CROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. Provisional Application No.

62/810,084, filed on February 25, 2019, the entire content of which is hereby incorporated by reference in its entirety.

FIELD

[0002] This disclosure relates generally to certain diacylglycerol lactone compounds, pharmaceutical compositions comprising said compounds, and methods of making and using said compounds and pharmaceutical compositions.

BACKGROUND

[0003] Over thirty million people are currently living with HIV infection. Combination antiretroviral therapies (cART) and highly active antiretroviral therapies (HAART) have been able to reduce HIV viral loads, often below 50 copies of HIV RNA/ml of plasma, but no therapy has consistently induced HIV control after therapy is interrupted. This is due to the persistence of HIV-infected cells that contain quiescent virus, commonly referred to as the latent reservoir of HIV. “Kick and kill” strategies have been proposed for reservoir reduction and/or elimination. Compounds with“kick” activity have the potential to reverse latency and increase HIV protein expression in infected cells, making them more susceptible to immune-mediated killing. Compounds with“kill” activity have the potential to enhance killing of HIV-infected cells, e.g. by enhancing immune effector cell function.“Kick” programs have tested various agents, including histone deacetylase inhibitors, disulfiram, therapeutic vaccines, and pattern recognition receptors, as noted in Proviral Latency, Persistent Human Immunodeficiency Virus Infection, and the Development of Latency Reversing Agents, Margolis & Archin, J. Infect. Dis., Vol. 215, No. S3, pp. S111-S118; Targeting the Latent Reservoir for HIV- 1 , Sengupta & Siliciano, Immunity, Vol. 48, No. 5, pp. 872-895.

[0004] There remains a need for new agents and therapies capable of assisting in the activation of the latent HIV-infected cells to enhance the activity of antiretroviral therapies and immune responses. Protein Kinase C (PKC) agonists induce strong expression of latent HIV. When PKCs are activated, they translocate from the cytoplasm to cellular membranes, where they initiate a signaling cascade that leads to activation of NF-KB, P-TEFb and API. Upregulation of these factors induces HIV, as well as markers associated with T cell activation such as CD69. Despite the strong magnitude of latency reversal seen with PKC agonists, clinical trials indicate that dose limiting toxicities occur at levels that have insufficient exposure to induce HIV expression (Gutierrez et ak, AIDS, Vol. 30, No. 9, pp. 1385-1392). Thus, there remains a need for PKC agonists with reduced toxicity.

SUMMARY

[0005] In one aspect, provided herein is a compound of Formula I,

Formula I,

or a pharmaceutically acceptable salt thereof,

wherein,

each R ¹ is C _1-3 alkyl;

each R ² is Ci- ₆ alkyl;

one of R ³ and R ⁴ is H, Ci-15 alkyl, or C6-10 aryl, and the other of R ³ and R ⁴ is Ci-15 alkyl or C6-10 aryl, wherein each C 1 - 15 alkyl and each C6-10 aryl are optionally substituted with 1-3 groups independently selected from C5-10 monocyclic cycloalkyl, C5-10 bridged bicyclic cycloalkyl, and C5-10 bridged tricyclic cycloalkyl, or

R ³ and R ⁴ , together with the carbon to which they are attached, form a C _3-7 monocyclic cycloalkyl;

L is a bond, Ci-8 alkylene, or Ci-8 heteroalkylene, wherein the Ci-8 alkylene and the Ci-8 heteroalkylene are each optionally substituted with 1-3 R ⁵ ;

each R ⁵ is independently C1-3 alkyl, or

two R ⁵ are attached to the same carbon and the two R ⁵ , together with the carbon to which they are attached, form a C _3-7 monocyclic cycloalkyl;

A is a phenylene or naphthalenylene;

n is 0, 1, 2, or 3; and

m is 0, 1, 2, or 3;

provided that when A is phenylene, R ³ is methyl, and R ⁴ is methyl, then L is not a bond, and when A is phenylene, R ² is methyl, R ³ is methyl, and R ⁴ is methyl, then L is not -OCi-3 alkylene, wherein the O is attached to A, or provided that

when A is phenylene, R ² is methyl, R ³ is methyl, and R ⁴ is methyl, then L is Ci- ₈ alkylene or C4-8 heteroalkylene, wherein the Ci- ₈ alkylene and the C4-8 heteroalkylene are each optionally substituted with 1-3 R ⁵ .

[0006] In one aspect, provided herein are pharmaceutical compositions comprising a compound provided herein, or a pharmaceutically acceptable salt thereof, and a

pharmaceutically acceptable excipient or carrier. In some embodiments, the pharmaceutical compositions comprise a therapeutically effective amount of a compound provided herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient or carrier.

[0007] In some embodiments, the pharmaceutical compositions provided herein further comprise one or more (i.e., one, two, three, four; one or two; one to three; or one to four) additional therapeutic agents, or a pharmaceutically acceptable salt thereof. In some

embodiments, the pharmaceutical compositions further comprise a therapeutically effective amount of the one or more (i.e., one, two, three, or four; one or two; one to three; or one to four) additional therapeutic agents, or a pharmaceutically acceptable salt thereof.

[0008] In one aspect, the present disclosure provides methods of activating protein kinase C (PKC) in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound provided herein (i.e., a compound of Formula I, II, or Ila), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition provided herein.

[0009] In one aspect, the present disclosure provides methods of treating a disease or disorder associated with decreased PKC activity in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound provided herein (i.e., a compound of Formula I, II, or Ila), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition provided herein.

[0010] In one aspect, the present disclosure provides methods of treating or preventing a human immunodeficiency virus (HIV) infection in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound provided herein (i.e., a compound of Formula I, II, or Ila), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition provided herein.

[0011] In one aspect, the present disclosure provides methods of reducing the latent HIV reservoir in a human infected with HIV, comprising administering to the human a

therapeutically effective amount of a compound provided herein (i.e., a compound of Formula I, II, or Ila), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition provided herein.

[0012] In one aspect, the present disclosure provides methods of reducing HIV viremia in a human infected with HIV, comprising administering to the human a therapeutically effective amount of a compound provided herein (i.e., a compound of Formula I, II, or Ila), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition provided herein.

[0013] In one aspect, the present disclosure provides methods of inducing HIV gene expression in a human infected with HIV, comprising administering to the human a

therapeutically effective amount of a compound provided herein (i.e., a compound of Formula I, II, or Ila), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition provided herein.

[0014] In one aspect, the present disclosure provides methods of activating T cells in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound provided herein (i.e., a compound of Formula I, II, or Ila), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition provided herein.

DETAILED DESCRIPTION

I. Definitions

[0015] The description below is made with the understanding that the present disclosure is to be considered as an exemplification of the claimed subject matter, and is not intended to limit the appended claims to the specific embodiments illustrated. The headings used throughout this disclosure are provided for convenience and are not to be construed to limit the claims in any way. Embodiments illustrated under any heading may be combined with embodiments illustrated under any other heading.

[0016] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. It must be noted that as used herein and in the appended claims, the singular forms“a”,“and”, and“the” include plural referents unless the context clearly dictates otherwise. Thus, e.g, reference to“the compound” includes a plurality of such compounds and reference to“the assay” includes reference to one or more assays and equivalents thereof known to those skilled in the art, and so forth.

[0017] As used in the present disclosure, the following words, phrases and symbols are generally intended to have the meanings as set forth below, except to the extent that the context in which they are used indicates otherwise.

[0018] A dash that is not between two letters or symbols is used to indicate a point of attachment for a substituent. For example, -CONH2 is attached through the carbon atom. A dash at the front or end of a chemical group is a matter of convenience; chemical groups may be depicted with or without one or more dashes without losing their ordinary meaning. A wavy line drawn through a line in a structure indicates a point of attachment of a group. Unless chemically or structurally required, no directionality is indicated or implied by the order in which a chemical group is written or named. A solid line coming out of the center of a ring indicates that the point of attachment for a substituent on the ring can be at any ring atom. For example, R ^a in the below structure can be attached to any of the five carbon ring atoms or R ^a can replace the hydrogen attached to the nitrogen ring atom:

[0019] The prefix“C _u-v ” indicates that the following group has from u to v carbon atoms.

For example,“Ci- ₆ alkyl” indicates that the alkyl group has from 1 to 6 carbon atoms. Likewise, the term“x-y membered” rings, wherein x and y are numerical ranges, such as“3 tol2- membered heterocyclyl”, refers to a ring containing x-y atoms (i.e., 3-12), of which up to 80% may be heteroatoms, such as N, O, S, P, and the remaining atoms are carbon.

[0020] Also, certain commonly used alternative chemical names may or may not be used. For example, a divalent group such as a divalent“alkyl” group, a divalent“aryl” group, etc., may also be referred to as an“alkylene” group or an“alkylenyl” group, or alkylyl group, an “arylene” group or an“arylenyl” group, or arylyl group, respectively.

[0021] “A compound disclosed herein” or“a compound of the present disclosure” or“a compound provided herein” or“a compound described herein” refers to the compounds of Formula I, II, Ila, III, IV, and/or V. Also included are the specific compounds of Examples 1 to 195.

[0022] Reference to“about” a value or parameter herein includes (and describes) embodiments that are directed to that value or parameter per se. In certain embodiments, the term“about” includes the indicated amount ± 10%. In other embodiments, the term“about” includes the indicated amount ± 5%. In certain other embodiments, the term“about” includes the indicated amount ± 1%. Also, the term“about X” includes description of“X”.

[0023] “Alkyl” refers to an unbranched or branched saturated hydrocarbon chain. As used herein, alkyl has 1 to 20 carbon atoms (i.e., Ci-20 alkyl), 1 to 12 carbon atoms (i.e., Ci-12 alkyl), 1 to 8 carbon atoms (i.e., Ci- ₈ alkyl), 1 to 6 carbon atoms (i.e., Ci- ₆ alkyl), 1 to 4 carbon atoms (i.e., C1-4 alkyl), 1 to 3 carbon atoms (i.e., C1-3 alkyl), or 1 to 2 carbon atoms (i.e., C1-2 alkyl). Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl, and 3- methylpentyl. When an alkyl residue having a specific number of carbons is named by chemical name or identified by molecular formula, all positional isomers having that number of carbons may be encompassed; thus, for example,“butyl” includes n-butyl (i.e. -(CEh^CEE), sec-butyl (i.e. -CEhEEyCEhCEb), isobutyl (i.e. -CH2CH(CH3)2) and tert-butyl (i.e. -C(CH3)3); and “propyl” includes n-propyl (i.e. -(CEh^CEE) and isopropyl (i.e. -CH(CH3)2).

[0024] “Alkenyl” refers to an aliphatic group containing at least one carbon-carbon double bond and having from 2 to 20 carbon atoms (i.e., C2-20 alkenyl), 2 to 8 carbon atoms (i.e., C2-8 alkenyl), 2 to 6 carbon atoms (i.e., C2-6 alkenyl), or 2 to 4 carbon atoms (i.e., C2-4 alkenyl). Examples of alkenyl groups include ethenyl, propenyl, butadienyl (including 1,2-butadienyl and 1,3-butadienyl).

[0025] “Alkynyl” refers to an aliphatic group containing at least one carbon-carbon triple bond and having from 2 to 20 carbon atoms (i.e., C2-20 alkynyl), 2 to 8 carbon atoms (i.e., C2-8 alkynyl), 2 to 6 carbon atoms (i.e., C2-6 alkynyl), or 2 to 4 carbon atoms (i.e., C2-4 alkynyl). The term“alkynyl” also includes those groups having one triple bond and one double bond.

[0026] “Alkylene” refers to a divalent and unbranched saturated hydrocarbon chain. As used herein, alkylene has 1 to 20 carbon atoms (i.e., Ci-20 alkylene), 1 to 12 carbon atoms (i.e., Ci-12 alkylene), 1 to 8 carbon atoms (i.e., Ci- ₈ alkylene), 1 to 6 carbon atoms (i.e., Ci- ₆ alkylene), 1 to 4 carbon atoms (i.e., C1-4 alkylene), 1 to 3 carbon atoms (i.e., C1-3 alkylene), or 1 to 2 carbon atoms (i.e., C1-2 alkylene). Examples of alkylene groups include methylene, ethylene, propylene, butylene, pentylene, and hexylene. In some embodiments, an alkylene is optionally substituted with an alkyl group. Examples of substituted alkylene groups include -CH(CH ₃ )CH ₂ -, -CH ₂ CH(CH ₃ )-, -CH ₂ CH(CH ₂ CH ₃ )-, -CH ₂ C(CH ₃ ) ₂ -, -C(CH ₃ ) ₂ CH ₂ -,

-CH(CH )CH(CH )-, -CH ₂ C(CH ₂ CH )(CH )-, and -CH ₂ C(CH ₂ CH ) _2.

[0027] “Alkoxy” refers to the group“alkyl-O-”. Examples of alkoxy groups include methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n- hexoxy, and 1,2-dimethylbutoxy.“Haloalkoxy” refers to an alkoxy group as defined above, wherein one or more hydrogen atoms are replaced by a halogen.

[0028] “Acyl” refers to a group -C(=0)R, wherein R is hydrogen, alkyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may be optionally substituted, as defined herein. Examples of acyl include formyl, acetyl, cylcohexylcarbonyl,

cyclohexylmethyl-carbonyl, and benzoyl.

[0029] “Amido” refers to both a“C-amido” group which refers to the group

-C(=0)NR ^y R ^z and an“N-amido” group which refers to the group -NR ^y C(=0)R ^z , wherein R ^y and R ^z are independently selected from the group consisting of hydrogen, alkyl, aryl, haloalkyl, heteroaryl, cycloalkyl, or heterocyclyl; each of which may be optionally substituted.

[0030] “Amino” refers to the group -NR ^y R ^z wherein R ^y and R ^z are independently selected from the group consisting of hydrogen, alkyl, haloalkyl, aryl, heteroaryl, cycloalkyl, or heterocyclyl; each of which may be optionally substituted.

[0031] “Aryl” refers to an aromatic carbocyclic group having a single ring (e.g.

monocyclic) or multiple rings (e.g. bicyclic or tricyclic) including fused systems. As used herein, aryl has 6 to 20 ring carbon atoms (i.e., C _6-2 o aryl), 6 to 12 carbon ring atoms (i.e., C ₆ -i ₂ aryl), or 6 to 10 carbon ring atoms (i.e., C6-10 aryl). Examples of aryl groups include phenyl, naphthyl, fluorenyl, and anthryl. Aryl, however, does not encompass or overlap in any way with heteroaryl defined below. If one or more aryl groups are fused with a heteroaryl ring, the resulting ring system is heteroaryl.

[0032] “Cyano” or“carbonitrile” refers to the group -CN.

[0033] “Cycloalkyl” refers to a saturated or partially saturated cyclic alkyl group having a single ring or multiple rings including fused, bridged, and spiro ring systems. The term “cycloalkyl” includes cycloalkenyl groups (i.e. the cyclic group having at least one double bond). As used herein, cycloalkyl has from 3 to 20 ring carbon atoms (i.e., C _3.2 o cycloalkyl), 3 to 12 ring carbon atoms (i.e., C _3-12 cycloalkyl), 3 to 10 ring carbon atoms (i.e., C _3-10 cycloalkyl),

3 to 8 ring carbon atoms (i.e., C3-8 cycloalkyl), or 3 to 6 ring carbon atoms (i.e., C3-6 cycloalkyl). Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0034] “Bridged” refers to a ring fusion wherein non-adj acent atoms on a ring are j oined by a divalent substituent, such as an alkylenyl group, an alkylenyl group containing one or two heteroatoms, or a single heteroatom. Quinuclidinyl and admantanyl are examples of bridged ring systems.

[0035] The term“fused” refers to a ring which is bound to an adjacent ring.

[0036] “Spiro” refers to a ring substituent which is joined by two bonds at the same carbon atom. Examples of spiro groups include 1,1 -diethyl cyclopentane, dimethyl-dioxolane, and 4-benzyl-4-methylpiperidine, wherein the cyclopentane and piperidine, respectively, are the spiro substituents.

[0037] “Halogen” or“halo” includes fluoro, chloro, bromo, and iodo.“Haloalkyl” refers to an unbranched or branched alkyl group as defined above, wherein one or more hydrogen atoms are replaced by a halogen. For example, where a residue is substituted with more than one halogen, it may be referred to by using a prefix corresponding to the number of halogen moieties attached. Dihaloalkyl and trihaloalkyl refer to alkyl substituted with two (“di”) or three (“tri”) halo groups, which may be, but are not necessarily, the same halogen. Examples of haloalkyl include difluoromethyl (-CHF2) and tri fluorom ethyl (-CF3).

[0038] “Heteroalkyl ene” refers to a divalent and unbranched saturated hydrocarbon chain having one, two, or three heteroatoms selected from NH, O, or S. As used herein, a heteroalkylene has 1 to 20 carbon atoms and one, two, or three heteroatoms selected from NH,

O, and S (i.e., Ci- ₂₀ heteroalkylene); 1 to 8 carbon atoms and one, two, or three heteroatoms selected from NH, O, and S (i.e., Ci- ₈ heteroalkylene); 1 to 6 carbon atoms and one, two, or three heteroatoms selected from NH, O, and S S (i.e., Ci- ₆ heteroalkylene); 1 to 4 carbon atoms and one, two, or three heteroatoms selected from NH, O, and S (i.e., C _1-4 heteroalkylene); 1 to 3 carbon atoms and one, two, or three heteroatoms selected from NH, O, and S (i.e., C _1-3 heteroalkylene); or 1 to 2 carbon atoms and one, two, or three heteroatoms selected from NH, O, and S (i.e., C _1-3 heteroalkylene). For example, -CH ₂ O- is a Ci heteroalkylene and -CH ₂ SCH ₂ - is a C ₂ heteroalkylene. Examples of heteroalkylene groups include -CH ₂ CH ₂ OCH ₂ -,

-CH ₂ SCH ₂ OCH ₂ -, -CH ₂ O-, and -CH ₂ NHCH ₂ -. In some embodiments, a heteroalkylene is optionally substituted with an alkyl group. Examples of substituted heteroalkylene groups include -CH(CH ₃ )N(CH ₃ )CH ₂ -, -CH ₂ OCH(CH ₃ )-, -CH ₂ CH(CH ₂ CH ₃ )S-, -CH ₂ NHC(CH ₃ ) ₂ -, -C(CH ₃ ) ₂ SCH ₂ -, -CH(CH ₃ )N(CH ₃ )CH(CH ₃ )0-, -CH ₂ SC(CH ₂ CH ₃ )(CH ₃ )-, and

-CH ₂ C(CH ₂ CH ₃ ) ₂ NH-.

[0039] “Heteroaryl” refers to an aromatic group having a single ring, multiple rings, or multiple fused rings, with one or more ring heteroatoms independently selected from nitrogen, oxygen, and sulfur. As used herein, heteroaryl includes 1 to 20 carbon ring atoms (i.e., Ci- ₂ o heteroaryl), 3 to 12 carbon ring atoms (i.e., C ₃ -i ₂ heteroaryl), or 3 to 8 carbon ring atoms (i.e., C _3-8 heteroaryl); and 1 to 5 ring heteroatoms, 1 to 4 ring heteroatoms, 1 to 3 ring heteroatoms, 1 to 2 ring heteroatoms, or 1 ring heteroatom independently selected from nitrogen, oxygen, and sulfur. Examples of heteroaryl groups include pyrimidinyl, purinyl, pyridyl, pyridazinyl, benzothiazolyl, and pyrazolyl. Heteroaryl does not encompass or overlap with aryl as defined above.

[0040] “Heterocyclyl” or“heterocyclic ring” or“heterocycle” refers to a non-aromatic cyclic alkyl group, with one or more ring heteroatoms independently selected from nitrogen, oxygen and sulfur. As used herein,“heterocyclyl” or“heterocyclic ring” or“heterocycle” refer to rings that are saturated or partially saturated unless otherwise indicated, e.g ., in some embodiments“heterocyclyl” or“heterocyclic ring” or“heterocycle” refers to rings that are partially saturated where specified. The term“heterocyclyl” or“heterocyclic ring” or “heterocycle” includes heterocycloalkenyl groups (i.e., the heterocyclyl group having at least one double bond). A heterocyclyl may be a single ring or multiple rings wherein the multiple rings may be fused, bridged, or spiro. As used herein, heterocyclyl has 2 to 20 carbon ring atoms (i.e., C _2.2 o heterocyclyl), 2 to 12 carbon ring atoms (i.e., C ₂ -i ₂ heterocyclyl), 2 to 10 carbon ring atoms (i.e., C ₂ -io heterocyclyl), 2 to 8 carbon ring atoms (i.e., C _2-8 heterocyclyl), 3 to 12 carbon ring atoms (i.e., C ₃ -i ₂ heterocyclyl), 3 to 8 carbon ring atoms (i.e., C _3-8 heterocyclyl), or 3 to 6 carbon ring atoms (i.e., C _3-6 heterocyclyl); having 1 to 5 ring heteroatoms, 1 to 4 ring heteroatoms, 1 to 3 ring heteroatoms, 1 to 2 ring heteroatoms, or 1 ring heteroatom

independently selected from nitrogen, sulfur or oxygen. Examples of heterocyclyl groups include pyrrolidinyl, piperidinyl, piperazinyl, oxetanyl, dioxolanyl, azetidinyl, and morpholinyl. As used herein, the term“bridged- heterocyclyl” refers to a four- to ten-membered cyclic moiety connected at two non-adjacent atoms of the heterocyclyl with one or more (e.g., 1 or 2) four- to ten-membered cyclic moiety having at least one heteroatom where each heteroatom is independently selected from nitrogen, oxygen, and sulfur. As used herein,“bridged- heterocyclyl” includes bicyclic and tricyclic ring systems. Also as used herein, the term“spiro- heterocyclyl” refers to a ring system in which a three- to ten-membered heterocyclyl has one or more additional ring, wherein the one or more additional ring is three- to ten-membered cycloalkyl or three- to ten-membered heterocyclyl, where a single atom of the one or more additional ring is also an atom of the three- to ten-membered heterocyclyl. Examples of the spiro- heterocyclyl include bicyclic and tricyclic ring systems, such as 2-oxa-7- azaspiro[3.5]nonanyl, 2-oxa-6-azaspiro[3.4]octanyl, and 6-oxa-l-azaspiro[3.3]heptanyl. As used herein, the terms“heterocycle”,“heterocyclyl”, and“heterocyclic ring” are used

interchangeably. In some embodiments, a heterocyclyl is substituted with an oxo group.

[0041] “Hydroxy” or“hydroxyl” refers to the group -OH.

[0042] “Oxo” refers to the group (=0) or (O).

[0043] “Sulfonyl” refers to the group -S(0) ₂ R ^C , where R ^c is alkyl, haloalkyl, heterocyclyl, cycloalkyl, heteroaryl, or aryl. Examples of sulfonyl are methylsulfonyl, ethylsulfonyl, phenylsulfonyl, and toluenesulfonyl.

[0044] Whenever the graphical representation of a group terminates in a singly bonded nitrogen atom, that group represents an -NH group unless otherwise indicated. Similarly, unless otherwise expressed, hydrogen atom(s) are implied and deemed present where necessary in view of the knowledge of one of skill in the art to complete valency or provide stability.

[0045] The terms“optional” or“optionally” mean that the subsequently described event or circumstance may or may not occur, and that the description includes instances where said event or circumstance occurs and instances in which it does not. Also, the term“optionally substituted” means that any one or more hydrogen atoms on the designated atom or group may or may not be replaced by a moiety other than hydrogen.

[0046] The term“substituted” means that any one or more hydrogen atoms on the designated atom or group is replaced with one or more substituents other than hydrogen, provided that the designated atom’s normal valence is not exceeded. The one or more substituents include, but are not limited to, alkyl, alkenyl, alkynyl, alkoxy, acyl, amino, amido, amidino, aryl, azido, carbamoyl, carboxyl, carboxyl ester, cyano, guanidino, halo, haloalkyl, heteroalkyl, heteroaryl, heterocyclyl, hydroxy, hydrazino, imino, oxo, nitro, alkylsulfmyl, sulfonic acid, alkyl sulfonyl, thiocyanate, thiol, thione, or combinations thereof. Polymers or similar indefinite structures arrived at by defining substituents with further substituents appended ad infinitum (e.g., a substituted aryl having a substituted alkyl which is itself substituted with a substituted aryl group, which is further substituted by a substituted heteroalkyl group, etc.) are not intended for inclusion herein. Unless otherwise noted, the maximum number of serial substitutions in compounds described herein is three. For example, serial substitutions of substituted aryl groups with two other substituted aryl groups are limited to ((substituted aryl)substituted aryl) substituted aryl. Similarly, the above definitions are not intended to include impermissible substitution patterns (e.g., methyl substituted with 5 fluorines or heteroaryl groups having two adjacent oxygen ring atoms). Such impermissible substitution patterns are well known to the skilled artisan. When used to modify a chemical group, the term “substituted” may describe other chemical groups defined herein. For example, the term “substituted aryl” includes, but is not limited to,“alkylaryl” Unless specified otherwise, where a group is described as optionally substituted, any substituents of the group are themselves unsubstituted.

[0047] In some embodiments, the term“substituted alkyl” refers to an alkyl group having one or more substituents including hydroxyl, halo, amino, alkoxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl. In additional embodiments,“substituted cycloalkyl” refers to a cycloalkyl group having one or more substituents including alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, amino, alkoxy, halo, oxo, and hydroxyl;“substituted heterocyclyl” refers to a heterocyclyl group having one or more substituents including alkyl, amino, haloalkyl, heterocyclyl, cycloalkyl, aryl, heteroaryl, alkoxy, halo, oxo, and hydroxyl;“substituted aryl” refers to an aryl group having one or more substituents including halo, alkyl, amino, haloalkyl, cycloalkyl, heterocyclyl, heteroaryl, alkoxy, and cyano;“substituted heteroaryl” refers to an heteroaryl group having one or more substituents including halo, amino, alkyl, haloalkyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, alkoxy, and cyano and“substituted sulfonyl” refers to a group -S(0) ₂ R, in which R is substituted with one or more substituents including alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl. In other embodiments, the one or more substituents may be further substituted with halo, alkyl, haloalkyl, hydroxyl, alkoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is substituted. In other embodiments, the substituents may be further substituted with halo, alkyl, haloalkyl, alkoxy, hydroxyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each of which is unsubstituted.

[0048] In some embodiments, a substituted cycloalkyl, a substituted heterocyclyl, a substituted aryl, and/or a substituted heteroaryl includes a cycloalkyl, a heterocyclyl, an aryl, and/or a heteroaryl that has a substituent on the ring atom to which the cycloalkyl, heterocyclyl, aryl, and/or heteroaryl is attached to the rest of the compound. For example, in the below moiety, the cyclopropyl is substituted with a methyl group:

[0049] The compounds of the embodiments disclosed herein, or their pharmaceutically acceptable salts may contain one or more asymmetric centers and may thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that may be defined, in terms of absolute stereochemistry, as ( R )- or (S)- or, as (D)- or (L)- for amino acids. The present disclosure is meant to include all such possible isomers, as well as their racemic and optically pure forms. Optically active (+) and (-), ( R )- and (S)-, or (D)- and (L)- isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques, for example, chromatography and fractional crystallization. Conventional techniques for the

preparation/isolation of individual enantiomers include chiral synthesis from a suitable optically pure precursor or resolution of the racemate (or the racemate of a salt or derivative) using, for example, chiral high pressure liquid chromatography (HPLC). When the compounds described herein contain olefmic double bonds or other centers of geometric asymmetry, and unless specified otherwise, it is intended that the compounds include both E and Z geometric isomers. Likewise, all tautomeric forms are also intended to be included. Where compounds are represented in their chiral form, it is understood that the embodiment encompasses, but is not limited to, the specific diastereomerically or enantiomerically enriched form. Where chirality is not specified but is present, it is understood that the embodiment is directed to either the specific diastereomerically or enantiomerically enriched form; or a racemic or scalemic mixture of such compound(s). As used herein,“scalemic mixture” is a mixture of stereoisomers at a ratio other than 1: 1.

[0050] A“stereoisomer” refers to a compound made up of the same atoms bonded by the same bonds but having different three-dimensional structures, which are not interchangeable.

The present disclosure contemplates various stereoisomers and mixtures thereof and includes “enantiomers”, which refers to two stereoisomers whose molecules are non-superimposable mirror images of one another.

[0051] "Enantiomers" are a pair of stereoisomers that are non-superimposable mirror images of each other. A 1 : 1 mixture of a pair of enantiomers is a "racemic" mixture. A mixture of enantiomers at a ratio other than 1 : 1 is a“scalemic” mixture.

[0052] "Diastereoisomers" are stereoisomers that have at least two asymmetric atoms, but which are not mirror-images of each other.

[0053] A“tautomer” refers to a proton shift from one atom of a molecule to another atom of the same molecule. The present disclosure includes tautomers of any compounds provided herein.

[0054] Some of the compounds provided herein exist as tautomeric isomers. Tautomeric isomers are in equilibrium with one another. For example, amide containing compounds may exist in equilibrium with imidic acid tautomers. Regardless of which tautomer is shown, and regardless of the nature of the equilibrium among tautomers, the compounds are understood by one of ordinary skill in the art to comprise both amide and imidic acid tautomers. Thus, the amide containing compounds are understood to include their imidic acid tautomers. Likewise, the imidic acid containing compounds are understood to include their amide tautomers.

[0055] A“solvate” is formed by the interaction of a solvent and a compound. Solvates of salts of the compounds provided herein are also provided. Hydrates of the compounds provided herein are also provided.

[0056] Any formula or structure provided herein is also intended to represent unlabeled forms as well as isotopically labeled forms of the compounds. Isotopically labeled compounds have structures depicted by the formulas given herein except that one or more atoms are replaced by an atom having a selected atomic mass or mass number. Examples of isotopes that can be incorporated into compounds of the disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine and chlorine, such as, but not limited to ² H (deuterium, D), ³ H (tritium), ^U C, ¹³ C, ¹⁴ C, ¹⁵ N, ¹⁸ F, ³¹ P, ³² P, ³⁵ S, ³⁶ C1 and ¹²⁵ I. Various isotopically labeled compounds of the present disclosure, for example those into which radioactive isotopes such as ² H, ³ H, ¹³ C and ¹⁴ C are incorporated, are also provided herein. Such isotopically labelled compounds may be useful in metabolic studies, reaction kinetic studies, detection or imaging techniques, such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT) including drug or substrate tissue distribution assays or in radioactive treatment of patients.

[0057] The present disclosure also includes compounds of Formula I, II, or Ila, in which from 1 to n hydrogens attached to a carbon atom is/are replaced by deuterium, in which n is the number of hydrogens in the molecule. Such compounds exhibit increased resistance to metabolism and are thus useful for increasing the half-life of any compound of Formula I, II, or Ila, when administered to a mammal, particularly a human. See, for example, Foster, “Deuterium Isotope Effects in Studies of Drug Metabolism,” Trends Pharmacol. Sci. 5(12):524- 527 (1984). Such compounds are synthesized by means well known in the art, for example by employing starting materials in which one or more hydrogens have been replaced by deuterium.

[0058] Deuterium labelled or substituted therapeutic compounds of the present disclosure may have improved DMPK (drug metabolism and pharmacokinetics) properties, relating to absorption, distribution, metabolism and excretion (ADME). Substitution with heavier isotopes such as deuterium may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life, reduced dosage requirements and/or an improvement in therapeutic index. An ¹⁸ F labeled compound may be useful for PET or SPECT studies. Isotopically labeled compounds of this disclosure and prodrugs thereof can generally be prepared by carrying out the procedures disclosed in the schemes or in the examples and preparations described below by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent. It is understood that deuterium in this context is regarded as a substituent in the compound of Formula I, II, or Ila.

[0059] The concentration of such a heavier isotope, specifically deuterium, may be defined by an isotopic enrichment factor. In the compounds of this disclosure, any atom not specifically designated as a particular isotope is meant to represent any stable isotope of that atom. Unless otherwise stated, when a position is designated specifically as "H" or "hydrogen", the position is understood to have hydrogen at its natural abundance isotopic

composition. Accordingly, in the compounds of this disclosure, any atom specifically designated as a deuterium (D) is meant to represent deuterium.

[0060] In many cases, the compounds of this disclosure are capable of forming acid and/or base salts by virtue of the presence of amino and/or carboxyl groups or groups similar thereto.

[0061] The term“pharmaceutically acceptable salt” of a given compound refers to salts that retain the biological effectiveness and properties of the given compound, and which are not biologically or otherwise undesirable. Pharmaceutically acceptable base addition salts can be prepared from inorganic and organic bases. Salts derived from inorganic bases include, by way of example only, sodium, potassium, lithium, ammonium, calcium and magnesium salts. Salts derived from organic bases include, but are not limited to, salts of primary, secondary and tertiary amines, such as alkyl amines, dialkyl amines, trialkyl amines, substituted alkyl amines, di(substituted alkyl) amines, tri(substituted alkyl) amines, alkenyl amines, dialkenyl amines, trialkenyl amines, substituted alkenyl amines, di(substituted alkenyl) amines, tri (substituted alkenyl) amines, mono, di or tri cycloalkyl amines, mono, di or tri arylamines or mixed amines, and the like. Specific examples of suitable amines include, by way of example only,

isopropylamine, trimethyl amine, diethyl amine, tri (iso-propyl) amine, tri(n-propyl) amine, ethanolamine, 2-dimethylaminoethanol, piperazine, piperidine, morpholine, N-ethylpiperidine, and the like.

[0062] Pharmaceutically acceptable acid addition salts may be prepared from inorganic and organic acids. Salts derived from inorganic acids include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Salts derived from organic acids include acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluene-sulfonic acid, salicylic acid, and the like.

[0063] As used herein,“pharmaceutically acceptable carrier” or“pharmaceutically acceptable excipient” includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents and the like. The use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active ingredient, its use in the therapeutic compositions is contemplated. Supplementary active ingredients can also be incorporated into the compositions.

[0064] “Treatment” or“treating” is an approach for obtaining beneficial or desired results including clinical results. Beneficial or desired clinical results may include one or more of the following: a) inhibiting the disease or condition (i.e., decreasing one or more symptoms resulting from the disease or condition, and/or diminishing the extent of the disease or condition); b) slowing or arresting the development of one or more clinical symptoms associated with the disease or condition (i.e., stabilizing the disease or condition, preventing or delaying the worsening or progression of the disease or condition, and/or preventing or delaying the spread (i.e., metastasis) of the disease or condition); and/or c) relieving the disease, that is, causing the regression of clinical symptoms (i.e., ameliorating the disease state, providing partial or total remission of the disease or condition, enhancing effect of another medication, delaying the progression of the disease, increasing the quality of life, and/or prolonging survival).

[0065] “Prevention” or“preventing” means any treatment of a disease or condition that causes the clinical symptoms of the disease or condition not to develop. Compounds may, in some embodiments, be administered to a subject (including a human) who is at risk or has a family history of the disease or condition.

[0066] “Subject” refers to an animal, such as a mammal (including a human), that has been or will be the object of treatment, observation or experiment. The methods described herein may be useful in human therapy and/or veterinary applications. In some embodiments, the subject is a mammal. In one embodiment, the subject is a human.

[0067] The term“therapeutically effective amount” or“effective amount” of a compound described herein or pharmaceutically acceptable salts, isomer, or a mixture thereof means an amount sufficient to effect treatment when administered to a subject, to provide a therapeutic benefit such as amelioration of symptoms or slowing of disease progression. For example, a therapeutically effective amount may be an amount sufficient to decrease a symptom of a disease or condition responsive to activation of protein kinase C (PKC). The therapeutically effective amount may vary depending on the subject, and the disease or condition being treated, the weight and age of the subject, the severity of the disease or condition, and the manner of administering, which can readily be determined by one of ordinary skill in the art.

[0068] The term“activation” indicates an increase in the baseline activity of a biological activity or process. “Activation of PKC” or variants thereof refers to an increase in PKC activity as a direct or indirect response to the presence of a compound of the present disclosure relative to the PKC activity in the absence of the compound of the present disclosure.“Activation of PKC” refers to an increase in PKC activity as a direct or indirect response to the presence of a compound provided herein relative to the PKC activity in the absence of the compound provided herein. In some embodiments, the activation of PKC activity may be compared in the same subject prior to treatment, or other subjects not receiving the treatment.

[0069] As used herein, an“agonist” is a substance that stimulates its binding partner, typically a receptor. Stimulation is defined in the context of the particular assay, or may be apparent in the literature from a discussion herein that makes a comparison to a factor or substance that is accepted as an“agonist” or an“antagonist” of the particular binding partner under substantially similar circumstances as appreciated by those of skill in the art. Stimulation may be defined with respect to an increase in a particular effect or function that is induced by interaction of the agonist or partial agonist with a binding partner and can include allosteric effects. [0070] As used herein, an“antagonist” is a substance that inhibits its binding partner, typically a receptor. Inhibition is defined in the context of the particular assay, or may be apparent in the literature from a discussion herein that makes a comparison to a factor or substance that is accepted as an“agonist” or an“antagonist” of the particular binding partner under substantially similar circumstances as appreciated by those of skill in the art. Inhibition may be defined with respect to a decrease in a particular effect or function that is induced by interaction of the antagonist with a binding partner, and can include allosteric effects.

II. Compounds

[0071] In one aspect, provided herein is a compound of Formula I,

Formula I,

or a pharmaceutically acceptable salt thereof,

wherein,

each R ¹ is C _1-3 alkyl;

each R ² is Ci- ₆ alkyl;

one of R ³ and R ⁴ is H, Ci- ₁₅ alkyl, or C _6-10 aryl, and the other of R ³ and R ⁴ is Ci- ₁₅ alkyl or C _6-10 aryl, wherein each Ci- ₁₅ alkyl and each C _6-10 aryl are optionally substituted with 1 -3 groups independently selected from C _5-10 monocyclic cycloalkyl, C _5-10 bridged bicyclic cycloalkyl, and C _5-10 bridged tricyclic cycloalkyl, or

R ³ and R ⁴ , together with the carbon to which they are attached, form a C _3-7 monocyclic cycloalkyl;

L is a bond, Ci-8 alkylene, or Ci-8 heteroalkylene, wherein the Ci-8 alkylene and the Ci-8 heteroalkylene are each optionally substituted with 1-3 R ⁵ ;

each R ⁵ is independently C _1-3 alkyl, or

two R ⁵ are attached to the same carbon and the two R ⁵ , together with the carbon to which they are attached, form a C _3-7 monocyclic cycloalkyl;

A is a phenylene or naphthalenylene;

n is 0, 1, 2, or 3; and

m is 0, 1, 2, or 3; provided that

when A is phenylene, R ³ is methyl, and R ⁴ is methyl, then L is not a bond, and when A is phenylene, R ² is methyl, R ³ is methyl, and R ⁴ is methyl, then L is not -OCi-3 alkylene, wherein the O is attached to A, or provided that

when A is phenylene, R ² is methyl, R ³ is methyl, and R ⁴ is methyl, then L is Ci- ₈ alkylene or C4-8 heteroalkylene, wherein the Ci- ₈ alkylene and the C4-8 heteroalkylene are each optionally substituted with 1-3 R ⁵ .

[0072] In one aspect, provided herein is a compound of Formula I,

Formula I,

or a pharmaceutically acceptable salt thereof,

wherein,

each R ¹ is C _1-3 alkyl;

each R ² is Ci- ₆ alkyl;

one of R ³ and R ⁴ is H or C 1-3 alkyl, and the other of R ³ and R ⁴ is C i-12 alkyl or phenyl, wherein the Ci-12 alkyl is optionally substituted with adamantanyl, or

R ³ and R ⁴ , together with the carbon to which they are attached, form a C3-7 monocyclic cycloalkyl;

L is a bond, Ci-8 alkylene, or Ci-8 heteroalkylene;

A is a phenylene or naphthalenylene;

n is 0, 1, or 2; and

m is 1 or 2,

provided that

when A is phenylene, R ³ is methyl, and R ⁴ is methyl, then L is not a bond, and when A is phenylene, R ² is methyl, R ³ is methyl, and R ⁴ is methyl, then L is not -OC i-3 alkylene, wherein the O is attached to A, or provided that

when A is phenylene, R ² is methyl, R ³ is methyl, and R ⁴ is methyl, then L is Ci- ₈ alkylene or C4-8 heteroalkylene. [0073] In one aspect, provided herein is a compound of Formula I,

Formula I,

or a pharmaceutically acceptable salt thereof,

wherein,

each R ¹ is C _1-3 alkyl;

each R ² is Ci- ₆ alkyl;

one of R ³ and R ⁴ is H or C _1-3 alkyl, and the other of R ³ and R ⁴ is Ci- ₁₂ alkyl or phenyl, or R ³ and R ⁴ , together with the carbon to which they are attached, form a C _3-7 monocyclic cycloalkyl;

L is a bond, Ci-8 alkylene, or Ci-8 heteroalkylene;

A is a phenylene or naphthalenylene;

n is 0, 1, or 2; and

m is 1 or 2,

provided that

when A is phenylene, R ³ is methyl, and R ⁴ is methyl, then L is not a bond, and when A is phenylene, R ² is methyl, R ³ is methyl, and R ⁴ is methyl, then L is not

-OCi-3 alkylene, wherein the O is attached to A, or provided that

when A is phenylene, R ² is methyl, R ³ is methyl, and R ⁴ is methyl, then L is Ci- ₈ alkylene or C _4-8 heteroalkylene.

[0074] In some embodiments, the compound of Formula I is of Formula II,

Formula II,

or a pharmaceutically acceptable salt thereof. [0075] In some embodiments, the compound of Formula I or II is of Formula Ila,

Formula Ila,

or a pharmaceutically acceptable salt thereof.

[0076] In some embodiments of the compound of Formula I, or a pharmaceutically acceptable salt thereof, m is 0, 1, 2, or 3. In some embodiments of the compound of Formula I, or a pharmaceutically acceptable salt thereof, m is 1 or 2. In some embodiments of the compound of Formula I, or a pharmaceutically acceptable salt thereof, m is 0. In some embodiments of the compound of Formula I, or a pharmaceutically acceptable salt thereof, m is 1. In some embodiments of the compound of Formula I, or a pharmaceutically acceptable salt thereof, m is 2. In some embodiments of the compound of Formula I, or a pharmaceutically acceptable salt thereof, m is 3.

[0077] In some embodiments of the compound of Formula I, or a pharmaceutically acceptable salt thereof, each R ² is Ci- ₆ alkyl. In some embodiments of the compound of Formula I, or a pharmaceutically acceptable salt thereof, each R ² is Ci- ₄ alkyl. In some embodiments of the compound of Formula I, or a pharmaceutically acceptable salt thereof, each R ² is C2-4 alkyl. In some embodiments of the compound of Formula I, or a pharmaceutically acceptable salt thereof, each R ² is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, tert- butyl, iso-butyl, sec-butyl, pentyl, or hexyl. In some embodiments of the compound of Formula I, or a pharmaceutically acceptable salt thereof, each R ² is independently ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, iso-butyl, sec-butyl, pentyl, or hexyl. In some embodiments of the compound of Formula I, or a pharmaceutically acceptable salt thereof, each R ² is independently ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, iso-butyl, or sec-butyl. In some embodiments of the compound of Formula I, or a pharmaceutically acceptable salt thereof, each R ² is

independently ethyl, n-propyl, n-butyl, isobutyl, sec-butyl, pentyl, or hexyl. In some

embodiments of the compound of Formula I, or a pharmaceutically acceptable salt thereof, one, two, or three R ² is methyl, n-butyl, or tert-butyl. In some embodiments of the compound of Formula I, or a pharmaceutically acceptable salt thereof, one, two, or three R ² is n-butyl or tert- butyl. In some embodiments of the compound of Formula I, or a pharmaceutically acceptable salt thereof, one, two, or three R ² is methyl or tert-butyl. In some embodiments of the compound of Formula I, or a pharmaceutically acceptable salt thereof, one, two, or three R ² is methyl. In some embodiments of the compound of Formula I, or a pharmaceutically acceptable salt thereof, one, two, or three R ² is ethyl. In some embodiments of the compound of Formula I, or a pharmaceutically acceptable salt thereof, one, two, or three R ² is n-propyl. In some embodiments of the compound of Formula I, or a pharmaceutically acceptable salt thereof, one, two, or three R ² is isopropyl. In some embodiments of the compound of Formula I, or a pharmaceutically acceptable salt thereof, one, two, or three R ² is n-butyl. In some embodiments of the compound of Formula I, or a pharmaceutically acceptable salt thereof, one, two, or three R ² is tert-butyl. In some embodiments of the compound of Formula I, or a pharmaceutically acceptable salt thereof, one, two, or three R ² is isobutyl. In some embodiments of the compound of Formula I, or a pharmaceutically acceptable salt thereof, one, two, or three R ² is sec-butyl. In some embodiments of the compound of Formula I, or a pharmaceutically acceptable salt thereof, one, two, or three R ² is pentyl. In some embodiments of the compound of Formula I, or a pharmaceutically acceptable salt thereof, one, two, or three R ² is hexyl.

[0078] In some embodiments of the compound of Formula II or Ila, or a

pharmaceutically acceptable salt thereof, R ² is Ci- ₆ alkyl. In some embodiments of the compound of Formula II or Ila, or a pharmaceutically acceptable salt thereof, R ² is Ci-4 alkyl. In some embodiments of the compound of Formula II or Ila, or a pharmaceutically acceptable salt thereof, R ² is C2-4 alkyl. In some embodiments of the compound of Formula II or Ila, or a pharmaceutically acceptable salt thereof, R ² is methyl, ethyl, n-propyl, isopropyl, n-butyl, tert- butyl, iso-butyl, sec-butyl, pentyl, or hexyl. In some embodiments of the compound of Formula II or Ila, or a pharmaceutically acceptable salt thereof, R ² is ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, iso-butyl, sec-butyl, or pentyl. In some embodiments of the compound of Formula II or Ila, or a pharmaceutically acceptable salt thereof, R ² is ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, iso-butyl, or sec-butyl. In some embodiments of the compound of Formula II or Ila, or a pharmaceutically acceptable salt thereof, R ² is ethyl, n-propyl, n-butyl, iso-butyl, sec-butyl, pentyl, or hexyl. In some embodiments of the compound of Formula II or Ila, or a

pharmaceutically acceptable salt thereof, R ² is methyl, n-butyl, or tert-butyl. In some embodiments of the compound of Formula II or Ila, or a pharmaceutically acceptable salt thereof, R ² is n-butyl or tert-butyl. In some embodiments of the compound of Formula II or Ila, or a pharmaceutically acceptable salt thereof, R ² is methyl or tert-butyl. In some embodiments of the compound of Formula II or Ila, or a pharmaceutically acceptable salt thereof, R ² is methyl. In some embodiments of the compound of Formula II or Ila, or a pharmaceutically acceptable salt thereof, R ² is ethyl. In some embodiments of the compound of Formula II or Ila, or a pharmaceutically acceptable salt thereof, R ² is n-propyl. In some embodiments of the compound of Formula II or Ila, or a pharmaceutically acceptable salt thereof, R ² is isopropyl. In some embodiments of the compound of Formula II or Ila, or a pharmaceutically acceptable salt thereof, R ² is n-butyl. In some embodiments of the compound of Formula II or Ila, or a pharmaceutically acceptable salt thereof, R ² is tert-butyl. In some embodiments of the compound of Formula II or Ila, or a pharmaceutically acceptable salt thereof, R ² is isobutyl. In some embodiments of the compound of Formula II or Ila, or a pharmaceutically acceptable salt thereof, R ² is sec-butyl. In some embodiments of the compound of Formula II or Ila, or a pharmaceutically acceptable salt thereof, R ² is pentyl. In some embodiments of the compound of Formula II or Ila, or a pharmaceutically acceptable salt thereof, R ² is hexyl.

[0079] In some embodiments of the compound of Formula I, II, or Ila, or a

pharmaceutically acceptable salt thereof, when A is phenylene, then R ² is ethyl, n-propyl, n- butyl, iso-butyl, sec-butyl, or pentyl. In some embodiments of the compound of Formula I, II, or Ila, or a pharmaceutically acceptable salt thereof, when A is phenylene, then R ² is not methyl, isopropyl, or tert-butyl.

[0080] In some embodiments of the compound of Formula I, II, or Ila, or a

pharmaceutically acceptable salt thereof, one of R ³ and R ⁴ is H, C i-is alkyl, or C6-10 aryl, and the other of R ³ and R ⁴ is C i-is alkyl or C6-10 aryl, wherein each Ci-is alkyl and each C6-10 aryl are optionally substituted with 1-3 groups independently selected from C5-10 monocyclic cycloalkyl, C5-10 bridged bicyclic cycloalkyl, and C5-10 bridged tricyclic cycloalkyl; or R ³ and R ⁴ , together with the carbon to which they are attached, form a C3-7 monocyclic cycloalkyl.

[0081] In some embodiments of the compound of Formula I, II, or Ila, or a

pharmaceutically acceptable salt thereof, one of R ³ and R ⁴ is H and the other of R ³ and R ⁴ is C i- 15 alkyl or C6-10 aryl, wherein the C i-15 alkyl and the C6-10 aryl are optionally substituted with 1-3 groups independently selected from C5-10 monocyclic cycloalkyl, C5-10 bridged bicyclic cycloalkyl, and C5-10 bridged tricyclic cycloalkyl. In some embodiments of the compound of Formula I, II, or Ila, or a pharmaceutically acceptable salt thereof, one of R ³ and R ⁴ is Ci-15 alkyl and the other of R ³ and R ⁴ is Ci-15 alkyl or C6-10 aryl, wherein each C i-15 alkyl and the C6-10 aryl are optionally substituted with 1-3 groups independently selected from C5-10 monocyclic cycloalkyl, C5-10 bridged bicyclic cycloalkyl, and C5-10 bridged tricyclic cycloalkyl. In some embodiments of the compound of Formula I, II, or Ila, or a pharmaceutically acceptable salt thereof, one of R ³ and R ⁴ is C6-10 aryl and the other of R ³ and R ⁴ is Ci-15 alkyl or C6-10 aryl, wherein the Ci-15 alkyl and each C6-10 aryl are optionally substituted with 1-3 groups independently selected from C _5-10 monocyclic cycloalkyl, C _5-10 bridged bicyclic cycloalkyl, and C _5-10 bridged tricyclic cycloalkyl.

[0082] In some embodiments of the compound of Formula I, II, or Ila, or a

pharmaceutically acceptable salt thereof, one of R ³ and R ⁴ is H or C 1-3 alkyl, and the other of R ³ and R ⁴ is C i-12 alkyl or phenyl, wherein the C i-12 alkyl is optionally substituted with

adamantanyl. In some embodiments of the compound of Formula I, II, or Ila, or a

pharmaceutically acceptable salt thereof, one of R ³ and R ⁴ is H and the other of R ³ and R ⁴ is C i- 12 alkyl or phenyl, wherein the Ci-12 alkyl is optionally substituted with adamantanyl. In some embodiments of the compound of Formula I, II, or Ila, or a pharmaceutically acceptable salt thereof, one of R ³ and R ⁴ is C 1-3 alkyl, and the other of R ³ and R ⁴ is Ci-12 alkyl or phenyl, wherein the Ci-12 alkyl is optionally substituted with adamantanyl. In some embodiments of the compound of Formula I, II, or Ila, or a pharmaceutically acceptable salt thereof, one of R ³ and R ⁴ is methyl, and the other of R ³ and R ⁴ is Ci-12 alkyl or phenyl, wherein the C i-12 alkyl is optionally substituted with adamantanyl. In some embodiments of the compound of Formula I, II, or Ila, or a pharmaceutically acceptable salt thereof, one of R ³ and R ⁴ is ethyl, and the other of R ³ and R ⁴ is C i-12 alkyl or phenyl, wherein the C i-12 alkyl is optionally substituted with adamantanyl. In some embodiments of the compound of Formula I, II, or Ila, or a

pharmaceutically acceptable salt thereof, one of R ³ and R ⁴ is n-propyl, and the other of R ³ and R ⁴ is C i-12 alkyl or phenyl, wherein the Ci-12 alkyl is optionally substituted with adamantanyl. In some embodiments of the compound of Formula I, II, or Ila, or a pharmaceutically acceptable salt thereof, one of R ³ and R ⁴ is isopropyl, and the other of R ³ and R ⁴ is C i-12 alkyl or phenyl, wherein the Ci-12 alkyl is optionally substituted with adamantanyl.

[0083] In some embodiments of the compound of Formula I, II, or Ila, or a

pharmaceutically acceptable salt thereof, one of R ³ and R ⁴ is H or C 1-3 alkyl, and the other of R ³ and R ⁴ is C i-12 alkyl or phenyl. In some embodiments of the compound of Formula I, II, or Ila, or a pharmaceutically acceptable salt thereof, one of R ³ and R ⁴ is H and the other of R ³ and R ⁴ is C i-12 alkyl or phenyl. In some embodiments of the compound of Formula I, II, or Ila, or a pharmaceutically acceptable salt thereof, one of R ³ and R ⁴ is C 1-3 alkyl, and the other of R ³ and R ⁴ is C i-12 alkyl or phenyl. In some embodiments of the compound of Formula I, II, or Ila, or a pharmaceutically acceptable salt thereof, one of R ³ and R ⁴ is methyl, and the other of R ³ and R ⁴ is C i-12 alkyl or phenyl. In some embodiments of the compound of Formula I, II, or Ila, or a pharmaceutically acceptable salt thereof, one of R ³ and R ⁴ is ethyl, and the other of R ³ and R ⁴ is C i-12 alkyl or phenyl. In some embodiments of the compound of Formula I, II, or Ila, or a pharmaceutically acceptable salt thereof, one of R ³ and R ⁴ is n-propyl, and the other of R ³ and R ⁴ is C _M2 alkyl or phenyl. In some embodiments of the compound of Formula I, II, or Ila, or a pharmaceutically acceptable salt thereof, one of R ³ and R ⁴ is isopropyl, and the other of R ³ and R ⁴ is C _M2 alkyl or phenyl.

[0084] In some embodiments of the compound of Formula I, II, or Ila, or a

pharmaceutically acceptable salt thereof, one of R ³ and R ⁴ is H or methyl and the other of R ³ and R ⁴ is methyl, phenyl, or C _6-12 alkyl, wherein the C _6-12 alkyl is optionally substituted with adamantanyl. In some embodiments of the compound of Formula I, II, or Ila, or a

pharmaceutically acceptable salt thereof, one of R ³ and R ⁴ is H or methyl and the other of R ³ and R ⁴ is methyl, phenyl, or C _6-12 alkyl, wherein the methyl is optionally substituted with

adamantanyl. In some embodiments of the compound of Formula I, II, or Ila, or a

pharmaceutically acceptable salt thereof, one of R ³ and R ⁴ is H or methyl and the other of R ³ and R ⁴ is methyl, phenyl, or C _6-12 alkyl.

[0085] In some embodiments of the compound of Formula I, II, or Ila, or a

pharmaceutically acceptable salt thereof, one of R ³ and R ⁴ is H or methyl and the other of R ³ and R ⁴ is phenyl,

[0086] In some embodiments of the compound of Formula I, II, or Ila, or a

pharmaceutically acceptable salt thereof, one of R ³ and R ⁴ is H and the other of R ³ and R ⁴ is

[0087] In some embodiments of the compound of Formula I, II, or Ila, or a

pharmaceutically acceptable salt thereof, R ³ is H or methyl and R ⁴ is methyl, phenyl, or C _6-12 alkyl, wherein the C _6-12 alkyl is optionally substituted with adamantanyl. In some embodiments of the compound of Formula I, II, or Ila, or a pharmaceutically acceptable salt thereof, R ³ is H or methyl and R ⁴ is methyl, phenyl, or C _6-12 alkyl, wherein the methyl is optionally substituted with adamantanyl. In some embodiments of the compound of Formula I, II, or Ila, or a

pharmaceutically acceptable salt thereof, R ³ is H or methyl and R ⁴ is methyl, phenyl, or C _6-12 alkyl.

[0088] In some embodiments of the compound of Formula I, II, or Ila, or a

pharmaceutically acceptable salt thereof, R ³ is H, methyl, ethyl, or isopropyl. In some embodiments of the compound of Formula I, II, or Ila, or a pharmaceutically acceptable salt thereof, R ³ is H or methyl. In some embodiments of the compound of Formula I, II, or Ila, or a pharmaceutically acceptable salt thereof, R ³ is H. In some embodiments of the compound of Formula I, II, or Ila, or a pharmaceutically acceptable salt thereof, R ³ is methyl.

[0089] In some embodiments of the compound of Formula I, II, or Ila, or a

pharmaceutically acceptable salt thereof, R ⁴ is C i-12 alkyl or phenyl, wherein the C i-12 alkyl is optionally substituted with adamantanyl. In some embodiments of the compound of Formula I, II, or Ila, or a pharmaceutically acceptable salt thereof, R ⁴ is C i-12 alkyl or phenyl. In some embodiments of the compound of Formula I, II, or Ila, or a pharmaceutically acceptable salt thereof, R ⁴ is C 1-3 alkyl optionally substituted with adamantanyl. In some embodiments of the compound of Formula I, II, or Ila, or a pharmaceutically acceptable salt thereof, R ⁴ is C 1-2 alkyl optionally substituted with adamantanyl. In some embodiments of the compound of Formula I, II, or Ila, or a pharmaceutically acceptable salt thereof, R ⁴ is C6-12 alkyl optionally substituted with adamantanyl. In some embodiments of the compound of Formula I, II, or Ila, or a pharmaceutically acceptable salt thereof, R ⁴ is C6-12 alkyl. In some embodiments of the compound of Formula I, II, or Ila, or a pharmaceutically acceptable salt thereof, R ⁴ is phenyl.

[0090] In some embodiments of the compound of Formula I, II, or Ila, or a

pharmaceutically acceptable salt thereof, R ⁴ is methyl, phenyl,

[0091] In some embodiments of the compound of Formula I, II, or Ila, or a

pharmaceutically acceptable salt thereof, R ⁴ is methyl, phenyl,

[0092] In some embodiments of the compound of Formula I, II, or Ila, or a pharmaceutically acceptable salt thereof, R ⁴ is methyl, phenyl,

[0093] In some embodiments of the compound of Formula I, II, or Ila, or a

pharmaceutically acceptable salt thereof, R ⁴ is

[0094] In some embodiments of the compound of Formula I, II, or Ila, or a

pharmaceutically acceptable salt thereof, R ³ and R ⁴ , together with the carbon to which they are attached, form a C3-7 monocyclic cycloalkyl. In some embodiments of the compound of Formula I, II, or Ila, or a pharmaceutically acceptable salt thereof, R ³ and R ⁴ , together with the carbon to which they are attached, form a cyclobutyl, cyclopentyl, or cyclohexyl. In some embodiments of the compound of Formula I, II, or Ila, or a pharmaceutically acceptable salt thereof, R ³ and R ⁴ , together with the carbon to which they are attached, form a cyclopentyl or cyclohexyl. In some embodiments of the compound of Formula I, II, or Ila, or a

pharmaceutically acceptable salt thereof, R ³ and R ⁴ , together with the carbon to which they are attached, form a cyclopropyl. In some embodiments of the compound of Formula I, II, or Ila, or a pharmaceutically acceptable salt thereof, R ³ and R ⁴ , together with the carbon to which they are attached, form a cyclobutyl. In some embodiments of the compound of Formula I, II, or Ila, or a pharmaceutically acceptable salt thereof, R ³ and R ⁴ , together with the carbon to which they are attached, form a cyclopentyl. In some embodiments of the compound of Formula I, II, or Ila, or a pharmaceutically acceptable salt thereof, R ³ and R ⁴ , together with the carbon to which they are attached, form a cyclohexyl. In some embodiments of the compound of Formula I, II, or Ila, or a pharmaceutically acceptable salt thereof, R ³ and R ⁴ , together with the carbon to which they are attached, form a cycloheptanyl.

[0095] In some embodiments of the compound of Formula I, II, or Ila, or a

pharmaceutically acceptable salt thereof, when A is phenyl ene, then one of R ³ and R ⁴ is H, C _2-15 alkyl, or C _6-10 aryl, and the other of R ³ and R ⁴ is Ci- ₁₅ alkyl or C _6-10 aryl, wherein the C _2-15 alkyl, C _2-15 alkyl, and C _6-10 aryl are each optionally substituted with 1-3 groups independently selected from C _5-10 monocyclic cycloalkyl, C _5-10 bridged bicyclic cycloalkyl, and C _5-10 bridged tricyclic cycloalkyl. In some embodiments of the compound of Formula I, II, or Ila, or a pharmaceutically acceptable salt thereof, when A is phenyl ene, then one of R ³ and R ⁴ is H or C2- 3 alkyl, and the other of R ³ and R ⁴ is Ci-12 alkyl or phenyl, wherein the C i-12 alkyl is optionally substituted with adamantanyl. In some embodiments of the compound of Formula I, II, or Ila, or a pharmaceutically acceptable salt thereof, when A is phenyl ene, then one of R ³ and R ⁴ is H or C2-3 alkyl, and the other of R ³ and R ⁴ is Ci-12 alkyl or phenyl. In some embodiments of the compound of Formula I, II, or Ila, or a pharmaceutically acceptable salt thereof, when A is phenyl ene, then R ³ is not methyl. In some embodiments of the compound of Formula I, II, or Ila, or a pharmaceutically acceptable salt thereof, when A is phenylene, then R ⁴ is not methyl.

In some embodiments of the compound of Formula I, II, or Ila, or a pharmaceutically acceptable salt thereof, when A is phenylene, then R ³ is not methyl and R ⁴ is not methyl.

[0096] In some embodiments of the compound of Formula I, II, or Ila, or a

pharmaceutically acceptable salt thereof, L is a bond, Ci- ₈ alkylene, or Ci- ₈ heteroalkylene, wherein the Ci- ₈ alkylene and the Ci- ₈ heteroalkylene are each optionally substituted with 1-3 R ⁵ . In some embodiments of the compound of Formula I, II, or Ila, or a pharmaceutically acceptable salt thereof, L is a bond, Ci- ₈ alkylene, or Ci- ₈ heteroalkylene.

[0097] In some embodiments of the compound of Formula I, II, or Ila, or a

pharmaceutically acceptable salt thereof, L is a bond. In some embodiments of the compound of Formula I, II, or Ila, or a pharmaceutically acceptable salt thereof, when A is phenylene, R ³ is methyl, and R ⁴ is methyl, then L is not a bond.

[0098] In some embodiments of the compound of Formula I, II, or Ila, or a

pharmaceutically acceptable salt thereof, L is a Ci- ₈ alkylene optionally substituted with 1-3 R ⁵ . In some embodiments of the compound of Formula I, II, or Ila, or a pharmaceutically acceptable salt thereof, L is a Ci- ₈ alkylene optionally substituted with 1-3 R ⁵ , wherein two R ⁵ are attached to the same carbon and the two R ⁵ , together with the carbon to which they are attached, form a C3-7 monocyclic cycloalkyl. In some embodiments of the compound of Formula I, II, or Ila, or a pharmaceutically acceptable salt thereof, L is a Ci- ₆ alkylene optionally substituted with 1-3 R ⁵ . In some embodiments of the compound of Formula I, II, or Ila, or a pharmaceutically acceptable salt thereof, L is a Ci- ₆ alkylene optionally substituted with 2 R ⁵ , wherein the two R ⁵ are attached to the same carbon and the two R ⁵ , together with the carbon to which they are attached, form a C3-6 monocyclic cycloalkyl. In some embodiments of the compound of Formula I, II, or Ila, or a pharmaceutically acceptable salt thereof, L is a Ci- ₆ alkylene optionally substituted with 2 R ⁵ , wherein the two R ⁵ are attached to the same carbon and the two R ⁵ , together with the carbon to which they are attached, form a cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In some embodiments of the compound of Formula I, II, or Ila, or a pharmaceutically acceptable salt thereof, L is a Ci-4 alkylene optionally substituted with 1-3 R ⁵ . In some embodiments of the compound of Formula I, II, or Ila, or a pharmaceutically acceptable salt thereof, L is a Ci- ₃ alkylene optionally substituted with one R ⁵ . In some embodiments of the compound of Formula I, II, or Ila, or a pharmaceutically acceptable salt thereof, L is a Ci- ₃ alkylene optionally substituted with two R ⁵ .

[0099] In some embodiments of the compound of Formula I, II, or Ila, or a

pharmaceutically acceptable salt thereof, L is a Ci- ₈ alkylene. In some embodiments of the compound of Formula I, II, or Ila, or a pharmaceutically acceptable salt thereof, L is a Ci- ₆ alkylene. In some embodiments of the compound of Formula I, II, or Ila, or a pharmaceutically acceptable salt thereof, L is a Ci-4 alkylene. In some embodiments of the compound of Formula I, II, or Ila, or a pharmaceutically acceptable salt thereof, L is a Ci- ₃ alkylene.

[0100] In some embodiments of the compound of Formula I, II, or Ila, or a

pharmaceutically acceptable salt thereof, L is:

[0101] In some embodiments of the compound of Formula I, II, or Ila, or a

pharmaceutically acceptable salt thereof, L is:

[0102] In some embodiments of the compound of Formula I, II, or Ila, or a

pharmaceutically acceptable salt thereof, L is:

[0103] In some embodiments of the compound of Formula I, II, or Ila, or a

pharmaceutically acceptable salt thereof, L is methylene, ethylene, -CH(CH ₃ )CH ₂ -,

-CH ₂ CH(CH ₃ )-, -CH ₂ CH(CH ₂ CH ₃ )-, -CH ₂ C(CH ₃ ) ₂ -, -C(CH ₃ ) ₂ CH ₂ -, -CH(CH ₃ )CH(CH ₃ )-, -CH ₂ C(CH ₂ CH ₃ )(CH ₃ )-, -CH ₂ C(CH ₂ CH ₃ ) ₂ -, propylene, or butylene. [0104] In some embodiments of the compound of Formula I, II, or Ila, or a pharmaceutically acceptable salt thereof, L is methylene, ethylene, propylene, or butylene, each of which is optionally substituted with 1-3 R ⁵ . In some embodiments of the compound of Formula I, II, or Ila, or a pharmaceutically acceptable salt thereof, L is methylene, ethylene, propylene, or butylene.

[0105] In some embodiments of the compound of Formula I, II, or Ila, or a

pharmaceutically acceptable salt thereof, -A-L- is -A-m ethylene-, -A-ethylene-,

-A-CH(CH )CH ₂ -, -A-CH ₂ CH(CH )-, -A-CH ₂ CH(CH ₂ CH )-, -A-CH ₂ C(CH ) ₂ -,

-A-C(CH ) ₂ CH ₂ -, -A-CH(CH )CH(CH )-, -A-CH ₂ C(CH ₂ CH )(CH )-, -A-CH ₂ C(CH ₂ CH ) ₂ -, -A-n-propylene-, -A- n-butylene-,

[0106] In some embodiments of the compound of Formula I, II, or Ila, or a

pharmaceutically acceptable salt thereof, -A-L- is

[0107] In some embodiments of the compound of Formula I, II, or Ila, or a

pharmaceutically acceptable salt thereof, when A is phenyl ene, then L is Ci- ₈ alkylene optionally substituted with 1-3 R ⁵ . In some embodiments of the compound of Formula I, II, or Ila, or a pharmaceutically acceptable salt thereof, when A is phenylene, then L is a Ci- ₆ alkylene optionally substituted with 1-3 R ⁵ . In some embodiments of the compound of Formula I, II, or Ila, or a pharmaceutically acceptable salt thereof, when A is phenylene, then L is a Ci- ₆ alkylene optionally substituted with 2 R ⁵ , wherein the two R ⁵ are attached to the same carbon and the two R ⁵ , together with the carbon to which they are attached, form a cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In some embodiments of the compound of Formula I, II, or Ila, or a pharmaceutically acceptable salt thereof, when A is phenylene, then L is a Ci-4 alkylene optionally substituted with 1-3 R ⁵ . In some embodiments of the compound of Formula I, II, or Ila, or a pharmaceutically acceptable salt thereof, when A is phenylene, then L is a C _1-3 alkylene optionally substituted with one R ⁵ .

[0108] In some embodiments of the compound of Formula I, II, or Ila, or a

pharmaceutically acceptable salt thereof, when A is phenylene, then L is a Ci- ₈ alkylene. In some embodiments of the compound of Formula I, II, or Ila, or a pharmaceutically acceptable salt thereof, when A is phenylene, then L is a Ci- ₆ alkylene. In some embodiments of the compound of Formula I, II, or Ila, or a pharmaceutically acceptable salt thereof, when A is phenylene, then L is a C _1-4 alkylene. In some embodiments of the compound of Formula I, II, or Ila, or a pharmaceutically acceptable salt thereof, when A is phenylene, then L is a C _1-3 alkylene.

[0109] In some embodiments of the compound of Formula I, II, or Ila, or a

pharmaceutically acceptable salt thereof, L is a Ci- ₈ heteroalkyl ene optionally substituted with 1- 3 R ⁵ . In some embodiments of the compound of Formula I, II, or Ila, or a pharmaceutically acceptable salt thereof, L is a Ci- ₈ heteroalkyl ene optionally substituted with 1-3 R ⁵ , wherein two R ⁵ are attached to the same carbon and the two R ⁵ , together with the carbon to which they are attached, form a C _3-7 monocyclic cycloalkyl. In some embodiments of the compound of Formula I, II, or Ila, or a pharmaceutically acceptable salt thereof, L is a Ci- ₆ heteroalkylene optionally substituted with 2 R ⁵ , wherein the two R ⁵ are attached to the same carbon and the two R ⁵ , together with the carbon to which they are attached, form a C _3-6 monocyclic cycloalkyl. In some embodiments of the compound of Formula I, II, or Ila, or a pharmaceutically acceptable salt thereof, L is a Ci- ₆ heteroalkylene optionally substituted with 2 R ⁵ , wherein the two R ⁵ are attached to the same carbon and the two R ⁵ , together with the carbon to which they are attached, form a cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In some embodiments of the compound of Formula I, II, or Ila, or a pharmaceutically acceptable salt thereof, L is a C _1-5 heteroalkylene optionally substituted with 1-3 R ⁵ . In some embodiments of the compound of Formula I, II, or Ila, or a pharmaceutically acceptable salt thereof, L is a C _1-4 heteroalkylene optionally substituted with 1-3 R ⁵ . In some embodiments of the compound of Formula I, II, or Ila, or a pharmaceutically acceptable salt thereof, L is a C _1-3 heteroalkylene optionally substituted with one R ⁵ . In some embodiments of the compound of Formula I, II, or Ila, or a pharmaceutically acceptable salt thereof, L is a C _1-3 heteroalkylene optionally substituted with methyl.

[0110] In some embodiments of the compound of Formula I, II, or Ila, or a

pharmaceutically acceptable salt thereof, L is a Ci- ₈ heteroalkylene. In some embodiments of the compound of Formula I, II, or Ila, or a pharmaceutically acceptable salt thereof, L is a Ci- ₆ heteroalkyl ene. In some embodiments of the compound of Formula I, II, or Ila, or a pharmaceutically acceptable salt thereof, L is a Ci- ₆ heteroalkylene. In some embodiments of the compound of Formula I, II, or Ila, or a pharmaceutically acceptable salt thereof, L is a C _1-5 heteroalkylene. In some embodiments of the compound of Formula I, II, or Ila, or a pharmaceutically acceptable salt thereof, L is a C _1-4 heteroalkylene. In some embodiments of the compound of Formula I, II, or Ila, or a pharmaceutically acceptable salt thereof, L is a C _1-3 heteroalkylene. In some embodiments of the compound of Formula I, II, or Ila, or a pharmaceutically acceptable salt thereof, L is a C _1-2 heteroalkylene. In some embodiments of the compound of Formula I, II, or Ila, or a pharmaceutically acceptable salt thereof, L is a C _4-8 heteroalkylene.

[0111] In some embodiments of the compound of Formula I, II, or Ila, or a

pharmaceutically acceptable salt thereof, L is -OCi-8 alkylene, wherein the oxygen is attached to A. In some embodiments of the compound of Formula I, II, or Ila, or a pharmaceutically acceptable salt thereof, L is -OCi-6 alkylene, wherein the oxygen is attached to A. In some embodiments of the compound of Formula I, II, or Ila, or a pharmaceutically acceptable salt thereof, L is -OC _5-8 alkylene, wherein the oxygen is attached to A. In some embodiments of the compound of Formula I, II, or Ila, or a pharmaceutically acceptable salt thereof, L is -OC _4-8 alkylene, wherein the oxygen is attached to A. In some embodiments of the compound of Formula I, II, or Ila, or a pharmaceutically acceptable salt thereof, L is -OC _4-6 alkylene, wherein the oxygen is attached to A.

[0112] In some embodiments of the compound of Formula I, II, or Ila, or a

pharmaceutically acceptable salt thereof, L is:

[0113] In some embodiments of the compound of Formula I, II, or Ila, or a

pharmaceutically acceptable salt thereof, L is:

[0114] In some embodiments of the compound of Formula I, II, or Ila, or a

pharmaceutically acceptable salt thereof, L is -CH2NH- or -0¾N(0¾)-.

[0115] In some embodiments of the compound of Formula I, II, or Ila, or a pharmaceutically acceptable salt thereof, when A is naphthalenylene, then L is:

[0116] In some embodiments of the compound of Formula I, II, or Ila, or a

pharmaceutically acceptable salt thereof, when A is phenyl ene, R ² is methyl, R ³ is methyl, and R ⁴ is methyl, then L is Ci- ₈ alkylene or C _4-8 heteroalkylene, wherein the Ci- ₈ alkylene and the C _4-8 heteroalkylene are each optionally substituted with 1-3 R ⁵ . In some embodiments of the compound of Formula I, II, or Ila, or a pharmaceutically acceptable salt thereof, when A is phenyl ene, R ² is methyl, R ³ is methyl, and R ⁴ is methyl, then L is Ci- ₈ alkylene or C _4-6 heteroalkylene, wherein the Ci- ₈ alkylene and the C _4-6 heteroalkylene are each optionally substituted with 1-3 R ⁵ . In some embodiments of the compound of Formula I, II, or Ila, or a pharmaceutically acceptable salt thereof, when A is phenylene, R ² is methyl, R ³ is methyl, and R ⁴ is methyl, then L is Ci- ₆ alkylene or C _4-8 heteroalkylene, wherein the Ci- ₆ alkylene and the C ₄ - ₈ heteroalkylene are each optionally substituted with 1-3 R ⁵ . In some embodiments of the compound of Formula I, II, or Ila, or a pharmaceutically acceptable salt thereof, when A is phenylene, R ² is methyl, R ³ is methyl, and R ⁴ is methyl, then L is C _1-4 alkylene or C _4-8 heteroalkylene, wherein the C _1-4 alkylene and the C _4-8 heteroalkylene are each optionally substituted with 1-3 R ⁵ .

[0117] In some embodiments of the compound of Formula I, II, or Ila, or a

pharmaceutically acceptable salt thereof, when A is phenylene, R ² is methyl, R ³ is methyl, and R ⁴ is methyl, then L is Ci- ₈ alkylene or C _4-8 heteroalkylene. In some embodiments of the compound of Formula I, II, or Ila, or a pharmaceutically acceptable salt thereof, when A is phenylene, R ² is methyl, R ³ is methyl, and R ⁴ is methyl, then L is Ci- ₈ alkylene or C _4-6 heteroalkylene. In some embodiments of the compound of Formula I, II, or Ila, or a

pharmaceutically acceptable salt thereof, when A is phenylene, R ² is methyl, R ³ is methyl, and R ⁴ is methyl, then L is Ci- ₆ alkylene or C _4-8 heteroalkylene. In some embodiments of the compound of Formula I, II, or Ila, or a pharmaceutically acceptable salt thereof, when A is phenylene, R ² is methyl, R ³ is methyl, and R ⁴ is methyl, then L is C _1-4 alkylene or C _4-8 heteroalkylene.

[0118] In some embodiments of the compound of Formula I, II, or Ila, or a

pharmaceutically acceptable salt thereof, when A is phenylene, R ² is methyl, R ³ is methyl, and R ⁴ is methyl, then L is -OC _4-8 alkylene, wherein the oxygen is attached to A. In some embodiments of the compound of Formula I, II, or Ila, or a pharmaceutically acceptable salt thereof, when A is phenylene, R ² is methyl, R ³ is methyl, and R ⁴ is methyl, then L is -OC _4-6 alkylene, wherein the oxygen is attached to A.

[0119] In some embodiments of the compound of Formula I, II, or Ila, or a

pharmaceutically acceptable salt thereof, when A is phenylene, R ² is methyl, R ³ is methyl, and R ⁴ is methyl, then L is not -OC _1-3 alkylene, wherein the oxygen is attached to A.

[0120] In some embodiments of the compound of Formula I, II, or Ila, or a

pharmaceutically acceptable salt thereof, each R ⁵ is independently C _1-3 alkyl or two R ⁵ are attached to the same carbon and the two R ⁵ , together with the carbon to which they are attached, form a C _3-7 monocyclic cycloalkyl. In some embodiments of the compound of Formula I, II, or Ila, or a pharmaceutically acceptable salt thereof, each R ⁵ is independently C _1-3 alkyl. In some embodiments of the compound of Formula I, II, or Ila, or a pharmaceutically acceptable salt thereof, each R ⁵ is independently methyl, ethyl, n-propyl, or isopropyl. In some embodiments of the compound of Formula I, II, or Ila, or a pharmaceutically acceptable salt thereof, each R ⁵ is independently methyl or ethyl. In some embodiments of the compound of Formula I, II, or Ila, or a pharmaceutically acceptable salt thereof, each R ⁵ is methyl. In some embodiments of the compound of Formula I, II, or Ila, or a pharmaceutically acceptable salt thereof, each R ⁵ is ethyl. In some embodiments of the compound of Formula I, II, or Ila, or a pharmaceutically acceptable salt thereof, one, two, or three R ⁵ is methyl, ethyl, n-propyl, or isopropyl. In some embodiments of the compound of Formula I, II, or Ila, or a pharmaceutically acceptable salt thereof, one, two, or three R ⁵ is methyl or ethyl. In some embodiments of the compound of Formula I, II, or Ila, or a pharmaceutically acceptable salt thereof, one, two, or three R ⁵ is methyl. In some

embodiments of the compound of Formula I, II, or Ila, or a pharmaceutically acceptable salt thereof, one, two, or three R ⁵ is ethyl. In some embodiments of the compound of Formula I, II, or Ila, or a pharmaceutically acceptable salt thereof, one, two, or three R ⁵ is n-propyl. In some embodiments of the compound of Formula I, II, or Ila, or a pharmaceutically acceptable salt thereof, one, two, or three R ⁵ is isopropyl.

[0121] In some embodiments of the compound of Formula I, II, or Ila, or a

pharmaceutically acceptable salt thereof, L is optionally substituted with 1 -3 R ⁵ . In some embodiments of the compound of Formula I, II, or Ila, or a pharmaceutically acceptable salt thereof, L is optionally substituted with 1 -2 R ⁵ . In some embodiments of the compound of Formula I, II, or Ila, or a pharmaceutically acceptable salt thereof, L is optionally substituted with two R ⁵ . In some embodiments of the compound of Formula I, II, or Ila, or a

pharmaceutically acceptable salt thereof, L is optionally substituted with one R ⁵ . In some embodiments of the compound of Formula I, II, or Ila, or a pharmaceutically acceptable salt thereof, R ⁵ is methyl. In some embodiments of the compound of Formula I, II, or Ila, or a pharmaceutically acceptable salt thereof, R ⁵ is ethyl. In some embodiments of the compound of Formula I, II, or Ila, or a pharmaceutically acceptable salt thereof, R ⁵ is n-propyl. In some embodiments of the compound of Formula I, II, or Ila, or a pharmaceutically acceptable salt thereof, R ⁵ is isopropyl.

[0122] In some embodiments of the compound of Formula I, II, or Ila, or a

pharmaceutically acceptable salt thereof, L is optionally substituted with two R ⁵ . In some embodiments of the compound of Formula I, II, or Ila, or a pharmaceutically acceptable salt thereof, one R ⁵ is methyl and the other R ⁵ is methyl, ethyl, n-propyl, or isopropyl. In some embodiments of the compound of Formula I, II, or Ila, or a pharmaceutically acceptable salt thereof, one R ⁵ is ethyl and the other R ⁵ is methyl, ethyl, n-propyl, or isopropyl. In some embodiments of the compound of Formula I, II, or Ila, or a pharmaceutically acceptable salt thereof, one R ⁵ is n-propyl and the other R ⁵ is methyl, ethyl, n-propyl, or isopropyl. In some embodiments of the compound of Formula I, II, or Ila, or a pharmaceutically acceptable salt thereof, one R ⁵ is isopropyl and the other R ⁵ is methyl, ethyl, n-propyl, or isopropyl. In some embodiments of the compound of Formula I, II, or Ila, or a pharmaceutically acceptable salt thereof, one R ⁵ is methyl and the other R ⁵ is methyl. In some embodiments of the compound of Formula I, II, or Ila, or a pharmaceutically acceptable salt thereof, one R ⁵ is methyl and the other R ⁵ is ethyl.

[0123] In some embodiments of the compound of Formula I, II, or Ila, or a

pharmaceutically acceptable salt thereof, two R ⁵ are attached to the same carbon. In some embodiments of the compound of Formula I, II, or Ila, or a pharmaceutically acceptable salt thereof, one R ⁵ is methyl and the other R ⁵ is methyl, ethyl, or n-propyl. In some embodiments of the compound of Formula I, II, or Ila, or a pharmaceutically acceptable salt thereof, one R ⁵ is ethyl and the other R ⁵ is methyl, ethyl, or n-propyl. In some embodiments of the compound of Formula I, II, or Ila, or a pharmaceutically acceptable salt thereof, one R ⁵ is n-propyl and the other R ⁵ is methyl, ethyl, or n-propyl. In some embodiments of the compound of Formula I, II, or Ila, or a pharmaceutically acceptable salt thereof, one R ⁵ is methyl and the other R ⁵ is methyl. In some embodiments of the compound of Formula I, II, or Ila, or a pharmaceutically acceptable salt thereof, one R ⁵ is methyl and the other R ⁵ is ethyl. In some embodiments of the compound of Formula I, II, or Ila, or a pharmaceutically acceptable salt thereof, one R ⁵ is ethyl and the other R ⁵ is ethyl. [0124] In some embodiments of the compound of Formula I, II, or Ila, or a pharmaceutically acceptable salt thereof, two R ⁵ are attached to the same carbon, and the two R ⁵ , together with the carbon to which they are attached, form a C3-7 monocyclic cycloalkyl. In some embodiments of the compound of Formula I, II, or Ila, or a pharmaceutically acceptable salt thereof, two R ⁵ are attached to the same carbon, and the two R ⁵ , together with the carbon to which they are attached, form a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or

cycloheptanyl. In some embodiments of the compound of Formula I, II, or Ila, or a

pharmaceutically acceptable salt thereof, two R ⁵ are attached to the same carbon, and the two R ⁵ , together with the carbon to which they are attached, form a cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In some embodiments of the compound of Formula I, II, or Ila, or a pharmaceutically acceptable salt thereof, two R ⁵ are attached to the same carbon, and the two R ⁵ , together with the carbon to which they are attached, form a cyclopropyl. In some embodiments of the compound of Formula I, II, or Ila, or a pharmaceutically acceptable salt thereof, two R ⁵ are attached to the same carbon, and the two R ⁵ , together with the carbon to which they are attached, form a cyclobutyl. In some embodiments of the compound of Formula I, II, or Ila, or a pharmaceutically acceptable salt thereof, two R ⁵ are attached to the same carbon, and the two R ⁵ , together with the carbon to which they are attached, form a cyclopentyl. In some embodiments of the compound of Formula I, II, or Ila, or a pharmaceutically acceptable salt thereof, two R ⁵ are attached to the same carbon, and the two R ⁵ , together with the carbon to which they are attached, form a cyclohexyl. In some embodiments of the compound of Formula I, II, or Ila, or a pharmaceutically acceptable salt thereof, two R ⁵ are attached to the same carbon, and the two R ⁵ , together with the carbon to which they are attached, form a

cycloheptanyl.

[0125] In some embodiments of the compound of Formula I, II, or Ila, or a

pharmaceutically acceptable salt thereof, A is a phenylene or naphthalenylene. In some embodiments of the compound of Formula I, II, or Ila, or a pharmaceutically acceptable salt thereof, A is a phenylene. In some embodiments of the compound of Formula I, II, or Ila, or a pharmaceutically acceptable salt thereof, A is

[0126] In some embodiments of the compound of Formula I, II, or Ila, or a

pharmaceutically acceptable salt thereof, A is naphthalenylene. [0127] In some embodiments of the compound of Formula I, II, or Ila, or a pharmaceutically acceptable salt thereof, A is

[0128] In some embodiments of the compound of Formula I, II, or Ila, or a

pharmaceutically acceptable salt thereof, -A-L- is

[0129] In some embodiments of the compound of Formula I, II, or Ila, or a

pharmaceutically acceptable salt thereof, n is 0, 1, 2, or 3. In some embodiments of the compound of Formula I, II, or Ila, or a pharmaceutically acceptable salt thereof, n is 0, 1, or 2.

In some embodiments of the compound of Formula I, II, or Ila, or a pharmaceutically acceptable salt thereof, n is 0 or 1. In some embodiments of the compound of Formula I, II, or Ila, or a pharmaceutically acceptable salt thereof, n is 0. In some embodiments of the compound of Formula I, II, or Ila, or a pharmaceutically acceptable salt thereof, n is 1. In some embodiments of the compound of Formula I, II, or Ila, or a pharmaceutically acceptable salt thereof, n is 2. In some embodiments of the compound of Formula I, II, or Ila, or a pharmaceutically acceptable salt thereof, n is 3.

[0130] In some embodiments of the compound of Formula I, II, or Ila, or a

pharmaceutically acceptable salt thereof, each R ¹ is C 1-3 alkyl. In some embodiments of the compound of Formula I, II, or Ila, or a pharmaceutically acceptable salt thereof, each R ¹ is independently methyl, ethyl, n-propyl, or isopropyl. In some embodiments of the compound of Formula I, II, or Ila, or a pharmaceutically acceptable salt thereof, one, two, or three R ¹ is methyl. In some embodiments of the compound of Formula I, II, or Ila, or a pharmaceutically acceptable salt thereof, one, two, or three R ¹ is ethyl. In some embodiments of the compound of Formula I, II, or Ila, or a pharmaceutically acceptable salt thereof, one, two, or three R ¹ is n- propyl. In some embodiments of the compound of Formula I, II, or Ila, or a pharmaceutically acceptable salt thereof, one, two, or three R ¹ is isopropyl. In some embodiments of the compound of Formula I, II, or Ila, or a pharmaceutically acceptable salt thereof, one R ¹ is methyl. In some embodiments of the compound of Formula I, II, or Ila, or a pharmaceutically acceptable salt thereof, one R ¹ is ethyl. In some embodiments of the compound of Formula I, II, or Ila, or a pharmaceutically acceptable salt thereof, one R ¹ is n-propyl. In some embodiments of the compound of Formula I, II, or Ila, or a pharmaceutically acceptable salt thereof, one R ¹ is isopropyl.

[0131] In some embodiments of the compound of Formula I, II, or Ila, or a

pharmaceutically acceptable salt thereof, A is optionally substituted with one R ¹ . In some embodiments of the compound of Formula I, II, or Ila, or a pharmaceutically acceptable salt thereof, A is optionally substituted with one methyl. In some embodiments of the compound of Formula I, II, or Ila, or a pharmaceutically acceptable salt thereof, A is substituted with one R ¹ . In some embodiments of the compound of Formula I, II, or Ila, or a pharmaceutically acceptable salt thereof, A is substituted with one methyl.

[0132] In some embodiments of the compound of Formula I, II, or Ila, the compound selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

[0133] In some embodiments of the compound of Formula I, II, or Ila, the compound selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

[0134] In some embodiments of the compound of Formula I, II, or Ila, the compound is:

or a pharmaceutically acceptable salt thereof. [0135] In some embodiments of the compound of Formula I, II, or Ila, the compound is:

or a pharmaceutically acceptable salt thereof.

[0136] In some embodiments of the compound of Formula I, II, or Ila, the compound is:

or a pharmaceutically acceptable salt thereof.

[0137] In some embodiments of the compound of Formula I, II, or Ila, the compound is:

or a pharmaceutically acceptable salt thereof.

[0138] In some embodiments of the compound of Formula I, II, or Ila, the compound is:

or a pharmaceutically acceptable salt thereof.

[0139] In some embodiments of the compound of Formula I, II, or Ila, the compound is: or a pharmaceutically acceptable salt thereof.

[0140] In some embodiments of the compound of Formula I, II, or Ila, the compound is:

or a pharmaceutically acceptable salt thereof.

[0141] In some embodiments of the compound of Formula I, II, or Ila, the compound is not:

III. Compositions and Kits

[0142] Compounds provided herein are usually administered in the form of pharmaceutical compositions. Thus, provided herein are also pharmaceutical compositions that comprise one or more of the compounds provided herein or pharmaceutically acceptable salts, isomer, or a mixture thereof and one or more pharmaceutically acceptable vehicles selected from carriers, adjuvants and excipients. The compounds provided herein may be the sole active ingredient or one of the active ingredients of the pharmaceutical compositions. Suitable pharmaceutically acceptable vehicles may include, for example, inert solid diluents and fillers, diluents, including sterile aqueous solution and various organic solvents, permeation enhancers, solubilizers and adjuvants. Such compositions are prepared in a manner well known in the pharmaceutical art. See, e.g ., Remington’s Pharmaceutical Sciences, Mace Publishing Co., Philadelphia, Pa. 17th Ed. (1985); and Modern Pharmaceutics, Marcel Dekker, Inc. 3rd Ed.

(G.S. Banker & C.T. Rhodes, Eds.).

[0143] In one aspect, provided herein are pharmaceutical compositions comprising a compound provided herein (i.e., a compound of Formula I, II, or IIA), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient or carrier. In some embodiments, the pharmaceutical compositions comprise a therapeutically effective amount of a compound provided herein, or a pharmaceutically acceptable salt thereof, and a

pharmaceutically acceptable excipient or carrier.

[0144] In some embodiments, the pharmaceutical compositions provided herein further comprise one or more (i.e., one, two, three, four; one or two; one to three; or one to four) additional therapeutic agents, or a pharmaceutically acceptable salt thereof. In some

embodiments, the pharmaceutical compositions further comprise a therapeutically effective amount of the one or more (i.e., one, two, three, four; one or two; one to three; or one to four) additional therapeutic agents, or a pharmaceutically acceptable salt thereof.

[0145] In some embodiments, the one or more additional therapeutic agents include agents that are therapeutic for HIV infection. In some embodiments, the one or more additional therapeutic agents is selected from the group consisting of: 4'-ethynyl-2-fluoro-2'- deoxyadenosine, bictegravir or a pharmaceutically acceptable salt thereof, abacavir sulfate, tenofovir, tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir disoproxil

hemifumarate, tenofovir alafenamide, tenofovir alafenamide hemifumarate, emtricitabine, and lamivudine, or a pharmaceutically acceptable salt of any of the foregoing, or any combinations thereof.

[0146] The pharmaceutical compositions may be administered in either single or multiple doses. The pharmaceutical compositions may be administered by various methods including, for example, rectal, buccal, intranasal and transdermal routes. In some embodiments, the pharmaceutical compositions may be administered by intra-arterial injection, intravenously, intraperitoneally, parenterally, intramuscularly, subcutaneously, orally, topically, or as an inhalant.

[0147] One mode for administration is parenteral, for example, by injection. The forms in which the pharmaceutical compositions described herein may be incorporated for

administration by injection include, for example, aqueous or oil suspensions, or emulsions, with sesame oil, com oil, cottonseed oil, or peanut oil, as well as elixirs, mannitol, dextrose, or a sterile aqueous solution, and similar pharmaceutical vehicles.

[0148] Oral administration may be another route for administration of the compounds provided herein. Administration may be via, for example, capsule or enteric coated tablets. In making the pharmaceutical compositions that include at least one compound provided herein or pharmaceutically acceptable salts, isomer, or a mixture thereof, the active ingredient (such as a compound provided herein) is usually diluted by an excipient and/or enclosed within such a carrier that can be in the form of a capsule, sachet, paper or other container. When the excipient serves as a diluent, it can be in the form of a solid, semi-solid, or liquid material, which acts as a vehicle, carrier or medium for the active ingredient. Thus, the pharmaceutical compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments containing, for example, up to 10% by weight of the active compound, soft and hard gelatin capsules, sterile injectable solutions, and sterile packaged powders.

[0149] Some examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, sterile water, syrup, and methyl cellulose or any combinations thereof. The pharmaceutical compositions can

additionally include lubricating agents such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifying and suspending agents; preserving agents such as methyl and

propylhydroxy-benzoates; sweetening agents; and flavoring agents; or any combinations thereof.

[0150] The pharmaceutical compositions that include at least one compound described herein or pharmaceutically acceptable salts, isomer, or a mixture thereof can be formulated so as to provide quick, sustained or delayed release of the active ingredient (such as a compound provided herein) after administration to the subject by employing procedures known in the art. Controlled release drug delivery systems for oral administration include osmotic pump systems and dissolutional systems containing polymer-coated reservoirs or drug-polymer matrix formulations. Examples of controlled release systems are given in U.S. Patent Nos. 3,845,770; 4,326,525; 4,902,514; and 5,616,345. Another formulation for use in the methods of the present disclosure employs transdermal delivery devices (“patches”). Such transdermal patches may be used to provide continuous or discontinuous infusion of the compounds provided herein in controlled amounts. The construction and use of transdermal patches for the delivery of pharmaceutical agents is well known in the art. See, e.g ., U.S. Patent Nos. 5,023,252, 4,992,445 and 5,001,139. Such patches may be constructed for continuous, pulsatile, or on demand delivery of pharmaceutical agents.

[0151] For preparing solid compositions such as tablets, the principal active ingredient may be mixed with a pharmaceutical excipient to form a solid preformulation composition containing a homogeneous mixture of a compound described herein or pharmaceutically acceptable salts, isomer, or a mixture thereof. When referring to these preformulation compositions as homogeneous, the active ingredient may be dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules.

[0152] The tablets or pills of the compounds described herein may be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action, or to protect from the acid conditions of the stomach. For example, the tablet or pill can include an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former. The two components can be separated by an enteric layer that serves to resist disintegration in the stomach and permit the inner component to pass intact into the duodenum or to be delayed in release. A variety of materials can be used for such enteric layers or coatings, such materials including a number of polymeric acids and mixtures of polymeric acids with materials such as shellac, cetyl alcohol, and cellulose acetate.

[0153] Pharmaceutical compositions for inhalation or insufflation may include solutions and suspensions in pharmaceutically acceptable, aqueous or organic solvents, or mixtures thereof, and powders. The liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described supra. In some embodiments, the compositions are administered by the oral or nasal respiratory route for local or systemic effect. In other embodiments, compositions in pharmaceutically acceptable solvents may be nebulized by use of inert gases. Nebulized solutions may be inhaled directly from the nebulizing device or the nebulizing device may be attached to a facemask tent, or intermittent positive pressure breathing machine. Solution, suspension, or powder compositions may be administered, preferably orally or nasally, from devices that deliver the formulation in an appropriate manner.

[0154] In one aspect, provided herein are kits that comprise a compound provided herein, (i.e., a compound of Formula I, II, or Ila), or a pharmaceutically acceptable salt, stereoisomer, prodrug, or solvate thereof, and suitable packaging. In some embodiments, the kit further comprises instructions for use. In some embodiments, the kit comprises a compound provided herein (i.e., a compound of Formula I, II, or Ila), or a pharmaceutically acceptable salt, stereoisomer, prodrug, or solvate thereof, and a label and/or instructions for use of the compounds in the treatment of the indications, including the diseases or conditions, described herein.

[0155] In some embodiments, the kits further comprise one or more (i.e., one, two, three, four; one or two; one to three; or one to four) additional therapeutic agents, or a

pharmaceutically acceptable salt thereof.

[0156] In one aspect, provided herein are articles of manufacture that comprise a compound described herein or pharmaceutically acceptable salts, isomer, or a mixture thereof in a suitable container. In some embodiments, the container may be a vial, jar, ampoule, preloaded syringe, or intravenous bag.

IV. Methods

[0157] The methods provided herein may be applied to cell populations in vivo or ex vivo.“ In vivo” means within a living individual, as within an animal or human. In this context, the methods provided herein may be used therapeutically in an individual.“Ex vivo” means outside of a living individual. Examples of ex vivo cell populations include in vitro cell cultures and biological samples including fluid or tissue samples obtained from individuals. Such samples may be obtained by methods well known in the art. Exemplary biological fluid samples include blood, cerebrospinal fluid, urine, and saliva. Exemplary tissue samples include tumors and biopsies thereof. In this context, the present disclosure may be used for a variety of purposes, including therapeutic and experimental purposes. For example, the present disclosure may be used ex vivo to determine the optimal schedule and/or dosing of administration of a PKC agonist for a given indication, cell type, individual, and other parameters. Information gleaned from such use may be used for experimental purposes or in the clinic to set protocols for in vivo treatment. Other ex vivo uses for which the present disclosure may be suited are described below or will become apparent to those skilled in the art. The selected compounds may be further characterized to examine the safety or tolerance dosage in human or non-human subjects. Such properties may be examined using commonly known methods to those skilled in the art.

[0158] In one aspect, the present disclosure provides methods of activating PKC in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound provided herein (i.e., a compound of Formula I, II, or Ila), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition provided herein.

[0159] In one aspect, the present disclosure provides methods of treating a disease or disorder associated with decreased PKC activity in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound provided herein (i.e., a compound of Formula I, II, or Ila), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition provided herein.

[0160] In one aspect, the present disclosure provides methods of treating or preventing a human immunodeficiency virus (HIV) infection in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound provided herein (i.e., a compound of Formula I, II, or Ila), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition provided herein.

[0161] In one aspect, the present disclosure provides methods of reducing the latent HIV reservoir in a human infected with HIV, comprising administering to the human a

therapeutically effective amount of a compound provided herein (i.e., a compound of Formula I, II, or Ila), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition provided herein.

[0162] In one aspect, the present disclosure provides methods of reducing HIV viremia in a human infected with HIV, comprising administering to the human a therapeutically effective amount of a compound provided herein (i.e., a compound of Formula I, II, or Ila), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition provided herein.

[0163] In one aspect, the present disclosure provides methods of inducing HIV gene expression in a human infected with HIV, comprising administering to the human a

therapeutically effective amount of a compound provided herein (i.e., a compound of Formula I, II, or Ila), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition provided herein.

[0164] In some embodiments, the above methods further comprise administering a therapeutically effective amount of one or more additional therapeutic agents, or a

pharmaceutically acceptable salt thereof.

[0165] In some embodiments, the one or more additional therapeutic agents is selected from the group consisting of: combination drugs for HIV, other drugs for treating HIV, HIV protease inhibitors, HIV non-nucleoside or non-nucleotide inhibitors of reverse transcriptase, HIV nucleoside or nucleotide inhibitors of reverse transcriptase, HIV integrase inhibitors, HIV non-catalytic site (or allosteric) integrase inhibitors, HIV entry inhibitors, HIV maturation inhibitors, latency reversing agents, compounds that target the HIV capsid, immune-based therapies, phosphatidylinositol 3-kinase (PI3K) inhibitors, HIV antibodies, bispecific antibodies and“antibody-like” therapeutic proteins, HIV pl7 matrix protein inhibitors, IL-13 antagonists, peptidyl-prolyl cis-trans isomerase A modulators, protein disulfide isomerase inhibitors, complement C5a receptor antagonists, DNA methyltransferase inhibitor, HIV vif gene modulators, Vif dimerization antagonists, HIV-1 viral infectivity factor inhibitors, TAT protein inhibitors, HIV-1 Nef modulators, Hck tyrosine kinase modulators, mixed lineage kinase-3 (MLK-3) inhibitors, HIV-1 splicing inhibitors, Rev protein inhibitors, integrin antagonists, nucleoprotein inhibitors, splicing factor modulators, COMM domain containing protein 1 modulators, HIV ribonuclease H inhibitors, retrocyclin modulators, CDK-9 inhibitors, dendritic ICAM-3 grabbing nonintegrin 1 inhibitors, HIV GAG protein inhibitors, HIV POL protein inhibitors, Complement Factor H modulators, ubiquitin ligase inhibitors, deoxycytidine kinase inhibitors, cyclin dependent kinase inhibitors, proprotein convertase PC9 stimulators, ATP dependent RNA helicase DDX3X inhibitors, reverse transcriptase priming complex inhibitors, G6PD and NADH-oxidase inhibitors, pharmacokinetic enhancers, HIV gene therapy, and HIV vaccines, or a pharmaceutically acceptable salt of any of the foregoing, or any combinations thereof.

[0166] In some embodiments, the one or more additional therapeutic agents is selected from the group consisting of HIV protease inhibiting compounds, HIV non-nucleoside inhibitors of reverse transcriptase, HIV non-nucleotide inhibitors of reverse transcriptase, HIV nucleoside inhibitors of reverse transcriptase, HIV nucleotide inhibitors of reverse transcriptase, HIV integrase inhibitors, gp41 inhibitors, CXCR4 inhibitors, gpl20 inhibitors, CCR5 inhibitors, capsid polymerization inhibitors, pharmacokinetic enhancers, and other drugs for treating HIV, or a pharmaceutically acceptable salt of any of the foregoing, or any combinations thereof. [0167] In some embodiments, the one or more additional therapeutic agents is selected from the group consisting of 4'-ethynyl-2-fluoro-2'-deoxyadenosine, bictegravir, abacavir sulfate, tenofovir, tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, tenofovir alafenamide, and tenofovir alafenamide hemifumarate, or a

pharmaceutically acceptable salt of any of the foregoing, or any combinations thereof.

[0168] In some embodiments, the one or more additional therapeutic agents is selected from the group consisting of 4'-ethynyl-2-fluoro-2'-deoxyadenosine, bictegravir, tenofovir alafenamide, tenofovir alafenamide fumarate and tenofovir alafenamide hemifumarate, or a pharmaceutically acceptable salt of any of the foregoing, or any combinations thereof.

[0169] In some embodiments, the one or more additional therapeutic agents is selected from the group consisting of 4'-ethynyl-2-fluoro-2'-deoxyadenosine, bictegravir, tenofovir disoproxil, tenofovir disoproxil hemifumarate, and tenofovir disoproxil fumarate, or a pharmaceutically acceptable salt of any of the foregoing, or any combinations thereof.

[0170] In some embodiments, the one or more additional therapeutic agents is selected from the group consisting of emtricitabine and lamivudine, or a pharmaceutically acceptable salt of each thereof.

[0171] In some embodiments, the one or more additional therapeutic agents is emtricitabine or a pharmaceutically acceptable salt thereof.

[0172] In one aspect, the present disclosure provides methods of activating T-cells in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound provided herein (i.e., a compound of Formula I, II, or Ila), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition provided herein.

[0173] In some embodiments, the methods described herein comprise administering a therapeutically effective amount of a compound provided herein (i.e., a compound of Formula I, II, or Ila), or a pharmaceutically acceptable salt thereof. In some embodiments, the methods described herein comprise administering a therapeutically effective amount of a pharmaceutical composition provided herein.

[0174] In one aspect, provided herein is a compound disclosed herein, or a

pharmaceutically acceptable salt thereof, for use in therapy.

[0175] In one aspect, provided herein is a compound disclosed herein, or a pharmaceutically acceptable salt thereof, for use in a method of activating PKC in a subject in need thereof.

[0176] In one aspect, provided herein is a compound disclosed herein, or a

pharmaceutically acceptable salt thereof, for use in a method of treating a disease or disorder associated with decreased PKC activity in a subject in need thereof.

[0177] In one aspect, provided herein is a compound disclosed herein, or a

pharmaceutically acceptable salt thereof, for use in a method of treating or preventing a human immunodeficiency virus (HIV) infection in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound provided herein (i.e., a compound of Formula I, II, or Ila), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition provided herein.

[0178] In one aspect, provided herein is a compound disclosed herein, or a

pharmaceutically acceptable salt thereof, for use in a method of reducing the latent HIV reservoir in a human infected with HIV, comprising administering to the human a

therapeutically effective amount of a compound provided herein (i.e., a compound of Formula I, II, or Ila), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition provided herein.

[0179] In one aspect, provided herein is a compound disclosed herein, or a

pharmaceutically acceptable salt thereof, for use in a method of reducing HIV viremia in a human infected with HIV, comprising administering to the human a therapeutically effective amount of a compound provided herein (i.e., a compound of Formula I, II, or Ila), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition provided herein.

[0180] In one aspect, provided herein is a compound disclosed herein, or a

pharmaceutically acceptable salt thereof, for use in a method of inducing HIV gene expression in a human infected with HIV, comprising administering to the human a therapeutically effective amount of a compound provided herein (i.e., a compound of Formula I, II, or Ila), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition provided herein.

[0181] In some embodiments, the above uses further comprise administering a therapeutically effective amount of one or more additional therapeutic agents, or a

pharmaceutically acceptable salt thereof. [0182] In some embodiments, the above uses further comprise administering one or more additional therapeutic agents selected from the group consisting of: combination drugs for HIV, other drugs for treating HIV, HIV protease inhibitors, HIV non-nucleoside or non nucleotide inhibitors of reverse transcriptase, HIV nucleoside or nucleotide inhibitors of reverse transcriptase, HIV integrase inhibitors, HIV non-catalytic site (or allosteric) integrase inhibitors, HIV entry inhibitors, HIV maturation inhibitors, latency reversing agents, compounds that target the HIV capsid, immune-based therapies, phosphatidylinositol 3 -kinase (PI3K) inhibitors, HIV antibodies, bispecific antibodies and“antibody-like” therapeutic proteins, HIV pl7 matrix protein inhibitors, IL-13 antagonists, peptidyl-prolyl cis-trans isomerase A modulators, protein disulfide isomerase inhibitors, complement C5a receptor antagonists, DNA methyltransferase inhibitor, HIV vif gene modulators, Vif dimerization antagonists, HIV-1 viral infectivity factor inhibitors, TAT protein inhibitors, HIV-1 Nef modulators, Hck tyrosine kinase modulators, mixed lineage kinase-3 (MLK-3) inhibitors, HIV-1 splicing inhibitors, Rev protein inhibitors, integrin antagonists, nucleoprotein inhibitors, splicing factor modulators, COMM domain containing protein 1 modulators, HIV ribonuclease H inhibitors, retrocyclin modulators, CDK-9 inhibitors, dendritic ICAM-3 grabbing nonintegrin 1 inhibitors, HIV GAG protein inhibitors, HIV POL protein inhibitors, Complement Factor H modulators, ubiquitin ligase inhibitors, deoxycytidine kinase inhibitors, cyclin dependent kinase inhibitors, proprotein convertase PC9 stimulators, ATP dependent RNA helicase DDX3X inhibitors, reverse transcriptase priming complex inhibitors, G6PD and NADH-oxidase inhibitors, pharmacokinetic enhancers, HIV gene therapy, and HIV vaccines, or a pharmaceutically acceptable salt of any of the foregoing, or any combinations thereof.

[0183] In some embodiments, the above uses further comprise administering one or more additional therapeutic agents selected from the group consisting of HIV protease inhibiting compounds, HIV non-nucleoside inhibitors of reverse transcriptase, HIV non-nucleotide inhibitors of reverse transcriptase, HIV nucleoside inhibitors of reverse transcriptase, HIV nucleotide inhibitors of reverse transcriptase, HIV integrase inhibitors, gp41 inhibitors, CXCR4 inhibitors, gpl20 inhibitors, CCR5 inhibitors, capsid polymerization inhibitors, pharmacokinetic enhancers, and other drugs for treating HIV, or a pharmaceutically acceptable salt of any of the foregoing, or any combinations thereof.

[0184] In some embodiments, the above uses further comprise administering one or more additional therapeutic agents selected from the group consisting of 4'-ethynyl-2-fluoro-2'- deoxyadenosine, bictegravir, abacavir sulfate, tenofovir, tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, tenofovir alafenamide, and tenofovir alafenamide hemifumarate, or a pharmaceutically acceptable salt of any of the foregoing, or any combinations thereof.

[0185] In some embodiments, the above uses further comprise administering one or more additional therapeutic agents selected from the group consisting of 4'-ethynyl-2-fluoro-2'- deoxyadenosine, bictegravir, tenofovir alafenamide, tenofovir alafenamide fumarate and tenofovir alafenamide hemifumarate, or a pharmaceutically acceptable salt of any of the foregoing, or any combinations thereof.

[0186] In some embodiments, the above uses further comprise administering one or more additional therapeutic agents selected from the group consisting of 4'-ethynyl-2-fluoro-2'- deoxyadenosine, bictegravir, tenofovir disoproxil, tenofovir disoproxil hemifumarate, and tenofovir disoproxil fumarate, or a pharmaceutically acceptable salt of any of the foregoing, or any combinations thereof.

[0187] In some embodiments, the above uses further comprise administering one or more additional therapeutic agents selected from the group consisting of emtricitabine and lamivudine, or a pharmaceutically acceptable salt of each thereof.

[0188] In some embodiments, the above uses further comprise administering

emtricitabine or a pharmaceutically acceptable salt thereof.

[0189] In one aspect, provided herein is a compound disclosed herein, or a

pharmaceutically acceptable salt thereof, for use in a method of activating T-cells in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound provided herein (i.e., a compound of Formula I, II, or Ila), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition provided herein.

[0190] In some embodiments, the uses described herein comprise administering a therapeutically effective amount of a compound provided herein (i.e., a compound of Formula I, II, or Ila), or a pharmaceutically acceptable salt thereof.

V. Administration

[0191] The compounds of the present disclosure (also referred to herein as the active ingredients), can be administered by any route appropriate to the condition to be treated.

Suitable routes include oral, rectal, nasal, topical (including buccal and sublingual), transdermal, vaginal and parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intrathecal and epidural), and the like. It will be appreciated that the preferred route may vary with, for example, the condition of the recipient. An advantage of certain compounds disclosed herein is that they are orally bioavailable and can be dosed orally.

[0192] A compound of the present disclosure may be administered to an individual in accordance with an effective dosing regimen for a desired period of time or duration, such as at least about one month, at least about 2 months, at least about 3 months, at least about 6 months, or at least about 12 months or longer. In some embodiments, the compound is administered on a daily or intermittent schedule for the duration of the individual’s life.

[0193] The specific dose level of a compound of the present disclosure for any particular subject will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, and rate of excretion, drug combination and the severity of the particular disease in the subject undergoing therapy. For example, a dosage may be expressed as a number of milligrams of a compound described herein per kilogram of the subject’s body weight (mg/kg). Dosages of between about 0.1 and 150 mg/kg may be appropriate. In some embodiments, about 0.1 and 100 mg/kg may be appropriate. In other embodiments a dosage of between 0.5 and 60 mg/kg may be appropriate. Normalizing according to the subject’s body weight is particularly useful when adjusting dosages between subjects of widely disparate size, such as occurs when using the drug in both children and adult humans or when converting an effective dosage in a non-human subject such as dog to a dosage suitable for a human subject.

[0194] The daily dosage may also be described as a total amount of a compound described herein administered per dose or per day. Daily dosage of a compound of Formula I,

II, Ila, III, IV, or V, or a pharmaceutically acceptable salt or pharmaceutically acceptable tautomer thereof, may be between about 1 mg and 4,000 mg, between about 2,000 to 4,000 mg/day, between about 1 to 2,000 mg/day, between about 1 to 1,000 mg/day, between about 10 to 500 mg/day, between about 20 to 500 mg/day, between about 50 to 300 mg/day, between about 75 to 200 mg/day, or between about 15 to 150 mg/day.

[0195] The dosage or dosing frequency of a compound of the present disclosure may be adjusted over the course of the treatment, based on the judgment of the administering physician.

[0196] The compounds of the present disclosure may be administered to an individual

( e.g ., a human) in a therapeutically effective amount. In some embodiments, the compound is administered once daily.

[0197] The compounds provided herein can be administered by any useful route and means, such as by oral or parenteral (e.g., intravenous) administration. Therapeutically effective amounts of the compound may include from about 0.00001 mg/kg body weight per day to about 10 mg/kg body weight per day, such as from about 0.0001 mg/kg body weight per day to about 10 mg/kg body weight per day, or such as from about 0.001 mg/kg body weight per day to about 1 mg/kg body weight per day, or such as from about 0.01 mg/kg body weight per day to about 1 mg/kg body weight per day, or such as from about 0.05 mg/kg body weight per day to about 0.5 mg/kg body weight per day. In some embodiments, a therapeutically effective amount of the compounds provided herein include from about 0.3 mg to about 30 mg per day, or from about 30 mg to about 300 mg per day, or from about 0.3 pg to about 30 mg per day, or from about 30 pg to about 300 pg per day.

[0198] A compound of the present disclosure may be combined with one or more additional therapeutic agents in any dosage amount of the compound of the present disclosure (e.g., from 1 mg to 1000 mg of compound). Therapeutically effective amounts may include from about 0.1 mg per dose to about 1000 mg per dose, such as from about 50 mg per dose to about 500 mg per dose, or such as from about 100 mg per dose to about 400 mg per dose, or such as from about 150 mg per dose to about 350 mg per dose, or such as from about 200 mg per dose to about 300 mg per dose, or such as from about 0.01 mg per dose to about 1000 mg per dose, or such as from about 0.01 mg per dose to about 100 mg per dose, or such as from about 0.1 mg per dose to about 100 mg per dose, or such as from about 1 mg per dose to about 100 mg per dose, or such as from about 1 mg per dose to about 10 mg per dose, or such as from about 1 mg per dose to about 1000 mg per dose. Other therapeutically effective amounts of the compound of Formula I, II, Ila, III, IV, or V are about 1 mg per dose, or about 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or about 100 mg per dose. Other therapeutically effective amounts of the compound of the present disclosure are about 100, 125, 150, 175, 200, 225, 250, 275, 300, 325, 350, 375, 400, 425, 450, 475, 500, 525, 550, 575, 600, 625, 650, 675, 700, 725, 750, 775, 800, 825, 850, 875, 900, 925, 950, 975, or about 1000 mg per dose.

[0199] In some embodiments, the methods described herein comprise administering to the subject an initial daily dose of about 1 to 500 mg of a compound p herein and increasing the dose by increments until clinical efficacy is achieved. Increments of about 5, 10, 25, 50, or 100 mg can be used to increase the dose. The dosage can be increased daily, every other day, twice per week, once per week, once every two weeks, once every three weeks, or once a month.

[0200] When administered orally, the total daily dosage for a human subject may be between about 1 mg and 1,000 mg, between about 10-500 mg/day, between about 50-300 mg/day, between about 75-200 mg/day, or between about 100-150 mg/day. In some

embodiments, the total daily dosage for a human subject may be about 100, 200, 300, 400, 500, 600, 700, 800, 900, or 1000 mg/day administered in a single dose. In some embodiments, the total daily dosage for a human subject may be about 200, 300, 400, 500, 600, 700, or 800 mg/day administered in a single dose. In some embodiments, the total daily dosage for a human subject may be about 300, 400, 500, or 600 mg/day administered in a single dose.

[0201] In some embodiments, the total daily dosage for a human subject may be about

100 mg/day administered in a single dose. In some embodiments, the total daily dosage for a human subject may be about 150 mg/day administered in a single dose. In some embodiments, the total daily dosage for a human subject may be about 200 mg/day administered in a single dose. In some embodiments, the total daily dosage for a human subject may be about 250 mg/day administered in a single dose. In some embodiments, the total daily dosage for a human subject may be about 300 mg/day administered in a single dose. In some embodiments, the total daily dosage for a human subject may be about 350 mg/day administered in a single dose. In some embodiments, the total daily dosage for a human subject may be about 400 mg/day administered in a single dose. In some embodiments, the total daily dosage for a human subject may be about 450 mg/day administered in a single dose. In some embodiments, the total daily dosage for a human subject may be about 500 mg/day administered in a single dose. In some embodiments, the total daily dosage for a human subject may be about 550 mg/day administered in a single dose. In some embodiments, the total daily dosage for a human subject may be about 600 mg/day administered in a single dose. In some embodiments, the total daily dosage for a human subject may be about 650 mg/day administered in a single dose. In some embodiments, the total daily dosage for a human subject may be about 700 mg/day administered in a single dose. In some embodiments, the total daily dosage for a human subject may be about 750 mg/day administered in a single dose. In some embodiments, the total daily dosage for a human subject may be about 800 mg/day administered in a single dose. In some embodiments, the total daily dosage for a human subject may be about 850 mg/day administered in a single dose. In some embodiments, the total daily dosage for a human subject may be about 900 mg/day administered in a single dose. In some embodiments, the total daily dosage for a human subject may be about 950 mg/day administered in a single dose. In some embodiments, the total daily dosage for a human subject may be about 1000 mg/day administered in a single dose.

[0202] A single dose can be administered hourly, daily, weekly, or monthly. For example, a single dose can be administered once every 1 hour, 2, 3, 4, 6, 8, 12, 16 or once every 24 hours. A single dose can also be administered once every 1 day, 2, 3, 4, 5, 6, or once every 7 days. A single dose can also be administered once every 1 week, 2, 3, or once every 4 weeks.

In certain embodiments, a single dose can be administered once every week. A single dose can also be administered once every month. In some embodiments, a compound disclosed herein is administered once daily in a method disclosed herein. In some embodiments, a compound disclosed herein is administered twice daily in a method disclosed herein.

[0203] The frequency of dosage of the compound of the present disclosure will be determined by the needs of the individual patient and can be, for example, once per day or twice, or more times, per day. Administration of the compound continues for as long as necessary to treat the HBV infection, HIV infection, cancer, hyper-proliferative disease, or any other indication described herein. For example, a compound can be administered to a human being infected with HBV for a period of from 20 days to 180 days or, for example, for a period of from 20 days to 90 days or, for example, for a period of from 30 days to 60 days.

[0204] Administration can be intermittent, with a period of several or more days during which a patient receives a daily dose of the compound of the present disclosure followed by a period of several or more days during which a patient does not receive a daily dose of the compound. For example, a patient can receive a dose of the compound every other day, or three times per week. Again by way of example, a patient can receive a dose of the compound each day for a period of from 1 to 14 days, followed by a period of 7 to 21 days during which the patient does not receive a dose of the compound, followed by a subsequent period (e.g., from 1 to 14 days) during which the patient again receives a daily dose of the compound. Alternating periods of administration of the compound, followed by non-administration of the compound, can be repeated as clinically required to treat the patient.

[0205] The compounds of the present disclosure or the pharmaceutical compositions thereof may be administered once, twice, three, or four times daily, using any suitable mode described above. Also, administration or treatment with the compounds may be continued for a number of days; for example, commonly treatment would continue for at least 7 days, 14 days, or 28 days, for one cycle of treatment. Treatment cycles are well known in cancer

chemotherapy, and are frequently alternated with resting periods of about 1 to 28 days, commonly about 7 days or about 14 days, between cycles. The treatment cycles, in other embodiments, may also be continuous.

VI. Combination Therapy

[0206] In some embodiments, a compound of the present disclosure, or a

pharmaceutically acceptable salt thereof, is combined with one, two, three, four or more additional therapeutic agents. In some embodiments, a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is combined with two additional therapeutic agents. In some embodiments, a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is combined with three additional therapeutic agents. In some embodiments, a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, is combined with four additional therapeutic agents. The one, two, three, four or more additional therapeutic agents can be different therapeutic agents selected from the same class of therapeutic agents, and/or they can be selected from different classes of therapeutic agents.

[0207] In some embodiments, when a compound of the present disclosure is combined with one or more additional therapeutic agents as described herein, the components of the composition are administered as a simultaneous or sequential regimen. When administered sequentially, the combination may be administered in two or more administrations.

[0208] In some embodiments, a compound of the present disclosure is combined with one or more additional therapeutic agents in a unitary dosage form for simultaneous

administration to a patient, for example as a solid dosage form for oral administration.

[0209] In some embodiments, a compound of the present disclosure is co-administered with one or more additional therapeutic agents.

[0210] Co-administration includes administration of unit dosages of the compounds disclosed herein before or after administration of unit dosages of one or more additional therapeutic agents. The compounds disclosed herein may be administered within seconds, minutes, or hours of the administration of one or more additional therapeutic agents. For example, in some embodiments, a unit dose of a compound disclosed herein is administered first, followed within seconds or minutes by administration of a unit dose of one or more additional therapeutic agents. Alternatively, in other embodiments, a unit dose of one or more additional therapeutic agents is administered first, followed by administration of a unit dose of a compound disclosed herein within seconds or minutes. In some embodiments, a unit dose of a compound disclosed herein is administered first, followed, after a period of hours (i.e., 1-12 hours), by administration of a unit dose of one or more additional therapeutic agents. In other embodiments, a unit dose of one or more additional therapeutic agents is administered first, followed, after a period of hours (i.e., 1-12 hours), by administration of a unit dose of a compound disclosed herein.

[0211] In some embodiments, a compound of Formula I, II, or Ila is formulated as a tablet, which may optionally contain one or more other compounds useful for treating the disease being treated. In certain embodiments, the tablet can contain another active ingredient for treating a HIV infection. In some embodiments, such tablets are suitable for once daily dosing.

[0212] Also provided herein are methods of treatment in which a compound of Formula

I, II, or Ila, or a tautomer or pharmaceutically acceptable salt thereof, is given to a patient in combination with one or more additional therapeutic agents or therapy. In some embodiments, the total daily dosage of a compound of Formula I, II, or Ila, or a tautomer, or a

pharmaceutically acceptable salt thereof, may be about 300 mg/day administered in a single dose for a human subject.

HIV Combination Therapy

[0213] In certain embodiments, a method for treating or preventing an HIV infection in a human or animal having or at risk of having the infection is provided, comprising administering to the human or animal a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof, in combination with a therapeutically effective amount of one or more (i.e., one, two, three; one or two; or one to three) additional therapeutic agents. In one embodiment, a method for treating an HIV infection in a human or animal having or at risk of having the infection is provided, comprising administering to the human or animal a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof, in combination with a therapeutically effective amount of one or more (i.e., one, two, three; one or two; or one to three) additional therapeutic agents.

[0214] In one embodiment, pharmaceutical compositions comprising a compound disclosed herein, or a pharmaceutically acceptable salt thereof, in combination with one or more (i.e., one, two, three; one or two; or one to three) additional therapeutic agents, and a

pharmaceutically acceptable carrier, diluent, or excipient are provided. [0215] In certain embodiments, the present disclosure provides a method for treating an

HIV infection, comprising administering to a patient in need thereof a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof, in combination with a therapeutically effective amount of one or more additional therapeutic agents which are suitable for treating an HIV infection.

[0216] In certain embodiments, the compounds disclosed herein are formulated as a tablet, which may optionally contain one or more other compounds useful for treating HIV. In certain embodiments, the tablet can contain another active ingredient for treating HIV, such as HIV protease inhibitors, HIV non-nucleoside or non-nucleotide inhibitors of reverse

transcriptase, HIV nucleoside or nucleotide inhibitors of reverse transcriptase, HIV integrase inhibitors, HIV non-catalytic site (or allosteric) integrase inhibitors, pharmacokinetic enhancers, or any combinations thereof.

[0217] In certain embodiments, such tablets are suitable for once daily dosing.

[0218] In some embodiments, the additional therapeutic agent may be an anti-HIV agent.

In some embodiments, the additional therapeutic agent is selected from the group consisting of HIV combination drugs, HIV protease inhibitors, HIV non-nucleoside or non-nucleotide inhibitors of reverse transcriptase, HIV nucleoside or nucleotide inhibitors of reverse

transcriptase, HIV integrase inhibitors, HIV non-catalytic site (or allosteric) integrase inhibitors, HIV entry inhibitors, HIV maturation inhibitors, immunomodulators, immunotherapeutic agents, antibody-drug conjugates, gene modifiers, gene editors (such as CRISPR/Cas9, zinc finger nucleases, homing nucleases, synthetic nucleases, TALENs), cell therapies (such as chimeric antigen receptor T-cell, CAR-T, and engineered T cell receptors, TCR-T), latency reversing agents, compounds that target the HIV capsid (including capsid inhibitors), immune-based therapies, phosphatidylinositol 3-kinase (PI3K) inhibitors, alpha-4/beta-7 antagonists, HIV antibodies, bispecific antibodies and“antibody-like” therapeutic proteins, HIV pl7 matrix protein inhibitors, IL-13 antagonists, peptidyl-prolyl cis-trans isomerase A modulators, protein disulfide isomerase inhibitors, complement C5a receptor antagonists, DNA methyltransferase inhibitor, HIV vif gene modulators, Vif dimerization antagonists, HIV-1 viral infectivity factor inhibitors, TAT protein inhibitors, HIV-1 Nef modulators, Hck tyrosine kinase modulators, mixed lineage kinase-3 (MLK-3) inhibitors, HIV-1 splicing inhibitors, Rev protein inhibitors, integrin antagonists, nucleoprotein inhibitors, splicing factor modulators, COMM domain containing protein 1 modulators, HIV ribonuclease H inhibitors, retrocyclin modulators, CDK-9 inhibitors, dendritic ICAM-3 grabbing nonintegrin 1 inhibitors, HIV GAG protein inhibitors, HIV POL protein inhibitors, Complement Factor H modulators, ubiquitin ligase inhibitors, deoxycytidine kinase inhibitors, cyclin dependent kinase inhibitors, proprotein convertase PC9 stimulators, ATP dependent RNA helicase DDX3X inhibitors, reverse transcriptase priming complex inhibitors, G6PD and NADH-oxidase inhibitors, pharmacokinetic enhancers, HIV gene therapy, HIV vaccines, and other HIV therapeutic agents, or any combinations thereof.

[0219] In some embodiments, the additional therapeutic agent is selected from the group consisting of combination drugs for HIV, other drugs for treating HIV, HIV protease inhibitors, HIV reverse transcriptase inhibitors, HIV integrase inhibitors, HIV non-catalytic site (or allosteric) integrase inhibitors, HIV entry (fusion) inhibitors, HIV maturation inhibitors, latency reversing agents, capsid inhibitors, immune-based therapies, PI3K inhibitors, HIV antibodies, and bispecific antibodies, and“antibody-like” therapeutic proteins, or any combinations thereof.

HIV Combination Drugs

[0220] Examples of combination drugs include ATRIPLA ^® (efavirenz, tenofovir disoproxil fumarate, and emtricitabine); COMPLERA ^® (EVIPLERA ^® ; rilpivirine, tenofovir disoproxil fumarate, and emtricitabine); STRIBILD ^® (elvitegravir, cobicistat, tenofovir disoproxil fumarate, and emtricitabine); TRUVADA ^® (tenofovir disoproxil fumarate and emtricitabine; TDF+FTC); DESCOVY® (tenofovir alafenamide and emtricitabine);

ODEFSEY® (tenofovir alafenamide, emtricitabine, and rilpivirine); GENVOYA® (tenofovir alafenamide, emtricitabine, cobicistat, and elvitegravir); BIKTARVY® (bictegravir,

emtricitabine, tenofovir alafenamide); darunavir, tenofovir alafenamide hemifumarate, emtricitabine, and cobicistat; efavirenz, lamivudine, and tenofovir disoproxil fumarate;

lamivudine and tenofovir disoproxil fumarate; tenofovir and lamivudine; tenofovir alafenamide and emtricitabine ;tenofovir alafenamide hemifumarate and emtricitabine; tenofovir alafenamide hemifumarate, emtricitabine, and rilpivirine; tenofovir alafenamide hemifumarate, emtricitabine, cobicistat, and elvitegravir; COMBIVIR ^® (zidovudine and lamivudine; AZT+3TC); EPZICOM ^® (LIVEXA ^® ; abacavir sulfate and lamivudine; ABC+3TC); KALETRA ^® (ALUVIA ^® ; lopinavir and ritonavir); TRIUMEQ ^® (dolutegravir, abacavir, and lamivudine); TRIZIVIR ^® (abacavir sulfate, zidovudine, and lamivudine; ABC+AZT+3TC); atazanavir and cobicistat; atazanavir sulfate and cobicistat; atazanavir sulfate and ritonavir; darunavir and cobicistat; dolutegravir and rilpivirine; dolutegravir and rilpivirine hydrochloride; dolutegravir, abacavir sulfate, and lamivudine; lamivudine, nevirapine, and zidovudine; raltegravir and lamivudine; doravirine, lamivudine, and tenofovir disoproxil fumarate; doravirine, lamivudine, and tenofovir disoproxil; dolutegravir + lamivudine, lamivudine + abacavir + zidovudine, lamivudine + abacavir, lamivudine + tenofovir disoproxil fumarate, lamivudine + zidovudine + nevirapine, lopinavir + ritonavir, lopinavir + ritonavir + abacavir + lamivudine, lopinavir + ritonavir + zidovudine + lamivudine, tenofovir + lamivudine, and tenofovir disoproxil fumarate + emtricitabine + rilpivirine hydrochloride, lopinavir , ritonavir, zidovudine and lamivudine; Vacc-4x and romidepsin; and APH-0812, or any combinations thereof.

HIV Protease Inhibitors

[0221] Examples of HIV protease inhibitors include amprenavir, atazanavir, brecanavir, darunavir, fosamprenavir, fosamprenavir calcium, indinavir, indinavir sulfate, lopinavir, nelfmavir, nelfmavir mesylate, ritonavir, saquinavir, saquinavir mesylate, tipranavir, DG-17, TMB-657 (PPL- 100), T-169, BL-008, and TMC-310911.

HIV Reverse Transcriptase Inhibitors

[0222] Examples of HIV non -nucleoside or non-nucleotide inhibitors of reverse transcriptase include dapivirine, delavirdine, delavirdine mesylate, doravirine, efavirenz, etravirine, lentinan, nevirapine, rilpivirine, ACC-007, AIC-292, KM-023, PC-1005, and VM- 1500.

[0223] Examples of HIV nucleoside or nucleotide inhibitors of reverse transcriptase include adefovir, adefovir dipivoxil, azvudine, emtricitabine, tenofovir, tenofovir alafenamide, tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, VIDEX ^® and VIDEX EC ^® (didanosine, ddl), abacavir, abacavir sulfate, alovudine, apricitabine, censavudine, didanosine, elvucitabine, festinavir, fosalvudine tidoxil, CMX-157, dapivirine, doravirine, etravirine, OCR- 5753, tenofovir disoproxil orotate, fozivudine tidoxil, lamivudine, phosphazid, stavudine, zalcitabine, zidovudine, GS-9131, GS-9148, MK-8504 and KP-1461.

HIV Integrase Inhibitors

[0224] Examples of HIV integrase inhibitors include elvitegravir, curcumin, derivatives of curcumin, chicoric acid, derivatives of chicoric acid, 3,5-dicaffeoylquinic acid, derivatives of 3,5-dicaffeoylquinic acid, aurintricarboxylic acid, derivatives of aurintricarboxylic acid, caffeic acid phenethyl ester, derivatives of caffeic acid phenethyl ester, tyrphostin, derivatives of tyrphostin, quercetin, derivatives of quercetin, raltegravir, dolutegravir, JTK-351, bictegravir, AVX-15567, cabotegravir (long-acting injectable), diketo quinolin-4-1 derivatives, integrase- LEDGF inhibitor, ledgins, M-522, M-532, NSC-310217, NSC-371056, NSC-48240, NSC- 642710, NSC-699171, NSC-699172, NSC-699173, NSC-699174, stilbenedisulfonic acid, T- 169 and cabotegravir.

[0225] Examples of HIV non-catalytic site, or allosteric, integrase inhibitors (NCINI) include CX-05045, CX-05168, and CX-14442.

HIV Entry Inhibitors

[0226] Examples of HIV entry (fusion) inhibitors include cenicriviroc, CCR5 inhibitors, gp41 inhibitors, CD4 attachment inhibitors, gpl20 inhibitors, and CXCR4 inhibitors.

[0227] Examples of CCR5 inhibitors include aplaviroc, vicriviroc, maraviroc, cenicriviroc, PRO-140, adaptavir (RAP-101), nifeviroc (TD-0232), anti-GP120/CD4 or CCR5 bispecific antibodies, B-07, MB-66, polypeptide C25P, TD-0680, and vMIP (Haimipu).

[0228] Examples of gp41 inhibitors include albuvirtide, enfuvirtide, BMS-986197, enfuvirtide biobetter, enfuvirtide biosimilar, HIV-1 fusion inhibitors (P26-Bapc), ITV-1, ITV-2, ITV-3, ITV-4, PIE-12 trimer and sifuvirtide.

[0229] Examples of CD4 attachment inhibitors include ibalizumab and CADA analogs.

[0230] Examples of gpl20 inhibitors include Radha-108 (receptol) 3B3-PE38, BanLec, bentonite-based nanomedicine, fostemsavir tromethamine, IQP-0831, and BMS-663068.

[0231] Examples of CXCR4 inhibitors include plerixafor, ALT-1188, N15 peptide, and vMIP (Haimipu).

HIV Maturation Inhibitors

[0232] Examples of HIV maturation inhibitors include BMS-955176 and GSK-2838232.

Latency Reversing Agents

[0233] Examples of latency reversing agents include histone deacetylase (HD AC) inhibitors, proteasome inhibitors such as velcade, protein kinase C (PKC) activators, Smyd2 inhibitors, BET-bromodomain 4 (BRD4) inhibitors, ionomycin, PMA, SAHA

(suberanilohydroxamic acid, or suberoyl, anilide, and hydroxamic acid), AM-0015, ALT-803, NIZ-985, NKTR-255, IL-15 modulating antibodies, JQ1, disulfiram, amphotericin B, and ubiquitin inhibitors such as largazole analogs, GSK-343, GSK3beta inhibitors, SMAC mimetics, and Gal 9.

[0234] Examples of HD AC inhibitors include romidepsin, vorinostat, and panobinostat.

[0235] Examples of PKC activators include indolactam, prostratin, ingenol B, and DAG- lactones.

[0236] Examples of GSK3 beta inhibitors include tideglusib, LY2090314, CHIR99021, and AZD1080.

[0237] Examples of SMAC mimetics include birinapant, AZD5582, LCL161, and

AT406.

Capsid Inhibitors

[0238] Examples of capsid inhibitors include capsid polymerization inhibitors or capsid disrupting compounds, HIV nucleocapsid p7 (NCp7) inhibitors such as azodicarbonamide, HIV p24 capsid protein inhibitors, AVI-621, AVI-101, AVI-201, AVI-301, and AVI-CANl-15 series.

Immune-based Therapies

[0239] Examples of immune-based therapies include toll-like receptors modulators such as TLR1, TLR2, TLR3, TLR4, TLR5, TLR6, TLR7, TLR8, TLR9, TLR10, TLR11, TLR12, and TLR13; programmed cell death protein 1 (Pd-1) modulators; programmed death-ligand 1 (Pd- Ll) modulators; IL-15 modulators; DermaVir; interleukin-7; plaquenil (hydroxychloroquine); proleukin (aldesleukin, IL-2); interferon alfa; interferon alfa-2b; interferon alfa-n3; pegylated interferon alfa; interferon gamma; hydroxyurea; mycophenolate mofetil (MPA) and its ester derivative mycophenolate mofetil (MMF); ribavirin; rintatolimod, polymer polyethyleneimine (PEI); gepon; rintatolimod; IL-12; WF-10; VGV-1; MOR-22; BMS-936559; CYT-107;

interleukin-15/Fc fusion protein; normferon; peginterferon alfa-2a; peginterferon alfa-2b;

recombinant interleukin- 15; RPI-MN; GS-9620; STING modulators; RIG-I modulators; NOD2 modulators; and IR-103.

[0240] Examples of TLR8 modulators include motolimod, resiquimod, 3M-051, 3M-

052, MCT-465, IMO-4200, VTX-763, VTX-1463 and those disclosed in US20140045849 (Janssen), US20140073642 (Janssen), WO2014/056953 (Janssen), WO2014/076221 (Janssen), WO2014/128189 (Janssen), US20140350031 (Janssen), WO2014/023813 (Janssen),

US20080234251 (Array Biopharma), US20080306050 (Array Biopharma), US20100029585 (Ventirx Pharma), US20110092485 (Ventirx Pharma), US20110118235 (Ventirx Pharma), US20120082658 (Ventirx Pharma), US20120219615 (Ventirx Pharma), US20140066432 (Ventirx Pharma), US20140088085 (VentirxPharma), US20140275167 (Novira therapeutics), US20130251673 (Novira therapeutics), US Patent No. 9670205 (Gilead Sciences Inc.),

US20160289229 (Gilead Sciences Inc.), US Patent Application No. 15/692161 (Gilead Sciences Inc.), and US Patent Application No. 15/692093 (Gilead Sciences Inc.).

Phosphatidylinositol 3-kinase (PI3K) Inhibitors

[0241] Examples of PI3K inhibitors include idelalisib, alpelisib, buparlisib, CAI orotate, copanlisib, duvelisib, gedatolisib, neratinib, panulisib, perifosine, pictilisib, pilaralisib, puquitinib mesylate, rigosertib, rigosertib sodium, sonolisib, taselisib, AMG-319, AZD-8186, BAY-1082439, CLR-1401, CLR-457, CUDC-907, DS-7423, EN-3342, GSK-2126458, GSK- 2269577, GSK-2636771, INCB-040093, LY-3023414, MLN-1117, PQR-309, RG-7666, RP- 6530, RV-1729, SAR-245409, SAR-260301, SF-1126, TGR-1202, UCB-5857, VS-5584, XL- 765, and ZSTK-474. alpha-4/beta-7 antagonists

[0242] Examples of Integrin alpha-4/beta-7 antagonists include PTG-100, TRK-170, abrilumab, etrolizumab, carotegrast methyl, and vedolizumab.

HIV Antibodies, Bispecific Antibodies, and“Antibody-like” Therapeutic Proteins

[0243] Examples of HIV antibodies, bispecific antibodies, and“antibody-like” therapeutic proteins include DARTs ^® , DUOBODIES ^® , BITES ^® , XmAbs ^® , TandAbs ^® , Fab derivatives, bnABs (broadly neutralizing HIV-1 antibodies), BMS-936559, TMB-360, and those targeting HIV gpl20 or gp41, antibody-Recruiting Molecules targeting HIV, anti-CD63 monoclonal antibodies, anti-GB virus C antibodies, anti-GP120/CD4, CCR5 bispecific antibodies, anti-nef single domain antibodies, anti -Rev antibody, camelid derived anti-CD 18 antibodies, camelid-derived anti-ICAM-1 antibodies, DCVax-001, gpl40 targeted antibodies, gp41-based HIV therapeutic antibodies, human recombinant mAbs (PGT-121), ibalizumab, Immuglo, and MB-66.

[0244] Further examples include bavituximab, UB-421, C2F5, 2G12, C4E10, C2F 5+C2G12+C4E10, 8ANC195, 3BNC117, 3BNC60, 10-1074, PGT145, PGT121, PGT-151, PGT-133, MDX010 (ipilimumab), DH511, N6, VRC01 PGDM1400, A32, 7B2, 10E8, 10E8v4, CAP256-VRC26.25, DRVIA7, VRC-07-523, VRC-HIVMAB080-00-AB, VRC-HIVMAB060- 00-AB, MGD-014 and VRC07.

[0245] Additional examples of HIV bispecific antibodies include MGD014.

Pharmacokinetic Enhancers

[0246] Examples of pharmacokinetic enhancers include cobicistat and ritonavir.

HIV Vaccines

[0247] Examples of HIV vaccines include peptide vaccines, recombinant subunit protein vaccines, live vector vaccines, DNA vaccines, CD4-derived peptide vaccines, vaccine combinations, rgpl20 (AIDSVAX), ALVAC HIV (vCP1521)/AIDSVAX B/E (gpl20) (RV144), monomeric gpl20 HIV-1 subtype C vaccine, Remune, ITV-1, Contre Vir, Ad5-ENVA-48, DCVax-001 (CDX-2401), Vacc-4x, Vacc-C5, VAC-3S, multiclade DNA recombinant adenovirus-5 (rAd5), Pennvax-G, Pennvax-GP, HIV-TriMix-mRNA vaccine, HIV-LAMP-vax, Ad35, Ad35-GRIN, NAcGM3/VSSP ISA-51, poly-ICLC adjuvanted vaccines, Tatlmmune, GTU-multiHIV (FIT-06), gpl40[delta]V2.TVl+MF-59, rVSVIN HIV-1 gag vaccine, SeV-Gag vaccine, AT-20, DNK-4, ad35-Grin/ENV, TBC-M4, HIVAX, HIVAX-2, NYVAC-HIV-PT1, NYVAC-HIV-PT4, DNA-HIV -PT 123 , rAAVl-PG9DP, GOVX-B11, GOVX-B21, TVI-HIV-1, Ad-4 (Ad4-env Clade C+Ad4-mGag), EN41-UGR7C, EN41-FPA2, PreVaxTat, AE-H, MYM- V101, CombiHIVvac, AD VAX, MYM-V201, MVA-CMDR, DNA-Ad5 gag/pol/nef/nev (HVTN505), MVATG-17401, ETV-01, CDX-1401, rcAD26.MOSl.HIV-Env, Ad26.Mod.HIV vaccine, AGS-004, AVX-101, AVX-201, PEP-6409, SAV-001, ThV-01, TL-01, TUTI-16, VGX-3300, IHV-001, and virus-like particle vaccines such as pseudovirion vaccine,

CombiVICHvac, LFn-p24 B/C fusion vaccine, GTU-based DNA vaccine, HIV gag/pol/nef/env DNA vaccine, anti-TAT HIV vaccine, conjugate polypeptides vaccine, dendritic-cell vaccines, gag-based DNA vaccine, GI-2010, gp41 HIV-1 vaccine, HIV vaccine (PIKA adjuvant), I i- key/MHC class II epitope hybrid peptide vaccines, ITV-2, ITV-3, ITV-4, LIPO-5, multiclade Env vaccine, MVA vaccine, Pennvax-GP, pp71 -deficient HCMV vector HIV gag vaccine, recombinant peptide vaccine (HIV infection), NCI, rgpl60 HIV vaccine, RNActive HIV vaccine, SCB-703, Tat Oyi vaccine, TBC-M4, therapeutic HIV vaccine, UBI HIV gpl20, Vacc- 4x + romidepsin, variant gpl20 polypeptide vaccine, rAd5 gag-pol env A/B/C vaccine,

DNA.HTI and MVA.HTI. Additional HIV Therapeutic Agents

[0248] Examples of additional HIV therapeutic agents include the compounds disclosed in WO 2004/096286 (Gilead Sciences), WO 2006/015261 (Gilead Sciences), WO 2006/110157 (Gilead Sciences), WO 2012/003497 (Gilead Sciences), WO 2012/003498 (Gilead Sciences), WO 2012/145728 (Gilead Sciences), WO 2013/006738 (Gilead Sciences), WO 2013/159064 (Gilead Sciences), WO 2014/100323 (Gilead Sciences), US 2013/0165489 (University of Pennsylvania), US 2014/0221378 (Japan Tobacco), US 2014/0221380 (Japan Tobacco), WO 2009/062285 (Boehringer Ingelheim), WO 2010/130034 (Boehringer Ingelheim), WO

2013/006792 (Pharma Resources), US 20140221356 (Gilead Sciences), US 20100143301 (Gilead Sciences) and WO 2013/091096 (Boehringer Ingelheim).

[0249] Examples of other drugs for treating HIV include acemannan, alisporivir,

BanLec, deferiprone, Gamimune, metenkefalin, naltrexone, Prolastin, REP 9, RPI-MN, VSSP, Hlviral, SB-728-T, 1,5-dicaffeoylquinic acid, rHIV7-shl-TAR-CCR5RZ, AAV-eCD4-Ig gene therapy, MazF gene therapy, BlockAide, ABX-464, AG-1105, APH-0812, BIT-225, CYT-107, HGTV-43, HPH-116, HS-10234, IMO-3100, IND-02, MK-1376, MK-8507, MK-8591, NOV- 205, PA-1050040 (PA-040), PGN-007, SCY-635, SB-9200, SCB-719, TR-452, TEV-90110, TEV-90112, TEV-90111, TEV-90113, RN-18, Immuglo, and VIR-576.

Gene Therapy and Cell Therapy

[0250] Gene therapy and cell therapy include the genetic modification to silence a gene; genetic approaches to directly kill the infected cells; the infusion of immune cells designed to replace most of the patient’s own immune system to enhance the immune response to infected cells, or activate the patient’s own immune system to kill infected cells, or find and kill the infected cells; and genetic approaches to modify cellular activity to further alter endogenous immune responsiveness against the infection.

[0251] Examples of dendritic cell therapy include AGS-004.

Gene Editors

[0252] Examples of gene editing systems include a CRISPR/Cas9 system, a zinc finger nuclease system, a TALEN system, a homing endonucleases system, and a meganuclease system.

[0253] Examples of HIV targeting CRISPR/Cas9 systems include EBT101. CAR-T cell therapy

[0254] CAR-T cell therapy includes a population of immune effector cells engineered to express a chimeric antigen receptor (CAR), wherein the CAR comprises an HIV antigen-binding domain. The HIV antigens include an HIV envelope protein or a portion thereof, gpl20 or a portion thereof, a CD4 binding site on gpl20, the CD4-induced binding site on gpl20, N glycan on gpl20, the V2 of gpl20, and the membrane proximal region on gp41. In some embodiments, the immune effector cell is a T cell or an NK cell. In some embodiments, the T cell is a CD4+ T cell, a CD8+ T cell, or a combination thereof.

[0255] Examples of HIV CAR-T cell therapy include VC-CAR-T.

TCR-T cell therapy

[0256] TCR-T cell therapy includes T cells engineered to target HIV derived peptides present on the surface of virus-infected cells.

[0257] It will be appreciated by one of skill in the art that the additional therapeutic agents listed above may be included in more than one of the classes listed above. The particular classes are not intended to limit the functionality of those compounds listed in those classes.

[0258] In a specific embodiment, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with an HIV nucleoside or nucleotide inhibitor of reverse transcriptase and an HIV non-nucleoside inhibitor of reverse transcriptase. In another specific embodiment, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with an HIV nucleoside or nucleotide inhibitor of reverse transcriptase, and an HIV protease inhibiting compound. In an additional embodiment, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with an HIV nucleoside or nucleotide inhibitor of reverse transcriptase, an HIV non-nucleoside inhibitor of reverse transcriptase, and a pharmacokinetic enhancer. In certain embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with at least one HIV nucleoside inhibitor of reverse transcriptase, an integrase inhibitor, and a pharmacokinetic enhancer. In another embodiment, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with two HIV nucleoside or nucleotide inhibitors of reverse transcriptase.

[0259] In a particular embodiment, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with one, two, three, four or more additional therapeutic agents selected from ATRIPLA ^® (efavirenz, tenofovir disoproxil fumarate, and emtricitabine); COMPLERA ^® (EVIPLERA ^® ; rilpivirine, tenofovir disoproxil fumarate, and emtricitabine); STRIBILD ^® (elvitegravir, cobicistat, tenofovir disoproxil fumarate, and emtricitabine);

TRUVADA ^K (tenofovir disoproxil fumarate and emtricitabine; TDF +FTC); DESCOVY® (tenofovir alafenamide and emtricitabine); ODEFSEY® (tenofovir alafenamide, emtricitabine, and rilpivirine); GENVOYA® (tenofovir alafenamide, emtricitabine, cobicistat, and

elvitegravir); BIKTARVY® (bictegravir, emtricitabine, tenofovir alafenamide); adefovir;

adefovir dipivoxil; cobicistat; emtricitabine; tenofovir; tenofovir disoproxil; tenofovir disoproxil fumarate; tenofovir alafenamide; tenofovir alafenamide hemifumarate; TRIUMEQ ^®

(dolutegravir, abacavir, and lamivudine); dolutegravir, abacavir sulfate, and lamivudine;

raltegravir; raltegravir and lamivudine; maraviroc; enfuvirtide; ALUVIA ^K (KALETRA ^® ;

lopinavir and ritonavir); COMBIVIR ^® (zidovudine and lamivudine; AZT+3TC); EPZICOM ^® (LIVEXA ^® ; abacavir sulfate and lamivudine; ABC+3TC); TRIZIVIR ^® (abacavir sulfate, zidovudine, and lamivudine; ABC+AZT+3TC); rilpivirine; rilpivirine hydrochloride; atazanavir sulfate and cobicistat; atazanavir and cobicistat; darunavir and cobicistat; atazanavir; atazanavir sulfate; dolutegravir; elvitegravir; ritonavir; atazanavir sulfate and ritonavir; darunavir;

lamivudine; prolastin; fosamprenavir; fosamprenavir calcium efavirenz; etravirine; nelfmavir; nelfmavir mesylate; interferon; didanosine; stavudine; indinavir; indinavir sulfate; tenofovir and lamivudine; zidovudine; nevirapine; saquinavir; saquinavir mesylate; aldesleukin; zalcitabine; tipranavir; amprenavir; delavirdine; delavirdine mesylate; Radha-108 (receptol); lamivudine and tenofovir disoproxil fumarate; efavirenz, lamivudine, and tenofovir disoproxil fumarate;

phosphazid; lamivudine, nevirapine, and zidovudine; abacavir; and abacavir sulfate.

[0260] In a particular embodiment, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with abacavir sulfate, tenofovir, tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, tenofovir alafenamide, tenofovir alafenamide hemifumarate, or bictegravir.

[0261] In a particular embodiment, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with tenofovir, tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir alafenamide, tenofovir alafenamide hemifumarate, or bictegravir.

[0262] In a particular embodiment, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with a first additional therapeutic agent selected from the group consisting of abacavir sulfate, tenofovir, tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir alafenamide, tenofovir alafenamide hemifumarate, and bictegravir and a second additional therapeutic agent selected from the group consisting of emtricitabine and lamivudine.

[0263] In a particular embodiment, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with a first additional therapeutic agent selected from the group consisting of tenofovir, tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir alafenamide, tenofovir alafenamide hemifumarate, and bictegravir and a second additional therapeutic agent, wherein the second additional therapeutic agent is emtricitabine.

[0264] A compound as disclosed herein may be combined with one or more additional therapeutic agents in any dosage amount of the compound (e.g., from 1 mg to 500 mg of compound).

[0265] In certain embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with 5-30 mg tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, or tenofovir alafenamide, and 200 mg emtricitabine. In certain embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with 5-10, 5-15, 5-20, 5-25, 25-30, 20-30, 15-30, or 10-30 mg tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, or tenofovir alafenamide, and 200 mg emtricitabine. In certain embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with 10 mg tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, or tenofovir alafenamide, and 200 mg emtricitabine. In certain embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with 25 mg tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, or tenofovir alafenamide, and 200 mg emtricitabine. A compound as disclosed herein (i.e., a compound of Formula I, II, or IIA) may be combined with the agents provided herein in any dosage amount of the compound (i.e., from 1 mg to 500 mg of compound) as if each combination of dosages were specifically and individually listed.

[0266] In certain embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with 200-400 mg tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, or tenofovir disoproxil, and 200 mg emtricitabine. In certain embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with 200-250, 200-300, 200-350, 250-350, 250-400, 350-400, 300-400, or 250-400 mg tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, or tenofovir disoproxil, and 200 mg emtricitabine. In certain embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with 300 mg tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, or tenofovir disoproxil, and 200 mg emtricitabine. A compound as disclosed herein (i.e., a compound of Formula I, II, or Ila) may be combined with the agents provided herein in any dosage amount of the compound (i.e., from 1 mg to 500 mg of compound) as if each combination of dosages were specifically and individually listed.

VII. Compound Preparation

[0267] Some embodiments of the present disclosure are directed to processes and intermediates useful for preparing the compounds provided herein or pharmaceutically acceptable salts thereof.

[0268] Compounds described herein can be purified by any of the means known in the art, including chromatographic means, such as high performance liquid chromatography

(HPLC), preparative thin layer chromatography, flash column chromatography and ion exchange chromatography. Any suitable stationary phase can be used, including normal and reversed phases as well as ionic resins. Most typically the disclosed compounds are purified via silica gel and/or alumina chromatography.

[0269] During any of the processes for preparation of the compounds provided herein, it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules concerned. This may be achieved by means of conventional protecting groups as described in standard works, such as T. W. Greene and P. G. M. Wuts,“Protective Groups in Organic Synthesis,” 4 ^th ed., Wiley, New York 2006. The protecting groups may be removed at a convenient subsequent stage using methods known from the art.

[0270] Exemplary chemical entities useful in methods of the embodiments will now be described by reference to illustrative synthetic schemes for their general preparation herein and the specific examples that follow. Artisans will recognize that, to obtain the various compounds herein, starting materials may be suitably selected so that the ultimately desired substituents will be carried through the reaction scheme with or without protection as appropriate to yield the desired product. Alternatively, it may be necessary or desirable to employ, in the place of the ultimately desired substituent, a suitable group that may be carried through the reaction scheme and replaced as appropriate with the desired substituent. Furthermore, one of skill in the art will recognize that the transformations shown in the schemes below may be performed in any order that is compatible with the functionality of the particular pendant groups. Each of the reactions depicted in the general schemes is preferably run at a temperature from about 0 °C to the reflux temperature of the organic solvent used.

[0271] The methods of the present disclosure generally provide a specific enantiomer or diastereomer as the desired product, although the stereochemistry of the enantiomer or diastereomer was not determined in all cases. When the stereochemistry of the specific stereocenter in the enantiomer or diastereomer is not determined, the compound is drawn without showing any stereochemistry at that specific stereocenter even though the compound can be substantially enantiomerically or disatereomerically pure.

[0272] Representative syntheses of compounds of the present disclosure are described in the schemes below, and the particular examples that follow.

List of Abbreviations and Acronyms

ACN acetonitrile

aq aqueous

BH ₃ SMe ₂ Borane complex with Dimethylsulfide

Bn Benzyl

BOPC1 bis(2-oxo-3-oxazolidinyl)phosphinic chloride

brine water saturated with sodium chloride

°C degrees Celsius

calc’d calculated

CH2CI2 di chi or om ethane

CS2CO3 Cesium Carbonate

Cul Copper(I) Iodide

C11SO4 Copper(II) Sulfate

Cy ₂ NMe Dicyclohexylmethylamine

DBU l,8-diazabicyclo[5.4.0]undec-7 -ene

DCC Dicyclohexylcarbodiimide

DCM dichloromethane

DMAP 4-(N,N-dimethylamino)-Pyridine

DMF N,N-dimethylformamide

ESI Electrospray Ionization

Et Ethyl

Et ₃ N Triethylamine

Et ₂ 0 Diethyl ether

EtOAc Ethyl Acetate H ₂ Molecular Hydrogen

HC1 Hydrogen Chloride or Hydrochloric Acid

H ₂ O Water

H ₂ SO ₄ Sulfuric Acid

LCMS liquid chromatography mass spectrometry

LiHMDS Lithium Hexamethyldisilazide

Me Methyl

MeCN Acetonitrile

MeOH Methanol

MgS0 ₄ Magnesium Sulfate

MsCl Methanesulfonyl chloride

MTBE Methyl, tert-butyl ether

N ₂ Molecular Nitrogen

NaH Sodium Hydride

NaHCOs Sodium Hydrogen Carbonate or Sodium Bicarbonate

NaI0 ₄ Sodium Periodate

NaOH Sodium Hydroxide

Na ₂ S0 ₄ Sodium Sulfate

NBS N-bromosuccinimide

NH ₄ C1 Ammonium Chloride

NMR Nuclear Magnetic Resonance

0s0 ₄ Osmium(VIII) Oxide or Osmium Tetraoxide

PCC Pyridinium Chlorochromate

PDC Pyridinium Dichromate

Pd/C Palladium on Carbon

Pd(OAc) ₂ Palladium(II) Acetate

Pd(PPh ₃ ) ₂ Cl ₂ Palladium(II) Dichloride bis-Triphenylphosphine complex

Pd(t-Bu ₃ P) ₂ Palladium(O) bis(tri-tert-Butylphosphine) complex

Ph Phenyl

PhI(OAc) ₂ (Diacetoxyiodo)benzene or iodosobenzene diacetate

POCl ₃ Phosphorus(V) Oxychloride

RT room temperature

SFC Supercritical Fluid Chromatography

Si0 ₂ Silica or Silica gel S.M. Starting Material

SOCh Thionyl Chloride

TBAF tetra-n-butylammonium fluoride

TBDPS tert-butyl diphenyl silyl

tBuOOH tert-butyl hydroperoxide

TEMPO tetram ethyl pi p eri di ne-N- oxyl radi cal .

TFA Trifluoroacetic acid

THF Tetrahydrofuran

TLC Thin layer chromatography

3 A MS 3 Angstrohm Molecular Sieves

General Synthetic Schemes

[0273] General Reaction Scheme I is provided as further embodiments of the present disclosure and illustrate general methods which were used to prepare certain compounds of the present disclosure and which can be used to prepare additional compounds of the present disclosure. Each of the variables (e.g. R ¹ , R ² , R ³ , R ⁴ ) of formulas C l, C3, FB-C, FB I, FB2,

FB3, FB4, and FB5 are as defined herein.

[0274] The compounds of the present disclosure may be prepared using the methods disclosed herein and routine modifications thereof, which will be apparent to a skilled artisan given the disclosure herein and methods well known in the art. Conventional and well-known synthetic methods may be used in addition to the teachings herein. The synthesis of typical compounds described herein may be accomplished as described in the following examples. If available, reagents may be purchased commercially, e.g., from Sigma Aldrich or other chemical suppliers. In general, compounds described herein are typically stable and isolatable at room temperature and pressure.

[0275] Typical embodiments of compounds disclosed herein may be synthesized using the general reaction schemes described below. It will be apparent to a skilled artisan given the description herein that the general schemes may be altered by substitution of the starting materials with other materials having similar structures to result in products that are

correspondingly different. Descriptions of syntheses follow to provide numerous examples of how the starting materials may vary to provide corresponding products. Given a desired product for which the substituent groups are defined, the necessary starting materials generally may be determined by inspection. Starting materials are typically obtained from commercial sources or synthesized using published methods. For synthesizing compounds which are embodiments disclosed in the present disclosure, inspection of the structure of the compound to be synthesized will provide the identity of each substituent group. The identity of the final product will generally render apparent the identity of the necessary starting materials by a simple process of inspection, given the examples herein.

[0276] The terms“solvent”,“inert organic solvent”, or“inert solvent” refer to a solvent inert under the conditions of the reaction being described in conjunction therewith (including, for example, benzene, toluene, acetonitrile, tetrahydrofuran (“THF”), dimethylformamide (“DMF”), chloroform, methylene chloride (or di chi orom ethane), diethyl ether, methanol, and the like). Unless specified to the contrary, the solvents used in the reactions of the present disclosure are inert organic solvents, and the reactions are carried out under an inert gas, preferably nitrogen or argon.

General Reaction Scheme I

Formula 1

[0277] The general scheme depicts general methods to make compounds of Formula 1.

Compound Cl is a molecule in which PG ¹ and PG ² are each independently a hydrogen atom or protecting group known to those skilled in the art, and wherein PG ¹ and PG ² may be the same or different. Compound Cl may be racemic or enantioenriched to a degree, having R or S stereochemistry in the lactone ring as shown in cases where PG ¹ and PG ² are different.

Compound Cl is treated with a base followed by a carbonyl-containing Compound C2 having groups R ³ and R ⁴ as defined herein. Activation of the intermediate aldol addition product, commonly with dicyclohexylcarbodiimide and a copper salt promoter, or alternatively with a sulfonyl chloride is followed by elimination to give aldol condensation product Compound C3. Compound C3 is treated with an additive, commonly an acid, to remove PG ¹ , and the additive may also remove or change the identity of PG ² to give Compound FB-C. In cases where both PG ¹ and PG ² are silyl-type groups, the fluoride source, such as tetra -//-butyl a monium fluoride may be used to remove both silyl groups from Compound C3, giving a version of Compound FB-C where both PG ¹ and PG ² are hydrogen atoms. Separately, Compound FBI, with groups A, L, R ¹ , and alkyl as defined herein is treated with an appropriate R ² -containing alkyne

Compound FB2 in the presence of a palladium catalyst and optionally a copper salt promoter or additive such as a trialkylamine base to give Sonogashira product Compound FB3. In cases where the alkyl group of Compound FB3 is methyl or ethyl treatment with a base such as lithium hydroxide or sodium hydroxide in the presence of water and a cosolvent system can provide Compound FB4. Alternatively, when the alkyl group of Compound FB3 is t-butyl group, an acid, such as boron trichloride, may be used to convert Compound FB3 into

Compound FB4. In some but not all cases Compound FB4 may be subjected to chiral chromatography to give enantioenriched and or diastereomerically enriched versions of

Compound FB4. The terminal carboxylic acid group of Compound FB4 is activated, commonly with oxalyl chloride (giving an intermediate acid chloride) or with a

chlorophosphorane, followed by addition to Compound FB-C optionally in the presence of a base to give Compound FB5. In the cases where PG ² is not a proton, a step is needed to remove PG ² from Compound FB5 and commonly the protecting group itself is removed by treatment with a Lewis Acid such as boron trichloride to give compounds of Formula I. In cases of

Compound FB5 where PG ² is a hydrogen atom, Compound FB5 is effectively a compound of Formula I in and of itself.

VIII. Examples

[0278] Exemplary chemical entities of the present disclosure are provided in the specific examples that follow. Those skilled in the art will recognize that, to obtain the various compounds herein, starting materials may be suitably selected so that the ultimately desired substituents will be carried through the reaction scheme with or without protection as appropriate to yield the desired product. Alternatively, it may be necessary or desirable to employ, in the place of the ultimately desired substituent, a suitable group that may be carried through the reaction scheme and replaced as appropriate with the desired substituent.

Furthermore, one of skill in the art will recognize that the transformations shown in the schemes below may be performed in any order that is compatible with the functionality of the particular pendant groups. [0279] The Examples provided herein describe the synthesis of compounds disclosed herein as well as intermediates used to prepare the compounds. It is to be understood that individual steps described herein may be combined. It is also to be understood that separate batches of a compound may be combined and then carried forth in the next synthetic step.

[0280] In the following description of the Examples, specific embodiments are described. These embodiments are described in sufficient detail to enable those skilled in the art to practice certain embodiments of the present disclosure. Other embodiments may be utilized and logical and other changes may be made without departing from the scope of the disclosure. The following description is, therefore, not intended to limit the scope of the present disclosure.

Compound Q1

[0281] Compound Q1B: At -78 °C, to a THF solution (10 mL) of Compound Q1A (2.2 g, 15.5 mmol) was added dropwise vinylmagnesium bromide (31 mL, 1 M in THF). The reaction mixture was allowed to reach RT and stirred for 1 hour. The reaction was quenched by the slow addition of MLCl aq. (15 mL, saturated). The resulting mixture was extracted with Et ₂ 0 (100 mL) and the combined organic layers were washed with water and brine, dried over MgSCri and concentrated in vacuo. The residue was purified by flash column chromatography (silica, EtO Ac/Hexanes). Compound Q1B. LCMS ESI ⁺ calc’d for C11H22O : 171.2 [M+H ⁺ ] ; found: compound does not ionize. ¾NMR (400 MHz, chloroform-<7i) d 5.84 (dd, J= 17.3, 10.8 Hz, 1H), 5.21 (dd, J= 17.3, 1.5 Hz, 1H), 5.09 (dd, J= 10.8, 1.4 Hz, 1H), 1.78 - 1.66 (m, 2H), 1.48 - 1.36 (m, 4H), 0.96 - 0.88 (m, 12H).

[0282] Compound QIC: A stirred solution of PCC (6.8 g, 31.8 mmol) in DCM (50 mL, dried over 3 A MS) was stirred at RT and to the solution was slowly added Compound Q1B (1.8 g, 10.6 mmol, 10 mL DCM solution). The reaction mixture was stirred at RT overnight. The mixture was diluted with Et ₂ 0 (200 mL) and stirred at RT for 1 hour. The mixture was filtered over silica and celite and concentrated. The residue was diluted with Et ₂ 0 (100 mL). The suspension was filtered over silica and Celite, and concentrated. Compound QIC was carried to the next step without further purification. LCMS ESI ⁺ calc’d for C11H20O : 169.2 [M+H ⁺ ] ; found: compound does not ionize. ¾ NMR (400 MHz, chloroform-7i) d 9.97 (d, J= 8.3 Hz, 1H), 5.92 (d, J= 8.2 Hz, 1H), 2.42 (d, J= 7.4 Hz, 2H), 2.06 (dt, J= 8.5, 4.2 Hz, 2H), 1.86 (dp, J = 13.4, 6.7 Hz, 2H), 0.95 (d, J= 6.6 Hz, 6H), 0.91 (d, 7= 1.6 Hz, 3H), 0.90 (app. s, 3H).

[0283] Compound Ql: Crude Compound QIC (1.8 g, 10.7 mmol) was dissolved in

DCM (20 mL) and to this solution was added Pd/C (360 mg, 10% on charcoal). The reaction was stirred under 1 atm of ¾ for 3 hours. The reaction mixture was filtered and concentrated to give Compound Ql. LCMS ESI ⁺ calc’d for C11H22O : 171.2 [M+H ⁺ ] ; found: compound does not ionize. ¾ NMR (400 MHz, chloroform-^) d 9.74 (t, J= 2.5 Hz, 1H), 2.29 (dt, J= 6.3, 3.1 Hz, 2H), 2.12 - 2.03 (m, 1H), 1.61 (dp, 7= 19.8, 6.6 Hz, 2H), 1.21 - 1.06 (m, 4H), 0.88 (app. s, 6H), 0.87 (app. s, 3H), 0.85 (app. s, 3H).

Compound Q2

[0284] Compound Q2B: 7¾r/-butylchlorodiphenylsilane (63.5 mL, 244 mmol) was added over a period of 1 h to an ice-cooled solution of Compound Q2A (10.0 g, 111 mmol) and DMAP (3.39 g, 27.8 mmol) in dry pyridine (140 mL). The reaction mixture was allowed to warm to rt, and stirred for 16 hours. The reaction mixture was poured into ice-water (600 mL) and stirred for 1 hour. The precipitated solid was filtered and washed with 400 mL of water followed by 200 mL of MeCN. The resulting material was then stirred in 200 mL of MeCN for 30 minutes and collected by filtration. The filtrate was then dried in vacuo to afford Compound Q2B ¾ NMR (400 MHz, CDCh) d 7.60 - 7.55 (m, 8H), 7.45 - 7.39 (m, 4H), 7.38 - 7.31 (m, 8H), 4.40 (s, 4H), 1.01 (s, 18H). LCMS ESI ⁺ calc’d for CssH^ChSh: 567.3 [M+H ⁺ ] ; Found:

585.3 [M+H ₂ 0+H ⁺ ]

[0285] Compound Q2C: A stirred solution of Compound Q2B (10.00 g, 17.64 mmol) in dry THF (90 mL) at 0 °C was added dropwise to a solution of allylmagnesium bromide (1.0 M in Et ₂ 0, 26.5 mL, 123 mmol) over a period of 10 min. The reaction mixture was stirred at 0 °C for an additional 1 h, the reaction was quenched with IN HC1 (50 mL). 100 mL of EtOAc was added and the aqueous layer was removed. The organic extract was washed 2 times with water and once with brine. The organic layer was dried over sodium sulfate, condensed and purified by column chromatography (0-20% EtOAc in Hexanes, 220g column). Compound Q2C ¾ NMR (400 MHz, CDCh) d 7.69 - 7.60 (m, 8H), 7.45 - 7.38 (m, 4H), 7.38 - 7.30 (m, 8H), 5.83 - 5.67 (m, 1H), 5.08 - 4.95 (m, 2H), 3.63 (ddd, J= 21.5, 9.8, 1.6 Hz, 4H), 2.52 (d, J =

1.3 Hz, 1H), 2.33 (d, J= 7.1 Hz, 2H), 1.03 (s, 18H). LCMS EST calc’d for C ₂₀ H ₂₂ O ₅ :

CssH^ChSh: 607.3 [M-H ] ; Found: 607.7 [M-H ].

[0286] Compound Q2D: A stirred solution of Compound Q2C (9.02 g, 14.8 mmol) in dry THF (99 mL) at -78 °C was treated dropwise with a THF solution of B¾ SMe ₂ (2.0 M in THF, 14.8 mL, 29.6 mmol) while being maintained under a blanket of N ₂ . The reaction mixture was stirred at rt for 6 h after the addition, and then it was concentrated in vacuo. The residue obtained was dissolved in dry DCM (400 mL) and treated with pyridinium dichlorochromate (79.8 g, 370 mol). The mixture was stirred at rt for 24 h. 15 more equivalents of PCC were added and the solution was stirred for 22 hours. 15 more equivalents of PCC were added and the reaction was stirred for 16 hours. The reaction was filtered on a silica pad and washed several time with DCM. The resulting solution was condensed and purified by column chromatography (0-20% EtOAc in hexanes, 220g column) giving Compound Q2D. ¹ H MR (400 MHz, CDCh) d 7.64 - 7.56 (m, 8H), 7.45 - 7.39 (m, 4H), 7.36 (d, J= 7.5 Hz, 8H), 3.72 (d, J= 10.8 Hz, 2H), 3.64 (d, J= 10.9 Hz, 2H), 2.62 (t, J= 8.5 Hz, 2H), 2.16 (d, J= 8.8 Hz, 2H), 1.01 (s, 18H).

LCMS ESI ⁺ calc’d for C ₃₈ H ₄₆ 0 ₄ Si ₂ : 623.3 [M+H ⁺ ] ; Found: 641.3 [M+H ₂ 0+H ⁺ ].

[0287] Compound Q2F: To a solution of Compound Q2D (4.23 g, 6.79 mmol) in 28 mL of THF was added LiHMDS (10.19 mL, 1.0 M in THF 10.19 mmol) dropwise at -78 °C, then the reaction was stirred at the same temperature for 60 min, after which acetone (2.49 mL, 33.95 mmol) was added to the reaction solution slowly. After 30 min, the reaction was quenched with saturated aqueous NH ₄ CI solution (25 mL). The mixture was diluted with 75 mL of EtOAc and 25 mL of a saturated solution of ammonium chloride. The aqueous layer was removed and the organic phase was washed with a saturated solution of ammonium chloride followed by brine. The organic layer was dried and condensed to afford the crude product, Compound Q2E. The crude product was diluted in 27 mL of DCM. Et3N (4.73 mL, 33.95 mmol) was added and the solution was cooled to 0 °C and MsCl (1.05 mL, 13.58 mmol) was added dropwise. The reaction was stirred at this temperature for 30 mins and at room temperature for 90 mins. One equivalent of MsCl was added and the reaction was allowed to stir at room temperature for 30 mins. Another equivalent of MsCl was added and the reaction was stirred at room temperature for 20 minutes. The reaction was cooled to 0 °C and DBU (5.08 mL, 33.95 mmol) was added dropwise. The reaction mixture was allowed to stir at room temperature for 2 hours. The reaction mixture was diluted with 75 mL of EtOAc and washed twice with a saturated solution of ammonium chloride followed by brine. The organic phase was dried, condensed and purified by flash chromatography to afford crude Compound Q2F. The product was taken as is for the next step. LCMS ESI ⁺ calc’d for C _4i H ₅ o0 ₄ Si ₂ : 663.3 [M+H ⁺ ] ; found : compound does not ionize.

[0288] Compound Q2: To a crude solution of Compound Q2F (4.502 g, 6.79 mmol) in

THF (136 mL) was added TBAF (13.58 mL, 1 M in THF, 13.58 mmol) at 0 °C, then the reaction was allowed to warm to room temperature for 45 minutes. The reaction mixture was

concentrated and purified by column chromatography (80g column, 0-10 % MeOH in DCM) to afford crude Compound Q2. The mixture was re-purified using a gradient of 50% EtOAc in hexanes to EtOAc (40g column) and Compound Q2 was obtained. ¾ NMR (400 MHz, CDCb) d 3.76 (dd, J= 12.0, 6.8 Hz, 2H), 3.68 (dd, J= 12.0, 6.4 Hz, 2H), 2.73 (dd, J= 2.1, 1.7 Hz, 2H), 2.42 (b s, 1H), 2.25 (t, J= 2.1 Hz, 3H), 1.88 (d, J= 1.3 Hz, 3H), 1.67 (b s, 1H). LCMS ESI ⁺ calc’d for C9H14O4: 187.1 [M+H ⁺ ] ; found: 187.3 [M+H ⁺ ]

Compound 03

[0289] Compound Q3C: A vessel was charged with Compound Q3A (20.0 g, 90.9 mmol, 1.00 eq ) in DMF (308 mL). Compound Q3B (18.4 g, 94.5 mmol, 1.04 eq ) and CS2CO3 (44.4 g, 136 mmol, 1.50 eq) were added to the solution. The reaction was stirred at 25°C for 16 h. Reaction was diluted with H2O (200 mL). System was extracted with EtOAc (3 x 200 mL), and the organic layers dried over Na ₂ SC> _4. The solution was concentrated under reduced pressure to provide crude Compound Q3C (30.0 g, crude). ¹ H NMR: (CDCb, 400 MHz): d, 7.54 (d, J = 8.8 Hz, 2H), 6.66 (d, J= 8.4 Hz, 2H), 4.18-4.12 (m, 2H), 3.98-3.95 (m, 2H), 2.52-2.48 (m, 2H), 2.11-2.08 (m, 2H), 1.28-1.24 (m, 3H).

[0290] Compound Q3D: A vessel was charged with Compound Q3C (5.00 g, 14.9 mmol, 0.98 eq ), 4-ethynyl-l-tButyl benzene (2.42 g, 15.2 mmol, 1.00 eq ), and THF (50.0 mL). Pd(PPh3)2Ch (214 mg, 0.305 mmol, 0.02 eq), Cul (116 mg, 0.610 mmol, 0.04 eq) and Et3N (2.24 g, 22.1 mmol, 1.45 eq) were added to the solution. The system was degassed and purged with N2 a total of 3 times. Reaction was stirred at 25°C under N2 for 16 h. Reaction was filtered and the organic phase of the filtrate was concentrated. The resulting residue (3.2 g) was stirred with n-hexane (6.00 mL) for 16 h. Filtration provided Compound Q3D. ¾ NMR: (CDCI3, 400 MHz): d 7.46-7.44 (m, 4H), 7.37-7.27 (m, 2H), 6.86 (d, J= 8.4 Hz, 2H), 4.17-4.15 (m, 2H), 4.05-4.01 (m, 2H), 2.54-2.51 (m, 2H), 2.14-2.10 (m, 2H), 1.33 (s, 9H), 1.29-1.25 (m, 3H).

[0291] Compound Q3: A vessel was charged with Compound Q3D (1.70 g, 4.66 mmol, 1.00 eq) in THF (17.0 mL) and H2O (17.0 mL). NaOH (3.73 g, 93.2 mmol, 20.0 eq) was added to the solution. Reaction was stirred at 70°C for 16 h. The mixture was concentrated under reduced pressure to remove THF. The mixture was dispersed in CH2CI2 (5.00 mL) and stirred for 1 h, then filtered to provide a cake. The cake was diluted with CH2CI2 (20.0 mL) and acidified with 3M HC1 solution to pH=3. The cake was slurried in CH2CI2 and filtered (3 x 20.0 mL). The combined filtrates were concentrated to provide Compound Q3. LCMS ESI ⁺ calc’d for C22H24O3 : 337.2 [M+H ⁺ ] ; found 337.2 [M+H ⁺ ] ¾ NMR (400 MHz, dmso-^e) d 7.45-7.42 (m, 6H), 6.95 (d, J= 8.8 Hz, 2H), 4.02-3.99 (m, 2H), 2.50-2.48 (m, 2H), 2.34-2.30 (m, 2H), 1.27 (s, 9H).

Compound 04

[0292] Compound Q4A: A vessel was charged with Compound Q3C (5.00 g, 14.9 mmol, 0.98 eq), ethynylbenzene (1.56 g, 15.2 mmol, 1.00 eq), and THF (50.0 mL). Pd(PPh3)2Ch (214 mg, 0.305 mmol, 0.02 eq ), Cul (116 mg, 0.610 mmol, 0.04 eq) and Et3N (2.24 g, 22.1 mmol, 1.45 eq) were added to the solution. The system was degassed and purged with N2 a total of 3 times. Reaction was stirred at 25°C under N2 for 16 h. Reaction was filtered and the organic phase of the filtrate was concentrated. The resulting residue was purified by column

chromatography (S1O2, Petroleum ether/Ethyl acetate=20/l to 2/1), giving Compound Q4A. 'H NMR: (CDCb, 400 MHz): d 7.50-7.30 (m, 7H), 6.85-6.83 (m, 2H), 4.16-4.11 (m, 2H), 4.03-4.00 (m, 2H), 2.52-2.48 (m, 2H), 2.14-2.08 (m, 2H), 1.26-1.22 (m, 3H).

[0293] Compound Q4: A vessel was charged with Compound Q4A (2.50 g, 8.11 mmol, 1.00 eq) in THF (25.0 mL) and H2O (25.0 mL). NaOH (6.49 g, 162 mmol, 20.0 eq) was added to the solution. Reaction was stirred at 70°C for 16 h. The mixture was concentrated under reduced pressure to remove THF. The mixture was dispersed in CH2CI2 (5.00 mL) and stirred for 1 h, then filtered to provide a cake. The cake was diluted with CH2CI2 (20.0 mL) and acidified with 3M HC1 solution to pH=3. The cake was slurried in CH2CI2 and filtered (3 x 20.0 mL). The combined filtrates were concentrated, triturated with MTBE (3.00 mL), and filtered to provide Compound Q4. LCMS ESI ⁺ calc’d for C18H16O3 : 281.1 [M+H ⁺ ] ; found 281.1

[M+H ⁺ ] ¾ NMR (400 MHz, dmso-i/e) d 12.17 (s, 1H), 7.52-7.39 (m, 7H), 6.97 (d, J= 8.8 Hz, 2H), 4.03-4.00 (m, 2H), 2.50-2.40 (m, 2H), 1.97-1.91 (m, 2H). Compound 05

[0294] Compound Q5B: Compound Q5A (12.3 g, 105 mmol, 1.00 eq) was placed in a vessel and 4-iodophenol (22.8 g, 103 mmol, 0.98 eq) in THF (370 mL) was added. Cul (806 mg, 4.24 mmol, 0.04 eq), Pd(PPh ₃ ) ₂ Ch (1.49 g, 2.12 mmol, 0.02 eq) and Et3N (15.5 g, 153 mmol,

1.45 eq) were added to the solution. System was degassed and was purged with N2 a total of 3 times. Reaction was stirred at 25°C under N2 for 16 h. Mixture was filtered to give an organic layer. Organic layer was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (S1O2, Petroleum ether/Ethyl acetate = 100/1 to 20/1) giving Compound Q5B. The material was used in the next step.

[0295] Compound Q5C: A vessel was charged with Compound Q5B (6.00 g, 28.8 mmol, 1.00 eq) and DMF (95.0 mL). Ethyl 6-bromohexanoate (6.69 g, 29.9 mmol, 1.04 eq) and CS2CO3 (14.0 g, 43.2 mmol, 1.50 eq) were added. Reaction was stirred at 25°C under N2 for 16 h. Reaction was diluted with H2O (200 mL) and extracted with EtOAc (3x 200 mL). Combined organic layers were dried over Na ₂ SC> ₄ , filtered, and concentrated. The resulting residue was purified by column chromatography (S1O2, Petroleum ether/Ethyl acetate=20/l to 2/1), giving Compound Q5C LCMS ESI ⁺ calc’d for C23H26O3 : 351.2 [M+H ⁺ ] ; found 351.2 [M+H ⁺ ] ¾ NMR: (CDCb, 400 MHz): d 7.46-7.39 (m, 4H), 7.22-7.20 (m, 2H), 6.96-6.94 (m, 2H), 4.12-4.10 (m, 2H), 4.00-3.97 (m, 2H), 2.20-2.15 (m, 5H), 1.89-1.79 (m, 2H), 1.78-1.66 (m, 2H), 1.60-1.55 (m, 2H), 1.29-1.20 (m, 3H).

[0296] Compound Q5: A vessel was charged with Compound Q5C (6.10 g, 17.4 mmol, 1.00 eq) in THF (60.0 mL) and H2O (60.0 mL). NaOH (13.9 g, 348 mmol, 20.0 eq) was added to the solution. Reaction was stirred at 70°C for 16 h. The mixture was concentrated under reduced pressure to remove THF. The mixture was dispersed in CH2CI2 (60.0 mL) and stirred for 1 h, then filtered to provide a cake. The cake was diluted with CH2CI2 (60.0 mL) and acidified with 3M HC1 solution to pH=3. The slurry was filtered. The filtrates were concentrated to provide Compound Q5. LCMS ESI ⁺ calc’d for C21H22O3 : 323.2 [M+H ⁺ ] ; found 323.1

[M+H ⁺ ] ¾ NMR (400 MHz, dmso-^e) d 12.01 (s, 1H), 7.46-7.39 (m, 4H), 7.22-7.20 (m, 2H), 6.96-6.94 (m, 2H), 4.00-3.97 (m, 2H), 2.32 (s, 3H), 2.25-2.21 (m, 2H), 1.73-1.69 (m, 2H), 1.57- 1.56 (m, 2H), 1.54-1.41 (m, 2H).

Compound 06

Q6

[0297] Compound Q6A: A vessel was charged with Compound Q5B (4.70 g, 22.5 mmol, 1.00 eq ) and DMF (75.0 mL). Compound Q3B (4.58 g, 23.4 mmol, 1.04 eq ) and CS2CO3 (11.0 g, 33.8 mmol, 1.50 eq) were added. Reaction was stirred at 25°C under N2 for 16 h.

Reaction was diluted with H2O (200 mL) and extracted with EtOAc (3x 200 mL). Combined organic layers were dried over Na ₂ SC> ₄ , filtered, and concentrated. The resulting residue was treated with n-hexane (12.0 mL), captured via filtration, and dried under reduced pressure giving Compound Q6A, which was immediately used in the next reaction.

[0298] Compound Q6: A vessel was charged with Compound Q6A (3.00 g, 9.31 mmol, 1.00 eq) in THF (30.0 mL) and H2O (30.0 mL). NaOH (7.44 g, 186 mmol, 20.0 eq) was added to the solution. Reaction was stirred at 70°C for 16 h. The mixture was concentrated under reduced pressure to remove THF. The mixture was dispersed in CH2CI2 (30.0 mL) and stirred for 1 h, then filtered to provide a cake. The cake was diluted with CH2CI2 (30.0 mL) and acidified with 3M HC1 solution to pH=3. The slurry was filtered. The filtrate was concentrated, triturated with n-hexane (5.00 mL), and filtered. Drying the cake in vacuo provided Compound Q6. LCMS ESI ⁺ calc’d for C19H18O3 : 295.1 [M+H ⁺ ] ; found 295.1 [M+H ⁺ ] ¾ NMR (400 MHz, dmso-i/e) d 12.13 (s, 1H), 7.42 (d, J= 8.8 Hz, 2H), 7.37 (d, J= 8.0 Hz, 2H), 7.18 (d, J = 8.4 Hz, 2H), 6.93 (d, J= 8.8 Hz, 2H), 4.00-3.97 (m, 2H), 2.37-2.33 (m, 2H), 2.29 (s, 3H), 1.92- 1.89 (m, 2H). Compound 07

[0299] Compound Q7B: A vessel was charged with Compound Q5A (5.00 g, 43.0 mmol, 1.00 eq), Compound Q7A (11.8 g, 43.0 mmol, 1.00 eq ) and THF (50.0 mL). Cul (327 mg, 1.72 mmol, 0.04 eq ), Pd(PPh ₃ ) ₂ Ch (604 mg, 860 umol, 0.02 eq), and Et3N (6.32 g, 62.41 mmol, 1.45 eq) were added to the solution. The reaction mixture was stirred at 25°C under N2 for 16 h. The reaction was filtered and the organic layer of the filtrate was collected. The organic layer was concentrated to provide a residue, which was purified by column chromatography (S1O2, Petroleum ether/Ethyl acetate=100/l to 20/1) providing Compound Q7B.

[0300] Compound Q7: A vessel was charged with Compound Q7B (3.80 g, 14.3 mmol, 1.00 eq) in THF (40.0 mL) and H2O (40.0 mL). NaOH (11.5 g, 287 mmol, 20.0 eq) was added to the solution. The reaction was stirred at 70°C for 16 h. The system was concentrated under reduced pressure. The mixture was treated with DCM (15.0 mL) for 1 h and filtered. The cake was treated with DCM (50.0 mL) and H2O (50.0 mL), then acidified with 3M HC1 to pH = 3. The system was filtered once more. The filtrate was allowed to separate, and the organic phase was concentrated in vacuo, providing Compound Q7. LCMS ESI ⁺ calc’d for C16H12O2 : 237.1 [M+H ⁺ ] ; found 237.1 [M+H ⁺ ] ¾ NMR (400 MHz, dmso-i/e) d 7.91 (d, J= 8.0 Hz, 2H), 7.54 (d, J= 8.0 Hz, 2H), 7.46 (d, J= 8.0 Hz, 2H), 7.25 (d, J= 8.0 Hz, 2H), 2.34 (s, 3H).

Compound 08

[0301] Compound Q8B: A vessel was charged with Compound Q8A (10.0 g, 56.1 mmol, 1.00 eq), HIO ₄ (2.56 g, 11.2 mmol, 2.56 mL, 0.20 eq), and I ₂ (5.70 g, 22.4 mmol, 4.52 mL, OAOeq). A solution of H ₂ SO ₄ (2.50 mL), AcOH (82.0 mL) and H ₂ O (18.0 mL) was added to the mixture. The system was degassed and purged by N2 (3x). The reaction was stirred at 75°C for 16 h. The reaction was cooled to room temperature. Deionized water (50.0 mL) was added to the solution, which was filtered to give a cake. The cake was treated with DCM (100 mL) then washed with deionized water (2 x 50.0 mL) and sodium thiosulfate (2 x 50.0 mL). The organic layer was dried over Na2SC>4 and filtered. The filtrate was concentrated under reduced pressure to provide crude Compound Q8B. ¹ H NMR (400 MHz, dmso-i¾) d 11.98 (s, 1H), 7.61 (d, J= 8.0 Hz, 2H), 7.01 (d, J= 8.4 Hz, 2H), 2.54-2.50 (m, 2H), 2.23-2.19 (m, 2H), 1.54-1.47 (m, 4H).

[0302] Compound Q8C: A vessel was charged with Compound Q8B (12.0 g, 39.4 mmol, 1.00 eq) and MeOH (80.0 mL). The solution was cooled to 0 °C in an ice bath. SOCb (7.04 g, 59.1 mmol, 4.29 mL, 1.50 eq) was added dropwise. Reaction was stirred at 20 °C for 2 h. The reaction was concentrated in vacuo, and the resulting residue was dissolved in DCM (50.0 mL). The system was washed with H2O (2 x 20.0 mL), dried over Na ₂ SC> ₄ , and filtered. The filtrate was concentrated to obtain Compound Q8C.

[0303] Compound Q8D: A vessel was charged with Compound Q8C (5.00 g, 15.7 mmol, 1 eq) and Compound Q5A (1.90 g, 16.3 mmol, 1.04 eq) in THF (35.0 mL). Cul (119 mg, 628 umol, 0.04 eq), Pd(PPh ) ₂ Cl ₂ (220 mg, 314 umol, 0.02 eq) and Et N (2.31 g, 22.7 mmol, 3.17 mL, 1.45 eq) were added to the solution. The system was degassed and purged with N ₂ (3X). The reaction mixture was stirred at 25°C under N ₂ for 16 h. The mixture was filtered. The organic layer of the filtrate was concentrated under reduced pressure, and the resulting residue was purified by column chromatography (Si0 ₂ , Petroleum ether/Ethyl acetate=20/l to 1/1), giving Compound Q8D. LCMS ESI ⁺ calc’d for C _2i H ₂₂ 0 ₂ : 307.2 [M+EC] ; found 307.1 [M+EC] ¾ NMR (400 MHz, dmso-i/e) d 7.43 (t, J= 6.4 Hz, 4H), 7.22 (d, J= 8.0 Hz, 4H), 3.57 (s, 3H), 2.60 (t, J= 6.0 Hz, 2H), 2.32-2.31 (m, 5H), 1.57-1.52 (m, 4H).

[0304] Compound Q8: A vessel was charged with Compound Q8D (3.30 g, 10.7 mmol, 1.00 eq) in THF (33.0 mL) and H ₂ 0 (33.0 mL). Then NaOH (8.62 g, 215 mmol, 20.00 eq) was added. The reaction was stirred for 16 h at 70°C. The reaction was concentrated under reduced pressure. DCM (50 mL) was added to the mixture. The system was filtered and the cake was diluted with H ₂ 0 (50.0 mL). 3M HC1 was added until the pH = 3. The system was filtered to give another cake, which was dried in vacuo giving Compound Q8. LCMS ESC calc’d for C ₂₀ H ₂₀ O ₂ : 293.2 [M+H ⁺ ]; found 293.1 [M+H ⁺ ] ¾ NMR (400 MHz, dmso-i¾) d 11.97 (s, 1H), 7.43 (t, J= 7.6 Hz, 4H), 7.24-7.22 (m, 4H), 2.61 (t, J= 7.2 Hz, 2H), 2.33 (s, 3H), 2.23 (t, J= 14 Hz, 2H) 1.58-1.50 (m, 4H).

Compound 09

[0305] Compound Q9B: A vessel was charged with Compound Q9A (10.0 g, 63.2 mmol, 1 eq ) and Compound Q3A (12.5 g, 56.8 mmol, 0.90 eq ) in THF (100 mL). Cul (240 mg, 1.26 mmol, 0.02 eq ), Pd(PPh3)2Ch (1.77 g, 2.53 mmol, 0.04 eq), and Et3N (9.27 g, 91.6 mmol, 12.7 mL, 1.45 eq) were added to the solution. The system was degassed and purged with N2 (3x). The reaction mixture was stirred at 25°C under N2 for 16 h. The reaction was filtered and the organic layer of the filtrate was collected. The organic layer was concentrated in vacuo and the residue was purified by column chromatography (S1O2, Petroleum ether/Ethyl acetate=20/l to 1/1) providing Compound Q9B. ¾ NMR (400 MHz, dmso- is) d 9.87 (s, 1H), 7.40-7.34 (m, 4H), 7.21 (d, J= 8.4 Hz, 2H), 6.79 (d, J= 6.8 Hz, 2H), 2.59-2.52 (m, 2H), 1.55-1.53 (m, 2H), 1.31-1.29 (m, 2H), 0.90 (t, J= 7.2 Hz, 3H).

[0306] Compound Q9C: A vessel was charged with Compound Q9B (4.00 g, 15.9 mmol, 1.00 eq) in DMF (40.0 mL). Next, Compound Q3B (3.01 g, 16.6 mmol, 1.04 eq) and CS2CO3 (7.81 g, 23.9 mmol, 1.50 eq) were added to the solution. The reaction mixture was stirred at 25°C for 16 h. H2O (50.0 mL) was added to the mixture, which was extracted with Ethyl acetate (3 x 50.0 mL). Combined organic extracts were washed with brine (50.0 mL), dried over Na ₂ S0 ₄ , filtered, and concentrated under reduced pressure. The residue was treated with n-hexane (12.0 mL) for lh. This gave a cake, which was collected via filtration. The cake was dried in vacuo, providing Compound Q9C. ¹ H MR (400 MHz, dmso-i/is) d 7.46-7.40 (m, 4H), 7.22 (d, J= 8.0 Hz, 2H), 6.95 (d, J= 8.8 Hz, 2H), 4.03-4.00 (m, 2H),3.60 (s, 3H), 2.59-2.50 (m,2H), 1.99-1.96 (m, 2H), 1.60-1.55 (m,2H), 1.31-1.29 (m,2H), 0.90 (t, J= 7.2 Hz, 3H).

[0307] Compound Q9: A vessel was charged with Compound Q9C (1.60 g, 4.57 mmol, 1.00 eq) in THF (12.0 mL) and H ₂ 0 (12.0 mL). Then NaOH (3.65 g, 91.3 mmol, 20.00 eq) was added. The reaction was stirred for 16 h at 70°C. The reaction was concentrated under reduced pressure. DCM (30.0 mL) was added to the mixture, which was stirred for 1 h. The system was filtered and the cake was diluted with H2O (30.0 mL). 3M HC1 was added until the pH = 3. The system was filtered to give a cake, which was dried in vacuo giving Compound Q9. ¾ NMR (400 MHz, methanol-^) d 7.42-7.36 (m, 4H), 7.17 (d, J= 8.4 Hz, 2H), 6.91 (d, J = 8.8 Hz, 2H), 2.64-2.60 (m, 2H), 2.49-2.45 (m, 2H), 2.09-2.05 (m, 2H), 1.62-1.58 (m,2H), 1.37-1.35 (m,2H), 0.96-0.92 (m, 3H). Compound Q10

[0308] Compound Q10A: A vessel was charged with Compound Q5B (4.00 g, 19.2 mmol, 1.00 eq ) in DMF (40.0 mL). Methyl 5-bromopentanoate (3.90 g, 19.9 mmol, 2.86 mL, 1.04 eq) and CS2CO3 (9.39 g, 28.8 mmol, 1.50 eq) were added to the solution. Reaction was stirred at 25°C for 16 h. Mixture was diluted with H2O (50.0 mL) and extracted with EtOAc (3 x 50.0 mL). Combined organic extracts were washed with brine (50.0 mL), dried over Na2SC>4, filtered, and concentrated to provide a residue. The residue was treated with n-hexane (12.0 mL) for 1 h. The system was filtered, and the cake was dried in vacuo to provide Compound Q10A. The material was used in the next step. ¾ NMR (400 MHz, dmso-i¾) d 7.45 (d, J= 8.8 Hz, 2H), 7.40 (d, J= 8.0 Hz, 2H), 7.22 (d, J= 8.0 Hz, 2H), 6.96 (d, J= 8.8 Hz, 2H), 4.02-3.99 (m, 2H), 3.59 (s, 3H), 2.41-2.37 (m, 2H), 2.33 (s, 3H), 1.72-1.69 (m, 4H).

[0309] Compound Q10: A vessel was charged with Compound Q10A (3.40 g, 10.5 mmol, 1.00 eq) in THF (25.0 mL) and H2O (25.0 mL). NaOH (8.44 g, 210 mmol, 20.0 eq) was added to the solution. Reaction was stirred at 70°C for 16 h. System was concentrated under reduced pressure. DCM (30.0 mL) was added to the mixture and the system was stirred for 1 h. Filtration provided a cake that was dispersed in H2O (30.0 mL). Acidification to pH = 3 with 3M HC1 gave a new mixture that was subsequently filtrered. The filtered cake was placed under reduced pressure, giving Compound Q10. LCMS ESI ⁺ calc’d for C20H20O3 : 309.1 [M+H ⁺ ] ; found 309.1 [M+H ⁺ ] ¾ NMR (400 MHz, dmso-^e) d 7.45-7.39 (m, 4H), 7.21 (d, J= 8.0 Hz, 2H), 6.95 (d, J= 8.8 Hz, 2H), 4.01-3.98 (m, 2H),2.32 (s, 3H), 2.23-2.20 (m, 2H), 1.74-1.60 (m, 4H). Compound Oil

[0310] Compound QUA: LiHMDS (1.0 M in THF, 2.42 mL, 2.42 mmol) was added dropwise to solution of Compound Q2D (1000 mg, 1.61 mmol) in THF (6.50 mL) at -78°C.

The reaction mixture was allowed to stir for 60 minutes at that temperature. Benzaldehyde (0.82 mL, 8.05 mmol) was then added and the reaction was allowed to stir for another 60 minutes at that temperature. The reaction was quenched by the addition of 5 mL of saturated aqueous NH4CI. 10 mL of EtOAc was added and the phases were separated. The organic phase was washed with water followed by brine. The organic layer was then dried and purified by column chromatography (0-20% EtOAc in hexane, 80 g column) giving Compound Q11A. LCMS ESI ⁺ calc’d for C45H52O5S12 : 729.3 [M+H ⁺ ] ; found 729.0 [M+H ⁺ ] ¹ H NMR (400 MHz, CDCh) d 7.61 - 7.52 (m, 8H), 7.45 - 7.28 (m, 17H), 4.68 (d, J= 9.8 Hz, 1H), 4.64 (s, 1H), 3.62 (d, J = 11.0 Hz, 2H), 3.49 (dd, J= 11.1, 3.2 Hz, 2H), 3.33 - 3.20 (m, 1H), 1.91 - 1.74 (m, 2H), 1.06 - 0.99 (m, 18H).

[0311] Compound Q11B: To a stirred solution of Compound Q11A (355 mg, 0.49 mmol) in dry THF (2.4 mL) at 0 °C was added triphenylphosphine (257 mg, 0.98 mmol) followed by DEAD (0.15 mL, 0.98 mmol). The reaction mixture was stirred at that temperature for 3 hours. The reaction was concentrated and purified by column chromatography (0-20% EtOAc in hexanes, 40 g column), giving Compound Q11B. LCMS ESC calc’d for C45H50O4S12 : 711.3 [M+H ⁺ ] ; found 711.1 [M+H ⁺ ] ¾ NMR (400 MHz, CDCh) d 7.61 - 7.53 (m, 8H), 7.53 - 7.50 (m, 1H), 7.46 - 7.27 (m, 17H), 3.79 (d, J= 10.8 Hz, 2H), 3.70 (d, J= 10.8 Hz, 2H), 3.06 (d, J= 2.6 Hz, 2H), 0.99 - 0.94 (m, 18H).

[0312] Compound Qll: To a stirred solution of Compound Q11B (90 mg, 0.13 mmol) in dry THF (2.5 mL) at 0 °C was added TBAF (1.0 M in THF, 0.39 mL, 0.39 mmol) dropwise. The reaction mixture was stirred at that temperature for 30 minutes. The reaction was concentrated and purified by column chromatography (0-20% MeOH in DCM, 12 g column) giving Compound Qll. LCMS ESI ⁺ calc’d for C13H14O4 : 235.1 [M+H ⁺ ] ; found 235.0

[M+H ⁺ ] ¾ NMR (400 MHz, CDCh) d 7.58 (t, 7= 3.0 Hz, 1H), 7.55 - 7.48 (m, 2H), 7.48 - 7.36 (m, 3H), 3.86 (dd, 7= 12.0, 6.6 Hz, 2H), 3.77 (dd, 7= 12.0, 6.4 Hz, 2H), 3.14 (d, 7= 2.9 Hz, 2H), 1.91 (t, 7= 6.5 Hz, 2H).

[0313] Compound Q12A: To a solution of Compound Q2D (0.200 g, 0.321 mmol) in dry tetrahydrofuran (1.28 mL) cooled to -78 °C under a nitrogen atmosphere was added lithium bis(trimethylsilyl)amide solution (1 M in tetrahydrofuran, 0.48 mL, 0.482 mmol) dropwise and the solution was stirred at -78 °C for 1 h. Compound Q1 (0.109 g, 0.642 mmol) was then added to the mixture and it was stirred an additional 2 h at -78 °C. The reaction was then quenched at - 78 °C with saturated aqueous ammonium chloride (10 mL) and the mixture was diluted with ethyl acetate (25 mL). The phases were separated and the organic layer was dried over sodium sulfate, filtered and concentrated in vacuo , and purified by normal-phase chromatography (0 - 20% ethyl acetate in hexanes) to give Compound Q12A. LCMS ESI ⁺ calc’d for C49H68O5S12: 793.5 [M+LL] ; found 793.5 [M+H ⁺ ] ¾ NMR (400 MHz, CDCh) d 7.62 - 7.57 (m, 8H), 7.46 - 7.32 (m, 12H), 3.90 (t, 7 = 1.7 Hz, 1H), 3.75 - 3.55 (m, 4H), 2.73 (dd, 7 = 19.4, 10.3 Hz, 1H), 2.16 (dt, 7 = 10.1, 8.3 Hz, 1H), 1.90 (dd, 7= 12.7, 10.9 Hz, 1H), 1.77 (dt, 7= 12.6, 6.1 Hz, 1H), 1.71 - 1.60 (m, 1H), 1.48 (ddd, 7= 13.6, 12.6, 5.4 Hz, 1H), 1.36 (dd, 7= 5.9, 0.8 Hz, 1H), 1.16 (tdd, 7= 13.2, 8.7, 4.6 Hz, 1H), 1.03 (s, 9H), 1.02 - 0.99 (m, 9H), 0.97 (td, 7= 6.5, 4.1 Hz, 4H), 0.92 - 0.83 (m, 12H). [0314] Compound Q12: To a solution of Compound Q12A (0.140 g, 0.176 mmol) in toluene (1.51 mL) was added copper(I) bromide (0.0026 g, 0.018 mmol) and

dicyclohexylcarbodiimide (0.055 g, 0.265 mmol). The resulting solution was heated to 110 °C and stirred overnight. The crude product was concentrated in vacuo then dissolved in dichloromethane (0.8 mL). To this solution was added a 1 M solution of tetrabutylammonium fluoride in tetrahydrofuran (0.98 mL, 0.98 mmol) at 0 °C and the solution was allowed to attain room temperature and was stirred overnight. The crude product was concentrated in vacuo and purified by normal -phase chromatography (0 - 100% ethyl acetate in hexanes), then triturated with cold dichloromethane and filtered. The filtrate was concentrated to give Compound Q12. LCMS ESC calc’d for C17H30O4: 298.2 [M+H ⁺ ] ; found 298.3 [M+H ⁺ ]

Compound 013

[0315] Compound Q13B: A vessel was charged with Compound Q13A (10.0 g, 69.3 mmol, 25.0 mL, 1.00 eq ) in CLLCN (70.0 mL). NBS (16.0 g, 90.1 mmol, 1.30 eq) was added to the mixture. The reaction was stirred at 25 °C for 16 h. The reaction was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (S1O2, Petroleum ether/Ethyl acetate = 100/1 to 1/1), providing Compound Q13B. The material was used without further characterization.

[0316] Compound Q13C: A vessel was charged with Compound Q13B (10.0 g, 44.8 mmol, 1.00 eq) in DMF (70.0 mL). To this mixture was added methyl -4-bromobutanoate (8.44 g, 46.6 mmol, 1.04 eq) and CS ₂ CO ₃ (21.9 g, 67.2 mmol, 1.50 eq). The reaction was stirred at 25 °C for 16 h. H ₂ O (200 mL) was added to the mixture, which was then extracted with Ethyl acetate (3 x 200 mL). Combined organic extracts were washed with brine (200 mL), dried over Na ₂ SC> ₄ , filtered, and concentrated to provide a residue. The residue was treated with n-hexane (80.0 mL) for lh, then filtered to obtain a cake. The cake was dried under reduced pressure, giving Compound Q13C. ¾ NMR (400 MHz, dmso-^) d 8.21 (d, J= 8.0 Hz, 1H), 8.06 (d, J = 8.4 Hz, 1H), 7.75 (d, J= 8.0 Hz, 1H), 7.70-7.61 (m, 2H), 7.92 (d, J= 8.4 Hz, 1H), 4.18 (t, J = 5.6 Hz, 2H), 3.60 (s, 3H), 2.60-2.57 (m, 2H), 2.15-2.11 (m, 2H).

[0317] Compound Q13D: A vessel was charged with Compound Q13C (5.60 g, 17.3 mmol, 1.00 eq) and Compound Q5A (2.09 g, 18.0 mmol, 1.04 eq) in THF (40.0 mL). Cul (66.0 mg, 346 umol, 0.02 eq), Pd(PPh3)2Ch (486 mg, 693 umol, 0.04 eq) and Et3N (2.54 g, 25.1 mmol, 3.50 mL, 1.45 eq) were added to the solution. The system was degassed and purged with N2 (3x). The reaction was stirred at 75 °C under N2 for 16 h. The reaction was filtered and the organic layer of the filtrate was collected and concentrated under reduced pressure. The residue was purified by column chromatography (S1O2, Petroleum ether/Ethyl acetate=20/l tol/1), giving Compound Q13D. ¾ NMR (400 MHz, dmso-^e) d 8.30 (d, J= 8.0 Hz, 1H), 8.22 (d, J = 8.4 Hz, 1H), 7.73-7.69 (m, 2H), 7.60-7.60 (m, 1H), 7.54 (d, J= 8.0 Hz, 2H), 7.27 (d, J= 8.0 Hz, 2H), 7.01 (d, J= 8.4 Hz, 1H), 4.23 (t, J= 6.4 Hz, 2H), 3.64 (s, 3H), 2.36-2.32 (m, 2H), 1.19- 1.10 (m, 3H).

[0318] Compound Q13: A vessel was charged with Compound Q13D (2.70 g, 7.53 mmol, 1.00 eq) in THF (20.0 mL) and H ₂ O (20.0 mL). NaOH (6.03 g, 150 mmol, 20.0 eq) was added to the mixture. The reaction was stirred at 70 °C for 16 h. The mixture was concentrated under reduced pressure. The mixture was treated with DCM (30.0 mL) for lh, and filtered to give a cake. The cake was treated with H ₂ O (30.0 mL), followed by acidification with aq HC1 (3M) to pH = 3. The resulting system was filtered, and the cake was dried under reduced pressure giving Compound Q13. LCMS ESI ⁺ calc’d for C ₂₃ H ₂₀ O ₃ : 345.1 [M+H ⁺ ] ; found: compound does not ionize. ¾ NMR (400 MHz, methanol-<¾) d 8.32 (d, J= 8.0 Hz, 1H), 8.29 (d, J= 8.0 Hz, 1H), 7.64 (d, J= 8.0 Hz, 1H), 7.61 (d, J= 7.6 Hz, 1H), 7.54 (d, J= 8.0 Hz, 1H), 7.48 (d, J= 8.0 Hz, 2H), 7.22 (d, J= 8.0 Hz, 2H), 6.93 (d, J= 8.0 Hz, 1H), 4.26 (t, J= 6.4 Hz 2H), 2.61 (t, J= 7.2 Hz, 2H), 2.38 (s, 3H), 2.28-2.22 (m, 2H). Compound 014

[0319] Compound Q14B: At 0 °C, to a solution of Compound Q14A (50 g, 567 mmol) and Et3N (158.19 mL, 1.13 mmol) in CH2CI2 (350 mL) was added trityl chloride (158.19 g, 567 mmol). The reaction was stirred at 0 °C for 1 hour and warmed up to room temperature and stirred for an additional 1 hour. The reaction mixture was diluted with EtOAc (200 mL) and the precipitate was removed by filtration. The filtrate was then washed with H2O (2 x 210 mL).

The aqueous phases were combined and extracted once with EtOAc ( 300 mL). The combined organic layers were washed with brine (200 mL), dried over MgS0 ₄ and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (1 kg) with

EtOAc:hexanes (10-25%) as eluent to give Compound Q14B. LCMS ESI ⁺ calc’d for C23H22O2 : 331.2 [M+H ⁺ ] ; found: does not ionize. ¹ H NMR: (CDCI3, 400 MHz): d 7.48-7.43 (m, 6H), 7.34-7.21 (m, 9H), 5.26 (dd, J= 1.5, 0.7 Hz, 1H), 5.18 (dd, J= 2.4, 1.1 Hz, 1H), 4.17-4.12 (m, 2H), 3.70 (s, 2H), 1.69 (t, J= 6.2 Hz, 1H).

[0320] Compound Q14C: In an oven dried round bottom flask equipped with a magnetic stir bar and a nitrogen inlet was charged dry CH2CI2 (75 mL). The flask was then cooled to -20° C and (+)-diethyl L-tartrate (1.86 mL, 10.9 mmol) and Ti[OCH(CH3)2]4 (2.69 ml, 9.1 mmol) were added sequentially and stirred for 40 min. While still at -20°C, /-BuOOH (5.5 M in nonane, 33 mL, 181 mmol) was added dropwise over 15 minutes and the reaction mixture was stirred for an additional 40 min. A solution of Compound Q14B (30 g, 91 mmol) in CH2CI2 (75 mL) was then added dropwise over 20 min and stirring was continued for 90 min at -20°C (around 75% conversion by LC-MS). The reaction mixture was then treated with a 3M NaOH (300 mL) solution saturated with sodium chloride under vigorous stirring. After 1 h, the reaction mixture was diluted with LhO (1 L) and stirred for 1 h. The mixture was diluted with DCM (500 mL) and the water phase was decanted. The DCM phase was filtered over celite. The filtrate was transferred in a seperatory funnel. The layers were separated and the aqueous phase was washed with CLLCh (2 x 300 mL). The combined organic layers were washed with brine (300 mL), dried over MgSCL, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel with EtOAc:hexanes (20-60%) as eluent to give Compound Q14C. LCMS ESI ⁺ calc’d for C23H22O4 : 347.2 [M+EL] ; found: does not ionize. ¾ NMR: (CDCb, 400 MHz): d 7.47-7.38 (m, 6H), 7.35-7.19 (m, 9H), 3.93 (dd, J= 12.3, 4.7 Hz, 1H), 3.80-3.71 (m, 1H), 3.33-3.24 (m, 2H), 2.88 (t, J= 6.7 Hz, 1H), 2.72 (d, J= 4.8 Hz, 1H), 1.77-1.69 (m, 1H).

[0321] Compound Q14D: To a 0 °C solution of Compound Q14C (25.14 g, 72.6 mmol) in dry DMF (130 mL) was added NaH (3.48 g, 87.1 mmol) in one portion. The solution was stirred for 20 minutes. Benzyl bromide (9.1 mL, 76.2 mmol) was added dropwise at 0 °C over 5 min. The reaction was then stirred at room temperature for 20 min, diluted slowly with water (500 mL) and the organic material was extracted with ethyl acetate (3 x 200 mL). All organic phases were combined and washed with brine (2 x 200 mL). The organic phase was dried over MgSCL, filtered and purified using column chromatography eluting with

EtOAc:hexanes (5-30%, final product come out at around 25% EtOAc in Hexanes) to afford Compound Q14D (90.4% ee). LCMS ESI ⁺ calc’d for C30H28O3 : 437.2 [M+H ⁺ ] ; found: does not ionize. ¹ H NMR: (CDCI3, 400 MHz): d 7.43 (ddd, J= 4.7, 3.7, 0.2 Hz, 6H), 7.33-7.19 (m, 14H), 4.57-4.47 (m, 2H), 3.73 (q, J= 11.0 Hz, 2H), 3.29 (dd, J= 28.6, 10.2 Hz, 2H), 2.76 (dd, J = 19.3, 5.0, 2H).

[0322] Compound Q14E: A solution of Compound Q14D (23 g, 53 mmol) in anhydrous THF (250 mL) was cooled to 0 °C and a solution (2M in THF) of allylmagnesium chloride (66 mL, 131.7 mmol) was added slowly over 30 min, keeping the internal temperature between 2 °C to 5 °C. The reaction was stirred at 2 °C for an extra 1 hour. The reaction was quenched with the addition of saturated aqueous ammonium chloride (400 mL). The aqueous layer was extracted with ethyl acetate (3 x 200 mL). The combined organic extracts were washed with brine (1 x 200 mL), dried over MgSCL, and filtered. The solvent was removed under reduced pressure to afford crude Compound Q14E (92.6% ee) that was used without any further purification for the next step. LCMS ESI ⁺ calc’d for C33H34O3 : 479.3 [M+H ⁺ ] ; found: does not ionize. ¾ NMR: (CDCh, 400 MHz): 5 7.41 (ddd, 7= 4.8, 3.8, 2.1 Hz, 6H), 7.36-7.19 (m, 14H), 5.96-5.65 (m, 1H), 5.20-5.08 (m, 1H), 4.98-4.81 (m, 2H), 4.61-4.49 (m, 2H), 3.66- 3.46 (m, 2H), 3.13 (q, J= 8.7 Hz, 2H), 2.03-1.81 (m, 2H), 1.61 (ddd, J= 10.4, 7.8, 4.6 Hz, 2H).

[0323] Compound Q14F: To a tert-butanol/acetone/water (1 : 1 : 1, 240 mL) room temperature solution of Compound Q14E (24g, 50 mmol) and N-methylmorpholine N-oxide (6.46 g, 55 mmol) was added an aqueous solution of OsCri 4% (1 mL) . The reaction mixture was stirred for 12 h and diluted with EtOAc (500 mL) before being washed with sodium thiosulfate (2 x 250 mL), NH4CI (250 mL, saturated aqueous solution), NaHCCh (250 mL, saturated aqueous solution), brine (250 mL), dried over MgSCh, filtered and concentrated under reduced pressure. Purification using a pad of silica eluting with EtOAc/Hexanes (50-100%) afforded Compound Q14F. LCMS ESI ⁺ calc’d for C33H36O5 : 513.3 [M+H ⁺ ] ; found: does not ionize. ¾ NMR: (CDCh, 400 MHz): 5 7.43-7.37 (m, 6H), 7.37-7.19 (m, 14H), 4.54 (t, J= 6.0 Hz, 2H), 3.66 (dd, J= 8.9, 4.9 Hz, 1H), 3.57 (ddd, J= 11.6, 7.5, 3.8 Hz, 1H), 3.53-3.46 (m, 2H), 3.38-3.28 (m, 1H), 3.21-3.08 (m, 2H), 2.90-2.84 (m, 1H), 2.78 (d, J= 3.8 Hz, 1H), 1.96-1.87 (m, 1H), 1.71-1.62 (m, 2H), 1.40-1.27 (m, 2H).

[0324] Compound Q14G: To a solution of the Compound Q14F (22.3 g, 43.5 mmol) in CH3CN/Water (1 : 1, 250 mL) at 0 °C, was added NalCh (11.2 g, 52.2 mmol). After 90 min, the reaction was diluted with brine (400 mL) and the organic material was extracted with EtOAc (2 X 300 mL). The organic layers were combined, dried over MgS0 ₄ , filtered and concentrated under reduced pressure to afford Compound Q14G that was used without any further purification in the next step. LCMS ESI ⁺ calc’d for C32H32O5 : 481.2 [M+H ⁺ ] ; found: does not ionize. ¾ NMR: (CDCh, 400 MHz): 5 7.47-7.39 (m, 6H), 7.37-7.19 (m, 14H), 5.53-5.38 (m, 1H), 4.67-4.45 (m, 2h), 3.71 (d, J= 8.4 Hz, 1H), 3.57 (dd, J= 25.8, 9.5 Hz, 1H), 3.50-3.40 (m, 1H), 3.32-3.24 (m, 1H), 3.04 (dd, = 25.9, 9.2 Hz, 1H), 2.15-2.04 (m, 1H), 2.04-1.74 (m, 3H).

[0325] Compound Q14: The crude Compound Q14G was diluted with DCM (250 mL), and PDC (32.7 g, 108.8 mmol) was added in one portion at room temperature. The reaction was stirred at room temperature for 48 h and the mixture was diluted with DCM (200 mL). The precipitate was filtered through celite and the filtrate was concentrated under reduced pressure. The crude product was then purified by flash chromatography eluting with EtOAc:Hexanes (10- 40%) to afford Compound Q14 (90.9%). LCMS ESI ⁺ calc’d for C32H30O4 : 479.2 [M+H ⁺ ] ; found: does not ionize. ¾ NMR: (CDCh, 400 MHz): d 7.43-7.39 (m, 6H), 7.35-7.21 (m, 14H), 4.58-4.46 (m, 2H), 3.59 (dd, = 44.8, 10.3 Hz, 2H), 3.23 (dd, 7= 45.1, 9.9 Hz, 2H), 2.69-2.54 (m, 2H), 2.14 (ddd, J= 12.9, 9.9, 7.1 Hz, 1H), 2.08-1.93 (m, 1H).

Compound 015

[0326] Compound Q15A: To a solution of Compound Q14 (500 mg, 1.04 mmol) in

THF (4.2 mL) was added LiHMDS (1.56 mL, 1.0 M in THF 1.56 mmol) dropwise at -78 °C, then the reaction was stirred at this temperature for 60 min. Acetone (0.38 mL, 5.20 mmol) was then added slowly to the reaction. After 45 min, the reaction was quenched at -78 °C with saturated aqueous NLLCl solution (15 mL) and diluted with EtOAc (25 mL). The aqueous layer was removed and the organic phase was washed with NLLCl sat. aq. solution followed by brine. The organic layer was dried with NaiSCL, filtered and concentrated under reduced pressure to afford the crude product. This residue was dissolved in Pyridine (5 mL) and cooled to 0 °C, and then POCh (0.29 mL, 3.12 mmol) was added. The resulting solution was heated to 50 °C and stirred for 1 hour. The reaction mixture was cooled to 0 °C, diluted with Et ₂ 0 (20 mL) and quenched with 10% CuSCL solution (10 mL). The layers were separated and the organic layer was washed twice with 10% CuSCL solution (10 mL) followed by water (10 mL) and brine (10 mL). The organic phase was dried over NaiSC , filtered and concentrated under reduced pressure to afford Compound Q15A. The product was used without any further purification for the next step. LCMS ESI ⁺ calc’d for C35H34CL : 519.3 [M+H ⁺ ] ; found 519.2 [M+H ⁺ ]

[0327] Compound Q15: To a solution of Compound Q15A (485 mg, 0.94 mmol) in

DCM (3.75 mL) at ambient temperature was added formic acid (1 mL) and the reaction was stirred for 24 hours. The reaction was cooled to 0 °C and quenched by the slow addition of an aqueous saturated solution of NaElCCL. The layers were separated and the aqueous phase was extracted 3 times with DCM. The combined organic layers were dried over NaiSC , filtered concentrated under reduced pressure and purified by column chromatography (0-70% EtOAc in hexanes, 40 g column) giving Compound Q15. LCMS ESI ⁺ calc’d for C16H20O4 : 277.1

[M+H ⁺ ] ; found 277.1 [M+H ⁺ ]

Compound 016

[0328] Compound Q16A: In an oven dried round bottom flask equipped with a magnetic stir bar and a nitrogen inlet was charged dry CH2CI2 (75 mL). The flask was then cooled to -20° C and (+)-diethyl L-tartrate (1.86 mL, 10.9 mmol) and Ti[OCH(CH3)2]4 (2.69 ml, 9.1 mmol) were added sequentially and stirred for 40 min. While still at -20°C, /-BuOOH (5.5 M in nonane, 33 mL, 181 mmol) was added dropwise over 15 minutes and the reaction mixture was stirred for an additional 40 min. A solution of Compound Q14B (30 g, 91 mmol) in CH2CI2 (75 mL) was then added dropwise over 20 min and stirring was continued for 90 min at -20°C (around 75% conversion by LC-MS). The reaction mixture was then treated with a 3M NaOH (300 mL) solution saturated with sodium chloride under vigorous stirring. After 1 h, the reaction mixture was diluted with H2O (1 L) and stirred for 1 h. The mixture was diluted with DCM (500 mL) and the water phase was decanted. The DCM phase was filtered over celite. The filtrate was transferred in a separatory funnel. The layers were separated and the aqueous phase was washed with CH2CI2 (2 x 300 mL). The combined organic layers were washed with brine (300 mL), dried over MgSCL, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel with EtOAc:hexanes (20-60%) as eluent to give

Compound Q16A. LCMS ESI ⁺ calc’d for C23H22O4 : 347.2 [M+EL] ; found: does not ionize. ¾ NMR: (CDCb, 400 MHz): d 7.42 (tt, J= 5.2, 1.4 Hz, 6H), 7.33-7.22 (m, 9H), 3.84 (ddd, J = 20.8, 12.3, 6.6 Hz, 2H), 3.29 (q, J= 10.5 Hz, 2H), 2.89 (d, J= 4.8 Hz, 1H), 2.72 (d, J= 4.8 Hz, 1H), 1.71 42 (dd, J= 8.5, 4.7 Hz, 1H).

[0329] Compound Q16B: To a 0 °C solution of Compound Q16A (29 g, 83.9 mmol) in dry DMF (140 mL) was added NaH (4.03 g, 100.7 mmol) in one portion. The solution was stirred for 20 minutes. Benzyl bromide (10.47 mL, 88.1 mmol) was added dropwise at 0 °C over 5 min. The reaction was then stirred at room temperature for 20 min. Upon completion of the reaction, the reaction was diluted slowly with water (500 mL) and the organic material was extracted with ethyl acetate (3 x 200 mL). All organic phases were combined and washed with brine (2 x 200 mL). The organic phase was dried over MgSCL, filtered and purified using column chromatography eluting with EtOAc: hexanes (5-30%, EtOAc in Hexanes) to afford Compound Q16B. LCMS ESI ⁺ calc’d for C30H28O3 : 437.2 [M+H ⁺ ] ; found: does not ionize. ¾ NMR: (CDCb, 400 MHz): d 7.46-7.40 (m, 6H), 7.34-7.20 (m, 14H), 4.58-4.47 (m, 2H), 3.73 (q, J= 11.0 Hz, 2H), 3.29 (dd, = 28.5, 10.2 Hz, 2H), 2.76 (td, = 19.4, 9.3, 2H).

[0330] Compound Q16C: A solution of Compound Q16B (27 g, 61.9 mmol) in anhydrous THF (270 mL) was cooled to 0 °C and a solution (2M in THF) of allylmagnesium chloride (77.3 mL, 154.6 mmol) was added slowly over 30 min, keeping the internal

temperature between 2 °C to 5 °C. The reaction was stirred at 2 °C for an extra 1 hour. The reaction was quenched with the addition of saturated aqueous ammonium chloride (400 mL).

The aqueous layer was extracted with ethyl acetate (3 x 200 mL). The combined organic extracts were washed with brine (1 x 200 mL), dried over MgSCL, and filtered. The solvent was removed under reduced pressure to afford crude Compound Q16C (90.4% ee) that was used without any further purification for the next step. LCMS ESI ⁺ calc’d for C33H34O3 : 479.3

[M+H ⁺ ] ; found: does not ionize. ¾ NMR: (CDCb, 400 MHz): d 7.44-7.39 (m, 6H), 7.36-7.19 (m, 14H), 5.93-5.66 (m, 1H), 5.20-5.08 (m, 1H), 4.97-4.82 (m, 2H), 4.54 (d, J= 7.6 Hz, 2H), 3.65-3.46 (m, 2H), 3.13 (q, J= 8.7 Hz, 2H), 2.03-1.81 (m, 2H), 1.69-1.58 (m, 2H).

[0331] Compound Q16D: To a /t V-butanol/acetone/water (1 : 1 : 1, 240 mL) room temperature solution of Compound Q16C (29g, 60.6 mmol) and N-methylmorpholine N-oxide (7.8 g, 66.6 mmol) was added an aqueous solution of OsCb 4% (1.25 mL). The reaction mixture was stirred for 12 h and diluted with EtOAc (500 mL) before being washed with sodium thiosulfate (2 x 250 mL), NH4CI (250 mL, saturated aqueous solution), NaHC0 ₃ (250 mL, saturated aqueous solution), brine (250 mL), dried over MgS0 ₄ , filtered and concentrated under reduced pressure. Purification using a pad of silica eluting with EtOAc/Hexanes (50-100%) afforded Compound Q16D. LCMS ESI ⁺ calc’d for C33H36O5 : 513.3 [M+H ⁺ ] ; found: does not ionize. ¹ H NMR: (CDCh, 400 MHz): d 7.43-7.37 (m, 6H), 7.37-7.19 (m, 14H), 4.55 (d, J= 1.9 Hz, 2H), 3.66 (dd, J= 8.5, 4.9 Hz, 1H), 3.57 (td, J= 7.8, 4.0 Hz, 1H), 3.54-3.46 (m, 2H), 3.38- 3.27 (m, 1H), 3.21-3.08 (m, 2H), 2.84 (dt, J= 9.6, 4.8 Hz, 1H), 2.77 (d, J= 3.1 Hz, 1H), 1.92- 1.84 (m, 1H), 1.66 (t, J= 7.3 Hz, 2H), 1.32 (ddd, J= 14.0, 9.3, 6.5 Hz, 2H).

[0332] Compound Q16E: To a solution of the Compound Q16D (30 g, 58.5 mmol) in

CH3CN/Water (1 : 1, 250 mL) at 0 °C, was added NaI0 ₄ (15 g, 70.2 mmol). After 90 min, the reaction was diluted with brine (400 mL) and the organic material was extracted with EtOAc (2 x 300 mL). The organic layers were combined, dried over MgSCL, filtered and concentrated under reduced pressure to afford Compound Q16E that was used without any further purification in the next step. LCMS ESI ⁺ calc’d for C32H32O5 : 481.2 [M+H ⁺ ] ; found: does not ionize. ¹ H NMR: (CDCh, 400 MHz): d 7.46-7.39 (m, 6H), 7.37-7.19 (m, 14H), 5.52-5.38 (m, 1H), 4.59 (dd, J= 28.1, 11.8 Hz, 2H), 4.50 (s, 1H), 3.57 (dd, J= 25.8, 9.5 Hz, 1H), 3.50-3.39 (m, 1H), 3.32-3.25 (m, 1H), 3.04 (dd, 7= 25.9, 9.2 Hz, 1H), 2.15-1.73 (m, 4H).

[0333] Compound Q16: The crude Compound Q16E was diluted with DCM (300 mL), and PDC (44 g, 117 mmol) was added in one portion at room temperature. The reaction was stirred at room temperature for 48 h and the mixture was diluted with DCM (200 mL). The precipitate was filtered through celite and the filtrate was concentrated under reduced pressure. The crude product was then purified by flash chromatography eluting with EtOAc:Hexanes (10- 40%) to afford Compound Q16. LCMS ESI ⁺ calc’d for C32H30O4 : 479.2 [M+H ⁺ ] ; found: does not ionize. ¹ H NMR: (CDCh, 400 MHz): d 7.44-7.39 (m, 6H), 7.35-7.21 (m, 14H), 4.52 (q, J = 12.0 Hz, 2H), 3.59 (dd, J= 45.0, 10.3 Hz, 2H), 3.23 (dd, J= 45.2, 9.9 Hz, 2H), 2.70-2.53 (m, 2H), 2.14 (ddd, 7= 12.9, 9.9, 7.0 Hz, 1H), 2.07-1.95 (m, 1H).

Compound 017

[0334] Compound Q17A: To a solution of Compound Q16 (500 mg, 1.04 mmol) in

THF (4.2 mL) was added LiHMDS (1.56 mL, 1.0 M in THF 1.56 mmol) dropwise at -78 °C, then the reaction was stirred at this temperature for 60 min. Acetone (0.38 mL, 5.20 mmol) was then added slowly to the reaction. After 45 min, the reaction was quenched at -78 °C with saturated aqueous NLLCl solution (15 mL) and diluted with EtOAc (25 mL). The aqueous layer was removed and the organic phase was washed with NLLCl sat. aq. solution followed by brine. The organic layer was dried with Na ₂ S0 ₄ , filtered and concentrated under reduced pressure to afford the crude product. This residue was dissolved in Pyridine (5 mL) and cooled to 0 °C, and then POCh (0.29 mL, 3.12 mmol) was added. The resulting solution was heated to 50 °C and stirred for 1 hour. The reaction mixture was cooled to 0 °C, diluted with Et ₂ 0 (20 mL) and quenched with 10% CuSCL solution (10 mL). The layers were separated and the organic layer was washed twice with 10% CuSCL solution (10 mL) followed by water (10 mL) and brine (10 mL). The organic phase was dried over Na ₂ S0 ₄ , filtered and concentrated under reduced pressure to afford Compound Q17A. The product was used without any further purification for the next step. LCMS ESI ⁺ calc’d for C35H34CL : 519.3 [M+H ⁺ ] ; found 519.2 [M+H ⁺ ]

[0335] Compound Q17: To a solution of Compound Q17A (542 mg, 1.05 mmol) in

DCM (4.0 mL) at ambient temperature was added TFA (1 mL) and the reaction was stirred for 3 hours. The reaction was concentrated under reduced pressure. The combined organic layers were dried over Na ₂ S0 ₄ , filtered, concentrated under reduced pressure and purified by column chromatography (0-70% EtOAc in hexanes, 40 g column), giving Compound Q17. LCMS ESI ⁺ calc’d for Ci ₆ H ₂ o0 ₄ : 277.1 [M+H ⁺ ] ; found 277.1 [M+H ⁺ ]

Compound 018

[0336] Compound Q18A: To a solution of Compound Q14 (1.00 g, 2.09 mmol) in anhydrous tetrahydrofuran (8.4 mL) cooled to -78 °C under a nitrogen atmosphere was added dropwise a lithium bis(trimethylsilyl)amide solution (1 M in tetrahydrofuran, 3.14 mL, 3.14 mmol) and the reaction was stirred at -78 °C for 1 h. Compound Q1 (0.71g, 4.18 mmol) was then added to the mixture and it was stirred an additional 1 h at -78 °C. The reaction was then quenched at -78 °C with saturated aqueous ammonium chloride (25 mL) and the mixture was diluted with ethyl acetate (45 mL). The layers were separated and the organic layer was dried over sodium sulfate, concentrated in vacuo and purified by normal-phase chromatography (0 - 20% ethyl acetate in hexanes) to give Compound Q18A. LCMS ESI ⁺ calc’d for C ₄₃ H ₅₂ O ₅ : 648.4 [M+LL] ; found: 666.3 [M+H ₂ 0+H ⁺ ]

[0337] Compound Q18B: To a solution of Compound Q18A (1.28 g, 1.97 mmol) in anhydrous toluene (19.7 mL) was added a DCC (611 mg, 2.97 mmol) followed by CuBr (29 mg, 0.20 mmol) and the reaction was stirred at reflux for 4 hours. The solution was cooled to room temperature, filtered through celite, concentrated in vacuo and purified by normal-phase chromatography (0 - 20% ethyl acetate in hexanes) to give Compound Q18B. LCMS ESI ⁺ calc’d for C ₄₃ H ₅₀ O ₄ : 630.4 [M+H ⁺ ] ; found: 648.3 [M+H ₂ 0+H ⁺ ]

[0338] Compound Q18: To a solution of Compound Q18B (0.885 g, 1.40 mmol) in dry dichloromethane (70 mL) was added hydrogen chloride (4.0 M solution in dioxane, 2700 mL, 28.00 mmol) at rt and the mixture was stirred for 5 min. The reaction mixture was concentrated in vacuo. The residue was diluted with ethyl acetate (50 mL) and washed with saturated aqueous sodium bicarbonate (50 mL). The organic layer was then dried over sodium sulfate, concentrated in vacuo and purified by normal-phase chromatography (0 - 60 % ethyl acetate in hexanes) to give Compound Q18. LCMS ESI ⁺ calc’d for C ₂₄ H ₃₆ 0 ₄ : 389.3 [M+EC] ; found: 389.1 [M+H ⁺ ] ¹ H NMR: (CDCb, 400 MHz): d 7.39 - 7.32 (m, 2H), 7.30 (t, J= 5.4 Hz, 3H), 6.81 - 6.73 (m, 1H), 4.62 - 4.51 (m, 2H), 3.77 (d, J= 12.0 Hz, 1H), 3.68 (d, J= 12.1 Hz, 1H), 3.61 (d, J= 9.9 Hz, 1H), 3.54 (d, J= 9.9 Hz, 1H), 2.86 - 2.59 (m, 2H), 2.11 (t, = 6.7 Hz, 2H), 1.87 (s, 1H), 1.74 - 1.57 (m, 3H), 1.13 - 1.03 (m, 4H), 0.86 (d, J= 6.5 Hz, 12H). Compound 019

[0339] Compound Q19B: A vessel was charged with Compound Q19A (14 g, 57.5 mmol, 1.00 eq) in MeOH (60 mL). H2SO4 (5.65 g, 57.5 mmol, 3.07 mL, 1.00 eq ) was added to the mixture under N2 _. The reaction was stirred at 85 °C under N2 for 16 h. The reaction was concentrated under reduced pressure to give a residue. H2O (70 mL) was added, and the reaction was extracted with EtOAc (70, 50, 30 mL). The combined organic phases were washed with brine (70, 50mL). The final organic phase was concentrated under reduced pressure to give crude Compound Q19B that was used in the next step without further purification.

[0340] Compound Q19C: A vessel was charged with Compound Q19B (13.4 g, 52.1 mmol, 1.00 eq) and Compound Q5A (7.26 g, 62.5 mmol, 7.93 mL, 1.20 eq) in dioxane (90 mL). Cul (397 mg, 2.09 mmol, 0.04 eq ), Pd(PPh3)2Ch (731 mg, 1.04 mmol, 0.02 eq) and Et3N (7.65 g, 75.6 mmol, 10.5 mL, 1.45 eq) were introduced to the mixture. The system was degassed and purged with N2 (3x). Reaction was stirred at 90°C under N2 for 16 h. The mixture was filtered, and the cake washed with DCM (50 mL). The filtrate was concentrated under reduced pressure to give a residue, which was purified by column chromatography (S1O2, Petroleum ether/Ethyl acetate = 100/1 to 20/1) to give Compound Q19C.

[0341] Compound Q19: A vessel was charged with Compound Q19C (3.6 g, 12.3 mmol, 1.00 eq) in THF (25 mL) and H2O (25 mL). NaOH (9.85 g, 246 mmol, 20.0 eq) was added to the mixture. The reaction was stirred at 70 °C under N2 for 16 h. The mixture was concentrated under reduced pressure to give a residue, which was triturated with DCM (20.0 mL) and filtered. The cake was dissolved in H2O (100 mL) and acidified to pH = 3 with 6M aq HC1. Filtration provided another cake, which was also washed with FLO (100 mL). The final cake was dried under reduced pressure, giving Compound Q19. LCMS ESI ⁺ calc’d for

C19H18O2 : 279.1 [M+FL] ; found 279.1 [M+H ⁺ ] ¾ NMR (400 MHz, CDCb) d 7.44 (dd, J = 12.4 Hz, J= 8.0 Hz 4H), 7.18-7.15 (m, 4H), 2.69 (t, J= 7.6 Hz, 2H), 2.41-2.37 (m, 5H), 2.02- 1.95 (m, 2H).

Compound 020

Q20C Q20

[0342] Compound Q20B: A vessel was charged with Compound Q20A (10 g, 36.2 mmol, 1.00 eq ) in MeOH (60 mL). H2SO4 (3.55 g, 36.2 mmol, 1.93 mL, 1.00 eq ) was added to the mixture under N2 _. The reaction was stirred at 85 °C under N2 for 16 h. The reaction was concentrated under reduced pressure to give a residue. H2O (70 mL) was added, and the reaction was extracted with EtOAc (70, 50, 30 mL). The combined organic phases were washed with brine (70, 50mL). The final organic phase was concentrated under reduced pressure to give crude Compound Q20B, which was used without further purification. ¾ NMR (400 MHz, CDCb) d 7.61 (d, J= 7.6 Hz, 2H), 6.96 (d, J= 8.4 Hz, 2H), 3.67 (s, 3H), 2.90 (t, J= 7.6 Hz,

2H), 2.61 (t, 7= 7.6 Hz, 2H).

[0343] Compound Q20C: A vessel was charged with Compound Q20B (10 g, 34.4 mmol, 1.00 eq) and Compound Q5A (4.80 g, 41.3 mmol, 5.25 mL, 1.20 eq) in THF (70 mL). Cul (262 mg, 1.38 mmol, 0.04 eq), Pd(PPh3)2Ch (483 mg, 689 pmol, 0.02 eq) and Et3N (5.06 g, 49.9 mmol, 6.96 mL, 1.45 eq) were introduced to the mixture. The system was degassed and purged with N2 (3x). Reaction was stirred at 25°C under N2 for 16 h. The mixture was filtered, and the cake washed with DCM (50 mL). The filtrate was concentrated under reduced pressure to give a residue, which was purified by column chromatography (S1O2, Petroleum ether/Ethyl acetate = 100/1 to 20/1) to give Compound Q20C.

[0344] Compound Q20: A vessel was charged with Compound Q20C (7.7 g, 27.6 mmol, 1.00 eq) in THF (55 mL) and H2O (55 mL). NaOH (22.1 g, 553 mmol, 20.0 eq) was added to the mixture. The reaction was stirred at 70 °C under N2 for 16 h. The mixture was concentrated under reduced pressure to give a residue, which was triturated with DCM (20.0 mL) and filtered. The cake was dissolved in H2O (100 mL) and acidified to pH = 3 with 6M aq HC1. Filtration provided another cake, which was also washed with H2O (100 mL). The final cake was dried under reduced pressure, giving Compound Q20. LCMS ESI ⁺ calc’d for CisHieOi : 265.1 [M+H ⁺ ] ; found 265.1 [M+H ⁺ ] ¾ NMR (400 MHz, CDCh) d 7.46 (d, J= 8.0 Hz, 2H), 7.42 (d, J= 8.0 Hz, 2H), 7.20 (d, J= 8.0 Hz, 2H), 7.16 (d, J= 7.6 Hz, 2H), 2.98 (t, J = 7.6 Hz, 2H), 2.70 (t, J= 7.6 Hz, 2H), 2.37 (s, 3H).

Compound 021

[0345] Compound Q21B: A vessel was charged with Compound Q21A (10 g, 38.1 mmol, 1.00 eq ) in MeOH (60 mL). H2SO4 (3.74 g, 38.1 mmol, 2.03 mL, 1.00 eq ) was added to the mixture under N2 _. The reaction was stirred at 85 °C under N2 for 16 h. The reaction was concentrated under reduced pressure to give a residue. H2O (70 mL) was added, and then reaction was extracted with EtOAc (70, 50, 30 mL). The combined organic phases were washed with saturated aq NaHCCh (70, 50mL). The final organic phase was concentrated under reduced pressure to give Compound Q21B. ¾ NMR (400 MHz, CDCh) d 7.65 (d, J= 8.4 Hz, 2H), 7.04 (d, J= 8.4 Hz, 2H), 3.70 (s, 3H), 3.57 (s, 2H).

[0346] Compound Q21C: A vessel was charged with Compound Q21B (6.8 g, 24.6 mmol, 1.00 eq) and Compound Q5A (3.43 g, 29.5 mmol, 3.74 mL, 1.20 eq) in THF (50 mL). Cul (187 mg, 985 pmol, 0.04 eq), Pd(PPh3)2Ch (345 mg, 492 pmol, 0.02 eq) and Et3N (3.61 g, 35.7 mmol, 4.97 mL, 1.45 eq) were introduced to the mixture. The system was degassed and purged with N2 (3x). Reaction was stirred at 90°C under N2 for 16 h. The mixture was filtered, and the cake washed with DCM (50 mL). The filtrate was concentrated under reduced pressure to give a residue, which was purified by column chromatography (S1O2, Petroleum ether/Ethyl acetate = 100/1 to 20/1) to give Compound Q21C.

[0347] Compound Q21: A vessel was charged with Compound Q21C (3.1 g, 11.7 mmol, 1.00 eq) in THF (25 mL) and H2O (25 mL). NaOH (9.38 g, 234 mmol, 20.0 eq) was added to the mixture. The reaction was stirred at 70 °C under N2 for 16 h. The mixture was concentrated under reduced pressure to give a residue, which was triturated with DCM (20.0 mL) and filtered. The cake was dissolved in H2O (100 mL) and acidified to pH = 3 with 6M aq HC1. Filtration provided another cake, which was also washed with H2O (100 mL). The final cake was dried under reduced pressure, giving Compound Q21. LCMS ESI ⁺ calc’d for

C17H14O2 : 251.1 [M+H ⁺ ] ; found 251.1 [M+H ⁺ ] ¾ NMR (400 MHz, CDCh) d 7.50 (d, J= 8.0 Hz, 2H), 7.42 (d, J= 8.4 Hz, 2H), 7.28 (d, J= 8.4 Hz, 2H), 7.16 (d, J= 8.0 Hz, 2H), 3.68 (s, 2H), 2.37 (s, 3H).

Compound 022

Q22

[0348] Compound Q22B: A vessel was charged with Compound Q22A (5.00 g, 18.8 mmol, 1.00 eq ) and Compound Q5A (4.38 g, 37.7 mmol, 4.78 mL, 2.00 eq) in dioxane (70.0 mL). Cul (287 mg, 1.51 mmol, 0.08 eq ), Pd(t-Bu3P)2 (385 mg, 754 umol, 0.04 eq) and Et3N (2.77 g, 27.3 mmol, 3.81 mL, 1.45 eq) were introduced to the mixture. The system was degassed and purged with N2 for (3x). The reaction was stirred at 90°C for 16 h. The mixture was concentrated under reduced pressure to give a residue, which was purified by column

chromatography (S1O2, Petroleum ether/Ethyl acetate = 100/1 to 5/1), giving Compound Q22B.

[0349] Compound Q22: A vessel was charged with Compound Q22B (2.20 g, 7.32 mmol, 1.00 eq), THF (10.0 mL), and H2O (10.0 mL). NaOH (5.86 g, 146 mmol, 20.0 eq) was added to the mixture. The reaction was stirred at 70°C for 16 h. The reaction was concentrated under reduced pressure to give a residue. The material was washed with DCM (100 mL) and then filtered. The cake was diluted with H2O (100 mL), and 6M aq. HC1 was added until the pH was ~3. Filtration gave another cake, which was dried under reduced pressure. The residue was purified via column chromatography (S1O2, THF/MeOH=50/l), giving Compound Q22. LCMS ESI ⁺ calc’d for C20H14O2 : 287.1 [M+H ⁺ ] ; found 287.0 [M+H ⁺ ] ¾ NMR (400 MHz, CDCh) d 8.58 (s, 1H), 8.21 (s, 1H), 8.12 (d, J= 8.4 Hz, 1H), 8.02-7.98 (m, 2H), 7.65 (d, J= 8.4 Hz, 1H), 7.50 (d, J= 8.0 Hz, 2H), 7.27 (d, J= 8.0 Hz, 2H), 2.35 (s, 3H). Compound 023

[0350] Compound Q23B: A vessel was charged with Compound Q23A (24.0 g, 83.9 mmol, 1.00 eq ) in DMF (160 mL). 3,3-dimethoxyprop-l-ene (9.00 g, 88.1 mmol, 10.4 mL, 1.05 eq), TBAC (24.5 g, 88.2 mmol, 24.6 mL, 1.05 eq), and TEA (13.5 g, 134 mmol, 18.6 mL, 1.60 eq) were added to the mixture. The system was degassed and purged with N2 (3x). The reaction was stirred at 25°C for 0.5 h. Pd(OAc)2 (753 mg, 3.36 mmol, 0.04 eq) was added to the mixture. Once more, the system was degassed and purged with N2 (3x). The reaction was stirred at 90°C for 15.5 h. The reaction was filtered, and H2O (300 mL) was added to the filtrate; the system was extracted with EtOAc (3 x 300 mL). Combined organic layers were washed with brine (300 mL), dried (Na ₂ S0 ₄ ), filtered, and concentrated. The residue was purified by column

chromatography (S1O2, Petroleum ether/Ethyl acetate = 100/1 to 1/1), giving Compound Q23B. ¹ H NMR (400 MHz, CDCh) d 7.97 (s, 1H), 7.68 (d, J= 8.4 Hz, 1H), 7.62 (d, J= 11.2 Hz, 2H), 7.53 (d, J= 8.8 Hz, 1H), 3.68 (s, 1H), 3.11 (d, 7= 7.6 Hz, 2H), 2.72 (d, J= 8.0 Hz, 2H).

[0351] Compound Q23C: A vessel was charged with Compound Q23B (2.50 g, 8.53 mmol, 1.00 eq) in ACN (25.0 mL). Compound Q5A (1.98 g, 17.0 mmol, 2.16 mL, 2.00 eq ), Cy2NMe (3.33 g, 17.0 mmol, 3.62 mL, 2.00 eq), and Pd Sphos G2 (614 mg, 852 umol, 0.10 eq) were added to the mixture. The system was degassed and purged with N2 (3x). The reaction was stirred at 80°C for 4 h. The reaction was filtered, and H2O (100 mL) was added to the mixture. The system was extracted with EtOAc (3 x 100 mL). Combined organic extracts were dried (Na ₂ S0 ₄ ), filtered, and concentrated. The residue was purified by column chromatography (S1O2, Petroleum ether/Ethyl acetate = 100/1 to 1/1), giving Compound Q23C. LCMS ESI ⁺ calc’d for C23H20O2 : 329.2 [M+H ⁺ ] ; found 329.3 [M+H ⁺ ] ¾ NMR (400 MHz, DMSO-de) d 8.11 (s, 1H), 7.86 (d, J= 8.4 Hz, 2H), 7.74 (s, 1H), 7.55 (d, J= 8.4 Hz, 2H), 7.47 (t, J= 8.0 Hz, 3H), 7.25 (d, J= 7.6 Hz, 2H), 3.58 (s, 1H), 3.02 (d, J= 8.0 Hz, 2H), 2.74 (d, J= 8.0 Hz, 2H), 2.34 (s, 1H).

[0352] Compound Q23: A vessel was charged with Compound Q23C (3.00 g, 9.14 mmol, 1.00 eq) in THF (21.0 mL) and H2O (21.0 mL). NaOH (7.31 g, 182 mmol, 20.0 eq ) was added to the mixture. The reaction was stirred at 70°C for 12 h. The reaction was concentrated under reduced pressure. The material was treated with DCM (100 mL). 6M aq. HC1 was added until the pH was ~3. The organic phase was collected and concentrated under reduced pressure. The residue was purified via column chromatography (S1O2, THF/MeOH=50/l), giving

Compound Q23. LCMS ESI ⁺ calc’d for C22H18O2 : 315.1 [M+H ⁺ ] ; found 315.0 [M+H ⁺ ] ¾ NMR (400 MHz, DMSO-de) d 8.10 (s, 1H), 7.86 (d, J= 8.4 Hz, 2H), 7.74 (s, 1H), 7.55 (d, J = 8.4 Hz, 2H), 7.45 (d, J= 8.0 Hz, 3H), 7.25 (d, J= 8.0 Hz, 2H), 2.99 (d, J= 8.0 Hz, 2H), 2.63 (t, J= 8.0 Hz, 2H), 2.34 (s, 1H).

Compound 024

[0353] Compound Q24B: To a stirred solution of Compound Q24A (232 mg, 2.00 mmol) in anhydrous Pentane:DCM ( 9: 1, 10.00 mL) at ambient temperature was added TEMPO (32 mg, 0.200 mmol) followed by PhI(OAc)2 (709 mg, 2.20 mmol). The reaction mixture was stirred at room temperature overnight. The reaction was quenched by the addition of an aqueous saturated solution of NaHC0 ₃ (10 mL). The layers were separated, the aqueous layer was extracted with DCM, the combined organic phases were dried over Na ₂ S0 ₄ , filtered and kept as a stock solution of desired aldehyde with iodobenzene due to volatility. This stock solution of Compound Q24B was used without further characterization in the next reaction. [0354] Compound Q24C: A solution of LiHMDS (1.0 M in THF, 1.20 mL, 1.20 mmol) was added dropwise to solution of Compound Q2D (500 mg, 0.80 mmol) in THF (3.21 mL) at -78 °C. The reaction was stirred at that temperature for 1 hour. The solution of

Compound Q24B from the previous step was then added slowly to the mixture at -78 °C and the resulting solution was stirred for 1 hour. The reaction was quenched at -78 °C by the addition of 5 mL of aqueous saturated MLCl. EtOAc (10 mL) was added and the layers were separated. The organic layer was washed with water and brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by column chromatography on silica (0-20% EtOAc in hexane, 80 g column). Compound Q24C was obtained as a single diastereoisomer. LCMS ESI ⁺ calc’d for C45H60O5S12: 737.4 [M+H ⁺ ] ; found 738.0 [M+H ⁺ ]

[0355] Compound Q24D: To a solution of Compound Q24C (0.290 g, 0.40 mmol) in toluene (4.00 mL) was added copper(I) bromide (0.006 g, 0.04 mmol) and

dicyclohexylcarbodiimide (0.123 g, 0.60 mmol). The resulting solution was heated to 110 °C and stirred overnight. The reaction was cooled to ambient temperature, filtered over celite, concentrated and purified by column chromatography on silica (0-10% EtOAc in hexanes, 40 g column) to obtain Compound Q24D as a single alkene isomer. LCMS ESC calc’d for

C45H58O4S12: 719.4 [M+H ⁺ ] ; found 719.3 [M+H ⁺ ] and 737.3 [M+H ₂ 0+H ⁺ ]

[0356] Compound Q24: To a solution of Compound Q24D (0.227 g, 0.32 mmol) in

THF (6.30 mL) at 0 °C was added a solution of TBAF (1.0 M in THF, 0.96 mL, 0.96 mmol) dropwise. The resulting solution was stirred at 0 °C for 30 minutes. The reaction was concentrated and purified by column chromatography on silica (0-100% EtOAc in hexanes, 40 g column) to obtain Compound Q24. LCMS ESC calc’d for C13H22O4: 243.2 [M+H ⁺ ] ; found 243.3 [M+H ⁺ ]

Example A1

[0357] Compound E1A: Oxalyl Chloride (102 pL, 1.2 mmol) was added dropwise to an ice-cooled solution of Compound Q3 (101 mg, 0.30 mmol), pyridine (1 drop) and

dichloromethane (1 mL). The reaction mixture was allowed to warm to rt, and stirred for 30 mins. The reaction was condensed in vacuo to afford Compound E1A. This material was used without further purification. LCMS ESI ⁺ calc’d for C22H23O2CI: 351.2 in MeOH [M+CH3OH- HC1+H ⁺ ] ; found 351.2 [M+CH OH-HCl+H ⁺ ].

[0358] Example Al: A stirred solution of Compound Q2 (35.0 mg, 0.19 mmol) and pyridine (46 pL, 0.57 mmol) in dry DCM (2.50 mL) at 0 °C was added dropwise a solution of Compound El A (102 mg, 0.29 mmol) in 1.25 mL of DCM. The reaction mixture was stirred at room temperature for an additional 1 h. The reaction was condensed and purified by column chromatography (0-40% EtOAc in Hexanes, 12 g column) giving crude Example Al. This sample of crude Example Al was purified a second time using 0-50% EtOAc in Hexane, giving purified Example Al.

[0359] Example Al. LCMS ESC calc’d for C _3I H ₃₆ 0 ₆ : 505.3 [M+H ⁺ ] Found: 505.1

[M+H ⁺ ] ¾ NMR (400 MHz, CDCb) d 7.47 - 7.42 (m, 4H), 7.37 - 7.33 (m, 2H), 6.87 - 6.82 (m, 2H), 4.31 - 4.25 (m, 1H), 4.19 (d, J = 11.8 Hz, 1H), 4.01 (t, J = 6.0 Hz, 2H), 3.69 (dd, J = 12.1, 7.3 Hz, 1H), 3.62 (dd, J = 12.1, 6.5 Hz, 1H), 2.85 - 2.76 (m, 1H), 2.70 - 2.61 (m, 1H), 2.58 (t, J = 7.3 Hz, 2H), 2.26 (t, J = 2.2 Hz, 3H), 2.17 - 1.99 (m, 3H), 1.86 (t, J = 1.4 Hz, 3H), 1.32 (s, 9H).

Example A2

[0360] Compound E2A: Oxalyl Chloride (102 pL, 1.2 mmol) was added dropwise to an ice-cooled solution of Compound Q4 (84 mg, 0.30 mmol), pyridine (1 drop) and

dichloromethane (1 mL). The reaction mixture was allowed to warm to rt, and stirred for 30 mins. The reaction was condensed in vacuo to afford the desired Compound E2A. This material was used without further purification. Exact mass calculated for C18H15O2CI: 295.1 in MeOH [M+CH OH-HCl+H ⁺ ] ; found Found: 295.3 [M+CH OH-HCl+H ⁺ ]

[0361] Example A2: A stirred solution of Compound Q2 (35.0 mg, 0.19 mmol) and pyridine (46 pL, 0.57 mmol) in dry DCM (2.50 mL) at 0 °C was added dropwise a solution of Compound E2A (87 mg, 0.29 mmol) in 1.25 mL of DCM. The reaction mixture was stirred at room temperature for an additional 1 h. The reaction was condensed and purified by column chromatography (0-10% EtOAc in DCM, 12 g column) giving crude Example A2. The crude Example A2 was purified a second time using 0-50% EtOAc in Hexane giving Example A2. LCMS ESC calc’d for CivHisOe: 449.2 [M+H ⁺ ] Found: 449.1 [M+H ⁺ ] ¾ NMR (400 MHz, CDCh) d 7.51 (dd, J= 7.4, 2.0 Hz, 2H), 7.46 (d, J= 8.8 Hz, 2H), 7.37 - 7.30 (m, 3H), 6.85 (d, J = 8.8 Hz, 2H), 4.28 (d, J= 11.8 Hz, 1H), 4.20 (d, J= 11.8 Hz, 1H), 4.02 (t, J= 6.0 Hz, 2H), 3.69 (dd, J= 12.1, 7.3 Hz, 1H), 3.62 (dd, = 12.1, 6.5 Hz, 1H), 2.81 (d, = 16.5 Hz, 1H), 2.65 (d, 7 = 16.4 Hz, 1H), 2.58 (t, J= 7.3 Hz, 2H), 2.26 (t, J= 2.1 Hz, 3H), 2.16 - 2.07 (m, 2H), 2.07 - 1.99 (m, 1H), 1.86 (s, 3H).

Example A3

[0362] Compound E3A: Oxalyl Chloride (102 pL, 1.2 mmol) was added dropwise to an ice-cooled solution of Compound Q5 (97 mg, 0.30 mmol), pyridine (1 drop) and

dichloromethane (1 mL). The reaction mixture was allowed to warm to rt, and stirred for 30 min. The reaction was condensed in vacuo to afford the desired product Compound E3A. This material was used without further purification. LCMS ESI ⁺ calc’d for C21H21O2CI: 337.2 in MeOH [M+CH OH-HCl+H ⁺ ] ; found Found: 337.1 [M+CH OH-HCl+H ⁺ ]

[0363] Example A3: A stirred solution of Compound Q2 (35.0 mg, 0.19 mmol) and pyridine (46 pL, 0.57 mmol) in dry DCM (2.50 mL) at 0 °C was added dropwise a solution of Compound E3A (98 mg, 0.29 mmol) in 1.25 mL of DCM. The reaction mixture was stirred at room temperature for an additional 1 h. The reaction was condensed and purified by column chromatography (0-60% EtOAc in hexanes, 12 g column) giving Example A3. LCMS ESI ⁺ calc’d for C30H34O6: 491.2 [M+H ⁺ ] Found: 491.1 [M+H ⁺ ] ¾ NMR (400 MHz, CDCh) 7.46 - 7.42 (m, 2H), 7.42 - 7.38 (m, 2H), 7.14 (dd, J= 8.5, 0.6 Hz, 2H), 6.89 - 6.81 (m, 2H), 4.28 (d, J = 11.8 Hz, 1H), 4.16 (d, J= 11.8 Hz, 1H), 3.97 (t, J= 6.3 Hz, 2H), 3.69 (d, J= 12.0 Hz, 1H), 3.62 (d, J= 12.1 Hz, 1H), 2.88 - 2.77 (m, 1H), 2.70 - 2.59 (m, 1H), 2.43 - 2.34 (m, J= 13.6, 6.0 Hz, 5H), 2.26 (t, J= 2.2 Hz, 3H), 1.87 (t, J= 1.4 Hz, 3H), 1.85 - 1.76 (m, 2H), 1.70 (dt, J =

15.2, 7.4 Hz, 2H), 1.53 - 1.45 (m, 2H).

Example A4

[0364] Compound E4A: To a solution of Compound Q2D (400 mg, 0.64 mmol) in

THF (2.57 mL, dried over MgSCL prior to the reaction) was added a LiHMDS solution (0.960 mL, 1.0 M in THF, 0.96 mmol) dropwise at -78°C. The solution was stirred at that temperature for 1 hour. Cyclohexanone (0.332 mL, 3.20 mmol) was then added and the solution was stirred at -78°C for 1 hour. The reaction was quenched by the addition of 2.5 mL of saturated NH ₄ CI and the solution was diluted with 7.5 mL of EtOAc. The aqueous layer was removed and the organic phase was washed with a saturated solution of NH4CI followed by brine. The organic layer was dried and condensed in vacuo to afford the crude product. The crude product was dissolved in 3 mL of pyridine and POCI3 (0.18 mL, 1.92 mmol) was added dropwise at 0°C. The solution was stirred at 50°C overnight. The reaction was dissolved with 20 mL of Et ₂ 0 and washed twice with a 10% CuS0 ₄ solution followed by water and brine. The organic phase was dried and condensed in vacuo to afford the crude product. The crude product was dissolved in THF (13 mL) and a TBAF solution (1.92 mL, 1.0 M in THF, 1.92 mmol) was added dropwise at 0°C. The reaction was stirred at room temperature for 1 hour. The reaction was condensed in vacuo and purified by column chromatography using 50-100% EtOAc in hexanes giving

Compound E4A. LCMS ESC calc’d for C _I2 H _I8 0 ₄ : 227.1 [M+H ⁺ ] ; found 227.7 [M+H ⁺ ] ¾ NMR (400 MHz, CDCh) d 3.87 - 3.58 (m, 6H), 2.99 - 2.87 (m, 2H), 2.75 (s, 2H), 2.24 - 2.17 (m, 2H), 1.72 - 1.52 (m, 6H).

[0365] Compound E4B: Oxalyl Chloride (170 pL, 2.0 mmol) was added dropwise to an ice-cooled solution of Compound Q6 (147 mg, 0.50 mmol), pyridine (1 drop) and

dichloromethane (1.70 mL). The reaction mixture was allowed to warm to rt, and stirred for 30 mins. The reaction was condensed in vacuo to afford the desired Compound E4B. LCMS ESC calc’d for C19H17O2CI: 309.1 in MeOH [M+CH ₃ OH-HCl+H ⁺ ] ; found Found: 309.3

[M+CH ₃ OH-HCl+H ⁺ ]

[0366] Example A4: A stirred solution of Compound E4A (70.0 mg, 0.31 mmol) and pyridine (75 pL, 0.93 mmol) in dry DCM (4.75 mL) at 0 °C was added dropwise a solution of Compound E4B (147 mg, 0.47 mmol) in 1.50 mL of DCM. The reaction mixture was stirred at room temperature for an additional 1 h. The reaction was condensed and purified by column chromatography (0-50% EtOAc in hexanes, 12 g column) giving crude Example A4. The crude Example A4 was purified a second time using 0-50% EtOAc in Hexane giving Example A4. LCMS ESC calc’d for C _3i H ₃₄ 0 ₆ : 503.2 [M+H ⁺ ] Found: 503.3 [M+H ⁺ ] ¾ NMR (400 MHz, CDCh) d 7.47 - 7.42 (m, 2H), 7.42 - 7.37 (m, 2H), 7.14 (d, J = 7.8 Hz, 2H), 6.87 - 6.81 (m,

2H), 4.34 - 4.08 (m, 2H), 4.01 (t, J = 5.9 Hz, 2H), 3.66 (qd, J = 12.1, 6.9 Hz, 2H), 2.94 (s, 2H), 2.82 (d, J = 16.4 Hz, 1H), 2.66 (d, J = 16.4 Hz, 1H), 2.58 (t, J = 7.3 Hz, 2H), 2.36 (s, 3H), 2.21 - 2.00 (m, 6H), 1.65 - 1.58 (m, 4H). Example A5, Example A6, Example A7, and Example A8:

[0367] Compound Qll and Compound E5A (As a mixture of olefin isomers): To a solution of Compound Q2D (1.54 g, 2.48 mmol) in tetrahydrofuran (10 mL) cooled to -78 °C under N2 atmosphere was added lithium bis(trimethylsilyl)amide solution (1 M in

tetrahydrofuran, 3.72 mL, 3.72 mmol) dropwise and the solution was stirred at -78 °C for 40 min. A./V’-Dimethylpropylene urea (0.45 mL, 3.72 mmol) was added to the cold solution and it was stirred for 20 min. Benzaldehyde (0.47 mL, 4.96 mmol) was then added to the cold mixture and it was stirred for an additional 60 min. The reaction was quenched at -78 °C with saturated aqueous ammonium chloride (10 mL) and the mixture was diluted with ethyl acetate (25 mL). The phases were separated and the organic layer was washed with saturated aqueous ammonium chloride (10 mL) followed by saturated aqueous sodium chloride (10 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to afford the intermediate alcohol. The alcohol was then dissolved in pyridine (10 mL) and cooled to 0 °C. To this solution was added phosphorus(V) oxychloride (0.69 mL, 7.44 mmol) dropwise and the mixture was then heated to 50 °C and stirred overnight. The solution was then diluted with diethyl ether (25 mL) and the solution was washed with 10% aqueous copper sulfate solution (2 ^c 25 mL), then with water (2 ^c 25 mL). The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. The oil was then dissolved in di chi orom ethane (33 mL), cooled to 0 °C under a nitrogen atmosphere, and a solution of tetrabutyl ammonium fluoride (1 M in tetrahydrofuran, 14.9 mL, 14.9 mmol) was added. The reaction was stirred at rt over the weekend. The mixture was then diluted with ethyl acetate (50 mL) and washed with water (25 mL). The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. The residue was then purified by normal-phase chromatography (0 - 100 % ethyl acetate in dichloromethane) to give Compound Qll and Compound E5A as a 3: 1 mixture of E and Z isomers. LCMS ESI ⁺ calc’d for C13H14O4 : 235.1 [M+EC] ; found 235.3 [M+EC] Compound Qll (E-isomer): ¹ H NMR (400 MHz, CDCh) d 7.81 (dd, J= 7.6, 1.8 Hz, 2H), 7.47 - 7.34 (m, 3H), 7.02 (t, J= 2.5 Hz, 1H), 3.89 - 3.71 (m, 4H), 3.04 (d, J= 2.5 Hz, 2H), 2.02 (t, J= 6.1 Hz, 2H). Compound E5A (Z-isomer): ¾ NMR (400 MHz, CDCh) d 7.57 (t, J= 2.9 Hz, 1H), 7.52 (dd, J= 8.0, 1.5 Hz, 2H), 7.47 - 7.34 (m, 3H), 3.89 - 3.71 (m, 4H), 3.14 (d, J= 2.9 Hz, 2H),

2.02 (t, 7= 6.1 Hz, 2H).

[0368] Compound E5B: To a solution of Compound Q7 (0.200 g, 0.846 mmol) in dichloromethane (2.8 mL) cooled to 0 °C, was added pyridine (1 drop) followed by oxalyl chloride (0.29 mL, 3.38 mmol) dropwise. The mixture was warmed up to 40 °C and stirred for 45 min. The reaction mixture was then concentrated in vacuo to give Compound E5B. The crude product was not further purified. Exact mass calculated for C16H11CIO: 254.05. Found: 251.3 (M+H of methyl ester-sample prepared in MeOH). LCMS ESC calc’d for C16H11OCI: 251.1 in MeOH [M+CH ₃ OH-HCl+H ⁺ ] ; found: 251.3 [M+CH ₃ OH-HCl+H ⁺ ].

[0369] Compound E5C and Compound E5D (as a racemic mixture of olefin isomers): To a solution of Compound Qll and Compound E5A (As a mixture of olefin isomers) (0.252 g, 1.08 mmol) and pyridine (0.26 mL, 3.23 mmol) in dichloromethane (15.0 mL) under a nitrogen atmosphere was added a solution of acid chloride (0.301 g, 1.18 mmol) in dichloromethane (5.0 mL) dropwise at 0 °C. The reaction was then warmed to rt and stirred for 1 h. The crude reaction mixture was concentrated in vacuo and the residue was purified by normal-phase chromatography (dry load - dichloromethane) (0 - 60 % ethyl acetate in dichloromethane) to give a Compound E5C and Compound E5D (as a racemic mixture of olefin isomers).

[0370] Example A5, Example A6, Example A7, and Example A8: The mixture was subjected to chiral SFC and each enantiomer of each olefin isomer was obtained individually, for a total of 4 compounds. Semi-preparative SFC conditions for chiral analysis and purification were as follows: Column ChiralPack IA 10 x 250 mm, 5pm, isocratic 30% isopropanol, 10 mL/min, 100 bar, 35 °C.

[0371] Example A5 (First Peak to Elute): LCMS ESI ⁺ calc’d for C29H24O5: 453.2

[M+H ⁺ ] Found: 453.1 [M+H ⁺ ] ¾ NMR (400 MHz, CD2CI2) d 7.95 - 7.89 (m, 2H), 7.59 - 7.52 (m, 5H), 7.49 - 7.41 (m, 5H), 7.20 (d, J= 8.0 Hz, 2H), 4.56 (d, 7= 11.9 Hz, 1H), 4.46 (d, J = 11.9 Hz, 1H), 3.90 (d, 7= 12.1 Hz, 1H), 3.82 (d, 7= 12.1 Hz, 1H), 3.29 (dd, 7= 17.7, 3.0 Hz, 1H), 3.17 (dd, J= 17.8, 2.7 Hz, 1H), 2.37 (s, 3H), 2.28 (br s, 1H). Chiral SFC retention time: 10.83 minutes.

[0372] Example A6 (Second Peak to Elute): LCMS ESI ⁺ calc’d for C29H24O5: 453.2

[M+H ⁺ ] Found: 453.1 [M+H ⁺ ] ¾ NMR (400 MHz, CD2CI2) d 7.95 - 7.89 (m, 2H), 7.59 - 7.52 (m, 5H), 7.49 - 7.41 (m, 5H), 7.20 (d, J= 8.0 Hz, 2H), 4.56 (d, 7= 11.9 Hz, 1H), 4.46 (d, J = 11.9 Hz, 1H), 3.90 (d, 7 = 12.1 Hz, 1H), 3.82 (d, 7 = 12.1 Hz, 1H), 3.29 (dd, 7 = 17.7, 3.0 Hz, 1H), 3.17 (dd, 7 = 17.8, 2.7 Hz, 1H), 2.37 (s, 3H), 2.28 (br s, 1H). Chiral SFC retention time: 12.43 minutes.

[0373] Example A7 (Third Peak to Elute): LCMS ESI ⁺ calc’d for C29H24O5: 453.2

[M+H ⁺ ] Found: 453.1 [M+H ⁺ ] ¾ NMR (400 MHz, CD2CI2) d 7.98 - 7.93 (m, 2H), 7.79 - 7.74 (m, 2H), 7.52 - 7.47 (m, 2H), 7.46 - 7.42 (m, 2H), 7.38 (qd, 7 = 5.3, 2.9 Hz, 3H), 7.20 (dd, 7 = 8.4, 0.6 Hz, 2H), 7.04 (t, 7= 2.4 Hz, 1H), 4.54 (d, 7 = 11.9 Hz, 1H), 4.49 (d, 7 = 11.9 Hz, 1H), 3.86 (d, 7= 12.1 Hz, 1H), 3.79 (d, 7= 12.1 Hz, 1H), 3.21 (dd, 7= 17.0, 2.7 Hz, 1H), 3.06 (dd, 7= 16.9, 2.2 Hz, 1H), 2.38 (s, 3H), 2.22 (br s, 1H). Chiral SFC retention time 13.78 minutes.

[0374] Example A8 (Fourth Peak to Elute): LCMS ESI ⁺ calc’d for C29H24O5: 453.2

[M+H ⁺ ] Found: 453.1 [M+H ⁺ ] ¾ NMR (400 MHz, CD2CI2) d 7.98 - 7.93 (m, 2H), 7.79 - 7.74 (m, 2H), 7.52 - 7.47 (m, 2H), 7.46 - 7.42 (m, 2H), 7.38 (qd, 7= 5.3, 2.9 Hz, 3H), 7.20 (dd, 7= 8.4, 0.6 Hz, 2H), 7.04 (t, 7= 2.4 Hz, 1H), 4.54 (d, 7= 11.9 Hz, 1H), 4.49 (d, 7= 11.9 Hz, 1H), 3.86 (d, 7= 12.1 Hz, 1H), 3.79 (d, 7= 12.1 Hz, 1H), 3.21 (dd, 7= 17.0, 2.7 Hz, 1H), 3.06 (dd, 7= 16.9, 2.2 Hz, 1H), 2.38 (s, 3H), 2.22 (br s, 1H). Chiral SFC retention time 16.33 minutes.

Example A9

[0375] Compound E9A: Oxalyl Chloride (102 pL, 1.2 mmol) was added dropwise to an ice-cooled solution of Compound Q8 (88 mg, 0.30 mmol), pyridine (1 drop) and

dichloromethane (1.00 mL). The reaction mixture was allowed to warm to rt and stirred for 30 minutes. The reaction was concentrated under reduced pressure to afford Compound E9A. This material was used without further purification. LCMS ESI ⁺ calc’d for C20H19O2CI: 307.1 in MeOH [M+CH OH-HCl+H ⁺ ] ; found Found: 307.0 [M+CH OH-HCl+H ⁺ ]

[0376] Example A9: To a solution of Compound Q2 (35.0 mg, 0.19 mmol) and pyridine (46 pL, 0.57 mmol) in anhydrous DCM (2.50 mL) at 0 °C was added dropwise a solution of Compound E9A (96 mg, 0.29 mmol) in DCM (1.25 mL). The reaction mixture was warmed to ambient temperature and stirred for an additional hour. The reaction was

concentrated under reduced pressure and purified by column chromatography (0-60% EtOAc in Hexanes, 12 g column) giving Example A9. LCMS ESI ⁺ calc’d for C ₂₉ ¾ ₂ 0 ₆ : 461.2 [M+H ⁺ ] Found: 460.9 [M+H ⁺ ] ¾ NMR (400 MHz, CDCh) d 7.45 - 7.38 (m, 4H), 7.17 - 7.12 (m, 4H), 4.26 (d, 7= 11.8 Hz, 1H), 4.16 (d, J= 11.8 Hz, 1H), 3.67 (dd, J= 12.1, 7.2 Hz, 1H), 3.60 (dd, J = 12.1, 6.3 Hz, 1H), 2.86 - 2.76 (m, 1H), 2.68 - 2.57 (m, 3H), 2.41 - 2.32 (m, 5H), 2.26 (t, J = 2.2 Hz, 3H), 2.05 (t, J = 6.8 Hz, 1H), 1.86 (t, J = 1.4 Hz, 3H), 1.69 - 1.60 (m, 4H).

Example A10

[0377] Compound E10A: A stirred solution of Compound Q9 (101.0 mg, 0.30 mmol) and pyridine (1 drop) in dry DCM (1.00 mL) at 0 °C was added dropwise a solution of oxalyl chloride. The reaction mixture was stirred at room temperature for an additional 30 minutes. The reaction was condensed to afford the desired Compound E10A. This material was used without further purification. LCMS ESC calc’d for C ₂₂ H ₂₃ 0 ₂ C1: 351.1 in MeOH [M+CH OH-HCl+H ⁺ ] ; found: 351.3 [M+CH OH-HCl+H ⁺ ] ¾ NMR (400 MHz, CDCh) d 7.48 - 7.37 (m, 4H), 7.14 (dd, J = 8.0, 2.1 Hz, 2H), 6.90 - 6.77 (m, 2H), 4.03 (td, J = 5.8, 2.9 Hz, 2H), 3.15 (t, J= 7.1 Hz, 1H), 2.68 (t, J = 7.1 Hz, 1H), 2.61 (t, J = 7.7 Hz, 2H), 2.25 - 2.09 (m, 2H), 1.59 (dt, J = 15.3, 7.5 Hz, 4H), 1.41 - 1.29 (m, 2H), 0.92 (t, J = 7.3 Hz, 3H). [0378] Example A10: Compound E10A (102 mg, 0.29 mmol) in DCM (1.25 mL) was added dropwise to an ice-cooled solution of Compound Q2 (35 mg, 0.19 mmol), pyridine (46 pL, 0.57 mmol) and di chi orom ethane (2.50 mL). The reaction mixture was allowed to warm to room temperature, and stirred for 30 mins. The reaction was condensed in vacuo and purified by column chromatography (0-60% EtOAC in hexanes, 12g column) giving Example A10. LCMS ESC calc’d for CsifEeOe: 505.3 [M+H ⁺ ] Found: 505.0 [M+H ⁺ ] ¾ NMR (400 MHz, CDCh) d 7.51 - 7.36 (m, 4H), 7.13 (d, J= 7.0 Hz, 2H), 6.83 (d, J= 7.3 Hz, 2H), 4.28 (d, 7= 11.8 Hz,

1H), 4.19 (d, J= 11.8 Hz, 1H), 4.01 (t, J = 6.0 Hz, 2H), 3.69 (dd, J= 12.1, 7.2 Hz, 1H), 3.62 (dd, J = 12.0, 6.4 Hz, 1H), 2.81 (d, J = 16.6 Hz, 1H), 2.68 - 2.53 (m, 5H), 2.26 (s, 3H), 2.15 - 2.08 (m, 2H), 2.06 (t, J= 7.0 Hz, 1H), 1.86 (s, 3H), 1.64 - 1.53 (m, 4H), 1.42 - 1.28 (m, 2H), 0.92 (t, J = 7.3 Hz, 3H).

Example All

[0379] Compound E11A: To a solution of Compound Q2D (0.511 g, 0.820 mmol) in dry tetrahydrofuran (3.3 mL) cooled to -78 °C under a nitrogen atmosphere was added lithium bis(trimethylsilyl)amide solution (1 M in tetrahydrofuran, 1.23 mL, 1.23 mmol) dropwise and the solution was stirred at -78 °C for 1 h. Cyclopentanone (0.36 mL, 4.10 mmol) was then added to the mixture and it was stirred for an additional 1 h at -78 °C. The reaction was quenched at the same temperature with saturated aqueous ammonium chloride (15 mL) and the mixture was diluted with ethyl acetate (30 mL). The phases were separated and the organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to afford the intermediate alcohol. The crude alcohol was dissolved in pyridine (3.28 mL) and cooled to 0 °C. To this solution was added phosphorus(V) oxychloride (0.23 mL, 2.46 mmol) dropwise and the mixture was then heated to 50 °C and stirred overnight. The solution was then diluted with diethyl ether (25 mL) and washed with 10% aqueous copper sulfate solution (2 ^c 25 mL). The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by normal -phase chromatography (0 - 20% ethyl acetate in hexanes) to give purified material. The purified material was then dissolved in dichloromethane (1.75 mL) and to this solution was added a 1 M solution of tetrabutylammonium fluoride in tetrahydrofuran (1.31 mL, 1.31 mmol) at 0 °C and the solution was slowly allowed to attain room temperature and stirred overnight.

The crude product was then concentrated in vacuo and purified by normal -phase

chromatography (0 - 10% methanol in dichloromethane) to give Compound Ell A. LCMS ESI ⁺ calc’d for CnHi ₆ 0 ₄ : 213.1 [M+H ⁺ ] ; found 213.4 [M+H ⁺ ] ¾ NMR (400 MHz, CDCh) d 3.74 (d, J= 12.1 Hz, 2H), 3.67 (d, J= 12.0 Hz, 2H), 3.38 (br s, 2H), 2.78 (br s, 2H), 2.66 - 2.59 (m, 2H), 2.31 (br s, 2H), 1.73 (dq, J= 9.1, 7.3 Hz, 4H).

[0380] Example All: To a solution Compound E11A (0.022 g, 0.104 mmol) and pyridine (0.025 mL, 0.311 mmol) in dichloromethane (1.7 mL) under a nitrogen atmosphere was added a solution of Compound E4B (0.036 g, 0.114 mmol) in dichloromethane (0.4 mL) dropwise at 0 °C. The reaction was then warmed to rt and stirred for 30 min. The crude reaction mixture was concentrated in vacuo and the residue was purified by normal-phase

chromatography (0 - 60 % ethyl acetate in hexanes) to give Example All. LCMS ESI ⁺ calc’d for C30H32O6: 489.2 [M+H ⁺ ] Found: 489.3 [M+H ⁺ ] ¾ NMR (400 MHz, CDCh) d 7.44 (d, J = 8.9 Hz, 2H), 7.40 (d, J= 8.0 Hz, 2H), 7.16 - 7.12 (m, 2H), 6.86 - 6.81 (m, 2H), 4.25 (dd, J = 34.1, 11.8 Hz, 2H), 4.01 (t, = 6.0 Hz, 2H), 3.66 (ddd, J= 18.6, 12.1, 6.9 Hz, 2H), 2.86 - 2.79 (m, 2H), 2.78 - 2.70 (m, 1H), 2.63 - 2.52 (m, 3H), 2.36 (s, 3H), 2.30 (dd, 7= 5.1, 2.6 Hz, 2H), 2.15 - 2.01 (m, 3H), 1.82 - 1.68 (m, 4H). Example A12

[0381] Compound E12A: To a solution of Compound Q10 (0.055 g, 0.178 mmol) in dichloromethane (0.59 mL) cooled to 0 °C, was added pyridine (1 drop) followed by oxalyl chloride (0.060 mL, 0.713 mmol) dropwise. The mixture was warmed up to rt and stirred for 1 h. The reaction mixture was concentrated in vacuo to give Compound E12A. This material was used without further purification. LCMS ESI ⁺ calc’d for C20H19O2CI in MeOH [M+CH3OH- HCI+TL] ; 323.1. Found: 323.2 [M+CH OH-HCl+H ⁺ ].

[0382] Example A12: To a solution of Compound Q2 (0.030 g, 0.161 mmol) and pyridine (0.039 mL, 0.483 mmol) in dichloromethane (2.5 mL) was added a solution of

Compound E12A (0.058 g, 0.177 mmol) in dichloromethane (0.8 mL) dropwise at 0 °C. The reaction was then warmed to rt and stirred for 30 min. The crude reaction mixture was concentrated in vacuo and the residue was purified by normal-phase chromatography (0 - 60 % ethyl acetate in hexanes). Pure fractions were lyophilized to give Example A12. LCMS ESI ⁺ calc’d for C29H32O6: 477.2 [M+H ⁺ ] Found: 477.1 [M+H ⁺ ] ¾ NMR (400 MHz, CDCh) d 7.44 (d, J= 8.9 Hz, 2H), 7.40 (d, J= 8.1 Hz, 2H), 7.14 (d, J= 7.9 Hz, 2H), 6.88 - 6.81 (m, 2H), 4.28 (d, J= 11.8 Hz, 1H), 4.17 (d, J= 11.8 Hz, 1H), 3.98 (t, J= 5.5 Hz, 2H), 3.66 (ddd, J= 28.0, 12.1, 6.9 Hz, 2H), 2.87 - 2.78 (m, 1H), 2.69 - 2.61 (m, 1H), 2.44 (t, J= 6.9 Hz, 2H), 2.36 (s, 3H), 2.26 (t, J= 2.1 Hz, 3H), 2.09 (t, J= 6.9 Hz, 1H), 1.87 (s, 3H), 1.82 (dt, J= 6.4, 3.2 Hz, 4H). Example A13

[0383] Example A13: Compound E4B (24 mg, 0.80 mmol) in DCM (0.3 mL) was added dropwise to an ice-cooled solution of Compound Qll (12 mg, 0.05 mmol), pyridine (12 pL, 0.15 mmol) and di chi orom ethane (0.70 mL). The reaction mixture was allowed to warm to rt, and stirred for 30 mins. The reaction was condensed in vacuo and purified by column chromatography (0-60% EtOAc in hexanes, 12g column) giving Example A13. LCMS ESI ⁺ calc’d for C32H30O6 : 511.2 [M+H ⁺ ] ; found 511.1 [M+H ⁺ ] ¾ NMR (400 MHz, CDCb) d 7.58 (t, J= 2.9 Hz, 1H), 7.53 - 7.37 (m, 9H), 7.14 (dd, J= 8.5, 0.6 Hz, 2H), 6.82 - 6.76 (m, 2H), 4.35 (d, 7= 11.9 Hz, 1H), 4.27 (d, J= 11.9 Hz, 1H), 3.95 (t, J= 6.0 Hz, 2H), 3.79 (dd, J= 12.1, 6.9 Hz, 1H), 3.71 (dd, J= 12.1, 6.5 Hz, 1H), 3.21 (dd, J= 17.7, 3.0 Hz, 1H), 3.04 (dd, J= 17.7, 2.8 Hz, 1H), 2.55 (t, 7= 7.2 Hz, 2H), 2.36 (s, 3H), 2.12 - 2.03 (m, 3H).

Example A14

[0384] Example A14: To a solution Compound Q12 (0.030 g, 0.101 mmol) and pyridine (0.024 mL, 0.302 mmol) in dichloromethane (1.5 mL) was added a solution of

Compound E4B (0.035 g, 0.111 mmol) in dichloromethane (0.5 mL) dropwise at 0 °C. The reaction was then warmed to rt and stirred for 30 min. The crude reaction mixture was concentrated in vacuo and the residue was purified by normal-phase chromatography (0 - 60 % ethyl acetate in hexanes) to give, after lyophilisation, Example A14. LCMS ESI ⁺ calc’d for CselLeOe: 575.3 [M+H ⁺ ] Found: 575.0 [M+H ⁺ ] ¾NMR (400 MHz, CDCh) d 7.47 - 7.42 (m, 2H), 7.40 (d, 7 = 8.1 Hz, 2H), 7.14 (dd, 7 = 8.5, 0.6 Hz, 2H), 6.87 - 6.83 (m, 2H), 6.82 - 6.76 (m, 1H), 4.32 (d, 7 = 11.9 Hz, 1H), 4.19 (d, 7 = 11.9 Hz, 1H), 4.01 (t, 7= 6.0 Hz, 2H), 3.68 (ddd, 7= 28.4, 12.1, 6.9 Hz, 2H), 2.80 (dd, 7= 17.1, 2.9 Hz, 1H), 2.67 - 2.60 (m, 1H), 2.57 (t, 7= 7.3 Hz, 2H), 2.36 (s, 3H), 2.15 - 2.07 (m, 4H), 2.01 (t, 7= 6.8 Hz, 1H), 1.70 (dd, 7= 12.8, 6.1 Hz, 1H), 1.61 (dt, 7= 13.3, 6.6 Hz, 2H), 1.08 (dd, 7= 14.4, 7.4 Hz, 4H), 0.86 (d, 7= 6.5 Hz, 12H). Example A15

[0385] Example A15: Compound E4B (28 mg, 0.09 mmol) in DCM (0.50 mL) was added dropwise to an ice-cooled solution of Compound Q24 (15 mg, 0.06 mmol), pyridine (16 pL, 0.18 mmol) and di chi orom ethane (0.80 mL). The reaction mixture was allowed to warm to room temperature, and stirred for 30 min. The reaction was condensed in vacuo and purified by column chromatography on silica (0-60% EtOAc in hexanes, 12g column) giving Example A15. LCMS ESC calc’d for CsifEsOe : 519.3 [M+H ⁺ ] ; found 518.9 [M+H ⁺ ] ¹ HNMR (400 MHz, CDCh) d 7.47 - 7.42 (m, 2H), 7.43 - 7.37 (m, 2H), 7.18 - 7.11 (m, 2H), 6.88 - 6.81 (m, 2H), 6.77 (tt, 7 = 7.6, 2.9 Hz, 1H), 4.31 (d, 7= 11.9 Hz, 1H), 4.21 (d, 7= 11.9 Hz, 1H), 4.01 (t, 7 = 6.0 Hz, 2H), 3.75 - 3.68 (m, 1H), 3.69 - 3.61 (m, 1H), 2.84 - 2.76 (m, 1H), 2.69 - 2.60 (m, 1H), 2.57 (t, 7= 7.3 Hz, 2H), 2.36 (s, 3H), 2.18 - 2.07 (m, 4H), 2.01 (t, 7= 6.6 Hz, 1H), 1.52 - 1.42 (m, 3H), 1.27 - 1.15 (m, 4H), 0.87 (d, 7= 6.6 Hz, 6H).

Example A16 and Example A17

[0386] Compound E16A and Compound E17A: To a solution of Compound Q2D

(1.00 g, 1.61 mmol) in tetrahydrofuran (6.4 mL) cooled to -78 °C under N2 atmosphere was added lithium bis(trimethylsilyl)amide solution (1 M in tetrahydrofuran, 2.40 mL, 2.40 mmol) dropwise and the solution was stirred at -78 °C for 40 min. Acetophenone (0.94 mL, 8.00 mmol) was then added and the resulting cold mixture was stirred for an additional 60 min. The reaction was quenched at -78 °C with saturated aqueous ammonium chloride (5 mL) and the mixture was diluted with ethyl acetate (10 mL). The phases were separated and the organic layer was washed with saturated aqueous ammonium chloride (5 mL) followed by saturated aqueous sodium chloride (5 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure to afford the intermediate alcohol. The intermediate alcohol was then dissolved in pyridine (3 mL) and the solution was cooled to 0 °C. To this solution was added phosphorus(V) oxychloride (0.45 mL, 4.83 mmol) dropwise and the mixture was then stirred at 50 °C overnight. The solution was then diluted with diethyl ether (20 mL) and washed with 10% aqueous copper sulfate solution (2 x 10 mL) followed by water (2 x 10 mL). The organic layer was dried over sodium sulfate, filtered and concentrated under reduced 1. The residue was passed through a silica pad using 10% EtOAC in hexanes. The crude product was then dissolved in THF (5 mL), cooled to 0 °C under a nitrogen atmosphere, and treated with a tetrabutyl ammonium fluoride solution (1 M in tetrahydrofuran, 0.72 mL, 0.72 mmol). The reaction was stirred at room temperature for 30 minutes and was condensed under reduced pressure. The corresponding residue was purified by normal -phase chromatography (0 - 100 % ethyl acetate in dichloromethane). Compound E16A and Compound E17A were obtained together (mixture of E and Z isomers). LCMS ESI ⁺ calc’d for C14H16O4 : 249.1 [M+EL] ; found 248.9 [M+EL].

[0387] Example A16 and Example A17: To a solution of a mixture of Compound

E16A and Compound E17A (59 mg total, 0.24 mmol) and 2,64utidine (0.09 mL, 0.72 mmol) in dichloromethane (3.25 mL) under a nitrogen atmosphere at 0 °C was added dropwise a solution of Compound E4B (0.113 g, 0.36 mmol) in dichloromethane (1.50 mL) . The reaction was then warmed to room temperature and stirred for 1 h. The crude reaction mixture was concentrated under reduced pressure and the residue was purified by normal-phase

chromatography (0 - 50 % EtOAc in hexanes). Example A16 was obtained (first to elute) and Example A17 was also obtained (second to elute):

[0388] Example A16: LCMS ESI ⁺ calc’d for C33H32O6 : 525.2 [M+H ⁺ ] ; found 525.1

[M+EL]. ¾ NMR (500 MHz, CDCb) d 7.50 - 7.44 (m, 2H), 7.45 - 7.34 (m, 5H), 7.28 - 7.25 (m, 2H), 7.17 (d, 7 = 7.9 Hz, 2H), 6.89 - 6.83 (m, 2H), 4.26 (d, 7 = 11.9 Hz, 1H), 4.16 (d, 7 =

11.9 Hz, 1H), 4.02 (t, 7= 6.1 Hz, 2H), 3.72 - 3.65 (m, 1H), 3.65 - 3.57 (m, 1H), 2.90 (dq, 7 = 16.8, 2.4 Hz, 1H), 2.68 - 2.62 (m, 1H), 2.62 - 2.55 (m, 4H), 2.39 (s, 3H), 2.17 - 2.08 (m, 2H), 2.02 (m, 1H).

[0389] Example A17: LCMS ESI ⁺ calc’d for C33H32O6 : 525.2 [M+H ⁺ ] ; found 524.9

[M+H ⁺ ] ¾ NMR (400 MHz, CDCb) d 7.47 - 7.31 (m, 7H), 7.24 - 7.18 (m, 2H), 7.14 (d, 7 =

7.9 Hz, 2H), 6.88 - 6.80 (m, 2H), 4.32 (d, 7= 11.8 Hz, 1H), 4.26 (d, 7= 11.8 Hz, 1H), 4.03 (t, 7 = 6.2 Hz, 2H), 3.76 (dd, 7= 12.1, 6.9 Hz, 1H), 3.67 (dd, 7= 12.1, 6.4 Hz, 1H), 3.00 (dd, 7 = 17.0, 1.8 Hz, 1H), 2.82 (dd, 7= 17.0, 1.7 Hz, 1H), 2.61 (t, 7= 7.3 Hz, 2H), 2.36 (s, 3H), 2.18 -

2.10 (m, 5H), 2.06 (t, 7= 6.9 Hz, 1H). Example A18

[0390] Compound E18A: To a solution of Compound Q13 (0.065 g, 0.189 mmol) in dichloromethane (0.63 mL) cooled to 0 °C, was added pyridine (1 drop) followed by oxalyl chloride (0.064 mL, 0.755 mmol) dropwise. The mixture was warmed up to rt and stirred for 1 h. The reaction mixture was concentrated in vacuo to give Compound E18A. The crude product was not further purified. LCMS ESI ⁺ calc’d for C23H19O2CI in MeOH [M+CH3OH-HCI+TL] ;

359.1. Found: 359.3 [M+CH OH-HCl+H ⁺ ].

[0391] Example A18: To a solution Compound Q2 (0.032 g, 0.172 mmol) and pyridine

(0.042 mL, 0.516 mmol) in dichloromethane (2.5 mL) at 0 °C was added a solution of

Compound E18A (0.068 g, 0.189 mmol) in dichloromethane (0.9 mL) dropwise. The reaction was then warmed to rt and stirred for 30 min. The crude reaction mixture was concentrated in vacuo and the residue was purified by normal-phase chromatography (0 - 60 % ethyl acetate in hexanes). Pure fractions were lyophilized to give Example A18. LCMS ESI ⁺ calc’d for

C32H32O6: 513.2 [M+EL] Found: 513.1 [M+H ⁺ ] ¾ NMR (400 MHz, CDCb) d 8.38 (d, J= 8.1 Hz, 1H), 8.25 (d, J= 8.4 Hz, 1H), 7.66 (d, J= 8.0 Hz, 1H), 7.64 - 7.58 (m, 1H), 7.56 - 7.49 (m, 3H), 7.19 (d, J= 7.9 Hz, 2H), 6.79 (d, 7= 8.1 Hz, 1H), 4.30 - 4.16 (m, 4H), 3.62 (ddd, J = 18.2,

12.1, 6.6 Hz, 2H), 2.77 - 2.65 (m, 3H), 2.58 (d, J= 16.6 Hz, 1H), 2.39 (s, 3H), 2.29 (dd, J =

12.5, 6.5 Hz, 2H), 2.23 (t, J = 2.1 Hz, 3H), 1.97 (t, J = 6.7 Hz, 1H), 1.79 (s, 3H). Example A19

Example A19

[0392] Compound E19A: To a solution of Compound Q15 (48 mg, 0.17 mmol) and pyridine (46 pL, 0.57 mmol) in anhydrous DCM (2.50 mL) at 0 ^° C was added dropwise a solution of Compound E1A (90 mg, 0.26 mmol) in DCM (1.25 mL). The reaction mixture was stirred at room temperature for an additional hour. The reaction was concentrated under reduced pressure and purified by column chromatography on silica (0-30% EtOAc in Hexanes, 24 g column) giving Compound E19A. LCMS ESI ⁺ calc’d for C38H42O6: 595.3 [M+H ⁺ ] Found: 595.3 [M+H ⁺ ]

[0393] Example A19: To a solution of Compound E19A (47 mg, 0.08 mmol) in anhydrous DCM (1.50 mL) at -78 °C was added dropwise a solution of BCE (0.24 mL, 1.0 M in heptane, 0.24 mmol). The reaction mixture was stirred for 30 minutes and quenched at -78 °C with a saturated solution of NaHCCh (3 mL). The layers were separated and the aqueous phase was extracted 3 times with DCM. The combined organic layers were dried overNaiSCL, filtered, concentrated under reduced pressure and purified by column chromatography on silica (0-60% EtOAc in Hexanes, 12 g column) giving Example A19. LCMS ESI ⁺ calc’d for

C _3i H ₄₆ 0 ₆ : 505.3 [M+H ⁺ ] ; found 505.2 [M+H ⁺ ] ¾NMR (400 MHz, CDCb) d 7.47 - 7.41 (m, 4H), 7.38 - 7.33 (m, 2H), 6.87 - 6.81 (m, 2H), 4.28 (d, J= 11.8 Hz, 1H), 4.19 (d, J= 11.8 Hz, 1H), 4.01 (t, = 6.0 Hz, 2H), 3.69 (dd, 7= 12.1, 7.3 Hz, 1H), 3.62 (dd, = 12.1, 6.5 Hz, 1H), 2.85 - 2.75 (m, 1H), 2.69 - 2.60 (m, 1H), 2.57 (t, J= 7.3 Hz, 2H), 2.26 (t, J= 2.2 Hz, 3H), 2.16 - 2.06 (m, 2H), 2.06 - 1.99 (m, 1H), 1.86 (t, J= 1.4 Hz, 3H), 1.32 (s, 9H).

Example A20

[0394] Compound E20A: To a solution of Compound Q17 (96 mg, 0.35 mmol) and pyridine (85 pL, 1.05 mmol) in anhydrous DCM (5.00 mL) at 0 °C was added dropwise a solution of Compound E1A (180 mg, 0.52 mmol) in DCM (2.00 mL). The reaction mixture was stirred at room temperature for an additional hour. The reaction was concentrated under reduced pressure and purified by column chromatography on silica (0-30% EtOAc in Hexanes, 24 g column) giving Compound E20A. LCMS ESI ⁺ calc’d for C38H42O6: 595.3 [M+H ⁺ ] Found: 595.3 [M+H ⁺ ]

[0395] Example A20: To a solution of Compound E20A (43 mg, 0.08 mmol) in anhydrous DCM (1.50 mL) at -78 °C was added dropwise a solution of BCE (0.21 mL, 1.0 M in heptane, 0.21 mmol). The reaction mixture was stirred for 30 minutes and quenched at -78 °C with a saturated solution of NaHCCh (3 mL). The layers were separated and the aqueous phase was extracted 3 times with DCM. The combined organic layers were dried over NaiSCL, filtered, concentrated under reduced pressure and purified by column chromatography on silica (0-60% EtOAc in Hexanes, 12 g column) giving Example A20. LCMS ESI ⁺ calc’d for

C _3i H ₄₆ 0 ₆ : 505.3 [M+H ⁺ ] ; found 505.2 [M+H ⁺ ] ¾ NMR (400 MHz, CDCh) d 7.47 - 7.41 (m, 4H), 7.38 - 7.33 (m, 2H), 6.87 - 6.81 (m, 2H), 4.28 (d, J= 11.8 Hz, 1H), 4.19 (d, J= 11.8 Hz, 1H), 4.01 (t, J= 6.0 Hz, 2H), 3.69 (dd, 7= 12.1, 7.3 Hz, 1H), 3.62 (dd, = 12.1, 6.5 Hz, 1H), 2.85 - 2.75 (m, 1H), 2.69 - 2.60 (m, 1H), 2.57 (t, J= 7.3 Hz, 2H), 2.26 (t, J= 2.2 Hz, 3H), 2.16 - 2.06 (m, 2H), 2.06 - 1.99 (m, 1H), 1.86 (t, J= 1.4 Hz, 3H), 1.32 (s, 9H).

Example A21

[0396] Compound E21A: To a solution of Compound Q18 (50 mg, 0.13 mmol) and pyridine (30 pL, 0.19 mmol) in anhydrous DCM (1.50 mL) at 0 ^° C was added dropwise a solution of Compound E4B (60 mg, 0.19 mmol) in DCM (1.00 mL). The reaction mixture was stirred at room temperature for an additional 2 hours. The reaction was concentrated under reduced pressure and purified by column chromatography on silica (0-30% EtOAc in Hexanes, 12 g column) giving Compound E21A. LCMS ESI ⁺ calc’d for C43H52O6 : 665.4 [M+H ⁺ ] ; found 665.1 [M+H ⁺ ] [0397] Example A21: To a solution of Compound E21A (59 mg, 0.09 mmol) in anhydrous DCM (1.80 mL) at -78 °C was added dropwise a solution of BCh (0.27 mL, 1.0 M in heptane, 0.27 mmol). The reaction mixture was stirred for 15 minutes and quenched at -78 °C with a saturated solution of NaHCCb (6 mL). The layers were separated and the aqueous phase was extracted 3 times with DCM. The combined organic layers were dried over NaiSCL, filtered, concentrated under reduced pressure and purified by column chromatography on silica (0-50% EtOAc in Hexanes, 12 g column) giving Example A21. LCMS ESI ⁺ calc’d for C ₃₆ H ₄₆ 0 ₆ : 575.3 [M+H ⁺ ] ; found 575.3 [M+H ⁺ ] ¾ NMR (400 MHz, CDCh) d 7.44 (d, 7 = 8.8 Hz, 2H), 7.40 (d, 7 = 8.0 Hz, 2H), 7.14 (d, 7 = 7.9 Hz, 2H), 6.86 - 6.75 (m, 3H), 4.32 (d, 7 =

11.9 Hz, 1H), 4.19 (d, 7= 11.8 Hz, 1H), 4.01 (t, 7= 6.0 Hz, 2H), 3.75 - 3.68 (m, 1H), 3.68 - 3.61 (m, 1H), 2.79 (d, 7 = 16.4 Hz, 1H), 2.63 (d, 7 = Ml Hz, 1H), 2.57 (t, J= 7.3 Hz, 2H), 2.36 (s, 3H), 2.11 (t, 7= 6.6 Hz, 4H), 2.05 - 1.97 (m, 1H), 1.75 - 1.66 (m, 1H), 1.66 - 1.57 (m, 2H), 1.16 - 1.00 (m, 4H), 0.86 (d, 7= 6.5 Hz, 12H).

Example A22

[0398] Compound E22A: To a solution of Compound Q18 (25 mg, 0.06 mmol) and pyridine (15 pL, 0.18 mmol) in anhydrous DCM (0.80 mL) at 0 °C was added dropwise a solution of Compound E5B (25 mg, 0.10 mmol) in DCM (0.50 mL). The reaction mixture was stirred at room temperature for an additional 3 hours. The reaction was concentrated under reduced pressure and purified by column chromatography on silica (0-30% EtOAc in Hexanes, 12 g column) giving Compound E22A. LCMS ESI ⁺ calc’d for C ₄₀ H ₄₆ O ₅ : 607.3 [M+H ⁺ ] ; found 607.1 [M+H ⁺ ]

[0399] Example A22: To a solution of Compound E22A (30 mg, 0.05 mmol) in anhydrous DCM (1.00 mL) at -78 °C was added dropwise a solution of BCE (0.15 mL, 1.0 M in heptane, 0.15 mmol). The reaction mixture was stirred for 15 minutes and quenched at -78 °C with a saturated solution of NaHCCh (3 mL). The layers were separated and the aqueous phase was extracted 3 times with DCM. The combined organic layers were dried overNaiSCL, filtered, concentrated under reduced pressure and purified by column chromatography on silica (0-50% EtOAc in Hexanes, 12 g column) giving Example A22. LCMS ESI ⁺ calc’d for C ₃₃ H ₄₀ O ₅ : 516.3 [M+H ⁺ ] ; found 517.2 [M+H ⁺ ] ¾ NMR (400 MHz, CDCb) d 7.97 (d, J= 6.7 Hz, 2H), 7.57 (d, J= 8.2 Hz, 2H), 7.44 (d, J= 8.0 Hz, 2H), 7.18 (d, J= 8.1 Hz, 2H), 6.88 - 6.79 (m, 1H), 4.58 - 4.40 (m, 2H), 3.82 (dd, J= 12.1, 6.6 Hz, 1H), 3.75 (dd, J= 12.2, 5.8 Hz, 1H), 2.89 (d, J= 17.1 Hz, 1H), 2.73 (d, J= 17.1 Hz, 1H), 2.38 (s, 3H), 2.17 - 2.08 (m, 3H), 1.74 - 1.65 (m, 1H), 1.65 - 1.57 (m, 2H), 1.15 - 0.99 (m, 4H), 0.90 - 0.78 (m, 12H).

Example A23

[0400] Compound E23A: To a solution of Compound Q18 (0.050 g, 0.129 mmol) in anhydrous dichloromethane (2.57 mL) was added Compound Q5 (0.041 g, 0.129 mmol), followed by 4-(dimethylamino)pyridine (0.039 g, 0.322 mmol) and bis(2-oxo-3- oxazolidinyl)phosphinic chloride (BOPC1, 0.082 g, 0.322 mmol) at rt. The solution was stirred for 30 min. The reaction mixture was then quenched with saturated aqueous ammonium chloride (2 mL) and extracted with dichloromethane (3 x 5 mL). The combined organic layers were dried over sodium sulfate and concentrated in vacuo. The residue was purified by normal-phase chromatography (10 - 20% ethyl acetate in hexanes) to give Compound E23A. LCMS ESI ⁺ calc’d for C ₄₅ H ₅₆ 0 ₆ : 693.4 [M+H ⁺ ] ; found 693.6 [M+H ⁺ ]

[0401] Example A23: To a solution of Compound E23A (0.076 g, 0.110 mmol) in toluene (4.4 mL) cooled to -78 °C was added boron trichloride (1 M solution in

dichloromethane, 0.329 mL, 0.329 mmol) dropwise. After stirring for 10 min at -78 °C, the reaction was quenched with saturated aqueous sodium bicarbonate (6 mL) and stirred at rt for 20 min. The organic layer was dried over sodium sulfate and concentrated in vacuo. The residue was then purified by normal -phase chromatography (10 - 30 % ethyl acetate in hexanes) to give, after lyophilization, Example A23. LCMS ESI ⁺ calc’d for C38H50O6 : 603.4 [M+H ⁺ ] ; found 603.3 [M+H ⁺ ] ¾ NMR (400 MHz, CDCh) d 7.44 (d, 7 = 8.8 Hz, 2H), 7.40 (d, 7 = 8.1 Hz, 2H), 7.14 (d, 7 = 7.9 Hz, 2H), 6.85 (d, 7 = 8.9 Hz, 2H), 6.83 - 6.77 (m, 1H), 4.32 (d, 7= 11.9 Hz,

1H), 4.16 (d, 7= 11.9 Hz, 1H), 3.97 (t, 7 = 6.3 Hz, 2H), 3.68 (ddd, 7 = 28.7, 12.1, 6.9 Hz, 2H), 2.81 (d, 7 = 17.1 Hz, 1H), 2.63 (d, 7= 17.1 Hz, 1H), 2.42 - 2.36 (m, 2H), 2.36 (s, 3H), 2.12 (dd, 7= 7.5, 6.0 Hz, 2H), 2.06 (t, 7= 6.8 Hz, 1H), 1.86 - 1.76 (m, 2H), 1.76 - 1.66 (m, 3H), 1.66 - 1.59 (m, 2H), 1.53 - 1.46 (m, 2H), 1.18 - 1.00 (m, 4H), 0.86 (d, 7= 6.6 Hz, 12H).

Example A24

[0402] Compound E24A: To a solution of Compound Q18 (30 mg, 0.08 mmol) in dichloromethane (1.60 mL) was added Compound Q19 (21 mg, 0.08 mmol) followed by DMAP (24 mg, 0.19 mmol) and BOPC1 (49 mg, 0.19 mmol). The mixture was stirred at room temperature for 30 min. The reaction mixture was quenched by the addition of saturated ammonium chloride (2 mL) and extracted 3 times with DCM (3X 3 mL). The combined organic phases were dried (NaiSCL), filtered and concentrated. The residue was purified by column chromatography (0 to 30% EtOAc in hexanes) to afford Compound E24A. LCMS ESI ⁺ calc’d for C43H52O5 : 649.4 [M+H ⁺ ] ⁺ ] ; found 649.3 [M+H ⁺ ]

[0403] Example A24: To a solution of Compound E24A (41 mg, 0.07 mmol) in anhydrous toluene (1.30 mL) at -78 °C was added dropwise a solution of BCE (0.19 mL, 1.0 M in dichloromethane, 0.19 mmol). The reaction mixture was stirred for 10 minutes and quenched at -78 °C with a saturated solution of NaElCCb (5 mL). The resulting solution was warmed to room temperature and stirred for 30 minutes. The layers were separated and the aqueous phase was extracted 3 times with EtOAc. The combined organic layers were dried overNa ₂ S0 ₄ , filtered, concentrated under reduced pressure and purified by column chromatography on silica (0-60% EtOAc in Hexanes, 12 g column) giving Example A24. LCMS ESI ⁺ calc’d for C36H46O5 : 559.3 [M+H ⁺ ] ; found 559.3 [M+H ⁺ ] ¾ NMR (400 MHz, CDCb) d 7.49 - 7.41 (m, 4H), 7.17 (dd, J= 8.1, 3.6 Hz, 4H), 6.85 - 6.79 (m, 1H), 4.35 - 4.28 (m, 1H), 4.22 - 4.16 (m, 1H), 3.74 (dd, J= 11.9, 6.2 Hz, 1H), 3.67 (dd, J= 11.9, 5.7 Hz, 1H), 2.87 - 2.79 (m, 1H), 2.72 - 2.62 (m, 3H), 2.44 - 2.34 (m, 5H), 2.14 (t, J= 6.0 Hz, 2H), 2.08 - 2.01 (m, 1H), 2.01 - 1.93 (m, 2H), 1.77 - 1.69 (m, 1H), 1.68 - 1.60 (m, 2H), 1.18 - 1.05 (m, 4H), 0.91 - 0.86 (m, 12H).

Example A25

[0404] Compound E25A: To a solution of Compound Q18 (30 mg, 0.08 mmol) in dichloromethane (1.60 mL) was added Compound Q20 (20 mg, 0.08 mmol) followed by DMAP (24 mg, 0.19 mmol) and BOPC1 (49 mg, 0.19 mmol). The mixture was stirred at room temperature for 30 min. The reaction mixture was quenched by the addition of saturated ammonium chloride (2 mL) and extracted 3 times with DCM (3X 3 mL). The combined organic phases were dried (NaiSCL), filtered and concentrated. The residue was purified by column chromatography (0 to 30% EtOAc in hexanes) to afford Compound E25A. LCMS ESI ⁺ calc’d for C ₄₂ H ₅₀ O ₅ : 635.4 [M+H ⁺ ] ⁺ ] ; found 635.4 [M+H ⁺ ]

[0405] Example A25: To a solution of Compound E25A (38 mg, 0.07 mmol) in anhydrous toluene (1.20 mL) at -78 °C was added dropwise a solution of BCE (0.18 mL, 1.0 M in dichloromethane, 0.19 mmol). The reaction mixture was stirred for 10 minutes and quenched at -78 °C with a saturated solution of NaElCCh (5 mL). The resulting solution was warmed to room temperature and stirred for 30 minutes. The layers were separated and the aqueous phase was extracted 3 times with EtOAc. The combined organic layers were dried overNa ₂ S0 ₄ , filtered, concentrated under reduced pressure and purified by column chromatography on silica (0-60% EtOAc in Hexanes, 12 g column) giving Example A25. LCMS ESI ⁺ calc’d for C ₃₅ H ₄₄ O ₅ : 545.3 [M+H ⁺ ] ; found 545.2 [M+H ⁺ ] ¾ NMR (400 MHz, CDCb) d 7.42 (dd, J = 14.2, 8.0 Hz, 4H), 7.19 - 7.12 (m, 4H), 6.82 - 6.75 (m, 1H), 4.29 (d, J= 11.9 Hz, 1H), 4.15 (d, J = 11.9 Hz, 1H), 3.60 (dd, J= 31.9, 11.6 Hz, 2H), 2.95 (t, J= 7.6 Hz, 2H), 2.79 - 2.64 (m, 3H), 2.54 (d, 7= 18.2 Hz, 1H), 2.36 (s, 3H), 2.11 (t, J= 6.6 Hz, 2H), 1.99 (s, 1H), 1.75 - 1.66 (m,

1H), 1.64 - 1.58 (m, 2H), 1.15 - 0.99 (m, 4H), 0.85 (d, J= 6.4 Hz, 12H).

Example A26

[0406] Compound E26A: To a solution of Compound Q18 (30 mg, 0.08 mmol) in dichloromethane (1.60 mL) was added Compound Q21 (19 mg, 0.08 mmol) followed by DMAP (24 mg, 0.19 mmol) and BOPC1 (49 mg, 0.19 mmol). The mixture was stirred at room temperature for 30 min. The reaction mixture was quenched by the addition of saturated ammonium chloride (2 mL) and extracted 3 times with DCM (3X 3 mL). The combined organic phases were dried (NaiSCL), filtered and concentrated. The residue was purified by column chromatography (0 to 30% EtOAc in hexanes) to afford Compound E26A. LCMS ESI ⁺ calc’d for C41H48O5 : 621.4 [M+H ⁺ ] ⁺ ] ; found 621.3 [M+H ⁺ ]

[0407] Example A26: To a solution of Compound E26A (40 mg, 0.07 mmol) in anhydrous toluene (1.30 mL) at -78 °C was added dropwise a solution of BCE (0.19 mL, 1.0 M in dichloromethane, 0.19 mmol). The reaction mixture was stirred for 10 minutes and quenched at -78 °C with a saturated solution of NaElCCh (5 mL). The resulting solution was warmed to room temperature and stirred for 30 minutes. The layers were separated and the aqueous phase was extracted 3 times with EtOAc. The combined organic layers were dried overNa ₂ S0 ₄ , filtered, concentrated under reduced pressure and purified by column chromatography on silica (0-60% EtOAc in Hexanes, 12 g column) giving Example A26. LCMS ESI ⁺ calc’d for C34H42O5 : 531.3 [M+H ⁺ ] ; found 531.2 [M+H ⁺ ] ¾ NMR (400 MHz, CDCh) d 7.47 (d, J= 8.0 Hz, 2H), 7.41 (d, J= 8.0 Hz, 2H), 7.22 (d, J= 8.0 Hz, 2H), 7.15 (d, J= 7.9 Hz, 2H), 6.80 - 6.73 (m, 1H), 4.36 - 4.27 (m, 1H), 4.24 - 4.15 (m, 1H), 3.70 - 3.53 (m, 4H), 2.71 (d, 7= 16.7 Hz, 1H), 2.53 (d, J= 17.6 Hz, 1H), 2.37 (s, 3H), 2.07 (dd, J = 13.8, 7.0 Hz, 2H), 1.94 (s, 1H), 1.74 - 1.65 (m, 1H), 1.65 - 1.58 (m, 2H), 1.16 - 1.00 (m, 4H), 0.85 (d, J= 6.5 Hz, 12H).

Example A27

[0408] Compound E27A: To a solution of Compound Q18 (30 mg, 0.08 mmol) in anhydrous dichloromethane (1.54 mL) was added Compound Q22 (22 mg, 0.08 mmol), followed by 4-(dimethylamino)pyridine (24 mg, 0.19 mmol) and bis(2-oxo-3- oxazolidinyl)phosphinic chloride (BOPC1, 49 mg, 0.19 mmol) at rt. The solution became was stirred for 30 min. The reaction mixture was then quenched with saturated aqueous ammonium chloride (3 mL) and extracted with dichloromethane (3 x 3 mL). The combined organic layers were dried over sodium sulfate and concentrated in vacuo. The residue was purified by normal- phase chromatography (0 - 30% ethyl acetate in hexanes) to give Compound E27A. LCMS ESI ⁺ calc’d for C ₄₈ H ₄₈ 0 ₅ : 657.4 [M+H ⁺ ] ; found 657.5 [M+H ⁺ ]

[0409] Example All: To a solution of Compound E27A (30 mg, 0.05 mmol) in toluene (1.0 mL) cooled to -78 °C was added boron trichloride (1 M solution in

dichloromethane, 0.150 mL, 0.150 mmol) dropwise. After stirring for 15 min at -78 °C, the reaction was quenched with saturated aqueous sodium bicarbonate (2 mL) and the mixture was stirred at rt for 20 min. The layers were separated and the aqueous phase was extracted 3 times with EtOAc. The combined organic layers was dried over sodium sulfate and concentrated in vacuo. The residue was then purified by normal-phase chromatography (0 - 60 % ethyl acetate in hexanes) to give, after lyophilisation, Example A27. LCMS ESI ⁺ calc’d for C ₃₇ H ₄₂ O ₅ : 567.3

[M+H ⁺ ] ; found 567.2 [M+H ⁺ ] ¾ NMR (400 MHz, CDCh) d 8.53 (s, 1H), 8.06 (s, 1H), 8.03 - 7.97 (m, 1H), 7.90 (d, J= 8.5 Hz, 1H), 7.84 (d, J= 8.7 Hz, 1H), 7.64 (d, J= 8.5 Hz, 1H), 7.48 (d, J= 8.0 Hz, 2H), 7.19 (d, J= 7.9 Hz, 2H), 6.90 - 6.79 (m, 1H), 4.62 - 4.57 (m, 1H), 4.52 (d, J = 11.9 Hz, 1H), 3.85 (dd, J= 12.2, 7.2 Hz, 1H), 3.78 (dd, J= 12.2, 6.6 Hz, 1H), 2.97 - 2.87 (m, 1H), 2.77 (d, J= 17.1 Hz, 1H), 2.39 (s, 3H), 2.23 (t, = 6.8 Hz, 1H), 2.16 - 2.07 (m, 2H), 1.72 - 1.64 (m, 1H), 1.62 - 1.49 (m, 2H), 1.12 - 0.99 (m, 4H), 0.81 (ddd, J= 11.6, 7.8, 3.5 Hz, 12H).

Example A28

Example A28 [0410] Compound E28A: To a solution of Compound Q18 (30 mg, 0.08 mmol) in anhydrous dichloromethane (1.54 mL) was added Compound Q23 (24 mg, 0.08 mmol), followed by 4-(dimethylamino)pyridine (24 mg, 0.19 mmol) and bis(2-oxo-3- oxazolidinyl)phosphinic chloride (BOPC1, 49 mg, 0.19 mmol) at rt. The solution was stirred for 30 min. The reaction mixture was then quenched with saturated aqueous ammonium chloride (2 mL) and extracted with dichloromethane (3 x 2 mL). The combined organic layers were dried over sodium sulfate and concentrated in vacuo. The residue was purified by normal-phase chromatography (0 - 30% ethyl acetate in hexanes) to give Compound E28A. LCMS ESI ⁺ calc’d for C46H52O5 : 685.4 [M+H ⁺ ] ; found 685.7 [M+H ⁺ ]

[0411] Example A28:To a solution of Compound E28A (31 mg, 0.05 mmol) in toluene

(0.91 mL) cooled to -78 °C was added boron trichloride (1 M solution in dichloromethane, 0.15 mL, 0.15 mmol) dropwise. After stirring for 10 min at -78 °C, the reaction was quenched with saturated aqueous sodium bicarbonate (2 mL) and the mixture was stirred at rt for 20 min. The mixture was diluted and extracted with dichloromethane (3 x 2 mL) and the combined organic layers were dried over sodium sulfate, filtered and concentrated. The residue was then purified by normal -phase chromatography (0 - 60 % ethyl acetate in hexanes) to give, after

lyophilisation, Example A28. LCMS ESI ⁺ calc’d for C39H46O5 : 595.3 [M+EL] ; found 595.3 [M+EL] ¾ NMR (400 MHz, CDCh) d 8.00 (s, 1H), 7.76 (d, 7 = 3.2 Hz, 1H), 7.74 (d, 7 = 3.3 Hz, 1H), 7.61 (s, 1H), 7.56 (dd, 7 = 8.5, 1.5 Hz, 1H), 7.46 (d, 7= 8.1 Hz, 2H), 7.34 (dd, 7= 8.5, 1.6 Hz, 1H), 7.17 (d, 7 = 7.9 Hz, 2H), 6.77 (td, 7 = 7.6, 3.8 Hz, 1H), 4.29 (d, 7 = 11.9 Hz, 1H), 4.14 (d, 7 = 11.8 Hz, 1H), 3.60 (dd, 7= 12.1, 7.1 Hz, 1H), 3.52 (dd, 7= 12.0, 6.3 Hz, 1H), 3.11 (t, 7= 7.5 Hz, 2H), 2.80 - 2.74 (m, 2H), 2.73 - 2.65 (m, 1H), 2.54 - 2.46 (m, 1H), 2.38 (s, 3H), 2.04 (dd, 7= 7.5, 5.9 Hz, 2H), 1.94 (t, 7= 6.8 Hz, 1H), 1.74 - 1.64 (m, 1H), 1.59 (dt, 7= 12.0, 6.0 Hz, 2H), 1.15 - 0.98 (m, 4H), 0.84 (dd, 7= 6.5, 1.4 Hz, 12H).

PKC Isoform Translocation Assays

[0412] The specificity of PKC isoform activation was determined in eight A549 cell lines, each stably expressing a single PKC isoform fused to tGFP. Cells were plated in clear bottom 384-well plates in 80 mΐ at 100K cells/mL in RPMI with 10% FBS one day before adding compounds in 10-point dose responses. Cells were incubated with compound for 60 min at 37°C. Within the last 15 minutes of this incubation, Hoechst was added to stain nuclei. Plates were then washed with cold DPBS (IX, 20 mM Hepes) to remove all compounds and fixed with 2% paraformaldehyde for 30 minutes at 4°C. Cells were stained with membrane dye WGA-647 for 10 minutes at 4°C and then washed vigorously with cold DPBS (IX, 20 mM Hepes) to remove excess dye. Cells were quickly imaged using a Cellomics Array Scan (Thermo Fisher) with 20x objective at room temperature (22°C). The images were analyzed using a Cellomics automated image analysis algorithm to quantify cytoplasm and plasma membrane localization. This algorithm quantified the mean percentage of GFP that co-localized with the plasma membrane dye relative to the total GFP. The values are plotted against concentrations of the compound to determine EC50 values.

Induced HIV-1 Expression in CD4 T cell Cultures from HIV-1 Infected Subjects on cART Treated with PKC Agonists

[0413] To assess the ability to activate HIV-1 expression in CD4 T cells, leukapheresis samples were obtained from HIV-1 infected human subjects on cART and virally suppressed with plasma HIV RNA < 50 copies/mL for at least 1 year. The leukapheresis product was diluted 1 : 1 with PBS and layered over Ficoll for isolation of PBMCs. PBMCs were treated with red blood cell lysis buffer and rested overnight (10 million cells/ml) in tissue culture medium (RPMI 1640 supplemented with 10% FBS and Pen/Strep). Total CD4 T cells were isolated using bead-based purification methods. Purified CD4 T cells were cultured and treated with 10 mM of each compound or with dimethyl sulfoxide (DMSO, vehicle control) for 3 days, using 4 replicates per condition. The cultures were maintained in the presence of antivirals (100 nM elvitegravir, 100 nM efavirenz) to prevent viral spread and amplification. At the end of the incubation period, cell-free culture supernatants were harvested and HIV-1 RNA levels were quantified by the COBAS ^® AmpliPrep/COBAS ^® TaqMan HIV-1 Test, v2.0 (Sizmann et ak, J Clin. Virology, 2010, Vol. 49, pp. 41-46). Geometric mean of the 4 replicates was calculated for each donor. HIV-1 RNA was normalized to 5 pM Prostratin (% prostratin) and separately, to the DMSO vehicle control (fold increase). The number of donors tested for each is also shown (N).

Induced CD69 activation in CD4 T cell Cultures from Subjects Treated with PKC Agonists

[0414] To assess the ability to activate CD69 on CD4 T cells, leukapheresis samples were obtained from healthy (HIV-1 uninfected) human subjects. PBMCs were isolated by Ficoll method and CD4 T cells were isolated from PBMCs. Purified CD4 T cells were cultured in 96- well tissue culture plates and treated with PKC modulating compounds ranging from 1 to 25000 nM or with dimethyl sulfoxide (DMSO, vehicle control) for 24 hrs. At the end of the incubation, cells were stained with live dead dye and antibodies specific for CD4 and CD69. The percent CD69+ CD4 T cells were measured by flow cytometry using the BD Fortessa instrument, analyzed using FlowJo software and plotted against compound concentration to determine EC50 values.

[0415] Analytical data for Examples A1 to A28 are set forth in Table 1. Analytical data for reference compounds are set forth in Table 2.

Table 1.

Table 2.