NZ747452B2 - Neuroactive steroids and methods of use thereof - Google Patents

Description

NEUROACTIVE STEROIDS AND METHODS OF USE THEREOF Related Applications This application is a divisional application of New Zealand Patent Application No. 712141, filed on 13 March 2014, and is related to International Patent Application No. , filed on 13 March 2014, and claims priority under 35 U.S.C. § l19(e) to U.S. Provisional Patent Application U.S.S.N 61/779,735, filed on 13 March 2013, each of which is incorporated herein by reference in its entirety.

Background of the Invention Brain excitability is defined as the level of arousal of an animal, a continuum that ranges from coma to sions, and is regulated by various neurotransmitters. In general, neurotransmitters are responsible for regulating the conductance of ions across neuronal membranes. At rest, the neuronal membrane possesses a potential (or membrane voltage) of approximately -70 m V, the cell interior being negative with t to the cell exterior. The potential ge) is the result of ion (K+, Na+, Cl-, organic anions) balance across the neuronal semipermeable membrane. Neurotransmitters are stored in presynaptic vesicles and are released as a result of neuronal action ials. When released into the synaptic cleft, an excitatory chemical transmitter such as acetylcholine will cause membrane depolarization (change of potential from -70 m V to -50 m V). This effect is mediated by naptic nicotinic ors which are stimulated by acetylcholine to increase the membrane permeability of Na+ ions. The reduced membrane potential increases the probability of ting a postsynaptic action ial, which amounts to an increase in neuronal excitability.

NMDA receptors are highly expressed in the CNS and are involved in excitatory synaptic ission. Activating these receptors contributes to synaptic plasticity in some circumstances and excitotoxicity in others. These receptors are ligand-gated ion channels that admit Ca2+ after g of the ransmitters glutamate and glycine, and are fundamental to excitatory neurotransmission and normal CNS function. NMDA receptors are heteromeric complexes comprised of NRI, NR2, and/or NR3 subunits and possess distinct recognition sites for exogenous and nous ligands. These recognition sites include binding sites for glycine, and glutamate agonists and modulators. Positive modulators may be useful as therapeutic agents with potential clinical uses as cognitive enhancers and in the treatment of psychiatric disorders in which glutamatergic ission is reduced or defective (see, e.g., Horak et al., J. of Neuroscience, 2004, 24(46), 10318-10325). In contrast, negative modulators may be useful as therapeutic agenst with ial clinical uses in the treatment of psychiatric disorders in which glutamatergic transmission is pathologically increased (cg, ent resistant depression). [0004} Neuroactive steroids such as nolone sulfate (PS) have been shown to exert direct modulatory effects on several types of neurotransmitter receptors, such as GABAA, glycine, AMPA, kainate, and NMDA receptors. NMDA receptors are positively modulated by PS; however, the degree of modulation varies considerably, e.g., depending upon the t composition of the receptor. [0005} In addition to PS, several other 3B-hydroxy steroids have been shown to potentiate NMDA receptors (see, e.g., Paul et al., J. Pharm. and Exp. Ther. 1994, 271, 677-682).

Recently, a 3B-hydroxy-ergost-5—ene steroid derivative, referred to as Org—l was reported as positive modulator ofNMDA (NRla/NRZA). Org-l was found to selectively modulate NMDA over GABAA (see, e.g., Madau et al., Program No. 6132/1387. 2009 cience Meeting Planner. Chicago, IL: Society for Neuroscience, 2009; k et al., Program No. 613.1/B86. 2009 Neuroscience Meeting r. Chicago, IL: Society for Neuroscience, 2009; Paul el al., J.

Neurosci. 2013, 33, l7290—l7300).

HO Org- l [0006} New and improved neuroactive steroids are needed that modulate brain excitability for the prevention and ent of CNS-related conditions. The compounds, compositions, and methods described herein are directed toward this end.

Summary of the Invention [0007} The inventors of the t invention, during an on-going exploration of Org-I analogs for NMDA modulation, a portion of which is described in PCT/U82012/054261, incorporated herein by nce, discovered several specific combination of elements which provides NMDA modulators with comparatively superior properties. For example, as shown in Table 1, compounds bearing a beta-hydrogen at C5 are disfavored compared to compounds bearing either alpha—hydrogen C5 or double bond across C5-C6 due to loss of potentiation of the NMDA receptor. The l of the methyl at C21 also results in significant loss ofNMDA potentiation. Disubstitution at C3 is expected to increase metabolic stability of these nds and is thus a preferrred e of the invention. nation on the Cu side chain has been shown to improve potency and limit maximum potentiation of the NMDA receptor when tested as high as '1 uM concentration of compound. A secondary or tertiary terminal alcohol on the C17 side chain has been shown to to improve potency and limit maximum potentiation of the NMDA receptor when tested as high as 1 uM concentration of nd, and is thus a preferred feature of the invention, with a preference for bulkier groups at the terminating end containing 2-3 carbons, or a group comprising fluorine substitution. Such properties are expected limit the risk of inducing glutamate driven neurotoxicity relative to compounds that achieve a r maximum potentiation of the NMDA receptor. Compounds of the present invention encompass various ations of these specified features to provide superior NMDA modulators. [0008} Thus, in one aspect, provided are compounds of Formula (I), and pharmaceutically acceptable salts thereof; wherein: R1 is substituted or unsubstituted aliphatic; R2 is hydrogen, halogen, tuted or unsubstituted Cmalkyl, substituted or unsubstituted cyclopropyl, or —ORA2, wherein RA2 is en or substituted or unsubstituted alkyl; R321 is hydrogen or —ORA3, wherein RA3 is en or substituted or unsubstituted. alkyl, and R3b is hydrogen; or R38 and R3b are joined to form an oxo (=0) group; R4 is hydrogen, substituted or unsubstituted alkyl, or halogen; X is —C(RX)3— or —O-, wherein RX is hydrogen or fluorine, or one RX group and R5b are joined to form a double bond; each ce of RSH and R5b is independently hydrogen or fluorine; R6a is a non-hydrogen group selected from the group consisting of substituted and unsubstituted alkyl, substituted and unsubstituted alkenyl, substituted and unsubstituted alkynyl, substituted and unsubstituted carbocyclyl, substituted and unsubstituted heterocyclyl, substituted and unsubstituted aryl, and substituted and unsubstituted heteroaryl group, wherein the non- hydrogen group is optionally substituted with fluorine; and R6b is hydrogen or a tuted or unsubstituted alkyl group optionally substituted with fluorine; — represents a single or double bond, provided ifa single bond is present, then the hydrogen at C5 is in the alpha configuration; and further provided that: ( i) at least one of RX, R53, and RSb is fluorine; or (2) at least one of R611 and R6b is a non—hydrogen group substituted with a e; or (3) R6a is a non-hydrogen group comprising between two and ten carbon atoms. [0009} In another aspect, provided are pharmaceutical itions comprising a compound ofFormula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically able excipient. [0010} In yet another aspect, provided is a method for ng or preventing a CNS- related ion associated with NMDA modulation sing administering to a subject in need thereof an effective amount of a compound or ceutically acceptable salt thereof, or pharmaceutical composition thereof in certain embodiments, the CNS-related condition is an adjustment disorder, anxiety disorder (including obsessive-compulsive disorder, aumatic stress disorder, social , and generalized anxiety disorder), cognitive disorder (including Alzheimer’s disease and other forms of ia), dissociative disorder, eating disorder, mood er (including depression, bipolar disorder, and dysthymic disorder), schizophrenia or other psychotic disorder (including schizoaffective disorder), sleep disorder (including insomnia), substance abuse-related disorder, personality disorder (including obsessive-compulsive personality disorder), autism spectrum disorders (including those involving mutations to the Shank group of proteins), neurodevelopmental disorder (including Rett syndrome), pain (including acute and chronic pain), seizure disorder (including status ticus and monogenic forms of epilepsy such as Dravet’s disease, and Tuberous Sclerosis complex (TSC)), stroke, traumatic brain injury, movement disorder (including gton’s disease and Parkinson’s disease) and tinnitus. In certain ments, these nds can be used to induce sedation or anesthesia. [0011} Other objects and advantages will become apparent to those skilled in the art from a consideration of the g Detailed Description, Examples, and Claims.

Definitions Chemical Definitions [0012} Definitions of specific functional groups and al terms are described in more detail below. The chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook ofC/temistigv and Physics, 75th Ed., 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 reactivity, are described in Thomas Sorrell, Organic Chemistry, University Science Books, Sausalito, 1999; Smith and March, March ’5 ed Organic Chemistry, 5th n, John Wiley & Sons, Inc, New York, 2001‘, Larock, Comprehensive Organic Transformations, VCH Publishers, Inc, New York, 1989; and Carruthers, Some Modern iMetlzods ofOrganic iS‘jvtnthesis, 3rd Edition, Cambridge University Press, Cambridge, 1987. [0013} Compounds described herein can comprise one or more asymmetric centers, and thus can exist in various isomeric forms, e.g, enantiomers and/or diastereomers. For example, the nds described herein can be in the form of an individual enantiomer, diastereomer or geometric , or can be in the form of a mixture of stereoisomers, including racemic mixtures and es enriched in one or more stereoisomer. s can be isolated from mixtures by methods known to those skilled in the art, including chiral high pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or preferred isomers can be prepared by asymmetric ses. See, for example, Jacques et al, Enantiomers, Race/notes and Resolutions (Wiley Interscience, New York, 1981); Wilen et al, Tetrahedron 3312725 (1977); Eliel, Stereoclzemistry ofCarbon Con'zpozmds (McGraw—Hill, NY, 1962); and Wilen, Tables of‘Resolving Agents and Optical Resolutions p. 268 (EL. Eliel, Ed, Univ. of Notre Dame Press, Notre Dame, IN 1972). The invention additionally encompasses compounds described herein as individual isomers substantially free of other isomers, and alternatively, as mixtures of various isomers. [0014} When a range of values is listed, it is intended to encompass each value and sub— range within the range. For example “CH alkyl” is intended to encompass, C1, C2, C3, C4, C5, C6, C1 6, Ci 5, C1 47 C1 3, Ci 2. C2 6) C275, C274, C273, C343; C375, C34, C44,; C475, and Cir alkyl. [0015} The following terms are intended to have the meanings presented therewith below and are useful in understanding the ption and ed scope of the present invention.

When bing the invention, which may include compounds, pharmaceutical compositions containing such compounds and methods of using such compounds and compositions, the following terms, if present, have the following meanings unless otherwise indicated. It should also be understood that when described herein any of the es defined forth below may be substituted with a variety of substituents, and that the respective tions are intended to include such substituted moieties within their scope as set out below. Unless otherwise stated, the term “substituted” is to be defined as set out below. It should be further understood that the terms “groups” and als” can be considered interchangeable when used herein. The articles “a” and “an” may be used herein to refer to one or to more than one (Le. at least one) of the grammatical objects of the article. By way of example “an analogue” means one analogue or more than one analogue. [0016} atic” refers to an alkyl, alkenyl, alkynyl, or carbocyclyl group, as defined herein. [0017} “Alkyl” refers to a l of a straight—chain or branched saturated hydrocarbon group having from l to 20 carbon atoms (“C n20 alkyl”). In some ments, an alkyl group has I to 12 carbon atoms (“C142 alkyl”). In some embodiments, an alkyl group has 1 to 10 carbon atoms (“CHo alkyl”). In some embodiments, an aikyi group has l to 9 carbon atoms (“Chg alkyl”). In some embodiments, an alkyl group has 1 to 8 carbon atoms (“C1_g alkyl”). In some embodiments, an alkyl group has 1 to 7 carbon atoms (“CH alkyl”). In some embodiments, an alkyl group has l to 6 carbon atoms (“CM alkyl”, also referred to herein as “lower alkyl”). In some embodiments, an alkyl group has 1 to 5 carbon atoms (“C 1-5 alkyl”). In some embodiments, an alkyl group has I to 4 carbon atoms (“CH ). In some embodiments, an alkyl group has 1 to 3 carbon atoms (“CH ). In some embodiments, an alkyl group has 1 to 2 carbon atoms (“CH alkyl”). In some embodiments, an alkyl group has 1 carbon atom (“C1 alkyl”). In some ments, an alkyl group has 2 to 6 carbon atoms (“CH ). Examples of C145 alkyl groups include methyl (C1), ethyl (C2), n—propyl (C3), isopropyl (C3), n—butyl (C4), tert—butyl (C4), sec—butyl (C4), iso—butyl (C4), n—pentyl (C5), 3—pentanyl (C5), amyl (C5), neopentyl (C5), 3—methyl—2—butanyl (C5), tertiary amyl (C5), and n—hexyl (C6).

Additional es of alkyl groups include n—heptyl (C7), n—octyl (C3) and the like. Unless otherwise specified, each instance of an alkyl group is independently optionally substituted, z".e., unsubstituted (an “unsubstituted alkyl”) or substituted (a “substituted alkyl”) with one or more substituents; e.g., for instance from 1 to 5 substituents, l to 3 substituents, or 1 substituent. In certain embodiments, the alkyl group is unsubstituted CHO alkyl (cg, —Cl—l3). In certain embodiments, the alkyl group is tuted C1_ l0 alkyl. Common alkyl abbreviations include Me (—CH3), Et (-CHZCH3), iPr (-CH(CH3)2), nPr (-CHgCH2CH3), n-Bu (—CHZCHZCHZCHg), or i- Bu (-CHZCH(CH3)2). [0018} As used herein, “alkylene,” “alkenylene,” and “alkynylene,” refer to a divalent radical of an alkyl, alkenyl, and alkynyl group, respectively. When a range or number of carbons is ed for a particular “alkylene,37 ‘4alkenylene,” and “alkynylene” group, it is understood that the range or number refers to the range or number of carbons in the linear carbon divalent chain. “Alkylene,” “alkenylene,” and ylene” groups may be substituted or unsubstituted with one or more substituents as described herein. [0019} “Alkylene” refers to an alkyl group wherein two hydrogens are d to provide a divalent radical, and which may be tuted or unsubstituted. Unsubstituted alkylene groups include, but are not d to, methylene (-CH2-), ethylene (-CH2CH2-), propylene (- CH3CH2CH2-), butylene (-CHgCHzCHzCH2-), ene (-CHZCHZCHgCHgCHg-L hexylene (- CH;CH2CH2CH2CH2CH2—), and the like. Exemplary substituted alkylene groups, e.g., substituted with one or more alkyl (methyl) groups, include but are not limited to, substituted ene (-CH(CH3)-, (-C(CH3)2—), tuted ethylene (-CH(CH3)CH2-,—CH2CH(CH3)-, - C(CH3)2CH2-,—CH2C(CH3)2-), substituted propylene (-CH(CH3)CH2CH2-, (CH3)CH2-, - CH3CH3CH(CH3)-, -C(CH3)3CH2CH2-, -CH2C(CH3)2CH2-, -CH2CH2C(CH3)2—), and the like. [0020} “Alkenyl” refers to a radical of a straight—chain or branched hydrocarbon group having from 2 to 20 carbon atoms, one or more carbon—carbon double bonds (eg, 1, 2, 3, or 4 carbon—carbon double bonds), and optionally one or more carbon—carbon triple bonds (e.g., l, 2, 3, or 4 carbon—carbon triple bonds) (“€240 alkenyl”). In certain embodiments, alkenyl does not contain any triple bonds. In some ments, an alkenyl group has 2 to 10 carbon atoms (“C2, m alkenyl”). In some embodiments, an alkenyl group has 2 to 9 carbon atoms (“C329 alkenyl”).

In some embodiments, an alkenyl group has 2 to 8 carbon atoms (“C24, alkenyl”). In some embodiments, an alkenyl group has 2 to 7 carbon atoms (“C227 alkenyl”). In some embodiments, an alkenyl group has 2 to 6 carbon atoms (“CH alkenyl”). In some embodiments, an l group has 2 to 5 carbon atoms (“C24 alkenyl”). In some embodiments, an alkenyl group has 2 to 4 carbon atoms (“CH alkenyl”). In some embodiments, an l group has 2 to 3 carbon atoms (“CH alkenyl”). In some embodiments, an alkenyl group has 2 carbon atoms (“C2 alkenyl”). The one or more carbon—carbon double bonds can be internal (such as in nyl) or terminal (such as in l—butenyl). Examples of C24, alkenyl groups include ethenyl (C2), 1— propenyl (C3), 2—propenyl (C3), l—butenyl (C4), 2—butenyl (C4), butadienyl (C4), and the like.

Examples ofCH alkenyl groups include the aforementioned C24 alkenyl groups as well as yl (C5), pentadienyl (C5), hexenyl (C6), and the like. Additional examples of alkenyl include heptenyl (C7), octenyl (Cg), octatrienyl (C3), and the like. Unless ise specified, each instance of an alkenyl group is independently optionally substituted, i.e., unsubstituted (an “unsubstituted alkenyl”) or tuted (a “substituted alkenyl”) with one or more substituents e.g., for instance from 1 to 5 substituents, l to 3 substituents, or I substituent. In certain embodiments, the l group is unsubstituted C2210 alkenyl. In certain embodiments, the alkenyl group is substituted C2210 alkenyl. [0021} “Alkenylene” refers to an alkenyl group wherein two hydrogens are removed to provide a divalent radical, and which may be substituted or unsubstituted. Exemplary unsubstituted nt alkenylene groups include, but are not limited to, ethenylene (—CH=CH-) and propenylene (e.g., -CH=CHCHg-, -CH2-CH=CH-). Exemplary substituted alkenylene groups, e.g., substituted with one or more alkyl (methyl) , include but are not limited to, substituted ethylene 3)=CH-, -CH=C(CH3)-), substituted propylene (e.g., - C(CH3)=CHCH2-, CH3)CH2-, -CH=CHCH(CH3)-, -CH=CHC(CH3)z-, -CH(CH3)- CH=CH-,-C(CH3)g-CH=CH-, -CHg-C(CH3)=CH-, -CH2-CH=C(CH3)-), and the like. [0022} “Alkynyl” refers to a radical of a straight—chain or branched hydrocarbon group having from 2 to 20 carbon atoms, one or more carbon—carbon triple bonds (e.g., l, 2, 3, or 4 carbon—carbon triple bonds), and optionally one or more —carbon double bonds (e.g., l, 2, 3, or 4 carbon—carbon double bonds) (“C340 alkynyl”). In certain embodiments, alkynyl does not contain any double bonds. In some embodiments, an alkynyl group has 2 to 10 carbon atoms (“C240 alkynyl”). In some embodiments, an alkynyl group has 2 to 9 carbon atoms (“C229 alkynyl”). In some embodiments, an l group has 2 to 8 carbon atoms (“CH3 alkynyl”). In some embodiments, an alkynyl group has 2 to 7 carbon atoms (“C24 alkynyl”). In some embodiments, an l group has 2 to 6 carbon atoms (“C24, alkynyl”). In some embodiments, an alkynyl group has 2 to 5 carbon atoms (“CH l”). In some embodiments, an l group has 2 to 4 carbon atoms (“C24 alkynyl”). In some embodiments, an alkynyl group has 2 to 3 carbon atoms (“CH alkynyl”). In some embodiments, an alkynyl group has 2 carbon atoms (“CZ alkynyl”). The one or more carbon—carbon triple bonds can be internal (such as in 2— butynyl) or terminal (such as in l—butynyl). Examples of C24 alkynyl groups include, Without limitation, ethynyl (C3), ynyl (C3), 2—propynyl (C3), I—butynyl (C4), 2—butynyl (C4), and the like. es of CH, alkenyl groups e the aforementioned C24 alkynyl groups as well as pentynyl (C5), hexynyl (C6), and the like. Additional examples of alkynyl include heptynyl (C7), octynyl (C3), and the like. Unless otherwise specified, each ce of an l group is independently optionally substituted, 17.6., unsubstituted (an “unsubstituted alkynyl”) or substituted (a “substituted alkynyl”) with one or more tuents; e.g., for instance from I to 5 substituents, l to 3 substituents, or I tuent. In certain embodiments, the alkynyl group is unsubstituted C2210 alkynyl. In certain embodiments, the alkynyl group is substituted C2710 alkynyl. [0023} “Alkynylene” refers to a linear alkynyl group wherein two hydrogens are removed to provide a divalent radical, and 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.

The term “heteroalkyl,” as used herein, refers to an alkyl group, as defined herein, which further comprises 1 or more (e.g., I, 2, 3, or 4) heteroatoms (eg. oxygen, sulfur, nitrogen, boron, silicon, phosphorus) within the parent chain, wherein the one or more heteroatoms is inserted between adjacent carbon atoms within the parent carbon chain and/or one or more heteroatoms is inserted between a carbon atom and the parent molecule, i.e., n the point of attachment. In certain embodiments, a heteroalkyl group refers to a saturated group having from I to 10 carbon atoms and l, 2, 3, or 4 heteroatoms (“heteron 10 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having I to 9 carbon atoms and l, 2, 3, or 4 heteroatoms (“heteroCng alkyl”). In some embodiments, a heteroalkyl group is a saturated group having I to 8 carbon atoms and l, 2, 3, or 4 heteroatoms (“heteroCHg alkyl”). In some embodiments, a heteroalkyl group is a ted group having I to 7 carbon atoms and l, 2, 3, or 4 heteroatoms (“heteroCH alkyl”). In some embodiments, a heteroalkyl group is a group having 1 to 6 carbon atoms and l, 2, or 3 heteroatoms (“heteroCM alkyl”). In some embodiments, a heteroalkyl group is a saturated group having I to 5 carbon atoms and l or 2 heteroatoms (“heteroC 1_5 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 4 carbon atoms and lor 2 atoms (“heteroCH alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 3 carbon atoms and I heteroatom (“heteroC1_3 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 2 carbon atoms and l heteroatom (“heteroCH alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 carbon atom and l heteroatom (“heteroC1 aikyl”). In some embodiments, a heteroalkyl group is a saturated group having 2 to 6 carbon atoms and I or 2 heteroatoms (“heterosz alkyl”). Unless otherwise ied, each instance of a heteroalkyl group is ndently unsubstituted (an “unsubstituted alkyl”) or substituted (a “substituted heteroalkyl”) with one or more substituents. In certain embodiments, the heteroalkyl group is an unsubstituted heteroCHO alkyl. In certain embodiments, the heteroalkyl group is a substituted heteroC 1,10 alkyl. [0025} The term “heteroalkenyl,” as used , refers to an alkenyl group, as defined , which r comprises one or more (e.g., l, 2, 3, or 4) heteroatoms (6g, oxygen, sulfur, nitrogen, boron, silicon, phosphorus) n the one or more heteroatoms is inserted between adjacent carbon atoms within the parent carbon chain and/or one or more heteroatoms is inserted between a carbon atom and the parent molecule, 128., between the point of attachment. In certain embodiments, a heteroalkenyl group refers to a group having from 2 to ID carbon atoms, at least one double bond, and I, 2, 3, or 4 heteroatoms (“heterng_10 alkenyl”). In some embodiments, a heteroalkenyl group has 2 to 9 carbon atoms at least one double bond, and l, 2, 3, or 4 heteroatoms (“heteroCH alkenyl”). In some ments, a heteroalkenyl group has 2 to 8 carbon atoms, at least one double bond, and l, 2, 3, or 4 heteroatoms roC3_8 alkenyl”). In some embodiments, a alkenyl group has 2 to 7 carbon atoms, at least one double bond, and l, 2, 3, or 4 heteroatoms (“heteroCzq alkenyl”). In some embodiments, a heteroalkenyl group has 2 to 6 carbon atoms, at least one double bond, and 1, 2, or 3 heteroatoms (“heteroCH l”). In some embodiments, a heteroalkenyl group has 2 to 5 carbon atoms, at least one double bond, and I or 2 heteroatoms (“heteroCH alkenyl”). In some ments, a heteroalkenyl group has 2 to 4 carbon atoms, at least one double bond, and Ior 2 heteroatoms (“heteroCH alkenyl”). In some embodiments, a heteroalkenyl group has 2 to 3 carbon atoms, at least one double bond, and l heteroatom (“heteroCH aikenyl”). In some embodiments, a heteroalkenyl group has 2 to 6 carbon atoms, at least one double bond, and I or 2 heteroatoms (“heteroCH alkenyl”). Unless otherwise specified, each instance of a heteroalkenyl group is independently unsubstituted (an “unsubstituted heteroalkenyl”) or substituted (a “substituted heteroalkenyl”) with one or more substituents. In certain embodiments, the heteroalkenyl group is an tituted heteroCHo alkenyl. In certain embodiments, the heteroalkenyl group is a substituted heteroCHo alkenyl. [0026} The term “heteroalkynyl,” as used herein, refers to an alkynyl group, as defined herein, which further comprises one or more (eg, I, 2, 3, or 4) heteroatoms (tag, oxygen, sulfur, nitrogen, boron, silicon, phosphorus) wherein the one or more heteroatoms is inserted n adjacent carbon atoms within the parent carbon chain and/or one or more heteroatoms is inserted between a carbon atom and the parent molecule, i.€., between the point of attachment. In certain embodiments, a heteroalkynyl group refers to a group having from 2 to 10 carbon atoms, at least one triple bond, and l, 2, 3, or 4 heteroatoms (“heteroCHo alkynyl”). In some ments, a heteroalkynyl group has 2 to 9 carbon atoms, at least one triple bond, and I, 2, 3, or 4 heteroatoms (“heteroC2,9 alkynyl”). In some embodiments, a heteroalkynyl group has 2 to 8 carbon atoms, at least one triple bond, and 1, 2, 3, or 4 heteroatoms (“heteroCH l”). In some embodiments, a heteroalkynyl group has 2 to 7 carbon atoms, at least one triple bond, and I, 2, 3, or 4 heteroatoms (“heteroC-H l”). In some embodiments, a heteroalkynyl group has 2 to 6 carbon atoms, at least one triple bond, and l, 2, or 3 heteroatoms (“heteroC2,6 alkynyl”). In some embodiments, a heteroaikynyl group has 2 to 5 carbon atoms, at least one triple bond, and I or 2 heteroatoms (“heteroC2_5 alkynyl”). In some embodiments, a alkynyl group has 2 to 4 carbon atoms, at least one tripie bond, and Ior 2 heteroatoms (“heteroCH alkynyl”). In some embodiments, a alkynyl group has 2 to 3 carbon atoms, at least one triple bond, and I heteroatom (“heteroCH alkynyl”). In some embodiments, a heteroalkynyl group has 2 to 6 carbon atoms, at least one triple bond, and l or 2 atoms roCH alkynyl”). Unless otherwise specified, each instance of a heteroalkynyl group is independently unsubstituted (an “unsubstituted lieteroalkynyl”) or substituted (a “substituted heteroalkynyl”) with one or more substituents. In certain ments, the heteroalkynyl group is an unsubstituted heteroCHo alkynyl. In certain embodiments, the heteroalkynyl group is a substituted heteroCHo alkynyl. [0027} As used , “alkylene,” “alkenylene, .5, LCalkynylene,” “heteroalkylene,” oalkenylene,” and “heteroalkynylene,” refer to a divalent radical of an alkyl, alkenyl, alkynyl group, heteroalkyl, heteroalkenyl, and heteroalkynyi group respectively. When a range 7) 6L 7) c: or number of carbons is provided for a particular “alkylene, alkenylene, alkynylene,” oalkylene,” “heteroalkenylene,” or “heteroalkynyiene,” group, it is understood that the range or number refers to the range or number of carbons in the linear carbon divalent chain.

“Alkylene,” “alkenylene, 7'! LCalkynylene,” “heteroalkylene,” “heteroalkenylene,” and oalkynylene” groups may be substituted or unsubstituted with one or more substituents as described . [0028} “‘Aryl” refers to a l of a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (8g, having 6, 10, or 14 1t ons shared in a cyclic array) having 6—14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system (“C644 aryl”). In some embodiments, an aryl group has six ring carbon atoms (“C6 aryl”; ag phenyl). In some embodiments, an aryl group has ten ring carbon atoms (“C 10 aryl”; e.g., naphthyl such as l—naphthyl and 2—naphthyl). In some embodiments, an aryl group has fourteen ring carbon atoms (“C14 aryl”; 6g, cyl). “Aiyl” also es ring systems wherein the aryl ring, as defined above, is fused with one or more yclyl or heterocyclyl groups wherein the radical or point of attachment is on the aryl ring, and in such ces, the number of carbon atoms continue to designate the number of carbon atoms in the aryl ring system. Typical aryl groups include, but are not limited to, groups derived from aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, coronene, fluoranthene, fluorene, hexacene, hexaphene, hexalene, acene, s-indacene, indane, , naphthalene, octacene, octaphene, octalene, ovalene, penta—2,4-diene, pentacene, pentalene, pentaphene, perylene, phenalene, phenanthrene, picene, pleiadene, pyrene, pyranthrene, rubicene, triphenylene, and trinaphthalene. Particularly aryl groups include phenyl, naphthyl, indenyl, and tetrahydronaphthyl. Unless otherwise specified, each instance of an aryl group is independently optionally substituted, 126., unsubstituted (an “unsubstituted aryl”) or substituted (a “substituted aryl”) with one or more substituents. In certain embodiments, the aryl group is unsubstituted C6714 aryl. In certain embodiments, the aryl group is tuted CH4 aryl. [0029} In certain embodiments, an aryl group substituted with one or more of groups selected from halo, C1-C3 alkyl, C1-C3 kyl, cyano, hydroxy, C1-C8 alkoxy, and amino. [0030} Examples of representative substituted aryls include the following R57 and R57 R57 . wherein one of R56 and R57 may be hydrogen and at least one of R56 and R57 is each independently ed from C1—C3 alkyl, C1-C3 haloalkyl, 4—10 ed heterocyclyl, yl, C 1-Cg alkoxy, heteroaryloxy, alkylamino, arylamino, heteroarylamino, NngCOng, NRSSSOR59NRSSSOQR5", COOalkyl, COOaryl, CONR58R59, CONRSSOR”, NR58R59, SOZNRS‘gRSQ, S-alkyl, SOalkyl, SOgalkyl, Saryl, SOaryl, SOgaryl; or R56 and R57 may be joined to form a cyclic ring (saturated or unsaturated) from 5 to 8 atoms, optionally ning one or more heteroatoms selected from the group N, O, or S. R60 and R61 are independently hydrogen, C1-C3 alkyl, C1-C4 haloalkyl, C3-Cm cycloalkyl, 4-10 menibered heterocyclyl, C6-C10 aryl, substituted (Ts-Cm aryl, 5-10 membered heteroaryl, or substituted 5-10 membered heteroaryl . [0031} Other representative aryl groups having a fused heterocyclyl group include the following: @1171, £61 mpg? n each W is selected from C(R66 2, NR“, 0, and S; and each Y is selected from carbonyl, NR“, 0 and S; and R66 is independently hydrogen, C g-Cg alkyl, C3-C10 cycloalkyl, 4—10 membered heterocyclyl, C6-C10 aryl, and 5—10 membered heteroaryl. [0032} “Fused aryl” refers to an aryl having two of its ring carbon in common with a second aryl or heteroaryl ring or with a carbocyclyl or heterocyclyl ring. [0033} “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. [0034} oaryl” refers to a radical of a 5—10 membered monocyclic or bicyclic 4n+2 aromatic ring system (e.g., having 6 or 10 TC electrons shared in a cyclic array) having ring carbon atoms and 1—4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen and sulfur (“5—10 membered heteroaryl”). In heteroaryl groups that contain one or more en atoms, the point of attachment can be a carbon or nitrogen atom, as valency permits, Heteroaryl ic ring s can include one or more heteroatoms in one or both rings. “Heteroaryl” es ring systems wherein the heteroaryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups wherein the point of attachment is on the heteroaryl ring, and in such instances, the number of ring members continue to designate the number of ring members in the heteroaryl ring system. “Heteroaryl” also includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more aryl groups n the point of attachment is either on the aryl or heteroaryl ring, and in such instances, the number of ring members designates the number of ring members in the fused (aryl/heteroaryl) ring system. Bicyclic heteroaryl groups wherein one ring does not contain a heteroatom (cg, indolyl, quinolinyl, olyl, and the like) the point of attachment can be on either ring, i.e., either the ring bearing a heteroatom (rag, 2—indolyl) or the ring that does not contain a heteroatom (6g, 5—indolyl). [0035} In some embodiments, a heteroaryl group is a 5—10 membered aromatic ring system having ring carbon atoms and 1—4 ring heteroatoms provided in the aromatic ring system, n each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5—10 membered heteroaryl”). In some embodiments, a heteroaryl group is a 5—8 membered aromatic ring system having ring carbon atoms and 1—4 ring heteroatoms ed in the ic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5—8 membered heteroaryl”). In some embodiments, a heteroaryl group is a 5—6 membered aromatic ring system having ring carbon atoms and 1—4 ring heteroatoms ed in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5—6 membered heteroaryl”). In some embodiments, the 5—6 membered heteroaryl has l—3 ring heteroatoms selected from en, , and sulfur. In some embodiments, the —6 membered heteroaryl has 1—2 ring heteroatoms selected from nitrogen, oxygen, and sulfur.

In some embodiments, the 5—6 membered heteroaryl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur. Unless otherwise specified, each instance of a heteroaryl group is independently optionally substituted, £16., unsubstituted (an stituted heteroaryl”) or substituted (a “substituted heteroaryl”) with one or more substituents. In certain embodiments, the heteroaryl group is unsubstituted 5—14 membered heteroaryl. In certain embodiments, the heteroaryl group is substituted 5—14 membered heteroaryl. [0036} Exemplary 5—membered heteroaryl groups containing one heteroatom include, without limitation, pyrrolyl, furanyl and thiophenyl. Exemplary 5—membered heteroaryl groups containing two heteroatoms include, without limitation, imidazolyl, pyrazolyl, oxazoiyl, isoxazolyl, thiazolyl, and azolyl. Exemplary S—nieinbered heteroaryl groups ning three heteroatoms include, without limitation, triazolyl, oxadiazolyl, and azolyl.

Exemplary 5—membered heteroaryl groups containing four heteroatoms include, without limitation, tetrazolyl. Exemplary 6—membered heteroaryl groups containing one heteroatom include, without limitation, pyridinyl. Exemplary 6—membered heteroaryl groups containing two heteroatoms include, without limitation, pyridazinyl, dinyl, and pyrazinyl. Exemplary 6— membered heteroaryl groups containing three or four heteroatoms include, without limitation, triazinyl and tetrazinyl, respectively. Exemplary 7—membered heteroaryl groups containing one heteroatom include, without limitation, yl, oxepinyl, and thiepinyl. Exemplary 5,6— bicyclic aryl groups include, without limitation, indoiyl, olyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl, idazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzthiazolyl, benzisothiazolyl, benzthiadiazolyl, indolizinyi, and purinyl. ary 6,6—bicyclic aryl groups include, without limitation, naphthyridinyl, inyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl. [0037} Examples of representative heteroaryls include the ing: 8 fl {E",0O, I \\ 973\\ \ ME\N\ IN; @7-\\ (N\: /\/N\\ MN IL;— Tt— UNVN v’ n each Y is selected from carbonyl, N, NR“, 0, and S; and R65 is independently hydrogen, C1-C8 alkyl, C3—Cm cycloalkyl, 4—10 membered heterocyclyl, C6-C10 aryl, and 5-10 membered heteroaryl. [0038} oaralkyl” is a subset of alkyl and aryl, as defined herein, and refers to an optionally substituted alkyl group substituted by an optionally substituted heteroaryl group. [0039} “Carbocyclyl” or “carbocyclic” refers to a radical of a non—aromatic cyclic hydrocarbon group having from 3 to 10 ring carbon atoms (“C340 carbocyclyl”) and zero heteroatoms in the non—aromatic ring system. In some embodiments, a yclyl group has 3 to 8 ring carbon atoms (“C3_g carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 6 ring carbon atoms (“CH carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 6 ring carbon atoms (“C34, carbocyclyl”). In some ments, a carbocyclyl group has 5 to 10 ring carbon atoms (“C5,10 yclyl”). Exemplary C34, carbocyclyl groups include, without limitation, cyclopropyl (C3), cyclopropenyi (C3), cyclobutyl (C4), utenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyi (C6), cyclohexadienyl (C6), and the like.

Exemplary CH carbocyclyl groups include, without limitation, the aforementioned C34, carbocyclyl groups as well as cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooetyl (Cg), cyclooctenyl (Cg), bicyclo[2.2. l]heptanyl (C7), o[2.2.2]octanyl (C8), and the like. Exemplary C3710 carbocyclyl groups include, without tion, the aforementioned CH, carbocyclyl groups as well as cyclononyl (C9), cyclononenyl (C9), cyclodecyl (Cm), cyclodecenyl (C10), octahydro—lH—indenyl (C9), decahydronaphthalenyl (C10), spiro[4.5}decanyl (C10), and the like. As the foregoing examples illustrate, in certain embodiments, the carbocyclyl group is either monocyciic (“monocyclic carbocyclyl”) or contain a fused, d or spiro ring system such as a bicyclic system (“bicyclic carbocyclyl”) and can be ted or can be partially unsaturated. cyciyl” also includes ring systems wherein the carbocyclyl ring, as defined above, is fused with one or more aryl or heteroaryl groups wherein the point of attachment is on the carbocyclyl ring, and in such instances, the number of carbons continue to designate the number of carbons in the carbocyclic ring system. Unless otherwise specified, each instance of a earbocyclyl group is independently optionally substituted, 17.8., unsubstituted (an “unsubstituted carbocyclyl”) or substituted (a “substituted. carbocyclyl”) with one or more substituents. In n embodiments, the carbocyclyl group is unsubstituted C340 carbocyclyl. In certain embodiments, the carbocyclyl group is a substituted C340 carbocyclyl. [0040} In some embodiments, “carbocyclyl” is a monccyclic, saturated carbocyclyl group having from 3 to 10 ring carbon atoms (“C7340 cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 8 ring carbon atoms (“Gag cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 6 ring carbon atoms (“Cs—6 cycloalkyl”). In some embodiments, a cycloalkyl group has 5 to 6 ring carbon atoms (“C54 cycloalkyl”). In some embodiments, a cycloalkyl group has 5 to 10 ring carbon atoms (“CH0 cycloalkyl”). Examples of CH,- lkyl groups include cyclopentyl (Cs) and exyl (C5). Examples of C3_6 cycloalkyl groups include the aforementioned C54, cycloalkyl groups as well as cyclopropyl (C3) and cyclobutyl (C4). es ofCH cycloalkyl groups e the aforementioned C34, lkyl groups as well as cycloheptyl (C7) and cyclooctyl (C8). Unless otherwise specified, each instance of a cycloalkyl group is independently unsubstituted (an “unsubstituted cycloalkyl”) or substituted (a “substituted cycloalkyl”) with one or more substituents. In certain embodiments, the cycloalkyl group is unsubstituted C340 cycloalkyl. In certain embodiments, the cycloalkyl group is substituted C3,10 cycloalkyl. [0041} “Heterocyclyl” or “heterocyclic” refers to a radical of a 3— to lO—membered non— aromatic ring system having ring carbon atoms and l to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon (“3—10 membered heterocyclyl”). In heterocyclyl groups that contain one or more nitrogen atoms, the point of attachment can be a carbon or en atom, as valency permits. A heterocyclyl group can either be monocyclic (“monocyclic heterocyclyl”) or a fused, d or spiro ring system such as a bicyclic system (“bicyclic heterocyclyl”), and can be saturated or can be partially unsaturated. Heterocyclyl bicyclic ring systems can include one or more heteroatoms in one or both rings. “Heterocyclyl” also includes ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more carbocyclyl groups wherein the point of attachment is either on the carbocyclyl or heterocyclyl ring, or ring systems wherein the cyclyl ring, as defined above, is fused with one or more aryl or heteroaryl groups, n the point of attachment is on the cyclyl ring, and in such instances, the number of ring members continue to designate the number of ring members in the heterocyclyl ring .

Unless otherwise specified, each instance of cyclyl is independently ally substituted, lie. unsubstituted (an “unsubstituted heterocyclyl”) or substituted (a “substituted heterocycly ”) with one or more substituents. In certain embodiments, the heterocyclyl group is unsubstituted 3—10 ed heterocyclyl. In certain embodiments, the heterocyclyl group is substituted 3— membered heterocyclyl. [0042} In some ments, a heterocyclyl group is a 5—10 membered non—aromatic ring system having ring carbon atoms and 14 ring heteroatoms, wherein each heteroatom is independently selected from en, oxygen, sulfur, boron, phosphorus, and silicon (“5—10 membered heterocyclyl”). In some embodiments, a heterocyclyl group is a 5—8 membered non— aromatic ring system having ring carbon atoms and 1—4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5—8 ed heterocyclyl”). In some embodiments, a heterocyclyl group is a 5—6 membered non—aromatic ring system having ring carbon atoms and 1—4 ring heteroatoms, wherein each atom is independently selected from nitrogen, oxygen, and sulfur (“5—6 membered heterocyclyl”). In some embodiments, the 5—6 membered heterocyclyl has 1—3 ring heteroatoms ed from nitrogen, oxygen, and sulfur. In some embodiments, the 5—6 membered heterocyclyl has 1—2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5—6 niembered heterocyclyl has one ring heteroatom selected from nitrogen, , and sulfur. [0043} Exemplary 3—membered heterocyclyl groups containing one heteroatom include, without limitation, azirdinyl, yl, thiorenyl. Exemplary 4—menibered heterocyclyl groups containing one heteroatom include, without limitation, azetidinyl, oxetanyl and thietanyl. ary 5—membered heterocyclyl groups containing one heteroatoni include, without limitation, tetrahydrofuranyl, dihydrofuranyi, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl and pyrrolyl—2,5—dione. Exemplary ered heterocyclyl groups containing two heteroatoms include, without limitation, anyl, oxasulfuranyl, disulfuranyl, and idin-Z-one. Exemplary 5—membered heterocyclyl groups containing three heteroatoms include, t limitation, triazolinyl, oxadiazolinyl, and thiadiazolinyl.

Exemplary 6—membered heterocyclyl groups containing one heteroatom include, without limitation, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary 6— membered heterocyclyl groups containing two heteroatoms include, without limitation, piperazinyl, morpholinyl, dithianyl, dioxanyl. Exemplary ered cyclyl groups containing two heteroatoms e, without tion, triazinanyl. Exemplary 7—membered heterocyclyl groups containing one atom include, without tion, azepanyl, oxepanyl and nyl. Exemplary 8—membered heterocyclyl groups containing one heteroatom include, without limitation, azocanyl, yl and thiocanyl. Exemplary 5-membered heterocyclyl groups fused to a C6 aryl ring (also referred to herein as a 5,6-bicyclic heterocyclic ring) include, without limitation, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, azolinonyl, and the like. ary 6-membered heterocyclyl groups fused to an aryl ring (also referred to herein as a 6,6-bicyclic heterocyclic ring) include, without limitation, tetrahydroquinolinyl, tetrahydroisoquinoiinyl, and the like. [0044} Particular examples of heterocyclyl groups are shown in the following illustrative {”1 to Q r; Qr‘ffi —3 Q C11? wherein each W is selected from CR67, C(R67)2, NR“, 0, and S; and each Y is selected from NR“, 0, and S; and R67 is independently hydrogen, C 1-Cg alkyl, C3-C10 cycloalkyl, 4-10 membered heterocyclyl, C6-C10 aryl, 5—10 membered heteroaryl. These heterocyclyl rings may be optionally substituted with one or more groups selected from the group consisting of acyl, acylamino, acyloxy, alkoxy, alkoxycarbonyl, carbonyiamino, amino, substituted amino, aminocarbonyl (carbamoyl or amido), aminocarbonylamino, aminosulfonyl, sulfonylamino, aryl, aryloxy, azido, carboxyl, cyano, ikyi, halogen, hydroxy, keto, nitro, thiol, -S-a1ky1, —S- aryl, -S(O)—all<yl,—S(O)-aryl, —S(O)2-alkyl, and -S(O)2-aryi. Substituting groups include carbonyl or thiocarbonyl which provide, for example, lactam and urea derivatives. [0045} “Hetero” when used to describe a compound or a group present on a compound means that one or more carbon atoms in the compound or group have been ed, by a en, oxygen, or sulfur heteroatom. Hetero may be applied to any of the hydrocarbyl groups described above such as alkyl, cg... heteroalkyl, cycloaikyi, rag, heterocyclyl, aryl, e.g_,. heteroaryl, cycloalkenyl, e.g,. cycloheteroalkenyl, and the like having from 1 to 5, and ularly from 1 to 3 heteroatorns. [0046} “Acyl” refers to a radical -C(O)R2°, where R20 is hydrogen, substituted or unsubstitued alkyl, substituted or unsubstitued alkenyl, tuted or unsubstitued alkynyl, substituted or unsubstitued carbocyclyl, substituted or tituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstitued heteroaryl, as defined herein. oyl” is an acyl group wherein R20 is a group other than hydrogen. Representative acyl groups e, but are not limited to, formyl (-CHO), acetyl (-C(=O)CH3), cyclohexylcarbonyl, cyclohexylmethylcarbonyl, l (-C(=O)Ph), benzylcarbonyl (-C(=O)CHgPh), —C(O)-C1-Cg alkyl, (CH2)K(C6-C10 aryl), —C(O)-(CH2):(5—10 niembered heteroaryl), (CH2)t(C C 10 cycloalkyl), and —C(O)-(CH2)t(4-l 0 membered heterocyciyl), wherein t is an integer from 0 to 4. In certain embodiments; R21 is C1-C3 alkyl, substituted with halo or y; or C3-C10 lkyl, 4-10 nieinbered heterocyclyl, C6-C7 10 aryl; arylaikyl, 5—10 inernbered heteroaryl or heteroarylalkyl, each of which is substituted with unsubstituted C1-C4 alkyl, halo, unsubstituted C1-C4 alkoxy, unsubstituted C1-C4 haloalkyl; unsubstituted C 1—C4 hydroxyalkyl, or unsubstituted C1-C4 haloalkoxy 0r hydroxy. [0047} “Acylaniino” refers to a radical -NR22C(O)R23, where each instance of R22 and R23 is independently en, substituted or unsubstitued alkyl, tuted or unsubstitued alkenyl, substituted or unsubstitued alkynyl, substituted or unsubstitued carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstitued heteroaryl,, as defined herein, or R22 is an amino protecting group. Exemplary niino” groups include, but are not limited to, forniylamino, acetyiamino, cyclohexylcarbonylaniino, cyclohexyhnethyl-carbonylaniino, benzoylamino and benzylcarbonylamino. Particular exemplary “acylarnino” groups are —NR24C(O)-C1-Cg alkyi, —NR24C(O)-(CH3)I(C6-Cm aryl), — NR24C(O)-(CH2)t(5—10 membered heteroaryl), —NR24C(O)-(CH2)I(C3-Cm cycloalkyl), and — NR24C(O)-(CH2)I(4-10 nieinbered heterocyclyl), wherein t is an integer from 0 to 4, and each R24 independently represents H or C1-C8 alkylln n embodiments, R25 is H, Ci-Cg alkyl, substituted with halo or hydroxy; C3-C m cycloalkyl, 4-10 membered heterocyclyl, C6-ny aryl, arylalkyl, 5-10 ineinbered heteroaryl or heteroarylalkyi, each of which is substituted with unsubstituted C1-C4 alkyl, halo, unsubstituted C1—C4 alkoxy, unsubstituted C1-C4 haloalkyl, unsubstituted C1-C4 hydroxyalkyl; or unsubstituted C 1-C4 haloalkoxy or hydroxy; and R26 is H C1-Cs alkyl, substituted with halo or y; C3-C m cycloalkyl, 4-10 ed heterocyclyl, C6-C3“) aryl, arylalkyl, 5-10 membered heteroaryl or heteroarylalkyl, each of which is tuted with unsubstituted C 1-C4 alkyl, halo, unsubstituted C1-C4 alkoxy, unsubstituted C 1-C4 haloalkyl, unsubstituted C1-C4 hydroxyalkyl, or unsubstituted C 1-C4 haloalkoxy or hydroxyl; provided at least one of R25 and R26 is other than H. [0048} “Acyloxy” refers to a radical -OC(O)R27, where R27 is hydrogen, tuted or unsubstitued alkyl, substituted or unsubstitued alkenyl, substituted or unsubstitued alkynyl, substituted. or titued carbocyclyl, substituted or unsubstituted heterocyclyl, substituted. or tituted aryl, or substituted or unsubstitued heteroaryi, as defined herein. Representative examples include, but are not limited to, formyl, acetyl, cyclohexylcarbonyl, cyclohexylmethylcarbonyl, l and benzylcarbonyl. in certain embodiments, R28 is C 1-Cg alkyl, substituted with halo or hydroxy; C3-C10 cycloalkyl, 4-10 membered heterocyclyl, C6-C10 aryl, arylalkyl, 5-10 membered heteroaryl or heteroarylalkyl, each of which is substituted with unsubstituted C1-C4 alkyl, halo, unsubstituted C1-C4 alkoxy, unsubstituted C1-C4 haloalkyl, unsubstituted C 1-C4 hydroxyalkyl, or unsubstituted C 1—0; haloalkoxy or hydroxy. [0049} “Alkoxy” refers to the group —OR29 where R29 is substituted or unsubstituted alkyl, substituted or unsubstitued alkenyl, substituted or unsubstitued alkynyl, substituted or unsubstitued carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstitued heteroaryl. Particular alkoxy groups are methoxy, ethoxy, n- y, poxy, n-butoxy, tert-butoxy, sec—butoxy, n-pentoxy, n-hexoxy, and 1,2- dimethylbutoxy. ular alkoxy groups are lower alkoxy, tie. with between 1 and 6 carbon atoms. r particular alkoxy groups have between i and 4 carbon atoms. [0050} In certain embodiments, Rz9 is a group that has 1 or more substituents, for instance from 1 to 5 substituents, and particularly from i to 3 substituents, in particular 1 substituent, selected from the group consisting of amino, substituted amino, C6-C10 aryl, aryloxy, carboxyl, cyano, C3-C 10 cycloalkyl, 4-10 membered heterocyclyl, halogen, 5-10 membered heteroaryl, hydroxyl, nitro, thioalkoxy, yloxy, thiol, alkyl-S(O)-, aryl—S(O)-, alkyl—S(O)2- and (O)2-. Exemplary ‘substituted alkoxy’ groups include, but are not limited to, —O- (C6-C10 aryl), —O-(CH2):(5—10 membered heteroaryl), —O-(CH3)t(C3-Cm cycloalkyl), and — O-(CH2)t(4—10 membered heterocyclyl), wherein t is an integer from 0 to 4 and any aryl, heteroaryl, cycloalkyl or heterocyclyl groups present, may lves be substituted by unsubstituted C 1-C4 alkyl, halo, unsubstituted C1-C4 alkoxy, unsubstituted C 1-C4 haloalkyl, tituted C1-C4 hydroxyalkyl, or unsubstituted C1-C4 haloalkoxy or hydroxy. Particular exemplary ituted alkoxy’ groups are -OCF3, -OCH2CF3, -OCH2Ph, -OCH2-cyclopropyl, - OCH2CH20H, and -OCH2CH2NMe2. [0051} “Amino” refers to the l -NH3. [0052} “Substituted amino” refers to an amino group of the formula -N(R38)2 wherein R38 is en, substituted or unsubstituted alkyl, substituted or unsubstitued alkenyl, substituted or unsubstitued alkynyl, substituted or unsubstitued yclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or titued heteroaryl, or an amino protecting group, wherein at least one of R38 is not a hydrogen. In certain embodiments, each R38 is independently selected from hydrogen, Cg-Cg alkyl, C3-C8 alkenyl, C3-C8 alkynyl, C6- C10 aryl, 5-10 membered heteroaryl, 4-10 niembered heterocyclyl, or C3—C10cycloalkyl; or C1-C3 alkyl, substituted with halo or hydroxy; C3-C3 l, substituted with halo or y; C3-C8 alkynyl, substituted with halo or hydroxy, or -(CH2)1(C6—C10 aryl), -(CH2)[(5-10 membered heteroaryl), -(CH2)I(C3-Cm cycloalkyl), or -(CH2)((_4-10 membered heterocyclyl), wherein t is an r between 0 and 8, each of which is substituted by unsubstituted C1-C4 alkyl, halo, unsubstituted C1-C4 alkoxy, unsubstituted C1-C4 kyl, tituted C 1-C4 hydroxyalkyl, or unsubstituted C1-C4 haloalkoxy or hydroxy; or both R38 groups are joined to form an alkylene group. [0053} Exemplary “substituted amino” groups include, but are not limited to, —NR39-C 1- C8 alkyl, —NR39-(CHg)t(C5-Cm aryli), (CH2)1(5—10 membered heteroaryl), —NR39- (CH3)1(C3-C10 cycloalkyl), and —NR39-(CH2)t(4-10 membered heterocyclyl), wherein t is an integer from 0 to 4, for instance 1 or 2, each R39 independently represents H or C1-C8 alkyl; and any alkyl groups present, may lves be substituted by halo, substituted or unsubstituted amino, or hydroxy; and any aryl, heteroaryi, cycloalkyl, or heterocyciyl groups present, may themselves be substituted by unsubstituted C 1-C4 alkyl, halo, unsubstituted C1-C4 alkoxy, unsubstituted C1-C4 haloalkyl, unsubstituted C {-C4 hydroxyalkyl, or unsubstituted C1-C4 haloalkoxy or hydroxy. For the avoidance of doubt the term ‘substituted amino’ includes the groups alkylamino, substituted alkylamino, alkylarylamino, substituted alkylarylamino, arylamino, substituted arylamino, dialkylarnino, and tuted dialkylamino as defined below.

Substituted amino encompasses both monosubstituted amino and disubstituted amino groups. [0054} “Azido” refers to the radical -N-3. [0055} “Carbarnoyl” or “amido” refers to the radical -C(O)NH2. [0056} “Substituted carbamoyl” or “substituted amide” refers to the radical -C(O)N(R62)2 wherein each R62 is independently hydrogen, substituted or unsubstituted alkyl, tuted or unsubstitued alkenyl, substituted or unsubstitued alkynyl, substituted or unsubstitued yclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, tuted or unsubstitued heteroaryl, or an amino protecting group, n at least one of R62 is not a hydrogen. In certain embodiments, R63 is selected from H, C1-C3 alkyl, C3-Cm cycloalkyl, 4-10 membered heterocyclyl, C5-Clo aryl, aralkyl, 5-10 membered heteroaryl, and heteroaralkyl; or C 1-Cs alkyl substituted with halo or hydroxy; or C3-C 10 cycloalkyl, 4-10 inernbered heterocyc-lyl, C6—C10 aryl, aralkyl, 5-10 membered heteroaryl, or heteroaralkyl, each of which is tuted by unsubstituted C 1—C4 alkyl, halo, tituted C1-C4 alkoxy, unsubstituted C1-C4 haloalkyl, unsubstituted C g-C4 hydroxyalkyl, or unsubstituted C 1-C4 haloalkoxy or hydroxy; provided that at least one R62 is other than H. [0057} Exemplary “substituted carbanioyl” groups include, but are not d to, —C(O) NRM-Cl-Cg alkyl, —c(0)1xiR‘54—(ennui,—c10 aryl), —C(O)N64-(CH2)t(5-10 membered heteroaryl), —C(O)NR64-(CH2)t(C3-Cm cycloalkyl), and —C(O)NR64-(CH2)t(4-10 membered heterocyclyl), wherein t is an integer from 0 to 4, each R64 independently ents H or C1-C8 alkyl and any aryl, heteroaryl, cycloalkyl or heterocyclyl groups present, may themselves be substituted by unsubstituted C1-C4 alkyl, halo, unsubstituted C1-C4 alkoxy, unsubstituted C1-C4 haloalkyl, tituted C1-C4 hydroxyalkyl, or unsubstituted C1-C4 haloalkoxy or hydroxy. [0058} “Carboxy” refers to the l -C(O)OH. [0059} “Cyano” refers to the radical -CN “Halo” or ”halogen” refers to fluoro (F), chloro (Cl), bromo (Br), and iodo (I). In certain embodiments, the halo group is either fluoro or chioro. [0061} “Hydroxy” refers to the radical -OH. [0062} “Nitro” refers to the radical —NO;. [0063} “Cycloalkylalkyl” refers to an alkyl radical in which the alkyl group is substituted with a cycloalkyl group. Typical lkylalkyl groups include, but are not limited to, cyclopropylmethyl, cyclobutylrnethyl, cyclopentylmethyl, cyclohexylmethyl, cycloheptylrnethyl, cyclooctylmethyl, cyclopropylethyl, cyclobutylethyl, cyclopentylethyl, cyclohexylethyl, eptylethyl, and cyclooctylethyl, and the like. [0064} “Heterocyclylalkyl” refers to an alkyl radical in which the alkyl group is substituted with a heterocyclyl group. Typical heterocyclyialkyl groups include, but are not limited to, idinylmethyl, piperidinylmethyl, piperazinyimethyl, linylmethyl, pyrrolidinylethyl, piperidinylethyl, piperazinylethyl, morpholinylethyl, and the like. [0065} “Cycloalkenyl” refers to substituted or tituted carbocyclyl group having from 3 to 10 carbon atoms and having a single cyclic ring or multiple condensed rings, including fused and bridged ring systems and having at least one and ularly from l to 2 sites of olefinic unsaturation. Such cycloalkenyl groups e, by way of example, single ring structures such as cyclohexenyl, cyclopentenyl, cyclopropenyl> and the like. [0066} “Fused lkenyl” refers to a cycloalkenyl having two of its ring carbon atoms in common with a second aliphatic or aromatic ring and having its olefinic unsaturation located to impart aromaticity to the cycloalkenyl ring. [0067} “Ethenyl” refers to substituted or unsubstituted —(C=C)—. [0068} ene” refers to substituted or unsubstituted —. [0069} “Ethynyl” refers to —(CEC)-. [0070} “Nitrogen-containing cyclyl” group means a 4- to 7- membered non— aromatic cyclic group containing at least one nitrogen atom, for example, but Without limitation, morpholine, piperidine (e.g. 2-piperidinyl, 3-piperidinyl and 4-piperidinyl), pyrrolidine (e.g. 2— pyrrolidinyl and 3-pyrrolidinyl), azetidine> pyrrolidone, imidazoline, imidazolidinone, 2- pyrazoline, pyrazolidine, piperazine, and N-alkyl piperazines such as N—methyl piperazine.

Particular examples include azetidine, piperidone and piperazone. [0071} “Thioketo” refers to the group =S. [0072} Alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl groups, as defined herein, are optionally substituted (eg, “substituted” or stituted” alkyl, “substituted” or “unsubstituted” alkenyl, “substituted” or “unsubstituted” alkynyl, “substituted” or “unsubstituted” carbocyclyl, “substituted” or “unsubstituted” heterocyclyl, “substituted” or stituted” aryl or “substituted” or “unsubstituted” heteroaryl group). In general, the term “substituted”, Whether preceded by the term “optionally” or not, means that at least one hydrogen present on a group (e.g., a carbon or nitrogen atom) is replaced with a permissible substituent, e.g., a substituent which upon substitution results in a stable compound, e.g., a compound which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, or other reaction. Unless otherwise indicated, a ituted” group has a substituent at one or more tutable ons of the group, and when more than one on in any given structure is substituted, the tuent is either the same or different at each position. The term “substituted” is contemplated to include substitution with all permissible substituents of organic compounds, any of the substituents described herein that results in the formation of a stable compound. The present invention contemplates any and all such combinations in order to arrive at a stable compound. For purposes of this invention, heteroatoms such as nitrogen may have hydrogen substituents and/or any suitable substituent as described herein which satisfy the valencies of the heteroatoms and results in the formation of a stable moiety. [0073} Exemplary carbon atom substituents include, but are not limited to; n; —CN, —N02, —N3, —s02H, —s03H, —OH, —OR“‘”, —ON(Rbb)2, —N(Rbb)2, —N(R"“)3+Xj —N(0R°°)Rbb, — SH, —SR”3 —SSR°C, —C(=O)Raa, —C03H, —CHO, —C(OR°°)3, —C03Ra“, )R3“, —OC02Raa3 — C(=O)N(Rbb)g, —OC(=O)N(Rbb)2, —NRbbC(=0)R““, —NRbbCOzRaa, —NRbbC(=O)N(Rbb)2, — C(=NRbb)Ra'~‘, —C(=NRbb)ORaa, Rbb)R3“, —OC(=NRbb)OR“a, —C(=NR"")N(R"")2, — OC(=NRbb)N(Rbb)2, —NRbbC(=NRbb)N(Rbb)2, —C(=O)NRbbSOZRaa, —NRbbSOgRaa, —sozN(R"b)2, — sour“, —sozoR“, —OSOgRaa, —S(=O)Raa, —03(=0)Raa, —Si(R“"‘)3, —OSi(R'”“‘)3 —C(=S)N(Rbb)m — C(=O)SR""“? —C(=S)SRaa, )SR“, —SC(=O)SR“, —OC(=O)SR‘”, )OR‘”’, — SC(=O)Raa, —P(=O‘_)2Raa, —OP(=O)2R‘“, —P(=O)(Raa)2, —OP(=O)(R“)2, —OP(=O)(OR“)2, — P(=O)3N(Rbb)2, —OP(=O)2N(Rbb)2, —P(=O)(NRbb)g, —OP(=O)(NRbb)23 —NRbbp(=0)(0R°“‘)2, — NRbbP<=0i<NRbb)2, —P<R“)2, —P(RC°)3, —0P<R“)2, —0P<R°°‘>3, —B<R‘“ 2, —B<0R“)2, —BR“<0R”), C 1710 alkyl, C Ho perhaloalkylj C240 alkenyl, C2,“) alkynyl, C3,“) carbocyclyl, 3—14 membered heterocyclyl, C644 aryl, and 5—14 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, cyclyl, aryl, and heteroaryl is independently substituted with 0, l, 2, 3, 4, or 5 Rdd groups; or two geminal ens on a carbon atom are replaced with the group =0, =S, =NN(Rbb)2, =NNRbbC(=O)Raa, =NNRbbC(=O)ORa3, S(=O)2R‘“, =NRbb, or =N0RC“; each instance of RE18 is, ndently, selected from CHO alkyl, C1710 perhaloalkyl, C340 alkenyl, C3,“) alkynyl, C3,“) carbocyclyl, 3—14 membered heterocyclyl, C644 aryl, and 5—14 inenibered heteroaryl, or two Ram groups are joined to form a 3—14 membered cyclyl or 5— 14 ed heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, l, 2, 3; 4, or 5 Rdd groups; each instance of Rbb is, independently, selected from en, —OH, —OR"‘B, —N(RC°)2, — CN, —C(=O)Raa, —C(=O)N(RCC)2, a, —SOgR“a, —C{=NR°C)ORM, —C(=NRCC)N(RC°)2, — SOgN(RCC)2, °, CC, ‘, —C(,=SI)N(R°°)2, —C(=O)SR°°, —C(=S)SR°°, — P(=O)2Raa, —P(=O)(Raa)2, —P(=O)2N(R°c)3, —P(=O)(NR°°)2, C 1—10 alkyl, C1_10 perhaloalkyl, C340 alkenyl: C340 alkynyl, C3—10 carbocyclyl, 3—14 membered heterocyclyl, C644 aryl, and 5—14 nieinbered heteroaryl, or two Rbb groups are joined to form a 3—141nembered heterocyclyl or 5— 14 menibered heteroaiyl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, hetei‘ocyclyl, aryl, and heteroaryl is independently substituted with 0, l: 2, 3, 4, or 5 Rdd groups; each instance of Rcc is; independently, selected from hydrogen, CHO alkyl, C140 perhaloalkyl, C340 alkenyl, C240 alkynyl, C340 carbocyclyl, 3—14 rnembered heterocyclyl, CH4 aryl, and 5—14 niembered aryl, or two RCC groups arejoined to form a 3—14 ed heterocyclyl or 5—14 memhered heteroaryl ring, wherein each alkyl, l, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, l, 2 3 3, 4, or 5 Rdd groups; each instance of Rdd is, independently, selected from halogen, CN, N02, N3, SOgH, sogH, —OH, —0Re€, —ON(Rfi)2, —N(Rff)2, —N(R‘"“)3*>C, —N(0R6‘=)Rfi°, —SH, —SR*, —SSR*, — C(=0)Rti —C02H, —C02Ree, —OC(=O)Re°, —ocozR“, —C(=O)N(Rff)g, —0C(=0)N(Rfl)2, — NRffC(=O)Ree, —NRfiC02R€e, —NRfi‘C(=0)N(R“)2, —C(=NRff)ORee, Rff)Ree, — OC(=NRff)ORee, —C(=NRff)N(Rfi)2, —OC(=NRff)N(RH)2, —NREC(=NRE)N(Rif)2,—NRfi802Ree3 — soZN(Rfl‘)z, —s02Rei —sozonei —osozn'~‘t, —S(=O)Re€, 5102“)?” —OSi(Ree)3, N(Rff)2, — C(=O)SR“’, —C(=S)SRee, —SC(=S)SR“, 2Ree, —P(=O)(Ree)2, —OP(=O)(Ree)2, — OP(=O)(OR6€)2, CH; alkyl, C1_6 perhaloalkyl, CH. alkenyi, C24, alkynyl, C3_10 carbocyclyl, 3—10 nieinbered heterocyclyl, C640 aryl, 5—10 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, l, 2, 3, 4, or 5 Rgg groups, or two geniinal Rdd substituents can be joined to form =O or =S; each instance of Re6 is, independently, selected from CW alkyl, CM oalkyl, C245 l, C24; alkynyl, C340 carbocyclyl, C540 aryl, 3—10 niembered heterocyclyl, and 3—l0 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aiyl, and heteroaryl is independently substituted with 0, l 2 or 5 Rgg groups; , , 3, 4, each instance of Rff is; independently, selected from hydrogen, CH, alkyl, C 1,6 perhaloaikyl, C24 alkenyl, C24 alkynyl, C340 carbocyclyi, 3—10 rneinbered heterocyclyl, Cam aryl and 5—10 menibered heteroaryL or two Rff groups are joined to form a 3—14 ed heterccyclyl or 5—14 membered heteroaryl ring, n each alkyl, alkenyl, l, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rgg groups; and each instance of Rgg is, independently, halogen, —CNa —N02, —N3, —SOZH, —SO3H, —OH> —OC1_(, alkyl, _6 alkyl); —N(C1_6 alkyl); —N(C1_(, alkyl)3+X_, —NH(C1_6 alkyl)2+X_, — NH2(CH; alkyl) +X’, —NH3+X’, —N(OCM alkyl)(C1,6 alkyi), —N(OH)(CH, alkyl), —NH(OH), — SH, —SCH, alkyl,—SS(C1,6 alkyl), (C1,6 alkyl), —COgH, —C02(CH, alkyl), —OC(=O)(C1,6 alkyl), —OC02(C1,6 alkyl), —C(=O)NH2, —C(=O)N(CH; alkyl)2, —OC(=O)NH(C1,6 alkyl); — NHC(=O)( CH; alkyl), —N(CH, alkyl)C(=O)( CH; alkyi), —NHC02(CH, alkyl), —NHC(=O)N(C1, 6 all<yl)2,—NHC(=O)NH(C1,6 alkyl); —NHC(=O)NH2, —C(=NH)O(C% ;—OC(=NH)(C1,6 alkyl), —OC(=NH)OC1,6 alkyl, —C(=NH)N(C1,6 alkyl); —C(=NH)NH(C1,6 alkyl), —C(=NH)NH2, —OC(=NH)N(C1,6 alkyl)3, —OC(NH)NH(CH, alkyl), —OC(NH)NH3, —NHC(NH)N(CH, ; — NHC(=NH)NH3, —NHSOZ(C1,6 alkyl), —SOZN(CH, alkyl)2, —SOZNH(C1,6 , —SO;NH3,— SOZCM alkyl, —SOgOCH, alkyl, —OSOZCH, alkyl, —SOCH, alkyl, —Si(CH, alkyl)3, —OSi(CM ; —C(=S)N(CH; alkyl)2, C(=S)NH(CH, alkyl), C(=S)NH2, —C(=O)S(CH alkyl), — C(=S)SCH, alkylg —SC(=S)SC1,6 alkyl, —P(=O)2(CH, aikyl), —P(=O)(CH, alkylh, —OP(=O)(C1$ alkyl); )(OC H; alkyl); C175 alkyl, CH) perhaloaikyi, C243 i, C24, alkynyl, C340 carbocyciyl, C5,10 aryl, 3—10 membered heterocyclyl, 5—10 membered heteroaryl; or two geniinal Rgg substituents can be joined to form =0 or =S; wherein X’ is a counterion [0074} A “counterion” or ic counterion” is a negatively charged group ated with a ic nary amino group in order to maintain onic neutrality. Exemplary counterions include halide ions (cg, F‘, Ci‘, Br‘, 1"),N03_, (7104—, OH‘, H2PO4‘, H804: 304' 2sulfonate ions (e.g., metliansulfonate, trifluoromethanesuifonate, p—toluenesulfonate, benzenesulfonate, lO—camphor sulfonate, naphtlialene—Z—suifonate, naphthalene—l—sulfonic acid—S—sulfonate, ethan—l—sulfonic acid—Z—sulfonate, and the like), and carboxylate ions (e.g., acetate, ethanoate, propanoate, benzoate, glycerate, lactate, tartrate, glycolate, and the like). [0075} Nitrogen atoms can be substituted or unsubstituted as valency permits, and include primary, secondary, tertiary, and quarternary nitrogen atoms. Exemplary nitrogen atom substitutents include, but are not limited to, hydrogen, —OH, —OR“, —N(Rc°)2, —CN, —C(=O)R"“’, —C(=O)N(R“)2, —C02R”, 5021i”, —C(=NRbb)R“, —C(=NR“)OR”, —C(=NR°°)N(R°“)2, — SO;N(RCC)2, —SOgR°°, —SOzORCC, —SOR3“, —C(=S)N(RC°)2, —C(=O)SR°°, —C(=S)SRCC, — P(=O)2Rm, —P(=O)(R“)2, —P(=O)2N(Rc°‘)g, —P(=O)(NR°C)2, C 1_10 alkyl, Cv1_m perhaloalkyl, C2—10 l, C240 alkynyl, C340 carbocyclyl, 3—14 membered cyclyl, C644 aryl, and 5—14 membered heteroaryl, or two Rcc groups attached to a nitrogen atom are joined to form a 3—14 membered heterocyclyl or 5—14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independentiy substituted with 0, l, 2, 3, 4, or 5 Rdd groups, and wherein R“, Rbb, RCC and Rdd are as defined above. [0076} These and other exemplary substituents are described in more detail in the Detailed Description, Examples, and . The invention is not intended to be limited in any manner by the above exemplary listing of substituents.

Other tions [0077} The term aceutically acceptable salt” refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a able benefit/risk ratio. Phannaceutically acceptable salts are well known in the art. For example, Berge et all, bes pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences (l977) 66:1—19. Pharmaceutically acceptable salts of the compounds of this ion include those derived from suitable inorganic and organic acids and bases. Examples of ceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, romic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange. Other ceutically able salts e adipate, alginate, ascorbate, ate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, sulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2—hydroxy—ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2—naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, ate, persulfate, 3—phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, ate, sulfate, tartrate, thiocyanate, enesulfonate, undecanoate, valerate salts, and the like. Pharmaceutically acceptable salts derived from appropriate bases e alkali metal, alkaline earth metal, ammonium and N+(C14alkyl)4 salts.

Representative alkali or alkaline earth metal salts include sodium, m, ium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate, and aryl sulfonate. [0078} A ct” to which administration is contemplated includes, but is not limited to, humans (126., a male or female of any age group, ag. a pediatric t (e.g, infant, child, adolescent) or adult t (e.g., young adult, middle—aged adult or senior adult» and/or a non- human animal, e.g., a mammal such as primates (e.g, cynomolgus monkeys, rhesus s), , pigs, horses, sheep, goats, rodents, cats, and/or dogs. In certain embodiments, the subject is a human. In n embodiments, the subject is a non-human animal. The terms “human,” “patient,” and “subject” are used interchangeably herein. [0079} Disease, disorder, and condition are used interchangeably herein. [0080} As used herein, and unless otherwise specified, the terms , 7‘! LLtreating” and “treatment” contemplate an action that occurs while a subject is suffering from the specified disease, disorder or condition, which reduces the ty of the e, disorder or condition, or retards or slows the progression of the disease, disorder or condition (“therapeutic treatment”), and also contemplates an action that occurs before a subject begins to suffer from the specified disease, disorder or condition (“prophylactic ent”), [0081} In general, the “effective amount” of a compound refers to an amount sufficient to elicit the desired ical response. As will be appreciated by those of ordinary skill in this art, the effective amount of a compound of the invention may vary depending on such factors as the desired biological endpoint, the pharmacokinetics of the compound, the disease being treated, the mode of administration, and the age, health, and condition of the subject. An effective amount encompasses therapeutic and prophylactic treatment. [0082} As used herein, and unless otherwise specified, a “therapeutically effective amount” of a compound is an amount sufficient to provide a therapeutic benefit in the treatment of a disease, disorder or condition, or to delay or ze one or more symptoms associated with the disease, er or condition. A therapeutically effective amount of a compound means an amount of therapeutic agent, alone or in combination with other therapies, which provides a therapeutic t in the treatment of the disease, disorder or ion. The term “therapeutically effective amount” can encompass an amount that improves overall therapy, reduces or avoids symptoms or causes of disease or ion, or enhances the therapeutic efficacy of r therapeutic agent. [0083} As used herein, and unless otherwise specified, a “prophylactically effective amount” of a compound is an amount sufficient to t a disease, disorder or condition, or one or more symptoms associated with the disease, disorder or condition, or prevent its recurrence. A prophylactically effective amount of a compound means an amount of a therapeutic agent, alone or in combination with other agents, which provides a prophylactic benefit in the prevention of the disease, er or condition. The term “prophylactically effective amount” can encompass an amount that improves overall prophylaxis or enhances the prophylactic efficacy of another lactic agent.

Detailed Description of Certain Embodiments of the Invention [0084} The inventors of the present invention, during an ng exploration of Org—l analogs for NMDA modulation, a portion of which is described in l, incorporated herein by nce, ered several specific combination of ts which provides NMDA modulators with comparatively superior properties. For example, as shown in Table 1, compounds bearing a beta-hydrogen at C5 are disfavored ed to compounds bearing either alpha-hydrogen C5 or double bond across C5-C6 due to loss of potentiation of the NMDA receptor. The removal of the methyl at C2; also results in significant loss ofNMDA potentiation. Disubstitution at C3 is expected to increase metabolic stability of these compounds and is thus a preferrred feature of the ion. Fluorination on the C17 side chain has been shown to improve potency and limit maximum potentiation of the NMDA receptor when tested as high as 1 uM concentration of compound. A secondary or ry terminal alcohol on the C 17 side chain has been shown to improve potency and limit maximum potentiation of the NMDA receptor when tested as high as 1 uM tration of compound, and is thus a preferred feature of the invention, with a preference for bulkier groups at the terminating end containing 2-3 carbons, or a group sing fluorine substitution. Such properties are expected limit the risk of inducing ate driven oxicity relative to compounds that achieve a greater maximum potentiation of the NMDA receptor Compounds of the t ion encompass various combinations of these specified features to provide superior NMDA modulators.

Compozmds [0085} In one aspect, provided herein are compounds according to a (I): and pharmaceutically acceptable salts thereof; R1 is tuted or unsubstituted aliphatic; R2 is hydrogen, halogen, substituted or unsubstituted C;_6alkyl, substituted or unsubstituted cyclopropyl, or —ORA'3, wherein RA2 is hydrogen or substituted or unsubstituted alkyl; R33 is hydrogen or —ORA3, wherein R“ is hydrogen or substituted or unsubstituted alkyl, and R3b is hydrogen; or R3a and R3b are joined to form an oxo (=0) group; R4 is hydrogen, substituted or unsubstituted alkyl, or halogen; X is —C(RX)2— or —O-, wherein RX is hydrogen or fluorine, or one RX group and R5b are joined to form a double bond; each instance of R5a and R5b is independently hydrogen or fluorine; R6a is a non-hydrogen group selected from the group consisting of substituted and unsubstituted alkyl, substituted and unsubstituted alkenyl, substituted and unsubstituted alkynyl, substituted and tituted carboc-yclyl, substituted and unsubstituted heterocyclyl, substituted and unsubstituted aryl, and substituted and unsubstituted heteroaryl group, wherein the non- hydrogen group is optionally substituted with fluorine; and R6b is hydrogen or a substituted or unsubstituted alkyl group optionally substituted with -._—_~; represents a single or double bond, ed if a single bond is present, then the hydrogen at C5 is in the alpha configuration; and further provided that: (l) at least one of RX, Rsa, and RSb is fluorine; or (2) at least one of R6a and R6b is a non-hydrogen group substituted with a fluorine; or (3) R6a is a drogen group sing between two and ten carbon atoms. [0086} As generally described herein, compounds n the hydrogen at C5 is provided in the hem configuration demonstrate loss ofNMDA iation compared to compounds wherein the hydrogen at C5 is alpha, or wherein a double bond is present at C5-C6. Thus, the compound of Formula (I) encompasses only compounds of Formula (I-A) and (LB): (I-A) (1-8) and pharmaceutically acceptable salts thereof.

Group R1 [0087} As generally defined herein, R1 is substituted or unsubstituted alphatic, 17.6., tuted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, or substituted or unsubstituted carbocyclyl. [0088} In certain embodiments, R1 is substituted or unsubstituted alkyl, e.g., substituted or unsubstituted C 1_6all<yl, substituted or unsubstituted l, substituted or unsubstituted C2_ galkyl, substituted or unsubstituted CHaikyl, substituted or unsubstituted C4_5alkyl, or substituted or unsubstituted kyl. Exemplary R1 Cmaikyl groups include, but are not limited to, substituted or unsubstituted methyl (C1), ethyl (C2), n—propyl (C 3), 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—butanyi (C5), tertiary amyi (C5), n—hexyl (C6), (31,6 alkyl substituted with i, 2, 3, 4, S, 6, 7, 8, 9, 10, or more fluoro groups (e.g., —CF3, —CH2F, —CHF2, difluoroethyl, and 2,2,2—trifluoro—I,l—dimethyl—ethyl), CM alkyl substituted with l, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more chloro groups (gag, —CH2Cl, —CHClz), and C14 alkyl tuted with alkoxy groups (8g, —CH20CH3, —CH30CH2CH3, —CH20-cyclopropyl). In certain embodiments, R1 is substituted alkyl, e.g., R1 is haloalkyl, aikoxyaikyi, or aminoalkyl. In certain embodiments, R1 is Me, Et, n-Pr, u—Bu, i-Bu, fluoromethyi, chloromethyi, difluoromethyl, trifluoromethyl, trifluoroethyl, difluoroethyl, 2 ,2,2-trifluoro- l ,I-dimethyi-ethyl, methoxymethyl, methoxyethyl, or ethoxymethyl. [0089} In certain embodiments, R1 is unsubstituted CH, alkyl, e.g., R1 is —CH3, -CH2CH3, 01‘ —CH2CH2CH3. [0090} In certain ments, R1 is alkyl substituted with one or more fluorine atoms; e.g., R1 is —CH3F, curl, or —CF3. [0091} In certain embodiments, R1 is alkyl substituted with one or more —ORAl groups, wherein RA1 is hydrogen or substituted or unsubstitued alkyl. In certain embodiments, R1 is — CHgORAi, e.g., wherein RA1 is hydrogen, —CH3, —CH2CH3, or —CH3CH3CH3. [0092} In certain embodiments, R1 is substituted or unsubstituted alkenyl, e.g., substituted or tituted C2,6alkenyl, substituted or tituted CHalkenyl, substituted or unsubstituted CHalkenyl, substituted or unsubstituted C475alkenyl, or substituted or unsubstituted Csfigalkenyl. In certain embodiments, R1 is ethenyl (C2), propenyl (C3), or butenyl (C4), unsubstituted or substituted with one or more substituents selected from the group consisting of alkyl, halo, haloalkyl, alkoxyalkyl, or yl. In certain embodiments, R1 is ethenyl, propenyl, or butenyl, unsubstituted or substituted with alkyi, halo, kyl, alkyl, or hydroxy. In n embodiments, R1 is ethenyl.

In certain embodiments, R1 is substituted or unsubstituted alkynyl, e.g., substituted or unsubstituted Cgmalkynyi, substituted or unsubstituted kynyl, substituted or unsubstituted Cgualkynyl, tuted or unsubstituted C4_5aikynyl, or substituted or unsubstituted Csnalkynyl. Exemplary substituted or tituted R1 l groups include, but are not limited to, ethynyl, propynyi, or butynyl, unsubstituted or substituted with alkyl, halo, haloalkyl (ag C133), alkoxyalkyl, cycloalkyl (rag, cyclopropyl or cyclobutyl), or hydroxyl. In certain embodiments, R1 is ed from the group consisting of trifluoroethynyl, cyclopropylethynyl, cyclobutylethynyl, and propynyi, fluoropropynyl, and chloroethynyl. In certain embodiments, R1 is ethynyl (C2), propynyl (C3), or butynyl (C4), unsubstituted or substituted with one or more substituents selected from the group consisting of substituted or unsubstituted aryl, substituted or unsubstituted heteroaryi, substituted or unsubstituted carbocyclyl, and tuted or tituted heterocyclyl, In certain embodiments, R1 is ethynyl (C2), propynyl (C3), or butynyl (C4) substituted with substituted phenyl. In certain ments, the phenyl substitutent is further substituted with one or more substituents ed from the group ting of halo, alkyl, trifluoroalkyl, alkoxy, acyl, amino or amido. In certain embodiments, R1 is ethynyl (C2), propynyl (C3), or butynyi (C4) substituted with substituted or tituted pyrrolyl, imidazolyl, pyrazolyl, oxazoyi, thiazolyl, oyl, 1,2,3-triazolyl, 1,2,4- triazolyl, oxadiazolyl, thiadiazolyl, or tetrazolyl. [0094} In n embodiments, R1 is ethynyl, propynyl, or butynyl, unsubstituted or substituted with alkyl, halo, haloalkyl, alkoxyalkyl, or hydroxyl. In certain ments, R1 is ethynyl or propynyl, tuted with substituted or unsubstituted aryl. In n embodiments, R1 is ethynyl or propynyl, substituted with phenyl unsubstituted or substituted with halo, alkyl, alkoxy, haloalkyl, trihaloalkyl, or acyl. In certain embodiments, R1 is ethynyl or propynyl, substituted with substituted or unsubstituted carbocyc-lyl. In certain embodiments, R3a is ethynyl or yl, substituted with substituted or unsubstituted cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In n ments, R1 is ethynyl or propynyl, substituted with substituted or unsubstituted heteroaryl. In certain ments, R1 is ethynyl or propynyl, substituted with substituted or unsubstituted pyridinyl, or pyrimidinyl. In certain embodiments, R1 is ethynyl or propynyl, substituted with substituted or unsubstituted pyrrolyl, imidazolyl, pyrazolyl, oxazoyl, thiazolyl, isoxazoyl, l,2,3—triazolyl, 1,2,4-triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl. In certain embodiments, R1 is ethynyl or propynyl, substituted with substituted or unsubstituted heterocyclyl. In certain embodiments, RI is ethynyl or propynyl, substituted with substituted or tituted pyrrolidinyl, piperidinyl, piperazinyl, or mopholinyl. In certain embodiments, R1 is propynyl or butynyl, substituted with hydroxyl or alkoxy. In certain embodiments, R1 is propynyl or butynyl, substituted with methoxy or ethoxy. In certain embodiments, R1 is ethynyl or propynyl, substituted with chloro. In certain ments, R1 is ethynyl or propynyl, substituted with trifluoromethyl. [0095} In certain embodiments, R1 is substituted or unsubstituted carbocyclyl, e.g., substituted or tituted C3,6carbocyclyl, substituted or unsubstituted CHcarbocyclyl, substituted or unsubstituted C475 carbocyclyi, or substituted or unsubstituted C5,6 yclyl. In certain embodiments, R1 is substituted or unsubstituted cyclopropyl or substituted or unsubstituted cyclobutyl.

Groups R2, R3”, R37), and R4 [0096} As generally defined herein, R2 is hydrogen, halogen, substituted or unsubstituted C1_5alkyl, substituted or unsubstituted cyclopropyl, or —ORA2, wherein RA2 is en or substituted. or unsubstituted alkyl. In certain ments, R2 is hydrogen. In certain embodiments, R2 is n, e.g, fluoro, chioro, bromo, or iodo. In certain embodiments, R2 is fluoro or chloro. In certain embodiments, R2 is substituted or unsubstituted C1_6alkyl, e.g., substituted or tituted Cygalkyl, substituted or unsubstituted CHalkyl, tuted or unsubstituted analkyl, substituted or tituted Cmgaikyl, or substituted or unsubstituted C5, 6alkyl. In certain embodiments, R2 is —CH3, -CH3CH3, —CH2CH2CH3, or cyclopropyl. In certain ments, R2 is —ORA2. In certain embodiments, RA2 is en. In certain embodiments, RA2 is substituted or unsubstituted alkyl, e.g., substituted or unsubstituted C t, galkyl, substituted or unsubstituted C1,3alkyl, tuted or unsubstituted CHalkyl, substituted or unsubstituted CHalkyl, substituted or unsubstituted Cmsalkyl, or substituted or unsubstituted yl. In certain embodiments, RA2 is hydrogen, —CH3, -CH3CH3, or —CH2CH2CH3, i. (2., to provide a group R2 of formula —OH, —OCH3, -OCH2CH3, or —OCH2CH3CH3. In certain embodiments, R2 is a non-hydrogen substitutent in the alpha configuration. In certain embodiments, R2 is a drogen substituent in the beta configuration. [0097} As generally defined herein, R33‘ is hydrogen or —ORM, wherein RAS is hydrogen or substituted or unsubstituted alkyl, and R3b is en; or R3a and R3b are joined to form an oxo (=0) group. [0098} In certain embodiments, both R33 and R3b are both hydrogen. [0099} In certain embodiments, R3‘1 and R3b are joined to form an oxo (=0) group.

In certain embodiments, R3“ is —ORA3 and R31) is hydrogen. In certain . . 2, m ments, wherein R‘ a is —ORA. 3 R” is in the alpha or baa. configuration. In certain. . . . . . 1 . 1 embodiments, wherein R"a is —ORA', R3 ‘ is in the alpha configuration. In certain embodiments,; . . . . . wherem R. 3 a . . . . . . .

A 3 3‘q . 3 is —OR"‘ R is in the beta configuration. In certain embodiments, R‘i‘ is hydrogen.

In certain embodiments, RA; is substituted or unsubstituted alkyl, e.g., substituted or unsubstituted C trgalkyl, substituted or unsubstituted Ctrzalkyl, substituted or tituted C2, 3alkyl, substituted or unsubstituted CHalkyl, substituted or unsubstituted CHalkyl, or substituted or unsubstituted Csréalkyl. In certain embodiments, RA3 is hydrogen, —CH3, - CH3CH3, or —CH2CH2CH3, 116., to provide a group R33 of formula —OH, —OCH3, -OCH2CH3, or —OCH2CH2CH3.

As generally defined herein, R4 is hydrogen, substituted or unsubstituted alkyl, or halogen. In certain embodiments, R4 is hydrogen. In certain embodiments, R4 is halogen, e.g, fluoro. In certain embodiments, R4 is substituted or unsubstituted alkyl, e.g, substituted or tituted Cmalkyl, substituted or unsubstituted C ;_3aikyl., substituted or unsubstituted C3. 3alky1, substituted or unsubstituted CHalkyl, tuted or unsubstituted C4_5alkyl, or substituted or unsubstituted Cwalkyl. In certain embodiments, R4 is C; alkyl, e.g., —CH3 or -CF3.

In certain embodiments, R,4 is hydrogen, -CH3, or —F. In certain embodiments, n :2: ents a single bond, R4 is a non-hydrogen substitutent in the alpha configuration. In certain embodiments, wherein — represents a single bond, R4 is a non—hydrogen substituent in the beta configuration.

GroupX, R5”, R57), R6“, and R65 As lly defined herein, X is —C(RX)2— or —O—, wherein RX is hydrogen or fluorine, or one RX group and R5b are joined to form a double bond; each of RS‘1 and R5b is independently hydrogen or fluorine; R63 is a drogen group selected from the group consisting of substituted and unsubstituted alkyl, substituted and unsubstituted alkenyl, substituted and unsubstituted alkynyl, tuted and unsubstituted carbocyclyl, substituted and unsubstituted cyclyl, substituted and unsubstituted aryl, and substituted and unsubstituted heteroaryl group, wherein the non-hydrogen group is ally substituted with fluorine; and R6b is hydrogen or a substituted or unsubstituted alkyl group optionally substituted with fluorine; provided: ( I) at least one of RX, R5“, and R5b is e; or (2) at least one of R6a and R6b is a non-hydrogen group substituted with fluorine; or (3) Rf"3 is a non-hydrogen group comprising between two and ten carbon atoms.

In certain embodiments, X is —0—. In n embodiments, X is —CH3—. In certain embodiments, X is —CF2—.

In certain embodiments, at least one of Rsa and R5b is hydrogen. In certain ments, at least one of R58 and R5b is fluorine. In certain embodiments, R53 and R5b are both hydrogen. In certain embodiments, R53 and R5b are both fluorine. In certain embodiments, RX and RSb are joined to form a double bond, e.g., cis or 1mm double bond.

In n embodiments, R6“ is a non-hydrogen group, as described herein, which is not substituted with fluorine. In certain ments, R63 is substituted or unsubstituted alkyl (e.g., —CH3, —CH2CH3, —CH(CH3)2), substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, or substituted or unsubstituted carbocyclyl (e.g., isopropanol). In n embodiments, R621 is a non-hydrogen group, as described herein, which is substituted with fluorine.

In certain embodiments, R68 is a non-hydrogen group, as described herein, and R6b is hydrogen. In certain embodiments, R6‘1 is a non-hydrogen group, as described herein, and R6b is a substituted or unsubstituted alkyl group ally substituted by fluorine. In certain embodiments, R6b is an alkyl group which is not tuted with fluorine. In certain embodiments, R6“ is an alkyl group which is substituted with fluorine.

In certain embodiments, R6b is hydrogen. In certain embodiments, R6b is substituted or unsubstituted alkyl, e.g., substituted or unsubstituted C 1,6alkyl, substituted or unsubstituted CHalkyl, tuted or unsubstituted C273alkyl, substituted or unsubstituted C3, 4alkyl, substituted or unsubstituted Crusaikyi, or substituted or unsubstituted CHalkyl, optionally substituted by e. In certain embodiments, R6b is C; alkyl ally substituted by fluorine, e.g., —CH3 or —CF3.

In certain embodiments, R621 is substituted or unsubstituted alkyl, e.g., substituted or tituted Cmalkyl, substituted or unsubstituted CHalkyl, substituted or unsubstituted C2, galkyl, substituted or unsubstituted CHalkyi, substituted or unsubstituted CHalkyl, or substituted or unsubstituted CHalkyl. ary R63 C 1_6alkyl groups include, but are not d to, substituted or unsubstituted methyi (C 1), substituted or unsubstituted ethyl (C 3), substituted or unsubstituted n—propyl (C3), substituted or unsubstituted pyl (C 3), substituted or unsubstituted n—butyl (C4), substituted or unsubstituted tert—butyl (C4), substituted or unsubstituted sec—butyl (C4), substituted or unsubstituted tyl (C4), substituted or unsubstituted n—pentyl (C5), substituted or unsubstituted 3—pentanyl (C5), substituted or unsubstituted amyl (C5), substituted or tituted neopentyl (C5), substituted or unsubstituted 3—methyl—2—butanyl (C5), substituted or unsubstituted tertiary amyl (C5), substituted or unsubstituted n—hexyl (C5). In certain embodiments, R63 is alkyl, as described above, tuted with one or more fluorines, e.g., l, 2, 3, 4, or more fluorines. In certain embodiments, R6a is — C173, —CH;F, —CHFg~ difluoroethyl, or 2,2,2—trifluoro—l ,l—dimethyl—ethyl). In certain embodiments, R68 is alkyl, as described above, substituted with one or more —ORA6 , n RA6 is hydrogen or substituted or titued alkyl. In certain embodiments, R63 is — CHZORA6, —CH2CH20RA6, or —CH3CH3CH20RA6, e.g., H3, —CH2CH20CH3, or — CH2CH2CH20CH3.

In certain ments, R63 is substituted or unsubstituted alkenyl, e.g., substituted or unsubstituted C2_6all<enyl, substituted or unsubstituted C3_3alkenyl, substituted or tituted CHalkenyl, substituted or unsubstituted C4,5a1kenyl, or substituted or unsubstituted CHalkenyl, optionally substituted with fluorine. In n embodiments, R6a is substituted or unsubstituted Vinyl (C2) or substituted or unsubstituted allyl (C 3).

In certain embodiments, R68 is substituted or unsubstituted alkynyl, tag substituted or unsubstituted Cgmalkynyl, substituted or unsubstituted CHalkynyl, substituted or unsubstituted nyl, substituted or unsubstituted Casalkynyl, or substituted or unsubstituted CHalkynyl, optionally substituted with fluorine. In certain embodiments, R6a is substituted or unsubstituted ethynyl (C3) or substituted or unsubstituted gyl (C3).

In certain embodiments, R6a is substituted or unsubstituted carbocyclyl, e.g., substituted or unsubstituted C3%carbocyclyl, substituted or unsubstituted Cgucarbocyclyl, substituted or unsubstituted C44 carbocyclyl, or substituted or unsubstituted Cam carbocyclyl, optionally substituted with fluorine. In certain embodiments, R63 is tuted or unsubstituted cyclopropyl.

In certain embodiments, R63 is substituted or unsubstituted heterocyclyl, e.g., substituted or unsubstituted C34, cyclyl, substituted or unsubstituted C3—4 heterocyclyl, substituted or unsubstituted C4_5 heterocyclyl, or substituted or unsubstituted C54) heterocyclyl, optionally substituted with fluorine.

In certain embodiments, R6‘1 is substituted or unsubstituted aiyl, tag, substituted or unsubstituted phenyl, optionally substituted with e.

In n embodiments, R62‘ is substituted or unsubstituted heteroaryl, e.g., optionally tuted 5— to 6—membered heteroaryl, optionally substituted with fluorine.

In certain embodiments, R6a is a non-hydrogen group comprising between two and ten carbon atoms, e.g., between two and nine, two and eight, two and seven, two and six, two and five, two and four, or two and three carbon atoms, inclusive. For example, in certain embodiments, R621 is tuted or unsubstituted C33 alkyi, substituted or unsubstituted C23 l, substituted or unsubstituted C2-3 alkynyl, or substituted or unsubstituted C3 carbocyclyl.

In certain embodiments, wherein at least one of RX, R53, and R5b is fluorine; or at least one of R63 and R6b is a drogen group substituted with fluorine; R621 is substituted or unsubstituted Cm alkyl, substituted or unsubstituted C 1-3 alkenyl, substituted or unsubstituted C r- 3 alkynyl, or substituted or unsubstituted C3 carbocyclyl.

In certain embodiments, R6a and R6b are the same group. In certain embodiments, R6a and R6b are different groups, and the carbon to R68 is attached is in the (S) or (R) configuration. In certain embodiments, the carbon to which R6a is attached is in the (S) configuration. In certain embodiments, the carbon to which R6a is ed is in the (R) uration. In n embodiments, R6a is —CF3 and R6b is hydrogen or C14 alkyl. In certain embodiments, R6“ is a non—hydrogen group substituted with fluorine, and R6b is —CH3. In certain embodiments, R6a is substituted with one or more —ORA6 groups, n RA6 is hydrogen or tuted or unsubstitued alkyl. In certain embodiments, R62‘ is a substituted or unsubstituted (32-4 alkyl, tuted or unsubstituted C23 alkenyl, substituted or unsubstituted C33 alkynyl, or substituted or unsubstituted C3 carbocyclyl, and R6b is —CH3. In certain embodiments, R6a is a unsubstituted C24 alkyl, unsubstituted C2_3 alkenyl, or unsubstituted C2_3 alkynyl, or unsubstituted C3 carbocyclyl, and R6b is —CH3. In certain embodiments, R6a is a non-hydrogen group substituted with fluorine, and R6b is —CH3.

Various Combinations of Certain Embodiments Various combinations of certain embodiments are futher plated herein.

For example, in n ments, wherein X is —CH2- and R5a and R51) are both hydrogen, provided is a compound of Formula (1-21): (1-21) or a pharmaceutically acceptable salt thereof. In certain ments, R63 is a non-hydrogen group comprising between two and ten carbon atoms. In certain embodiments, at least one of R6a and R6b is a non-hydrogen group substituted with fluorine. In certain embodiments, the carbon to which R6a is attached is in the (S) configuration. In certain embodiments, the carbon to which R6a is attached is in the (R) configuration. In certain embodiments, R63 is methyl (C 1) optionally substituted with one or more fluorines, e.g., -CH3 or -CF3. In certain embodiments, R681 is substituted or unsubstituted ethyl (C3), substituted or unsubstituted n—propyl (C 3), or substituted or unsubstituted pyl (C3). In certain embodiments, R6“ is —CHZORA6, — CH2CH30RA6, or —CH2CH2CH20RA6. In certain embodiments, R6“ is substituted or unsubstituted Vinyl (C2) or tuted or tituted allyl (C13). In certain embodiments, R6“ is substituted or unsubstituted ethynyl (C3) or substituted or unsubstituted propargyl (C3). In certain embodiments, R6“ is substituted or unsubstituted cyclopropyl. In certain embodiments, R6b is hydrogen. In certain embodiments, R6b is —CH3 or —CF3. In certain embodiments, — represents a single bond, and the hydrogen at C5 is alpha. In certain ments, — represents a double bond. In certain embodiments, R1 is —CH3 or —CH2CH3. In certain ments, R2 is hydrogen, —OH, —OCH -OCH2CH3, —OCH3CH2CH3, —CH3, 3, —CH2CH2CH3, cyclopropyl, fluoro, or chloro. In certain embodiments, R2 is a drogen substitutent in the alpha configuration. In n embodiments, R2 is a drogen substituent in the beta configuration. In certain embodiments, R3“ and R3b are both hydrogen. In certain embodiments, R3a and R3b are joined to form =0 (0x0). In certain embodiments, R4 is hydrogen.

In n embodiments, wherein X is —CH2- and R52! and R5b are both fluorine, provided is a compound of Formula (I-b): (Lb) or a pharmaceutically acceptable salt thereof. In certain embodiments, R6a is a non-hydrogen group sing between two and ten carbon atoms. In certain embodiments, at least one of R6a and R6b is a non-hydrogen group substituted with fluorine. In certain embodiments, the carbon to which R6a is attached is in the (S) configuration. In certain embodiments, the carbon to which R621 is attached is in the (R) ration. In certain embodiments, R63 is methyl (C 1), optionally tuted with one or more fluorines, e.g., -CH3 or -CF3. In certain embodiments, R681 is substituted or unsubstituted ethyl (C3), substituted or unsubstituted n—propyl (C 3), or substituted or unsubstituted isopropyl (C3). In certain embodiments, R6“ is —CHZORA6, — CH2CH30RA6, or —CH2CH2CH20RA6. In certain embodiments, R6“ is tuted or unsubstituted Vinyl (C2) or substituted or unsubstituted allyl (C3). In certain embodiments, R6“ is substituted or unsubstituted ethynyl (C3) or substituted or unsubstituted propargyl (C3). In certain embodiments, R6“ is substituted or unsubstituted cyclopropyl. In certain ments, R6b is hydrogen. In certain embodiments, R6b is —CH3 or —CF3. In certain embodiments, — represents a single bond, and the hydrogen at C5 is alpha. In certain embodiments, — represents a double bond. In certain embodiments, R1 is —CH3 or —CH2CH3 In certain embodiments, R2 is hydrogen, —OH, —OCH -OCH2CH3, —OCH2CH2CH3, —CH3, -CH2CH3, 2CH3, cyclopropyl, fluoro, or chloro. In certain embodiments, R2 is a drogen substitutent in the alpha configuration. In certain embodiments, R2 is a non-hydrogen substituent in the beta configuration. In certain embodiments, R3“ and R3b are both hydrogen. In n embodiments, R3a and R3b are joined to form =0 (0x0). In n embodiments, R4 is hydrogen.

In n embodiments, wherein X is —C(RX)2- and one RX group and R5b are joined to form a trans double bond, provided is a compound of Formula (Le): (I-C) or a pharmaceutically acceptable salt thereof. In n embodiments, R6a is a non-hydrogen group comprising between two and ten carbon atoms. In n embodiments, at least one of R6a and R6b is a non-hydrogen group tuted with fluorine. In certain embodiments, the carbon to which R6a is attached is in the (S) configuration. In certain embodiments, the carbon to which R621 is attached is in the (R) configuration. In certain embodiments, R63 is methyl (C 1) optionally substituted with one or more fluorines, 6g, -CH3 or -CF3. In certain ments, R681 is substituted or tituted ethyl (C3), substituted or unsubstituted n—propyl (C 3), or substituted or tituted isopropyl (C3). In certain embodiments, R6“ is —CHZORA6, — CH2CH30RA6, or —CH2CH2CH20RA6. In certain embodiments, R6“ is tuted or unsubstituted Vinyl (C2) or substituted or unsubstituted allyl (C3). In certain embodiments, R6“ is substituted or unsubstituted ethynyl (C3) or substituted or unsubstituted propargyl (C3). In n embodiments, R621 is substituted or unsubstituted cyclopropyl. In certain embodiments, R6b is hydrogen. In certain embodiments, R6b is —CH3 or —CF3. In certain embodiments, — represents a single bond, and the hydrogen at C5 is alpha. In certain embodiments, — represents a double bond. In certain ments, R1 is —CH:, or —CH2CH3. In certain embodiments, R2 is hydrogen, —OH, —OCH3, -OCH2CH3, —OCH2CH2CH3, —CH3, -CH2CH3, — CH2CH2CH3, cyclopropyl, fluoro, or chloro. In n embodiments, R2 is a non-hydrogen substitutent in the alpha configuration. In certain embodiments, R2 is a non-hydrogen substituent in the beta configuration. In certain embodiments, R33 and R3b are both hydrogen. In certain ments, R33 and R3b are joined to form =0 (0x0). In certain embodiments, R4 is hydrogen.

In certain embodiments, the compound of Formula (I) is selected from a compound of Formula (II): c5 R1 (H) or a pharmaceutically acceptable salt thereof. In certain embodiments, R621 is a drogen group comprising between two and ten carbon atoms. In certain embodiments, at least one of R63 and R6b is a non-hydrogen group substituted with fluorine. In certain embodiments, the carbon to which R68 is attached is in the (S) configuration. In certain embodiments, the carbon to which R63 is attached is in the (R) configuration. In certain embodiments, R621 is methyl (C1) optionally substituted with one or more fluorines, e.g., -CH3 or -CF3. In certain embodiments, R63 is substituted or unsubstituted ethyl (C2), substituted or unsubstituted n—propyl (C3), or substituted or tituted isopropyl (C3). In certain embodiments, R6a is —CH20RA(’, — CH2CH20RA6, or —CH2CH2CH20RA6. In certain embodiments, R6'“ is substituted or unsubstituted Vinyl (C2) or substituted or tituted ailyl (C 3). In certain embodiments, R6a is tuted or unsubstituted l (C2) or substituted or unsubstituted propargyi (C3). In certain embodiments, R63 is substituted or unsubstituted cyclopropyl. In certain embodiments, R6b is en. In certain embodiments, Rbb is —CH3 or —CF3. In certain embodiments, — represents a single bond, and the hydrogen at C5 is alpha. In certain embodiments, —- ents a double bond. In certain embodiments, R1 is —CH3 or —CH2CH3.

In certain embodiments, the compound of Formula (I) is selected from a compound of Formula (II-A): (II-A) or a pharmaceutically acceptable salt thereof. In certain embodiments, R6a is a non-hydrogen group sing between two and ten carbon atoms. In certain ments, at least one of R63 and R6b is a non-hydrogen group substituted with fluorine. In certain embodiments, the carbon to which Rm1 is attached is in the (S) configuration In certain embodiments, the carbon to which R68 is attached is in the (R) configuration. In n embodiments, R6a is methyl (C1) optionally substituted with one or more fluorines, e.g., -CH3 or -CF3. In certain embodiments, R6a is substituted or unsubstituted ethyl (C2), substituted or unsubstituted n—propyl (C3), or substituted. or unsubstituted isopropyl (C3). In certain embodiments, R621 is —CH20RA6, — CHZCHZORM", or —CH2CH2CH20RAG. In certain embodiments, R6“ is substituted or unsubstituted Vinyl (C2) or substituted or unsubstituted allyi (C3). In certain embodiments, R6a is substituted or unsubstituted ethynyl (C2) or substituted or unsubstituted propargyi (C3). In certain embodiments, R68 is tuted or unsubstituted ropyl. In certain embodiments, R6b is hydrogen. In certain embodiments, R6b is —CH3 or —CF3. In certain embodiments, R1 is — CH3 OI‘ —CH2CH3.

In certain embodiments, the compound of Formula (I) is selected from a compound of Formula (II-B): R R (II-B) or a pharmaceutically able salt thereof. In certain embodiments, R6“ is a non-hydrogen group sing between two and ten carbon atoms. In certain embodiments, at least one of R6"1 and R61) is a drogen group substituted with fluorine. In certain embodiments, the carbon to which RGa is attached is in the (S) configuration. In certain embodiments, the carbon to which R621 is attached is in the (R) configuration. In n embodiments, R6“ is methyl (C 1) optionally substituted with one or more fluorines, cg -CH3 or -CF3. In certain embodiments, R661 is substituted or unsubstituted ethyl (C3), substituted or unsubstituted n—propyl (C 3), or tuted or unsubstituted pyl (C3). In certain embodiments, R61‘ is —CHZORA6, — CH2CH20RA6, or —CH2CH2CH20RA6. In n embodiments, R6a is tuted or unsubstituted Vinyl (C2) or substituted or unsubstituted ailyi (C3). In certain embodiments, R621 is substituted or unsubstituted ethynyl (C2) or substituted or unsubstituted propargyl (C 3). In certain embodiments, RGa is substituted or unsubstituted cyciopropyl. In certain embodiments, R6b is hydrogen. In n embodiments, R6b is —CH3 or —CF34 In certain embodiments, R1 is — CH3 01‘ —CH2CH3.

In certain embodiments, a compound of Formula (I) is selected from the group consisting of: 6-12 6-1 6 6-1 8 1 0-8 -7 -12 1 D-12A -123 10-13 -14 -20 10-21 1 0-22 10-23 11-15 11-16 11-17 11-18 11-19 11-20 and pharmaceutically acceptable salts f Pharmaceutical Compositions In another , the invention provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a ive amount of a compound of Formula (I).

When employed as pharmaceuticals, the compounds ed herein are typically administered in the form of a pharmaceutical ition. Such compositions can be prepared in a manner well known in the pharmaceutical art and comprise at least one active compound.

In one embodiment, with respect to the pharmaceutical composition, the carrier is a parenteral carrier, oral or l carrier.

The present invention also relates to a compound of Formula (I) or pharmaceutical composition thereof for use as a pharmaceutical or a medicament.

Generally, the compounds ed herein are administered in a therapeutically effective amount. The amount of the compound actually administered will typically be determined by a physician, in the light of the relevant stances, including the condition to be treated, the chosen route of administration, the actual compound administered, the age, weight, and response of the individual patient, the severity of the patient’s symptoms, and the like.

] The pharmaceutical compositions provided herein can be administered by a variety of routes including oral, rectal, transdermal, subcutaneous, enous, intramuscular, and intranasal. Depending on the intended route of delivery, the compounds provided herein are preferably formulated as either in] ectable or oral compositions or as salves, as lotions or as patches all for transdermal administration.

The compositions for oral administration can take the form of bulk liquid solutions or sions, or bulk powders. More commonly, however, the compositions are presented in unit dosage forms to facilitate accurate dosing. The term “unit dosage forms” refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material ated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient. Typical unit dosage forms include prefilled, premeasured ampules or syringes of the liquid compositions or pills, tablets, es or the like in the case of solid itions. 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) with the remainder being various vehicles or carriers and processing aids helpful for forming the desired dosing form.

Liquid forms suitable for oral administration may include a suitable aqueous or nonaqueous e with buffers, suspending and dispensing agents, colorants, flavors and the like. Solid forms may include, for example, any of the following ingredients, or compounds of a r nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or e, a disintegrating agent such as alginic acid, Primogel, or corn starch; a lubricant such as ium stearate; a glidant such as colloidal silicon dioxide; a ning agent such as sucrose or rin; or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring. lnjectable compositions are typically based upon injectable sterile saline or phosphate-buffered saline or other injectable carriers known in the art. As before, the active nd in such itions is lly a minor component, often being from about 0.05 to % by weight with the remainder being the injectable carrier and the like.

Transdermal compositions are typically formulated as a topical ointment or cream containing the active ingredient(s), generally in an amount ranging from about 0.01 to about 20% by , preferably from about 0.1 to about 20% by weight, preferably from about 0.1 to about % by weight, and more preferably from about 0.5 to about 15% by weight. When formulated as a ointment, the active ingredients will typically be combined with either a paraffinic or a water-miscible ointment base. atively, the active ingredients may be formulated in a cream with, for example an oil-in-water cream base. Such transdermal formulations are well- known in the art and generally include additional ingredients to enhance the dermal penetration of stability of the active ingredients or the formulation. All such known transdermal formulations and ingredients are included within the scope provided herein.

The compounds provided herein can also be administered by a ermal device. Accordingly, transdermal administration can be accomplished using a patch either of the reservoir or porous ne type, or of a solid matrix variety.

The above-described components for orally administrable, inj ectable or topically administrable compositions are merely representative. Other materials as well as processing techniques and the like are set forth in Part 8 of Remingfon ’5 Pharmaceutical Sciences, 17th n, 1985, Mack Publishing Company, Easton, Pennsylvania, which is incorporated herein by reference.

The above-described components 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 ’5 The Science and Practice of Pharmacy, let edition, 2005, Publisher: Lippincott Williams & Wilkins, which is incorporated herein by reference.

The compounds of this invention can also be stered in sustained release forms or from sustained release drug delivery systems. A description of representative sustained release als can be found in Remington ’5 Pharmaceutical es.

The present invention also s to the pharmaceutically acceptable formulations of a compound of Formula (I). In one embodiment, the formulation comprises water. In another embodiment, the formulation comprises a cyclodextrin derivative. The most common cyclodextrins are (1—, [3— and y— cyclodextrins consisting of 6, 7 and 8 d—l ,4—linked glucose units, respectively, optionally comprising one or more tuents on the linked sugar moieties, which include, but are not limited to, ated, yalkylated, acylated, and sulfoalkylether substitution. In certain ments, the cyclodextrin is a sulfoalkyl ether [i—cyclodextrin, e. g., for example, sulfobutyl ether B—cyclodextrin, also known as Captisol®. See, e.g., U.S. ,376,645. In certain embodiments, the formulation comprises hexapropyl-B—cyclodextrin. In a more particular embodiment, the ation comprises hexapropyl-B-cyclodextrin % in water).

The present invention also relates to the pharmaceutically acceptable acid addition salt of a compound. of Formula (I). The acid which may be used to e the pharmaceutically acceptable salt is that which forms a non-toxic acid addition salt, i.e., a salt containing pharmacologically acceptable anions such as the hydrochloride, hydroiodide, hydrobromide, nitrate, sulfate, bisulfate, phosphate, acetate, lactate, citrate, taitrate, succinate, maleate, fumarate, benzoate, para-toluenesulfonate, and the like.

The following ation examples illustrate representative ceutical compositions that may be prepared in accordance with this invention. The present invention, however, is not limited to the following ceutical itions.

Exemplary Formulation I — Tablets: A compound of Formula (I), or pharmaceutically able salt thereof, may be admixed as a dry powder with a dry gelatin binder in an approximate 1:2 weight ratio. A minor amount of magnesium stearate is added as a lubricant. The mixture is formed into 240-270 mg tablets (80-90 mg of active compound per tablet) in a tablet press.

Exemplary Formulation 2 — Capsules: A compound of Formula (I), or pharmaceutically acceptable salt thereof, may be admixed as a dry powder with a starch diluent in an approximate 1:1 weight ratio. The e is filled into 250 mg capsules (125 mg of active compound per capsule).

Exemplary Formulation 3 — Liquid: A compound of Formula (I), or pharmaceutically acceptable salt thereof, (125 mg) may be admixed with sucrose (1.75 g) and xanthan gum (4 mg) and the resultant mixture may be blended, passed through a No. 10 mesh US. sieve, and then mixed with a previously made solution of microcrystalline cellulose and sodium carboxymethyl cellulose (l 1:89, 50mg) in water. Sodium benzoate (10 mg), flavor, and color are diluted with water and added with stirring, ent water may then be added to produce a total volume of 5 mL.

Exemplary Formulation 4 — Tablets: A compound of a (I), or pharmaceutically acceptable salt thereof, may be admixed as a dry powder with a dry gelatin binder in an approximate 1:2 weight ratio. A minor amount of magnesium stearate is added as a lubricant. The mixture is formed into 450—900 mg tablets (150-300 mg of active compound) in a tablet press.

Exemplary Formulation 5 - Injection: A nd of a (I), or pharmaceutically able salt thereof, may be dissolved or suspended in a buffered sterile saline injectable aqueous medium to a concentration of approximately 5 mg/mL.

Exemplary ation 6 — Tablets: A compound of Formula (I), or pharmaceutically acceptable salt thereof, may be admixed as a dry powder with a dry gelatin binder in an approximate 1:2 weight ratio. A minor amount of magnesium stearate is added as a lubricant. The mixture is formed into 90—150 mg s (30-50 mg of active compound per tablet) in a tablet press.

Exemplary Formulation 7 — Tablets: v may be admixed as a dry powder with a dry gelatin binder in an approximate 1:2 weight ratio. A minor amount of ium stearate is added as a lubricant. The mixture is formed into 30-90 mg tablets (10-30 mg of active nd per tablet) in a tablet press.

Exemplary Formulation 8 — Tablets: A compound of Formula (I), or pharmaceutically acceptable salt thereof, may be admixed as a dry powder with a dry gelatin binder in an approximate 1:2 weight ratio. A minor amount of magnesium stearate is added as a lubricant. The mixture is formed into 03-30 mg tablets 0 mg of active compound per tablet) in a tablet press.

Exemplary Formulation 9 — Tablets: A compound of Formula (I), or pharmaceutically acceptable salt thereof, may be admixed as a dry powder with a dry gelatin binder in an approximate 1:2 weight ratio. A minor amount of magnesium stearate is added as a lubricant. The mixture is formed into 150-240 mg tablets (50-80 mg of active compound per tablet) in a tablet press.

] Exemplary Formulation 10 — Tablets: A compound of Formula (I), or pharmaceutically acceptable salt thereof, may be admixed as a dry powder with a dry gelatin binder in an approximate 1:2 weight ratio. A minor amount of magnesium te is added as a ant. The mixture is formed into 270-450 mg tablets (90—150 mg of active compound per tablet) in a tablet press.

Injection dose levels range from about 0.1 mg/kg/hour to at least 10 mg/kg/hour, all for from about 1 to about l20 hours and especially 24 to 96 hours. A preloading bolus of from about 0.1 rug/kg to about 10 mg/kg or more may also be administered to achieve adequate steady state levels. The maximum total dose is not expected to exceed about 2 g/day for a 40 to 80 kg human t.

For the tion and/or ent of erm conditions the regimen for treatment usually stretches over many months or years so oral dosing is preferred for patient convenience and tolerance. With oral dosing, one to five and especially two to four and typically three oral doses per day are representative regimens. Using these dosing patterns, each dose provides from about 0.01 to about 20 mg/kg of the compound provided , with preferred doses each providing from about 0.1 to about 10 mg/kg, and especially about 1 to about 5 mg/kg.

Transdermal doses are generally ed to e similar or lower blood levels than are achieved using injection doses.

When used to prevent the onset of a CNS-disorder, the compounds provided herein will be administered to a subject at risk for developing the condition, typically on the advice and under the supervision of a physician, at the dosage levels described above. Subjects at risk for developing a ular condition generally include those that have a family history of the condition, or those who have been identified by genetic g or ing to be particularly susceptible to developing the condition.

,Mellzods ofTreatment and Use ] Compounds of Formula (I), and pharmaceutically acceptable salts thereof, as described herein, are generally designed to te NMDA function, and therefore to act as neuroactive steroids for the treatment and prevention of CNS—related conditions in a subject.

Modulation, as used herein, refers to the inhibition or potentiation of NMDA or function.

In certain embodiments, the compound of Formula (I), or pharmaceutically acceptable salt thereof, may act as a negative allosteric tor (NAM) ofNMDA, and inhibit NMDA receptor function. In certain ments, the nd ofFormula (I), or pharmaceutically able salt thereof, may act as positive allosteric modulators (PAM) ofNMDA, and potentiate NMDA receptor function.

Exemplary CNS conditions related to NMDA-modulation include, but are not limited to, adjustment disorders, anxiety disorders (including obsessive-compulsive disorder, posttraumatic stress disorder, social phobia, generalized anxiety disorder), cognitive disorders (including Alzheimer’s disease and other forms of dementia), dissociative disorders, eating disorders, mood disorders (including depression, bipolar disorder, and dysthymic disorder), schizophrenia or other psychotic disorders (including schizoaffective disorder), sleep disorders (including insomnia), substance abuse-related disorders, personality disorders (including obsessive-compulsive personality disorder), autism spectrum disorders (including those involving mutations to the Shank group of proteins), neurodevelopmental disorders ding Rett syndrome), pain (including acute and chronic pain), seizure disorders (including status epilepticus and monogenic forms of epilepsy such as Dravet’s disease, and Tuberous Sclerosis Complex (TSC)), stroke, traumatic brain injury, movement disorders (including Huntington’s disease and Parkinson’s disease) and tinnitus. In certain embodiments, the compound of Formula (I), or pharmaceutically acceptable salt thereof, can be used to induce sedation or anesthesia. In certain embodiments, the compound of Formula (I), or pharrnaceutically acceptable salt f, is useful in the treatment or prevention of adjustment disorders, anxiety disorders, cognitive disorders, dissociative ers, eating disorders, mood disorders, schizophrenia or other psychotic disorders, sleep disorders, substance-related ers, personality disorders, autism spectrum disorders, neurodevelopmental disorders, pain, seizure disorders, , traumatic brain , movement disorders and tinnitus.

In another aspect, provided is a method of treating or preventing brain excitability in a subject susceptible to or afflicted with a ion associated with brain excitability, comprising administering to the subject an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt f.

In yet another aspect, the present invention provides a combination of a compound of Formula (I), or pharmaceutically acceptable salt f, and another pharmacologically active agent. The compounds provided herein can be administered as the sole active agent or they can be stered in combination with other agents. Administration in combination can d by any technique apparent to those of skill in the art including, for example, separate, sequential, rent and alternating administration.

In order that the invention described herein may be more fully understood, the following es are set forth. The synthetic and biological examples described in this application are offered to illustrate the compounds, pharmaceutical compositions and methods provided herein and are not to be construed in any way as limiting their scope. als and Methods The compounds provided herein can be prepared from readily available starting materials using the following general methods and ures. It will be appreciated that where typical or preferred process conditions (17.6., reaction temperatures, times, mole ratios of reactants, solvents, pressures, etc.) are given, other process conditions can also be used unless otherwise stated. Optimum reaction conditions may vary with the particular reactants or solvent used, but such ions can be determined by one skilled in the art by routine optimization.

Additionally, as will be apparent to those d in the art, conventional protecting groups may be necessary to prevent certain functional groups from undergoing undesired ons. The choice of a suitable protecting group for a particular functional group as well as le conditions for protection and deprotection are well known in the art. For example, numerous protecting , and their introduction and removal, are described in T. W.

Greene and P. G. M. Wuts, Protecting Groups in Organic Synthesis, Second Edition, Wiley, New York, 1991, and references cited n.

] The compounds provided herein may be isolated and purified by known standard ures. Such procedures include (but are not d to) recrystallization, column chromatography, HPLC, or supercritical fluid chromatography (SFC). The following schemes are presented with details as to the preparation of representative substituted biarylamides that have been listed herein. The compounds provided herein may be ed from known or commercially available starting materials and reagents by one skilled in the art of organic synthesis. Exemplary chiral columns available for use in the separation/purification of the enantiomers/diastereomers provided herein include, but are not limited to, CHIRALPAK® AD- , CHIRALCEL® OB, CHIRALCEL® OB-H, CHIRALCEL® OD, CHIRALCEL® OD-H, CHIRALCEL® OF, CEL® OG, CHIRALCEL® OJ and CHIRALCEL® OK.

General method for supercritical fluid chromatography (SFC): SFC purification was carried out using a Thar 200 preparative SFC instrument equipped with a ChiralPak AD-lO uM, 200x50 mm ID. The compounds were separated eluting with mixtures of carbon dioxide and methanol or ethanol . 20-35% methanol or ethanol and 0.l% ammonium hydroxide) at a flow rate of 55-200 mL/min and monitored at 220 nm wavelength.

] Single pure isomers were obtained after SFC chromatographic separation, yielding two isomers with a diasteriomeric ratio 2 95:5, as determined by SFC chromatography.

The configuration of the steroid C-24 stereocenter of 1-13 and 1-14, and 2-20 and 2-21 s was determined by the Mosher Method (Dale, J. A., Dull, D. L., and Mosher, H. S. (1969) J. Org. Chem. 34, 2543). The C-24 configuration of subsequent derivatives that employed such intermediates, for example 1-15 and 1-17, were assigned accordingly.

For all other single diastereomers, for which the C—24 stereocenter was not determined by the Mosher Method, the first g diastereomer from the SFC was tentatively assigned to be attached in the (R) configuration at C-24, whereas the second eluting diastereomer from the SFC was tentatively assigned to be attached in the (S) configuration at C—24. The ments were not unambiguously confirmed by the Mosher Method or other ques.

Example 1.

O o/\| Ho/\/OH Bess-Martin. MeMgBr, MAD —> —> —> PTSA, toluene, CHZC'Z toluene reflux DHEA aq. HCI Ph3PEtBr THF/acetone t—BuOK, THF DIBAL-H Pd/C, H2 F’d/C, H2 (1 atm) (50 psi) EtOAc EtOAc Pd/C, H2 (131m) EtOAc PdlC, H2 (1atm) EtOAc ] Preparation ofCompound 1-2. To a solution of ketone 1-1 (50.0 g, 0.17 mol) and ethylene glycol (62 mL) in toluene (600 mL) was added p—toluenesulfonic acid (1.4 g, 7.28 mmol). The reaction mixture was refluxed overnight with a tark trap. The mixture was cooled to room temperature, diluted with ethyl acetate (500 mL)) and washed with saturated aqueous sodium bicarbonate (300 mL x 2) and brine (300 mL x 2). The organic phase was dried over sodium sulfate and trated in vacuum to afford crude product 1-2 (64.0 g, 100%) which was directly used in the next step Without further purification. 1H NMR: (400 MHz, CDCl3) 6 5.35 (d, J=5.6 Hz, lH), 397—38201], 4H), 3.59—3.47 (m lH), 2.34-2.21(rn, 2H), 2.06- 1.94011, 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), .93 (m, 1H), 0.86 (s, 3H).

Preparation ofCompound 1-3. To a on of compound 1-2 (32 g, 96 mmol) in dry CHgClg (1200 mL) was added Bess-Martin reagent (81 g, 192 mmol) in portions at 0°C.

Then the reaction mixture was stirred at room temperature for 3 h. TLC (petroleum ether: ethyl acetate: 3: 1) showed the starting material was consumed completely. The mixture was quenched with saturated aqueous NaHC03/Na28303 = 1:3 (1 L). The organic phase was washed with brine (500 mL) and dried over Na2804, and the solvent was evaporated to afford crude product 1-3 (33.0 g, 100%), which was directly used in the next step without r ation. 1H NMR: (400 MHz, CDCl3) 5 5.34 (d, J=5.2 Hz, 1H), 3.77—4.00 (in. 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 (111.211), 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). ation ofAIAD. To a solution of 2,6-di-tert-butyl—4—methylphenol (40 g, 180 mmol) in toluene (200 mL) was added a on ofAlMe; (45 mL, 90 mmol, 2 M in hexane) at room temperature. The resulting mixture was stirred at room ature for l h and used as a solution ofMAD in toluene in the next step without any purification.

Preparation ofCompound 1-4. To a solution ofMAD (90 mmol, freshly prepared) in toluene (200 mL) was added dropwise a solution of compound 1-3 (10 g, 30 mmol) in toluene (80 mL) at -78°C during a period of 1 h under nitrogen. Then the reaction mixture was stirred for 30 min. a solution of r (30 mL, 90 mmol, 1.0 M in toluene) was added dropwise at —78°C. The on mixture was warmed to 40°C and stirred at this temperature for 3 h. TLC (petroleum ether: ethyl acetate = 3: 1) showed that the ng material was consumed completely. The mixture was poured into saturated aqueous NH4Cl solution (200 mL) and extracted with EtOAc (150 1nL x 2). The combined c phases were dried over Na2804‘ and the solvent was evaporated to afford crude product, which was purified by column chromatography on silica gel (eluent: petroleum ether: ethyl acetate = 15:1) to give compound 1- 4 (4 g, 38 %) as white powder. 1H NMR: (400 MHz, CDCl3) 6 5.30 (d, J=5.2 Hz, 1H), 3.75-4.04 (m, 4H). 2.42 (d, J=13.6 Hz, 1H), .12(m,3H), 1.73-1.86 (m, 2H), 1.64—1.72 (111,211), l.52-l.63 (m, 4H), l.35—l.51(m, 4H), 1.19-1.32 (m, 1H). l.l2-l.18 (m, 1H), l.l0 (s, 3H). 0.99- 1.03 (m, 3H). 0.92-0.98 (m, 1H), 0.86 (s, 3H).

Preparation ofCompound 1-5. To a solution of compound 1-4 (6.0 g, 17.3 mmol) in THF (200 mL) was added aqueous HCl solution (35 mL, 1 M) and acetone (35 mL).

The reaction mixture was stirred for 20°C at room temperature. TLC (petroleum ether: ethyl acetate = 3:1) indicated that the reaction was complete. Then the reaction mixture was diluted with EtOAc (200 mL), washed with saturated aqueous NaHC03 solution (200 mL), dried over Na3804 and ated under reduced pressure to give 1-5 (5.2 g, 99.2%). 1H NMR: (400 MHZ, CDC13) 6 5.27 (d, J=6.8 Hz, 1H), 2.45-2.35 (m, 2H), 2.09-1.84 (m, 4 H), .57 (m, 6H), 1.50-1.35 (m, 4H), 1.26-1.08 (m, 4H), 1.05 (s, 3 H), 0.95 (s, 3 H), 0.86 (s, 3 H).

Preparation ofCompound 1-6. To a solution of Ph3PEtBr (12.25 g, 33.00 mmol) in dry THF (15 mL) was added dropwise a solution of I-BuOK (3.70 g, 33.00 mmol) in dry THF (10 mL) under N2 at 0°C. The mixture was stirred at room temperature for 1.5 h. Then a solution of 1-5 (1.00 g, 3.31 mmol) in THF (10 mL) was added dropwise and the resulting mixture was stirred at 70°C for 4 h. TLC (petroleum ether: ethyl acetate = 3: 1) indicated that the starting material was consumed completely. The on was quenched with saturated aqueous NH4C1 solution (50 mL) and extracted with EtOAc (30 mL x 2). The combined organic phases were dried over Na2804 and concentrated in vacuum. The residue was purified by column chromatography on silica gel (eluent: petroleum ether: ethyl acetate = 12: 1) to give 1-6 (900 mg, 90.9%) as white powder. 1H NMR: (400 MHz, CDC13) 5 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 (m3 3 H), 1.12 (s, 3H), 1.02 (s, 3H), 0.95—1.01 (m, 1H), 0.90 (s, 3H).

Preparation ound 1-7. To a solution of compound 1-6 (1.00 g, 3.20 mmol) and methyl propiolate (0.67 g, 8.00 mmol) in dry CH2C12 (15 mL) was added dropwise a solution of Et2A1C1 (12.8 mL. 12.8 mmol, l M in toluene) with stirring at 0°C. Then the reaction was warmed to room temperature and stirred for 20 h. TLC leum ether: ethyl acetate = 5: 1) ted that the starting material was consumed tely. The mixture was ed with saturated aqueous NaHC03 solution (30 mL) and extracted with CH3C13 (30 mL x 2). The combined c phases were dried over Na3804 and concentrated in vacuum. The residue was purified by column chromatography on silica gel (eluent: petroleum ether: ethyl acetate = 10: 1) to give 1-7 (1.00 g, 78.7%) as white powder. 1H NMR: (400 MHz, CDCl3) 6 6.97-6.91 (m. 1 H) .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), .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), r21— 1.26 (m, 1H), 1.18 (d, J=6.78 Hz, 3H), 1.12 (s, 3H), 1.04 (s, 3H), 0.82 (s, 3H).

Preparation ofCompound 1-8. To a solution of nd 1-7 (1.75 g, 4.4 mmol) in dry THF (20 mL), DIBAL-H ( l M in THF, 22 mL, 22.0 mmol) was added dropwise at —78°C under nitrogen. The reaction mixture was warmed to 30°C and then d for 2 h at 300C. The reaction was quenched with on of H20 (2 mL), diluted with EtOAc (200 mL) and dried over anhydrous Na2804, filtered through a pad of celite and the pad was washed with EtOAc (50 mL x 3). The combined filtrates were concentrated in vacuum to give the crude product 1-8 (l .6 g, 98%) which was directly used in the next step without further purification.

] Preparation ofCompound 1-9. A e of 1-8 (1.6 g, 4.3 mmol) and lVlllOz (7.5 g, 86.0 mmol) in CHgClg (50 mL) was stirred at 30°C for 20 h. The reaction mixture was filtered through a pad of celite and the pad was washed with CH2Cl2 (50 mL x 3). The combined filtrates were concentrated to dryness to give the crude product 1-9 (1.3 g, 82%) which was directly used in the next step without purificationlfl NMR: (400 MHz, CDCl3) 5 9.54 (d, J=7.6 Hz, lH), 6.84-6.78 (dd, J1=15.6 HZ, J2=7.6 Hz, 1H), 5.54—5.49 (dd, .]1=15.6 HZ, 112:7.6 Hz, 1H), .45—5.44 (m, 1H), 5.32 (d, J=5.2Hz, 1H),3.19-3.12(m, 1 H), 2.42 (d, J=12.8 Hz, 1H), 2.14-2.08 (m, 1H), 2.00—1.52 (m, 13H), 1.42—1.35 (m, 3H), 1.24 (d, J=6.8 Hz, 3H), 1.12 (s, 3H), 1.05 (s, 3H), 0.80 (s, 3H).

Preparation ofCompound 1-10. To a suspension of 1-9 (600 mg, 1.63 mmol) and CsF (120 mg, 0.82 mmol) in e/THF (18 mL, 8/1) was added TMSCF3 (2.4 mL, 16.3 mmol) and the mixture was stirred for 20°C at room temperature under nitrogen. TLC (petroleum ether: ethyl acetate = 3/1) showed the starting material was consumed completely. A solution of TBAF (6.8 mL, 1 M in THF) was added and the e was stirred for 4 h at room temperature.

The mixture was diluted with MTBE (200 mL), washed with a saturated NaHCO; solution (30 mL x 3) and trated in vacuum. The residue was purified by column chromatography on silica gel (eluent: petroleum ether: ethyl acetate = 12/ 1) to afford 1-10 (300 mg, 42%) as white solid. 1H NMR: (400 MHz, CDC13) 8 5.97-5.91 (dd, J;=15.6 Hz, J2=7.6 Hz, 1H), 5.54-5.49 (dd, J1=l56 Hz, J2=6.8 Hz, lH), 5.42-5.38 (m, 1H), 5.30 (d, J=5.2 Hz, 1H), 4.44-4.36 (m, 1 H), 2.97- 2.94 (m, l H), 2.42 (d, J=12.0 Hz, 1H), 2.01-1.98 (m, 2H), 1.88-1.64 (m, 6H), 1.40-1.32 (m, 3H), 1.26—1.21 (m, 2H), 1.17 (d, J=6.8 Hz, 3H), 1.12 (s, 3H), 1.05 (s, 3H), 1.00—0.95 (m, 2H), 0.79 (s, 3H). 1 Preparation ofCompound 1-11. A mixture of 1-10 (40 mg, 0.09 mmol) and 5% Pd/C (10 mg) in BA (10 mL) was hydrogenated for 2 h at 30 0C under 1 atm of hydrogen pressure. The reaction mixture was filtered through a pad of celite and the pad was washed with BA (10 mL x 3). The combined filtrates were concentrated. The residue was purified by column chromatography on silica gel (eluent: PEI/EA: 8/ 1) to afford 1-11 (20 mg. 50%) as white solid. 1H NlVIR: (400 MHZ, CDClS) 8 5.31 (d, J:5.2 Hz, 1H), 3.87-3.86 (in, 1H), 2.42 (d, J=12.8 Hz, 1H), 2.15—2.12(m, 1H), 2.05-1.96 (m, 3H), 1.86—1.41 (m, 16H), 1.38-1.11 (m, 5H), 1.11 (s, 3H), 1.08-1.04 (m, 1H), 1.01 (s, 3H), 0.95 (d, .J=6.6 Hz, 3H), 0.69 (s, 3H).

Preparation ofCompound 1-13 and 1-14. 1-13 (120 mg, 40 %) and 1-14 (120 mg, 40 %) were obtained by SFC purification from 1-10 (300 mg, 0.814 mmol). The configuration of 1-13 and 1-14 was confirmed by Mosher method.

] Preparation ofCompound 1-15. A mixture of l-l3 (120 mg. 0.27 rmrrol) and 5% lld/C {20 mg) in EEQAC {:10 mL) was enated for 20 ii at room temperature under H; {1 arm). The reaction mixture was filtered through a pad of cellte and the pad was washed with EtOAe (10 ml; x 3). The combined filtrates were concentrated. The residue was purified by column chromatography on silica gel tz eum ether: ethyl acetate = 8/1) to afford 1-15 {:70 mg, ) as. white powder. 1H NMR: (400 MHZ, CDCl3) 6 5.30 ((1, .]=5.2 Hz, 1H), 4.00—3.90 (m, 1H). 2.42 (d, J=13.2 Hz, 1H), 2.02—1.29 (m, 18H), 1.28-1.08 (m, 6H), 1.03 (s. 3H), 1.02 (s, 3H), 0.97 (d, J=6.8 Hz, 3H), 0.73 (s, 3H). {00182} ation ofCompound 1-17. A mixture. of 1—14 ( 120 mg, 0.27 rnmol) and 59/2: Pd/C‘ {20 mg) a; EtOAe {10 ml.) was hytlrogenated for 20 h at room temperature under 1:12 {1 arm). The reaction mixture was filtered through a pad of celite and the pad was washed with EtOAe (10 mL 7; 3). The combined filtrates were concentrated. The e was purified by column chromatography on silica gel {elueht‘ petroleum ether: ethyl acetate 8/1) to afford 1-17 {71 mg, 59%) as white powder. 1H NMR: (400 MHz, CDCB) 8 5.27 (d, J=5.6 Hz, 1H), 4.00-3.90 (m, 1H), 2.42 (d, J=13.2 Hz, 1H), 2.03-1.28 (m, 19H), 1.25-1.03 (m, 5H), 1.03 (s, 3H), 1.02 (s, 3H), 0.97 (d, J=6.4 Hz, 3H), 0.73 (s, 3H).

Examyie 2t [N’O\ LIAIH4 THF, -78°C , CsF TBAF, THF 2-1 5 2-16 Hw/O1DIBAL-HJHFsovc 2h 1w.

EtzAICI. CHZCIZ rt 20 h \Ho.@H 2Mrro2 CH2CI2 rt 20h 2‘ TBAF, rt. 4 h 2-17 M14 OH HO”- CFa CFS H 3 9. \, 5% Pct/C. H2 (1atm) \, % Pd/C. H2 (50psi) HO" EtOAc. 30°C, 72 h H0 EtOAc, 50°C, 20 h 2-20 9H pH 2-19 \ o \CFg 0": 0‘ 5% Pd/C. H2 (1am) —’ \ 9:.

\ .Q 9 % Pd/C, H2 (50psi) H —’ EtOAc. 30°C 72 h .3 EtOAc 50°C 20 h . H0 . , 2-21 2-8 Preparation 0f2-2. To a solution ofMAD (28.87 mmol, freshly prepared) in toluene (20 mL) was added dropwise a solution of 2-1 (4 g, 9.62 mmol) in toluene (20 mL) at - 78°C during a period of 1 h under nitrogen. Then the reaction e was stirred for 30 min, a on ofEtMgBr (29 mL, 28.87 mmol, 1.0 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 (petroleum ether: ethyl acetate = 3: 1) showed that the ng material was consumed completely. The mixture was poured into aqueous ted NH4C1 solution (200 mL) and extracted with EtOAc (150 mL x 2). The combined organic phases were dried over NaZSOa‘ and the solvent was ated to afford crude product. The crude product was purified by column chromatography on silica gel (eluent: petroleum ether: ethyl acetate = 15: 1) to give the product 2-2 (2.0 g, 47.6%) as white powder. 1H NMR: (400 MHZ, CDC13)6 5.28 ((17 #52 Hz, 1H), 3.69 (s, 3H), 3.17 (s, 3H), 2.45-2.34 (m, 3H), .95 (m, 3H), 1.94-1.61 (m, 4H), 1.62-1.60 (m, 2H). .26 (m, 10H), 1.19-1.01 (m, 4H), 1.10 (s, 3H), 0.98-0.90 (m, 4H), 0.85 (t, J=6.8 Hz, 3H), 0.68 (s, 3H).

Preparation 0f2-3. To a suspension of LiAlH4 (852.6 mg, 22.43 mmol) in THF (20 ml) was added 2-2 (2.0 g, 4.48 mol) at —78°C, then the solution was stirred at -78°C for 2 hours. The mixture was poured into aqueous saturated NaOH solution (2 mL) and extracted with EtOAc (50 mL x 2). The combined organic phases were dried over NaZSO4, and the solvent was evaporated to afford crude product. The crude product was purified by column tography on silica gel (eluent: petroleum ether: ethyl acetate = 20: 1) to give the product 2-3 (600 mg. %) as white powder. 1H NMR: (400 MHz. CDCB) 5 9.78 (s, 1H), 5.28 (d, J=5.2 Hz, 1H), .22 (m, 3H), 2.03—1.91 (m, 3H), 1.89-1.73 (m, 3H), .61 (m, 2H), 1.65-1.629 (m. 1H). 1.50-1.21 (m, 10H), 1.19-1.06 (m. 4H), 1.02 (s, 3H), 1.01-0.99 (m, 1H), 0.98—0.93 (m, 4H), 0.87 (t, J=6.8 Hz, 3H), 0.68 (s, 3H).

Preparation 0f2-4. To a mixture on-3 {0.3 g, 0.78 mmol) and (is? (0.06 g, 0.39 mural} in toiuene/THF (18 mL, 8/1) was added TMSCP; {1.2 mi, 7.8 mmol} and the reaction mixture was stirred at. room temperature overnight under nitrogen. TLC (petroleum ether: ethyl acetate = 3/1) showed the starting material was consumed completely. A solution of ’I'BAF (7.8 in}... 7.8 rru'noi. i M in THF) was added and the mixture was stirred for Li h at. room temperature.

The reaction e was diluted with tert—Butyl methyl ether (301101;), washed with aq. saturated NaHCG; solution (10 mL X 3} and concentrated in vacuum. The residue was purified by i chromatography on silica gei {eluentr petroleum ether: ethyl acetate 20:1) to afford 24 {80 mg, 2.2 as) as white powder. 1H NMR: (400 MHz, CDC13) 5 5.29 (d, J:5.2 Hz, 1H), .84 (m, 1H). 2.36 (d, J=13.2 Hz, 1H), 2.05—1.95 (m, 3H), 1.86-1.61 (m. 6H), 1.54-1.06 (m, 17H), 1.03 (s, 3H), 1.02—0.91 (m, 5H). 0.85 (t, .]=6.8 Hz, 3H), 0.68 (s, 3H).

Preparation of2-5 and 2-6. A, mixture ot‘zwet {0.07 g. 0.15 mmol} and 10% Pot/C {20 mg) in EtOAc { 30 mL) was hydrogenated for 35 h at 500C under H2 {’50 psi). The reaction mixture was fiitered through a pad te and the part was washed with EtOAc (20 rnL x 3}.

The combined filtrates were concentrated. The resithte was hurified by column chromatography on siiica gel {eluent petroleum ether: ethyl acetate 335%) to give 25 {25 mg, 35.7 945'} and 2« n (20 mg 28.6 9-0;) as White powder. 1H NMR (2-5): (400 MHz, CDC13) 5 .82 (m, 1H), 2.05—1.94 (m, 2H), 1.86-1.58 (m, 6H), 1.56-1.17 (m, 16H), 1.13-0.96 (m, 6H), 0.93 (d, J=6.8Hz, 3H), 0.88 (t, J=6.8 Hz, 3H), 086-084(11), 1H), 0.83 (s, 3H), 0.67-0.61 (m, 4H). 1H NMR (2-6): (400 MHz, CDCl3) 6 3.83-3.76 (m, 1H), 1.95-1.52 (m, 10H), 1.43-0.98 (m, 22H), 0.89 (s, 3H), 82011. 6H), 0.59 (s, 3H).

Preparation 0f2-14. To a solution of MAD (91 mmol, freshly prepared) in toluene (200 mL) was added dropwise a solution of compound 2-13 (10 g, 30 mmol) in toluene (80 mL) at 478°C during a period of 1 h under nitrogen. Then the reaction mixture was stirred for min, a on of EtMgBr (91 mL, 91 mmol, 1.0 M THF) was added dropwise at -78°C. The reaction mixture was warmed to -40°C and d at this temperature for 3 11. TLC (petroleum ether: ethyl acetate = 3: 1) showed that the starting material was consumed completely. The mixture was poured into saturated aqueous NH4C1 solution (200 mL) and extracted with EtOAc (150 mL x 2). The combined organic phases were dried over fi and the solvent was evaporated to afford crude t) which was purified by column tography on silica gel (eluent: petroleum ether: ethyl acetate=15: 1) to give compound 2-14 (4 g, 40%) as white powder. ation of2-15. To a solution of 2-14 (4.0 g, 111 mmol) in THE (200 mL) was added. aqueous HCl solution (35 mL, 1 M) and acetone (35 mL). The reaction mixture was stirred for 20°C at room ature. ‘TLC (petroleum ether: ethyl acetate=3:1) indicated that the reaction was complete. Then the reaction e was diluted with EtOAc (200 mL), washed with saturated aqueous NaHC03 solution (200 mL), dried over NaZSO4 and evaporated under reduced pressure to give 2-15 (3 g, 88%) as white solid.

Preparation of2-16. To a solution of P113PEtBI‘ (15.8 g, 42.6 mmol) in dry THF (50 mL) was added dropwise a solution of t—BuOK (4.8 g, 42.6 mmol) in dry THF (20 mL) under N2 at 0°C. The mixture was stirred at room temperature for 1.5 h. Then a solution of 2-15 (2.7 g, 8.5 mmol) in THF (20 mL) was added dropwise and the ing mixture was stirred at 800C for 16 h. TLC (petroleum ether: ethyl acetate=3:1) indicated that the starting material was consumed completely. The reaction was quenched with saturated aqueous NHiCl solution (l00 mL) and extracted with EtOAc (30 mL x 2). The combined organic phases were dried over NagSO4 and concentrated in vacuum. The residue was purified by column chromatography on silica gel (eluent: petroleum ether: ethyl acetate = 12:1) to give 2-16 (1.8 g, 64%) as white solid.

Preparation of2-1 7. To a solution of nd 2-16 (1.8 g; 5.5 mmol) and methyl late (l.1 g, 13.7 mmol) in dry CH2C12 (20 mL) was added dropwise a solution of Et2A1C1 (22 mL, 22 mmol, 1 M in toluene) with ng at 0°C. Then the reaction was warmed to room temperature and stirred for 20 h. TLC (petroleum ether: ethyl e = 5: 1) ted that the starting material was consumed completely. The mixture was quenched with saturated aqueous NaHC03 solution (30 mL) and extracted with CH3C13 (30 mL x 2). The combined organic phases were dried over Na2804 and concentrated in vacuum. The residue was purified by column chromatography on silica gel (eluent: petroleum ether: ethyl acetate = 10: 1) to give 2-17 (2.0 g 88%) as white powder. 1H NMR: (300 MHz, CDC13)5 6.99-6.92 (m, 1 H) 5.84 (d, J=10.5 Hz, 1 H), 5.45—5.41 (m, 1H), 5.32 (d, J=5.2 Hz; 1H), 3.75 (s, 3 H), 3.06-2.99 (m, 1 H), 2.38 (d, J=12.6 Hz, 1H), 2.14-1.67 (m, 10H), 1.54—1.25 (m, 7H), 1.21 (d, J=6.8 Hz, 3H), 1.15 —0.99 (m, 5H), 0.87(t, J=7.2 Hz, 3H), 0.80 (s, 3H).

Preparation of2-18. To a soiution of compound 2-17 (2.2 g, 5.3 mmol) in dry ‘THF (20 mL), DIBAL-H (l M in THF, 27 mL, 27.0 mmoi) was added dropwise at —780C under nitrogen. The reaction mixture was warmed to 30°C and then stirred for 2 h at 30°C. The reaction was quenched with addition of water (3mL), diluted with EtOAc (200 mL) and dried over anhydrous Nast4, d through a pad of celite and the pad was washed with EtOAc (50 mL x 3). The combined tes were concentrated in vacuum to give 1.9 g of the crude product, which was directly used in the next step without r purification. A mixture of the crude product (1.9 g, 4.9 mmol) and M1102 (8.6 g, 98 mmol) in CH2C12 (50 mL) was stirred at room temperature for 20 h. The reaction mixture was filtered through a pad of celite and the pad was washed with CH2C12 (50 mL x 3). The combined filtrates were concentrated. The residue was purified by column chromatography on silica gel (eluent: petroleum ether: ethyl acetate = 15: 1) to give 2-18 (1.5 g, 79%) as white solid. 1H NMR: (400 MHZ, CDC13) 5 9.55—9.53 (m, 1H), .78 (in, 1H), 6.15-6.09 (in, 1H), 5.45—5.41 (m, 1H), 5.30 (d, J=5.2Hz, 1H),3.15-3_14(m, 1 H) 2.36 (d, J=i3.2 Hz, 1H), 2.10-2.03 (m, 3H), .60 (m, 9H), 1.59-1.27 (m, 7H), 1.24 (d, J=6.8 Hz, 3H), 1.10—1.22 (m, 6H), 0.87-0.83 (m, 4H), 0.80 (s, 3H).

Preparation of2-19. To a suspension of 2-18 (1.5 g, 3.92 mmol) and CsF (0.3 g, 1.96 mmol) in e/ THF (22mL, 9/1) was added TMSCF3 (5.8 mL, 39.2 mmol) and the mixture was stirred for 20 h at room ature under nitrogen. TLC (petroleum ether: ethyl acetate = 3/1) showed the starting material was ed completely. A solution ofTBAF (39.2 mL, 39.2 mmol, 1 M in THF) was added and the mixture was stirred for 4 h at room temperature.

The mixture was diluted with MTBE (200 mL), washed with a saturated NaHCO; on (30 mL x 3) and concentrated in vacuum. The residue was purified by column chromatography on silica gel (eluent: petroleum ether: ethyl acetate = 25/ 1) to afford 2-19 (0.65 g, 37%) as white solid.

Preparation of2-20 & 2-21. 2-20 (210 mg, 32%) and 2-21 (210 mg, 32%) were obtained by SFC purification from 2-19 (650 mg, 1.44 mmol). The configuration of 2-20 and 2- 21 was confirmed by Mosher method. 1H NMR (2-20): (400 MHZ, CDC13) 5 5.92 (dd, J1=15 .6 Hz, 1:72 Hz, 1H), 5.53(dd, J;=15.6 Hz, 1227.2 Hz, 1H), 5.40—5.37 (m, 1H), 5.30 (d, J=5.2 Hz, 1H), 4.43—4.40 (m, l H), 2.95—2.94 (in, l H), 2.37 (d, J=13.6 Hz, 1H), 2.09-1.98 (m, 4H), 1.87- 1.18 (m, 18H), 1.16 (d, .]=6.8 Hz, 3H), .97 (m, 6H), 0.85 (t, J=6.8 Hz, 3H), 0.78 (s, 3H).

‘H NMR(2-21): (400 MHz, CDC13) 5 5.95 (dd, J,=15.6 Hz, J2=7.2 Hz, 1H), 5.53 (dd, J1=15.6 Hz, J3=6.8 Hz, 1H), 5.39-5.36 (m, 1H), 5.30 (d, J=5.2 Hz, 1H), 4.44—4.41 (m, 1 H), 2.99—2.92 (m, 1 H), 2.37 (d,J=13.2 Hz, 1H), 2.10-1.98 (m, 4H), 187—125(111, 18H), 1.16 (d, J=6.8 Hz, 3H), 1.09—0.99 (m, 6H), 0.85 (t, J=7.2 Hz, 3H), 0.80 (s, 3H).

Preparation 0f2- 7. A mixture ef2-20 {200 mg, 0.44- mmel) and 5% Pd/C {50 mg} in EtfilAe (:20 1111..) was hydrogenated fer 72 h at 30°C under 1-120 aim). The reaction. mixture was filtered threugh a pad efeehte and the pad was washed with EtOAe (10 ml 1: 3).

The committed ti l hates were concentrated The residue was gratified by cohu‘hrr chromatography 011 silica gel (eluentz petroleum ether: ethyl acetate = 25/1} to afferd crude 2-7, which was purified. by pre—HPLC to afford 2-7 {'64 mg 52%) as white powder. 1H NMR (2-7) : (400 MHZ, CDCl3) 5 5.29 (d, J=4.8 Hz, 1H), .80 (m, 1H), 2.36 (d, .]=l3.6 Hz, 1H), .60 (m, 11H), 1.53 -1.06 (m, 15H), 1.03 (s, 3H), 1.02-0.89 (m, 5H), 0.85 (t, J1=l4.8 Hz, J3=7.2 Hz, 3H), 0.69 (s, 3H).

Preparation 0f2-8. A mixture of 2-21 {200 mg. 0.4-4 mmol) and 5% Pd/C {50 mg} in EtflAe {:20 ml.) was hydrogenated fer 72 it at 30°C under H; (I aim}. The reaction, mixture was filtered through a pad of eehte and the pad was washed with EtOAe {10 mL )1 3).

The combined filtrates were concentrated. The residue was d by eehirhri chromatography err silica gel {eluentz petroleum ether: ethyl e = 25/1) to afferd 2-8 (105 111g, 52%) as white powder. 1H NMR: (400 MHz, CDClg) 5 5.29 (d, J=4.8 Hz, 1H), 3.86-3.83 (m, 1H), 2.36 (d, .]=l3.2 HZ, 1H), .95 (m, 4H), l.86-l.60 (m, 7H), 1.54 -l.08 (m, 15H), 1.03 (s, 3H), 1.01— 0.90 (m, 5H), 0.85 (t, J=6.8 Hz, 3H), 0.68 (s, 3H).

Preparation of2-10 and 2-12. A 131ixter‘e 015241; {30 mg, 0.067 mmel) and lQ‘F/Ez- Pei/C. ( l0 mg) in EtCAc {10 mL) was hydrogenated for 2.0 h at 500C under H; {5.0 psi). The reaction mixture was filtered through a pad of eelite and the pad was washed. with EYUAC {.20 ml; x 3). The combined filtrates were concentrated. The residue was hurified by column tegmplry on silica gel {eluerrt petroleum ether: ethyl acetate 3325/1} to give 24.0 {_ l ‘1. mg, 37%} and 2-12 (7 mg, 23%) as white powder. 1H NMR (2-10): (400 MHz, CDCl3) 5 .82 (m, 1H), 2.04—1.93 (m, 2H), 1.84-1.59 (m, 6H), 1.56—1.20 (m, 14H), .96 (m, 7H), 0.93 (d, .]=6.8Hz, 3H), 0.88-0.84 (m, 4H). 0.83 (s, 3H) 0.67-0.61 (m, 4H). 1H NMR (2-12): (400 MHz, CDC13) 6 3.89-3.80 (m, 1H), 2.08—1.93 (m, 2H), 1.91 —1.66 (m, 6H), 1.52—1.01 (m, 23H), 0.97 (s, 3H), 0.95—0.90 (m, 6H), 0.66 (s, 3H).

Example 3.

,,,,, ‘ " HO ; H 3 7_ . CF: Pd/C, H2 (SOpsi) 3'5 ' M” i EtOAc, 50 EM: H CFs lllll HO 3.

H 3 7A 9. H 9“ TMSCF3.CSF ng 1; fl, ’(CFS [I .3 TBAF,THF H0 3.1 3-2 0 a: OH H .....

\\\\\ HO ; 3-3 @. CF3 Pd/C, H2 (505251). 9H 50 °c IIIII.g m CF3 Ho 0 .....00 3-BA Preparation 0f3-2. To a suspension of 3-1 (400 mg, 1.035 mmol) and CsF (76 mg) in toluene/THF (20 mL; 8/1) was added TMSCF3 (1.53 mL, 10.35 mmol) and the mixture was stirred for 20°C at room temperature under nitrogen. TLC (petroleum ether: ethyl acetate = 3/ 1) showed the starting material was consumed completely. A solution ofTBAF (6.8 mL, 1 M in THF) was added and the mixture was d for 4 h at room temperature. The mixture was diluted with MTBE (200 mL)1 washed with aq, saturated NaHCOg solution (30 mL x 3) and concentrated in vacuum. The residue was d by column chromatography on silica gel (eluent: petroleum ether: ethyl acetate = 20:1) to afford 3-2 (220 mg, 46 %) as white solid. 1H NMR:(400 MHZ, CDClB) 5 5.31 (d, J=2.0 Hz, 1H), 2.44-2.41 (m, 1H), 2.04-1.96 (in, 3H), 1.81— 1.67 (m, 5H), 1.65-1.39 (m, 11H), 1.34-1.32 (m, 3H), 1.31-1.25 (m, 1H), 1.21-1.10 (m, 3H), 1.12-0.98 (m, 4H); 0.96 (s, 3H), 0.98-0.90 (m, 4H), 0.68 (5, 31-1.) ation of3—3 am! 3-4. To a solution of compound 3-2 (220 mg, 0.569 mmol) in EtOAc (10 mL) was added Pd/C (20 mg), then the mixture was stirred under hydrogen (50 psi) at 50°C ovemight. The e was filtered through a pad of celite and the filtrate was ated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: petroleum ether: ethyl acetate = 20:1) to afford the pure t 3-3 (100 mg, 38.5 %) and 3-4 (51 mg, 19.3 %) as white powder. 1H NMR (3-3): (400 MHZ, CDCl3) 6 2.01- 1.95 (m, 1H). 1.89-1.75 (m, 2H), .55 (m, 9H), 1.52-1.43 (m, 5H), 1.32-1.28 (m, 4H), 1.27— 1.20011, 7H), 1.17-1.08 (m, 4H), 1.06-0.96 (m, 3H), 0.96-0.91 (m, 3H), 0.80 (s, 3H), 0.68-0.49 (m. 4H). 1H NlVIR (3-4): (400 MHZ, CDCl3) 5 2.01-1.95 (m, 1H), l.89—l .67 (m, 5H), .60 (m, 2H), 1.63-1.36 (m, 8H), 1.35-1.31 (in, 4H). 1.29-1.24 (m, 4H), 1.22 (s, 3H), 1.28—1.06 (m, 6H), 0.96 (s, 3H), 0.95-0.92 (m, 3H), 0.68 (s, 3H).

Preparation of3-5 and 3-6. Compound 3-2 (1.2 g. 2.63 mmol) was split by SFC to get Product 3-5 (400 mg) and 3-6(400 mg) as white powder (total yield: 66.7%). 1H NNIR (3- ): (400 MHz, CDClg) 5 5.32 (d, J=4.0 Hz, 1H), 2.50-2.40 (m, 1H), 2.08-1.95 (m, 3H). 1.90—0.90 (m, 35H), 0.70 (s, 3H). 1H NMR (3-6): (400 MHz. CDC13)5 5.32 (d, J=4.0 Hz, 1H), 2.50—2.40 (m. 1H). 2.08-1.95 (m, 3H). 1.90—0.92 (m, 35H). 0.70 (s, 3H).

Preparation of 3-7 To a on of nd 3-6 (300 mg, 0.66 mmol) in EtOAc (8 mL) was added Pd/C (10%, 200 mg) under N2. The suspension was degassed under vacuum and purged with H2 several times. Then the mixture was stirred under H2 (50 psi) at 50 0C for 24 h. The suspension was filtered h a pad of celite and the pad was washed with EtOAc (50 mL x 2). The combined filtrates were concentrated to dryness to give the crude product. which was purified by column chromatography on silica gel (petroleum ether: ethyl acetate=20: 1) to afford 3-7 (142 mg, 47%) as white solid. 1H NMR: (3-7) (400 MHz, CDCl3) 5 1.96-1.92 (m, 1H), 1.90—1.75 (m, 1H), 1.70—1.57 (m, 5H), 1.55—1.35 (m. 6H). 1.30—1.20 (m, 12H), 1.20-1.06 (m, 12H), 1.19-0.81 (m, 11H), 0.80 (s, 3H), 0.70-0.60 (m, 4H). 1H NlVIR: (3-7A) (400 MHz, CDClg) a 1.96-1.92 (m, 1H), 1.90—1.75 (m, 3H), 1.70—1.57 (m, 2H), 1.55—1.25 (m, 13H), 1.21—1.00 (m. 15H). 0.96-0.86 (m. 8H), 0.65 (s, 3H) ation of 3-8 To a solution of compound 3-5 (300 mg, 0.66 mmol) in EtOAc (8 mL) was added Pd/C (10%, 200 mg) under N2. The suspension was degassed under vacuum and purged with H; l times. Then the mixture was stirred under H; (50 psi) at 50 0C for 24 h. The suspension was filtered through a pad of celite and the pad was washed with EtOAc (50 mL x 2). The combined filtrates were concentrated to dryness to give the crude product, which was purified by column chromatography on silica gel (petroleum ether: ethyl acetate=20: l) to afford 3-8 (1416 mg, 47%) as white solid. 1H NMR: (3-8) (400 MHz, CDCl3) 6 1.96-1.92 (m, 1H), 1.90—1.70 (m, 2H), 1.69-1.57 (m, 5H). 1.55—1.20 (m, 18H), 1.19-0.81 (m, 10H), 0.80 (s, 3H), 0.70-0.60 (m, 4H). 1H NMR: (3-8A) (400 MHz, CDC13)5 1.97—1.70 (m, 6H), 1.70—1.57 (m, 2H), 150—13001}, 13H), 1.25—1.05 (m, 15H), LOO-0.86011, 7H), 0.65 (s, 3H) Example 4. o o \ / \ ¢0 0. OH a a. IN \ Dess-Martin .3E |PEA : CHch2 H .3H “.3 H0 4.1 “0 4-2 0.4.3 MAD, MeMgBr N’O\ MeMgB, EtMgBr toluene é THF 1,". 9H , 0H .6a 4-11 0. SFC —> + to O“ llll ‘ I ‘ ll 46 0 .....as 4-12 EtOAc szc, H2(5OPSI) EtOAc Preparation ound 4-2. To a solution of 4-1 (38 g, 101.5 mmol) in THF (400 mL) at room temperature was added HATU (46.3 g; 121.8 nimol), DIPEA (45.9 g, 3552 mmol). The mixture was stirred for 1 h, and N,O—dimethyihydroxylamine hydrochloride (19.8 g; 203 mmol) was added. The mixture was stirred at room temperature for another 6 h. The reaction mixture was concentrated, poured into water, extracted with EtOAc, washed with water, dried over N32804, and concentrated to give crude t. The crude t was purified by column chromatography on silica gel (eluent: PE: EA = 3:1) to afford the desired t 4-2 (24 g, 57%) as white solid. 1H NMR: (300 MHz, CDCB) 5: ppm 5.25 (d, 3: 5.2Hz, 1H), 3.59 (s, 3H), 3.46-3.37 (m, 1H), 3.07 (s, 3H), 2.70 (s, 1H), .09 (m, 4H), 1.92-1.63 (m, 6H), 1.44—1.33 (m, 6H), .15 (m; 3H); 1.11-0.93 (m, 5H), 0.90 (s, 3H), 0.85 (d, J=6.4 HZ, 3H), 0.82—0.78 (m, 1H), 0.58 (s, 3H).

Preparation ofCompound 4-3. To a solution of compound 4-2 (14 g, 33.52 mmol, 10 eq) in dry CH2Cl2 (600 mL) was added Dess-Martin (28 g, 67.04 mmol, 2.0 eq) in portions at 0 0C. Then the reaction e was stirred at room temperature for 6.5 h. TLC (PE: EA = 3: 1) showed the ng material was consumed completely. The mixture was quenched with saturated aqueous NaHCOg/Nagngg = 1:3 (800 mL). The organic phase was washed with brine (500 mL) and dried over Na2504, and the solvent was evaporated to afford crude product 4- 3 (14.0 g, 100%), which was directly used in the next step without further purification.

Preparation 0fC(mzpound 4-4. To a solution ofMAD (101 mmol, 3.0 eq) in toluene, freshly prepared by addition of a solution of Me3Al (50.5 mL, 101.00 mmol, 2 M in hexane) to a stirred solution of 2,6—di-tert—butylmethylphenol (44.4 g, 202 mmol) in toluene (200 mL) followed by stirring for 1 h at room temperature, was added dropwise a solution of 4-3 (14.0 g, 33.7mmol, 1.0 eq) in toluene (10 mL) at -78 0C under nitrogen. Then the reaction mixture was stirred for 30 min, a solution of MeMgBr (33.7 mL, 101 mmol, 3.0 eq, 3 M in ether) was added dropwise at -78 0C. The reaction mixture was warmed to 25 °C and stirred at this temperature for 12 h. TLC (PE: EA = 3:1) showed that the starting material was consumed completely. The e was poured into aqueous ted NH4C1 solution (200 mL) and extracted with EtOAc (200 mL x 2). The combined organic phases were dried over , and the solvent was evaporated to afford crude product. The crude product was purified by column chromatography on silica gel (eluent: PE: EA = 3: 1) to give the pure target (7.5 g, 52%) as white . 1H NMR: (400 MHZ, CDC13) 8 5.30 (d,J=5.21—12, 1H), 3.69 (s, 3H), 3.17 (s, 3H), 2.50—2.30 (m, 3H). 2.05—1.70 (m, 7H), 1.52—1.30 (m, 9H), 1.20—0.90 (m, 15H), 0.68 (s, 3H). ation ofCompound 4-5. To a on of compound 4-4 (7.5 g> 17.4 mmol, 1.0 eq) in THF (150 mL) was added dropwise a soiution of MeMgBr (29mL, 87 inmol, .0 eq, 3 M in THF) at room temperature during a period of 30 min under nitrogen. Then the reaction mixture was stirred at room temperature for 12 h. TLC (PE:EA=1:1) showed that the starting material was consumed completely. The mixture was poured into aqueous saturated NH4C1 solution (200 mL) and extracted with EtOAc (150 mL x 2). The combined organic phases were dried over NagSOr and the solvent was evaporated to afford crude product. The crude product was ed by column chromatography on silica gel (eluent: PE: EA = 4: 1) to give the product 4-5 (5.2 g, 77%) as white . 1H NMR: (400 MHz, CDCl3) 5 5.30 (d. J=5.2Hz. 1H). 2.50—2.30 (m, 3H), 2.14 (s, 3H) 2.03—1.93 (m, 3H), 1.87—1.68 (m, 4H), 1.60-1.18 (m, 12H), 1.12 (s, 3H), 1.11—1.03 (m, 1H), 1.01 (s, 3H},1.00-0.94(m, 1H), 0.91 (d, J=6.4Hz, 3H), 0.68 (s, 3H).

Preparation of4-6. To a solution of compound 4—5 (300 mg, 0.777 mmol, 1.0 eq) in toluene (5 mL) was added dropwise a solution of EtMgBr (4.5 mL. 4.5 mmol, 6.0 eq, 1 M in THF) at room temperature during a period of 10 min under nitrogen. Then the reaction mixture was stirred at room temperature for 12 h. TLC =3: 1) showed that the ng material was consumed completely. The mixture was poured into aqueous saturated NH4C1 solution (20mL) and extracted with EtOAc (50 mL x 2). The combined organic phases were dried over Na3804,‘ and. the solvent was evaporated to afford crude product. The crude t purified by column chromatography on silica gel (eluent: PE: EA = 8:1) to give the product 4—6 (200 mg, 6 %) as white powder. 1H NMR: (400 MHZ, CDC13) 5 5.23 (d, J=5.6Hz, 1H), 240—23001], 1H), 2.00—1.55. (m, 7H), 1.50-1.98 (m, 25H), 0.95 (s, 3H), 0.94-0.80 (m, 8H), 0.62 (s, 3H).

Preparation of4-7 and 4-8. To a solution of compound 4-6 (175 mg, 0.42 mmol) in EtOAc (10 mL) was added 10% Pd/C (40 mg) under argon. The suspension was degassed under vacuum and purged with H2 several times. The mixture was stirred under H2 (50 Psi) at 50°C overnight. The suspension was filtered through a pad of celite and the pad was washed with BA (20 mL x 3). The combined filtrates were trated in vacuum and the residue was purified by column tography on silica gel (eluent: PE: EA = 8: 1) to give 4-7 (84 mg, 48%) and 4-8 (25 mg, 14%) as white powder. 1H NMR (4-7): (400 MHZ, CDC13) 5 1.98-1.92 (m, 1H), .78 (m, 1H), 1.70—1.60 (m, 2H), 1.58-1.20 (m, 21H), 120—097(11), 11H), 0.95— 0.82 (m, 7H), 0.80 (s, 3H), 0.70—0.61 (m, 4H). 1H NMR (4-8): (400 MHz, CDC13) 5 2.00-1.78 (m. 4H), 1.68-1.63 (m, 1H), 1.57—1.55 (m. 1H), 1.53 4.35 (m, 10H), 1.32 —1.12 (m, 16H), 1.11 — 0.99 (m, 5H), 0.97 (s, 3H), 0.95-0.83 (m, 6H), 0.67 (s, 3H).

Preparation of4-9 To a solution of compound 10-123 (80 mg, 0.193 mmol) in EtOAc (20 mL) was added 10% Pd/C (20 mg) under N2. The suspension was degassed under vacuum and purged with H2 several times. Then the e was d under H2 (50 psi) at 50°C for 12 hours. The mixture was filtered through a pad of celite and the pad was washed with EtOAc (5 mL x 2). The combined filtrates were concentrated to dryness to give the product, which was purified by column chromatography on silica gel (eluent: petroleum ether: ethyl acetate 12:1 to 10: 1) to afford the 4-9 (40 mg, 50 0fly) as white powder. 1H NMR (4-9): (400 MHZ, CDCl3) 5 .93 (m, 1H), 1.92—1.80 (m, 1H), .85 (m, 41H), 0.82 (s, 3H), 0.67 (s, 3H).

Preparation 0f4-10 To a solution of compound 10-12A (80 mg, 0.193 mmol) in EtOAc (20 mL) was added 10% Pd/C (20 mg) under N2. The suspension was degassed under vacuum and purged with H2 several times. Then the mixture was stirred under H2 (50 psi) at 50°C for 48 hours. The mixture was filtered through a pad of celite and the pad was washed with EtOAc (5 mL x 2). The combined filtrates were trated to dryness to give the t, which was purified by column cinematography on silica gel (eluent: petroleum ether: ethyl acetate = 12:1 to 10:1) to afford the 4-10 (40 mg, 50 9/5) as white powder. 1H NMR (4-10): (400 MHZ, CDC13)5 2.02—1.93 (m, 1H), 1.92—1.80 (m, 1H), 1.70—0.85 (m, 41H), 0.82 (s, 3H), 0.67 (s, 3H).

Prepamtion of 4-11 and 4-12. 4-11 (100 mg 15. 38 %) and 4-12 (90 mg 1385 0AS) were obtained by SFC purification from 4-6 (600 mg, 1.55 mmol). H NMR (Isomer 1): (400 MHz, CDCl3) 5 5.30 (m, 1H), 2.43-2.40 (d, J=12.4 Hz. 1H), 2.14-1.99 (111, 3H), 1.96-1.68 (m, 3H), .52 (m, 5H), 461}, 13H)> 1.19-1.09 (m, 8H) 1.02 (s, 3H), 0.96-0.93 (m, 3H), 0.93-0.87 (m, 3H), 0.69 (s, 3H). 1H NMR (Isomer 2): (400 MHz, CDCB) 5 5.30 (m, 1H), 2.44—2.40 (d, J=l4 Hz, 1H), 2.17-1.96 (m. 3H), 1.96-1.67 (m, 3H); 1.67—1.18 (m, 18H), 1.16-1.09 (m, 8H) 1.06 (s, 3H), .93 (m, 3H), 0.93-0.87 (m, 3H), 0.69 (s, 3H).

Example 5. -8A Preparation ound 5-2. To a on of 5-1 (200 mg, 0.52 mmol) in toluene (5 mL) at -78 0C was added n-PngBr (1.3 mL. 2 M in THF, 2.6 mmol) dropwise. The mixture was warmed up to room temperature gradually and stirred for 6 h. The reaction mixture was quenched with NH4C1 aqueous, extracted with EtOAc. The organic layer was dried over Na2804, and concentrated to give crude product. The crude product was purified by column chromatography on silica gel (eluent: PE: EA = 15:1) to afford 5-2 (130 mg, 58 %) as white solid. 1H NMR: (300 MHz, CDC13) 5: ppm 5.30 (d, J: 4.8 Hz, 1H), 2.48-2.38 (m, 1H), 2.02— 1.95 (m, 3H), 1.88-1.66 (m, 3H), 1.63—1.52 (1n, 5H), 1.52—1.46 (m. 4H), 1.43-1.41 (m, 1H), 1.41— 1.35 (m, 4H), 1.30—1.22 (m, 3H), 1.20—1.14 (m. 4H), 1.13-1.08 (m, 4H), 1.03 (s, 3H), 0.95—0.90 (m, 3H), 0.90-0.87 (m, 3H), 0.87-0.85 (m, 1H) 0.68 (s, 3H).

Preparation of 5-3and 5-4. To a solution of compound 5-2 (400 mg, 0.93 mmol) in EtOAc (20 mL) was added 10% Pd/C (100 mg). Then the mixture was stirred under hydrogen (50 psi) at 50 0C overnight. The mixture was filtered through a pad of celite and the filtrate was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: petroleum ether: ethyl acetate= 15:1) to afford the pure product 5-3(150 mg, 37.3 %) and 5-4 (27 mg, 6.7 %) as white powder. 1H NMR (5-3): (300 MHz, CDC13) 6 1.97- 1.94 (m, 1 H), .77 (in, 1 H), 1.67-1.62 (m, 3H), 1.56-1.51 (m, 6H), .30 (m, 11H), 1.24 (s, 6H), 1.20 (s, 1H), 1.13 (s, 5H), 1.09—0.99 (111,411), 0.94-0.90(m, 6H), 0.80 (s, 3H), 0.65 (s, 3H). 1H NMR (5—4); (300 MHz, CDCB) 6 1.98-1.94 (m, 2H), 1.91-1.78 (m, 5H), 1.65—1.51 (m, 5H), 1.47—1.46 (m, 3H), l.38-l.35 (m, 9H), 1.32—1.30 (m, 2H), 1.25 (s, 3H), 1.22 (s, 6H), 1.16-1.10 (m, 4H), 1.06—1.04 (m, 4H), .94 (m, 4H), 0.92-0.89 (m, 6H), 0.86-0.83 (m, 1H), 0.64 (s, 3H). ation 0f5-5 and 5-6 To a solution of compound 5-1 (1500 mg, 3.88 mmol) in dry THF (30 mL) was added a solution of n—PngBr (11.6 mL, 23.3 mmol) dropwise at 0°C.

The mixture was stirred at 40°C for 16 h. TLC (PE/EtOAc = 2/1) showed the reaction was complete. Saturated s NH4C1 (5 mL) was added slowly to quench the reaction. The resulting on was separated between EtOAc (30 mL x 3) and H20 (30 mL). The combined organic layers were concentrated in vacuum and the residue was d by silica gel column eluted with PE/EtOAc = 10/1 to give the mixture of the diastereomeric pair (1.1 g) as white power. The reimeric pair was separated by prep-SFC to give 5-6 (380 mg, 22.8%) as a white solid and 5-5 (385 mg, 23.1%) as a white solid. 1H NMR (5-5): (400 MHZ, CDClg) 6 5.31— .30(m, 1H), 2.44-2.41(d, 1H, J: 12.8 Hz), 2.01—1.96 (m, 3H), 1.86-1.69 (m, 3H),1.58-1.25 (m, 16H), 1.14-1.08 (m, 11H), 1.06-0.99 (m, 4H), 0.94-0.91 (m, 6H), 0.68 (s, 3H). 1H NMR (5-6): (400 MHZ, CDClg) 5 5.3 l-5.30(m, 1H,), 2.44-2.41(d, 1H, J= 12.4 Hz), 2.02-1.96 (in, 3H), 1.87- 1.68 (m, 3H), 1.57-1.25 (m. 16H). .08 (m, 10H), 1.02-0.99(m, 4H), 0.94-0.91(m, 6H), 0.68 (s, 3H).

Preparation of 5-8 A mixture of 5-6 (200 mg, 0.464 mmol) and Pd/C (100 mg, cat.) in EtOAc (30 mL) was hydrogenated under 50 psi of hydrogen for 48 h at 500C. The reaction mixture was d through a celite pad. The pad was washed with EtOAc (50 mL).

The filtrate was concentrated in vacuum and the residue was purified by silica gel column eluted with Ac = 20/l to give 5-8 (111.3 mg, 55.4%) as a white solid. 1H NMR(5-8) (400 MHZ, CDCl3), 6 (ppm) 1.97—1.94 (d. 1H, J=12.0 Hz), 1.83-1.78 (m, 1H), 1.65-1.61 (m. 3H), 1.50—1.24 (m, 20H), 1.13—1.00 (m, 11H), 0.94-0.85 (m, 7H), 0.80 (s, 3H), 0.68-0.65 (m, 4H). 1H NMR(5- 8A) (400 MHz,CDC13), 5 (ppm) 1.98-1.95 (d, 1H, J=l 1.2 Hz), 1.88-1.80 (m, 3H), .60 (m, 1H), 1.51-1.47 (m, 1H), 1.40-1.31 (m, 12H), l.28-1.20(m, 8H), .01 (m, 11H), 0.96-0.80 (m, 10H), 0.65 (s, 3H). ation of 5-7 A mixture of 5-5 (200 mg, 0.464 mmol) and Pd/C (100 mg, cat.) in EtOAc (30 mL) was hydrogenated under 50 psi of en for 48 h at 50°C. The reaction mixture was filtered through a celite pad. The pad was washed with EtOAc (50 mL).

The filtrate was concentrated in vacuum and the residue was purified by silica gel column eluted with PE/EtOAc = 20/l to give 5-7 (1185 mg, 59.0%) as a white solid. 1H NMR(5-7) (400 MHZ.

CDClg), 5 (ppm) l.97-l.94 (d, 1H, J=12.8 Hz), 1.88—1.79 (m, lH); l.7l—l.6l (m: 3H), 1.51—1.24 (m, 20H), 1.13—1.00 (m, 11H), 0.94-0.85 (m, 7H), 0.80 (s, 3H), 0.68-0.65 (m, 4H). 1H NMR(5— 7A) (400 MHz, CD03), 5 (ppm) 1.98-1.95 (d, 1H, J=l 1.2 Hz), 1.88-1.79 (m, 3H), 1.65-1.59 (m, 1H), 1.52-1.47 (m; lH), l.4l-l.31 (m, llH), 1.27—1.22 (m, 9H), 1.13-1.11 (m, 7H), 1.06-1.01 (m, 4H), 0.96-0.90 (m. 10H). 0.65 (s, 3H). e 6. 9-8BN H202, NaOH Pd/C, H2 EtOAc 9-BBN, H202 NaOH 9-BBN, H202 NaOH BzCl 682 6-1 1 SFC UOH " : THF.MeOH, H20 Preparation of6-2. To a solution of 6-1 (150 mg, 0.39 mmoie) in THF (4 mL) was added allylmagnesium bromide (2.34 mL, 2.34 mmole, 1M in ether) at -78°C. Then the reaction mixture was warmed to room temperature and stirred for 12 hours. The mixture was quenched with NH4C1 (20 mL) solution and extracted with EtOAc (10 mL x 2). The organic phase was dried by Na2804 and purified by column chromatography on silica gel (eluent: PE: EA = 10:1) to get the 6-2 (100 mg, 59%). 1H NMR: (400 MHz, CDClg) 5 .82 (m, 1H), .3l (d, J=5.2Hz, 2H), 5. l5-5.09 (m, 2H), .40 (m, 1H), 2.22-2.20 (d, J=7.6Hz, 2H), 2.04- 1.96 (m, 3H), 1.95—1.57 (m, 3H), 1.54—1.24 (m, 12H), .11 (m, 5H), 1.09—1.05 (m, 6H), 1.03 (s, 3H), 0.98-0.92 (m, 5H), 0.68 (s, 3H).

Preparation of 6-3. To a solution of 9-BBN ( 3.2 mL, 1.6 mmol, 2M in THF) was added dropwise a solution of 6-2 (70 mg, 0.16 mmol) in THF (2 1nL) at 0 0C. The reaction mixture was heated at 60 0C and stirred for 12 hours. The mixture was cooled to 0 °C and aq.

NaOl-I (10%) solution (2 mL) was added followed by H302 (30%, lmL). The mixture was stirred for 2 hours at 0 OC and then extracted with EtOAc .The combined organic layer was washed with brine, dried over NagSO4 and trated to to give crude product. The crude product was purified by column chromatography on silica gel (eluent: petroleum ether: ethyl acetate=2:l) to afford 6-3 (30 mg, 42 %) as white solid. 1H NMR: (300 MHZ, CDCB) 6: 5.30 (d, J=5.2Hz, 1H), 3.68-3.65 (m, 2H), 2.43—2.39 (m, 1H), 2.03—1.80 (m, 6H), 1.79-1.62 (m, 6H), 1.47-1.36 (m, 5H), 1.32—1.25 (m, 7H), 1.17—1.13 (m, 4H), 1.11—1.07 (m, 6H), 105—098 (m, 4H), 0.94—0.90 (m, 5H), 0.68 (s, 3H).

Preparation of 6-4 and 6-5. A mixture of 6-1 (1.0 g. 2.59 mmoi) and 10% de’C {1-40 mg) in EtOAc {30 ml.) was. hydrogenated for 15 h at 500C under H; (50 psi). The reaction e was filtered through a pad ot‘ceiite and the pad was washed with EtOAc (20 mL x 3}.

The combined filtrates were concentrated. The residue was purified by column chromatography on silica gel (eluent: petroleum ether: ethyl acetate=15:1) to afford 6—4 {500 mg, 49.5%) and an '3 (200 mg, 19.80453) as white solid.

Preparation of 6-6. To a solution of 6-4 (70 mg, 0.18 mmol) in dry THF (2 mL) at —78 °C was added C3H5MgBr (1.1 mL, 1.08 mmol) dropwise under N2. The e was warmed up to room temperature gradually and stirred for 12 h. The reaction was quenched with NHiCl aqueous and extracted by EtOAc. The c layer was dried over Na2804, filtered and concentrated to give crude product. The crude product was purified by column chromatography on silica gel (eluent: petroleum ether: ethyl acetate = 15: l) to afford the pure product 6-6 (40 mg, 51.9 0/5) as White powder. 1H NMR: (300 MHz, CDC13) 5: ppm 5.92—5.79 (m, 1H), 5.15 (d, J: 4.2 Hz, 1H), 5.11 (d, J: 13.2 Hz, 1H), 2.21 (d, J: 7.5 Hz, 2H), .75 (1n, 5H), 1.67-1.34 (m, 19H), 1.30—0.94 (m, 11H), 0.91 (d, J: 6.3 Hz, 3H), 0.80 (s, 3H), 0.69-0.61 (m, 4H).

Preparation of6-7 and 6-8 Compound 6-2 (400 mg, 0.849 mmol) was split by SFC to get 6-7 (96 mg) and 6-8 (162 mg) as white powder (total yield: 65%). 1H NMR(6—7) (400 MHZ, CDC13), 5 5.90-5.81 (m, 1H), 5.31 (d, J=5.2Hz, 3H)? 5.20-5.09 (m, 2H), 2.45—2.35 (m, 1H), 2.25—2.15 (m, 2H), 2.04—0.90 (m, 36H), 0.68 (s, 3H). 1H NMR(6—8) (400 MHz. ,6 5.90-5.80 (m, 1H). 5.31 (d, J=5.2Hz, 1H), 5.21-5.09 (m. 2H), 2.45—2.34 (m, 1H), 2.25— 2.15 (m, 2H), 2.04-0.89 (m, 36H), 0.68 (s, 3H).

Preparation of 635 To a solution of 6-6 (100 mg, 0.23 mmol) in pyridine (3 mL) was added BzCl (64.4 mg. 0.46 mmol ) dropwise at room temperature. Then the reaction mixture was stirred at 40°C for 12 hours. TLC showed the starting material was consumed completely. The mixture was quenched by saturated aqueous water and extracted with EtOAc.

The combined organic phase was washed with 1 M HCl (30 mL) and brine, dried over ous Na2804 then concentrated in vacuum. The residue was d by column chromatography on silica gel (petroleum ether: ethyl acetate=80:1) to afford 632 (60 mg, 48%) as a white solid.

Preparation of 631, Compound 63: (60 mg, 0.11 mmol) was split by SFC to get 6Bz (40 mg, 66%) as a white. solid. ‘H NMR: (400 MHz. CDClg) 6 7.99-7.98 (d. 1:7.2 Hz, 2H), 7.53—7.49 (t. J=7.2 HZ, 1H), 7.42-7.38 (t, J=7.2 Hz. 2H), .20 (d, J=7.6 Hz. 2H), .57 (m, 11H), 1.54-1.26 (m, 16H), 1.15 (s, 3H), 1.12—1.10 (m. 6H), 0.92—0.91 (d. 3:6.0 Hz, 3H), 0.80 (s, 3H), 0 (m, 4H) Preparation of 6-1] To a solution of compound 6Bz (40 mg, 0.075 mmol) in a mixture solvent of THF (2 mL) and MeOH (1 mL) was added a solution of LiOH (90 mg, 3.75 mmol) in H30 (1 mL). The mixture was d at 40°C for 3 days. TLC showed the ng material was consumed completely. The reaction mixture was treated with water and extracted with EtOAc. The combined organic phase was washed with brine, dried over anhydrous NaZSO4 then concentrated by vacuum. The residue was purified by column chromatography on silica gel (petroleum ether: ethyl acetate=8:1) to afford 6-11 (23 mg, 71%) as a white solid. 1IrI NNIR: (400 MHz, CDC13) 6 5.86-5.84 (m, 1H), 5.13-5.09 (m, 2H), .19 (d, J=7.6 Hz, 2H), 1.84- 1.25 (m, 19H), 1.24 (s, 3H), 1.14 (s, 3H), 1.13-1.09 (m, 7H), 0.91-0.90 (d, J=6.8 Hz, 3H), 0.80 (s, 3H), 0.64-0.60 (m, 4H.) Example 7.

Pd/Ct H2(50 Psi) n-BuLi —> W EtOAQ 50°C HO HO Pd/C, H2(50 psi) EtOH. 50°C Pd/C, H2(50 psi) EtOH, 50°C Preparation ofCompound 7-2. To a solution of 7-1 (193 mg, 0.5 mmol, 1.0 eq) in dry THF (3 mL), n-BuLi (1.6 mL, 4 mmol, 8.0 eq) was added dropwise at -78 OC. The resulting e was stirred at this temperature for 0.5 h; and then the temperature was allowed to warm to room temperature and stirred at this temperature for r 18 h. TLC (PE/EA = 5/1) showed the reaction was complete. The mixture was quenched with saturated aqueous NH4Cl and extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine (10 1nL), dried over sodium sulfate and concentrated in vacuum. The residue was purified by column chromatography on silica gel (eluent: PE: EA = 20: l) to give the product 7-2 (85 mg, 38.6%) as white powder. 1H NMR: (400 MHz, CDC13)6 5.31 (d, J=S.2 Hz, 1H), 2.41 (d, J=13.2Hz, 1H), 2.10—1.95 (m, 3H), 1.94—1.62 (m, 42H), 1.52—1.22 (m, 17H), 1.22—1.20 (m, 1H), 1.15 (s, 3H), 1.10 (s, 3H), 1.05 (s, 3H), 1.04-1.00 (m, 3H), 1.00-0.85 (m, 9H), 0.67 (s, 3H).

Preparation of Compound 7-3. A mixture of 7-2 (100 mg, 2.59 mmci) and 10% Pol/C (140 mg) in EtOAc (30 mL,} was hydrogenated tor 16 h at 50°C under H; (50 psi). The reaction mixture was filtered through a pad of celite and the pad was washed with EtOAe (20 mi. 24' 3). The combined fiitrates were concentrated. The residue was purified by rnti chromatography on silica gei {:eluent: petroleum ether: ethyl acetate = 15:1) to afford 7-3 {3.5 mg, 3.5%) and 763A (39 mg, 19 (3725) as. white . 3H NMR (7-3): (400 MHz, CDCl3) 5 2.02- 1.92 (m, 1 H), 1.90—1.77 (1n, 1 H), 1.70-1.38 (m, 14 H), 1.36—1.29 (m, 6H), .20 (m, 8 H), .08 (m, 6 H), 1.07-0.96 (m, 4 H), 0.96-0.84 (m, 7 H), 0.82 (s, 3 H), 0.70-0.60 (m, 4 H). 1H NMR (7-3A): (400 MHz, CDC13) 5 1.98-1.80 (m, 4 H), .48 (m, 6 H), 1.45—1.33 (m, 9 H), .23 (m, 10H), 1.22-1.18 (m, 4 H), 1.17—1.10(m, 6 H), .97(m,4 H), 0.94 (s, 3 H), 0.93-0.87 (m, 6 H), 0.64 (s, 3 H) ] Preparation of 7-4 and 7-5 To a solution of compound 7-1 (1.5 g, 3.88 mmol) in dry THF (15 mL) was added n-BuLi (12.5. mL, 31 mmoi, 2.5 M in THF) dropwise at —78 OC. The resulting mixture was stirred at this temperature for 0.5 h, and then the temperature was allowed to warm to room temperature and d at this temperature for another 18 h. TLC (PE/EA = 5/ 1) showed the reaction was complete. The mixture was quenched with saturated aqueous NH4Cl and extracted with EtOAc (301nL x 3). The combined organic layers were washed with brine (10 mL), dried over sodium sulfate and concentrated in vacuum. The residue was purified by column chromatography on silica gel (eluent: PE: EA = 20:1) to give 7-2 (800 mg, 46.4%) as white powder, which was split by SFC to give 7-4 (207 mg) and 7-5 (360 mg) as white powder. 1H NMR (7-4): (400 MHz, CDC13) 8 5.38-5.29 (m, 1 H), 2.44 (d, 1H, J=12.5 Hz), .69 (m, 6H), 1.57-1.25 (m, 18H), 1.20-0.89 (m, 23H), 0.70 (s, 3H). 1H NMR (7-5): (400 MHZ, CDC13) 6 5.32 (s, 1H), 2.44 (d, 1H, J=12.3 Hz), 2.08-1.68 (m, 6H), 2.55-1.25 (1n, 17H), 2.22-0.85 (m, 24H), 0.70 (s, 3H).

Preparation of 7-6 To a solution of 7—4 (0.17 g, 0.38 mmol) in 15 mL EtOH was added Pd/C (100 mg) then the reaction mixture was stirred under hydrogen (50 psi) at 50 0C for 24 h. The resulting solution was filtered and concentrated. The t was purified by column chromatograph on silica gel elude with (PE: 1) to give 7-6 (40 mg, yield: 23.42%) as white solid. IH Nl\’IR(7-6) (400 MHZ, CDClg), 8 1.97-1.94 (in, 1H,), l.88-l.76 (in, 1H), 1.71- 1.59 (in, 3H). 3.56—3.23 (m. 21H), l.23-{).86 (m, 19H), 0.81 (s, 3H), 0.65 (s, 3H).

Preparation of 7-7 To a solution of 7-5 (0.23 g) 0.52 mmol) in 15 mL EtOH was added Pd/C (200 mg), then the reaction mixture was stirred under en (50 psi) at 50 0C for 24 h. The resulting solution was filtered and concentrated. The product was purified by column chromatograph on silica gel elude with (PE: EA=20 :1) to give 7-7 (70 mg as , yield: 30.3%) white solid. 1H NMR(7-7) (400 MHz, CDClg), 8 (ppm) 1.99-1.92 (m> 1H,), .78 (n1, 1H),, 1.70-1.52 (m, 6H), 3.46—1.20 (m, 21H), £.IE8~€}.87 (m, 20H). 0.81 (s, 3H}, 0.65 (s, 3H}.

Example 8.

Pd/C, H2(50Psi) EtOAc. 50°C 1,,“ i OH 0‘ i—PngBr SFC r @e T.....00 HO HO 8-1 8-2 Pd/C, H2(50Psi) EtOAc,50°C Pd/C, 142(50931) EtOAc. 50 0C ation of8-2. To a solution of compound 8-1 (100 mg, 0.25 mmol) in toluene (8 mL) was added dropwise a solution of i-PngBr (1.5 mL, 1.5 mmol, l M in THF) at room temperature during a period of 10 min under nitrogen. Then the reaction mixture was stirred at room temperature for 12 h. TLC showed that the starting material was consumed tely. The mixture was poured into aqueous saturated NH4Cl solution (ZOmL) and extracted with EtOAc (50 mL x 2). The combined organic phases were dried over NaQSO4_ and the solvent was evaporated to afford crude product. The crude t purified by column chromatography on silica gel (eluent: petroleum ether: ethyl acetate = 8:1) to give the product 8- 2 (66 mg, 59.46 %) as white powder. 1H NMR: (400 MHZ, CDCl3) 8 5.30 (d, z, 1H); 2.43-2.40 (m, 1H), 2.04—1.55 (m, 3H), 1.88-1.66 (m, 5H), 1.58-1.13 (m; l5H)5 l.ll (s, 3H), 1.08 (s, 3H) 1.01 , (s, 3H), 0.96-0.90 (m, 6H), 0.90-0.86 (m, 3H), 0.68 (s, 3H).

Preparation 0f8-3 and 8—4. To a solution of compound 8-2 (60 mg, 0.14 mmol) in EtOAc (15 mL) was added 10% Pd/C (20 mg) under argon. The suspension was degassed under vacuum and purged with H; several times. The e was stirred under H2 (50 Psi) at 50°C overnight. The suspension was filtered through a pad of celite and the pad was washed with EA (20 mL x 3). The combined filtrates were trated in vacuum and the residue was purified by column chromatography on silica gel (eluent: eum ether: ethyl acetate=10: l) to give 8-3 (27 mg, 45 %) and 8-4 (9 mg. 15 %) as white powder. 1H NMR (8-3) : (400 MHz, CDCB) 5 1.97-1.94 (m, 1H). 1.85-1.78 (m, 2H), 1.74-1.42 (m, 12H), 1.48-1.20 (m, l2H), 1.18- 1.09 (m, 3H), l.07 (s, 3H) 1.02-0.98 (m, 2H), 0.93—0.88 (m, 6H), 0.88-0.86 (m. 3H), 0.80 (s. 3H), 0.63 (s, 3H). 1H NMR(8—4) : (400 MHz. CDC13) 95 (m, 1H), 1.89-1.79 (m, 3H), 1.75—1.54 (m, 7H). 1.48—1.24 (m, 16H), 1.23 (s, 3H), 1.19—1.11 (m, 4H) 1.08 (s. 4H), 0.95 (s, 3H), 0.94-0.88 (m, 6H), 0.88-0.86 (m, 3H), 0.63 (s, 3H). ] ation of 63- 7am] 8-8. To a solution of compound 8-1 (1500 mg, 3.88 mmol) in dry THF (30 mL) was added a solution of i—PngCl (11.6 mL, 23.3 mmol) dropwise at 0 OC.

The mixture was stirred at 40°C for 16 h. TLC OAc = 2/1) showed the reaction was complete. Saturated s NH4Cl (5 mL) was added slowly to quench the reaction. The resulting solution was separated between EtOAc (30 mL x 3) and H20 (30 mL). The combined organic layers were concentrated in vacuum and the e was purified by silica gel column eluted with PE/EtOAc = 10/1 to give the mixture of the diastereomeric pair (800 mg) as white power. The diastereimeric pair was separated by prep-SFC to give 8-8 (317 mg, 19.0%) and 8-7 (250 mg, 15.0%) as white solid. 1H NMR (8—8): (400 MHZ, CDC-lg) 5 5.30 (s, 1H), 2.42 (d, J: 12.4 Hz, 1H), 2.01—1.99 (m, 3H), 1.89-1.65 (m, 4H), 1.59-1.58 (m, 1H), 1.51—1.26 (m, 9H), 1.20— 1.05 (m, 12H), 1.04—0.99 (m, 4H), 0.94-0.88 (m, 10H), 0.68 (s, 3H). 1H NMR (8—7): (400 MHZ, CDC13)5 5.30 (d, J = 3.6 Hz, 1H), 2.42 (d, J = 12.4 Hz, 1H), 2.00—1.97 (m, 3H), 1.89-1.68 (m, 4H), 1.58-1.25 (m, 10H), 1.19-1.08 (m, 10H), 1.03-0.98 (m, 4H), 0.95-0.88 (m, 10H), 0.68 (s, 3H).

Preparation of 8-6. A mixture of 8—8 (200 mg, 0.464 mrnol) and Pd/C (100 mg, cat.) in EtOAc (30 mL) was hydrogenated under 50 psi of hydrogen for 48 h at 50°C. The reaction mixture was filtered through a celite pad. The pad was washed with EtOAc (50 mL).

The filtrate was concentrated in vacuum and the residue was purified by silica gel column eluted with PE/EtOAc = 20/1 to give 8-6 (85.9 mg, 42.8%) as a white solid and 8-6A (17.6 mg, 8.8%) as a white solid. lH NMR(8—6) (400 MHz, CDClg), 5 (ppm) .94 (d, 1H, J=12.8 Hz), 1.88- 1.79 (m, 1H), 1.71-1.61 (m, 3H), 1.54—1.45 (m, 3H), 1.36-1.19 (m, 13H), 1.16-0.96 (m, 12H), .87 (m, 10H), 0.80 (s, 3H), 0.68—0.65 (m, 4H). ‘H NMR(8—6A) (400 MHz,CDC13),6 (ppm) 1.98-1.95 (d, 1H, J=10.8 Hz), .79 (m, 3H), 1.71—1.59 (m, 3H), 1.53-1.48 (m, 2H), 1.42—1.31 (m, 6H), 1.27-0.96 (m, 20H), 0.92-0.87 (m, 12H), 0.80 (s, 3H), 0.64 (s, 3H).

Preparation of 8-5 A mixture of 8-7 (150 mg, 0.348 mmol, 1.0 eq) and Pd/C (75 mg, cat.) in EtOAc (20 mL) was hydrogenated under 50 psi of hydrogen for 48 h at 500C. The reaction mixture was filtered through a celite pad. The pad was washed with EtOAc (50 mL).

The filtrate was trated in vacuum and the residue was purified by silica gel column eluted. with PE/EtOAc = 20/ i to give 8-5 (89.0 mg, 44.3%) as a white solid and 8-5A (4.6 mg, 2.3%) as a white solid. lH NMR(8-5) (400 MHz, CDCl_;), 5 (ppm) 1.97—1.94 (d, 1H, J=12.8 Hz), 1.88- 1.79 (m, 1H), 1.71—1.61 (m. 3H). 1.54—1.45 (m, 3H), 1.36-1.19 (m, 13H), 1.16-0.96 (m, 12H), 0.92-0.87 (m, 10H), 0.80 (s? 3H), 0.68-0.65 (m, 4H). 1H NMR(8-5A) (400 MHz? CDClg), 6 (ppm) .95 (d, 1H, J=10.8 Hz), 1.91—1.79 (m, 3H); 1.72—1.64 (m, 2H); 1.54—1.50 (m, 1H), .00 (m, 28H), 0.96-0.87 (m, 12H), 0.64 (s. 3H). e 9. """" 9.3 EtoAc, 50 °c .....

..... H0 A .....to 9-7A 9H ......3 a. Pd/C, H2(50Psi) ‘ "1.. OH i ElOAc, 50 [7C . : H F) H 9-8A Preparation 0f9-2. To a solution of compound 9-1 (100 mg, 0.25 1nrnol) in THF (2 mL) was added dropwise a on of CyclopropylmagnesiumBromide (2.5 inLa 2.5 minol, l M in THF) at room temperature during a period of 10 min under nitrogen. Then the reaction mixture was stirred at room temperature for 12 h. TLC showed that the starting material was consumed completely. The mixture was poured into aqueous saturated NH4Cl solution (ZOmL) and extracted with EtOAc (50 mL x 2). The combined organic phases were dried over NaZSOr and the solvent was ated to afford crude product. The crude product purified by column chromatography on silica gel (eluent: petroleum ether: ethyl acetate=10:l) to give the product 9- 2 (33 mg, 30 9/0) as white powder. 1H NMR: (400 MHZ, CDCl3) 6: 5.31 (d> J=5.2Hz, 1H), 2.42 (d, Hz, 1H),2.08—1.93 (m. 3H); 1.90-1.65 (111,311), 1.62-1.27 (m, 13H), 1.22-1.08 (m, 11H), 1.01 (s, 3H), 1.00-0.85 (m, 6H), 0.68 (s, 3H),0.40-0.25 (m, 4H).

Preparation of 9-3 and 9-4 Compound 9-2 (200 mg, 0.46 mmol) was separated by SFC to get 9-3 (90 mg) and 9-4 (lOO mg) as white solid, (total yield: 95%). 1H NMR: (9-3) (400 MHz, CDClg) 5 5.31—5.30 (m, 1H), 2.44—2.41 (m, 1H), 2.02—1.99 (m, 3H), 1.95-1.60 (m, 3H), 1.50—1.25 (m, 9H), 1.20—1.05 (m, 11H), 1.02-0.93 (m, llH), 0.68 (s, 3H), 0.35-0.28 (m, 4H). 1H NMR: (9-4) (400 MHz, CDClg) 5 5.31—5.30 (m, 1H), 2.44—2.41 (m, 1H), 2.02—1.95 (m, 3H), 1.93-1.60 (m, 3H), 1.50-1.25 (m, 10H), 1.20-1.05 (m, 11H), 1.02-0.93 (m, 11H), 0.68 (s, 3H), 0.36-0.24 (m, 4H) Preparation of 9-7 To a solution of compound 9-3 (100 mg, 0.23 mmol) in EtOAc (8 mL) was added Pd/C (10%., 200 mg) under N2. The suspension was ed under vacuum and purged with H2 several times. Then the mixture was stirred under H2 (50 psi) at 50 0C for 24 hours. The suspension was filtered through a pad of celite and the pad was washed with EtOAc (30 mL x 2). The combined filtrates were concentrated to dryness to give the crude t, which was purified by column chromatography on silica gel leum ether: ethyl acetate=20:l) to afford 9-7 (27.8 mg, 27.8%) as white solid. 1H NMR: (9-7) (400 MHZ, CDClg) 1.97-1.94 (m, 1H), 1.90-1.80 (m, 1H), l.64-l.57 (m, 3H), .30 (m, 7 H), 1.28—0.85 (m, 25H), 0.80 (s, 3H), 0.65-0.60 (m, 4H), 0.36-0.33 (m, 4H). 1H NMR: (9-7A) (400 MHz, CDClg) 5 1.95-1.83 (m, 4H), 1.70-1.57 (m, 1H), 1.45—1.11 (m, 22H), .85 (m, 17 H), 0.65 (s, 3H), .34 (in, 4H) Preparation of 9-8 To a solution of compound 9-4 (100 mg, 0.23 mmol) in EtOAc (8 mL) was added Pd/C (10%, 200 mg) under N2. The suspension was degassed under vacuum and purged with H; several times. Then the mixture was stirred under H2 (50 psi) at 50 0C for 24 hours. The suspension was filtered through a pad of celite and the pad was washed with EtOAc (30 mL x 2). The combined filtrates were concentrated to dryness to give the crude product, which was purified by HPLC to afford 9-8 (18.3 mg, 18%) as white solid. 1H NMR: (9- 8) (400 MHZ, CDClg) 6 1.97-1.94 (m, lH), 1.90-1.80 (m, 1H), 1.60-1.57 (m, 3H), 1.54-1.20 (m, 16 H), 1.19-0.82 (m, 16H), 0.80 (s, 3H), 0.65-0.60 (m, 4H), .28 (m, 4H) Example 10.

Bng : -1 Pd/C: H2 (5095i) :'—.MgBr BzCl —> . _.

EKOAC, 50°C THF pyridine -1 19.5 10-6 THFMeOH, H20 LiOH THFMeOH, H20 -9 r cat.

H2(1atm), EtOAc NaH, Mel OH PdlC, H2(50 psi) EtOAc 50 “C -16 PdlC, H2(50 psi) EYOAC 50 °C -18 :~—'MgBr BZCI —> 6 pyndme -5 10-7 2 LiOH THF,MeOH, H20 -10 LiOH THF,MeOH, H20 '" 1032 Pd/C, H2(50 psi) EtOAc 50 °C -17 Pd/C, H2(50 psi) EtOAc 50°C 1043 -19 Preparation 0f10-2. To a solution of compound 10-1 (100 mg, 0.25 mmol) in e (8 mL) was added dropwise a solution of ethynylmagnesium bromide (4 mL, 2.0 mmol, 0.5 M in THF) at room temperature during a period of 10 min under en. Then the reaction mixture was stirred at 50 0C over night. TLC showed that the starting material was consumed completely. The mixture was poured into aqueous saturated NH4C1 on (10 mL) and extracted with EtOAc (25 mL x 2). The ed organic phases were dried over Na2804, and the solvent was evaporated to afford crude product. The crude product purified by column chromatography on silica gel (eluent: petroleum ether: ethyl acetate= 10:1) to give the product -2 (80 mg, 74.98 %) as White powder. 1H NMR: (400 MHZ, CDCB) 5 5.30 (d, J=5.2Hz, lH), 2.43—2.40 (m, 2H), 2.06-1.81 (m, 5H), l.80—l.67 (m, 3H), 1.67-1.59 (m 2H); 1.49 (s, 3H), 1.48- 1.42 (m, 2H) 1.40—1.24 (m, 4H), 1.20—1.13 (m, 2H), 1.10 (s, 3H), 0.96-0.92 (m, 3H), 0.69 (s; 3H).

Preparation of 10-3 and 10-4. Compound 10-2 (350 mg, 0.849 mmol) was split by SFC to get 10-3 (82 mg) and 10-4 (94 mg) as white powder (total yield: 50%). 1H NMR(“10- 3) (400 MHz,CDC13),6 5.29 (d, J=5.2Hz, 1H), 2.43—2.40 (m, 2H), .95 (m, 38H), 0.68 (s, 3H). lH NMR(10-4) (400 MHz, CDCl;;),85.29 (d, i=52Hz, 1H), 2.43—2.40 (m, 2H), 2.05-0.95 (m, 38H), 0.68 (s, 3H).

Preparation 0f 10-5. To a on of compound 10-1 (3.0 g) 7.76 mmol) in a mixture solvent of EtOAc (20 mL) and EtOH (10 mL) was added PdI’C (33%, 1.0 g) under N2.

The suspension was degassed under vacuum and purged with H2 several times. Then the mixture was stirred under H2 (50 psi) at 50 0C for 6 days. The suspension was d through a pad of celite and the pad was washed with EtOAc (100 mL x 3). The combined filtrates were concentrated to dryness to give the crude product. which was purified by column chromatography on silica gel (petroleum ether: ethyl acetate=20z l) to afford 10-5 (1.7 g, 56%) as a white solid. 1H NMR: (400 MHz, CDClg) 5 .44 (m, 1H), 2.43—2.40 (m, 1H), 2.13 (s, 3H), 1.95—1.25 (m, 20H), 1.23 (s, 3H), 1.22—1.00 (m, 8H), 0.90-0.88 (d, J=6.4 Hz, 3H), 0.80 (s, 3H), 0.63-0.60 (m. 4H) Preparation 0f10-6. To a solution of 10-5 (550 mg, 1.41 mmol) in dry THF (10 mL) was added ethynylmagnesium bromide (28.2 mL, l4.1 mmol) se at 0°C under N2.

Then the reaction mixture was stirred at room temperature for 12 hours. TLC showed the starting material was consumed completely. The mixture was quenched by ted s NH4C1 (80 mL) and extracted with EtOAc. The organic phase was washed with brine, dried over anhydrous Na2304 then concentrated by vacuum. The e was purified by column chromatography on silica gel (petroleum ether: ethyl acetate=15:l) to afford 10-6 (380 mg, 64%) as a white solid. 1H NMR: (400 MHz, CDC13) 5 2.42 (s, 1H), 1.97-1.48 (m, 14H), 1.47 (s, 3H), 1.29-1.26 (m, 7H), 1.24 (s, 3H), 1.23-0.94 (m, 7H), 0.93—0.92 (d, J=6.4 Hz, 3 H), 0.80 (s, 3H), 0.65-0.62 (m, ation 0f10Bz To a solution of 10-6 (250 mg. 0.60 mmol) in pyridine (3 mL) was added BzCl (168 mg, 1.2 mmol ) dropwise at room temperature. Then the reaction mixture was stirred. at 45°C for 12 hours. TLC showed the starting material was consumed completely. The mixture was quenched by saturated aqueous water and extracted with EtOAc.

The combined organic phase was washed with 1 M HCl (20 mL) and brine, dried over anhydrous Na2804 then concentrated by vacuum. The residue was purified by column chromatography on silica gel (petroleum ether: ethyl acetate=80: l) to 10Bz (200 mg, 64%) as a white solid.

] Preparation of]0Bz and 10Bz Compound 1082 (200 mg, 0.39 mmol) was split by SFC to afford 10Bz (80 mg, 40%) and 1032 (70 mg, 35%) as white solid. 1H NMR: (1082) (400 MHZ, CDCl3) 5 7.99—7.98 (d, J=7.6 Hz, 2H), 7.51-7.49 ((1, 1:72 HZ, 1H), 7.42-7.38 (t, J=7.2 Hz, 2H), 2.42 (s, 1H), 2.05-1.68 (m, 8H), 1.65 (s, 3H), 1.60-1.49 (m, 7H), 1.48 (s, 3H), .11 (m, 16H), 0.94-0.92 (d, J=6.4 Hz, 3 H), 0.87 (s, 3H), 0.66-0.62 (m, 4H). 1H NMR: (10Bz) (400 MHz, CDCi3) 6 .98 (d, J=7.6 Hz, 2H), 7.51-7.49 (d, J=7.2 Hz, 1H), 7.42-7.38 (t, J=7.6 Hz, 2H), 2.43 (s, 1H), .67 (m, 8H), 1.65 (s, 3H), 1.60-1.48 (m, 5H), 1.47 (s, 3H), .20 (m, 11H), 1.19—0.95 (m, 9 H), 0.94—0.92 (d, J=6.8 Hz), 0.87 (s, 3H), 0.66-0.62 (m, 4H) Preparation of 10-8 To a solution of compound 10Bz (80 mg, 0.15 mmol) in a mixture solvent of THF (3 mL) and MeOH (1.5 mL) was added a solution of LiOH (180 mg, 7.5 mmol) in H20 (15 mL). The mixture was d at 40 0C for 3 days. TLC showed the starting material was consumed completely. The reaction mixture was treated with water and extracted with EtOAc. The combined organic phase was washed with brine, dried over anhydrous Na2$O4 then concentrated by vacuum. The e was purified by column chromatography on silica gel (petroleum ether: ethyl acetate=8:l) to afford 10-8 (57 mg, 92%) as a white solid. 1H NlVIR: (400 MHz, CDClg) 5 2.42 (s, 1H), 1.93—1.49 (m, 11H), 1.48 (s, 3H), 1.35—1.20 (m, 16H), 1.19— 0.94 (m, 5H), 0.93—0.92 (d, J=6.4 Hz, 3 H), 0.80 (s, 3H), 0.65-0.62 (m, 4H) Preparation of 10-9 To a solution of compound 10Bz (70 mg, 0.14 mmol) in a mixture solvent of THF (3 mL) and MeOH (1.5 mL) was added a solution of LiOH (168 mg, 7.0 mmol) in H20 (1.5 mL). The mixture was stirred at 40 0C for 3 days. TLC showed the ng material was consumed completely. The reaction mixture was d with water and extracted with EtOAc. The combined organic phase was washed with brine, dried over anhydrous Na2804 then concentrated by vacuum. The residue was purified by column chromatography on silica gel (petroleum ether: ethyl acetate=8:1) to afford 10-9 (53 mg, 91%) as a white solid. 1H NAIR: (400 MHZ, CDCl3) 6 2.42 (s, 1H), 1.93-1.49 (m, 111-1), 1.48 (s, 3H), 1.29-0.94 (m, 21H), 0.93- 0.92 (d, J=6.4 Hz, 3 H), 0.80 (s, 3H), .62 (m, 4H) Preparation of 10-7 To a solution of 10-5 (550 mg, 1.41 mmol) in dry THF (10 mL) was added Vinylmagnesium bromide (9.87 mL, 9.87 mmol) dropwise at 0 0C under N2.

Then the reaction mixture was stirred at room temperature for 12 hours. TLC showed the starting material was ed completely. The mixture was quenched by saturated aqueous NH4C1 (30 mL) and extracted with EtOAc. The organic phase was washed with brine, dried over anhydrous Na2$O4 then concentrated by vacuum. The residue was purified by column chromatography on silica gel (petroleum ether: ethyl acetate=15:l) to afford 10-7 (300 mg, 51%) as a white solid. 1H NMR: (400 MHZ, CDClg) 6 5.93-5.86 (m, 1H), 5.20-5.16 (d, J=17.6 HZ, 1H), 5.05-5.02 (d, 3:108 HZ, 11-1,), 196-1933 (m, 1H), .57 (m, 4H), 1.51-1.20 (m, 20H), 1.19-1.00 (m, 8H), 0.91-0.89 (d, J=6 HZ, 3H), 0.80 (s, 3H), 0.64-0.60 (m, 4H) Preparation Qf10- 7-Bz. To a on of 10-7 (220 mg, 0.53 mmol) in ne (3 mL) was added BZCl (150 mg, 1.06 mmol ) dropwise at room temperature. Then the reaction mixture was stirred at 40C for 12 hours. TLC showed the starting material was consumed tely. The mixture was quenched by saturated aqueous water and extracted with EtOAc.

The combined organic phase was washed with l M HCl (30 mL) and brine, dried over anhydrous Na2804 then concentrated by vacuum. The residue was purified by column tography on silica gel (petroleum ether: ethyl acetate=80:l) to afford 10Bz (150 mg, 54%) as a white solid.

Preparation of 10—10-Bz and 10—11-Bz Compound 10—7-BZ (190 mg, 0.37 mmol) was split by SFC to get 10—10—Bz (75 mg, 39%) and 10—11-BZ (70 mg, 37%) as white solid. 1H NlVIR: (lO-lO-Bz) (400 MHZ, CDClg) 5 7.99-7.97 (d, J=‘7.2 HZ, lH), 7.51-7.49 (d, J=7.6 HZ, lH), 7.42—7.38 (t, J=8.0 HZ, 2H), 5.93-5.86 (dd, 3E1 1.2 HZ, J2=17.2,1H), 5.21—5.16(d, 1:176 Hz, 1H), 5.05—5.02 (d, J=10.4 HZ, 1H), 2.05—1.75 (m, 8H), 1.65-1.27 (m, 19 H), 1.26 (s, 3H), .93 (m, 10 H), .90 (d, 6.0 HZ, 3H), 0.86 (s, 3H), 0.70-0.64 (m, 4H) 1H NMR: (lO-ll-BZ) (400 MHZ, CDCl3) 8 7.99-7.97 (d, J=7.2 HZ, 1H), 7.51—7.49 (d, J=7.6 HZ, lH), 7.42- 7.38 (t, J=8.0 HZ, 2H), 5.93—5.86 (dd, J;=10.8 HZ, 12:17.6, 1H), 5.20-5.16 (d, J=l7.2 HZ, 1H), .02 (d, J=10.4 HZ, 1H), 2.05—1.75 (m, 8H), 1.65-1.27 (m, 10 H), 1.26 (s, 3H), 1.25—0.93 (m, 10 H), 0.91-0.90 (d, 6.4 HZ, 3H), 0.86 (s, 3H), 0.70-0.64 (m, 4H) Preparation 0f10-10. To a solution of compound 10Bz (75 mg, 0.14 mmol) in a mixture solvent of THF (3 mL) and MeOI—I (1.5 ml.) was added a solution of LiOI-l (168 mg, 7.0 mmol) in H20 (1.5 mL). The mixture was stirred at 40 0C for 3 days. TLC showed the starting material was consumed completely. The reaction mixture was treated with water and ted with EtOAc. The combined organic phase was washed with brine, dried over anhydrous NaQSO4 then concentrated by vacuum. The residue was purified by column chromatography on silica gel (petroleum ether: ethyl acetate=8: 1) to afford 10—10 (55 mg, 94%/ as a White solid. 1H NMR: (400 MHZ, CDC13) 5 1.96-1.92 (m, 1H), l.90-l.70 (m, 2H). 1.69-1.57 (m, 5H), 155—120(11), 18H), 1.19-0.81 (m, 10H), 0.80 (s, 3H), 0.70-0.60 (m, 4H) Preparation of 10—11-Bz. To a solution of compound 10Bz (70 mg, 0.13 mmol) in a mixture solvent of THF (3 ml.) and MeOH (1.5 mL) was added a solution of LiOH (168 mg, 7.0 mmol) in H20 (1.5 mL). The mixture was stirred at 40 0C for 3 days. TLC showed. the ng material was consumed completely. The reaction mixture was treated with water and extracted with EtOAc. The combined organic phase was washed with brine, dried over anhydrous Na2804 then trated by vacuum. The residue was purified by column chromatography on silica gel (petroleum ether: ethyl acetate=8:1) to afford 10—11 (49 mg, 91% as a White solid. 1H NMR: (400 MHZ, CDCI3) 5 1.96-1.92 (m, 1H), l.90-l.70 (m, 2H), l.69-l.57 (m, 5H), 1.55—1.20 (m, 18H), 1.19-0.81 (m, 10H), 0.80 (s, 3H), .60 (m, 4H) Preparation of 10—22 and 10-23. To a solution of 10-14 (550 mg, 1.27 mmol) in THF (10 mL) was added NaH (254 mg, 6.36 mmol) at 0°C, and stirred at the same temperature for 30 minutes. Then CH31 (127 mg, 0.770 mmol) was added dropwise to the mixture. The reaction was monitored by TLC. After 1 h, 127 mg of CH31 was added in two portions. After stirring at room temperature for 1.5 h, the on mixture was quenched with s NH4C1 (20 mL), extracted with EtOAc (20 mL x 3), dried over Na2$O4 and concentrated to give crude product. The crude product was purified by column chromatography on silica gel leum ether/ethyl acetate = 15/1) to give 10—14 as a white powder. The diastereomeric pairs (340 mg) were separated by prep-SFC to give 10-22 (130 mg, 22.9%) as a white power and 10-23 (135 mg, 23.8%) as a white power. lH NMR(10-22): (400 MHZ, CDClg) 5 5.30 (s, 1H), 3.65-3.53 (m, 2H), 3.35 (s, 3H), 3.04 (br. 1H). 2.44-2.40 (d, 1H, J=13.6 HZ). 2.02—1.95 (m, 3H), .64 (m, 5H), 1.62-1.58 (m, 1H), 1.52—1.23 (m, 9H), 1.17—1.05 (m, 11H), 1.04-0.98 (m, 4H), 0.95—0.93 (d, 4H, J=6.8 Hz), 0.68 (s, 3H). 1H NMR (10-23): (400 MHZ, CDCi3) 85.30 (s, 1H), 3.61 (t, 2H, J=6.0 Hz), 3.35 (s, 3H), 3.04 (br, 1H), 2.44-2.40 (d, 1H, 8 Hz), 2.02-1.95 (m, 3H), 1.86- 1.64 (m, 5H), 1.57-1.25 (m, 12H), 1.16-0.93 (m, 17H), 0.68 (s, 3H).

Preparation of 10-17. A mixture of 10—22 (100 mg, 0.224 mmol) and Pd/C (50 mg, cat.) in EtOAc (10 mL) was hydrogenated under 50 psi of hydrogen for 48 h at 50°C. The reaction mixture was filtered h a celite pad. The pad was washed with EtOAc (40 mL).

The filtrate was concentrated in vacuum and the residue was purified by silica gel column eluted with PE/EtOAc = 15/1 to give 10—17 (68.4 mg, 68.1%) as a white solid. 1H NMR(10—17) (400 MHz, CDClg), 5 3.62-3.58 (m, 2H), 3.35 (s, 3H), 3.07 (br, 1H), 197—1 .93 (d, 1H, J=12.8 Hz), 1.83-1.74 (m, 2H), 1.69-1.55 (m, 5H), 1.50—1.43 (m, 3H), 1.37—1.23 (m, 12H), 1.16-0.97 (m, 10H), 0.93—0.91 (d, 1H, J=6.0 Hz), , 3H), 0.68-0.64 (m, 3H).

Preparation of 10-19. A mixture of 10-23 (100 mg, 0.224 mmol) and Pd/C (50 mg, cat.) in EtOAc (10 mL) was hydrogenated under 50 psi of hydrogen for 48 h at 50°C. The on mixture was filtered h a celite pad. The pad was washed with EtOAc (40 mL).

The filtrate was concentrated in vacuum and the residue was purified by silica gel column eluted with PE/EtOAc = 15/1 to give 10-19 (68.6 mg, 68.3%) as a white solid. 1H NMR(10—l9) (400 MHz, CDC13), 5 3.60 (t, 2H, J=6.0 Hz), 3.35 (s, 3H), 3.07 (br, 1H), 1.97—1.94 (d, 1H, J=12.8 Hz), 1.81-1.57 (m, 6H), 1.54-1.43 (m, 4H), 1.36-1.22 (m, 12H), .97 (m, 10H), 0.92—0.91 (d, 1H, J=6.0 Hz), 080(5, 3H), 0.68-0.6i (m, 3H).

Preparation of]0- 7. To a solution of 10-6 (60 mg, 0.14 mmol) in EtOAc (2 mL) was adde lindlar cat (24 mg). Then the mixture was stirred under hydrogen (latm) at room temperature for 1.5 hours. The e was filtered through a pad of celite and the filtrate was evaporated under reduced re. The residue was purified by column chromatography on silica gel (eluent: petroleum ether: ethyl acetate = 10: Z) to afford the pure t 10—7 (26 mg, 43.0 %) as white powder. 1H NMR: (400 MHz, CDCB) 5 5.93-5.85 (m, 1H), 5.20-5.16 (d, Hz, 1H), 5.05—5.02 (d, .]=10.8Hz, 1H), 1.96-1.93 (m, lH), 1.79-1.67 (m, 1H), 1.66-1.57 (m, 4H), 1.55-1.36 (m, 11H), 1.35—1.27 (m, 9H) 1.26-0.97 (m, 8H), 0.96-0.89 (m, 3H). 0.81 , (s, 3H), 0.68-0.62 (m, 4H).

Preparation ofCompound 10-12. To a on of 10—1 (50 mg, 0.13 mmol) in THF (2 mL), vinyl magnesium bromide solution (1 mmol, 1 M in THF, 1 mL) was added drop-wise at —50“‘C. The reaction mixture was warmed to room temperature and stirred at room temperature for 16 hours. TLC (petroleum ether: ethyl e = 3:1) showed the reaction was finished, the reaction mixture was quenched with aq. saturated NH4C1 solution (10 mL) and then ted with EtOAc (10 mL x 3). The combined organic layer was washed with brine ('10 mL x 2), dried over anhydrous Na2804 and concentrated in vacuum. The residue was purified by column chromatography on silica gel (eluent: petroleum ether: ethyl acetate = 15/ 1) to afford 10- 12 (27 mg, 54%) as white powder. 1H NVIR: (400 MHZ, CDCB) 8 5.94—5.86 (m, 1H), 5.30 (d, J=5.2Hz, 1H), 5.19 (d, J=17.2Hz, 1H), 5.04 (d, J=10.4Hz, 1H), 2.42 (d, J=12.8Hz, 1H), 2.01— 1.95 (m, 3H), 1.80-1.61 (m, 4H). .37 (m. 10H). 1.27 (s, 3H), 1.18-1.13 (m, 3H) 1.11 , (s, 3H). 1.10—1.04 (m, 3H), 1.01 (s, 3H), 1.00—0.95 (m. 2H), 0.92 (d, z, 3H). 0.67 (s, 3H).

Preparation of 10—12A and 10-12B. Compound 10—12 (350 mg, 0.84 mmol) was sp1it by SFC to give 10-12A (160 mg) and 10-12B (110 mg) as a white solid (total yield: 77%). 1H NMR (10A): (400 MHz. CDCIg) a 5.94-5.86 (m, 1H), 5.30 (d. J=5.2Hz, 1H), 5.19 (d, J=17.2Hz, 1H), 5.04 (d. J=10.4Hz, 1H), 2.50-2.40 (m, 1H), 2.05-0.85 (m, 36H), 0.67 (s, 3H). 1H NMR (10B): (400 MHz. CDC13) 6 5.94-5.86 (m, 1H), 5.30 (d, .]=5.2Hz, 1H), 5.19 (d, J=17.2Hz, 1H), 5.04 (d, J=10.4Hz, 1H), 2.50-2.40 (m, 1H). 2.05-0.85 (m, 36H), 0.67 (s, 3H).

Preparation of Compound 10-13. To a soiution of 10-12 (500 mg> 1.21 mmol) in THF (5 mL) was added 9-BBN (24.2 mL, 12.1 mmol) lly at 0°C under N2 protection. The mixture was d at 60°C for 16 hours. Then the reaction mixture was cooled to 0°C, and 10% aqueous NaOH (10 mL), 30% H202 (5 mL) was added. The resulting mixture was stirred at 0°C for 2 hours. The on mixture was quenched with aqueous Na2$203 (10 mL), extracted with EtOAc (10 mL x 3), dried over Na2$O4 and concentrated to give crude product. The crude product was purified by pre-HPLC to give 10—13 (100 mg, 19.2%) as white solid.1H NMR: (300 MHZ, CD3OD) 5 5.32 (d, J=5.2 Hz, 1H), 3.70 (d, J=6.4 Hz, 2H). 2.51-2.35 (m, 1H), 2.14-1.84 (m, 4H), 1.82-1.26 (m. 16H), 1.24—1.10 (m, 7H). 1.08-1.00 (m, 7H), 1.00—0.93 (m, 4H), 0.73 (s, 3H).

Preparation ofCompound 10-14. To a solution of 10-13 (50 mg, 0.11 mmol) in THF (5 mL) was added NaH (13.2 mg, 0.55 mmol) at 0°C, and stirred at the same ature for 30 minutes. Then CH31 ('78 mg. 0.55 mmol) was added drop-wise to the mixture. The mixture was stirred at room temperature for 1 hour. The reaction mixture was quenched with aqueous NH4C1 (10 mL), extracted with EtOAc (10 mL x 3), dried over NaZSO4 and concentrated to give crude product. The crude product was purified by column chromatography on silica gel (petroleum ether: ethyl acetate = 5: 1) to give 10-14 (13 mg. 25.2%) as white powder. 1H NMR: (300 MHz, CDC13) 6 5.23 (d, J=5.2 Hz, 1H), 3.54 (d, J=6.4 Hz, 2H), 3.29 (s, 3H), 2.38-2.34 (m, 1H), .88 (m, 3H). 1.74-1.58 (m, 5H), 1.52-1.19 (m, 14H), 1.10 (s, 3H), 1.09-1.05 (m, 1H), 1.04 (s, 3H), 1.02-0.94 (m, 2H), 0.91 (s, 3 H), 0.87 (d, J= 6.4 Hz, 3H), 0.61 (s, 3H).

Preparation of 10—20 and 10-21. The crude product 10-13 was washed. with EtOAc (30 mL) to give the reomeric pair (900 mg. 53.9%) as a white so1id. The mixture (400 mg) was separated by SFC to give 10-20 (30 mg, 4.0%) as a white solid and 10—21 (68 mg, 9.2%) as a white solid. 1H NMR(10—20)z (400 MHz, Methaol-d4) 5 5.28 (s, 1H), 3.69 (t, 2H, J=7.2 Hz), 2.42—2.39 (d, 1H, J=11.6 Hz), 2.04—1.90 (m, 5H), 1.78-1.28 (m, 17H), 1.17—1.02 (m, 12H), 0.95—0.93 (d, 4H, J=6.8 Hz), 0.71 (s, 3H). lH NMR(10—21): (400 MHz, Methaol-CM) 5 .28 (s, 1H), 3.68 (t, 2H, J=7.2 Hz), 2.42—2.39 (d, 1H, 1:1 1.6 Hz), 2.04—1.90 (1n, 5H), .28 (m, 16H), 1.18-0.98 (m, 13H), 0.95-0.93 (d, 4H, J=7.0 Hz), 0.71 (s, 3H).

] Preparation of10-16. A mixture of 10-20 (20 mg, 0.046 mmol) and Pd/C (20 mg, cat.) in EtOAc (5 mL) was hydrogenated under 50 psi of hydrogen for 48 h at 50°C. The reaction mixture was filtered through a celite pad. The pad was washed with EtOAc (50 mL). The filtrate was concentrated in vacuum and the residue was purified by silica gel column eluted with PE/E-tOAc = 5/1 to give 10-16 (7.6 mg, 39.3%) as a white solid. 1H NMR(10-16) (400 MHz, Methaol—d4), 5 3.70 (t, 2H, J=7.2 Hz), 2.01-1.98 (d, 1H, J=12.4 Hz), 1.93-1.82 (m, 1H)> 1.72- 1.57 (m, 5H), 1.53—1.39 (m, 5H), 1.35—0.99 (m, 22H), 0.96-0.94 (d, 4H, J=6.4 Hz), 0.84 (s, 3H), 0.70-0.66 (m, 4H).

Preparation of10-18. A mixture of 10-21 (40 mg, 0.092 mmol, 1.0 eq) and Pd/C (20 mg, cat.) in EtOAc (5 mL) was hydrogenated under 50 psi of hydrogen for 48 h at 50°C. The reaction mixture was filtered h a celite pad. The pad was washed with EtOAc (50 mL).

The filtrate was concentrated in vacuum and the residue was purified by silica gel column eluted with PE/EtOAc = 5/1 to give 10—18 (12.9 mg, 32.1%) as a white solid. 1H NMR(10—18) (400 MHz, Methaol—d4), 5 3.68 (t, 2H, J=7.2 Hz), 1.99-1.96 (d, 1H, .]=12.4 Hz), 1.92-1.82 (m, 1H), 1.68-1.58 (m, 5H), 1.52—1.41 (m, 5H), 1.37—0.97 (m, 22H), .92 (d, 4H, J=6.4 Hz), 0.82 (s, 3H), 0.67-0.65 (m, 4H).

Example 11.

TBSCI LDA 02 imidazole, CH2C|2 3 THF TBSO -78°C ~ 15 DC TBSO 11-1 11-2 Bess-Martin DAST,CHZC|2 11-1 11-9 11-8 Bess-Martin MAD MeMgBr CHZCI2 toluene SFC sr=c Preparation ofCompound 11-2. To a solution of crude compound 11-1 (30 g, 77 1nrnol) in dichloromethane (200 mL-) was added imidazole (10.4 g, 154 mmol) and tert- butylchlorodimethylsilane (13.8 g, 92 nnnol). The mixture was then d at 15°C for 16 h. The mixture was washed with water, dried over anhydrous Na2804 and concentrated. The residue was purified by column chromatography on siiica get. (petroleum ether: ethyl acetate =150:1 to 80:1) to give crude product of 11-2 (38 g, 98%) as white solid.

Preparation ofCompound 11-3. To a solution of diisopropylamine (34.3 g, 340 mmol) in THF (1 L) was added butyl lithium (136 mL, 11101, 2.5 M in hexane) under nitrogen atmosphere at -78°C. The mixture was then d at -78°C for 10 minutes and then °C for 10 s and at last -78°C for 10 minutes. A solution of crude compound 11-2 (34 g, 68 rnmol) in THF (100 mL) was then added and stirred for 1 h at -78°C. To the mixture was then added triethyl phosphite (22.6 g, 136 mmol), the mixture was then stirred under oxygen atmosphere for 3 h at -78°C and then 16 h at 25°C. To the mixture was then added ammonium chloride (aq). The organic layer was separated, purified by column chromatography on siiica gei leum ether: ethyl e =10:l to 3: 1) to give crude product of 11-3 ( 10 g, 28%) as yellow solid.

Preparation ofCompound 11-4. To a solution of crude 11-3 (10 g, 19 mmol) in dichloromethane (100 mL) was added Dess-Matin t (16 g, 38 mmol) at 0°C under nitrogen atmosphere. The mixture was then stirred at 30°C for 3 h. To the mixture was then added a mixed solution of sodium bicarbonate and sodium thiosulfate in water. The c layer was separated, washed with water, dried over anhydrous sodium sulfate, concentrated under vacuum to give crude compound 11-4 as (5.9 g, 59%) white solid.

Preparation ofCompound 11-5. To a solution of crude 11-4 (5.9 g, 11 nnnol) in THF (60 mL) was added hydrogen chloride (aq., 6mL, 6 mmol, 1M). The mixture was stirred at °C for 16 h. To the mixture was then added sodium bicarbonate (aq.). The organic layer was separated, dried over anhydrous sodium sulfate, concentrated under vacuum to give crude 11-5 (3.2 g, yield: 70 0/o) as white solid.

Preparation ofCompound 11-6. To a solution of crude 11-5 (3.2 g, 7.9 mmol) in ne (50 mL), acetyl chloride (1.5 g, 19 mmol) was added dropwise at 0°C as monitored by TLC until the reaction was comp1eted. To the mixture was then added water, concentrated under . To the residue was added water, extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate, purified by column chromatography on silica gel (eluent: petroleum ether: ethyl acetate =100: 1) to give crude 11-6 (2.8 g, 79 %) as white solid.

Preparation ofCompound 11-7. To a soiution of crude 11-6 (2.8 g, 6.3 mmol) in dichloromethane (10 mL) was added diethylaminosulfur trifluoride (8 g, 50 mmol) at 0°C. dropwise. The e was then stirred for 16 h at 30°C, The mixture was then added to sodium onate (aq) The organic layer was ted, dried over anhydrous sodium sulfate, purified by column chromatography on silica gel (eluent: petroleum ether : ethyl acetate=100:l to 33:1) to give crude 11-7 (2 g, 68%) as white solid.

Preparation ofCompound 11-8. To a solution of crude 11-7 (2 g, 4.2 mmol) in THF (10 mL) wad added a solution of lithium hydroxide monohydrate (900 mg, 21 mmol) in water (10 mL) and then was added methanol (5 mL). The e was then stirred at 30°C for 16 h. The mixture was then concentrated under vacuum. To the e was added water, filtered.

The solid was washed with water, dried under vacuum to give 11-8 (1 .5 g, 85%) as white solid. 1H NMR: (400 MHZ, methanol-d4) 8 5.34 (d, J=5.2Hz, 1H), 3.45—3.35(m, 1H), 2.30—2.10(m, 3H), 2.10-1.68(m, 7H), l.68—1.44(m, 6H), l.35-l.28(m, 2H), l.28-l.l2(m, 3H), 1.12-0.98(m, 8H), 0.74(s, 3H).

Preparation ofCompound 11-9. To a solution of 11—8 ( l g, 2.4 mmol) in methanol (15 mL) was added hydrogen chloride (5 mL, 4 M in methanol). The mixture was stirred at 30°C for 15 minutes. Sodium bicarbonate (aq) was added till pH=7. The mixture was then concentrated under vacuum. To the residue was added water, extracted with ethyl acetate, The organic layer was separated, dried over anhydrous sodium sulfate, concentrated under vacuum, purified by column chromatography on silica gel (eluent: petroleum ether : ethyl acetate =10:l to 5:1) to give 11-9 (970 mg, 93%) as white solid. 1H NMR: (400 MHz, CDCl3) 5 5.34 (d J=5.2Hz, 1H), 3.87(s, 3H), 3.60-3.48(m, 1H), 2.32—2.15(m, 2H), 2.l0-l.95(m, 2H), l.95-l.70(m, 5H), l.65-l.40(m, 8H), l.30—0.90(m, 13H), , 3H). ] ation ofCompound 11-10. To a solution of 11-9 (0.97 g, 2.3 mmol) in romethane (50 mL) was added Dess-Matin t (2.3 g, 5.4 mmol) at 0 0C under nitrogen here. The mixture was then stirred at 30°C for 3 h. To the mixture was then added a mixed solution of sodium bicarbonate and sodium thiosulfate in water. The organic layer was separated, washed with water, dried over anhydrous sodium sulfate, concentrated under vacuum to give crude compound of 11-10 (1 g, 100%) as yellow oil.

Preparation ofCompound 11-11 and 11-12. To a solution of butylated hydroxytoluene (3. lg, l4.2 mmol) in toluene (20mL) was added Me-3A1 (3.6mL, 7.2 mmol, 2 M in toluene) at 150C. The mixture was then stirred at 15°C for 30 minutes. A solution of 11-11 (0.9 g, 2.4 mmol) in toluene (5 mL) was added at -78“C. The mixture was then stirred at —780C for l h. methylmagnesium e (24 mL, 7.2 mmol, 3M in ether) was then added at -78°C. The mixture was then stirred at -78°C for 1 hour. To the mixture was then added ammonium chloride (aq), d. The organic layer was separated and the aqueous phase was extracted with ethyl acetate. The combined organic layer was dried over anhydrous sodium sulfate, concentrated under , purified by column chromatography on silica gel (eluent: petroleum ether: ethyl e=20:l to lO:l) to give 240 mg of crude 11-11 (yield: 28 %) and 210 mg of crude 11-12 (yield: 25 9/5). 1H NMR (400 MHz, CDCB): 5 5.33—5.25 (m, in), 3.87 (s, 3H), 2.50—0.75 (m, 33H), 0.70 (s, 3H). 1H NMR: (400 MHz, CDC13) 5 5.35—5.27 (m, 1H), .37 (m. 1H), 2.32 (s, 3H), 2.20—0.75 (m, 32H), 0.70 (s, 3H).

Preparation ound 11-13. To a solution of 11-12 (70 mg, 0.16 mmol) in ethanol (2 mL) was added sodium borohydride (100 mg, 2.6 mol) at 150C. The mixture was stirred at 150C for 30 minutes. To the mixture was then added ammonium chloride (aq.), concentrated under vacuum. To the residue was added water, extracted with ethyl acetate. The organic layer was separated, dried over anhydrous sodium e. concentrated under vacuum. purified by column chromatography on silica gel (eluent: petroleum ether : ethyl acetate=10:1 to 8:1) to give 11-13 (40 mg, 57%) as white solid. 1H NMR: (400 MHz, ol-d4) 8 5.35-5.28 (m, 1H). 3.88-3.68 (m, 1H), 2.49—2.37 (m. 1H), .22 (m, 20H), 1.19 (d, J=6.0Hz, 3H), 1.18- 1.14 (m, 1H), 1.11—1.08 (m. 3H), 1.06 (s, 3H), 1.04 (s. 3H), 1.02—0.95 (m, 1H), 0.76 (s, 3H).

Preparation ofCompound 11-15 and 11-16. Diastereomeric mixture 11-13 (30 mg, 0.071 mmol) was split by SFC to get 11-15 (12.2 mg) and 11-16 (14.7 mg) as white powder (total yield: 90%). 1H NMR (11—15): (400 MHz, MeOD) 8 5.32 (d, J=5.2 Hz, 1H), 3.85-3.72 (m, 1H), 2.50—2.40 (m, 1H), 2.20—1.57 (m, 11H). 1.52-0.85 (111,23H), 0.78 (s, 3H). 1H NMR ): (400 MHZ, MeOD) 5 5.32 (d, J=5.2 Hz, 1H), 3.85—3.72 (m, 1H), 2.50-2.40 (m, 1H), 2.20-1.45 (m, 15H), .85 (m, 20H), 0.78 (s, 3H).

Preparation ofCompound 11-19. To a solution of 11-12 (70 mg, 0.16 mmol) in THF (2 mL) was added methylmagnesium bromide (l 1nL, 3 mmol, 3M in ether) at -78°C. The mixture was stirred at 15°C for 30 minutes. To the mixture was then added ammonium chloride (aq), concentrated under vacuum. To the residue was added water, extracted with ethyl acetate.

The organic layer was separated, dried over anhydrous sodium sulfate, concentrated under vacuum, purified by column chromatography on silica gel (eluent: petroleum ether : ethyl acetate=10z1 to 8:1) to give 11-19 (39 mg, 55%) as white solid. 1H NMR: (400 MHz, ol- d4) 6 .28 (m, 1H), 2.48-2.38 (m, 1H), 2.12-1.70 (m. 17H), 1.23 (s, 6H), 1.20-1.12 (m, 3H), 1.10 (d. .]=6.4Hz, 3H), 1.06 (s. 3H), 1.04 (s, 3H), 1.03-0.91 (m, 2H), 0.76 (s, 3H).

Example 12. ation of Intermediate 0-9 0-1 0-2 0-3 0-4 O HATU Bess Martin MeMgBr aq LiOH MAD THF.@0. HOWEt—>2N CHZCIZ CHZCIZ 0-5 0.1 0. /N‘O\ MeMgBr : THF Preparation of 0-2. To a solution of compound 0-1 (100 g, 255 mmol; 1.0 eq) in dry MeOH (500 mL) was added concentrated H3504 (14 mL). The mixture was heated to reflux overnight and then cooled to room temperature. The mixture was ed with aq. saturated NaHC03 on (0.5 L) and then evaporated to remove MeOH. The residue mixture was extracted with EtOAc (300 mL x 3). The combined organic layers were washed with brine (200 mL), dried over NaZSO4 and evaporated to give the product (100 g crude, 96%) as off-white powder. 1H NMR: (400 MHZ, CDCl3) 8 4.09-4.02 (m, 1H), 3.66 (s, 3H), 3.63-3.58 (m, 1H), 2.39-2.31 (m, 1H), 2.25-2.15 (m, 1H), 1.97-1.91 (m, l H)? 1.91-1.55 (m, 10H)> 1.52-1.02 (m, 14H), 0.95-0.88 (m, 6 H), 0.62 (s, 3 H).

Preparation of 0-3. To a solution of nd 0-2 (250 g, 615 mmoL 1.0 eq) in dry pyridine (0.8 L) was added a on of TsCl (352 g, 1844 mmol, 30 eq) in dry pyridine (200 mL). The mixture was stirred at room temperature for 18 h. Ice chips were added gradually to the mixture and the precipitated solid was filtered, Washed with aq 100-0 HCl solution (400 mL x 3) and water (400 mL x 2), and then evaporated to dryness to give crude product (500 g, crude) as a off-white powder, which was used to next step directly ] Preparation 0f 0-4. A mixture of nd 0—3 (250 g crude), CHgCOOK (24 g, 245 mmol, 0.77 eq), water (150 mL) and DMF (900 mL) was heated at reflux for 24 h. The solution was cooled to room temperature, with ice chips added gradually. The itated solid was filtered off and. washed with water (100 mL x 2). The crude solid was purified on silica gel column (PE/EtOAc = 811) to give compound 0-4 (40 g, yield 343% of two steps) as white solid. 1H NMR (400 MHz, CDClg) 6 5.32-5.38 (m, lH). 3.66 (s, 3H). 3.47-3.57 (m, 1H), 2. l6-2.4l (m, 4H), 1.93-2.04 (m, 2H), 1.74-1.92 (m, 4H), 1.30-1.59 (m. 9H), 0.90-1.19 (m, 12H)> 0.68 (s, 3H) Preparation 0f0-5. To a solution of compound 0-4 (33 g, 85 mmol, 10 eq) in dry CH2Clz (700 mL) was added artin t (72 g, 170 mmol, 20 eq) in ns at 0 0C.

Then the reaction mixture was stirred at room temperature for l h. TLC (PE: EA = 3: l) showed the starting material was consumed completely. The reaction mixture were quenched with a saturated aqueous solution O3,/N328203 = 1:3 (250 mL). The organic phase was washed with brine (200 mL x 2) and dried over Na2304, and the solvent was evaporated to afford desired product (35 g, crude), which was used in the next step without further purification.

Preparation of 0-6. To a on ofMAD (0.42 mol, 3.0 eq) in toluene, freshly prepared by addition of a solution of NIC3A1 (210 mL, 0.42 mol, 2 M in hexane) to a stirred solution of 2,6-di-Zerl—butylmethylphenol (185 g, 0.84 mol) in toluene (200 mL) followed by ng for l h at room ature, was added dropwise a solution of compound 0-5 (54 g, 0. l4 mol, l.0 eq) in toluene (200 mL) at -78 0C under nitrogen. Then the reaction mixture was stirred for 30 min, a solution of MeMgBr (140 mL, 0.42mol, 3.0 eq, 3 M in ether) was added dropwise at -78 OC. The reaction mixture was warmed to -40 0C and stirred at this temperature for 3 h.

TLC (PE: EA = 3:1) showed that the starting material was consumed completely. The mixture was poured into aqueous saturated NH4Cl solution (100 mL) and extracted with EtOAc (300 mL x 2). The combined organic phases were dried over Na2804, and the solvent was evaporated to afford crude product. The crude product was d on silica gel chromatography eluted with PE: EA = 10:1 to give the pure target (30 g, 53%) as white powder. 1H NMR: (400 MHz, CDCl3) 5 531-529(1)}, 1H), 3.66 (s, 3H), 2.39—2.33 (m, 2H). 2.24-2.22 (m, lH), 1.99—1.95 (m. 3H), 1.85-1.68 (m, 4H), 1.59—1.40 (m. 8H), 1.31-1.26 (m> 2H), 1.17—1.01 (m, llH), 0.93-0.91 (m. 4H), 0.67 (s, 3H). ation of 0-7. To a solution of compound 0—6 (30.0 g, 74.51 mmol) in THF/HgO (800 inL-, 1/1) was added LiOH.H20 (17.51 g, 417.28 mmol). The reaction was stirred at room temperature for 18 h. TLC (PE/EA = 2/ l) showed that compound 0—6 was consumed completely. The mixture was concentrated in vacuum, d with water (2 L), and then acidified to pH = 4 with 1 M aqueous HCl. The precipitate was collected by filtration and dried in vacuum to give the product compound 0-7 (33 g, crude) as off—white solid. 1H NMR: (400 MHz, CDC13) 6 5.31-5.30 (m, 1H), 2.44-2.36 (m, 21-1), 2.29-2.24 (m) 1H), 2.01-1.95 (m, 3H), 1.87-1.71 (m, 5H), 1.61-1.56 (m, 2H), 1.50-1.32 (m, 8H). .09 (m, 7H), 1.01 (s, 3H), 0.95- 0.93 (m, 4H), 0.68 (s, 3H).

Preparation 0f0-8. A mixture of compound 0-7 (32.0 g, 82.35 mmol), N,O- dimethylhydroxylamine (16.07 g, 164.70 mmol), HATU (37.57 g, 98.82 mmol) and Eth (46.0 mL, 329.40 mmol) in 500 mL anhydrous CH3C12 was stirred for 18 h at room temperature. TLC showed the reaction was completed. Then CH2C12 was added to the mixture and the resulting on was washed with water, 1 N HCI aqueous. saturated aqueous NaHC03 and brine, dried over anhydrous Na2804, filtered and concentrated, purified by silica gel (PE:EtOAc=10:1 to 3: 1) to afford the target compound 0-8 (17.0 g, yield:47.8%) as off—White solid. 1H NMR: (400 MHz.

CDC13) 5 5.31—5.29 (m. 1H), 3.69 (s, 3H), 3.17 (s, 3H), 3.03 (s. 2H), 2.47—2.29 (m, 3H), 2.04— 1.68 (m, 7H), 1.60-1.43 (m, 7H), 1.38-1.30 (m, 2H),, 1.20-1.08 (m, 6H), 1.03—0.91 (m. 8H), 0.68 (s, 3H).

Preparation ofKey Intermediate 0-9. To a solution of compound 0—8 ( 17.0 g, 39.38 mmol) in 300 mL anhydrous THF was added dropwise MeMgBr (65.6 mL, 196.92 mmol, 3 M in ether) under N2 at 0°C. After the on was completed, the reaction mixture was stirred for 2 h at room temperature. TLC showed the on was completed. Then saturated aqueous NH4C1 was slowly added to the mixture at 0°C. then the mixture was poured to water, extracted with EtOAc (2*200 mL), the organic layers were washed with brine, dried over anhydrous , filtered and concentrated, purified on silica gel (PE: EtOAc=20:1 to 6: 1) to afford the target compound 0-9 (11.0 g, yield: 72%) as white solid. 1H NNIR : (400 MHz, CDC13) 8 5.31- .30 (m, 1H), 250-230(11), 3H), 2.17 (s, 2H), 2.14 (s, 3H), 202-194(11), 3H), 1.88-1.67 (m, 4H), l.61-l.58(m, 1H), 1.56-1.49 (m, 5H), 1.47—1.41 (m. 2H), 1.31—1.11 (m, 7H), 1.08-0.91 (m, 8H), 0.68 (s, SH).

Assay Methods Compounds of the present invention can be evaluated using s in vitro and in viva assays described in the literature; examples of which are described below.

The following es are offered to illustrate the biological activity of the compounds, pharmaceutical compositions, and methods provided herein and are not to be construed in any way as limiting the scope thereof.

NMDA potentiatz'on NMDA potentiation was assessed using either whole cell patch clamp of mammalian cells which expressed NMDA receptors, or using two-electrode e clamp (TEVC) ofXenopus Laevis s sing NMDA receptors.

Whole-cell Patch Clamp of Mammalian Cells The whole—cell patch-clamp technique was used to investigate the effects of compounds (0.1 mM and 1.0 mM) on the NlVTDA receptor (C1le .1" GRINZA subunits) expressed in HEK cells. NMDA / Glycine peak and steady-state currents were recorded from stably transfected cells expressing the NMDA receptor and the modulatory s of the test items on these currents were investigated. Results are shown on Table 1.

Cells were stably transfected with human GRlNl (variant NRl-3). These cells were transiently ected (Lipofectaminen'1) with GRINZA cDNA and CD8 (pLeu) antigene cDNA. About 24-72 hours ing ection 1 ul Dynabeads M-45 CD8 was added to identify successfully transfected cells (lurman et 61]., Biotechniques (1994) 171876—881). Cells were passaged to a confluence of 50-80%. Cells were seeded onto Poly-L-Lysine coated cover slips covered with culture complete medium in a 35 mm culture dish. Confluent clusters of cells are electrically coupled hett at 612., Science (1988), 242:1306-8). Because responses in distant cells are not adequately voltage d and because of uncertainties about the extent of coupling (Verdoorn er (1]., Neuron (1990), 4:919-28), cells were ated at a density that enables single cells (without Visible connections to neighboring cells) to be measured. Cells were incubated at 370C in a humidified atmosphere with 5% CO; (rel. humidity about 95%).

The cells were continuously maintained in and passaged in sterile culture flasks containing a l:1 mixture of Dulbecco’s modified eagle medium and nutrient mixture F-l2 (D-MEM/F-lz ix, liquid, with L-Glutamine) supplemented with 9% fetal bovine serum and 0.9% Penicillin/Streptomycin solution. The complete medium was supplemented with 3.0 itng Puromycin.

Whole cell currents were measured with HEKA EPC-l 0 ers using PatchMaster software. Cell culture dishes for recordings were placed on the dish holder of the microscope and continuously perfused (1 ) with “bath solution” (NaCl 137 mM. KCl 4 mM, CaClg 1.8 mM, MgClz 1 mM, HEPES 10 mM, D-Giucose 10 mM, pH (NaOH) 7.4). All solutions applied to cells including the pipette solution were maintained at room temperature (19°C - 30°C). After formation of a Gigaohm seal n the patch electrodes and transfected individual HEK 293 cells (pipette resistance range: 2.5 MQ - 60 M0; seal resistance >l G9) the cell membrane across the pipette tip was ruptured to assure electrical access to the cell interior (whole-cell patch—configuration). At this point the bath solution is ed to “NMDA bath solution” (NaCl 137 mM, KCl 4 mM, C302 28 niM) HEPES 10 mM; D-Glucose l0 mM, Cremophore 0.02%, pH (NaOH) 7.4). NMDA inward currents were measured upon application of 30 uM NMDA (and 5.0 uM Glycine) to patch-clamped cells (2 applications) for 5 s. The cells were voltage clamped at a holding potential of -80 mV. For the analysis of test es, NMDA receptors were stimulated by 30 uM NMDA and 5.0 uM e after tial pre-incubation of increasing concentrations of the test article. Pre—incubation duration was 30 s. Stimulation duration was 55 Test articles were dissolved in DMSO to form stock solutions of 0.1 mM and 1 mM. Test articles were diluted to 0.1 [.M and 1 uM in “NMDA bath solution”. Both concentrations of test articles were tested on each cell. The same concentration was applied at least three times or until the steady state current amplitude was reached. Every day one cell was tested with 50 uM PREGS (positive control ) using the same application protocol to test whether cells were successfully transfected with NMDA receptors.

Comparison nd 3 Comparison compound 3 For Table 1. “A” indicates 10— 75% potentiation, “B” indicates potentiation of >75% to 150%, and “C” indicates potentiation of > 150 to 250 %; and “D indicates potentiation of >250%.

Oocy_tes The Two Electrode Voltage Clamp (TEVC) technique was used to investigate the effects of nds (lOuM) on the NMDA receptor (GRINl/GRINZA) expressed in s oocytes. Glutamate/Glycine peak and steady-state currents were recorded from oocytes that expressed the NMDA receptor and the tory effects of the test items on these currents were investigated. Results are shown on Table 2.

Ovaries were harvested from Xenopus Laew’s females that had been deeply anesthetized by g at 4 °C and immersion in Tricaine methanesulfonare (MS-222 at a concentration of 150 mg/L) in sodium bicarbonate (300 mg/L). Once anesthetized the animal was decapitated and pithed following the rules of animal rights from the Geneva canton. A small piece of ovary was isolated for immediate preparation while the remaining part was placed at 4 0C in a sterile Barth on containing in inM NaCl 88, KCl 1, NaHCO; 2.4, HEPES 10, MgSO4.7H30 0.82, Ca(N03)2.4H20 0.33, CaCl3.6H20 0.41, at pH 7.4, and supplemented with ug/ml of kanamycin, 100 unit/ml llin and 100 rig/ml streptomycin. All ings were performed at 18 0C and cells were super-fused with medium containing in mM: NaCl 82.5, KC12.5, HEPES 5, CaClZEHZO, .6H20 1, pH 7.4.

Oocytes were injected with either cDNAs encoding for the human GRlNl and GRINZA subunits, using a proprietary automated injection device (Hogg 6! £11., J. Neurosci. s, (2008) 169: 65-75) and receptor expression was ed using electrophysiology at least two days later. The ratio of cDNA injection for GRINl and GRIN2A was 1:1.

Electrophysiological recordings were made using an automated s equipped with standard TEVC and data were captured and analyzed using a proprietary data acquisition and is software running under Matlab (Mathworks inc.) The membrane potential of the oocytes was maintained at -80mV throughout the experiments. To e the effects of proprietary compounds, currents were evoked by applying 3uM Giutamate and lOuM Glycine for 10s.

Oocytes were then washed for 905 before being exposed to the test e at a concentration of louM for 1205. Following this, 3uM ate and NM Glycine were immediately reapplied for 105. Potentiation of both the peak current and the steady state current was assessed. For statistical analysis values were computed either with Excel (Microsoft) or Matlab (Mathworks Inc). To obtain mean measurements with standard deviations, all experiments were carried out using at least three cells.

Glutamate was prepared as a concentrated stock solution (10" M) in water and then diluted in the recording medium to obtain the desired test concentration. Glycine was ed as a stock solution at l M in water. Compounds were prepared as stock solution (HY2 M) in DMSO and then diluted in the recording medium to obtain the desired test concentration.

Residual DMSO did not exceed the concentration of l% a concentration that has been shown to have no effects on Xenopus oocytes function.

For Table 2, “A” indicates 10-50% potentiation, “B” indicates iation of >50% to 100%, and “C” indicates potentiation of > 100%.

As shown in Table 1, compounds bearing a beta-hydrogen at C5 are disfavored compared to compounds bearing either alpha-hydrogen C5 or double bond across C5-C6 due to loss of iation of the NMDA receptor. This is illustrated by Comparison Compound 5 vs 4- 6 and 4-7. The removal of the methyl at C2; also s in significant loss ofNMDA potentiation, for example Comparison Compound 4 lost five fold potentiation compared to ison Compozmd 3 when measured at 0.1 uM concentration. Therefore the compounds in this ion bear both a methyl group in C2; and either a double bond across C5-C5 or an alpha- hydrogen in C5. In addition, compounds in this selection showed improved potency and limited maximum potentiation of the NNIDA receptor when tested as high as 1 nM concentrations of compound (for example Comparison Compound 2 vs 4-6 and 1-11). Such properties are expected limit the risk of inducing glutamate driven oxicity relative to nds that achieve a greater maximum potentiation of the NMDA receptor.

Other Embodiments In the claims articles such as “a,” “an,” and “the” may mean one or more than one unless indicated to the contrary or ise evident from the context. Claims or descriptions that include “or” between one or more s of a group are considered satisfied if one, more than one, or all of the group members are t in, employed in, or otherwise relevant to a given product or process unless indicated to the contrary or otherwise evident from the context.

The invention includes embodiments in which exactly one member of the group is present in, employed in, or ise relevant to a given product or process. The invention includes embodiments in which more than one, or all of the group members are present in, employed in, or otherwise relevant to a given t or process.

Furthermore, the invention encompasses all variations, combinations, and permutations in which one or more limitations, elements, clauses, and descriptive terms from one or more of the listed claims is introduced into another claim. For example, any claim that is dependent on another claim can be modified to include one or more tions found in any other claim that is dependent on the same base claim. Where elements are presented as lists, e.g., in Markush group format, each subgroup of the elements is also sed, and any element(s) can be removed from the group. It should it be understood that, in general, Where the invention, or aspects of the invention, is/are referred to as comprising particular elements and/or features, n embodiments of the invention or aspects of the invention consist. or consist essentially of, such elements and/or features. For purposes of simplicity, those embodiments have not been specifically set forth in haec verba herein. It is also noted that the terms “comprising” and “containing” are intended to be open and s the inclusion of additional elements or steps.

Where ranges are given, endpoints are included. Furthermore, unless otherwise indicated or otherwise evident from the t and understanding of one of ordinary skill in the art, values that are expressed as ranges can assume any specific value or sub—range within the stated. ranges in different embodiments of the invention, to the tenth of the unit of the lower limit of the range, unless the t clearly dictates otherwise.

This application refers to various issued patents: published patent applications, journal articles. and other publications. all of which are incorporated herein by reference. If there is a conflict between any of the incorporated references and the instant specification, the specification shall control. In addition, any particular ment of the present invention that falls within the prior art may be itly excluded from any one or more of the claims.

Because such embodiments are deemed to be known to one of ordinary skill in the art, they may be excluded even if the exclusion is not set forth explicitly herein. Any particular embodiment of the ion can be excluded from any claim, for any reason, whether or not related to the existence of prior art.

Those d in the art will recognize or be able to ascertain using no more than routine experimentation many equivalents to the specific embodiments described . The scope of the present embodiments described herein is not intended to be limited to the above Description. but rather is as set forth in the ed claims. Those of ordinary skill in the art will appreciate that various changes and modifications to this ption may be made without departing from the spirit or scope of the present invention, as defined in the following claims.

Claims (23)

We claim:

1. Use of a compound in the cture of a medicament for treating or preventing a CNS-related condition in a subject in need thereof, wherein the compound is selected from the group consisting of: OH OH CF3 CF3 H H H H H H 2-8 HO , HO , OH OH CF3 CF3 H 3-5 H H H H H 3-6 HO , HO , OH OH H H H H H H HO 4-11 HO , 4-12 , H H H H HO 8-7 , 8-8 , OH OH F F H F H F H H H H HO HO 11-15 , 11-16 , and pharmaceutically acceptable salts thereof.

2. The use of claim 1, wherein the compound is: H H HO .

3. The use of claim 1, wherein the compound is: H H 2-8 HO .

4. The use of claim 1, wherein the compound is: H 3-5 H H HO .

5. The use of claim 1, wherein the compound is: H H 3-6 HO .

6. The use of claim 1, wherein the nd is: H H HO 4-11 .

7. The use of claim 1, wherein the compound is: H H 4-12 .

8. The use of claim 1, wherein the compound is: H H 8-7 HO .

9. The use of claim 1, wherein the compound is: H H HO 8-8 .

10. The use of claim 1, wherein the compound is: H F H H 11-15 .

11. The use of claim 1, n the compound is: H F H H 11-16 .

12. Use of a pharmaceutically acceptable salt of a compound in the manufacture of a ment for treating or preventing a CNS-related condition in a subject in need thereof, wherein the compound is selected from the group consisting of: OH OH CF3 CF3 H H H H H H 2-8 HO , HO , OH OH CF3 CF3 H 3-5 H H H H H 3-6 HO , HO , OH OH H H H H H H HO 4-11 HO , 4-12 , H H H H HO 8-7 , 8-8 , OH OH F F H F H F H H H H HO HO 11-15 , and 11-16 .

13. The use of claim 12, wherein the compound is: H H HO .

14. The use of claim 12, wherein the compound is: H H 2-8 HO .

15. The use of claim 12, wherein the nd is: H 3-5 H H HO .

16. The use of claim 12, wherein the compound is: H H 3-6 HO .

17. The use of claim 12, wherein the compound is: H H 4-11 .

18. The use of claim 12, wherein the compound is: H H HO 4-12 .

19. The use of claim 12, n the compound is: H H 8-7 HO .

20. The use of claim 12, wherein the compound is: H H HO 8-8 .

21 The use of claim 12, wherein the compound is: H F H H 11-15 .

22. The use of claim 12, wherein the compound is: H F H H 11-16 .

23. The use according to any one of claims 1-22, wherein the CNS-related condition is an ment disorder, anxiety disorder (including obsessive-compulsive disorder, posttraumatic stress disorder, and social phobia), cognitive disorder (including Alzheimer’s disease and other forms of dementia), dissociative er, eating disorder, mood disorder (including depression, bipolar disorder, and dysthymic disorder), schizophrenia or other psychotic disorder (including schizoaffective disorder), sleep er (including insomnia), substance-related disorder, personality disorder (including ive-compulsive personality disorder), autism spectrum disorders (including those involving mutations to the Shank group of ns), neurodevelopmental disorder (including Rett syndrome, Tuberous Sclerosis complex), pain (including acute and chronic pain), alopathy secondary to a medical condition (including hepatic encephalopathy and anti-NMDA or encephalitis), seizure disorder (including status epilepticus and monogenic forms of epilepsy such as Dravet’s disease), stroke, traumatic brain injury, movement disorder (including Huntington’s disease and Parkinson’s e) or tinnitus. SAGE THERAPEUTICS INC. By the Attorneys for the Applicant N & FERGUSON Per: