Phosphoramidate monosaccharides, pharmaceutical compositions, and diagnostic and therapeutic applications

Abstract

Provided herein are monosaccharides, e.g., compounds of Formula (I), and pharmaceutical compositions thereof. Also provided herein are methods of their use for cell labeling for diagnostic and / or therapeutic applications. [Formula 1] TIFF2025541836000133.tif18170

Description

[Technical Field]

[0001] (CROSS-REFERENCE TO RELATED APPLICATIONS) This application claims priority under U.S. § 119(a) of International Application No. PCT / CN2022 / 137519, filed December 8, 2022; the entire disclosure of which is incorporated herein by reference.

[0002] (Field) Provided herein are monosaccharides and pharmaceutical compositions thereof. Also provided herein are methods of their use for cell labeling for diagnostic and / or therapeutic applications. [Background technology]

[0003] (background) Glycosylation is an enzymatic process responsible for the attachment of glycans to glycosyl acceptors, e.g., cell surface proteins. Reily et al., Nat. Rev. Nephrol. 2019, 15, 346-66. Glycosylation is important for physiological and pathological cellular functions. Ibid. Alterations in glycosylation have been identified in almost all types of cancer and have profound effects on cancer progression, tumor immunity, and clinical outcome. Hauselmann and Borsig, Front. Oncol. 2014, 4, 28; Stowell et al., Annu. Rev. Pathol.: Mech. Dis. 2015, 10, 473-510; Pin and Reis, Nat. Rev. Cancer 2015, 15, 540-55; Munkley and Elliott, Oncotarget 2016, 7, 35478-89; Reily et al., Nat. Rev. Nephrol. 2019, 15, 346-66.

[0004] Metabolic glycoengineering is a technique for introducing unnatural sugars into cellular glycans. See Prescher et al., Nature 2004, 430, 873-7; Agatemor et al., Nat. Rev. Chem. 2019, 3, 605-20; Wang and Mooney, Nat. Chem. 2020, 12, 1102-14. Metabolic glycoengineering exploits cellular sugar metabolism to tag cells with chemical reporters. Ibid. The chemical reporters (e.g., azides) expressed on the cell surface can then be used for in vivo imaging or targeted drug delivery via bioorthogonal chemistry. Laughlin et al., Science 2008, 320, 664-7; Sletten and Bertozzi, Acc. Chem. Res. 2011, 44, 666-76; Wang et al., Nat. Chem. Biol. 2017, 13, 415; Wang and Mooney, Nat. Chem. 2020, 12, 1102-14.

[0005] Despite advances in cancer diagnosis and treatment, cancer remains a major global public health problem. Wang and Mooney, Nat. Chem. 2020, 12, 1102-14. It is estimated that in 2022, 1,918,030 new cases of cancer will be diagnosed and 609,360 cancer deaths will occur in the United States alone. Cancer Facts & Figures 2022. Therefore, effective methods and therapies for cancer diagnosis and treatment are needed. Bargahi et al., Biol. Proced. Online 2022, 24, 5. Summary of the Invention

[0006] (Disclosure Summary) Provided herein are compounds of formula (I): [ka] (In the formula, R 1 and R 5are each independently (i) hydrogen; or (ii) —C(O)R 5a , -C(O)OR 5a , -C(O)NR 5b R 5c , or -L 2 -P(X)(OR 5a )(NR 5b R 5c ) and R 1 and R 5 At least one of the following is -L 2 -P(X)(OR 5a )(NR 5b R 5c ) and; R 2 is (i) hydrogen; (ii) C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) —C(O)R 1a , -C(O)OR 1a , -C(O)NR 1b R 1c , -C(O)SR 1a , -C(NR 1a )NR 1b R 1c , ‐C(S)R 1a , ‐C(S)OR 1a , ‐C(S)NR 1b R 1c , ‐S(O)R 1a , -S(O)2R 1a , -S(O)NR 1b R 1c , -S(O)2NR 1b R 1c , or -Si(R 1a )3; R 3 and R 4 are each independently: (i) halo; or (ii) -OR 5a , ‐OC(O)R 5a , ‐OC(O)OR 5a , or -OC(O)NR5b R 5c or R 3 and R 4 Or R 4 and R 5 are bonded together to form a lactone ring; Each R 5a , R 5b , and R 5c are independently hydrogen, C 1-30 Alkyl, C 1-30 Heteroalkyl, C 2-30 Alkenyl, C 2-30 Alkynyl, C 3-30 Cycloalkyl, C 6-30 Aryl, C 7-30 aralkyl, heteroaryl, or heterocyclyl; A is a bond, O, or N(R 1b ) and; L 1 is C 1-6 Alkylene, C 1-6 Heteroalkylene, C 2-6 Alkenylene, C 2-6 Alkynylene, C 3-10 Cycloalkylene, C 6-14 Arylene, C 7-15 aralkylene, heteroarylene, or heterocyclylene; Each L 2 are independently (i) a bond; or (ii) -O-C 1-6 Alkylene, -O-C 1-6 Heteroalkylene, -O-C 2-6 Alkenylene, -O-C 2-6 Alkynylene, -O-C 3-10 Cycloalkylene, -O-C 6-14 Arylene, -O-C 7-15 aralkylene, -O-heteroarylene, or -O-heterocyclylene; each X is independently O or S; Z can be hydrogen, azido, halo, isocyano, -C=C(R 1a )R 1a , ‐C≡CR 1a , [ka] -C(O)R 1a or -SH; and Each R 1a , R 1b , and R 1c are independently hydrogen, deuterium, and C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl; wherein each alkyl, alkylene, heteroalkyl, heteroalkylene, alkenyl, alkenylene, alkynyl, alkynylene, cycloalkyl, cycloalkylene, aryl, arylene, aralkyl, aralkylene, heteroaryl, heteroarylene, heterocyclyl, and heterocyclylene is optionally substituted with one or more, and in one embodiment, one, two, three, or four, substituents Q, wherein each Q is independently: (a) deuterium, cyano, halo, nitro, and oxo; (b) one or more, and in one embodiment, one, two, three, or four, substituents Q a each optionally further substituted C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 aralkyl, heteroaryl, and heterocyclyl; and (c)—C(O)R a , -C(O)OR a , -C(O)NR b R c , -C(O)SR a , -C(NR a )NR b R c , ‐C(S)R a , ‐C(S)OR a , ‐C(S)NR b R c , -OR a , ‐OC(O)Ra 、‐OC(O)OR a 、‐OC(O)NR b R c 、‐OC(O)SR a 、‐OC(NR a )NR b R c 、‐OC(S)R a 、‐OC(S)OR a 、‐OC(S)NR b R c 、‐OP(O)(OR b )OR c 、‐OS(O)R a 、‐OS(O)2R a 、‐OS(O)NR b R c 、‐OS(O)2NR b R c 、‐NR b R c 、‐NR a C(O)R d 、‐NR a C(O)OR d 、‐NR a C(O)NR b R c 、‐NR a C(O)SR d 、‐NR a C(NR d )NR b R c 、‐NR a C(S)R d 、‐NR a C(S)OR d 、‐NR a C(S)NR b R c 、‐NR a S(O)R d 、‐N=S(O)R a R d 、‐NR a S(O)2R d 、‐NR a S(O)NR b R c 、‐NR a S(O)2NR b R c 、‐SR a 、‐S(O)R a 、‐S(O)2Ra , -S(O)NR b R c , and -S(O)2NR b R c where each R a , R b , R c , and R d are independently (i) hydrogen or deuterium; (ii) one or more, in one embodiment, 1, 2, 3, or 4, substituents Q a C, each of which is arbitrarily substituted 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) R b and R c together with the N atom to which they are attached, one or more, in one embodiment 1, 2, 3, or 4, substituents Q a forming an optionally substituted heterocyclyl; Here, each Q a are independently: (a) deuterium, cyano, halo, nitro, and oxo; (b) C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 aralkyl, heteroaryl, and heterocyclyl; and (c)—C(O)R e , -C(O)OR e , -C(O)NR f R g , -C(O)SR e , -C(NR e )NR f R g , ‐C(S)R e , ‐C(S)OR e , ‐C(S)NR f R g , -OR e , ‐OC(O)Re 、‐OC(O)OR e 、‐OC(O)NR f R g 、‐OC(O)SR e 、‐OC(NR e )NR f R g 、‐OC(S)R e 、‐OC(S)OR e 、‐OC(S)NR f R g 、‐OP(O)(OR f )OR g 、‐OS(O)R e 、‐OS(O)2R e 、‐OS(O)NR f R g 、‐OS(O)2NR f R g 、‐NR f R g 、‐NR e C(O)R h 、‐NR e C(O)OR f 、‐NR e C(O)NR f R g 、‐NR e C(O)SR f 、‐NR e C(NR h )NR f R g 、‐NR e C(S)R h 、‐NR e C(S)OR f 、‐NR e C(S)NR f R g 、‐NR e S(O)R h 、‐N=S(O)R e R h 、‐NR e S(O)2R h 、‐NR e S(O)NR f R g 、‐NR e S(O)2NR f R g 、‐SR e 、‐S(O)R e 、‐S(O)2Re , -S(O)NR f R g , and -S(O)2NR f R g where each R e , R f , R g , and R h are independently (i) hydrogen or deuterium; (ii) C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) R f and R g form a heterocyclyl together with the N atom to which they are attached) or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0007] Also provided herein is a pharmaceutical composition comprising a compound of Formula (I), or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; and a pharmaceutically acceptable excipient.

[0008] Further provided herein is a method of labeling cells in a subject with an azido group, comprising administering to the subject in need thereof an effective amount of a compound of formula (I), or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0009] Further provided herein is a method of labeling a cell with an azido group, comprising contacting the cell with an effective amount of a compound of formula (I), or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof. DETAILED DESCRIPTION OF THE INVENTION

[0010] (Detailed explanation) To facilitate understanding of the disclosure set forth herein, several terms are defined below.

[0011] Generally, the nomenclature used herein and the laboratory methods of organic chemistry, medicinal chemistry, biochemistry, biology, and pharmacology described herein are those well known and commonly employed in the art. Unless defined otherwise, all technical and scientific terms used herein generally have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs.

[0012] The term "subject" refers to an animal, including, but not limited to, a primate (e.g., a human), cow, pig, sheep, goat, horse, dog, cat, rabbit, rat, or mouse. The terms "subject" and "patient" are used interchangeably herein in reference to a mammalian subject, such as, for example, a human subject. In one embodiment, the subject is a human.

[0013] The terms "contacting" or "contacting" refer to bringing a therapeutic agent and a biomolecule (e.g., a protein, enzyme, RNA, or DNA), cell, or tissue together such that a physiological and / or chemical effect occurs as a result of such contact. Contacting can occur in vitro, ex vivo, or in vivo. In one embodiment, a therapeutic agent is contacted with a biomolecule in vitro to determine the effect of the therapeutic agent on the biomolecule. In another embodiment, a therapeutic agent is contacted with cells in cell culture (in vitro) to determine the effect of the therapeutic agent on the cells. In yet another embodiment, contacting a therapeutic agent with a biomolecule, cell, or tissue comprises administering the therapeutic agent to a subject having the biomolecule, cell, or tissue to be contacted.

[0014] The term "therapeutically effective amount" or "effective amount" is intended to include the amount of a compound that, when administered, is sufficient to prevent the onset of, or alleviate to some extent, one or more of the symptoms of the disorder, disease, or condition being treated. The term "therapeutically effective amount" or "effective amount" also means the amount of a compound that is sufficient to elicit the biological or medical biomolecule (e.g., protein, enzyme, RNA, or DNA), cell, tissue, system, animal, or human response that is sought by a researcher, veterinarian, medical doctor, or clinician.

[0015] The terms "pharmaceutically acceptable carrier," "pharmaceutically acceptable excipient," "physiologically acceptable carrier," or "physiologically acceptable excipient" refer to a pharmaceutically acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, solvent, or encapsulating material. In one embodiment, each component is "pharmaceutically acceptable" in the sense of being compatible with the other components of the pharmaceutical formulation, and suitable for use in contact with the tissues or organs of a subject (e.g., a human) without undue toxicity, irritation, allergic response, immunogenicity, or other problem or complication, and commensurate with a reasonable benefit / risk ratio. See, e.g., Remington: The Science and Practice of Pharmacy, 23rd ed.; edited by Adejare; Academic Press, 2020; Handbook of Pharmaceutical Excipients, 9th ed.; edited by Sheskey et al.; Pharmaceutical Press, 2020; Handbook of Pharmaceutical Additives, 3rd ed.; edited by Ash and Ash; Synapse Information Resources, 2007; Pharmaceutical Preformulation and Formulation, 2nd ed.; edited by Gibson; CRC Press, 2009.

[0016] The term "about" or "approximately" refers to an acceptable error for a particular value as determined by one of ordinary skill in the art, which depends in part on how the value is measured or determined. In certain embodiments, the term "about" or "approximately" means within 1, 2, or 3 standard deviations. In certain embodiments, the term "about" or "approximately" means within 25%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, or 0.05% of a given value or range.

[0017] The term "alkyl" refers to a linear or branched saturated monovalent hydrocarbon radical, which alkyl is optionally substituted with one or more substituents Q as described herein. For example, C 1-6 Alkyl refers to a linear saturated monovalent hydrocarbon group of 1 to 6 carbon atoms or a branched saturated monovalent hydrocarbon group of 3 to 6 carbon atoms. In certain embodiments, alkyl refers to a group having 1 to 30 (C 1-30 ), 1~20(C 1-20 ), 1~15(C 1-15 ), 1 to 10 (C 1-10 ), or 1-6 (C 1-6 ) straight-chain saturated monovalent hydrocarbon group having carbon atoms, or 3 to 30 carbon atoms (C 3-30 ), 3~20(C 3-20 ), 3~15(C 3-15 ), 3~10(C 3-10 ), or 3 to 6 (C 3-6 ) branched saturated monovalent hydrocarbon groups. As used herein, linear C 1-6 and branched C 3-6 An alkyl group is also referred to as a “lower alkyl.” Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl (including all isomeric forms, e.g., n-propyl and isopropyl), butyl (including all isomeric forms, e.g., n-butyl, isobutyl, sec-butyl, and t-butyl), pentyl (including all isomeric forms, e.g., n-pentyl, isopentyl, sec-pentyl, neopentyl, and tert-pentyl), and hexyl (including all isomeric forms, e.g., n-hexyl, isohexyl, and sec-hexyl).

[0018] The terms "alkylene" and "alkanediyl" are used interchangeably herein to refer to a linear or branched saturated divalent hydrocarbon radical, where the alkanediyl is optionally substituted with one or more substituents Q as described herein. For example, C 1-6Alkanediyl refers to a linear saturated divalent hydrocarbon group of 1 to 6 carbon atoms or a branched saturated divalent hydrocarbon group of 3 to 6 carbon atoms. In certain embodiments, alkanediyl refers to a group having 1 to 30 (C 1-30 ), 1~20(C 1-20 ), 1~15(C 1-15 ), 1 to 10 (C 1-10 ), or 1-6 (C 1-6 ) straight-chain saturated divalent hydrocarbon group having carbon atoms, or 3 to 30 carbon atoms (C 3-30 ), 3~20(C 3-20 ), 3~15(C 3-15 ), 3~10(C 3-10 ), or 3 to 6 (C 3-6 ) branched saturated divalent hydrocarbon groups. As used herein, linear C 1-6 and branched C 3-6 Alkanediyl groups are also referred to as “lower alkanediyl.” Examples of alkanediyl groups include methanediyl, ethanediyl (including all isomeric forms, for example, ethane-1,1-diyl and ethane-1,2-diyl), propanediyl (including all isomeric forms, for example, propane-1,1-diyl, propane-1,2-diyl, and propane-1,3-diyl), butanediyl (including all isomeric forms, for example, butane-1,1-diyl, butane-1,2-diyl, butane-1,3-diyl, and butane-1,4-diyl), pentanediyl (including all isomeric forms, for example, pentane-1,1-diyl, pentane-1,2-diyl, pentane-1,3-diyl, and pentane-1,5-diyl), and hexanediyl (including all isomeric forms, for example, hexane-1,1-diyl, hexane-1,2-diyl, hexane-1,3-diyl, and hexane-1,6-diyl). Examples of substituted alkanediyl groups include -C(O)CH2-, -C(O)(CH2)2-, -C(O)(CH2)3-, -C(O)(CH2)4-, -C(O)(CH2)5-, -C(O)(CH2)6-, -C(O)(CH2)7-, -C(O)(CH2)8-, -C(O)(CH2)9-, and -C(O)(CH2) 10Examples include, but are not limited to, -, -C(O)CHC(O)-, -C(O)(CH)C(O)-, -C(O)(CH)C(O)-, -C(O)(CH)C(O)-, or -C(O)(CH)C(O)-.

[0019] The term "heteroalkyl" means a linear or branched saturated monovalent hydrocarbon group having one or more heteroatoms in its backbone, each independently selected from O, S, and N. Heteroalkyl is optionally substituted with one or more substituents Q as described herein. For example, C 1-6 Heteroalkyl means a linear saturated monovalent hydrocarbon radical of 1 to 6 carbon atoms or a branched saturated monovalent hydrocarbon radical of 3 to 6 carbon atoms. In certain embodiments, heteroalkyl is a group having 1 to 30 (C 1-30 ), 1~20(C 1-20 ), 1~15(C 1-15 ), 1 to 10 (C 1-10 ), or 1-6 (C 1-6 ) straight-chain saturated monovalent hydrocarbon group having carbon atoms, or 3 to 30 carbon atoms (C 3-30 ), 3~20(C 3-20 ), 3~15(C 3-15 ), 3~10(C 3-10 ), or 3 to 6 (C 3-6 ) branched saturated monovalent hydrocarbon groups. As used herein, linear C 1-6 and branched C 3-6 Heteroalkyl groups are also referred to as "lower heteroalkyl." Examples of heteroalkyl groups include, but are not limited to, -OCH, -OCHCH, -CHOCH, -NHCH, -ONHCH, -NHOCH, -SCH, -CHNHCHCH, and -NHCHCHCH. Examples of substituted heteroalkyl groups include, but are not limited to, -CHNHC(O)CH and -NHC(O)CHCH.

[0020] The terms "heteroalkylene" and "heteroalkanediyl" are used interchangeably herein to refer to a linear or branched saturated divalent hydrocarbon radical having one or more heteroatoms in its backbone, each independently selected from O, S, and N. The heteroalkylene is optionally substituted with one or more substituents Q as described herein. For example, C 1-6 Heteroalkylene refers to a linear saturated divalent hydrocarbon group of 1 to 6 carbon atoms or a branched saturated divalent hydrocarbon group of 3 to 6 carbon atoms. In certain embodiments, heteroalkylene refers to a group having 1 to 30 (C 1-30 ), 1~20(C 1-20 ), 1~15(C 1-15 ), 1 to 10 (C 1-10 ), or 1-6 (C 1-6 ) carbon atoms or a linear saturated divalent hydrocarbon group having 3 to 30 carbon atoms (C 3-30 ), 3~20(C 3-20 ), 3~15(C 3-15 ), 3~10(C 3-10 ), or 3 to 6 (C 3-6 ) branched saturated divalent hydrocarbon groups. As used herein, linear C 1-6 and branched C 3-6 Heteroalkylene groups are also referred to as "lower heteroalkylene." Examples of heteroalkylene groups include -CHO-, -CHCHO-, -CHCHCHO-, -(CH)O-, -(CH)O-, -(CH)O-, -(CH)O-, -(CH)O-, -(CH)O-, -(CH)O-, -(CH) 10These include, but are not limited to, O-, -CHOCH-, -CHCHO-, -(CHCHO)-, -(CHCHO)-, -(CHCHO)-, -(CHCHO)-, -(CHCHO)-, -CHNH-, -CHNHCH-, -CHCHNH-, -CHCHCHNH-, -(CH)NH-, -CHS-, -CHSCH-, and -CHCHS-. Examples of substituted heteroalkylene groups include -C(O)CHO-, -C(O)(CH)O-, -C(O)CHCHCHO-, -C(O)CHCHCHCHO-, -C(O)(CH)O-, -C(O)(CH)O-, -C(O)(CH)O-, -C(O)(CH)O-, -C(O)(CH)O-, -C(O)(CH)O-, -C(O)(CH)O-, -C(O)(CH) 10 Examples include, but are not limited to, O-, -C(O)CHOCHCHO-, -C(O)CHO(CHCHO)-, -C(O)CHO-(CH-CHO)-, -C(O)CHO(CHCHO)-, -C(O)CHO(CHCHO)-, -CHNHC(O)CH-, -CHCHC(O)NH-, -CHN(CH)-, -(CH)N(CH)-, -(CH)N(CH)-, or -(CH)N(CH)-.

[0021] The term "alkenyl" refers to a linear or branched monovalent hydrocarbon group having one or more, in one embodiment 1, 2, 3, or 4, and in another embodiment 1, carbon-carbon double bonds. The alkenyl is optionally substituted with one or more substituents Q as described herein. The term "alkenyl" encompasses groups having a "cis" or "trans" configuration or a mixture thereof, or a "Z" or "E" configuration or a mixture thereof, as recognized by one of ordinary skill in the art. For example, C 2-6 Alkenyl refers to a linear unsaturated monovalent hydrocarbon group of 2 to 6 carbon atoms or a branched unsaturated monovalent hydrocarbon group of 3 to 6 carbon atoms. In some embodiments, alkenyl refers to a group having 2 to 30 carbon atoms (C 2-30 ), 2~20(C 2-20 ), 2~15(C 2-15), 2~10(C 2-10 ), or 2-6 (C 2-6 ) linear monovalent hydrocarbon group or 3 to 30 carbon atoms (C 3-30 ), 3~20(C 3-20 ), 3~15(C 3-15 ), 3~10(C 3-10 ), or 3 to 6 (C 3-6 ) branched monovalent hydrocarbon group. Examples of alkenyl groups include, but are not limited to, ethenyl, propenyl (including all isomeric forms, e.g., propen-1-yl, propen-2-yl, and allyl), and butenyl (including all isomeric forms, e.g., buten-1-yl, buten-2-yl, buten-3-yl, and 2-buten-1-yl).

[0022] The terms "alkenylene" and "alkenediyl" are used interchangeably herein to refer to a straight-chain or branched divalent hydrocarbon group having one or more, in one embodiment 1, 2, 3, or 4, and in another embodiment 1, carbon-carbon double bonds. The alkenediyl is optionally substituted with one or more substituents Q as described herein. The term "alkenediyl" encompasses groups having "cis" or "trans" configurations or mixtures thereof, or "Z" or "E" configurations or mixtures thereof, as recognized by those skilled in the art. For example, C 2-6 Alkenediyl refers to a linear unsaturated divalent hydrocarbon group having 2 to 6 carbon atoms or a branched unsaturated divalent hydrocarbon group having 3 to 6 carbon atoms. In some embodiments, alkenediyl refers to a group having 2 to 30 carbon atoms (C 2-30 ), 2~20(C 2-20 ), 2~15(C 2-15 ), 2~10(C 2-10 ), or 2-6 (C 2-6 ) linear divalent hydrocarbon group or 3 to 30 carbon atoms (C 3-30 ), 3~20(C 3-20 ), 3~15(C 3-15 ), 3~10(C 3-10 ), or 3 to 6 (C 3-6) branched divalent hydrocarbon group. Examples of alkenediyl groups include ethenediyl (including all isomeric forms, for example, ethene-1,1-diyl and ethene-1,2-diyl), propenediyl (including all isomeric forms, for example, 1-propene-1,1-diyl, 1-propene-1,2-diyl, and 1-propene-1,3-diyl), butenediyl (including all isomeric forms, for example, 1-butene-1,1-diyl, 1-butene-1,2-diyl, and 1-butene-1,4-diyl), pentendiyl, and the like. Examples of hexene dialkyl groups include, but are not limited to, hexenediyl (including all isomeric forms, for example, 1-pentene-1,1-diyl, 1-pentene-1,2-diyl, and 1-pentene-1,5-diyl), and hexenediyl (including all isomeric forms, for example, 1-hexene-1,1-diyl, 1-hexene-1,2-diyl, 1-hexene-1,3-diyl, 1-hexene-1,4-diyl, 1-hexene-1,5-diyl, and 1-hexene-1,6-diyl).

[0023] The term "alkynyl" refers to a linear or branched monovalent hydrocarbon group having one or more, in one embodiment one, two, three, or four, and in another embodiment one, carbon-carbon triple bonds. An alkynyl group does not have a carbon-carbon double bond. An alkynyl is optionally substituted with one or more substituents Q as described herein. For example, C 2-6 Alkynyl refers to a linear unsaturated monovalent hydrocarbon group of 2 to 6 carbon atoms or a branched unsaturated monovalent hydrocarbon group of 4 to 6 carbon atoms. In some embodiments, alkynyl refers to a group having 2 to 30 carbon atoms (C 2-30 ), 2~20(C 2-20 ), 2~15(C 2-15 ), 2~10(C 2-10 ), or 2-6 (C 2-6 ) linear monovalent hydrocarbon group or 4 to 30 carbon atoms (C 4-30 ), 4~20(C 4-20 ), 4~15(C 4-15 ), 4~10(C 4-10 ), or 4~6(C 4-6) branched monovalent hydrocarbon group. Examples of alkynyl groups include, but are not limited to, ethynyl (—C≡CH), propynyl (including all isomeric forms, e.g., 1-propynyl (—C≡CCH) and propargyl (—CHC≡CH)), butynyl (including all isomeric forms, e.g., 1-butyn-1-yl and 2-butyn-1-yl), pentynyl (including all isomeric forms, e.g., 1-pentyn-1-yl and 1-methyl-2-butyn-1-yl), and hexynyl (including all isomeric forms, e.g., 1-hexyn-1-yl and 2-hexyn-1-yl).

[0024] The terms "alkynylene" and "alkynediyl" are used interchangeably herein to refer to a linear or branched divalent hydrocarbon group having one or more, in one embodiment 1, 2, 3, or 4, and in another embodiment 1, carbon-carbon triple bonds. An alkynylene group does not have any carbon-carbon double bonds. An alkynediyl is optionally substituted with one or more substituents Q as described herein. For example, C 2-6 Alkynediyl refers to a linear unsaturated divalent hydrocarbon group having 2 to 6 carbon atoms or a branched unsaturated divalent hydrocarbon group having 4 to 6 carbon atoms. In some embodiments, alkynediyl refers to a divalent hydrocarbon group having 2 to 30 carbon atoms (C 2-30 ), 2~20(C 2-20 ), 2~15(C 2-15 ), 2~10(C 2-10 ), or 2-6 (C 2-6 ) linear divalent hydrocarbon group or 4 to 30 carbon atoms (C 4-30 ), 4~20(C 4-20 ), 4~15(C 4-15 ), 4~10(C 4-10 ), or 4 to 6 (C 4-6) branched divalent hydrocarbon group. Examples of alkynediyl groups include, but are not limited to, ethynediyl, propynediyl (including all isomeric forms, for example, 1-propyne-1,3-diyl and 1-propyne-3,3-diyl), butynediyl (including all isomeric forms, for example, 1-butyne-1,3-diyl, 1-butyne-1,4-diyl, and 2-butyne-1,1-diyl), pentynediyl (including all isomeric forms, for example, 1-pentyne-1,3-diyl, 1-pentyne-1,4-diyl, and 2-pentyne-1,1-diyl), and hexynediyl (including all isomeric forms, for example, 1-hexyne-1,3-diyl, 1-hexyne-1,4-diyl, and 2-hexyne-1,1-diyl).

[0025] The term "cycloalkyl" refers to a cyclic monovalent hydrocarbon group optionally substituted with one or more substituents Q as described herein. In one embodiment, cycloalkyl is a saturated or unsaturated but non-aromatic, and / or bridged or non-bridged, and / or fused bicyclic group. In certain embodiments, cycloalkyl is a cyclic group having 3 to 20 carbon atoms (C 3-30 ), 3~20(C 3-20 ), 3~15(C 3-15 ), 3~10(C 3-10 ), or 3 to 7 (C 3-7 ) carbon atoms. In one embodiment, the cycloalkyl is monocyclic. In another embodiment, the cycloalkyl is bicyclic. In yet another embodiment, the cycloalkyl is tricyclic. In yet another embodiment, the cycloalkyl is polycyclic. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptenyl, bicyclo[1.1.1]pentyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, decalinyl, and adamantyl.

[0026] The terms "cycloalkylene" and "cycloalkanediyl" are used interchangeably herein to refer to a cyclic divalent hydrocarbon group, which may be optionally substituted with one or more substituents Q as described herein. In one embodiment, a cycloalkanediyl group may be a saturated or unsaturated, but non-aromatic, and / or bridged, and / or non-bridged, and / or fused bicyclic group. In certain embodiments, a cycloalkanediyl is a cyclic group having 3 to 30 carbon atoms (C 3-30 ), 3~20(C 3-20 ), 3~15(C 3-15 ), 3~10(C 3-10 ), or 3 to 7 (C 3-7 ) carbon atoms. Examples of cycloalkanediyl groups include cyclopropanediyl (including all isomeric forms, for example, cyclopropane-1,1-diyl and cyclopropane-1,2-diyl), cyclobutanediyl (including all isomeric forms, for example, cyclobutane-1,1-diyl, cyclobutane-1,2-diyl, and cyclobutane-1,3-diyl), cyclopentanediyl (including all isomeric forms, for example, cyclopentane-1,1-diyl, cyclopentane-1,2-diyl, and cyclopentane-1,3-diyl), cyclohexanediyl (including all isomeric forms, for example, cyclohexane-1,1-diyl, cyclohexane-1,2-diyl, cyclohexane-1,3-diyl, and cyclohexa-1,4-diyl), cycloheptanediyl (including all isomeric forms, for example, cycloheptane-1,1-diyl, cycloheptane-1,2-diyl, cycloheptane-1,3-diyl, and cycloheptane-1,4-diyl), decalindiyl (including all isomeric forms, for example, decalin-1,1-diyl, decalin-1,2-diyl, and decalin-1,8-diyl), and adamantodiyl (including all isomeric forms, for example, adamant-1,2-diyl, adamant-1,3-diyl, and adamant-1,8-diyl).

[0027] The term "aryl" refers to a monovalent monocyclic aromatic hydrocarbon group and / or a monovalent polycyclic aromatic hydrocarbon group having at least one aromatic carbocyclic ring. In certain embodiments, aryl refers to a group having 6 to 30 carbon atoms. 6-30 ), 6~20(C 6-20 ), 6~15(C 6-15 ), or 6 to 10 (C 6-10 ) ring carbon atoms. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, fluorenyl, azulenyl, anthryl, phenanthryl, pyrenyl, biphenyl, and terphenyl. Aryl also refers to bicyclic or tricyclic carbocyclic rings in which one ring is aromatic and the other ring may be saturated, partially unsaturated, or aromatic, such as dihydronaphthyl, indenyl, indanyl, or tetrahydronaphthyl (tetralinyl). In one embodiment, an aryl is monocyclic. In another embodiment, an aryl is bicyclic. In yet another embodiment, an aryl is tricyclic. In yet another embodiment, an aryl is polycyclic. In certain embodiments, an aryl is optionally substituted with one or more substituents Q as described herein.

[0028] The terms "arylene" and "arenediyl" are used interchangeably herein to refer to a divalent monocyclic aromatic hydrocarbon group or a divalent polycyclic aromatic hydrocarbon group having at least one aromatic hydrocarbon ring. In certain embodiments, an arylene is a 6-30 (C 6-30 ), 6~20(C 6-20 ), 6~15(C 6-15 ), or 6 to 10 (C 6-10) ring atoms. Examples of arylene groups include phenylene (including all isomeric forms, for example, phen-1,2-diyl, phen-1,3-diyl, and phen-1,4-diyl), naphthylene (including all isomeric forms, for example, naphth-1,2-diyl, naphth-1,3-diyl, and naphth-1,8-diyl), fluorenylene (including all isomeric forms, for example, fluorene-1,2-diyl, fluorene-1,3-diyl, and fluorene-1,8-diyl), azulenylene (including all isomeric forms, for example, azulene-1,2-diyl, azulene-1,3-diyl, and azulene-1,8-diyl), anthrylene (including all isomeric forms, for example, anthri-1,2-diyl, anthri-1,3-diyl), and the like. and anthra-1,8-diyl), phenanthrylene (including all isomeric forms, for example, phenanthra-1,2-diyl, phenanthra-1,3-diyl, and phenanthra-1,8-diyl), pyrenylene (including all isomeric forms, for example, pyrene-1,2-diyl, pyrene-1,3-diyl, and pyrene-1,8-diyl), biphenylene (including all isomeric forms, for example, biphen-2,3-diyl, biphen-3,4'-diyl, and biphen-4,4'-diyl), and terphenylene (including all isomeric forms, for example, terphen-2,3-diyl, terphen-3,4'-diyl, and terphen-4,4'-diyl).Arylene also means a bicyclic or tricyclic carbocyclic ring in which one ring is aromatic and the other rings may be saturated, partially unsaturated, or aromatic, such as dihydronaphthylene (including all isomeric forms, for example, dihydronaphth-1,2-diyl and dihydronaphth-1,8-diyl), indenylene (including all isomeric forms, for example, indene-1,2-diyl, indene-1,5-diyl, and indene-1,7-diyl), indanylene (including all isomeric forms, for example, indan-1,2-diyl, indan-1,5-diyl, and indan-1,7-diyl), or tetrahydronaphthylene (tetralinylene) (including all isomeric forms, for example, tetrahydronaphth-1,2-diyl, tetrahydronaphth-1,5-diyl, and tetrahydronaphth-1,8-diyl). In certain embodiments, the arylene is optionally substituted with one or more substituents Q as described herein.

[0029] The terms "aralkyl" or "arylalkyl" refer to a monovalent alkyl group substituted with one or more aryl groups. In certain embodiments, an aralkyl is an alkyl group having 7 to 30 carbon atoms (C 7-30 ), 7~20(C 7-20 ), or 7 to 16 (C 7-16 ) carbon atoms. Examples of aralkyl groups include, but are not limited to, benzyl, phenylethyl (including all isomeric forms, e.g., 1-phenylethyl and 2-phenylethyl), and phenylpropyl (including all isomeric forms, e.g., 1-phenylpropyl, 2-phenylpropyl, and 3-phenylpropyl). In certain embodiments, the aralkyl is optionally substituted with one or more substituents Q as described herein.

[0030] The terms "aralkylene" or "arylalkylene" refer to a divalent alkyl group substituted with one or more aryl groups. In certain embodiments, the aralkylene has a carbon number of 7 to 30 (C 7-30 ), 7~20(C 7-20 ), or 7 to 16 (C 7-16) carbon atoms. Examples of aralkylene groups include, but are not limited to, benzylene (including all isomeric forms, e.g., phenylmethadiyl), phenylethylene (including all isomeric forms, e.g., 2-phenyl-ethane-1,1-diyl and 2-phenyl-ethane-1,2-diyl), and phenylpropylene (including all isomeric forms, e.g., 3-phenyl-propane-1,1-diyl, 3-phenyl-propane-1,2-diyl, and 3-phenyl-propane-1,3-diyl). In certain embodiments, the aralkylene is optionally substituted with one or more substituents Q as described herein.

[0031] The term "heteroaryl" refers to a monovalent monocyclic aromatic or polycyclic aromatic group having at least one aromatic ring, wherein at least one aromatic ring has one or more heteroatoms independently selected from O, S, and N within the ring. In the case of heteroaryl groups containing aromatic and non-aromatic heterocycles, the heteroaryl group is not attached to the remainder of the molecule through the non-aromatic heterocycle. Each ring of a heteroaryl group can have 1 or 2 O atoms, 1 or 2 S atoms, and / or 1 to 4 N atoms; provided that the total number of heteroatoms in each ring is 4 or less and each ring has at least 1 carbon atom. In certain embodiments, a heteroaryl has 5 to 20, 5 to 15, or 5 to 10 ring atoms. In one embodiment, a heteroaryl is monocyclic. Examples of monocyclic heteroaryl groups include, but are not limited to, furanyl, imidazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, thiadiazolyl, thiazolyl, thienyl, tetrazolyl, triazinyl, and triazolyl. In another embodiment, the heteroaryl is bicyclic.Examples of bicyclic heteroaryl groups include benzofuranyl, benzimidazolyl, benzisoxazolyl, benzopyranyl, benzothiadiazolyl, benzothiazolyl, benzothienyl, benzotriazolyl, benzoxazolyl, furopyrindyl (including all isomeric forms, e.g., furo[2,3-b]pyridinyl, furo[2,3-c]pyridinyl, furo[3,2-b]pyridinyl, furo[3,2-c]pyridinyl, furo[3,4-b]pyridinyl, and furo[3,4-c]pyridinyl), imidazopyridinyl (including all isomeric forms, e.g., furo[2,3-b]pyridinyl, furo[2,3-c]pyridinyl, furo[3,4-b]pyridinyl, and furo[3,4-c]pyridinyl), and benzopyridinyl (including all isomeric forms, e.g., furo[2,3-b]pyridinyl, furo[2,3-c]pyridinyl, furo[3,4-b]pyridinyl, and furo[3,4-c]pyridinyl). imidazo[1,2-a]pyridinyl, imidazo[4,5-b]pyridinyl, and imidazo[4,5-c]pyridinyl), imidazothiazolyl (including all isomeric forms, for example, imidazo[2,1-b]thiazolyl and imidazo[4,5-d]thiazolyl), indazolyl, indolizinyl, indolyl, isobenzofuranyl, isobenzothienyl (i.e., benzo[c]thienyl), isoindolyl, isoquinolinyl, naphthyridinyl (including all isomeric forms, for example, 1,5-naphthyridinyl, 1 ,6-naphthyridinyl, 1,7-naphthyridinyl, and 1,8-naphthyridinyl), oxazolopyridinyl (including all isomeric forms, for example, oxazolo[4,5-b]pyridinyl, oxazolo[4,5-c]pyridinyl, oxazolo[5,4-b]pyridinyl, and oxazolo[5,4-c]pyridinyl), phthalazinyl, pteridinyl, purinyl, pyrrolopyridyl (including all isomeric forms, for example, pyrrolo[2,3-b]pyridinyl, pyrrolo[2,3-c]pyridinyl, pyrrolo[3,2-b]pyridinyl, and pyrrolo[5,4-c]pyridinyl). In yet another embodiment, heteroaryl includes, but is not limited to, thiadiazolopyrimidyl (including [1,2,5]thiadiazolo[3,4-d]pyrimidinyl and [1,2,3]thiadiazolo[4,5-d]pyrimidinyl), quinolinyl, quinoxalinyl, quinazolinyl, thiadiazolopyrimidyl (including all isomeric forms, e.g., [1,2,5]thiadiazolo[3,4-d]pyrimidinyl and [1,2,3]thiadiazolo[4,5-d]pyrimidinyl), and thieno-pyridyl (including all isomeric forms, e.g., thieno[2,3-b]pyridinyl, thieno[2,3-c]pyridinyl, thieno[3,2-b]pyridinyl, and thieno[3,2-c]pyridinyl). In yet another embodiment, heteroaryl is tricyclic.Examples of tricyclic heteroaryl groups include, but are not limited to, acridinyl, benz-indolyl, carbazolyl, dibenzofuranyl, perimidinyl, phenanthrolinyl, phenanthridinyl (including all isomeric forms, for example, 1,5-phenanthrolinyl, 1,6-phenanthrolinyl, 1,7-phenanthrolinyl, 1,9-phenanthrolinyl, and 2,10-phenanthrolinyl), phenarsazinyl, phenazinyl, phenothiazinyl, phenoxazinyl, and xanthenyl. In some embodiments, heteroaryl is optionally substituted with one or more substituents Q as described herein.

[0032] The terms "heteroarylene" and "heteroarenediyl" are used interchangeably herein to refer to a divalent monocyclic aromatic group or a divalent polycyclic aromatic group having at least one aromatic ring, wherein at least one aromatic ring has one or more heteroatoms, each independently selected from O, S, and N, within the ring. In the case of heteroarylene groups containing an aromatic heterocycle and a non-aromatic heterocycle, the heteroarylene group is not attached to the remainder of the molecule through the non-aromatic heterocycle. Each ring of a heteroarylene group can have 1 or 2 O atoms, 1 or 2 S atoms, and / or 1 to 4 N atoms, provided that the total number of heteroatoms in each ring is 4 or less and each ring has at least 1 carbon atom. In certain embodiments, a heteroarylene has 5 to 20, 5 to 15, or 5 to 10 ring atoms. Examples of monocyclic heteroarylene groups include, but are not limited to, furandiyl, imidazolediyl, isothiazolediyl, isoxazolediyl, oxadiazolediyl, oxazolediyl, pyrazinediyl, pyrazolediyl, pyridazinediyl, pyridinediyl, pyrimidinediyl, pyrrolediyl, thiadiazolediyl, thiazolidinyl, thienediyl, tetrazolidinyl, triazinediyl, and triazolediyl. Examples of bicyclic heteroarylene groups include benzofurandiyl, benzimidazolediyl, benzisoxazolediyl, benzopyrandiyl, benzothiadiazolediyl, benzothienediyl, benzotriazolediyl, benzoxazolediyl, furopyridinediyl (all isomeric forms, e.g., furo[2,3-b]pyridinediyl, furo[2,3-c]pyridinediyl, furo[3,2-b]pyridinediyl). , furo[3,2-c]pyridinediyl, furo[3,4-b]pyridinediyl, and furo[3,4-c]pyridinediyl), imidazopyridinediyl (including all isomeric forms, for example, imidazo[1,2-a]pyridinediyl, imidazo[4,5-b]pyridinediyl, and imidazo[4,5-c]pyridinediyl), imidazothiazoldiyl (including all isomeric forms, for example, imidazo[2,1-b]thiazoldiyl and imidazo[4,5-d]thiazolediyl), indazolediyl, indolizinediyl, indolediyl, isobenzofurandiyl, isobenzothienediyl (i.e., benzo[c]thienediyl), isoindolediyl, isoquinolinediyl, naphthyridinediyl (including all isomeric forms, for example, 1,5-naphthyridinediyl, 1,6-naphthyridinediyl, 1,7-naphthyridinediyl, and 1,8-naphthyridinediyl), oxazolopyridinediyl (including all isomeric forms, for example, oxazolo[4,5-b]pyridinediyl, oxazolo[4,5-c]pyridinediyl, oxazolo[5,4-b]pyridinediyl, and oxazolo[5,4-c]pyridinediyl), phthalazinediyl, pteridinediyl, purinediyl, pyrrolopyridinediyl benzol (including all isomeric forms, for example, pyrrolo[2,3-b]pyridinediyl, pyrrolo[2,3-c]pyridinediyl, pyrrolo[3,2-b]pyridinediyl, and pyrrolo[3,2-c]pyridinediyl), quinolinediyl, quinoxalinediyl, quinazolinediyl, thiadiazolopyrimidinediyl (including all isomeric forms, for example, [1,2,5]thiadiazolo[3,4 [1,2,3]thiadiazolo[4,5-d]pyrimidinediyl and [1,2,3]thiadiazolo[4,5-d]pyrimidinediyl), and thienopyridinediyl (including all isomeric forms, for example, thieno[2,3-b]pyridinediyl, thieno[2,3-c]pyridinediyl, thieno[3,2-b]pyridinediyl, and thieno[3,2-c]pyridinediyl). Examples of tricyclic heteroarylene groups include, but are not limited to, acridinediyl, benzoindolediyl, carbazolediyl, dibenzofurandiyl, perimidinediyl, phenanthrolinediyl (including all isomeric forms, e.g., 1,5-phenanthrolinediyl, 1,6-phenanthrolinediyl, 1,7-phenanthrolinediyl, 1,9-phenanthrolinediyl, and 2,10-phenanthrolinediyl), phenanthridinediyl, phenarsazinediyl, phenazinediyl, phenothiazinediyl, phenoxazinediyl, and xanthenediyl. In certain embodiments, heteroarylene is optionally substituted with one or more substituents Q as described herein.

[0033] The term "heterocyclyl" or "heterocyclic" refers to a monovalent monocyclic non-aromatic ring system or a monovalent polycyclic ring system containing at least one non-aromatic ring, in which one or more of the non-aromatic ring atoms is a heteroatom, each independently selected from O, S, and N; and the remaining ring atoms are carbon atoms. In the case of heterocyclyl groups containing aromatic and non-aromatic heterocycles, the heterocyclyl group is not attached to the remainder of the molecule via an aromatic heterocycle. In certain embodiments, a heterocyclyl or heterocyclic group has 3 to 20, 3 to 15, 3 to 10, 3 to 8, 4 to 7, or 5 to 6 ring atoms. In certain embodiments, a heterocyclyl is a monocyclic, bicyclic, tricyclic, or tetracyclic ring system that may be fused or bridged, and in which nitrogen or sulfur atoms may be optionally oxidized, nitrogen atoms may be optionally quaternized, and some rings may be partially saturated, fully saturated, or aromatic. The heterocyclyl may be attached to the main structure at any heteroatom or carbon atom that results in the creation of a stable compound.Examples of heterocyclyl and heterocyclic groups include azepinyl, benzodioxanyl, benzodioxolyl, benzofuranonyl, chromanyl, decahydroisoquinolinyl, dihydrobenzofuranyl, dihydrobenzisothiazolyl, dihydro-benzisoxazinyl (including all isomeric forms, e.g., 1,4-dihydrobenzo[d][1,3]oxazinyl, 3,4-dihydrobenzo[c][1,2]-oxazinyl, and 3,4-dihydrobenzo[d][1,2]oxazinyl), dihydrobenzothienyl, dihydroisobenzofuranyl, dihydrobenzo[c]thienyl, dihydrofuryl, dihydroisoindolyl, dihydro-pyranyl, dihydropyrazolyl, dihydropyrazinyl, dihydropyridinyl, dihydropyrimidinyl, Examples of heterocyclyl include, but are not limited to, dihydropyrrolyl, dioxolanyl, 1,4-dithianyl, furanonyl, imidazolidinyl, imidazolinyl, indolinyl, isochromanyl, isoindolinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, oxazolidinonyl, oxazolidinyl, oxiranyl, piperazinyl, piperidinyl, 4-piperidonyl, pyrazolidinyl, pyrazolinyl, pyrrolidinyl, pyrrolinyl, quinuclidinyl, tetrahydrofuryl, tetrahydroisoquinolinyl, tetrahydropyranyl, tetrahydrothienyl, thiamorpholinyl, thiazolidinyl, thiochromanyl, tetrahydroquinolinyl, and 1,3,5-trithianyl. In certain embodiments, the heterocyclyl is optionally substituted with one or more substituents Q as described herein.

[0034] The term "heterocyclylene" refers to a divalent monocyclic non-aromatic ring system or a bivalent polycyclic ring system containing at least one non-aromatic ring, wherein one or more of the non-aromatic ring atoms is a heteroatom independently selected from O, S, and N; and the remaining ring atoms are carbon atoms. In heterocyclylene groups containing aromatic and non-aromatic heterocycles, the heterocyclylene group has at least one bond to the remainder of the molecule through the non-aromatic heterocycle. In certain embodiments, heterocyclylene groups have 3 to 20, 3 to 15, 3 to 10, 3 to 8, 4 to 7, or 5 to 6 ring atoms. In certain embodiments, heterocyclylene is a monocyclic, bicyclic, tricyclic, or tetracyclic ring system that may be fused or bridged, and in which nitrogen or sulfur atoms may be optionally oxidized, nitrogen atoms may be optionally quaternized, and some rings may be partially saturated, fully saturated, or aromatic. The heterocyclylene may be attached to the main structure at any heteroatom or carbon atom that results in the creation of a stable compound.Examples of such heterocyclylene groups are azepinediyl, benzodioxanediyl, benzodioxolediyl, benzofuranonediyl, chromandiyl, decahydroisoquinolinediyl, dihydrobenzofurandiyl, dihydrobenzisothiazolediyl, dihydrobenzisoxazinediyl (including all isomeric forms, e.g., 1,4-dihydrobenzo[d][1,3]oxazinediyl, 3,4-dihydrobenzo[c][1,2]oxazinediyl, and 3,4-dihydrobenzo[d][1,2]oxazinediyl), dihydrobenzothienediyl, dihydroisobenzofurandiyl, dihydrobenzo[c]thienediyl, dihydrofurdiyl, dihydroisoindolediyl, dihydropyrandiyl, dihydro-pyrazolediyl, dihydropyrazinediyl, dihydropyridinediyl, dihydropyrimidinediyl, dihydropyrrolediyl, dioxanediyl, dihydrobenzo[d][1,3]oxazine ...d][1,3]oxazinediyl, Solanediyl, 1,4-dithianediyl, furanonediyl, imidazolidinediyl, imidazolinediyl, indolinediyl, isochromanediyl, isoindolinediyl, isothiazolidinediyl, isoxazolidinediyl, morpholinediyl, octahydro-indolediyl, octahydroisoindolediyl, oxazolidinonediyl, oxazolidinediyl, oxiranediyl, piperazinediyl, piperidinediyl, 4-piperidonediyl In certain embodiments, heterocyclylene is optionally substituted with one or more substituents Q as described herein.

[0035] The terms "halogen," "halide," or "halo" mean fluoro, chloro, bromo, and / or iodo.

[0036] The term “optionally substituted” refers to a group or substituent, such as an alkyl, alkylene, heteroalkyl, heteroalkylene, alkenyl, alkenylene, alkynyl, alkynylene, cycloalkyl, cycloalkylene, aryl, arylene, aralkyl, aralkylene, heteroaryl, heteroarylene, heterocyclyl, or heterocyclylene group, that is optionally substituted with, for example, (a) deuterium (—D), cyano (—CN), halo, nitro (—NO), and oxo (═O); (b) one or more, and in one embodiment, 1, 2, 3, or 4, substituents Q a each optionally further substituted C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 aralkyl, heteroaryl, and heterocyclyl; and (c)—C(O)R a , -C(O)OR a , -C(O)NR b R c , -C(O)SR a , -C(NR a )NR b R c , ‐C(S)R a , ‐C(S)OR a , ‐C(S)NR b R c , -OR a , ‐OC(O)R a , ‐OC(O)OR a , ‐OC(O)NR b R c , ‐OC(O)SR a , ‐OC(NR a )NR b R c , ‐OC(S)R a , ‐OC(S)OR a , ‐OC(S)NR b R c , -OP(O)(OR b ) OR c , ‐OS(O)R a , ‐OS(O)2R a , ‐OS(O)NRb R c , -OS(O)2NR b R c , ‐NR b R c , ‐NR a C(O)R d , ‐NR a C(O)OR d , ‐NR a C(O)NR b R c , ‐NR a C(O)SR d , ‐NR a C(NR d )NR b R c , ‐NR a C(S)R d , ‐NR a C(S)OR d , ‐NR a C(S)NR b R c , ‐NR a S(O)R d , -N=S(O)R a R d , ‐NR a S(O)2R d , ‐NR a S(O)NR b R c , ‐NR a S(O)NR b R c , ‐SR a , ‐S(O)R a , -S(O)2R a , -S(O)NR b R c , and -S(O)2NR b R c (In the formula, each R a , R b , R c , and R d are independently (i) hydrogen or deuterium; (ii) one or more, in one embodiment, 1, 2, 3, or 4, substituents Q a C, each of which is arbitrarily substituted 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C 2-6Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) R b and R c together with the N atom to which they are attached, one or more, in one embodiment 1, 2, 3, or 4, substituents Q a Q is intended to mean optionally substituted with one or more, and in one embodiment, 1, 2, 3, or 4, substituents Q each independently selected from:

[0037] In one embodiment, each Q a are independently: (a) deuterium, cyano, halo, nitro, and oxo; (b) C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 aralkyl, heteroaryl, and heterocyclyl; and (c)—C(O)R e , -C(O)OR e , -C(O)NR f R g , -C(O)SR e , -C(NR e )NR f R g , ‐C(S)R e , ‐C(S)OR e , ‐C(S)NR f R g , -OR e , ‐OC(O)R e , ‐OC(O)OR e , ‐OC(O)NR f R g , ‐OC(O)SR e , ‐OC(NR e )NR f R g , ‐OC(S)R e, ‐OC(S)OR e , ‐OC(S)NR f R g , -OP(O)(OR f ) OR g , ‐OS(O)R e , ‐OS(O)2R e , ‐OS(O)NR f R g , -OS(O)2NR f R g , ‐NR f R g , ‐NR e C(O)R h , ‐NR e C(O)OR f , ‐NR e C(O)NR f R g , ‐NR e C(O)SR f , ‐NR e C(NR h )NR f R g , ‐NR e C(S)R h , ‐NR e C(S)OR f , ‐NR e C(S)NR f R g , ‐NR e S(O)R h , -N=S(O)R e R h , ‐NR e S(O)2R h , ‐NR e S(O)NR f R g , ‐NR e S(O)NR f R g , ‐SR e , ‐S(O)R e , -S(O)2R e , -S(O)NR f R g , and -S(O)2NR f R g where each R e , R f , R g , and R hare independently (i) hydrogen or deuterium; (ii) C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) R f and R g together with the N atom to which they are attached form a heterocyclyl.

[0038] In certain embodiments, "optically active" and "enantiomerically active" refer to a collection of molecules having an enantiomeric excess of about 80% or more, about 90% or more, about 91% or more, about 92% or more, about 93% or more, about 94% or more, about 95% or more, about 96% or more, about 97% or more, about 98% or more, about 99% or more, about 99.5% or more, or about 99.8% or more. In certain embodiments, an optically active compound contains about 95% or more of one enantiomer and about 5% or less of the other enantiomer, based on the total weight of the enantiomeric mixture. In certain embodiments, an optically active compound contains about 98% or more of one enantiomer and about 2% or less of the other enantiomer, based on the total weight of the enantiomeric mixture. In certain embodiments, an optically active compound contains about 99% or more of one enantiomer and about 1% or less of the other enantiomer, based on the total weight of the enantiomeric mixture.

[0039] In describing an optically active compound, the prefixes R and S are used to refer to the absolute configuration of the compound about its chiral center. (+) and (-) are used to refer to the optical rotation of the compound, i.e., the direction in which a plane of polarized light is rotated by the optically active compound. The prefix (-) indicates that the compound is levorotatory, i.e., the compound rotates the plane of polarized light to the left, i.e., counterclockwise. The prefix (+) indicates that the compound is dextrorotatory, i.e., the compound rotates the plane of polarized light to the right, i.e., clockwise. However, the signs of optical rotation (+) and (-) are not related to the absolute configuration R and S of the compound.

[0040] The term "isotopically enriched" refers to a compound that contains unnatural proportions of isotopes at one or more of the atoms that constitute such compound. In certain embodiments, isotopically enriched compounds include, but are not limited to, hydrogen ( 1 H), deuterium ( 2 H), tritium ( 3 H), carbon-11( 11 C), carbon-12( 12 C), carbon-13( 13 C), carbon-14( 14 C), nitrogen-13( 13 N), nitrogen-14( 14 N), nitrogen-15( 15 N), oxygen-14( 14 O), oxygen-15( 15 O), oxygen-16( 16 O), oxygen-17( 17 O), oxygen-18( 18 O), fluorine-17( 17 F), fluorine-18( 18 F), Phosphorus-31( 31 P), phosphorus-32( 32 P), phosphorus-33( 33 P), sulfur-32( 32 S), sulfur-33( 33 S), sulfur-34( 34 S), sulfur-35( 35 S), sulfur-36( 36 S), chlorine-35(35 Cl), chlorine-36( 36 Cl), chlorine-37( 37 Cl), Bromine-79( 79 Br), Bromine-81( 81 Br), iodine-123( 123 I), iodine-125( 125 I), iodine-127( 127 I), iodine-129( 129 I), and iodine-131( 131 In some embodiments, the isotopically enriched compound is in a stable form, i.e., is non-radioactive. In some embodiments, the isotopically enriched compound contains one or more isotopes, such as, but not limited to, hydrogen (I). 1 H), deuterium ( 2 H), carbon-12( 12 C), carbon-13( 13 C), nitrogen-14( 14 N), nitrogen-15( 15 N), oxygen-16( 16 O), oxygen-17( 17 O), oxygen-18( 18 O), fluorine-17( 17 F), Phosphorus-31( 31 P), sulfur-32( 32 S), sulfur-33( 33 S), sulfur-34( 34 S), sulfur-36( 36 S), chlorine-35( 35 Cl), chlorine-37( 37 Cl), Bromine-79( 79 Br), Bromine-81( 81 Br), and iodine-127( 127 In some embodiments, the isotopically enriched compound contains one or more isotopes, such as, but not limited to, tritium (I), in unnatural proportions. In some embodiments, the isotopically enriched compound is in an unstable form, i.e., is radioactive. In some embodiments, the isotopically enriched compound contains one or more isotopes, such as, but not limited to, tritium (I). 3 H), carbon-11( 11 C), carbon-14( 14 C), nitrogen-13( 13 N), oxygen-14( 14 O), oxygen-15(15 O), fluorine-18( 18 F), phosphorus-32( 32 P), phosphorus-33( 33 P), sulfur-35( 35 S), chlorine-36( 36 Cl), iodine-123( 123 I), iodine-125( 125 I), iodine-129( 129 I), and iodine-131( 131 In the compounds provided herein, any hydrogen atom may be substituted, for example, with one or more isotopes, such as 1), 2), 3), 4), 5), 6), 7), 8), 9), 10), 11), 12), 13), 14), 15), 16), 17), 18), 19), 20), 21), 22), 23), 24), 25), 26), 27), 28), 29), 30), 31), 32), 33), 34), 35), 36), 37), 38), 39), 39), 40), 41), 42), 43), 44), 45), 46), 47), 48), 49), 50), 51), 52), 53), 54), 55), 56), 57), 58), 2 H, or any carbon can be, for example, 13 C, or any nitrogen can be, for example, 15 N, and any oxygen, e.g. 18 It will be understood that the number of

[0041] The term "isotopic enrichment" refers to the percentage of incorporation of a less common isotope of an element (e.g., D for deuterium or hydrogen-2) in place of a more common isotope of that element (e.g., 1H for protium or hydrogen-1) at a given position in a molecule. As used herein, when an atom at a particular position in a molecule is designated as being a particular less common isotope, it is understood that the abundance of that isotope at that position is substantially greater than its natural abundance.

[0042] The term "isotopic enrichment factor" means the ratio between the abundance of an isotope in an isotopically enriched compound and the natural abundance of the specified isotope.

[0043] The term "hydrogen" or the symbol "H" refers to protium ( 1 H), deuterium ( 2 H or D), and tritium ( 3"H" refers to the composition of naturally occurring hydrogen isotopes, including hydrogen (H) at their natural abundance. Protium is the most common hydrogen isotope, with a natural abundance of greater than 99.98%. Deuterium is a less common hydrogen isotope, with a natural abundance of about 0.0156%.

[0044] The term "deuterium enrichment" refers to the percentage of deuterium incorporation in place of hydrogen at a given position in a molecule. For example, a deuterium enrichment of 1% at a given position means that 1% of the molecules in a given sample contain deuterium at that specified position. Because the natural distribution of deuterium averages about 0.0156%, the deuterium enrichment at any position in a compound synthesized using non-enriched starting materials will average about 0.0156%. As used herein, when a particular position in an isotopically enriched compound is designated as having deuterium, it is understood that the abundance of deuterium at that position in the compound is substantially greater than its natural abundance (0.0156%).

[0045] The term "carbon" or the symbol "C" refers to carbon-12 ( 12 C) and carbon-13 ( 13 Carbon-12 refers to a composition of naturally occurring carbon isotopes, including carbon-12, carbon-13, and carbon-14, carbon-15, carbon-16, carbon-17, carbon-18, carbon-19, carbon-20, carbon-21, carbon-22, carbon-23, carbon-24, carbon-25, carbon-26, carbon-27, carbon-28, carbon-29, carbon-30, carbon-31, carbon-32, carbon-33, carbon-34, carbon-35, carbon-36, carbon-37, carbon-38, carbon-39, carbon-40, carbon-41, carbon-42, carbon-43, carbon-44, carbon-45, carbon-46, carbon-47, carbon-48, carbon-49, carbon-50, carbon-51, carbon-52, carbon-53, carbon-54, carbon-55, carbon-56, carbon-57, carbon-58, carbon-

[0046] "Carbon-13 enrichment factor" or " 13The term "C enrichment" refers to the percentage of incorporation of carbon-13 in place of carbon at a given position in a molecule. For example, a carbon-13 enrichment of 10% at a given position means that 10% of the molecules in a given sample contain carbon-13 at that specified position. Because the natural distribution of carbon-13 averages about 1.11%, the carbon-13 enrichment at any position in a compound synthesized using non-enriched starting materials will average about 1.11%. As used herein, when a particular position in an isotopically enriched compound is designated as having carbon-13, it is understood that the abundance of carbon-13 at that position in the compound is substantially greater than its natural abundance (1.11%).

[0047] The terms "substantially pure" and "substantially homogeneous," when referring to a substance, mean sufficiently homogeneous to appear free of readily detectable impurities as determined by standard analytical methods used by those of skill in the art, including, but not limited to, thin layer chromatography (TLC), gel electrophoresis, high performance liquid chromatography (HPLC), gas chromatography (GC), nuclear magnetic resonance (NMR), and mass spectrometry (MS); or sufficiently pure that further purification would not detectably alter the physical, chemical, biological, and / or pharmacological properties of the substance, such as enzymatic activity and biological activity. In certain embodiments, "substantially pure" or "substantially homogeneous" refers to a population of molecules in which at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or at least about 99.5% by weight of the molecules are a single compound, such as a single enantiomer, a racemic mixture, or a mixture of enantiomers, as determined by standard analytical methods. As used herein, when an atom at a particular position in an isotopically enriched molecule is designated to be a particular less common isotope, molecules containing other than the designated isotope at that designated position are impurities with respect to that isotopically enriched compound. Thus, for a deuterated compound having an atom at a particular position designated to be deuterium, a compound containing protium at the same position is an impurity.

[0048] The term "solvate" refers to a complex or aggregate formed by one or more molecules of a solute, e.g., a compound provided herein, and one or more molecules of a solvent present in a stoichiometric or non-stoichiometric amount. Suitable solvents include, but are not limited to, water, methanol, ethanol, n-propanol, isopropanol, and acetic acid. In certain embodiments, the solvent is pharmaceutically acceptable. In one embodiment, the complex or aggregate is in a crystalline form. In another embodiment, the complex or aggregate is in a non-crystalline form. When the solvent is water, the solvate is a hydrate. Examples of hydrates include, but are not limited to, hemihydrate, monohydrate, dihydrate, trihydrate, tetrahydrate, and pentahydrate.

[0049] For divalent groups described herein, no orientation is implied by the direction in which the divalent group is depicted. For example, the formula -C(O)NH- represents both -C(O)NH- and -NHC(O)- unless a particular orientation is specified.

[0050] The phrase "an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof" has the same meaning as the phrase "(i) an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant of the compound referred to therein; (ii) a pharmaceutically acceptable salt, solvate, hydrate, or prodrug of the compound referred to therein; or (iii) a pharmaceutically acceptable salt, solvate, hydrate, or prodrug of an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant of the compound referred to therein."

[0051] (compound) In one embodiment, provided herein is a compound of formula (I): [ka] (In the formula, R 1 and R 5 are each independently (i) hydrogen; or (ii) —C(O)R 5a , -C(O)OR 5a , -C(O)NR 5b R 5c , or -L 2 -P(X)(OR 5a )(NR 5b R 5c ) where R 1 and R 5 At least one of the following is -L 2 -P(X)(OR 5a )(NR 5b R 5c ) and; R 2 is (i) hydrogen; (ii) C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) —C(O)R 1a , -C(O)OR 1a , -C(O)NR 1b R 1c , -C(O)SR 1a , -C(NR 1a )NR 1b R 1c , ‐C(S)R 1a , ‐C(S)OR 1a , ‐C(S)NR 1b R 1c , ‐S(O)R 1a , -S(O)2R 1a , -S(O)NR 1b R 1c , -S(O)2NR 1b R 1c , or -Si(R 1a)3; R 3 and R 4 are each independently: (i) halo; or (ii) -OR 5a , ‐OC(O)R 5a , ‐OC(O)OR 5a , or -OC(O)NR 5b R 5c or R 3 and R 4 Or R 4 and R 5 are bonded together to form a lactone ring; Each R 5a , R 5b , and R 5c are independently hydrogen, C 1-30 Alkyl, C 1-30 Heteroalkyl, C 2-30 Alkenyl, C 2-30 Alkynyl, C 3-30 Cycloalkyl, C 6-30 Aryl, C 7-30 aralkyl, heteroaryl, or heterocyclyl; A is a bond, O, or N(R 1b ) and; L 1 is C 1-6 Alkylene, C 1-6 Heteroalkylene, C 2-6 Alkenylene, C 2-6 Alkynylene, C 3-10 Cycloalkylene, C 6-14 Arylene, C 7-15 aralkylene, heteroarylene, or heterocyclylene; Each L 2 are independently (i) a bond; or (ii) -O-C 1-6 Alkylene, -O-C 1-6 Heteroalkylene, -O-C 2-6 Alkenylene, -O-C 2-6 Alkynylene, -O-C 3-10 Cycloalkylene, -O-C 6-14 Arylene, -O-C 7-15 aralkylene, -O-heteroarylene, or -O-heterocyclylene; each X is independently O or S; Z can be hydrogen, azido, halo, isocyano, -C=C(R 1a )R 1a , ‐C≡CR 1a , [ka] -C(O)R 1a or -SH; and Each R 1a , R 1b , and R 1c are independently hydrogen, deuterium, and C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl; wherein each alkyl, alkylene, heteroalkyl, heteroalkylene, alkenyl, alkenylene, alkynyl, alkynylene, cycloalkyl, cycloalkylene, aryl, arylene, aralkyl, aralkylene, heteroaryl, heteroarylene, heterocyclyl, and heterocyclylene is optionally substituted with one or more, and in one embodiment, one, two, three, or four, substituents Q, wherein each Q is independently: (a) deuterium, cyano, halo, nitro, and oxo; (b) one or more, and in one embodiment, one, two, three, or four, substituents Q a each optionally further substituted C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 aralkyl, heteroaryl, and heterocyclyl; and (c)—C(O)R a , -C(O)OR a , -C(O)NR b R c , -C(O)SR a , -C(NRa )NR b R c 、‐C(S)R a 、‐C(S)OR a 、‐C(S)NR b R c 、‐OR a 、‐OC(O)R a 、‐OC(O)OR a 、‐OC(O)NR b R c 、‐OC(O)SR a 、‐OC(NR a )NR b R c 、‐OC(S)R a 、‐OC(S)OR a 、‐OC(S)NR b R c 、‐OP(O)(OR b )OR c 、‐OS(O)R a 、‐OS(O)2R a 、‐OS(O)NR b R c 、‐OS(O)2NR b R c 、‐NR b R c 、‐NR a C(O)R d 、‐NR a C(O)OR d 、‐NR a C(O)NR b R c 、‐NR a C(O)SR d 、‐NR a C(NR d )NR b R c 、‐NR a C(S)R d 、‐NR a C(S)OR d 、‐NR a C(S)NR b R c 、‐NR a S(O)R d 、‐N=S(O)R a R d 、‐NR a S(O)2R d, ‐NR a S(O)NR b R c , ‐NR a S(O)NR b R c , ‐SR a , ‐S(O)R a , -S(O)2R a , -S(O)NR b R c , and -S(O)2NR b R c where each R a , R b , R c , and R d are independently (i) hydrogen or deuterium; (ii) one or more, in one embodiment, 1, 2, 3, or 4, substituents Q a C, each of which is arbitrarily substituted 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) R b and R c together with the N atom to which they are attached, one or more, in one embodiment 1, 2, 3, or 4, substituents Q a forming an optionally substituted heterocyclyl; Here, each Q a are independently: (a) deuterium, cyano, halo, nitro, and oxo; (b) C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 aralkyl, heteroaryl, and heterocyclyl; and (c)—C(O)R e , -C(O)OR e , -C(O)NR f R g , -C(O)SR e、‐C(NR e )NR f R g 、‐C(S)R e 、‐C(S)OR e 、‐C(S)NR f R g 、‐OR e 、‐OC(O)R e 、‐OC(O)OR e 、‐OC(O)NR f R g 、‐OC(O)SR e 、‐OC(NR e )NR f R g 、‐OC(S)R e 、‐OC(S)OR e 、‐OC(S)NR f R g 、‐OP(O)(OR f )OR g 、‐OS(O)R e 、‐OS(O)2R e 、‐OS(O)NR f R g 、‐OS(O)2NR f R g 、‐NR f R g 、‐NR e C(O)R h 、‐NR e C(O)OR f 、‐NR e C(O)NR f R g 、‐NR e C(O)SR f 、‐NR e C(NR h )NR f R g 、‐NR e C(S)R h 、‐NR e C(S)OR f 、‐NR e C(S)NR f R g 、‐NR e S(O)R h 、‐N=S(O)R e R h 、‐NR e S(O)2Rh , ‐NR e S(O)NR f R g , ‐NR e S(O)NR f R g , ‐SR e , ‐S(O)R e , -S(O)2R e , -S(O)NR f R g , and -S(O)2NR f R g where each R e , R f , R g , and R h are independently (i) hydrogen or deuterium; (ii) C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) R f and R g form a heterocyclyl together with the N atom to which they are attached) or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0052] In one embodiment, in formula (I), R 3 is halo. In certain embodiments, in formula (I), R 3 is fluoro. In certain embodiments, in formula (I), R 3 is -OR 5a (In the formula, R 5a is as defined herein. In some embodiments, in formula (I), R 3 is hydroxyl. In some embodiments, in formula (I), R 3 is -OC(O)R 5a(In the formula, R 5a is as defined herein. In some embodiments, in formula (I), R 3 is -OC(O)OR 5a (In the formula, R 5a is as defined herein. In some embodiments, in formula (I), R 3 is -OC(O)NR 5b R 5c (In the formula, R 5b and R 5c are each as defined herein).

[0053] In one embodiment, in formula (I), R 4 is halo. In certain embodiments, in formula (I), R 4 is fluoro. In certain embodiments, in formula (I), R 4 is -OR 5a (In the formula, R 5a is as defined herein. In some embodiments, in formula (I), R 4 is hydroxyl. In some embodiments, in formula (I), R 4 is -OC(O)R 5a (In the formula, R 5a is as defined herein. In some embodiments, in formula (I), R 4 is -OC(O)OR 5a (In the formula, R 5a is as defined herein. In some embodiments, in formula (I), R 4 is -OC(O)NR 5b R 5c (In the formula, R 5b and R 5c are each as defined herein).

[0054] In another embodiment, provided herein is a compound of formula (II): [ka] (In the formula, R 3a and R 4aare each independently R 5a , ‐C(O)R 5a , -C(O)OR 5a , or -C(O)NR 5b R 5c and R 1 , R 2 , R 5 , R 5a , R 5b , R 5c , A, L 1 and Z are each as defined herein. or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0055] In some embodiments, in Formula (I) or Formula (II), R 1 is (i) hydrogen; or (ii) -C(O)R 5a , -C(O)OR 5a , or -C(O)NR 5b R 5c and R 5 ,-L 2 -P(X)(OR 5a )(NR 5b R 5c ) where each R 5a , R 5b , R 5c , L 2 and X are as defined herein. In certain embodiments, in Formula (I) or Formula (II), R 1 is hydrogen or -C(O)R 5a and R 5 ,-L 2 -P(X)(OR 5a )(NR 5b R 5c ) where each R 5a , R 5b , R 5c , L 2and X are as defined herein. In certain embodiments, in Formula (I) or Formula (II), R 1 is hydrogen; and R 5 ,-L 2 -P(X)(OR 5a )(NR 5b R 5c ) where each R 5a , R 5b , R 5c , L 2 and X are as defined herein. In certain embodiments, in Formula (I) or Formula (II), R 1 is -C(O)R 5a and R 5 ,-L 2 -P(X)(OR 5a )(NR 5b R 5c ) where each R 5a , R 5b , R 5c , L 2 and X are as defined herein. In certain embodiments, in Formula (I) or Formula (II), R 1 is -C(O)OR 5a and R 5 ,-L 2 -P(X)(OR 5a )(NR 5b R 5c ) where each R 5a , R 5b , R 5c , L 2 and X are as defined herein. In certain embodiments, in Formula (I) or Formula (II), R 1 is -C(O)NR 5b R 5c and R 5 ,-L 2 -P(X)(OR 5a )(NR 5b R 5c ) where each R 5a , R 5b , R 5c , L 2 , and X are as defined herein.

[0056] In some embodiments, in Formula (I) or Formula (II), R 1 ,-L 2 -P(X)(OR 5a )(NR 5b R 5c ) and R 5 is (i) hydrogen; or (ii) -C(O)R 5a , -C(O)OR 5a , or -C(O)NR 5b R 5c where each R 5a , R 5b , R 5c , L 2 and X are as defined herein. In certain embodiments, in Formula (I) or Formula (II), R 1 ,-L 2 -P(X)(OR 5a )(NR 5b R 5c ) and R 5 is hydrogen or -C(O)R 5a where each R 5a , R 5b , R 5c , L 2 and X are as defined herein. In certain embodiments, in Formula (I) or Formula (II), R 1 ,-L 2 -P(X)(OR 5a )-(NR 5b R 5c ) and R 5 is hydrogen; where each R 5a , R 5b , R 5c , L 2 and X are as defined herein. In certain embodiments, in Formula (I) or Formula (II), R 1 ,-L 2 -P(X)(OR 5a )(NR 5b R 5c ) and R 5 is -C(O)R 5a where each R 5a , R 5b , R 5c , L2 and X are as defined herein. In certain embodiments, in Formula (I) or Formula (II), R 1 ,-L 2 -P(X)(OR 5a )(NR 5b R 5c ) and R 5 is -C(O)OR 5a where each R 5a , R 5b , R 5c , L 2 and X are as defined herein. In certain embodiments, in Formula (I) or Formula (II), R 1 ,-L 2 -P(X)-(OR 5a )(NR 5b R 5c ) and R 5 is -C(O)NR 5b R 5c where each R 5a , R 5b , R 5c , L 2 , and X are as defined herein.

[0057] In some embodiments, in Formula (I) or Formula (II), R 1are ((S)-1-isopropoxycarbonyl-ethylamino)(phenoxy)phosphoryl, ((S)-1-butoxycarbonylethylamino)(phenoxy)phosphoryl, ((1S)-1-sec-butoxycarbonylethylamino)(phenoxy)phosphoryl, ((S)-1-tert-butoxycarbonylethylamino)(phenoxy)phosphoryl, ((S)-1-pentoxycarbonylethylamino)(phenoxy)phosphoryl, ((S)-1-hexoxycarbonylethylamino)(phenoxy)phosphoryl, ((S) -1-(2-ethylbutoxy)carbonylethylamino)-(phenoxy)phosphoryl, ((1S)-1-(1-phenylethoxycarbonyl)ethylamino)(phenoxy)phosphoryl, ((S)-1-pyridin-3-ylmethoxycarbonylethylamino)(phenoxy)phosphoryl, ((S)-1-pyridin-4-ylmethoxy-carbonylethylamino)(phenoxy)phosphoryl, ((S)-1-quinolin-4-yl-methoxycarbonylethylamino)-(phenoxy)phosphoryl, ((S)-1-quinolin-5-yl methoxycarbonylethylamino)(phenoxy)phosphoryl, ((S)-1-(4-methyltetrahydropyran-4-yloxy)carbonylethylamino)(phenoxy)phosphoryl, ((S)-1-isopropoxycarbonylethylamino)(quinolin-5-yloxy)phosphoryl, 3-(((S)-1-isopropoxycarbonyl-ethylamino)(phenoxy)phosphoryloxy)propanoyl, (1-methyl-1-(1-phenylethoxycarbonyl)ethyl-amino)(phenoxy)phosphoryl, (1-methyl- 1-(1-methyl-1-phenylethoxycarbonyl)ethylamino)-(phenoxy)phosphoryl, ((1S)-1-(1-phenylethoxycarbonyl)-2-methylpropylamino)(phenoxy)phosphoryl, ((1S)-1-(1-(4-(tert-butoxycarbonylamino)phenyl)ethoxycarbonyl)-2-methylpropyl-amino)(phenoxy)phosphoryl, or ((1S)-1-(1-methyl-1-phenylethoxycarbonyl)-2-methylpropyl-amino)(phenoxy)phosphoryl.

[0058] In some embodiments, in Formula (I) or Formula (II), R 1 is (((R)-1-(benzyloxy)-3-methyl-1-oxobutan-2-yl)amino)(phenoxy)phosphoryl, (((S)-3-methyl-1-oxo-1-(1-phenyl-cyclopropoxy)butan-2-yl)amino)(phenoxy)phosphoryl, (((S)-1-oxo-1-((tetrahydro-2H-pyran-4-yl)oxy)propan-2-yl)amino)(phenoxy)phosphoryl, (((S)-1-((1-methylpiperidin-4-yl)oxy)-1-oxo-propan-2-yl)amino)(phenoxy)phosphoryl, or (((S)-1-oxo-1-(pentyloxy)propan-2-yl)-amino)-(quinolin-5-yloxy)phosphoryl.

[0059] In some embodiments, in Formula (I) or Formula (II), R 5are ((S)-1-isopropoxycarbonyl-ethylamino)(phenoxy)phosphoryl, ((S)-1-butoxycarbonylethylamino)(phenoxy)phosphoryl, ((1S)-1-sec-butoxycarbonylethylamino)(phenoxy)phosphoryl, ((S)-1-tert-butoxycarbonylethylamino)(phenoxy)phosphoryl, ((S)-1-pentoxycarbonylethylamino)(phenoxy)phosphoryl, ((S)-1-hexoxycarbonylethylamino)(phenoxy)phosphoryl, ((S) -1-(2-ethylbutoxy)carbonylethylamino)-(phenoxy)phosphoryl, ((1S)-1-(1-phenylethoxycarbonyl)ethylamino)(phenoxy)phosphoryl, ((S)-1-pyridin-3-ylmethoxycarbonylethylamino)(phenoxy)phosphoryl, ((S)-1-pyridin-4-ylmethoxy-carbonylethylamino)(phenoxy)phosphoryl, ((S)-1-quinolin-4-yl-methoxycarbonylethylamino)-(phenoxy)phosphoryl, ((S)-1-quinolin-5-yl methoxycarbonylethylamino)(phenoxy)phosphoryl, ((S)-1-(4-methyltetrahydropyran-4-yloxy)carbonylethylamino)(phenoxy)phosphoryl, ((S)-1-isopropoxycarbonylethylamino)(quinolin-5-yloxy)phosphoryl, 3-(((S)-1-isopropoxycarbonyl-ethylamino)(phenoxy)phosphoryloxy)propanoyl, (1-methyl-1-(1-phenylethoxycarbonyl)ethyl-amino)(phenoxy)phosphoryl, (1-methyl- 1-(1-methyl-1-phenylethoxycarbonyl)ethylamino)-(phenoxy)phosphoryl, ((1S)-1-(1-phenylethoxycarbonyl)-2-methylpropylamino)(phenoxy)phosphoryl, ((1S)-1-(1-(4-(tert-butoxycarbonylamino)phenyl)ethoxycarbonyl)-2-methylpropyl-amino)(phenoxy)phosphoryl, or ((1S)-1-(1-methyl-1-phenylethoxycarbonyl)-2-methylpropyl-amino)(phenoxy)phosphoryl.

[0060] In some embodiments, in Formula (I) or Formula (II), R 5 is (((R)-1-(benzyloxy)-3-methyl-1-oxobutan-2-yl)amino)(phenoxy)phosphoryl, (((S)-3-methyl-1-oxo-1-(1-phenyl-cyclopropoxy)butan-2-yl)amino)(phenoxy)phosphoryl, (((S)-1-oxo-1-((tetrahydro-2H-pyran-4-yl)oxy)propan-2-yl)amino)(phenoxy)phosphoryl, (((S)-1-((1-methylpiperidin-4-yl)oxy)-1-oxo-propan-2-yl)amino)(phenoxy)phosphoryl, or (((S)-1-oxo-1-(pentyloxy)propan-2-yl)-amino)-(quinolin-5-yloxy)phosphoryl.

[0061] In yet another embodiment, provided herein is a compound of formula (III): [ka] (In the formula, R 1 , R 2 , R 3a , R 4a , R 5a , R 5b , R 5c , A, L 1 , L 2 , X, and Z are each as defined herein. or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0062] In yet another embodiment, provided herein is a compound of formula (IV): [ka] (In the formula, R 2 , R 5 , R 3a , R4a , R 5a , R 5b , R 5c , A, L 1 , L 2 , X, and Z are each as defined herein. or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0063] In one embodiment, in any of Formulas (I) to (IV), R 5c is a C optionally substituted with one or more substituents Q 1-10 Alkyl or C 7-15 In one embodiment, in any of Formulas (I) to (IV), R 5c is C optionally substituted with one or more substituents Q 1-10 In one embodiment, in any of Formulas (I) to (IV), R 5c is methyl, ethyl, propyl, butyl, pentyl, or hexyl, each optionally substituted with one or more substituents Q. In certain embodiments, in any of Formulas (I) through (IV), R 5c is C optionally substituted with one or more substituents Q 7-15 In one embodiment, in any of Formulas (I) to (IV), R 5care 1-isopropoxycarbonylethyl, 1-butoxycarbonylethyl, 1-tert-butoxycarbonylethyl, 1-(1-phenylethoxycarbonyl)ethyl, 1-methyl-1-(1-phenylethoxycarbonyl)ethyl, 1-sec-butoxycarbonylethyl, 1-pentoxycarbonylethyl, 1-hexoxycarbonylethyl, 1-(2-ethylbutoxy)carbonylethyl, 1-pyridin-3-ylmethoxycarbonylethyl, 1-pyridin-4-ylmethoxycarbonylethyl, In certain embodiments, in any of Formulas (I) to (IV), R 5c is 1-isopropoxycarbonylethyl. In certain embodiments, in any of Formulas (I) to (IV), R 5c is 1-((tetrahydropyran-4-yl)oxycarbonyl)ethyl, 1-(benzyloxycarbonyl)-2-methylpropyl, 1-(phenyl-cyclopropoxycarbonyl)-2-methylpropyl, or 1-((1-methylpiperidin-4-yl)oxycarbonyl)-2-methyl-propyl.

[0064] In yet another embodiment, provided herein is a compound of formula (V): [ka] (In the formula, R 6a is a C optionally substituted with one or more substituents Q 1-30 Alkyl, C 1-30 Heteroalkyl, C 2-30 Alkenyl, C 2-30 Alkynyl, C 3-30 Cycloalkyl, C6-30 Aryl, C 7-30 aralkyl, heteroaryl, and heterocyclyl; R 6b and R 6c are each independently (i) hydrogen or deuterium; or (ii) C, each optionally substituted with one or more substituents Q. 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 aralkyl, heteroaryl, and heterocyclyl; or R 6b and R 6c together with the carbon atoms to which they are attached, represent C optionally substituted with one or more substituents Q 3-10 forming a cycloalkylene; and R 1 , R 2 , R 3a , R 4a , R 5a , R 5b , A, L 1 , L 2 , X, and Z are each as defined herein. or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0065] In yet another embodiment, provided herein is a compound of formula (VI): [ka] (In the formula, R 2 , R 5 , R 3a , R 4a , R 5a , R 5b , R 6a , R 6b , R 6c, A, L 1 , L 2 , X, and Z are each as defined herein. or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0066] In one embodiment, in any of Formulas (I) to (VI), each L 2 are independently a bond or —O—C optionally substituted with one or more substituents Q 1-6 In one embodiment, in any of Formulas (I) to (VI), L 2 is a bond. In one embodiment, in any of Formulas (I) to (VI), each L 2 are independently —O—C optionally substituted with one or more substituents Q 1-6 In one embodiment, in any of Formulas (I) to (VI), each L 2 are independently -OCH2CH2C(O)-.

[0067] In yet another embodiment, provided herein is a compound of formula (VII): [ka] (In the formula, R 1 , R 2 , R 3a , R 4a , R 5a , R 5b , R 6a , R 6b , R 6c , A, L 1 , X, and Z are each as defined herein. or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0068] In yet another embodiment, provided herein is a compound of formula (VIII): [ka] (In the formula, R 1 , R 2 , R 3a , R 4a , R 5a , R 5b , R 6a , R 6b , R 6c , A, L 1 , X, and Z are each as defined herein. or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0069] In yet another embodiment, provided herein is a compound of formula (IX): [ka] (In the formula, R 1 , R 2 , R 3 , R 4 , R 5a , R 5b , R 6a , R 6b , R 6c , A, L 1 and X are each as defined herein. or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0070] In some embodiments, in any of Formulas (I) to (III), Formula (V), and Formulas (VII) to (IX), R 1 is hydrogen or -C(O)R 5a (In the formula, R 5a is as defined herein. In certain embodiments, in any of Formulas (I) to (III), Formula (V), and Formulas (VII) to (IX), R 1 In some embodiments, in any of Formulas (I) to (III), Formula (V), and Formulas (VII) to (IX), R 1 is -C(O)R 5a (In the formula, R 5a is as defined herein. In certain embodiments, in any of Formulas (I) to (III), Formula (V), and Formulas (VII) to (IX), R 1 is -C(O)R 5a (In the formula, R 5a is a C optionally substituted with one or more substituents Q 1-10 Alkyl, C 6-14 In some embodiments, in any of Formulas (I) to (III), Formula (V), and Formulas (VII) to (IX), R 1 is -C(O)R 5a (In the formula, R 5a is C optionally substituted with one or more substituents Q 1-10 In some embodiments, in any of Formulas (I) to (III), Formula (V), and Formulas (VII) to (IX), R 1 is acetyl, propanoyl, butanoyl, pentanoyl, hexanoyl, heptanoyl, octanoyl, nonanoyl, or decanoyl, each optionally substituted with one or more substituents Q.

[0071] In some embodiments, in any of Formulas (I) to (III), Formula (V), and Formulas (VII) to (IX), R 1 is -C(O)R 5a (In the formula, R 5a is C optionally substituted with one or more substituents Q 6-14 In some embodiments, in any of Formulas (I) to (III), Formula (V), and Formulas (VII) to (IX), R 1 is benzoyl optionally substituted with one or more substituents Q.

[0072] In some embodiments, in any of Formulas (I) to (III), Formula (V), and Formulas (VII) to (IX), R 1 is -C(O)R 5a (In the formula, R 5a is heteroaryl optionally substituted with one or more substituents Q. In certain embodiments, in any of Formulas (I) to (III), Formula (V), and Formulas (VII) to (IX), R 1 is -C(O)R 5a (In the formula, R 5a is monocyclic heteroaryl optionally substituted with one or more substituents Q. In certain embodiments, in any of Formulas (I) to (III), Formula (V), and Formulas (VII) to (IX), R 1 is -C(O)R 5a (In the formula, R 5a is 5- or 6-membered heteroaryl, each optionally substituted with one or more substituents Q. In certain embodiments, in any of Formulas (I) to (III), Formula (V), and Formulas (VII) to (IX), R 1 is -C(O)R 5a (In the formula, R 5a is a 5-membered heteroaryl optionally substituted with one or more substituents Q. In certain embodiments, in any of Formulas (I) to (III), Formula (V), and Formulas (VII) to (IX), R 1 is -C(O)R 5a (In the formula, R5a is a 6-membered heteroaryl optionally substituted with one or more substituents Q. In certain embodiments, in any of Formulas (I) to (III), Formula (V), and Formulas (VII) to (IX), R 1 is pyrrolylcarbonyl or pyridinylcarbonyl, each optionally substituted with one or more substituents Q.

[0073] In some embodiments, in any of Formulas (I) to (III), Formula (V), and Formulas (VII) to (IX), R 1 is -C(O)R 5a (In the formula, R 5a is heterocyclyl optionally substituted with one or more substituents Q. In certain embodiments, in any of Formulas (I) to (III), Formula (V), and Formulas (VII) to (IX), R 1 is -C(O)R 5a (In the formula, R 5a is monocyclic heterocyclyl optionally substituted with one or more substituents Q. In certain embodiments, in any of Formulas (I) to (III), Formula (V), and Formulas (VII) to (IX), R 1 is -C(O)R 5a (In the formula, R 5a is a 3-, 4-, 5-, 6-, or 7-membered heterocyclyl, each optionally substituted with one or more substituents Q. In certain embodiments, in any of Formulas (I) through (III), Formula (V), and Formulas (VII) through (IX), R 1 is -C(O)R 5a (In the formula, R 5a is a 3-membered heterocyclyl optionally substituted with one or more substituents Q. In certain embodiments, in any of Formulas (I) to (III), Formula (V), and Formulas (VII) to (IX), R 1 is -C(O)R 5a (In the formula, R 5a is a 4-membered heterocyclyl optionally substituted with one or more substituents Q. In certain embodiments, in any of Formulas (I) to (III), Formula (V), and Formulas (VII) to (IX), R 1is -C(O)R 5a (In the formula, R 5a is a 5-membered heterocyclyl optionally substituted with one or more substituents Q. In certain embodiments, in any of Formulas (I) to (III), Formula (V), and Formulas (VII) to (IX), R 1 is -C(O)R 5a (In the formula, R 5a is a 6-membered heterocyclyl optionally substituted with one or more substituents Q. In certain embodiments, in any of Formulas (I) to (III), Formula (V), and Formulas (VII) to (IX), R 1 is -C(O)R 5a (In the formula, R 5a is 7-membered heterocyclyl optionally substituted with one or more substituents Q. In certain embodiments, in any of Formulas (I) to (III), Formula (V), and Formulas (VII) to (IX), R 1 is tetrahydropyranylcarbonyl or piperidinylcarbonyl, each optionally substituted with one or more substituents Q.

[0074] In some embodiments, in any of Formulas (I) to (III), Formula (V), and Formulas (VII) to (IX), R 1 is acetyl, propanoyl, butanoyl, pentanoyl, hexanoyl, heptanoyl, octanoyl, nonanoyl, decanoyl, benzoyl, pyrrolylcarbonyl, pyridinylcarbonyl, tetrahydropyranylcarbonyl, or piperidinylcarbonyl, each of which is optionally substituted with one or more substituents Q. In certain embodiments, in any of Formulas (I) to (III), Formula (V), and Formulas (VII) to (IX), R 1is acetyl, propanoyl, butanoyl, pentanoyl, hexanoyl, nonanoyl, benzoyl, pyrrol-2-ylcarbonyl, pyridin-3-ylcarbonyl, tetrahydropyran-4-yl-carbonyl, or piperidin-4-ylcarbonyl, each of which is optionally substituted with one or two substituents, each of which is independently methyl, pyridin-3-yl, pyrrolidin-1-yl, morpholino, 4-methyl-piperazin-1-yl, 4-acetylpiperazin-1-yl, or 4-dimethylamino. In certain embodiments, in any of Formulas (I) to (III), Formula (V), and Formulas (VII) to (IX), R 1 is acetyl, pyridin-3-ylacetyl, pyrrolidin-1-ylacetyl, 3-morpholinopropanoyl, 4-methylpiperazin-1-ylpropanoyl, 4-acetylpiperazin-1-ylpropanoyl, 2-methylbutanoyl, pentanoyl, hexanoyl, nonanoyl, 4-dimethylaminobenzoyl, pyrrol-2-ylcarbonyl, pyridin-3-ylcarbonyl, tetrahydropyran-4-ylcarbonyl, or 1-methylpiperidin-4-ylcarbonyl. In certain embodiments, in any of Formulas (I) to (III), Formula (V), and Formulas (VII) to (IX), R 1 is acetyl, propanoyl, or butanoyl. In certain embodiments, in any of Formulas (I) to (III), Formula (V), and Formulas (VII) to (IX), R 1 In some embodiments, in any of Formulas (I) to (III), Formula (V), and Formulas (VII) to (IX), R 1 is pivaloyl, 3-(morpholinomethyl)benzoyl, 3-((4-methylpiperazin-1-yl)methyl)benzoyl, 3-morpholinobenzoyl, or 3-(4-methylpiperazin-1-yl)benzoyl.

[0075] In yet another embodiment, provided herein is a compound of formula (X): [ka] (In the formula, R2 , R 5 , R 3a , R 4a , R 5a , R 5b , R 6a , R 6b , R 6c , A, L 1 , X, and Z are each as defined herein. or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0076] In yet another embodiment, provided herein is a compound of formula (XI): [ka] (In the formula, R 2 , R 5 , R 3a , R 4a , R 5a , R 5b , R 6a , R 6b , R 6c , A, L 1 , X, and Z are each as defined herein. or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0077] In yet another embodiment, provided herein is a compound of formula (XII): [ka] (In the formula, R 2 , R 5 , R 3a , R 4a , R5a , R 5b , R 6a , R 6b , R 6c , A, L 1 , X, and Z are each as defined herein. or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0078] In one embodiment, in any of Formulas (I) to (XII), R 2 is hydrogen.

[0079] In some embodiments, in any of Formula (I), Formula (II), Formula (IV), Formula (VI), and Formulas (X) to (XII), R 5 is hydrogen or -C(O)R 5a (In the formula, R 5a is as defined herein. In certain embodiments, in any of Formula (I), Formula (II), Formula (IV), Formula (VI), and Formulas (X) to (XII), R 5 In some embodiments, in any of Formula (I), Formula (II), Formula (IV), Formula (VI), and Formulas (X) to (XII), R 5 is -C(O)R 5a (In the formula, R 5a is as defined herein. In certain embodiments, in any of Formula (I), Formula (II), Formula (IV), Formula (VI), and Formulas (X) to (XII), R 5 is —C(O)—C optionally substituted with one or more substituents Q 1-6 In some embodiments, in any of Formulas (I) to (XI), R 4 is hydrogen, acetyl, propanoyl, or butanoyl. In certain embodiments, in any of Formula (I), Formula (II), Formula (IV), Formula (VI), and Formulas (X) to (XII), R 5is acetyl.

[0080] In one embodiment, in any of Formulas (II) to (XII), R 3a is hydrogen or -C(O)R 5a (In the formula, R 5a is as defined herein. In certain embodiments, in any of Formulas (II) to (XII), R 3a is hydrogen. In one embodiment, in any of Formulas (II) to (XII), R 3a is -C(O)R 5a (In the formula, R 5a is as defined herein. In certain embodiments, in any of Formulas (II) to (XII), R 3a is —C(O)—C optionally substituted with one or more substituents Q 1-6 In one embodiment, in any of Formulas (II) to (XII), R 3a is acetyl, propanoyl, or butanoyl. In certain embodiments, in any of Formulas (II) to (XII), R 3a is acetyl.

[0081] In one embodiment, in any of Formulas (II) to (XII), R 4a is hydrogen or -C(O)R 5a (In the formula, R 5a is as defined herein. In certain embodiments, in any of Formulas (II) to (XII), R 4a is hydrogen. In one embodiment, in any of Formulas (II) to (XII), R 4a is -C(O)R 5a (In the formula, R 5a is as defined herein. In certain embodiments, in any of Formulas (II) to (XII), R 4a is —C(O)—C optionally substituted with one or more substituents Q 1-6 In one embodiment, in any of Formulas (II) to (XII), R4a is acetyl, propanoyl, or butanoyl. In certain embodiments, in any of Formulas (II) to (XII), R 4a is acetyl.

[0082] In one embodiment, in any of Formulas (I) to (XII), R 5a is a C optionally substituted with one or more substituents Q 6-14 In one embodiment, in any of Formulas (I) to (XII), R 5a is C optionally substituted with one or more substituents Q 6-14 In one embodiment, in any of Formulas (I) to (XII), R 5a is phenyl optionally substituted with one or more substituents Q. In certain embodiments, in any of Formulas (I) to (XII), R 5a is heteroaryl optionally substituted with one or more substituents Q. In certain embodiments, in any of Formulas (I) to (XII), R 5a is a bicyclic heteroaryl optionally substituted with one or more substituents Q. In certain embodiments, in any of Formulas (I) to (XII), R 5a is 5,5-, 5,6-, or 6,6-fused heteroaryl, each optionally substituted with one or more substituents Q. In certain embodiments, in any of Formulas (I) through (XII), R 5a is a 5,5-fused heteroaryl optionally substituted with one or more substituents Q. In certain embodiments, in any of Formulas (I) to (XII), R 5a is a 5,6-fused heteroaryl optionally substituted with one or more substituents Q. In certain embodiments, in any of Formulas (I) to (XII), R 5a is a 6,6-fused heteroaryl optionally substituted with one or more substituents Q. In certain embodiments, in any of Formulas (I) to (XII), R 5ais phenyl or quinolin-5-yl. In certain embodiments, in any of Formulas (I) to (XII), R 5a is phenyl.

[0083] In one embodiment, in any of Formulas (I) to (XII), R 5b is hydrogen.

[0084] In one embodiment, in any of Formulas (V) to (XII), R 6a is a C optionally substituted with one or more substituents Q 1-6 Alkyl, C 3-10 Cycloalkyl, C 7-15 In some embodiments, in any of Formulas (V) to (XII), R 6a is a C optionally substituted with one or more substituents Q 1-6 Alkyl or C 7-15 In one embodiment, in any of Formulas (V) to (XII), R 6a is C optionally substituted with one or more substituents Q 1-6 In some embodiments, in any of Formulas (V) to (XII), R 6a is C optionally substituted with one or more substituents Q 1-6 In some embodiments, in any of Formulas (V) to (XII), R 6a is C optionally substituted with one or more substituents Q 1-6 alkylene-(monocyclic heteroaryl). In some embodiments, in any of Formulas (V) to (XII), R 6a is a C optionally substituted with one or more substituents Q 1-6 alkylene-(5- or 6-membered heteroaryl). In some embodiments, in any of Formulas (V) to (XII), R 6a is C optionally substituted with one or more substituents Q 1-6 In some embodiments, in any of Formulas (V) to (XII), R6a is C optionally substituted with one or more substituents Q 1-6 alkylene-(bicyclic heteroaryl). In some embodiments, in any of Formulas (V) to (XII), R 6a is a C optionally substituted with one or more substituents Q 1-6 In some embodiments, in any of Formulas (V) to (XII), R 6a is C optionally substituted with one or more substituents Q 1-6 In some embodiments, in any of Formulas (V) to (XII), R 6a is propyl, butyl, pentyl, or hexyl, each optionally substituted with one or more substituents Q. In certain embodiments, in any of Formulas (V) through (XII), R 6a is C optionally substituted with one or more substituents Q 7-15 In one embodiment, in any of Formulas (V) to (XII), R 6a is a monocyclic C optionally substituted with one or more substituents Q 7-15 In one embodiment, in any of Formulas (V) to (XII), R 6a is isopropyl, butyl, 2-butyl, tert-butyl, pentyl, hexyl, 2-ethylbutyl, 1-phenylethyl, 2-phenylprop-2-yl, pyridin-3-ylmethyl, pyridin-4-ylmethyl, quinolin-4-ylmethyl, or quinolin-5-ylmethyl. In certain embodiments, in any of Formulas (V) to (XII), R 6a is isopropyl.

[0085] In one embodiment, in any of Formulas (V) to (XII), R 6a is C optionally substituted with one or more substituents Q 3-10 In some embodiments, in any of Formulas (V) to (XII), R 6ais a monocyclic C optionally substituted with one or more substituents Q 3-10 In some embodiments, in any of Formulas (V) to (XII), R 6a is heterocyclyl optionally substituted with one or more substituents Q. In certain embodiments, in any of Formulas (V) through (XII), R 6a is monocyclic heterocyclyl optionally substituted with one or more substituents Q. In certain embodiments, in any of Formulas (V) to (XII), R 6a is a 3-, 4-, 5-, 6-, or 7-membered heterocyclyl, each optionally substituted with one or more substituents Q. In certain embodiments, in any of Formulas (V) through (XII), R 6a is a 6-membered heterocyclyl optionally substituted with one or more substituents Q. In certain embodiments, in Formula (I) or Formula (II), R 6a is 1-phenylcyclopropyl, benzyl, tetrahydropyran-4-yl, or 1-methyl-piperidin-4-yl.

[0086] In one embodiment, in any of Formulas (V) to (XII), R 6b is C optionally substituted with one or more substituents Q 1-6 In some embodiments, in any of Formulas (V) to (XII), R 6a is methyl or isopropyl.

[0087] In one embodiment, in any of Formulas (V) to (XII), R 6c is hydrogen or C optionally substituted with one or more substituents Q 1-6 In some embodiments, in any of Formulas (V) to (XII), R 6c is hydrogen or methyl. In one embodiment, in any of Formulas (V) to (XII), R 6c is hydrogen. In one embodiment, in any of Formulas (V) to (XII), R 6c is methyl.

[0088] In one embodiment, in any of Formulas (V) to (XII), R 6b and R 6c together with the carbon atoms to which they are attached, represent C optionally substituted with one or more substituents Q 3-10 In one embodiment, in any of Formulas (V) to (XII), R 6b and R 6c together with the carbon atoms to which they are attached, form a monocyclic C 3-10 In one embodiment, in any of Formulas (V) to (XII), R 6b and R 6c together with the carbon atoms to which they are attached form cyclopropane-1,1-diyl, cyclobutene-1,1-diyl, cyclopentane-1,1-diyl, or cyclohexane-1,1-diyl, each optionally substituted with one or more substituents Q.

[0089] In certain embodiments, in any of Formulas (I) to (XII), A is a bond or O. In certain embodiments, in any of Formulas (I) to (XII), A is a bond. In certain embodiments, in any of Formulas (I) to (XII), A is O.

[0090] In one embodiment, in any of Formulas (I) to (XII), L 1 is C optionally substituted with one or more substituents Q 1-6 In one embodiment, in any of Formulas (I) to (XII), L 1 is methanediyl, ethane-1,2-diyl, propane-1,2-diyl, or butane-1,4-diyl, each of which is optionally substituted with one or more substituents Q. In certain embodiments, in any of Formulas (I) to (XII), L 1 is methanediyl.

[0091] In certain embodiments, in any of Formulas (I) to (XII), X is O.

[0092] In certain embodiments, in any of Formulas (I) to (XII), Z is selected from azido, fluoro, iodo, isocyano, —C═CH, —C≡CH, [ka] In certain embodiments, in any of Formulas (I) to (XII), Z is azide (-N).

[0093] In certain embodiments, in any of Formulas (I) to (XII), A is a bond and Z is azide. In certain embodiments, in Formula (I), A is a bond and Z is azide. In certain embodiments, in Formula (II), A is a bond and Z is azide. In certain embodiments, in Formula (III), A is a bond and Z is azide. In certain embodiments, in Formula (IV), A is a bond and Z is azide. In certain embodiments, in Formula (V), A is a bond and Z is azide. In certain embodiments, in Formula (VI), A is a bond and Z is azide. In certain embodiments, in Formula (VII), A is a bond and Z is azide. In certain embodiments, in Formula (VIII), A is a bond and Z is azide. In some embodiments, in Formula (IX), A is a bond and Z is azide. In some embodiments, in Formula (X), A is a bond and Z is azide. In some embodiments, in Formula (XI), A is a bond and Z is azide. In some embodiments, in Formula (XII), A is a bond and Z is azide.

[0094] The group R in the formulae described herein, including formulae (I) to (XII), 1 , R 2 , R 3 , R 4 , R 5 , R 3a , R 4a , R 5a , R 5b, R 5c , R 6a , R 6b , R 6c , A, L 1 , L 2 , X, and Z are further defined in the embodiments described herein. All combinations of the embodiments provided herein for such groups are within the scope of the present disclosure.

[0095] In some embodiments, R 1 is hydrogen. In certain embodiments, R 1 is -C(O)R 5a (In the formula, R 5a is as defined herein. In certain embodiments, R 1 is —C(O)—C optionally substituted with one or more substituents Q 1-30 In some embodiments, R 1 is —C(O)—C optionally substituted with one or more substituents Q 1-20 In some embodiments, R 1 is —C(O)—C optionally substituted with one or more substituents Q 1-10 In some embodiments, R 1 is —C(O)—C optionally substituted with one or more substituents Q 1-6 In some embodiments, R 1 is —C(O)—C optionally substituted with one or more substituents Q 1-10 In some embodiments, R 1 is —C(O)—C optionally substituted with one or more substituents Q 1-10 alkylene-(monocyclic heteroaryl). In certain embodiments, R 1 is —C(O)—C, each optionally substituted with one or more substituents Q 1-10 alkylene-(5- or 6-membered heteroaryl). In certain embodiments, R 1 is —C(O)—C optionally substituted with one or more substituents Q 1-10 alkylene-(5-membered heteroaryl). In certain embodiments, R 1is —C(O)—C optionally substituted with one or more substituents Q 1-10 alkylene-(6-membered heteroaryl). In certain embodiments, R 1 is —C(O)—C optionally substituted with one or more substituents Q 1-10 alkylene-(bicyclic heteroaryl). In certain embodiments, R 1 is —C(O)—C, each optionally substituted with one or more substituents Q 1-10 alkylene-(5,5-, 5,6-, or 6,6-heteroaryl). In certain embodiments, R 1 is —C(O)—C optionally substituted with one or more substituents Q 1-10 alkylene-(5,5-heteroaryl). In some embodiments, R 1 is —C(O)—C optionally substituted with one or more substituents Q 1-10 alkylene-(5,6-heteroaryl). In some embodiments, R 1 is optionally substituted with one or more substituents Q. 1-10 It is alkylene-(6,6-heteroaryl).

[0096] In some embodiments, R 1 is —C(O)—C optionally substituted with one or more substituents Q 1-10 In certain embodiments, R 1 is —C(O)—C optionally substituted with one or more substituents Q 1-10 alkylene-(monocyclic heterocyclyl). In certain embodiments, R 1 is —C(O)—C, each optionally substituted with one or more substituents Q 1-10 alkylene-(3-, 4-, 5-, 6-, or 7-membered heterocyclyl). In certain embodiments, R 1 is —C(O)—C optionally substituted with one or more substituents Q 1-10 alkylene-(3-membered heterocyclyl). In certain embodiments, R 1 is —C(O)—C optionally substituted with one or more substituents Q 1-10alkylene-(4-membered heterocyclyl). In certain embodiments, R 1 is —C(O)—C optionally substituted with one or more substituents Q 1-10 alkylene-(5-membered heterocyclyl). In certain embodiments, R 1 is —C(O)—C optionally substituted with one or more substituents Q 1-10 alkylene-(6-membered heterocyclyl). In certain embodiments, R 1 is —C(O)—C optionally substituted with one or more substituents Q 1-10 alkylene-(7-membered heterocyclyl). In certain embodiments, R 1 is pyrrolidin-1-ylacetyl, 3-morpholinopropanoyl, 4-methylpiperazin-1-ylpropanoyl, or 4-acetylpiperazin-1-ylpropanoyl. 1 is —C(O)—C optionally substituted with one or more substituents Q 1-10 alkylene-(bicyclic heterocyclyl). In certain embodiments, R 1 is —C(O)—C, each optionally substituted with one or more substituents Q 1-10 alkylene-(bridged, fused, or spiroheterocyclyl). In certain embodiments, R 1 is —C(O)—C optionally substituted with one or more substituents Q 1-10 alkylene-(bridged heterocyclyl). In certain embodiments, R 1 is —C(O)—C optionally substituted with one or more substituents Q 1-10 alkylene-(fused heterocyclyl). In certain embodiments, R 1 is —C(O)—C optionally substituted with one or more substituents Q 1-10 It is alkylene-(spiroheterocyclyl).

[0097] In some embodiments, R 1 is acetyl, propanoyl, butanoyl, pentanoyl, hexanoyl, heptanoyl, octanoyl, nonanoyl, or decanoyl, each optionally substituted with one or more substituents Q. In certain embodiments, R1 is acetyl or propanoyl, each optionally substituted with one or more substituents Q. In certain embodiments, R 1 is one or more substituents Q a In certain embodiments, R is acetyl or propanoyl, each optionally substituted with 5- or 6-membered heteroaryl or 5- or 6-membered heterocyclyl, each further substituted with 1 is acetyl or propanoyl, each optionally substituted with pyridin-3-yl, pyrrolidin-1-yl, morpholino, 4-methylpiperazin-1-yl, or 4-acetylpiperazin-1-yl. 1 is acetyl or pivaloyl.

[0098] In some embodiments, R 1 is —C(O)—C optionally substituted with one or more substituents Q 1-10 In some embodiments, R 1 is —C(O)—C optionally substituted with one or more substituents Q 2-10 In some embodiments, R 1 is —C(O)—C optionally substituted with one or more substituents Q 2-10 In certain embodiments, R 1 is —C(O)—C optionally substituted with one or more substituents Q 3-10 In certain embodiments, R 1 is —C(O)—C optionally substituted with one or more substituents Q 6-14 In some embodiments, R 1 is benzoyl optionally substituted with one or more substituents Q. In certain embodiments, R 1 is 4-dimethylaminobenzoyl. In certain embodiments, R 1 is 3-(morpholino-methyl)benzoyl, 3-((4-methylpiperazin-1-yl)methyl)benzoyl, 3-morpholinobenzoyl, or 3-(4-methylpiperazin-1-yl)benzoyl. In certain embodiments, R 1is -C(O)-(bicyclic C) optionally substituted with one or more substituents Q 8-14 aryl). In some embodiments, R 1 is —C(O)—C optionally substituted with one or more substituents Q 7-15 It is aralkyl.

[0099] In some embodiments, R 1 is —C(O)-heteroaryl optionally substituted with one or more substituents Q. In certain embodiments, R 1 is —C(O)-(monocyclic heteroaryl) optionally substituted with one or more substituents Q. In certain embodiments, R 1 is —C(O)—(5- or 6-membered heteroaryl), each optionally substituted with one or more substituents Q. In certain embodiments, R 1 is —C(O)—(5-membered heteroaryl) optionally substituted with one or more substituents Q. In certain embodiments, R 1 is —C(O)-(6-membered heteroaryl) optionally substituted with one or more substituents Q. In certain embodiments, R 1 is pyrrolylcarbonyl or pyridinylcarbonyl, each optionally substituted with one or more substituents Q. In certain embodiments, R 1 is pyrrol-2-ylcarbonyl or pyridin-3-ylcarbonyl, each optionally substituted with one or more substituents Q. In certain embodiments, R 1 is —C(O)-(bicyclic heteroaryl) optionally substituted with one or more substituents Q. In certain embodiments, R 1 is —C(O)—(5,5-, 5,6-, or 6,6-fused heteroaryl), each optionally substituted with one or more substituents Q. In certain embodiments, R 1 is —C(O)-(5,5-fused heteroaryl) optionally substituted with one or more substituents Q. In certain embodiments, R 1 is —C(O)-(5,6-fused heteroaryl) optionally substituted with one or more substituents Q. In certain embodiments, R 1is —C(O)-(6,6-fused heteroaryl) optionally substituted with one or more substituents Q.

[0100] In some embodiments, R 1 is —C(O)-heterocyclyl optionally substituted with one or more substituents Q. In certain embodiments, R 1 is —C(O)-monocyclic heterocyclyl optionally substituted with one or more substituents Q. In certain embodiments, R 1 is —C(O)—(3-, 4-, 5-, 6-, or 7-membered heterocyclyl), each optionally substituted with one or more substituents Q. In certain embodiments, R 1 is —C(O)-(3-membered heterocyclyl) optionally substituted with one or more substituents Q. In certain embodiments, R 1 is —C(O)-(4-membered heterocyclyl) optionally substituted with one or more substituents Q. In certain embodiments, R 1 is —C(O)-(5-membered heterocyclyl) optionally substituted with one or more substituents Q. In certain embodiments, R 1 is —C(O)-(6-membered heterocyclyl) optionally substituted with one or more substituents Q. In certain embodiments, R 1 is tetrahydropyranylcarbonyl, piperidinyl-carbonyl, or piperazinylcarbonyl, each optionally substituted with one or more substituents Q. In certain embodiments, R 1 is tetrahydropyran-4-ylcarbonyl or piperidin-4-ylcarbonyl, each optionally substituted with one or more substituents Q. In certain embodiments, R 1 is tetrahydropyran-4-ylcarbonyl or 1-methylpiperidin-4-ylcarbonyl. 1 is —C(O)-(7-membered heterocyclyl) optionally substituted with one or more substituents Q. In certain embodiments, R 1 is —C(O)-bicyclic heterocyclyl optionally substituted with one or more substituents Q. In certain embodiments, R 1is —C(O)—(bridged, fused, or spiroheterocyclyl), each optionally substituted with one or more substituents Q. In certain embodiments, R 1 is —C(O)-(bridged heterocyclyl) optionally substituted with one or more substituents Q. In certain embodiments, R 1 is —C(O)-(fused heterocyclyl) optionally substituted with one or more substituents Q. In certain embodiments, R 1 is —C(O)-(spiroheterocyclyl) optionally substituted with one or more substituents Q. In certain embodiments, R 1 is -OC(O)OR 5a (In the formula, R 5a is as defined herein. In certain embodiments, R 1 is -OC(O)NR 5b R 5c (In the formula, R 5b and R 5c are each as defined herein).

[0101] In some embodiments, R 1 ,-L 2 -P(X)(OR 5a )(NR 5b R 5c )(wherein, R 5a , R 5b , R 5c , L 2 and X are each as defined herein. In some embodiments, R 1 ,-L 2 -P(O)(OR 5a )(NR 5b R 5c )(wherein, R 5a , R 5b , R 5c , and L 2 and R are each as defined herein. In some embodiments, R 1 is -P(X)(OR 5a )(NR 5b R 5c )(wherein, R 5a , R 5b , R5c and X are each as defined herein. In some embodiments, R 1 is -P(O)(OR 5a )(NR 5b R 5c )(wherein, R 5a , R 5b , and R 5c and R are each as defined herein. In some embodiments, R 1are ((S)-1-isopropoxycarbonylethylamino)(phenoxy)phosphoryl, ((S)-1-butoxycarbonylethylamino)(phenoxy)phosphoryl, ((1S)-1-sec-butoxycarbonylethylamino)-(phenoxy)phosphoryl, ((S)-1-tert-butoxycarbonylethylamino)(phenoxy)phosphoryl, ((S)-1-pentoxycarbonylethylamino)(phenoxy)phosphoryl, ((S)-1-hexoxycarbonylethylamino)-(phenoxy)phosphoryl, ((S )-1-(2-ethylbutoxy)carbonylethylamino)(phenoxy)phosphoryl, ((1S)-1-(1-phenylethoxycarbonyl)ethylamino)(phenoxy)phosphoryl, ((S)-1-pyridin-3-ylmethoxy-carbonylethylamino)(phenoxy)phosphoryl, ((S)-1-pyridin-4-ylmethoxycarbonylethylamino)-(phenoxy)phosphoryl, ((S)-1-quinolin-4-yl-methoxycarbonylethylamino)(phenoxy)phosphoryl, ((S)-1-quinolin-5-yl (Methoxycarbonylethylamino)(phenoxy)phosphoryl, ((S)-1-(4-methyl-tetrahydropyran-4-yloxy)carbonylethylamino)(phenoxy)phosphoryl, ((S)-1-isopropoxycarbonyl-ethylamino)(quinolin-5-yloxy)phosphoryl, 3-(((S)-1-isopropoxycarbonylethylamino)(phenoxy)-phosphoryloxy)propanoyl, (1-methyl-1-(1-phenylethoxycarbonyl)ethylamino)(phenoxy)-phosphoryl, (1-methyl In certain embodiments, R is ((1S)-1-(1-methyl-1-phenylethoxycarbonyl)ethylamino)(phenoxy)phosphoryl, ((1S)-1-(1-phenylethoxycarbonyl)-2-methylpropylamino)(phenoxy)phosphoryl, ((1S)-1-(1-(4-(tert-butoxycarbonylamino)phenyl)ethoxycarbonyl)-2-methylpropylamino)(phenoxy)phosphoryl, or ((1S)-1-(1-methyl-1-phenylethoxycarbonyl)-2-methylpropylamino)(phenoxy)phosphoryl. 1is ((S)-1-isopropoxycarbonylethylamino)(phenoxy)-phosphoryl. In certain embodiments, R 1 is (((R)-1-(benzyloxy)-3-methyl-1-oxobutan-2-yl)amino)(phenoxy)phosphoryl, (((S)-3-methyl-1-oxo-1-(1-phenyl-cyclopropoxy)butan-2-yl)amino)(phenoxy)phosphoryl, (((S)-1-oxo-1-((tetrahydro-2H-pyran-4-yl)oxy)propan-2-yl)amino)(phenoxy)phosphoryl, (((S)-1-((1-methylpiperidin-4-yl)oxy)-1-oxo-propan-2-yl)amino)(phenoxy)phosphoryl, or (((S)-1-oxo-1-(pentyloxy)propan-2-yl)-amino)-(quinolin-5-yloxy)phosphoryl.

[0102] In some embodiments, R 2 is hydrogen. In certain embodiments, R 2 is C optionally substituted with one or more substituents Q 1-6 In some embodiments, R 2 is methyl optionally substituted with one or more substituents Q. In certain embodiments, R 2 is C optionally substituted with one or more substituents Q 1-6 In some embodiments, R 2 is C optionally substituted with one or more substituents Q 2-6 In some embodiments, R 2 is C optionally substituted with one or more substituents Q 2-6 In certain embodiments, R 2 is C optionally substituted with one or more substituents Q 3-10 In certain embodiments, R 2 is C optionally substituted with one or more substituents Q 6-14 In some embodiments, R 2 is C optionally substituted with one or more substituents Q 7-15 In some embodiments, R2 is heteroaryl optionally substituted with one or more substituents Q. In certain embodiments, R 2 is heterocyclyl optionally substituted with one or more substituents Q.

[0103] In some embodiments, R 2 is -C(O)R 1a (In the formula, R 1a is as defined herein. In certain embodiments, R 2 is -C(O)OR 1a (In the formula, R 1a is as defined herein. In certain embodiments, R 2 is -C(O)NR 1b R 1c (In the formula, R 1b and R 1c and R are each as defined herein. In some embodiments, R 2 is -C(O)SR 1a (In the formula, R 1a is as defined herein. In certain embodiments, R 2 is -C(NR 1a )NR 1b R 1c (In the formula, R 1a , R 1b , and R 1c and R are each as defined herein. In some embodiments, R 2 is -C(S)R 1a (In the formula, R 1a is as defined herein. In certain embodiments, R 2 is -C(S)OR 1a (In the formula, R 1a is as defined herein. In certain embodiments, R 2 is -C(S)NR 1b R 1c (In the formula, R 1b and R 1c and R are each as defined herein. In some embodiments, R 2 is -S(O)R1a (In the formula, R 1a is as defined herein. In certain embodiments, R 2 is -S(O)2R 1a (In the formula, R 1a is as defined herein. In certain embodiments, R 2 is -S(O)NR 1b R 1c (In the formula, R 1b and R 1c and R are each as defined herein. In some embodiments, R 2 is -S(O)NR 1b R 1c (In the formula, R 1b and R 1c and R are each as defined herein. In some embodiments, R 2 is -Si(R 1a )3(wherein, R 1a and R are each as defined herein. In some embodiments, R 2 is a -Si(C) optionally substituted with one or more substituents Q 1-6 alkyl)3.

[0104] In some embodiments, R 3 is halo. In certain embodiments, R 3 is fluoro. In certain embodiments, R 3 is -OR 5a (In the formula, R 5a is as defined herein. In certain embodiments, R 3 is hydroxyl. In certain embodiments, R 3 is -OC(O)R 5a (In the formula, R 5a is as defined herein. In certain embodiments, R 3 is —OC(O)—C optionally substituted with one or more substituents Q 1-30 In some embodiments, R 3 is —OC(O)—C optionally substituted with one or more substituents Q1-20 In some embodiments, R 3 is —OC(O)—C optionally substituted with one or more substituents Q 1-10 In some embodiments, R 3 is —OC(O)—C optionally substituted with one or more substituents Q 1-6 In some embodiments, R 3 is acetyloxy, propanoyloxy, or butanoyloxy, each optionally substituted with one or more substituents Q. In certain embodiments, R 3 is acetyloxy. In certain embodiments, R 3 is —OC(O)—C optionally substituted with one or more substituents Q 1-10 In some embodiments, R 3 is —OC(O)—C optionally substituted with one or more substituents Q 2-10 In some embodiments, R 3 is —OC(O)—C optionally substituted with one or more substituents Q 2-10 In certain embodiments, R 3 is —OC(O)—C optionally substituted with one or more substituents Q 3-10 In certain embodiments, R 3 is —OC(O)—C optionally substituted with one or more substituents Q 6-14 In some embodiments, R 3 is benzoyloxy optionally substituted with one or more substituents Q. In certain embodiments, R 3 is -OC(O)- (bicyclic C optionally substituted with one or more substituents Q) 8-14 aryl). In some embodiments, R 3 is —OC(O)—C optionally substituted with one or more substituents Q 7-15 In some embodiments, R 3 is —OC(O)-heteroaryl optionally substituted with one or more substituents Q. In certain embodiments, R 3is —OC(O)-(monocyclic heteroaryl) optionally substituted with one or more substituents Q. In certain embodiments, R 3 is —OC(O)—(5- or 6-membered heteroaryl), each optionally substituted with one or more substituents Q. In certain embodiments, R 3 is —OC(O)-(bicyclic heteroaryl) optionally substituted with one or more substituents Q. In certain embodiments, R 3 is —OC(O)-(5,5-, 5,6-, or 6,6-fused heteroaryl), each optionally substituted with one or more substituents Q. In certain embodiments, R 3 is —OC(O)-heterocyclyl optionally substituted with one or more substituents Q. In certain embodiments, R 3 is —OC(O)-monocyclic heterocyclyl optionally substituted with one or more substituents Q. In certain embodiments, R 3 is —OC(O)-(3-, 4-, 5-, 6-, or 7-membered heterocyclyl), each optionally substituted with one or more substituents Q. In certain embodiments, R 3 is —OC(O)-bicyclic heterocyclyl optionally substituted with one or more substituents Q. In certain embodiments, R 3 is —OC(O)— (bridged, fused, or spiroheterocyclyl), each optionally substituted with one or more substituents Q. In certain embodiments, R 3 is -OC(O)OR 5a (In the formula, R 5a is as defined herein. In certain embodiments, R 3 is -OC(O)NR 5b R 5c (In the formula, R 5b and R 5c are each as defined herein).

[0105] In some embodiments, R 4 is halo. In certain embodiments, R 4 is fluoro. In certain embodiments, R 4 is -OR 5a (In the formula, R5a is as defined herein. In certain embodiments, R 4 is hydroxyl. In certain embodiments, R 4 is -OC(O)R 5a (In the formula, R 5a is as defined herein. In certain embodiments, R 4 is —OC(O)—C optionally substituted with one or more substituents Q 1-30 In some embodiments, R 4 is —OC(O)—C optionally substituted with one or more substituents Q 1-20 In some embodiments, R 4 is —OC(O)—C optionally substituted with one or more substituents Q 1-10 In some embodiments, R 4 is —OC(O)—C optionally substituted with one or more substituents Q 1-6 In some embodiments, R 4 is acetyloxy, propanoyloxy, or butanoyloxy, each optionally substituted with one or more substituents Q. In certain embodiments, R 4 is acetyloxy. In certain embodiments, R 4 is —OC(O)—C optionally substituted with one or more substituents Q 1-10 In some embodiments, R 4 is —OC(O)—C optionally substituted with one or more substituents Q 2-10 In some embodiments, R 4 is —OC(O)—C optionally substituted with one or more substituents Q 2-10 In certain embodiments, R 4 is —OC(O)—C optionally substituted with one or more substituents Q 3-10 In certain embodiments, R 4 is —OC(O)—C optionally substituted with one or more substituents Q 6-14 In some embodiments, R 4is benzoyloxy optionally substituted with one or more substituents Q. In certain embodiments, R 4 is -OC(O)- (bicyclic C optionally substituted with one or more substituents Q) 8-14 aryl). In some embodiments, R 4 is —OC(O)—C optionally substituted with one or more substituents Q 7-15 In some embodiments, R 4 is —OC(O)-heteroaryl optionally substituted with one or more substituents Q. In certain embodiments, R 4 is —OC(O)-(monocyclic heteroaryl) optionally substituted with one or more substituents Q. In certain embodiments, R 4 is —OC(O)—(5- or 6-membered heteroaryl), each optionally substituted with one or more substituents Q. In certain embodiments, R 4 is —OC(O)-(bicyclic heteroaryl) optionally substituted with one or more substituents Q. In certain embodiments, R 4 is —OC(O)-(5,5-, 5,6-, or 6,6-fused heteroaryl), each optionally substituted with one or more substituents Q. In certain embodiments, R 4 is —OC(O)-heterocyclyl optionally substituted with one or more substituents Q. In certain embodiments, R 4 is —OC(O)-monocyclic heterocyclyl optionally substituted with one or more substituents Q. In certain embodiments, R 4 is —OC(O)-(3-, 4-, 5-, 6-, or 7-membered heterocyclyl), each optionally substituted with one or more substituents Q. In certain embodiments, R 4 is —OC(O)-bicyclic heterocyclyl optionally substituted with one or more substituents Q. In certain embodiments, R 4 is —OC(O)— (bridged, fused, or spiroheterocyclyl), each optionally substituted with one or more substituents Q. In certain embodiments, R 4 is -OC(O)OR 5a (In the formula, R 5ais as defined herein. In certain embodiments, R 4 is -OC(O)NR 5b R 5c (In the formula, R 5b and R 5c are each as defined herein).

[0106] In some embodiments, R 5 is hydrogen. In certain embodiments, R 5 is -C(O)R 5a (In the formula, R 5a is as defined herein. In certain embodiments, R 5 is —C(O)—C optionally substituted with one or more substituents Q 1-30 In some embodiments, R 5 is —C(O)—C optionally substituted with one or more substituents Q 1-20 In some embodiments, R 5 is —C(O)—C optionally substituted with one or more substituents Q 1-10 In some embodiments, R 5 is —C(O)—C optionally substituted with one or more substituents Q 1-6 In some embodiments, R 5 is —C(O)—C optionally substituted with one or more substituents Q 1-10 In some embodiments, R 5 is —C(O)—C optionally substituted with one or more substituents Q 1-10 alkylene-(monocyclic heteroaryl). In certain embodiments, R 5 is —C(O)—C, each optionally substituted with one or more substituents Q 1-10 alkylene-(5- or 6-membered heteroaryl). In certain embodiments, R 5 is —C(O)—C optionally substituted with one or more substituents Q 1-10 alkylene-(5-membered heteroaryl). In certain embodiments, R 5 is —C(O)—C optionally substituted with one or more substituents Q1-10 alkylene-(6-membered heteroaryl). In certain embodiments, R 5 is —C(O)—C optionally substituted with one or more substituents Q 1-10 alkylene-(bicyclic heteroaryl). In certain embodiments, R 5 is —C(O)—C, each optionally substituted with one or more substituents Q 1-10 alkylene-(5,5-, 5,6-, or 6,6-heteroaryl). In certain embodiments, R 5 is —C(O)—C optionally substituted with one or more substituents Q 1-10 alkylene-(5,5-heteroaryl). In some embodiments, R 5 is —C(O)—C optionally substituted with one or more substituents Q 1-10 alkylene-(5,6-heteroaryl). In some embodiments, R 5 is —C(O)—C optionally substituted with one or more substituents Q 1-10 It is alkylene-(6,6-heteroaryl).

[0107] In some embodiments, R 5 is —C(O)—C optionally substituted with one or more substituents Q 1-10 In certain embodiments, R 5 is —C(O)—C optionally substituted with one or more substituents Q 1-10 alkylene-(monocyclic heterocyclyl). In certain embodiments, R 5 is —C(O)—C, each optionally substituted with one or more substituents Q 1-10 alkylene-(3-, 4-, 5-, 6-, or 7-membered heterocyclyl). In certain embodiments, R 5 is —C(O)—C optionally substituted with one or more substituents Q 1-10 alkylene-(3-membered heterocyclyl). In certain embodiments, R 5 is —C(O)—C optionally substituted with one or more substituents Q 1-10 alkylene-(4-membered heterocyclyl). In certain embodiments, R 5is —C(O)—C optionally substituted with one or more substituents Q 1-10 alkylene-(5-membered heterocyclyl). In certain embodiments, R 5 is —C(O)—C optionally substituted with one or more substituents Q 1-10 alkylene-(6-membered heterocyclyl). In certain embodiments, R 5 is —C(O)—C optionally substituted with one or more substituents Q 1-10 alkylene-(7-membered heterocyclyl). In certain embodiments, R 5 is pyrrolidin-1-ylacetyl, 3-morpholinopropanoyl, 4-methylpiperazin-1-ylpropanoyl, or 4-acetylpiperazin-1-ylpropanoyl. 5 is —C(O)—C optionally substituted with one or more substituents Q 1-10 alkylene-(bicyclic heterocyclyl). In certain embodiments, R 5 is —C(O)—C, each optionally substituted with one or more substituents Q 1-10 alkylene-(bridged, fused, or spiroheterocyclyl). In certain embodiments, R 5 is —C(O)—C optionally substituted with one or more substituents Q 1-10 alkylene-(bridged heterocyclyl). In certain embodiments, R 5 is —C(O)—C optionally substituted with one or more substituents Q 1-10 alkylene-(fused heterocyclyl). In certain embodiments, R 5 is —C(O)—C optionally substituted with one or more substituents Q 1-10 It is alkylene-(spiroheterocyclyl).

[0108] In some embodiments, R 5 is acetyl, propanoyl, butanoyl, pentanoyl, hexanoyl, heptanoyl, octanoyl, nonanoyl, or decanoyl, each optionally substituted with one or more substituents Q. In certain embodiments, R 5is acetyl or propanoyl, each optionally substituted with one or more substituents Q. In certain embodiments, R 5 is one or more substituents Q a In certain embodiments, R is acetyl or propanoyl, each optionally substituted with 5- or 6-membered heteroaryl or 5- or 6-membered heterocyclyl, each further substituted with 5 is acetyl or propanoyl, each optionally substituted with pyridin-3-yl, pyrrolidin-1-yl, morpholino, 4-methylpiperazin-1-yl, or 4-acetylpiperazin-1-yl.

[0109] In some embodiments, R 5 is —C(O)—C optionally substituted with one or more substituents Q 1-10 In some embodiments, R 5 is —C(O)—C optionally substituted with one or more substituents Q 2-10 In some embodiments, R 5 is —C(O)—C optionally substituted with one or more substituents Q 2-10 In certain embodiments, R 5 is —C(O)—C optionally substituted with one or more substituents Q 3-10 In certain embodiments, R 5 is —C(O)—C optionally substituted with one or more substituents Q 6-14 In some embodiments, R 5 is benzoyl optionally substituted with one or more substituents Q. In certain embodiments, R 5 is 4-dimethylaminobenzoyl. In certain embodiments, R 5 is -C(O)-(bicyclic C) optionally substituted with one or more substituents Q 8-14 aryl). In some embodiments, R 5 is —C(O)—C optionally substituted with one or more substituents Q 7-15 It is aralkyl.

[0110] In some embodiments, R5 is —C(O)-heteroaryl optionally substituted with one or more substituents Q. In certain embodiments, R 5 is —C(O)-(monocyclic heteroaryl) optionally substituted with one or more substituents Q. In certain embodiments, R 5 is —C(O)—(5- or 6-membered heteroaryl), each optionally substituted with one or more substituents Q. In certain embodiments, R 5 is —C(O)—(5-membered heteroaryl) optionally substituted with one or more substituents Q. In certain embodiments, R 5 is —C(O)-(6-membered heteroaryl) optionally substituted with one or more substituents Q. In certain embodiments, R 5 is pyrrolylcarbonyl or pyridinylcarbonyl, each optionally substituted with one or more substituents Q. In certain embodiments, R 5 is pyrrol-2-ylcarbonyl or pyridin-3-ylcarbonyl, each optionally substituted with one or more substituents Q. In certain embodiments, R 5 is —C(O)-(bicyclic heteroaryl) optionally substituted with one or more substituents Q. In certain embodiments, R 5 is —C(O)—(5,5-, 5,6-, or 6,6-fused heteroaryl), each optionally substituted with one or more substituents Q. In certain embodiments, R 5 is —C(O)-(5,5-fused heteroaryl) optionally substituted with one or more substituents Q. In certain embodiments, R 5 is —C(O)-(5,6-fused heteroaryl) optionally substituted with one or more substituents Q. In certain embodiments, R 5 is —C(O)-(6,6-fused heteroaryl) optionally substituted with one or more substituents Q.

[0111] In some embodiments, R 5 is —C(O)-heterocyclyl optionally substituted with one or more substituents Q. In certain embodiments, R 5is —C(O)-monocyclic heterocyclyl optionally substituted with one or more substituents Q. In certain embodiments, R 5 is —C(O)—(3-, 4-, 5-, 6-, or 7-membered heterocyclyl), each optionally substituted with one or more substituents Q. In certain embodiments, R 5 is —C(O)-(3-membered heterocyclyl) optionally substituted with one or more substituents Q. In certain embodiments, R 5 is —C(O)-(4-membered heterocyclyl) optionally substituted with one or more substituents Q. In certain embodiments, R 5 is —C(O)-(5-membered heterocyclyl) optionally substituted with one or more substituents Q. In certain embodiments, R 5 is —C(O)-(6-membered heterocyclyl) optionally substituted with one or more substituents Q. In certain embodiments, R 5 is tetrahydropyranylcarbonyl, piperidinyl-carbonyl, or piperazinylcarbonyl, each optionally substituted with one or more substituents Q. In certain embodiments, R 5 is tetrahydropyran-4-ylcarbonyl or piperidin-4-ylcarbonyl, each optionally substituted with one or more substituents Q. In certain embodiments, R 5 is tetrahydropyran-4-ylcarbonyl or 1-methylpiperidin-4-ylcarbonyl. 5 is —C(O)-(7-membered heterocyclyl) optionally substituted with one or more substituents Q. In certain embodiments, R 5 is —C(O)-bicyclic heterocyclyl optionally substituted with one or more substituents Q. In certain embodiments, R 5 is —C(O)—(bridged, fused, or spiroheterocyclyl), each optionally substituted with one or more substituents Q. In certain embodiments, R 5 is —C(O)-(bridged heterocyclyl) optionally substituted with one or more substituents Q. In certain embodiments, R 5is —C(O)-(fused heterocyclyl) optionally substituted with one or more substituents Q. In certain embodiments, R 5 is —C(O)-(spiroheterocyclyl) optionally substituted with one or more substituents Q. In certain embodiments, R 5 is -OC(O)OR 5a (In the formula, R 5a is as defined herein. In certain embodiments, R 5 is -OC(O)NR 5b R 5c (In the formula, R 5b and R 5c are each as defined herein).

[0112] In some embodiments, R 5 ,-L 2 -P(X)(OR 5a )(NR 5b R 5c )(wherein, R 5a , R 5b , R 5c , L 2 and X are each as defined herein. In some embodiments, R 5 Ha-L 2 -P(O)(OR 5a )(NR 5b R 5c )(wherein, R 5a , R 5b , R 5c , and L 2 and R are each as defined herein. In some embodiments, R 5 is -P(X)(OR 5a )(NR 5b R 5c )(wherein, R 5a , R 5b , R 5c and X are each as defined herein. In some embodiments, R 5 is -P(O)(OR 5a )(NR 5b R 5c )(wherein, R 5a , R 5b, and R 5c and R are each as defined herein. In some embodiments, R 5are ((S)-1-isopropoxycarbonylethylamino)(phenoxy)phosphoryl, ((S)-1-butoxycarbonylethylamino)(phenoxy)phosphoryl, ((1S)-1-sec-butoxycarbonylethylamino)-(phenoxy)phosphoryl, ((S)-1-tert-butoxycarbonylethylamino)(phenoxy)phosphoryl, ((S)-1-pentoxycarbonylethylamino)(phenoxy)phosphoryl, ((S)-1-hexoxycarbonylethylamino)-(phenoxy)phosphoryl, ((S )-1-(2-ethylbutoxy)carbonylethylamino)(phenoxy)phosphoryl, ((1S)-1-(1-phenylethoxycarbonyl)ethylamino)(phenoxy)phosphoryl, ((S)-1-pyridin-3-ylmethoxy-carbonylethylamino)(phenoxy)phosphoryl, ((S)-1-pyridin-4-ylmethoxycarbonylethylamino)-(phenoxy)phosphoryl, ((S)-1-quinolin-4-yl-methoxycarbonylethylamino)(phenoxy)phosphoryl, ((S)-1-quinolin-5-yl (Methoxycarbonylethylamino)(phenoxy)phosphoryl, ((S)-1-(4-methyl-tetrahydropyran-4-yloxy)carbonylethylamino)(phenoxy)phosphoryl, ((S)-1-isopropoxycarbonyl-ethylamino)(quinolin-5-yloxy)phosphoryl, 3-(((S)-1-isopropoxycarbonylethylamino)(phenoxy)-phosphoryloxy)propanoyl, (1-methyl-1-(1-phenylethoxycarbonyl)ethylamino)(phenoxy)-phosphoryl, (1-methyl In certain embodiments, R is ((1S)-1-(1-methyl-1-phenylethoxycarbonyl)ethylamino)(phenoxy)phosphoryl, ((1S)-1-(1-phenylethoxycarbonyl)-2-methylpropylamino)(phenoxy)phosphoryl, ((1S)-1-(1-(4-(tert-butoxycarbonylamino)phenyl)ethoxycarbonyl)-2-methylpropylamino)(phenoxy)phosphoryl, or ((1S)-1-(1-methyl-1-phenylethoxycarbonyl)-2-methylpropylamino)(phenoxy)phosphoryl. 5is ((S)-1-isopropoxycarbonylethylamino)(phenoxy)-phosphoryl. In certain embodiments, R 5 is (((R)-1-(benzyloxy)-3-methyl-1-oxobutan-2-yl)amino)(phenoxy)phosphoryl, (((S)-3-methyl-1-oxo-1-(1-phenyl-cyclopropoxy)butan-2-yl)amino)(phenoxy)phosphoryl, (((S)-1-oxo-1-((tetrahydro-2H-pyran-4-yl)oxy)propan-2-yl)amino)(phenoxy)phosphoryl, (((S)-1-((1-methylpiperidin-4-yl)oxy)-1-oxo-propan-2-yl)amino)(phenoxy)phosphoryl, or (((S)-1-oxo-1-(pentyloxy)propan-2-yl)-amino)-(quinolin-5-yloxy)phosphoryl.

[0113] In some embodiments, R 3 and R 4 are joined together to form a lactone ring optionally substituted with one or more substituents Q. In certain embodiments, R 4 and R 5 are joined together to form a lactone ring optionally substituted with one or more substituents Q.

[0114] In some embodiments, R 3a is R as defined herein 5a In some embodiments, R 3a is hydrogen. In certain embodiments, R 3a is -C(O)R 5a (In the formula, R 5a is as defined herein. In certain embodiments, R 3a is —C(O)—C optionally substituted with one or more substituents Q 1-30 In some embodiments, R 3a is —C(O)—C optionally substituted with one or more substituents Q 1-20 In some embodiments, R 3a is —C(O)—C optionally substituted with one or more substituents Q1-10 In some embodiments, R 3a is —C(O)—C optionally substituted with one or more substituents Q 1-6 In some embodiments, R 3a is acetyl, propanoyl, or butanoyl, each optionally substituted with one or more substituents Q. In certain embodiments, R 3a is acetyl. In certain embodiments, R 3a is —C(O)—C optionally substituted with one or more substituents Q 1-10 In some embodiments, R 3a is —C(O)—C optionally substituted with one or more substituents Q 2-10 In some embodiments, R 3a is —C(O)—C optionally substituted with one or more substituents Q 2-10 In certain embodiments, R 3a is —C(O)—C optionally substituted with one or more substituents Q 3-10 In certain embodiments, R 3a is —C(O)—C optionally substituted with one or more substituents Q 6-14 In some embodiments, R 3a is benzoyl optionally substituted with one or more substituents Q. In certain embodiments, R 3a is -C(O)-(bicyclic C) optionally substituted with one or more substituents Q 8-14 aryl). In some embodiments, R 3a is —C(O)—C optionally substituted with one or more substituents Q 7-15 In some embodiments, R 3a is —C(O)-heteroaryl optionally substituted with one or more substituents Q. In certain embodiments, R 3a is —C(O)-(monocyclic heteroaryl) optionally substituted with one or more substituents Q. In certain embodiments, R 3a is —C(O)—(5- or 6-membered heteroaryl), each optionally substituted with one or more substituents Q. In certain embodiments, R3a is —C(O)-(bicyclic heteroaryl) optionally substituted with one or more substituents Q. In certain embodiments, R 3a is —C(O)—(5,5-, 5,6-, or 6,6-fused heteroaryl), each optionally substituted with one or more substituents Q. In certain embodiments, R 3a is —C(O)-heterocyclyl optionally substituted with one or more substituents Q. In certain embodiments, R 3a is —C(O)-monocyclic heterocyclyl optionally substituted with one or more substituents Q. In certain embodiments, R 3a is —C(O)—(3-, 4-, 5-, 6-, or 7-membered heterocyclyl), each optionally substituted with one or more substituents Q. In certain embodiments, R 3a is —C(O)-bicyclic heterocyclyl optionally substituted with one or more substituents Q. In certain embodiments, R 3a is —C(O)—(bridged, fused, or spiroheterocyclyl), each optionally substituted with one or more substituents Q. In certain embodiments, R 3a is -C(O)OR 5a (In the formula, R 5a is as defined herein. In certain embodiments, R 3a is -C(O)NR 5b R 5c (In the formula, R 5b and R 5c are each as defined herein).

[0115] In some embodiments, R 4a is R as defined herein 5a In some embodiments, R 4a is hydrogen. In certain embodiments, R 4a is -C(O)R 5a (In the formula, R 5a is as defined herein. In certain embodiments, R 4a is —C(O)—C optionally substituted with one or more substituents Q 1-30In some embodiments, R 4a is —C(O)—C optionally substituted with one or more substituents Q 1-20 In some embodiments, R 4a is —C(O)—C optionally substituted with one or more substituents Q 1-10 In some embodiments, R 4a is —C(O)—C optionally substituted with one or more substituents Q 1-6 In some embodiments, R 4a is acetyl, propanoyl, or butanoyl, each optionally substituted with one or more substituents Q. In certain embodiments, R 4a is acetyl. In certain embodiments, R 4a is —C(O)—C optionally substituted with one or more substituents Q 1-10 In some embodiments, R 4a is —C(O)—C optionally substituted with one or more substituents Q 2-10 In some embodiments, R 4a is —C(O)—C optionally substituted with one or more substituents Q 2-10 In certain embodiments, R 4a is —C(O)—C optionally substituted with one or more substituents Q 3-10 In certain embodiments, R 4a is —C(O)—C optionally substituted with one or more substituents Q 6-14 In some embodiments, R 4a is benzoyl optionally substituted with one or more substituents Q. In certain embodiments, R 4a is -C(O)-(bicyclic C) optionally substituted with one or more substituents Q 8-14 aryl). In some embodiments, R 4a is —C(O)—C optionally substituted with one or more substituents Q 7-15 In some embodiments, R 4a is —C(O)-heteroaryl optionally substituted with one or more substituents Q. In certain embodiments, R 4ais —C(O)-(monocyclic heteroaryl) optionally substituted with one or more substituents Q. In certain embodiments, R 4a is —C(O)—(5- or 6-membered heteroaryl), each optionally substituted with one or more substituents Q. In certain embodiments, R 4a is —C(O)-(bicyclic heteroaryl) optionally substituted with one or more substituents Q. In certain embodiments, R 4a is —C(O)—(5,5-, 5,6-, or 6,6-fused heteroaryl), each optionally substituted with one or more substituents Q. In certain embodiments, R 4a is —C(O)-heterocyclyl optionally substituted with one or more substituents Q. In certain embodiments, R 4a is —C(O)-monocyclic heterocyclyl optionally substituted with one or more substituents Q. In certain embodiments, R 4a is —C(O)—(3-, 4-, 5-, 6-, or 7-membered heterocyclyl), each optionally substituted with one or more substituents Q. In certain embodiments, R 4a is —C(O)-bicyclic heterocyclyl optionally substituted with one or more substituents Q. In certain embodiments, R 4a is —C(O)—(bridged, fused, or spiroheterocyclyl), each optionally substituted with one or more substituents Q. In certain embodiments, R 4a is C(O)OR 5a (In the formula, R 5a is as defined herein. In certain embodiments, R 4a is -C(O)NR 5b R 5c (In the formula, R 5b and R 5c are each as defined herein).

[0116] In some embodiments, R 5a is hydrogen. In certain embodiments, R 5a is C optionally substituted with one or more substituents Q 1-30 In some embodiments, R 5ais C optionally substituted with one or more substituents Q 1-20 In some embodiments, R 5a is C optionally substituted with one or more substituents Q 1-10 In some embodiments, R 5a is C optionally substituted with one or more substituents Q 1-6 In some embodiments, R 5a is methyl, ethyl, propyl, or butyl, each optionally substituted with one or more substituents Q. In certain embodiments, R 5a is C optionally substituted with one or more substituents Q 1-30 In some embodiments, R 5a is C optionally substituted with one or more substituents Q 1-20 In some embodiments, R 5a is C optionally substituted with one or more substituents Q 1-10 In some embodiments, R 5a is C optionally substituted with one or more substituents Q 1-6 In some embodiments, R 5a is C optionally substituted with one or more substituents Q 2-30 In some embodiments, R 5a is C optionally substituted with one or more substituents Q 2-20 In some embodiments, R 5a is C optionally substituted with one or more substituents Q 2-10 In some embodiments, R 5a is C optionally substituted with one or more substituents Q 2-6 In some embodiments, R 5a is C optionally substituted with one or more substituents Q 2-30 In certain embodiments, R 5a is C optionally substituted with one or more substituents Q 2-20 In certain embodiments, R 5a is C optionally substituted with one or more substituents Q 2-10In certain embodiments, R 5a is C optionally substituted with one or more substituents Q 2-6 In certain embodiments, R 5a is C optionally substituted with one or more substituents Q 3-30 In certain embodiments, R 5a is C optionally substituted with one or more substituents Q 3-20 In certain embodiments, R 5a is C optionally substituted with one or more substituents Q 3-10 In certain embodiments, R 5a is C optionally substituted with one or more substituents Q 6-30 In some embodiments, R 5a is C optionally substituted with one or more substituents Q 6-14 In some embodiments, R 5a is phenyl optionally substituted with one or more substituents Q. In certain embodiments, R 5a is a bicyclic C optionally substituted with one or more substituents Q 8-14 In some embodiments, R 5a is C optionally substituted with one or more substituents Q 7-30 In some embodiments, R 5a is C optionally substituted with one or more substituents Q 7-15 In some embodiments, R 5a is heteroaryl optionally substituted with one or more substituents Q. In certain embodiments, R 5a is monocyclic heteroaryl optionally substituted with one or more substituents Q. In certain embodiments, R 5a is a 5- or 6-membered heteroaryl, each optionally substituted with one or more substituents Q. In certain embodiments, R 5a is a 5-membered heteroaryl optionally substituted with one or more substituents Q. In certain embodiments, R 5a is a 6-membered heteroaryl optionally substituted with one or more substituents Q. In certain embodiments, R5a is a bicyclic heteroaryl optionally substituted with one or more substituents Q. In certain embodiments, R 5a is 5,5-, 5,6-, or 6,6-fused heteroaryl, each optionally substituted with one or more substituents Q. In certain embodiments, R 5a is a 5,5-fused heteroaryl optionally substituted with one or more substituents Q. In certain embodiments, R 5a is a 5,6-fused heteroaryl optionally substituted with one or more substituents Q. In certain embodiments, R 5a is a 6,6-fused heteroaryl optionally substituted with one or more substituents Q. In certain embodiments, R 5a is quinolinyl optionally substituted with one or more substituents Q. In certain embodiments, R 5a is quinolin-5-yl optionally substituted with one or more substituents Q. In certain embodiments, R 5a is heterocyclyl optionally substituted with one or more substituents Q. In certain embodiments, R 5a is monocyclic heterocyclyl optionally substituted with one or more substituents Q. In certain embodiments, R 5a is 3-, 4-, 5-, 6-, or 7-heterocyclyl, each optionally substituted with one or more substituents Q. In certain embodiments, R 5a is bicyclic heterocyclyl optionally substituted with one or more substituents Q. In certain embodiments, R 5a is a bridged, fused, or spiro heterocyclyl, each optionally substituted with one or more substituents Q.

[0117] In some embodiments, R 5b is hydrogen. In certain embodiments, R 5b is C optionally substituted with one or more substituents Q 1-30 In some embodiments, R 5b is C optionally substituted with one or more substituents Q 1-20 In some embodiments, R 5b is C optionally substituted with one or more substituents Q1-10 In some embodiments, R 5b is C optionally substituted with one or more substituents Q 1-6 In some embodiments, R 5b is methyl, ethyl, propyl, or butyl, each optionally substituted with one or more substituents Q. In certain embodiments, R 5b is C optionally substituted with one or more substituents Q 1-30 In some embodiments, R 5b is C optionally substituted with one or more substituents Q 1-20 In some embodiments, R 5b is C optionally substituted with one or more substituents Q 1-10 In some embodiments, R 5b is C optionally substituted with one or more substituents Q 1-6 In some embodiments, R 5b is C optionally substituted with one or more substituents Q 2-30 In some embodiments, R 5b is C optionally substituted with one or more substituents Q 2-20 In some embodiments, R 5b is C optionally substituted with one or more substituents Q 2-10 In some embodiments, R 5b is C optionally substituted with one or more substituents Q 2-6 In some embodiments, R 5b is C optionally substituted with one or more substituents Q 2-30 In certain embodiments, R 5b is C optionally substituted with one or more substituents Q 2-20 In certain embodiments, R 5b is C optionally substituted with one or more substituents Q 2-10 In certain embodiments, R 5b is C optionally substituted with one or more substituents Q 2-6 In certain embodiments, R5b is C optionally substituted with one or more substituents Q 3-30 In certain embodiments, R 5b is C optionally substituted with one or more substituents Q 3-20 In certain embodiments, R 5b is C optionally substituted with one or more substituents Q 3-10 In certain embodiments, R 5b is C optionally substituted with one or more substituents Q 6-30 In some embodiments, R 5b is C optionally substituted with one or more substituents Q 6-14 In some embodiments, R 5b is phenyl optionally substituted with one or more substituents Q. In certain embodiments, R 5b is a bicyclic C optionally substituted with one or more substituents Q 8-14 In some embodiments, R 5b is C optionally substituted with one or more substituents Q 7-30 In some embodiments, R 5b is C optionally substituted with one or more substituents Q 7-15 In some embodiments, R 5b is heteroaryl optionally substituted with one or more substituents Q. In certain embodiments, R 5b is monocyclic heteroaryl optionally substituted with one or more substituents Q. In certain embodiments, R 5b is a 5- or 6-membered heteroaryl, each optionally substituted with one or more substituents Q. In certain embodiments, R 5b is a 5-membered heteroaryl optionally substituted with one or more substituents Q. In certain embodiments, R 5b is a 6-membered heteroaryl optionally substituted with one or more substituents Q. In certain embodiments, R 5b is a bicyclic heteroaryl optionally substituted with one or more substituents Q. In certain embodiments, R 5bis 5,5-, 5,6-, or 6,6-fused heteroaryl, each optionally substituted with one or more substituents Q. In certain embodiments, R 5b is a 5,5-fused heteroaryl optionally substituted with one or more substituents Q. In certain embodiments, R 5b is a 5,6-fused heteroaryl optionally substituted with one or more substituents Q. In certain embodiments, R 5b is a 6,6-fused heteroaryl optionally substituted with one or more substituents Q. In certain embodiments, R 5b is quinolinyl optionally substituted with one or more substituents Q. In certain embodiments, R 5b is quinolin-5-yl optionally substituted with one or more substituents Q. In certain embodiments, R 5b is heterocyclyl optionally substituted with one or more substituents Q. In certain embodiments, R 5b is monocyclic heterocyclyl optionally substituted with one or more substituents Q. In certain embodiments, R 5b is 3-, 4-, 5-, 6-, or 7-heterocyclyl, each optionally substituted with one or more substituents Q. In certain embodiments, R 5b is bicyclic heterocyclyl optionally substituted with one or more substituents Q. In certain embodiments, R 5b is a bridged, fused, or spiro heterocyclyl, each optionally substituted with one or more substituents Q.

[0118] In some embodiments, R 5c is hydrogen. In certain embodiments, R 5c is C optionally substituted with one or more substituents Q 1-30 In some embodiments, R 5c is C optionally substituted with one or more substituents Q 1-20 In some embodiments, R 5c is C optionally substituted with one or more substituents Q 1-10 In some embodiments, R 5c is C optionally substituted with one or more substituents Q1-6 In some embodiments, R 5c is methyl, ethyl, propyl, butyl, pentyl, or hexyl, each optionally substituted with one or more substituents Q. In certain embodiments, R 5c is C optionally substituted with one or more substituents Q 1-10 In some embodiments, R 5c is C optionally substituted with one or more substituents Q 2-30 In some embodiments, R 5c is C optionally substituted with one or more substituents Q 2-20 In some embodiments, R 5c is C optionally substituted with one or more substituents Q 2-10 In some embodiments, R 5c is C optionally substituted with one or more substituents Q 2-6 In some embodiments, R 5c is C optionally substituted with one or more substituents Q 2-30 In certain embodiments, R 5c is C optionally substituted with one or more substituents Q 2-20 In certain embodiments, R 5c is C optionally substituted with one or more substituents Q 2-10 In certain embodiments, R 5c is C optionally substituted with one or more substituents Q 2-6 In certain embodiments, R 5c is C optionally substituted with one or more substituents Q 3-30 In certain embodiments, R 5c is C optionally substituted with one or more substituents Q 3-20 In certain embodiments, R 5c is C optionally substituted with one or more substituents Q 3-10 In certain embodiments, R 5c is C optionally substituted with one or more substituents Q 6-30In some embodiments, R 5c is C optionally substituted with one or more substituents Q 6-14 In some embodiments, R 5c is phenyl optionally substituted with one or more substituents Q. In certain embodiments, R 5c is a bicyclic C optionally substituted with one or more substituents Q 8-14 In some embodiments, R 5c is C optionally substituted with one or more substituents Q 7-30 In some embodiments, R 5c is C optionally substituted with one or more substituents Q 7-15 In some embodiments, R 5c is heteroaryl optionally substituted with one or more substituents Q. In certain embodiments, R 5c is heterocyclyl optionally substituted with one or more substituents Q. In certain embodiments, R 5c are 1-isopropoxycarbonylethyl, 1-butoxycarbonylethyl, 1-tert-butoxycarbonylethyl, 1-(1-phenylethoxycarbonyl)ethyl, 1-methyl-1-(1-phenylethoxycarbonyl)ethyl, 1-sec-butoxycarbonylethyl, 1-pentoxycarbonylethyl, 1-hexoxycarbonylethyl, 1-(2-ethylbutoxy)carbonylethyl, 1-pyridin-3-ylmethoxycarbonylethyl, 1-pyridin-4-ylmethoxycarbonylethyl, In certain embodiments, R is 1-(4-methyltetrahydropyran-4-yl-oxy)carbonylethyl, 1-quinolin-4-yl-methoxycarbonylethyl, 1-quinolin-5-ylmethoxycarbonylethyl, 1-(4-methyltetrahydropyran-4-yl-oxy)carbonylethyl, 1-(1-phenylethoxycarbonyl)-2-methylpropyl, 1-(1-methyl-1-phenylethoxycarbonyl)-2-methylpropyl, or 1-(1-(4-(tert-butoxycarbonylamino)phenyl)ethoxycarbonyl)-2-methylpropyl. 5c is 1-isopropoxycarbonylethyl. In certain embodiments, R 5cis 1-((tetrahydropyran-4-yl)oxycarbonyl)ethyl, 1-(benzyloxycarbonyl)-2-methylpropyl, 1-(phenylcyclopropoxycarbonyl)-2-methylpropyl, or 1-((1-methylpiperidin-4-yl)-oxycarbonyl)-2-methylpropyl.

[0119] In some embodiments, R 6a is C optionally substituted with one or more substituents Q 1-30 In some embodiments, R 6a is C optionally substituted with one or more substituents Q 1-20 In some embodiments, R 6a is C optionally substituted with one or more substituents Q 1-10 In some embodiments, R 6a is C optionally substituted with one or more substituents Q 1-6 In some embodiments, R 6a is C optionally substituted with one or more substituents Q 1-6 In some embodiments, R 6a is C optionally substituted with one or more substituents Q 1-6 alkylene-(monocyclic heteroaryl). In certain embodiments, R 6a is a C optionally substituted with one or more substituents Q 1-6 alkylene-(5- or 6-membered heteroaryl). In certain embodiments, R 6a is C optionally substituted with one or more substituents Q 1-6 alkylene-(5-membered heteroaryl). In certain embodiments, R 6a is C optionally substituted with one or more substituents Q 1-6 alkylene-(6-membered heteroaryl). In certain embodiments, R 6a is C optionally substituted with one or more substituents Q 1-6 alkylene-(bicyclic heteroaryl). In certain embodiments, R 6a is a C optionally substituted with one or more substituents Q 1-6alkylene-(5,5-, 5,6-, or 6,6-fused heteroaryl). In certain embodiments, R 6a is C optionally substituted with one or more substituents Q 1-6 alkylene-(5,5-fused heteroaryl). In some embodiments, R 6a is C optionally substituted with one or more substituents Q 1-6 alkylene-(5,6-fused heteroaryl). In some embodiments, R 6a is C optionally substituted with one or more substituents Q 1-6 alkylene-(6,6-fused heteroaryl). In some embodiments, R 6a is methyl, ethyl, propyl, butyl, pentyl, or hexyl, each optionally substituted with one or more substituents Q. In certain embodiments, R 6a is propyl, butyl, pentyl, or hexyl, each optionally substituted with one or more substituents Q.

[0120] In some embodiments, R 6a is C optionally substituted with one or more substituents Q 1-30 In some embodiments, R 6a is C optionally substituted with one or more substituents Q 1-20 In some embodiments, R 6a is C optionally substituted with one or more substituents Q 1-10 In some embodiments, R 6a is C optionally substituted with one or more substituents Q 1-6 In some embodiments, R 6a is C optionally substituted with one or more substituents Q 2-30 In some embodiments, R 6a is C optionally substituted with one or more substituents Q 2-20 In some embodiments, R 6a is C optionally substituted with one or more substituents Q 2-10 In some embodiments, R 6ais C optionally substituted with one or more substituents Q 2-6 In some embodiments, R 6a is C optionally substituted with one or more substituents Q 2-30 In certain embodiments, R 6a is C optionally substituted with one or more substituents Q 2-20 In certain embodiments, R 6a is C optionally substituted with one or more substituents Q 2-10 In certain embodiments, R 6a is C optionally substituted with one or more substituents Q 2-6 In certain embodiments, R 6a is C optionally substituted with one or more substituents Q 3-30 In certain embodiments, R 6a is C optionally substituted with one or more substituents Q 3-20 In certain embodiments, R 6a is C optionally substituted with one or more substituents Q 3-10 In certain embodiments, R 6a is a monocyclic C optionally substituted with one or more substituents Q 3-10 In certain embodiments, R 6a is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, each optionally substituted with one or more substituents Q. In certain embodiments, R 6a is a bicyclic C optionally substituted with one or more substituents Q 4-10 In certain embodiments, R 6a is a bridged, fused, or spiro C, each optionally substituted with one or more substituents Q; 4-10 In certain embodiments, R 6a is C optionally substituted with one or more substituents Q 6-30 In some embodiments, R 6a is C optionally substituted with one or more substituents Q 6-14 In some embodiments, R 6ais phenyl optionally substituted with one or more substituents Q. In certain embodiments, R 6a is a bicyclic C optionally substituted with one or more substituents Q 8-14 In some embodiments, R 6a is C optionally substituted with one or more substituents Q 7-30 In some embodiments, R 6a is C optionally substituted with one or more substituents Q 7-15 In some embodiments, R 6a is a bicyclic C optionally substituted with one or more substituents Q 8-15 In some embodiments, R 6a is heteroaryl optionally substituted with one or more substituents Q. In certain embodiments, R 6a is heterocyclyl optionally substituted with one or more substituents Q. In certain embodiments, R 6a is monocyclic heterocyclyl optionally substituted with one or more substituents Q. In certain embodiments, R 6a is a 3-, 4-, 5-, 6-, or 7-membered heterocyclyl, each optionally substituted with one or more substituents Q. In certain embodiments, R 6a is a 6-membered heterocyclyl optionally substituted with one or more substituents Q. In certain embodiments, R 6a is bicyclic heterocyclyl optionally substituted with one or more substituents Q. In certain embodiments, R 6a is a bridged, fused, or spiroheterocyclyl, each optionally substituted with one or more substituents Q. In certain embodiments, R 6a is isopropyl, butyl, 2-butyl, tert-butyl, pentyl, hexyl, 2-ethylbutyl, 1-phenylethyl, 2-phenylprop-2-yl, pyridin-3-ylmethyl, pyridin-4-ylmethyl, quinolin-4-ylmethyl, or quinolin-5-ylmethyl. 6a is 1-phenyl-cyclopropyl, benzyl, tetrahydropyran-4-yl, or 1-methyl-piperidin-4-yl.

[0121] In some embodiments, R 6b is hydrogen. In certain embodiments, R 6b is deuterium. In certain embodiments, R 6b is C optionally substituted with one or more substituents Q 1-6 In some embodiments, R 6b is methyl, ethyl, propyl, or butyl, each optionally substituted with one or more substituents Q. In certain embodiments, R 6b is methyl, ethyl, isopropyl, 2-methylpropyl, or 2-butyl. 6b is methyl or isopropyl. In certain embodiments, R 6b is methyl. In certain embodiments, R 6b is isopropyl. In certain embodiments, R 6b is C optionally substituted with one or more substituents Q 1-6 In some embodiments, R 6b is C optionally substituted with one or more substituents Q 2-6 In some embodiments, R 6b is C optionally substituted with one or more substituents Q 2-6 In certain embodiments, R 6b is C optionally substituted with one or more substituents Q 3-10 In certain embodiments, R 6b is C optionally substituted with one or more substituents Q 6-14 In some embodiments, R 6b is C optionally substituted with one or more substituents Q 7-15 In some embodiments, R 6b is heteroaryl optionally substituted with one or more substituents Q. In certain embodiments, R 6b is heterocyclyl optionally substituted with one or more substituents Q. In certain embodiments, R 6bis hydrogen, methyl, imidazol-4-yl-methyl, indol-3-ylmethyl, carboxymethyl, hydroxymethyl, aminocarbonylmethyl, 2-thiolmethyl, 2-carboxyethyl, 1-hydroxyethyl, 2-aminocarbonylethyl, 2-methylthioethyl, isopropyl, 2-methyl-propyl, 3-guanidinylpropyl, 2-butyl, 4-aminobutyl, benzyl, or 4-hydroxybenzyl.

[0122] In some embodiments, R 6c is hydrogen. In certain embodiments, R 6c is deuterium. In certain embodiments, R 6c is C optionally substituted with one or more substituents Q 1-6 In some embodiments, R 6c is methyl, ethyl, propyl, or butyl, each optionally substituted with one or more substituents Q. In certain embodiments, R 6c is methyl, ethyl, isopropyl, 2-methylpropyl, or 2-butyl. 6c is methyl. In certain embodiments, R 6c is C optionally substituted with one or more substituents Q 1-6 In some embodiments, R 6c is C optionally substituted with one or more substituents Q 2-6 In some embodiments, R 6c is C optionally substituted with one or more substituents Q 2-6 In certain embodiments, R 6c is C optionally substituted with one or more substituents Q 3-10 In certain embodiments, R 6c is C optionally substituted with one or more substituents Q 6-14 In some embodiments, R 6c is C optionally substituted with one or more substituents Q 7-15 In some embodiments, R 6cis heteroaryl optionally substituted with one or more substituents Q. In certain embodiments, R 6c is heterocyclyl optionally substituted with one or more substituents Q. In certain embodiments, R 6c is hydrogen, methyl, imidazol-4-yl-methyl, indol-3-ylmethyl, carboxymethyl, hydroxymethyl, aminocarbonylmethyl, 2-thiolmethyl, 2-carboxyethyl, 1-hydroxyethyl, 2-aminocarbonylethyl, 2-methylthioethyl, isopropyl, 2-methylpropyl, 3-guanidinylpropyl, 2-butyl, 4-aminobutyl, benzyl, or 4-hydroxybenzyl. 6c is hydrogen or methyl.

[0123] In some embodiments, R 6b and R 6c together with the carbon atoms to which they are attached, represent C optionally substituted with one or more substituents Q 3-10 In some embodiments, R 6b and R 6c together with the carbon atoms to which they are attached, form a monocyclic C 3-10 In some embodiments, R 6b and R 6c together with the carbon atoms to which they are attached, form a bicyclic C optionally substituted with one or more substituents Q 3-10 In some embodiments, R 6b and R 6c together with the carbon atoms to which they are attached form a bridged, fused, or spiro C group, each optionally substituted with one or more substituents Q. 3-10 In some embodiments, R 6b and R 6c together with the carbon atoms to which they are attached form cyclopropane-1,1-diyl, cyclobutene-1,1-diyl, cyclopentane-1,1-diyl, or cyclohexane-1,1-diyl, each optionally substituted with one or more substituents Q.

[0124] In some embodiments, A is a bond. In some embodiments, A is O. In some embodiments, A is N(R 1b )(wherein, R 1b is as defined herein. In certain embodiments, A is N(H).

[0125] In some embodiments, L 1 is C optionally substituted with one or more substituents Q 1-6 In some embodiments, L is alkylene. 1 is methanediyl, ethane-1,2-diyl, propane-1,2-diyl, or butane-1,4-diyl, each optionally substituted with one or more substituents Q. In certain embodiments, L 1 is C optionally substituted with one or more substituents Q 1-6 In certain embodiments, L is heteroalkylene. 1 is C optionally substituted with one or more substituents Q 2-6 In certain embodiments, L is alkenylene. 1 is C optionally substituted with one or more substituents Q 2-6 In certain embodiments, L is alkynylene. 1 is C optionally substituted with one or more substituents Q 3-10 In certain embodiments, L is cycloalkylene. 1 is C optionally substituted with one or more substituents Q 6-14 In certain embodiments, L 1 is C optionally substituted with one or more substituents Q 7-15 In certain embodiments, L 1 is heteroarylene optionally substituted with one or more substituents Q. In certain embodiments, L 1 is heterocyclylene optionally substituted with one or more substituents Q.

[0126] In some embodiments, L 2 is a bond. In certain embodiments, L 2is —O—C optionally substituted with one or more substituents Q 1-6 In some embodiments, L is alkylene. 2 is —OCH2CH2C(O)—. In certain embodiments, L 2 is —O—C optionally substituted with one or more substituents Q 1-6 In certain embodiments, L is heteroalkylene. 2 is —O—C optionally substituted with one or more substituents Q 2-6 In certain embodiments, L is alkenylene. 2 is —O—C optionally substituted with one or more substituents Q 2-6 In certain embodiments, L is alkynylene. 2 is —O—C optionally substituted with one or more substituents Q 3-10 In certain embodiments, L is cycloalkylene. 2 is —O—C optionally substituted with one or more substituents Q 6-14 In certain embodiments, L 2 is —O—C optionally substituted with one or more substituents Q 7-15 In certain embodiments, L 2 is —O-heteroarylene optionally substituted with one or more substituents Q. In certain embodiments, L 2 is —O-heterocyclylene optionally substituted with one or more substituents Q.

[0127] In certain embodiments, X is O. In certain embodiments, X is S.

[0128] In some embodiments, Z is hydrogen. In some embodiments, Z is azido. In some embodiments, Z is halo. In some embodiments, Z is fluoro or iodo. In some embodiments, Z is fluoro. In some embodiments, Z is iodo. In some embodiments, Z is isocyano (—NC). In some embodiments, Z is —C═C(R 1a )R 1a (In the formula, each R 1ais as defined herein. In certain embodiments, Z is -C=CH2. In certain embodiments, Z is -C≡CR 1a (In the formula, R 1a is as defined herein. In certain embodiments, Z is -C≡CH. In certain embodiments, Z is [ka] (In the formula, R 1a is as defined herein. In certain embodiments, Z is [ka] In some embodiments, Z is [ka] In some embodiments, Z is [ka] In some embodiments, Z is [ka] (In the formula, R 1a is as defined herein. In certain embodiments, Z is [ka] In some embodiments, Z is —C(O)R 1a (In the formula, R 1a is as defined herein. In certain embodiments, Z is —C(O)CH 3 . In certain embodiments, Z is —SH.

[0129] In one embodiment, provided herein is: Acetyl 2-(2-azidoacetylamino)-2-deoxy-3,4-di-O-acetyl-6-O-(((S)-1-isopropoxy-carbonylethylamino)(phenoxy)phosphoryl)-D-mannopyranoside A1; 2-(2-azidoacetylamino)-2-deoxy-3,4-di-O-acetyl-6-O-(((S)-1-isopropoxy-carbonylethylamino)(phenoxy)phosphoryl)-D-mannopyranoside A2; 2-(2-Azidoacetylamino)-2-deoxy-3,4-di-O-acetyl-6-O-(((1S)-1-(1-phenylethoxy-carbonyl)ethylamino)(phenoxy)phosphoryl)-D-mannopyranoside A3; 2-(2-azidoacetylamino)-2-deoxy-3,4-di-O-acetyl-6-O-((1-methyl-1-(1-phenyl-ethoxycarbonyl)ethylamino)(phenoxy)phosphoryl)-D-mannopyranoside A4; 2-(2-Azidoacetylamino)-2-deoxy-3,4-di-O-acetyl-6-O-(((1S)-1-(1-phenylethoxy-carbonyl)-2-methylpropylamino)(phenoxy)phosphoryl)-D-mannopyranoside A5; 2-(2-azidoacetylamino)-2-deoxy-3,4-di-O-acetyl-6-O-((1-methyl-1-(1-methyl-1-phenylethoxycarbonyl)ethylamino)(phenoxy)phosphoryl)-D-mannopyranoside A6; 2-(2-Azidoacetylamino)-2-deoxy-3,4-di-O-acetyl-6-O-(((1S)-1-(1-methyl-1-phenylethoxycarbonyl)-2-methylpropylamino)(phenoxy)phosphoryl)-D-mannopyranoside A7; Pyridin-3-ylacetyl 2-(2-azidoacetylamino)-2-deoxy-3,4-di-O-acetyl-6-O-(((S)-1-isopropoxycarbonylethylamino)(phenoxy)phosphoryl)-D-mannopyranoside A8; 3-Morpholinopropanoyl 2-(2-azidoacetylamino)-2-deoxy-3,4-di-O-acetyl-6-O-(((S)-1-isopropoxy-carbonylethylamino)(phenoxy)phosphoryl)-D-mannopyranoside A9; 4-Methylpiperazin-1-ylpropanoyl 2-(2-azidoacetylamino)-2-deoxy-3,4-di-O-acetyl-6-O-(((S)-1-isopropoxy-carbonylethylamino)(phenoxy)phosphoryl)-D-mannopyranoside A10; 4-Acetylpiperazin-1-ylpropanoyl 2-(2-azidoacetylamino)-2-deoxy-3,4-di-O-acetyl-6-O-(((S)-1-isopropoxy-carbonylethylamino)(phenoxy)phosphoryl)-D-mannopyranoside A11; Tetrahydropyran-4-ylcarbonyl 2-(2-azidoacetylamino)-2-deoxy-3,4-di-O-acetyl-6-O-(((S)-1-isopropoxy-carbonylethylamino)(phenoxy)phosphoryl)-D-mannopyranoside A12; 1-Methylpiperidin-4-ylcarbonyl 2-(2-azidoacetylamino)-2-deoxy-3,4-di-O-acetyl-6-O-(((S)-1-isopropoxy-carbonylethylamino)(phenoxy)phosphoryl)-D-mannopyranoside A13; Pyrrolidin-1-ylacetyl 2-(2-azidoacetylamino)-2-deoxy-3,4-di-O-acetyl-6-O-(((S)-1-isopropoxy-carbonylethylamino)(phenoxy)phosphoryl)-D-mannopyranoside A14; 4-Dimethylaminobenzoyl 2-(2-azidoacetylamino)-2-deoxy-3,4-di-O-acetyl-6-O-(((S)-1-isopropoxycarbonylethylamino)(phenoxy)phosphoryl)-D-mannopyranoside A15; Pyridin-3-ylcarbonyl 2-(2-azidoacetylamino)-2-deoxy-3,4-di-O-acetyl-6-O-(((S)-1-isopropoxycarbonylethylamino)(phenoxy)phosphoryl)-D-mannopyranoside A16; Pyrrol-2-ylcarbonyl 2-(2-azidoacetylamino)-2-deoxy-3,4-di-O-acetyl-6-O-(((S)-1-isopropoxycarbonylethylamino)(phenoxy)phosphoryl)-D-mannopyranoside A17; Acetyl 2-(2-azidoacetylamino)-2-deoxy-3,4-di-O-acetyl-6-O-(((S)-1-butoxy-carbonylethylamino)(phenoxy)phosphoryl)-D-mannopyranoside A18; Acetyl 2-(2-azidoacetylamino)-2-deoxy-3,4-di-O-acetyl-6-O-(((1S)-1-sec-butoxy-carbonylethylamino)(phenoxy)phosphoryl)-D-mannopyranoside A19; Acetyl 2-(2-azidoacetylamino)-2-deoxy-3,4-di-O-acetyl-6-O-(((S)-1-tert-butoxy-carbonylethylamino)(phenoxy)phosphoryl)-D-mannopyranoside A20; Acetyl 2-(2-azidoacetylamino)-2-deoxy-3,4-di-O-acetyl-6-O-(((S)-1-pentoxy-carbonylethylamino)(phenoxy)phosphoryl)-D-mannopyranoside A21; Acetyl 2-(2-azidoacetylamino)-2-deoxy-3,4-di-O-acetyl-6-O-(((S)-1-hexoxy-carbonylethylamino)(phenoxy)phosphoryl)-D-mannopyranoside A22; Acetyl 2-(2-azidoacetylamino)-2-deoxy-3,4-di-O-acetyl-6-O-(((S)-1-(2-ethyl-butoxy)carbonylethylamino)(phenoxy)phosphoryl)-D-mannopyranoside A23; Acetyl 2-(2-azidoacetylamino)-2-deoxy-3,4-di-O-acetyl-6-O-(((S)-1-pyridin-3-ylmethoxycarbonylethylamino)(phenoxy)phosphoryl)-D-mannopyranoside A24; Acetyl 2-(2-azidoacetylamino)-2-deoxy-3,4-di-O-acetyl-6-O-(((S)-1-pyridin-4-ylmethoxycarbonylethylamino)(phenoxy)phosphoryl)-D-mannopyranoside A25; Acetyl 2-(2-azidoacetylamino)-2-deoxy-3,4-di-O-acetyl-6-O-(((S)-1-quinolin-4-ylmethoxycarbonylethylamino)(phenoxy)phosphoryl)-D-mannopyranoside A26; Acetyl 2-(2-azidoacetylamino)-2-deoxy-3,4-di-O-acetyl-6-O-(((S)-1-quinolin-5-ylmethoxycarbonylethylamino)(phenoxy)phosphoryl)-D-mannopyranoside A27; Pentanoyl 2-(2-azidoacetylamino)-2-deoxy-3,4-di-O-acetyl-6-O-(((S)-1-quinolin-5-ylmethoxycarbonylethylamino)(phenoxy)phosphoryl)-D-mannopyranoside A28; 2-Methylbutanoyl 2-(2-azidoacetylamino)-2-deoxy-3,4-di-O-acetyl-6-O-(((S)-1-quinolin-5-ylmethoxycarbonylethylamino)(phenoxy)phosphoryl)-D-mannopyranoside A29; Hexanoyl 2-(2-azidoacetylamino)-2-deoxy-3,4-di-O-acetyl-6-O-(((S)-1-quinolin-5-ylmethoxycarbonylethylamino)(phenoxy)phosphoryl)-D-mannopyranoside A30; Nonanoyl 2-(2-azidoacetylamino)-2-deoxy-3,4-di-O-acetyl-6-O-(((S)-1-quinolin-5-ylmethoxycarbonylethylamino)(phenoxy)phosphoryl)-D-mannopyranoside A31; Acetyl 2-(2-azidoacetylamino)-2-deoxy-3,4-di-O-acetyl-6-O-(((S)-1-(4-methyl-tetrahydropyran-4-yloxy)carbonylethylamino)(phenoxy)phosphoryl)-D-mannopyranoside A32; Acetyl 2-(2-azidoacetylamino)-2-deoxy-3,4-di-O-acetyl-6-O-(((1S)-1-(1-(4-(tert-butoxycarbonylamino)phenyl)ethoxycarbonyl)-2-methylpropylamino)(phenoxy)-phosphoryl)-D-mannopyranoside A33; Acetyl 2-(2-azidoacetylamino)-2-deoxy-3,4-di-O-acetyl-6-O-(((S)-1-isopropoxy-carbonylethylamino)(quinolin-5-yloxy)phosphoryl)-D-mannopyranoside A34; or Acetyl 2-(2-azidoacetylamino)-2-deoxy-3,4-di-O-acetyl-6-O-(3-(((S)-1-isopropoxycarbonylethylamino)(phenoxy)phosphoryloxy)propanoyl)-D-mannopyranoside A35; or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0130] In another embodiment, provided herein is: (3S,4R,5S,6R)-3-(2-azidoacetamido)-6-((((((R)-1-(benzyloxy)-3-methyl-1-oxobutan-2-yl)amino)(phenoxy)phosphoryl)oxy)methyl)tetrahydro-2H-pyran-2,4,5-triyl triacetate A36; (3S,4R,5S,6R)-3-(2-azidoacetamido)-6-((((((S)-3-methyl-1-oxo-1-(1-phenyl-cyclopropoxy)butan-2-yl)amino)(phenoxy)phosphoryl)oxy)methyl)tetrahydro-2H-pyran-2,4,5-triyl triacetate A37; (2R,3S,4R,5S)-5-(2-azidoacetamido)-2-((((((S)-1-oxo-1-(pentyloxy)propan-2-yl)-amino)(phenoxy)phosphoryl)oxy)methyl)-6-((tetrahydro-2H-pyran-4-carbonyl)oxy)tetrahydro-2H-pyran-3,4-diyl diacetate A38; (2R,3S,4R,5S)-5-(2-azidoacetamido)-6-((3-morpholinobenzoyl)oxy)-2-((((((S)-1-oxo-1-(pentyloxy)propan-2-yl)amino)(phenoxy)phosphoryl)oxy)methyl)tetrahydro-2H-pyran-3,4-diyl diacetate A39; (2R,3S,4R,5S)-5-(2-azidoacetamido)-6-((3-(4-methylpiperazin-1-yl)benzoyl)-oxy)-2-((((((S)-1-oxo-1-(pentyloxy)propan-2-yl)amino)(phenoxy)phosphoryl)oxy)methyl)-tetrahydro-2H-pyran-3,4-diyl diacetate A40; (2R,3S,4R,5S)-5-(2-azidoacetamido)-6-((3-(morpholinomethyl)benzoyl)oxy)-2-((((((S)-1-oxo-1-(pentyloxy)propan-2-yl)amino)(phenoxy)phosphoryl)oxy)methyl)tetrahydro-2H-pyran-3,4-diyl diacetate A41; (2R,3S,4R,5S)-5-(2-azidoacetamido)-6-((3-((4-methylpiperazin-1-yl)methyl)-benzoyl)oxy)-2-((((((S)-1-oxo-1-(pentyloxy)propan-2-yl)amino)(phenoxy)phosphoryl)oxy)-methyl)tetrahydro-2H-pyran-3,4-diyl diacetate A42; (2R,3S,4R,5S)-5-(2-azidoacetamido)-2-((((((S)-1-oxo-1-(quinolin-4-ylmethoxy)-propan-2-yl)amino)(phenoxy)phosphoryl)oxy)methyl)-6-(pentanoyloxy)tetrahydro-2H-pyran-3,4-diyl diacetate A43; (2R,3S,4R,5S)-5-(2-azidoacetamido)-6-((2-methylbutanoyl)oxy)-2-((((((S)-1-oxo-1-(quinolin-4-ylmethoxy)propan-2-yl)amino)(phenoxy)phosphoryl)oxy)methyl)tetrahydro-2H-pyran-3,4-diyl diacetate A44; (2R,3S,4R,5S)-5-(2-azidoacetamido)-6-(hexanoyloxy)-2-((((((S)-1-oxo-1-(quinolin-4-ylmethoxy)propan-2-yl)amino)(phenoxy)phosphoryl)oxy)methyl)tetrahydro-2H-pyran-3,4-diyl diacetate A45; (2R,3S,4R,5S)-5-(2-azidoacetamido)-6-(nonanoyloxy)-2-((((((S)-1-oxo-1-(quinolin-4-ylmethoxy)propan-2-yl)amino)(phenoxy)phosphoryl)oxy)methyl)tetrahydro-2H-pyran-3,4-diyl diacetate A46; (2R,3S,4R,5S)-5-(2-azidoacetamido)-2-((((((S)-1-oxo-1-(quinolin-4-ylmethoxy)-propan-2-yl)amino)(phenoxy)phosphoryl)oxy)methyl)-6-((tetrahydro-2H-pyran-4-carbonyl)-oxy)tetrahydro-2H-pyran-3,4-diyl diacetate A47; (3S,4R,5S,6R)-3-(2-azidoacetamido)-6-((((((S)-1-oxo-1-((tetrahydro-2H-pyran-4-yl)oxy)propan-2-yl)amino)(phenoxy)phosphoryl)oxy)methyl)tetrahydro-2H-pyran-2,4,5-triyl triacetate A48; (3S,4R,5S,6R)-3-(2-azidoacetamido)-6-((((((S)-1-((1-methylpiperidin-4-yl)oxy)-1-oxopropan-2-yl)amino)(phenoxy)phosphoryl)oxy)methyl)tetrahydro-2H-pyran-2,4,5-triyl triacetate A49; (3S,4R,5S,6R)-3-(2-azidoacetamido)-6-((((((S)-1-isopropoxy-1-oxopropan-2-yl)-amino)(quinolin-5-yloxy)phosphoryl)oxy)methyl)tetrahydro-2H-pyran-2,4,5-triyl triacetate A50; (2R,3S,4R,5S)-5-(2-azidoacetamido)-2-((((((S)-1-isopropoxy-1-oxopropan-2-yl)-amino)(quinolin-5-yloxy)phosphoryl)oxy)methyl)-6-(pentanoyloxy)tetrahydro-2H-pyran-3,4-diyl diacetate A51; (2R,3S,4R,5S)-5-(2-azidoacetamido)-2-((((((S)-1-isopropoxy-1-oxopropan-2-yl)-amino)(quinolin-5-yloxy)phosphoryl)oxy)methyl)-6-(pivaloyloxy)tetrahydro-2H-pyran-3,4-diyl diacetate A52; (2R,3S,4R,5S)-5-(2-azidoacetamido)-6-(hexanoyloxy)-2-((((((S)-1-isopropoxy-1-oxopropan-2-yl)amino)(quinolin-5-yloxy)phosphoryl)oxy)methyl)tetrahydro-2H-pyran-3,4-diyl diacetate A53; (2R,3S,4R,5S)-5-(2-azidoacetamido)-2-((((((S)-1-isopropoxy-1-oxopropan-2-yl)-amino)(quinolin-5-yloxy)phosphoryl)oxy)methyl)-6-(nonanoyloxy)tetrahydro-2H-pyran-3,4-diyl diacetate A54; or (3S,4R,5S,6R)-3-(2-azidoacetamido)-6-((((((S)-1-oxo-1-(pentyloxy)propan-2-yl)-amino)(quinolin-5-yloxy)phosphoryl)oxy)methyl)tetrahydro-2H-pyran-2,4,5-triyl triacetate A55; or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0131] In yet another embodiment, provided herein is (((1S)-1-(1-phenylethoxy-carbonyl)ethylamino)(phenoxy)phosphoryl) 2-(2-azidoacetylamino)-2-deoxy-3,4,6-tri-O-acetyl-D-mannopyranoside B1; or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0132] In some embodiments, the compounds provided herein are isolated or purified. In some embodiments, the compounds provided herein have a purity of at least about 90%, at least about 95%, at least about 98%, at least about 99%, or at least about 99.5% by weight. In some embodiments, the compounds provided herein have a purity of at least about 90% by weight. In some embodiments, the compounds provided herein have a purity of at least about 95% by weight. In some embodiments, the compounds provided herein have a purity of at least about 98% by weight. In some embodiments, the compounds provided herein have a purity of at least about 99% by weight. In some embodiments, the compounds provided herein have a purity of at least about 99.5% by weight.

[0133] The compounds provided herein are intended to encompass all possible stereoisomers unless a particular stereochemistry is specified. When the compounds provided herein contain an alkenyl group, the compounds may exist as one or a mixture of geometric cis / trans (or Z / E) isomers. When structural isomers are interconvertible, the compounds may exist as a single tautomer or a mixture of tautomers. This can take the form of, for example, proton tautomerism in compounds with imino, keto, or oxime groups; or so-called valence tautomerism in compounds with aromatic moieties. This means that a single compound may exhibit two or more types of isomerism.

[0134] The compounds provided herein can be enantiomerically pure, such as a single enantiomer or a single diastereomer, or can be a mixture of enantiomers, e.g., a racemic mixture of two enantiomers; or a stereoisomeric mixture, such as a mixture of two or more diastereomers. Thus, those skilled in the art will recognize that for compounds that undergo epimerization in vivo, administration of the compound in its (R) form is equivalent to administration of the compound in its (S) form. Conventional techniques for the preparation / isolation of individual enantiomers include synthesis from appropriate optically pure precursors, asymmetric synthesis from achiral starting materials, or resolution of enantiomeric mixtures, e.g., chiral chromatography, recrystallization, resolution, diastereomeric salt formation, or derivatization to diastereomeric adducts followed by separation.

[0135] When the compound provided herein has an acidic or basic moiety, it can also be provided as a pharmaceutically acceptable salt.See Berge et al., J. Pharm. Sci. 1977, 66, 1-19; Stahl and Wermuth, eds., "Handbook of Pharmaceutical Salts: Properties, Selection, and Use", 2nd Edition; John Wiley & Sons, 2011.In some embodiments, the pharmaceutically acceptable salt of the compound provided herein is a solvate.In some embodiments, the pharmaceutically acceptable salt of the compound provided herein is a hydrate.

[0136] Suitable acids for use in preparing the pharmaceutically acceptable salts of the compounds provided herein include acetic acid, 2,2-dichloroacetic acid, acylated amino acids, adipic acid, alginic acid, ascorbic acid, L-aspartic acid, benzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, boric acid, (+)-camphoric acid, camphorsulfonic acid, (+)-(1S)-camphor-10-sulfonic acid, capric acid, caproic acid, caprylic acid, cinnamic acid, citric acid, cyclamic acid, cyclohexanesulfamic acid, dodecyl sulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, 2-hydroxy-ethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid, D-gluconic acid, D-glucuronic acid, L-glutamic acid, α- These include, but are not limited to, oxoglutaric acid, glycolic acid, hippuric acid, hydrobromic acid, hydrochloric acid, hydroiodic acid, (+)-L-lactic acid, (±)-DL-lactic acid, lactobionic acid, lauric acid, maleic acid, (-)-L-malic acid, malonic acid, (±)-DL-mandelic acid, methanesulfonic acid, naphthalene-2-sulfonic acid, naphthalene-1,5-disulfonic acid, 1-hydroxy-2-naphthoic acid, nicotinic acid, nitric acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, perchloric acid, phosphoric acid, L-pyroglutamic acid, saccharic acid, salicylic acid, 4-amino-salicylic acid, sebacic acid, stearic acid, succinic acid, sulfuric acid, tannic acid, (+)-L-tartaric acid, thiocyanic acid, p-toluenesulfonic acid, undecylenic acid, and valeric acid.

[0137] Suitable bases for use in preparing the pharmaceutically acceptable salts of the compounds provided herein include inorganic bases such as magnesium hydroxide, calcium hydroxide, potassium hydroxide, zinc hydroxide, and sodium hydroxide; and bases including, but not limited to, L-arginine, benethamine, benzathine, choline, deanol, diethanolamine, diethylamine, dimethylamine, dipropylamine, diisopropylamine, 2-(diethyl-amino)ethanol, ethanolamine, ethylamine, ethylenediamine, isopropylamine, N-methyl-glucamine, hydrabamine. , 1H-imidazole, L-lysine, morpholine, 4-(2-hydroxyethyl)-morpholine, methylamine, piperidine, piperazine, propylamine, pyrrolidine, 1-(2-hydroxyethyl)-pyrrolidine, pyridine, quinuclidine, quinoline, isoquinoline, triethanolamine, trimethylamine, triethylamine, N-methyl-D-glucamine, 2-amino-2-(hydroxymethyl)-1,3-propanediol, and tromethamine, and other organic bases.

[0138] The compounds provided herein may also be provided as prodrugs, which are functional derivatives of the compounds and can be easily converted into the parent compounds in vivo. Prodrugs are often useful because, in certain situations, they may be easier to administer than the parent compounds. They may be bioavailable by oral administration, whereas the parent compounds are not, for example, bioavailable by oral administration. Prodrugs may also have improved solubility in pharmaceutical compositions compared to the parent compounds. Prodrugs can be converted into the parent drugs by various mechanisms, including enzymatic processes and metabolic hydrolysis.

[0139] (Pharmaceutical composition) In one embodiment, provided herein is a pharmaceutical composition comprising a compound provided herein, e.g., a compound of Formula (I), or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; and a pharmaceutically acceptable excipient.

[0140] The pharmaceutical compositions provided herein can be formulated into various dosage forms, including, but not limited to, oral, parenteral, and topical administration dosage forms. The pharmaceutical compositions can also be formulated as modified-release dosage forms, such as delayed-release, extended-release, prolonged-release, sustained-release, pulsed-release, controlled-release, accelerated-release, rapid-release, targeted-release, programmed-release, and gastroretentive dosage forms. These dosage forms can be prepared by conventional methods and techniques known to those skilled in the art. See, for example, the above-mentioned publications "Remington: The Science and Practice of Pharmacy"; "Modified-Release Drug Delivery Technology," 2nd Edition; Rathbone et al. (eds.); Drugs and the Pharmaceutical Sciences 184; CRC Press: Boca Raton, FL, 2008.

[0141] In one embodiment, the pharmaceutical compositions provided herein are formulated in a dosage form for oral administration.In another embodiment, the pharmaceutical compositions provided herein are formulated in a dosage form for parenteral administration.In yet another embodiment, the pharmaceutical compositions provided herein are formulated in a dosage form for intravenous administration.In yet another embodiment, the pharmaceutical compositions provided herein are formulated in a dosage form for intramuscular administration.In yet another embodiment, the pharmaceutical compositions provided herein are formulated in a dosage form for subcutaneous administration.In yet another embodiment, the pharmaceutical compositions provided herein are formulated in a dosage form for topical administration.

[0142] The pharmaceutical compositions provided herein can be provided in unit-dosage form or multiple-dosage form. Unit-dosage form, as used herein, refers to a physically discrete unit suitable for administration to a subject and packaged individually as known in the art. Each unit dose contains a predetermined amount of active ingredient (e.g., a compound provided herein) sufficient to produce the desired therapeutic effect, in association with the required pharmaceutical excipients. Examples of unit-dosage forms include, but are not limited to, ampoules, syringes, and individually packaged tablets and capsules. Unit-dosage forms may be administered in fractions or multiples thereof. A multiple-dosage form is a plurality of identical unit-dosage forms packaged in a single container to be administered in segregated unit-dosage form. Examples of multiple-dosage forms include, but are not limited to, vials, bottles of tablets or capsules, or bottles of pints or gallons.

[0143] The pharmaceutical compositions provided herein can be administered once or multiple times at intervals.It is understood that the exact dosage and duration of treatment can vary with the age, weight and condition of the subject being treated, and can be determined experimentally using known testing protocols or by extrapolating from in vivo or in vitro testing or diagnostic data.It is also understood that for any particular individual, the specific dosage regimen should be adjusted over time according to the needs of the subject and the professional judgment of the person administering or supervising the administration of the pharmaceutical composition.

[0144] (A. Oral Administration) The pharmaceutical compositions provided herein for oral administration can be provided in solid, semi-solid, or liquid dosage forms for oral administration. As used herein, oral administration also includes buccal, lingual, and sublingual administration. Suitable oral dosage forms include, but are not limited to, tablets, fast melts, chewable tablets, capsules, pills, strips, troches, lozenges, pastilles, cachets, pellets, medicated chewing gum, bulk powders, effervescent or non-effervescent powders or granules, oral mists, solutions, emulsions, suspensions, wafers, sprinkles, elixirs, and syrups. In addition to the active ingredient, the pharmaceutical composition can contain one or more pharmaceutically acceptable carriers or excipients, including, but not limited to, binders, fillers, diluents, disintegrants, wetting agents, lubricants, flow agents, colorants, dye transfer inhibitors, sweeteners, flavoring agents, emulsifiers, suspending and dispersing agents, preservatives, solvents, non-aqueous liquids, organic acids, and carbon dioxide sources.

[0145] Binders or granulators impart cohesion to tablets and ensure that the tablets remain intact after compression. Suitable binders or granulators include starches such as corn starch, potato starch, and pregelatinized starch (e.g., Starch 1500®); gelatin; sugars such as sucrose, glucose, dextrose, molasses, and lactose; gum arabic, alginic acid, alginates, chestnut extract, panwar gum, ghatti gum, isabgol husk, and the like. Natural and synthetic gums include, but are not limited to, husk mucilage, carboxymethylcellulose, methylcellulose, polyvinylpyrrolidone (PVP), VEEGUM®, larch arabinogalactan, powdered tragacanth, and guar gum; celluloses such as ethylcellulose, cellulose acetate, carboxymethylcellulose calcium, sodium carboxymethylcellulose, methylcellulose, hydroxyethylcellulose (HEC), hydroxypropylcellulose (HPC), and hydroxypropylmethylcellulose (HPMC); and microcrystalline celluloses such as AVICEL® PH-101, AVICEL® PH-103, AVICEL® PH-105, and AVICEL® RC-581. Suitable fillers include, but are not limited to, talc, calcium carbonate, microcrystalline cellulose, powdered cellulose, dextrates, kaolin, mannitol, silicic acid, sorbitol, starch, and pregelatinized starch. The amount of binder or filler in the pharmaceutical compositions provided herein varies upon the type of formulation, and is readily discernible to one of ordinary skill in the art. The binder or filler may be present in the pharmaceutical compositions provided herein from about 50 to about 99 weight percent.

[0146] Suitable diluents include, but are not limited to, dicalcium phosphate, calcium sulfate, lactose, sorbitol, sucrose, inositol, cellulose, kaolin, mannitol, sodium chloride, dry starch, and powdered sugar. Certain diluents, such as mannitol, lactose, sorbitol, sucrose, and inositol, when present in sufficient amounts, can impart properties to some compressed tablets that allow them to disintegrate in the mouth by chewing. Such compressed tablets can be used as chewable tablets. The amount of diluent in the pharmaceutical compositions provided herein varies depending on the type of formulation, and is readily discernible by those skilled in the art.

[0147] Suitable disintegrants include, but are not limited to, agar; bentonite; celluloses such as methylcellulose and carboxymethylcellulose; wood products; natural sponge; cation exchange resins; alginic acid; gums such as guar gum and VEEGUM® HV; citrus pulp; cross-linked celluloses such as croscarmellose; cross-linked polymers such as crospovidone; cross-linked starch; calcium carbonate; microcrystalline celluloses such as sodium starch glycolate; polacrilin potassium; starches such as corn starch, potato starch, tapioca starch, and pregelatinized starch; clay; and algin. The amount of disintegrant in the pharmaceutical compositions provided herein varies depending on the type of formulation and is readily discernible to those skilled in the art. The pharmaceutical compositions provided herein may contain about 0.5 to about 15% or about 1 to about 5% by weight of disintegrant.

[0148] Suitable lubricants include, but are not limited to, calcium stearate; magnesium stearate; mineral oil; light mineral oil; glycerin; sorbitol; mannitol; glycols such as glyceryl behenate and polyethylene glycol (PEG); stearic acid; sodium lauryl sulfate; talc; hydrogenated vegetable oils such as peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, and soybean oil; zinc stearate; ethyl oleate; ethyl laurate; agar; starch; lycopodium; and silica or silica gels such as AEROSIL® 200 and CAB-O-SIL®. The amount of lubricant in the pharmaceutical compositions provided herein will vary depending on the type of formulation and is readily discernible to one of skill in the art. The pharmaceutical compositions provided herein may contain about 0.1 to about 5% by weight of lubricant.

[0149] Suitable flow agents include, but are not limited to, colloidal silicon dioxide, CAB-O-SIL®, and asbestos-free talc. Suitable coloring agents include, but are not limited to, any of the approved, certified, water-soluble FD&C dyes, water-insoluble FD&C dyes suspended on alumina hydrate, and color lakes. Color lakes are the combination of a water-soluble dye by absorption onto a hydrous oxide of a heavy metal, resulting in an insoluble form of the dye. Suitable flavoring agents include, but are not limited to, natural flavors extracted from plants such as fruits, and synthetic mixtures of compounds that produce a pleasant taste, such as peppermint and methyl salicylate. Suitable sweetening agents include, but are not limited to, sucrose, lactose, mannitol, syrup, glycerin, and artificial sweeteners such as saccharin and aspartame. Suitable emulsifying agents include, but are not limited to, gelatin, gum arabic, tragacanth, bentonite, and surfactants such as polyoxyethylene sorbitan monooleate (TWEEN® 20), polyoxyethylene sorbitan 80 monooleate (TWEEN® 80), and triethanolamine oleate. Suitable suspending and dispersing agents include, but are not limited to, sodium carboxymethylcellulose, pectin, tragacanth, VEEGUM®, gum arabic, sodium carboxymethylcellulose, hydroxypropyl methylcellulose, and polyvinylpyrrolidone. Suitable preservatives include, but are not limited to, glycerin, methyl and propylparaben, benzoic acid, and sodium benzoate and alcohol. Suitable wetting agents include, but are not limited to, propylene glycol monostearate, sorbitan monooleate, diethylene glycol monolaurate, and polyoxyethylene lauryl ether. Suitable solvents include, but are not limited to, glycerin, sorbitol, ethyl alcohol, and syrup. Suitable non-aqueous liquids utilized in emulsions include, but are not limited to, mineral oil and cottonseed oil.Suitable organic acids include, but are not limited to, citric acid and tartaric acid. Suitable carbon dioxide sources include, but are not limited to, sodium bicarbonate and sodium carbonate.

[0150] It should be understood that many carriers and excipients may serve several functions, even within the same formulation.

[0151] The pharmaceutical compositions for oral administration provided herein may be provided as compressed tablets, molded tablets, chewable lozenges, quick-dissolving tablets, multiple compressed tablets, or enteric-coated, sugar-coated, or film-coated tablets. Enteric-coated tablets are compressed tablets coated with a substance that resists the action of stomach acid but dissolves or disintegrates in the intestine, thus protecting the active ingredient from the acidic environment of the stomach. Enteric coatings include, but are not limited to, fatty acids, fats, phenyl salicylate, waxes, shellac, ammoniated shellac, and cellulose acetate phthalate. Sugar-coated tablets are compressed tablets surrounded by a sugar coating, which can be beneficial for masking unpleasant tastes or odors and protecting the tablets from oxidation. Film-coated tablets are compressed tablets covered with a thin layer or film of a water-soluble material. Film coatings include, but are not limited to, hydroxyethylcellulose, sodium carboxymethylcellulose, polyethylene glycol 4000, and cellulose acetate phthalate. Film coatings impart the same general properties as sugar coatings. Multiple compressed tablets are compressed tablets made by more than one compression cycle, and include multi-layer tablets and press-coated or dry-coated tablets.

[0152] Tablet dosage forms can be prepared from the active ingredient(s) in powdered, crystalline, or granular form, alone or in combination with one or more carriers or excipients described herein, including binders, disintegrants, controlled-release polymers, lubricants, diluents, and / or colorants. Flavoring and sweetening agents are particularly useful in the formation of chewable tablets and lozenges.

[0153] The pharmaceutical compositions for oral administration provided herein may be provided as soft or hard capsules, which can be made from gelatin, methylcellulose, starch, or calcium alginate. Hard gelatin capsules, also known as dry-filled capsules (DFCs), consist of two sections, one over the other, completely enclosing the active ingredient. Soft elastic capsules (SECs) are soft, globular shells, such as gelatin shells, which are plasticized by the addition of glycerin, sorbitol, or similar polyols. Soft gelatin shells may contain preservatives to prevent microbial growth. Suitable preservatives include those described herein, including methyl- and propyl-parabens and sorbic acid. Liquid, semi-solid, and solid dosage forms provided herein may be encapsulated. Suitable liquid and semi-solid dosage forms include solutions and suspensions in propylene carbonate, vegetable oils, or triglycerides. Capsules containing such a solution can be prepared as described in U.S. Patent Nos. 4,328,245; 4,409,239; and 4,410,545. The capsules may be coated as known to those skilled in the art to alter or maintain dissolution of the active ingredient(s).

[0154] The pharmaceutical compositions for oral administration provided herein can be provided in liquid and semisolid dosage forms, including emulsions, solutions, suspensions, elixirs, and syrups. Emulsions are two-phase systems in which one liquid is dispersed in the form of small globules throughout another liquid, which can be oil-in-water or water-in-oil. Emulsions may contain a pharmaceutically acceptable non-aqueous liquid or solvent, an emulsifier, and a preservative. Suspensions may contain a pharmaceutically acceptable suspending agent and a preservative. Hydroalcoholic solutions may contain a pharmaceutically acceptable acetal, such as a di(lower alkyl)acetal of a lower alkyl aldehyde, e.g., acetaldehyde diethyl acetal; and a water-miscible solvent having one or more hydroxyl groups, such as propylene glycol and ethanol. Elixirs are clear, sweetened hydroalcoholic solutions. Syrups are concentrated aqueous solutions of a sugar, e.g., sucrose, and also contain a preservative. For a liquid dosage form, the solution, for example, for example, in a polyethylene glycol, may be diluted with a sufficient quantity of a pharmaceutically acceptable liquid carrier, e.g., water, to be conveniently measured for administration.

[0155] Other useful liquid and semisolid dosage forms include, but are not limited to, those containing an active ingredient(s) and dialkylated mono- or poly-alkylene glycols, including 1,2-dimethoxymethane, diglyme, triglyme, tetraglyme, polyethylene glycol-350-dimethyl ether, polyethylene glycol-550-dimethyl ether, and polyethylene glycol-750-dimethyl ether (where 350, 550, and 750 refer to the approximate average molecular weights of the polyethylene glycol). These dosage forms may further contain one or more antioxidants, such as butylhydroxytoluene (BHT), butylhydroxyanisole (BHA), propyl gallate, vitamin E, hydroquinone, hydroxycoumarin, ethanolamine, lecithin, cephalin, ascorbic acid, malic acid, sorbitol, phosphoric acid, bisulfite, sodium metabisulfite, thiodipropionic acid and its esters, and dithiocarbamates.

[0156] The pharmaceutical compositions for oral administration provided herein may also be provided in the form of liposomes, micelles, microspheres, or nanosystems. Micelle dosage forms can be prepared as described in U.S. Patent No. 6,350,458.

[0157] The pharmaceutical compositions for oral administration provided herein may be provided as non-effervescent or effervescent granules and powders to be reconstituted into a liquid dosage form. Pharmaceutically acceptable carriers and excipients used in non-effervescent granules or powders may include diluents, sweeteners, and wetting agents. Pharmaceutically acceptable carriers and excipients used in effervescent granules or powders may include organic acids and a carbon dioxide source.

[0158] Coloring and flavoring agents can be used in all of the dosage forms described herein.

[0159] The pharmaceutical compositions for oral administration provided herein can be formulated as immediate or controlled release dosage forms, including delayed-, sustained-, pulsed-, controlled-, targeted-, and programmed-release forms.

[0160] (B. Parenteral Administration) The pharmaceutical compositions provided herein can be administered parenterally by injection, infusion, or implant for local or systemic administration. As used herein, parenteral administration includes intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, ​​intrasternal, intracranial, intramuscular, intrasynovial, intravesical, and subcutaneous administration.

[0161] The pharmaceutical compositions provided herein for parenteral administration can be formulated in any dosage form suitable for parenteral administration, including, but not limited to, solutions, suspensions, emulsions, micelles, liposomes, microspheres, nanosystems, and solid forms suitable for solution or suspension in liquid prior to injection. Such dosage forms can be prepared by conventional methods known to those skilled in the art of pharmaceutical science. See, for example, Remington: The Science and Practice of Pharmacy, supra.

[0162] Pharmaceutical compositions for parenteral administration provided herein can include one or more pharmaceutically acceptable carriers and excipients including, but not limited to, aqueous vehicles, water-miscible vehicles, non-aqueous vehicles, antimicrobial agents or preservatives against microbial growth, stabilizers, solubility enhancers, isotonicity agents, buffers, antioxidants, local anesthetics, suspending and dispersing agents, wetting or emulsifying agents, complexing agents, sequestering or chelating agents, cryoprotectants, lyoprotectants, thickening agents, pH adjusting agents, and inert gases.

[0163] Suitable aqueous vehicles include, but are not limited to, water, saline, normal saline or phosphate-buffered saline (PBS), sodium chloride injection, Ringer's injection, isotonic dextrose injection, sterile water for injection, and lactated Ringer's injection. Suitable non-aqueous vehicles include, but are not limited to, fixed oils of vegetable origin, castor oil, corn oil, cottonseed oil, olive oil, peanut oil, peppermint oil, safflower oil, sesame oil, soybean oil, hydrogenated vegetable oil, hydrogenated soybean oil, and medium-chain triglycerides of coconut oil and palm kernel oil. Suitable water-miscible vehicles include, but are not limited to, ethanol, 1,3-butanediol, liquid polyethylene glycols (e.g., polyethylene glycol 300 and polyethylene glycol 400), propylene glycol, glycerin, N-methyl-2-pyrrolidone, N,N-dimethylacetamide, and dimethyl sulfoxide.

[0164] Suitable antimicrobial agents or preservatives include, but are not limited to, phenol, cresol, mercurials, benzyl alcohol, chlorobutanol, methyl and propyl p-hydroxybenzoate, thimerosal, benzalkonium chloride (e.g., benzethonium chloride), methyl- and propyl-paraben, and sorbic acid. Suitable isotonicity agents include, but are not limited to, sodium chloride, glycerin, and dextrose. Suitable buffering agents include, but are not limited to, phosphates and citrates. Suitable antioxidants include those described herein, such as bisulfite and sodium metabisulfite. Suitable local anesthetics include, but are not limited to, procaine hydrochloride. Suitable suspending and dispersing agents include those described herein, such as sodium carboxymethylcellulose, hydroxypropylmethylcellulose, and polyvinylpyrrolidone. Suitable emulsifying agents include those described herein, such as polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan 80 monooleate, and triethanolamine oleate. Suitable sequestering or chelating agents include, but are not limited to, EDTA. Suitable pH adjusting agents include, but are not limited to, sodium hydroxide, hydrochloric acid, citric acid, and lactic acid. Suitable complexing agents include, but are not limited to, cyclodextrins, including α-cyclodextrin, β-cyclodextrin, hydroxypropyl-β-cyclodextrin, sulfobutylether-β-cyclodextrin, and sulfobutylether 7-β-cyclodextrin (CAPTISOL®).

[0165] When the pharmaceutical compositions provided herein are formulated for multiple dose administration, the multiple dose parenteral formulation must contain an antimicrobial agent in a bacteriostatic or fungistatic concentration. All parenteral formulations must be sterile, as known and practiced in the art.

[0166] In one embodiment, the pharmaceutical composition for parenteral administration is provided as a ready-to-use sterile solution. In another embodiment, the pharmaceutical composition is provided as a sterile dry soluble product, including lyophilized powder and hypodermic tablets, which is reconstituted with a vehicle before use. In yet another embodiment, the pharmaceutical composition is provided as a ready-to-use sterile suspension. In yet another embodiment, the pharmaceutical composition is provided as a sterile dry insoluble product, which is reconstituted with a vehicle before use. In yet another embodiment, the pharmaceutical composition is provided as a ready-to-use sterile emulsion.

[0167] The pharmaceutical compositions provided herein for parenteral administration can be formulated as immediate or controlled release dosage forms, including delayed-, sustained-, pulsed-, controlled-, targeted-, and programmed-release forms.

[0168] The pharmaceutical compositions provided herein for parenteral administration can be formulated as a suspension, solid, semisolid, or thixotropic liquid for administration as an implant depot. In one embodiment, the pharmaceutical compositions provided herein are dispersed in a solid internal matrix that is insoluble in body fluids but is surrounded by an outer polymeric membrane through which the active ingredient(s) in the pharmaceutical composition can diffuse.

[0169] Suitable inner matrices include, but are not limited to, polymethyl methacrylate, polybutyl methacrylate, plasticized or unplasticized polyvinyl chloride, plasticized nylon, plasticized polyethylene terephthalate, natural rubber, polyisoprene, polyisobutylene, polybutadiene, polyethylene, ethylene-vinyl acetate copolymer, silicone rubber, polydimethylsiloxane, silicone-carbonate copolymer, hydrophilic polymers (such as hydrogels of acrylic and methacrylic acid esters), collagen, cross-linked polyvinyl alcohol, and cross-linked partially hydrolyzed polyvinyl acetate.

[0170] Suitable polymeric outer membranes include, but are not limited to, polyethylene, polypropylene, ethylene / propylene copolymers, ethylene / ethyl acrylate copolymers, ethylene / vinyl acetate copolymers, silicone rubber, polydimethylsiloxane, neoprene rubber, chlorinated polyethylene, polyvinyl chloride, vinyl acetate, vinylidene chloride, vinyl chloride copolymers with ethylene and propylene, ionomeric polyethylene terephthalate, butyl rubber, epichlorohydrin rubber, ethylene / vinyl alcohol copolymers, ethylene / vinyl acetate / vinyl alcohol terpolymers, and ethylene / vinyloxyethanol copolymers.

[0171] (C. Topical Administration) The pharmaceutical compositions provided herein can be administered topically to the skin, orifices, or mucosa. As used herein, topical administration includes (intradermal) dermal, conjunctival, intracorneal, intraocular, ophthalmic, auricular, transdermal, nasal, vaginal, urethral, ​​respiratory, and rectal administration.

[0172] The pharmaceutical compositions provided herein can be formulated in any dosage form suitable for topical administration for local or systemic effect, including, but not limited to, emulsions, solutions, suspensions, creams, gels, hydrogels, ointments, dusting powders, dressings, elixirs, lotions, suspensions, tinctures, pastes, foams, films, aerosols, irrigations, sprays, suppositories, bandages, and transdermal patches. Topical formulations of the pharmaceutical compositions provided herein may also include liposomes, micelles, microspheres, and nanosystems.

[0173] Pharmaceutically acceptable carriers and excipients suitable for use in topical formulations include, but are not limited to, aqueous vehicles, water-miscible vehicles, non-aqueous vehicles, antimicrobial agents or preservatives against microbial growth, stabilizers, solubility enhancers, isotonicity agents, buffers, antioxidants, local anesthetics, suspending and dispersing agents, wetting or emulsifying agents, complexing agents, sequestering or chelating agents, penetration enhancers, cryoprotectants, lyoprotectants, viscosity enhancing agents, and inert gases.

[0174] Pharmaceutical compositions may also be administered locally by electroporation, iontophoresis, phonophoresis, sonophoresis, or microneedle or needle-free injection such as POWDERJECT™ and BIOJECT™.

[0175] The pharmaceutical compositions provided herein can be provided in the form of ointments, creams, and gels. Suitable ointment vehicles include oily or hydrocarbon vehicles, including lard, benzoic lard, olive oil, cottonseed oil, and other oils, white petrolatum; emulsifiable or absorbent vehicles, such as hydrophilic petrolatum, hydroxystearin sulfate, and anhydrous lanolin; water-removable vehicles, such as hydrophilic ointments; water-soluble ointment vehicles, including polyethylene glycols of various molecular weights; and emulsion vehicles, including cetyl alcohol, glyceryl monostearate, lanolin, and stearic acid, either water-in-oil (W / O) emulsions or oil-in-water (O / W) emulsions. See, for example, Remington: The Science and Practice of Pharmacy, supra. These vehicles are emollients, but generally require the addition of antioxidants and preservatives.

[0176] Suitable cream bases may be oil-in-water or water-in-oil. Suitable cream vehicles will be water-washable and contain an oil phase, an emulsifier, and an aqueous phase. The oil phase, also known as the "internal" phase, is generally composed of petrolatum and a fatty alcohol such as cetyl or stearyl alcohol. The aqueous phase usually, though not necessarily, exceeds the oil phase in volume and generally contains a humectant. The emulsifier in a cream formulation may be a nonionic, anionic, cationic, or amphoteric surfactant.

[0177] Gels are semi-solid suspension-type systems. Single-phase gels contain organic macromolecules distributed substantially uniformly throughout the liquid carrier. Suitable gelling agents include, but are not limited to, cross-linked acrylic acid polymers such as carbomer, carboxypolyalkylene, and CARBOPOL®; hydrophilic polymers such as polyethylene oxide, polyoxyethylene-polyoxypropylene copolymers, and polyvinyl alcohol; cellulose-based polymers such as hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropylmethylcellulose, hydroxypropylmethylcellulose phthalate, and methylcellulose; gums such as tragacanth and xanthan gum; sodium alginate; and gelatin. To prepare a uniform gel, a dispersing agent such as alcohol or glycerin can be added, or the gelling agent can be dispersed by trituration, mechanical mixing, and / or stirring.

[0178] The pharmaceutical compositions provided herein can be administered rectally, intraurethrally, vaginally, or perivaginally in the form of a suppository, pessary, bougie, compress or poultice, paste, powder, dressing, cream, plaster, contraceptive, ointment, solution, emulsion, suspension, tampon, gel, foam, spray, or enema. These dosage forms can be produced using conventional processes, such as those described in Remington: The Science and Practice of Pharmacy, supra.

[0179] Rectal, urethral, ​​and vaginal suppositories are solids for insertion into body orifices; they are solid at room temperature but melt or soften at body temperature, releasing the active ingredient(s) into the orifice. Pharmaceutically acceptable carriers used in rectal and vaginal suppositories include bases or vehicles, such as stiffening agents, that, when formulated with the active ingredient(s), produce a melting point close to body temperature; and antioxidants, as described herein, including bisulfites and sodium metabisulfite. Suitable vehicles include, but are not limited to, cocoa butter (theobroma oil), glycerin-gelatin, carbowax (polyoxyethylene glycol), spermaceti, paraffin, white wax and yellow wax, and appropriate mixtures of mono-, di-, and triglycerides of fatty acids, and hydrogels, such as polyvinyl alcohol, hydroxyethyl methacrylate, and polyacrylic acid. Combinations of various vehicles can also be used. Rectal and vaginal suppositories may be prepared by compression or molding. The typical weight of a rectal and vaginal suppository is about 2 to about 3 g.

[0180] The pharmaceutical compositions provided herein can be administered to the eye in the form of solutions, suspensions, ointments, emulsions, gel-forming solutions, powders for solution, gels, ocular inserts, and implants.

[0181] The pharmaceutical compositions provided herein can be administered intranasally or by inhalation into the respiratory tract. The pharmaceutical compositions can be provided in the form of an aerosol or solution for delivery using a pressurized container, pump, spray, atomizer (such as an electrohydrodynamic atomizer that generates a fine mist), or nebulizer, alone or in combination with a suitable propellant such as 1,1,1,2-tetrafluoroethane or 1,1,1,2,3,3,3-heptafluoropropane. The pharmaceutical compositions can also be provided as dry powders for insufflation, alone or in combination with an inert carrier such as lactose or phospholipids; and as nasal drops. For intranasal use, the powder can include a bioadhesive agent such as chitosan or cyclodextrin.

[0182] Solutions or suspensions for use in pressurized containers, pumps, sprays, atomizers, or nebulizers can be formulated to contain ethanol, aqueous ethanol, or another suitable agent to disperse, solubilize, or prolong the release of the active ingredient(s); a propellant as a solvent; and / or a surfactant such as sorbitan trioleate, oleic acid, or oligolactic acid.

[0183] The pharmaceutical compositions provided herein can be micronized to a size suitable for delivery by inhalation, such as about 50 micrometers or less, or about 10 micrometers or less. Particles of such sizes can be prepared using comminution methods known to those skilled in the art, such as spiral jet milling, fluidized bed jet milling, supercritical fluid processing to create nanoparticles, high pressure homogenization, or spray drying.

[0184] Capsules, blisters, and cartridges for use in inhalers or insufflators can be formulated to contain a powder mixture of the pharmaceutical composition provided herein; a suitable powder base such as lactose or starch; and a performance modifier such as l-leucine, mannitol, or magnesium stearate. Lactose can be anhydrous or in the form of a monohydrate. Other suitable excipients or carriers include, but are not limited to, dextran, glucose, maltose, sorbitol, xylitol, fructose, sucrose, and trehalose. The pharmaceutical compositions for inhalation / intranasal administration provided herein may further contain a suitable flavoring agent, such as menthol and levomenthol; and / or a sweetener, such as saccharin and saccharin sodium.

[0185] The pharmaceutical compositions provided herein for topical administration can be formulated to be immediate or modified release, including delayed-, sustained-, pulsed-, controlled-, targeted-, and programmed-release.

[0186] (D. Modified release) The pharmaceutical compositions provided herein can be formulated as modified-release dosage forms. As used herein, the term "modified-release" refers to a dosage form in which the rate or location of release of an active ingredient(s) differs from that of an immediate-release dosage form when administered by the same route. Modified-release dosage forms include, but are not limited to, delayed-release, extended-release, prolonged-release, sustained-release, pulsed-release, controlled-release, accelerated and rapid-release, targeted-release, programmed-release, and gastroretentive dosage forms. Modified-release pharmaceutical compositions can be prepared using various modified-release devices and methods known to those skilled in the art, including, but not limited to, matrix-controlled release devices, osmotic-controlled release devices, multiparticulate-controlled release devices, ion-exchange resins, enteric coatings, multilayer coatings, microspheres, liposomes, and combinations thereof. The release rate of an active ingredient(s) can also be modified by varying the particle size and polymorphism of the active ingredient.

[0187] (1. Matrix Controlled Release Devices) The pharmaceutical compositions of the controlled release dosage forms provided herein can be prepared using matrix controlled release devices known to those skilled in the art.For example, see Takada et al., in Encyclopedia of Controlled Drug Delivery, edited by Mathiowitz; Wiley, 1999; Vol. 2.

[0188] In certain embodiments, the modified-release dosage forms of the pharmaceutical compositions provided herein are formulated using erodible matrix devices, which are water-swellable, erodible, or soluble polymers, including but not limited to synthetic polymers and natural polymers and derivatives such as polysaccharides and proteins.

[0189] Materials useful for making erodible matrices include chitin, chitosan, dextran, and pullulan; agar gum, gum arabic, karaya gum, locust bean gum, tragacanth gum, carrageenan, gum ghatti, guar gum, xanthan gum, and scleroglucan; starches such as dextrin and maltodextrin; hydrophilic colloids such as pectin; phosphatides such as lecithin; alginates; propylene glycol alginate; gelatin; collagen; ethyl cellulose (EC), methyl ethyl cellulose (MEC), carboxymethyl cellulose (CMC), CMEC, hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC), cellulose acetate (CA), cellulose propionate (CP), cellulose butyrate (CB), cellulose acetate butyrate (CAB), CAP, CAT, hydroxypropyl methylcellulose (HPMC), HPMCP, HPMCA. poly(2-hydroxyethyl-methacrylate); polylactic acid; copolymers of L-glutamic acid and ethyl-L-glutamate; degradable lactic acid-glycolic acid copolymers; poly-D-(-)-3-hydroxybutyric acid; and other acrylic acid derivatives such as homopolymers and copolymers of butyl methacrylate, methyl methacrylate, ethyl methacrylate, ethyl acrylate, (2-dimethylaminoethyl) methacrylate, and (trimethylaminoethyl) methacrylate chloride.

[0190] In certain embodiments, the pharmaceutical compositions provided herein are formulated using a non-erodible matrix device: the active ingredient(s) are dissolved or dispersed in an inert matrix and, upon administration, are released primarily by diffusion through the inert matrix. Materials suitable for use as non-erodible matrix devices include, but are not limited to, insoluble plastics such as polyethylene, polypropylene, polyisoprene, polyisobutylene, polybutadiene, polymethyl methacrylate, polybutyl methacrylate, chlorinated polyethylene, polyvinyl chloride, methyl acrylate-methyl methacrylate copolymer, ethylene-vinyl acetate copolymer, ethylene / propylene copolymer, ethylene / ethyl acrylate copolymer, vinyl acetate, vinylidene chloride, vinyl chloride copolymers with ethylene and propylene, ionomeric polyethylene terephthalate, butyl rubber, epichlorohydrin rubber, ethylene / vinyl alcohol copolymer, ethylene / vinyl acetate / vinyl alcohol terpolymer, ethylene / vinyloxyethanol copolymer, polyvinyl chloride, plasticized nylon, plasticized polyethylene terephthalate, natural rubber, silicone rubber, polydimethylsiloxane, and silicone-carbonate copolymer; hydrophilic polymers such as ethyl cellulose, cellulose acetate, crospovidone, and cross-linked partially hydrolyzed polyvinyl acetate; and fatty compounds such as carnauba wax, microcrystalline wax, and triglycerides.

[0191] In matrix controlled-release systems, the desired release kinetics can be controlled, for example, by the type of polymer employed, the polymer viscosity, the particle size of the polymer and / or the active ingredient(s), the ratio of active ingredient(s) to polymer, and other excipients or carriers in the composition.

[0192] The modified-release pharmaceutical compositions provided herein can be prepared by methods known to those skilled in the art, including direct compression, dry or wet granulation followed by compression, and melt granulation followed by compression.

[0193] (2. Osmotic Controlled Release Devices) The pharmaceutical compositions of the modified release dosage forms provided herein can be prepared using osmotic controlled release devices, including, but not limited to, one-chamber systems, two-chamber systems, asymmetric membrane technology (AMT), and extruded core systems (ECS). Generally, such devices have at least two components: (a) a core containing an active ingredient; and (b) a semipermeable membrane with at least one delivery port that encapsulates the core. The semipermeable membrane controls the influx of water from an aqueous use environment into the core, causing drug release by extrusion through the delivery port(s).

[0194] In addition to the active ingredient(s), the core of the osmotic device optionally contains an osmotic agent that creates a driving force for the transport of water from the environment of use into the core of the device. One class of osmotic agents are water-swellable hydrophilic polymers, also referred to as "osmopolymers" and "hydrogels." Water-swellable hydrophilic polymers suitable as osmotic agents include, but are not limited to, hydrophilic vinyl and acrylic polymers, polysaccharides (such as calcium alginate), polyethylene oxide (PEO), polyethylene glycol (PEG), polypropylene glycol (PPG), poly(2-hydroxyethyl methacrylate), poly(acrylic) acid, poly(methacrylic) acid, polyvinylpyrrolidone (PVP), crosslinked PVP, polyvinyl alcohol (PVA), PVA / PVP copolymers, PVA / PVP copolymers with hydrophobic monomers such as methyl methacrylate and vinyl acetate, hydrophilic polyurethanes containing large PEO blocks, sodium croscarmellose, carrageenan, hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose (HPMC), carboxymethyl cellulose (CMC) and carboxyethyl cellulose (CEC), sodium alginate, polycarbophil, gelatin, xanthan gum, and sodium starch glycolate.

[0195] Another class of osmotic agents is osmogens, which can absorb water and affect the osmotic pressure gradient of the surrounding membrane barrier. Suitable osmogens include, but are not limited to, inorganic salts such as magnesium sulfate, magnesium chloride, calcium chloride, sodium chloride, lithium chloride, potassium sulfate, potassium phosphate, sodium carbonate, sodium sulfite, lithium sulfate, potassium chloride, and sodium sulfate; sugars such as dextrose, fructose, glucose, inositol, lactose, maltose, mannitol, raffinose, sorbitol, sucrose, trehalose, and xylitol; organic acids such as ascorbic acid, benzoic acid, fumaric acid, citric acid, maleic acid, sebacic acid, sorbic acid, adipic acid, edetic acid, glutamic acid, p-toluenesulfonic acid, succinic acid, and tartaric acid; urea; and mixtures thereof.

[0196] Osmotic agents with different dissolution rates can be employed to affect how rapidly the active ingredient(s) are initially delivered from the dosage form. For example, amorphous sugars such as MANNOGEM™ EZ can be used to provide a faster delivery in the first two hours that produces an immediate desired therapeutic effect, and a slower, continuous release of the remaining amount that maintains the desired level of therapeutic or prophylactic action over an extended period of time. In this case, the active ingredient(s) is released at a rate that replaces the amount of the active ingredient that is metabolized and excreted.

[0197] The core may also include a variety of other excipients and carriers as described herein that improve the performance of the dosage form or facilitate stability or processing.

[0198] Materials useful for forming semipermeable membranes include various grades of acrylics, vinyls, ethers, polyamides, polyesters, and cellulosics that are water-permeable and water-insoluble at physiologically relevant pH and are easily rendered water-insoluble by chemical modification, such as crosslinking. Examples of suitable polymers useful for forming coatings include plasticized, unplasticized, and reinforced cellulose acetate (CA), cellulose diacetate, cellulose triacetate, CA propionate, cellulose nitrate, cellulose acetate butyrate (CAB), CA ethyl carbamate, CAP, CA methyl carbamate, CA succinate, cellulose acetate trimellitate (CAT), CA dimethylaminoacetate, CA ethyl carbonate, CA chloroacetate, CA ethyl oxalate, CA methyl sulfonate, CA butyl sulfonate, CA p-toluenesulfonate, agar acetate (agaracetate), amylose triacetate, beta-glucan acetate, beta-glucan triacetate, acetaldehyde dimethyl acetate, triacetate of locust bean gum, hydroxylated ethylene-vinyl acetate, EC, PEG, PPG, PEG / PPG copolymers, PVP, HEC, HPC, CMC, CMEC, HPMC, HPMCP, HPMCAS, HPMCAT, poly(acrylic) acids and esters and poly-(methacrylic) acids and esters and copolymers thereof, starch, dextran, dextrin, chitosan, collagen, gelatin, polyalkenes, polyethers, polysulfones, polyethersulfones, polystyrene, polyvinyl halides, polyvinyl esters and ethers, natural waxes, and synthetic waxes.

[0199] The semipermeable membrane may also be a hydrophobic microporous membrane in which the pores are substantially filled with gas and are not wetted by aqueous media but are permeable to water vapor, as disclosed in U.S. Patent No. 5,798,119. Such hydrophobic but water vapor permeable membranes are typically composed of hydrophobic polymers such as polyalkenes, polyethylene, polypropylene, polytetrafluoroethylene, polyacrylic acid derivatives, polyethers, polysulfones, polyethersulfones, polystyrene, polyvinyl halides, polyvinylidene fluoride, polyvinyl esters and ethers, natural waxes, and synthetic waxes.

[0200] The delivery port(s) on the semipermeable membrane can be formed by mechanical or laser drilling after coating. The delivery port(s) can also be formed in situ by erosion of a plug of water-soluble material or by rupture of a thin section of the membrane covering a core cavity. Additionally, delivery ports can be formed during the coating process, such as in the coating of asymmetric membranes of the type disclosed in U.S. Patent Nos. 5,612,059 and 5,698,220.

[0201] The total amount and rate of release of the active ingredient(s) can be substantially controlled by the thickness and porosity of the semipermeable membrane, the composition of the core, and the number, size, and location of the delivery ports.

[0202] The osmotic controlled-release dosage form of the pharmaceutical composition may further comprise additional conventional excipients or carriers as described herein that facilitate performance or processing of the formulation.

[0203] Osmotic controlled-release dosage forms can be prepared by conventional methods and techniques known to those skilled in the art (see, for example, Remington: The Science and Practice of Pharmacy, supra; Santus and Baker, J. Controlled Release, 1995, 35, 1-21; Verma et al., Drug Dev. Ind. Pharm., 2000, 26, 695-708; Verma et al., J. Controlled Release, 2002, 79, 7-27).

[0204] In some embodiments, the pharmaceutical compositions provided herein are formulated as AMT controlled-release dosage forms, comprising an asymmetric osmotic membrane surrounding a core comprising an active ingredient(s) and other pharmaceutically acceptable excipients or carriers.See, for example, U.S. Patent No. 5,612,059 and WO2002 / 17918.AMT controlled-release dosage forms can be prepared by conventional methods and techniques known to those skilled in the art, such as direct compression, dry granulation, wet granulation, and dip-coating.

[0205] In certain embodiments, the pharmaceutical compositions provided herein are formulated as ESC controlled-release dosage forms comprising an osmotic membrane covering a core comprising the active ingredient(s), hydroxyethylcellulose, and other pharmaceutically acceptable excipients or carriers.

[0206] 3. Multiparticulate Controlled Release Devices The pharmaceutical compositions provided herein in modified-release dosage forms can be prepared as multiparticulate controlled-release devices comprising a variety of particles, granules, or pellets ranging in diameter from about 10 μm to about 3 mm, about 50 μm to about 2.5 mm, or about 100 μm to about 1 mm. Such multiparticulates can be prepared by processes known to those skilled in the art, such as wet and dry granulation, extrusion-spheronization, roller compaction, melt-congealing, and by spray-coating seed cores. See, for example, "Multiparticulate Oral Drug Delivery," edited by Ghebre-Sellassie; Drugs and the Pharmaceutical Sciences 65; CRC Press: 1994; and "Pharmaceutical Palletization Technology," edited by Ghebre-Sellassie; Drugs and the Pharmaceutical Sciences 37; CRC Press: 1989.

[0207] Other excipients or carriers, as described herein, can be mixed with the pharmaceutical composition to aid in the processing and formation of the multiparticulates. The resulting particles can themselves constitute the multiparticulate device or can be coated with various film-forming materials, such as enteric polymers, water-swellable, and water-soluble polymers. The multiparticulates can be further processed into capsules or tablets.

[0208] (4. Targeted delivery) The pharmaceutical compositions provided herein can also be formulated to be targeted to specific tissues, receptors, or other areas of the body of the subject being treated, such as with liposomes, resealed erythrocytes, and antibody-based delivery systems. Examples include U.S. Patent Nos. 6,316,652; 6,274,552; 6,271,359; 6,253,872; 6,139,865; 6,131,570; 6,120,751; 6,071,495; 6,060,082; and 6,048,733. Nos. 6,039,975; 6,004,534; 5,985,307; 5,972,366; 5,900,252; 5,840,674; 5,759,542; and 5,709,874.

[0209] (Method of use) In one embodiment, provided herein is a method of labeling cells in a subject with an azido group, comprising administering to the subject in need thereof an effective amount of a compound provided herein, e.g., a compound of Formula (I), or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0210] In another embodiment, provided herein is a method of labeling a cell surface with an azido group in a subject, comprising administering to the subject in need thereof an effective amount of a compound provided herein, e.g., a compound of Formula (I), or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0211] In certain embodiments, the subject is a mammal, hi certain embodiments, the subject is a human.

[0212] In certain embodiments, the cells are cancerous cells.

[0213] In certain embodiments, an effective amount of a compound provided herein is in the range of about 0.1 to about 100 mg / kg / day, about 0.1 to about 50 mg / kg / day, about 0.1 to about 25 mg / kg / day, about 0.1 to about 20 mg / kg / day, about 0.1 to about 15 mg / kg / day, about 0.1 to about 10 mg / kg / day, or about 0.1 to about 5 mg / kg / day. In one embodiment, an effective amount of a compound provided herein is in the range of about 0.1 to about 100 mg / kg / day. In another embodiment, an effective amount of a compound provided herein is in the range of about 0.1 to about 50 mg / kg / day. In yet another embodiment, an effective amount of a compound provided herein is in the range of about 0.1 to about 25 mg / kg / day. In yet another embodiment, an effective amount of a compound provided herein is in the range of about 0.1 to about 20 mg / kg / day. In yet another embodiment, an effective amount of a compound provided herein is in the range of about 0.1 to about 15 mg / kg / day. In yet another embodiment, an effective amount of a compound provided herein ranges from about 0.1 to about 10 mg / kg / day. In yet another embodiment, an effective amount of a compound provided herein ranges from about 0.1 to about 5 mg / kg / day.

[0214] In certain embodiments, an effective amount of a compound provided herein is in the range of about 1 to about 1,000 mg per day, about 1 to about 500 mg per day, about 1 to about 200 mg per day, or about 1 to about 100 mg per day. In one embodiment, an effective amount of a compound provided herein is in the range of about 1 to about 1,000 mg per day. In another embodiment, an effective amount of a compound provided herein is in the range of about 1 to about 500 mg per day. In yet another embodiment, an effective amount of a compound provided herein is in the range of about 1 to about 200 mg per day. In yet another embodiment, an effective amount of a compound provided herein is in the range of about 1 to about 100 mg per day.

[0215] Depending on the disorder, disease, or condition to be treated and the condition of the subject, the compounds provided herein can be administered by oral, parenteral (e.g., intramuscular, intraperitoneal, intravenous, CIV, intracisternal injection or infusion, subcutaneous injection, or implant), inhalation, nasal, vaginal, rectal, sublingual, or topical (e.g., transdermal or topical) routes of administration. The compounds provided herein can be formulated into suitable dosage units using pharmaceutically acceptable excipients, carriers, adjuvants, or vehicles appropriate for each route of administration.

[0216] In one embodiment, the compounds provided herein are administered orally. In another embodiment, the compounds provided herein are administered parenterally. In yet another embodiment, the compounds provided herein are administered intravenously. In yet another embodiment, the compounds provided herein are administered intramuscularly. In yet another embodiment, the compounds provided herein are administered subcutaneously. In yet another embodiment, the compounds provided herein are administered topically. In yet another embodiment, the compounds provided herein are administered by topical instillation.

[0217] The compounds provided herein can be administered as a single dose, e.g., as a single bolus injection or oral tablet or pill; or delivered over time, e.g., by continuous infusion or divided bolus doses over time. The compounds provided herein can be administered repeatedly, if necessary, e.g., until the subject experiences stable disease or regression, or until the subject experiences disease progression or unacceptable toxicity.

[0218] The compounds provided herein can be administered once daily (QD) or divided into multiple daily doses, such as twice daily (BID) and three times daily (TID). In addition, administration can be continuous, i.e., daily, or intermittent. The terms "intermittent" or "intermittently," as used herein, are intended to mean stopping and starting at either regular or irregular intervals. For example, intermittent administration of the compounds provided herein can be administration 1 to 6 days per week, cyclical administration (e.g., daily administration for 2 to 8 consecutive weeks, followed by a rest period of up to 1 week during which no administration occurs), or every other day administration.

[0219] The compounds provided herein may also be combined or used in combination with therapeutic agents useful in the treatment and / or prevention of the conditions, disorders, or diseases defined herein.

[0220] As used herein, the term "in combination" includes the use of two or more therapies (e.g., one or more prophylactic and / or therapeutic agents). However, the use of the term "in combination" does not restrict the order in which therapies (e.g., prophylactic and / or therapeutic agents) are administered to a subject with a condition, disorder, or disease. A first therapy (e.g., a prophylactic or therapeutic agent, such as a compound provided herein) can be administered prior to (e.g., 5 minutes, 15 minutes, 50 minutes, 65 minutes, 1 hour, 2 hours, 6 hours, 6 hours, 12 hours, 26 hours, 68 hours, 72 hours, 96 hours, 1 week, 2 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks before), concurrently with, or subsequent to (e.g., 5 minutes, 15 minutes, 50 minutes, 65 minutes, 1 hour, 2 hours, 6 hours, 12 hours, 26 hours, 68 hours, 72 hours, 96 hours, 1 week, 2 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks after) administration of a second therapy (e.g., a prophylactic or therapeutic agent) to a subject. Triple combination therapies are also contemplated herein.

[0221] The route of administration of the compound provided herein is independent of the route of administration of the second therapy. In one embodiment, the compound provided herein is administered orally. In another embodiment, the compound provided herein is administered intravenously. In another embodiment, the compound provided herein is administered topically. Thus, according to these embodiments, the compound provided herein is administered orally, intravenously, or topically, and the second therapy can be administered orally, parenterally, intraperitoneally, intravenously, intraarterially, transdermally, sublingually, intramuscularly, rectally, bucally, intranasally, liposomally, inhalationally, vaginally, intraocularly, via local delivery by catheter or stent, subcutaneously, intraadiposally, intraarticularly, intrathecally, topically, or in a sustained release dosage form. In one embodiment, the compound provided herein and the second therapy are administered topically using the same administration method. In another embodiment, the compound provided herein is administered by one administration method, for example, topically, and the second agent (anticancer agent) is administered by another administration method, for example, orally.

[0222] In one embodiment, provided herein is a method of labeling a cell with an azido group, comprising contacting the cell with an effective amount of a compound provided herein, e.g., a compound of Formula (I), or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0223] In another embodiment, provided herein is a method of labeling a cell surface with an azide group, comprising contacting a cell with an effective amount of a compound provided herein, e.g., a compound of Formula (I), or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0224] In certain embodiments, the cells are cancerous cells.

[0225] The compounds provided herein can also be provided as products using packaging materials well known to those skilled in the art.For example, see U.S. Patent No. 5,525,907; U.S. Patent No. 5,052,558; and U.S. Patent No. 5,055,252.Examples of pharmaceutical packaging materials include, but are not limited to, blister packs, bottles, tubes, inhalers, pumps, bags, vials, containers, syringes, and any packaging material suitable for the selected formulation and intended administration mode and treatment.

[0226] In some embodiments, provided herein are kits that, when used by a physician, can simplify the administration of an appropriate amount of a compound provided herein as an active ingredient to a subject. In some embodiments, the kits provided herein include a container and a dosage form of a compound provided herein.

[0227] The kits provided herein may further include a device used to administer the active ingredient. Examples of such devices include, but are not limited to, syringes, needleless injectors, drip bags, patches, and inhalers. The kits provided herein may also include condoms for administering the active ingredient.

[0228] The kits provided herein can further include a pharmaceutically acceptable vehicle that can be used to administer one or more active ingredients. For example, if the active ingredient is provided in a solid form that must be reconstituted for parenteral administration, the kit can include a sealed container of a suitable vehicle in which the active ingredient can be dissolved to form a particulate-free, sterile solution suitable for parenteral administration. Examples of pharmaceutically acceptable vehicles include, but are not limited to: aqueous vehicles, including, but not limited to, Water for Injection, USP, Sodium Chloride Injection, Ringer's Injection, Dextrose Injection, Dextrose and Sodium Chloride Injection, and Lactated Ringer's Injection; water-miscible vehicles, including, but not limited to, ethyl alcohol, polyethylene glycol, and polypropylene glycol; and non-aqueous vehicles, including, but not limited to, corn oil, cottonseed oil, peanut oil, sesame oil, ethyl oleate, isopropyl myristate, and benzyl benzoate.

[0229] The present disclosure will be further understood by the following non-limiting examples. [Example]

[0230] (Example) As used herein, the symbols and terminology used in the methods, schemes, and examples are consistent with those used in modern scientific literature, e.g., the Journal of the American Chemical Society, the Journal of Medicinal Chemistry, or the Journal of Biological Chemistry, regardless of whether a particular abbreviation is specifically defined. Specifically, but not by way of limitation, the following abbreviations may be used in the examples and throughout the specification: g (grams); mg (milligrams); mL (milliliters); μL (microliters); mM (millimoles); μM (micromolar); mmol (millimolar); min (minute); h (hour); Ac (acetyl); ACN (acetonitrile); t-Bu (tert-butyl); DCC (N,N'-dicyclohexylcarbodiimide); DCM (dichloromethane); DMAP (4-dimethylaminopyridine); DMSO (dimethyl sulfoxide); EDCI (1-ethyl-3-(3-dimethylaminopropyl)carbodiimide); EtOAc (ethyl acetate); EtO (ethyl ether); Fmoc (fluorenylmethyloxycarbonyl); IPA (isopropyl alcohol); MeOH (methanol); PE (petroleum ether); TBAF (tetra-n-butylammonium fluoride); TEA (triethylamine); THF (tetrahydrofuran); TIPS (triisopropylsilyl); MS (mass spectrometry); NMR (nuclear magnetic resonance); and prep-HPLC (preparative high-performance liquid chromatography).

[0231] For all of the following examples, standard work-up and purification methods known to those skilled in the art can be used. Unless otherwise indicated, all temperatures are in °C (degrees Celsius). Unless otherwise specified, all reactions are conducted at room temperature. The synthetic methods described herein are intended to illustrate applicable chemistry through the use of specific examples and do not represent the scope of the present disclosure.

[0232] Example 1 (Preparation of acetyl 2-(2-azidoacetylamino)-2-deoxy-3,4-di-O-acetyl-6-O-(((S)-1-isopropoxy-carbonylethylamino)(phenoxy)phosphoryl)-D-mannopyranoside A1) [ka] Compound A1 was prepared as shown in Scheme 1.

[0233] Preparation of isopropyl (chloro(phenoxy)phosphoryl)-L-alaninate 1.2 To a solution of isopropyl L-alaninate 1.1 (2 g, 11.9 mmol) and phenyl phosphorodichloridate (2.51 g, 11.9 mmol) in dry DCM (30.0 mL) was added TEA (2.41 g, 23.8 mmol) dropwise over 20 min at −78 °C under N. The reaction mixture was stirred at −78 °C for 30 min, then slowly warmed to room temperature and stirred for an additional 3.5 h. The reaction mixture was concentrated in vacuo, diluted with EtO (20 mL), filtered through Celite, and concentrated in vacuo to give compound 1.2 (2.51 g), which was used directly in the next step without further purification. [ka]

[0234] (Preparation of acetyl 2-(2-azidoacetylamino)-2-deoxy-3,4-di-O-acetyl-6-O-(((S)-1-isopropoxy-carbonylethylamino)(phenoxy)phosphoryl)-D-mannopyranoside A1) To a solution of acetyl 2-(2-azidoacetylamino)-2-deoxy-3,4-di-O-acetyl-D-mannopyranoside 1.3 (3.2 g, 8.24 mmol) in anhydrous THF (20.0 mL) was added 1 M t-BuMgCl in THF (12.4 mL, 12.4 mmol) dropwise over 10 min at 0 °C under N. After stirring the solution at 0 °C for 30 min, compound 1.2 (2.51 g) in anhydrous THF (10 mL) was added dropwise over 10 min at 0 °C. After slowly warming to room temperature and stirring for 12 h, the reaction mixture was concentrated to give the crude product, which was purified by silica gel column chromatography eluting with EtOAc in PE to give compound A1 (4.4 g, α:β ratio: 61:39) in 81% yield. [ka]

[0235] Example 2 (Preparation of 2-(2-azidoacetylamino)-2-deoxy-3,4-di-O-acetyl-6-O-(((S)-1-isopropoxy-carbonylethylamino)(phenoxy)phosphoryl)-D-mannopyranoside A2 and pyridin-3-ylacetyl 2-(2-azidoacetylamino)-2-deoxy-3,4-di-O-acetyl-6-O-(((S)-1-isopropoxycarbonylethylamino)(phenoxy)phosphoryl)-D-mannopyranoside A8) [ka] Compounds A2 and A8 were prepared as shown in Scheme 2. [ka]

[0236] (Preparation of 2-(2-azidoacetylamino)-2-deoxy-3,4-di-O-acetyl-6-O-(((S)-1-isopropoxy-carbonylethylamino)(phenoxy)phosphoryl)-D-mannopyranoside A2) To a solution of compound A1 (200 mg, 0.304 mmol) in MeOH / THF (2 mL / 2 mL) was added ammonium carbonate (87.6 mg, 0.912 mmol) in three portions at room temperature. After stirring at room temperature for 3 hours, the reaction mixture was concentrated to give the crude product, which was purified by silica gel column chromatography eluting with EtOAc in PE to give compound A2 (50 mg) in 26% yield. MS (ESI) m / z: 616.5 [M+H] + .

[0237] (Preparation of pyridin-3-ylacetyl 2-(2-azidoacetylamino)-2-deoxy-3,4-di-O-acetyl-6-O-(((S)-1-isopropoxycarbonylethylamino)(phenoxy)phosphoryl)-D-mannopyranoside A8) To a solution of compound A2 (10 mg, 0.16 mmol) and 2-(pyridin-3-yl)acetic acid (5.62 mg, 0.32 mmol) was added DMAP (0.99 mg, 0.0081 mmol) and EDCI (9.3 mg, 0.049 mmol) in dry dioxane (0.50 mL) at 0° C. After warming to room temperature and stirring for 12 h, the reaction mixture was concentrated in vacuo to give the crude product, which was purified by reverse-phase preparative HPLC to give compound A8 (38.2 mg, α:β ratio: 54:46) in 32% yield. [ka]

[0238] Example 3 (Preparation of acetyl 2-(2-azidoacetylamino)-2-deoxy-3,4-di-O-acetyl-6-O-(((S)-1-butoxy-carbonylethylamino)(phenoxy)phosphoryl)-D-mannopyranoside A18) [ka] Compound A18 was prepared as shown in Scheme 3.

[0239] Preparation of butyl (((9H-fluoren-9-yl)methoxy)carbonyl)-L-alaninate 3.2 To a solution of Fmoc-L-alanine 3.1 (1 g, 3.21 mmol) and butanol (470 mg, 6.34 mmol) in dry DCM (20 mL) was added EDCI (1.84 g, 9.60 mmol) and DMAP (80 mg, 0.655 mmol) at room temperature. After stirring at room temperature for 3 hours, the reaction mixture was concentrated to give the crude product, which was purified by silica gel column chromatography eluting with EtOAc in PE to give compound 3.2 (310 mg) in 31% yield. MS (ESI) m / z: 368.2 [M+H] + .

[0240] Preparation of butyl L-alaninate 3.3 To a solution of compound 3.2 (290 mg, 0.789 mmol) in dry ACN (3 mL) was added diethylamine (115 mg, 1.58 mmol) at room temperature. After stirring at 60° C. for 12 hours, the reaction mixture was concentrated to give the crude product, which was purified by silica gel column chromatography eluting with acetone in DCM to give compound 3.3 (69 mg) in 60% yield. MS (ESI) m / z: 146.1 [M+H] + . [ka]

[0241] Preparation of butyl (chloro(phenoxy)phosphoryl)-L-alaninate 3.4 To a stirred solution of compound 3.3 (69 mg, 0.475 mmol) and phenyl phosphorodichloridate (100 mg, 0.474 mmol) in dry DCM (1.0 mL) was added TEA (96 mg, 0.949 mmol) under N at −78° C. After stirring for 30 min at −78° C. and then at room temperature for 3 h, the reaction mixture was concentrated in vacuo, diluted with anhydrous THF (2 mL), filtered through Celite, and concentrated in vacuo to give compound 3.4 (75 mg), which was used directly in the next step without further purification.

[0242] (Preparation of acetyl 2-(2-azidoacetylamino)-2-deoxy-3,4-di-O-acetyl-6-O-(((S)-1-butoxy-carbonylethylamino)(phenoxy)phosphoryl)-D-mannopyranoside A18) To a solution of acetyl 2-(2-azidoacetylamino)-2-deoxy-3,4-di-O-acetyl-D-mannopyranoside 1.3 (185 mg, 0.476 mmol) in dry THF (1 mL) was added t-BuMgCl (0.7 mL, 0.713 mmol) at 0 °C under N. After stirring the mixture at 0 °C for 30 min, compound 3.4 (152 mg, 0.475 mmol) in THF (1 mL) was added. The reaction mixture was slowly warmed to room temperature and stirred for 12 h. The reaction mixture was purified by reverse-phase preparative HPLC to give compound A18 (50.8 mg, α:β ratio: 65:35) in 16% yield. [ka]

[0243] Example 4 (Preparation of acetyl 2-(2-azidoacetylamino)-2-deoxy-3,4-di-O-acetyl-6-O-(((S)-1-tert-butoxy-carbonylethylamino)(phenoxy)phosphoryl)-D-mannopyranoside A20) [ka] Compound A20 was prepared as shown in Scheme 4. [ka]

[0244] Preparation of tert-butyl ((perfluorophenoxy)(phenoxy)phosphoryl)-L-alaninate 4.2 To a mixture of compound 4.1 (700 mg, 4.82 mmol) in THF (20 mL) was added TEA (1.46 g, 14.46 mmol) and phenylphosphorodichloridate (1.02 g, 4.82 mmol). The mixture was stirred at −78° C. under N for 1 h and then warmed to 0° C. over 2 h, after which 2,3,4,5,6-pentafluorophenol (887 mg, 4.82 mmol) was added under N. The reaction mixture was stirred at 0° C. for 2 h and then concentrated to give the crude product, which was purified by silica gel column chromatography eluting with IPA in DCM to give compound 4.2 (600 mg) in 27% yield. MS (ESI) m / z: 490.1 [M+Na] + .

[0245] (Preparation of acetyl 2-(2-azidoacetylamino)-2-deoxy-3,4-di-O-acetyl-6-O-(((S)-1-tert-butoxy-carbonylethylamino)(phenoxy)phosphoryl)-D-mannopyranoside A20) To a mixture of acetyl 2-(2-azidoacetylamino)-2-deoxy-3,4-di-O-acetyl-D-mannopyranoside 1.3 (500 mg, 1.28 mmol) in THF (10 mL) was added t-BuMgCl (1.93 mL, 1.93 mmol) at 0 °C under N. After the mixture was stirred at 0 °C under N for 30 min, compound 4.2 (600 mg, 1.28 mmol) was added at 0 °C under N. After stirring at 0 °C under N for 1 h, the reaction was quenched with NH.sub.4Cl (20 mL), and the reaction mixture was extracted with EtOAc. The combined organic layers were washed with brine (100 mL × 3), dried over anhydrous Na.sub.2SO.sub.4, filtered, and concentrated to give the crude product, which was purified by reverse-phase preparative HPLC to give compound A20 (102 mg, α:β ratio: 66:34) in 12% yield. [ka]

[0246] Example 5 (Preparation of acetyl 2-(2-azidoacetylamino)-2-deoxy-3,4-di-O-acetyl-6-O-(((S)-1-isopropoxy-carbonylethylamino)(quinolin-5-yloxy)phosphoryl)-D-mannopyranoside A34) [ka] Compound A34 was prepared as shown in Scheme 5. [ka]

[0247] Preparation of quinolin-5-yl phosphorodichloridate 5.2 To a solution of POCl (1.06 g, 6.9 mmol) in anhydrous DCM (5.00 mL) was added dropwise (5 min) quinolin-5-ol 5.1 (1 g, 6.9 mmol) and TEA (0.7 g, 6.9 mmol) in anhydrous DCM (15.0 mL) at −78° C. under N. After stirring at room temperature for 2 h, the reaction mixture was concentrated in vacuo to give compound 5.2 (2 g), which was used directly in the next step without further purification.

[0248] (Preparation of acetyl 2-(2-azidoacetylamino)-2-deoxy-3,4-di-O-acetyl-6-O-(((S)-1-isopropoxy-carbonylethylamino)(quinolin-5-yloxy)phosphoryl)-D-mannopyranoside A34) Compound A34 (α:β ratio: 57:43) was prepared by the procedure described in Example 1. [ka]

[0249] Example 6 Preparation of (3S,4R,5S,6R)-3-(2-azidoacetamido)-6-(((3-(((((S)-1-isopropoxy-1-oxopropan-2-yl)amino)(phenoxy)phosphoryl)oxy)propanoyl)oxy)methyl)tetrahydro-2H-pyran-2,4,5-triyl triacetate A35 [ka] Compound A35 was prepared as shown in Scheme 6. [ka]

[0250] Preparation of (3S,4R,5S,6R)-3-(2-azidoacetamido)-6-(((3-((triisopropylsilyl)-oxy)propanoyl)oxy)methyl)tetrahydro-2H-pyran-2,4,5-triyl triacetate 6.2 To a stirred solution of 3-((triisopropylsilyl)oxy)propanoic acid 6.1 (190 mg, 773 μmol) in dry DCM (2 mL) was added DMAP (31.3 mg, 257 μmol) and acetyl 2-(2-azidoacetylamino)-2-deoxy-3,4-di-O-acetyl-D-mannopyranoside 1.3 (100 mg, 257 μmol), followed by DCC (79.4 mg, 385 μmol) at 0° C. After stirring at 0° C. for 5 min and at 30° C. overnight, the reaction mixture was concentrated and purified by silica gel column chromatography eluting with EtOAc in PE to give compound 6.2 (60 mg) in 38% yield. [ka]

[0251] Preparation of (3S,4R,5S,6R)-3-(2-azidoacetamido)-6-(((3-hydroxypropanoyl)-oxy)methyl)tetrahydro-2H-pyran-2,4,5-triyl triacetate 6.3. A mixture of compound 6.2 (200 mg, 324 μmol) and TBAF (0.6 mL) in THF (4.0 mL) was stirred overnight. The reaction mixture was then concentrated and purified by silica gel column chromatography eluting with EtOAc in PE to give compound 6.3 (61 mg) in 41% yield. [ka]

[0252] Preparation of (3S,4R,5S,6R)-3-(2-azidoacetamido)-6-(((3-(((((S)-1-isopropoxy-1-oxopropan-2-yl)amino)(phenoxy)phosphoryl)oxy)propanoyl)oxy)methyl)tetrahydro-2H-pyran-2,4,5-triyl triacetate A35 To a solution of compound 6.3 (61 mg, 132 μmol) in THF (3 mL) at 0° C., 1 M t-BuMgCl in THF (0.2 mL) was added dropwise under Ar. The resulting mixture was stirred at 0° C. for 1 h, followed by the addition of a solution of compound 6.4 (120 mg, 264 μmol) in THF (2 mL) at 0° C. The reaction mixture was stirred at 0° C. for 1 h, then diluted with saturated aqueous NH4Cl and extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated to give the crude product, which was purified by silica gel column chromatography eluting with EtOAc in PE and further purified by reverse-phase preparative HPLC to give compound A35 (19.3 mg, α:β ratio: 31:69) in 20% yield. [ka]

[0253] The following compounds were similarly prepared according to the synthetic procedures or methodologies exemplified herein.

[0254] 2-(2-Azidoacetylamino)-2-deoxy-3,4-di-O-acetyl-6-O-(((1S)-1-(1-phenylethoxy-carbonyl)ethylamino)(phenoxy)phosphoryl)-D-mannopyranoside A3 (α:β ratio: 65:35). [ka]

[0255] 2-(2-Azidoacetylamino)-2-deoxy-3,4-di-O-acetyl-6-O-((1-methyl-1-(1-phenyl-ethoxycarbonyl)ethylamino)(phenoxy)phosphoryl)-D-mannopyranoside A4 (α:β ratio: 55:45). [ka]

[0256] 2-(2-Azidoacetylamino)-2-deoxy-3,4-di-O-acetyl-6-O-(((1S)-1-(1-phenylethoxy-carbonyl)-2-methylpropylamino)(phenoxy)phosphoryl)-D-mannopyranoside A5 (α:β ratio: 70:30). [ka] [ka]

[0257] 2-(2-Azidoacetylamino)-2-deoxy-3,4-di-O-acetyl-6-O-((1-methyl-1-(1-methyl-1-phenylethoxycarbonyl)ethylamino)(phenoxy)phosphoryl)-D-mannopyranoside A6 (α:β ratio: 64:36). [ka]

[0258] 2-(2-Azidoacetylamino)-2-deoxy-3,4-di-O-acetyl-6-O-(((1S)-1-(1-methyl-1-phenylethoxycarbonyl)-2-methylpropylamino)(phenoxy)phosphoryl)-D-mannopyranoside A7 (α:β ratio: 65:35). [ka] [ka]

[0259] 3-Morpholinopropanoyl 2-(2-azidoacetylamino)-2-deoxy-3,4-di-O-acetyl-6-O-(((S)-1-isopropoxycarbonylethylamino)(phenoxy)phosphoryl)-D-mannopyranoside A9 (α:β ratio: 45:55). [ka]

[0260] 4-Methylpiperazin-1-ylpropanoyl 2-(2-azidoacetylamino)-2-deoxy-3,4-di-O-acetyl-6-O-(((S)-1-isopropoxy-carbonylethylamino)(phenoxy)phosphoryl)-D-mannopyranoside A10 (α:β ratio: 58:42). [ka] [ka]

[0261] 4-Acetylpiperazin-1-ylpropanoyl 2-(2-azidoacetylamino)-2-deoxy-3,4-di-O-acetyl-6-O-(((S)-1-isopropoxy-carbonylethylamino)(phenoxy)phosphoryl)-D-mannopyranoside A11 (α:β ratio: 54:46). [ka]

[0262] Tetrahydropyran-4-ylcarbonyl 2-(2-azidoacetylamino)-2-deoxy-3,4-di-O-acetyl-6-O-(((S)-1-isopropoxy-carbonylethylamino)(phenoxy)phosphoryl)-D-mannopyranoside A12 (α:β ratio: 66:34). [ka] [ka]

[0263] 1-Methylpiperidin-4-ylcarbonyl 2-(2-azidoacetylamino)-2-deoxy-3,4-di-O-acetyl-6-O-(((S)-1-isopropoxycarbonylethylamino)(phenoxy)phosphoryl)-D-mannopyranoside A13 (α:β ratio: 49:51). [ka]

[0264] Pyrrolidin-1-ylacetyl 2-(2-azidoacetylamino)-2-deoxy-3,4-di-O-acetyl-6-O-(((S)-1-isopropoxycarbonylethylamino)(phenoxy)phosphoryl)-D-mannopyranoside A14 (α:β ratio: 54:46). [ka] [ka]

[0265] 4-Dimethylaminobenzoyl 2-(2-azidoacetylamino)-2-deoxy-3,4-di-O-acetyl-6-O-(((S)-1-isopropoxycarbonylethylamino)(phenoxy)phosphoryl)-D-mannopyranoside A15 (α:β ratio: 40:60). [ka]

[0266] Pyridin-3-ylcarbonyl 2-(2-azidoacetylamino)-2-deoxy-3,4-di-O-acetyl-6-O-(((S)-1-isopropoxycarbonylethylamino)(phenoxy)phosphoryl)-D-mannopyranoside A16 (α:β ratio: 46:54). [ka] [ka]

[0267] Pyrrol-2-ylcarbonyl 2-(2-azidoacetylamino)-2-deoxy-3,4-di-O-acetyl-6-O-(((S)-1-isopropoxycarbonylethylamino)(phenoxy)phosphoryl)-D-mannopyranoside A17 (α:β ratio: 36:64). [ka]

[0268] Acetyl 2-(2-azidoacetylamino)-2-deoxy-3,4-di-O-acetyl-6-O-(((1S)-1-sec-butoxycarbonylethylamino)(phenoxy)phosphoryl)-D-mannopyranoside A19 (α:β ratio: 66:34). [ka] [ka]

[0269] Acetyl 2-(2-azidoacetylamino)-2-deoxy-3,4-di-O-acetyl-6-O-(((S)-1-pentoxy-carbonylethylamino)(phenoxy)phosphoryl)-D-mannopyranoside A21 (α:β ratio: 67:33). [ka]

[0270] Acetyl 2-(2-azidoacetylamino)-2-deoxy-3,4-di-O-acetyl-6-O-(((S)-1-hexoxy-carbonylethylamino)(phenoxy)phosphoryl)-D-mannopyranoside A22 (α:β ratio: 64:36). [ka] [ka]

[0271] Acetyl 2-(2-azidoacetylamino)-2-deoxy-3,4-di-O-acetyl-6-O-(((S)-1-(2-ethyl-butoxy)carbonylethylamino)(phenoxy)phosphoryl)-D-mannopyranoside A23 (α:β ratio: 67:33). [ka]

[0272] Acetyl 2-(2-azidoacetylamino)-2-deoxy-3,4-di-O-acetyl-6-O-(((S)-1-pyridin-3-ylmethoxycarbonylethylamino)(phenoxy)phosphoryl)-D-mannopyranoside A24 (α:β ratio: 72:26). [ka]

[0273] Acetyl 2-(2-azidoacetylamino)-2-deoxy-3,4-di-O-acetyl-6-O-(((S)-1-pyridin-4-ylmethoxycarbonylethylamino)(phenoxy)phosphoryl)-D-mannopyranoside A25 (α:β ratio: 60:40). [ka] [ka]

[0274] Acetyl 2-(2-azidoacetylamino)-2-deoxy-3,4-di-O-acetyl-6-O-(((S)-1-quinolin-4-ylmethoxycarbonylethylamino)(phenoxy)phosphoryl)-D-mannopyranoside A26 (α:β ratio: 70:30). [ka]

[0275] Acetyl 2-(2-azidoacetylamino)-2-deoxy-3,4-di-O-acetyl-6-O-(((S)-1-quinolin-5-ylmethoxycarbonylethylamino)(phenoxy)phosphoryl)-D-mannopyranoside A27 (α:β ratio: 70:30). [ka] [ka]

[0276] Pentanoyl 2-(2-azidoacetylamino)-2-deoxy-3,4-di-O-acetyl-6-O-(((S)-1-quinolin-5-ylmethoxycarbonylethylamino)(phenoxy)phosphoryl)-D-mannopyranoside A28 (α:β ratio: 56:44). [ka]

[0277] 2-Methylbutanoyl 2-(2-azidoacetylamino)-2-deoxy-3,4-di-O-acetyl-6-O-(((S)-1-quinolin-5-ylmethoxycarbonylethylamino)(phenoxy)phosphoryl)-D-mannopyranoside A29 (α:β ratio: 33:67). [ka] [ka]

[0278] Hexanoyl 2-(2-azidoacetylamino)-2-deoxy-3,4-di-O-acetyl-6-O-(((S)-1-quinolin-5-ylmethoxycarbonylethylamino)(phenoxy)phosphoryl)-D-mannopyranoside A30 (α:β ratio: 55:45). [ka]

[0279] Nonanoyl 2-(2-azidoacetylamino)-2-deoxy-3,4-di-O-acetyl-6-O-(((S)-1-quinolin-5-ylmethoxycarbonylethylamino)(phenoxy)phosphoryl)-D-mannopyranoside A31 (α:β ratio: 45:55). [ka] [ka]

[0280] Acetyl 2-(2-azidoacetylamino)-2-deoxy-3,4-di-O-acetyl-6-O-(((S)-1-(4-methyl-tetrahydropyran-4-yloxy)carbonylethylamino)(phenoxy)phosphoryl)-D-mannopyranoside A32 (α:β ratio: 90:10). [ka]

[0281] Acetyl 2-(2-azidoacetylamino)-2-deoxy-3,4-di-O-acetyl-6-O-(((1S)-1-(1-(4-(tert-butoxycarbonylamino)phenyl)ethoxycarbonyl)-2-methylpropylamino)(phenoxy)-phosphoryl)-D-mannopyranoside A33 (α:β ratio: 31:69). [ka]

[0282] (3S,4R,5S,6R)-3-(2-azidoacetamido)-6-((((((R)-1-(benzyloxy)-3-methyl-1-oxobutan-2-yl)amino)(phenoxy)phosphoryl)oxy)methyl)tetrahydro-2H-pyran-2,4,5-triyl triacetate A36 (α:β ratio: 74:26). [ka] [ka]

[0283] (3S,4R,5S,6R)-3-(2-azidoacetamido)-6-((((((S)-3-methyl-1-oxo-1-(1-phenyl-cyclopropoxy)butan-2-yl)amino)(phenoxy)phosphoryl)oxy)methyl)tetrahydro-2H-pyran-2,4,5-triyl triacetate A37 (α:β ratio: 61:39). [ka]

[0284] (2R,3S,4R,5S)-5-(2-azidoacetamido)-2-((((((S)-1-oxo-1-(pentyloxy)propan-2-yl)-amino)(phenoxy)phosphoryl)oxy)methyl)-6-((tetrahydro-2H-pyran-4-carbonyl)oxy)tetrahydro-2H-pyran-3,4-diyl diacetate A38 (α:β ratio: 57:43). [ka] [ka]

[0285] (2R,3S,4R,5S)-5-(2-Azidoacetamido)-6-((3-morpholinobenzoyl)oxy)-2-((((((S)-1-oxo-1-(pentyloxy)propan-2-yl)amino)(phenoxy)phosphoryl)oxy)methyl)tetrahydro-2H-pyran-3,4-diyl diacetate A39 (α:β ratio: 46:54). [ka]

[0286] (2R,3S,4R,5S)-5-(2-Azidoacetamido)-6-((3-(4-methylpiperazin-1-yl)benzoyl)-oxy)-2-((((((S)-1-oxo-1-(pentyloxy)propan-2-yl)amino)(phenoxy)phosphoryl)oxy)methyl)-tetrahydro-2H-pyran-3,4-diyl diacetate A40 (α:β ratio: 50:50). [ka] [ka]

[0287] (2R,3S,4R,5S)-5-(2-azidoacetamido)-6-((3-(morpholinomethyl)benzoyl)oxy)-2-((((((S)-1-oxo-1-(pentyloxy)propan-2-yl)amino)(phenoxy)phosphoryl)oxy)methyl)tetrahydro-2H-pyran-3,4-diyl diacetate A41 (α:β ratio: 48:52). [ka]

[0288] (2R,3S,4R,5S)-5-(2-Azidoacetamido)-6-((3-((4-methylpiperazin-1-yl)methyl)-benzoyl)oxy)-2-((((((S)-1-oxo-1-(pentyloxy)propan-2-yl)amino)(phenoxy)phosphoryl)oxy)-methyl)tetrahydro-2H-pyran-3,4-diyl diacetate A42 (α:β ratio: 40:60). [ka] [ka]

[0289] (2R,3S,4R,5S)-5-(2-azidoacetamido)-2-((((((S)-1-oxo-1-(quinolin-4-ylmethoxy)-propan-2-yl)amino)(phenoxy)phosphoryl)oxy)methyl)-6-(pentanoyloxy)tetrahydro-2H-pyran-3,4-diyl diacetate A43 (α:β ratio: 40:60). [ka]

[0290] (2R,3S,4R,5S)-5-(2-azidoacetamido)-6-((2-methylbutanoyl)oxy)-2-((((((S)-1-oxo-1-(quinolin-4-ylmethoxy)propan-2-yl)amino)(phenoxy)phosphoryl)oxy)methyl)tetrahydro-2H-pyran-3,4-diyl diacetate A44 (α:β ratio: 40:60). [ka] [ka]

[0291] (2R,3S,4R,5S)-5-(2-azidoacetamido)-6-(hexanoyloxy)-2-((((((S)-1-oxo-1-(quinolin-4-ylmethoxy)propan-2-yl)amino)(phenoxy)phosphoryl)oxy)methyl)tetrahydro-2H-pyran-3,4-diyl diacetate A45 (α:β ratio: 39:61). [ka]

[0292] (2R,3S,4R,5S)-5-(2-azidoacetamido)-6-(nonanoyloxy)-2-((((((S)-1-oxo-1-(quinolin-4-ylmethoxy)propan-2-yl)amino)(phenoxy)phosphoryl)oxy)methyl)tetrahydro-2H-pyran-3,4-diyl diacetate A46 (α:β ratio: 46:54). [ka] [ka]

[0293] (2R,3S,4R,5S)-5-(2-azidoacetamido)-2-((((((S)-1-oxo-1-(quinolin-4-ylmethoxy)-propan-2-yl)amino)(phenoxy)phosphoryl)oxy)methyl)-6-((tetrahydro-2H-pyran-4-carbonyl)-oxy)tetrahydro-2H-pyran-3,4-diyl diacetate A47 (α:β ratio: 54:46). [ka]

[0294] (3S,4R,5S,6R)-3-(2-azidoacetamido)-6-((((((S)-1-oxo-1-((tetrahydro-2H-pyran-4-yl)oxy)propan-2-yl)amino)(phenoxy)phosphoryl)oxy)methyl)tetrahydro-2H-pyran-2,4,5-triyl triacetate A48 (α:β ratio: 44:56). [ka] [ka]

[0295] (3S,4R,5S,6R)-3-(2-azidoacetamido)-6-((((((S)-1-((1-methylpiperidin-4-yl)oxy)-1-oxopropan-2-yl)amino)(phenoxy)phosphoryl)oxy)methyl)tetrahydro-2H-pyran-2,4,5-triyl triacetate A49 (α:β ratio: 28:72). [ka]

[0296] (3S,4R,5S,6R)-3-(2-azidoacetamido)-6-((((((S)-1-isopropoxy-1-oxopropan-2-yl)-amino)(quinolin-5-yloxy)phosphoryl)oxy)methyl)tetrahydro-2H-pyran-2,4,5-triyl triacetate A50 (α:β ratio: 57:43). [ka] [ka]

[0297] (2R,3S,4R,5S)-5-(2-azidoacetamido)-2-((((((S)-1-isopropoxy-1-oxopropan-2-yl)-amino)(quinolin-5-yloxy)phosphoryl)oxy)methyl)-6-(pentanoyloxy)tetrahydro-2H-pyran-3,4-diyl diacetate A51 (α:β ratio: 75:25). [ka]

[0298] (2R,3S,4R,5S)-5-(2-azidoacetamido)-2-((((((S)-1-isopropoxy-1-oxopropan-2-yl)-amino)(quinolin-5-yloxy)phosphoryl)oxy)methyl)-6-(pivaloyloxy)tetrahydro-2H-pyran-3,4-diyl diacetate A52 (α:β ratio: 60:40). [ka] [ka]

[0299] (2R,3S,4R,5S)-5-(2-azidoacetamido)-6-(hexanoyloxy)-2-((((((S)-1-isopropoxy-1-oxopropan-2-yl)amino)(quinolin-5-yloxy)phosphoryl)oxy)methyl)tetrahydro-2H-pyran-3,4-diyl diacetate A53 (α:β ratio: 56:44). [ka]

[0300] (2R,3S,4R,5S)-5-(2-azidoacetamido)-2-((((((S)-1-isopropoxy-1-oxopropan-2-yl)-amino)(quinolin-5-yloxy)phosphoryl)oxy)methyl)-6-(nonanoyloxy)tetrahydro-2H-pyran-3,4-diyl diacetate A54 (α:β ratio: 41:59). [ka]

[0301] (3S,4R,5S,6R)-3-(2-azidoacetamido)-6-((((((S)-1-oxo-1-(pentyloxy)propan-2-yl)-amino)(quinolin-5-yloxy)phosphoryl)oxy)methyl)tetrahydro-2H-pyran-2,4,5-triyl triacetate A55 (α:β ratio: 61:38). [ka] [ka]

[0302] (((1S)-1-(1-phenylethoxy-carbonyl)ethylamino)(phenoxy)phosphoryl) 2-(2-azidoacetylamino)-2-deoxy-3,4,6-tri-O-acetyl-D-mannopyranoside B1 (α:β ratio: 45:55). [ka]

[0303] Example B1 Flow cytometry analysis of cell labeling cells (2.0×10 5Cells (2 mL, cells / mL) were seeded into 6-well culture plates and allowed to attach overnight at 37°C. After washing three times with PBS, the cells were incubated with the azide compound provided herein (25 μM) at 37°C for 48 hours. After washing three times with PBS, the cells were incubated with DBCO-biotin (50 μM) in 500 μL of serum-free DMEM for 1 hour at 37°C. The cells were washed three times with PBS and then incubated with streptavidin-Cy5 (5 μg / mL) in 500 μL of serum-free DMEM for 1 hour at 37°C. The cells were washed three times with PBS, followed by the addition of 300 μL of 1× trypsin / EDTA for digestion. The detached cells were transferred to a 1.5 mL EP tube, centrifuged at 1,000 rpm for 3 minutes, and washed once with PBS. Finally, 500 μL of PBS containing 4% PFA was added to the cell pellet to fix the cells. The cell suspension was transferred to a flow tube and mixed with 10 μL of PI working solution (50 μg / mL) at room temperature for 30 min before being subjected to flow cytometry.

[0304] Flow cytometry was used to characterize the labeling efficiency of the compounds provided herein. After labeling cells with azide groups, DBCO-biotin was added to specifically react with the azide groups. Avidin-Cy5 was added to bind to cell surface biotin for flow cytometry analysis. Dead cells were stained with PI and excluded from analysis. Results are shown as the mean fluorescence of live cells compared to PBS as a negative control and Ac4ManNAz (AAM), Ac4ManNAz (AAM, CAS: 361154-30-5) as a positive control. The results are summarized in Tables 1 to 3. Table 1. Labeling efficiency of azide compounds in A549 cells. [Table 1] Table 2. Labeling efficiency of azide compounds in MDA-MB-231 [Table 2] Table 3. Labeling efficiency of azide compounds in OVCAR3 [Table 3]

[0305] (Example B2) (LCMS analysis of cell labeling) The labeling efficiency of the azide compounds provided herein was determined using LCMS. After cells were labeled with azide compounds, they were lysed. The protein content in the lysate was quantified by BCA assay, and the cell number was determined by comparing the protein content with a standard curve of protein content-cell number. Azido-sialic acid (N3-SA) was cleaved from glycoproteins in the lysate by incubation with acetic acid at 80°C for 1 hour, and then derivatized with DBCO reagent as shown in the following scheme. The cycloaddition product was then quantified by LCMS to obtain the amount of N3-SA in the cell lysate. N3-SA / cell was calculated as n(N3-SA) / number of cells.

[0306] Briefly, cells (2.0 × 10 5 Cells (2 mL, 2 cells / mL) were seeded into 6-well culture plates and allowed to attach overnight at 37°C. After washing three times with PBS, the cells were incubated with the azide compound (25 μM) at 37°C for 48 hours. After washing three times with PBS, the cells were lysed using RIPA (200 μL) at 4°C for 0.5 hours. The protein content of the lysate (20 μL) was determined using a BCA assay kit. The lysate (126 μL) was transferred to an Eppendorf (1.5 mL) and mixed with glacial acetic acid (14 μL). The suspension was incubated at 80°C for 1 hour. The suspension was centrifuged at 15,000 rpm for 5 minutes, and the supernatant (80 μL) was reacted with DIBO reagent (20 μL, 50 μg / mL in 0.1% formic acid) in 100 μL of 0.1% formic acid at 37°C for 2 hours. The mixture was centrifuged at 15,000 rpm for 5 minutes, and the supernatant (180 μL) was transferred to a sample vial. The cycloaddition products were quantified by LC-MS using a standard calibration curve. [ka]

[0307] The examples set forth above are provided so as to provide those of ordinary skill in the art with a complete disclosure and description of how to make and use the claimed embodiments, and are not intended to limit the scope of what is disclosed herein. Modifications obvious to those of ordinary skill in the art are intended to be within the scope of the following claims. All publications, patents, and patent applications cited herein are hereby incorporated by reference as if each such publication, patent, or patent application was specifically and individually indicated to be incorporated by reference herein.

Claims

1. Formula (I): 【Chemistry 1】 (In the formula, R 1 is (i)‐C(O)R 5a , -C(O)OR 5a , or -C(O)NR 5b R 5c or (ii) hydrogen; and R 5 ,-L 2 -P(X)(OR 5a )(NR 5b R 5c ) or R 1 ,-L 2 -P(X)(OR 5a )(NR 5b R 5c ) and R 5 is (i) hydrogen; or (ii) -C(O)R 5a , -C(O)OR 5a , or -C(O)NR 5b R 5c and; R 2 is (i) hydrogen; (ii) C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) —C(O)R 1a , -C(O)OR 1a , -C(O)NR 1b R 1c , -C(O)SR 1a , -C(NR 1a )NR 1b R 1c , ‐C(S)R 1a , ‐C(S)OR 1a , ‐C(S)NR 1b R 1c , ‐S(O)R 1a , -S(O) 2 R 1a , -S(O)NR 1b R 1c , -S(O) 2 NR 1b R 1c , or -Si(R 1a ) 3 and; R 3 and R 4 are each independently: (i)-OR 5a , ‐OC(O)R 5a , ‐OC(O)OR 5a , or -OC(O)NR 5b R 5c or (ii) halo; or R 3 and R 4 Or R 4 and R 5 are bonded together to form a lactone ring; Each R 5a , R 5b , and R 5c are independently hydrogen, C 1-30 Alkyl, C 1-30 Heteroalkyl, C 2-30 Alkenyl, C 2-30 Alkynyl, C 3-30 Cycloalkyl, C 6-30 Aryl, C 7-30 aralkyl, heteroaryl, or heterocyclyl; A is a bond, O, or N(R 1b ) and; L 1 is C 1-6 Alkylene, C 1-6 Heteroalkylene, C 2-6 Alkenylene, C 2-6 Alkynylene, C 3-10 Cycloalkylene, C 6-14 Arylene, C 7-15 aralkylene, heteroarylene, or heterocyclylene; Each L 2 are independently (i) a bond; or (ii) -O-C 1-6 Alkylene, -O-C 1-6 Heteroalkylene, -O-C 2-6 Alkenylene, -O-C 2-6 Alkynylene, -O-C 3-10 Cycloalkylene, -O-C 6-14 Arylene, -O-C 7-15 aralkylene, -O-heteroarylene, or -O-heterocyclylene; each X is independently O or S; Z can be azide, hydrogen, halo, isocyano, -C=C(R 1a )R 1a , ‐C≡CR 1a , 【Chemistry 2】 -C(O)R 1a or -SH; and Each R 1a , R 1b , and R 1c are independently hydrogen, deuterium, and C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl; wherein each alkyl, alkylene, heteroalkyl, heteroalkylene, alkenyl, alkenylene, alkynyl, alkynylene, cycloalkyl, cycloalkylene, aryl, arylene, aralkyl, aralkylene, heteroaryl, heteroarylene, heterocyclyl, and heterocyclylene is optionally substituted with one or more, and in one embodiment, one, two, three, or four, substituents Q, where each Q is independently: (a) deuterium, cyano, halo, nitro, and oxo; (b) one or more, and in one embodiment, one, two, three, or four, substituents Q a each optionally further substituted C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 aralkyl, heteroaryl, and heterocyclyl; and (c)—C(O)R a , -C(O)OR a , -C(O)NR b R c , -C(O)SR a , -C(NR a )NR b R c , ‐C(S)R a , ‐C(S)OR a , ‐C(S)NR b R c , -OR a , ‐OC(O)R a , ‐OC(O)OR a , ‐OC(O)NR b R c , ‐OC(O)SR a , ‐OC(NR a )NR b R c , ‐OC(S)R a , ‐OC(S)OR a , ‐OC(S)NR b R c , -OP(O)(OR b ) OR c , ‐OS(O)R a , ‐OS(O) 2 R a , ‐OS(O)NR b R c , ‐OS(O) 2 NR b R c , ‐NR b R c , ‐NR a C(O)R d , ‐NR a C(O)OR d , ‐NR a C(O)NR b R c , ‐NR a C(O)SR d , ‐NR a C(NR d )NR b R c , ‐NR a C(S)R d , ‐NR a C(S)OR d , ‐NR a C(S)NR b R c , ‐NR a S(O)R d , -N=S(O)R a R d , ‐NR a S(O) 2 R d , ‐NR a S(O)NR b R c , ‐NR a S(O) 2 NR b R c , ‐SR a , ‐S(O)R a , -S(O) 2 R a , -S(O)NR b R c , and -S(O) 2 NR b R c where each R a , R b , R c , and R d are independently (i) hydrogen or deuterium; (ii) one or more, in one embodiment, 1, 2, 3, or 4, substituents Q a C, each of which is arbitrarily substituted 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) R b and R c together with the N atom to which they are attached, one or more, in one embodiment 1, 2, 3, or 4, substituents Q a forming an optionally substituted heterocyclyl; Here, each Q a are independently: (a) deuterium, cyano, halo, nitro, and oxo; (b) C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 aralkyl, heteroaryl, and heterocyclyl; and (c)—C(O)R e , -C(O)OR e , -C(O)NR f R g , -C(O)SR e , -C(NR e )NR f R g , ‐C(S)R e , ‐C(S)OR e , ‐C(S)NR f R g , -OR e , ‐OC(O)R e , ‐OC(O)OR e , ‐OC(O)NR f R g , ‐OC(O)SR e , ‐OC(NR e )NR f R g , ‐OC(S)R e , ‐OC(S)OR e , ‐OC(S)NR f R g , -OP(O)(OR f ) OR g , ‐OS(O)R e , ‐OS(O) 2 R e , ‐OS(O)NR f R g , ‐OS(O) 2 NR f R g , ‐NR f R g , ‐NR e C(O)R h , ‐NR e C(O)OR f , ‐NR e C(O)NR f R g , ‐NR e C(O)SR f , ‐NR e C(NR h )NR f R g , ‐NR e C(S)R h , ‐NR e C(S)OR f , ‐NR e C(S)NR f R g , ‐NR e S(O)R h , -N=S(O)R e R h , ‐NR e S(O) 2 R h , ‐NR e S(O)NR f R g , ‐NR e S(O) 2 NR f R g , ‐SR e , ‐S(O)R e , -S(O) 2 R e , -S(O)NR f R g , and -S(O) 2 NR f R g where each R e , R f , R g , and R h are independently (i) hydrogen or deuterium; (ii) C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) R f and R g form a heterocyclyl together with the N atom to which they are attached) or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

2. R 3 However, (i)-OR 5a , ‐OC(O)R 5a , ‐OC(O)OR 5a , or -OC(O)NR 5b R 5c or (ii) halo.

3. R 3 3. The compound of claim 1 or 2, wherein is halo.

4. R 3 The compound of any one of claims 1 to 3, wherein is fluoro.

5. R 4 However, (i)-OR 5a , ‐OC(O)R 5a , ‐OC(O)OR 5a , or -OC(O)NR 5b R 5c or (ii) halo.

6. R 4 The compound of any one of claims 1 to 5, wherein is halo.

7. R 4 The compound of any one of claims 1 to 6, wherein is fluoro.

8. Formula (II): 【Transformation 3】 (In the formula, R 3a and R 4a are each independently -C(O)R 5a , -C(O)OR 5a , -C(O)NR 5b R 5c , or hydrogen) 10. The compound of any one of claims 1, 2, and 5, having the structure: or an enantiomer, mixture of enantiomers, diastereomer, mixture of two or more diastereomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

9. R 1 But (i)-C(O)R 5a , -C(O)OR 5a , or -C(O)NR 5b R 5c or (ii) hydrogen; and R 5 But, -L 2 -P(X)(OR 5a )(NR 5b R 5c 9. The compound according to any one of claims 1 to 8, wherein

10. Formula (III): 【Chemistry 4】 10. The compound of claim 8 or 9, having the structure: or an enantiomer, mixture of enantiomers, diastereomer, mixture of two or more diastereomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

11. R 1 But, -L 2 -P(X)(OR 5a )-(NR 5b R 5c ) and R 5 is (i) hydrogen; or (ii) -C(O)R 5a , -C(O)OR 5a , or -C(O)NR 5b R 5c 9. The compound according to any one of claims 1 to 8, wherein

12. Formula (IV): 【Transformation 5】 12. The compound of claim 8 or 11, having the structure: or an enantiomer, mixture of enantiomers, diastereomer, mixture of two or more diastereomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

13. R 5c C, each optionally substituted with one or more substituents Q 1-30 Alkyl or C 7-30 13. The compound of any one of claims 1 to 12, which is aralkyl.

14. R 5c C optionally substituted with one or more substituents Q 1-6 14. The compound of any one of claims 1 to 13, wherein said compound is alkyl.

15. R 5c 15. The compound of any one of claims 1-14, wherein is methyl, ethyl, propyl, butyl, pentyl, or hexyl, each optionally substituted with one or more substituents Q.

16. R 5c C optionally substituted with one or more substituents Q 7-15 14. The compound of any one of claims 1 to 13, which is aralkyl.

17. Formula (V): 【Transformation 6】 (In the formula, R 6a is a C optionally substituted with one or more substituents Q 1-30 Alkyl, C 1-30 Heteroalkyl, C 2-30 Alkenyl, C 2-30 Alkynyl, C 3-30 Cycloalkyl, C 6-30 Aryl, C 7-30 aralkyl, heteroaryl, and heterocyclyl; and R 6b and R 6c are each independently (i) hydrogen or deuterium; or (ii) C, each optionally substituted with one or more substituents Q. 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 aralkyl, heteroaryl, and heterocyclyl; or R 6b and R 6c together with the carbon atoms to which they are attached, represent C optionally substituted with one or more substituents Q 3-10 forming a cycloalkylene) 17. The compound of any one of claims 8-10 and 13-16, having the structure: or an enantiomer, mixture of enantiomers, diastereomer, mixture of two or more diastereomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

18. Formula (V): 【Transformation 7】 (In the formula, R 6a is a C optionally substituted with one or more substituents Q 1-30 Alkyl, C 1-30 Heteroalkyl, C 2-30 Alkenyl, C 2-30 Alkynyl, C 3-30 Cycloalkyl, C 6-30 Aryl, C 7-30 aralkyl, heteroaryl, and heterocyclyl; and R 6b and R 6c are each independently (i) hydrogen or deuterium; or (ii) C, each optionally substituted with one or more substituents Q. 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 aralkyl, heteroaryl, and heterocyclyl; or R 6b and R 6c together with the carbon atoms to which they are attached, represent C optionally substituted with one or more substituents Q 3-10 forming a cycloalkylene) 17. The compound of any one of claims 8 and 11-16, having the structure: or an enantiomer, mixture of enantiomers, diastereomer, mixture of two or more diastereomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

19. Each L 2 are independently a bond or —O—C optionally substituted with one or more substituents Q 1-6 19. The compound of any one of claims 1 to 18, which is alkylene.

20. Each L 2 20. The compound of any one of claims 1 to 19, wherein is a bond.

21. Formula (VII): 【Transformation 8】 21. The compound of claim 17, 19, or 20, having the structure: or an enantiomer, mixture of enantiomers, diastereomer, mixture of two or more diastereomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

22. Formula (VIII): 【Chemistry 9】 22. The compound of any one of claims 17 and 19-21, having the structure: or an enantiomer, mixture of enantiomers, diastereomer, mixture of two or more diastereomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

23. Formula (IX): 【Chemistry 10】 22. The compound of any one of claims 17 and 19-21, having the structure: or an enantiomer, mixture of enantiomers, diastereomer, mixture of two or more diastereomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

24. R 1 The compound of any one of claims 1 to 10 and 13 to 23, wherein is hydrogen.

25. R 1 But, -C(O)R 5a 24. The compound according to any one of claims 1 to 10 and 13 to 23, wherein

26. R 1 But, -C(O)R 5a (In the formula, R 5a is a C optionally substituted with one or more substituents Q 1-10 Alkyl, C 6-14 26. The compound of any one of claims 1 to 10, 13 to 23, and 25, wherein R is aryl, heteroaryl, or heterocyclyl.

27. R 1 But, -C(O)R 5a (In the formula, R 5a is C optionally substituted with one or more substituents Q 1-10 27. The compound of any one of claims 1 to 10, 13 to 23, 25, and 26, wherein:

28. R 1 is acetyl, propanoyl, butanoyl, pentanoyl, hexanoyl, heptanoyl, octanoyl, nonanoyl, or decanoyl, each optionally substituted with one or more substituents Q.

29. R 1 29. The compound of any one of claims 1-10, 13-23, and 25-28, wherein is acetyl, propanoyl, or butanoyl.

30. R 1 But, -C(O)R 5a (In the formula, R 5a is C optionally substituted with one or more substituents Q 6-14 27. The compound of any one of claims 1 to 10, 13 to 23, 25, and 26, wherein:

31. R 1 But, -C(O)R 5a (In the formula, R 5a is benzoyl optionally substituted with one or more substituents Q.

32. R 1 But, -C(O)R 5a (In the formula, R 5a is heteroaryl optionally substituted with one or more substituents Q.

33. R 1 But, -C(O)R 5a (In the formula, R 5a is a monocyclic heteroaryl optionally substituted with one or more substituents Q.

34. R 1 But, -C(O)R 5a (In the formula, R 5a is a 5- or 6-membered heteroaryl, each optionally substituted with one or more substituents Q.

35. R 1 But, -C(O)R 5a (In the formula, R 5a is pyrrolylcarbonyl or pyridinylcarbonyl, each optionally substituted with one or more substituents Q.

36. R 1 But, -C(O)R 5a (In the formula, R 5a is heterocyclyl optionally substituted with one or more substituents Q.

37. R 1 But, -C(O)R 5a (In the formula, R 5a is monocyclic heterocyclyl optionally substituted with one or more substituents Q.

38. R 1 But, -C(O)R 5a (In the formula, R 5a is a 3-, 4-, 5-, 6-, or 7-membered heterocyclyl, each optionally substituted with one or more substituents Q.

39. R 1 But, -C(O)R 5a (In the formula, R 5a is pyrrolylcarbonyl or pyridinylcarbonyl, each optionally substituted with one or more substituents Q.

40. R 1 is acetyl, pivaloyl, pyridin-3-ylacetyl, pyrrolidin-1-ylacetyl, propanoyl, 3-morpholinopropanoyl, 4-methylpiperazin-1-ylpropanoyl, 4-acetylpiperazin-1-ylpropanoyl, butanoyl, 2-methylbutanoyl, pentanoyl, hexanoyl, nonanoyl, 4-dimethylaminobenzoyl, 3-(morpholinomethyl)benzoyl, 3-((4-methylpiperazin-1-yl)methyl)benzoyl, 3-morpholinobenzoyl, 3-(4-methylpiperazin-1-yl)benzoyl, pyrrol-2-ylcarbonyl, pyridin-3-ylcarbonyl, tetrahydropyran-4-ylcarbonyl, or 1-methylpiperidin-4-ylcarbonyl.

41. R 1 The compound of any one of claims 1-10, 13-23, 25, 26, and 40, wherein is acetyl.

42. Formula (X): 【Chemistry 11】 21. The compound of any one of claims 18-20, having the structure: or an enantiomer, mixture of enantiomers, diastereomer, mixture of two or more diastereomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

43. Formula (XI): 【Chemistry 12】 43. The compound of any one of claims 18-20 and 42, having the structure: or an enantiomer, mixture of enantiomers, diastereomer, mixture of two or more diastereomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

44. Formula (XII): 【Chemistry 13】 43. The compound of any one of claims 18-20 and 42, having the structure: or an enantiomer, mixture of enantiomers, diastereomer, mixture of two or more diastereomers, tautomer, mixture of two or more tautomers, or isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

45. R 5 The compound of any one of claims 1 to 8, 11 to 16, and 42 to 44, wherein is hydrogen.

46. R 5 But, -C(O)R 5a 45. The compound of any one of claims 1 to 8, 11 to 16, and 42 to 44, wherein

47. R 5 is —C(O)—C optionally substituted with one or more substituents Q 1-6 47. The compound of any one of claims 1-8, 11-16, 42-44, and 46, wherein the compound is alkyl.

48. R 5 48. The compound of any one of claims 1-8, 11-16, 42-44, 46, and 47, wherein is acetyl, propanoyl, or butanoyl.

49. R 5 The compound of any one of claims 1-8, 11-16, 42-44, and 46-48, wherein is acetyl.

50. R 2 50. The compound of any one of claims 1 to 49, wherein is hydrogen.

51. R 3a The compound of any one of claims 8 to 50, wherein is hydrogen.

52. R 3a But, -C(O)R 5a 51. The compound of any one of claims 8 to 50, wherein

53. R 3a is —C(O)—C optionally substituted with one or more substituents Q 1-6 53. The compound of any one of claims 8 to 50 and 52, wherein the compound is alkyl.

54. R 3a 54. The compound of any one of claims 8-50, 52, and 53, wherein is acetyl, propanoyl, or butanoyl.

55. R 3a The compound of any one of claims 8 to 50 and 52 to 54, wherein is acetyl.

56. R 4a 56. The compound of any one of claims 8 to 55, wherein is hydrogen.

57. R 4a But, -C(O)R 5a 56. The compound of any one of claims 8 to 55, wherein:

58. R 4a is —C(O)—C optionally substituted with one or more substituents Q 1-6 58. The compound of any one of claims 8 to 55 and 57, wherein said compound is alkyl.

59. R 4a 59. The compound of any one of claims 8-55, 57, and 58, wherein is acetyl, propanoyl, or butanoyl.

60. R 4a The compound of any one of claims 8 to 55 and 57 to 59, wherein is acetyl.

61. R 5a C, each optionally substituted with one or more substituents Q 6-14 61. The compound of any one of claims 1 to 60, which is aryl or heteroaryl.

62. R 5a C optionally substituted with one or more substituents Q 6-14 62. The compound of any one of claims 1 to 61, which is aryl.

63. R 5a 63. The compound of any one of claims 1-62, wherein is phenyl optionally substituted with one or more substituents Q.

64. R 5a 62. The compound of any one of claims 1-61, wherein is heteroaryl optionally substituted with one or more substituents Q.

65. R 5a 65. The compound of any one of claims 1-61 and 64, wherein is a bicyclic heteroaryl optionally substituted with one or more substituents Q.

66. R 5a 66. The compound of any one of claims 1-61, 64, and 65, wherein is a 5,5-, 5,6-, or 6,6-fused heteroaryl, each optionally substituted with one or more substituents Q.

67. R 5a 67. The compound of any one of claims 1-61 and 64-66, wherein is a 6,6-fused heteroaryl optionally substituted with one or more substituents Q.

68. R 5a 68. The compound of any one of claims 1-61 and 64-67, wherein is quinolinyl optionally substituted with one or more substituents Q.

69. R 5a 62. The compound of any one of claims 1-61, wherein is phenyl or quinolin-5-yl.

70. R 5b 70. The compound of any one of claims 1-69, wherein is hydrogen.

71. R 6a C, each optionally substituted with one or more substituents Q 1-6 Alkyl, C 3-10 Cycloalkyl, C 7-15 71. The compound of any one of claims 1 to 70, which is aralkyl or heterocyclyl.

72. R 6a C optionally substituted with one or more substituents Q 1-6 72. The compound of any one of claims 1 to 71, which is alkyl.

73. R 6a is one or more substituents Q a C optionally substituted with 1-6 73. The compound of any one of claims 1 to 72, which is alkylene-heteroaryl.

74. R 6a is one or more substituents Q a C optionally substituted with 1-6 74. The compound of any one of claims 1-73, which is alkylene-(monocyclic heteroaryl).

75. R 6a is one or more substituents Q a C, each of which is arbitrarily substituted 1-6 75. The compound of any one of claims 1 to 74, which is alkylene-(5 or 6 membered heteroaryl).

76. R 6a is one or more substituents Q a C optionally substituted with 1-6 74. The compound of any one of claims 1-73, which is alkylene-(bicyclic heteroaryl).

77. R 6a is one or more substituents Q a C, each of which is arbitrarily substituted 1-6 77. The compound of any one of claims 1 to 73 and 76, which is alkylene-(5,5-, 5,6-, or 6,6-fused heteroaryl).

78. R 6a C optionally substituted with one or more substituents Q 3-10 72. The compound of any one of claims 1 to 71, which is cycloalkyl.

79. R 6a is a monocyclic C optionally substituted with one or more substituents Q 3-10 80. The compound of any one of claims 1 to 71 and 78, which is cycloalkyl.

80. R 6a C optionally substituted with one or more substituents Q 7-15 72. The compound of any one of claims 1 to 71, which is aralkyl.

81. R 6a is a monocyclic C optionally substituted with one or more substituents Q 7-15 81. The compound of any one of claims 1 to 71 and 80, which is aralkyl.

82. R 6a 72. The compound of any one of claims 1-71, wherein is heterocyclyl optionally substituted with one or more substituents Q.

83. R 6a 83. The compound of any one of claims 1-71 and 82, wherein is monocyclic heterocyclyl optionally substituted with one or more substituents Q.

84. R 6a 84. The compound of any one of claims 1-71, 82, and 83, wherein is a 3-, 4-, 5-, 6-, or 7-membered heterocyclyl, each optionally substituted with one or more substituents Q.

85. R 6a is isopropyl, butyl, 2-butyl, tert-butyl, pentyl, hexyl, 2-ethylbutyl, 1-phenylcyclopropyl, benzyl, 1-phenylethyl, 2-phenylprop-2-yl, pyridin-3-ylmethyl, pyridin-4-ylmethyl, quinolin-4-ylmethyl, quinolin-5-ylmethyl, tetrahydropyran-4-yl, or 1-methyl-piperidin-4-yl.

86. R 6a 86. The compound of any one of claims 1 to 71 and 85, wherein is isopropyl.

87. R 6b C optionally substituted with one or more substituents Q 1-6 87. The compound of any one of claims 1 to 86, which is alkyl.

88. R 6b 88. The compound of any one of claims 1-87, wherein is methyl or isopropyl.

89. R 6b The compound of any one of claims 1 to 88, wherein is methyl.

90. R 6c is optionally substituted with hydrogen or one or more substituents Q 1-6 90. The compound of any one of claims 1 to 89, which is alkyl.

91. R 6c 91. The compound of any one of claims 1 to 90, wherein is hydrogen or methyl.

92. R 6c 92. The compound of any one of claims 1 to 91, wherein is hydrogen.

93. R 6b and R 6c together with the carbon atoms to which they are attached, optionally substituted with one or more substituents Q 3-10 87. The compound of any one of claims 1 to 86, which forms a cycloalkylene.

94. R 6b and R 6c together with the carbon atoms to which they are attached, are monocyclic C optionally substituted with one or more substituents Q 3-10 94. The compound of any one of claims 1 to 86 and 93, which forms a cycloalkylene.

95. 95. The compound of any one of claims 1 to 94, wherein A is a bond or O.

96. 96. The compound of any one of claims 1 to 95, wherein A is a bond.

97. L 1 C optionally substituted with one or more substituents Q 1-6 97. The compound of any one of claims 1 to 96, which is alkylene.

98. L 1 is methanediyl, ethane-1,2-diyl, propane-1,2-diyl, or butane-1,4-diyl, each optionally substituted with one or more substituents Q.

99. L 1 99. The compound of any one of claims 1-98, wherein is methanediyl.

100. 100. The compound of any one of claims 1 to 99, wherein X is O.

101. Z is hydrogen, azido, fluoro, iodo, isocyano, -C=CH 2 , ‐C≡CH, 【Chemistry 14】 -C(O)CCH 3 101. The compound of any one of claims 1 to 100, wherein the compound is -SH.

102. 102. The compound of any one of claims 1-101, wherein Z is azide.

103. below: Acetyl 2-(2-azidoacetylamino)-2-deoxy-3,4-di-O-acetyl-6-O-(((S)-1-isopropoxy-carbonylethylamino)(phenoxy)phosphoryl)-D-mannopyranoside A1; 2-(2-azidoacetylamino)-2-deoxy-3,4-di-O-acetyl-6-O-(((S)-1-isopropoxy-carbonylethylamino)(phenoxy)phosphoryl)-D-mannopyranoside A2; 2-(2-Azidoacetylamino)-2-deoxy-3,4-di-O-acetyl-6-O-(((1S)-1-(1-phenylethoxy-carbonyl)ethylamino)(phenoxy)phosphoryl)-D-mannopyranoside A3; 2-(2-azidoacetylamino)-2-deoxy-3,4-di-O-acetyl-6-O-((1-methyl-1-(1-phenyl-ethoxycarbonyl)ethylamino)(phenoxy)phosphoryl)-D-mannopyranoside A4; 2-(2-Azidoacetylamino)-2-deoxy-3,4-di-O-acetyl-6-O-(((1S)-1-(1-phenylethoxy-carbonyl)-2-methylpropylamino)(phenoxy)phosphoryl)-D-mannopyranoside A5; 2-(2-azidoacetylamino)-2-deoxy-3,4-di-O-acetyl-6-O-((1-methyl-1-(1-methyl-1-phenylethoxycarbonyl)ethylamino)(phenoxy)phosphoryl)-D-mannopyranoside A6; 2-(2-Azidoacetylamino)-2-deoxy-3,4-di-O-acetyl-6-O-(((1S)-1-(1-methyl-1-phenylethoxycarbonyl)-2-methylpropylamino)(phenoxy)phosphoryl)-D-mannopyranoside A7; Pyridin-3-ylacetyl 2-(2-azidoacetylamino)-2-deoxy-3,4-di-O-acetyl-6-O-(((S)-1-isopropoxycarbonylethylamino)(phenoxy)phosphoryl)-D-mannopyranoside A8; 3-Morpholinopropanoyl 2-(2-azidoacetylamino)-2-deoxy-3,4-di-O-acetyl-6-O-(((S)-1-isopropoxy-carbonylethylamino)(phenoxy)phosphoryl)-D-mannopyranoside A9; 4-Methylpiperazin-1-ylpropanoyl 2-(2-azidoacetylamino)-2-deoxy-3,4-di-O-acetyl-6-O-(((S)-1-isopropoxy-carbonylethylamino)(phenoxy)phosphoryl)-D-mannopyranoside A10; 4-Acetylpiperazin-1-ylpropanoyl 2-(2-azidoacetylamino)-2-deoxy-3,4-di-O-acetyl-6-O-(((S)-1-isopropoxy-carbonylethylamino)(phenoxy)phosphoryl)-D-mannopyranoside A11; Tetrahydropyran-4-ylcarbonyl 2-(2-azidoacetylamino)-2-deoxy-3,4-di-O-acetyl-6-O-(((S)-1-isopropoxy-carbonylethylamino)(phenoxy)phosphoryl)-D-mannopyranoside A12; 1-Methylpiperidin-4-ylcarbonyl 2-(2-azidoacetylamino)-2-deoxy-3,4-di-O-acetyl-6-O-(((S)-1-isopropoxy-carbonylethylamino)(phenoxy)phosphoryl)-D-mannopyranoside A13; Pyrrolidin-1-ylacetyl 2-(2-azidoacetylamino)-2-deoxy-3,4-di-O-acetyl-6-O-(((S)-1-isopropoxy-carbonylethylamino)(phenoxy)phosphoryl)-D-mannopyranoside A14; 4-Dimethylaminobenzoyl 2-(2-azidoacetylamino)-2-deoxy-3,4-di-O-acetyl-6-O-(((S)-1-isopropoxycarbonylethylamino)(phenoxy)phosphoryl)-D-mannopyranoside A15; Pyridin-3-ylcarbonyl 2-(2-azidoacetylamino)-2-deoxy-3,4-di-O-acetyl-6-O-(((S)-1-isopropoxycarbonylethylamino)(phenoxy)phosphoryl)-D-mannopyranoside A16; Pyrrol-2-ylcarbonyl 2-(2-azidoacetylamino)-2-deoxy-3,4-di-O-acetyl-6-O-(((S)-1-isopropoxycarbonylethylamino)(phenoxy)phosphoryl)-D-mannopyranoside A17; Acetyl 2-(2-azidoacetylamino)-2-deoxy-3,4-di-O-acetyl-6-O-(((S)-1-butoxy-carbonylethylamino)(phenoxy)phosphoryl)-D-mannopyranoside A18; Acetyl 2-(2-azidoacetylamino)-2-deoxy-3,4-di-O-acetyl-6-O-(((1S)-1-sec-butoxy-carbonylethylamino)(phenoxy)phosphoryl)-D-mannopyranoside A19; Acetyl 2-(2-azidoacetylamino)-2-deoxy-3,4-di-O-acetyl-6-O-(((S)-1-tert-butoxy-carbonylethylamino)(phenoxy)phosphoryl)-D-mannopyranoside A20; Acetyl 2-(2-azidoacetylamino)-2-deoxy-3,4-di-O-acetyl-6-O-(((S)-1-pentoxy-carbonylethylamino)(phenoxy)phosphoryl)-D-mannopyranoside A21; Acetyl 2-(2-azidoacetylamino)-2-deoxy-3,4-di-O-acetyl-6-O-(((S)-1-hexoxy-carbonylethylamino)(phenoxy)phosphoryl)-D-mannopyranoside A22; Acetyl 2-(2-azidoacetylamino)-2-deoxy-3,4-di-O-acetyl-6-O-(((S)-1-(2-ethyl-butoxy)carbonylethylamino)(phenoxy)phosphoryl)-D-mannopyranoside A23; Acetyl 2-(2-azidoacetylamino)-2-deoxy-3,4-di-O-acetyl-6-O-(((S)-1-pyridin-3-ylmethoxycarbonylethylamino)(phenoxy)phosphoryl)-D-mannopyranoside A24; Acetyl 2-(2-azidoacetylamino)-2-deoxy-3,4-di-O-acetyl-6-O-(((S)-1-pyridin-4-ylmethoxycarbonylethylamino)(phenoxy)phosphoryl)-D-mannopyranoside A25; Acetyl 2-(2-azidoacetylamino)-2-deoxy-3,4-di-O-acetyl-6-O-(((S)-1-quinolin-4-ylmethoxycarbonylethylamino)(phenoxy)phosphoryl)-D-mannopyranoside A26; Acetyl 2-(2-azidoacetylamino)-2-deoxy-3,4-di-O-acetyl-6-O-(((S)-1-quinolin-5-ylmethoxycarbonylethylamino)(phenoxy)phosphoryl)-D-mannopyranoside A27; Pentanoyl 2-(2-azidoacetylamino)-2-deoxy-3,4-di-O-acetyl-6-O-(((S)-1-quinolin-5-ylmethoxycarbonylethylamino)(phenoxy)phosphoryl)-D-mannopyranoside A28; 2-Methylbutanoyl 2-(2-azidoacetylamino)-2-deoxy-3,4-di-O-acetyl-6-O-(((S)-1-quinolin-5-ylmethoxycarbonylethylamino)(phenoxy)phosphoryl)-D-mannopyranoside A29; Hexanoyl 2-(2-azidoacetylamino)-2-deoxy-3,4-di-O-acetyl-6-O-(((S)-1-quinolin-5-ylmethoxycarbonylethylamino)(phenoxy)phosphoryl)-D-mannopyranoside A30; Nonanoyl 2-(2-azidoacetylamino)-2-deoxy-3,4-di-O-acetyl-6-O-(((S)-1-quinolin-5-ylmethoxycarbonylethylamino)(phenoxy)phosphoryl)-D-mannopyranoside A31; Acetyl 2-(2-azidoacetylamino)-2-deoxy-3,4-di-O-acetyl-6-O-(((S)-1-(4-methyl-tetrahydropyran-4-yloxy)carbonylethylamino)(phenoxy)phosphoryl)-D-mannopyranoside A32; Acetyl 2-(2-azidoacetylamino)-2-deoxy-3,4-di-O-acetyl-6-O-(((1S)-1-(1-(4-(tert-butoxycarbonylamino)phenyl)ethoxycarbonyl)-2-methylpropylamino)(phenoxy)-phosphoryl)-D-mannopyranoside A33; Acetyl 2-(2-azidoacetylamino)-2-deoxy-3,4-di-O-acetyl-6-O-(((S)-1-isopropoxy-carbonylethylamino)(quinolin-5-yloxy)phosphoryl)-D-mannopyranoside A34; Acetyl 2-(2-azidoacetylamino)-2-deoxy-3,4-di-O-acetyl-6-O-(3-(((S)-1-isopropoxycarbonylethylamino)(phenoxy)phosphoryloxy)propanoyl)-D-mannopyranoside A35; (3S,4R,5S,6R)-3-(2-azidoacetamido)-6-((((((R)-1-(benzyloxy)-3-methyl-1-oxobutan-2-yl)amino)(phenoxy)phosphoryl)oxy)methyl)tetrahydro-2H-pyran-2,4,5-triyl triacetate A36; (3S,4R,5S,6R)-3-(2-azidoacetamido)-6-((((((S)-3-methyl-1-oxo-1-(1-phenyl-cyclopropoxy)butan-2-yl)amino)(phenoxy)phosphoryl)oxy)methyl)tetrahydro-2H-pyran-2,4,5-triyl triacetate A37; (2R,3S,4R,5S)-5-(2-azidoacetamido)-2-((((((S)-1-oxo-1-(pentyloxy)propan-2-yl)-amino)(phenoxy)phosphoryl)oxy)methyl)-6-((tetrahydro-2H-pyran-4-carbonyl)oxy)tetrahydro-2H-pyran-3,4-diyl diacetate A38; (2R,3S,4R,5S)-5-(2-azidoacetamido)-6-((3-morpholinobenzoyl)oxy)-2-((((((S)-1-oxo-1-(pentyloxy)propan-2-yl)amino)(phenoxy)phosphoryl)oxy)methyl)tetrahydro-2H-pyran-3,4-diyl diacetate A39; (2R,3S,4R,5S)-5-(2-azidoacetamido)-6-((3-(4-methylpiperazin-1-yl)benzoyl)-oxy)-2-((((((S)-1-oxo-1-(pentyloxy)propan-2-yl)amino)(phenoxy)phosphoryl)oxy)methyl)-tetrahydro-2H-pyran-3,4-diyl diacetate A40; (2R,3S,4R,5S)-5-(2-azidoacetamido)-6-((3-(morpholinomethyl)benzoyl)oxy)-2-((((((S)-1-oxo-1-(pentyloxy)propan-2-yl)amino)(phenoxy)phosphoryl)oxy)methyl)tetrahydro-2H-pyran-3,4-diyl diacetate A41; (2R,3S,4R,5S)-5-(2-azidoacetamido)-6-((3-((4-methylpiperazin-1-yl)methyl)-benzoyl)oxy)-2-((((((S)-1-oxo-1-(pentyloxy)propan-2-yl)amino)(phenoxy)phosphoryl)oxy)-methyl)tetrahydro-2H-pyran-3,4-diyl diacetate A42; (2R,3S,4R,5S)-5-(2-azidoacetamido)-2-((((((S)-1-oxo-1-(quinolin-4-ylmethoxy)-propan-2-yl)amino)(phenoxy)phosphoryl)oxy)methyl)-6-(pentanoyloxy)tetrahydro-2H-pyran-3,4-diyl diacetate A43; (2R,3S,4R,5S)-5-(2-azidoacetamido)-6-((2-methylbutanoyl)oxy)-2-((((((S)-1-oxo-1-(quinolin-4-ylmethoxy)propan-2-yl)amino)(phenoxy)phosphoryl)oxy)methyl)tetrahydro-2H-pyran-3,4-diyl diacetate A44; (2R,3S,4R,5S)-5-(2-azidoacetamido)-6-(hexanoyloxy)-2-((((((S)-1-oxo-1-(quinolin-4-ylmethoxy)propan-2-yl)amino)(phenoxy)phosphoryl)oxy)methyl)tetrahydro-2H-pyran-3,4-diyl diacetate A45; (2R,3S,4R,5S)-5-(2-azidoacetamido)-6-(nonanoyloxy)-2-((((((S)-1-oxo-1-(quinolin-4-ylmethoxy)propan-2-yl)amino)(phenoxy)phosphoryl)oxy)methyl)tetrahydro-2H-pyran-3,4-diyl diacetate A46; (2R,3S,4R,5S)-5-(2-azidoacetamido)-2-((((((S)-1-oxo-1-(quinolin-4-ylmethoxy)-propan-2-yl)amino)(phenoxy)phosphoryl)oxy)methyl)-6-((tetrahydro-2H-pyran-4-carbonyl)-oxy)tetrahydro-2H-pyran-3,4-diyl diacetate A47; (3S,4R,5S,6R)-3-(2-azidoacetamido)-6-((((((S)-1-oxo-1-((tetrahydro-2H-pyran-4-yl)oxy)propan-2-yl)amino)(phenoxy)phosphoryl)oxy)methyl)tetrahydro-2H-pyran-2,4,5-triyl triacetate A48; (3S,4R,5S,6R)-3-(2-azidoacetamido)-6-((((((S)-1-((1-methylpiperidin-4-yl)oxy)-1-oxopropan-2-yl)amino)(phenoxy)phosphoryl)oxy)methyl)tetrahydro-2H-pyran-2,4,5-triyl triacetate A49; (3S,4R,5S,6R)-3-(2-azidoacetamido)-6-((((((S)-1-isopropoxy-1-oxopropan-2-yl)-amino)(quinolin-5-yloxy)phosphoryl)oxy)methyl)tetrahydro-2H-pyran-2,4,5-triyl triacetate A50; (2R,3S,4R,5S)-5-(2-azidoacetamido)-2-((((((S)-1-isopropoxy-1-oxopropan-2-yl)-amino)(quinolin-5-yloxy)phosphoryl)oxy)methyl)-6-(pentanoyloxy)tetrahydro-2H-pyran-3,4-diyl diacetate A51; (2R,3S,4R,5S)-5-(2-azidoacetamido)-2-((((((S)-1-isopropoxy-1-oxopropan-2-yl)-amino)(quinolin-5-yloxy)phosphoryl)oxy)methyl)-6-(pivaloyloxy)tetrahydro-2H-pyran-3,4-diyl diacetate A52; (2R,3S,4R,5S)-5-(2-azidoacetamido)-6-(hexanoyloxy)-2-((((((S)-1-isopropoxy-1-oxopropan-2-yl)amino)(quinolin-5-yloxy)phosphoryl)oxy)methyl)tetrahydro-2H-pyran-3,4-diyl diacetate A53; (2R,3S,4R,5S)-5-(2-azidoacetamido)-2-((((((S)-1-isopropoxy-1-oxopropan-2-yl)-amino)(quinolin-5-yloxy)phosphoryl)oxy)methyl)-6-(nonanoyloxy)tetrahydro-2H-pyran-3,4-diyl diacetate A54; (3S,4R,5S,6R)-3-(2-azidoacetamido)-6-((((((S)-1-oxo-1-(pentyloxy)propan-2-yl)-amino)(quinolin-5-yloxy)phosphoryl)oxy)methyl)tetrahydro-2H-pyran-2,4,5-triyl triacetate A55; or (((1S)-1-(1-phenylethoxycarbonyl)-ethylamino)(phenoxy)phosphoryl) 2-(2-azidoacetylamino)-2-deoxy-3,4,6-tri-O-acetyl-D-mannopyranoside B1; or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

104. A compound according to any one of claims 1 to 103, or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, or hydrate thereof; and Pharmaceutically acceptable excipients A pharmaceutical composition comprising:

105. 105. The pharmaceutical composition of claim 104, in a unitary dosage form.

106. 106. The pharmaceutical composition of claim 104 or 105, in oral, parenteral, or intravenous dosage form.

107. 107. The pharmaceutical composition of claim 106, formulated in an oral dosage form.

108. 108. The pharmaceutical composition of claim 107, wherein the oral dosage form is a tablet or a capsule.

109. 109. A method of labeling cells with an azide group in a subject, the method comprising administering to said subject in need thereof an effective amount of a compound according to any one of claims 1-103 or a pharmaceutical composition according to any one of claims 104-108.

110. 110. The method of claim 109, wherein the subject is a human.

111. 109. A method for labeling a cell with an azide group, the method comprising contacting the cell with an effective amount of a compound according to any one of claims 1 to 103 or a pharmaceutical composition according to any one of claims 104 to 108.

112. The method of any one of claims 109 to 111, wherein the cell is a cancerous cell.

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