Neuroactive steroids, compositions, and uses thereof

Abstract

To provide compounds and pharmaceutical compositions useful for the prevention and treatment of CNS-related conditions.SOLUTION: Compounds according to Formula (I), pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof are provided. Compounds of the present invention are contemplated useful for the prevention and treatment of various CNS-related conditions in mammals.SELECTED DRAWING: None

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 an animal's arousal (a continuum ranging from coma to convulsions) 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 inside of the cell negative relative to the outside of the cell. This potential (voltage) is determined by the flow of ions (K + , Na + , Cl - Neurotransmitters are stored in presynaptic vesicles and released as a result of neuronal action potentials. When released into the synaptic cleft, an excitatory chemical transmitter 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+is a ligand-gated ion channel that is essential for excitatory neurotransmission and neuronal CNS function. The NMDA receptor is a heteromeric complex consisting of NR1, NR2 and / or NR3 subunits and possesses distinct recognition sites for exogenous and endogenous ligands. These recognition sites include a binding site for glycine as well as for glutamate agonists and modulators. These modulators may be useful as therapeutic agents with potential for clinical use as cognition enhancers and may be useful in the treatment of mental disorders in which glutamatergic transmission is reduced or defective (see, for example, Non-Patent Document 1 (Horak et al., J. of Neuroscience, 2004, 24(46), 10318-10325)).

[0004] Neurosteroids such as pregnenolone sulfate (PS) have been shown to exert a direct modifying effect on several types of neurotransmitter receptors, such as the GABA A receptor, glycine receptor, AMPA-kainate receptor and NMDA receptor. The NMDA receptor is positively modified by PS; however, the degree of modification varies considerably.

[0005] In addition to PS, several other 3β-hydroxy steroids have been shown to potentiate the NMDA receptor (see, for example, Non-Patent Document 2 (Paul et al., J. Pharm. and Exp. Ther. 1994, 271, 677-682)). Recently, a 3β-hydroxy-ergosta-5-ene steroid derivative (1) was reported as a positive modulator of NMDA (NR1a / NR2A). Compound (1) (also called Org-1) is a GABA AIt has been found that NMDA is selectively modified as compared with

Chemical Formula

Prior Art Documents

Non-Patent Documents

[0006]

Non-Patent Document 1

Non-Patent Document 2

Non-Patent Document 3

Non-Patent Document 4

Summary of the Invention

Problems to be Solved by the Invention

[0007] There is a need for novel and improved neuroactive steroids that modify brain excitability for the prevention and treatment of CNS-related disorders. The compounds, compositions and methods described herein are directed to this end.

Means for Solving the Problems

[0008] The novel 3-α and 3β-hydroxy steroids described herein are potential NMDA receptor modulators and are therefore useful for the prevention and / or treatment of a wide range of CNS-related disorders 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 disorder, post-traumatic stress disorder (PTSD), autism spectrum disorder (ASD), dysthymia (minor 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, addiction 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 aspect, a compound of formula (I):

Chemical formula

Chemical formula

[0010] For example, in certain embodiments, the compound of formula (I) is of formula (I - w): [Chemical formula] (wherein, Z is a group of formula (i), (ii), (iii), (iv) or (v): [Chemical formula] and L 1 and L 2 are 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 hetero C1 - C6 alkylene, substituted or unsubstituted hetero C2 - C6 alkenylene, and substituted or unsubstituted hetero C2 - C6 alkynylene; L 3is a substituted or unsubstituted C1-C6 alkylene, substituted or unsubstituted C2-C6 alkenylene, substituted or unsubstituted C2-C6 alkynylene, substituted or unsubstituted hetero C1-C6 alkylene, substituted or unsubstituted hetero C2-C6 alkenylene, or 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 (wherein, 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

Chemical formula

Chemical formula

[0011] In certain embodiments, Z is a group of the formula:

Chemical formula

[0012] In certain embodiments, L 3 is of the formula:

Chemical formula

[0013] In certain embodiments, L 3 is of the formula:

Chemical formula

[0014] In certain embodiments, L 3 is of the formula:

Chemical formula

[0015] In certain embodiments, L 3 is of the formula:

Chemical formula

[0016] In certain embodiments, L 3 is of the formula:

Chemical formula

[0017] In certain embodiments, Z is of the formula

Chemical formula

[0018] In certain embodiments, the group

Chem.

Chem.

Chem.

[0019] In certain embodiments, Z is of the formula

Chem.

[0020] In certain embodiments, Y in the formula is -O-, and L 3 is an alkylene or heteroalkylene group.

[0021] In certain embodiments, the group

Chem.

Chem.

[0022] In certain embodiments, Z is of the formula

Chem.

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

[0024] In certain embodiments, the group

Chem.

Chem.

[0025] In certain embodiments, the group -X 1 R 3b is at the beta position and R 3a is at the alpha position. In certain embodiments, -X 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 together form an oxo group. In certain embodiments,

Chem.

Chem.

[0026] In another aspect, the present invention provides a pharmaceutical composition comprising a compound of the present invention and a pharmaceutically acceptable single entity. 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 aspects, the compound of the present invention is provided as a negative allosteric modulator (NAM) of the NMDA receptor, and thus the compound of the present invention is useful for preventing and / or treating a wide range of CNS pathologies including schizophrenia, depression, bipolar disorder (I and II), schizoaffective disorder, mood disorder, anxiety disorder, personality disorder, psychosis, tic disorder, post-traumatic stress disorder (PTSD), autism spectrum disorder (ASD), dysthymia (minor 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, addiction disorders (including opioids and cocaine and alcohol), autism, Huntington's disease, insomnia, Parkinson's disease, withdrawal syndrome or tinnitus (but not limited to these). For example, in one aspect, there is provided a method of modifying an NMDA receptor, the method comprising administering to a subject in need thereof an effective amount of a compound of the present invention. In another aspect, there is provided a method of modifying CNS activity, the method comprising administering to a subject in need thereof an effective amount of a compound of the present invention. In yet another aspect, there is provided a method of modifying brain excitability, the method comprising administering to a subject in need thereof an effective amount of the compound of the present invention.

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

Mode for Carrying Out the Invention

[0029] Definitions Chemical Definitions The definitions of specific functional groups and chemical terms are described in further detail below. Chemical elements are identified according to the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75th Edition, inside cover, and specific functional groups are generally defined as described therein. Additionally, general principles of organic chemistry, as well as specific functional moieties and reactivities, 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 in this specification may contain one or more chiral centers and, therefore, may exist in various isomeric forms, such as enantiomers and / or diastereomers. For example, the compounds described in this specification may be in the form of individual enantiomers, diastereomers or geometric isomers, or in the form of mixtures of stereoisomers including racemic mixtures and mixtures enriched in one or more stereoisomers. Isomers can be isolated from the mixtures by methods known to those skilled in the art, such as chiral high performance liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or the preferred isomers can be prepared by asymmetric synthesis. For example, Jacques et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen et al., Tetrahedron 33:2725 (1977); Eliel, Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); and Wilen, Tables of Resolving Agents and Optical Resolutions p.268 (edited by E.L. Eliel, Univ. of Notre Dame Press, Notre Dame, IN 1972) are hereby incorporated by reference. The present invention further encompasses the compounds described herein as individual isomers substantially free of other isomers and, alternatively, as various isomer mixtures.

[0031] When listing a range of values, it is intended to include each value and sub-range within that range. For example, "C 1-6 alkyl" means 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 is intended to include alkyl.

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

[0033] "Alkyl" refers to a radical of a straight-chain or branched saturated hydrocarbon group having from 1 to 20 carbon atoms ("C 1-20 alkyl"). In some embodiments, the alkyl group has from 1 to 12 carbon atoms ("C 1-12 alkyl"). In some embodiments, the alkyl group has from 1 to 10 carbon atoms ("C 1-10 alkyl"). In some embodiments, the alkyl group has from 1 to 9 carbon atoms ("C 1-9 alkyl"). In some embodiments, the alkyl group has from 1 to 8 carbon atoms ("C 1-8"alkyl"). In some embodiments, the alkyl group has from 1 to 7 carbon atoms ("C 1-7 alkyl"). In some embodiments, the alkyl group has from 1 to 6 carbon atoms ("C 1-6 alkyl", also referred to herein as "lower alkyl"). In some embodiments, the alkyl group has from 1 to 5 carbon atoms ("C 1-5 alkyl"). In some embodiments, the alkyl group has from 1 to 4 carbon atoms ("C 1-4 alkyl"). In some embodiments, the alkyl group has from 1 to 3 carbon atoms ("C 1-3 alkyl"). In some embodiments, the alkyl group has from 1 to 2 carbon atoms ("C 1-2 alkyl"). In some embodiments, the alkyl group has 1 carbon atom ("C1 alkyl"). In some embodiments, the alkyl group has from 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-butanil (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, e.g., as examples, from 1 to 5 substituents, from 1 to 3 substituents or 1 substituent ("substituted alkyl"). In certain embodiments, the alkyl group is unsubstituted C 1-10 alkyl (e.g., -CH3). In certain embodiments, the alkyl group is substituted C 1-10It is alkyl. Common alkyl abbreviations include Me (-CH3), Et (-CH2CH3), iPr (-CH(CH3)2), nPr (-CH2CH2CH3), n-Bu (-CH2CH2CH2CH3), or i-Bu (-CH2CH(CH3)2).

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

[0035] "Alkylene" is an alkyl group from which two hydrogens have been removed to give a divalent radical, which may be substituted or unsubstituted. Examples of unsubstituted alkylene groups include methylene (-CH2-), ethylene (-CH2CH2-), propylene (-CH2CH2CH2-), butylene (-CH2CH2CH2CH2-), pentylene (-CH2CH2CH2CH2CH2-), hexylene (-CH2CH2CH2CH2CH2CH2-) and the like, but are not limited thereto. Exemplary substituted alkylene groups, for example, exemplary substituted alkylene groups substituted with one or more alkyl (methyl) groups include substituted methylene (-CH(CH3)-, (-C(CH3)2-), substituted ethylene (-CH(CH3)CH2-, -CH2CH(CH3)-, -C(CH3)2CH2-, -CH2C(CH3)2-), substituted propylene (-CH(CH3)CH2CH2-, -CH2CH(CH3)CH2-, -CH2CH2CH(CH3)-, -C(CH3)2CH2CH2-, -CH2C(CH3)2CH2-, -CH2CH2C(CH3)2-) and the like, but are not limited thereto.

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

[0037] "Alkenylene" refers to an alkenyl group from which two hydrogens have been removed to give a divalent radical, which may be substituted or unsubstituted. Exemplary unsubstituted divalent alkenylene groups include ethenylene (-CH=CH-) and propenylene (e.g., -CH=CHCH2-, -CH2-CH=CH-), but are not limited thereto. Exemplary substituted alkenylene groups, e.g., exemplary substituted alkenylene groups 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, but are not limited thereto.

[0038] "Alkynyl" is 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 2-20refers to a radical of "alkynyl"). An alkynyl group having one or more triple bonds and one or more double bonds is also referred to as an "ene-yne" group. In some embodiments, the alkynyl group has from 2 to 10 carbon atoms ("C 2-10 alkynyl"). In some embodiments, the alkynyl group has from 2 to 9 carbon atoms ("C 2-9 alkynyl"). In some embodiments, the alkynyl group has from 2 to 8 carbon atoms ("C 2-8 alkynyl"). In some embodiments, the alkynyl group has from 2 to 7 carbon atoms ("C 2-7 alkynyl"). In some embodiments, the alkynyl group has from 2 to 6 carbon atoms ("C 2-6 alkynyl"). In some embodiments, the alkynyl group has from 2 to 5 carbon atoms ("C 2-5 alkynyl"). In some embodiments, the alkynyl group has from 2 to 4 carbon atoms ("C 2-4 alkynyl"). In some embodiments, the alkynyl group has from 2 to 3 carbon atoms ("C 2-3 alkynyl"). In some embodiments, the alkynyl group has 2 carbon atoms ("C2 alkynyl"). The one or more carbon-carbon triple bonds may be internal (e.g., in the case of 2-butynyl) or terminal (e.g., in the case of 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. C 2-6 Examples of alkenyl groups include the above-described 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 example of an alkynyl group is independently optionally substituted, i.e., unsubstituted ( "unsubstituted alkynyl") or substituted with one or more substituents, e.g., as examples, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent ( "substituted alkynyl"). In certain embodiments, the alkynyl group is unsubstituted C 2-10 alkynyl. In certain embodiments, the alkynyl group is substituted C 2-10 alkynyl.

[0039] "Alkynylene" refers to an alkynyl group from which two hydrogens have been removed to give a divalent radical, which may be substituted or unsubstituted. 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 that further includes one or more (e.g., 1, 2, 3, or 4) heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus) within the parent chain, wherein said one or more heteroatoms are inserted between adjacent carbon atoms within the parent carbon chain and / or one or more heteroatoms are inserted between a carbon atom and the parent molecule, i.e., between the points of attachment. In certain embodiments, the heteroalkyl group refers to a saturated group having 1 to 10 carbon atoms and 1, 2, 3, or 4 heteroatoms ( "heteroC 1-10 alkyl"). In some embodiments, the heteroalkyl group is a saturated group having 1 to 9 carbon atoms and 1, 2, 3, or 4 heteroatoms ( "heteroC 1-9 alkyl"). In some embodiments, the heteroalkyl group has 1 to 8 carbon atoms and 1, 2, 3 or a saturated group having four heteroatoms ( "heteroC 1-8 alkyl"). In some embodiments, the heteroalkyl group is a saturated group having from 1 to 7 carbon atoms and 1, 2, 3, or 4 heteroatoms ( "heteroC 1-7 alkyl"). In some embodiments, the heteroalkyl group is a saturated group having from 1 to 6 carbon atoms and 1, 2, or 3 heteroatoms ( "heteroC 1-6 alkyl"). In some embodiments, the heteroalkyl group is a saturated group having from 1 to 5 carbon atoms and 1 or 2 heteroatoms ( "heteroC 1-5 alkyl"). In some embodiments, the heteroalkyl group is a saturated group having from 1 to 4 carbon atoms and 1 or 2 heteroatoms ( "heteroC 1-4 alkyl"). In some embodiments, the heteroalkyl group is a saturated group having from 1 to 3 carbon atoms and 1 heteroatom ( "heteroC 1-3 alkyl"). In some embodiments, the heteroalkyl group is a saturated group having from 1 to 2 carbon atoms and 1 heteroatom ( "heteroC 1-2 alkyl"). In some embodiments, the heteroalkyl group is a saturated group having 1 carbon atom and 1 heteroatom ( "heteroC1 alkyl"). In some embodiments, the heteroaryl group is a saturated group having from 2 to 6 carbon atoms and 1 or 2 heteroatoms ( "heteroC 2-6 alkyl"). Unless otherwise specified, each instance of the heteroalkyl group is independently unsubstituted ( "unsubstituted heteroalkyl") or substituted with one or more substituents ( "substituted heteroalkyl"). In certain embodiments, the heteroalkyl group is unsubstituted heteroC 1-10 alkyl. In certain embodiments, the heteroalkyl group is substituted heteroC 1-10 alkyl.

[0041] As used herein, the term "heteroalkenyl" 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 within the parent carbon chain and / or one or more heteroatoms are inserted between a carbon atom and the parent molecule, i.e., between the points of attachment. In certain embodiments, a heteroalkenyl group is a group having from 2 to 10 carbon atoms, at least one double bond, and 1, 2, 3, or 4 heteroatoms ("heteroC 3-10 alkenyl"). In some embodiments, a heteroalkenyl group has from 2 to 9 carbon atoms, at least one double bond, and 1, 2, 3, or 4 heteroatoms ("heteroC 2-9 alkenyl"). In some embodiments, a heteroalkenyl group has from 2 to 8 carbon atoms, at least one double bond, and 1, 2, 3, or 4 heteroatoms ("heteroC 2-8 alkenyl"). In some embodiments, a heteroalkenyl group has from 2 to 7 carbon atoms, at least one double bond, and 1, 2, 3, or 4 heteroatoms ("heteroC 2-7 alkenyl"). In some embodiments, a heteroalkenyl group has from 2 to 6 carbon atoms, at least one double bond, and 1, 2, or 3 heteroatoms ("heteroC 2-6 alkenyl"). In some embodiments, a heteroalkenyl group has from 2 to 5 carbon atoms, at least one double bond, and 1 or 2 heteroatoms ("heteroC 2-5 alkenyl"). In some embodiments, a heteroalkenyl group has from 2 to 4 carbon atoms, at least one double bond, and 1 or 2 heteroatoms ("heteroC 2-4 alkenyl"). In some embodiments, a heteroalkenyl group has from 2 to 3 carbon atoms, at least one double bond, and 1 heteroatom ("heteroC 2-3"(alkenyl)". In some embodiments, a heteroalkenyl group has from 2 to 6 carbon atoms, at least one double bond, and 1 or 2 heteroatoms ("heteroC 2-6 alkenyl)". Unless otherwise specified, each instance of a heteroalkenyl group is independently unsubstituted ("unsubstituted heteroalkenyl") or substituted with one or more substituents ("substituted heteroalkenyl"). In certain embodiments, a heteroalkenyl group is unsubstituted heteroC 2-10 alkenyl. In certain embodiments, a heteroalkenyl group is substituted heteroC 2-10 alkenyl.

[0042] As used herein, the term "heteroalkynyl" refers to an alkynyl group as defined herein that further includes 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 one or more heteroatoms are inserted between a carbon atom and the parent molecule, i.e., between the points of attachment. In certain embodiments, a heteroalkynyl group is a group having from 2 to 10 carbon atoms, at least one triple bond, and 1, 2, 3, or 4 heteroatoms ("heteroC 2-10 alkynyl)". In some embodiments, a heteroalkynyl group has from 2 to 9 carbon atoms, at least one triple bond, and 1, 2, 3, or 4 heteroatoms ("heteroC 2-9 alkynyl)". In some embodiments, a heteroalkynyl group has from 2 to 8 carbon atoms, at least one triple bond, and 1, 2, 3, or 4 heteroatoms ("heteroC 2-8 alkynyl)". In some embodiments, a heteroalkynyl group has from 2 to 7 carbon atoms, at least one triple bond, and 1, 2, 3, or 4 heteroatoms ("heteroC 2-7("alkynyl"). In some embodiments, a heteroalkynyl group has from 2 to 6 carbon atoms, at least one triple bond, and 1, 2, or 3 heteroatoms ("heteroC 2-6 ("alkynyl"). In some embodiments, a heteroalkynyl group has from 2 to 5 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms ("heteroC 2-5 ("alkynyl"). In some embodiments, a heteroalkynyl group has from 2 to 4 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms ("heteroC 2-4 ("alkynyl"). In some embodiments, a heteroalkynyl group has from 2 to 3 carbon atoms, at least one triple bond, and 1 heteroatom ("heteroC 2-3 ("alkynyl"). In some embodiments, a heteroalkynyl group has from 2 to 6 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms ("heteroC 2-6 ("alkynyl"). Unless otherwise specified, each instance of a heteroalkynyl group is independently unsubstituted ("unsubstituted heteroalkynyl") or substituted with one or more substituents ("substituted heteroalkynyl"). In certain embodiments, a heteroalkynyl group is unsubstituted heteroC 2-10 alkynyl. In certain embodiments, a heteroalkynyl group is substituted heteroC 2-10 alkynyl.

[0043] As used herein, "alkylene", "alkenylene", "alkynylene", "heteroalkylene", "heteroalkenylene" and "heteroalkynylene" each refer to a divalent radical of an alkyl, alkenyl, alkynyl group, heteroalkyl, heteroalkenyl and heteroalkynyl group, respectively. When giving a range or number of carbons for a particular "alkylene", "alkenylene", "alkynylene", "heteroalkylene", "heteroalkenylene" or "heteroalkynylene" group, that range or number is understood to refer to the range or number of carbons in a divalent linear carbon chain. The "alkylene", "alkenylene", "alkynylene", "heteroalkylene", "heteroalkenylene" and "heteroalkynylene" groups may or may not be substituted with one or more substituents as described herein.

[0044] "Aryl" is a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system having 6 to 14 ring carbon atoms and zero heteroatoms in the aromatic ring system (e.g., having 6, 10 or 14 π atoms shared in a cyclic arrangement) (the "C 6~14 aryl") radical. In some embodiments, the aryl group has 6 ring carbon atoms ("C6 aryl", e.g., phenyl). In some embodiments, the aryl group has 10 ring carbon atoms ("C 10 aryl", e.g., 1-naphthyl and 2-naphthyl). In some embodiments, the aryl group has 14 ring carbon atoms ("C 14 aryl", e.g., anthracyl). " "Aryl" is a ring system in which one or more aryl rings as defined above are fused with one or more carbocyclic or heterocyclic groups, and also includes a ring system in which its radical or bonding point is on the aryl ring. In such a case, the number of carbon atoms still indicates the number of carbon atoms in the aryl ring system. Typical aryl groups include groups derived from acenanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, coronene, fluoranthene, fluorene, hexacene, hexaphene, hexalene, as-indacene, s-indacene, indane, indene, naphthalene, octacene, octaphene, octalene, ovalene, penta-2,4-diene, pentacene, pentalene, pentaphene, perylene, phenalene, phenanthrene, picene, preiadene, pyrene, pyranthrene, rubicene, triphenylene and trinaphthalene, but are not limited thereto. 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, the aryl group is unsubstituted C 6-14 aryl. In certain embodiments, the aryl group is substituted C 6-14 aryl.

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

[0046] Examples of representative substituted aryls include the following

Chemical formula

[0047] Other representative aryls having a fused heterocyclyl group include the following:

Chemical formula

[0048] "Fused aryl" refers to an aryl in which two of its ring carbons are shared with a second aryl or heteroaryl or with a carbocyclic or heterocyclic 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 therein (e.g., having 6 or 10 shared π electrons in a cyclic arrangement), each heteroatom being independently selected from nitrogen, oxygen, and sulfur ("5- to 10-membered heteroaryl"). In a heteroaryl group containing one or more nitrogen atoms, the point of attachment may be a carbon atom or a nitrogen atom if the valence permits. The bicyclic heteroaryl ring system 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 carbocyclic or heterocyclic groups and the point of attachment is on the heteroaryl ring, in which case the number of ring members still indicates 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 which case the number of ring members indicates the number of ring members in the fused (aryl / heteroaryl) ring system. For a bicyclic heteroaryl group in which one ring contains no heteroatoms (e.g., indolyl, quinolinyl, carbazolyl, and the like), the point of attachment may be on either ring, i.e., on the ring having heteroatoms (e.g., 2-indolyl) or on the ring containing no heteroatoms (e.g., 5-indolyl).

[0051] In some embodiments, the heteroaryl group is a 5- to 10-membered aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms therein, each heteroatom being independently selected from nitrogen, oxygen, and sulfur (a "5- to 10-membered heteroaryl"). In some embodiments, the heteroaryl group is a 5- to 8-membered aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms therein, each heteroatom being independently selected from nitrogen, oxygen, and sulfur (a "5- to 8-membered heteroaryl"). In some embodiments, the heteroaryl group is a 5- to 6-membered aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms therein, each heteroatom being independently selected from nitrogen, oxygen, and sulfur (a "5- to 6-membered heteroaryl"). In some embodiments, the 5- to 6-membered heteroaryl has 1 to 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 the heteroaryl group is independently either 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, pyridinyl. Exemplary 6-membered heteroaryl groups containing two heteroatoms include, but are not limited to, pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6-membered heteroaryl groups containing three or four heteroatoms include, but are not limited to, triazinyl and tetrazinyl, respectively. Exemplary 7-membered heteroaryl groups containing one heteroatom include, but are not limited to, azepinyl, oxepinyl, and thiepinyl. Exemplary 5,6-fused bicyclic heteroaryl groups include, but are not limited to, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzothiazolyl, benzisothiazolyl, benzothiadiazolyl, indolizinyl, and purinyl. Exemplary 6,6-fused bicyclic heteroaryl groups include, but are not limited to, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl.

[0053] Examples of representative heteroaryls include the following:

Chemical Structure

[0054] "Heteroalkyl" 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] "Carbocyclic" or "carbocyclic" refers to a non-aromatic cyclic hydrocarbon group having 3 to 10 ring carbon atoms ("C 3-10 carbocyclic"), and refers to the radical of a group having zero heteroatoms within the non-aromatic ring system. In some embodiments, the carbocyclic group has 3 to 8 ring carbon atoms ("C 3-8 carbocyclic"). In some embodiments, the carbocyclic group has 3 to 6 ring carbon atoms ("C 3-6 carbocyclic"). In some embodiments, the carbocyclic group has 3 to 6 ring carbon atoms ("C 3-6 carbocyclic"). In some embodiments, the carbocyclic group has 5 to 10 ring carbon atoms ("C 5-10 carbocyclic"). Exemplary C 3-6 carbocyclic groups include, but are not limited to, cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6) and the like. Exemplary C 3-8 carbocyclic groups include, but are not limited to, the above C 3-6Carbocyclic 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 Examples of carbocyclic groups include, but are not limited to, the above-mentioned C 3-8 Carbocyclic groups include, of course, 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 illustrated by the above examples, in certain embodiments, the carbocyclic group is monocyclic (a "monocyclic carbocyclic"), or contains a fused, bridged or spiro ring system, such as a bicyclic system (a "bicyclic carbocyclic"), and may be saturated or partially saturated. "Carbocyclic" also includes a ring system in which a carbocyclic ring as defined above is fused to one or more aryl or heteroaryl groups, with the point of attachment on the carbocyclic ring, and in such cases, the number of carbons still indicates the number of carbons within the carbocyclic ring system. Unless otherwise specified, each instance of a carbocyclic group is independently optionally substituted, i.e., unsubstituted (an "unsubstituted carbocyclic") or substituted with one or more substituents (a "substituted carbocyclic"). In certain embodiments, the carbocyclic group is unsubstituted C 3-10 carbocyclic. In certain embodiments, the carbocyclic group is substituted C 3-10 carbocyclic.

[0056] In some embodiments, "carbocyclic" is a monocyclic, saturated carbocyclic group having 3 to 10 ring carbon atoms (a "C 3-10 cycloalkyl"). In some embodiments, the "cycloalkyl group" has 3 to 8 ring carbon atoms (a "C3-8 "cycloalkyl"). In some embodiments, a "cycloalkyl group" has from 3 to 6 ring carbon atoms ("C 3-6 cycloalkyl"). In some embodiments, a "cycloalkyl group" has from 5 to 6 ring carbon atoms ("C 5-6 cycloalkyl"). In some embodiments, a "cycloalkyl group" has from 5 to 10 ring carbon atoms ("C 5-10 cycloalkyl"). C 5-6 Examples of cycloalkyl groups include cyclopentyl (C5) and cyclohexyl (C5). C 3-6 Examples of cycloalkyl groups include the above-mentioned C 5-6 cycloalkyl groups, as well as cyclopropyl (C3) and cyclobutyl (C4). C 3-8 Examples of cycloalkyl groups include the above-mentioned C 3-6 cycloalkyl groups, as well as cycloheptyl (C7) and cyclooctyl (C8). Unless otherwise specified, each instance of a cycloalkyl group is independently unsubstituted ("unsubstituted cycloalkyl") or substituted with one or more substituents ("substituted cycloalkyl"). In certain embodiments, the cycloalkyl group is unsubstituted C 3-10 cycloalkyl. In certain embodiments, the cycloalkyl group is substituted C 3-10 cycloalkyl.

[0057] "heterocyclyl" or "heterocyclic" refers to a ring carbon atom and from 1 to 4 ring heteroatoms and Refers to a radical of a 3- to 10-membered non-aromatic ring system having each heteroatom independently selected from nitrogen, oxygen, sulfur, boron, phosphorus and silicon (a "3- to 10-membered heterocyclyl"). In a heterocyclyl group containing one or more nitrogen atoms, the point of attachment may, if valency permits, be a carbon atom or a nitrogen atom. The heterocyclyl group may be monocyclic (a "monocyclic heterocyclyl") or may be a fused, bridged or spiro ring system, for example a bicyclic system (a "bicyclic heterocyclyl"), and may be saturated or partially unsaturated. The bicyclic heterocyclyl ring system may contain one or more heteroatoms in one or both rings. "Heterocyclyl" includes a ring system in which a heterocyclyl ring as defined above is fused to one or more carbocyclic groups and the point of attachment is on either the carbocyclic ring or the heterocyclyl ring, or a ring system in which a heterocyclyl ring as defined above is fused to one or more aryl or heteroaryl groups and the point of attachment is on the heterocyclyl ring. In such cases, the number of ring members still indicates the number of ring members within the heterocyclyl ring system. Unless otherwise specified, each instance of heterocyclyl is independently optionally substituted, i.e., unsubstituted (an "unsubstituted heterocyclyl") or substituted with one or more substituents (a "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, the heterocyclyl group is a 5- to 10-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon (a "5- to 10-membered heterocyclyl"). In some embodiments, the heterocyclyl group is a 5- to 8-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (a "5- to 8-membered heterocyclyl"). In some embodiments, the heterocyclyl group is a 5- to 6-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (a "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, azirdinyl, oxiranyl, and thiirenyl. 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 pyrrol-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. Containing one heteroatom 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 fused to a C6 aryl ring (also referred to herein as 5,6-bicyclic heterocyclic rings) include, but are not limited to, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, benzoxazolinonyl, and the like. Exemplary 6-membered heterocyclyl groups fused to an aryl ring (also referred to herein as 6,6-bicyclic heterocyclic rings) include, but are not limited to, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and the like.

[0060] Specific examples of heterocyclyl groups are shown in the examples useful in the following description:

Chemical Structure

[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 nitrogen, oxygen or sulfur heteroatoms. Hetero can be applied to any of the hydrocarbyl groups described above, for example, it can be applied to alkyl, for example heteroalkyl, it can be applied to cycloalkyl, for example heterocyclyl, it can be applied to aryl, for example heteroaryl, it can be applied to cycloalkenyl, for example cycloheteroalkenyl, and to those similar thereto having from 1 to 5 and especially from 1 to 3 heteroatoms.

[0062] "Acyl" refers to the radical -C(O)R 20 wherein R 20 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 he teroaryl as defined herein. "Alkanoyl" is R 20is a group other than hydrogen, and is an acyl group. 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, -C(O)-(CH2) t (C6-C 10 aryl), -C(O)-(CH2) t (5- to 10-membered heteroaryl), -C(O)-(CH2) t (C3-C 10 cycloalkyl), and -C(O)-(CH2) t (4- to 10-membered heterocyclyl) are included, but are not limited thereto, and in this case, t is an integer from 0 to 4. In certain embodiments, R 21 is C1-C8 alkyl substituted with halo or hydroxy; unsubstituted C1-C4 alkyl, halo, unsubstituted C1-C4 alkoxy, unsubstituted C1-C4 haloalkyl, unsubstituted C1-C4 hydroxyalkyl or unsubstituted C1-C4 haloalkoxy or hydroxy, each substituted C3-C 10 cycloalkyl, 4- to 10-membered heterocyclyl, C6-C 10 aryl, arylalkyl, 5- to 10-membered heteroaryl or heteroarylalkyl.

[0063] "Acylamino" refers to the radical -NR 22 C(O)R 23 and in this case, each example of R 22 and 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. Specific 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- to 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 in this case is an integer from 0 to 4, and each R 24 independently represents hydrogen or C1-C8 alkyl. In certain embodiments, R 25 is H; C1-C8 alkyl substituted with halo or hydroxy; unsubstituted C1-C4 alkyl, halo, unsubstituted C1-C4 alkoxy, unsubstituted C1-C4 haloalkyl, unsubstituted C1-C4 hydroxyalkyl or unsubstituted C1-C4 haloalkoxy or hydroxy-substituted, C3-C 10 cycloalkyl, 4- to 10-membered heterocyclyl, C6-C 10 aryl, arylalkyl, 5- to 10-membered heteroaryl or heteroarylalkyl; and R 26 is H; C1-C8 alkyl substituted with halo or hydroxy; unsubstituted C1-C4 alkyl, halo, unsubstituted C1-C4 alkoxy, unsubstituted C1-C4 haloalkyl, unsubstituted C1-C4 hydroxyalkyl or unsubstituted C1-C4 haloalkoxy or hydroxy-substituted, C3-C 10 cycloalkyl, 4- to 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 of which is 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, 5-10 membered heteroaryl or heteroarylalkyl.

[0065] "Alkoxy" refers to the group -OR 29 In this case, R 29is a substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclic, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. Certain alkoxy groups are methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, and 1,2-dimethylbutoxy. Certain alkoxy groups are lower alkoxy, i.e., those having between 1 and 6 carbon atoms. Further certain alkoxy groups have between 1 and 4 carbon atoms.

[0066] In certain embodiments, R 29 is one or more substituents selected from the group consisting of amino, substituted amino, C6-C 10 aryl, aryloxy, carboxyl, cyano, C3-C 10 cycloalkyl, 4- to 10-membered heterocyclic, 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-, for example, 1 to 5 substituents, and in particular 1 to 3 substituents, especially a group having 1 substituent. Exemplary "substituted alkoxy" groups include -O-(CH2) t (C6-C 10 aryl), -O-(CH2) t (5- to 10-membered heteroaryl), -O-(CH2) t (C3-C 10 cycloalkyl), and -O-(CH2) t(4- to 10-membered heterocyclyl) is exemplified but not limited thereto, where t in this case is an integer from 0 to 4, and any aryl, heteroaryl, cycloalkyl or heterocyclyl group present may, by itself, be unsubstituted or alternatively substituted with unsubstituted C1-C4 alkyl, halo, unsubstituted C1-C4 alkoxy, unsubstituted C1-C4 haloalkyl, unsubstituted C1-C4 hydroxyalkyl or unsubstituted C1-C4 haloalkoxy or hydroxy. Specific exemplary "substituted alkoxy" groups are -OCF3, -OCH2CF3, -OCH2Ph, -OCH2-cyclopropyl, -OCH2CH2OH, and -OCH2CH2NMe2.

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

[0068] "Substituted amino" refers to an amino group of the formula -N(R 38 )2, where R 38 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl, or an amino protecting group, and at least one of R 38 is not hydrogen. In certain embodiments, each R 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- to 10-membered heteroaryl), -(CH2) t (C3-C 10 cycloalkyl) or -(CH2) t(4- to 10-membered heterocyclyl) (wherein t in this case is an integer from 0 to 8), independently selected, each of which is unsubstituted C1-C4 alkyl, halo, unsubstituted C1-C4 alkoxy, unsubstituted C1-C4 haloalkyl, unsubstituted C1-C4 hydroxyalkyl or unsubstituted C1-C4 haloalkoxy or substituted with hydroxy; or both R groups together form an alkylene group. 38 Exemplary "substituted amino" groups include -NR

[0069] -C1-C8 alkyl, -NR 39 -(CH2) 39 (C6-C t aryl), -NR 10 -(CH2) 39 (5- to 10-membered heteroaryl), -NR t -(CH2) 39 (C3-C t cycloalkyl) and -NR 10 -(CH2) 39 (4- to 10-membered heterocyclyl), but are not limited thereto, where t in this case is an integer from 0 to 4, for example 1 or 2, each R t represents independently H or C1-C8 alkyl; and any alkyl group may itself be substituted with halo, substituted or unsubstituted amino, or hydroxy; and any aryl, heteroaryl, cycloalkyl or heterocyclyl group may itself be substituted with unsubstituted C1-C4 alkyl, halo, unsubstituted C1-C4 alkoxy, unsubstituted C1-C4 haloalkyl, unsubstituted C1-C4 hydroxyalkyl or unsubstituted C1-C4 haloalkoxy or hydroxy. To avoid doubt, the term "substituted amino" includes groups alkylamino, substituted alkylamino, alkylarylamino, substituted alkylarylamino, arylamino, substituted arylamino, dialkylamino and substituted dialkylamino as defined below. Substituted amino includes both mono-substituted amino groups and di-substituted amino groups. 39

[0070] ​"Azido" refers to radical -N3.

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

[0072] "Substituted carbamoyl" or "substituted amide" refers to radical -C(O)N(R 62 )2, where each R 62 is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclic, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl, or an amino protecting group, and at least one of R 62 is not hydrogen. In certain embodiments, R 62 is H, C1-C8 alkyl, C3-C 10 cycloalkyl, 4-10 membered heterocyclic, C6-C 10 aryl, aralkyl, 5-10 membered heteroaryl and heteroaralkyl; or C1-C8 alkyl substituted with halo or hydroxy; or C1-C4 alkyl, halo, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 hydroxyalkyl or C1-C4 haloalkoxy or hydroxy, each substituted with unsubstituted C1-C4 alkyl, C3-C 10 cycloalkyl, 4-10 membered heterocyclic, C6-C 10 aryl, aralkyl, 5-10 membered heteroaryl or heteroaralkyl, selected from; provided that at least one of R 62 is other than 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) are included but not limited thereto, where t in this case is an integer from 0 to 4, and each R 64 independently represents H or C1-C8 alkyl, and any aryl, heteroaryl, cycloalkyl or heterocyclyl group present may itself 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, the 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 by 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 carbocyclic group having from 3 to 10 carbon atoms, and having a single cyclic ring or a plurality of fused rings (including fused and bridged ring systems), and having at least one, particularly from 1 to 2 olefinically unsaturated sites. Such cycloalkenyl groups include, by way of example, monocyclic structures such as cyclohexenyl, cyclopentenyl, cyclopropenyl and the like.

[0082] "Fused cycloalkenyl" refers to a cycloalkenyl that is a cycloalkenyl having 2 of its ring carbon atoms shared with a second aliphatic or aromatic ring and having its olefinic unsaturation positioned so as to impart aromaticity to the cycloalkenyl ring.

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

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

[0085] "Ethynyl" refers to -(C≡C)-.

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

[0087] "Thioketone" refers to the group =S.

[0088] As defined herein, alkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl and heteroaryl groups are optionally substituted (e.g., "substituted" or "unsubstituted" alkyl, "substituted" or "unsubstituted" alkenyl, "substituted" or "unsubstituted" alkynyl, "substituted" or "unsubstituted" carbocyclic, "substituted" or "unsubstituted" heterocyclic, "substituted" or "unsubstituted" aryl or "substituted" or "unsubstituted" heteroaryl groups). Generally, the term "substituted" means that at least one hydrogen present on a group (e.g., a carbon or nitrogen atom), whether or not the term "optionally" precedes it, is replaced by an acceptable substituent, i.e., a substituent that results in a stable compound, e.g., a compound that does not undergo spontaneous transformation such as rearrangement, cyclization, elimination or other reactions. Unless otherwise indicated, a "substituted" group has substituents at one or more substitutable positions of that group, and when one or more positions in any given structure are substituted, the substituents are the same or different for each position. The term "substituted" is intended to include substitution with any and all such combinations of organic compound acceptable substituents described herein that result in the formation of a stable compound. The present invention contemplates any and all such combinations for reaching stable compounds. For the purposes of the present invention, a heteroatom such as nitrogen may have a hydrogen substituent and / or may have 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 carbocyclic, 3- to 14-membered heterocyclic, C 6-14 aryl, and 5- to 14-membered heteroaryl, including but not limited to these. In this case, each alkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R dd groups; or two geminal hydrogens on a carbon atom are replaced by 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 ; R aa each example of which is independently C 1-10 alkyl, C 1-10Perhaloalkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C3-C 10 Carbocyclic, 3- to 14-membered heterocyclic, C 6-14 Aryl and 5- to 14-membered heteroaryl, or two R aa groups together form a 3- to 14-membered heterocyclic or 5- to 14-membered heteroaryl ring, where each alkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, and heteroaryl in this case is independently substituted with 0, 1, 2, 3, 4, or 5 R dd groups; R bb Each example of which 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 Carbocyclic, 3- to 14-membered heterocyclic, C 6~14 Aryl, and 5- to 14-membered heteroaryl, or two R bbThe groups combine to form a 3- to 14-membered heterocyclyl or 5- to 14-membered heteroaryl ring, where each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl is independently substituted with 0, 1, 2, 3, 4 or 5 R dd groups; R cc each instance of which is independently selected from hydrogen, 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 cc groups combine to form a 3- to 14-membered heterocyclyl or 5- to 14-membered heteroaryl ring, where each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl is independently substituted with 0, 1, 2, 3, 4 or 5 R dd groups; R dd each instance of which is independently 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 carbocyclic, 3 - to 10 - membered heterocyclic, C 6-10 aryl, 5 - to 10 - membered heteroaryl, and each alkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, and heteroaryl in this case is independently substituted with 0, 1, 2, 3, 4, or 5 R gg groups, or two geminal R dd substituents may combine together to form =O or =S; R ee each example of which is independently, C 1-6 alkyl, C 1-6Perhaloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Carbocyclic, C 6-10 Selected from aryl, 3- to 10-membered heterocyclic, and 3- to 10-membered heteroaryl, where each alkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R gg groups; ; R ff Each example of which is independently hydrogen, C 1-6 alkyl, C 1-6 perhaloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 carbocyclic, 3- to 10-membered heterocyclic, C 6-10 aryl, and 3- to 10-membered heteroaryl, or two R ff groups together form a 3- to 14-membered heterocyclic or 5- to 14-membered heteroaryl ring, where each alkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R gg groups; R gg Each example of which is independently halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OC 1-6 alkyl, -ON(C 1-6 alkyl)2, -N(C 1-6 alkyl)2, -N(C 1-6 alkyl)3 + X - , -NH(C 1-6 alkyl)2 + X - , -NH2(C 1-6 alkyl) + X - , -NH3 + X - , -N(OC 1-6 alkyl)(C 1-6 alkyl), -N(OH)(C 1-6(alkyl), -NH(OH), -SH, -SC 1-6 (alkyl), -SS(C 1-6 (alkyl), -C(=O)(C 1-6 (alkyl), -CO2H, -CO2(C 1-6 (alkyl), -OC(=O)(C 1-6 (alkyl), -OCO2(C 1-6 (alkyl), -C(=O)NH2, -C(=O)N(C 1-6 (alkyl)2, -OC(=O)NH(C 1-6 (alkyl), -NHC(=O)(C 1-6 (alkyl), -N(C 1-6 (alkyl)C(=O)(C 1-6 (alkyl), -NHCO2(C 1-6 (alkyl), -NHC(=O)N(C 1-6 (alkyl)2, -NHC(=O)NH(C 1-6 (alkyl), -NHC(=O)NH2, -C(=NH)O(C 1-6 (alkyl), -OC(=NH)(C 1-6 (alkyl), -OC(=NH)OC 1-6 (alkyl), -C(=NH)N(C 1-6 (alkyl)2, -C(=NH)NH(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 1-6(alkyl), C(=S)NH2, -C(=O)S(C 1-6 (alkyl), -C(=S)SC 1-6 (alkyl, -SC(=S)SC 1-6 (alkyl, -P(=O)2(C 1-6 (alkyl), -P(=O)(C 1-6 (alkyl)2, -OP(=O)(C 1-6 (alkyl)2, -OP(=O)(OC 1-6 (alkyl)2, C 1-6 (alkyl, C 1-6 (perhaloalkyl, C 2-6 (alkenyl, C 2-6 (alkynyl, C 3-10 (carbocyclic, C 6-10 (selected from aryl, 3- to 10-membered heterocyclyl, 5- to 10-membered heteroaryl; or two geminal R gg (substituents may together form =O or =S; in which case X - (is a counterion.

[0090] (The term "counterion" or "anionic counterion" refers to a group having a negative charge that associates with a cationic quaternary amino group to maintain electronic neutrality. Exemplary counterions include halide ions (e.g., F - (, Cl - (, Br - (, I - ), NO3 - (, ClO4 - (, OH - (, H2PO4 - (, HSO4 - (, sulfonate ions (e.g., methanesulfonate ion, trifluoromethanesulfonate ion, p-toluenesulfonate ion, benzenesulfonate ion, 10-camphorsulfonate ion, naphthalene-2-sulfonate ion, naphthalene-1-sulfonate-5-sulfonate ion, ethane-1-sulfonate-2-sulfonate ion, and the like), and carboxylate ions (e.g., acetate ion, ethanate ion, propionate ion, benzoate ion, glycerate ion, lactate ion, tartrate ion, glycolate ion, and the like).

[0091] The nitrogen atom may be substituted or unsubstituted if its valence permits, and includes 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 carbocyclic, 3- to 14-membered heterocyclic, C 6~14 aryl, and 5- to 14-membered heteroaryl, among others, and the two R cc groups attached to the nitrogen atom may together form a 3- to 14-membered heterocyclic or 5- to 14-membered heteroaryl ring, in which case each alkyl, alkenyl, alkynyl, carbocyclic, heterocyclic, aryl, and heteroaryl is independently substituted with 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). Examples of 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, but are not limited thereto. In this case, each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aralkyl, aryl and heteroaryl is independently substituted with 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. Wuts, 3rd Edition, John Wiley & Sons, 1999, which is hereby incorporated by reference.

[0093] For example, amino protecting groups such as amide groups (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'-dithiobenzyl-oxyacylamino)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 ) include, but are not limited to, methyl carbamate, ethyl carbamate, 9-flu Olenylmethyl carbamate (Fmoc), 9-(2-sulfo)fluorenylmethyl carbamate, 9-(2,7-dibromo)fluoroenylmethyl carbamate, 2,7-di-t-butyl-[9-(10,10-dioxo-10,10,10,10-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-dicyclohexylcarboxamido)ethyl carbamate, t-butyl carbamate (BOC), 1-adamantyl carbamate (Adoc), vinyl carbamate (Voc), allyl carbamate (Alloc), 1-isopropylallyl carbamate (Ipaoc), cinnamyl carbamate (Coc), 4-nitrocinnamyl carbamate (Noc), 8-quinolyl carbamate, N-hydroxypiperidinyl carbamate, alkyldithiocarbamate, benzyl carbamate (Cbz), p-methoxybenzyl carbamate (Moz), p-nitrobenzyl carbamate, p-bromobenzyl carbamate, p-chlorobenzyl carbamate, 2,4-dichlorobenzyl carbamate, 4-methylsulfinylbenzyl carbamate (Msz), 9-anthrylmethyl carbamate, diphenylmethyl carbamate, 2-methylthioethyl carbamate, 2-methylsulfonylethyl carbamate, 2-(p-toluenesulfonyl)ethyl carbamate, [2-(1,3-dithianyl)]methylcarbamate (Dmoc), 4-methylthiophenylcarbamate (Mtpc), 2,4-dimethylthiophenylcarbamate (Bmpc), 2-phosphonioethylcarbamate (Peoc), 2-triphenylphosphonioisopropylcarbamate (Ppoc), 1,1-dimethyl-2-cyanoethylcarbamate, m-chloro-p-acetyloxybenzylcarbamate, p-(dihydroxyboronyl)benzylcarbamate, 5-benzisoxazolylmethylcarbamate, 2-(trifluoromethyl)-6-chromonylmethylcarbamate (Tcroc), m-nitrophenylcarbamate, 3,5-dimethoxybenzylcarbamate, o-nitrobenzylcarbamate, 3,4-dimethoxy-6-nitrobenzylcarbamate, phenyl(o-nitrophenyl)methylcarbamate, t-amylcarbamate, S-benzylthiocarbamate, p-cyanobenzylcarbamate, cyclobutylcarbamate, cyclohexylcarbamate, cyclopentylcarbamate, cyclopropylmethylcarbamate, p-decyloxybenzylcarbamate, 2,2-dimethoxyacylvinylcarbamate, o-(N,N-dimethylcarboxamide)benzylcarbamate, 1,1-dimethyl-3-(N,N-dimethylcarboxamide)propylcarbamate, 1,1-dimethylpropynylcarbamate, di(2-pyridyl)methylcarbamate, 2-furanylmethylcarbamate, 2-iodoethylcarbamate, isoborynl carbamate, isobutylcarbamate, isonicotinylcarbamate, p-(p’-methoxyphenylazo)benzylcarbamate, 1-methylcyclobutylcarbamate, 1-methylcyclohexylcarbamate, 1-methyl-1-cyclopropylmethylcarbamate, 1-methyl-1-(3,5-dimethoxyphenyl)ethylcarbamate, 1-methyl-1-(p-phenylazophenyl)ethylcarbamate, 1-methyl-1-phenylethylcarbamate, 1-methyl-1-(4-pyridyl)ethylcarbamate, phenylcarbamate, p-(phenylazo)benzylcarbamate, 2,4,6-tri-t-butylphenylcarbamate, 4-(trimethylammonium)benzylcarbamate, and 2,4,Examples include, but are not limited to, 6-trimethylbenzyl carbamate.,

[0095] Examples of amino protecting groups such as sulfonamide groups (e.g., -S(=O)2R aa ) include p-toluenesulfonamide (Ts), benzenesulfonamide, 2,3,6-trimethyl-4-methoxybenzenesulfonamide (Mtr), 2,4,6-trimethoxybenzenesulfonamide (Mtb), 2,6-dimethyl-4-methoxybenzenesulfonamide (Pme), 2,3,5,6-tetramethyl-4-methoxybenzenesulfonamide (Mte), 4-methoxybenzenesulfonamide (Mbs), 2,4,6-trimethylbenzenesulfonamide (Mts), 2,6-dimethoxy-4-methylbenzenesulfonamide (iMds), 2,2,5,7,8-pentamethylchroman-6-sulfonamide (Pmc), methanesulfonamide (Ms), β-trimethylsilylethanesulfonamide (SES), 9-anthracenesulfonamide, 4-(4’,8’-dimethoxynaphthylmethyl)benzenesulfonamide (DNMBS), benzylsulfonamide, trifluoromethylsulfonamide, and phenacylsulfonamide, but are not limited thereto.

[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, N-1,1,4,4-tetramethyldisilylazacyclopentane adduct (STABASE), 5-substituted 1,3-dimethyl-1,3,5-triazacyclohexan-2-one, 5-substituted 1,3-dibenzyl-1,3,5-triazacyclohexan-2-one, 1-substituted 3,5-dinitro-4-pyridone, N-methylamine, N-allylamine, N-[2-(trimethylsilyl)ethoxy]methylamine (SEM), N-3-acetoxypropylamine, N-(1-isopropyl-4-nitro-2-oxo-3-pyrroline-3-yl)amine, quaternary ammonium salts, N-benzylamine, N-di(4-methoxyphenyl)methylamine, N-5-dibenzorbornylamine, 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-dimethylthiomethyleneamine, N-benzylideneamine, N-p-methoxybenzylideneamine, N-diphenylmethyleneamine, N-[(2-pyridyl)mesityl]methyleneamine, N-(N',N'-dimethylaminomethylene)amine, N,N'-isopropylidenediamine, N-p-nitrobenzylideneamine, N-salicylideneamine, N-5-chlorosalicylideneamine, N-(5-chloro-2-hydroxyphenyl)phenylmethyleneamine, N-cyclohexylideneamine, N-(5,5-dimethyl-3-oxo-1-cyclohexenyl)amine, N-borane derivative, N-diphenylboric acid derivative, N-[phenyl(pentaacylchromium- or tungsten)acyl]amine, N-copper chelate, N-zinc chelate, N-nitroamine, N-nitrosoamine, amine N-oxide, diphenylphosphine amide (Dpp), dimethylthiophosphine amide (Mpt), diphenylthiophosphine amide (Ppt), dialkylphosphoramidate, dibenzylphosphoramidate, diphenylphosphoramidate, benzenesulfenamide, o-nitrobenzenesulfenamide (Nps), 2,4-dinitrobenzenesulfenamide, pentachlorobenzenesulfenamide, 2-nitro-4-methoxybenzenesulfenamide, triphenylmethylsulfenamide, and 3-nitropyridinesulfenamide (Npys), but are not limited thereto.,

[0097] In certain embodiments, the substituent present on the oxygen atom is an oxygen protecting group (also referred to as a hydroxyl protecting group). Examples of oxygen 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) Examples include, but are not limited to, 2, and in this case R aa , R bb and R cc are 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. Wuts, 3rd Edition, John Wiley & Sons, 1999, which is hereby incorporated by reference into this specification.

[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-pentenyl-oxymethyl (POM), siloxymethyl, 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-anthryl, 9-(9-phenyl)xanthenyl, 9-(9-phenyl-10-oxo)anthryl, 1,3-benzodisulfuran-2-yl, benzisothiazolyl S,S-dioxide, trimethylsilyl (TMS), triethylsilyl (TES), triisopropylsilyl (TIPS), dimethylisopropylsilyl (IPDMS), diethylisopropylsilyl (DEIPS), dimethyltexylsilyl, t-butyldimethylsilyl (TBDMS), t-butyldiphenylsilyl (TBDPS), tribenzylsilyl, tri-p-xylylsilyl, triphenylsilyl, diphenylmethylsilyl (DPMS), t-butylmethoxyphenylsilyl (TBMPS), formate, be, enzoate, 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-phenylbenzoate, 2,4,6-trimethylbenzoate (mesitoate), alkyl methyl carbonate, 9-fluorenylmethyl carbonate (Fmoc), alkyl ethyl carbonate, alkyl 2,2,2-trichloroethyl carbonate (Troc), 2-(trimethylsilyl)ethyl carbonate (TMSEC), 2-(phenylsulfonyl)ethyl carbonate (Psec), 2-(triphenylphosphonio)ethyl carbonate (Peoc), alkyl isobutyl carbonate, alkyl vinyl carbonate, alkyl 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, 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’Examples 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 referred to as a thiol protecting group). Examples of 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, but are not limited thereto, where R aa , R bb and R cc are 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. Wuts, 3rd Edition, John Wiley & Sons, 1999, which is hereby incorporated by reference in its entirety.

[0100] The term "compound of the invention" and like expressions are intended to embrace the compounds described above, in particular compounds of any of the formulas enumerated and / or described in this specification, and this expression includes, where the context permits, prodrugs, pharmaceutically acceptable salts, and solvates, such as hydrates. Similarly, references to intermediates are intended to include, where the context permits, their salts and solvates, whether or not they themselves are claimed in the claims.

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

[0102] Other definitions "Pharmaceutically acceptable" means approved or approvable by a regulatory agency of the Federal or a State government or the corresponding agency in a country other than the United States, or listed in the U.S. Pharmacopeia or other generally recognized pharmacopeias for use in animals and more particularly in humans.

[0103] "Pharmaceutically acceptable salts" refer to salts of the compounds of the present invention that are pharmaceutically acceptable and retain the desired pharmacological activity of the parent compound. Specifically, such salts are non-toxic and can be inorganic or organic acid addition salts and base addition salts. Specifically, such salts include (1) acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid 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-methylbicyclo[2.2.2]-oct-2-ene-1-carboxylic acid, glucoheptanoic 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 the 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 by coordination with an organic base such as ethanolamine, diethanolamine, triethanolamine, N-methylglucamine and the like. Examples of salts further include, but are not limited to, 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 for an acidic functional group.Such cations are exemplified by sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium cations, and the like (see, for example, 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 the compounds of the invention are administered, i.e., a diluent, adjuvant, excipient or carrier used to administer the compounds of the invention.

[0105] "Pharmaceutically acceptable metabolically cleavable group" refers to a group that is cleaved in vivo to yield the parent compound of the structural formula shown herein. Examples of metabolically cleavable groups include -COR, -COOR, -CONRR and -CH2OR radicals, where R is independently selected at each occurrence 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 having a cleavable group and being pharmaceutically active in vivo, which is formed by solvolysis or under physiological conditions from the compound of the present invention (including derivatives of the compound of the present invention). Such examples include, but are not limited to, choline ester derivatives and the like, N-alkylmorpholine esters and the like. Other derivatives of the compound of the present invention are active in both their acid and acid derivative forms, but in many cases, the acid-sensitive form provides advantages such as solubility, tissue compatibility, or delayed release in mammalian organisms (see Bundgard, H., Design of Prodrugs, pp. 7-9, 21-24, Elsevier, Amsterdam 1985). Prodrugs are acid derivatives well-known to those skilled in the art, such as esters prepared by the reaction of a suitable alcohol with a parent acid, or amides prepared by the reaction of a parent acid compound with a substituted or unsubstituted amine, or an acid anhydride, or a mixed anhydride. Simple aliphatic or aromatic esters, amides, and anhydrides derived from pendant acidic groups on the compound of the present invention are special prodrugs. In some cases, it is desirable to prepare double ester type prodrugs, such as (acyloxy)alkyl esters or ((alkoxycarbonyl)oxy)alkyl esters. Specifically, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, aryl, C7-C 12 substituted aryl and C7-C 12 arylalkyl esters.

[0107] "Solvate" usually refers to a form of a compound associated with a solvent or a form of a compound associated with water (also called "hydrate") through a solvolysis reaction. 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, the solvate may be isolable, for example, when one or more solvent molecules are incorporated into the crystal lattice of the crystalline solid. "Solvate" encompasses both the solution phase and isolable solvates. Representative solvates include hydrates, ethanolates, and methanolates.

[0108] The "subject" for which administration is contemplated includes humans (i.e., males or females of any age group, such as pediatric subjects (e.g., infants, children, adolescents) or adult subjects (e.g., young adults, middle-aged adults, or the elderly)) and / or non-human animals, such as mammals, such as primates (e.g., cynomolgus monkeys, rhesus monkeys), cows, pigs, sheep, goats, rodents, cats, and / or dogs, but is not limited thereto. 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 is sufficient to effect such treatment or prevention when administered to a subject for treating or preventing a disease. The "effective amount" can vary depending on the compound, the disease and its severity, and the age, weight, etc. of the subject to be treated. "Therapeutically effective amount" refers to an amount effective for a therapeutic treatment. "Preventively effective amount" refers to an amount effective for a preventive treatment.

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

[0111] The term "prevention" is related to "prevention" and refers to measures or procedures whose purpose is not the treatment or cure of a disease but prevention. Non-limiting examples of preventive measures include administration of a vaccine; administration of low molecular weight heparin to hospitalized patients at risk of thrombosis, for example due to immobility; and administration of antimalarial drugs such as chloroquine prior to travel to geographical areas where malaria is endemic or where there is a high risk of exposure to malaria.

[0112] "Treating" any disease or disorder or "treatment" or "therapeutic treatment" of any disease or disorder, in one embodiment, refers to improving the disease or disorder (i.e., arresting the disease or reducing the manifestation, degree or severity of at least one of its clinical symptoms). In another embodiment, "treating" or "treatment" refers to improving at least one physical parameter that may not be recognizable to the subject. In yet another embodiment, "treating" or "treatment" refers to either or both of a physical modification of the disease or disorder (e.g., stabilization of recognizable symptoms) and a 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 isomer" refers to a compound that contains an unnatural ratio of isotopes with respect to one or more of the atoms that make up such compound. For example, an "isotopic isomer" of a compound is one or more non-radioactive isotopes, such as deuterium ( 2 H or D), carbon-13 ( 13 C), nitrogen-15 ( 15(N) or may contain the like. In such an isotope-substituted compound, the following atoms, if present, for example, any hydrogen may be 2 H / D, any carbon may be 13 C, or any nitrogen may be 15 N, and it will be understood that they can be various and that the presence and position of such atoms can be determined within the scope of the art. Similarly, the present invention may include the preparation of isotopomers having a radioactive isotope, in which case, for example, the resulting compound can be used for drug and / or substrate tissue distribution studies. Radioactive isotope tritium, i.e., 3 H, and carbon-14, i.e., 14 C are particularly useful for this purpose in view of their ease of incorporation and easy means of detection. Furthermore, positron-emitting isotopes, for example, 11 C, 18 F, 15 O and 13 N substituted compounds can be prepared, and such compounds will be useful for investigating substrate receptor occupancy in positron emission tomography (PET) studies. All isotopomers of the compounds provided herein, whether radioactive or not, are intended to be encompassed within the scope of the present invention.

[0114] It should also be understood that compounds having the same molecular formula but different in the nature or order of atomic bonds or the spatial arrangement of atoms are referred to as "isomers". Isomers having different spatial arrangements of atoms are referred to as "stereoisomers".

[0115] Stereoisomers that are not mirror images of each other 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 centers, described by the Cahn and Prelog R- and S-sequencing rules, or by the way the molecule rotates the plane of polarization, designated as dextrorotatory or levorotatory (i.e., as the (+) or (-)-isomers, respectively). Chiral compounds can exist as individual enantiomers or as mixtures thereof. A mixture containing equal ratios of enantiomers is called a "racemic mixture".

[0116] "Tautomers" are compounds that are interchangeable forms of a particular compound structure, referring to compounds with different arrangements of hydrogen atoms and electrons. Thus, the two structures can be in equilibrium by the movement of π electrons and atoms (usually H). For example, enol and ketone are tautomers because they are rapidly interconverted by treatment with either an acid or a base. Another example of tautomerism is the aci- and nitro-forms of phenylnitromethane, which are likewise formed by treatment with an acid or a base. Tautomeric forms can be significant in achieving the optical and chemical reactivity and biological activity of the compound in question.

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

[0118] As used herein, unless otherwise indicated, the term "enantiomerically pure R-compound" refers to at least about 80% by weight R-compound and at most about 20% by weight S-compound, at least about 90% by weight R-compound and at most about 10% by weight S-compound, at least about 95% by weight R-compound and at most about 5% by weight S-compound, at least about 99% by weight R-compound and at most about 1% by weight S-compound, at least about 99.9% by weight R-compound and at most about 0.1% by weight S-compound. In certain embodiments, the weight is based on the total weight of the compound.

[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 the S-compound and at most about 20% by weight of the R-compound, at least about 90% by weight of the S-compound and at most about 10% by weight of the R-compound, at least about 95% by weight of the S-compound and at most about 5% by weight of the R-compound, at least about 99% by weight of the S-compound and at most about 1% by weight of the R-compound, at least about 99.9% by weight of the S-compound and at most about 0.1% by weight of the R-compound. In certain embodiments, said weight is based on the total weight of the compound.

[0120] In the compositions provided herein, an enantiomerically pure compound or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof 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% excipient and about 10% enantiomerically pure R-compound. In certain embodiments, the enantiomerically pure R-compound in such a composition may contain, for example, at least about 95% by weight of the R-compound and at most 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% excipient and about 10% enantiomerically pure S-compound. In certain embodiments, the enantiomerically pure S-compound in such a composition may contain, for example, at least about 95% by weight of the R-compound and at most 5% by weight of the R-compound, based on the total weight of the compound. In certain embodiments, the active ingredient can be formulated without, or with very little, excipient or carrier.

[0121] The compounds of the present invention may possess one or more chiral centers; thus, 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 this specification and the claims is intended to include both the individual enantiomers and their racemic or non-racemic mixtures. Methods for determining stereochemistry and methods for separating stereoisomers are well known in the art.

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

[0124] Detailed description of certain embodiments of the invention In certain aspects, provided herein are 3-α and 3β-hydroxy steroid compounds that are useful as NMDA receptor modulators and thus for the prevention and / or treatment of a wide range of CNS pathologies, including, among others, schizophrenia, depression, bipolar disorder (e.g., I and / or II), schizoaffective disorder, mood disorders, anxiety disorders, personality disorders, psychosis, tic disorders, post-traumatic stress disorder (PTSD), autism spectrum disorder (ASD), dysthymia (minor 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, addiction 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, formulation potential, stability and / or safety.

[0125] Compound In one aspect, a compound as shown in formula (I):

Chemical formula

Chemical formula

Chemical formula

[0126] In certain embodiments, when R 3a is H, n is 1, and R 19 is Me, then R 1 is other than H, alkyl, alkenyl or alkynyl. In certain embodiments, when R 3a is H, R 3b is -COMe, R 19 is Me, and n is 0, then R 1 is OH. In certain embodiments, when R 3a is H, n is 0, and R 20 is alkyl, then R 1 is other than OH. In certain embodiments, when R 19 is Me, then R 1 is other than H, alkyl, alkenyl or alkynyl. In certain embodiments, R 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, when R 3a is H, then R 1 is other than H, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl or substituted or unsubstituted alkynyl. In certain embodiments, when R 3a is H, then R 1is a 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 , -S-S(=O)2R A2 , -S-S(=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 compounds:

Chemical formula

[0129] R 3a various embodiments As generally defined above, R 3a is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclic, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. R 3a is generally understood to be optionally in the alpha (lower) position or in 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 substituted or unsubstituted alkyl, for example, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 1-2 alkyl, substituted or unsubstituted C 2-3 alkyl, substituted or unsubstituted C 3-4 alkyl, substituted or unsubstituted C 4-5 alkyl, or substituted or unsubstituted C 5-6 alkyl. Exemplary R 3a C 1-6 a Examples of the Ruqil group 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-butanil (C5), tertiary amyl (C5), n-hexyl (C6); C 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 alkyl; and C substituted with an alkoxy group (e.g., -CH2OCH3 and -CH2OCH2CH3) 1-6 Examples of the alkyl include, but are not limited to these. In certain embodiments, R 3a is a substituted alkyl, for example, R 3a is a 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. In certain embodiments, R 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. In certain embodiments, R 3a is trifluoromethyl.

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

[0133] In certain embodiments, R 3a is substituted or unsubstituted alkynyl, for example, 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 3aExamples of the alkynyl group include, but are not limited to, unsubstituted, or substituted with alkyl, halo, haloalkyl (e.g., CF3), alkoxyalkyl, cycloalkyl (e.g., cyclopropyl or cyclobutyl), or hydroxyl, ethynyl, propynyl, or butynyl. In certain embodiments, R 3a is selected from the group consisting of trifluoroethynyl, cyclopropylethynyl, cyclobutylethynyl, and propynyl, fluoropropynyl, and chloroethynyl. In certain embodiments, R 3a is ethynyl (C2), propynyl (C3), or butynyl (C4) that is unsubstituted, or substituted with substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted carbocyclic, and substituted or unsubstituted heterocyclic. In certain embodiments, R 3a is ethynyl (C2), propyn yl (C3), or butynyl (C4) substituted with substituted phenyl. 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 amide. In certain embodiments, R 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 that is 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 phenyl which is unsubstituted or substituted with phenyl substituted with halo, alkyl, alkoxy, haloalkyl, trihaloalkyl or acyl. In certain embodiments, R 3a is ethynyl or propynyl substituted with substituted or unsubstituted carbocyclic. In certain embodiments, R 3a is ethynyl or propynyl substituted with substituted or unsubstituted cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. In certain embodiments, R 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. In certain embodiments, R 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. In certain embodiments, R 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 carbocyclic, for example, substituted or unsubstituted C 3-6 carbocyclic, substituted or unsubstituted C 3-4 carbocyclic, substituted or unsubstituted C 4-5 carbocyclic, or substituted or unsubstituted C 5-6 carbocyclic.

[0136] In certain embodiments, R 3a is a substituted or unsubstituted heterocyclic, for example, substituted or unsubstituted 3- to 6-membered heterocyclic, substituted or unsubstituted 3- to 4-membered heterocyclic, substituted or unsubstituted 4- to 5-membered heterocyclic, or substituted or unsubstituted 5- to 6-membered heterocyclic.

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

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

[0139] Further embodiments of R, such as substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl and substituted or unsubstituted alkynyl groups, are illustrated below: 3a

Chemical formula

[0140] In certain embodiments, at least one R 3c is hydrogen. In certain embodiments, at least two Rs 3c are hydrogen. In certain embodiments, each R 3c is hydrogen. In certain embodiments, at least one R 3c is a halogen (e.g., fluoro, chloro, bromo, iodo). In certain embodiments, at least two Rs 3c are a halogen (e.g., fluoro, chloro, bromo, iodo). In certain embodiments, each R 3c is a halogen (e.g., fluoro to give the group -CF3). In certain embodiments, at least one R 3c is -OR F1 (e.g., OMe or OEt). In certain embodiments, at least two Rs 3c are -OR F1 (e.g., OMe or OEt). In certain embodiments, at least one R 3c is hydrogen, F, -OMe, or -OEt. In certain embodiments, one of the Rs 3c is F, -OMe, or -OEt; the remainder 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 a halogen (e.g., fluoro, chloro, bromo, iodo). In certain embodiments, each R 3d is a halogen (e.g., fluoro, chloro, bromo, iodo). In certain embodiments, each of the Rs 3d is alkyl, e.g., each of the Rs 2c is Me. In certain embodiments, one of the Rs 3d is alkyl and the others are hydrogen, e.g., one of the Rs 3d is Me and the others are hydrogen. In certain embodiments, each of the Rs 3dOne of them is a substituted or unsubstituted carbocyclic, such as cyclopropyl or cyclobutyl, and the others are hydrogen. In certain embodiments, at least one R 3d is hydrogen, -F, -Br, -Cl, -I, -CH3, -CF3, cyclopropyl, or cyclobutyl. In certain embodiments, R 3d each instance is H. In certain embodiments, R 3d each instance is a halogen (e.g., fluoro, chloro, bromo, iodo). In certain embodiments, R 3d each instance is an alkyl, such as -CH3, -CF3, -CH2CH2Cl. In certain embodiments, R 3d each instance is a substituted or unsubstituted carbocyclic, such as cyclopropyl or cyclobutyl. In certain embodiments, R 3d is a substituted or unsubstituted cyclopropyl. In certain embodiments, R 3d each instance is hydrogen, -F, -Br, -Cl, -I, -CH3, -CF3, -CH2CH2Cl, cyclopropyl, or cyclobutyl. In certain embodiments, R 3d is Me or Cl. In certain embodiments, R 3d is a substituted or unsubstituted heterocyclic.

[0142] -X 1 -R 3b For various embodiments of group -X 1 -R 3b as generally defined above, X 1 is independently -O-, -S-, or -N(R X )-, where each instance of R X is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclic, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl, substituted or unsubstituted 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 ) and in this case, R C1 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclic, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, an oxygen protecting group when attached to an oxygen atom, a sulfur protecting group when attached to a sulfur atom, a nitrogen protecting group when attached to a nitrogen atom, or two R C1 groups together form a substituted or unsubstituted heterocyclic ring. The group -X 1 -R 3b may be in the alpha (lower) position or in the beta (upper) position, as is generally understood. In certain embodiments, the group -X 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, that is, 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 ) is.

[0146] In certain embodiments, R C1 at least one example of is hydrogen or a protecting group, that is, 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. In certain embodiments, R C1 at least one example of is hydrogen.

[0147] In certain embodiments, R C1 at least one example of is substituted or unsubstituted alkyl, for example, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 1-2 alkyl, substituted or unsubstituted C 2-3 alkyl, substituted or unsubstituted C3-4 Alkyl, substituted or unsubstituted C 4-5 Alkyl, or substituted or unsubstituted C 5-6 is alkyl. Exemplary R C1 C 1-6 Examples of 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-butanil (C5), tertiary amyl (C5), n-hexyl (C6); C 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); C 1-6 alkyl; C substituted with 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more chloro groups (e.g., -CH2Cl, -CHCl2); C 1-6 alkyl; and C substituted with alkoxy groups (e.g., -CH2OCH3 and -CH2OCH2CH3). 1-6 Examples of alkyl include, but are not limited to, these.

[0148] In certain embodiments, at least one example of R C1 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 is alkenyl.

[0149] In certain embodiments, at least one example of R C1 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 is alkynyl.

[0150] In certain embodiments, at least one instance of R C1 is substituted or unsubstituted carbocyclic, e.g., substituted or unsubstituted C 3-6 carbocyclic, substituted or unsubstituted C 3-4 carbocyclic, substituted or unsubstituted C 4-5 carbocyclic, or substituted or unsubstituted C 5-6 is carbocyclic.

[0151] In certain embodiments, at least one instance of R C1 is substituted or unsubstituted heterocyclic, e.g., substituted or unsubstituted 3- to 6-membered heterocyclic, substituted or unsubstituted 3- to 4-membered heterocyclic, substituted or unsubstituted 4- to 5-membered heterocyclic, or substituted or unsubstituted 5- to 6-membered heterocyclic.

[0152] In certain embodiments, at least one instance of R C1 is substituted or unsubstituted aryl, e.g., substituted or unsubstituted phenyl.

[0153] In certain embodiments, at least one instance of R C1 is substituted or unsubstituted heteroaryl, e.g., optionally substituted 5- to 6-membered heteroaryl.

[0154] In certain instances, two R C1 groups together form a substituted or unsubstituted heterocyclic ring, e.g., 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, by way of 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)R C1 . In certain embodiments, R 3b is -C(=O)CH3. In certain embodiments, R 3b is -C(=O)(CH2) m CO2H, and in this case m is an integer between 2 and 5 (including both end values). 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)CH2CH2C(=O)OH.

[0157] In certain embodiments, R 3b is -C(=O)OR C1 , for example, by way of 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 as follows.

[0158] In certain embodiments, R 3b is -C(=O)SR C1 ; for example, by way of 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-butanil (C5), tertiary amyl (C5) or n-hexyl (C6), -C(=O)SR C1 is as follows.

[0159] In certain embodiments, R 3b is R C1 wherein, 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-butanil (C5), tertiary amyl (C5) or n-hexyl (C6), -C(=O)N(R C1 )2, for example, -C(=O)NH2 or -C(=O)NHR 1 is as follows, or R C1 is such that two R C1 groups 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, -C(=O)N(R

[0160] In certain embodiments, R 3b is -S(=O)2R C1 or -S(=O)2OR C1 and 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-butanil (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 in each case R C1 is, 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-butanil (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 is. In certain embodiments, R 3b is -P(=O)(R C1 )(OR C1 ).

[0162] In various embodiments where Z is a group of formula (i) or (ii) In certain embodiments, Z is of formula (i): [Chemical formula] is a group of.

[0163] In certain embodiments, Z is of formula (ii): [Chemical formula] is a group of.

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

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

[0166] In certain embodiments, L 1 or L 2 is substituted or unsubstituted C1-C6 alkylene. In certain embodiments, L 1 or L 2 is substituted or unsubstituted C1-C4 alkylene. In certain embodiments, L 1 or L 2 is 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 C1 alkylene. In certain embodiments, L 1 or L 2 is a substituted or unsubstituted C2 alkylene. In certain embodiments, L 1 or L 2 is a substituted or unsubstituted C3 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 C6 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. In certain embodiments, L 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 a substituted or unsubstituted C2-C6 alkenylene. In certain embodiments, L 1 or L 2 is a substituted or unsubstituted C2-C5 alkenylene. In certain embodiments, L 1 or L 2 is a substituted or unsubstituted C2-C4 alkenylene. In certain embodiments, L 1 or L 2 is a substituted or un substituted C2-C3 alkenylene. In certain embodiments, L 1or L 2 is a substituted or unsubstituted C2 alkenylene. In certain embodiments, L 1 or L 2 is a substituted or unsubstituted C3 alkenylene. In certain embodiments, L 1 or L 2 is a substituted or unsubstituted C4 alkenylene. In certain embodiments, L 1 or L 2 is a substituted or unsubstituted C5 alkenylene. In certain embodiments, L 1 or L 2 is a 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 a substituted or unsubstituted C2-C6 alkynylene. In certain embodiments, L 1 or L 2 is a substituted or unsubstituted C2-C5 alkynylene. In certain embodiments, L 1 or L 2 is a substituted or unsubstituted C2-C4 alkynylene. In certain embodiments, L 1 or L 2 is a substituted or unsubstituted C2-C3 alkynylene. In certain embodiments, L 1 or L 2 is a substituted or unsubstituted C2 alkynylene. In certain embodiments, L 1 or L 2 is a substituted or unsubstituted C3 alkynylene. In certain embodiments, L 1 or L 2 is a substituted or unsubstituted C4 alkynylene. In certain embodiments, L 1 or L 2 is a substituted or unsubstituted C5 alkynylene. In certain embodiments, L1 or L 2 is a substituted or unsubstituted C6 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] Furthermore, in certain embodiments, L 1 or L 2 is a substituted or unsubstituted hetero-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 alkylene. In certain embodiments, L 1 or L 2 is a substituted or unsubstituted hetero-C 2-6 alkenylene, e.g., 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 alkenylene. In certain embodiments, L 1 or L 2 is a substituted or unsubstituted hetero-C 2-6 alkynylene, e.g., 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 alkynylene. 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 carbocyclic, substituted or unsubstituted heterocyclic, 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 , -S-S(=O)2R A2 , -S-S(=O)2O R A1 , -S(=O)R A2 , -SO2R A2 , -NRA1 SO2R A2 、 or -SO2N(R A1 )2, where R A1 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclic, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, an oxygen protecting group when attached to an oxygen atom, a sulfur protecting group when attached to a sulfur atom, a nitrogen protecting group when attached to a nitrogen atom, or two R A1 groups 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 carbocyclic, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, or the R A1 group and the R A2 group 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, for example, 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. In certain embodiments, R 1 is substituted or unsubstituted alkynyl.

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

[0174] In certain embodiments, R 1 is a substituted or unsubstituted aryl, such as phenyl.

[0175] In certain embodiments, R 1 is a substituted or unsubstituted heteroaryl, such as, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, isoxazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, quinolinyl, isoquinolinyl, quinazolinyl, 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 -SO-aryl, substituted or unsubstituted -SO2-aryl, substituted or unsubstituted -SO-heteroaryl, substituted or unsubstituted -SO2-heteroaryl, amino, cyano and acyl. In certain embodiments, R 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 -CF3. 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 -CF3.

[0176] In certain embodiments, R 1 is -OR A1 In certain embodiments, R 1 is -O-quinolyl, -O-isoquinolyl, -O-purinyl, each of which is unsubstituted or substituted with one or two groups independently selected from Me, F, Cl, -CN and -CF3. In certain embodiments, R 1 is -OH or -O-CO-CH2-CH2-CO2H.

[0177] In certain embodiments, R 1 is -SR A1 In certain embodiments, R 1 is -S-quinolyl, -S-isoquinolyl, or -S-purinyl, each of which is unsubstituted or substituted with one or two groups independently selected from Me, F, Cl, -CN and -CF3. 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 -S-S(=O)2R A2 In certain embodiments, R 1 is -S-S(=O)2OR A1 , for example, -S-SO3H.

[0179] As generally defined above, R 20 is 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., -CH3).

[0180] As generally defined above, R 23a and R 23b each instance of which is, independently, hydrogen, a halogen, or a substituted or unsubstituted alkyl, or R 23a and R 23b together with each other form a substituted or unsubstituted C3-C6 cycloalkyl. In certain embodiments, R 23a and R 23b each instance of which is hydrogen. In certain embodiments, one of R 23a and R 23b is a halogen, for example fluoro, and the other of R 23a and R 23b is hydrogen, a halogen, or a substituted or unsubstituted alkyl. In certain embodiments, R 23a and R 23b each instance of which is a halogen, for example fluoro. In certain embodiments, R 23a and R 23b each instance of which is, independently, a substituted or unsubstituted alkyl. In certain embodiments, each of R 23a and R 23b is Me. In certain embodiments, one of R 23a and R 23b is H. In certain embodiments, one of R 23a and R 23b is H; and the other is a substituted or unsubstituted alkyl. In certain embodiments, one of R 23a and R 23b is H; and the other is Me or Et. In certain embodiments, R 23a and R 23b together with each other form a substituted or unsubstituted C3-C6 cycloalkyl. In certain embodiments, R 23a and R 23b together with each other form a substituted or unsubstituted cyclopropyl.

[0181] In certain embodiments, the group

Chemical formula

[0182] As generally defined above, X 2 is independently -O-, -S-, or -N(R X ), where each instance of R X is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclic, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl, substituted or unsubstituted 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 carbocyclic, substituted or unsubstituted heterocyclic, 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 substituted or unsubstituted carbocyclic. In certain embodiments, R 24 is substituted or unsubstituted heterocyclic. In certain embodiments, R 24 is substituted or unsubstituted aryl. In certain embodiments, R 24 is substituted or unsubstituted heteroaryl.

[0188] In certain embodiments, R 24 is -C(=O)R E1 ; for example, R 24 is -C(=O)(CH2) p CO2H, 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 E1It is. In 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] In various embodiments where Z is a group of formula (iii), (iv), or (v) In certain embodiments, Z is a group of formula (iii), (iv), or (v):

Chemical formula

[0191] In certain embodiments, L 3 is 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 alkylene. In certain embodiments, L 3 is 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 alkenylene. In certain embodiments, L3 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 alkynylene. 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 substituted alkylene, alkenylene or alkynylene.

[0192] Furthermore, in certain embodiments, L 3 is a substituted or unsubstituted hetero C 1-6 alkylene, for example, 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 alkylene. In certain embodiments, L 3 is a substituted or unsubstituted hetero 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 alkenylene. In certain embodiments, L 3 is a substituted or unsubstituted hetero 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 5-6is an alkynylene. In any of the above examples, in certain embodiments, L 3 is unsubstituted, or is substituted with halo (e.g., fluoro) or substituted or unsubstituted C 1-6 alkyl and / or -OR Z5 and is a heteroalkylene, heteroalkenylene or heteroalkynylene.

[0193] In any of 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, at least one instance of R Z5 is substituted or unsubstituted alkyl, e.g., substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 1-2 alkyl, substituted or unsubstituted C 2-3 alkyl, substituted or unsubstituted C 3-4 alkyl, substituted or unsubstituted C 4-5 alkyl, or substituted or unsubstituted C 5-6 alkyl. Exemplary R 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-butanil (C5), tertiary amyl (C5), n-hexyl (C6); C 1-6 alkyl 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); C 1-6Alkyl; and C substituted with an alkoxy group (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 a substituted or unsubstituted alkenyl, e.g., a substituted or unsubstituted C 2-6 Alkenyl, a substituted or unsubstituted C 2-3 Alkenyl, a substituted or unsubstituted C 3-4 Alkenyl, a substituted or unsubstituted C 4-5 Alkenyl, or a substituted or unsubstituted C 5-6 Alkenyl.

[0196] In any of the above or below examples, in certain embodiments, R Z5 At least one example of is a substituted or unsubstituted alkynyl, e.g., a substituted or unsubstituted C 2-6 Alkynyl, a substituted or unsubstituted C 2-3 Alkynyl, a substituted or unsubstituted C 3-4 Alkynyl, a substituted or unsubstituted C 4-5 Alkynyl, or a substituted or unsubstituted C 5-6 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 carbocyclic, e.g., a substituted or unsubstituted C 3-6 Carbocyclic, a substituted or unsubstituted C 3-4 Carbocyclic, a substituted or unsubstituted C 4-5 Carbocyclic, or a substituted or unsubstituted C 5-6 Carbocyclic.

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

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

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

[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, and a nitrogen protecting group when attached to a nitrogen atom.

[0202] In certain embodiments, when two Rs Z5 are attached to a nitrogen atom, these two Rs Z5 groups 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.

[0203] Furthermore, in any of the above or below examples, in certain embodiments, each example of R Z6 is independently hydrogen, substituted or unsubstituted alkyl, or two Rs Z6 groups together form a C 3-6 carbocyclic ring.

[0204] In certain embodiments, at least one example of R Z6 is hydrogen.

[0205] In certain embodiments, R Z6 At least one example of 1-6 is a substituted or unsubstituted alkyl, for example, a substituted or unsubstituted C 1-2 alkyl, a substituted or unsubstituted C 2-3 alkyl, a substituted or unsubstituted C 3-4 alkyl, a substituted or unsubstituted C 4-5 alkyl, or a substituted or unsubstituted C 5-6 alkyl. Exemplary R 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-butanil (C5), tertiary amyl (C5), n-hexyl (C6); C 1-6 alkyl substituted with 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more fluoro groups (for example, -CF3, -CH2F, CHF2, difluoroethyl, and 2,2,2-trifluoro-1,1-dimethyl-ethyl); C 1-6 alkyl substituted with 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more chloro groups (for example, -CH2Cl, -CHCl2); and C 1-6 alkyl substituted with an alkoxy group (for example, -CH2OCH3 and -CH2OCH2CH3), but are not limited thereto.

[0206] In certain embodiments, two R Z6 groups together form a C 3-6 carbocyclic ring, for example, a substituted or unsubstituted cyclopropyl, a substituted or unsubstituted cyclobutyl, a substituted or unsubstituted cyclopentyl, or a 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- 5Alkyl, or substituted or unsubstituted C 5-6 is alkyl. Exemplary R Z4 C 1-6 Examples of 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-butanil (C5), tertiary amyl (C5), n-hexyl (C6); C 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 alkyl; and C substituted with an alkoxy group (e.g., -CH2OCH3 and -CH2OCH2CH3) 1-6 Examples of alkyl include, but are not limited to, these.

[0208] In certain embodiments, R Z4 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 is alkenyl

[0209] In certain embodiments, R Z4is a substituted or unsubstituted alkynyl, for example, 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, 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 carbocyclyl

[0211] In certain embodiments, R Z4 is a substituted or unsubstituted heterocyclyl, for example, substituted or unsubstituted 3- to 6-membered heterocyclyl, substituted or unsubstituted 3- to 4-membered heterocyclyl, substituted or unsubstituted 4- to 5-membered heterocyclyl, or substituted or unsubstituted 5- to 6-membered heterocyclyl

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

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

[0214] In certain embodiments, R Z4 is -OR Z5 and 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-butanil (C5), tertiary amyl (C5), or n-hexyl (C6).

[0215] In certain embodiments, R Z4 is -SR Z5 wherein 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-butanil (C5), tertiary amyl (C5), or n-hexyl (C6).

[0216] In certain embodiments, R Z4 is R Z5 wherein 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-butanil (C5), tertiary amyl (C5), or n-hexyl (C6), -N(R Z5 )2, for example, R Z4 is -NH2 or -NHR Z5 ; or alternatively, two R Z5 groups 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, -N(R Z5) It is 2.

[0217] Specific L 3 An alkylene group is contemplated herein. For example, in certain embodiments, L 3 is of the formula:

Chemical formula

[0218] Specific L 3 An alkenylene group is also contemplated herein. For example, in certain embodiments, L 3 is of the formula:

Chemical formula

[0219] Specific L 3 A heteroalkylene group is also contemplated herein, and for example, in certain embodiments, L 3 is of the formula:

Chemical 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:

Chemical formula

[0222] In certain embodiments, when w is 1, the formula:

Chemical formula

[0223] In certain embodiments, at least one instance of R Z7 is hydrogen. In any of the above instances, in certain embodiments, at least one instance of R Z7 is halo, such as fluoro. In any of the above instances, in certain embodiments, at least one instance of R Z7 is substituted or unsubstituted C 1-6 alkyl, such as substituted or unsubstituted C 1-2 alkyl, substituted or unsubstituted C 2-3 alkyl, substituted or unsubstituted C 3-4 alkyl, substituted or unsubstituted C 4-5 alkyl, or substituted or unsubstituted C 5-6 alkyl. Exemplary R 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-butanil (C5), tertiary amyl (C5), n-hexyl (C6); C 1-6 alkyl substituted with 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more fluoro groups (such as -CF3, -CH2F, CHF2, difluoroethyl, and 2,2,2-trifluoro-1,1-dimethyl-ethyl); C 1-6 alkyl substituted with 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more chloro groups (such as -CH2Cl, -CHCl2); and C 1-6 alkyl substituted with an alkoxy group (such as -CH2OCH3 and -CH2OCH2CH3), but are not limited thereto. In any of the above instances, in certain embodiments, at least one instance of R Z7 is -CH3, -CF3, -CH2CH3 (Et), or -CH(CH3)2 (iPr). In any of the above instances, in certain embodiments, at least one instance of R Z7At least one example of -OR Z5 is, for example, -OH.

[0224] In certain embodiments, at least one example of R Z8 is hydrogen. In any of the above examples, in certain embodiments, at least one example of R is halo, for example fluoro. In any of the above examples, in certain embodiments, at least one example of R Z8 is substituted or unsubstituted C Z8 alkyl, for example, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 1-2 alkyl, substituted or unsubstituted C 2-3 alkyl, substituted or unsubstituted C 3-4 alkyl, substituted or unsubstituted C 4-5 alkyl, or substituted or unsubstituted C 5-6 alkyl. Exemplary R 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-butanil (C5), tertiary amyl (C5), n-hexyl (C6); C 1-6 alkyl substituted with 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more fluoro groups (for example, -CF3, -CH2F, CHF2, difluoroethyl, and 2,2,2-trifluoro-1,1-dimethyl-ethyl); C 1-6 alkyl substituted with 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more chloro groups (for example, -CH2Cl, -CHCl2); and C 1-6 alkyl substituted with an alkoxy group (for example, -CH2OCH3 and -CH2OCH2CH3), but are not limited thereto. In any of the above examples, in certain embodiments, R Z8At least one example of is -CH3, -CF3, -CH2CH3 (Et), or -CH(CH3)2 (iPr). In any of the above examples, in certain embodiments, R Z8 At least one example of is -OR Z5 , for example -OH.

[0225] Exemplary L 3 Examples of the alkylene group include,

Chemical formula

[0226] Exemplary L 3 Examples of the alkenylene group include,

Chemical formula

[0227] Exemplary L 3 Examples of the heteroalkylene group include,

Chemical formula

[0228] In certain embodiments, the group

Chemical formula

Chemical formula

Chemical formula

[0229] In certain embodiments, the group

Chemical formula

Chemical formula

[0230] In certain embodiments, the group

Chemical formula

Chemical formula

[0231] In certain embodiments, the group

Chemical formula

Chemical formula

[0232] In certain embodiments, the group

Chemical formula

Chemical formula

[0233] R 2 、R 11a and R 11b in various embodiments As generally defined above, R 2 、R 11a and R 11b each example of which, independently, is H, -OH, halo, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclic, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -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)OR B1 、-SC(=O)SR B1 、-SC(=O)N(R B1 )2、-OS(=O)2R B2 、-OS(=O)2OR B1 、-S-S(=O)2R B2 、-S-S(=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 is -OR B1 . In certain embodiments, R 2 is -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 is F, Cl, Me, Et, n-Pr, methoxy, ethoxy, propoxy, butoxy, ethynyl, hydroxybutynyl, meth xypropynyl, chloroethynyl, or cyclopropynyl. In certain embodiments, R 2 is CF3, 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 at the beta position.

[0235] In certain embodiments, R 11a and R 11bEach example of is hydrogen. In certain embodiments, R 11a and R 11b One of them is hydrogen. In certain embodiments, R 11a and R 11b One of them is hydrogen, and the other is -OR B1 , -SR B1 , or -N(R B1 )2. In certain embodiments, R 11a and R 11b One of them is hydrogen, and the other is -OH, -OMe, amino, or dialkylamino. In certain embodiments, R 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 In various embodiments As generally defined above, each example of R 4a , R 4b , R 7a , and R 7b is independently hydrogen, -OH, halo, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclic, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -N3, -NO2, -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 、 -S-S(=O)2R B2 、 -S-S(=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 carbocyclic, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, an oxygen protecting group when attached to an oxygen atom, a sulfur protecting group when attached to a sulfur atom, a nitrogen protecting group when attached to a nitrogen atom, or two R B1 groups together form a substituted or unsubstituted heterocyclic ring; and R B2is a substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclic, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, or R B1 group and R B2 groups together form a substituted or unsubstituted heterocyclic ring); or optionally, R 4a and R 4b , and / or R 7a and R 7b each together form an oxo (=O) group.

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

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

[0240] As generally defined above, R 6a and R 6bEach of them is independently hydrogen, halo, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl, and

Chemical formula

[0241] In certain embodiments,

Chemical formula

[0242] In certain embodiments,

Chemical formula

[0243] In certain embodiments,

Chemical Structure

[0244] In certain embodiments, [Chem.] When represents a double bond, R 6a is hydrogen. In certain embodiments, [Chem.] When represents a double bond, R 6a is halo, for example fluoro. In certain embodiments, [Chem.] When represents a double bond, R 6a is substituted or unsubstituted alkyl, for example, substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 1-2 alkyl, substituted or unsubstituted C 2-3 alkyl, substituted or unsubstituted C 3-4 alkyl, substituted or unsubstituted C 4-5 alkyl, or substituted or unsubstituted C 5-6 alkyl, for example, methyl, ethyl, propyl or isopropyl. In certain embodiments, [Chem.] When represents a double bond, R 6a is substituted or unsubstituted alkenyl. In certain embodiments, [Chem.] When represents a double bond, R 6a is 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 carbocyclic, substituted or unsubstituted heterocyclic, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or -OR D1It is. In 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 carbocyclic. In certain embodiments, R 17 is substituted or unsubstituted heterocyclic. 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 is -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., -CH3).

[0247] As generally defined above, R 18 is 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., -CH3).

[0248] As generally defined above, R 19 is 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., -CH3).

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

[0250] In certain embodiments, R 14 is hydrogen, 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 (I-w):

Chemical formula

Chemical formula

Chemical formula

[0252] In certain embodiments, the compound of formula (I) is of formula (I-x):

Chemical formula

Chemical formula

Chemical formula

[0253] In certain embodiments, the compound of formula (I) is of formula (I-y):

Chemical formula

Chemical formula

Chemical formula

[0254] In certain embodiments, the compound of formula (I) is of formula (I-z):

Chemical formula

Chemical formula

Chemical formula

[0255] In certain embodiments, the compound of formula (I) is of formula (I-a1), (I-a2) or (I-a3):

Chemical formula

[0256] In certain embodiments, the compound of formula (I) is of formula (I-b1), (I-b2) or (I-b3):

Chemical formula

[0257] In certain embodiments, the compound of formula (I) is of formula (I-c1), (I-c2) or (I-c3):

Chemical formula

[0258] In certain embodiments, the compound is of formula (I-d):

Chemical formula

Chemical formula

Chemical formula

[0259] In certain embodiments, the compound is of formula (I-e):

Chemical formula

Chemical formula

Chemical formula

[0260] In certain embodiments, the compound of formula (I) is of formula (I-f):

Chemical formula

Chemical formula

Chemical formula

[0261] In certain embodiments, the compound is of formula (I-g):

Chemical formula

Chemical formula

Chemical formula

[0262] In certain embodiments, the compound is of formula (I-h):

Chemical formula

Chemical formula

Chemical formula

[0263] In certain embodiments, the compound is of formula (I-i):

Chemical formula

Chemical formula

Chemical formula

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

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0265] In certain embodiments, the compound is the following compound:

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0266] In certain embodiments, the compound is the following compound: [Chemical formula] [Chemical formula] [Chemical formula] [Chemical formula] Any one of the following, or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, tautomer, isotopologue or N-oxide thereof, or a combination thereof.

[0267] In certain embodiments, the compound is the following compound: [Chemical formula] [Chemical formula] Any one of the following, or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, tautomer, isotopologue or N-oxide thereof, or a combination thereof.

[0268] In certain embodiments, the compound is the following compound: [Chemical formula] [Chemical formula] [Chemistry] Any one of them, or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, tautomer, isotopomer or N-oxide thereof, or a combination thereof.

[0269] In certain embodiments, the compound is the following compound: [Chemistry] [Chemistry] Any one of them, or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, tautomer, isotopomer or N-oxide thereof, or a combination thereof.

[0270] In certain embodiments, the compound is the following compound: [Chemistry] Any one of them, or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, tautomer, isotopomer or N-oxide thereof, or a combination thereof.

[0271] In certain embodiments, the compound is the following compound: [Chemistry] Any one of them, or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, tautomer, isotopomer or N-oxide thereof, or a combination thereof.

[0272] In certain embodiments, the compound of the present invention is a pharmaceutically acceptable salt.

[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 a medicine, the compounds provided herein are typically administered in the form of a pharmaceutical composition. Such compositions can be prepared by methods well known in the pharmaceutical art, and such compositions contain at least one active compound.

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

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

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

[0278] The pharmaceutical compositions provided herein can be administered by various routes including oral, rectal, transdermal, subcutaneous, intravenous, intramuscular and intranasal. Depending on the desired route of delivery, the compounds provided herein are preferably formulated as either an injectable composition or an oral composition, or as an ointment, as a lotion or as a patch (all for transdermal administration).

[0279] Compositions for oral administration may take the form of bulk liquid solutions or suspensions, or the form of the drug substance powder. However, more commonly, the compositions are provided in unit dosage forms to facilitate accurate dosing. The term "unit dosage form" refers to unit dosages for human subjects and other mammals Refers to a physically distinct unit that is suitable and contains a predetermined amount of active material calculated to produce the desired therapeutic effect, together with a suitable pharmaceutical excipient. Typical unit dosage forms include filled, measured ampoules or syringes of liquid compositions or, in the case of solid compositions, pills, tablets, capsules or the like. In such compositions, the compound is usually a minor component (from about 0.1 to about 50% by weight or preferably from about 1 to about 40% by weight), and the remainder consists of various vehicles or carriers and processing aids useful in forming the desired dosage form.

[0280] Liquid forms suitable for oral administration will include a suitable aqueous or non-aqueous vehicle together with buffers, suspending and dispersing agents, coloring agents, flavoring and sweetening agents and the like. Solid forms may contain, for example, any of the following ingredients, or compounds of similar nature: binders such as microcrystalline cellulose, 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; sweetening agents such as sucrose or saccharin; or flavoring agents such as peppermint, methyl salicylate or orange flavor.

[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 and often ranges from about 0.05 to 10% by weight, and the remainder consists of 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 will typically be combined with a paraffinic or water-miscible ointment base. Alternatively, the active ingredient can be formulated into a cream using, for example, an oil-in-water cream base. Such transdermal formulations are well known in the art and generally include additional ingredients to improve the 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. Thus, transdermal delivery can be achieved using a patch of either the reservoir or porous membrane type or the solid matrix variety.

[0284] The above ingredients for orally administrable, injectable or topically administrable compositions are merely representative. Other materials as well as processing techniques and the like are set forth in Part 8 of Remington’s Pharmaceutical Sciences (17th Edition, 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 as well as processing techniques and the like are set forth in Part 8 of Remington’s The Science and Practice of Pharmacy (21st Edition, 2005, Publisher:Lippincott Williams & Wilkins), which reference is incorporated herein by reference.

[0286] The compounds of the present invention can also be administered in sustained release form or from a sustained release drug delivery system. 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 comprises water. In another embodiment, the formulation comprises a cyclodextrin derivative. The most common cyclodextrins are α-, β- and γ-cyclodextrins, each consisting of 6, 7 and 8 α-1,4-linked glucose units, optionally containing one or more substituents on their linked sugar chains, which include (but are not limited to) methylation, hydroxyalkylation, acylation and sulfoalkyl ether substitution. In certain embodiments, the cyclodextrin is a sulfoalkyl ether β-cyclodextrin, for example, sulfobutyl ether β-cyclodextrin, also known as Captisol®. See, for example, U.S. Patent No. 5,376,645. In certain embodiments, the formulation comprises hexapropyl-β-cyclodextrin. In a more particular embodiment, the formulation comprises 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 the pharmaceutically acceptable salts are those that can form non-toxic acid addition salts, i.e., salts containing pharmacologically acceptable anions, such as hydrochloride, hydroiodide, hydrobromide, nitrate, sulfate, bisulfate, phosphate, acetate, lactate, citrate, tartrate, succinate, maleate, fumarate, benzoate, para-toluenesulfonate and the like.

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

[0290] Exemplary formulation 1 - Tablet: The compound of the present invention can be mixed as a dry powder with a dry gelatin binder in a weight ratio of approximately 1:2. A small amount of magnesium stearate is added as a lubricant. The mixture is made into 240 - 270 mg tablets (80 - 90 mg of the active compound per tablet) using a tableting machine.

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

[0292] Exemplary formulation 3 - Liquid: The compound of the present invention (125 mg) can be mixed with sucrose (1.75 g) and xanthan gum (4 mg), the resulting mixture is blended and passed through a No. 10 mesh U.S. sieve, and then can be mixed with a pre - made solution of microcrystalline cellulose and sodium carboxymethylcellulose in water (11:89, 50 mg). Sodium benzoate (10 mg), flavoring and coloring agents are diluted with water and added with stirring. Then, sufficient water can be added to produce a total volume of 5 mL.

[0293] Exemplary formulation 4 - Tablet: The compound of the present invention can be mixed as a dry powder with a dry gelatin binder in a weight ratio of approximately 1:2. A small amount of magnesium stearate is added as a lubricant. The mixture is made into 450 - 900 mg tablets (150 - 300 mg of the active compound) using a tableting machine.

[0294] Exemplary formulation 5 - Injection: The compound of the present invention can be dissolved or suspended in a buffered sterile saline injectable aqueous medium to a concentration of approximately 5 mg / mL.

[0295] Exemplary formulation 6 - tablets: The compound of the present invention can be mixed as a dry powder with a dry gelatin binder in a weight ratio of approximately 1:2. A small amount of magnesium stearate is added as a lubricant. The mixture is made into tablets of 90 - 150 mg (30 - 50 mg of the active compound per tablet) using a tableting machine.

[0296] Exemplary formulation 7 - tablets: The compound of the present invention can be mixed as a dry powder with a dry gelatin binder in a weight ratio of approximately 1:2. A small amount of magnesium stearate is added as a lubricant. The mixture is made into tablets of 30 - 90 mg (10 - 30 mg of the active compound per tablet) using a tableting machine.

[0297] Exemplary formulation 8 - tablets: The compound of the present invention can be mixed as a dry powder with a dry gelatin binder in a weight ratio of approximately 1:2. A small amount of magnesium stearate is added as a lubricant. The mixture is made into tablets of 0.3 - 30 mg (0.1 - 10 mg of the active compound per tablet) using a tableting machine.

[0298] Exemplary formulation 9 - tablets: The compound of the present invention can be mixed as a dry powder with a dry gelatin binder in a weight ratio of approximately 1:2. A small amount of magnesium stearate is added as a lubricant. The mixture is made into tablets of 150 - 240 mg (50 - 80 mg of the active compound per tablet) using a tableting machine.

[0299] Exemplary formulation 10 - tablets: The compound of the present invention can be mixed as a dry powder with a dry gelatin binder in a weight ratio of approximately 1:2. A small amount of magnesium stearate is added as a lubricant. The mixture is made into tablets of 270 - 450 mg (90 - 150 mg of the active compound per tablet) using a tableting machine.

[0300] The infusion dosage level ranges 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 can also be administered to achieve an appropriate steady-state level. The maximum total dosage for a 40 to 80 kg human patient is expected not to exceed about 2 g / day.

[0301] Treatment regimens for the prevention and / or treatment of chronic conditions are usually for months or years, so oral administration is preferred for patient convenience and tolerance. For oral administration, 1 to 5 and especially 2 to 4 and typically 3 oral dosages per day are representative regimens. Using these dosing patterns, each dosage results in a compound provided herein of about 0.01 to about 20 mg / kg, and preferred dosages each result in about 0.1 to about 10 mg / kg, and especially about 1 to about 5 mg / kg.

[0302] Transdermal dosages are generally selected to provide blood levels similar to or lower than those achieved using infusion dosages.

[0303] When used to prevent the onset of CNS disorders, the compounds provided herein are administered at the dosing levels described above to patients at risk of developing the condition, typically based on and under the advice of a physician. Subjects at risk of developing a particular condition generally include subjects with a family history of the condition, or subjects identified by genetic testing or screening as particularly prone to developing the condition.

[0304] Methods of 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 than others as modulators of GRC (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 can only have much lower levels of effectiveness. In vitro and in vivo experimental data now demonstrate that the high potency of these steroids makes them therapeutically useful for the modification of brain excitability by GRC (see, e.g., Gee et al., European Journal of Pharmacology, 136:419-423 (1987); Wieland et al., Psychopharmacology 118(l):65-71 (1995)).

[0305] A variety of synthetic steroids have also been prepared as neuroactive steroids. See, for example, U.S. Patent No. 5,232,917, which discloses neuroactive steroid compounds useful for the treatment of stress, anxiety, insomnia, seizure disorders, and mood disorders, which are capable of being treated with GRC activators in a therapeutically useful manner, such as suppression. Further, these steroids have previously elicited a therapeutically beneficial effect on stress, anxiety, sleep, mood disorders and seizure disorders at other known interaction sites (e.g., barbiturates, benzodiazepines, and GABA) (e.g., Gee, K.W. and Yamamura, H.I., "Benzodiazepines and Barbiturates: Drugs for the Treatment of Anxiety, Insomnia and Seizure Disorders", in Central Nervous System Disorders, Horvell ed., Marcel-Dekker, New It has previously been demonstrated to interact at distinct sites on the GRC that are different from those described in York (1985), pp. 123 - 147; Lloyd, K.G. and Morselli, P.L., “Psychopharmacology of GABAergic Drugs”, in Psychopharmacology: The Third Generation of Progress, H.Y. Meltzer, ed., Raven Press, N.Y. (1987), pp. 183 - 195; and Gee et al., European Journal of Pharmacology, 136:419 - 423 (1987). These compounds are desirable because of their duration, potency and oral activity (along with other dosage forms).

[0306] Accordingly, the compounds and pharmaceutical compositions provided herein are used as therapeutics for the prevention and / or treatment of CNS pathologies in mammals, including humans and non - human mammals. Thus, as previously mentioned, the present invention includes within its scope the recited methods of treatment, as well as compounds for such methods, and the use of such compounds for the preparation of pharmaceuticals useful for such methods, and such methods, of course, extend to such compounds and such uses. The novel 3α - and 3β - hydroxysteroids of the present invention can act as negative allosteric modulators of the NMDA receptor and, therefore, are considered to be potentially useful for the prevention and / or treatment of a wide range of CNS pathologies.

[0307] In one aspect, the compounds of the invention are used as therapeutics, for example, for the treatment of CNS pathologies in mammals, such as schizophrenia, depression, bipolar disorder (e.g., I and / or II), schizoaffective disorder, mood disorders, anxiety disorders, personality disorders, psychosis, tic disorders, post - traumatic stress disorder (PTSD), autism spectrum disorder (ASD), dysthymia (minor 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 It is contemplated as a therapeutic agent for the treatment of traumatic brain injury (TBI), stroke, addiction disorders (e.g., opioid, cocaine and / or alcohol addiction), autism, Huntington's disease, insomnia, Parkinson's disease, withdrawal syndrome or tinnitus. In certain embodiments, the compounds of the invention are useful for the treatment of depression, anxiety, mood disorders, sleep disorders, memory disorders, traumatic brain injury, stroke, epilepsy and schizophrenia.

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

[0309] In yet another aspect, provided is the use of the compounds of the invention as a medicament, e.g., particularly in the treatment or prevention of the above-mentioned conditions and diseases.

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

[0311] In still yet another aspect, the invention provides a method of preventing, treating, ameliorating or managing a disease or condition, the method comprising administering a prophylactically or therapeutically effective amount of a compound of the invention or a pharmaceutical composition thereof to a subject in need of such prevention, treatment, amelioration or management.

[0312] In yet another aspect, the invention provides the use of a compound of the invention for the manufacture of a medicament for treating a disease or condition associated with brain excitability. In one embodiment, the disease or condition is selected from depression, anxiety, schizophrenia, sleep disorder, memory disorder and mood disorder.

[0313] In yet another aspect, the invention provides a method of treating a mammal, e.g., a human, for a disease associated with brain excitability, the method comprising treating the mammal with an effective amount of a compound of the invention or a composition thereof.

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

[0315] The compounds provided herein can be administered as a single active agent or in combination with other agents. Administration in combination can proceed by any technique obvious to those skilled in the art, including, for example, separate, sequential, simultaneous, and alternating administrations.

Examples

[0316] The following examples are provided to more fully understand the invention described herein. The synthetic and biological examples described in this application are presented to illustrate the compounds, pharmaceutical compositions, and methods provided herein and should not be construed as limiting their scope in any way.

[0317] Materials and Methods The compounds provided herein can be prepared from readily available starting materials using the following general methods and procedures. When 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 be used unless otherwise stated. Optimal reaction conditions can vary depending on the specific reactants or solvents used, but those skilled in the art can determine such conditions by routine optimization.

[0318] In addition, as will be apparent to those skilled in the art, conventional protecting groups may be necessary to prevent certain functional groups from undergoing unwanted reactions. The selection of suitable protecting groups for specific functional groups, as well as the selection of suitable protecting and deprotecting conditions, are well known in the art. For example, a very large number of protecting groups, as well as their introduction and removal, are described in T.W. Greene and P.G.M. Wuts, Protecting Groups in Organic Synthesis, 2nd Edition, Wiley, New York, 1991 and the references cited therein.

[0319] The compounds provided in this specification can be isolated and purified by known standard procedures. Such procedures include, but are not limited to, recrystallization, column chromatography or HPLC. The following schemes are presented along with a detailed description of the preparation of representative substituted biaryl amides included in this specification. A person skilled in the art of organic synthesis can prepare the compounds provided in this specification from known or commercially available starting materials and reagents.

[0320] The enantiomerically pure compounds provided in this specification 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 by any conventional technique, such as chromatographic resolution using a chiral column, TLC, or by the preparation, separation and regeneration of the desired enantiomer from diastereoisomers. For example, "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 See also Optical Resolutions 268 (ed. E. L. Eliel, Univ. of Notre Dame Press, Notre Dame, IN, 1972, Stereochemistry of Organic Compounds, Ernest L. Eliel, Samuel H. Wilen and Lewis N. Manda (1994 John Wiley & Sons, Inc.), and Stereoselective Synthesis A Practical Approach, Mihaly Nogradi (1995 VCH Publishers, Inc., NY, NY).

[0321] In certain embodiments, enantiomerically pure compounds of the invention can be obtained by reaction of a racemate with a suitable optically active acid or base. Suitable acids or bases include those described in Bighley et al., 1995, Salt Forms of Drugs and Adsorption, in Encyclopedia of Pharmaceutical Technology, 13th ed., eds. 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 references are hereby incorporated by reference in their entirety.

[0322] Depending on the specific acidic resolving agent utilized and the dissolution characteristics of the specific acid enantiomer employed, enantiomerically pure compounds can be recovered either from the crystallized diastereomers or the mother liquor. The identity and optical purity of the specific compounds thus recovered can be determined by polarimetric analysis or other analytical methods known in the art. Subsequently, those diasteroisomers can be separated, for example, by chromatography or fractional crystallization, and the desired enantiomer can be regenerated by treatment with an appropriate base or acid. The other enantiomer can likewise be obtained from the racemate or finished from the initial separation liquor. In certain embodiments, enantiomerically pure compounds can be separated from racemic compounds by chiral chromatography. A variety of chiral columns and eluents are available for use in the separation of enantiomers, and suitable separation conditions can be determined experimentally by methods known to those skilled in the art. Exemplary columns available for use in the separation of 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] Synthetic Procedures General processes for preparing the compounds of the present invention are provided as further embodiments of the present invention and are illustrated in General Schemes 1-13 and Examples 1-36. For Schemes 1-13, unless otherwise 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 in this specification. Scheme 1. Synthesis of 3α-Substituted-3β-Hydroxysteroids

Chemical Structure

Chemical Structure

Chemical Structure

Chemical Structure

Chemical Structure

Chemical Structure

Chemical Structure

Chemical Structure

Chemical Structure

Chemical Structure

Chem.

Chem.

Chem.

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

Chem.

[0325] Preparation of Compound 2: p-Toluenesulfonic acid (1.4 g, 7.28 mmol) was added to a solution of ketone 1 (50.0 g, 0.17 mol, 1.0 eq) and ethylene glycol (62 mL) in toluene (600 mL). The reaction mixture was heated under reflux overnight using a Dean-Stark trap. LCMS indicated that the starting material had been completely consumed. 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. 11H 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: Dess-Martin (81 mg, 192 mmol, 2.0 equiv) was added portionwise to a solution of Compound 2 (32 g, 96 mmol, 1.0 equiv) in dry CH2Cl2 (1200 mL) at 0 °C. The reaction mixture was then stirred at room temperature for 3 h. TLC (PE:EA = 3:1) indicated complete consumption of the starting material. The mixture was quenched with a saturated aqueous solution of NaHCO3 / Na2S2O3 = 1:3 (1 L). The organic phase was washed with brine (500 mL), dried over Na2SO4, 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 1H 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: A solution of compound 5 (96 g, 436 mmol, 1.0 equiv) in toluene (300 mL) was added dropwise with a solution of AlMe3 (109 mL, 218 mmol, 0.5 equiv, 2 M in hexane) at room temperature, and at this time, methane gas was immediately generated. The resulting mixture was stirred at room temperature for 1 hour 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 over a period of 1 hour. Then, the reaction mixture was stirred for 30 minutes, 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 hours. TLC (PE:EA = 3:1) indicated that the starting material was completely consumed. The mixture was poured into a saturated aqueous solution of NH4Cl (200 mL) and extracted with EA (150 mL × 2). The combined organic phases were dried over Na2SO4 and the solvent was evaporated to obtain the crude product. The crude product was purified by silica gel chromatography eluting with PE:EA (15:1) to obtain 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 eq) in THF (200 mL) were added aqueous HCl solution (35 mL, 1 M) and toluene (35 mL). The reaction mixture was stirred overnight at room temperature. TLC (PE:EA = 3:1) indicated the completion of the reaction. Subsequently, the reaction mixture was diluted with EA (200 mL), washed with saturated aqueous NaHCO3 (200 mL), dried over Na2SO4, and evaporated under reduced pressure to obtain the product (5.2 g, 99.2%). 1 1H NMR: (400 MHz, CDCl3) δ 5.27 (d, J = 6.8 Hz, 1H), 2.45 - 2.35 (m, 2H), 2.09 - 1.84 (m, 4H), 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 hour, INT A (4.0 g, 13.22 mmol) dissolved in THF (10 mL) was added dropwise. The reaction mixture was refluxed for 3 hours. 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 obtain a 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. 11H 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 CH2Cl2 (5 mL) was added Et2AlCl (4 mL, 4.0 mmol, 1 M in toluene) dropwise with stirring at 25 °C, and then the reaction mixture was stirred overnight. TLC (PE / EA = 3 / 1) indicated complete consumption of the starting materials. The solution was washed with saturated aqueous NaHCO3 (5 mL), dried over Na2SO4, concentrated under reduced pressure to obtain 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 1H NMR: (400 MHz, CDCl3) δ 7.03-6.97 (m, 1H), 5.86 (dd, J1=1.2Hz, J2=15.6Hz, 1H), 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: Pd / C (5%, 40 mg) was added to a solution of compound A_001_2 (192 mg, 0.5 mmol, 1.0 equiv) in EA (5 mL) under N2. The suspension was degassed under vacuum and purged several times with H2. Then, the mixture was stirred at 30 °C for 1 h under a H2 balloon. TLC (PE:EA = 3:1) indicated that 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 afford 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: To a solution of compound A_001_3 (150 mg, 0.386 mmol, 1.0 equiv) in THF (5 mL) was added MeLi (2 mL, 3.200 mmol, 8.3 equiv, 1.6 M in THF) dropwise at -78 °C under nitrogen. After addition, the reaction mixture was warmed to -40 °C and stirred for 1 h. TLC (PE:EA = 3:1) indicated that 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 a crude product, which was purified by silica gel chromatography eluting with PE:EA (10:1) to afford the product (91 mg, 60%) as a white powder. 11H 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 [Chemical formula]

[0335] Preparation of Compound A_003_1: A solution of t-BuOK (3.70 g, 33.00 mmol, 10.0 eq) in dry THF (10 mL) was added dropwise to a solution of PPh3PEtBr (12.25 g, 33.00 mmol, 10.0 eq) in THF (15 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 eq) in THF (10 mL) was added dropwise, and the resulting mixture was mixed at 70 °C for 4 h. TLC (PE:EA = 3:1) indicated 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 phases were dried over Na2SO4 and concentrated under vacuum. 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 1H 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, 3 H), 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: 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 stirred at 0 °C, and a solution of Et2AlCl (12.8 mL, 12.8 mmol, 4.0 equiv, 1 M in toluene) was added dropwise. Then, the reaction mixture was warmed to room temperature and stirred overnight. TLC (PE:EA = 5:1) indicated complete consumption of the starting material. The mixture was quenched with saturated aqueous NaHCO3 (30 mL) and extracted with DCM (30 mL × 2). The combined organic phases were dried over Na2SO4 and concentrated under vacuum. The residue was purified by silica gel chromatography (eluent: PE:EA = 10:1) to afford 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, 1 H), 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, 3 H), 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: Pd / C (30 mg, 5%) was added to a solution of compound A_003_2 (160 mg, 0.40 mmol) in EA (15 mL). The reaction mixture was stirred at room temperature for 2 hours under H2 at 15 psi. TLC (PE / EA = 3 / 1) indicated that the starting material was completely consumed. The reaction mixture was then filtered and the filtrate was evaporated under reduced pressure to obtain 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, 3 H), 0.95 - 0.93 (m, 2H), 0.70 - 0.66 (m, 2 H).

[0338] Preparation of compound ST - 200 - A - 003: MeLi (1.56 mL, 2.50 mmol, 1.6 M in THF) was added dropwise to a solution of compound A_003_2 (100 mg, 0.25 mmol, 1.0 equivalent) in dry THF (1 mL) at -78 °C, and the mixture was stirred at this temperature for 30 minutes. TLC (PE:EA = 3:1) indicated that 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 obtain the crude product, which was purified by silica gel chromatography eluting with PE:EA (10:1) to obtain 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 [Chemical formula]

[0340] Preparation of Compound INTE: A solution of A_001_1 (2.0 g, 6.66 mmol, 1.0 equivalent) in THF (10 mL) was added dropwise to a solution of 9-BBN (0.5 M in THF, 133 mL, 66.6 mmol, 10.0 equivalents) under an ice bath. The reaction mixture was heated to 60 °C and stirred for 20 hours. The mixture was cooled to 0 °C, and 10% aqueous NaOH solution (20 mL) and then 30% aqueous H2O2 solution (30%, 10 mL) were added. The mixture was stirred at 0 °C for 2 hours and then extracted with EA (30 mL × 3). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, and concentrated under vacuum to obtain a crude product, which was purified by flash column chromatography eluting with PE / EA (10 / 1) to give INTE (1.0 g, 47%) as a white solid. 1 H NMR: (400 MHz, CDCl3) δ 5.30 (d, J = 5.2 Hz, 1H), 3.75 - 3.71 (dd, J1 = 10.4 Hz, J2 = 6.8 Hz, 1H), 3.58 - 3.53 (dd, J1 = 10.4 Hz, J2 = 7.6 Hz, 1H), 2.43 - 2.41 (d, J = 10.4 Hz, 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 an ice bath was added Dess-Martin reagent (265 mg, 0.628 mmol, 2.0 equiv). The reaction mixture was warmed to room temperature and stirred for 2 hours. The mixture was poured into a solution of NaS2O3 (4.5 g) and NaHCO3 (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 Na2SO4, and concentrated under vacuum 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: A mixture of INT B (100 mg, 0.316 mmol, 1.0 equiv) and Ph3P=CHCOOCH3 (634 mg, 1. 89 mmol, 6.0 equiv) in toluene (10 mL) was stirred at 80 °C for 3 hours and then concentrated under vacuum. 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 at room temperature for 2 hours under H2 (1 atm). The mixture was filtered and the filtrate was concentrated under vacuum 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 was added CH3Li (1.6 M in THF, 1 mL, 1.7 mmol, 10.0 equiv) dropwise under nitrogen. The reaction mixture was warmed to room temperature and stirred for 1 hour. 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 under vacuum to give a 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

Chemical Structure

[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), CeCl3·7H2O (2.45 g, 6.58 mmol, 1.0 equiv) was added. The reaction mixture was stirred at room temperature for 10 min. Then, NaBH4 (0.50 g, 13.16 mmol, 2.0 equiv) was added slowly and the resulting mixture was stirred at room temperature for 30 min. TLC (PE / EA = 3 / 1) indicated the completion of the reaction. 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 afford 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) indicated the completion of the reaction. The reaction mixture was washed with saturated aqueous NaHCO3 (20 mL) and brine (20 mL), dried over Na2SO4 and evaporated to dryness to give a crude product. The residue was purified by silica gel chromatography eluting with PE:EA (15:1) to afford the desired product (274 mg, 43%) as a white solid. 11H 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: 5% Pd / C (50%, 25 mg) was added to a solution of Compound A_011_1 (50 mg, 0.128 mmol) in EA (5 mL) under argon. The suspension was degassed under vacuum and purged several times with H2. The mixture was stirred at room temperature for 4 h under a H2 balloon. TLC (PE / EA = 3 / 1) indicated that the starting material had been 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 1H 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 dropwise MeLi (1 mL, 1.60 mmol, 10.0 equiv, 1.6 M in Et2O) at -78 °C under N2. The reaction mixture was stirred at -78 °C for 30 minutes and then warmed to room temperature for an additional 30 minutes. TLC (PE / EA = 3 / 1) indicated complete consumption of the starting material. The reaction mixture was quenched with saturated aqueous NH4Cl solution (5 mL). The resulting solution was extracted with EA (5 mL × 3). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, and concentrated under vacuum. The residue was purified by silica gel chromatography eluting with PE:EA (10:1) to afford the target product (25 mg, 42%) as a white solid. 1 1H NMR: (400 MHz, CDCl3) δ 5.29 (d, J = 4.8 Hz, 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 [Chemical formula]

[0351] To a solution of INTE (150 mg, 0.471 mmol, 1.0 equiv) in DMSO (1 mL), KOH (53 mg, 0.942 mmol, 2.0 equiv) and 2,2-dimethyloxirane (340 mg, 4.717 mmol, 10.0 equiv) were added. The reaction mixture was stirred at 50 °C for 16 h. TLC (PE / EA = 3 / 1) indicated that the starting material had been completely consumed. The mixture was cooled to room temperature, diluted with ethyl acetate (20 mL), and washed with saturated aqueous NH4Cl solution (10 mL × 2) and water (10 mL × 2). The organic phase was dried over sodium sulfate and concentrated under vacuum to obtain the crude product, which was purified by column chromatography and subsequently by preparative HPLC to give the pure product ST- 200-A-013 (14 mg, 8%). 1 H NMR (400 MHz, CDCl3) δ 5.30 (d, J = 5.2 Hz, 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

Chemical Structure

[0353] A solution of compound INT D (150 mg, 0.49 mmol, 1.0 equiv) and 2,2-dimethyloxirane (1.5 g, 20.8 mmol, 42.0 equiv) in DMSO (3 mL) was added with KOH (56 mg, 1.0 mmol, 2.0 equiv), and then the reaction mixture was stirred at 60 °C for 5 h. TLC (PE:EA = 3:1) indicated the completion of the reaction. The solution was cooled to room temperature, diluted with water (10 mL), and extracted with EA (5 mL × 2). The combined organic layers were concentrated under reduced pressure to obtain a 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 = 5.2 Hz, 1H), 3.33 (t, J = 8.0 Hz, 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

Chemical formula

[0355] To a solution of compound A_001_3 (150 mg, 0.39 mmol, 1.0 equiv) in THF / H2O (4 mL, 1 / 1) was added LiOH (90 mg, 2.20 mmol, 5.6 equiv). The reaction mixture was stirred at room temperature overnight. TLC (PE / EA = 3 / 1) indicated 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, 4 H), 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

Chemical Structure

[0357] Preparation of Compound 7: p-Toluenesulfonic acid (418 mg, 2.20 mmol) was added to a solution of ketone 6 (16.7 g, 52.71 mmol, 1.0 equiv) and ethylene glycol (20 mL) in toluene (450 mL). The reaction mixture was heated under reflux overnight using a Dean-Stark trap. LCMS indicated that the starting material had been completely consumed. 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: Dess-Martin (45.0 g, 105.42 mmol, 2.0 equiv) was added portionwise to a solution of compound 7 (19.0 g, 52.71 mmol, 1.0 equiv) in dry CH2Cl2 (700 mL) at 0 °C. The reaction mixture was then stirred at room temperature for 3 h. TLC (PE / EA = 3 / 1) indicated that the starting material had been completely consumed. The mixture was deactivated with saturated aqueous NaHCO3 / Na2S2O3 (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. 11H 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: A solution of MAD (158 mL, 158 mmol, 3.0 equiv., prepared by the method described for the synthesis of ST-200-A-001, 1 M in toluene) was added dropwise to a solution of Compound 8 (19.0 g, 52.71 mmol, 1.0 equiv.) in toluene at -78 °C under nitrogen. The reaction mixture was stirred at this temperature for 30 minutes. A solution of MeMgBr (53 mL, 159 mmol, 3.0 equiv., 3 M in Et2O) was added dropwise at -78 °C. The reaction mixture was warmed to -40 °C and stirred at this temperature for 3 hours. TLC (PE:EA = 3:1) indicated complete consumption of the starting material. The mixture was poured into a saturated aqueous solution of 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 obtain 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 1H 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) was added aqueous HCl solution (10 mL, 1 M) and acetone (10 mL). The reaction mixture was stirred at room temperature overnight. TLC (PE:EA = 3:1) indicated the completion of the reaction. Thereafter, the reaction mixture was diluted with EA (50 mL), washed with saturated aqueous NaHCO3 solution (50 mL × 2), dried over Na2SO4, and evaporated under reduced pressure to obtain the product (2.10 g, 88.2%) as a white powder. 1 1H 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), NaBH4 (160 mg, 4.2 mmol, 2.0 feq) was added portionwise in 5 portions. The reaction mixture was stirred at room temperature for 1 h. TLC (PE / EA = 3 / 1) indicated complete consumption of the starting material. 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 afford 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) were added TEA (867 mg, 8.585 mmol, 5.0 equiv) and DMAP (63 mg, 0.515 mmol, 0.3 equiv). Then, BzCl (961 mg, 6.867 mmol, 4.0 equiv) was 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 extracted with DCM (1 0 mL×3). The combined organic layers were washed with saturated aqueous NaHCO3 (10 mL) and brine (10 mL), dried over sodium sulfate and concentrated in vacuo. The residue was purified by chromatography on silica gel eluting with PE:EA (15:1) to afford the product (360 mg, 46.6%) as a white solid (write solid), which was subjected to SFC separation to afford the 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

Chemical Structure

[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 N2. The suspension was degassed under vacuum and purged several times with H2. Then, the mixture was stirred at 60 °C for 24 h under a hydrogen pressure of 50 psi. TLC (PE:EA = 3:1) indicated the completion of the reaction. The suspension was filtered through a pad of celite, and the pad was washed with ethanol (5 mL × 2). The combined filtrate was concentrated to dryness to obtain 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. 11H 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

Chemical Structure

[0366] Pd / C (10 mg) was added to a solution of compound ST-200-A-003 (40.0 mg, 0.10 mmol, 1.0 equivalent) in EtOH (30 mL). The mixture was stirred at 60 °C overnight under a hydrogen pressure of 50 psi. 1 1H NMR indicated 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 afford the 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 1H 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, 3 H), 0.81 (s, 3 H), 0.65 (s, 3 H). 1 1H 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 [Chemical Structure Diagram]

[0368] Preparation of Compound 10: A mixture of Compound 1 (28.0 g, 0.097 mol, 1.0 equivalent) and Pd / C (3.5 g) in ethanol (400 mL) was hydrogenated at room temperature overnight under a hydrogen pressure of 40 psi. The suspension was filtered through a pad of Celite and washed with ethanol (20 mL × 3). The combined filtrate was concentrated to dryness to obtain 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), 1.96 - 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 equivalent) and ethylene glycol (30 mL) in toluene (300 mL), p - toluenesulfonic acid Luhong acid (0.7 g, 3.64 mmol) was added. Using a Dean-Stark trap, the reaction mixture was heated under reflux overnight. LCMS indicated that the starting material had been completely consumed. The mixture was cooled to room temperature, diluted with ethyl acetate (250 mL), and washed with saturated aqueous sodium bicarbonate solution (100 mL × 2) and brine (100 mL × 2). The organic phase was dried over sodium sulfate and concentrated under vacuum to obtain 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, 3 H), 0.80 (s, 3 H), 0.72-0.61 (m, 1 H).

[0370] Preparation of Compound 12: Dess-Martin oxidant (76.0 g, 0.180 mol, 2.0 equiv) was added to a solution of Compound 11 (30.0 g, 0.90 mol, 1.0 equiv) in dry DCM (300 mL) at 0 °C. The reaction mixture was stirred at 0 °C for 30 minutes and then at room temperature for 2 hours. LCMS indicated that the starting material had been completely consumed. The mixture was deactivated with a saturated aqueous mixture of NaHCO3 / Na2SO3 (200 mL, 1 / 3), and then diluted with DCM (250 mL). The organic layer was washed with saturated aqueous sodium bicarbonate solution (100 mL × 2) and brine (100 mL × 2), dried over sodium sulfate, and concentrated under vacuum to obtain 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 minutes 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 hours. LCMS indicated that the starting material was completely consumed. The reaction mixture was poured into a saturated aqueous solution of 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 under vacuum. The residue was purified by silica gel chromatography eluting with PE:EA (15:1) to afford 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 NaHCO3 until no more CO2 was evolved. 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 under vacuum to afford the product INT G (14.0 g, 46.0 mmol, 100%) as a white solid. 1 1H 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: A solution of PPh3CH3Br (1.4 g, 3.94 mmol, 5.0 equivalents) in THF (10 mL) was added dropwise with a solution of t - BuOK (442 mg, 3.94 mmol, 5.0 equivalents) in THF (5 mL) at room temperature. After stirring for 1 hour, a solution of INT G (0.2 g, 0.657 mmol, 1.0 equivalent) in THF (5 mL) was added drop by drop. The reaction mixture was refluxed for 3 hours, then cooled to room temperature, quenched with saturated aqueous NH4Cl solution (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 under vacuum to obtain a 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 1H NMR: (400 MHz, CDCl3) δ 4.62 (d, J = 6.4 Hz, 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: A solution of Compound 14 (0.95 g, 3.14 mmol, 1.0 equiv) in THF (10 mL) was added dropwise to a solution of 9-BBN (0.5 M in THF, 50 mL, 25.00 mmol, 8.0 equiv) under an ice bath. 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) and then 30% aqueous H2O2 solution (10 mL) were added. The resulting mixture was stirred at 0 °C for 2 h and then extracted with EA (10 mL × 2). The combined organic layers were washed with brine (10 mL), dried over sodium sulfate, and concentrated under vacuum to obtain a 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 = 10.4 Hz, J2 = 6.8 Hz, 1H), 3.56 - 3.52 (dd, J1 = 10.4 Hz, J2 = 7.6 Hz, 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: Dess-Martin reagent (1.3 g, 3.12 mmol, 2.0 equiv) was added to a solution of INT I (500 mg, 1.56 mmol, 1.0 equiv) in DCM (20 mL) under an ice bath. The reaction mixture was warmed to room temperature and stirred for 2 h. The mixture was poured into a solution of NaS2O3 (5 g) and NaHCO3 (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 under vacuum to obtain a 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 at 80 °C for 3 h. The mixture was concentrated under vacuum and the residue was purified by flash column chromatography (eluent: PE / EA = 12 / 1) to afford 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 at room temperature under H2 (1 atm) for 2 h. The mixture was filtered and the filtrate was concentrated under vacuum to give the 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 was added dropwise CH3Li (1.6 M in THF, 1.6 mL, 2.6 mmol, 10.0 equiv) under nitrogen. The reaction mixture was warmed to room temperature and stirred for 1 h. Saturated aqueous NH4Cl solution (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 under vacuum to give a crude product, which was purified by flash column chromatography (eluent: PE / EA = 8 / 1) to afford 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

Chemical Structure

[0380] Preparation of Compound INT H: CeCl3·7H2O (1.22 g, 3.28 mmol, 1.0 equiv) was added to a solution of INT G (1.00 g, 3.28 mmol, 1.0 equiv) in MeOH (20 mL) and THF (8 mL). Then, NaBH4 (0.25 g, 6.56 mmol, 2.0 equiv) was added in 5 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 under vacuum to give the desired product (0.97 g, 97%) as a white solid. 1 H NMR: (400 MHz, 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: NMM (830 mg, 8.21 mmol, 5.0 equiv) and methyl propiolate (690 mg, 8.21 mmol, 5.0 equiv) were added to a solution of INT H (500 mg, 1.63 mmol, 1.0 equiv) in DCM (20 mL). The mixture was stirred at room temperature for 16 h, then washed with water (30 mL) and brine (30 mL), dried over sodium sulfate, and concentrated under vacuum. The residue was purified by silica gel chromatography eluting with PE: EA (15:1) to give the product (500 mg, 78.6%) as a white solid. 11H NMR: (400 MHz, 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: Pd / C (10%, 50 mg) was added to a solution of C_011_1 (500 mg, 1.289 mmol, 1.0 equivalent) in EA (20 mL). The suspension was degassed under vacuum and purged several times with H2. The mixture was stirred at 30 °C for 16 h under a hydrogen pressure of 30 psi. TLC (PE / EA = 3 / 1) indicated the completion of the reaction. The suspension was filtered through a pad of celite, and the pad was washed with EA (20 mL × 5). The combined filtrate was 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 equivalent) in dry THF (1 mL), MeLi (1.3 mL, 2.048 mmol, 8.0 equivalents) was added dropwise at - 78 °C under N2. The resulting mixture was stirred at this temperature for 0.5 h, then left to warm to room temperature and stirred at this temperature for an additional 1 h. TLC (PE / EA = 3 / 1) indicated the completion of the reaction. 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 under vacuum. 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. 11H NMR (400 MHz, CDCl3) δ 3.86 (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

Chemical Structure

[0385] To a solution of INT I (150 mg, 0.469 mmol, 1.0 equiv) in DMSO (1 mL) were 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) indicated 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 solution (10 mL × 2) and water (10 mL × 2). The organic phase was dried over sodium sulfate and concentrated in vacuo to give a crude product, which was purified by column chromatography and subsequently by preparative HPLC to give the pure product. ST - 200 - C - 013 (26 mg, 15.8%). 1 1H 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

Chemical Structure

[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 a hydrogen pressure of 50 psi for 16 h. The reaction solution was filtered through a pad of Celite, and the filtrate was concentrated under vacuum. The residue was purified by silica gel chromatography eluting with PE:EA (20:1) to afford ST-200-C-017 (21 mg) and ST-200-C-017A (4.6 mg) as white solids. 1 1H NMR (ST-200-C-017): (400 MHz, CDCl3) δ 3.73-3.71 (m, 1H), 3.31 (t, J = 8.4 Hz, 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). 11H NMR (ST-200-C-017a): (400 MHz, CDCl3) δ 3.33 (t, J = 8.4 Hz, 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 [Chemical formula]

[0389] Preparation of Compound BB-2: 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 under nitrogen. Methylmagnesium chloride (22% (w / w) in THF, 19.5 mL, 58.1 mmol) was added dropwise. Stirring at 0 °C was continued for 15 minutes, and the reaction mixture was allowed to warm to room temperature and stirring was continued for 2 hours. A saturated aqueous solution of NH4Cl (5 mL) was added slowly. A precipitate formed and it 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 under vacuum. 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: Under nitrogen, a solution of oxalyl chloride (0.622 mL, 7.26 mmol) in dichloromethane (19 mL) in an oven-dried flask was cooled to -78 °C. Dimethyl sulfoxide (0.60 mL, 8.47 mmol) was slowly added. After 25 minutes, a solution of BB-2 (0.470 g, 1.209 mmol) in CHCl3 (38 mL) was added dropwise over 25 minutes. The solution was stirred at -78 °C for 2.5 hours. Triethylamine (3.36 mL, 24.19 mmol) was added dropwise at -78 °C. Stirring was continued for 15 minutes. The cooling bath was removed and stirring was continued for 10 minutes. A saturated aqueous solution of NH4Cl (10 mL) was added and the reaction mixture was stirred for 5 minutes. 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 Na2SO4 and the solvent was removed under vacuum. Flash chromatography (heptane, 5% - 30% EtOAc) gave 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 Compound 3-α-OH A2 and 3-β-OH A2: In a flame-dried flask in a glove box, THF (degassed, 3 mL) was added to anhydrous cerium(III) chloride (0.319 g, 1.29 mmol). The suspension was stirred overnight at room temperature. The white fine suspension was taken out of the glove box. THF (dry, 1 mL) was added and the (thew) mixture was stirred for 15 minutes at room temperature under argon. The white fine suspension was cooled to -78 °C under argon. At this temperature, 1.6 M methyllithium in Et2O (0.79 mL, 1.27 mmol) was added dropwise one by one. A yellow suspension formed and it was stirred at -78 °C for 1.5 hours. A solution of BB-3 (0.100 g, 0.259 mmol) in THF (dry, 2 mL) was added dropwise one by one over 5 minutes. 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 colorless transparent solution. EtOAc (10 mL) was added. The mixture was left to warm to room temperature. The layers were separated and the aqueous layer was extracted with EtOAc (2 × 10 mL). The combined organic layers were dried over sodium sulfate and the solvent was removed under vacuum. Compound A2 (3α-OH) (33 mg, 0.082 mmol; 63.5%) and Compound A2 (3β-OH) (13 mg, 0.032 mmol; 25.0%) were obtained by flash chromatography (H, 5% - 20% EtOAc). (3α-OH): 1 1H-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 1H-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 Compounds 3-alpha-A28 and 3-beta-A28 [Chemical formula]

[0393] In a flame-dried flask inside a glove box, THF (degassed, 1.5 mL) was added to anhydrous cerium(III) chloride (0.207 g, 0.841 mmol). The suspension was stirred at room temperature overnight. The white fine suspension was taken out of the glove box and stirred under argon for 15 minutes. The white fine suspension was cooled to -78 °C under argon. At this temperature, 0.5 M ethyl lithium in benzene / cyclohexane (1.68 mL, 0.841 mmol) was added dropwise. A yellow suspension formed and was stirred at -78 °C for 30 minutes. A solution of BB-3 (0.065 g, 0.168 mmol) in THF (dry, 1.5 mL) was added dropwise over 3 minutes. The color of the reaction mixture changed from yellow to brown. The reaction mixture was stirred at -78 °C for 45 minutes. A brown milky suspension was obtained and TLC (H.E; 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 minutes. 5% aqueous AcOH (2 mL) was added. After the addition of brine (2 mL), the reaction mixture became a colorless transparent solution. EtOAc (5 mL) was added. The mixture was left to warm to room temperature. The layers were separated and the aqueous layer was extracted with EtOAc (2 × 5 mL). The combined organic layers were dried over sodium sulfate and the solvent was removed under vacuum. 60 mg of a white solid was obtained. Separation on silica gel impregnated with AgNO3 (H, 5% - 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 1H-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 1H-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

Chemical formula

[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 h. 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 deactivate the excess acetic anhydride. After stirring for 1 h, the white solid was filtered and washed thoroughly with water (9 × 250 mL). The white solid was dried in a 40 °C vacuum oven over the weekend in the presence of a beaker full of sodium hydroxide to obtain the product B6a (24.63 g, 54.2 mmol, yield = 99%) as a white powder. B6a was used as such in subsequent experiment(s). 1 1H NMR (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, stirred vigorously, and the solution prepared above was added dropwise over 2.5 hours under a nitrogen atmosphere to keep the solution pale yellow. The resulting solution was stirred overnight and then filtered. TLC [heptane (9): ethyl acetate (1)] showed complete conversion to a slightly lower eluting product after vanillin staining. The solution was concentrated in vacuo until dry. The residue was purified by column (900 g) chromatography [heptane (95): diisopropyl ether (5)]. The fractions containing the pure product were collected and evaporated under reduced pressure to give B6b (9.06 g, 14.7 mmol, yield = 50%) as a white powder. B6b 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 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. An ozone - rich oxygen stream was passed through the solution for 1 hour using a sintered glass atomizer. The color of the reaction mixture became slightly blue. TLC [heptane (9): ethyl acetate (1)] was carried out under UV 254Complete consumption of the starting material was shown below. The ozonolysis reaction was stopped. The reaction mixture was immediately poured into a mixture of glacial acetic acid (33.2 mL, 581 mmol) and zinc powder (21.57 g, 330 mmol) and stirred overnight at room temperature. The solution was filtered and washed successively with water (200 mL), 10% aqueous sodium bicarbonate solution (200 mL), 5% aqueous sodium hydroxide solution (200 mL) and brine (200 mL), and then dried over anhydrous sodium sulfate. The solvent was evaporated to give crude cholesta-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 give cholesta-5-en-3β-ol-22-al B6c (2.58 g, 6.93 mmol, 53% yield) as a white powder. B6c was used as such 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. Under an argon atmosphere, 1.6 M n-BuLi (1.342 mL, 2.15 mmol) in hexane was added to a solution of (methoxymethyl)triphenyl-phosphonium chloride (0.789 g, 2.30 mmol) in dry THF (6.4 mL) at -10 °C. The solution was stirred at room temperature for 5 minutes, and then B6c (0.2 g, 0.54 mmol) in dry THF (1.3 mL) was added. The mixture was stirred at room temperature for 30 minutes. The reaction mixture was poured into a saturated aqueous solution of NH4Cl (75 mL) and extracted twice with CH2Cl2 (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 1H NMR (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 hours. Water (60 mL) was added to the reaction mixture to deactivate the excess acetic anhydride. After stirring for 1 hour, the white solid was filtered and washed thoroughly with water (9 × 250 mL). The white solid was dried in a vacuum oven at 40 °C overnight to obtain the 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. 0.1 M aqueous HCl (1 mL, 0.10 mmol) was added to a solution of B6e (0.111 g, 0.28 mmol) in acetone (9 mL). The resulting white suspension was stirred at room temperature for 1 hour, then at 70 °C for 1 hour, and then at room temperature overnight. The mixture was heated at 70 °C for 2 hours, cooled to room temperature, and diluted with H2O (50 mL). The reaction mixture was evaporated to dryness and co-evaporated with MeOH (50 mL) and CH2Cl2 (10 mL). This appears to be a mixture of the desired product and dimethyl acetal. 0.1 M aqueous HCl (1 mL, 0.10 mmol) was added to a solution of this mixture (0.12 g, 0.28 mmol) in acetone (10 mL). The resulting white suspension was stirred at 70 °C for 2 hours. 1,4-Dioxane (5 mL) was added, thereby dissolving the insoluble material. The reaction mixture was further heated at 70 °C for 2 hours, allowed to stand and cool to room temperature, and stirred over the weekend. The reaction mixture was diluted with H2O (50 mL) and extracted with CH2Cl2 (3 × 50 mL). The combined organic layers were washed with brine, dried over Na2SO4, and the solvent was evaporated. The crude product was co-evaporated with CH2Cl2 (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 NaClO2 (0.028 g, 0.313 mmol) and K2HPO4 (0.043 g, 0.313 mmol) in deionized water (3 mL) was slowly added to the solution over 5 minutes, and the mixture was stirred at 0 °C for 2 hours. The mixture was stirred at room temperature overnight. Additional NaClO2 (0.028 g, 0.313 mmol) and K2HPO4 (0.043 g, 0.313 mmol) dissolved in H2O (3 mL) were slowly added to the reaction mixture, and stirring was continued for 2 hours. The reaction mixture was poured into a saturated aqueous solution of 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 triturated in petroleum ether 40-60 (10 mL). The white solid was filtered, washed twice with petroleum ether 40-60 (5 mL), and dried in air for 0.5 hour to give B6g (0.089 g, 0.22 mmol, yield = 78%). 0-60 (10 mL). The white solid was filtered, washed twice with petroleum ether 40-60 (5 mL), and dried in air for 0.5 hour to give B6g (0.089 g, 0.22 mmol, yield = 78%). 1 1H NMR (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. Oxalyl chloride (0.048 mL, 0.56 mmol) and DMF (catalytic amount) were added to a solution of B6g (0.09 g, 0.224 mmol) in CH2Cl2 (10 mL). The solution was stirred at room temperature for 2 hours. 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 co-evaporated with THF twice 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 at 0 °C for 1 hour and then at room temperature for 2 hours. 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 3 times with CH2Cl2 (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. 11H NMR (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 [Chemical formula]

[0405] Preparation of Compound B7d: Cholesta-5-en-3β-ol-22-al B7c (1.33 g, 3.57 mmol) was dissolved in t-butanol (75 mL), dry tetrahydrofuran (15 mL), and 2-methyl-2-butene (13.22 mL, 125 mmol). The solution was stirred and cooled in an ice bath. To the solution, a freshly prepared solution of sodium chloride (0.355 g, 3.93 mmol) and potassium phosphate, monobasic, p.a. (0.534 g, 3.93 mmol) in deionized water (45 mL) was slowly added over 30 minutes, and the mixture was stirred at 0 °C for 2 hours. The ice bath was removed, the temperature of the mixture was raised to room temperature, and the mixture was 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, p.a. (0.534 g, 3.93 mmol) dissolved in water (45 mL) were slowly added to the reaction mixture, and stirring was continued for 2 hours. TLC [heptane (2): ethyl acetate (1)] showed complete conversion to the lower eluting product after vanillin staining. The reaction mixture was poured into a 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 hour. 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 hour to give B7d (1.27 g, 3.26 mmol, yield = 91%) as a white powder. B7d was used as such in subsequent experiment(s). 11H NMR (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 hour. A sample of the reaction was poured into methanol and evaporated to dryness, and analyzed by TLC [heptane (3): ethyl acetate (1)], and the TLC showed complete conversion to the methyl ester after vanillin staining. The reaction mixture was diluted with methanol (50 mL, 1234 mmol, dried over molecular sieves), 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)]. The 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 as such 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 dry tetrahydrofuran (2.6 mL) and cooled in an ice bath under argon. After 20 minutes, 3.0 M methylmagnesium chloride in THF (0.861 mL, 2.58 mmol) was added dropwise by syringe. Some gas evolution was observed. The reaction mixture was stirred for 0.5 hour, then the cooling bath was removed and stirring was continued for 2 hours. TLC [heptane (3): ethyl acetate (1)] showed complete conversion of the starting material to two lower eluting products after vanillin staining. Stirring was continued for 1 hour. The reaction mixture was poured into a saturated aqueous solution of ammonium chloride (75 mL) with stirring and extracted with dichloromethane (3 × 50 mL). The extracts were combined, dried over sodium sulfate and evaporated. The residue was triturated in methanol (2 mL) for 0.5 hour, the white solid was filtered and the filter residue was washed with methanol (2 mL). Little material remained on the filter and most of it was present in the filtrate. The filtrate and filter residue were combined and purified by flash column chromatography [heptane (99 => 70): ethyl acetate (1 => 30)]. The product-containing fractions were collected and evaporated under reduced pressure. The residue was dried in a vacuum oven at 40 °C overnight to give B7 (0.044 g, 0.122 mmol, yield = 47%) as a white solid. 1H NMR (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). 1 1H NMR (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

Chemical formula

[0409] Preparation of Compound B8b: In a flame-dried round-bottom flask, a solution of NaHMDS (0.070 mL, 0.349 mmol) in dry tetrahydrofuran (1 mL) was added to a solution of silyloxyphosphonate B8a (0.143 g, 0.403 mmol) in dry tetrahydrofuran (1 mL) at -78 °C. The solution was stirred at -78 °C for 15 minutes under an argon atmosphere. Then, a solution of cholesta-5-en-3β-ol-22-al B7c (0.1 g, 0.268 mmol) in dry tetrahydrofuran (1 mL) was slowly added via syringe. The reaction mixture was slowly warmed 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 solution (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 under vacuum. The residue was purified by flash column (4 g) chromatography [heptane (100 => 90): diisopropyl ether (0 => 10)]. The 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 the E isomer and the Z isomer 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 anhydrous acetonitrile (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) indicated that there was little conversion of the starting material to a product with an unclear product mass. Dichloromethane (2 mL) was added to the reaction mixture, which immediately turned into a yellow transparent 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 hours. TLC [heptane (3): ethyl acetate (1)] indicated only a little starting material present in the reaction mixture, but the reaction mixture was diluted with dichloromethane (75 mL) and washed with a saturated aqueous solution of sodium hydrogen carbonate (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 the remaining starting material (visible only by TLC). The product-containing fractions were collected and evaporated under reduced pressure to obtain 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 left 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)] still did not show complete consumption of the starting material after vanillin staining. The acetic acid group is removed [M - CH3COOH + H] + , LCMS - ELSD (base): At room temperature, 47% product = 3.43 with m / z(+) = 421, which is 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 1H NMR (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 dry tetrahydrofuran (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 slowly added. Some gas evolution was observed. The reaction mixture was cooled and stirred for 1 hour. TLC [heptane (3): ethyl acetate (1)] showed complete conversion mainly 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 thr...

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