GEMCITABINE PRODRUGS

BACKGROUND

[0001] A need exists in the medicinal arts for compositions and methods for gemcitabine prodrugs in the course of treating numerous types of cancer.

BRIEF SUMMARY OF THE INVENTION

[0002] Provided herein are prodrugs of phosphorylated gemcitabine derivatives, pharmaceutical

compositions comprising said compounds, and methods for using said compounds for the treatment of cancer.

[0003] One embodiment provides a compound, or a pharmaceutically acceptable salt thereof, having the structure of Formula (I):

wherein

R is selected from fatty alcohol, glycerolipid, glycerophospholipids, sphingolipids, sterol-lipids, prenol lipids, saccharolipids and polyketides;

R ¹ is hydrogen, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted

heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; and R ² is hydrogen, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C ₂ -C ₄

alkenyl, substituted or unsubstituted C ₂ -C ₄ alkynyl, -C(=0)Ci-C ₄ alkyl, -C(=0)0(Ci-C ₄ alkyl), substituted or unsubstituted aryl, or substituted or unsubstituted benzyl,

wherein a substituted group is substituted with 1, 2, or 3 groups independently selected from halogen, -OH, -SH, -NH ₂ , -CN, -C(=0)0H, -C(=0)0(Ci-C ₄ alkyl), -C(=0)NH ₂ , - C(=0)NH(C _I -C ₄ alkyl), -C(=0)N(Ci-C ₄ alkyl) ₂ , Ci-C ₄ alkyl, -S(Ci-C ₄ alkyl), Ci-C ₄ alkoxy, C3-C6 cycloalkyl, C ₂ -Cs heterocyclyl, -NH(C _I -C4 alkyl), -N(Ci-C ₄ alkyl) ₂ , phenyl, -C6H4OH, imidazole, and arginine.

[0004] Another embodiment provides a compound, or a pharmaceutically acceptable salt thereof, having the structure of Formula (II):

wherein

R is selected from fatty alcohol, glycerolipid, glycerophospholipids, sphingolipids, sterol-lipids, prenol lipids, saccharolipids and polyketides;

R ¹ is hydrogen, substituted or unsubstituted Ci-Cio alkyl, substituted or unsubstituted

heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; and R ² is hydrogen, substituted or unsubstituted C ₁ -C ₄ alkyl, substituted or unsubstituted C ₂ -C ₄

alkenyl, substituted or unsubstituted C ₂ -C ₄ alkynyl, -C(=0)Ci-C ₄ alkyl, -C(=0)0(Ci-C ₄ alkyl), substituted or unsubstituted aryl, or substituted or unsubstituted benzyl,

L is a linker selected from an alkylene amide group, an alkylene ester group, an alkylene

carbamate group, a disulfide group, a phosphodiester group, and a phosphoramidate group; and

G is a cytotoxic chemotherapy agent,

wherein a substituted group is substituted with 1, 2, or 3 groups independently selected from halogen, -OH, -SH, -NH ₂ , -CN, -C(=0)0H, -C(=0)0(Ci-C ₄ alkyl), -C(=0)NH ₂ , - C(=0)NH(C _I -C ₄ alkyl), -C(=0)N(Ci-C ₄ alkyl) ₂ , C1-C4 alkyl, -S(Ci-C ₄ alkyl), C1-C4 alkoxy, C3-C6 cycloalkyl, C2-C5 heterocyclyl, -NH(C _I -C ₄ alkyl), -N(C _I -C ₄ alkyl) ₂ , phenyl, -C6H4OH, imidazole, and arginine.

[0005] Another embodiment provides a compound, or a pharmaceutically acceptable salt thereof, having the structure of Formula (III):

R is selected from fatty alcohol, glycerolipid, glycerophospholipids, sphingolipids, sterol-lipids, prenol lipids, saccharolipids and polyketides;

R ¹ is hydrogen, substituted or unsubstituted Ci-Cio alkyl, substituted or unsubstituted

heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; and R ² is hydrogen, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C2-C4

alkenyl, substituted or unsubstituted C2-C4 alkynyl, -C(=0)Ci-C ₄ alkyl, -C(=0)0(Ci-C ₄ alkyl), substituted or unsubstituted aryl, or substituted or unsubstituted benzyl,

wherein a substituted group is substituted with 1, 2, or 3 groups independently selected from halogen, -OH, -SH, -NH ₂ , -CN, -C(=0)OH, -C(=0)0(Ci-C ₄ alkyl), -C(=0)NH ₂ , - C(=0)NH(C _I -C ₄ alkyl), -C(=0)N(Ci-C ₄ alkyl) ₂ , C1-C4 alkyl, -S(Ci-C ₄ alkyl), C1-C4 alkoxy, C3-C6 cycloalkyl, C2-C5 heterocyclyl, -NH(C _I -C ₄ alkyl), -N(C _I -C ₄ alkyl) ₂ , phenyl, -C6H4OH, imidazole, and arginine.

[0006] Another embodiment provides a pharmaceutical composition comprising a compound of any one of Formula (I), Formula (II), or Formula (III), or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0007] Another embodiment provides a method of treating cancer in a patient in need thereof,

comprising administering to the patient a composition comprising a compound of any one of Formula (I), Formula (II), or Formula (III), or pharmaceutically acceptable salt thereof.

INCORPORATION BY REFERENCE

[0008] All publications, patents, and patent applications mentioned in this specification are herein

incorporated by reference for the specific purposes identified herein.

PET ATT, ED DESCRIPTION OF THE INVENTION

[0009] 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, for example, reference to "an agent" includes a plurality of such agents, and reference to "the cell" includes reference to one or more cells (or to a plurality of cells) and equivalents thereof known to those skilled in the art, and so forth. When ranges are used herein for physical properties, such as molecular weight, or chemical properties, such as chemical formulae, all combinations and subcombinations of ranges and specific embodiments therein are intended to be included. The term "about" when referring to a number or a numerical range means that the number or numerical range referred to is an approximation within experimental variability (or within statistical experimental error), and thus the number or numerical range, in some instances, will vary between 1% and 15% of the stated number or numerical range. The term "comprising" (and related terms such as "comprise" or "comprises" or "having" or "including") is not intended to exclude that in other certain embodiments, for example, an embodiment of any composition of matter, composition, method, or process, or the like, described herein, "consist of or "consist essentially of the described features.

Definitions

[0010] As used in the specification and appended claims, unless specified to the contrary, the following terms have the meaning indicated below.

[0011] "Amino" refers to the -NH2 radical.

[0012] "Cyano" refers to the -CN radical.

[0013] "Nitro" refers to the -NO2 radical.

[0014] "Oxa" refers to the -O- radical.

[0015] "Oxo" refers to the =0 radical.

[0016] "Thioxo" refers to the =S radical.

[0017] "Imino" refers to the =N-H radical.

[0018] "Oximo" refers to the =N-OH radical.

[0019] "Hydrazino" refers to the =N-NH2 radical.

[0020] "Alkyl" refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing no unsaturation, having from one to fifteen carbon atoms ( e.g ., Ci- Ci5 alkyl). In certain embodiments, an alkyl comprises one to thirteen carbon atoms (e.g., C1-C13 alkyl). In certain embodiments, an alkyl comprises one to eight carbon atoms (e.g., C _| -Cx alkyl). In other embodiments, an alkyl comprises one to five carbon atoms (e.g., C1-C5 alkyl). In other embodiments, an alkyl comprises one to four carbon atoms (e.g., C1-C4 alkyl). In other embodiments, an alkyl comprises one to three carbon atoms (e.g., C1-C3 alkyl). In other embodiments, an alkyl comprises one to two carbon atoms (e.g., C1-C2 alkyl). In other embodiments, an alkyl comprises one carbon atom (e.g., Ci alkyl). In other embodiments, an alkyl comprises five to fifteen carbon atoms (e.g., C5-C15 alkyl). In other embodiments, an alkyl comprises five to eight carbon atoms (e.g., Cs-Cs alkyl). In other embodiments, an alkyl comprises two to five carbon atoms (e.g., C2-C5 alkyl). In other embodiments, an alkyl comprises three to five carbon atoms ( e.g ., C3-C5 alkyl). In other embodiments, the alkyl group is selected from methyl, ethyl, 1 -propyl (//-propyl), 1-methylethyl ( .vo-propyl), 1 -butyl (//-butyl), 1- methylpropyl (sec-butyl), 2-methylpropyl (/so-butyl), 1,1-dimethylethyl (/tvV-butyl), 1 -pentyl (//- pentyl). The alkyl is attached to the rest of the molecule by a single bond. Unless stated otherwise specifically in the specification, an alkyl group is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo,

trimethylsilanyl, -OR ^a , -SR ^a , -0C(0)-R ^a , -N(R ^a ) ₂ , -C(0)R ^a , -C(0)0R ^a , -C(0)N(R ^a ) ₂ , - N(R ^a )C(0)0R ^a , -0C(0)-N(R ^a ) ₂ , -N(R ^a )C(0)R ^a , -N(R ^a )S(0) _t R ^a (where t is 1 or 2), -S(0) _t 0R ^a (where t is 1 or 2), -S(0) _t R ^a (where t is 1 or 2) and -S(0) _t N(R ^a ) ₂ (where t is 1 or 2) where each R ^a is independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, carbocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), carbocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or

trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl).

[0021] "Alkoxy" refers to a radical bonded through an oxygen atom of the formula -O-alkyl, where alkyl is an alkyl chain as defined above.

[0022] "Alkenyl" refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one carbon-carbon double bond, and having from two to twelve carbon atoms. In certain embodiments, an alkenyl comprises two to eight carbon atoms. In other embodiments, an alkenyl comprises two to four carbon atoms. The alkenyl is attached to the rest of the molecule by a single bond, for example, ethenyl (/. ., vinyl), prop-l-enyl (/. ., allyl), but-l-enyl, pent-l-enyl, penta-l,4-dienyl, and the like. Unless stated otherwise specifically in the specification, an alkenyl group is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo,

trimethylsilanyl, -OR ^a , -SR ^a , -OC(0)-R ^a , -N(R ^a ) ₂ , -C(0)R ^a , -C(0)OR ^a , -C(0)N(R ^a ) ₂ , - N(R ^a )C(0)OR ^a , -OC(0)-N(R ^a ) ₂ , -N(R ^a )C(0)R ^a , -N(R ^a )S(0) _t R ^a (where t is 1 or 2), -S(0) _t OR ^a

(where t is 1 or 2), -S(0) _t R ^a (where t is 1 or 2) and -S(0) _t N(R ^a ) ₂ (where t is 1 or 2) where each R ^a is independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, carbocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), carbocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or

trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroaryl alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl).

[0023] "Alkynyl" refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one carbon-carbon triple bond, having from two to twelve carbon atoms. In certain embodiments, an alkynyl comprises two to eight carbon atoms. In other embodiments, an alkynyl comprises two to six carbon atoms. In other embodiments, an alkynyl comprises two to four carbon atoms. The alkynyl is attached to the rest of the molecule by a single bond, for example, ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like. Unless stated otherwise specifically in the specification, an alkynyl group is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -OR ^a , -SR ^a , -OC(0)-R ^a , -N(R ^a )2, -C(0)R ^a , -C(0)OR ^a , - C(0)N(R ^a ) ₂ , -N(R ^a )C(0)OR ^a , -OC(0)-N(R ^a ) ₂ , -N(R ^a )C(0)R ^a , -N(R ^a )S(0) _t R ^a (where t is 1 or 2), -S(0) _t OR ^a (where t is 1 or 2), -S(0) _t R ^a (where t is 1 or 2) and -S(0) _t N(R ^a ) ₂ (where t is 1 or 2) where each R ^a is independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, carbocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), carbocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroaryl alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl). [0024] "Alkylene" or "alkylene chain" refers to a straight or branched divalent hydrocarbon chain linking the rest of the molecule to a radical group, consisting solely of carbon and hydrogen, containing no unsaturation and having from one to twelve carbon atoms, for example, methylene, ethylene, propylene, «-butylene, and the like. The alkylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond. The points of attachment of the alkylene chain to the rest of the molecule and to the radical group is through one carbon in the alkylene chain or through any two carbons within the chain. In certain embodiments, an alkylene comprises one to eight carbon atoms ( e.g ., C _| -Cx alkylene). In other embodiments, an alkylene comprises one to five carbon atoms (e.g., C1-C5 alkylene). In other embodiments, an alkylene comprises one to four carbon atoms (e.g., C1-C4 alkylene). In other embodiments, an alkylene comprises one to three carbon atoms (e.g., C1-C3 alkylene). In other embodiments, an alkylene comprises one to two carbon atoms (e.g., C1-C2 alkylene). In other embodiments, an alkylene comprises one carbon atom (e.g., Ci alkylene). In other embodiments, an alkylene comprises five to eight carbon atoms (e.g., Cs-Cx alkylene). In other embodiments, an alkylene comprises two to five carbon atoms (e.g., C2-C5 alkylene). In other embodiments, an alkylene comprises three to five carbon atoms (e.g., C3-C5 alkylene). Unless stated otherwise specifically in the specification, an alkylene chain is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -OR ^a , - SR ^a , -OC(0)-R ^a , -N(R ^a ) ₂ , -C(0)R ^a , -C(0)OR ^a , -C(0)N(R ^a ) ₂ , -N(R ^a )C(0)OR ^a , -OC(0)-N(R ^a ) ₂ , - N(R ^a )C(0)R ^a , -N(R ^a )S(0) _t R ^a (where t is 1 or 2), -S(0) _t OR ^a (where t is 1 or 2), -S(0) _t R ^a (where t is 1 or 2) and -S(0) _t N(R ^a ) ₂ (where t is 1 or 2) where each R ^a is independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, carbocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), carbocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl

(optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl

(optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl).

[0025] "Alkenylene" or "alkenylene chain" refers to a straight or branched divalent hydrocarbon chain linking the rest of the molecule to a radical group, consisting solely of carbon and hydrogen, containing at least one carbon-carbon double bond, and having from two to twelve carbon atoms. The alkenylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond. In certain embodiments, an alkenylene comprises two to eight carbon atoms ( e.g ., C2-C8 alkenylene). In other embodiments, an alkenylene comprises two to five carbon atoms (e.g., C2-C5 alkenylene). In other embodiments, an alkenylene comprises two to four carbon atoms (e.g., C2-C4 alkenylene). In other embodiments, an alkenylene comprises two to three carbon atoms (e.g., C2-C3 alkenylene). In other embodiments, an alkenylene comprises two carbon atoms (e.g., C2 alkenylene). In other embodiments, an alkenylene comprises five to eight carbon atoms (e.g., Cs-Cx alkenylene). In other embodiments, an alkenylene comprises three to five carbon atoms (e.g., C ₃ -C ₅ alkenylene). Unless stated otherwise specifically in the specification, an alkenylene chain is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo,

trimethylsilanyl, -OR ^a , -SR ^a , -0C(0)-R ^a , -N(R ^a ) ₂ , -C(0)R ^a , -C(0)0R ^a , -C(0)N(R ^a ) ₂ , - N(R ^a )C(0)0R ^a , -0C(0)-N(R ^a ) ₂ , -N(R ^a )C(0)R ^a , -N(R ^a )S(0) _t R ^a (where t is 1 or 2), -S(0) _t 0R ^a (where t is 1 or 2), -S(0) _t R ^a (where t is 1 or 2) and -S(0) _t N(R ^a ) ₂ (where t is 1 or 2) where each R ^a is independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, carbocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), carbocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or

trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroaryl alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl).

[0026] "Alkynylene" or "alkynylene chain" refers to a straight or branched divalent hydrocarbon chain linking the rest of the molecule to a radical group, consisting solely of carbon and hydrogen, containing at least one carbon-carbon triple bond, and having from two to twelve carbon atoms. The alkynylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond. In certain embodiments, an alkynylene comprises two to eight carbon atoms (e.g., C -Cx alkynylene). In other embodiments, an alkynylene comprises two to five carbon atoms (e.g., C2-C5 alkynylene). In other embodiments, an alkynylene comprises two to four carbon atoms ( e.g ., C2-C4 alkynylene). In other embodiments, an alkynylene comprises two to three carbon atoms (e.g., C2-C3 alkynylene). In other embodiments, an alkynylene comprises two carbon atoms (e.g., C2 alkynylene). In other embodiments, an alkynylene comprises five to eight carbon atoms (e.g., Cs-Cx alkynylene). In other embodiments, an alkynylene comprises three to five carbon atoms (e.g., C ₃ -C ₅ alkynylene). Unless stated otherwise specifically in the specification, an alkynylene chain is optionally substituted by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo,

trimethylsilanyl, -OR ^a , -SR ^a , -0C(0)-R ^a , -N(R ^a ) ₂ , -C(0)R ^a , -C(0)0R ^a , -C(0)N(R ^a ) ₂ , - N(R ^a )C(0)0R ^a , -0C(0)-N(R ^a ) ₂ , -N(R ^a )C(0)R ^a , -N(R ^a )S(0) _t R ^a (where t is 1 or 2), -S(0) _t 0R ^a (where t is 1 or 2), -S(0) _t R ^a (where t is 1 or 2) and -S(0) _t N(R ^a ) ₂ (where t is 1 or 2) where each R ^a is independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, carbocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), carbocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or

trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroaryl alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl).

[0027] "Aryl" refers to a radical derived from an aromatic monocyclic or multi cyclic hydrocarbon ring system by removing a hydrogen atom from a ring carbon atom. The aromatic monocyclic or multicyclic hydrocarbon ring system contains only hydrogen and carbon from five to eighteen carbon atoms, where at least one of the rings in the ring system is fully unsaturated, i.e., it contains a cyclic, delocalized (4n+2) p-electron system in accordance with the Hiickel theory. The ring system from which aryl groups are derived include, but are not limited to, groups such as benzene, fluorene, indane, indene, tetralin and naphthalene. Unless stated otherwise specifically in the specification, the term "aryl" or the prefix "ar-" (such as in "aralkyl") is meant to include aryl radicals optionally substituted by one or more substituents independently selected from alkyl, alkenyl, alkynyl, halo, fluoroalkyl, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -R ^b -OR ^a , -R ^b -0C(0)-R ^a , -R ^b -0C(0)-0R ^a , -R ^b -0C(0)- N(R ^a ) ₂ , -R ^b -N(R ^a ) ₂ , -R ^b -C(0)R ^a , -R ^b -C(0)0R ^a , -R ^b -C(0)N(R ^a ) ₂ , -R ^b -0-R ^c -C(0)N(R ^a ) ₂ , -R ^b - N(R ^a )C(0)0R ^a , -R ^b -N(R ^a )C(0)R ^a , -R ^b -N(R ^a )S(0) _t R ^a (where t is 1 or 2), -R ^b -S(0) _t R ^a (where t is 1 or 2), -R ^b -S(0) _t 0R ^a (where t is 1 or 2) and -R ^b -S(0) _t N(R ^a ) ₂ (where t is 1 or 2), where each R ^a is independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, cycloalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), cycloalkylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or

trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or

trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), each R ^b is independently a direct bond or a straight or branched alkylene or alkenylene chain, and R ^c is a straight or branched alkylene or alkenylene chain, and where each of the above substituents is unsubstituted unless otherwise indicated.

[0028] "Aralkyl" refers to a radical of the formula -R ^c -aryl where R ^c is an alkylene chain as defined above, for example, methylene, ethylene, and the like. The alkylene chain part of the aralkyl radical is optionally substituted as described above for an alkylene chain. The aryl part of the aralkyl radical is optionally substituted as described above for an aryl group.

[0029] "Aralkenyl" refers to a radical of the formula -R ^d -aryl where R ^d is an alkenylene chain as

defined above. The aryl part of the aralkenyl radical is optionally substituted as described above for an aryl group. The alkenylene chain part of the aralkenyl radical is optionally substituted as defined above for an alkenylene group.

[0030] "Aralkynyl" refers to a radical of the formula -R ^e -aryl, where R ^e is an alkynylene chain as

defined above. The aryl part of the aralkynyl radical is optionally substituted as described above for an aryl group. The alkynylene chain part of the aralkynyl radical is optionally substituted as defined above for an alkynylene chain.

[0031] "Aralkoxy" refers to a radical bonded through an oxygen atom of the formula -0-R ^c -aryl where R ^c is an alkylene chain as defined above, for example, methylene, ethylene, and the like. The alkylene chain part of the aralkyl radical is optionally substituted as described above for an alkylene chain. The aryl part of the aralkyl radical is optionally substituted as described above for an aryl group.

[0032] "Carbocyclyl" refers to a stable non-aromatic monocyclic or polycyclic hydrocarbon radical consisting solely of carbon and hydrogen atoms, which includes fused or bridged ring systems, having from three to fifteen carbon atoms. In certain embodiments, a carbocyclyl comprises three to ten carbon atoms. In other embodiments, a carbocyclyl comprises five to seven carbon atoms. The carbocyclyl is attached to the rest of the molecule by a single bond. Carbocyclyl is saturated (i.e., containing single C-C bonds only) or unsaturated (i.e., containing one or more double bonds or triple bonds). A fully saturated carbocyclyl radical is also referred to as

"cycloalkyl." Examples of monocyclic cycloalkyls include, e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. An unsaturated carbocyclyl is also referred to as "cycloalkenyl." Examples of monocyclic cycloalkenyls include, e.g.,

cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. Polycyclic carbocyclyl radicals include, for example, adamantyl, norbomyl (i.e., bicyclo[2.2.1]heptanyl), norbornenyl, decalinyl, 7,7-dimethyl-bicyclo[2.2.1]heptanyl, and the like. Unless otherwise stated specifically in the specification, the term "carbocyclyl" is meant to include carbocyclyl radicals that are optionally substituted by one or more substituents independently selected from alkyl, alkenyl, alkynyl, halo, fluoroalkyl, oxo, thioxo, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -R ^b -OR ^a , -R ^b -OC(0)-R ^a , -R ^b -OC(0)-OR ^a , -R ^b -OC(0)-N(R ^a ) ₂ , -R ^b -N(R ^a ) ₂ , -R ^b - C(0)R ^a , -R ^b -C(0)OR ^a , -R ^b -C(0)N(R ^a ) ₂ , -R ^b -0-R ^c -C(0)N(R ^a ) ₂ , -R ^b -N(R ^a )C(0)OR ^a , -R ^b - N(R ^a )C(0)R ^a , -R ^b -N(R ^a )S(0) _t R ^a (where t is 1 or 2), -R ^b -S(0) _t R ^a (where t is 1 or 2), -R ^b -S(0) _t OR ^a (where t is 1 or 2) and -R ^b -S(0) _t N(R ^a ) ₂ (where t is 1 or 2), where each R ^a is independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, cycloalkyl (optionally substituted with halogen, hydroxy, methoxy, or

trifluoromethyl), cycloalkylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or

trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or

trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroaryl alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), each R ^b is independently a direct bond or a straight or branched alkylene or alkenylene chain, and R ^c is a straight or branched alkylene or alkenylene chain, and where each of the above substituents is unsubstituted unless otherwise indicated.

[0033] "Carbocyclylalkyl" refers to a radical of the formula -R ^c -carbocyclyl where R ^c is an alkylene chain as defined above. The alkylene chain and the carbocyclyl radical is optionally substituted as defined above.

[0034] "Carbocyclylalkynyl" refers to a radical of the formula -R ^c -carbocyclyl where R ^c is an

alkynylene chain as defined above. The alkynylene chain and the carbocyclyl radical is optionally substituted as defined above.

[0035] "Carbocyclylalkoxy" refers to a radical bonded through an oxygen atom of the formula -O- R ^c -carbocyclyl where R ^c is an alkylene chain as defined above. The alkylene chain and the carbocyclyl radical is optionally substituted as defined above.

[0036] As used herein,“carboxylic acid bioisostere” refers to a functional group or moiety that exhibits similar physical, biological and/or chemical properties as a carboxylic acid moiety. Examples of carboxylic acid bioisosteres include, but are not limited to,

.

[0037] "Halo" or "halogen" refers to bromo, chloro, fluoro or iodo substituents.

[0038] "Fluoroalkyl" refers to an alkyl radical, as defined above, that is substituted by one or more fluoro radicals, as defined above, for example, trifluoromethyl, difluoromethyl, fluoromethyl, 2,2,2-trifluoroethyl, l-fluoromethyl-2-fluoroethyl, and the like. In some embodiments, the alkyl part of the fluoroalkyl radical is optionally substituted as defined above for an alkyl group.

[0039] "Heterocyclyl" refers to a stable 3- to 18-membered non-aromatic ring radical that comprises two to twelve carbon atoms and from one to six heteroatoms selected from nitrogen, oxygen and sulfur. Unless stated otherwise specifically in the specification, the heterocyclyl radical is a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which optionally includes fused or bridged ring systems. The heteroatoms in the heterocyclyl radical are optionally oxidized. One or more nitrogen atoms, if present, are optionally quaternized. The heterocyclyl radical is partially or fully saturated. The heterocyclyl is attached to the rest of the molecule through any atom of the ring(s). Examples of such heterocyclyl radicals include, but are not limited to, dioxolanyl, thienyl[l,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl,

2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, and

1, 1-dioxo-thiomorpholinyl. Unless stated otherwise specifically in the specification, the term "heterocyclyl" is meant to include heterocyclyl radicals as defined above that are optionally substituted by one or more substituents selected from alkyl, alkenyl, alkynyl, halo, fluoroalkyl, oxo, thioxo, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted

heteroarylalkyl, -R ^b -OR ^a , -R ^b -0C(0)-R ^a , -R ^b -0C(0)-0R ^a , -R ^b -0C(0)-N(R ^a ) ₂ , -R ^b -N(R ^a ) ₂ , -R ^b - C(0)R ^a , -R ^b -C(0)0R ^a , -R ^b -C(0)N(R ^a ) ₂ , -R ^b -0-R ^c -C(0)N(R ^a ) ₂ , -R ^b -N(R ^a )C(0)0R ^a , -R ^b - N(R ^a )C(0)R ^a , -R ^b -N(R ^a )S(0) _t R ^a (where t is 1 or 2), -R ^b -S(0) _t R ^a (where t is 1 or 2), -R ^b -S(0) _t 0R ^a (where t is 1 or 2) and -R ^b -S(0) _t N(R ^a ) ₂ (where t is 1 or 2), where each R ^a is independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, cycloalkyl (optionally substituted with halogen, hydroxy, methoxy, or

trifluoromethyl), cycloalkylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or

trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or

trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroarylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), each R ^b is independently a direct bond or a straight or branched alkylene or alkenylene chain, and R ^c is a straight or branched alkylene or alkenylene chain, and where each of the above substituents is unsubstituted unless otherwise indicated. [0040] "A _' -heterocyclyl" or“N-attached heterocyclyl” refers to a heterocyclyl radical as defined above containing at least one nitrogen and where the point of attachment of the heterocyclyl radical to the rest of the molecule is through a nitrogen atom in the heterocyclyl radical. An

A -heterocyclyl radical is optionally substituted as described above for heterocyclyl radicals. Examples of such A-heterocyclyl radicals include, but are not limited to, 1 -morpholinyl, 1- piperidinyl, 1-piperazinyl, 1-pyrrolidinyl, pyrazolidinyl, imidazolinyl, and imidazolidinyl.

[0041] "C-heterocyclyl" or“C-attached heterocyclyl” refers to a heterocyclyl radical as defined above containing at least one heteroatom and where the point of attachment of the heterocyclyl radical to the rest of the molecule is through a carbon atom in the heterocyclyl radical. A C-heterocyclyl radical is optionally substituted as described above for heterocyclyl radicals. Examples of such C-heterocyclyl radicals include, but are not limited to, 2-morpholinyl, 2- or 3- or 4-piperidinyl, 2-piperazinyl, 2- or 3-pyrrolidinyl, and the like.

[0042] "Heterocyclylalkyl" refers to a radical of the formula -R ^c -heterocyclyl where R ^c is an alkylene chain as defined above. If the heterocyclyl is a nitrogen-containing heterocyclyl, the

heterocyclyl is optionally attached to the alkyl radical at the nitrogen atom. The alkylene chain of the heterocyclylalkyl radical is optionally substituted as defined above for an alkylene chain. The heterocyclyl part of the heterocyclylalkyl radical is optionally substituted as defined above for a heterocyclyl group.

[0043] "Heterocyclylalkoxy" refers to a radical bonded through an oxygen atom of the formula -O- R ^c -heterocyclyl where R ^c is an alkylene chain as defined above. If the heterocyclyl is a nitrogen-containing heterocyclyl, the heterocyclyl is optionally attached to the alkyl radical at the nitrogen atom. The alkylene chain of the heterocyclylalkoxy radical is optionally substituted as defined above for an alkylene chain. The heterocyclyl part of the heterocyclylalkoxy radical is optionally substituted as defined above for a heterocyclyl group.

[0044] "Heteroaryl" refers to a radical derived from a 3- to 18-membered aromatic ring radical that comprises two to seventeen carbon atoms and from one to six heteroatoms selected from nitrogen, oxygen and sulfur. As used herein, the heteroaryl radical is a monocyclic, bicyclic, tricyclic or tetracyclic ring system, wherein at least one of the rings in the ring system is fully unsaturated, i.e., it contains a cyclic, delocalized (4n+2) p-electron system in accordance with the Hiickel theory. Heteroaryl includes fused or bridged ring systems. The heteroatom(s) in the heteroaryl radical is optionally oxidized. One or more nitrogen atoms, if present, are optionally quatemized. The heteroaryl is attached to the rest of the molecule through any atom of the ring(s). Examples of heteroaryls include, but are not limited to, azepinyl, acridinyl,

benzimidazolyl, benzindolyl, 1,3-benzodioxolyl, benzofuranyl, benzooxazolyl,

benzo[d]thiazolyl, benzothiadiazolyl, benzo[£][l,4]dioxepinyl, benzo[b][l,4]oxazinyl,

1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl), benzothieno[3,2-d]pyrimidinyl, benzotriazolyl, benzo[4,6]imidazo[l,2-a]pyridinyl, carbazolyl, cinnolinyl, cyclopenta[d]pyrimidinyl, 6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-d]pyrimidinyl,

5.6-dihydrobenzo[h]quinazolinyl, 5,6-dihydrobenzo[h]cinnolinyl, 6,7-dihydro-5H- benzo[6,7]cyclohepta[l,2-c]pyridazinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furanonyl, furo[3,2-c]pyridinyl, 5,6,7,8,9,10-hexahydrocycloocta[d]pyrimidinyl,

5,6,7,8,9,10-hexahydrocycloocta[d]pyridazinyl, 5,6,7,8,9,10-hexahydrocycloocta[d]pyridinyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, 5,8-methano-5,6,7,8-tetrahydroquinazolinyl, naphthyridinyl,

1.6-naphthyridinonyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl,

5, 6, 6a, 7, 8,9, 10,1 Oa-octahydrobenzo[h]quinazolinyl, 1 -phenyl- 1/7-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl,

pyrazolo[3,4-d]pyrimidinyl, pyridinyl, pyrido[3,2-d]pyrimidinyl, pyrido[3,4-d]pyrimidinyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl, quinazolinyl, quinoxalinyl, quinolinyl,

isoquinolinyl, tetrahydroquinolinyl, 5,6,7,8-tetrahydroquinazolinyl,

5.6.7.8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidinyl,

6.7.8.9-tetrahydro-5H-cyclohepta[4,5]thieno[2,3-d]pyrimidiny l,

5,6,7,8-tetrahydropyrido[4,5-c]pyridazinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, thieno[2,3-d]pyrimidinyl, thieno[3,2-d]pyrimidinyl, thieno[2,3-c]pridinyl, and thiophenyl ( i.e . thienyl). Unless stated otherwise specifically in the specification, the term "heteroaryl" is meant to include heteroaryl radicals as defined above which are optionally substituted by one or more substituents selected from alkyl, alkenyl, alkynyl, halo, fluoroalkyl, haloalkenyl, haloalkynyl, oxo, thioxo, cyano, nitro, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, optionally substituted aralkynyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, -R ^b -OR ^a , -R ^b -0C(0)-R ^a , -R ^b -0C(0)-0R ^a , -R ^b -0C(0)-N(R ^a ) ₂ , -R ^b -N(R ^a ) ₂ , -R ^b - C(0)R ^a , -R ^b -C(0)0R ^a , -R ^b -C(0)N(R ^a ) ₂ , -R ^b -0-R ^c -C(0)N(R ^a ) ₂ , -R ^b -N(R ^a )C(0)0R ^a , -R ^b - N(R ^a )C(0)R ^a , -R ^b -N(R ^a )S(0) _t R ^a (where t is 1 or 2), -R ^b -S(0) _t R ^a (where t is 1 or 2), -R ^b -S(0) _t 0R ^a (where t is 1 or 2) and -R ^b -S(0) _t N(R ^a ) ₂ (where t is 1 or 2), where each R ^a is independently hydrogen, alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), fluoroalkyl, cycloalkyl (optionally substituted with halogen, hydroxy, methoxy, or

trifluoromethyl), cycloalkylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), aryl (optionally substituted with halogen, hydroxy, methoxy, or

trifluoromethyl), aralkyl (optionally substituted with halogen, hydroxy, methoxy, or

trifluoromethyl), heterocyclyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heterocyclylalkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), heteroaryl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), or heteroaryl alkyl (optionally substituted with halogen, hydroxy, methoxy, or trifluoromethyl), each R ^b is independently a direct bond or a straight or branched alkylene or alkenylene chain, and R ^c is a straight or branched alkylene or alkenylene chain, and where each of the above substituents is unsubstituted unless otherwise indicated.

[0045] "A-heteroaryl" refers to a heteroaryl radical as defined above containing at least one nitrogen and where the point of attachment of the heteroaryl radical to the rest of the molecule is through a nitrogen atom in the heteroaryl radical. An A-heteroaryl radical is optionally substituted as described above for heteroaryl radicals.

[0046] "C-heteroaryl" refers to a heteroaryl radical as defined above and where the point of attachment of the heteroaryl radical to the rest of the molecule is through a carbon atom in the heteroaryl radical. A C-heteroaryl radical is optionally substituted as described above for heteroaryl radicals.

[0047] "Heteroarylalkyl" refers to a radical of the formula -R ^c -heteroaryl, where R ^c is an alkylene chain as defined above. If the heteroaryl is a nitrogen-containing heteroaryl, the heteroaryl is optionally attached to the alkyl radical at the nitrogen atom. The alkylene chain of the heteroarylalkyl radical is optionally substituted as defined above for an alkylene chain. The heteroaryl part of the heteroarylalkyl radical is optionally substituted as defined above for a heteroaryl group.

[0048] "Heteroarylalkoxy" refers to a radical bonded through an oxygen atom of the formula -O- R ^c -heteroaryl, where R ^c is an alkylene chain as defined above. If the heteroaryl is a

nitrogen-containing heteroaryl, the heteroaryl is optionally attached to the alkyl radical at the nitrogen atom. The alkylene chain of the heteroarylalkoxy radical is optionally substituted as defined above for an alkylene chain. The heteroaryl part of the heteroarylalkoxy radical is optionally substituted as defined above for a heteroaryl group.

[0049] The compounds disclosed herein, in some embodiments, contain one or more asymmetric centers and thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that are defined, in terms of absolute stereochemistry, as ( R )- or (S)-. Unless stated otherwise, it is intended that all stereoisomeric forms of the compounds disclosed herein are contemplated by this disclosure. When the compounds described herein contain alkene double bonds, and unless specified otherwise, it is intended that this disclosure includes both E and Z geometric isomers ( e.g ., cis or trans.) Likewise, all possible isomers, as well as their racemic and optically pure forms, and all tautomeric forms are also intended to be included. The term“geometric isomer” refers to E or Z geometric isomers (e.g., cis or trans) of an alkene double bond. The term“positional isomer” refers to structural isomers around a central ring, such as ortho-, meta-, and para- isomers around a benzene ring.

[0050] A "tautomer" refers to a molecule wherein a proton shift from one atom of a molecule to another atom of the same molecule is possible. The compounds presented herein, in certain

embodiments, exist as tautomers. In circumstances where tautomerization is possible, a chemical equilibrium of the tautomers will exist. The exact ratio of the tautomers depends on several factors, including physical state, temperature, solvent, and pH. Some examples of tautomeric equilibrium include:

[0051] The compounds disclosed herein, in some embodiments, are used in different enriched isotopic forms, e.g., enriched in the content of 2 H, 3 H, 11 C, 13 C and/or 14 C. In one particular embodiment, the compound is deuterated in at least one position. Such deuterated forms can be made by the procedure described in U.S. Patent Nos. 5,846,514 and 6,334,997. As described in U.S. Patent Nos. 5,846,514 and 6,334,997, deuteration can improve the metabolic stability and or efficacy, thus increasing the duration of action of drugs.

[0052] Unless otherwise stated, structures depicted herein are intended to include compounds which differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures except for the replacement of a hydrogen by a deuterium or tritium, or the replacement of a carbon by ¹³ C- or ¹⁴ C-enriched carbon are within the scope of the present disclosure.

[0053] The compounds of the present disclosure optionally contain unnatural proportions of atomic isotopes at one or more atoms that constitute such compounds. For example, the compounds may be labeled with isotopes, such as for example, deuterium ( ² H), tritium (¾), iodine-125 ( ¹²⁵ I) or carbon-14 ( ¹⁴ C). Isotopic substitution with ² H, ^U C, ¹³ C, ¹⁴ C, ¹⁵ C, ¹² N, ¹³ N, ¹⁵ N, ¹⁶ N, ¹⁶ 0, ¹⁷ 0, ¹⁴ F, 1 ⁵ F, ¹⁶ F, ¹⁷ F, ¹⁸ F, ³³ S, ³⁴ S, ³⁵ S, ³⁶ S, ³⁵ C1, ³⁷ C1, ⁷⁹ Br, ⁸¹ Br, ¹²⁵ I are all contemplated. All isotopic variations of the compounds of the present invention, whether radioactive or not, are

encompassed within the scope of the present invention.

[0054] In certain embodiments, the compounds disclosed herein have some or all of the ¾ atoms

replaced with ² H atoms. The methods of synthesis for deuterium-containing compounds are known in the art and include, by way of non-limiting example only, the following synthetic methods.

[0055] Deuterium substituted compounds are synthesized using various methods such as described in:

Dean, Dennis C.; Editor. Recent Advances in the Synthesis and Applications of Radiolabeled Compounds for Drug Discovery and Development. [In: Curr., Pharm. Des., 2000; 6(10)] 2000, 110 pp; George W.; Varma, Rajender S. The Synthesis of Radiolabeled Compounds via

Organometallic Intermediates, Tetrahedron, 1989, 45(21), 6601-21; and Evans, E. Anthony. Synthesis of radiolabeled compounds, J. Radioanal. Chem., 1981, 64(1-2), 9-32.

[0056] Deuterated starting materials are readily available and are subjected to the synthetic methods described herein to provide for the synthesis of deuterium-containing compounds. Large numbers of deuterium-containing reagents and building blocks are available commerically from chemical vendors, such as Aldrich Chemical Co.

[0057] Deuterium-transfer reagents suitable for use in nucleophilic substitution reactions, such as

iodomethane-d3 (CD ₃ I), are readily available and may be employed to transfer a deuterium- substituted carbon atom under nucleophilic substitution reaction conditions to the reaction substrate. The use of CD ₃ I is illustrated, by way of example only, in the reaction schemes below.

[0058] Deuterium-transfer reagents, such as lithium aluminum deuteride (LiAlD ), are employed to transfer deuterium under reducing conditions to the reaction substrate. The use of LiAlD ₄ is illustrated, by way of example only, in the reaction schemes below.

[0059] Deuterium gas and palladium catalyst are employed to reduce unsaturated carbon-carbon

linkages and to perform a reductive substitution of aryl carbon-halogen bonds as illustrated, by way of example only, in the reaction schemes below.

[0060] In one embodiment, the compounds disclosed herein contain one deuterium atom. In another embodiment, the compounds disclosed herein contain two deuterium atoms. In another embodiment, the compounds disclosed herein contain three deuterium atoms. In another embodiment, the compounds disclosed herein contain four deuterium atoms. In another embodiment, the compounds disclosed herein contain five deuterium atoms. In another embodiment, the compounds disclosed herein contain six deuterium atoms. In another embodiment, the compounds disclosed herein contain more than six deuterium atoms. In another embodiment, the compound disclosed herein is fully substituted with deuterium atoms and contains no non-exchangeable 'H hydrogen atoms. In one embodiment, the level of deuterium incorporation is determined by synthetic methods in which a deuterated synthetic building block is used as a starting material. [0061] "Pharmaceutically acceptable salt" includes both acid and base addition salts. A

pharmaceutically acceptable salt of any one of the gemcitabine prodrug compounds described herein is intended to encompass any and all pharmaceutically suitable salt forms. Preferred pharmaceutically acceptable salts of the compounds described herein are pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.

[0062] "Pharmaceutically acceptable acid addition salt" refers to those salts which retain the biological effectiveness and properties of the free bases, which are not biologically or otherwise

undesirable, and which are formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, hydroiodic acid, hydrofluoric acid, phosphorous acid, and the like. Also included are salts that are formed with organic acids such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxy alkanoic acids, alkanedioic acids, aromatic acids, aliphatic and. aromatic sulfonic acids, etc. and include, for example, acetic acid, trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like. Exemplary salts thus include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates, monohydrogenphosphates, dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, trifluoroacetates, propionates, caprylates, isobutyrates, oxalates, malonates, succinate suberates, sebacates, fumarates, maleates, mandelates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, phthalates, benzenesulfonates,

toluenesulfonates, phenyl acetates, citrates, lactates, malates, tartrates, methanesulfonates, and the like. Also contemplated are salts of amino acids, such as arginates, gluconates, and galacturonates (see, for example, Berge S.M. et al., "Pharmaceutical Salts," Journal of Pharmaceutical Science, 66: 1-19 (1997)). Acid addition salts of basic compounds are, in some embodiments, prepared by contacting the free base forms with a sufficient amount of the desired acid to produce the salt according to methods and techniques with which a skilled artisan is familiar.

[0063] "Pharmaceutically acceptable base addition salt" refers to those salts that retain the biological effectiveness and properties of the free acids, which are not biologically or otherwise

undesirable. These salts are prepared from addition of an inorganic base or an organic base to the free acid. Pharmaceutically acceptable base addition salts are, in some embodiments, formed with metals or amines, such as alkali and alkaline earth metals or organic amines. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts and the like. Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, for example, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, 2-dimethylaminoethanol,

2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, N,N- dibenzylethylenediamine, chloroprocaine, hydrabamine, choline, betaine, ethylenediamine, ethylenedianiline, /V-methylglucamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, /V-ethylpiperidine, polyamine resins and the like. See Berge et ak, supra.

[0064] As used herein,“treatment” or“treating,” or“palliating” or“ameliorating” are used

interchangeably. These terms refer to an approach for obtaining beneficial or desired results including but not limited to therapeutic benefit and/or a prophylactic benefit. By“therapeutic benefit” is meant eradication or amelioration of the underlying disorder being treated. Also, a therapeutic benefit is achieved with the eradication or amelioration of one or more of the physiological symptoms associated with the underlying disorder such that an improvement is observed in the patient, notwithstanding that the patient is still afflicted with the underlying disorder. For prophylactic benefit, the compositions are, in some embodiments, administered to a patient at risk of developing a particular disease, or to a patient reporting one or more of the physiological symptoms of a disease, even though a diagnosis of this disease has not been made. Phosphorylated Gemcitabine Derivatives

[0065] A number of nucleoside analogs such as cytarabine, fludarabine, cladribine, capecitabine,

gemcitabine and pentostatin are used clinically as highly effective anti -neoplastic agents. Among these, gemcitabine (2',2'-difluoro-2'-deoxycytidine) is of particular interest due to its unique activity against solid tumors. It is currently approved to treat breast, non-small cell lung, ovarian and pancreatic cancers and widely used to treat a variety of other cancers including bladder, biliary, colorectal and lymphoma.

(gemcitabine) [0066] Several self-potentiating mechanisms unique to this nucleoside analog are believed responsible for the activity of gemcitabine against solid tumors. The diphosphate metabolite of gemcitabine inhibits ribonucleotide reductase, which results in lower concentrations of intracellular deoxycytidine triphosphate (dCTP) and thus, increased incorporation of the triphosphate gemcitabine metabolite into DNA, which results in inhibition of DNA synthesis and blocks completion of the cell division cycle. Additionally, reduction in dCTP concentration upregulates the enzyme cytidine kinase, which is responsible for initial phosphorylation of gemcitabine, a necessary step in the inhibition of DNA synthesis by the drug. Finally, the triphosphate metabolite of gemcitabine is an inhibitor of cytidine deaminase, which is responsible for gemcitabine inactivation by conversion to the uridine metabolite. Accordingly, the additive nature of the above factors may explain the efficacy of gemcitabine in treating solid tumors.

[0067] Previous studies have characterized multiple cellular transport mechanisms for nucleoside analog drugs and their derivatives (for a review, see Balimane et ah, Adv. Drug Delivery Rev. 1999, 39, 183-209). A relatively hydrophilic compound, gemcitabine has limited ability to permeate plasma membranes via passive diffusion and several studies have demonstrated that gemcitabine is a substrate for equilibrative and concentrative nucleoside transporters (ENT's and CNT's respectively). Specifically, gemcitabine is transported by human ENT1, ENT2, CNT1 and CNT3, but not the purine-selective concentrative transporter CNT2 (see Mackey et ah, Cancer Res. 1998, 58, 4349-4357; Mackey et ah, J. Natl. Cancer Inst. 1999, 91, 1876-1881; and Fang et ak, Biochem. J. 1996, 317, 457465).

[0068] Gemcitabine is itself a prodrug that is activated in a series of phosphorylation steps to its

activated form of 5’ -triphosphate. Typically, once gemcitabine enters the tumor cell, it undergoes a series of phosphorylations, which are generally believed to make it active. First, it is generally phosphorylated to a monophosphate compound (dFdCMP) by deoxycytidine kinase (dCK). It then often undergoes a second modification to become gemcitabine diphosphate (dFdCDP), and finally can be converted to gemcitabine triphosphate (dFdCTP). These forms can be catalyzed by the enzymes nucleoside monophosphate kinase (UMP / CMP) and diphosphate kinase, respectively. Gemcitabine can be inactivated by cytidine deaminase (CD A). The deamination of gemcitabine monophosphate, which is catalysed by deoxycytidylate deaminase (DCTD), also deactivates the drug. Phosphorylated metabolites of gemcitabine can be reduced by cellular 5'- nucleotidase (5'-NT), and dFdCMP can also be converted and inactivated by DCTD into 2'- deoxy-2',2'-difluorouridine monophosphate (dFdUMP). Resistance to gemcitabine comes from at least 3 potential pathways: 1) deficiency of hENT pathway that helps dFdC cross into cells, 2) down regulation of cDK involved in phosphorylation and/or upregulation of cytidine deaminase (CDA) responsible for deamination of dFdC to 2’,2’-difluorodeoxyuridine (dFdU), of which the activity is uncertain, and 3) high efflux of drug by transporters such as ABC transporters.

[0069] Accordingly, there is a need for gemcitabine analogs, which are not susceptible to the various resistance pathways while retaining the efficacious anti-tumor activity of the parent drug. One of the solutions to overcome the problem of gemcitabine resistance is to use phosphorylated gemcitabine prodrug compounds which provide a long, sustained, and controlled release of the biologically active phosphorylated gemcitabine derivatives upon administration into the body. Administration of the phosphorylated gemcitabine derivatives may provide a more convenient dosing regimen, greater efficacy, and reduce side effects in comparison with a traditional intravenous infusion of gemcitabine as typically used in cancer therapy.

[0070] As used in this disclosure, the term "prodrug" is meant to indicate a compound that is converted under physiological conditions to gemcitabine, or the phosphorylated forms thereof. A prodrug, in some embodiments, is inactive when administered to a subject, but is converted in vivo to an active compound, for example, by hydrolysis. Thus, the term "prodrug" refers to a precursor compound that is pharmaceutically acceptable, and in some embodiments, is devoid of the pharmacological properties of gemcitabine. The prodrug compound often offers advantages of solubility, tissue compatibility or delayed release in a mammalian organism (see, e.g., Bundgard, FL, Design of Prodrugs (1985), pp. 7-9, 21-24 (Elsevier, Amsterdam).

[0071] A discussion of prodrugs is provided in Higuchi, T., et al., "Pro-drugs as Novel Delivery

Systems," A.C.S. Symposium Series, Vol. 14, and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987.

[0072] The term "prodrug" is also meant to include any covalently bonded carriers that release the active compound in vivo when such prodrug is administered to a mammalian subject. Prodrugs of gemcitabine, as described herein, are prepared by modifying functional groups present in the active compound in such a way that the modifications are cleaved to the parent active compound. Prodrugs include compounds wherein a hydroxy group is bonded to any group that, when the prodrug of the active compound is administered to a mammalian subject, cleaves to form a free hydroxy group.

[0073] Provided herein are phosphorylated gemcitabine derivative prodrugs. The prodrugs described herein offer several exemplary advantages. First, the prodrugs generally comprise a modified mono-phosphate form of gemcitabine. Use of a mono-phosphate form of gemcitabine may allow the prodrugs to be converted to the active forms of the compound without undergoing the phosphorylation events described above. Thus, the prodrug might be less susceptible to certain forms of resistance that can develop when a subject becomes unable to convert gemcitabine to the phosphorylated active forms.

[0074] Second, the prodrugs described herein are often engineered to be lipophilic. Lipophilic

gemcitabine derivative prodrugs may exhibit increased uptake by cancer cells, exhibit advantageous toxicity profiles, or provide enhance the therapeutic windows compared to gemcitabine. Lipophilic gemcitabine derivative prodrugs may also bypass traditional pathways to enter a cell, modulate distribution of the drug in the body, and allow for alternative delivery mechanisms and formulations as comparied to gemcitabine.

[0075] In one aspect, provided herein is a compound, or pharmaceutically acceptable salt thereof,

having a structure provided in Formula (I),

wherein

R is selected from fatty alcohol, glycerolipid, glycerophospholipids, sphingolipids, sterol-lipids, prenol lipids, saccharolipids and polyketides;

R ¹ is hydrogen, substituted or unsubstituted Ci-Cio alkyl, substituted or unsubstituted

heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; and R ² is hydrogen, substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C2-C4

alkenyl, substituted or unsubstituted C2-C4 alkynyl, -C(=0)Ci-C ₄ alkyl, -C(=0)0(Ci-C ₄ alkyl), substituted or unsubstituted aryl, or substituted or unsubstituted benzyl,

wherein a substituted group is substituted with 1, 2, or 3 groups independently selected from halogen, -OH, -SH, -NH ₂ , -CN, -C(=0)0H, -C(=0)0(Ci-C ₄ alkyl), -C(=0)NH ₂ , - C(=0)NH(C _I -C ₄ alkyl), -C(=0)N(Ci-C ₄ alkyl) ₂ , C1-C4 alkyl, -S(Ci-C ₄ alkyl), C1-C4 alkoxy, C3-C6 cycloalkyl, C2-C5 heterocyclyl, -NH(C _I -C4 alkyl), -N(C _I -C4 alkyl) ₂ , phenyl, -C6H4OH, imidazole, and arginine.

[0076] In some embodiments, R ¹ is hydrogen. In some embodiments, R ² is hydrogen. In some

embodiments, R ¹ and R ² are hydrogen.

[0077] In some embodiments, R ¹ is not hydrogen. In some embodiments, R ¹ is not hydrogen, and R and R ¹ are selected independently. In some embodiments, R ¹ is not hydrogen, and R and R ¹ are the same. In some embodiments, R ¹ is not hydrogen and R ² is hydrogen. In some embodiments, R ¹ is substituted or unsubstituted aryl and R ² is hydrogen. In some embodiments, R ¹ is substituted or unsubstituted phenyl and R ² is hydrogen. In some embodiments, R ¹ phenyl and R ² is hydrogen.

[0078] In some embodiments, R ² is not hydrogen. In some embodiments, R ² is not hydrogen, and R and R ² are selected independently. In some embodiments, R ² is not hydrogen, and R and R ² are the same. In some embodiments, R ¹ is hydrogen and R ² is not hydrogen.

[0079] In some embodiments, R and R ¹ are independently selected from a fatty alcohol. In some

embodiments, R is a fatty alcohol, and R ¹ is hydrogen. In some embodiments, R and R ² are independently selected from a fatty alcohol. In some embodiments, R is a fatty alcohol, and R ² is hydrogen.

[0080] In some embodiments, R ¹ and R ² are both hydrogen.

[0081] In some embodiments, each fatty alcohol is independently selected from a saturated,

monounsaturated, or polyunsaturated fatty alcohol.

[0082] In some embodiments, each fatty alcohol is a C2-C26 fatty alcohol. In some embodiments, each fatty alcohol is a C2-C3 fatty alcohol. In some embodiments, each fatty alcohol is a C2-C4 fatty alcohol. In some embodiments, each fatty alcohol is a C2-C5 fatty alcohol. In some

embodiments, each fatty alcohol is a C2-C6 fatty alcohol. In some embodiments, each fatty alcohol is a C2-C7 fatty alcohol. In some embodiments, each fatty alcohol is a C2-C8 fatty alcohol. In some embodiments, each fatty alcohol is a C2-C9 fatty alcohol. In some

embodiments, each fatty alcohol is a C2-C10 fatty alcohol. In some embodiments, each fatty alcohol is a C2-C11 fatty alcohol. In some embodiments, each fatty alcohol is a C2-C12 fatty alcohol. In some embodiments, each fatty alcohol is a C2-C13 fatty alcohol. In some

embodiments, each fatty alcohol is a C2-C14 fatty alcohol. In some embodiments, each fatty alcohol is a C2-C15 fatty alcohol. In some embodiments, each fatty alcohol is a C2-C16 fatty alcohol. In some embodiments, each fatty alcohol is a C2-C17 fatty alcohol. In some

embodiments, each fatty alcohol is a C2-C18 fatty alcohol. In some embodiments, each fatty alcohol is a C2-C19 fatty alcohol. In some embodiments, each fatty alcohol is a C2-C20 fatty alcohol. In some embodiments, each fatty alcohol is a C2-C21 fatty alcohol. In some embodiments, each fatty alcohol is a C2-C22 fatty alcohol. In some embodiments, each fatty alcohol is a C2-C23 fatty alcohol. In some embodiments, each fatty alcohol is a C2-C24 fatty alcohol. In some embodiments, each fatty alcohol is a C2-C25 fatty alcohol. In some embodiments, each fatty alcohol is a C2-C26 fatty alcohol. In some embodiments, each fatty alcohol is a C3-C4 fatty alcohol. In some embodiments, each fatty alcohol is a C3-C5 fatty alcohol. In some embodiments, each fatty alcohol is a C3-C6 fatty alcohol. In some embodiments, each fatty alcohol is a C3-C7 fatty alcohol. In some embodiments, each fatty alcohol is a C3-C8 fatty alcohol. In some embodiments, each fatty alcohol is a C3-C9 fatty alcohol. In some embodiments, each fatty alcohol is a C3-C10 fatty alcohol. In some embodiments, each fatty alcohol is a C3-C11 fatty alcohol. In some embodiments, each fatty alcohol is a C3-C12 fatty alcohol. In some embodiments, each fatty alcohol is a C3-C13 fatty alcohol. In some embodiments, each fatty alcohol is a C3-C14 fatty alcohol. In some embodiments, each fatty alcohol is a C3-C15 fatty alcohol. In some embodiments, each fatty alcohol is a C3-C16 fatty alcohol. In some embodiments, each fatty alcohol is a C3-C17 fatty alcohol. In some embodiments, each fatty alcohol is a C3-C18 fatty alcohol. In some embodiments, each fatty alcohol is a C3-C19 fatty alcohol. In some embodiments, each fatty alcohol is a C3-C20 fatty alcohol. In some embodiments, each fatty alcohol is a C3-C21 fatty alcohol. In some embodiments, each fatty alcohol is a C3-C22 fatty alcohol. In some embodiments, each fatty alcohol is a C3-C23 fatty alcohol. In some embodiments, each fatty alcohol is a C3-C24 fatty alcohol. In some embodiments, each fatty alcohol is a C3-C25 fatty alcohol. In some embodiments, each fatty alcohol is a C3-C26 fatty alcohol. In some embodiments, each fatty alcohol is a C4-C5 fatty alcohol. In some embodiments, each fatty alcohol is a C4-C6 fatty alcohol. In some embodiments, each fatty alcohol is a C4-C7 fatty alcohol. In some embodiments, each fatty alcohol is a C4-C8 fatty alcohol. In some embodiments, each fatty alcohol is a C4-C9 fatty alcohol. In some embodiments, each fatty alcohol is a C4-C10 fatty alcohol. In some embodiments, each fatty alcohol is a C4-C11 fatty alcohol. In some embodiments, each fatty alcohol is a C4-C12 fatty alcohol. In some embodiments, each fatty alcohol is a C4-C13 fatty alcohol. In some embodiments, each fatty alcohol is a C4-C14 fatty alcohol. In some embodiments, each fatty alcohol is a C4-C15 fatty alcohol. In some embodiments, each fatty alcohol is a C4-C16 fatty alcohol. In some embodiments, each fatty alcohol is a C4-C17 fatty alcohol. In some embodiments, each fatty alcohol is a C4-C18 fatty alcohol. In some embodiments, each fatty alcohol is a C4-C19 fatty alcohol. In some embodiments, each fatty alcohol is a C4-C20 fatty alcohol. In some embodiments, each fatty alcohol is a C4-C21 fatty alcohol. In some embodiments, each fatty alcohol is a C4-C22 fatty alcohol. In some embodiments, each fatty alcohol is a C4-C23 fatty alcohol. In some embodiments, each fatty alcohol is a C4-C24 fatty alcohol. In some embodiments, each fatty alcohol is a C4-C25 fatty alcohol. In some embodiments, each fatty alcohol is a C4-C26 fatty alcohol. In some embodiments, each fatty alcohol is a C5-C6 fatty alcohol. In some embodiments, each fatty alcohol is a C5-C7 fatty alcohol. In some embodiments, each fatty alcohol is a C5-C8 fatty alcohol. In some embodiments, each fatty alcohol is a C5-C9 fatty alcohol. In some embodiments, each fatty alcohol is a C5-C10 fatty alcohol. In some embodiments, each fatty alcohol is a C5-C11 fatty alcohol. In some embodiments, each fatty alcohol is a C5-C12 fatty alcohol. In some embodiments, each fatty alcohol is a C5-C13 fatty alcohol. In some embodiments, each fatty alcohol is a C5-C14 fatty alcohol. In some embodiments, each fatty alcohol is a C5-C15 fatty alcohol. In some embodiments, each fatty alcohol is a C5-C16 fatty alcohol. In some embodiments, each fatty alcohol is a C5-C17 fatty alcohol. In some embodiments, each fatty alcohol is a C5-C18 fatty alcohol. In some embodiments, each fatty alcohol is a C5-C19 fatty alcohol. In some embodiments, each fatty alcohol is a C5-C20 fatty alcohol. In some embodiments, each fatty alcohol is a C5-C21 fatty alcohol. In some embodiments, each fatty alcohol is a C5-C22 fatty alcohol. In some embodiments, each fatty alcohol is a C5-C23 fatty alcohol. In some embodiments, each fatty alcohol is a C5-C24 fatty alcohol. In some embodiments, each fatty alcohol is a C5-C25 fatty alcohol. In some embodiments, each fatty alcohol is a C5-C26 fatty alcohol. In some embodiments, each fatty alcohol is a C6-C7 fatty alcohol. In some embodiments, each fatty alcohol is a C6-C8 fatty alcohol. In some embodiments, each fatty alcohol is a C6-C9 fatty alcohol. In some embodiments, each fatty alcohol is a C6-C10 fatty alcohol. In some embodiments, each fatty alcohol is a C6-C11 fatty alcohol. In some embodiments, each fatty alcohol is a C6-C12 fatty alcohol. In some embodiments, each fatty alcohol is a C6-C13 fatty alcohol. In some embodiments, each fatty alcohol is a C6-C14 fatty alcohol. In some embodiments, each fatty alcohol is a C6-C15 fatty alcohol. In some embodiments, each fatty alcohol is a C6-C16 fatty alcohol. In some embodiments, each fatty alcohol is a C6-C17 fatty alcohol. In some embodiments, each fatty alcohol is a C6-C18 fatty alcohol. In some embodiments, each fatty alcohol is a C6-C19 fatty alcohol. In some embodiments, each fatty alcohol is a C6-C20 fatty alcohol. In some embodiments, each fatty alcohol is a C6-C21 fatty alcohol. In some embodiments, each fatty alcohol is a C6-C22 fatty alcohol. In some embodiments, each fatty alcohol is a C6-C23 fatty alcohol. In some embodiments, each fatty alcohol is a C6-C24 fatty alcohol. In some embodiments, each fatty alcohol is a C6-C25 fatty alcohol. In some embodiments, each fatty alcohol is a C6-C26 fatty alcohol. In some embodiments, each fatty alcohol is a C7-C8 fatty alcohol. In some embodiments, each fatty alcohol is a C7-C9 fatty alcohol. In some embodiments, each fatty alcohol is a C7-C10 fatty alcohol. In some embodiments, each fatty alcohol is a C7-C11 fatty alcohol. In some embodiments, each fatty alcohol is a C7-C12 fatty alcohol. In some embodiments, each fatty alcohol is a C7-C13 fatty alcohol. In some embodiments, each fatty alcohol is a C7-C14 fatty alcohol. In some embodiments, each fatty alcohol is a C7-C15 fatty alcohol. In some embodiments, each fatty alcohol is a C7-C16 fatty alcohol. In some embodiments, each fatty alcohol is a C7-C17 fatty alcohol. In some embodiments, each fatty alcohol is a C7-C18 fatty alcohol. In some embodiments, each fatty alcohol is a C7-C19 fatty alcohol. In some embodiments, each fatty alcohol is a C7-C20 fatty alcohol. In some embodiments, each fatty alcohol is a C7-C21 fatty alcohol. In some embodiments, each fatty alcohol is a C7-C22 fatty alcohol. In some embodiments, each fatty alcohol is a C7-C23 fatty alcohol. In some embodiments, each fatty alcohol is a C7-C24 fatty alcohol. In some embodiments, each fatty alcohol is a C7-C25 fatty alcohol. In some embodiments, each fatty alcohol is a C7-C26 fatty alcohol. In some embodiments, each fatty alcohol is a C8-C9 fatty alcohol. In some embodiments, each fatty alcohol is a C8-C10 fatty alcohol. In some embodiments, each fatty alcohol is a C8-C11 fatty alcohol. In some embodiments, each fatty alcohol is a C8-C12 fatty alcohol. In some embodiments, each fatty alcohol is a C8-C13 fatty alcohol. In some embodiments, each fatty alcohol is a C8-C14 fatty alcohol. In some embodiments, each fatty alcohol is a C8-C15 fatty alcohol. In some embodiments, each fatty alcohol is a C8-C16 fatty alcohol. In some embodiments, each fatty alcohol is a C8-C17 fatty alcohol. In some embodiments, each fatty alcohol is a C8-C18 fatty alcohol. In some embodiments, each fatty alcohol is a C8-C19 fatty alcohol. In some embodiments, each fatty alcohol is a C8-C20 fatty alcohol. In some embodiments, each fatty alcohol is a C8-C21 fatty alcohol. In some embodiments, each fatty alcohol is a C8-C22 fatty alcohol. In some embodiments, each fatty alcohol is a C8-C23 fatty alcohol. In some embodiments, each fatty alcohol is a C8-C24 fatty alcohol. In some embodiments, each fatty alcohol is a C8-C25 fatty alcohol. In some embodiments, each fatty alcohol is a C8-C26 fatty alcohol. In some embodiments, each fatty alcohol is a C9-C10 fatty alcohol. In some embodiments, each fatty alcohol is a C9-C11 fatty alcohol. In some embodiments, each fatty alcohol is a C9-C12 fatty alcohol. In some embodiments, each fatty alcohol is a C9-C13 fatty alcohol. In some embodiments, each fatty alcohol is a C9-C14 fatty alcohol. In some embodiments, each fatty alcohol is a C9-C15 fatty alcohol. In some embodiments, each fatty alcohol is a C9-C16 fatty alcohol. In some embodiments, each fatty alcohol is a C9-C17 fatty alcohol. In some embodiments, each fatty alcohol is a C9-C18 fatty alcohol. In some embodiments, each fatty alcohol is a C9-C19 fatty alcohol. In some embodiments, each fatty alcohol is a C9-C20 fatty alcohol. In some embodiments, each fatty alcohol is a C9-C21 fatty alcohol. In some embodiments, each fatty alcohol is a C9-C22 fatty alcohol. In some embodiments, each fatty alcohol is a C9-C23 fatty alcohol. In some embodiments, each fatty alcohol is a C9-C24 fatty alcohol. In some embodiments, each fatty alcohol is a C9-C25 fatty alcohol. In some embodiments, each fatty alcohol is a C9-C26 fatty alcohol. In some embodiments, each fatty alcohol is a C10-C11 fatty alcohol. In some embodiments, each fatty alcohol is a C10-C12 fatty alcohol. In some embodiments, each fatty alcohol is a C10-C13 fatty alcohol. In some embodiments, each fatty alcohol is a C10-C14 fatty alcohol. In some embodiments, each fatty alcohol is a C10-C15 fatty alcohol. In some embodiments, each fatty alcohol is a C10-C16 fatty alcohol. In some embodiments, each fatty alcohol is a C10-C17 fatty alcohol. In some embodiments, each fatty alcohol is a C10-C18 fatty alcohol. In some embodiments, each fatty alcohol is a C10-C19 fatty alcohol. In some embodiments, each fatty alcohol is a C10-C20 fatty alcohol. In some embodiments, each fatty alcohol is a C10-C21 fatty alcohol. In some embodiments, each fatty alcohol is a C10-C22 fatty alcohol. In some embodiments, each fatty alcohol is a C10-C23 fatty alcohol. In some embodiments, each fatty alcohol is a C10-C24 fatty alcohol. In some embodiments, each fatty alcohol is a C10-C25 fatty alcohol. In some embodiments, each fatty alcohol is a C10-C26 fatty alcohol. In some embodiments, each fatty alcohol is a Cl 1-C12 fatty alcohol. In some embodiments, each fatty alcohol is a Cl 1-C13 fatty alcohol. In some embodiments, each fatty alcohol is a Cl 1-C14 fatty alcohol. In some embodiments, each fatty alcohol is a Cl 1-C15 fatty alcohol. In some embodiments, each fatty alcohol is a Cl 1-C16 fatty alcohol. In some embodiments, each fatty alcohol is a Cl 1-C17 fatty alcohol. In some embodiments, each fatty alcohol is a Cl 1-C18 fatty alcohol. In some embodiments, each fatty alcohol is a Cl 1-C19 fatty alcohol. In some embodiments, each fatty alcohol is a Cl 1-C20 fatty alcohol. In some embodiments, each fatty alcohol is a Cl 1-C21 fatty alcohol. In some embodiments, each fatty alcohol is a Cl 1-C22 fatty alcohol. In some embodiments, each fatty alcohol is a Cl 1-C23 fatty alcohol. In some embodiments, each fatty alcohol is a Cl 1-C24 fatty alcohol. In some embodiments, each fatty alcohol is a Cl 1-C25 fatty alcohol. In some embodiments, each fatty alcohol is a Cl 1-C26 fatty alcohol. In some embodiments, each fatty alcohol is a C12-C13 fatty alcohol. In some embodiments, each fatty alcohol is a C12-C14 fatty alcohol. In some embodiments, each fatty alcohol is a C12-C15 fatty alcohol. In some embodiments, each fatty alcohol is a C12-C16 fatty alcohol. In some embodiments, each fatty alcohol is a C12-C17 fatty alcohol. In some embodiments, each fatty alcohol is a C12-C18 fatty alcohol. In some embodiments, each fatty alcohol is a C12-C19 fatty alcohol. In some embodiments, each fatty alcohol is a C12-C20 fatty alcohol. In some embodiments, each fatty alcohol is a C12-C21 fatty alcohol. In some embodiments, each fatty alcohol is a C12-C22 fatty alcohol. In some embodiments, each fatty alcohol is a C12-C23 fatty alcohol. In some embodiments, each fatty alcohol is a C12-C24 fatty alcohol. In some embodiments, each fatty alcohol is a C12-C25 fatty alcohol. In some embodiments, each fatty alcohol is a C12-C26 fatty alcohol. In some embodiments, each fatty alcohol is a C13-C14 fatty alcohol. In some embodiments, each fatty alcohol is a C13-C15 fatty alcohol. In some embodiments, each fatty alcohol is a C13-C16 fatty alcohol. In some embodiments, each fatty alcohol is a C13-C17 fatty alcohol. In some embodiments, each fatty alcohol is a C13-C18 fatty alcohol. In some embodiments, each fatty alcohol is a C13-C19 fatty alcohol. In some embodiments, each fatty alcohol is a C13-C20 fatty alcohol. In some embodiments, each fatty alcohol is a C13-C21 fatty alcohol. In some embodiments, each fatty alcohol is a C13-C22 fatty alcohol. In some embodiments, each fatty alcohol is a C13-C23 fatty alcohol. In some embodiments, each fatty alcohol is a C13-C24 fatty alcohol. In some embodiments, each fatty alcohol is a C13-C25 fatty alcohol. In some embodiments, each fatty alcohol is a C13-C26 fatty alcohol. In some embodiments, each fatty alcohol is a C14-C15 fatty alcohol. In some embodiments, each fatty alcohol is a C14-C16 fatty alcohol. In some embodiments, each fatty alcohol is a C14-C17 fatty alcohol. In some embodiments, each fatty alcohol is a C14-C18 fatty alcohol. In some embodiments, each fatty alcohol is a C14-C19 fatty alcohol. In some embodiments, each fatty alcohol is a C14-C20 fatty alcohol. In some embodiments, each fatty alcohol is a C14-C21 fatty alcohol. In some embodiments, each fatty alcohol is a C14-C22 fatty alcohol. In some embodiments, each fatty alcohol is a C14-C23 fatty alcohol. In some embodiments, each fatty alcohol is a C14-C24 fatty alcohol. In some embodiments, each fatty alcohol is a C14-C25 fatty alcohol. In some embodiments, each fatty alcohol is a C14-C26 fatty alcohol. In some embodiments, each fatty alcohol is a C15-C16 fatty alcohol. In some embodiments, each fatty alcohol is a C15-C17 fatty alcohol. In some embodiments, each fatty alcohol is a C15-C18 fatty alcohol. In some embodiments, each fatty alcohol is a C15-C19 fatty alcohol. In some embodiments, each fatty alcohol is a C15-C20 fatty alcohol. In some embodiments, each fatty alcohol is a C15-C21 fatty alcohol. In some embodiments, each fatty alcohol is a C15-C22 fatty alcohol. In some embodiments, each fatty alcohol is a C15-C23 fatty alcohol. In some embodiments, each fatty alcohol is a C15-C24 fatty alcohol. In some embodiments, each fatty alcohol is a C15-C25 fatty alcohol. In some embodiments, each fatty alcohol is a C15-C26 fatty alcohol. In some embodiments, each fatty alcohol is a C16-C17 fatty alcohol. In some embodiments, each fatty alcohol is a C16-C18 fatty alcohol. In some embodiments, each fatty alcohol is a C16-C19 fatty alcohol. In some embodiments, each fatty alcohol is a C16-C20 fatty alcohol. In some embodiments, each fatty alcohol is a C16-C21 fatty alcohol. In some embodiments, each fatty alcohol is a C16-C22 fatty alcohol. In some embodiments, each fatty alcohol is a C16-C23 fatty alcohol. In some embodiments, each fatty alcohol is a C16-C24 fatty alcohol. In some embodiments, each fatty alcohol is a C16-C25 fatty alcohol. In some embodiments, each fatty alcohol is a C16-C26 fatty alcohol. In some embodiments, each fatty alcohol is a C17-C18 fatty alcohol. In some embodiments, each fatty alcohol is a C17-C19 fatty alcohol. In some embodiments, each fatty alcohol is a C17-C20 fatty alcohol. In some embodiments, each fatty alcohol is a C17-C21 fatty alcohol. In some embodiments, each fatty alcohol is a C17-C22 fatty alcohol. In some embodiments, each fatty alcohol is a C17-C23 fatty alcohol. In some embodiments, each fatty alcohol is a C17-C24 fatty alcohol. In some embodiments, each fatty alcohol is a C17-C25 fatty alcohol. In some embodiments, each fatty alcohol is a C17-C26 fatty alcohol. In some embodiments, each fatty alcohol is a C18-C19 fatty alcohol. In some embodiments, each fatty alcohol is a C18-C20 fatty alcohol. In some embodiments, each fatty alcohol is a C18-C21 fatty alcohol. In some embodiments, each fatty alcohol is a C18-C22 fatty alcohol. In some embodiments, each fatty alcohol is a C18-C23 fatty alcohol. In some embodiments, each fatty alcohol is a C18-C24 fatty alcohol. In some embodiments, each fatty alcohol is a C18-C25 fatty alcohol. In some embodiments, each fatty alcohol is a C18-C26 fatty alcohol. In some embodiments, each fatty alcohol is a C19-C20 fatty alcohol. In some embodiments, each fatty alcohol is a C19-C21 fatty alcohol. In some embodiments, each fatty alcohol is a C19-C22 fatty alcohol. In some embodiments, each fatty alcohol is a C19-C23 fatty alcohol. In some embodiments, each fatty alcohol is a C19-C24 fatty alcohol. In some embodiments, each fatty alcohol is a C19-C25 fatty alcohol. In some embodiments, each fatty alcohol is a C19-C26 fatty alcohol. In some embodiments, each fatty alcohol is a C20-C21 fatty alcohol. In some embodiments, each fatty alcohol is a C20-C22 fatty alcohol. In some embodiments, each fatty alcohol is a C20-C23 fatty alcohol. In some embodiments, each fatty alcohol is a C20-C24 fatty alcohol. In some embodiments, each fatty alcohol is a C20-C25 fatty alcohol. In some embodiments, each fatty alcohol is a C20-C26 fatty alcohol. In some embodiments, each fatty alcohol is a C21-C22 fatty alcohol. In some embodiments, each fatty alcohol is a C21-C23 fatty alcohol. In some embodiments, each fatty alcohol is a C21-C24 fatty alcohol. In some embodiments, each fatty alcohol is a C21-C25 fatty alcohol. In some embodiments, each fatty alcohol is a C21-C26 fatty alcohol. In some embodiments, each fatty alcohol is a C22-C23 fatty alcohol. In some embodiments, each fatty alcohol is a C22-C24 fatty alcohol. In some embodiments, each fatty alcohol is a C22-C25 fatty alcohol. In some embodiments, each fatty alcohol is a C22-C26 fatty alcohol. In some embodiments, each fatty alcohol is a C23-C24 fatty alcohol. In some embodiments, each fatty alcohol is a C23-C25 fatty alcohol. In some embodiments, each fatty alcohol is a C23-C26 fatty alcohol. In some embodiments, each fatty alcohol is a C24-C25 fatty alcohol. In some embodiments, each fatty alcohol is a C24-C26 fatty alcohol. In some embodiments, each fatty alcohol is a C25-C26 fatty alcohol. In some embodiments, each fatty alcohol is a C2 fatty alcohol. In some embodiments, each fatty alcohol is a C3 fatty alcohol. In some embodiments, each fatty alcohol is a C4 fatty alcohol. In some embodiments, each fatty alcohol is a C5 fatty alcohol. In some embodiments, each fatty alcohol is a C6 fatty alcohol. In some embodiments, each fatty alcohol is a C7 fatty alcohol. In some embodiments, each fatty alcohol is a C8 fatty alcohol. In some embodiments, each fatty alcohol is a C9 fatty alcohol. In some embodiments, each fatty alcohol is a CIO fatty alcohol. In some embodiments, each fatty alcohol is a Cl 1 fatty alcohol. In some embodiments, each fatty alcohol is a C12 fatty alcohol. In some embodiments, each fatty alcohol is a C13 fatty alcohol. In some embodiments, each fatty alcohol is a C14 fatty alcohol. In some embodiments, each fatty alcohol is a C15 fatty alcohol. In some embodiments, each fatty alcohol is a C16 fatty alcohol. In some embodiments, each fatty alcohol is a C17 fatty alcohol. In some embodiments, each fatty alcohol is a C18 fatty alcohol. In some embodiments, each fatty alcohol is a C19 fatty alcohol. In some embodiments, each fatty alcohol is a C20 fatty alcohol. In some embodiments, each fatty alcohol is a C21 fatty alcohol. In some embodiments, each fatty alcohol is a C22 fatty alcohol. In some embodiments, each fatty alcohol is a C23 fatty alcohol. In some embodiments, each fatty alcohol is a C24 fatty alcohol. In some embodiments, each fatty alcohol is a C25 fatty alcohol. In some embodiments, each fatty alcohol is a C26 fatty alcohol.

[0083] In some embodiments, each fatty alcohol is independently selected from docosahexaenol or eicosapentaenol.

[0084] In some embodiments, each fatty alcohol is independently selected from docosahexaenol,

eicosapentaenol, (Z)-octadec-9-en-l-ol, octadecan-l-ol, (9Z,12Z)-octadeca-9,12-dien-l-ol, (Z)- docos-13-en-l-ol, docosanol, (E)-octadec-9-en, icosanol, (9Z,12Z,15Z)-octadeca-9,12,15-trien- l-ol, or palmitol.

[0085] In some embodiments, each fatty alcohol is independently selected from butanol, pentanol, hexanol, heptanol, octanol, nonanol, decanol, undecanol, dodecanol, tridecanol, tetradecanol, pentadecanol, hexadecanol, heptadecanol, octadecanol, nonadecanol, eicosanol, heneicosanol, docosanol, tricosanol, tetracosanol, pentacosanol, and hexacosanol.

[0086] In some embodiments, each fatty alcohol is independently selected from (E)-but-2-en-l-ol, (Z)- tetradec-9-en-l-ol, (Z)-hexadec-9-en-l-ol, (Z)-hexadec-6-en-l-ol, (Z)-octadec-9-en-l-ol, (E)- octadec-9-en-l-ol, (E)-octadec-l l-en-l-ol, (Z)-icos-9-en-l-ol, eicosenol, (Z)-docos-13-en-l-ol, and (Z)-tetracos-15-en-l-ol.

[0087] In some embodiments, each fatty alcohol is independently selected from (9Z,12Z)-octadeca- 9,12-dien-l-ol, eicosadienol, and docosadienol.

[0088] In some embodiments, each fatty alcohol is independently selected from (9Z,12Z,15Z)-octadeca- 9,12,15-trien-l-ol, (5Z,9Z,12Z)-octadeca-5,9,12-trien-l-ol, (9Z,1 lE,13E)-octadeca-9,l 1,13- trien-l-ol, (5Z,8Z,1 lZ)-icosa-5,8,l 1-trien-l-ol, (8Z,1 lZ,14Z)-icosa-8,l 1,14-trien-l-ol, and eicosatrienol.

[0089] In some embodiments, each fatty alcohol is independently selected from (6Z,9Z,12Z,15Z)- octadeca-6,9,12,15-tetraen-l-ol, (5Z,8Z,l lZ,14Z)-icosa-5,8,l l,14-tetraen-l-ol, eicosatetraenol, and (7Z, 10Z, 13Z, 16Z)-docosa-7, 10,13,16-tetraen- 1 -ol .

[0090] In some embodiments, the phosphorylated gemcitabine derivative prodrug of Formula (I)

described herein has a structure provided in Table 1. TABLE 1

[0091] In another aspect, provided herein is a compound, or pharmaceutically acceptable salt thereof, having a structure provided in Formula (II),

wherein

R is selected from fatty alcohol, glycerolipid, glycerophospholipids, sphingolipids, sterol-lipids, prenol lipids, saccharolipids and polyketides;

R ¹ is hydrogen, substituted or unsubstituted Ci-Cio alkyl, substituted or unsubstituted

heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; and R ² is hydrogen, substituted or unsubstituted C ₁ -C ₄ alkyl, substituted or unsubstituted C ₂ -C ₄ alkenyl, substituted or unsubstituted C ₂ -C ₄ alkynyl, -C(=0)Ci-C ₄ alkyl, -C(=0)0(Ci-C ₄ alkyl), substituted or unsubstituted aryl, or substituted or unsubstituted benzyl,

L is a linker selected from an alkylene amide group, an alkylene ester group, an alkylene

carbamate group, a disulfide group, a phosphodiester group, and a phosphoramidate group; and

G is a cytotoxic chemotherapy agent,

wherein a substituted group is substituted with 1, 2, or 3 groups independently selected from halogen, -OH, -SH, -NH ₂ , -CN, -C(=0)0H, -C(=0)0(Ci-C ₄ alkyl), -C(=0)NH ₂ , - C(=0)NH(C _I -C ₄ alkyl), -C(=0)N(Ci-C ₄ alkyl) ₂ , C1-C4 alkyl, -S(Ci-C ₄ alkyl), C1-C4 alkoxy, C3-C6 cycloalkyl, C2-C5 heterocyclyl, -NH(C _I -C ₄ alkyl), -N(C _I -C ₄ alkyl) ₂ , phenyl, -C6H4OH, imidazole, and arginine.

[0092] In some embodiments, the cytotoxic chemotherapy agent G is selected from methotrexate,

doxorubicin, vincristine, procarbazine, prednisolone, bleomycin, vinblastine, dacarbazine, bleomycin, etoposide, curcumin, SN38, rapamycin, geldanamycin, tanespimycin, or IDN5404.

[0093] In some embodiments, the cytotoxic chemotherapy agent G is selected from abiraterone, afatinib, axitinib, azacitidine, bortezomib, cabazitaxel, cabozantinib, capecitabine, carfilzomib, ceritinib, crizotinib, cyclophosphamide, cytarabine, dabrafenib, dactinomycin, dasatinib, daunorubicin, decarbazine, decitabine, docetaxel, doxorubicin, epirubicin, erlotinib, etoposide, everrolimus, floxuridine, gefitinib, ibrutinib, idarubicin, idelalisib, lapatinib, lenvatinib, leucovorin, methotrexate, mitomycin, olaparib, palbociclib, pazopanib, ponatinib, pralatrexate, prednisone, regorafenib, ruxolitinib, sorafenib, streptozocin, sunitinib, thalidomide, topotecan, vemurafenib, vincristine, vinorelbine, and zoledronic acid.

[0094] In some embodiments, L is an alkylene carbamate group.

[0095] In some embodiments, R ¹ is hydrogen. In some embodiments, R ² is hydrogen. In some

embodiments, R ¹ and R ² are hydrogen. [0096] In some embodiments, R ¹ is not hydrogen. In some embodiments, R ¹ is not hydrogen, and R and R ¹ are selected independently. In some embodiments, R ¹ is not hydrogen, and R and R ¹ are the same. In some embodiments, R ¹ is not hydrogen and R ² is hydrogen. In some embodiments, R ¹ is substituted or unsubstituted aryl and R ² is hydrogen. In some embodiments, R ¹ is substituted or unsubstituted phenyl and R ² is hydrogen. In some embodiments, R ¹ phenyl and R ² is hydrogen.

[0097] In some embodiments, R ² is not hydrogen. In some embodiments, R ² is not hydrogen, and R and R ² are selected independently. In some embodiments, R ² is not hydrogen, and R and R ² are the same. In some embodiments, R ¹ is hydrogen and R ² is not hydrogen.

[0098] In some embodiments, R and R ¹ are independently selected from a fatty alcohol. In some

embodiments, R is a fatty alcohol, and R ¹ is hydrogen. In some embodiments, R and R ² are independently selected from a fatty alcohol. In some embodiments, R is a fatty alcohol, and R ² is hydrogen.

[0099] In some embodiments, R ¹ and R ² are both hydrogen.

[00100] In some embodiments, each fatty alcohol is independently selected from a saturated,

monounsaturated, or polyunsaturated fatty alcohol.

[00101] In some embodiments, each fatty alcohol is a C2-C26 fatty alcohol. In some embodiments, each fatty alcohol is a C2-C3 fatty alcohol. In some embodiments, each fatty alcohol is a C2-C4 fatty alcohol. In some embodiments, each fatty alcohol is a C2-C5 fatty alcohol. In some

embodiments, each fatty alcohol is a C2-C6 fatty alcohol. In some embodiments, each fatty alcohol is a C2-C7 fatty alcohol. In some embodiments, each fatty alcohol is a C2-C8 fatty alcohol. In some embodiments, each fatty alcohol is a C2-C9 fatty alcohol. In some

embodiments, each fatty alcohol is a C2-C10 fatty alcohol. In some embodiments, each fatty alcohol is a C2-C11 fatty alcohol. In some embodiments, each fatty alcohol is a C2-C12 fatty alcohol. In some embodiments, each fatty alcohol is a C2-C13 fatty alcohol. In some

embodiments, each fatty alcohol is a C2-C14 fatty alcohol. In some embodiments, each fatty alcohol is a C2-C15 fatty alcohol. In some embodiments, each fatty alcohol is a C2-C16 fatty alcohol. In some embodiments, each fatty alcohol is a C2-C17 fatty alcohol. In some

embodiments, each fatty alcohol is a C2-C18 fatty alcohol. In some embodiments, each fatty alcohol is a C2-C19 fatty alcohol. In some embodiments, each fatty alcohol is a C2-C20 fatty alcohol. In some embodiments, each fatty alcohol is a C2-C21 fatty alcohol. In some

embodiments, each fatty alcohol is a C2-C22 fatty alcohol. In some embodiments, each fatty alcohol is a C2-C23 fatty alcohol. In some embodiments, each fatty alcohol is a C2-C24 fatty alcohol. In some embodiments, each fatty alcohol is a C2-C25 fatty alcohol. In some embodiments, each fatty alcohol is a C2-C26 fatty alcohol. In some embodiments, each fatty alcohol is a C3-C4 fatty alcohol. In some embodiments, each fatty alcohol is a C3-C5 fatty alcohol. In some embodiments, each fatty alcohol is a C3-C6 fatty alcohol. In some embodiments, each fatty alcohol is a C3-C7 fatty alcohol. In some embodiments, each fatty alcohol is a C3-C8 fatty alcohol. In some embodiments, each fatty alcohol is a C3-C9 fatty alcohol. In some embodiments, each fatty alcohol is a C3-C10 fatty alcohol. In some embodiments, each fatty alcohol is a C3-C11 fatty alcohol. In some embodiments, each fatty alcohol is a C3-C12 fatty alcohol. In some embodiments, each fatty alcohol is a C3-C13 fatty alcohol. In some embodiments, each fatty alcohol is a C3-C14 fatty alcohol. In some embodiments, each fatty alcohol is a C3-C15 fatty alcohol. In some embodiments, each fatty alcohol is a C3-C16 fatty alcohol. In some embodiments, each fatty alcohol is a C3-C17 fatty alcohol. In some embodiments, each fatty alcohol is a C3-C18 fatty alcohol. In some embodiments, each fatty alcohol is a C3-C19 fatty alcohol. In some embodiments, each fatty alcohol is a C3-C20 fatty alcohol. In some embodiments, each fatty alcohol is a C3-C21 fatty alcohol. In some embodiments, each fatty alcohol is a C3-C22 fatty alcohol. In some embodiments, each fatty alcohol is a C3-C23 fatty alcohol. In some embodiments, each fatty alcohol is a C3-C24 fatty alcohol. In some embodiments, each fatty alcohol is a C3-C25 fatty alcohol. In some embodiments, each fatty alcohol is a C3-C26 fatty alcohol. In some embodiments, each fatty alcohol is a C4-C5 fatty alcohol. In some embodiments, each fatty alcohol is a C4-C6 fatty alcohol. In some embodiments, each fatty alcohol is a C4-C7 fatty alcohol. In some embodiments, each fatty alcohol is a C4-C8 fatty alcohol. In some embodiments, each fatty alcohol is a C4-C9 fatty alcohol. In some embodiments, each fatty alcohol is a C4-C10 fatty alcohol. In some embodiments, each fatty alcohol is a C4-C11 fatty alcohol. In some embodiments, each fatty alcohol is a C4-C12 fatty alcohol. In some embodiments, each fatty alcohol is a C4-C13 fatty alcohol. In some embodiments, each fatty alcohol is a C4-C14 fatty alcohol. In some embodiments, each fatty alcohol is a C4-C15 fatty alcohol. In some embodiments, each fatty alcohol is a C4-C16 fatty alcohol. In some embodiments, each fatty alcohol is a C4-C17 fatty alcohol. In some embodiments, each fatty alcohol is a C4-C18 fatty alcohol. In some embodiments, each fatty alcohol is a C4-C19 fatty alcohol. In some embodiments, each fatty alcohol is a C4-C20 fatty alcohol. In some embodiments, each fatty alcohol is a C4-C21 fatty alcohol. In some embodiments, each fatty alcohol is a C4-C22 fatty alcohol. In some embodiments, each fatty alcohol is a C4-C23 fatty alcohol. In some embodiments, each fatty alcohol is a C4-C24 fatty alcohol. In some embodiments, each fatty alcohol is a C4-C25 fatty alcohol. In some embodiments, each fatty alcohol is a C4-C26 fatty alcohol. In some embodiments, each fatty alcohol is a C5-C6 fatty alcohol. In some embodiments, each fatty alcohol is a C5-C7 fatty alcohol. In some embodiments, each fatty alcohol is a C5-C8 fatty alcohol. In some embodiments, each fatty alcohol is a C5-C9 fatty alcohol. In some embodiments, each fatty alcohol is a C5-C10 fatty alcohol. In some embodiments, each fatty alcohol is a C5-C11 fatty alcohol. In some embodiments, each fatty alcohol is a C5-C12 fatty alcohol. In some embodiments, each fatty alcohol is a C5-C13 fatty alcohol. In some embodiments, each fatty alcohol is a C5-C14 fatty alcohol. In some embodiments, each fatty alcohol is a C5-C15 fatty alcohol. In some embodiments, each fatty alcohol is a C5-C16 fatty alcohol. In some embodiments, each fatty alcohol is a C5-C17 fatty alcohol. In some embodiments, each fatty alcohol is a C5-C18 fatty alcohol. In some embodiments, each fatty alcohol is a C5-C19 fatty alcohol. In some embodiments, each fatty alcohol is a C5-C20 fatty alcohol. In some embodiments, each fatty alcohol is a C5-C21 fatty alcohol. In some embodiments, each fatty alcohol is a C5-C22 fatty alcohol. In some embodiments, each fatty alcohol is a C5-C23 fatty alcohol. In some embodiments, each fatty alcohol is a C5-C24 fatty alcohol. In some embodiments, each fatty alcohol is a C5-C25 fatty alcohol. In some embodiments, each fatty alcohol is a C5-C26 fatty alcohol. In some embodiments, each fatty alcohol is a C6-C7 fatty alcohol. In some embodiments, each fatty alcohol is a C6-C8 fatty alcohol. In some embodiments, each fatty alcohol is a C6-C9 fatty alcohol. In some embodiments, each fatty alcohol is a C6-C10 fatty alcohol. In some embodiments, each fatty alcohol is a C6-C11 fatty alcohol. In some embodiments, each fatty alcohol is a C6-C12 fatty alcohol. In some embodiments, each fatty alcohol is a C6-C13 fatty alcohol. In some embodiments, each fatty alcohol is a C6-C14 fatty alcohol. In some embodiments, each fatty alcohol is a C6-C15 fatty alcohol. In some embodiments, each fatty alcohol is a C6-C16 fatty alcohol. In some embodiments, each fatty alcohol is a C6-C17 fatty alcohol. In some embodiments, each fatty alcohol is a C6-C18 fatty alcohol. In some embodiments, each fatty alcohol is a C6-C19 fatty alcohol. In some embodiments, each fatty alcohol is a C6-C20 fatty alcohol. In some embodiments, each fatty alcohol is a C6-C21 fatty alcohol. In some embodiments, each fatty alcohol is a C6-C22 fatty alcohol. In some embodiments, each fatty alcohol is a C6-C23 fatty alcohol. In some embodiments, each fatty alcohol is a C6-C24 fatty alcohol. In some embodiments, each fatty alcohol is a C6-C25 fatty alcohol. In some embodiments, each fatty alcohol is a C6-C26 fatty alcohol. In some embodiments, each fatty alcohol is a C7-C8 fatty alcohol. In some embodiments, each fatty alcohol is a C7-C9 fatty alcohol. In some embodiments, each fatty alcohol is a C7-C10 fatty alcohol. In some embodiments, each fatty alcohol is a C7-C11 fatty alcohol. In some embodiments, each fatty alcohol is a C7-C12 fatty alcohol. In some embodiments, each fatty alcohol is a C7-C13 fatty alcohol. In some embodiments, each fatty alcohol is a C7-C14 fatty alcohol. In some embodiments, each fatty alcohol is a C7-C15 fatty alcohol. In some embodiments, each fatty alcohol is a C7-C16 fatty alcohol. In some embodiments, each fatty alcohol is a C7-C17 fatty alcohol. In some embodiments, each fatty alcohol is a C7-C18 fatty alcohol. In some embodiments, each fatty alcohol is a C7-C19 fatty alcohol. In some embodiments, each fatty alcohol is a C7-C20 fatty alcohol. In some embodiments, each fatty alcohol is a C7-C21 fatty alcohol. In some embodiments, each fatty alcohol is a C7-C22 fatty alcohol. In some embodiments, each fatty alcohol is a C7-C23 fatty alcohol. In some embodiments, each fatty alcohol is a C7-C24 fatty alcohol. In some embodiments, each fatty alcohol is a C7-C25 fatty alcohol. In some embodiments, each fatty alcohol is a C7-C26 fatty alcohol. In some embodiments, each fatty alcohol is a C8-C9 fatty alcohol. In some embodiments, each fatty alcohol is a C8-C10 fatty alcohol. In some embodiments, each fatty alcohol is a C8-C11 fatty alcohol. In some embodiments, each fatty alcohol is a C8-C12 fatty alcohol. In some embodiments, each fatty alcohol is a C8-C13 fatty alcohol. In some embodiments, each fatty alcohol is a C8-C14 fatty alcohol. In some embodiments, each fatty alcohol is a C8-C15 fatty alcohol. In some embodiments, each fatty alcohol is a C8-C16 fatty alcohol. In some embodiments, each fatty alcohol is a C8-C17 fatty alcohol. In some embodiments, each fatty alcohol is a C8-C18 fatty alcohol. In some embodiments, each fatty alcohol is a C8-C19 fatty alcohol. In some embodiments, each fatty alcohol is a C8-C20 fatty alcohol. In some embodiments, each fatty alcohol is a C8-C21 fatty alcohol. In some embodiments, each fatty alcohol is a C8-C22 fatty alcohol. In some embodiments, each fatty alcohol is a C8-C23 fatty alcohol. In some embodiments, each fatty alcohol is a C8-C24 fatty alcohol. In some embodiments, each fatty alcohol is a C8-C25 fatty alcohol. In some embodiments, each fatty alcohol is a C8-C26 fatty alcohol. In some embodiments, each fatty alcohol is a C9-C10 fatty alcohol. In some embodiments, each fatty alcohol is a C9-C11 fatty alcohol. In some embodiments, each fatty alcohol is a C9-C12 fatty alcohol. In some embodiments, each fatty alcohol is a C9-C13 fatty alcohol. In some embodiments, each fatty alcohol is a C9-C14 fatty alcohol. In some embodiments, each fatty alcohol is a C9-C15 fatty alcohol. In some embodiments, each fatty alcohol is a C9-C16 fatty alcohol. In some embodiments, each fatty alcohol is a C9-C17 fatty alcohol. In some embodiments, each fatty alcohol is a C9-C18 fatty alcohol. In some embodiments, each fatty alcohol is a C9-C19 fatty alcohol. In some embodiments, each fatty alcohol is a C9-C20 fatty alcohol. In some embodiments, each fatty alcohol is a C9-C21 fatty alcohol. In some embodiments, each fatty alcohol is a C9-C22 fatty alcohol. In some embodiments, each fatty alcohol is a C9-C23 fatty alcohol. In some embodiments, each fatty alcohol is a C9-C24 fatty alcohol. In some embodiments, each fatty alcohol is a C9-C25 fatty alcohol. In some embodiments, each fatty alcohol is a C9-C26 fatty alcohol. In some embodiments, each fatty alcohol is a C10-C11 fatty alcohol. In some embodiments, each fatty alcohol is a C10-C12 fatty alcohol. In some embodiments, each fatty alcohol is a C10-C13 fatty alcohol. In some embodiments, each fatty alcohol is a C10-C14 fatty alcohol. In some embodiments, each fatty alcohol is a C10-C15 fatty alcohol. In some embodiments, each fatty alcohol is a C10-C16 fatty alcohol. In some embodiments, each fatty alcohol is a C10-C17 fatty alcohol. In some embodiments, each fatty alcohol is a C10-C18 fatty alcohol. In some embodiments, each fatty alcohol is a C10-C19 fatty alcohol. In some embodiments, each fatty alcohol is a C10-C20 fatty alcohol. In some embodiments, each fatty alcohol is a C10-C21 fatty alcohol. In some embodiments, each fatty alcohol is a C10-C22 fatty alcohol. In some embodiments, each fatty alcohol is a C10-C23 fatty alcohol. In some embodiments, each fatty alcohol is a C10-C24 fatty alcohol. In some embodiments, each fatty alcohol is a C10-C25 fatty alcohol. In some embodiments, each fatty alcohol is a C10-C26 fatty alcohol. In some embodiments, each fatty alcohol is a Cl 1-C12 fatty alcohol. In some embodiments, each fatty alcohol is a Cl 1-C13 fatty alcohol. In some embodiments, each fatty alcohol is a Cl 1-C14 fatty alcohol. In some embodiments, each fatty alcohol is a Cl 1-C15 fatty alcohol. In some embodiments, each fatty alcohol is a Cl 1-C16 fatty alcohol. In some embodiments, each fatty alcohol is a Cl 1-C17 fatty alcohol. In some embodiments, each fatty alcohol is a Cl 1-C18 fatty alcohol. In some embodiments, each fatty alcohol is a Cl 1-C19 fatty alcohol. In some embodiments, each fatty alcohol is a Cl 1-C20 fatty alcohol. In some embodiments, each fatty alcohol is a Cl 1-C21 fatty alcohol. In some embodiments, each fatty alcohol is a Cl 1-C22 fatty alcohol. In some embodiments, each fatty alcohol is a Cl 1-C23 fatty alcohol. In some embodiments, each fatty alcohol is a Cl 1-C24 fatty alcohol. In some embodiments, each fatty alcohol is a Cl 1-C25 fatty alcohol. In some embodiments, each fatty alcohol is a Cl 1-C26 fatty alcohol. In some embodiments, each fatty alcohol is a C12-C13 fatty alcohol. In some embodiments, each fatty alcohol is a C12-C14 fatty alcohol. In some embodiments, each fatty alcohol is a C12-C15 fatty alcohol. In some embodiments, each fatty alcohol is a C12-C16 fatty alcohol. In some embodiments, each fatty alcohol is a C12-C17 fatty alcohol. In some embodiments, each fatty alcohol is a C12-C18 fatty alcohol. In some embodiments, each fatty alcohol is a C12-C19 fatty alcohol. In some embodiments, each fatty alcohol is a C12-C20 fatty alcohol. In some embodiments, each fatty alcohol is a C12-C21 fatty alcohol. In some embodiments, each fatty alcohol is a C12-C22 fatty alcohol. In some embodiments, each fatty alcohol is a C12-C23 fatty alcohol. In some embodiments, each fatty alcohol is a C12-C24 fatty alcohol. In some embodiments, each fatty alcohol is a C12-C25 fatty alcohol. In some embodiments, each fatty alcohol is a C12-C26 fatty alcohol. In some embodiments, each fatty alcohol is a C13-C14 fatty alcohol. In some embodiments, each fatty alcohol is a C13-C15 fatty alcohol. In some embodiments, each fatty alcohol is a C13-C16 fatty alcohol. In some embodiments, each fatty alcohol is a C13-C17 fatty alcohol. In some embodiments, each fatty alcohol is a C13-C18 fatty alcohol. In some embodiments, each fatty alcohol is a C13-C19 fatty alcohol. In some embodiments, each fatty alcohol is a C13-C20 fatty alcohol. In some embodiments, each fatty alcohol is a C13-C21 fatty alcohol. In some embodiments, each fatty alcohol is a C13-C22 fatty alcohol. In some embodiments, each fatty alcohol is a C13-C23 fatty alcohol. In some embodiments, each fatty alcohol is a C13-C24 fatty alcohol. In some embodiments, each fatty alcohol is a C13-C25 fatty alcohol. In some embodiments, each fatty alcohol is a C13-C26 fatty alcohol. In some embodiments, each fatty alcohol is a C14-C15 fatty alcohol. In some embodiments, each fatty alcohol is a C14-C16 fatty alcohol. In some embodiments, each fatty alcohol is a C14-C17 fatty alcohol. In some embodiments, each fatty alcohol is a C14-C18 fatty alcohol. In some embodiments, each fatty alcohol is a C14-C19 fatty alcohol. In some embodiments, each fatty alcohol is a C14-C20 fatty alcohol. In some embodiments, each fatty alcohol is a C14-C21 fatty alcohol. In some embodiments, each fatty alcohol is a C14-C22 fatty alcohol. In some embodiments, each fatty alcohol is a C14-C23 fatty alcohol. In some embodiments, each fatty alcohol is a C14-C24 fatty alcohol. In some embodiments, each fatty alcohol is a C14-C25 fatty alcohol. In some embodiments, each fatty alcohol is a C14-C26 fatty alcohol. In some embodiments, each fatty alcohol is a C15-C16 fatty alcohol. In some embodiments, each fatty alcohol is a C15-C17 fatty alcohol. In some embodiments, each fatty alcohol is a C15-C18 fatty alcohol. In some embodiments, each fatty alcohol is a C15-C19 fatty alcohol. In some embodiments, each fatty alcohol is a C15-C20 fatty alcohol. In some embodiments, each fatty alcohol is a C15-C21 fatty alcohol. In some embodiments, each fatty alcohol is a C15-C22 fatty alcohol. In some embodiments, each fatty alcohol is a C15-C23 fatty alcohol. In some embodiments, each fatty alcohol is a C15-C24 fatty alcohol. In some embodiments, each fatty alcohol is a C15-C25 fatty alcohol. In some embodiments, each fatty alcohol is a C15-C26 fatty alcohol. In some embodiments, each fatty alcohol is a C16-C17 fatty alcohol. In some embodiments, each fatty alcohol is a C16-C18 fatty alcohol. In some embodiments, each fatty alcohol is a C16-C19 fatty alcohol. In some embodiments, each fatty alcohol is a C16-C20 fatty alcohol. In some embodiments, each fatty alcohol is a C16-C21 fatty alcohol. In some embodiments, each fatty alcohol is a C16-C22 fatty alcohol. In some embodiments, each fatty alcohol is a C16-C23 fatty alcohol. In some embodiments, each fatty alcohol is a C16-C24 fatty alcohol. In some embodiments, each fatty alcohol is a C16-C25 fatty alcohol. In some embodiments, each fatty alcohol is a C16-C26 fatty alcohol. In some embodiments, each fatty alcohol is a C17-C18 fatty alcohol. In some embodiments, each fatty alcohol is a C17-C19 fatty alcohol. In some embodiments, each fatty alcohol is a C17-C20 fatty alcohol. In some embodiments, each fatty alcohol is a C17-C21 fatty alcohol. In some embodiments, each fatty alcohol is a C17-C22 fatty alcohol. In some embodiments, each fatty alcohol is a C17-C23 fatty alcohol. In some embodiments, each fatty alcohol is a C17-C24 fatty alcohol. In some embodiments, each fatty alcohol is a C17-C25 fatty alcohol. In some embodiments, each fatty alcohol is a C17-C26 fatty alcohol. In some embodiments, each fatty alcohol is a C18-C19 fatty alcohol. In some embodiments, each fatty alcohol is a C18-C20 fatty alcohol. In some embodiments, each fatty alcohol is a C18-C21 fatty alcohol. In some embodiments, each fatty alcohol is a C18-C22 fatty alcohol. In some embodiments, each fatty alcohol is a C18-C23 fatty alcohol. In some embodiments, each fatty alcohol is a C18-C24 fatty alcohol. In some embodiments, each fatty alcohol is a C18-C25 fatty alcohol. In some embodiments, each fatty alcohol is a C18-C26 fatty alcohol. In some embodiments, each fatty alcohol is a C19-C20 fatty alcohol. In some embodiments, each fatty alcohol is a C19-C21 fatty alcohol. In some embodiments, each fatty alcohol is a C19-C22 fatty alcohol. In some embodiments, each fatty alcohol is a C19-C23 fatty alcohol. In some embodiments, each fatty alcohol is a C19-C24 fatty alcohol. In some embodiments, each fatty alcohol is a C19-C25 fatty alcohol. In some embodiments, each fatty alcohol is a C19-C26 fatty alcohol. In some embodiments, each fatty alcohol is a C20-C21 fatty alcohol. In some embodiments, each fatty alcohol is a C20-C22 fatty alcohol. In some embodiments, each fatty alcohol is a C20-C23 fatty alcohol. In some embodiments, each fatty alcohol is a C20-C24 fatty alcohol. In some embodiments, each fatty alcohol is a C20-C25 fatty alcohol. In some embodiments, each fatty alcohol is a C20-C26 fatty alcohol. In some embodiments, each fatty alcohol is a C21-C22 fatty alcohol. In some embodiments, each fatty alcohol is a C21-C23 fatty alcohol. In some embodiments, each fatty alcohol is a C21-C24 fatty alcohol. In some embodiments, each fatty alcohol is a C21-C25 fatty alcohol. In some embodiments, each fatty alcohol is a C21-C26 fatty alcohol. In some embodiments, each fatty alcohol is a C22-C23 fatty alcohol. In some embodiments, each fatty alcohol is a C22-C24 fatty alcohol. In some embodiments, each fatty alcohol is a C22-C25 fatty alcohol. In some embodiments, each fatty alcohol is a C22-C26 fatty alcohol. In some embodiments, each fatty alcohol is a C23-C24 fatty alcohol. In some embodiments, each fatty alcohol is a C23-C25 fatty alcohol. In some embodiments, each fatty alcohol is a C23-C26 fatty alcohol. In some embodiments, each fatty alcohol is a C24-C25 fatty alcohol. In some embodiments, each fatty alcohol is a C24-C26 fatty alcohol. In some embodiments, each fatty alcohol is a C25-C26 fatty alcohol. In some embodiments, each fatty alcohol is a C2 fatty alcohol. In some embodiments, each fatty alcohol is a C3 fatty alcohol. In some embodiments, each fatty alcohol is a C4 fatty alcohol. In some embodiments, each fatty alcohol is a C5 fatty alcohol. In some embodiments, each fatty alcohol is a C6 fatty alcohol. In some embodiments, each fatty alcohol is a C7 fatty alcohol. In some embodiments, each fatty alcohol is a C8 fatty alcohol. In some embodiments, each fatty alcohol is a C9 fatty alcohol. In some embodiments, each fatty alcohol is a CIO fatty alcohol. In some embodiments, each fatty alcohol is a Cl 1 fatty alcohol. In some embodiments, each fatty alcohol is a C12 fatty alcohol. In some embodiments, each fatty alcohol is a C13 fatty alcohol. In some embodiments, each fatty alcohol is a C14 fatty alcohol. In some embodiments, each fatty alcohol is a C15 fatty alcohol. In some embodiments, each fatty alcohol is a C16 fatty alcohol. In some embodiments, each fatty alcohol is a C17 fatty alcohol. In some embodiments, each fatty alcohol is a C18 fatty alcohol. In some embodiments, each fatty alcohol is a C19 fatty alcohol. In some embodiments, each fatty alcohol is a C20 fatty alcohol. In some embodiments, each fatty alcohol is a C21 fatty alcohol. In some embodiments, each fatty alcohol is a C22 fatty alcohol. In some embodiments, each fatty alcohol is a C23 fatty alcohol. In some embodiments, each fatty alcohol is a C24 fatty alcohol. In some embodiments, each fatty alcohol is a C25 fatty alcohol. In some embodiments, each fatty alcohol is a C26 fatty alcohol.

[00102] In some embodiments, each fatty alcohol is independently selected from docosahexaenol or eicosapentaenol.

[00103] In some embodiments, each fatty alcohol is independently selected from docosahexaenol,

eicosapentaenol, (Z)-octadec-9-en-l-ol, octadecan-l-ol, (9Z,12Z)-octadeca-9,12-dien-l-ol, (Z)- docos-13-en-l-ol, docosanol, (E)-octadec-9-en, icosanol, (9Z,12Z,15Z)-octadeca-9,12,15-trien- l-ol, or palmitol.

[00104] In some embodiments, each fatty alcohol is independently selected from butanol, pentanol, hexanol, heptanol, octanol, nonanol, decanol, undecanol, dodecanol, tridecanol, tetradecanol, pentadecanol, hexadecanol, heptadecanol, octadecanol, nonadecanol, eicosanol, heneicosanol, docosanol, tricosanol, tetracosanol, pentacosanol, and hexacosanol.

[00105] In some embodiments, each fatty alcohol is independently selected from (E)-but-2-en-l-ol, (Z)- tetradec-9-en-l-ol, (Z)-hexadec-9-en-l-ol, (Z)-hexadec-6-en-l-ol, (Z)-octadec-9-en-l-ol, (E)- octadec-9-en-l-ol, (E)-octadec-l l-en-l-ol, (Z)-icos-9-en-l-ol, eicosenol, (Z)-docos-13-en-l-ol, and (Z)-tetracos-15-en-l-ol.

[00106] In some embodiments, each fatty alcohol is independently selected from (9Z,12Z)-octadeca- 9,12-dien-l-ol, eicosadienol, and docosadienol.

[00107] In some embodiments, each fatty alcohol is independently selected from (9Z,12Z,15Z)-octadeca- 9,12,15-trien-l-ol, (5Z,9Z,12Z)-octadeca-5,9,12-trien-l-ol, (9Z,1 lE,13E)-octadeca-9,l 1,13- trien-l-ol, (5Z,8Z,1 lZ)-icosa-5,8,l 1-trien-l-ol, (8Z,1 lZ,14Z)-icosa-8,l 1,14-trien-l-ol, and eicosatrienol.

In some embodiments, each fatty alcohol is independently selected from (6Z,9Z,12Z,15Z)- octadeca-6,9,12,15-tetraen-l-ol, (5Z,8Z,l lZ,14Z)-icosa-5,8,l l,14-tetraen-l-ol, eicosatetraenol, and (7Z, 10Z, 13Z, 16Z)-docosa-7, 10,13,16-tetraen- 1 -ol .

[00108] In some embodiments, the compound of Formula (II) has the structure of Formula (Ha):

wherein

R is selected from fatty alcohol, glycerolipid, glycerophospholipids, sphingolipids, sterol-lipids, prenol lipids, saccharolipids and polyketides;

R ¹ is hydrogen, substituted or unsubstituted Ci-Cio alkyl, substituted or unsubstituted

heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; and R ² is hydrogen, substituted or unsubstituted C ₁ -C ₄ alkyl, substituted or unsubstituted C ₂ -C ₄ alkenyl, substituted or unsubstituted C ₂ -C ₄ alkynyl, -C(=0)Ci-C ₄ alkyl, -C(=0)0(Ci-C ₄ alkyl), substituted or unsubstituted aryl, or substituted or unsubstituted benzyl,

G is a cytotoxic chemotherapy agent, and

n is 1 to 6,

wherein a substituted group is substituted with 1, 2, or 3 groups independently selected from halogen, -OH, -SH, -NH ₂ , -CN, -C(=0)0H, -C(=0)0(Ci-C ₄ alkyl), -C(=0)NH ₂ , - C(=0)NH(C _I -C ₄ alkyl), -C(=0)N(Ci-C ₄ alkyl) ₂ , C1-C4 alkyl, -S(Ci-C ₄ alkyl), C1-C4 alkoxy, C3-C6 cycloalkyl, C2-C5 heterocyclyl, -NH(C _I -C ₄ alkyl), -N(C _I -C ₄ alkyl) ₂ , phenyl, -C6H4OH, imidazole, and arginine.

[00109] In some embodiments, R ¹ is hydrogen.

[00110] In some embodiments, R and R ¹ are independently selected from a fatty alcohol.

[00111] In some embodiments, each fatty alcohol is independently selected from a saturated,

monounsaturated, or polyunsaturated fatty alcohol.

[00112] In some embodiments, each fatty alcohol is independently selected from docosahexaenol or

eicosapentaenol.

[00113] In some embodiments, each fatty alcohol is independently selected from docosahexaenol,

eicosapentaenol, (Z)-octadec-9-en-l-ol, octadecan-l-ol, (9Z,12Z)-octadeca-9,12-dien-l-ol, (Z)- docos-13-en-l-ol, docosanol, (E)-octadec-9-en, icosanol, (9Z,12Z,15Z)-octadeca-9,12,15-trien- l-ol, or palmitol. [00114] In some embodiments, each fatty alcohol is independently selected from butanol, pentanol, hexanol, heptanol, octanol, nonanol, decanol, undecanol, dodecanol, tridecanol, tetradecanol, pentadecanol, hexadecanol, heptadecanol, octadecanol, nonadecanol, eicosanol, heneicosanol, docosanol, tricosanol, tetracosanol, pentacosanol, and hexacosanol.

[00115] In some embodiments, each fatty alcohol is independently selected from (E)-but-2-en-l-ol, (Z)- tetradec-9-en-l-ol, (Z)-hexadec-9-en-l-ol, (Z)-hexadec-6-en-l-ol, (Z)-octadec-9-en-l-ol, (E)- octadec-9-en-l-ol, (E)-octadec-l l-en-l-ol, (Z)-icos-9-en-l-ol, eicosenol, (Z)-docos-13-en-l-ol, and (Z)-tetracos-15-en-l-ol.

[00116] In some embodiments, each fatty alcohol is independently selected from (9Z,12Z)-octadeca- 9,12-dien-l-ol, eicosadienol, and docosadienol.

[00117] In some embodiments, each fatty alcohol is independently selected from (9Z,12Z,15Z)-octadeca- 9,12,15-trien-l-ol, (5Z,9Z,12Z)-octadeca-5,9,12-trien-l-ol, (9Z,1 lE,13E)-octadeca-9,l 1,13- trien-l-ol, (5Z,8Z,1 lZ)-icosa-5,8,l 1-trien-l-ol, (8Z,1 lZ,14Z)-icosa-8,l 1,14-trien-l-ol, and eicosatrienol.

[00118] In some embodiments, each fatty alcohol is independently selected from (6Z,9Z,12Z,15Z)- octadeca-6,9,12,15-tetraen-l-ol, (5Z,8Z,l lZ,14Z)-icosa-5,8,l l,14-tetraen-l-ol, eicosatetraenol, and (7Z, 10Z, 13Z, 16Z)-docosa-7, 10,13,16-tetraen- 1 -ol .

[00119] In another aspect, provided herein is a compound, or pharmaceutically acceptable salt thereof, having a structure provided in Formula (III):

wherein

R is selected from fatty alcohol, glycerolipid, glycerophospholipids, sphingolipids, sterol-lipids, prenol lipids, saccharolipids and polyketides;

R ¹ is hydrogen, substituted or unsubstituted Ci-Cio alkyl, substituted or unsubstituted

heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; and R ² is hydrogen, substituted or unsubstituted C ₁ -C ₄ alkyl, substituted or unsubstituted C ₂ -C ₄ alkenyl, substituted or unsubstituted C ₂ -C ₄ alkynyl, -C(=0)Ci-C ₄ alkyl, -C(=0)0(Ci-C ₄ alkyl), substituted or unsubstituted aryl, or substituted or unsubstituted benzyl,

wherein a substituted group is substituted with 1, 2, or 3 groups independently selected from

halogen, -OH, -SH, -NH ₂ , -CN, -C(=0)0H, -C(=0)0(Ci-C ₄ alkyl), -C(=0)NH ₂ , - C(=0)NH(C _I -C ₄ alkyl), -C(=0)N(Ci-C ₄ alkyl) ₂ , Ci-C ₄ alkyl, -S(Ci-C ₄ alkyl), C ₁ -C ₄ alkoxy, C ₃ -C ₆ cycloalkyl, C ₂ -C ₅ heterocyclyl, -NH(C _I -C ₄ alkyl), -N(C _I -C ₄ alkyl) ₂ , phenyl, -C ₆ H ₄ OH, imidazole, and arginine.

[00120] In some embodiments, R ¹ is hydrogen. In some embodiments, R ² is hydrogen. In some

embodiments, R ¹ and R ² are hydrogen.

[00121] In some embodiments, R ¹ is not hydrogen. In some embodiments, R ¹ is not hydrogen, and R and R ¹ are selected independently. In some embodiments, R ¹ is not hydrogen, and R and R ¹ are the same. In some embodiments, R ¹ is not hydrogen and R ² is hydrogen. In some embodiments, R ¹ is substituted or unsubstituted aryl and R ² is hydrogen. In some embodiments, R ¹ is substituted or unsubstituted phenyl and R ² is hydrogen. In some embodiments, R ¹ phenyl and R ² is hydrogen.

[00122] In some embodiments, R ² is not hydrogen. In some embodiments, R ² is not hydrogen, and R and R ² are selected independently. In some embodiments, R ² is not hydrogen, and R and R ² are the same. In some embodiments, R ¹ is hydrogen and R ² is not hydrogen.

[00123] In some embodiments, R and R ¹ are independently selected from a fatty alcohol. In some

embodiments, R is a fatty alcohol, and R ¹ is hydrogen. In some embodiments, R and R ² are independently selected from a fatty alcohol. In some embodiments, R is a fatty alcohol, and R ² is hydrogen.

[00124] In some embodiments, each fatty alcohol is independently selected from a saturated,

monounsaturated, or polyunsaturated fatty alcohol.

[00125] In some embodiments, R and R ¹ are independently selected from a fatty alcohol.

[00126] In some embodiments, each fatty alcohol is independently selected from a saturated,

monounsaturated, or polyunsaturated fatty alcohol.

[00127] In some embodiments, each fatty alcohol is independently selected from docosahexaenol or eicosapentaenol.

[00128] In some embodiments, each fatty alcohol is independently selected from docosahexaenol,

eicosapentaenol, (Z)-octadec-9-en-l-ol, octadecan-l-ol, (9Z,12Z)-octadeca-9,12-dien-l-ol, (Z)- docos-13-en-l-ol, docosanol, (E)-octadec-9-en, icosanol, (9Z,12Z,15Z)-octadeca-9,12,15-trien- l-ol, or palmitol.

[00129] In some embodiments, each fatty alcohol is independently selected from butanol, pentanol, hexanol, heptanol, octanol, nonanol, decanol, undecanol, dodecanol, tridecanol, tetradecanol, pentadecanol, hexadecanol, heptadecanol, octadecanol, nonadecanol, eicosanol, heneicosanol, docosanol, tricosanol, tetracosanol, pentacosanol, and hexacosanol.

[00130] In some embodiments, each fatty alcohol is independently selected from (E)-but-2-en-l-ol, (Z)- tetradec-9-en-l-ol, (Z)-hexadec-9-en-l-ol, (Z)-hexadec-6-en-l-ol, (Z)-octadec-9-en-l-ol, (E)- octadec-9-en-l-ol, (E)-octadec-l l-en-l-ol, (Z)-icos-9-en-l-ol, eicosenol, (Z)-docos-13-en-l-ol, and (Z)-tetracos-15-en-l-ol.

[00131] In some embodiments, each fatty alcohol is independently selected from (9Z,12Z)-octadeca- 9,12-dien-l-ol, eicosadienol, and docosadienol.

[00132] In some embodiments, each fatty alcohol is independently selected from (9Z,12Z,15Z)-octadeca- 9,12,15-trien-l-ol, (5Z,9Z,12Z)-octadeca-5,9,12-trien-l-ol, (9Z,1 lE,13E)-octadeca-9,l 1,13- trien-l-ol, (5Z,8Z,1 lZ)-icosa-5,8,l 1-trien-l-ol, (8Z,1 lZ,14Z)-icosa-8,l 1,14-trien-l-ol, and eicosatrienol.

[00133] In some embodiments, each fatty alcohol is independently selected from (6Z,9Z,12Z,15Z)- octadeca-6,9,12,15-tetraen-l-ol, (5Z,8Z,l lZ,14Z)-icosa-5,8,l l,14-tetraen-l-ol, eicosatetraenol, and (7Z, 10Z, 13Z, 16Z)-docosa-7, 10,13,16-tetraen- 1 -ol .

Preparation of Compounds

[00134] The compounds used in the reactions described herein are made according to organic synthesis techniques known to those skilled in this art, starting from commercially available chemicals and/or from compounds described in the chemical literature. "Commercially available chemicals" are obtained from standard commercial sources including Acros Organics (Pittsburgh, PA),

Aldrich Chemical (Milwaukee, WI, including Sigma Chemical and Fluka), Apin Chemicals Ltd. (Milton Park, UK), Avocado Research (Lancashire, U.K.), BDH Inc. (Toronto, Canada), Bionet (Cornwall, U.K.), Chemservice Inc. (West Chester, PA), Crescent Chemical Co. (Hauppauge,

NY), Eastman Organic Chemicals, Eastman Kodak Company (Rochester, NY), Fisher Scientific Co. (Pittsburgh, PA), Fisons Chemicals (Leicestershire, UK), Frontier Scientific (Logan, UT), ICN Biomedicals, Inc. (Costa Mesa, CA), Key Organics (Cornwall, U.K.), Lancaster Synthesis (Windham, NH), Maybridge Chemical Co. Ltd. (Cornwall, U.K.), Parish Chemical Co. (Orem, UT), Pfaltz & Bauer, Inc. (Waterbury, CN), Polyorganix (Houston, TX), Pierce Chemical Co. (Rockford, IL), Riedel de Haen AG (Hanover, Germany), Spectrum Quality Product, Inc. (New Brunswick, NJ), TCI America (Portland, OR), Trans World Chemicals, Inc. (Rockville, MD), and Wako Chemicals USA, Inc. (Richmond, VA).

[00135] Suitable reference books and treatise that detail the synthesis of reactants useful in the

preparation of compounds described herein, or provide references to articles that describe the preparation, include for example, "Synthetic Organic Chemistry", John Wiley & Sons, Inc., New York; S. R. Sandler et ah, "Organic Functional Group Preparations," 2nd Ed., Academic Press, New York, 1983; H. O. House, "Modem Synthetic Reactions", 2nd Ed., W. A. Benjamin, Inc. Menlo Park, Calif. 1972; T. L. Gilchrist, "Heterocyclic Chemistry", 2nd Ed., John Wiley & Sons, New York, 1992; J. March, "Advanced Organic Chemistry: Reactions, Mechanisms and

Structure", 4th Ed., Wiley-Interscience, New York, 1992. Additional suitable reference books and treatise that detail the synthesis of reactants useful in the preparation of compounds described herein, or provide references to articles that describe the preparation, include for example, Fuhrhop, J. and Penzlin G. "Organic Synthesis: Concepts, Methods, Starting

Materials", Second, Revised and Enlarged Edition (1994) John Wiley & Sons ISBN: 3-527- 29074-5; Hoffman, R.V. "Organic Chemistry, An Intermediate Text" (1996) Oxford University Press, ISBN 0-19-509618-5; Larock, R. C. "Comprehensive Organic Transformations: A Guide to Functional Group Preparations" 2nd Edition (1999) Wiley -VCH, ISBN: 0-471-19031-4;

March, J. "Advanced Organic Chemistry: Reactions, Mechanisms, and Structure" 4th Edition (1992) John Wiley & Sons, ISBN: 0-471-60180-2; Otera, J. (editor) "Modern Carbonyl

Chemistry" (2000) Wiley-VCH, ISBN: 3-527-29871-1; Patai, S. "Patai's 1992 Guide to the Chemistry of Functional Groups" (1992) Interscience ISBN: 0-471-93022-9; Solomons, T. W. G. "Organic Chemistry" 7th Edition (2000) John Wiley & Sons, ISBN: 0-471-19095-0; Stowell, J.C., "Intermediate Organic Chemistry" 2nd Edition (1993) Wiley-Interscience, ISBN: 0-471- 57456-2; "Industrial Organic Chemicals: Starting Materials and Intermediates: An Ullmann's Encyclopedia" (1999) John Wiley & Sons, ISBN: 3-527-29645-X, in 8 volumes; "Organic Reactions" (1942-2000) John Wiley & Sons, in over 55 volumes; and "Chemistry of Functional Groups" John Wiley & Sons, in 73 volumes.

[00136] Specific and analogous reactants are optionally identified through the indices of known

chemicals prepared by the Chemical Abstract Service of the American Chemical Society, which are available in most public and university libraries, as well as through on-line databases (contact the American Chemical Society, Washington, D.C. for more details). Chemicals that are known but not commercially available in catalogs are optionally prepared by custom chemical synthesis houses, where many of the standard chemical supply houses ( e.g ., those listed above) provide custom synthesis services. A reference for the preparation and selection of pharmaceutical salts of the gemcitabine prodrug compounds described herein is P. H. Stahl & C. G. Wermuth

"Handbook of Pharmaceutical Salts", Verlag Helvetica Chimica Acta, Zurich, 2002.

Pharmaceutical Compositions

[00137] In certain embodiments, the phosphorylated gemcitabine derivative prodrug as described herein is administered as a pure chemical. In other embodiments, the phosphorylated gemcitabine derivative prodrug described herein is combined with a pharmaceutically suitable or acceptable carrier (also referred to herein as a pharmaceutically suitable (or acceptable) excipient, physiologically suitable (or acceptable) excipient, or physiologically suitable (or acceptable) carrier) selected on the basis of a chosen route of administration and standard pharmaceutical practice as described, for example, in Remington: The Science and Practice of Pharmacy (Gennaro, 21 ^st Ed. Mack Pub. Co., Easton, PA (2005)).

[00138] Provided herein is a pharmaceutical composition comprising at least one phosphorylated

gemcitabine derivative prodrug, or a stereoisomer, pharmaceutically acceptable salt, hydrate, or solvate thereof, together with one or more pharmaceutically acceptable carriers. The carrier(s)

(or excipient(s)) is acceptable or suitable if the carrier is compatible with the other ingredients of the composition and not deleterious to the recipient ( i.e the subject) of the composition.

[00139] One embodiment provides a pharmaceutical composition comprising a pharmaceutically

acceptable excipient and a compound of any one of Formula (I), (II), (Ha), and (III), or a compound disclosed in Table 1, or a pharmaceutically acceptable salt thereof.

[00140] In certain embodiments, the phosphorylated gemcitabine derivative prodrug as described by any one of Formula (I), (II), (Ha), and (III), or a compound disclosed in Table 1, is substantially pure, in that it contains less than about 5%, or less than about 1%, or less than about 0.1%, of other organic small molecules, such as unreacted intermediates or synthesis by-products that are created, for example, in one or more of the steps of a synthesis method.

[00141] Suitable oral dosage forms include, for example, tablets, pills, sachets, or capsules of hard or soft gelatin, methylcellulose or of another suitable material easily dissolved in the digestive tract. In some embodiments, suitable nontoxic solid carriers are used which include, for example, pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, talcum, cellulose, glucose, sucrose, magnesium carbonate, and the like. (See, e.g., Remington: The Science and Practice of Pharmacy (Gennaro, 21 ^st Ed. Mack Pub. Co., Easton, PA (2005)).

[00142] In some embodiments, the phosphorylated gemcitabine derivative prodrug as described by any one of Formula (I), (II), (Ha), and (III), or a compound disclosed in Table 1, or pharmaceutically acceptable salt thereof, is formulated for administration by injection. In some instances, the injection formulation is an aqueous formulation. In some instances, the injection formulation is a non-aqueous formulation. In some instances, the injection formulation is an oil-based

formulation, such as sesame oil, or the like.

[00143] In some embodiments, the phosphorylated gemcitabine derivative prodrug as described by any one of Formula (I), (II), (Ha), and (III), or a compound disclosed in Table 1, or pharmaceutically acceptable salt thereof, is formulated as a nanoparticle. Various forms of nanoparticles are contemplated herein. In some embodiments, the nanoparticle comprises an outer layer comprising a polymer or protein such as albumin while an inner core contains the gemcitabine derivative prodrug. In some embodiments, the albumin is human serum albumin (HSA). In some embodiments, the nanoparticle comprises a mixture of polymer or protein. For example, the mixture can comprise albumin and the gemcitabine derivative prodrug. Nanoparticles can exhibit less toxicity, higher activity, higher distributions at drug target sites (including tumors), better uptake, and better efficacy as compared to free gemcitabine or free gemcitabine derivative prodrugs. In some embodiments, the use of a lipophilic gemcitabine derivative prodrug can be advantageous in nanoparticle formulations, for example, by increasing or enhacing binding or compatibility of the prodrug with the materials in core of the nanoparticle, release of the prodrug at the site of desired activity, or transport within the body.

[00144] In some embodiments, the ratio of albumin to the gemcitabine derivative prodrug in the

pharmaceutical composition is about 25:1 or less. In some embodiments, the ratio of albumin to the gemcitabine derivative prodrug in the pharmaceutical composition is about 20: 1 or less. In some embodiments, the ratio of albumin to the gemcitabine derivative prodrug in the

pharmaceutical composition is about 17:1 or less. In some embodiments, the ratio of albumin to the gemcitabine derivative prodrug in the pharmaceutical composition is about 15: 1 or less. In some embodiments, the ratio of albumin to the gemcitabine derivative prodrug in the

pharmaceutical composition is about 12:1 or less. In some embodiments, the ratio of albumin to the gemcitabine derivative prodrug in the pharmaceutical composition is about 10: 1 or less. [00145] In some embodiments, the pharmaceutical composition comprises from about 0.1% to about 20% by weight of albumin. In some embodiments, the pharmaceutical composition comprises about 0.5% to about 15% by weight of albumin. In some embodiments, the pharmaceutical composition comprises about 1% to about 10% by weight of albumin. In some embodiments, the pharmaceutical composition comprises about 2% to about 8% by weight of albumin. In some embodiments, the pharmaceutical composition comprises about 3% to about 6% by weight of albumin. In some embodiments, the pharmaceutical composition comprises about 0.5%, about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about 16%, about 17%, about 18%, about 19%, or about 20% by weight of albumin.

[00146] In some embodiments, the nanoparticle comprises a calcium phosphate lipid nanoparticle. In some embodiments, the nanoparticle comprises a lipid-based nanoparticle. In some

embodiments, the phosphorylated gemcitabine derivative prodrug is incorporated in the lipid bilayer of a liposomal nanoparticle. In some embodiments, the phosphorylated gemcitabine derivative prodrug is incorporated inside the liposomal nanoparticle. In some embodiments, the nanoparticle comprises an albumin-coated nanoparticle. In some embodiments, the albumin- coated nanoparticle comprises albumin covalently bound, non-covalently bound, or both covalently and non-covalently bound to the gemcitabine derivative prodrugs described herein. Exemplary methods of covalently binding the prodrug to albumin include chemical conjugation of the drug, which includes conjugation to lysines, tyrosines, or the free SH-group on the cys34. Such conjugations can include conjugations using chemical linkers, including, for example, maleimide or an an acid sensitive hydrazone linker. In some embodiments, the phosphorylated gemcitabine derivative prodrug is incorporated in a polymeric nanoparticle. In some

embodiments, the phosphorylated gemcitabine derivative prodrug is incorporated in a polymeric or lipid nanoparticle that is coated with polyethylene glycol polymer. In some embodiments, the polymeric nanoparticle comprises a core made of biodegradable polymers such as poly lactic acid, poly glycolic acid or copolymers of poly (lactic-co-glycolic acid), poly caprolactone, copolymers of poly (caprolactone-co-lactic acid), poly (caprolactone-co-glycolic acid). In some embodiments, the molecular weight of the biogdegradable polymers ranges from 500 daltons to 5000 daltons. In some embodiments, the molecular weight of the biogdegradable polymers ranges from 5000 daltons to 100000 daltons. In some embodiments, the poly ethylene glycol polymer molecular weight of polyethylene glycol is 500 to 20000 daltons. [00147] In some embodiments, the phosphorylated gemcitabine derivative prodrug as described by any one of Formula (I), (II), (Ha), and (III), or a compound disclosed in Table 1, or pharmaceutically acceptable salt thereof, is formulated as or comprises a hydrogel, a liposome, a polymeric nanoparticle, a silica-based nanoparticle, a dendrimer, a nanotube, a polymersome, a quantum dot, and/or an XPclad nanoparticle.

[00148] In some embodiments, the nanoparticle has a diameter between about 10 nm and about 10000 nm. In some embodiments, the nanoparticle has a diameter between about 30 nm and about 70 nm, between about 70 nm and about 120 nm, between about 120 nm and about 200 nm, between about 200 nm and about 5000 nm, or between about 500 nm and about 1000 nm.

[00149] The dose of the composition comprising at least one phosphorylated gemcitabine derivative prodrug as described herein differ depending upon the subject or patient's (e.g., human) condition. Such factors can include general health status, age, and other factors.

[00150] In some embodiments, the pharmaceutical composition can be dehydrated, for example, by

lyophilization, spray-drying, fluidized-bed drying, wet granulation, and other suitable methods known in the art. In some embodiments, the composition is prepared in solid form, such as by wet granulation, fluidized-bed drying, and other methods known to those skilled in the art. In some embodiments, a polymer or protein such as albumin is applied to the gemcitabine derivative prodrug, and other excipients if present, as a solution.

[00151] Pharmaceutical compositions are administered in a manner appropriate to the disease to be

treated (or prevented). An appropriate dose and a suitable duration and frequency of

administration will be determined by such factors as the condition of the patient, the type and severity of the patient's disease, the particular form of the active ingredient, and the method of administration. In general, an appropriate dose and treatment regimen provides the

composition(s) in an amount sufficient to provide therapeutic and/or prophylactic benefit (e.g., an improved clinical outcome, such as more frequent complete or partial remissions, or longer disease-free and/or overall survival, or a lessening of symptom severity. Optimal doses are generally determined using experimental models and/or clinical trials. The optimal dose depends upon the body mass, weight, or blood volume of the patient.

Formulations

[00152] In some embodiments, formulations suitable for oral administration of the the phosphorylated gemcitabine derivative prodrug comprise (a) liquid solutions, such as an effective amount of the compound dissolved in diluents, such as water, saline, or orange juice, (b) capsules, sachets or tablets, each containing a predetermined amount of the active ingredient, as solids or granules,

(c) suspensions in an appropriate liquid, and (d) suitable emulsions. Tablet forms can include one or more of lactose, mannitol, com starch, potato starch, microcrystalline cellulose, acacia, gelatin, colloidal silicon dioxide, croscarmellose sodium, talc, magnesium stearate, stearic acid, and other excipients, colorants, diluents, buffering agents, moistening agents, preservatives, flavoring agents, and pharmacologically compatible excipients. Lozenge forms can comprise the active ingredient in a flavor, usually sucrose and acacia or tragacanth, as well as pastilles comprising the active ingredient in an inert base, such as gelatin and glycerin, or sucrose and acacia, emulsions, gels, and the like containing, in addition to the active ingredient, such excipients as are known in the art.

[00153] In some embodiments, formulations suitable for parenteral administration include aqueous and non-aqueous, isotonic sterile injection solutions, which can contain anti-oxidants, buffers, bacteriostats, and solutes that render the formulation isotonic with the blood of the intended recipient, and aqueous and non-aqueous sterile suspensions that can include suspending agents, solubilizers, thickening agents, stabilizers, and preservatives. The formulations can be presented in unit-dose or multi-dose sealed containers, such as ampules and vials, and can be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid excipient, for example, water, for injections, immediately prior to use. Extemporaneous injection solutions and suspensions can be prepared from sterile powders, granules, and tablets of the kind previously described. In some embodiments, the pharmaceutical composition is prepared as injectable formulation.

[00154] In some embodiments, formulations suitable for aerosol administration comprise the inventive pharmaceutical composition include aqueous and non-aqueous, isotonic sterile solutions, which can contain anti-oxidants, buffers, bacteriostats, and solutes, as well as aqueous and non-aqueous sterile suspensions that can include suspending agents, solubilizers, thickening agents, stabilizers, and preservatives, alone or in combination with other suitable components, which can be made into aerosol formulations to be administered via inhalation. These aerosol formulations can be placed into pressurized acceptable propellants, such as dichlorodifluoromethane, propane, nitrogen, and the like. They also can be formulated as pharmaceuticals for non-pressured preparations, such as in a nebulizer or an atomizer.

[00155] Other suitable formulations are possible, for example, suppositories can be prepared by use of a variety of bases such as emulsifying bases or water-soluble bases. Formulations suitable for vaginal administration can be presented as pessaries, tampons, creams, gels, pastes, foams, or spray formulas containing, in addition to the active ingredient, such carriers as are known in the art to be appropriate.

[00156] In some embodiments, the pharmaceutical composition is formulated to have a pH range of 4.5 to 9. In some embodiments, the pharmaceutical composition is formulated to have a pH range of 5 to 8. In some embodiments, the pharmaceutical composition is formulated to have a pH range of 5.5 to 8. In some embodiments, the pharmaceutical composition is formulated to have a pH range of 6 to 8. The pharmaceutical composition can also be made to be isotonic with blood by the addition of a suitable tonicity modifier, such as glycerol. In some embodiments, the pharmaceutically acceptable carrier also comprises pyrogen-free water or water for injection, USP. In some embodiments, the pharmaceutical composition is prepared as a sterile aqueous formulation, a nanoparticle, an oil-in-water emulsion, or a water-in-oil emulsion. In some embodiments, the pharmaceutical composition is an oil-in-water emulsion.

Dosing and Therapeutic Regimens

[00157] In some embodiments, the pharmaceutical compositions described herein are administered for therapeutic applications. In some embodiments, the pharmaceutical composition is administered once per day, twice per day, three times per day, four times per day or more. The pharmaceutical composition is administered daily, every day, every alternate day, two days a week, three days a week, four days a week, five days a week, once a week, every other week, two weeks per month, three weeks per month, once a month, twice a month, three times per month, or more. The pharmaceutical composition is administered for at least 1 week, 2 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months,

12 months, 18 months, 2 years, 3 years, or more.

[00158] In the case wherein the patient’s status does not improve, upon the physician’s discretion the administration of the composition is given continuously; alternatively, the dose of the composition being administered is temporarily reduced or temporarily suspended for a certain length of time (i.e., a“drug holiday”). In some instances, the length of the drug holiday varies between 2 days and 1 year, including by way of example only, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 10 days, 12 days, 15 days, 20 days, 28 days, 35 days, 50 days, 70 days, 100 days, 120 days, 150 days, 180 days, 200 days, 250 days, 280 days, 300 days, 320 days, 350 days, 365 days, or 366 days. The dose reduction during a drug holiday is from 10%-100%, including, by way of example only, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%.

[00159] Once improvement of the patient's conditions has occurred, a maintenance dose is administered if necessary. Subsequently, the dosage or the frequency of administration, or both, can be reduced, as a function of the symptoms, to a level at which the improved disease, disorder or condition is retained.

[00160] In some embodiments, the amount of given phosphorylated gemcitabine derivative prodrug

varies depending upon factors such as the particular compound, the severity of the disease, the identity (e.g., weight) of the subject or host in need of treatment, but nevertheless is routinely determined in a manner known in the art according to the particular circumstances surrounding the case, including, e.g., the specific agent being administered, the route of administration, and the subject or host being treated. In some instances, the desired dose is conveniently presented in a single dose or as divided doses administered simultaneously (or over a short period of time) or at appropriate intervals, for example as two, three, four or more sub-doses per day.

[00161] In some embodiments, the amount of given phosphorylated gemcitabine derivative prodrug will typically be in the range of about 0.02 mg to about 5000 mg per day. In some embodiments, the amount of given phosphorylated gemcitabine derivative prodrug is in the range of about 1 mg to about 1500 mg per day. In some embodiments, the amount of given phosphorylated gemcitabine derivative prodrug is in the range of about 10 mg to about 1000 mg per day. The desired dose may conveniently be presented in a single dose or as divided doses administered simultaneously (or over a short period of time) or at appropriate intervals, for example as two, three, four or more sub-doses per day.

[00162] In some embodiments, the daily dosages appropriate for the phosphorylated gemcitabine

derivative prodrug described herein are from about 0.01 mg/kg to about 100 mg/kg. In one embodiment, the daily dosages are from about 0.1 mg/kg to about 10 mg/kg. An indicated daily dosage in the larger mammal, including, but not limited to, humans, is in the range from about 0.5 mg to about 1000 mg, conveniently administered in a single dose or in divided doses.

Suitable unit dosage forms for oral administration include from about 1 to about 500 mg active ingredient. In one embodiment, the unit dosage is about 1 mg, about 5 mg, about, 10 mg, about 20 mg, about 50 mg, about 100 mg, about 200 mg, about 250 mg, about 400 mg, or about 500 mg. [00163] The foregoing ranges are merely suggestive, as the number of variables in regard to an individual treatment regime is large, and considerable excursions from these recommended values are not uncommon. Such dosages may be altered depending on a number of variables, not limited to the activity of the compound used, the disease or condition to be treated, the mode of administration, the requirements of the individual subject, the severity of the disease or condition being treated, and the judgment of the practitioner.

Treatment of Cancer

[00164] In some embodiments, described herein is a method of treating cancer in a subject in need

thereof, comprising administering to the subject a pharmaceutical composition comprising a phosphorylated gemcitabine derivative prodrug, or pharmaceutically acceptable salt thereof, as described herein.

[00165] In some embodiments, the cancer is pancreatic cancer, lung cancer, breast cancer, bladder

cancer, biliary tract cancer, urethral cancer, testicular cancer, colorectal cancer, head and neck cancer, or ovarian cancer. In some embodiments, the lung cancer is non small cell lung cancer (NSCLC). In some embodiments, the breast cancer is metastatic breast cancer. In some embodiments, the biliary tract cancer is cholangiocarcinoma.

[00166] Some embodiments provide the method of treating pancreatic cancer, wherein the pancreatic cancer is selected from an epitheliod carcinoma in the pancreatic duct tissue or an

adenocarcinoma in a pancreatic duct.

[00167] Provided herein is a method of treating cancer in a patient in need thereof comprising

administering to the patient a pharmaceutical composition comprising a compound of Formula (I), (II), (Ha), and (III), or a compound disclosed in Table 1, or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. In some embodiments, the cancer is pancreatic cancer, lung cancer, breast cancer, bladder cancer, biliary tract cancer, urethral cancer, testicular cancer, colorectal cancer, head and neck cancer, or ovarian cancer. In some

embodiments, the lung cancer is non small cell lung cancer. In some embodiments, the breast cancer is metastatic breast cancer. In some embodiments, the biliary tract cancer is

cholangiocarcinoma. Some embodiments provide the method of treating pancreatic cancer, wherein the pancreatic cancer is selected from an epitheliod carcinoma in the pancreatic duct tissue or an adenocarcinoma in a pancreatic duct. Provided herein is the method wherein the pharmaceutical composition is administered orally. Provided herein is the method wherein the pharmaceutical composition is administered by injection. Provided herein is the method wherein the pharmaceutical composition is administered by intramuscular injection. Provided herein is the method wherein the intramuscular injection is a depot injection. Provided herein is the method wherein the depot injection provides a therapeutically effective concentration for a period of 2 days to 3 months. Provided herein is the method wherein the depot injection provides a therapeutically effective concentration for a period of about 2 days. Provided herein is the method wherein the depot injection provides a therapeutically effective concentration for a period of about 4 days. Provided herein is the method wherein the depot injection provides a therapeutically effective concentration for a period of about 7 days. Provided herein is the method wherein the depot injection provides a therapeutically effective concentration for a period of about 10 days. Provided herein is the method wherein the depot injection provides a therapeutically effective concentration for a period of about 1 week. Provided herein is the method wherein the depot injection provides a therapeutically effective concentration for a period of about 2 weeks. Provided herein is the method wherein the depot injection provides a therapeutically effective concentration for a period of about 3 weeks. Provided herein is the method wherein the depot injection provides a therapeutically effective concentration for a period of about 4 weeks. Provided herein is the method wherein the depot injection provides a therapeutically effective concentration for a period of about 5 weeks. Provided herein is the method wherein the depot injection provides a therapeutically effective concentration for a period of about 6 weeks. Provided herein is the method wherein the depot injection provides a therapeutically effective concentration for a period of about 1 month. Provided herein is the method wherein the depot injection provides a therapeutically effective concentration for a period of about 2 months. Provided herein is the method wherein the depot injection provides a therapeutically effective concentration for a period of about 3 months.

[00168] Other embodiments and uses will be apparent to one skilled in the art in light of the present disclosures. The following examples are provided merely as illustrative of various embodiments and shall not be construed to limit the invention in any way.

EXAMPLES

I. Chemical Synthesis

[00169] In some embodiments, the phosphorylated gemcitabine derivative prodrug compounds disclosed herein are synthesized according to the following examples. [00170] General Scheme 1 for the synthesis of phosphorylated gemcitabine derivative prodrug compounds.

Scheme 1

Example 1: Synthesis of gemcitabine L-alanine docosahecaen ester phosphate (1-1)

G q 1-1

Boc

Step 1: Preparation of the 4-N-(tert-butoxycarbonyl) gemcitabine (A)

[00171] To a stirred mixture of gemcitabine hydrochloride (10 g, 0.033 mol) in DM water (40 ml) and dioxane (150 ml) was added K2CO3 (12.0 g, 0.082 mol) followed by Boc anhydride (8.0 g, 0.036 mol) at 25-30°C and the resulting mixture was stirred at the same temperature for 48 hrs. After reaction completion, DM water (600 ml) was added and the reaction mixture was extracted with EtOAc (150 ml). The organic layer was separated, dried over NaiSCE, and concentrated to dryness under reduced pressure. The obtained residue was slurried from a mixture of acetone and heptane to give the desired product (11.5 g).

Step 2: Preparation of the 4-N-3O-bis(tert-butoxycarbonyl) gemcitabine (B)

[00172] To a stirred solution of 4-N-(tert-butoxycarbonyl) gemcitabine (11 g, 0.030 mol) in dioxane (75 ml) was added Boc anhydride (6.5 g, 0.030 mol) at 25-30°C. The reaction mixture was stirred at 40-45°C for 48 hrs. After reaction completion, DM water (300 ml) was added and the mixture was extracted with EtOAc (375 ml). The organic layer was separated, dried over Na2S04, and concentrated to dryness under reduced pressure. The obtained residue was cooled to 25-30°C and slurried in EtOAc: heptane mixture to give the desired product (13.5 g).

Step 3: Preparation of docosahexaenoic acid ethyl ester (C)

[00173] Docosahexaenoic acid (15 g, 0.045 mol) and 1 mL of sulfuric acid were mixed in ethanol (250 ml). The mixture was refluxed for 12 hr. The reaction mass was concentrated under reduced pressure. The obtained residue was stirred with ethyl acetate and washed with aqueous NaHC03 followed by water wash. The organic layer was dried over Na2S04 and concentrated under reduced pressure to give the desired product (13.6 g).

Step 4: Preparation of docosahexaen-l-ol (D)

[00174] To a stirred solution of Docosahexaenoic acid ethyl ester (13 g, 0.036 mol) in THF (150 ml) was added LAH (2.5 g, 0.065 mol) at 5-10°C. The reaction mixture was heated and stirred at 30-35°C for 10 hrs. After reaction completion, the reaction mixture was quenched by aq. NaOH sol. (5ml) at 5-10°C. The solid was filtered and washed with ethyl acetate (100 ml). The filtrate was collected and concentrated under reduced pressure to give the desired product (10.5 g).

Step 5: Preparation of L-alanine docosahecaen ester TFA salt (E)

[00175] To a mixture of N-Boc-L- Alanine (6.0 g, 0.032mol) and HOBt (5.4 g, 0.035 mol) in 150 mL of THF chilled in an ice-water bath, DCC (7.22 g, 0.035 mol) was added in one portion. The mixture was stirred for 30 min, and the ice bath was removed. Formation of white precipitate (DCU) was observed. Docosahexaen-l-ol (10.0, 0.032mol) and TEA (4.4 ml, 0.035mol) were added. Stirring at RT was continued for 8 hr. After, 50 mL of hexanes was added into the mixture with shaking and the DCU was removed by filtration. The precipitate was washed on a fritted funnel with 50 mL of ethyl acetate. The combined filtrates were washed with saturated NaHCCri solution (25 mL), brine (30 mL), and the mixture was dried over anhydrous MgSCL and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane to 30 % ethyl acetate), Boc product (10.5 g) was stirred with mixture of TFA (10 ml) + DCM (100 ml) at RT for 12 hr. After completion, the reaction mixture was concentrated under reduced pressure to give the desired product (9.2 g) which was stored under nitrogen at 0-7°C.

Step 6: Preparation of L-alanine docosahecaen ester phosphate (F)

[00176] A suspension of L-alanine docosahecaen ester TFA salt (9.0 g, 0.018 mol) in DCM (200 ml), was charged with dichloro phenyl phosphate (3.8 g, 0.018 mol) at 25-30°C and cooled to -70°C to about -75°C. TEA (4.0 g, 0.039 mol) was added to the reaction mixture at -70°C to about - 75°C and the reaction mixture was stirred at the same temperature for 1 h. After warm up the reaction mixture was stirred at 25-30°C for 6 hrs and concentrated under reduced pressure. The obtained residue was treated with THF (200 ml), filtered and concentrated under reduced pressure to give the desired product which was stored under nitrogen at 0-7°C.

Step 7: Preparation of 4-N-3 ^, -0-bis(tert-butoxycarbonyl) gemcitabine L-alanine

docosahecaen ester phosphate (G)

[00177] To a stirred mixture of 4-N-3'-0-bis( tert-butoxycarbonyl) gemcitabine (B) (8.5 g 0.018 mol) in THF (200 ml), was added L-alanine docosahecaen ester phosphate (F) taken in 200 ml THF under nitrogen atmosphere and the resulting solution was cooled to -5 to 5°C. The mixture was charged with 1M t-BuMgCl (20 ml, 0.018mol), temperature raised to 25-30°C, and stirred for 30 mins. After reaction completion, the reaction mass was quenched in to water (200 ml) and extracted with EtOAc (200 ml). The organic layer was washed with 8% NaHCC^, water, and finally with 20% brine solution. The organic layer was separated, dried over sodium sulfate and concentrated under reduced pressure to give a residue. Residue was purified by silica gel column chromatography ( hexane to 30 % ethyl acetate) and 1.8 g of the desired product was collected. Step 8: Preparation of gemcitabine L-alanine docosahecaen ester phosphate (1-1)

[00178] The obtained 4-N-3’-0-bis(tert-butoxy carbonyl) gemcitabine L-alanine docosahecaen ester

phosphate (G) was taken up in DCM (50 ml) and TFA (10 ml) was added at 5 to 10°C. The reaction was stirred at 25°C for 6 hrs and quenched in to 10% sodium carbonate solution (2 Lit) at below 15°C. The mixture was extracted with EtOAc (800 ml), the organic layer was dried over sodium sulfate and evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (80-100 % ethyl acetate with hexane), to give 1.0 g of the title compound. *H NMR (500 MHz, DMSO-d ₆ ): 5H 7.60-7.40 (m, 3H), 7.35-7.25 (br s, 2H), 7.22- 7.05 (m, 3H), 6.45-6.35 (m, 1H), 6.20-6.05 (m, 2H) 5.70-5.65 (m, 1H), 5.42-5.05 (m, 9H), 4.42- 3.79 (m, 8H), 3.45-3.22 (m, 2H), 2.95-2.65 (m, 8H), 2.05-1.97 (m, 4H), 1.55-1.45 (m, 2H), 1.25- 1.05 (m, 6H), 0.95-0.85 (m, 3H). ³¹ P NMR (500 MHz, DMSO-d6): 5P 3.75, 3.72.

II. Biological Evaluation

Example 1: Plasma stability assay

[00179] Determining plasma stability of the test compounds is performed using HPLC-MS. Incubations are carried out in 96-well polypropylene plates in 5 aliquots of 70 pL each (one for each time point). Test compounds (10 mM, final solvent concentration 1 %) are incubated at 37 °C. Five time points over 120 minutes are analyzed (0, 20, 40, 60 and 120 min). All incubations are performed in duplicates. The samples are analyzed by HPLC-MS (API3000, AB Sciex). The percentage of parent compound remaining after incubation in plasma is plotted versus incubation time, and plasma half-life (T½) is calculated from the obtained curve.

Example 2: In vitro cytotoxicity assays using compound 1-1

[00180] The cytotoxicity of gemcitabine and compound 1-1 were evaluated in two pancreatic cell lines, MiaPaCa-2 and Panc-1. Cisplatin was used as a positive control. All the compounds were prepared in cell culture media containing 10% FBS. The various test articles were exposed to the cell lines for 4 hours. After the 4-hour incubation, the media containing the test articles was replaced with fresh media containing 10% FBS and incubated for 72 hours. The IC50 was measured using Cell Titer Glo luminescent viability assay. The compounds were evaluated in the presence and absence of dipyridamole (an inhibitor of nucleoside transporter, hENTl) in the Panc-1 cell lines. For Mia PaCa-2 cell lines, the compounds were tested in the presence and absence of 2- deoxycytidine (a substrate competitor of deoxycytidine kinase (dCK)). The results of the in vitro assays are presented in Tables 1 and 2.

Panc-1 : IC50 for compound 1-1 was 31.01 uM whereas for gemcitabine, the IC50 was 558.43 uM, indicating that compound 1-1 is 18-fold more potent than gemcitabine. The IC50 of compound 1-1 in the presence of 100 uM of dipyridamole was 9.16 uM. This indicates that compound 1-1 is not transported into Panc-1 cells via the hENTl nucleoside transporters.

Table 2:

Mia PaCa-2: The IC50 for compound 1-1 was 3.08 uM whereas for gemcitabine, the IC50 was 0.24 uM. In the presence of 2-deoxycytidine, which is a substrate for deoxycytidine kinase (dCK), the IC50 for compound 1-1 increased 2.36-fold to 7.26 uM, whereas the IC50 for gemcitabine increased 23.9-fold to 5.73 uM. Gemcitabine is converted to its monophosphate form by dCK. Inhibition of or competition for dCK will impact the conversion of gemcitabine to its monophosphate form. Compound 1-1 is a monophosphate and thus the presence of dCK or its inhibition does not impact its IC50.

Table 3:

III. Preparation of Pharmaceutical Dosage Forms

Example 1: Oral capsule

[00181] The active ingredient is a compound of Table 1, or a pharmaceutically acceptable salt thereof. A capsule for oral administration is prepared by mixing 1-1000 mg of active ingredient with starch or other suitable powder blend. The mixture is incorporated into an oral dosage unit such as a hard gelatin capsule, which is suitable for oral administration.

[00182] Example 2: Solution for injection

The active ingredient is a compound of Table 1, or a pharmaceutically acceptable salt thereof, and is formulated as a solution in sesame oil at a concentration of 50 mg-eq/mL.