution of compound 7 (19.0 g, 52.71 mmol, 1.0 equiv.) in dry CHCl (700 mL) was added Dess-Martin (45.0 g, 105.42 mmol, 2.0 equiv.) portionwise at 0 °C. The reaction mixture was then stirred at room temperature for 3 h. TLC (PE / EA = 3 / 1) showed that the starting material was completely consumed. The mixture was quenched with saturated aqueous NaHCO / NaSO (1 L, 1 / 3). The organic phase was washed with brine (500 mL), dried over Na2SO4, and the solvent was evaporated under reduced pressure to give crude product 8 (19.0 g, 100%), which was used directly in the next step without further purification. 1H NMR: (400 MHz, CDCl3) δ 5.33 (d, J=5.2 Hz, 2H), 4.01-3.85 (m, 4H), 3.34-3.21 (m, 1H), 2.82 (dd, J=16.31, 2.01 Hz, 1H), 2.59-2.40 (m, 1H), 2.37-2.25 (m, 1H), 2.13-1.95 (m, 5H), 1.87-1.41 (m, 13H), 1.30 (s, 3H), 1.21-1.15 (m, 5H), 0.81 (s, 3H).

[0359] Preparation of compound 9: To a solution of MAD (158 mL, 158 mmol, 3.0 equiv., 1 M in toluene, prepared by the method described for the synthesis of ST-200-A-001) under nitrogen at −78 °C was added a solution of compound 8 (19.0 g, 52.71 mmol, 1.0 equiv.) in toluene. The reaction mixture was stirred at this temperature for 30 min. A solution of MeMgBr (53 mL, 159 mmol, 3.0 equiv., 3 M in EtO) was added dropwise at −78 °C. The reaction mixture was warmed to −40 °C and stirred at this temperature for 3 h. TLC (PE:EA = 3:1) showed that the starting material was completely consumed. The mixture was poured into saturated aqueous NH4Cl (300 mL) and extracted with EA (150 mL × 2). The combined organic phases were dried over Na2SO4, and the solvent was evaporated under reduced pressure to give the crude product. The crude product was purified by silica gel chromatography eluting with PE:EA (15:1) to give the product (7.70 g, 39%) as a white powder. 1 H NMR: (400 MHz, CDCl3) δ 5.31 (d, J=5.2 Hz, 2H), 4.01-3.85 (m, 4H), 2.42 (d, J=12 Hz, 1H), 2.04-1.96 (m, 1H), 1.96-1.95 (m, 2H), 1.85-1.66 (m, 5H), 1.66-1.61 (m, 2H), 1.61 -1.36 (m, 7H), 1.33 (s, 3H), 1.26-1.13 (m, 3H), 1.11 (s, 3H), 1.05 (s, 3H), 0.91-1.00 (m, 2H), 0.80 (s, 3H).

[0360] Preparation of compound INT C: To a solution of compound 9 (2.7 g, 7.21 mmol, 1.0 equiv.) in THF (20 mL), aqueous HCl (10 mL, 1 M) and acetone (10 mL) were added. The reaction mixture was stirred at room temperature overnight. TLC (PE:EA = 3:1) showed that the reaction was complete. The reaction mixture was then diluted with EA (50 mL), washed with saturated aqueous NaHCO3 (50 mL x 2), dried over Na2SO4, and evaporated under reduced pressure to give the product (2.10 g, 88.2%) as a white powder. 1 H NMR: (400 MHz, CDCl3) δ 5.31 (d, J=5.2 Hz, 2H), 2.55-2.50 (m, 1H), 2.40 (d, J=12Hz, 1H), 2.20 -2.19 (m, 1H), 2.15-2.10 (m, 3H), 2.08-1.94 (m, 3H), 1.83-1.76 (m, 1H), 1.74 -1.65 (m, 3H), 1.62 (s, 3H), 1.61-1.39 (m, 7H), 1.30-1.13 (m, 4H), 1.12 (s, 3H), 1.01 (s, 3H), 0.61-0.65 (m, 3H).

[0361] Preparation of compound A_022_1: To a solution of INT C (700 mg, 2.1 mmol, 1.0 equiv) in MeOH (10 mL) and THF (5 mL) was added NaBH4 (160 mg, 4.2 mmol, 2.0 feq) in five portions. The reaction mixture was stirred at room temperature for 1 h. TLC (PE / EA = 3 / 1) showed that the starting material was completely consumed. The reaction was quenched with saturated aqueous NH4Cl (50 mL) and extracted with EA (20 mL × 2). The combined organic layers were washed with water (20 mL) and brine (20 mL), dried over sodium sulfate, and concentrated in vacuo to give the desired product A_022_1 (600 mg, 86%).

[0362] Preparation of compounds ST-200-A-022 and ST-200-A-023: To a solution of A_022_1 (570 mg, 1.717 mmol, 1.0 equiv.) in DCM (15 mL), TEA (867 mg, 8.585 mmol, 5.0 equiv.) and DMAP (63 mg, 0.515 mmol, 0.3 equiv.) were added. BzCl (961 mg, 6.867 mmol, 4.0 equiv.) was then added dropwise. The resulting mixture was stirred at room temperature for 16 h and then neutralized by the addition of 1 M aqueous HCl. The aqueous layer was separated and diluted with DCM (1 The residue was purified by chromatography on silica gel eluted with PE:EA (15:1) to give the product (360 mg, 46.6%) as a white solid, which was subjected to SFC separation to give target ST-200-A-022 (100 mg) and ST-200-A-023 (70 mg). 1 H NMR(ST-200-A-022): (400 MHz, CDCl3) δ 8.06 (d, J=7.2 Hz, 2H), 7.61-7.50 (m, 1H), 7.49-7.40 (m, 2H), 5.30 (d, J=5.2 Hz, 2H), 5.19-5.08 (m, 1H), 2.40 (d, J=12Hz, 1H), 2.03-1.86 (m, 3H), 1.85-1.64 (m, 5H), 1.58-1.30 (m, 7H), 1.27 (d, J=6.0 Hz, 3H), 1.23-1.06 (m, 6H), 1.01-0.83 (m, 5H), 0.68 (s, 3H). 1 H NMR(ST-200-A-023): (400 MHz, CDCl3) δ 8.01 (d, J=8.4Hz, 2H), 7.58-7.50 (m, 1H), 7.47-7.39 (m, 2H), 5.31 (d, J=6.0 Hz, 2H), 5.24-5.14 (m, 1H), 2.43 (d, J=13.2Hz, 1H), 2.05-1.87 (m, 4H), 1.82-1.61 (m, 5H), 1.55-1.38 (m, 4H), 1.36 (d, J=6.0 Hz, 3H), 1.29-1.14 (m, 4H), 1.12 (s, 3H), 1.04-0.95 (m, 4H), 0.74 (s, 3H).

[0363] Example 9. Preparation of compound ST-200-C-001 [ka]

[0364] To a solution of compound ST-200-A-001 (65 mg, 0.167 mmol, 1.0 equiv) in ethanol (10 mL) was added Pd / C (10%, 15 mg) under N. The suspension was degassed under vacuum and purged with H several times. The mixture was then stirred at 60 °C under 50 psi hydrogen pressure for 24 h. TLC (PE:EA = 3:1) showed that the reaction was complete. The suspension was filtered through a pad of Celite, and the pad was washed with ethanol (5 mL × 2). The combined filtrates were concentrated to dryness to give the crude product, which was purified by silica gel chromatography eluting with PE:EA (10:1) to give the product (28 mg, 43%) as a white powder. 1H NMR: (400 MHz, CDCl3) δ 1.90-1.87 (m, 1H), 1.75-1.60 (m, 4H), 1.82-1.65 (m, 2H), 1.55-1.30 (m, 12H), 1.27-1.23 (m, 6H), 1.22 (s, 6H), 1.18-0.95 (m, 8H), 0.82 (s, 3H), 0.72 -0.65 (m, 1H), 0.55 (s, 3H).

[0365] Example 10. Preparation of compounds ST-200-C-003 and ST-200-C-003A [ka]

[0366] To a solution of compound ST-200-A-003 (40.0 mg, 0.10 mmol, 1.0 equiv.) in EtOH (30 mL) was added Pd / C (10 mg), and the mixture was stirred at 60° C. overnight under 50 psi hydrogen pressure. 1 H NMR showed that the reaction was complete. The mixture was then filtered through a pad of Celite, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: PE:EA=2:1) ​​to give pure products ST-200-C-003 (12.0 mg, 29.8%) and ST-200-C-003A (0.8 mg, 2.3%) as white powders. 1 H NMR (ST-200-C-003): (400 MHz, CDCl3) δ 1.97-1.83 (m, 2H), 1.65-1.55 (m, 7H), 1.55-1.42 (m, 4H), 1.41-1.2841 (m, 6H), 1.27-1.21 (m, 5H), 1.20 (s, 6H), 1.16-0.95 (m, 7H), 0.92 (d, J=6.27 Hz, 3H), 0.81 (s, 3H), 0.65 (s, 3H). 1 H NMR (ST-200-C-003A): (400 MHz, CDCl3) δ 1.98-1.79 (m, 4H), 1.64-1.53 ​​(m, 6H), 1.52 -1.29 (m, 7H), 1.25-1.22 (m, 6H), 1.22 (s, 3H), 1.20 (s, 3H), 1.05 (s, 3H), 0.96 (s, 3H), 0.91 (d, J=6.53 Hz, 3H), 0.86-0.80 (m, 2H), 0.65 (s, 3H).

[0367] Example 11. Preparation of compound ST-200-C-007 [ka]

[0368] Preparation of compound 10: A mixture of compound 1 (28.0 g, 0.097 mol, 1.0 equiv.) and Pd / C (3.5 g) in ethanol (400 mL) was hydrogenated under 40 psi hydrogen pressure at room temperature overnight. The suspension was filtered through a pad of Celite and washed with ethanol (20 mL × 3). The combined filtrate was concentrated to dryness to give the product (28.0 g, 0.097 mol, 100%) as a white solid. 1 H NMR (400 MHz, CDCl3) δ 3.63-3.53 (m, 1H), 2.42 (dd, J=19.2, 8.4 Hz, 1H), 2.11-2.06 (m, 1H), 19.6-1.87 (m, 1H), 1.83-1.09 (m, 18H) , 1.04-0.91 (m, 2H), 0.85 (s, 3H), 0.82 (s, 3H).

[0369] Preparation of Compound 11: To a solution of Compound 10 (28.0 g, 0.097 mol, 1.0 equiv.) and ethylene glycol (30 mL) in toluene (300 mL) was added p-toluenesulfonyl ether. Sulfonic acid (0.7 g, 3.64 mmol) was added. The reaction mixture was heated at reflux overnight with a Dean-Stark trap. LCMS showed complete consumption of the starting material. The mixture was cooled to room temperature, diluted with ethyl acetate (250 mL), and washed with saturated aqueous sodium bicarbonate (100 mL × 2) and brine (100 mL × 2). The organic phase was dried over sodium sulfate and concentrated in vacuo to give crude product 11 (30.0 g, 0.090 mol, 93%), which was used directly in the next step without further purification. 1 H NMR: (400 MHz, CDCl3) δ4.02-3.78 (m, 4H), 3.68-3.48 (m, 1H), 2.04-1.92 (m, 1H), 1.80-1.54 (m, 8H), 1.46 -1.32 (m, 5H), 1.31-1.19(m, 5H), 1.14-1.05 (m, 1H), 1.02-0.86 (m, 2H), 0.83 (s, 3H), 0.80 (s, 3H), 0.72-0.61 (m, 1H).

[0370] Preparation of compound 12: To a solution of compound 11 (30.0 g, 0.90 mol, 1.0 equiv.) in dry DCM (300 mL) was added Dess-Martin oxidant (76.0 g, 0.180 mol, 2.0 equiv.) at 0 °C. The reaction mixture was stirred at 0 °C for 30 min and then at room temperature for 2 h. LCMS showed that the starting material was completely consumed. The mixture was quenched with a saturated aqueous solution of NaHCO3 / Na2SO3 (200 mL, 1 / 3) and then diluted with DCM (250 mL). The organic layer was washed with saturated aqueous sodium bicarbonate (100 mL × 2) and brine (100 mL × 2), dried over sodium sulfate, and concentrated in vacuo to give crude product 12 (24.0 g, 0.072 mol, 80%), which was used directly in the next step without further purification.

[0371] Preparation of compound 13: To a solution of MAD (2.16 mol, 3.0 equiv., prepared by the method described for the synthesis of ST-200-A-001) in dry toluene (300 mL) was added compound 12 (24.0 g, 0.072 mol, 1.0 equiv.) dropwise at −78 °C, and the mixture was stirred at −78 °C for 30 min under nitrogen. Then, MeMgBr (72 mL, 2.16 mol, 3.0 equiv., 3 M in ether) was added dropwise at −78 °C, and the resulting mixture was stirred at the same temperature for 2 h. LCMS showed that the starting material was completely consumed. The reaction mixture was poured into saturated aqueous NH4Cl4 (400 mL) and extracted with EA (300 mL × 2). The combined organic layers were washed with brine (200 mL × 2), dried over sodium sulfate, and concentrated in vacuo. The residue was purified by silica gel chromatography eluting with PE:EA (15:1) to give the product 13 (16.0 g, 0.046 mol, 72%) as a white solid. 1 H NMR: (400 MHz, CDCl3) δ 3.95-3.88 (m, 2 H), 3.87-3.82 (m, 2 H), 2.02-1.92 (m, 1 H), 1.84-1.73 (m, 1 H), 1.71-1.50 (m, 9 H), 1.50-1.43 (m, 1 H) ,1.42-1.33 (m, 4 H), 1.33-1.28 (m 1 H), 1.27-1.19 (m, 7 H) ,1.08-0.88 (m, 2 H), 0.83 (s, 3 H) ,0.81 (s, 3 H).

[0372] Preparation of compound INT G: A mixture of compound 13 (16.0 g, 46.0 mmol, 1.0 equiv) in 1 M aqueous HCl (60 mL), acetone (60 mL), and THF (350 mL) was stirred at room temperature overnight, then diluted with water (200 mL) and neutralized with solid NaHCO until no CO evolution occurred. The mixture was extracted with EA (300 mL × 2). The combined organic layers were washed with brine (200 mL × 2), dried over sodium sulfate, and concentrated in vacuo to give the product INT G (14.0 g, 46.0 mmol, 100%) as a white solid. 1 H NMR: (400 MHz, CDCl3) δ 2.44 (dd, J=19.20, 8.41 Hz, 1 H), 2.13-2.01 (m, 1 H) ,1.98-1.89 (m, 1 H) , 1.85-1.76 (m, 2 H), 1.69-1.60 (m, 3 H), 1.59-1.42 (m, 5 H),1.33-1.13 (m, 10 H), 1.08-0.94 (m, 2 H), 0.86 (s, 3 H), 0.84 (s, 3 H), 0.68-0.77 (m, 1 H).

[0373] Preparation of compound 14: PPhCHBr (1.4 g, 3.94 mL) in THF (10 mL) To a solution of INT G (0.2 g, 0.657 mmol, 1.0 equiv) in THF (5 mL) was added a solution of t-BuOK (442 mg, 3.94 mmol, 5.0 equiv) at room temperature. After stirring for 1 h, a solution of INT G (0.2 g, 0.657 mmol, 1.0 equiv) in THF (5 mL) was added dropwise. The reaction mixture was refluxed for 3 h, then cooled to room temperature, quenched with saturated aqueous NH4Cl (50 mL), and extracted with EA (20 mL × 2). The combined organic layers were washed with brine (20 mL), dried over sodium sulfate, and concentrated in vacuo to give the crude product, which was purified by flash column chromatography (eluent: PE / EA = 15 / 1) to give compound 14 (180 mg, 90%) as a white solid. 1 H NMR: (400 MHz, CDCl3) δ 4.62 (d, J=6.4Hz, 2H), 2.51-2.44 (m, 1H), 2.24-2.22 (m, 1H), 1.82-1.78 (m, 1H), 1.75-1.30 (m, 9H), 1.29-1.11 (m, 11H), 1.03-0.95 (m, 3H), 0.83 (s, 3H), 0.77 (s, 3H), 0.72-0.68 (m, 1H).

[0374] Preparation of compound INT I: To a solution of 9-BBN (0.5 M in THF, 50 mL, 25.00 mmol, 8.0 equiv.) under ice bath, a solution of compound 14 (0.95 g, 3.14 mmol, 1.0 equiv.) in THF (10 mL) was added dropwise. The reaction mixture was heated to 60 °C and stirred for 20 h. The mixture was cooled to 0 °C, and 10% aqueous NaOH solution (20 mL) was added, followed by 30% aqueous HO solution (10 mL). The resulting mixture was stirred for 2 h at 0 °C and then extracted with EA (10 mL × 2). The combined organic layers were washed with brine (10 mL), dried over sodium sulfate, and concentrated in vacuo to give the crude product, which was purified by flash column chromatography (eluent: PE / EA = 10 / 1) to give INT I (0.63 g, 63%) as a white solid. 1 H NMR: (400 MHz, CDCl3) δ 3.74-3.69 (dd, J1=10.4Hz, J2=6.8Hz, 1H), 3.56-3.52 (dd, J1=10.4Hz, J2=7.6Hz, 1H), 1.86-1.80 (m, 2H), 1.69-1.44 (m, 11H), 1.41-1.26 (m, 4H), 1.25-1.21 (m, 5H), 1.19-0.99 (m, 5H), 0.93-0.91 (m, 5H), 0.81 (s, 3H), 0.74-0.68 (m, 1H), 0.64 (s, 3H).

[0375] Preparation of compound INT J: To a solution of INT I (500 mg, 1.56 mmol, 1.0 equiv) in DCM (20 mL) was added Dess-Martin reagent (1.3 g, 3.12 mmol, 2.0 equiv) under ice bath. The reaction mixture was warmed to room temperature and stirred for 2 h. The mixture was poured into a solution of NaSO (5 g) and NaHCO (1.5 g) in water (20 mL) and extracted with EA (20 mL × 2). The combined organic layers were washed with brine (20 mL), dried over sodium sulfate, and concentrated in vacuo to give the crude product (500 mg, 100%), which was used directly in the next step without further purification.

[0376] Preparation of compound C_007_1: A mixture of INT J (500 mg, 1.57 mmol, 1.0 equiv) and Ph3P=CHCOOCH3 (3.1 g, 8.27 mmol, 6.0 equiv) in toluene (30 mL) was stirred for 3 h at 80° C. The mixture was concentrated in vacuo, and the residue was purified by flash column chromatography (eluent: PE / EA=12 / 1) to give the product C_007_1 (188 mg, 32%) as a white solid.

[0377] Preparation of compound C_007_2: A mixture of compound C_007_1 (188 mg, 0.5 mmol, 1.0 equiv) and Pd / C (5%, 60 mg) in EA (10 mL) was stirred for 2 h at room temperature under H2 (1 atm). The mixture was filtered, and the filtrate was concentrated in vacuo to give product C_007_2 (189 mg, 100%), which was used directly in the next step without further purification.

[0378] Preparation of compound ST-200-C-007: To a solution of compound C_007_2 (100 mg, 0.26 mmol, 1.0 equiv.) in THF (2 mL) at -78 °C, CH3Li (1.6 M in THF, 1.6 mL, 2.6 mmol, 10.0 equiv.) was added dropwise under nitrogen. The reaction mixture was warmed to room temperature and stirred for 1 h. Saturated aqueous NH4Cl (10 mL) was added to quench the reaction, and the mixture was extracted with EA (10 mL × 2). The combined organic layers were washed with brine (10 mL), dried over sodium sulfate, and concentrated in vacuo to give the crude product, which was purified by flash column chromatography (eluent: PE / EA = 8 / 1) to give the target ST-200-C-007 (32.7 mg, 32.7%) as a white solid. 1 H NMR: (400 MHz, CDCl3) δ 1.82-1.81 (m, 1H), 1.75-1.57 (m, 7H), 1.56-1.26 (m, 10H), 1.24 (s, 3H), 1.20 (s, 6H), 1.18-0.83 (m, 10H), 0.81 (s, 3H), 0.71-0.66 (m, 1H), 0.58 (s, 3H).

[0379] Example 12. Preparation of compound ST-200-C-011 [ka]

[0380] Preparation of compound INT H: To a solution of INT G (1.00 g, 3.28 mmol, 1.0 equiv) in MeOH (20 mL) and THF (8 mL) was added CeCl3·7H2O (1.22 g, 3.28 mmol, 1.0 equiv). NaBH4 (0.25 g, 6.56 mmol, 2.0 equiv) was then added in five portions, and the mixture was stirred at room temperature for 1 h. The reaction slurry was quenched with saturated aqueous NH4Cl (50 mL) and extracted with EA (20 mL × 3). The combined organic layers were washed with brine (30 mL), dried over sodium sulfate, and concentrated in vacuo to give the desired product (0.97 g, 97%) as a white solid. 1 H NMR: (400MHz, CDCl3) δ 3.62 (t, J=8.4 Hz, 1H), 2.10-2.04 (m, 1H), 1.79-1.77 (m, 1H), 1.70-1.35 (m, 13H), 1.31-1.15 (m, 11H), 1.14-0.84 (m, 5H), 0.81 (s, 3H), 0.72 (s, 3H), 0.70-0.61 (m, 1H)

[0381] Preparation of compound C_011_1: To a solution of INT H (500 mg, 1.63 mmol, 1.0 equiv.) in DCM (20 mL) was added NMM (830 mg, 8.21 mmol, 5.0 equiv.) and methyl propiolate (690 mg, 8.21 mmol, 5.0 equiv.). The mixture was stirred at room temperature for 16 hours, then washed with water (30 mL) and brine (30 mL), dried over sodium sulfate, and concentrated in vacuo. The residue was purified by PE: Purification by silica gel chromatography eluting with EA (15:1) gave the product (500 mg, 78.6%) as a white solid. 1H NMR: (400MHz, CDCl3) δ= 7.53 (d, J=12.4 Hz, 1H), 5.24 (d, J=12.4 Hz, 1H), 3.86 (t, J=8.4 Hz, 1H), 3.68 (s, 3H), 2.18-2.06 (m, 1H), 1.84-1.81 (m, 1H), 1.70-0.85 (m, 30H), 0.81 (s, 3H), 0.78 (s, 3H), 0.72-0.64 (m, 1H).

[0382] Preparation of compound C_011_2: To a solution of C_011_1 (500 mg, 1.289 mmol, 1.0 equiv) in EA (20 mL) was added Pd / C (10%, 50 mg). The suspension was degassed under vacuum and purged with H2 several times. The mixture was stirred at 30 °C for 16 h under 30 psi hydrogen pressure. TLC (PE / EA = 3 / 1) showed the reaction was complete. The suspension was filtered through a pad of Celite, and the pad was washed with EA (20 mL × 5). The combined filtrates were concentrated under vacuum to give the product (430 mg, 85.5%) as a white solid.

[0383] Preparation of compound ST-200-C-011: To a solution of C_011_2 (100 mg, 0.256 mmol, 1.0 equiv) in dry THF (1 mL) was added MeLi (1.3 mL, 2.048 mmol, 8.0 equiv) dropwise at −78 °C under N2. The resulting mixture was stirred at this temperature for 0.5 h, then allowed to warm to room temperature and stirred at this temperature for an additional 1 h. TLC (PE / EA = 3 / 1) showed the reaction was complete. The mixture was quenched with saturated aqueous NH4Cl and extracted with EA (10 mL × 3). The combined organic layers were washed with brine (10 mL), dried over sodium sulfate, and concentrated in vacuo. The residue was purified by silica gel chromatography eluting with PE:EA (10:1) to give the product (30 mg, 30%) as a white solid. 1H NMR (400MHz, CDCl3) δ3.86 (s, 1H), 3.78-3.61 (m, 2H), 3.29 (t, J=8.3 Hz, 1H), 2.10-1.95 (m, 1H), 1.90-1.81 (m, 1H), 1.74 (t, J=5.6 Hz, 2H), 1.69-1.61 (m, 3H), 1.55-1.28 (m, 9H), 1.24-1.22 (m, 9H), 1.22-0.83 (m, 8H), 0.81 (s, 3H), 0.74 (s, 3H), 0.69-0.62 (m, 1H).

[0384] Example 13. Preparation of compound ST-200-C-013 [ka]

[0385] To a solution of INT I (150 mg, 0.469 mmol, 1.0 equiv) in DMSO (1 mL) was added KOH (53 mg, 0.937 mmol, 2.0 equiv) and 2,2-dimethyloxirane (337 mg, 4.687 mmol, 10.0 equiv). The reaction mixture was stirred at 50 °C for 16 h. TLC (PE / EA = 10 / 1) showed complete consumption of the starting material. The mixture was cooled to room temperature, diluted with ethyl acetate (20 mL), and washed with saturated aqueous NH4Cl (10 mL × 2) and water (10 mL × 2). The organic phase was dried over sodium sulfate and concentrated in vacuo to give the crude product, which was purified by column chromatography followed by preparative HPLC to give the pure product. ST-200-C-013 (26 mg, 15.8%). 1 H NMR: (400 MHz, CDCl3) δ 3.72 (dd, J=7.3, 9.3 Hz, 1H), 3.35 (dd, J=6.8, 9.3 Hz, 1H), 3.21 (s, 2H), 2.34 (s, 1H), 1.84-1.80 (m, 1H), 1.79-1.63 (m, 5H), 1.54-1.27 (m, 8H), 1.25 (s, 3H), 1.19 (s, 6H), 1.18-0.83 (m, 7H), 0.81 (s , 3H), 0.74-0.65 (m, 1H), 0.63 (s, 3H)

[0386] Example 14. Preparation of compounds ST-200-C-017 and ST-200-C-017A [ka]

[0387] A solution of ST-200-A-017 (60 mg, 0.159 mmol, 1.0 equiv) and Pd / C (10 mg) in EtOH (10 mL) was stirred at 50 °C under 50 psi hydrogen pressure for 16 h. The reaction solution was filtered through a pad of Celite, and the filtrate was concentrated in vacuo. The residue was purified by silica gel chromatography eluting with PE:EA (20:1) to give ST-200-C-017 (21 mg) and ST-200-C-017A (4.6 mg) as white solids. 1 H NMR (ST-200-C-017): (400 MHz, CDCl3) δ 3.73-3.71 (m, 1H), 3.31 (t, J=8.4Hz, 1H), 3.27-3.22 (m, 2H), 2.48 (s, 1H), 2.01-1.91 (m, 1H), 1.88-1.84 (m, 1H), 1.68-1.52 (m, 4H), 1.51-1.49 (m, 4H), 1.47-1.42 (m, 1H), 1.31 - 1.24 (m, 7H), 1.20-1.83 (m, 6H), 1.15-1.10 (m, 1H), 1.03-0.95 (m, 2H), 0.90-0.85 (m, 1H), 0.81 (s, 3H), 0.65 (s,3H), 0.70-0.61 (m, 1H). 1H NMR (ST-200-C-017a): (400 MHz, CDCl3) δ 3.33 (t, J=8.4Hz, 1H), 3.27-3.22 (m, 2H), 2.45 (s, 1H), 2.10-1.91 (m, 1H), 1.89-1.78 (m, 3H), 1.69-1.61 (m, 1H), 1.58-1.51 (m, 1H), 1.50-1.30 (m, 7H), 1.29-1.24 (m, 5H), 1.20 (s, 3H), 1.29-1.10 (m, 8H), 1.09-1.01 (m, 1H), 0.98 (s, 3H), 0.75 (s, 3H).

[0388] Example 15. Preparation of compounds 3-alpha-A2 and 3-beta-A2 [ka]

[0389] Preparation of Compound BB-2: Under nitrogen, a solution of BB-1 (1.75 g, 4.06 mmol) in THF (35 mL), prepared as described in Steroids (2006) 71:18, was cooled to 0 °C. Methylmagnesium chloride (22% (w / w) in THF, 19.5 mL, 58.1 mmol) was added dropwise. Stirring at 0 °C was continued for 15 min, and the reaction mixture was allowed to warm to room temperature, and stirring was continued for 2 h. Saturated aqueous NH4Cl (5 mL) was added slowly. A precipitate formed, which was dissolved by the addition of water (10 mL). EtOAc (50 mL) and brine (20 mL) were added. The layers were separated. The aqueous layer was extracted with EtOAc (2 × 50 mL). The combined organic layers were dried over Na2SO4, and the solvent was removed in vacuo. The residue was co-evaporated with dichloromethane (50 mL). BB-2 (1.54 g, 3.95 mmol, 97%) was obtained as an off-white solid. 1HNMR (400 MHz, CDCl3): δ(ppm): 5.32 - 5.43 (1H, m), 3.46 - 3.61 (1H, m), 1.20 (3H, s), 1.19 (3H, s), 1.01 (3H, s), 0.93 (3H, d, J = 6.6 Hz), 0.68 (3H, s).

[0390] Preparation of compound BB-3: A solution of oxalyl chloride (0.622 mL, 7.26 mmol) in dichloromethane (19 mL) was cooled to −78 °C in an oven-dried flask under nitrogen. Dimethyl sulfoxide (0.60 mL, 8.47 mmol) was added slowly. After 25 min, a solution of BB-2 (0.470 g, 1.209 mmol) in CHCl (38 mL) was added dropwise over 25 min. The solution was stirred at −78 °C for 2.5 h. Triethylamine (3.36 mL, 24.19 mmol) was added dropwise at −78 °C. Stirring was continued for 15 min. The cooling bath was removed and stirring was continued for 10 min. Saturated aqueous NH Cl (10 mL) was added, and the reaction mixture was stirred for 5 min. Dichloromethane (50 mL) and water (20 mL) were added. The layers were separated, and the organic layer was washed with water (20 mL). The combined aqueous layers were diluted with brine (20 mL) and extracted with EtOAc (2 × 75 mL). The combined organic layers were dried over NaSO, and the solvent was removed in vacuo. Flash chromatography (heptane, 5% to 30% EtOAc) afforded BB-3 (238 mg, 0.616 mmol, 51%) as a white solid. 1 HNMR (400 MHz, CDCl3): δ(ppm): 5.31 - 5.38 (1H, m), 3.22 - 3.34 (1H, m), 2.83 (1H, dd, J = 16.4 Hz, 2.1 Hz), 2.41 - 2.54 (1H, m), 2.25 - 2.34 (1H, m), 1.95 - 2.08 (3H, m), 1.82 -1.93 (1H, m), 1.21 (3H, s), 1.20 (3H, s), 1.19 (3H, s), 0.94 (3H, d, J = 6.5 Hz), 0.71 (3H, s).

[0391] Preparation of Compounds 3-α-OH A2 and 3-β-OH A2: THF (degassed, 3 mL) was added to anhydrous cesium(III) chloride (0.319 g, 1.29 mmol) in a flame-dried flask in a glovebox. The suspension was stirred overnight at room temperature. The fine white suspension was removed from the glovebox. THF (dry, 1 mL) was added, and the mixture was stirred at room temperature for 15 min under argon. The fine white suspension was cooled to −78 °C under argon. At this temperature, 1.6 M methyllithium in EtO (0.79 mL, 1.27 mmol) was added dropwise. A yellow suspension formed, which was stirred at −78 °C for 1.5 h. A solution of BB-3 (0.100 g, 0.259 mmol) in THF (dry, 2 mL) was added dropwise over 5 min. The color of the reaction mixture changed from yellow to brown. The reaction mixture was stirred at -78°C for 45 minutes. The cooling bath was removed, and the reaction mixture was stirred for 10 minutes. 5% aqueous AcOH (2 mL) was added. The reaction mixture became a clear, colorless solution. EtOAc (10 mL) was added. The mixture was allowed to warm to room temperature. The layers were separated, and the aqueous layer was extracted with EtOAc (2 x 10 mL). The combined organic layers were dried over sodium sulfate, and the solvent was removed in vacuo. Flash chromatography (H, 5% to 20% EtOAc) afforded compound A2 (3α-OH) (33 mg, 0.082 mmol; 63.5%) and compound A2 (3β-OH) (13 mg, 0.032 mmol; 25.0%). (3α-OH): 1 H-NMR (400 MHz, CDCl3): δ(ppm): 5.43 - 5.38 (m, 1H), 2.46 - 2.37 (m, 1H), 2.05 - 1.80 (m, 4H), 1.73 - 1.23 (m, 15H), 1.22 (s, 3H), 1.20 (s, 3H), 1.19 (s, 3H), 1.18 - 0.99 (m, 9H), 0.98 (s, 1H), 0.94 (d, J = 6.5 Hz, 3H), 0.68 (s, 3H). (3β-OH): 1 H-NMR (400 MHz, CDCl3): δ(ppm): 5.34 - 5.28 (m, 1H), 2.47 - 2.38 (m, 1H), 2.07 - 1.92 (m, 3H), 1.91 - 1.66 (m, 3H), 1.63 - 1.24 (m, 13H), 1.20 (s, 3H), 1.19 (s, 3H), 1.18 - 1.12 (m, 3H), 1.11 (s, 3H), 1.10 - 1.02 (m, 2H), 1.01 (s, 3H), 1.00 - 0.94 (m, 1H), 0.93 (d, J = 6.5 Hz, 3H), 0.91 - 0.82 (m, 1H), 0.68 (s, 3H).

[0392] Example 16. Preparation of compound 3-アルファ-A28および3-ベータ-A28

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[0393] THF (degassed, 1.5 mL) was added to anhydrous cesium(III) chloride (0.207 g, 0.841 mmol) in a flame-dried flask inside a glovebox. The suspension was stirred at room temperature overnight. The fine white suspension was removed from the glovebox and stirred under argon for 15 min. The fine white suspension was cooled to −78°C under argon. At this temperature, 0.5 M ethyllithium in benzene / cyclohexane (1.68 mL, 0.841 mmol) was added dropwise. A yellow suspension formed, which was stirred at −78°C for 30 min. A solution of BB-3 (0.065 g, 0.168 mmol) in THF (dry, 1.5 mL) was added dropwise over 3 min. The color of the reaction mixture changed from yellow to brown. The reaction mixture was stirred at −78°C for 45 min. A brown milky suspension was obtained, and TLC (HE; 2 / 1) showed complete conversion of the starting material and the formation of a more polar spot. The cooling bath was removed and the reaction mixture was stirred for 10 min. 2 mL of 5% aqueous AcOH was added. After the addition of brine (2 mL), the reaction mixture became a clear, colorless solution. EtOAc (5 mL) was added. The mixture was allowed to warm to room temperature. The layers were separated, and the aqueous layer was extracted with EtOAc (2 x 5 mL). The combined organic layers were dried over sodium sulfate, and the solvent was removed in vacuo. 60 mg of a white solid was obtained. Separation on silica gel impregnated with AgNO3 (H, 5% to 20% EtOAc) gave compound A28 (3α-OH) (6 mg, 0.014 mmol; 8.56%) and compound A28 (3β-OH) (4 mg, 0.0096 mmol; 5.71%). (3α-OH): 1 H-NMR (400 MHz, CDCl3): δ(ppm): 5.45 - 5.38 (m, 1H), 2.40 - 2.33 (m, 1H), 2.05 -1.93 (m, 2H), 1.92 - 1.80 (m, 2H), 1.75 - 1.23 (m, 15H), 1.20 (s, 3H), 1.19 (s, 3H), 1.18 - 0.98 (m, 7H), 0.97 (s, 3H), 0.96 - 0.90 (m, 6H), 0.89 - 0.81 (m, 2H), 0.68 (s, 3H). (3β-OH): 1 H-NMR (400 MHz, CDCl3): δ(ppm): 5.33 - 5.25 (m, 1H), 2.41 - 2.31 (m, 1H), 2.06 - 1.93 (m, 3H), 1.90 - 1.78 (m, 1H), 1.77 - 1.23 (m, 20H), 1.20 (s, 3H), 1.19 (s, 3H), 1.17 - 1.05 (m, 5H), 1.03 (s, 3H), 1.01 - 0.95 (m, 1H), 0.93 (d, J = 6.5 Hz, 3H), 0.92 - 0.88 (m, 1H), 0.84 (t, J = 7.4 Hz, 3H), 0.67 (s, 3H).

[0394] Example 17. Preparation of compound B6

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[0395] Preparation of Compound B6a. Acetic anhydride (15.36 mL, 164 mmol) was added to a suspension of stigmasterol (22.5 g, 54.5 mmol) in pyridine (90 mL) under a nitrogen atmosphere, and the mixture was incubated at room temperature for 42 hours. TLC [heptane (2): ethyl acetate (1)] showed complete conversion to the upper eluting product after p-anisaldehyde staining. Water (300 mL) was added to the reaction mixture to quench excess acetic anhydride. After stirring for 1 hour, the white solid was filtered and thoroughly washed with water (9 × 250 mL). The white solid was dried in a vacuum oven at 40 °C in the presence of a beaker of sodium hydroxide over the weekend to give product B6a (24.63 g, 54.2 mmol, yield = 99%) as a white powder. B6a was used directly in subsequent experiments. 1 HNMR (400 MHz, CDCl3) δ(ppm): 5.38-5.37 (1H, m), 5.15 (1H, dd, J=15.1, 8.6 Hz), 5.01 (1H, dd, J=15.1, 8.6 Hz), 4.64-4.56 (1H, m), 2.33-2.31 (2H, m), 2.03 (3H, s), 1.90-1.82 (2H, m), 1.75-1.65 (1H, m), 1.02 (6H, t, J=3.2 Hz), 0.86-0.78 (9H, m), 0.68 (3H, s).

[0396] Preparation of Compound B6b. Bromine (1.754 mL, 34.1 mmol) was added to a solution of iodobenzene (3.66 mL, 32.7 mmol) in n-heptane (100 mL), and the solution was cooled to −5° C. under a nitrogen atmosphere. Stigmasteryl acetate B6a (13.5 g, 29.7 mmol) in n-heptane (700 mL) was also cooled to −5° C. under a nitrogen atmosphere and stirred vigorously. The solution prepared above was added dropwise over 2.5 hours under a nitrogen atmosphere, maintaining a pale yellow color. The resulting solution was stirred overnight and then filtered. TLC [heptane (9): ethyl acetate (1)] showed complete conversion to the slightly lower eluting product after vanillin staining. The solution was concentrated to dryness under vacuum. The residue was purified by column (900 g) chromatography [heptane (95): diisopropyl ether (5)]. The pure product-containing fractions were collected and evaporated under reduced pressure to give B6b (9.06 g, 14.7 mmol, yield=50%) as a white powder, which was used as such in subsequent experiment(s). 1 HNMR (400 MHz, CDCl3) δ(ppm): 5.48 (1H, sep, J=5.4 Hz), 5.15 (1H, dd, J=15.1, 8.6 Hz), 5.02 (1H, dd, J=15.1, 8.6 Hz), 4.84 (1H, brd), 2.05 (3H, s), 1.46 (3H, s), 1.01 (3H, d, J=6.6 Hz), 0.90-0.79 (15H, m), 0.72 (3H, s).

[0397] Preparation of Compound B6c. A solution of 5α,6β-dibromostigmastan-3β-yl acetate B6b (8.11 g, 13.20 mmol) in molecular sieve-dried dichloromethane (240 mL) and pyridine (3.05 mL, 37.7 mmol) was cooled in a liquid nitrogen / ethyl acetate bath. A stream of ozone-enriched oxygen was passed through the solution via a sintered-glass atomizer for 1 h. The reaction mixture turned slightly blue in color. TLC [heptane (9):ethyl acetate (1)] showed a UV 254Complete consumption of the starting material was indicated below. The ozonolysis reaction was quenched. The reaction mixture was immediately poured into a mixture of glacial acetic acid (33.2 mL, 581 mmol) and zinc dust (21.57 g, 330 mmol) and stirred at room temperature overnight. The solution was filtered and washed sequentially with water (200 mL), 10% aqueous sodium bicarbonate (200 mL), 5% aqueous sodium hydroxide (200 mL), and brine (200 mL), and then dried over anhydrous sodium sulfate. Evaporation of the solvent afforded crude cholest-5-en-3β-ol-22-al B6c, which was purified by flash column (300 g) chromatography [heptane (100 => 90):ethyl acetate (0 => 10)]. The product-containing fractions were collected and evaporated under reduced pressure to afford cholest-5-en-3β-ol-22-al B6c (2.58 g, 6.93 mmol, 53% yield) as a white powder. B6c was used directly in subsequent experiment(s). 1 HNMR (400 MHz, CDCl3) δ(ppm): 9.57 (1H, d, J=3.3 Hz), 5.38 (1H, brd), 4.65-4.56 (1H, m), 2.41-2.28 (3H, m), 2.04 (3H, s), 2.03-1.92 (2H, m), 1.91-1.81 (3H, m), 1.13 (3H, d, J=6.8 Hz), 1.03 (3H, s), 0.73 (3H, s).

[0398] Preparation of Compound B6d. To a solution of (methoxymethyl)triphenylphosphonium chloride (0.789 g, 2.30 mmol) in dry THF (6.4 mL) under an argon atmosphere at −10° C., 1.6 M n-BuLi (1.342 mL, 2.15 mmol) in hexane was added. The solution was stirred for 5 min at room temperature, and then B6c (0.2 g, 0.54 mmol) in dry THF (1.3 mL) was added. The mixture was stirred for 30 min at room temperature. The reaction mixture was poured into saturated aqueous NH4Cl (75 mL) and extracted twice with CHCl (50 mL). The combined organic layers were washed with brine, dried over Na2SO4, and the crude product was purified by flash column chromatography (silica, heptane / ethyl acetate 1:0→88:12) to give B6d (103 mg, 0.29 mmol, yield=54%). B6d was obtained as a 1:1 E / Z mixture according to NMR. 1 HNMR (400 MHz, CDCl3) δ(ppm): 6.24 (0.5H, d, J=12.6 Hz), 5.74 (0.5H, d, J=6.2 Hz), 5.34 (1H, brd), 4.59 (0.5H, dd, J=12.5, 9.3 Hz), 4.17 (0.5H, dd, J=9.8, 6.3 Hz), 3.58-3.46 (1H, m), 3.55 (1.5H, s), 3.47 (1.5H, s), 2.67-2.54 (0.5H, m), 2.33-2.18 (2H, m), 2.04-1.78 (6H, m), 1.77-1.65 (1H, m), 1.04 (1.5H, d, J=6.6 Hz), 1.01 (3H, s), 0.98 (1.5H, d, J=6.7 Hz), 0.72 (1.5H, s), 0.69 (1.5H, s).

[0399] Preparation of compound B6e. Acetic anhydride (0.079 mL, 0.84 mmol) was added to a suspension of B6d (0.1 g, 0.279 mmol) in pyridine (3 mL) under a nitrogen atmosphere, and the mixture was incubated at room temperature for 42 h. Water (60 mL) was added to the reaction mixture to quench excess acetic anhydride. After stirring for 1 h, the white solid was filtered and thoroughly washed with water (9 × 250 mL). The white solid was dried overnight in a vacuum oven at 40 °C to give product B6e (111 mg, 0.28 mmol, yield = 99%). 1 HNMR (400 MHz, CDCl3) δ(ppm): 6.24 (0.5H, d, J=12.6 Hz), 5.73 (0.5H, d, J=6.2 Hz), 5.37 (1H, brd), 4.66-4.55 (1H, m), 4.59 (0.5H, dd, J=12.5, 9.3 Hz), 4.17 (0.5H, dd, J=9.8, 6.3 Hz), 3.55 (1.5H, s), 3.47 (1.5H, s), 2.66-2.54 (0.5H, m), 2.35-2.28 (2H, m), 2.03 (3H, s), 2.02-1.91 (3H, m), 1.90-1.81 (2H, m), 1.77-1.66 (1H, m), 1.04 (1.5H, d, J=6.6 Hz), 1.02 (3H, s), 0.99 (1.5H, d, J=6.6 Hz), 0.72 (1.5H, s), 0.69 (1.5H, s).

[0400] Preparation of Compound B6f. To a solution of B6e (0.111 g, 0.28 mmol) in acetone (9 mL) was added 0.1 M aqueous HCl (1 mL, 0.10 mmol). The resulting white suspension was stirred for 1 h at room temperature, then 1 h at 70 °C, and overnight at room temperature. The mixture was heated at 70 °C for 2 h, cooled to room temperature, and diluted with HO (50 mL). The reaction mixture was evaporated to dryness and coevaporated with MeOH (50 mL) and CHCl (10 mL). This appeared to be a mixture of the desired product and dimethyl acetal. To a solution of this mixture (0.12 g, 0.28 mmol) in acetone (10 mL) was added 0.1 M aqueous HCl (1 mL, 0.10 mmol). The resulting white suspension was stirred for 2 h at 70 °C. 1,4-Dioxane (5 mL) was added, which dissolved the insoluble material. The reaction mixture was heated to 70 °C for an additional 2 h, allowed to cool to room temperature, and stirred over the weekend. The reaction mixture was diluted with HO (50 mL) and extracted with CHCl (3 × 50 mL). The combined organic layers were washed with brine, dried over NaSO, and the solvent was evaporated. The crude product was co-evaporated with CHCl (10 mL) to give B6f (119 mg, 0.31 mmol, yield = 111%). 1 HNMR (400 MHz, CDCl3) δ(ppm): 9.75 (1H, m), 5.37, (1H, brd), 4.66-.454 (1H, m), 2.47 (1H, dd, J=15.8, 2.4 Hz), 2.36-2.28 (2H, m), 2.17 (1H, ddd, J=15.8, 9.3, 3.3 Hz), 2.03 (3H, s), 1.02 (3H, d, J=6.4 Hz), 1.02 (3H, s), 0.70 (3H, s).

[0401] Preparation of Compound B6g. Compound B6f (0.11 g, 0.285 mmol) was dissolved in t-butanol (5 mL), dry THF (1 mL), and 2-methyl-2-butene (0.512 mL, 4.84 mmol). The solution was stirred and cooled in an ice bath. A solution of NaClO (0.028 g, 0.313 mmol) and KHPO (0.043 g, 0.313 mmol) in demineralized water (3 mL) was slowly added to the solution over 5 minutes, and the mixture was stirred for 2 hours at 0 °C. The mixture was stirred overnight at room temperature. Additional NaClO (0.028 g, 0.313 mmol) and KHPO (0.043 g, 0.313 mmol) dissolved in HO (3 mL) was slowly added to the reaction mixture, and stirring was continued for 2 hours. The reaction mixture was poured into saturated aqueous NH4Cl (250 mL) and extracted three times with CH2Cl2 (75 mL). The combined organic layers were dried over Na2SO4, filtered, and evaporated under reduced pressure. The white solid residue (2.26 g, 163%) was dissolved in petroleum ether 4 The white solid was triturated in petroleum ether 40-60 (10 mL), filtered, washed twice with petroleum ether 40-60 (5 mL), and air dried for 0.5 h to give B6f (0.089 g, 0.22 mmol, yield=78%). 1 HNMR (400 MHz, CDCl3) δ(ppm): 10.0 (1H, bs), 5.37 (1H, brd), 4.66-4.55 (1H, m), 2.53-2.44 (1H, m), 2.36-2.26 (2H, m), 2.04 (3H, s), 1.04 (3H, d, J=6.4 Hz), 1.02 (3H, s), 0.72 (3H, s).

[0402] Preparation of Compound B6h. To a solution of B6g (0.09 g, 0.224 mmol) in CHCl (10 mL) was added oxalyl chloride (0.048 mL, 0.56 mmol) and DMF (catalytic amount). The solution was stirred for 2 h at room temperature. The reaction mixture was diluted with dry MeOH (150 mL, 3703 mmol) and stirred at 40 °C until all solids dissolved. The reaction mixture was evaporated to dryness, and the crude product was purified by flash column chromatography (silica, heptane / ethyl acetate, 1:0->95:5) and coevaporated twice with THF to give B6h (85 mg, 0.20 mmol, yield=91%). 1 HNMR (400 MHz, CDCl3) δ(ppm): 5.37 (1H, brd), 4.66-4.55 (1H, m), 3.66 (3H, s), 2.43 (1H, dd, J=14.1, 2.9 Hz), 2.38-2.25 (2H, m), 2.04 (3H, s), 1.02 (3H, s), 0.99 (3H, d, J=6.2 Hz), 0.72 (3H, s).

[0403] Preparation of Compound B6. A solution of B6h (0.085 g, 0.20 mmol) in dry THF (3 mL) was cooled to 0 °C under an argon atmosphere. 3.0 M MeMgCl in THF (0.68 mL, 2.04 mmol) was added dropwise using a syringe. The reaction mixture was stirred for 1 h at 0 °C and then for 2 h at room temperature. 3.0 M MeMgCl in THF (0.68 mL, 2.04 mmol) was added again at room temperature, and stirring was continued overnight. The reaction mixture was quenched with saturated aqueous NH4Cl (75 mL) and extracted three times with CHCl (3 × 50 mL). The combined organic layers were washed with brine, dried over Na2SO4, and the crude product was purified by flash column chromatography (silica, heptane / ethyl acetate, 1:0->4:1) to give B6 (45 mg, 0.12 mmol, yield=59%) as a white fluffy solid. 1HNMR (400 MHz, CDCl3) δ(ppm): 5.35 (1H, brd), 3.53 (1H, sep, J=5.1 Hz), 2.34-2.17 (2H, m), 2.03 (1H, dt, J=12.6, 3.3 Hz), 2.01-1.94 (1H, m), 1.93-1.79 (3H, m), 1.23 (6H, s), 1.06 (3H, d, J=6.5 Hz), 1.01 (3H, s), 0.72 (3H, s).

[0404] Example 18. Preparation of compound B7

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[0405] Preparation of Compound B7d: Cholest-5-en-3β-ol-22-al B7c (1.33 g, 3.57 mmol) was dissolved in t-butanol (75 mL), tetrahydrofuran (dry) (15 mL), and 2-methyl-2-butene (13.22 mL, 125 mmol). The solution was stirred and cooled in an ice bath. A freshly prepared solution of sodium chloride (0.355 g, 3.93 mmol) and potassium phosphate, monobasic, PA (0.534 g, 3.93 mmol) in demineralized water (45 mL) was slowly added over 30 minutes, and the mixture was stirred for 2 hours at 0°C. The ice bath was removed, and the mixture was allowed to warm to room temperature and stirred overnight. TLC [heptane(2):ethyl acetate(1)] showed partial conversion to the lower-eluting product after vanillin staining. Additional sodium chloride (0.355 g, 3.93 mmol) and potassium phosphate, monobasic, pa (0.534 g, 3.93 mmol) dissolved in water (45 mL) were slowly added to the reaction mixture, and stirring was continued for 2 h. TLC [heptane(2):ethyl acetate(1)] showed complete conversion to the lower eluting product after vanillin staining. The reaction mixture was poured into saturated aqueous ammonium chloride solution (250 mL) and extracted three times with dichloromethane (100 mL). The combined organic layers were dried over sodium sulfate, filtered, and evaporated under reduced pressure. The residue was stripped twice with toluene (50 mL), followed by dichloromethane (50 mL). The white solid residue (2.26 g, 163%) was triturated in petroleum ether 40-60 (10 mL) for 0.5 h. The white solid was filtered, washed twice with petroleum ether 40-60 (10 mL), and dried in air (with the vacuum pump on) for 0.5 h to give B7d (1.27 g, 3.26 mmol, yield=91%) as a white powder, which was used directly in subsequent experiment(s). 1HNMR (400 MHz, CDCl3) δ(ppm): 10.31 (1H, bs), 5.37 (1H, brd), 4.65-4.56 (1H, m), 2.47-2.39 (1H, m), 2.36-2.26 (2H, m), 2.04 (3H, s), 2.01-1.92 (2H, m), 1.90-1.76 (3H, m), 1.24 (3H, d, J=6.8 Hz), 1.02 (3H, s), 0.71 (3H, s).

[0406] Preparation of Compound B7e. Carboxylic acid B7d (0.1 g, 0.257 mmol) was dissolved in dichloromethane (10 mL). Oxalyl chloride (0.044 mL, 0.515 mmol) and N,N-dimethylformamide (1 drop) were added, and the reaction mixture was stirred for 1 h. A sample of the reaction was poured into methanol, evaporated to dryness, and analyzed by TLC [heptane (3): ethyl acetate (1)], which showed complete conversion to the methyl ester after vanillin staining. The reaction mixture was diluted with (molecular sieve-dried) methanol (50 mL, 1234 mmol), evaporated under reduced pressure, and stripped with anhydrous toluene and dichloromethane. The residue was purified by flash column (4 g) chromatography [heptane (99:80): ethyl acetate (1:20)]. Product-containing fractions were collected and evaporated under reduced pressure to give B7e (0.104 g, 0.257 mmol, 100% yield). B7e was stripped with toluene (2 × 5 mL), dichloromethane (2 × 5 mL), and anhydrous tetrahydrofuran (2 × 5 mL) and used directly in the next step. 1H NMR (400 MHz, CDCl3) δ (ppm): 5.37 (1H, brd), 4.65-4.56 (1H, m), 3.65 (3H, s), 2.47-2.38 (1H, m), 2.36-2.26 (2H, m), 2.03 (3H, s), 2.01-1.92 (2H, m), 1.90-1.82 (2H, m), 1.19 (3H, d, J=6.8 Hz), 1.02 (3H, s), 0.69 (3H, s).

[0407] Preparation of Compound B7. Methyl ester B7e (0.104 g, 0.258 mmol) was dissolved in tetrahydrofuran (dry) (2.6 mL) and cooled in an ice bath under argon. After 20 min, 3.0 M methylmagnesium chloride in THF (0.861 mL, 2.58 mmol) was added dropwise via syringe. Some gas evolution was observed. The reaction mixture was stirred for 0.5 h, after which the cooling bath was removed and stirring was continued for 2 h. TLC [heptane(3):ethyl acetate(1)] showed complete conversion of the starting material to the two lower-eluting products after vanillin staining. Stirring was continued for 1 h. The reaction mixture was poured into a saturated aqueous solution of ammonium chloride (75 mL) with stirring and extracted with dichloromethane (3 x 50 mL). The extracts were combined, dried over sodium sulfate, and evaporated. The residue was triturated in methanol (2 mL) for 0.5 h, the white solid was filtered, and the filter residue was washed with methanol (2 mL). Little material remained on the filter; most was in the filtrate. The filtrate and filter residue were combined and purified by flash column chromatography [heptane (99%): ethyl acetate (1%)]. The product-containing fractions were collected and evaporated under reduced pressure. The residue was dried in a vacuum oven overnight at 40 °C to give B7 (0.044 g, 0.122 mmol, yield = 47%) as a white solid. 1 HNMR (400 MHz, CDCl3) δ(ppm): 5.35 (1H, m), 3.53 (1H, sep, J=5.2 Hz), 2.34-2.19 (2H, m), 2.10 (1H, dt, J=12.6, 3.4 Hz), 2.03-1.88 (2H, m), 1.88-1.79 (2H, m), 1.20 (3H, s), 1.15 (3H, s), 1.00 (3H, s), 0.98 (3H, d, J=6.9 Hz), 0.73 (3H, s).

[0408] Example 19. Preparation of Compound B8 [ka]

[0409] Preparation of compound B8b: In a flame-dried round-bottom flask, a solution of NaHMDS (0.070 mL, 0.349 mmol) in tetrahydrofuran (dry) (1 mL) was added to a solution of silyloxyphosphonate B8a (0.143 g, 0.403 mmol) in tetrahydrofuran (dry) (1 mL) at −78° C. The solution was stirred under argon at −78° C. for 15 minutes. Then, a solution of cholest-5-en-3β-ol-22-al B7c (0.1 g, 0.268 mmol) in tetrahydrofuran (dry) (1 mL) was added slowly via syringe. The reaction mixture was allowed to warm slowly to room temperature and stirred for 20 hours. TLC [heptane(3):ethyl acetate(1)] showed partial conversion to the upper eluting product after vanillin staining. The reaction mixture was quenched by the addition of saturated aqueous ammonium chloride (50 mL) and extracted with dichloromethane (3 × 50 mL). The combined organic layers were washed with water (50 mL), dried over sodium sulfate, and concentrated in vacuo. The residue was purified by flash column (4 g) chromatography [heptane (100 => 90):diisopropyl ether (0 => 10)]. Product-containing fractions were collected and evaporated under reduced pressure to give product B8b (0.117 g, 0.187 mmol, yield = 70%) as a white powder. A 7:3 mixture of E and Z isomers was obtained according to NMR. 1 HNMR (400 MHz, CDCl3) δ(ppm): 5.70 (1H, d, J=10.4 Hz), 5.23 (1H, brd), 5.17-5.13 (1H, m), 4.51-4.40 (1H, m), 4.11-4.00 (2H, m), 3.16-3.07 (0.3H[Z-isomer], m), 2.68-2.57 (0.7H[E-isomer], m), 2.20-2.10 (2H, m), 1.89 (3H, s), 1.89-1.77 (2H, m), 1.75-1.67 (2H, m), 0.89-0.85 (6H, m), 0.84-0.77 (10H, m), 0.59 (0.9H[Z-isomer], s), 0.57 (2.1H[E-isomer], s), 0.05-0.00 (6H, m).

[0410] Preparation of Compound B8c. Glacial acetic acid (0.060 mL, 1.047 mmol) and cesium fluoride (0.080 g, 0.524 mmol) were added to a suspension of B8b (0.1 g, 0.175 mmol) in acetonitrile (anhydrous) (4 mL) at 0 °C under a nitrogen atmosphere. The resulting mixture was stirred at 0 °C for 30 minutes and then at room temperature for 2 hours. LCMS-NQAD (acid) showed little conversion of the starting material to a product with an uncertain product mass. Dichloromethane (2 mL) was added to the reaction mixture, and the reaction mixture immediately turned into a clear yellow solution. The reaction mixture was stirred overnight. Additional cesium fluoride (0.080 g, 0.524 mmol) was added to the reaction mixture, and stirring was continued for 24 hours. Additional cesium fluoride (0.080 g, 0.524 mmol) was added to the reaction mixture again, and stirring was continued for 4 h. TLC [heptane (3): ethyl acetate (1)] showed only a small amount of starting material present in the reaction mixture, but the reaction mixture was diluted with dichloromethane (75 mL) and washed with saturated aqueous sodium bicarbonate (50 mL). The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by flash column (25 g) chromatography [heptane (100 => 90): ethyl acetate (0 => 10)] to remove remaining starting material (visible only by TLC). Product-containing fractions were collected and evaporated under reduced pressure to give product B8c (0.051 g, 0.111 mmol, yield = 64%). 1 HNMR (400 MHz, CDCl3) δ(ppm): 5.37 (1H, brd), 4.65-4.55 (1H, m), 4.31, (2H, q, J=7.1 Hz), 2.89 (1H, dd, J=16.8, 3.0 Hz), 2.57 (1H, dd, J=16.8, 9.9 Hz), 2.37-2.25 (2H, m), 2.04 (3H, s), 2.09-1.91 (2H, m), 1.90-1.77 (3H, m), 1.37 (3H, t, J=7.1 Hz), 1.02 (3H, s), 0.97 (3H, d, J=6.5 Hz), 0.72 (3H, s).

[0411] Preparation of Compound B8d: A solution of B8c (0.051 g, 0.111 mmol) in dichloromethane (1 mL) was cooled in an ice bath under nitrogen for 0.5 h. Diethylaminosulfur trifluoride (DAST) (0.027 mL, 0.222 mmol) was added, and the reaction mixture was allowed to warm to room temperature and stirred overnight. Additional diethylaminosulfur trifluoride (DAST) (0.027 mL, 0.222 mmol) was added, and stirring was continued for 20 h. TLC [heptane(3):ethyl acetate(1)] showed no complete consumption of the starting material after vanillin staining. The acetate group was removed [M-CH3COOH+H]. + LCMS-ELSD (base): 47% product at room temperature = 3.43 with m / z (+) = 421, consistent with the desired product. The reaction mixture was diluted with dichloromethane (50 mL) and washed with saturated sodium bicarbonate (50 mL). The aqueous layer was separated and extracted twice with dichloromethane (50 mL). The extracts were combined with the previous organic layer, dried over sodium sulfate, and evaporated under reduced pressure. The residue was purified by flash column chromatography [heptane (100 => 90):ethyl acetate (0 => 90)]. The product-containing fractions were collected, evaporated under reduced pressure, and stripped with dichloromethane (5 mL) to give product B8d (0.027 g, 0.056 mmol, yield = 51%). 1 HNMR (400 MHz, CDCl3) δ(ppm): 5.37 (1H, brd), 4.65-4.55 (1H, m), 4.32, (2H, q, J=7.1 Hz), 2.37-2.28 (2H, m), 2.27-2.09 (1H, m), 2.03 (3H, s), 2.04-1.92 (2H, m), 1.90-1.81 (3H, m), 1.35 (3H, t, J=7.1 Hz), 1.06 (3H, d, J=6.1 Hz), 1.02 (3H, s), 0.88 (6H, t, J=6.8 Hz), 0.70 (3H, s).

[0412] Preparation of Compound B8. Compound B8d (0.027 g, 0.056 mmol) was dissolved in tetrahydrofuran (dry) (1 mL) under an argon atmosphere. The mixture was cooled in an ice bath for 15 minutes, and 2.4 M lithium aluminum hydride in THF (0.047 mL, 0.112 mmol) was added slowly. Some gas evolution was observed. The reaction mixture was cooled. The mixture was stirred for 1 hour. TLC [heptane (3): ethyl acetate (1)] showed complete conversion, primarily to one lower-eluting product, after vanillin staining. The ice bath was removed, and stirring was continued for 1 hour. The reaction mixture was quenched with saturated aqueous ammonium chloride (50 mL) and extracted three times with dichloromethane (50 mL). The combined extracts were dried over sodium sulfate and evaporated under reduced pressure. The residue was purified by flash column (4 g silica) chromatography [heptane (100 => 85): ethyl acetate (0 => 15)]. Product-containing fractions were collected and evaporated under reduced pressure. The residue was transferred to a vial (4 mL) containing methanol and evaporated under a nitrogen stream at 37 °C. The residue was dried in a vacuum oven overnight at 40 °C to give product B8 (0.011 g, 0.028 mmol, yield = 49%). 1 HNMR (400 MHz, CDCl3) δ(ppm): 5.35 (1H, m), 3.71 (2H, t, J=12.8 Hz), 3.58-3.48 (1H, m), 2.35-2.18 (2H, m), 2.15-1.93 (3H, m), 1.92-1.73 (5H, m), 1.70-1.40 (9H, m), 1.08 (3H, d, J=6.5 Hz), 1.01 (3H, s), 0.72 (3H, s).

[0413] Example 20. Preparation of compound B10

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[0414] A solution of BB-1 (100 mg, 0.23 mmol) and titanium(IV) isopropoxide (0.07 mL, 0.23 mmol) in THF (dry, 2 mL) was cooled to 0 °C in a flame-dried flask under argon. Ethylmagnesium bromide (1.0 M in THF, 1.16 mL) was added dropwise. The reaction mixture was stirred at 0 °C for 15 min, and TLC (H / E; 2:1) showed starting material and two new spots. The reaction mixture was allowed to warm to room temperature and stirring was continued for 1 h, after which the reaction mixture was cooled to 0 °C, and ethylmagnesium bromide (1.0 M in THF, 1.16 mL) was added dropwise. The reaction mixture was stirred at 0 °C for 15 min. TLC (H / E; 2:1) showed complete conversion and a single new spot. The reaction mixture was diluted with EtO (2 mL). Saturated aqueous NH4Cl (2 mL) and HO (2 mL) were added at 0 °C. The solid was removed by filtration through cotton, and the filter cake was washed with Et2O (10 mL). The colorless layers were separated, and the aqueous layer was extracted with Et2O (20 mL) and a mixture of Et2O and EtOAc (20 mL; 1:1). The organic layer was dried over Na2SO4, and the solvent was removed in vacuo. 125 mg of a white solid was obtained. Flash chromatography (heptane, 5% to 30% EtOAc) afforded compound B10 (37 mg, 0.096 mmol; 41.2%). 1H-NMR (400 MHz, CDCl3) δ(ppm): 5.36-5.35 (m, 1H), 3.58 - 3.46 (m, 1H), 2.32 - 2.21 (m, 2H), 2.03 - 1.93 (m, 2H), 1.91 - 1.80 (m, 3H) 1.77 (s, 1H), 1.69 - 1.37 (m, 10H), 1.34 - 0.82 (m, 9H), 1.01 (s, 3H), 0.93 (d, J = 6.6 Hz, 3H), 0.75 - 0.71 (m, 2H), 0.69 (s, 3H), 0.46 - 0.39 (m, 2H).

[0415] Example 21. Preparation of Compounds B13a to B14 [ka]

[0416] Preparation of Compound B13a. To a solution of BB-2 (762 mg, 1.961 mmol) in pyridine (15 mL) at 0 °C, acetic anhydride (0.185 mL, 1.961 mmol) and DMAP (23.95 mg, 0.196 mmol) were added (a slightly yellowish suspension slowly dissolved). The mixture was stirred at room temperature overnight. TLC (heptane / EtOAc 2:1) showed complete conversion. The reaction mixture was diluted with EtOAc (100 mL) and water (100 mL), and the layers were separated. The aqueous layer was extracted with EtOAc (2x). The organic layers were combined, washed with water (3x) and brine, dried over Na2SO4, and concentrated. The resulting solid was coevaporated three times with toluene, EtOH, and DCM. The material was purified by flash chromatography (40 g silica, 4-40% EtOAc in heptane, loaded with DCM). Compound B13a (687 mg, 1.595 mmol; 81%) was obtained as a white solid. 1 HNMR (300MHz, CDCl3): δ(ppm): 5.37 (1H, d, 5.1 Hz), 4.60 (1H, m), 1.99 (3H, s), 1.20 (6H, s), 1.01 (3H, s), 0.93 (3H, d, J = 6.6 Hz), 0.68 (3H, s).

[0417] Preparation of Compound B13b: To a solution of Compound B13a (687 mg, 1.595 mmol) in dichloromethane (8.5 mL) under nitrogen, TMS-N3 (0.233 mL, 1.755 mmol) was added, followed by BF3·OEt2 (0.842 mL, 3.19 mmol). The mixture was stirred at room temperature for 2 h. TLC showed nearly complete conversion to the upper eluting spot. Impurities were present. After stirring for an additional 30 min, the reaction mixture was diluted with 2 M NaOH (25 mL) and DCM (25 mL). The layers were separated. The aqueous layer was extracted with DCM (2x). The organic layers were combined, washed with brine, dried over Na2SO4, concentrated, and purified by flash chromatography (40 g silica, 4-40% EtOAc in heptane, loaded with DCM) to give Compound B13b (660 mg, 1.376 mmol; 86%). 1 HNMR (300MHz, CDCl3): δ(ppm): 5.37 (1H, d, 4.8 Hz), 4.60 (1H, m), 2.03 (3H, s), 1.20 (6H, s), 1.01 (3H, s), 0.93 (3H, d, J = 6.6 Hz), 0.68 (3H, s).

[0418] Preparation of Compound B13. To a solution of Compound B13b (660 mg, 1.448 mmol) in diethyl ether (dry) (15 mL) under argon at 0 °C was added LiAlH (0.797 mL, 3.19 mmol) in EtO (a white suspension formed). The mixture was stirred at 0 °C for 30 minutes and at room temperature for 1 hour, after which TLC showed complete conversion of the starting material to the lower elution spot (amine). The mixture was cooled again to 0 °C, and water (0.057 mL, 3.19 mmol) and NaOH, 4 M aqueous solution (0.797 mL, 3.19 mmol) were added. Stirred at room temperature for 30 minutes and filtered through Celite with diethyl ether and THF. The organic layer was dried over Na SO and the solvent was evaporated. The crude product was purified by gravity column chromatography (100 g silica, loaded with DCM). First, the column was eluted with DCM:MeOH (95:5) to remove all impurities. The column was then eluted with DCM:7M NH in MeOH (95:5) to give compound B13 (400 mg, 1.032 mmol; 71.2%). 1 HNMR (300MHz, CDCl3): δ(ppm): 5.35 (1H, d, 5.1 Hz), 3.51 (1H, m), 1.07 (6H, s), 1.01 (3H, s), 0.93 (3H, d, J = 6.6 Hz), 0.68 (3H, s).

[0419] Preparation of Compound B14. Compound B13 (50 mg, 0.129 mmol) was dissolved in tetrahydrofuran (dry) (2 mL) with slight heating, followed by the addition of MeI (8.07 μL, 0.129 mmol) (1 mL from a stock solution of 81 microliters of MeI in 10 mL of THF) and K2CO3 (21.39 mg, 0.155 mmol). Stirred overnight at room temperature. The solid was filtered off, washed with water, and dried. The mixture was purified using a 12 g pre-packed flash column (GraceResolve™) running 7N NH3 in DCM / MeOH 97.5 / 2.5 at 15 mL / min in 1-minute fractions. Compound B14 (18 mg, 0.045 mmol, 34.7%) was thus obtained. 1 HNMR (400MHz, CDCl3): δ(ppm): 5.35 (1H, d, 4.8 Hz), 3.53 (1H, m), 2.30 (3H, s), 1.02 (9H, s), 0.93 (3H, d, J = 6.6 Hz), 0.68 (3H, s).

[0420] Example 22. Preparation of Compound B17 [ka]

[0421] Preparation of Compound B17a. 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI) (0.282 g, 1.468 mmol) and 1-hydroxy-7-azabenzotriazole (HOAt) (0.018 g, 0.133 mmol) were added to a solution of 3β-hydroxycholenic acid (0.5 g, 1.335 mmol), N,O-dimethylhydroxylamine hydrochloride (0.143 g, 1.468 mmol), and N,N-diisopropylethylamine (0.256 mL, 1.468 mmol) in dichloromethane (15 mL) under a nitrogen atmosphere at 0° C. The reaction mixture was allowed to warm to room temperature over the weekend. Additional 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI) (0.282 g, 1.468 mmol) and 1-hydroxy-7-azabenzotriazole (HOAt) (0.018 g, 0.133 mmol) were added, and stirring was continued for 2 h. The reaction was diluted with dichloromethane (100 mL), washed with 0.5 N aqueous potassium hydrogen sulfate (75 mL) and saturated aqueous sodium bicarbonate (75 mL), dried over s...

Claims

1. formula: 【Chemistry 1-1】 or a pharmaceutically acceptable salt thereof; where: Z is 【Chemistry 1-2】 and L ３ is a substituted or unsubstituted C １ -C ６ alkylene; X １ is —O—; R ３ｂ is hydrogen; R ３ａ is hydrogen; R ２ , R １１ａ , and R １１ｂ Each instance of is hydrogen; R ６ａ and R ６ｂ is independently hydrogen, and [Chemistry 1-3] represents a single bond and the hydrogen at C5 is in the alpha or beta position; R １９ is hydrogen; Y is —O—; R Ｚ５ is hydrogen; and Two R's Ｚ６ The bases come together to form C ３－６ forming a carbocyclic ring, A compound or a pharmaceutically acceptable salt thereof.

2. Group-X １ R ３ｂ is in the beta position, and R ３ａ The compound of claim 1 , wherein:

3. The compound described in claim 1, wherein the hydrogen at C5 is in the alpha position.

4. L ３ is a substituted or unsubstituted C ２ -C ６ The compound of claim 1 which is an alkylene.

5. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and an effective amount of a compound according to any one of claims 1 to 4.

6. A composition comprising a compound according to any one of claims 1 to 4 or a pharmaceutical composition according to claim 5 for treating a disease or condition in a patient in need thereof.

7. 7. The composition or pharmaceutical composition of claim 6, wherein the disease or condition is schizophrenia, depression, bipolar disorder (I and II), schizoaffective disorder, mood disorder, anxiety disorder, personality disorder, psychosis, stereotypic disorder, post-traumatic stress disorder (PTSD), autism spectrum disorder (ASD), dysthymia (mild depression), social anxiety disorder, obsessive-compulsive disorder (OCD), pain disorders, sleep disorders, memory disorders and dementia (including Alzheimer's disease, epilepsy and any seizure disorder), traumatic brain injury (TBI), stroke, addictive disorders (including opiates and cocaine and alcohol), autism, Huntington's disease, insomnia, Parkinson's disease, withdrawal syndrome, or tinnitus.

8. 8. The composition or pharmaceutical composition of claim 7, wherein the disease or condition is Alzheimer's disease.

9. 8. The composition or pharmaceutical composition of claim 7, wherein the disease or condition is Huntington's disease.

10. 8. The composition or pharmaceutical composition of claim 7, wherein the disease or condition is Parkinson's disease.

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