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 in cell labeling for diagnostic and / or therapeutic applications. # imgabs0 #

Description

Technical Field

[0001] The present disclosure provides monosaccharides and pharmaceutical compositions thereof. The present disclosure also provides methods of using them for cell labeling for diagnostic and / or therapeutic applications. Background Art

[0002] Glycosylation is an enzymatic process responsible for attaching glycans to glycosyl acceptors (e.g., cell surface proteins). Reily et al., Nat. Rev. Nephrol. 2019, 15, 346 - 66. Glycosylation is crucial for both physiological and pathological cell functions (ibid.). Alterations in glycosylation have been identified in almost every type of cancer and have a major impact on cancer progression, tumor immunity, and clinical outcomes. 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.

[0003] Metabolic glycoengineering is a technique for introducing unnatural sugars into cellular glycans. 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 utilizes the carbohydrate metabolism of cells to label cells with chemical reporters (ibid.). Then, chemical reporters (e.g., azides) expressed on the cell surface can be used for targeted drug delivery or in vivo imaging through 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.

[0004] Despite the progress made in cancer diagnosis and treatment, cancer remains a significant public health problem worldwide. Wang and Mooney, Nat. Chem. 2020, 12, 1102-14. It is estimated that in 2022, there will be 1,918,030 new cancer cases and 609,360 cancer deaths 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

[0005] The present invention provides compounds of formula (I): 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; wherein: R 1 is (i) hydrogen or deuterium; or (ii) C 1-20 alkyl, C 1-20 heteroalkyl, C 2-20 alkenyl, C 2-20 alkynyl, C 3-20 cycloalkyl, C 6-20 aryl, C 7-20 arylalkyl, heteroaryl, or heterocyclic group; R 2 is heteroaryl; R 3 are each independently (i) deuterium, cyano, halogen, or nitro; (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 arylalkyl, heteroaryl, or heterocyclic group; 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 R1c 、 –OR 1a 、 –OC(O)R 1a 、 –OC(O)OR 1a 、 –OC(O)NR 1b R 1c 、 –OC(O)SR 1a 、 –OC(NR 1a )NR 1b R 1c 、 –OC(S)R 1a 、 –OC(S)OR 1a 、 –OC(S)NR 1b R 1c 、 –OS(O)R 1a 、 –OS(O)2R 1a 、 –OS(O)NR 1b R 1c 、 –OS(O)2NR 1b R 1c 、 –NR 1b R 1c 、 –NR 1a C(O)R 1d 、 –NR 1a C(O)OR 1d 、 –NR 1a C(O)NR 1b R 1c 、 –NR 1a C(O)SR 1d 、 –NR 1a C(NR 1d )NR 1b R 1c 、 –NR 1a C(S)R 1d 、 –NR 1a C(S)OR 1d 、 –NR 1a C(S)NR 1b R 1c 、 –NR 1a S(O)R 1d 、 –N=S(O)R 1a R 1d 、 –NR 1a S(O)2R 1d 、 –NR 1a S(O)NR 1b R 1c 、 –NR 1a S(O)2NR 1b R 1c 、 –SR 1a 、 –S(O)R 1a 、 –S(O)2R1a 、 –S(O)NR 1b R 1c or –S(O)2NR 1b R 1c ; R 4 and R 6 are each independently (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 heterocyclic group; 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 5 is 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 heterocyclic group; R 7 and R 8 are each independently (i) halogen; or (ii) –OR 1a , –OC(O)R 1a , –OC(O)OR 1a or –OC(O)NR 1b R 1c ; and R 9 is (i) hydrogen; or (ii) –C(O)R 1a, –C(O)OR 1a or –C(O)NR 1b R 1c ; or R 7 and R 8 or R 8 and R 9 are linked together to form a lactone ring; A is a bond, O or N(R 1b ); E is hydrogen, azido, halogen, isocyano, –C═C(R 1a )R 1a , –C≡CR 1a , –C(O)R 1a or –SH; L 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 aralkyl, heteroaryl or heterocyclic group; R 1a , R 1b , R 1c and R 1d are each independently hydrogen, deuterium, 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 heterocyclic group; and m is an integer of 0, 1, 2, 3 or 4; wherein, alkyl, alkylene, heteroalkyl, heteroalkylene, alkenyl, alkenylene, alkynyl, alkynylene, cycloalkyl, cycloalkylene, aryl, arylene, aralkyl, aralkylene, heteroaryl, heteroarylene, heterocyclic group and heterocyclic group are each optionally substituted by one or more (in one embodiment, by one, two, three or four) substituents Q, wherein Q are each independently selected from: (a) deuterium, cyano, halogen, 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 7-15Arylalkyl, heteroaryl and heterocyclic groups, each of which is further optionally substituted by one or more (in one embodiment, by one, two, three or four) substituents Q a substituted; 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)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 aC(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)2R a , –S(O)NR b R c and –S(O)2NR b R c , where R a , R b , R c and R d are each independently (i) hydrogen or deuterium; (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, each of which is optionally substituted by one or more (in one embodiment, by one, two, three or four) substituents Q a or (iii) R b and R c Together with the N atom to which they are attached, they form a heterocyclic group, which is optionally substituted by one or more (in one embodiment, by one, two, three or four) substituents Q a replace; Among them, Q a are each independently selected from: (a) deuterium, cyano, halogen, 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)ORe 、 –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)2NR 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 ; wherein, R e , R f , R g and R h are each 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 heterocyclic group; or (iii) R f and R g together with the N atom to which they are attached form a heterocyclic group.

[0006] The present invention also provides a pharmaceutical composition, which comprises a compound of formula (I), or its enantiomer, a mixture of enantiomers, diastereomers, a mixture of two or more diastereomers, tautomers, a mixture of two or more tautomers, or isotope variants, or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof; and a pharmaceutically acceptable excipient.

[0007] In addition, the present invention provides a method for labeling cells in a subject with an azide group, the method comprising administering to a subject in need an effective amount of a compound of formula (I), or its enantiomer, a mixture of enantiomers, diastereomers, a mixture of two or more diastereomers, tautomers, a mixture of two or more tautomers, or isotope variants; or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof.

[0008] In addition, the present disclosure provides a method for labeling cells with an azide group, the method comprising contacting the cells 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

[0009] To facilitate understanding of the disclosure presented herein, a number of terms are defined below.

[0010] Generally, the nomenclature used herein and the experimental procedures described herein in organic chemistry, medicinal chemistry, biochemistry, biology and pharmacology are those well known and commonly used in the art. Unless otherwise defined, 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 pertains.

[0011] The term "subject" refers to an animal, including (but not limited to) primates (e.g., humans), cattle, pigs, sheep, goats, horses, dogs, cats, rabbits, rats or mice. The terms "subject" and "patient" are used interchangeably herein, e.g., when referring to a mammalian subject, e.g., a human subject. In one embodiment, the subject is a human.

[0012] The term "contacting / contact" means bringing a therapeutic agent and a biomolecule (e.g., a protein, an enzyme, an RNA or a DNA), a cell or a tissue together such that a physiological and / or chemical effect caused by such contact occurs. Contact 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 a 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, a cell or a tissue includes administering the therapeutic agent to a subject having the biomolecule, cell or tissue to be contacted.

[0013] The term "therapeutically effective amount" or "effective amount" means an amount of a compound that, when administered, is sufficient to prevent the development of one or more symptoms of the disorder, disease or condition being treated or to alleviate to some extent one or more symptoms of the disorder, disease or condition being treated. The term "therapeutically effective amount" or "effective amount" also refers to an amount of a compound that is sufficient to elicit a biological or medical response of a biomolecule (e.g., a protein, enzyme, RNA or DNA), cell, tissue, system, animal or human being sought by a researcher, veterinarian, physician or clinician.

[0014] The terms "pharmaceutically acceptable carrier", "pharmaceutically acceptable excipient", "physiologically acceptable carrier" or "physiologically acceptable excipient" refer to pharmaceutically acceptable materials, compositions or vehicles (e.g., liquid or solid fillers, diluents, solvents or encapsulating materials). In one embodiment, each component is "pharmaceutically acceptable" in the sense of being compatible with the other ingredients of the pharmaceutical formulation and suitable for contact with the tissues or organs of a subject (e.g., a human) without undue toxicity, irritation, allergic response, immunogenicity or other problems or complications and commensurate with a reasonable benefit / risk ratio. See, e.g., Remington: The Science and Practice of Pharmacy, 23rd Edition; edited by Adejare; Academic Press, 2020; Handbook of Pharmaceutical Excipients, 9th Edition; edited by Sheskey et al.; Pharmaceutical Press, 2020; Handbook of Pharmaceutical Additives, 3rd Edition; edited by Ash and Ash; Synapse Information Resources, 2007; Pharmaceutical Preformulation and Formulation, 2nd Edition; edited by Gibson; CRC Press, 2009.

[0015] The term "about" or "approximately" means an acceptable error of a particular value as determined by a person 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.

[0016] The term "alkyl" refers to a straight-chain or branched-chain saturated monovalent hydrocarbon group, wherein said alkyl group is optionally substituted with one or more substituents Q as described herein. For example, C 1-6 alkyl refers to a straight-chain saturated monovalent hydrocarbon group having 1 to 6 carbon atoms or a branched-chain saturated monovalent hydrocarbon group having 3 to 6 carbon atoms. In certain embodiments, said alkyl group is a straight-chain saturated monovalent hydrocarbon group having 1 to 30 (C 1-30 ), 1 to 20 (C 1-20 ), 1 to 15 (C 1-15 ), 1 to 10 (C 1-10 ) or 1 to 6 (C 1-6 ) carbon atoms, or a branched-chain saturated monovalent hydrocarbon group having 3 to 30 (C 3-30 ), 3 to 20 (C 3-20 ), 3 to 15 (C 3-15 ), 3 to 10 (C 3-10 ) or 3 to 6 (C 3-6 ) carbon atoms. As used herein, straight-chain C 1-6 and branched-chain C 3-6 alkyl groups are also referred to as "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 tert-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).

[0017] The terms "alkylene" and "alkanediyl" are used interchangeably herein when referring to a straight-chain or branched-chain saturated divalent hydrocarbon group, wherein said alkanediyl is optionally substituted with one or more substituents Q as described herein. For example, C 1-6 alkanediyl refers to a straight-chain saturated divalent hydrocarbon group having 1 to 6 carbon atoms or a branched-chain saturated divalent hydrocarbon group having 3 to 6 carbon atoms. In certain embodiments, said alkanediyl is a straight-chain saturated divalent hydrocarbon group having 1 to 30 (C 1-30 ), 1 to 20 (C 1-20 ), 1 to 15 (C 1-15 ), 1 to 10 (C 1-10 ) or 1 to 6 (C 1-6 ) carbon atoms, or a branched-chain saturated divalent hydrocarbon group having 3 to 30 (C 3-30 ), 3 to 20 (C 3-20 ), 3 to 15 (C 3-15 ), 3 to 10 (C 3-10 ) or 3 to 6 (C 3-6 ) carbon atoms. As used herein, straight-chain C 1-6 and branched-chain C3-6 An alkanediyl group is also referred to as a "lower alkanediyl". Examples of alkanediyl groups include, but are not limited to, methanediyl, ethanediyl (including all isomeric forms, e.g., ethane-1,1-diyl and ethane-1,2-diyl), propanediyl (including all isomeric forms, e.g., propane-1,1-diyl, propane-1,2-diyl and propane-1,3-diyl), butanediyl (including all isomeric forms, e.g., butane-1,1-diyl, butane-1,2-diyl, butane-1,3-diyl and butane-1,4-diyl), pentanediyl (including all isomeric forms, e.g., pentane-1,1-diyl, pentane-1,2-diyl, pentane-1,3-diyl and pentane-1,5-diyl) and hexanediyl (including all isomeric forms, e.g., hexane-1,1-diyl, hexane-1,2-diyl, hexane-1,3-diyl and hexane-1,6-diyl). Examples of substituted alkanediyl groups include, but are not limited to, –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–, –C(O)(CH2) 10 –, –C(O)CH2C(O)–, –C(O)(CH2)2C(O)–, –C(O)(CH2)3C(O)–, –C(O)(CH2)4C(O)– or –C(O)(CH2)5C(O)–.

[0018] The term "heteroalkyl" refers to a straight-chain or branched-chain saturated monovalent hydrocarbon group containing one or more heteroatoms in its backbone, said heteroatoms being independently selected from O, S and N. The heteroalkyl is optionally substituted with one or more substituents Q as described herein. For example, C 1-6 heteroalkyl refers to a straight-chain saturated monovalent hydrocarbon group of 1 to 6 carbon atoms or a branched-chain saturated monovalent hydrocarbon group of 3 to 6 carbon atoms. In certain embodiments, the heteroalkyl is a straight-chain saturated monovalent hydrocarbon group having 1 to 30 (C 1-30 ), 1 to 20 (C 1-20 ), 1 to 15 (C 1-15 ), 1 to 10 (C 1-10 ) or 1 to 6 (C 1-6 ) carbon atoms, or a branched-chain saturated monovalent hydrocarbon group of 3 to 30 (C 3-30 ), 3 to 20 (C 3-20 ), 3 to 15 (C 3-15 ), 3 to 10 (C 3-10 ) or 3 to 6 (C 3-6 ) carbon atoms. As used herein, straight-chain C 1-6 and branched-chain C3-6 Heteroalkyl groups are also referred to as "lower heteroalkyl". Examples of heteroalkyl groups include, but are not limited to, –OCH3, –OCH2CH3, –CH2OCH3, –NHCH3, –ONHCH3, –NHOCH3, –SCH3, –CH2NHCH2CH3, and –NHCH2CH2CH3. Examples of substituted heteroalkyl groups include, but are not limited to, –CH2NHC(O)CH3 and –NHC(O)CH2CH3.

[0019] The terms "heteroalkylene" and "heteroalkanediyl" are used interchangeably herein when referring to a straight or branched chain saturated divalent hydrocarbon group having one or more heteroatoms in its backbone, each heteroatom 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 straight chain saturated divalent hydrocarbon group of 1 to 6 carbon atoms or a branched chain saturated divalent hydrocarbon group of 3 to 6 carbon atoms. In certain embodiments, the heteroalkylene is a (C 1-30 ) having 1 to 30, a (C 1-20 ) having 1 to 20, a (C 1-15 ) having 1 to 15, a (C 1-10 ) having 1 to 10, or a (C 1-6 ) having 1 to 6 carbon atoms of a straight chain saturated divalent hydrocarbon group, or a (C 3-30 ) having 3 to 30, a (C 3-20 ) having 3 to 20, a (C 3-15 ) having 3 to 15, a (C 3-10 ) having 3 to 10, or a (C 3-6 ) having 3 to 6 carbon atoms of a branched chain saturated divalent hydrocarbon group. As used herein, straight chain C 1-6 and branched chain C 3-6 heteroalkylene groups are also referred to as "lower heteroalkylene". Examples of heteroalkylene groups include, but are not limited to, –CH2O–, –CH2CH2O–, –CH2CH2CH2O–, –(CH2)4O–, –(CH2)5O–, –(CH2)6O–, –(CH2)7O–, –(CH2)8O–, –(CH2)9O–, –(CH2) 10O–, –CH2OCH2–, –CH2CH2O–, –(CH2CH2O)2–, –(CH2CH2O)3–, –(CH2CH2O)4–, –(CH2CH2O)5–, –CH2NH–, –CH2NHCH2–, –CH2CH2NH–, –CH2CH2CH2NH–, –(CH2)4NH–, –CH2S–, –CH2SCH2–, and –CH2CH2S–. Examples of substituted heteroalkyl groups include, but are not limited to, –C(O)CH2O–, –C(O)(CH2)2O–, –C(O)CH2CH2CH2O–, –C(O)CH2CH2CH2CH2O–, –C(O)(CH2)5O–, –C(O)(CH2)6O–, –C(O)(CH2)7O–, –C(O)(CH2)8O–, –C(O)(CH2)9O–, –C(O)(CH2) 10 O–, –C(O)CH2OCH2CH2O–, –C(O)CH2O(CH2CH2O)2–, –C(O)CH2O-(CH2-CH2O)3–, –C(O)CH2O(CH2CH2O)4, –C(O)CH2O(CH2CH2O)5–, –CH2NHC(O)CH2–, –CH2CH2C(O)NH–, –CH2N(CH3)–, –(CH2)2N(CH3)–, –(CH2)3N(CH3)–, or –(CH2)4N(CH3)–.

[0020] The term "alkenyl" refers to a straight-chain or branched-chain monovalent hydrocarbon group containing one or more (in one embodiment, one, two, three, or four; in another embodiment, one) carbon-carbon double bonds. The alkenyl is optionally substituted with one or more substituents Q as described herein. As understood by those of ordinary skill in the art, the term "alkenyl" includes groups having "cis" or "trans" configurations or mixtures thereof, or groups having "Z" or "E" configurations or mixtures thereof. For example, C 2-6 alkenyl refers to a straight-chain unsaturated monovalent hydrocarbon group having 2 to 6 carbon atoms or a branched-chain unsaturated monovalent hydrocarbon group having 3 to 6 carbon atoms. In certain embodiments, the alkenyl is a straight-chain monovalent hydrocarbon group having 2 to 30 (C 2-30 ), 2 to 20 (C 2-20 ), 2 to 15 (C 2-15 ), 2 to 10 (C 2-10 ), or 2 to 6 (C 2-6 ) carbon atoms, or a branched-chain monovalent hydrocarbon group having 3 to 30 (C 3-30 ), 3 to 20 (C 3-20 ), 3 to 15 (C 3-15 ), 3 to 10 (C 3-10 ), or 3 to 6 (C3-6 ) A branched monovalent hydrocarbon group of carbon atoms. Examples of alkenyl groups include, but are not limited to, vinyl, propenyl (including all isomeric forms, e.g., prop-1-en-1-yl, prop-2-en-1-yl, and allyl), and butenyl (including all isomeric forms, e.g., but-1-en-1-yl, but-2-en-1-yl, but-3-en-1-yl, and 2-buten-1-yl).

[0021] The terms “alkenylene” and “alkenediyl” are used interchangeably herein when referring to a straight-chain or branched divalent hydrocarbon group containing one or more (in one embodiment, one, two, three, or four; in another embodiment, one) carbon-carbon double bonds. The alkenediyl is optionally substituted with one or more substituents Q as described herein. As understood by those of ordinary skill in the art, the term “alkenediyl” includes groups having “cis” or “trans” configurations or mixtures thereof, or groups having “Z” or “E” configurations or mixtures thereof. For example, C 2-6 Alkenediyl refers to a straight-chain unsaturated divalent hydrocarbon group of 2 to 6 carbon atoms or a branched unsaturated divalent hydrocarbon group of 3 to 6 carbon atoms. In certain embodiments, the alkenediyl is 2 to 30 (C 2-30 ), 2 to 20 (C 2-20 ), 2 to 15 (C 2-15 ), 2 to 10 (C 2-10 ), or 2 to 6 (C 2-6 ) carbon atoms in a straight-chain divalent hydrocarbon group, or 3 to 30 (C 3-30 ), 3 to 20 (C 3-20 ), 3 to 15 (C 3-15 ), 3 to 10 (C 3-10 ), or 3 to 6 (C 3-6 ) carbon atoms in a branched divalent hydrocarbon group. Examples of alkenediyl groups include, but are not limited to, ethylenediyl (including all isomeric forms, e.g., ethane-1,1-diyl and ethane-1,2-diyl), propenediyl (including all isomeric forms, e.g., 1-propene-1,1-diyl, 1-propene-1,2-diyl, and 1-propene-1,3-diyl), butenediyl (including all isomeric forms, e.g., 1-butene-1,1-diyl, 1-butene-1,2-diyl, and 1-butene-1,4-diyl), pentenediyl (including all isomeric forms, e.g., 1-pentene-1,1-diyl, 1-pentene-1,2-diyl, and 1-pentene-1,5-diyl), and hexenediyl (including all isomeric forms, e.g., 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 hexene-1,6-diyl).

[0022] The term "alkynyl" refers to a straight-chain or branched-chain monovalent hydrocarbon group containing one or more (in one embodiment, one, two, three, or four; in another embodiment, one) carbon-carbon triple bonds. The alkynyl group does not contain carbon-carbon double bonds. The alkynyl group is optionally substituted with one or more substituents Q as described herein. For example, C 2-6 Alkynyl refers to a straight-chain unsaturated monovalent hydrocarbon group having 2 to 6 carbon atoms or a branched-chain unsaturated monovalent hydrocarbon group having 4 to 6 carbon atoms. In certain embodiments, the alkynyl group is a straight-chain monovalent hydrocarbon group having 2 to 30 (C 2-30 ), 2 to 20 (C 2-20 ), 2 to 15 (C 2-15 ), 2 to 10 (C 2-10 ), or 2 to 6 (C 2-6 ) carbon atoms, or a branched-chain monovalent hydrocarbon group having 4 to 30 (C 4-30 ), 4 to 20 (C 4-20 ), 4 to 15 (C 4-15 ), 4 to 10 (C 4-10 ), or 4 to 6 (C 4-6 ) carbon atoms. Examples of alkynyl groups include, but are not limited to, ethynyl (-C≡CH), propynyl (including all isomeric forms, e.g., 1-propynyl (-C≡CCH3) and propargyl (-CH2C≡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).

[0023] The terms "alkynylene" and "diynyl" are used interchangeably herein when referring to a straight-chain or branched-chain divalent hydrocarbon group containing one or more (in one embodiment, one, two, three, or four; in another embodiment, one) carbon-carbon triple bonds. The alkynylene group does not contain carbon-carbon double bonds. The diynyl group is optionally substituted with one or more substituents Q as described herein. For example, C 2-6 Diynyl refers to a straight-chain unsaturated divalent hydrocarbon group having 2 to 6 carbon atoms or a branched-chain unsaturated divalent hydrocarbon group having 4 to 6 carbon atoms. In certain embodiments, the diynyl group is a straight-chain divalent hydrocarbon group having 2 to 30 (C 2-30 ), 2 to 20 (C 2-20 ), 2 to 15 (C 2-15 ), 2 to 10 (C 2-10 ), or 2 to 6 (C 2-6 ) carbon atoms, or a branched-chain divalent hydrocarbon group having 4 to 30 (C 4-30 ), 4 to 20 (C 4-20 ), 4 to 15 (C 4-15)), 4 to 10 (C 4-10 ) or 4 to 6 (C 4-6 ) branched divalent hydrocarbon groups having from 4 to 6 carbon atoms. Examples of the alkynediyl groups include, but are not limited to, ethynediyl, propynediyl (including all isomeric forms, e.g., 1-propyn-1,3-diyl and 1-propyn-3,3-diyl), butynediyl (including all isomeric forms, e.g., 1-butyn-1,3-diyl, 1-butyn-1,4-diyl and 2-butyn-1,1-diyl), pentynediyl (including all isomeric forms, e.g., 1-pentyn-1,3-diyl, 1-pentyn-1,4-diyl and 2-pentyn-1,1-diyl) and hexynediyl (including all isomeric forms, e.g., 1-hexyn-1,3-diyl, 1-hexyn-1,4-diyl and 2-hexyn-1,1-diyl).

[0024] The term "cycloalkyl" refers to a cyclic monovalent hydrocarbon group, which is optionally substituted with one or more substituents Q as described herein. In one embodiment, the cycloalkyl is saturated or unsaturated but non-aromatic, and / or bridged or non-bridged, and / or a fused bicyclic group. In certain embodiments, the cycloalkyl has 3 to 20 (C 3-30 ), 3 to 20 (C 3-20 ), 3 to 15 (C 3-15 ), 3 to 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 still 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, decahydronaphthyl and adamantyl.

[0025] The terms "subcycloalkyl" and "cycloalkanediyl" are used interchangeably herein when referring to a cyclic divalent hydrocarbon group, which may be optionally substituted with one or more substituents Q as described herein. In one embodiment, the cycloalkanediyl may be saturated or unsaturated but non-aromatic, and / or bridged or non-bridged, and / or a fused bicyclic group. In certain embodiments, the cycloalkanediyl has 3 to 30 (C 3-30 ), 3 to 20 (C 3-20 ), 3 to 15 (C 3-15 ), 3 to 10 (C 3-10 ) or 3 to 7 (C 3-7) carbon atoms. Examples of the cycloalkanediyl group include, but are not limited to, cyclopropanediyl (including all isomeric forms, e.g., cyclopropane-1,1-diyl and cyclopropane-1,2-diyl), cyclobutanediyl (including all isomeric forms, e.g., cyclobutane-1,1-diyl, cyclobutane-1,2-diyl and cyclobutane-1,3-diyl), cyclopentanediyl (including all isomeric forms, e.g., cyclopentane-1,1-diyl, cyclopentane-1,2-diyl and cyclopentane-1,3-diyl), cyclohexanediyl (including all isomeric forms, e.g., cyclohexane-1,1-diyl, cyclohexane-1,2-diyl, cyclohexane-1,3-diyl and cyclohex-1,4-diyl), cycloheptanediyl (including all isomeric forms, e.g., cycloheptane-1,1-diyl, cycloheptane-1,2-diyl, cycloheptane-1,3-diyl and cycloheptane-1,4-diyl), decahydronaphthalenediyl (including all isomeric forms, e.g., decahydronaphthalene-1,1-diyl, decahydronaphthalene-1,2-diyl and decahydronaphthalene-1,8-diyl) and adamantanediyl (including all isomeric forms, e.g., adamantane-1,2-diyl, adamantane-1,3-diyl and adamantane-1,8-diyl).

[0026] The term "aryl" refers to a monovalent monocyclic aromatic hydrocarbon group and / or a monovalent polycyclic aromatic hydrocarbon group containing at least one aromatic carbocyclic ring. In certain embodiments, the aryl has 6 to 30 (C 6-30 ), 6 to 20 (C 6-20 ), 6 to 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, anthracenyl, phenanthryl, pyrenyl, biphenyl and terphenyl. The aryl also refers to a bicyclic or tricyclic carbocyclic ring, wherein one ring is aromatic and the remaining ones can be saturated, partially unsaturated or aromatic, e.g., dihydronaphthyl, indenyl, indanyl or tetralinyl. In one embodiment, the aryl is monocyclic. In another embodiment, the aryl is bicyclic. In yet another embodiment, the aryl is tricyclic. In still another embodiment, the aryl is polycyclic. In certain embodiments, the aryl is optionally substituted with one or more substituents Q as described herein.

[0027] The terms "arylene" and "arenediyl" are used interchangeably herein when referring to a divalent monocyclic aromatic hydrocarbon group or a divalent polycyclic aromatic hydrocarbon group containing at least one aromatic hydrocarbon ring. In certain embodiments, the arylene has 6 to 30 (C 6-30 ), 6 to 20 (C 6-20 ), 6 to 15 (C 6-15 ) or 6 to 10 (C 6-10)Ring atoms. Examples of arylene groups include, but are not limited to, phenylene (including all isomeric forms, e.g., benzene-1,2-diyl, benzene-1,3-diyl, and benzene-1,4-diyl), naphthylene (including all isomeric forms, e.g., naphthalene-1,2-diyl, naphthalene-1,3-diyl, and naphthalene-1,8-diyl), fluorenylene (including all isomeric forms, e.g., fluorene-1,2-diyl, fluorene-1,3-diyl, and fluorene-1,8-diyl), azulylene (including all isomeric forms, e.g., azulene-1,2-diyl, azulene-1,3-diyl, and azulene-1,8-diyl), anthrylene (including all isomeric forms, e.g., anthracene-1,2-diyl, anthracene-1,3-diyl, and anthracene-1,8-diyl), phenanthrylene (including all isomeric forms, e.g., phenanthrene-1,2-diyl, phenanthrene-1,3-diyl, and phenanthrene-1,8-diyl), pyrenylene (including all isomeric forms, e.g., pyrene-1,2-diyl, pyrene-1,3-diyl, and pyrene-1,8-diyl), biphenylene (including all isomeric forms, e.g., biphenyl-2,3-diyl, biphenyl-3,4'-diyl, and biphenyl-4,4'-diyl), and terphenylenylene (including all isomeric forms, e.g., terphenyl-2,3-diyl, terphenyl-3,4'-diyl, and terphenyl-4,4'-diyl). Arylene also refers to bicyclic or tricyclic carbocycles, where one ring is aromatic and the rest can be saturated, partially unsaturated, or aromatic, e.g., dihydronaphthylene (including all isomeric forms, e.g., dihydronaphthalene-1,2-diyl and dihydronaphthalene-1,8-diyl), indenylene (including all isomeric forms, e.g., indene-1,2-diyl, indene-1,5-diyl, and indene-1,7-diyl), indanyl (including all isomeric forms, e.g., indane-1,2-diyl, indane-1,5-diyl, and indane-1,7-diyl), or tetrahydronaphthylene (tetralinylene) (including all isomeric forms, e.g., tetrahydronaphthalene-1,2-diyl, tetrahydronaphthalene-1,5-diyl, and tetrahydronaphthalene-1,8-diyl). In certain embodiments, the arylene is optionally substituted with one or more substituents Q as described herein.

[0028] The term "aralkyl" or "arylalkyl" refers to a monovalent alkyl group substituted with one or more aryl groups. In certain embodiments, the aralkyl has 7 to 30 carbon atoms (C 7-30 ), 7 to 20 carbon atoms (C 7-20 ), or 7 to 16 carbon atoms (C 7-16 ). Examples of aralkyl groups include, but are not limited to, benzyl, phenethyl (including all isomeric forms, e.g., 1-phenethyl and 2-phenethyl), 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.

[0029] The term "aralkylidene" or "arylalkylidene" refers to a divalent alkyl group substituted with one or more aryl groups. In certain embodiments, the aralkylidene has 7 to 30 (C 7-30 ), 7 to 20 (C 7-20 ), or 7 to 16 (C 7-16 ) carbon atoms. Examples of aralkylidene groups include, but are not limited to, benzylidene (including all isomeric forms, e.g., phenylmethanediyl), phenylethylidene (including all isomeric forms, e.g., 2-phenyl-eth-1,1-diyl and 2-phenyl-eth-1,2-diyl), and phenylpropylidene (including all isomeric forms, e.g., 3-phenyl-prop-1,1-diyl, 3-phenyl-prop-1,2-diyl, and 3-phenyl-prop-1,3-diyl). In certain embodiments, the aralkylidene is optionally substituted with one or more substituents Q as described herein.

[0030] The term "heteroaryl" refers to a monovalent monocyclic aromatic group or a monovalent polycyclic aromatic group containing at least one aromatic ring, wherein at least one aromatic ring contains one or more heteroatoms in the ring, and each of the heteroatoms is independently selected from O, S, and N. For a heteroaryl group containing a heteroaromatic ring and a non-aromatic heterocyclic ring, the heteroaryl group is not bonded to the remainder of the molecule through its non-aromatic heterocyclic ring. Each ring of the heteroaryl group may contain one or two O atoms, one or two S atoms, and / or one to four N atoms; provided that the total number of heteroatoms in each ring is less than four, and each ring contains at least one carbon atom. In certain embodiments, the heteroaryl has 5 to 20, 5 to 15, or 5 to 10 ring atoms. In one embodiment, the heteroaryl is monocyclic. Examples of monocyclic heteroaryl groups include, but are not limited to, furyl, 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, but are not limited to, benzofuranyl, benzimidazolyl, benzisoxazolyl, benzopyranyl, benzothiadiazolyl, benzothiazolyl, benzothienyl, benzotriazolyl, benzoxazolyl, furanopyridyl (including all isomeric forms, e.g., furano[2,3-b]pyridyl, furano[2,3-c]pyridyl, furano[3,2-b]pyridyl, furano[3,2-c]pyridyl, furano[3,4-b]pyridyl, and furano[3,4-c]pyridyl), imidazopyridyl (including all isomeric forms, e.g., imidazo[1,2-a]pyridyl, imidazo[4,5-b]pyridyl, and imidazo[4,5-c]pyridyl), imidazothiazolyl (including all isomeric forms, e.g., 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, e.g., 1,5-naphthyridinyl, 1,6-naphthyridinyl, 1,7-naphthyridinyl, and 1,8-naphthyridinyl), oxazolopyridyl (including all isomeric forms, e.g., oxazolo[4,5-b]pyridyl, oxazolo[4,5-c]pyridyl, oxazolo[5,4-b]pyridyl, and oxazolo[5,4-c]pyridyl), phthalazinyl, pteridinyl, purinyl, pyrrolopyridyl (including all isomeric forms, e.g., pyrrolo[2,3-b]pyridyl, pyrrolo[2,3-c]pyridyl, pyrrolo[3,2-b]pyridyl, and pyrrolo[3,2-c]pyridyl), quinolinyl, quinoxalinyl, quinazolinyl, thiadiazolopyrimidinyl (including all isomeric forms, e.g., [1,2,5]thiadiazolo[3,4-d]pyrimidinyl and [1,2,3]thiadiazolo[4,5-d]pyrimidinyl), and thiophenopyridyl (including all isomeric forms, e.g., thiopheno[2,3-b]pyridyl, thiopheno[2,3-c]pyridyl, thiopheno[3,2-b]pyridyl, and thiopheno[3,2-c]pyridyl). In yet another embodiment, the heteroaryl is tricyclic. Examples of tricyclic heteroaryl groups include, but are not limited to, acridinyl, benzindolyl, carbazolyl, dibenzofuranyl, perimidinyl, phenanthrolinyl, phenanthridinyl (including all isomeric forms, e.g., 1,5-phenanthrolinyl, 1,6-phenanthrolinyl, 1,7-phenanthrolinyl, 1,9-phenanthrolinyl, and 2,10-phenanthrolinyl), phenarsazinyl, phenazinyl, phenothiazinyl, phenoxazinyl, and xanthenyl. In certain embodiments, the heteroaryl is optionally substituted with one or more substituents Q as described herein.

[0031] The terms "heteroarylene" and "heteroarenediyl" are used interchangeably herein when referring to a divalent monocyclic aromatic group or a divalent polycyclic aromatic group containing at least one aromatic ring, wherein at least one aromatic ring contains one or more heteroatoms in the ring, each of which is independently selected from O, S, and N. For a heteroarylene group containing a heteroaromatic ring and a non-aromatic heterocyclic ring, the heteroarylene group is not bonded to the remainder of the molecule through its non-aromatic heterocyclic ring. Each ring of the heteroarylene group may contain one or two O atoms, one or two S atoms, and / or one to four N atoms, provided that the total number of heteroatoms in each ring is less than four and each ring contains at least one carbon atom. In certain embodiments, the heteroarylene has 5 to 20, 5 to 15, or 5 to 10 ring atoms. Examples of monocyclic heteroarylene include but are not limited to furandiyl, imidazolediyl, isothiazolediyl, isoxazolediyl, oxadiazolediyl, oxazolediyl, pyrazinediyl, pyrazolediyl, pyridazinediyl, pyridinediyl, pyrimidinediyl, pyrrolediyl, thiadiazolediyl, thiazolediyl, thiophenediyl, tetrazolediyl, triazinediyl, and triazolediyl.Examples of bicyclic heteroaryl groups include, but are not limited to, benzofurandiyl, benzimidazolediyl, benzisoxazolediyl, chromandiyl, benzothiadiazolediyl, benzothiazolediyl, benzothiophenediyl, benzotriazolediyl, benzoxazolediyl, furanopyridinyl (including all isomeric forms, e.g., furano[2,3-b]pyridinyl, furano[2,3-c]pyridinyl, furano[3,2-b]pyridinyl, furano[3,2-c]pyridinyl, furano[3,4-b]pyridinyl, and furano[3,4-c]pyridinyl), imidazopyridinyl (including all isomeric forms, e.g., imidazo[1,2-a]pyridinyl, imidazo[4,5-b]pyridinyl, and imidazo[4,5-c]pyridinyl), imidazothiazolyl (including all isomeric forms, e.g., imidazo[2,1-b]thiazolyl and imidazo[4,5-d]thiazolyl), indazolediyl, isoindolediyl, indolediyl, isobenzofurandiyl, isobenzothiophenediyl (i.e., benzothiophenediyl), isoindolediyl, isoquinolediyl, naphthyridinyl (including all isomeric forms, e.g., 1,5-naphthyridinyl, 1,6-naphthyridinyl, 1,7-naphthyridinyl, and 1,8-naphthyridinyl), oxazolopyridinyl (including all isomeric forms, e.g., oxazolo[4,5-b]pyridinyl, oxazolo[4,5-c]pyridinyl, oxazolo[5,4-b]pyridinyl, and oxazolo[5,4-c]pyridinyl), phthalazinyl, pteridinyl, purinyl, pyrrolopyridinyl (including all isomeric forms, e.g., pyrrolo[2,3-b]pyridinyl, pyrrolo[2,3-c]pyridinyl, pyrrolo[3,2-b]pyridinyl, and pyrrolo[3,2-c]pyridinyl), quinolinyl, quinoxalinyl, quinazolinyl, thiadiazolopyrimidinyl (including all isomeric forms, e.g., [1,2,5]thiadiazolo[3,4-d]pyrimidinyl and [1,2,3]thiadiazolo[4,5-d]pyrimidinyl), and thiophenopyridinyl (including all isomeric forms, e.g., thiopheno[2,3-b]pyridinyl, thiopheno[2,3-c]pyridinyl, thiopheno[3,2-b]pyridinyl, and thiopheno[3,2-c]pyridinyl). Examples of tricyclic heteroaryl groups include, but are not limited to, acridinyl, benzindolediyl, carbazolediyl, dibenzofurandiyl, phenanthridinyl, phenanthrolinyl (including all isomeric forms, e.g., 1,5-phenanthrolinyl, 1,6-phenanthrolinyl, 1,7-phenanthrolinyl, 1,9-phenanthrolinyl, and 2,10-phenanthrolinyl), phenanthridinyl, phenopyrazinyl, phenazinyl, phenothiazinyl, phenoxazinyl, and xanthenyl. In certain embodiments, the heteroaryl is optionally substituted with one or more substituents Q as described herein.

[0032] The term "heterocyclic group" or "heterocyclic" refers to a monovalent monocyclic non-aromatic ring system or a monovalent polycyclic system containing at least one non-aromatic ring, wherein one or more of the non-aromatic ring atoms are heteroatoms, each of said heteroatoms being independently selected from O, S, and N; and the remaining ring atoms being carbon atoms. For a heterocyclic group containing a heteroaromatic ring and a non-aromatic heterocycle, the heterocyclic group is not bonded to the remainder of the molecule through the heteroaromatic ring. In certain embodiments, the heterocyclic group or heterocyclic moiety 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, the heterocyclic group is a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may be fused or bridged, and wherein, the nitrogen or sulfur atoms may optionally be oxidized, the nitrogen atoms may optionally be quaternized, and some rings may be partially or fully saturated or aromatic. The heterocyclic group may be attached to the main structure at any heteroatom or carbon atom that results in a stable compound. Examples of heterocyclic groups and heterocyclic moieties include, but are not limited to, azetidinyl, benzodioxolanyl, benzodioxolenyl, benzofuranonyl, chromanyl, decahydroisoquinolinyl, dihydrobenzofuranyl, dihydrobenzisothiazolyl, dihydrobenzisoxazinyl (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, dihydrofuranyl, dihydroisoindolyl, dihydropyranyl, dihydropyrazolyl, dihydropyrazinyl, dihydropyridinyl, dihydropyrimidinyl, dihydropyrrolyl, dioxolanyl, 1,4-dithianyl, furanonyl, imidazolidinyl, imidazolinyl, dihydroindolyl, isochromanyl, isoindolinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, oxazolidinonyl, oxazolidinyl, oxiranyl, piperazinyl, piperidinyl, 4-piperidinonyl, pyrazolidinyl, pyrazolinyl, pyrrolidinyl, pyrrolinyl, quinuclidinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydropyranyl, tetrahydrothienyl, thiomorpholinyl, thiazolidinyl, thiochromanyl, tetrahydroquinolinyl, and 1,3,5-trithianyl. In certain embodiments, the heterocyclic group is optionally substituted with one or more substituents Q as described herein. Azetidinyl, benzodioxolanyl, benzodioxolenyl, benzofuranonyl, chromanyl, decahydroisoquinolinyl, dihydrobenzofuranyl, dihydrobenzisothiazolyl, dihydrobenzisoxazinyl (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, dihydrofuranyl, dihydroisoindolyl, dihydropyranyl, dihydropyrazolyl, dihydropyrazinyl, dihydropyridinyl, dihydropyrimidinyl, dihydropyrrolyl, dioxolanyl, 1,4-dithianyl, furanonyl, imidazolidinyl, imidazolinyl, dihydroindolyl, isochromanyl, isoindolinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, oxazolidinonyl, oxazolidinyl, oxiranyl, piperazinyl, piperidinyl, 4-piperidinonyl, pyrazolidinyl, pyrazolinyl, pyrrolidinyl, pyrrolinyl, quinuclidinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydropyranyl, tetrahydrothienyl, thiomorpholinyl, thiazolidinyl, thiochromanyl, tetrahydroquinolinyl, and 1,3,5-trithianyl. In certain embodiments, the heterocyclic group is optionally substituted with one or more substituents Q as described herein.

[0033] The term "subheterocyclic group" refers to a divalent monocyclic non-aromatic ring system or a divalent polycyclic ring system containing at least one non-aromatic ring, wherein one or more of the non-aromatic ring atoms are heteroatoms independently selected from O, S, and N; and the remaining ring atoms are carbon atoms. For a subheterocyclic group containing a heteroaromatic ring and a non-aromatic heterocycle, the subheterocyclic group has at least one bond to the rest of the molecule through its non-aromatic heterocycle. In certain embodiments, the subheterocyclic 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, the subheterocyclic group is a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may be fused or bridged, and wherein a nitrogen or sulfur atom may optionally be oxidized, a nitrogen atom may optionally be quaternized, and some rings may be partially or fully saturated or aromatic. The subheterocyclic group may be attached to the main structure at any heteroatom or carbon atom that results in a stable compound. Examples of such subheterocyclic groups include, but are not limited to, azo diyl, benzodioxanediyl, benzodioxolenediyl, 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), dihydrobenzothiophenediyl, dihydroisobenzofurandiyl, dihydrobenzo[c]thiophenediyl, dihydrofurandiyl, dihydroisoindolediyl, dihydropyrandiyl, dihydropyrazolediyl, dihydropyrazinediyl, dihydropyridinediyl, dihydropyrimidinediyl, dihydropyrrolediyl, dioxolandiyl, 1,4-dithiandiyl, furanonediyl, imidazolidinediyl, imidazolinediyl, indolindiyl, isochromandiyl, isoindolediyl, isothiazolidinediyl, isoxazolidinediyl, morpholinodiyl, octahydroindolediyl, octahydroisoindolediyl, oxazolidinonediyl, oxazolidinediyl, ethyleneoxidediyl, piperazinediyl, piperidinediyl, 4-piperidinediyl, pyrazolidinediyl, pyrazolinediyl, pyrrolidinediyl, pyrrolinediyl, quinuclidinediyl, tetrahydrofurandiyl, tetrahydroisoquinolinediyl, tetrahydropyrandiyl, tetrahydrothiophenediyl, thiomorpholinodiyl, thiazolidinediyl, thiochromandiyl, tetrahydroquinolinediyl, and 1,3,5-trithiandiyl. In certain embodiments, the subheterocyclic group is optionally substituted with one or more substituents Q as described herein.

[0034] The term "halogen", "halide", or "halo" refers to fluorine, chlorine, bromine, and / or iodine.

[0035] The term "optionally substituted with" means that a group or substituent (e.g., an alkyl, alkylene, heteroalkyl, heteroalkylene, alkenyl, alkenylene, alkynyl, alkynylene, cycloalkyl, cycloalkylene, aryl, arylene, aralkyl, aralkylene, heteroaryl, heteroarylene, heterocyclic or heterocyclylene group) can be substituted with one or more (in one embodiment, one, two, three or four) substituents Q, each of which is independently selected from, for example, (a) deuterium (-D), cyano (-CN), halogen, nitro (-NO2) and oxo (=O); (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 heterocyclic, each of which is further optionally substituted with one or more (in one embodiment, one, two, three or four) substituents Q a ; 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)NR b R c , -OS(O)2NR b Rc 、 –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)2R a 、 –S(O)NR b R c and –S(O)2NR b R c , where R a 、 R b 、 R c and R d are each independently (i) hydrogen or deuterium; (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 arylalkyl, heteroaryl or heterocyclic group, each of which is optionally substituted by one or more (in one embodiment, by one, two, three or four) substituents Q a substituted; or (iii) Rb and R c together with the N atom to which they are attached form a heterocyclic group, which is optionally substituted by one or more (in one embodiment, one, two, three or four) substituents Q a Substituted. As used herein, all groups that can be substituted are "optionally substituted".

[0036] In one embodiment, Q a are each independently selected from: (a) deuterium, cyano, halogen, 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 arylalkyl, heteroaryl and heterocyclic group; 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 , –NRe 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)2R e 、 –S(O)NR f R g and –S(O)2NR f R g ; wherein, R e 、 R f 、 R g and R h are each 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 arylalkyl, heteroaryl or heterocyclic group; or (iii) R f and R g together with the N atom to which they are attached form a heterocyclic group.

[0037] In certain embodiments, "optically active" and "enantiomerically active" refer to a collection of molecules having an enantiomeric excess of not less than about 80%, not less than about 90%, not less than about 91%, not less than about 92%, not less than about 93%, not less than about 94%, not less than about 95%, not less than about 96%, not less than about 97%, not less than about 98%, not less than about 99%, not less than about 99.5%, or not less than about 99.8%. In certain embodiments, based on the total weight of the enantiomeric mixture under discussion, an optically active compound comprises about 95% or more of one enantiomer and about 5% or less of the other enantiomer. In certain embodiments, based on the total weight of the enantiomeric mixture under discussion, an optically active compound comprises about 98% or more of one enantiomer and about 2% or less of the other enantiomer. In certain embodiments, based on the total weight of the enantiomeric mixture under discussion, an optically active compound comprises about 99% or more of one enantiomer and about 1% or less of the other enantiomer.

[0038] When describing an optically active compound, the prefixes R and S are used to denote the absolute configuration around the chiral center of the compound. (+) and (-) are used to denote the optical rotation of the compound, i.e., the direction in which the optically active compound rotates the plane of polarized light. The (-) prefix indicates that the compound is levorotatory, i.e., the compound rotates the plane of polarized light to the left or counterclockwise. The (+) prefix indicates that the compound is dextrorotatory, i.e., the compound rotates the plane of polarized light to the right or clockwise. However, the signs (+) and (-) of optical rotation are not related to the absolute configuration R and S of the compound.

[0039] The term "isotope-enriched" refers to a compound that contains a non-natural proportion of isotopes at one or more atoms that make up such a compound. In certain embodiments, an isotope-enriched compound contains a non-natural proportion of one or more isotopes, including but 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 I). In certain embodiments, the isotope-enriched compound is in a stable form, i.e., is non-radioactive. In certain embodiments, the isotope-enriched compound contains a non-natural proportion of one or more isotopes, including but not limited to hydrogen ( 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 I). In certain embodiments, the isotope-enriched compound is in an unstable form, i.e., is radioactive. In certain embodiments, the isotope-enriched compound contains a non-natural proportion of one or more isotopes, including but not limited to tritium ( 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 I). It should be understood that in the compounds provided herein, any hydrogen may be 2 H (by way of example); or any carbon may be 13 C (by way of example); or any nitrogen may be 15 N (by way of example); or any oxygen may be 18 O (by way of example).

[0040] The term "isotope enrichment" refers to the percentage of incorporation of the less common isotope of an element (e.g., D for deuterium or hydrogen-2) in place of the more common isotope of said element (e.g., 1 H for protium or hydrogen-1) at a given position in a molecule. As used herein, when an atom at a specific position in a molecule is designated as a specific less common isotope, it should be understood that the abundance of that isotope at that position is substantially greater than its natural abundance.

[0041] The term "isotope enrichment factor" refers to the ratio between the isotope abundance in an isotope-enriched compound and the natural abundance of a specific isotope.

[0042] The term "hydrogen" or the symbol "H" refers to the composition of the naturally occurring hydrogen isotopes, which includes protium ( 1 H), deuterium ( 2 H or D) and tritium ( 3 H) at their natural abundances. Protium is the most common hydrogen isotope, having a natural abundance of greater than 99.98%. Deuterium is the less common hydrogen isotope, having a natural abundance of approximately 0.0156%.

[0043] The term "deuterium enrichment" refers to the percentage of incorporation of deuterium in place of hydrogen at a given position in a molecule. For example, 1% deuterium enrichment at a given position means that 1% of the molecules in a given sample contain deuterium at that designated position. Since the natural abundance distribution of deuterium is on average about 0.0156%, the average deuterium enrichment at any position in a compound synthesized using non-enriched starting materials is 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%).

[0044] The term "carbon" or the symbol "C" refers to the composition of naturally occurring carbon isotopes, which includes carbon-12 ( 12 C) and carbon-13 ( 13 C) at their natural abundances. Carbon-12 is the most common carbon isotope, having a natural abundance greater than 98.89%. Carbon-13 is a less prevalent carbon isotope, having a natural abundance of about 1.11%.

[0045] The term "carbon-13 enrichment" or " 13 C enrichment" refers to the percentage of incorporation of carbon-13 in place of carbon at a given position in a molecule. For example, 10% carbon-13 enrichment at a given position means that 10% of the molecules in a given sample contain carbon-13 at that designated position. Since the natural abundance distribution of carbon-13 is on average about 1.11%, the average carbon-13 enrichment at any position in a compound synthesized using non-enriched starting materials is 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%).

[0046] The terms "substantially pure" and "substantially homogeneous" mean that, when referring to a substance, it is homogeneous enough to appear free of readily detectable impurities determined by standard analytical methods used by one of ordinary 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 pure enough such that further purification will not detectably alter the physical, chemical, biological, and / or pharmacological properties (e.g., enzymatic activity and biological activity) of the substance. In certain embodiments, "substantially pure" or "substantially homogeneous" refers to a collection 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 of a single compound, including 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 as a particular less prevalent isotope, a molecule containing at a specified position an isotope other than the indicated isotope is an impurity relative to the isotopically enriched compound. Thus, for a deuterated compound having an atom designated as deuterium at a particular position, a compound containing protium at the same position is an impurity.

[0047] The term "solvate" refers to a complex or aggregate formed by one or more solute molecules (e.g., a compound provided herein) and one or more solvent molecules (present in stoichiometric or non-stoichiometric amounts). 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 crystalline form. In another embodiment, the complex or aggregate is in 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.

[0048] For the divalent groups described herein, the direction presented by the divalent group does not imply orientation. For example, unless a specific orientation is specified, the formula -C(O)NH- represents both -C(O)NH- and -NHC(O)-.

[0049] The phrase “enantiomers, mixtures of enantiomers, diastereomers, mixtures of two or more diastereomers, tautomers, mixtures of two or more tautomers, or isotopic variants; or pharmaceutically acceptable salts, solvates, hydrates, or prodrugs thereof” has the same meaning as the following phrase: “(i) enantiomers, mixtures of enantiomers, diastereomers, mixtures of two or more diastereomers, tautomers, mixtures of two or more tautomers, or isotopic variants of the compound(s) mentioned therein; (ii) pharmaceutically acceptable salts, solvates, hydrates, or prodrugs of the compound(s) mentioned therein; or (iii) pharmaceutically acceptable salts, solvates, hydrates, or prodrugs of enantiomers, mixtures of enantiomers, diastereomers, mixtures of two or more diastereomers, tautomers, mixtures of two or more tautomers, or isotopic variants of the compound(s) mentioned therein.” Compound

[0050] In one embodiment, the present invention provides a compound of formula (I): 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; wherein: R 1 is (i) hydrogen or deuterium; or (ii) C 1-20 alkyl, C 1-20 heteroalkyl, C 2-20 alkenyl, C 2-20 alkynyl, C 3-20 cycloalkyl, C 6-20 aryl, C 7-20 arylalkyl, heteroaryl or heterocyclic group; R 2 is heteroaryl; R 3 are each independently (i) deuterium, cyano, halogen or nitro; (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 arylalkyl, heteroaryl or heterocyclic group; 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 , –OR 1a , –OC(O)R 1a , –OC(O)OR 1a , –OC(O)NR 1b R 1c , –OC(O)SR 1a , –OC(NR 1a )NR 1b R 1c , –OC(S)R 1a , –OC(S)OR 1a , –OC(S)NR 1b R 1c , –OS(O)R 1a , –OS(O)2R 1a , –OS(O)NR 1b R 1c , –OS(O)2NR 1b R 1c , –NR 1b R 1c , –NR 1a C(O)R 1d , –NR 1a C(O)OR 1d , –NR 1a C(O)NR 1b R 1c , –NR 1a C(O)SR 1d , –NR 1a , –NR 1d )NR 1b R 1c , –NR 1a C(S)R 1d , –NR 1a C(S)OR 1d , –NR 1a C(S)NR 1b R 1c , –NR 1a S(O)R 1d , –N=S(O)R 1a R 1d , –NR 1a S(O)2R 1d , –NR 1a S(O)NR1b R 1c ,–NR 1a S(O)2NR 1b R 1c ,–SR 1a , –S(O)R 1a , –S(O)2R 1a , –S(O)NR 1b R 1c or –S(O)2NR 1b R 1c ; R 4 and R 6 are each independently (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 5 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 heterocyclic group; R 7 and R 8 are each independently (i) halogen; or (ii) –OR 1a 、–OC(O)R1a 、 –OC(O)OR 1a or –OC(O)NR 1b R 1c ; and R 9 is (i) hydrogen; or (ii) –C(O)R 1a 、 –C(O)OR 1a or –C(O)NR 1b R 1c ; or R 7 and R 8 or R 8 and R 9 are joined together to form a lactone ring; A is a bond, O or N(R 1b ); E is hydrogen, azido, halogen, isocyano, –C═C(R 1a )R 1a 、 –C≡CR 1a 、 –C(O)R 1a or –SH; L 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 aralkyl, heteroarylene or heterocycloalkylene; R 1a 、 R 1b 、 R 1c and R 1d are each independently hydrogen, deuterium, 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 heterocycloalkyl; and m is an integer of 0, 1, 2, 3 or 4; wherein, alkyl, alkylene, heteroalkyl, heteroalkylene, alkenyl, alkenylene, alkynyl, alkynylene, cycloalkyl, cycloalkylene, aryl, arylene, aralkyl, aralkylene, heteroaryl, heteroarylene, heterocycloalkyl and heterocycloalkylene are each optionally substituted by one or more (in one embodiment, by one, two, three or four) substituents Q, wherein Q are each independently selected from: (a) deuterium, cyano, halogen, nitro and oxo; (b) C 1-6 alkyl, C 1-6Heteroalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, C 6-14 Aryl, C 7-15 Aralkyl, heteroaryl, and heterocyclic group, each of which is further optionally substituted by one or more (in one embodiment, by one, two, three, or four) substituents Q a ; 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)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(NRd )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)2R a , –S(O)NR b R c and –S(O)2NR b R c , where R a , R b , R c and R d are each independently (i) hydrogen or deuterium; (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, each of which is optionally substituted by one or more (in one embodiment, by one, two, three or four) substituents Q a or (iii) R b and R c Together with the N atom to which they are attached, they form a heterocyclic group, which is optionally substituted by one or more (in one embodiment, by one, two, three or four) substituents Q a replace; Among them, Q a are each independently selected from: (a) deuterium, cyano, halogen, nitro and oxo; (b) C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C3-10 Naphthenyl, C 6-14 Aryl, C 7-15 Aralkyl, heteroaryl and heterocyclic group; 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)ORf , –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)2R e , –S(O)NR f R g and –S(O)2NR f R g ; wherein, R e , R f , R g and R h are each 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 heterocyclic group; or (iii) R f and R g together with the N atom to which they are attached form a heterocyclic group.

[0051] In certain embodiments, in formula (I), R 7 is halogen. In certain embodiments, in formula (I), R 7 is fluorine. In certain embodiments, in formula (I), R 7 is -OR 1a , wherein, R 1a is as defined herein. In certain embodiments, in formula (I), R 7 is hydroxy. In certain embodiments, in formula (I), R 7 is –OC(O)R 1a , wherein, R 1a is as defined herein. In certain embodiments, in formula (I), R 7 is –OC(O)OR 1a , wherein, R 1aAs defined herein. In certain embodiments, in formula (I), R 7 is –OC(O)NR 1b R 1c , wherein R 1b and R 1c are each as defined herein.

[0052] In certain embodiments, in formula (I), R 8 is halogen. In certain embodiments, in formula (I), R 8 is fluorine. In certain embodiments, in formula (I), R 8 is –OR 1a , wherein R 1a is as defined herein. In certain embodiments, in formula (I), R 8 is hydroxy. In certain embodiments, in formula (I), R 8 is –OC(O)R 1a , wherein R 1a is as defined herein. In certain embodiments, in formula (I), R 8 is –OC(O)OR 1a , wherein R 1a is as defined herein. In certain embodiments, in formula (I), R 8 is –OC(O)NR 1b R 1c , wherein R 1b and R 1c are each as defined herein.

[0053] In yet another embodiment, the present invention provides a compound of formula (II): or its enantiomers, mixtures of enantiomers, diastereomers, mixtures of two or more diastereomers, tautomers, mixtures of two or more tautomers, or isotopic variants; or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof; wherein R 7a and R 8a are each independently R 1a , –C(O)R 1a , –C(O)OR 1a or –C(O)NR 1b R 1c ; and R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 9 , R1a and R 1b and R 1c , A, E, L, and m are each as defined herein.

[0054] In certain embodiments, in Formula (I) or Formula (II), R 1 is hydrogen.

[0055] In yet another embodiment, provided herein are compounds of Formula (III): 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; wherein R 2 and R 3 and R 4 and R 5 and R 6 and R 9 and R 7a and R 8a , A, E, L, and m are each as defined herein.

[0056] In certain embodiments, in any one of Formulas (I) to (III), R 2 is a monocyclic heteroaryl, which is optionally substituted by one or more substituents Q. In certain embodiments, in any one of Formulas (I) to (III), R 2 is a 5- or 6-membered heteroaryl, each optionally substituted by one or more substituents Q. In certain embodiments, in any one of Formulas (I) to (III), R 2 is a 5-membered heteroaryl, which is optionally substituted by one or more substituents Q. In certain embodiments, in any one of Formulas (I) to (III), R 2 is a 5-membered heteroaryl optionally substituted by C 1-6 alkyl, and the C 1-6 alkyl is further optionally substituted by one or more substituents Q a . In certain embodiments, in any one of Formulas (I) to (III), R 2 is a 6-membered heteroaryl, which is optionally substituted by one or more substituents Q. In certain embodiments, in any one of Formulas (I) to (III), R 2 is a 6-membered heteroaryl optionally substituted by C 1-6 alkyl, and the C 1-6 alkyl is further optionally substituted by one or more substituents Q ais substituted. In certain embodiments, in any one of formulas (I) to (III), R 2 is thienyl, pyrazolyl, imidazolyl, thiazolyl or pyridyl, each optionally substituted with one or more substituents Q. In certain embodiments, in any one of formulas (I) to (III), R 2 is thienyl, pyrazolyl, imidazolyl, thiazolyl or pyridyl, each optionally substituted with C 1-6 alkyl, and the C 1-6 alkyl is further optionally substituted with one or more substituents Q a . In certain embodiments, in any one of formulas (I) to (III), R 2 is thien-2-yl, thien-3-yl, pyrazol-3-yl, imidazol-4-yl, thiazol-2-yl, thiazol-5-yl, pyridin-3-yl or pyridin-4-yl, each optionally substituted with C 1-6 alkyl, and the C 1-6 alkyl is further optionally substituted with one or more substituents Q a . In certain embodiments, in any one of formulas (I) to (III), R 2 is thien-2-yl, thien-3-yl, 2-methylpyrazol-3-yl, imidazol-4-yl, 1-methylimidazol-4-yl, thiazol-2-yl, thiazol-5-yl, pyridin-3-yl or pyridin-4-yl.

[0057] In yet another embodiment, provided herein are compounds of formula (IV): 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; wherein: U is a bond, N or CR 2a ; and V, X, Y and Z are each independently N, O, S, CR 2a or NR 2b ; provided that at least one of U, V, X, Y and Z is not CR 2a ; R 2a are each independently (i) hydrogen, deuterium, cyano, halogen or nitro; (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 7-15An aralkyl group, a heteroaryl group, or a heterocyclic group, each of which is optionally substituted with one or more substituents Q; 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 、–OR 1a 、–OC(O)R 1a 、–OC(O)OR 1a 、–OC(O)NR 1b R 1c 、–OC(O)SR 1a 、–OC(NR 1a )NR 1b R 1c 、–OC(S)R 1a 、–OC(S)OR 1a 、–OC(S)NR 1b R 1c 、–OS(O)R 1a 、–OS(O)2R 1a 、–OS(O)NR 1b R 1c 、–OS(O)2NR 1b R 1c 、–NR 1b R 1c 、–NR 1a C(O)R 1d 、–NR 1a C(O)OR 1d 、–NR 1a C(O)NR 1b R 1c 、–NR 1a C(O)SR 1d 、–NR 1a C(NR 1d )NR 1b R 1c 、–NR 1a C(S)R 1d 、–NR 1a C(S)OR 1d 、–NR 1a C(S)NR 1b R 1c 、–NR1a S(O)R 1d , –N=S(O)R 1a R 1d ,–NR 1a S(O)2R 1d ,–NR 1a S(O)NR 1b R 1c ,–NR 1a S(O)2NR 1b R 1c ,–SR 1a , –S(O)R 1a , –S(O)2R 1a , –S(O)NR 1b R 1c or –S(O)2NR 1b R 1c ; R 2b are each independently (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, each of which is optionally substituted with one or more substituents Q; 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; and R 3 , R 4 , R 5 , R 6 , R 9 , R 1a , R 1b, R 1c , R 1d , R 7a , R 8a , A, E, L, and m are each as defined herein.

[0058] In certain embodiments, in any one of Formulas (I) through (IV), R 5 is C 1-6 alkyl, C 7-15 arylalkyl, or heterocyclic group, each of which is optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulas (I) through (IV), R 5 is C 1-6 alkyl, which is optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulas (I) through (IV), R 5 is C 1-6 alkyl optionally substituted with one, two, or three substituents; and wherein the substituents are each independently (i) C 1-6 alkyl, C 6-14 aryl, or heteroaryl, each of which is optionally substituted with one or more substituents Q a ; or (ii) –C(O)OR 1a , –C(O)NR 1b R 1c , –C(NR 1a )NR 1b R 1c , –OR 1a , –NR 1b R 1c , or –SR 1a , wherein R 1a , R 1b , and R 1c are each as defined herein. In certain embodiments, in any one of Formulas (I) through (IV), R 5 is C 1-6 alkyl optionally substituted with one or two substituents, wherein the substituents are each independently methyl, phenyl, 4-hydroxyphenyl, imidazol-4-yl, indol-3-yl, amino, acetamido, benzamido, benzyloxycarbonylamino, tert-butoxycarbonylamino, 9-fluorenylmethoxycarbonylamino, aminocarbonyl, carboxy, guanidino, hydroxy, mercapto, or methylthio. In certain embodiments, in any one of Formulas (I) through (IV), R 5 is methyl, ethyl, propyl, butyl, pentyl, or hexyl, each optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulas (I) through (IV), R 5is methyl, ethyl, propyl, butyl, pentyl or hexyl, each optionally substituted by one, two or three substituents; and wherein each substituent is independently (i) C 1-6 alkyl, C 6-14 aryl or heteroaryl, each optionally substituted by one or more substituents Q a ; or (ii) –C(O)OR 1a , –C(O)NR 1b R 1c , –C(NR 1a )NR 1b R 1c , –OR 1a , –NR 1b R 1c or –SR 1a , wherein R 1a , R 1b and R 1c are each as defined herein. In certain embodiments, in any one of Formulas (I) through (IV), R 5 is methyl, ethyl, propyl, butyl, pentyl or hexyl, each optionally substituted by one or two substituents; and wherein each substituent is independently methyl, phenyl, 4-hydroxyphenyl, imidazol-4-yl, indol-3-yl, amino, acetamido, benzamido, benzyloxycarbonylamino, tert-butoxycarbonylamino, 9-fluorenylmethoxycarbonylamino, carbamoyl, carbamoyl, carboxy, guanidino, hydroxy, mercapto or methylthio.

[0059] In certain embodiments, in any one of Formulas (I) through (IV), R 5 is C 7-15 aralkyl, which is optionally substituted by one or more substituents Q. In certain embodiments, in any one of Formulas (I) through (IV), R 5 is monocyclic C 7-15 aralkyl, which is optionally substituted by one or more substituents Q. In certain embodiments, in any one of Formulas (I) through (IV), R 5 is 1-amino-2-phenylethyl or 1-amino-2-(4-hydroxyphenyl)ethyl, wherein the amino groups are each independently and optionally protected by an amino protecting group. In one embodiment, the amino protecting groups are each independently –C(O)R a or –C(O)OR a , wherein R aEach as defined herein. In another embodiment, the amino protecting group is independently acetyl, benzoyl, tert-butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz), or 9-fluorenylmethoxycarbonyl (Fmoc). In certain embodiments, in any one of Formulas (I) to (IV), R 5 is a heterocyclic group, optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulas (I) to (IV), R 5 is a monocyclic heterocyclic group, optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulas (I) to (IV), R 5 is a 3-, 4-, 5-, 6-, or 7-membered heterocyclic group, each optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulas (I) to (IV), R 5 is a 5-membered heterocyclic group, optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulas (I) to (IV), R 5 is pyrrolidinyl, optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulas (I) to (IV), R 5 is pyrrolidin-2-yl, optionally substituted with one or more substituents Q.

[0060] In certain embodiments, in any one of Formulas (I) to (IV), R 5 is aminomethyl, 1-aminoethyl, 1-amino-2-carboxyethyl, 1-amino-2-aminocarbonylethyl, 1-amino-2-mercaptoethyl, 1-amino-2-hydroxyethyl, 1-amino-2-(imidazol-4-yl)ethyl, 1-amino-2-(indol-3-yl)ethyl, 1-amino-2-methylpropyl, 1-amino-3-carboxypropyl, 1-amino-3-aminocarbonylpropyl, 1-amino-2-hydroxypropyl, 1-amino-3-methylthiopropyl, 1-amino-2-methylbutyl, 1-amino-3-methylbutyl, 1-amino-4-guanidinobutyl, 1,4-diaminobutyl, 1,5-diaminopentyl, 1-amino-2-phenylethyl, 1-amino-2-(4-hydroxyphenyl)ethyl, or pyrrolidin-2-yl, wherein the amino groups are each independently and optionally protected by an amino protecting group. In one embodiment, the amino protecting group is independently –C(O)R a or –C(O)OR a wherein R a each as defined herein. In another embodiment, the amino protecting group is independently acetyl, benzoyl, Boc, Cbz, or Fmoc.

[0061] In certain embodiments, in any one of formulas (I) to (IV), R 5 is 1,5-diaminopentyl, which is optionally substituted with one or more substituents Q. In certain embodiments, in any one of formulas (I) to (IV), R 5 is 1,5-diaminopentyl, wherein the amino groups are each independently and optionally protected by an amino protecting group. In one embodiment, the amino protecting groups are each independently –C(O)R a or –C(O)OR a , wherein R a are each as defined herein. In another embodiment, the amino protecting groups are each independently acetyl, benzoyl, Boc, Cbz or Fmoc. In certain embodiments, in any one of formulas (I) to (IV), R 5 is 1,5-diethylamidopentyl or 5-ethylamido-1-(benzyloxycarbonylamino)pentyl.

[0062] In yet another embodiment, provided herein is a compound of formula (V): 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; wherein: R 5a , R 5b R 5c and R 5d are each independently (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 heterocyclic group, each of which is optionally substituted with one or more substituents Q; 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)R1a , –S(O)2R 1a , –S(O)NR 1b R 1c 、–S(O)2NR 1b R 1c or –Si(R 1a )3; and R 3 , R 4 , R 6 , R 9 , R 1a , R 1b , R 1c , R 7a , R 8a , A, E, L, U, V, X, Y, Z and m are each as defined herein.

[0063] In another embodiment, provided herein is a compound of formula (VI): 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; wherein R 3 , R 4 , R 6 , R 9 , R 5a , R 5b , R 5c , R 5d , R 7a , R 8a , A, E, L, U, V, X, Y, Z and m are each as defined herein.

[0064] In another embodiment, provided herein is a compound of formula (VII): 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; wherein R 3 , R 4 , R 6 , R 9 , R 5a , R 5b , R 5c , R 5d , R 7a , R 8a, A, E, L, U, V, X, Y, Z, and m are each as defined herein.

[0065] In yet another embodiment, the present disclosure provides a compound of formula (VIII): 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; wherein R 3 , R 4 , R 6 , R 9 , R 5a , R 5b , R 5c , R 5d , R 7a , R 8a , A, E, L, U, V, X, Y, Z, and m are each as defined herein.

[0066] In yet another embodiment, the present disclosure provides a compound of formula (IX): 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; wherein R 3 , R 4 , R 6 , R 9 , R 5a , R 5b , R 5c , R 5d , R 7a , R 8a , A, E, L, U, V, X, Y, Z, and m are each as defined herein.

[0067] In yet another embodiment, the present disclosure provides a compound of formula (X): 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; wherein R 3 , R 4 , R 6 , R 9 , R 5a, R 5b , R 5c , R 5d , R 7a , R 8a , A, E, L, U, V, X, Y, Z, and m are each as defined herein.

[0068] In certain embodiments, in any one of Formulas (IV) to (X), U is a bond. In certain embodiments, in any one of Formulas (IV) to (X), U is CR 2a , where R 2a is as defined herein. In certain embodiments, in any one of Formulas (IV) to (X), U is CH.

[0069] In certain embodiments, in any one of Formulas (IV) to (X), U is a bond; V is S; and X, Y, and Z are each independently CR 2a , where R 2a are each as defined herein. In certain embodiments, in any one of Formulas (IV) to (X), U is a bond; V is S; and X, Y, and Z are each CH.

[0070] In certain embodiments, in any one of Formulas (IV) to (X), U is a bond; V, Y, and Z are each independently CR 2a , where R 2a are each as defined herein; and X is S. In certain embodiments, in any one of Formulas (IV) to (X), U is a bond; V, Y, and Z are each CH; and X is S.

[0071] In certain embodiments, in any one of Formulas (IV) to (X), U is a bond; V is NR 2b , where R 2b is as defined herein; X is N; and Y and Z are each independently CR 2a , where R 2a are each as defined herein. In certain embodiments, in any one of Formulas (IV) to (X), U is a bond; V is N(CH3); X is N; and Y and Z are each CH.

[0072] In certain embodiments, in any one of Formulas (IV) to (X), U is a bond; V is N; X and Z are each independently CR 2a , where R 2a are each as defined herein; and Y is NR 2b , where R 2bAs defined herein. In certain embodiments, in any one of Formulas (IV) to (X), U is a bond; V is N; X and Z are each CH; and Y is NH or N(CH3).

[0073] In certain embodiments, in any one of Formulas (IV) to (X), U is a bond; V is S; X and Z are each independently CR 2a , where R 2a are each as defined herein; and Y is N. In certain embodiments, in any one of Formulas (IV) to (X), U is a bond; V is S; X and Z are each CH; and Y is N.

[0074] In certain embodiments, in any one of Formulas (IV) to (X), U is a bond; V is S; X and Y are each independently CR 2a , where R 2a are each as defined herein; and Z is N. In certain embodiments, in any one of Formulas (IV) to (X), U is a bond; V is S; X and Y are each CH; and Z is N.

[0075] In certain embodiments, in any one of Formulas (IV) to (X), U, X, Y, and Z are each independently CR 2a , where R 2a are each as defined herein; and V is N. In certain embodiments, in any one of Formulas (IV) to (X), U, X, Y, and Z are each CH; and V is N.

[0076] In certain embodiments, in any one of Formulas (IV) to (X), U, V, Y, and Z are each independently CR 2a , where R 2a are each as defined herein; and X is N. In certain embodiments, in any one of Formulas (IV) to (X), U, V, Y, and Z are each CH; and X is N.

[0077] In yet another embodiment, the present disclosure provides a compound of Formula (XI): 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; wherein R 3 , R 4 , R 6 , R 9 , R 5a , R 5b , R 5c , R5d and R 7a and R 8a , A, E, L, V, X, Y, Z, and m are each as defined herein.

[0078] In yet another embodiment, provided herein are compounds of formula (XII): 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; wherein R 3 and R 4 and R 6 and R 9 and R 5a and R 5b and R 5c and R 5d and R 7a and R 8a , A, E, L, V, X, Y, Z, and m are each as defined herein.

[0079] In yet another embodiment, provided herein are compounds of formula (XIII): 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; wherein R 3 and R 4 and R 6 and R 9 and R 5a and R 5b and R 5c and R 5d and R 7a and R 8a , A, E, L, V, X, Y, Z, and m are each as defined herein.

[0080] In yet another embodiment, provided herein are compounds of formula (XIV): 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; wherein R 3 and R 4 and R6 , R 9 , R 5a , R 5b , R 5c , R 5d , R 7a , R 8a , A, E, L, V, X, Y, Z, and m are each as defined herein.

[0081] In yet another embodiment, provided herein is a compound of formula (XV): 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; wherein, R 3 , R 4 , R 6 , R 9 , R 5a , R 5b , R 5c , R 5d , R 7a , R 8a , A, E, L, V, X, Y, Z, and m are each as defined herein.

[0082] In yet another embodiment, provided herein is a compound of formula (XVI): 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; wherein, R 3 , R 4 , R 6 , R 9 , R 5a , R 5b , R 5c , R 5d , R 7a , R 8a , A, E, L, V, X, Y, Z, and m are each as defined herein.

[0083] In certain embodiments, in any one of formulas (IV) to (XVI), V is N, S, CR 2a or NR 2b , wherein, R 2a and R 2bAs defined herein. In certain embodiments, in any one of Formulas (IV) to (XVI), V is N. In certain embodiments, in any one of Formulas (IV) to (XVI), V is S. In certain embodiments, in any one of Formulas (IV) to (XVI), V is CR 2a , wherein R 2a is as defined herein. In certain embodiments, in any one of Formulas (IV) to (XVI), V is CH. In certain embodiments, in any one of Formulas (IV) to (XVI), V is NR 2b , wherein R 2b is as defined herein. In certain embodiments, in any one of Formulas (IV) to (XVI), V is NH. In certain embodiments, in any one of Formulas (IV) to (XVI), V is N(CH3).

[0084] In certain embodiments, in any one of Formulas (IV) to (XVI), X is N, S, CR 2a or NR 2b , wherein R 2a and R 2b are as defined herein. In certain embodiments, in any one of Formulas (IV) to (XVI), X is N. In certain embodiments, in any one of Formulas (IV) to (XVI), X is S. In certain embodiments, in any one of Formulas (IV) to (XVI), X is CR 2a , wherein R 2a is as defined herein. In certain embodiments, in any one of Formulas (IV) to (XVI), X is CH. In certain embodiments, in any one of Formulas (IV) to (XVI), X is NR 2b , wherein R 2b is as defined herein. In certain embodiments, in any one of Formulas (IV) to (XVI), X is NH. In certain embodiments, in any one of Formulas (IV) to (XVI), X is N(CH3).

[0085] In certain embodiments, in any one of Formulas (IV) to (XVI), Y is N, S, CR 2a or NR 2b , wherein R 2a and R 2b are as defined herein. In certain embodiments, in any one of Formulas (IV) to (XVI), Y is N. In certain embodiments, in any one of Formulas (IV) to (XVI), Y is S. In certain embodiments, in any one of Formulas (IV) to (XVI), Y is CR2a , wherein, R 2a is as defined herein. In certain embodiments, in any one of Formulas (IV) to (XVI), Y is CH. In certain embodiments, in any one of Formulas (IV) to (XVI), Y is NR 2b , wherein, R 2b is as defined herein. In certain embodiments, in any one of Formulas (IV) to (XVI), Y is NH. In certain embodiments, in any one of Formulas (IV) to (XVI), Y is N(CH3).

[0086] In certain embodiments, in any one of Formulas (IV) to (XVI), Z is N, S, CR 2a or NR 2b , wherein, R 2a and R 2b are as defined herein. In certain embodiments, in any one of Formulas (IV) to (XVI), Z is N. In certain embodiments, in any one of Formulas (IV) to (XVI), Z is S. In certain embodiments, in any one of Formulas (IV) to (XVI), Z is CR 2a , wherein, R 2a is as defined herein. In certain embodiments, in any one of Formulas (IV) to (XVI), Z is CH. In certain embodiments, in any one of Formulas (IV) to (XVI), Z is NR 2b , wherein, R 2b is as defined herein. In certain embodiments, in any one of Formulas (IV) to (XVI), Z is NH. In certain embodiments, in any one of Formulas (IV) to (XVI), Z is N(CH3).

[0087] In certain embodiments, in any one of Formulas (XI) to (XVI), V is S; and X, Y, and Z are each independently CR 2a , wherein, R 2a are each as defined herein. In certain embodiments, in any one of Formulas (XI) to (XVI), V is S; and X, Y, and Z are each CH.

[0088] In certain embodiments, in any one of Formulas (XI) to (XVI), V, Y, and Z are each independently CR 2a , wherein, R 2a are each as defined herein; and X is S. In certain embodiments, in any one of Formulas (XI) to (XVI), V, Y, and Z are each CH; and X is S.

[0089] In certain embodiments, in any one of Formulas (XI) to (XVI), V is NR 2b , where R 2b is as defined herein; X is N; and Y and Z are each independently CR 2a , where R 2a are each as defined herein. In certain embodiments, in any one of Formulas (XI) to (XVI), V is N(CH3); X is N; and Y and Z are each CH.

[0090] In certain embodiments, in any one of Formulas (XI) to (XVI), V is N; X and Z are each independently CR 2a , where R 2a are each as defined herein; and Y is NR 2b , where R 2b is as defined herein. In certain embodiments, in any one of Formulas (XI) to (XVI), V is N; X and Z are each CH; and Y is NH or N(CH3).

[0091] In certain embodiments, in any one of Formulas (XI) to (XVI), V is S; X and Z are each independently CR 2a , where R 2a are each as defined herein; and Y is N. In certain embodiments, in any one of Formulas (XI) to (XVI), V is S; X and Z are each CH; and Y is N.

[0092] In certain embodiments, in any one of Formulas (XI) to (XVI), V is S; X and Y are each independently CR 2a , where R 2a are each as defined herein; and Z is N. In certain embodiments, in any one of Formulas (XI) to (XVI), V is S; X and Y are each CH; and Z is N.

[0093] In certain embodiments, in any one of Formulas (V) to (XVI), R 5a is (i) hydrogen; or (ii) –C(O)R 1a or –C(O)OR 1a , where R 1a are each as defined herein. In certain embodiments, in any one of Formulas (V) to (XVI), R 5a is hydrogen. In certain embodiments, in any one of Formulas (V) to (XVI), R 5a is an amino protecting group. In certain embodiments, in any one of Formulas (V) to (XVI), R 5a is –C(O)R1a or –C(O)OR 1a is an amino protecting group, wherein R 1a is as defined herein. In certain embodiments, in any one of formulas (V) to (XVI), R 5a is –C(O)R a wherein R a is as defined herein. In certain embodiments, in any one of formulas (V) to (XVI), R 5a is –C(O)R a wherein R a is C 1-6 alkyl, which is optionally substituted by one or more substituents Q. In certain embodiments, in any one of formulas (V) to (XVI), R 5a is –C(O)OR a wherein R a is as defined herein. In certain embodiments, in any one of formulas (V) to (XVI), R 5a is –C(O)OR a wherein R a is C 1-6 alkyl or C 7-15 arylalkyl, each of which is optionally substituted by one or more substituents Q. In certain embodiments, in any one of formulas (V) to (XVI), R 5a is acetyl, benzoyl, Boc, Cbz or Fmoc. In certain embodiments, in any one of formulas (V) to (XVI), R 5a is acetyl or Cbz.

[0094] In certain embodiments, in any one of formulas (V) to (XVI), R 5b is hydrogen.

[0095] In certain embodiments, in any one of formulas (V) to (XVI), R 5c is (i) hydrogen; or (ii) –C(O)R 1a or –C(O)OR 1a wherein R 1a is as defined herein. In certain embodiments, in any one of formulas (V) to (XVI), R 5c is hydrogen. In certain embodiments, in any one of formulas (V) to (XVI), R 5c is an amino protecting group. In certain embodiments, in any one of formulas (V) to (XVI), R 5c is –C(O)R 1a or –C(O)OR 1aamino protecting group, wherein R 1a are each as defined herein. In certain embodiments, in any one of formulas (V) to (XVI), R 5c is –C(O)R a wherein R a is as defined herein. In certain embodiments, in any one of formulas (V) to (XVI), R 5c is –C(O)R a wherein R a is C 1-6 alkyl, which is optionally substituted with one or more substituents Q. In certain embodiments, in any one of formulas (V) to (XVI), R 5c is –C(O)OR a wherein R a is as defined herein. In certain embodiments, in any one of formulas (V) to (XVI), R 5c is –C(O)OR a wherein R a is C 1-6 alkyl or C 7-15 aralkyl, each of which is optionally substituted with one or more substituents Q. In certain embodiments, in any one of formulas (V) to (XVI), R 5c is acetyl, benzoyl, Boc, Cbz or Fmoc. In certain embodiments, in any one of formulas (V) to (XVI), R 5c is acetyl or Cbz.

[0096] In certain embodiments, in any one of formulas (V) to (XVI), R 5d is hydrogen.

[0097] In certain embodiments, in any one of formulas (II) to (XVI), R 7a is hydrogen or -C(O)R 1a wherein R 1a is as defined herein. In certain embodiments, in any one of formulas (II) to (XVI), R 7a is hydrogen. In certain embodiments, in any one of formulas (II) to (XVI), R 7a is –C(O)R 1a wherein R 1a is as defined herein. In certain embodiments, in any one of formulas (II) to (XVI), R 7a is –C(O)–C 1-6An alkyl group, which is optionally substituted by one or more substituents Q. In certain embodiments, in any one of Formulas (II) to (XVI), R 7a is acetyl, propionyl or butyryl. In certain embodiments, in any one of Formulas (II) to (XVI), R 7a is acetyl.

[0098] In certain embodiments, in any one of Formulas (II) to (XVI), R 8a is hydrogen or –C(O)R 1a , where R 1a is as defined herein. In certain embodiments, in any one of Formulas (II) to (XVI), R 8a is hydrogen. In certain embodiments, in any one of Formulas (II) to (XVI), R 8a is –C(O)R 1a , where R 1a is as defined herein. In certain embodiments, in any one of Formulas (II) to (XVI), R 8a is –C(O)–C 1-6 An alkyl group, which is optionally substituted by one or more substituents Q. In certain embodiments, in any one of Formulas (II) to (XVI), R 8a is acetyl, propionyl or butyryl. In certain embodiments, in any one of Formulas (II) to (XVI), R 8a is acetyl.

[0099] In certain embodiments, in any one of Formulas (I) to (XVI), R 4 is hydrogen.

[0100] In certain embodiments, in any one of Formulas (I) to (XVI), R 6 is hydrogen.

[0101] In certain embodiments, in any one of Formulas (I) to (XVI), R 9 is hydrogen or -C(O)R 1a , where R 1a is as defined herein. In certain embodiments, in any one of Formulas (I) to (XVI), R 9 is hydrogen. In certain embodiments, in any one of Formulas (I) to (XVI), R 9 is –C(O)R 1a , where R 1a is as defined herein. In certain embodiments, in any one of Formulas (I) to (XVI), R 9 is –C(O)–C1-6 an alkyl group, which is optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulas (I) to (XVI), R 9 is acetyl, propionyl or butyryl. In certain embodiments, in any one of Formulas (I) to (XVI), R 9 is acetyl.

[0102] In certain embodiments, in any one of Formulas (I) to (XVI), A is a bond or O. In certain embodiments, in any one of Formulas (I) to (XVI), A is a bond. In certain embodiments, in any one of Formulas (I) to (XVI), A is O.

[0103] In certain embodiments, in any one of Formulas (I) to (XVI), E is azido, fluoro, iodo, isocyano, –C═CH2, –C≡CH, –C(O)CH3 or –SH. In certain embodiments, in any one of Formulas (I) to (XVI), E is azido (-N3).

[0104] In certain embodiments, in any one of Formulas (I) to (XVI), L is C 1-6 an alkylene group, which is optionally substituted with one or more substituents Q. In certain embodiments, in any one of Formulas (I) to (XVI), L 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 one of Formulas (I) to (XVI), L is methanediyl.

[0105] In certain embodiments, in any one of Formulas (I) to (XVI), m is the integer 0.

[0106] In certain embodiments, in any one of Formulas (I) to (XVI), A is a bond and E is an azide group. In certain embodiments, in Formula (I), A is a bond and E is an azide group. In certain embodiments, in Formula (II), A is a bond and E is an azide group. In certain embodiments, in Formula (III), A is a bond and E is an azide group. In certain embodiments, in Formula (IV), A is a bond and E is an azide group. In certain embodiments, in Formula (V), A is a bond and E is an azide group. In certain embodiments, in Formula (VI), A is a bond and E is an azide group. In certain embodiments, in Formula (VII), A is a bond and E is an azide group. In certain embodiments, in Formula (VIII), A is a bond and E is an azide group. In certain embodiments, in Formula (IX), A is a bond and E is an azide group. In certain embodiments, in Formula (X), A is a bond and E is an azide group. In certain embodiments, in Formula (XI), A is a bond and E is an azide group. In certain embodiments, in Formula (XII), A is a bond and E is an azide group. In certain embodiments, in Formula (XIII), A is a bond and E is an azide group. In certain embodiments, in Formula (XIV), A is a bond and E is an azide group. In certain embodiments, in Formula (XV), A is a bond and E is an azide group. In certain embodiments, in Formula (XVI), A is a bond and E is an azide group.

[0107] The group R in the formulas described herein (including Formulas (I) to (XVI)) 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 5a , R 5b , R 5c , R 5d , R 7a , R 8a , A, E, L, U, V, X, Y, Z, and m 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.

[0108] In certain embodiments, R 1 is hydrogen. In certain embodiments, R 1 is deuterium. In certain embodiments, R 1 is C 1-20 alkyl, which is optionally substituted with one or more substituents Q. In certain embodiments, R 1 is C 1-10An alkyl group, which is optionally substituted by one or more substituents Q. In certain embodiments, R 1 is C 1-6 An alkyl group, which is optionally substituted by one or more substituents Q. In certain embodiments, R 1 is methyl, which is optionally substituted by one or more substituents Q. In certain embodiments, R 1 is C 1-20 A heteroalkyl group, which is optionally substituted by one or more substituents Q. In certain embodiments, R 1 is C 1-10 A heteroalkyl group, which is optionally substituted by one or more substituents Q. In certain embodiments, R 1 is C 1-6 A heteroalkyl group, which is optionally substituted by one or more substituents Q. In certain embodiments, R 1 is C 2-20 An alkenyl group, which is optionally substituted by one or more substituents Q. In certain embodiments, R 1 is C 2-10 An alkenyl group, which is optionally substituted by one or more substituents Q. In certain embodiments, R 1 is C 2-6 An alkenyl group, which is optionally substituted by one or more substituents Q. In certain embodiments, R 1 is C 2-20 An alkynyl group, which is optionally substituted by one or more substituents Q. In certain embodiments, R 1 is C 2-10 An alkynyl group, which is optionally substituted by one or more substituents Q. In certain embodiments, R 1 is C 2-6 An alkynyl group, which is optionally substituted by one or more substituents Q. In certain embodiments, R 1 is C 3-20 A cycloalkyl group, which is optionally substituted by one or more substituents Q. In certain embodiments, R 1 is C 3-10 A cycloalkyl group, which is optionally substituted by one or more substituents Q. In certain embodiments, R 1 is C 6-20 An aryl group, which is optionally substituted by one or more substituents Q. In certain embodiments, R 1 is C 6-14 An aryl group, which is optionally substituted by one or more substituents Q. In certain embodiments, R 1 is C 7-20 An aralkyl group, which is optionally substituted by one or more substituents Q. In certain embodiments, R 1 is C 7-15An arylalkyl group, optionally substituted with one or more substituents Q. In certain embodiments, R 1 is a heteroaryl group, optionally substituted with one or more substituents Q. In certain embodiments, R 1 is a heterocyclic group, optionally substituted with one or more substituents Q.

[0109] In certain embodiments, R 2 is a monocyclic heteroaryl group, optionally substituted with one or more substituents Q. In certain embodiments, R 2 is a 5- or 6-membered heteroaryl group, optionally substituted with one or more substituents Q. In certain embodiments, R 2 is a 5-membered heteroaryl group, optionally substituted with one or more substituents Q. In certain embodiments, R 2 is a 5-membered heteroaryl group, optionally substituted with C 1-6 alkyl, said C 1-6 alkyl further optionally substituted with one or more substituents Q a substituted. In certain embodiments, R 2 is thiophenyl, pyrazolyl, imidazolyl, or thiazolyl, each optionally substituted with one or more substituents Q. In certain embodiments, R 2 is thiophenyl, pyrazolyl, imidazolyl or thiazolyl, each optionally substituted with C 1-6 alkyl, said C 1-6 alkyl further optionally substituted with one or more substituents Q a substituted. In certain embodiments, R 2 is thiophen-2-yl, thiophen-3-yl, pyrazol-3-yl, imidazol-4-yl, thiazol-2-yl or thiazol-5-yl, each optionally substituted with C 1-6 alkyl, said C 1-6 alkyl further optionally substituted with one or more substituents Q a substituted. In certain embodiments, R 2 is thiophen-2-yl, thiophen-3-yl, 2-methylpyrazol-3-yl, imidazol-4-yl, 1-methylimidazol-4-yl, thiazol-2-yl or thiazol-5-yl.

[0110] In certain embodiments, R 2 is a 6-membered heteroaryl group, optionally substituted with one or more substituents Q. In certain embodiments, R 2 is a 6-membered heteroaryl group, optionally substituted with C 1-6 alkyl, said C 1-6 alkyl further optionally substituted with one or more substituents Q a substituted. In certain embodiments, R 2is pyridyl, which is optionally substituted with one or more substituents Q. In certain embodiments, R 2 is pyridyl, which is optionally substituted with C 1-6 alkyl, and the C 1-6 alkyl is further optionally substituted with one or more substituents Q a substituted. In certain embodiments, R 2 is pyridin-3-yl or pyridin-4-yl, each of which is optionally substituted with C 1-6 alkyl, and the C 1-6 alkyl is further optionally substituted with one or more substituents Q a substituted. In certain embodiments, R 2 is bicyclic heteroaryl, which is optionally substituted with one or more substituents Q. In certain embodiments, R 2 is 5,5-fused heteroaryl, 5,6-fused heteroaryl or 6,6-fused heteroaryl, each of which is optionally substituted with one or more substituents Q. In certain embodiments, R 2 is 5,5-fused heteroaryl, which is optionally substituted with one or more substituents Q. In certain embodiments, iR 2 is 5,6-fused heteroaryl, which is optionally substituted with one or more substituents Q. In certain embodiments, R 2 is 6,6-fused heteroaryl, which is optionally substituted with one or more substituents Q.

[0111] In certain embodiments, R 3 is deuterium. In certain embodiments, R 3 is cyano. In certain embodiments, R 3 is halogen. In certain embodiments, R 3 is fluorine. In certain embodiments, R 3 is chlorine. In certain embodiments, R 3 is nitro. In certain embodiments, R 3 is C 1-6 alkyl, which is optionally substituted with one or more substituents Q. In certain embodiments, R 3 is methyl. In certain embodiments, R 3 is C 1-6 heteroalkyl, which is optionally substituted with one or more substituents Q. In certain embodiments, R 3 is trifluoromethyl. In certain embodiments, R 3 is C 2-6 alkenyl, which is optionally substituted with one or more substituents Q. In certain embodiments, R 3 is C 2-6 alkynyl, which is optionally substituted with one or more substituents Q. In certain embodiments, R3 is C 3-10 cycloalkyl, which is optionally substituted with one or more substituents Q. In certain embodiments, R 3 is C 6-14 aryl, which is optionally substituted with one or more substituents Q. In certain embodiments, R 3 is C 7-15 aralkyl, which is optionally substituted with one or more substituents Q. In certain embodiments, R 3 is heteroaryl, which is optionally substituted with one or more substituents Q. In certain embodiments, R 3 is heterocyclic, which is optionally substituted with one or more substituents Q.

[0112] In certain embodiments, R 3 is -C(O)R 1a , wherein, R 1a is as defined herein. In certain embodiments, R 3 is -C(O)OR 1a , wherein, R 1a is as defined herein. In certain embodiments, R 3 is -C(O)NR 1b R 1c , wherein, R 1b and R 1c are each as defined herein. In certain embodiments, R 3 is -C(O)SR 1a , wherein, R 1a is as defined herein. In certain embodiments, R 3 is -C(NR 1a )NR 1b R 1c , wherein, R 1a , R 1b and R 1c are each as defined herein. In certain embodiments, R 3 is -C(S)R 1a , wherein, R 1a is as defined herein. In certain embodiments, R 3 is -C(S)OR 1a , wherein, R 1a is as defined herein. In certain embodiments, R 3 is -C(S)NR 1b R 1c , wherein, R 1b and R 1c are each as defined herein. In certain embodiments, R 3 is -OR 1a , wherein, R1a As defined herein. In certain embodiments, R 3 is -OC(O)R 1a , where R 1a is as defined herein. In certain embodiments, R 3 is -OC(O)OR 1a , where R 1a is as defined herein. In certain embodiments, R 3 is -OC(O)NR 1b R 1c , where R 1b and R 1c are each as defined herein. In certain embodiments, R 3 is -OC(S)R 1a , where R 1a is as defined herein. In certain embodiments, R 3 is -OC(NR 1a )NR 1b R 1c , where R 1a , R 1b and R 1c are each as defined herein. In certain embodiments, R 3 is -OC(S)R 1a , where R 1a is as defined herein. In certain embodiments, R 3 is -OC(S)OR 1a , where R 1a is as defined herein. In certain embodiments, R 3 is -OC(S)NR 1b R 1c , where R 1b and R 1c are each as defined herein. In certain embodiments, R 3 is -OS(O)R 1a , where R 1a is as defined herein. In certain embodiments, R 3 is -OS(O)2R 1a , where R 1a is as defined herein. In certain embodiments, R 3 is -OS(O)NR 1b R 1c , where R 1b and R 1c are each as defined herein. In certain embodiments, R 3 is -OS(O)2NR 1b R 1c, wherein, R 1b and R 1c are each as defined herein. In certain embodiments, R 3 is -NR 1b R 1c , wherein, R 1b and R 1c are each as defined herein. In certain embodiments, R 3 is -NR 1a C(O)R 1d , wherein, R 1a and R 1d are each as defined herein. In certain embodiments, R 3 is -NR 1a C(O)OR 1d , wherein, R 1a and R 1d are each as defined herein. In certain embodiments, R 3 is -NR 1a C(O)NR 1b R 1c , wherein, R 1a , R 1b and R 1c are each as defined herein. In certain embodiments, R 3 is -NR 1a C(O)SR 1d , wherein, R 1a and R 1d are each as defined herein. In certain embodiments, R 3 is -NR 1a C(NR 1d )NR 1b R 1c , wherein, R 1a , R 1b , R 1c and R 1d are each as defined herein. In certain embodiments, R 3 is -NR 1a C(S)R 1d , wherein, R 1a and R 1d are each as defined herein. In certain embodiments, R 3 is -NR 1a C(S)OR 1d , wherein, R 1a and R 1d are each as defined herein. In certain embodiments, R 3 is -NR 1a C(S)NR 1b R 1c, wherein R 1a , R 1b and R 1c are each as defined herein. In certain embodiments, R 3 is -NR 1a S(O)R 1d , wherein R 1a and R 1d are each as defined herein. In certain embodiments, R 3 is -N═S(O)R 1a R 1d , wherein R 1a and R 1d are each as defined herein. In certain embodiments, R 3 is -NR 1a S(O)2R 1d , wherein R 1a and R 1d are each as defined herein. In certain embodiments, R 3 is -NR 1a S(O)NR 1b R 1c , wherein R 1a , R 1b and R 1c are each as defined herein. In certain embodiments, R 3 is -NR 1a S(O)2NR 1b R 1c , wherein R 1a , R 1b and R 1c are each as defined herein. In certain embodiments, R 3 is -SR 1a , wherein R 1a is as defined herein. In certain embodiments, R 3 is -S(O)R 1a , wherein R 1a is as defined herein. In certain embodiments, R 3 is -S(O)2R 1a , wherein R 1a is as defined herein. In certain embodiments, R 3 is -S(O)NR 1b R 1c , wherein R 1b and R 1c are each as defined herein. In certain embodiments, R 3 is -S(O)2NR 1b R 1c , wherein R 1b and R1c Each as defined herein.

[0113] In certain embodiments, R 4 is hydrogen. In certain embodiments, R 4 is C 1-6 alkyl, optionally substituted with one or more substituents Q. In certain embodiments, R 4 is methyl, optionally substituted with one or more substituents Q. In certain embodiments, R 4 is C 1-6 heteroalkyl, optionally substituted with one or more substituents Q. In certain embodiments, R 4 is C 2-6 alkenyl, optionally substituted with one or more substituents Q. In certain embodiments, R 4 is C 2-6 alkynyl, optionally substituted with one or more substituents Q. In certain embodiments, R 4 is C 3-10 cycloalkyl, optionally substituted with one or more substituents Q. In certain embodiments, R 4 is C 6-14 aryl, optionally substituted with one or more substituents Q. In certain embodiments, R 4 is C 7-15 aralkyl, optionally substituted with one or more substituents Q. In certain embodiments, R 4 is heteroaryl, optionally substituted with one or more substituents Q. In certain embodiments, R 4 is heterocyclic, optionally substituted with one or more substituents Q.

[0114] In certain embodiments, R 4 is -C(O)R 1a , wherein, R 1a is as defined herein. In certain embodiments, R 4 is -C(O)OR 1a , wherein, R 1a is as defined herein. In certain embodiments, R 4 is -C(O)NR 1b R 1c , wherein, R 1b and R 1c each is as defined herein. In certain embodiments, R 4 is -C(O)SR 1a , wherein, R 1a is as defined herein. In certain embodiments, R 4 is -C(NR 1a )NR1b R 1c , wherein R 1a , R 1b and R 1c are each as defined herein. In certain embodiments, R 4 is -C(S)R 1a , wherein R 1a is as defined herein. In certain embodiments, R 4 is -C(S)OR 1a , wherein R 1a is as defined herein. In certain embodiments, R 4 is -C(S)NR 1b R 1c , wherein R 1b and R 1c are each as defined herein. In certain embodiments, R 4 is -S(O)R 1a , wherein R 1a is as defined herein. In certain embodiments, R 4 is -S(O)2R 1a , wherein R 1a is as defined herein. In certain embodiments, R 4 is -S(O)NR 1b R 1c , wherein R 1b and R 1c are each as defined herein. In certain embodiments, R 4 is -S(O)2NR 1b R 1c , wherein R 1b and R 1c are each as defined herein. In certain embodiments, R 4 is -Si(R 1a )3, wherein R 1a are each as defined herein. In certain embodiments, R 4 is -Si(C 1-6 alkyl)3, each of which is optionally substituted by one or more substituents Q.

[0115] In certain embodiments, R 5 is C 1-6 alkyl, which is optionally substituted by one or more substituents Q. In certain embodiments, R 5 is C 1-6 alkyl, which is optionally substituted by one, two or three substituents, each of which is independently (i)C 1-6 alkyl, C 6-14Aryl or heteroaryl, each of which is optionally substituted with one or more substituents Q; or -C(O)OR 1a 、-C(O)NR 1b R 1c 、-C(NR 1a )NR 1b R 1c 、-OR 1a 、-NR 1b R 1c or -SR 1a , where R 1a , R 1b and R 1c Each is as defined herein. In certain embodiments, R 5 C 1-6 Alkyl, which is optionally substituted with one or two substituents, each of which is independently methyl, phenyl, 4-hydroxyphenyl, imidazol-4-yl, indol-3-yl, amino, acetamido, benzamido, benzyloxycarbonylamino, tert-butoxycarbonylamino, 9-fluorenylmethoxycarbonylamino, aminocarbonyl, aminocarbonyl, carboxyl, guanidino, hydroxyl, thiol or methylthio. In certain embodiments, R 5 is methyl, ethyl, propyl, butyl, pentyl or hexyl, each of which is optionally substituted with one or more substituents Q. In certain embodiments, R 5 is methyl, ethyl, propyl, butyl, pentyl or hexyl, each of which is optionally substituted with one, two or three substituents, each of which is independently (i) C 1-6 Alkyl, C 6-14 Aryl or heteroaryl, each of which is optionally substituted with one or more substituents Q; or -C(O)OR 1a 、-C(O)NR 1b R 1c 、-C(NR 1a )NR 1b R 1c 、-OR 1a 、-NR 1b R 1c or -SR 1a , where R 1a , R 1b and R 1c Each is as defined herein. In certain embodiments, R 5is methyl, ethyl, propyl, butyl, pentyl or hexyl, each optionally substituted by one or two substituents, each of which is independently methyl, phenyl, 4-hydroxyphenyl, imidazol-4-yl, indol-3-yl, amino, acetamido, benzamido, benzyloxycarbonylamino, tert-butoxycarbonylamino, 9-fluorenylmethoxycarbonylamino, aminocarbonyl, carbamoyl, carboxyl, guanidino, hydroxy, mercapto or methylthio. In certain embodiments, R 5 is aminomethyl, 1-aminoethyl, 1-amino-2-carboxyethyl, 1-amino-2-aminocarbonylethyl, 1-amino-2-mercaptoethyl, 1-amino-2-hydroxyethyl, 1-amino-2-(imidazol-4-yl)ethyl, 1-amino-2-(indol-3-yl)ethyl, 1-amino-2-methylpropyl, 1-amino-3-carboxypropyl, 1-amino-3-aminocarbonylpropyl, 1-amino-2-hydroxypropyl, 1-amino-3-methylthiopropyl, 1-amino-2-methylbutyl, 1-amino-3-methylbutyl, 1-amino-4-guanidinobutyl, 1,4-diaminobutyl, 1-amino-2-phenylethyl or 1-amino-2-(4-hydroxyphenyl)ethyl, wherein the amino groups are each independently and optionally protected by an amino protecting group (in one embodiment, by acetyl, benzoyl, Boc, Cbz or Fmoc).

[0116] In certain embodiments, R 5 is C 2-6 alkenyl, which is optionally substituted by one or more substituents Q. In certain embodiments, R 5 is C 2-6 alkynyl, which is optionally substituted by one or more substituents Q. In certain embodiments, R 5 is C 3-10 cycloalkyl, which is optionally substituted by one or more substituents Q. In certain embodiments, R 5 is C 6-14 aryl, which is optionally substituted by one or more substituents Q. In certain embodiments, R 5 is C 7-15 aralkyl, which is optionally substituted by one or more substituents Q. In certain embodiments, R 5 is monocyclic C 7-15 aralkyl, which is optionally substituted by one or more substituents Q. In certain embodiments, R 5 is 1-amino-2-phenylethyl or 1-amino-2-(4-hydroxyphenyl)ethyl, wherein the amino groups are each independently and optionally protected by an amino protecting group. In certain embodiments, R 5 is bicyclic C 8-15 aralkyl, which is optionally substituted by one or more substituents Q. In certain embodiments, R 5is a heteroaryl, which is optionally substituted by one or more substituents Q. In certain embodiments, R 5 is a monocyclic heteroaryl, which is optionally substituted by one or more substituents Q. In certain embodiments, R 5 is a 5- or 6-membered heteroaryl, which is optionally substituted by one or more substituents Q. In certain embodiments, R 5 is a bicyclic heteroaryl, which is optionally substituted by one or more substituents Q. In certain embodiments, R 5 is a 5,5-fused heteroaryl, 5,6-fused heteroaryl or 6,6-fused heteroaryl, each of which is optionally substituted by one or more substituents Q.

[0117] In certain embodiments, R 5 is a heterocyclic group, which is optionally substituted by one or more substituents Q. In certain embodiments, R 5 is a monocyclic heterocyclic group, which is optionally substituted by one or more substituents Q. In certain embodiments, R 5 is a 3-, 4-, 5-, 6- or 7-membered heterocyclic group, each of which is optionally substituted by one or more substituents Q. In certain embodiments, R 5 is a 3-membered heterocyclic group, which is optionally substituted by one or more substituents Q. In certain embodiments, R 5 is a 4-membered heterocyclic group, which is optionally substituted by one or more substituents Q. In certain embodiments, R 5 is a 5-membered heterocyclic group, which is optionally substituted by one or more substituents Q. In certain embodiments, R 5 is a 6-membered heterocyclic group, which is optionally substituted by one or more substituents Q. In certain embodiments, R 5 is a 7-membered heterocyclic group, which is optionally substituted by one or more substituents Q. In certain embodiments, R 5 is a pyrrolidinyl group, which is optionally substituted by one or more substituents Q. In certain embodiments, R 5 is a pyrrolidin-2-yl group, which is optionally substituted by one or more substituents Q. In certain embodiments, R 5 is a bicyclic heterocyclic group, which is optionally substituted by one or more substituents Q. In certain embodiments, R 5 is a bridged, fused or spiro heterocyclic group, each of which is optionally substituted by one or more substituents Q. In certain embodiments, R 5 is a bridged heterocyclic group, which is optionally substituted by one or more substituents Q. In certain embodiments, R 5 is a fused heterocyclic group, which is optionally substituted by one or more substituents Q. In certain embodiments, R 5 is a spiro heterocyclic group, which is optionally substituted by one or more substituents Q.

[0118] In certain embodiments, R 6 is hydrogen. In certain embodiments, R 6 is C 1-6 alkyl, optionally substituted with one or more substituents Q. In certain embodiments, R 6 is methyl, optionally substituted with one or more substituents Q. In certain embodiments, R 6 is C 1-6 heteroalkyl, optionally substituted with one or more substituents Q. In certain embodiments, R 6 is C 2-6 alkenyl, optionally substituted with one or more substituents Q. In certain embodiments, R 6 is C 2-6 alkynyl, optionally substituted with one or more substituents Q. In certain embodiments, R 6 is C 3-10 cycloalkyl, optionally substituted with one or more substituents Q. In certain embodiments, R 6 is C 6-14 aryl, optionally substituted with one or more substituents Q. In certain embodiments, R 6 is C 7-15 aralkyl, optionally substituted with one or more substituents Q. In certain embodiments, R 6 is heteroaryl, optionally substituted with one or more substituents Q. In certain embodiments, R 6 is heterocyclic, optionally substituted with one or more substituents Q.

[0119] In certain embodiments, R 6 is -C(O)R 1a , wherein R 1a is as defined herein. In certain embodiments, R 6 is -C(O)OR 1a , wherein R 1a is as defined herein. In certain embodiments, R 6 is -C(O)NR 1b R 1c , wherein R 1b and R 1c are each as defined herein. In certain embodiments, R 6 is -C(O)SR 1a , wherein R 1a is as defined herein. In certain embodiments, R 6 is -C(NR 1a )NR 1b R 1c, wherein R 1a , R 1b and R 1c are each as defined herein. In certain embodiments, R 6 is -C(S)R 1a , wherein R 1a is as defined herein. In certain embodiments, R 6 is -C(S)OR 1a , wherein R 1a is as defined herein. In certain embodiments, R 6 is -C(S)NR 1b R 1c , wherein R 1b and R 1c are each as defined herein. In certain embodiments, R 6 is -S(O)R 1a , wherein R 1a is as defined herein. In certain embodiments, R 6 is -S(O)2R 1a , wherein R 1a is as defined herein. In certain embodiments, R 6 is -S(O)NR 1b R 1c , wherein R 1b and R 1c are each as defined herein. In certain embodiments, R 6 is -S(O)2NR 1b R 1c , wherein R 1b and R 1c are each as defined herein. In certain embodiments, R 6 is -Si(R 1a )3, wherein R 1a are each as defined herein. In certain embodiments, R 6 is -Si(C 1-6 alkyl)3, each of which is optionally substituted with one or more substituents Q.

[0120] In certain embodiments, R 7 is halogen. In certain embodiments, R 7 is fluorine. In certain embodiments, R 7 is -OR 1a , wherein R 1a is as defined herein. In certain embodiments, R 7 is hydroxyl. In certain embodiments, R 7 is -OC(O)R 1a , wherein R 1aAs defined herein. In certain embodiments, R 7 is -OC(O)-C 1-30 alkyl, which is optionally substituted with one or more substituents Q. In certain embodiments, R 7 is -OC(O)-C 1-20 alkyl, which is optionally substituted with one or more substituents Q. In certain embodiments, R 7 is -OC(O)-C 1-10 alkyl, which is optionally substituted with one or more substituents Q. In certain embodiments, R 7 is -OC(O)-C 1-6 alkyl, which is optionally substituted with one or more substituents Q. In certain embodiments, R 7 is acetoxy, propionyloxy or butyryloxy, each of which is optionally substituted with one or more substituents Q. In certain embodiments, R 7 is acetoxy. In certain embodiments, R 7 is -OC(O)-C 1-10 heteroalkyl, which is optionally substituted with one or more substituents Q. In certain embodiments, R 7 is -OC(O)-C 2-10 alkenyl, which is optionally substituted with one or more substituents Q. In certain embodiments, R 7 is -OC(O)-C 2-10 alkynyl, which is optionally substituted with one or more substituents Q. In certain embodiments, R 7 is -OC(O)-C 3-10 cycloalkyl, which is optionally substituted with one or more substituents Q. In certain embodiments, R 7 is -OC(O)-C 6-14 aryl, which is optionally substituted with one or more substituents Q. In certain embodiments, R 7 is benzoyloxy, which is optionally substituted with one or more substituents Q. In certain embodiments, R 7 is -OC(O)-(bicyclic C 8-14 aryl), which is optionally substituted with one or more substituents Q. In certain embodiments, R 7 is -OC(O)-C 7-15 aralkyl, which is optionally substituted with one or more substituents Q. In certain embodiments, R 7 is -OC(O)-heteroaryl, which is optionally substituted with one or more substituents Q. In certain embodiments, R 7 is -OC(O)-(monocyclic heteroaryl), which is optionally substituted with one or more substituents Q. In certain embodiments, R 7is -OC(O)-(a 5- or 6-membered heteroaryl), each of which is optionally substituted by one or more substituents Q. In certain embodiments, R 7 is -OC(O)-(a bicyclic heteroaryl), which is optionally substituted by one or more substituents Q. In certain embodiments, R 7 is -OC(O)-(a 5,5-, 5,6- or 6,6-fused heteroaryl), each of which is optionally substituted by one or more substituents Q. In certain embodiments, R 7 is -OC(O)-heterocyclyl, which is optionally substituted by one or more substituents Q. In certain embodiments, R 7 is -OC(O)-monocyclic heterocyclyl, which is optionally substituted by one or more substituents Q. In certain embodiments, R 7 is -OC(O)-(a 3-, 4-, 5-, 6- or 7-membered heterocyclyl), each of which is optionally substituted by one or more substituents Q. In certain embodiments, R 7 is -OC(O)-bicyclic heterocyclyl, which is optionally substituted by one or more substituents Q. In certain embodiments, R 7 is -OC(O)-(a bridged, fused or spiro heterocyclyl), each of which is optionally substituted by one or more substituents Q. In certain embodiments, R 7 is -OC(O)OR 1a , wherein R 1a is as defined herein. In certain embodiments, R 7 is -OC(O)NR 1b R 1c , wherein R 1b and R 1c are each as defined herein.

[0121] In certain embodiments, R 8 is halogen. In certain embodiments, R 8 is fluorine. In certain embodiments, R 8 is -OR 1a , wherein R 1a is as defined herein. In certain embodiments, R 8 is hydroxy. In certain embodiments, R 8 is -OC(O)R 1a , wherein R 1a is as defined herein. In certain embodiments, R 8 is -OC(O)-C 1-30 alkyl, which is optionally substituted by one or more substituents Q. In certain embodiments, R 8 is -OC(O)-C 1-20An alkyl group, which is optionally substituted by one or more substituents Q. In certain embodiments, R 8 is -OC(O)-C 1-10 An alkyl group, which is optionally substituted by one or more substituents Q. In certain embodiments, R 8 is -OC(O)-C 1-6 An alkyl group, which is optionally substituted by one or more substituents Q. In certain embodiments, R 8 is acetoxy, propionyloxy or butyryloxy, each of which is optionally substituted by one or more substituents Q. In certain embodiments, R 8 is acetoxy. In certain embodiments, R 8 is -OC(O)-C 1-10 A heteroalkyl group, which is optionally substituted by one or more substituents Q. In certain embodiments, R 8 is -OC(O)-C 2-10 An alkenyl group, which is optionally substituted by one or more substituents Q. In certain embodiments, R 8 is -OC(O)-C 2-10 An alkynyl group, which is optionally substituted by one or more substituents Q. In certain embodiments, R 8 is -OC(O)-C 3-10 A cycloalkyl group, which is optionally substituted by one or more substituents Q. In certain embodiments, R 8 is -OC(O)-C 6-14 An aryl group, which is optionally substituted by one or more substituents Q. In certain embodiments, R 8 is benzoyloxy, which is optionally substituted by one or more substituents Q. In certain embodiments, R 8 is -OC(O)-(bicyclic C 8-14 aryl), which is optionally substituted by one or more substituents Q. In certain embodiments, R 8 is -OC(O)-C 7-15 An aralkyl group, which is optionally substituted by one or more substituents Q. In certain embodiments, R 8 is -OC(O)-heteroaryl, which is optionally substituted by one or more substituents Q. In certain embodiments, R 8 is -OC(O)-(monocyclic heteroaryl), which is optionally substituted by one or more substituents Q. In certain embodiments, R 8 is -OC(O)-(5-membered or 6-membered heteroaryl), each of which is optionally substituted by one or more substituents Q. In certain embodiments, R 8 is -OC(O)-(bicyclic heteroaryl), which is optionally substituted by one or more substituents Q. In certain embodiments, R 8is -OC(O)-(5,5-, 5,6- or 6,6-fused heteroaryl), each of which is optionally substituted by one or more substituents Q. In certain embodiments, R 8 is -OC(O)-heterocyclyl, which is optionally substituted by one or more substituents Q. In certain embodiments, R 8 is -OC(O)-monocyclic heterocyclyl, which is optionally substituted by one or more substituents Q. In certain embodiments, R 8 is -OC(O)-(3-membered, 4-membered, 5-membered, 6-membered or 7-membered heterocyclyl), each of which is optionally substituted by one or more substituents Q. In certain embodiments, R 8 is -OC(O)-bicyclic heterocyclyl, which is optionally substituted by one or more substituents Q. In certain embodiments, R 8 is -OC(O)-(bridged, fused or spiro heterocyclyl), each of which is optionally substituted by one or more substituents Q. In certain embodiments, R 8 is -OC(O)OR 1a , wherein, R 1a is as defined herein. In certain embodiments, R 8 is -OC(O)NR 1b R 1c , wherein, R 1b and R 1c are each as defined herein.

[0122] In certain embodiments, R 9 is hydrogen. In certain embodiments, R 9 is -C(O)R 1a , wherein, R 1a is as defined herein. In certain embodiments, R 9 is -C(O)-C 1-30 alkyl, which is optionally substituted by one or more substituents Q. In certain embodiments, R 9 is -C(O)-C 1-20 alkyl, which is optionally substituted by one or more substituents Q. In certain embodiments, R 9 is -C(O)-C 1-10 alkyl, which is optionally substituted by one or more substituents Q. In certain embodiments, R 9 is -C(O)-C 1-6 alkyl, which is optionally substituted by one or more substituents Q. In certain embodiments, R 9 is acetyl, propionyl or butyryl, each of which is optionally substituted by one or more substituents Q. In certain embodiments, R 9 is acetyl. In certain embodiments, R 9is -C(O)-C 1-6 a heteroalkyl group, optionally substituted by one or more substituents Q. In certain embodiments, R 9 is -C(O)-C 2-6 an alkenyl group, optionally substituted by one or more substituents Q. In certain embodiments, R 9 is -C(O)-C 2-6 an alkynyl group, optionally substituted by one or more substituents Q. In certain embodiments, R 9 -C(O)-C 3-10 a cycloalkyl group, optionally substituted by one or more substituents Q. In certain embodiments, R 9 -C(O)-C 6-14 an aryl group, optionally substituted by one or more substituents Q. In certain embodiments, R 9 is benzoyl, optionally substituted by one or more substituents Q. In certain embodiments, R 9 is -C(O)-(bicyclic C 8-14 aryl), optionally substituted by one or more substituents Q. In certain embodiments, R 9 is -C(O)-C 7-15 an aralkyl group, optionally substituted by one or more substituents Q. In certain embodiments, R 9 is -C(O)-heteroaryl, optionally substituted by one or more substituents Q. In certain embodiments, R 9 is -C(O)-(monocyclic heteroaryl), optionally substituted by one or more substituents Q. In certain embodiments, R 9 is -C(O)-(5 - or 6 - membered heteroaryl), each optionally substituted by one or more substituents Q. In certain embodiments, R 9 is -C(O)-(bicyclic heteroaryl), optionally substituted by one or more substituents Q. In certain embodiments, R 9 is -C(O)-(5,5 -, 5,6 - or 6,6 - fused heteroaryl), each optionally substituted by one or more substituents Q. In certain embodiments, R 9 is -C(O)-heterocyclic group, optionally substituted by one or more substituents Q. In certain embodiments, R 9 is -C(O)-monocyclic heterocyclic group, optionally substituted by one or more substituents Q. In certain embodiments, R 9 is -C(O)-(3 -, 4 -, 5 -, 6 - or 7 - membered heterocyclic group), each optionally substituted by one or more substituents Q. In certain embodiments, R 9is -C(O)-bicyclic heterocyclyl, which is optionally substituted by one or more substituents Q. In certain embodiments, R 9 is -C(O)-(bridged, fused or spiro heterocyclyl), each of which is optionally substituted by one or more substituents Q.

[0123] In certain embodiments, R 5a is hydrogen. In certain embodiments, R 5a is C 1-6 alkyl, which is optionally substituted by one or more substituents Q. In certain embodiments, R 5a is C 1-6 heteroalkyl, which is optionally substituted by one or more substituents Q. In certain embodiments, R 5a is C 2-6 alkenyl, which is optionally substituted by one or more substituents Q. In certain embodiments, R 5a is C 2-6 alkynyl, which is optionally substituted by one or more substituents Q. In certain embodiments, R 5a is C 3-10 cycloalkyl, which is optionally substituted by one or more substituents Q. In certain embodiments, R 5a is C 6-14 aryl, which is optionally substituted by one or more substituents Q. In certain embodiments, R 5a is C 7-15 aralkyl, which is optionally substituted by one or more substituents Q. In certain embodiments, R 5a is heteroaryl, which is optionally substituted by one or more substituents Q.

[0124] In certain embodiments, R 5a is -C(O)R 1a , wherein R 1a is as defined herein. In certain embodiments, R 5a is -C(O)R 1a , wherein R 1a is C 1-6 alkyl, which is optionally substituted by one or more substituents Q. In certain embodiments, R 5a is acetyl. In certain embodiments, R 5a is –C(O)R 1a , wherein R 1a is C 6-4 aryl, which is optionally substituted by one or more substituents Q. In certain embodiments, R 5a is benzoyl. In certain embodiments, R 5a is -C(O)OR 1a , wherein R1a As defined herein. In certain embodiments, R 5a is -C(O)OR 1a , where R 1a is C 1-6 alkyl or C 7-15 arylalkyl, each of which is optionally substituted with one or more substituents Q. In certain embodiments, R 5a is Boc, Cbz or Fmoc. In certain embodiments, R 5a is -C(O)NR 1b R 1c , where R 1b and R 1c are each as defined herein. In certain embodiments, R 5a is -C(O)SR 1a , where R 1a is as defined herein. In certain embodiments, R 5a is -C(NR 1a )NR 1b R 1c , where R 1a , R 1b and R 1c are each as defined herein. In certain embodiments, R 5a is -C(S)R 1a , where R 1a is as defined herein. In certain embodiments, R 5a is -C(S)OR 1a , where R 1a is as defined herein. In certain embodiments, R 5a is -C(S)NR 1b R 1c , where R 1b and R 1c are each as defined herein. In certain embodiments, R 5a is -S(O)R 1a , where R 1a is as defined herein. In certain embodiments, R 5a is -S(O)2R 1a , where R 1a is as defined herein. In certain embodiments, R 5a is -S(O)NR 1b R 1c , where R 1b and R 1c are each as defined herein. In certain embodiments, R 5a is -S(O)2NR 1b R 1c, wherein, R 1b and R 1c are each as defined herein. In certain embodiments, R 5a is -Si(R 1a )3, wherein, R 1a are each as defined herein. In certain embodiments, R 5a is -Si(C 1-6 alkyl)3, wherein the alkyls are each optionally substituted by one or more substituents Q.

[0125] In certain embodiments, R 5a is an amino protecting group. In certain embodiments, R 5a is an amino protecting group of -C(O)R 1a or -C(O)OR 1a , wherein, R 1a are each as defined herein. In certain embodiments, R 5a is an amino protecting group acetyl, benzoyl, Boc, Cbz or Fmoc.

[0126] In certain embodiments, R 5b is hydrogen. In certain embodiments, R 5b is C 1-6 alkyl, which is optionally substituted by one or more substituents Q. In certain embodiments, R 5b is C 1-6 heteroalkyl, which is optionally substituted by one or more substituents Q. In certain embodiments, R 5b is C 2-6 alkenyl, which is optionally substituted by one or more substituents Q. In certain embodiments, R 5b is C 2-6 alkynyl, which is optionally substituted by one or more substituents Q. In certain embodiments, R 5b is C 3-10 cycloalkyl, which is optionally substituted by one or more substituents Q. In certain embodiments, R 5b is C 6-14 aryl, which is optionally substituted by one or more substituents Q. In certain embodiments, R 5b is C 7-15 aralkyl, which is optionally substituted by one or more substituents Q. In certain embodiments, R 5b is heteroaryl, which is optionally substituted by one or more substituents Q.

[0127] In certain embodiments, R 5b is -C(O)R 1a , wherein, R 1a is as defined herein. In certain embodiments, R5b is -C(O)R 1a , wherein R 1a is C 1-6 alkyl, which is optionally substituted by one or more substituents Q. In certain embodiments, R 5b is acetyl. In certain embodiments, R 5b is -C(O)R 1a , wherein R 1a is C 6-4 aryl, which is optionally substituted by one or more substituents Q. In certain embodiments, R 5b is benzoyl. In certain embodiments, R 5b is -C(O)OR 1a , wherein R 1a is as defined herein. In certain embodiments, R 5b is -C(O)OR 1a , wherein R 1a is C 1-6 alkyl or C 7-15 arylalkyl, each of which is optionally substituted by one or more substituents Q. In certain embodiments, R 5b is Boc, Cbz or Fmoc. In certain embodiments, R 5b is -C(O)NR 1b R 1c , wherein R 1b and R 1c are each as defined herein. In certain embodiments, R 5b is -C(O)SR 1a , wherein R 1a is as defined herein. In certain embodiments, R 5b is -C(NR 1a )NR 1b R 1c , wherein R 1a , R 1b and R 1c are each as defined herein. In certain embodiments, R 5b is -C(S)R 1a , wherein R 1a is as defined herein. In certain embodiments, R 5b is -C(S)OR 1a , wherein R 1a is as defined herein. In certain embodiments, R 5b is -C(S)NR 1b R 1c , wherein R 1b and R 1cEach as defined herein. In certain embodiments, R 5b is -S(O)R 1a , where R 1a is as defined herein. In certain embodiments, R 5b is -S(O)2R 1a , where R 1a is as defined herein. In certain embodiments, R 5b is -S(O)NR 1b R 1c , where R 1b and R 1c are each as defined herein. In certain embodiments, R 5b is -S(O)2NR 1b R 1c , where R 1b and R 1c are each as defined herein. In certain embodiments, R 5b is -Si(R 1a )3, where R 1a are each as defined herein. In certain embodiments, R 5b is -Si(C 1-6 alkyl)3, where the alkyls are each optionally substituted with one or more substituents Q.

[0128] In certain embodiments, R 5b is an amino protecting group. In certain embodiments, R 5b is an amino protecting group of -C(O)R 1a or -C(O)OR 1a , where R 1a are each as defined herein. In certain embodiments, R 5b is an amino protecting group acetyl, benzoyl, Boc, Cbz or Fmoc.

[0129] In certain embodiments, R 5c is hydrogen. In certain embodiments, R 5c is C 1-6 alkyl, which is optionally substituted with one or more substituents Q. In certain embodiments, R 5c is C 1-6 heteroalkyl, which is optionally substituted with one or more substituents Q. In certain embodiments, R 5c is C 2-6 alkenyl, which is optionally substituted with one or more substituents Q. In certain embodiments, R 5c is C 2-6 alkynyl, which is optionally substituted with one or more substituents Q. In certain embodiments, R 5cis C 3-10 a cycloalkyl group, optionally substituted with one or more substituents Q. In certain embodiments, R 5c is C 6-14 an aryl group, optionally substituted with one or more substituents Q. In certain embodiments, R 5c is C 7-15 an aralkyl group, optionally substituted with one or more substituents Q. In certain embodiments, R 5c is a heteroaryl group, optionally substituted with one or more substituents Q.

[0130] In certain embodiments, R 5c is -C(O)R 1a , where R 1a is as defined herein. In certain embodiments, R 5c is -C(O)R 1a , where R 1a is C 1-6 an alkyl group, optionally substituted with one or more substituents Q. In certain embodiments, R 5c is acetyl. In certain embodiments, R 5c is -C(O)R 1a , where R 1a is C 6-4 an aryl group, optionally substituted with one or more substituents Q. In certain embodiments, R 5c is benzoyl. In certain embodiments, R 5c is -C(O)OR 1a , where R 1a is as defined herein. In certain embodiments, R 5c is -C(O)OR 1a , where R 1a is C 1-6 an alkyl group or C 7-15 an aralkyl group, each optionally substituted with one or more substituents Q. In certain embodiments, R 5c is Boc, Cbz or Fmoc. In certain embodiments, R 5c is -C(O)NR 1b R 1c , where R 1b and R 1c are each as defined herein. In certain embodiments, R 5c is -C(O)SR 1a , where R 1a is as defined herein. In certain embodiments, R 5c is -C(NR 1a )NR 1b R1c , wherein R 1a , R 1b and R 1c are each as defined herein. In certain embodiments, R 5c is -C(S)R 1a , wherein R 1a is as defined herein. In certain embodiments, R 5c is -C(S)OR 1a , wherein R 1a is as defined herein. In certain embodiments, R 5c is -C(S)NR 1b R 1c , wherein R 1b and R 1c are each as defined herein. In certain embodiments, R 5c is -S(O)R 1a , wherein R 1a is as defined herein. In certain embodiments, R 5c is -S(O)2R 1a , wherein R 1a is as defined herein. In certain embodiments, R 5c is -S(O)NR 1b R 1c , wherein R 1b and R 1c are each as defined herein. In certain embodiments, R 5c is -S(O)2NR 1b R 1c , wherein R 1b and R 1c are each as defined herein. In certain embodiments, R 5c is -Si(R 1a )3, wherein R 1a are each as defined herein. In certain embodiments, R 5c is -Si(C 1-6 alkyl)3, wherein the alkyls are each optionally substituted with one or more substituents Q.

[0131] In certain embodiments, R 5c is an amino protecting group. In certain embodiments, R 5c is an amino protecting group of -C(O)R 1a or -C(O)OR 1a , wherein R 1a is as defined herein. In certain embodiments, R 5c is an amino protecting group acetyl, benzoyl, Boc, Cbz or Fmoc.

[0132] In certain embodiments, R 5d is hydrogen. In certain embodiments, R 5d is C 1-6 alkyl, which is optionally substituted with one or more substituents Q. In certain embodiments, R 5d is C 1-6 heteroalkyl, which is optionally substituted with one or more substituents Q. In certain embodiments, R 5d is C 2-6 alkenyl, which is optionally substituted with one or more substituents Q. In certain embodiments, R 5d is C 2-6 alkynyl, which is optionally substituted with one or more substituents Q. In certain embodiments, R 5d is C 3-10 cycloalkyl, which is optionally substituted with one or more substituents Q. In certain embodiments, R 5d is C 6-14 aryl, which is optionally substituted with one or more substituents Q. In certain embodiments, R 5d is C 7-15 aralkyl, which is optionally substituted with one or more substituents Q. In certain embodiments, R 5d is heteroaryl, which is optionally substituted with one or more substituents Q.

[0133] In certain embodiments, R 5d is -C(O)R 1a , where R 1a is as defined herein. In certain embodiments, R 5d is -C(O)R 1a , where R 1a is C 1-6 alkyl, which is optionally substituted with one or more substituents Q. In certain embodiments, R 5d is acetyl. In certain embodiments, R 5d is -C(O)R 1a , where R 1a is C 6-4 aryl, which is optionally substituted with one or more substituents Q. In certain embodiments, R 5d is benzoyl. In certain embodiments, R 5d is -C(O)OR 1a , where R 1a is as defined herein. In certain embodiments, R 5d is -C(O)OR 1a , where R 1a is C 1-6 alkyl or C 7-15An arylalkyl group, each of which is optionally substituted by one or more substituents Q. In certain embodiments, R 5d is Boc, Cbz or Fmoc. In certain embodiments, R 5d is -C(O)NR 1b R 1c , wherein R 1b and R 1c are each as defined herein. In certain embodiments, R 5d is -C(O)SR 1a , wherein R 1a is as defined herein. In certain embodiments, R 5d is -C(NR 1a )NR 1b R 1c , wherein R 1a , R 1b and R 1c are each as defined herein. In certain embodiments, R 5d is -C(S)R 1a , wherein R 1a is as defined herein. In certain embodiments, R 5d is -C(S)OR 1a , wherein R 1a is as defined herein. In certain embodiments, R 5d is -C(S)NR 1b R 1c , wherein R 1b and R 1c are each as defined herein. In certain embodiments, R 5d is -S(O)R 1a , wherein R 1a is as defined herein. In certain embodiments, R 5d is -S(O)2R 1a , wherein R 1a is as defined herein. In certain embodiments, R 5d is -S(O)NR 1b R 1c , wherein R 1b and R 1c are each as defined herein. In certain embodiments, R 5d is -S(O)2NR 1b R 1c , wherein R 1b and R 1c are each as defined herein. In certain embodiments, R 5d is -Si(R 1a )3, wherein R 1aEach is as defined herein. In certain embodiments, R 5d is -Si(C 1-6 alkyl)3, wherein each alkyl is optionally substituted with one or more substituents Q.

[0134] In certain embodiments, R 5d is an amino protecting group. In certain embodiments, R 5d is -C(O)R 1a or -C(O)OR 1a amino protecting group, wherein R 1a each is as defined herein. In certain embodiments, R 5d is an amino protecting group acetyl, benzoyl, Boc, Cbz or Fmoc.

[0135] In certain embodiments, R 7a is R 1a as defined herein. In certain embodiments, R 7a is hydrogen. In certain embodiments, R 7a is -C(O)R 1a , wherein R 1a is as defined herein. In certain embodiments, R 7a is -C(O)-C 1-30 alkyl, which is optionally substituted with one or more substituents Q. In certain embodiments, R 7a is -C(O)-C 1-20 alkyl, which is optionally substituted with one or more substituents Q. In certain embodiments, R 7a is -C(O)-C 1-10 alkyl, which is optionally substituted with one or more substituents Q. In certain embodiments, R 7a is -C(O)-C 1-6 alkyl, which is optionally substituted with one or more substituents Q. In certain embodiments, R 7a is acetyl, propionyl or butyryl, each of which is optionally substituted with one or more substituents Q. In certain embodiments, R 7a is acetyl. In certain embodiments, R 7a is -C(O)-C 1-6 heteroalkyl, which is optionally substituted with one or more substituents Q. In certain embodiments, R 7a is -C(O)-C 2-6 alkenyl, which is optionally substituted with one or more substituents Q. In certain embodiments, R 7a is -C(O)-C 2-6 alkynyl, which is optionally substituted with one or more substituents Q. In certain embodiments, R7a is -C(O)-C 3-10 a cycloalkyl group, which is optionally substituted by one or more substituents Q. In certain embodiments, R 7a is -C(O)-C 6-14 an aryl group, which is optionally substituted by one or more substituents Q. In certain embodiments, R 7a is benzoyl, which is optionally substituted by one or more substituents Q. In certain embodiments, R 7a is -C(O)-(bicyclic C 8-14 aryl), which is optionally substituted by one or more substituents Q. In certain embodiments, R 7a is -C(O)-C 7-15 an aralkyl group, which is optionally substituted by one or more substituents Q. In certain embodiments, R 7a is -C(O)-heteroaryl, which is optionally substituted by one or more substituents Q. In certain embodiments, R 7a is -C(O)-(monocyclic heteroaryl), which is optionally substituted by one or more substituents Q. In certain embodiments, R 7a is -C(O)-(5 - or 6 - membered heteroaryl), each of which is optionally substituted by one or more substituents Q. In certain embodiments, R 7a is -C(O)-(bicyclic heteroaryl), which is optionally substituted by one or more substituents Q. In certain embodiments, R 7a is -C(O)-(5,5 -, 5,6 - or 6,6 - fused heteroaryl), each of which is optionally substituted by one or more substituents Q. In certain embodiments, R 7a is -C(O)-heterocyclic group, which is optionally substituted by one or more substituents Q. In certain embodiments, R 7a is -C(O)-monocyclic heterocyclic group, which is optionally substituted by one or more substituents Q. In certain embodiments, R 7a is -C(O)-(3 -, 4 -, 5 -, 6 - or 7 - membered heterocyclic group), each of which is optionally substituted by one or more substituents Q. In certain embodiments, R 7a is -C(O)-bicyclic heterocyclic group, which is optionally substituted by one or more substituents Q. In certain embodiments, R 7a is -C(O)-(bridged, fused or spiro heterocyclic group), each of which is optionally substituted by one or more substituents Q.

[0136] In certain embodiments, R 8a is R as defined herein 1a . In certain embodiments, R 8a is hydrogen. In certain embodiments, R 8ais -C(O)R 1a , wherein R 1a is as defined herein. In certain embodiments, R 8a is -C(O)-C 1-30 alkyl, which is optionally substituted with one or more substituents Q. In certain embodiments, R 8a is -C(O)-C 1-20 alkyl, which is optionally substituted with one or more substituents Q. In certain embodiments, R 8a is -C(O)-C 1-10 alkyl, which is optionally substituted with one or more substituents Q. In certain embodiments, R 8a is -C(O)-C 1-6 alkyl, which is optionally substituted with one or more substituents Q. In certain embodiments, R 8a is acetyl, propionyl or butyryl, each of which is optionally substituted with one or more substituents Q. In certain embodiments, R 8a is acetyl. In certain embodiments, R 8a is -C(O)-C 1-6 heteroalkyl, which is optionally substituted with one or more substituents Q. In certain embodiments, R 8a is -C(O)-C 2-6 alkenyl, which is optionally substituted with one or more substituents Q. In certain embodiments, R 8a is -C(O)-C 2-6 alkynyl, which is optionally substituted with one or more substituents Q. In certain embodiments, R 8a is -C(O)-C 3-10 cycloalkyl, which is optionally substituted with one or more substituents Q. In certain embodiments, R 8a is -C(O)-C 6-14 aryl, which is optionally substituted with one or more substituents Q. In certain embodiments, R 8a is benzoyl, which is optionally substituted with one or more substituents Q. In certain embodiments, R 8a is -C(O)-(bicyclic C 8-14 aryl), which is optionally substituted with one or more substituents Q. In certain embodiments, R 8a is -C(O)-C 7-15 aralkyl, which is optionally substituted with one or more substituents Q. In certain embodiments, R 8a is -C(O)-heteroaryl, which is optionally substituted with one or more substituents Q. In certain embodiments, R 8a is -C(O)-(monocyclic heteroaryl), which is optionally substituted with one or more substituents Q. In certain embodiments, R8a is -C(O)-(a 5- or 6-membered heteroaryl), each of which is optionally substituted by one or more substituents Q. In certain embodiments, R 8a is -C(O)-(a bicyclic heteroaryl), which is optionally substituted by one or more substituents Q. In certain embodiments, R 8a is -C(O)-(a 5,5-, 5,6- or 6,6-fused heteroaryl), each of which is optionally substituted by one or more substituents Q. In certain embodiments, R 8a is -C(O)-heterocyclyl, which is optionally substituted by one or more substituents Q. In certain embodiments, R 8a is -C(O)-monocyclic heterocyclyl, which is optionally substituted by one or more substituents Q. In certain embodiments, R 8a is -C(O)-(a 3-, 4-, 5-, 6- or 7-membered heterocyclyl), each of which is optionally substituted by one or more substituents Q. In certain embodiments, R 8a is -C(O)-bicyclic heterocyclyl, which is optionally substituted by one or more substituents Q. In certain embodiments, R 8a is -C(O)-(a bridged, fused or spiro heterocyclyl), each of which is optionally substituted by one or more substituents Q.

[0137] In certain embodiments, A is a bond. In certain embodiments, A is O. In certain embodiments, A is N(R 1b ), where R 1b is as defined herein. In certain embodiments, A is N(H).

[0138] In certain embodiments, E is hydrogen. In certain embodiments, E is azide. In certain embodiments, E is halogen. In certain embodiments, E is fluorine or iodine. In certain embodiments, E is fluorine. In certain embodiments, E is iodine. In certain embodiments, E is isocyano (-NC). In certain embodiments, E is -C=C(R 1a )R 1a , where R 1a are each as defined herein. In certain embodiments, E is -C=CH2. In certain embodiments, E is -C≡CR 1a , where R 1a is as defined herein. In certain embodiments, E is -C≡CH. In certain embodiments, E is where R 1a is as defined herein. In certain embodiments, E is In certain embodiments, E is In certain embodiments, E is In certain embodiments, E is wherein R 1a as defined herein. In certain embodiments, E is In certain embodiments, E is -C(O)R 1a wherein R 1a as defined herein. In certain embodiments, E is -C(O)CH3. In certain embodiments, E is -SH.

[0139] In certain embodiments, L is C 1-6 alkylene, optionally substituted with one or more substituents Q. In certain embodiments, L is methylene, 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 is C 1-6 heteroalkylene, optionally substituted with one or more substituents Q. In certain embodiments, L is C 2-6 alkenylene, optionally substituted with one or more substituents Q. In certain embodiments, L is C 2-6 alkynylene, optionally substituted with one or more substituents Q. In certain embodiments, L is C 3-10 cycloalkylene, optionally substituted with one or more substituents Q. In certain embodiments, L is C 6-14 arylene, optionally substituted with one or more substituents Q. In certain embodiments, L is C 7-15 aralkylene, optionally substituted with one or more substituents Q. In certain embodiments, L is heteroarylene, optionally substituted with one or more substituents Q. In certain embodiments, L is heterocycloalkylene, optionally substituted with one or more substituents Q.

[0140] In certain embodiments, U is a bond. In certain embodiments, U is N. In certain embodiments, U is CR 2a wherein R 2a as defined herein. In certain embodiments, U is CH. In certain embodiments, U is not CR 2a wherein R 2a as defined herein.

[0141] In certain embodiments, V is N. In certain embodiments, V is O. In certain embodiments, V is S. In certain embodiments, V is CR 2a wherein R 2a as defined herein. In certain embodiments, V is CH. In certain embodiments, V is NR 2b wherein R 2bAs defined herein. In certain embodiments, V is NR 2b , where R 2b is C 1-6 alkyl, which is optionally substituted with one or more substituents Q. In certain embodiments, V is NH or N(CH3). In certain embodiments, V is NH. In certain embodiments, V is N(CH3). In certain embodiments, V is not CR 2a , where R 2a is as defined herein.

[0142] In certain embodiments, X is N. In certain embodiments, X is O. In certain embodiments, X is S. In certain embodiments, X is CR 2a , where R 2a is as defined herein. In certain embodiments, X is CH. In certain embodiments, X is NR 2b , where R 2b is as defined herein. In certain embodiments, X is NR 2b , where R 2b is C 1-6 alkyl, which is optionally substituted with one or more substituents Q. In certain embodiments, X is NH or N(CH3). In certain embodiments, X is NH. In certain embodiments, X is N(CH3). In certain embodiments, X is not CR 2a , where R 2a is as defined herein.

[0143] In certain embodiments, Y is N. In certain embodiments, Y is O. In certain embodiments, Y is S. In certain embodiments, Y is CR 2a , where R 2a is as defined herein. In certain embodiments, Y is CH. In certain embodiments, Y is NR 2b , where R 2b is as defined herein. In certain embodiments, Y is NR 2b , where R 2b is C 1-6 alkyl, which is optionally substituted with one or more substituents Q. In certain embodiments, Y is NH or N(CH3). In certain embodiments, Y is NH. In certain embodiments, Y is N(CH3). In certain embodiments, Y is not CR 2a , where R 2a is as defined herein.

[0144] In certain embodiments, Z is N. In certain embodiments, Z is O. In certain embodiments, Z is S. In certain embodiments, Z is CR2a , wherein R 2a is as defined herein. In certain embodiments, Z is CH. In certain embodiments, Z is NR 2b , wherein R 2b is as defined herein. In certain embodiments, Z is NR 2b , wherein R 2b is C 1-6 alkyl, which is optionally substituted by one or more substituents Q. In certain embodiments, Z is NH or N(CH3). In certain embodiments, Y is NH. In certain embodiments, Z is N(CH3). In certain embodiments, Z is not CR 2a , wherein R 2a is as defined herein.

[0145] In certain embodiments, m is the integer 0. In certain embodiments, m is the integer 1. In certain embodiments, m is the integer 2. In certain embodiments, m is the integer 3. In certain embodiments, m is the integer 4.

[0146] In one embodiment, the present invention provides the following compounds: 1-O-(1-(imidazol-4-yl)-1-(4-(6-acetamido-2(S)-(benzyloxycarbonylamino)hexanamido)phenyl)methyl)-2-(2-azidoacetamido)-2-deoxy-3,4,6-tri-O-acetyl-D-mannopyranoside A1; 1-O-(1-(1-methylimidazol-4-yl)-1-(4-(6-acetamido-2(S)-(benzyloxycarbonylamino)hexanamido)phenyl)methyl)-2-(2-azidoacetamido)-2-deoxy-3,4,6-tri-O-acetyl-D-mannopyranoside A2; 1-O-(1-(thiazol-5-yl)-1-(4-(6-acetamido-2(S)-(benzyloxycarbonylamino)hexanamido)phenyl)methyl)-2-(2-azidoacetamido)-2-deoxy-3,4,6-tri-O-acetyl-D-mannopyranoside A3; 1-O-(1-(thiophen-2-yl)-1-(4-(6-acetamido-2(S)-(benzyloxycarbonylamino)hexanamido)phenyl)methyl)-2-(2-azidoacetamido)-2-deoxy-3,4,6-tri-O-acetyl-D-mannopyranoside A4; 1-O-(1-(thiophen-3-yl)-1-(4-(6-acetamido-2(S)-(benzyloxycarbonylamino)hexanamido)phenyl)methyl)-2-(2-azidoacetamido)-2-deoxy-3,4,6-tri-O-acetyl-D-mannopyranoside A5; 1-O-(1-(pyridin-3-yl)-1-(4-(6-acetamido-2(S)-(benzyloxycarbonyl)amino)hexanamido)phenyl)methyl)-2-(2-azidoacetamido)-2-deoxy-3,4,6-tri-O-acetyl-D-mannopyranoside A6; 1-O-(1-(pyridin-4-yl)-1-(4-(6-acetamido-2(S)-(benzyloxycarbonylamino)hexanamido)phenyl)methyl)-2-(2-azidoacetamido)-2-deoxy-3,4,6-tri-O-acetyl-D-mannopyranoside A7; 1-O-(1-(2-methylpyrazol-3-yl)-1-(4-(6-acetamido-2(S)-(benzyloxycarbonylamino)hexanamido)phenyl)methyl)-2-(2-azidoacetamido)-2-deoxy-3,4,6-tri-O-acetyl-D-mannopyranoside A8; 1-O-(1-(2-methylpyrazol-3-yl)-1-(4-(6-acetamido-2(S)-(benzyloxycarbonylamino)hexanamido)phenyl)methyl)-2-(2-azidoacetamido)-2-deoxy-3,4-di-O-acetyl-6-O-tetrahydropyran-4-ylcarbonyl-D-mannopyranoside A9; 1-O-(1-(2-methylpyrazol-3-yl)-1-(4-(6-acetamido-2(S)-(benzyloxycarbonylamino)hexanamido)phenyl)methyl)-2-(2-azidoacetamido)-2-deoxy-3,4-di-O-acetyl-6-O-(1-methylpiperidin-4-yl)carbonyl-D-mannopyranoside A10; 1-O-(1-(2-methylpyrazol-3-yl)-1-(4-(6-acetamido-2(S)-(benzyloxycarbonylamino)hexanamido)phenyl)methyl)-2-(2-azidoacetamido)-2-deoxy-3,4-di-O-acetyl-6-O-(pyrrolidin-1-ylacetyl)-D-mannopyranoside A11; 1-O-(1-(2-methylpyrazol-3-yl)-1-(4-(6-acetamido-2(S)-(benzyloxycarbonylamino)hexanamido)phenyl)methyl)-2-(2-azidoacetamido)-2-deoxy-3,4-di-O-acetyl-6-O-(pyridin-3-ylacetyl)-D-mannopyranoside A12; 1-O-(1-(2-methylpyrazol-3-yl)-1-(4-(6-acetamido-2(S)-(benzyloxycarbonylamino)hexanamido)phenyl)methyl)-2-(2-azidoacetamido)-2-deoxy-3,4-di-O-acetyl-6-O-(pyridin-3-ylcarbonyl)-D-mannopyranoside A13; 1-O-(1-(2-Methylpyrazol-3-yl)-1-(4-(2(S),6-diethylamidohexanamido)phenyl)methyl)-2-(2-azidoacetamido)-2-deoxy-3,4,6-tri-O-acetyl-D-mannopyranoside A14; 1-O-(1-(Thiazol-2-yl)-1-(4-(2(S),6-diethylamidohexanamido)phenyl)methyl)-2-(2-azidoacetamido)-2-deoxy-3,4,6-tri-O-acetyl-D-mannopyranoside A15; 1-O-(1-(Thiazol-5-yl)-1-(4-(2(S),6-diethylamidohexanamido)phenyl)methyl)-2-(2-azidoacetamido)-2-deoxy-3,4,6-tri-O-acetyl-D-mannopyranoside A16; 1-O-(1-(2-Methylpyrazol-3-yl)-1-(4-(2(S),6-diethylamidohexanamido)phenyl)methyl)-2-(2-azidoacetamido)-2-deoxy-3,4-di-O-acetyl-6-O-(pyridin-3-ylacetyl)-D-mannopyranoside A17; 1-O-(1-(2-Methylpyrazol-3-yl)-1-(4-(2(S),6-diethylamidohexanamido)phenyl)methyl)-2-(2-azidoacetamido)-2-deoxy-3,4-di-O-acetyl-6-O-(1-methylpiperidin-4-ylcarbonyl)-D-mannopyranoside A18; or 1-O-(1-(1-Methylimidazol-4-yl)-1-(4-(6-ethylamido-2(S)-(benzyloxycarbonylamino)hexanamido)phenyl)methyl)-2-deoxy-D-mannopyranoside A19; or its enantiomers, mixtures of enantiomers, diastereomers, mixtures of two or more diastereomers, tautomers, mixtures of two or more tautomers, or isotopic variants; or pharmaceutically acceptable salts, solvates, hydrates or prodrugs thereof.

[0147] In certain embodiments, the compounds provided herein are isolated or purified. In certain 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 certain embodiments, the compounds provided herein have a purity of at least about 90% by weight. In certain embodiments, the compounds provided herein have a purity of at least about 95% by weight. In certain embodiments, the compounds provided herein have a purity of at least about 98% by weight. In certain embodiments, the compounds provided herein have a purity of at least about 99% by weight. In certain embodiments, the compounds provided herein have a purity of at least about 99.5% by weight.

[0148] The compounds provided herein are intended to include all possible stereoisomers, unless a specific stereochemistry is specified. In the case where 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. Where structural isomers are interconvertible, the compounds may exist as a single tautomer or a mixture of tautomers. This may take the form of proton tautomerism in compounds containing, for example, imino, keto or oxime groups; or so-called valence tautomerism in compounds containing an aromatic moiety. Thus, a single compound may exhibit more than one type of isomerism.

[0149] The compounds provided herein may be enantiomerically pure, for example, a single enantiomer or a single diastereomer, or a stereoisomeric mixture, for example, a mixture of enantiomers, for example, a racemic mixture of two enantiomers; or a mixture of more than two diastereomers. Thus, one of ordinary skill in the art will recognize that for compounds that undergo epimerization in vivo, administering the compound in its (R) form is equivalent to administering the compound in its (S) form. Conventional techniques for preparing / isolating individual enantiomers include synthesis from a suitable optically pure precursor, asymmetric synthesis from achiral starting materials or resolution of enantiomeric mixtures, for example, chiral chromatography, recrystallization, resolution, formation of diastereomeric salts, or derivatization to form diastereomeric adducts followed by separation.

[0150] When the compounds provided herein contain acidic or basic moieties, they may also be provided as pharmaceutically acceptable salts. See, Berge et al., J. Pharm. Sci. 1977, 66, 1-19; Handbook of Pharmaceutical Salts: Properties, Selection, and Use, 2nd Edition; edited by Stahl and Wermuth; John Wiley & Sons, 2011. In certain embodiments, the pharmaceutically acceptable salts of the compounds provided herein are solvates. In certain embodiments, the pharmaceutically acceptable salts of the compounds provided herein are hydrates.

[0151] Suitable acids for preparing the pharmaceutically acceptable salts of the compounds provided herein include, but are not limited to, 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, dodecylsulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid, D-gluconic acid, D-glucuronic acid, L-glutamic acid, α-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-aminosalicylic acid, sebacic acid, stearic acid, succinic acid, sulfuric acid, tannic acid, (+)-L-tartaric acid, thiocyanic acid, p-toluenesulfonic acid, undecylenic acid, and valeric acid.

[0152] Suitable bases for preparing the pharmaceutically acceptable salts of the compounds provided herein include, but are not limited to, inorganic bases such as magnesium hydroxide, calcium hydroxide, potassium hydroxide, zinc hydroxide, and sodium hydroxide; and organic bases such as primary, secondary, tertiary, and quaternary, aliphatic and aromatic amines including, but not limited to, L-arginine, phenylethylbenzylamine, benzathine, choline, deanol, diethanolamine, diethylamine, dimethylamine, dipropylamine, diisopropylamine, 2-(diethylamino)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.

[0153] The compounds provided herein may also be provided as prodrugs, which are functional derivatives of the compounds and are readily convertible in vivo to the parent compound. Prodrugs are generally useful because in some instances they may be more readily administered than the parent compound. For example, they may be bioavailable when administered orally while the parent compound is not. Prodrugs may also have improved solubility in pharmaceutical compositions compared to the parent compound. Prodrugs can be converted to the parent drug by a variety of mechanisms including enzymatic processes and metabolic hydrolysis. Pharmaceutical compositions

[0154] In one embodiment, provided herein are pharmaceutical compositions 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.

[0155] The pharmaceutical compositions provided herein can be formulated into various dosage forms, including but not limited to dosage forms for oral, parenteral, and topical administration. The pharmaceutical compositions can also be formulated into modified-release dosage forms, including delayed release, sustained release, extended release, continuous release, pulsatile release, controlled release, accelerated release, rapid release, targeted release, programmed release, and gastric retention dosage forms. These dosage forms can be prepared according to conventional methods and techniques known to those skilled in the art. See, for example, Remington: The Science and Practice of Pharmacy, supra; Modified-Release Drug Delivery Technology, 2nd Edition; Rathbone et al., eds.; Drugs and the Pharmaceutical Sciences 184; CRC Press; Boca Raton; FL, 2008.

[0156] In one embodiment, the pharmaceutical compositions provided herein are formulated into a dosage form for oral administration. In another embodiment, the pharmaceutical compositions provided herein are formulated into a dosage form for parenteral administration. In yet another embodiment, the pharmaceutical compositions provided herein are formulated into a dosage form for intravenous administration. In yet another embodiment, the pharmaceutical compositions provided herein are formulated into a dosage form for intramuscular administration. In yet another embodiment, the pharmaceutical compositions provided herein are formulated into a dosage form for subcutaneous administration. In yet another embodiment, the pharmaceutical compositions provided herein are formulated into a dosage form for topical administration.

[0157] The pharmaceutical compositions provided herein can be provided in unit dosage forms or multiple dosage forms. As used herein, a unit dosage form refers to a physically discrete unit suitable for administration to a subject and individually packaged as known in the art. Each unit dose contains a predetermined amount of the active ingredient (e.g., the compounds provided herein) and the required pharmaceutical excipients, which are sufficient to produce the desired therapeutic effect. Examples of unit dosage forms include but are not limited to ampoules, syringes, and individually packaged tablets and capsules. The unit dosage form can be administered in part or in multiple portions. A multiple dosage form is a plurality of identical unit dosage forms packaged in a single container and administered as separate unit dosage forms. Examples of multiple dosage forms include but are not limited to vials, bottles of tablets or capsules, or pint or gallon bottles.

[0158] The pharmaceutical compositions provided herein can be administered once or multiple times at time intervals. It should be understood that the exact dosage and duration of treatment can vary depending on the age, weight, and condition of the subject being treated, and can be determined empirically using known test protocols or by extrapolation from in vivo or in vitro test or diagnostic data. It should be further 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. A. Oral administration

[0159] 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 administration, lingual administration and sublingual administration. Suitable oral dosage forms include, but are not limited to, tablets, fastmelts, chewable tablets, capsules, pills, strips, troches, lozenges, pastilles, cachets, pellets, medicated chewing gum, powders, effervescent or non-effervescent powders or granules, oral mists, solutions, emulsions, suspensions, wafers, granule sprinkles, elixirs and syrups. In addition to the active ingredient, the pharmaceutical compositions can contain one or more pharmaceutically acceptable carriers or excipients, including but not limited to binders, fillers, diluents, disintegrants, wetting agents, lubricants, glidants, colorants, dye migration inhibitors, sweeteners, flavorants, emulsifying agents, suspending and dispersing agents, preservatives, solvents, non-aqueous liquids, organic acids and carbon dioxide sources.

[0160] Binders or granulating agents impart cohesiveness to tablets to ensure that the tablets remain intact after compression. Suitable binders or granulating agents include, but are not limited to, starches such as corn starch, potato starch and pregelatinized starch (e.g., ); gelatin; sugars such as sucrose, glucose, dextrose, molasses and lactose; natural and synthetic gums such as gum arabic, alginic acid, alginates, Irish moss extract, Panwar gum, Ghatti gum, mucilage of isabgol husk, carboxymethyl cellulose, methyl cellulose, polyvinylpyrrolidone (PVP), larch arabinogalactan, powdered tragacanth and guar gum; celluloses such as ethyl cellulose, cellulose acetate, calcium carboxymethyl cellulose, sodium carboxymethyl cellulose, methyl cellulose, hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC), hydroxypropyl methyl cellulose (HPMC); and microcrystalline cellulose such as, and Suitable fillers include, but are not limited to, talc, calcium carbonate, microcrystalline cellulose, powdered cellulose, dextrin, kaolin, mannitol, silicic acid, sorbitol, starch and pregelatinized starch. The amount of binder or filler in the pharmaceutical compositions provided herein varies according to the type of formulation and can be readily discerned by one of ordinary skill in the art. The binder or filler can be present in the pharmaceutical compositions provided herein in an amount of about 50 to about 99% by weight.

[0161] 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 (e.g., mannitol, lactose, sorbitol, sucrose, and inositol) when present in sufficient amounts can impart to some compressed tablets the property of permitting disintegration 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 to one of ordinary skill in the art.

[0162] Suitable disintegrants include, but are not limited to, agar; bentonite; cellulose, e.g., methylcellulose and carboxymethylcellulose; wood products; natural sponges; cation exchange resins; alginic acid; gums, e.g., guar gum and HV; citrus pulp; cross-linked cellulose, e.g., cross-linked carboxymethylcellulose; cross-linked polymers, e.g., cross-linked povidone; cross-linked starch; calcium carbonate; microcrystalline cellulose, e.g., sodium starch glycolate; polacrilin potassium; starch, e.g., corn starch, potato starch, tapioca starch, and pregelatinized starch; clays; and algins. The amount of disintegrant in the pharmaceutical compositions provided herein varies depending on the type of formulation and is readily discernible to one of ordinary skill in the art. The pharmaceutical compositions provided herein may contain from about 0.5 to about 15% or from about 1 to about 5% by weight of the disintegrant.

[0163] Suitable lubricants include, but are not limited to, calcium stearate; magnesium stearate; mineral oil; light mineral oil; glycerin; sorbitol; mannitol; glycols, e.g., glyceryl behenate and polyethylene glycol (PEG); stearic acid; sodium lauryl sulfate; talc; hydrogenated vegetable oils, e.g., 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 gel, such as 200 and The amount of lubricant in the pharmaceutical compositions provided herein varies depending on the type of formulation and is readily discernible to one of ordinary skill in the art. The pharmaceutical compositions provided herein may contain from about 0.1 to about 5% by weight of the lubricant.

[0164] Suitable glidants include, but are not limited to, colloidal silica, And asbestos-free talc. Suitable colorants include, but are not limited to, any approved and certified water-soluble FD&C dyes and water-insoluble FD&C dyes suspended on hydrated alumina, as well as lakes. Lakes are combinations produced by adsorbing water-soluble dyes onto hydrated oxides of heavy metals, resulting in insoluble forms of the dyes. Suitable flavoring agents include, but are not limited to, natural flavoring agents extracted from plants (e.g., fruits), and synthetic admixtures of compounds that produce a pleasant taste sensation, such as, peppermint and methyl salicylate. Suitable sweeteners include, but are not limited to, sucrose, lactose, mannitol, syrups, glycerol, and artificial sweeteners, such as, saccharin and aspartame. Suitable emulsifiers include, but are not limited to, gelatin, gum arabic, tragacanth, bentonite, and surfactants, such as, polyoxyethylene sorbitan monooleate Polyoxyethylene sorbitan monooleate 80 And triethanolamine oleate. Suitable suspending and dispersing agents include, but are not limited to, sodium carboxymethyl cellulose, pectin, tragacanth, Gum arabic, sodium carboxymethyl cellulose, hydroxypropyl methyl cellulose, and polyvinylpyrrolidone. Suitable preservatives include, but are not limited to, glycerol, methyl paraben, propyl paraben, benzoic acid additives, and sodium benzoate and alcohols. 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, glycerol, sorbitol, ethanol, and syrups. Suitable non-aqueous liquids used 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.

[0165] It should be understood that many carriers and excipients can perform several functions, even in the same formulation.

[0166] The pharmaceutical compositions for oral administration provided herein can be provided as compressed tablets, tablet triturates, chewable lozenges, rapidly dissolving tablets, multi-compressed tablets or enteric-coated tablets, sugar-coated tablets or film-coated tablets. Enteric-coated tablets are compressed tablets coated with a material that resists the action of gastric acid but dissolves or disintegrates in the intestine, thereby 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 coated with a sugar coating, which can be beneficial for covering 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, hydroxyethyl cellulose, sodium carboxymethyl cellulose, polyethylene glycol 4000, and cellulose acetate phthalate. Film coatings impart the same general characteristics as sugar coatings. Multi-compressed tablets are compressed tablets made by more than one pressing cycle, including layered tablets and compressed-coated tablets or dry-coated tablets.

[0167] Tablet dosage forms can be prepared from the active ingredient in powder, crystalline or granular form, alone or in combination with one or more of the carriers or excipients described herein, including binders, disintegrants, controlled-release polymers, lubricants, diluents, and / or colorants. Flavoring agents and sweetening agents are particularly suitable for forming chewable tablets and lozenges.

[0168] The pharmaceutical compositions for oral administration provided herein can be provided as soft or hard capsules, which can be made of gelatin, methylcellulose, starch, or calcium alginate. Hard gelatin capsules, also known as dry-filled capsules (DFC), consist of two parts that slide over one another, thereby completely enclosing the active ingredient. Soft elastic capsules (SEC) are soft, spherical shells, e.g., gelatin shells, which are plasticized by the addition of glycerol, sorbitol, or similar polyols. Soft gelatin shells can contain preservatives to prevent microbial growth. Suitable preservatives are those described herein, including methyl paraben, propyl paraben, and sorbic acid. The liquid, semi-solid, and solid dosage forms provided herein can be encapsulated in capsules. Suitable liquid and semi-solid dosage forms include solutions and suspensions in propylene carbonate, vegetable oils, or triglycerides. Capsules containing such solutions can be prepared as described in U.S. Patent Nos. 4,328,245, 4,409,239, and 4,410,545. As known to those skilled in the art, capsules can also be coated to modify or maintain the dissolution of the active ingredient.

[0169] The pharmaceutical compositions for oral administration provided herein can be provided in liquid and semi-solid dosage forms, including emulsions, solutions, suspensions, elixirs, and syrups. An emulsion is a two-phase system in which one liquid is dispersed throughout in the form of small droplets in another liquid, which can be oil-in-water or water-in-oil. Emulsions can include pharmaceutically acceptable non-aqueous liquids or solvents, emulsifying agents, and preservatives. Suspensions can include pharmaceutically acceptable suspending agents and preservatives. Aqueous alcoholic solutions can include pharmaceutically acceptable acetals, such as bis(lower alkyl) acetals of lower alkyl aldehydes, such as acetaldehyde diethyl acetal; and water-miscible solvents having one or more hydroxyl groups, such as propylene glycol and ethanol. Elixirs are clear, sweetened, and hydroalcoholic solutions. Syrups are concentrated aqueous solutions of sugars (e.g., sucrose) and can also contain preservatives. For liquid dosage forms, for example, solutions in polyethylene glycol can be diluted with a sufficient amount of pharmaceutically acceptable liquid carrier (e.g., water) for ease of measurement for administration.

[0170] Other useful liquid and semi-solid dosage forms include, but are not limited to, dosage forms containing an active ingredient and a dialkylated monoalkylene glycol or polyalkylene glycol, including 1,2-dimethoxymethane, diethylene glycol dimethyl ether, triethylene glycol dimethyl ether, tetraethylene glycol dimethyl ether, polyethylene glycol-350-dimethyl ether, polyethylene glycol-550-dimethyl ether, polyethylene glycol-750-dimethyl ether, where 350, 550, and 750 refer to the approximate average molecular weight of the polyethylene glycol. These dosage forms can further include one or more antioxidants, such as butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), propyl gallate, vitamin E, hydroquinone, hydroxycoumarins, ethanolamine, lecithin, cephalin, ascorbic acid, malic acid, sorbitol, phosphoric acid, bisulfite, sodium metabisulfite, thiodipropionic acid and its esters, and dithiocarbamates / esters.

[0171] The pharmaceutical compositions for oral administration provided herein can also be provided in the form of liposomes, micelles, microspheres, or nano-systems. Micelle dosage forms can be prepared as described in U.S. Patent No. 6,350,458.

[0172] The pharmaceutical compositions for oral administration provided herein can be provided as non-effervescent or effervescent granules and powders for reconstitution into liquid dosage forms. Pharmaceutically acceptable carriers and excipients for non-effervescent granules or powders can include diluents, sweeteners, and wetting agents. Pharmaceutically acceptable carriers and excipients for effervescent granules or powders can include organic acids and a source of carbon dioxide.

[0173] Colorants and flavoring agents can be used in all dosage forms described herein.

[0174] The pharmaceutical compositions provided herein for oral administration can be formulated into immediate release or modified release dosage forms, including delayed release, sustained release, pulsatile release, controlled release, targeted release, and programmed release forms. B. Parenteral administration

[0175] The pharmaceutical compositions provided herein can be administered parenterally by injection, infusion, or implantation 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.

[0176] 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, suspension bases, emulsions, micelles, liposomes, microspheres, and nanosystems) and solid forms suitable for forming a solution or suspension in a liquid before 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.

[0177] The pharmaceutical compositions provided herein for parenteral administration can include one or more pharmaceutically acceptable carriers and excipients, including but not limited to aqueous media, water-miscible media, non-aqueous media, antimicrobial agents or preservatives against microbial growth, stabilizers, solubilizers, isotonic agents, buffers, antioxidants, local anesthetics, suspending and dispersing agents, wetting or emulsifying agents, complexing agents, masking or chelating agents, cryoprotectants, lyoprotectants, thickening agents, pH regulators, and inert gases.

[0178] Suitable aqueous media include but are not limited to water, saline, physiological saline or phosphate buffered saline (PBS), sodium chloride injection, Ringer's injection, isotonic dextrose injection, sterile water for injection, and dextrose and lactated Ringer's injection. Suitable non-aqueous media 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, medium-chain triglycerides of coconut oil, and palm oil. Suitable water-miscible media include but are not limited to ethanol, 1,3-butanediol, liquid polyethylene glycols (e.g., polyethylene glycol 300 and polyethylene glycol 400), propylene glycol, glycerol, N-methyl-2-pyrrolidone, N,N-dimethylacetamide, and dimethyl sulfoxide.

[0179] Suitable antimicrobial agents or preservatives include, but are not limited to, phenols, cresols, mercurials, benzyl alcohol, chlorobutanol, methylparaben and propylparaben, thimerosal, benzalkonium chloride (e.g., benzethonium chloride), methylparaben and methylpropylparaben, and sorbic acid. Suitable isotonic 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, e.g., bisulfite and sodium metabisulfite. Suitable local anesthetics include, but are not limited to, procaine hydrochloride. Suitable suspending and dispersing agents include those described herein, e.g., sodium carboxymethyl cellulose, hydroxypropylmethyl cellulose, and polyvinylpyrrolidone. Suitable emulsifying agents include those described herein, e.g., polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan monooleate 80, and triethanolamine oleate. Suitable masking agents or chelating agents include, but are not limited to, EDTA. Suitable pH adjusters 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, sulfobutyl ether-β-cyclodextrin, and sulfobutyl ether-7-β-cyclodextrin

[0180] When the pharmaceutical compositions provided herein are formulated for multi-dose administration, multi-dose parenteral formulations must contain an antimicrobial agent in bacteriostatic or fungistatic concentration. As is known and practiced in the art, all parenteral formulations must be sterile.

[0181] 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 freeze-dried powder and subcutaneous tablets) and reconstituted with a vehicle prior to 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 and reconstituted with a vehicle prior to use. In still another embodiment, the pharmaceutical composition is provided as a ready-to-use sterile emulsion.

[0182] The pharmaceutical compositions for parenteral administration provided herein can be formulated in immediate-release or modified-release dosage forms, including delayed-release, sustained-release, pulsatile-release, controlled-release, targeted-release, and programmed-release forms.

[0183] The pharmaceutical compositions for parenteral administration provided herein can be formulated as a suspension, solid, semi-solid, or thixotropic liquid for administration as an implant depot. In one embodiment, the pharmaceutical composition provided herein is dispersed within a solid internal matrix surrounded by an outer polymeric membrane that is insoluble in body fluids but permits diffusion of the active ingredient in the pharmaceutical composition therethrough.

[0184] Suitable internal matrices include, but are not limited to, polymethyl methacrylate, polybutyl methacrylate, plasticized or unplasticized polyvinyl chloride, plasticized nylon, plasticized polyethylene terephthalate, natural rubber, polyisoprene, polyisobutene, polybutadiene, polyethylene, ethylene-vinyl acetate copolymer, silicone rubber, polydimethylsiloxane, silicone carbonate copolymer, hydrophilic polymers (e.g., hydrogels of esters of acrylic acid and methacrylic acid), collagen, cross-linked polyvinyl alcohol, and cross-linked partially hydrolyzed polyvinyl acetate.

[0185] Suitable external polymer membranes include, but are not limited to, polyethylene, polypropylene, ethylene / propylene copolymer, ethylene / ethyl acrylate copolymer, ethylene / vinyl acetate copolymer, silicone rubber, polydimethylsiloxane, chloroprene rubber, chlorinated polyethylene, polyvinyl chloride, copolymers of vinyl chloride with vinyl acetate, vinylidene chloride, ethylene, and propylene, ionomeric polyethylene terephthalate, butyl rubber, epichlorohydrin rubber, ethylene / vinyl alcohol copolymer, ethylene / vinyl acetate / vinyl alcohol terpolymer, and ethylene / ethylene oxyethanol copolymer. C. Topical administration

[0186] The pharmaceutical compositions provided herein can be topically administered to the skin, orifice, or mucosa. As used herein, topical administration includes dermal (intradermal), conjunctival, intracorneal, intraocular, ocular, otic, transdermal, nasal, vaginal, urethral, respiratory, and rectal administration.

[0187] The pharmaceutical compositions provided herein can be formulated into any dosage form suitable for topical administration to achieve local or systemic effects, including but not limited to emulsions, solutions, suspensions, creams, gels, hydrogels, ointments, powders, dressings, elixirs, lotions, suspensions, tinctures, pastes, foams, films, aerosols, rinses, sprays, suppositories, bandages, and skin patches. The topical formulations of the pharmaceutical compositions provided herein may also include liposomes, micelles, microspheres, and nanosystems.

[0188] 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, solubilizers, isotonic agents, buffers, antioxidants, local anesthetics, suspending and dispersing agents, wetting or emulsifying agents, complexing agents, masking or chelating agents, penetration enhancers, cryoprotectants, lyoprotectants, thickening agents, and inert gases.

[0189] The pharmaceutical compositions can also be topically administered by electroporation, iontophoresis, sonophoresis, sonophoresis, or micro-needle or needleless injection (e.g., POWDERJECT TM and BIOJECT TM ).

[0190] The pharmaceutical compositions provided herein may be provided in the form of ointments, creams, and gels. Suitable ointment vehicles include oily or hydrocarbon vehicles, including lard, hydrogenated lard, olive oil, cottonseed oil, and other oils, white petrolatum; emulsifiable or absorbent vehicles, such as hydrophilic petrolatum, hydroxy stearin sulfate, and anhydrous lanolin; water removable vehicles, such as hydrophilic ointment; water-soluble ointment vehicles, including polyethylene glycols of different molecular weights; emulsion vehicles, water-in-oil (W / O) emulsions or oil-in-water (O / W) emulsions, including cetyl alcohol, glycerol monostearate, lanolin, and stearic acid. See, e.g., Remington: The Science and Practice of Pharmacy, supra. These vehicles have emollient effects, but generally require the addition of antioxidants and preservatives.

[0191] Suitable cream bases may be oil-in-water or water-in-oil. Suitable cream vehicles may be washable and comprise an oil phase, an emulsifier, and an aqueous phase. The oil phase is also referred to as the "internal" phase and generally includes petrolatum and fatty alcohols (e.g., cetyl alcohol or stearyl alcohol). The aqueous phase generally (but not necessarily) exceeds the oil phase in volume and generally contains a humectant. The emulsifier in a cream formulation may be a nonionic surfactant, anionic surfactant, cationic surfactant, or amphoteric surfactant.

[0192] A gel is a semi-solid, suspension-type system. A single-phase gel contains organic macromolecules substantially uniformly distributed in a liquid carrier. Suitable gelling agents include, but are not limited to, cross-linked acrylic polymers, such as carbomers, carboxyalkylenes, and hydrophilic polymers, such as polyethylene oxide, polyoxyethylene-polyoxypropylene copolymers, and polyvinyl alcohol; cellulose polymers, such as hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl methyl cellulose phthalate, and methyl cellulose; gums, such as tragacanth and xanthan gum; sodium alginate; and gelatin. To prepare a homogeneous gel, a dispersant (e.g., alcohol or glycerol) may be added, or the gelling agent may be dispersed by trituration, mechanical mixing, and / or agitation.

[0193] The pharmaceutical compositions provided herein may be administered rectally, urethrally, vaginally, or perivaginally in the form of suppositories, pessaries, bougies, cataplasms, pastes, powders, dressings, creams, plasters, contraceptives, ointments, solutions, emulsions, suspensions, tampons, gels, foams, sprays, or enemas. These dosage forms may be manufactured using conventional procedures as described in Remington: The Science and Practice of Pharmacy (supra).

[0194] Rectal, urethral, and vaginal suppositories are solid objects for insertion into body orifices, which are solid at room temperature but melt or soften at body temperature to release the active ingredient within the orifice. Pharmaceutically acceptable carriers used in rectal and vaginal suppositories include a base or vehicle, e.g., a hardening agent which, when formulated with the active ingredient, produces 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), glycerol-gelatin, carbowax (polyethylene glycol), cetyl alcohol, paraffin wax, white and yellow waxes, and suitable mixtures of mono-, di-, and triglycerides of fatty acids, as well as hydrogels, e.g., polyvinyl alcohol, hydroxyethyl methacrylate, and polyacrylic acid. Combinations of various vehicles may also be used. Rectal and vaginal suppositories can be prepared by compression or molding. The typical weight of rectal and vaginal suppositories is about 2 to about 3 g.

[0195] The pharmaceutical compositions provided herein can be administered ophthalmically in the form of solutions, suspensions, ointments, emulsions, gel-forming solutions, powders for solution, gels, ocular inserts, and implants.

[0196] The pharmaceutical compositions provided herein can be administered intranasally or by inhalation to the respiratory tract. The pharmaceutical compositions can be provided in the form of an aerosol or a solution for use with a pressurized container, pump, nebulizer, atomizer (e.g., an atomizer that produces a fine mist using electrohydrodynamics), or nebulizer alone or in combination with a suitable propellant (e.g., 1,1,1,2-tetrafluoroethane or 1,1,1,2,3,3,3-heptafluoropropane). The pharmaceutical compositions can also be provided as a dry powder for insufflation alone or in combination with an inert carrier (e.g., lactose or phospholipid); and as nasal drops. For intranasal use, the powder can include bioadhesives (including chitosan or cyclodextrin).

[0197] Solutions or suspensions formulated for use with a pressurized container, pump, nebulizer, atomizer, or nebulizer contain ethanol, aqueous ethanol, or a suitable alternative reagent for dispersing, dissolving, or retarding the release of the active ingredient; a propellant as a solvent; and / or a surfactant, e.g., sorbitan trioleate, oleic acid, or oligolactic acid.

[0198] The pharmaceutical compositions provided herein can be micronized to a size suitable for delivery by inhalation, e.g., about 50 microns or less, or about 10 microns or less. Particles of such size can be prepared using comminution methods known to those skilled in the art, e.g., spiral jet milling, fluidized bed jet milling, supercritical fluid processing to form nanoparticles, high pressure homogenization, or spray drying.

[0199] Capsules, blisters, and cartridges for use in inhalers or insufflators can be formulated to contain a powder mixture comprising: the pharmaceutical compositions provided herein; a suitable powder matrix (e.g., lactose or starch); and a performance modifier (e.g., l-leucine, mannitol, or magnesium stearate). Lactose can be anhydrous or in the form of the 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 inhaled / intranasal administration provided herein can further include a suitable flavorant, e.g., menthol and levomenthol; and / or a sweetener, e.g., saccharin and sodium saccharin.

[0200] The pharmaceutical compositions for topical administration provided herein can be formulated as immediate release or modified release, including delayed release, sustained release, pulsatile release, controlled release, targeted release, and programmed release. D. Modified Release

[0201] The pharmaceutical compositions provided herein can be formulated to be provided in a modified release dosage form. As used herein, the term "modified release" refers to a dosage form in which the rate or location of release of the active ingredient is different 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, retarded release, extended release, sustained release, pulsatile release, controlled release, accelerated release, rapid release, targeted release, programmed release, and gastric retention dosage forms. A variety of modified release devices and methods known to those of skill in the art can be used to prepare the pharmaceutical compositions in modified release dosage forms, including, but not limited to, matrix controlled release devices, osmotic controlled release devices, multi-particulate controlled release devices, ion exchange resins, enteric coatings, multi-layer coatings, microspheres, liposomes, and combinations thereof. The release rate of the active ingredient can also be altered by changing the particle size and polymorphic form of the active ingredient. 1. Matrix Controlled Release Devices

[0202] The pharmaceutical compositions of the modified release dosage forms provided herein can be made using matrix controlled release devices known to those of skill in the art. See, e.g., Takada et al., in Encyclopedia of Controlled Drug Delivery, Mathiowitz, ed.; Wiley, 1999; vol. 2.

[0203] In certain embodiments, the pharmaceutical compositions of the modified release dosage forms provided herein are formulated using an erodible matrix device, which is a water-swellable, erodible, or soluble polymer, including, but not limited to, synthetic polymers and naturally occurring polymers and derivatives, e.g., polysaccharides and proteins.

[0204] Materials that can be used to form an erodible matrix include, but are not limited to, chitin, chitosan, dextran, and pullulan; agarose, gum arabic, gum karaya, locust bean gum, tragacanth gum, carrageenan, ghatti gum, guar gum, xanthan gum, and scleroglucan; starches, such as dextrin and maltodextrin; hydrocolloids, such as pectin; phospholipids, such as lecithin; alginates; propylene glycol alginate; gelatin; collagen; cellulosic materials, such as ethylcellulose (EC), methyl ethylcellulose (MEC), carboxymethylcellulose (CMC), CMEC, hydroxyethylcellulose (HEC), hydroxypropylcellulose (HPC), cellulose acetate (CA), cellulose propionate (CP), cellulose butyrate (CB), cellulose acetate butyrate (CAB), CAP, CAT, hydroxypropylmethylcellulose (HPMC), HPMCP, HPMCAS, hydroxypropyl methyl cellulose acetate trimellitate (HPMCAT), and ethyl hydroxyethylcellulose (EHEC); polyvinylpyrrolidone; polyvinyl alcohol; polyvinyl acetate; fatty acid glycerides; polyacrylamide; polyacrylic acid; copolymers of ethyl acrylate or methyl acrylate Poly(2-hydroxyethyl methacrylate); polylactic acid; copolymers of L-glutamic acid and L-glutamic acid ethyl ester; biodegradable lactic acid-glycolic acid copolymers; poly-D-(-)-3-hydroxybutyric acid; and other acrylic derivatives, such as homopolymers and copolymers of butyl methacrylate, methyl methacrylate, ethyl methacrylate, ethyl acrylate, (2-dimethylaminoethyl) methacrylate, and (trimethylaminoethyl) methacrylate chloride.

[0205] In certain embodiments, the pharmaceutical compositions provided herein are formulated with non-erosive matrix devices. The active ingredient is dissolved or dispersed in an inert matrix and, upon administration, is released primarily by diffusion through the inert matrix. Materials suitable for use as non-erosive 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, copolymers of vinyl chloride with vinyl acetate, vinylidene chloride, ethylene and propylene, ionomeric polyethylene terephthalate, butyl rubber, epichlorohydrin rubber, ethylene / vinyl alcohol copolymer, ethylene / vinyl acetate / vinyl alcohol terpolymer, ethylene / ethyleneoxyethanol 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, crosslinked povidone, and crosslinked partially hydrolyzed polyvinyl acetate; and fatty compounds such as carnauba wax, microcrystalline wax, and triglycerides.

[0206] 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, the ratio of the active ingredient to the polymer, and other excipients or carriers in the composition.

[0207] The pharmaceutical compositions of the modified release dosage forms 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. 2. Osmotic-controlled release devices

[0208] The pharmaceutical compositions of the modified release dosage forms provided herein can be made using osmotic-controlled release devices, including but not limited to single-chamber systems, double-chamber systems, asymmetric membrane technology (AMT), and extruding core systems (ECS). Generally, such devices have at least two components: (a) a core containing the active ingredient; and (b) a semipermeable membrane having at least one delivery port that encapsulates the core. The semipermeable membrane controls the flow of water from the aqueous environment used into the core, thereby releasing the drug by extrusion through the delivery port.

[0209] In addition to the active ingredient, the core of the osmotic device optionally includes an osmotic agent that creates a driving force for transporting water from the use environment into the core of the device. One class of osmotic agents are water-swellable hydrophilic polymers, which are also referred to as "osmotic polymers" and "hydrogels". Water-swellable hydrophilic polymers suitable as osmotic agents include, but are not limited to, hydrophilic vinyl and acrylic polymers, polysaccharides (e.g., calcium alginate), poly(ethylene oxide) (PEO), poly(ethylene glycol) (PEG), poly(propylene 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 having hydrophobic monomers (e.g., methyl methacrylate and vinyl acetate), hydrophilic polyurethanes containing large PEO blocks, crosslinked sodium carboxymethylcellulose, 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.

[0210] Another class of osmotic agents are osmotically active agents that are capable of absorbing water to affect the osmotic pressure gradient across the surrounding coating barrier. Suitable osmotically active agents 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.

[0211] Osmotic agents with different dissolution rates can be employed to affect the rate at which the active ingredient is initially delivered from the dosage form. For example, the use of amorphous sugars (e.g., MANNOGEM TM EZ) can provide a faster delivery during the initial hours, thereby rapidly producing the desired therapeutic effect and gradually and continuously releasing the remaining amount to maintain the desired level of therapeutic or prophylactic effect over a prolonged period. In such cases, the active ingredient is released at a rate that replaces the metabolized and excreted active ingredient.

[0212] The core may also include a wide variety of other excipients and carriers as described herein to enhance the performance of the dosage form or to facilitate stability or processing.

[0213] Materials for forming the semipermeable membrane include various grades of acrylics, vinyls, ethers, polyamides, polyesters, and cellulose derivatives that are water-permeable and water-insoluble at physiologically relevant pHs or are readily rendered water-insoluble by chemical changes (e.g., crosslinking). Examples of suitable polymers for forming coatings include plasticized, unplasticized, and reinforced cellulose acetate (CA), diacetate cellulose, triacetate cellulose, CA propionate, cellulose nitrate, cellulose acetate butyrate (CAB), CA urethane, CAP, CA methylcarbamate, CA succinate, cellulose acetate trimellitate (CAT), CA dimethylaminoacetate, CA ethyl carbonate, CA chloroacetate, CA ethyl oxalate, CA methylsulfonate, CA butylsulfonate, CA tosylate, agar acetate, amylose triacetate, β-glucan acetate, β-glucan triacetate, glyoxal dimethylacetate, locust bean gum triacetate, 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 their copolymers, starch, dextran, dextrin, chitosan, collagen, gelatin, polyolefins, polyethers, polysulfones, polyethersulfones, polystyrene, polyvinyl halides, polyvinyl esters and ethers, natural waxes, and synthetic waxes.

[0214] The semipermeable membrane can also be a hydrophobic microporous membrane in which the pores are substantially filled with gas and are not wetted by an aqueous medium but are permeable to water vapor, as disclosed in U.S. Patent No. 5,798,119. Such hydrophobic but water vapor-permeable membranes typically consist of hydrophobic polymers such as polyolefins, polyethylene, polypropylene, polytetrafluoroethylene, polyacrylic acid derivatives, polyethers, polysulfones, polyethersulfones, polystyrene, polyvinyl halides, polyvinylidene fluoride, polyvinyl esters and ethers, natural waxes, and synthetic waxes.

[0215] Delivery ports on the semipermeable membrane can be formed by mechanical drilling or laser drilling after coating. Delivery ports can also be formed in situ by eroding a plug of a water-soluble material or by rupturing a thinner portion of the membrane over a notch in the core. Additionally, delivery ports can be formed during the coating process, as in the case of asymmetric membrane coatings of the type disclosed in U.S. Patent Nos. 5,612,059 and 5,698,220.

[0216] The total amount and release rate of the released active ingredient can be substantially regulated by the thickness and porosity of the semipermeable membrane, the composition of the core, and the number, size, and location of the delivery ports.

[0217] Additional conventional excipients or carriers as described herein may further be included in the pharmaceutical compositions of the osmotic controlled release dosage forms to facilitate the performance or processing of the formulations.

[0218] Osmotic controlled release dosage forms can be prepared according to conventional methods and techniques known to those skilled in the art. See, e.g., 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.

[0219] In certain embodiments, the pharmaceutical compositions provided herein are formulated as AMT controlled release dosage forms, which include an asymmetric osmotic membrane coating a core comprising the active ingredient and other pharmaceutically acceptable excipients or carriers. See, e.g., U.S. Patent No. 5,612,059 and WO 2002 / 17918. AMT controlled release dosage forms can be prepared according to conventional methods and techniques known to those skilled in the art, including direct compression, dry granulation, wet granulation, and dip coating methods.

[0220] In certain embodiments, the pharmaceutical compositions provided herein are formulated as ESC controlled release dosage forms, which include an osmotic membrane coating a core comprising the active ingredient, hydroxyethyl cellulose, and other pharmaceutically acceptable excipients or carriers. 3. Multi-Particulate Controlled Release Devices

[0221] The pharmaceutical compositions provided herein in a modulated release dosage form can be fabricated as a multi-particulate controlled release device, which includes a plurality of particles, granules or pellets having a diameter ranging 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 multi-particulates can be manufactured by methods known to those skilled in the art, including wet and dry granulation, extrusion / spheronization, roller-compaction, melt congealing, and spray-coating seed cores. See, e.g., 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.

[0222] Other excipients or carriers as described herein can be mixed with the pharmaceutical composition to assist in processing and forming the multi-particulates. The resultant particles themselves can constitute the multi-particulate device, or can be coated with various film-forming materials (e.g., enteric polymers, water-swellable and water-soluble polymers). The multi-particulates can be further processed into capsules or tablets. 4. Targeted Delivery

[0223] The pharmaceutical compositions provided herein can also be formulated for targeted delivery to a specific tissue, receptor, or other region of the body of a subject to be treated, including liposome-based, resealed erythrocyte, and antibody-based delivery systems. Examples include, but are not limited to, those disclosed in 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; 6,048,736; 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. Methods of Use

[0225] In one embodiment, provided herein is a method of labeling cells with an azide group in a subject, the method comprising administering to a subject in need thereof an effective amount of a compound provided herein, for example, 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.

[0225] In another embodiment, provided herein is a method of labeling the cell surface with an azide group in a subject, the method comprising administering to a subject in need thereof an effective amount of a compound provided herein, for example, 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.

[0226] In certain embodiments, the subject is a mammal. In certain embodiments, the subject is a human.

[0227] In certain embodiments, the cells are cancer cells.

[0228] In certain embodiments, the effective amount of the compound provided herein ranges from about 0.1 to about 100 mg / kg / day, from about 0.1 to about 50 mg / kg / day, from about 0.1 to about 25 mg / kg / day, from about 0.1 to about 20 mg / kg / day, from about 0.1 to about 15 mg / kg / day, from about 0.1 to about 10 mg / kg / day, or from about 0.1 to about 5 mg / kg / day. In one embodiment, the effective amount of the compound provided herein ranges from about 0.1 to about 100 mg / kg / day. In another embodiment, the effective amount of the compound provided herein ranges from about 0.1 to about 50 mg / kg / day. In yet another embodiment, the effective amount of the compound provided herein ranges from about 0.1 to about 25 mg / kg / day. In yet another embodiment, the effective amount of the compound provided herein ranges from about 0.1 to about 20 mg / kg / day. In yet another embodiment, the effective amount of the compound provided herein ranges from about 0.1 to about 15 mg / kg / day. In yet another embodiment, the effective amount of the compound provided herein ranges from about 0.1 to about 10 mg / kg / day. In still another embodiment, the effective amount of the compound provided herein ranges from about 0.1 to about 5 mg / kg / day.

[0229] In certain embodiments, the effective amount of the compounds provided herein ranges from about 1 to about 1000 mg per day, from about 1 to about 500 mg per day, from about 1 to about 200 mg per day, or from about 1 to about 100 mg per day. In one embodiment, the effective amount of the compounds provided herein ranges from about 1 to about 1000 mg per day. In another embodiment, the effective amount of the compounds provided herein ranges from about 1 to about 500 mg per day. In yet another embodiment, the effective amount of the compounds provided herein ranges from about 1 to about 200 mg per day. In still another embodiment, the effective amount of the compounds provided herein ranges from about 1 to about 100 mg per day.

[0230] Depending on the disorder, disease or condition to be treated and the condition of the subject, the compounds provided herein can be administered by the following routes of administration: oral, parenteral (e.g., intramuscular, intraperitoneal, intravenous, CIV, intracisternal injection or infusion, subcutaneous injection, or implantation), inhalation, nasal, vaginal, rectal, sublingual, or topical (e.g., transdermal or topical). The compounds provided herein can be formulated with pharmaceutically acceptable excipients, carriers, adjuvants or vehicles into appropriate dosage units suitable for each route of administration.

[0231] 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 still another embodiment, the compounds provided herein are administered by topical infusion.

[0232] The compounds provided herein can be delivered as a single dose, e.g., a single bolus injection, or an oral tablet or pill; or over time, e.g., by continuous infusion over time or by fractionated bolus doses over time. If necessary, the compounds provided herein can be administered repeatedly, e.g., until the subject shows disease stabilization or regression, or until the subject experiences disease progression or unacceptable toxicity.

[0233] The compounds provided herein can be administered once daily (QD), or divided into multiple daily doses, e.g., twice daily (BID) and three times daily (TID). In addition, the administration can be continuous, i.e., daily or intermittent. As used herein, the terms "intermittent" or "intermittently" are intended to mean stopping and starting at regular or irregular intervals. For example, intermittent administration of the compounds provided herein is administration one to six days per week, cyclic administration (e.g., daily administration for two to eight consecutive weeks, followed by a rest period of up to one week without administration), or alternate day administration.

[0234] The compounds provided herein can also be used in combination or conjunction with therapeutic agents for treating and / or preventing the conditions, disorders or diseases provided herein.

[0235] As used herein, the term "combination" includes the use of more than one therapy (e.g., one or more prophylactic agents and / or therapeutic agents). However, the use of the term "combination" does not limit the order in which the therapies (e.g., prophylactic agents and / or therapeutic agents) are administered to a subject having a condition, disorder or disease. The first therapy (e.g., a prophylactic agent or a therapeutic agent such as a compound provided herein) can be administered before (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), simultaneously with, or after (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) the administration of the second therapy (e.g., a prophylactic agent or a therapeutic agent) to the subject. Triple therapy is also contemplated herein.

[0236] The route of administration of the compounds provided herein is not relevant to the route of administration of the second therapy. In one embodiment, the compounds provided herein are administered orally. In another embodiment, the compounds provided herein are administered intravenously. In another embodiment, the compounds provided herein are administered topically. Thus, according to these embodiments, the compounds provided herein are administered orally, intravenously or topically, and the second therapy can be administered orally, parenterally, intraperitoneally, intravenously, intraarterially, transdermally, sublingually, intramuscularly, rectally, buccally, intranasally, liposomally, by inhalation, vaginally, intravitreally, locally via a catheter or a stent, subcutaneously, intradermally, intraarticularly, intrathecally, topically or in a sustained release formulation. In one embodiment, the compounds provided herein and the second therapy are administered by the same route of administration (topically). In another embodiment, the compounds provided herein are administered by one route of administration (e.g., topically), while the second agent (anticancer agent) is administered by another route of administration (e.g., orally).

[0237] In one embodiment, provided herein is a method of labeling a cell with an azide group, the method comprising contacting the cell with an effective amount of a compound provided herein, such as a compound of formula (I), or an enantiomer, a mixture of enantiomers, a diastereomer, a mixture of more than two diastereomers, a tautomer, a mixture of more than two tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof.

[0238] In another embodiment, provided herein are methods for labeling the cell surface with an azide group, the methods comprising contacting the cells with an effective amount of a compound provided herein, such as 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.

[0239] In certain embodiments, the cells are cancer cells.

[0240] The compounds provided herein may also be provided as articles using packaging materials well known to those skilled in the art. See, for example, U.S. Patent Nos. 5,525,907; 5,052,558 and 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 the intended mode of administration and treatment.

[0241] In certain embodiments, provided herein are kits that, when used by a medical practitioner, can simplify the administration of an appropriate amount of a compound provided herein as an active ingredient to a subject. In certain embodiments, the kits provided herein include a container and a dosage form of a compound provided herein.

[0242] The kits provided herein may further include a device for administering 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 a condom for administering the active ingredient.

[0243] The kits provided herein may 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 may 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 ethanol, 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.

[0244] The present disclosure will be further understood by the following non-limiting examples. Examples

[0245] As used herein, the symbols and conventions used in these procedures, schematic diagrams, and examples, whether a particular abbreviation is specifically defined or not, are consistent with those used in contemporary scientific literature (e.g., Journal of the American Chemical Society, Journal of Medicinal Chemistry, or Journal of Biological Chemistry). Specifically, but not limited to, the following abbreviations may be used in the examples and throughout the specification: g (gram); mg (milligram); mL (milliliter); μL (microliter); mM (millimole); μM (micromole); mmol (millimole); min (minute); h (hour); Ac (acetyl); ACN (acetonitrile); n-BuLi (n-butyllithium); Cbz (benzyloxycarbonyl); DBU (1,8-diazabicyclo[5.4.0]undec-7-ene); DCE (1,2-dichloroethane); DCM (dichloromethane); DIEA or DIPEA (N,N-diisopropylethylamine); DMAP (4-dimethylaminopyridine); DMF (N,N-dimethylformamide); DMSO (dimethyl sulfoxide); EDCI (1-ethyl-3-(3-dimethylaminopropyl)carbodiimide); EEDQ (N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline); EtMgCl (ethylmagnesium chloride); EtOAc (ethyl acetate); EtOH (ethanol); Et2O (diethyl ether); HOPO (2-hydroxypyridine N-oxide); MeOH (methanol); PE (petroleum ether); TBME (tert-butyl methyl ether); TEA (triethylamine); TfOH (trifluoromethanesulfonic acid); THF (tetrahydrofuran); TMEDA (N,N,N',N'-tetramethylethylenediamine); TMSI (trimethylsilyl iodide); TMSOTf (trimethylsilyl trifluoromethanesulfonate); TPPO (triphenylphosphine oxide); MS (mass spectrometry); NMR (nuclear magnetic resonance); and prep-HPLC (preparative high performance liquid chromatography).

[0246] For all of the following examples, standard processing and purification methods known to those skilled in the art may be utilized. Unless otherwise indicated, all temperatures are expressed in °C (degrees Celsius). Unless otherwise specified, all reactions are carried out at room temperature. The synthetic methodologies described herein are intended to illustrate applicable chemical methods by using specific examples and do not represent the scope of the present disclosure. Example 1 1-O-(1-(imidazol-4-yl)-1-(4-(6-acetamido-2(S)-(benzyloxycarbonylamino)hexanamido)phenyl)methyl)-2-(2-azidoacetamido)-2-deoxy-3,4,6-tri-O-acetyl-D-mannopyranoside Preparation of A1

[0247] Compound A1 was prepared as shown in Scheme 1.

[0248] Preparation of 1-O-(2,2,2-trichloro-1-iminoethyl)-2-(2-azidoacetamido)-2-deoxy-3,4,6-tri-O-acetyl-D-mannopyranoside 1.2. DBU (1.96 g, 1.29 mmol), molecular sieve (50 mg), and Cl3CN (1.80 g, 12.9 mmol) were added to a solution of 2-(2-azidoacetamido)-2-deoxy-3,4,6-tri-O-acetyl-D-mannopyranoside (500 mg, 1.29 mmol) in THF (5 mL). After stirring for 1 h at room temperature, the reaction mixture was purified by silica gel chromatography (eluting with EtOAc in PE) to give compound 1.2 (350 mg) in 50% yield. 1 H NMR (400 MHz, CDCl3) δ 8.80 (s, 1H), 6.60 (d, J = 7.2 Hz, 1H), 6.24 - 5.28 (m, 3H), 4.23 - 4.04 (m, 5H), 2.14 - 1.98 (m, 9H).

[0249] Preparation of 4-iodo-N,N-dimethyl-1H-imidazole-1-sulfonamide 1.3. Under N2, NaH (60% dispersed in mineral oil, 1.23 g, 31 mmol) was added portionwise to a solution of 4-iodo-1H-imidazole (5 g, 25 mmol) in DMF (40 mL) at 0 °C. After stirring the mixture for 30 min at 0 °C, dimethylaminosulfonyl chloride (4.07 g, 28 mmol) was added. The reaction was stirred at room temperature for 8 h and then quenched with water. The reaction mixture was extracted with EtOAc. The combined organic layers were washed with water and brine and concentrated to give the crude product, which was purified by silica gel column chromatography (eluting with EtOAc in PE) to give compound 1.3 (6.1 g) in 81% yield. MS (ESI) m / z: 301.1 [M+H] + 。

[0250] Preparation of 4-(hydroxy(4-nitrophenyl)methyl)-N,N-dimethyl-1H-imidazole-1-sulfonamide 1.4. Under N2, EtMgCl (1 M in THF, 9.3 mL, 9.3 mmol) was added dropwise to a solution of compound 1.3 (2.55 g, 8.5 mmol) in THF (30 mL) at 0 °C. After stirring the mixture at 0 °C for 0.5 h, 4-nitrobenzaldehyde (1.41 g, 9.3 mmol) was added portionwise at 0 °C. The reaction mixture was heated to room temperature and then stirred overnight. The reaction was quenched with NH4Cl (a.q.) and the reaction mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to obtain the crude product, which was purified by silica gel column chromatography (eluting with MeOH in DCM) to give compound 1.4 (1.4 g) in 50% yield. MS (ESI) m / z: 327.0 [M+H] + 。

[0251] Preparation of 4-((4-aminophenyl)(hydroxy)methyl)-N,N-dimethyl-1H-imidazole-1-sulfonamide 1.5. 10% Pd / C (w / w, 84 mg) was added to a solution of compound 1.4 (280 mg, 0.86 mmol) in MeOH (5 mL). After stirring for 16 h at room temperature and H2, the reaction mixture was filtered and concentrated under reduced pressure to give compound 1.5 (150 mg) in 59% yield. MS (ESI) m / z: 297.1 [M+H] + 。

[0252] Preparation of benzyl ((2S)-6-acetamido-1-((4-((1-(N,N-dimethylaminosulfonyl)-1H-imidazol-4-yl)(hydroxy)methyl)phenyl)amino)-1-oxohexan-2-yl)carbamate 1.7. EEDQ (734 mg, 2.97 mmol) was added to a solution of compound 1.5 (800 mg, 2.7 mmol) and N 6 -acetyl-N 2 -((benzyloxy)carbonyl)-L-lysine 1.6 (869 mg, 2.7 mmol) in 1,4-dioxane (4 mL) and EtOH (4 mL) at room temperature. After stirring for 16 h at room temperature, the reaction mixture was concentrated under reduced pressure to obtain the crude product, which was purified by reverse phase flash chromatography (eluting with ACN in H2O) to give compound 1.7 (850 mg) in 52% yield. MS (ESI) m / z: 601.3 [M+H] + 。

[0253] Preparation of 1-O-(1-(imidazol-4-yl)-1-(4-(6-acetamido-2(S)-(benzyloxycarbonylamino)hexanamido)phenyl)methyl)-2-(2-azidoacetamido)-2-deoxy-3,4,6-tri-O-acetyl-D-mannopyranoside A1. TMSOTf (76 mg, 0.34 mmol) was added dropwise to a mixture of compound 1.2 (106 mg, 0.20 mmol), compound 1.7 (100 mg, 0.17 mmol) and molecular sieve (100 mg) in THF (3 mL) at 0 °C. After stirring at room temperature for 15 min, the reaction mixture was purified by silica gel column chromatography (eluting with MeOH in DCM) to give compound A1 (37 mg) in 14% yield. 1 H NMR (400 MHz, CD3OD) δ 10.05 (s, 1H), 7.91 - 7.55 (m, 3H), 7.44 - 7.27 (m, 8H), 6.35 - 5.73 (m, 2H), 5.27 - 5.03 (m, 4H), 4.81 - 4.80 (m, 1H), 4.61 - 4.59 (m, 1H), 4.45 - 4.18 (m, 2H), 4.10 - 3.92 (m, 1H), 3.78 - 3.52 (m, 2H), 3.16 - 3.12 (m, 2H), 2.21 - 2.15 (m, 9H), 2.03 (s, 3H), 1.99 - 1.89 (m, 2H), 1.52 - 1.51 (m, 4H); MS (ESI) m / z: 864.5 [M + H] + . Example 2 Preparation of 1-O-(1-(1-methylimidazol-4-yl)-1-(4-(6-acetamido-2(S)-(benzyloxycarbonylamino)hexanamido)phenyl)methyl)-2-(2-azidoacetamido)-2-deoxy-3,4,6-tri-O-acetyl-D-mannopyranoside A2

[0254] Compound A2 was prepared as shown in Scheme 2.

[0255] Preparation of benzyl (S)-(6-acetamido-1-((4-formylphenyl)amino)-1-oxohexan-2-yl)carbamate 2.1. Compound 2.1 was prepared in a manner similar to that described for compound 1.7 in Example 1. MS (ESI) m / z: 426.1 [M + H] + .

[0256] Preparation of benzyl ((2S)-6-acetamido-1-((4-(hydroxy(1-methyl-1H-imidazol-4-yl)methyl)phenyl)amino)-1-oxohexan-2-yl)carbamate 2.2. Compound 2.2 was prepared in a manner similar to that described for compound 1.4 in Example 1. MS(ESI) m / z: 508.6 [M+H] + .

[0257] Preparation of 1-O-(1-(1-methylimidazol-4-yl)-1-(4-(6-acetamido-2(S)-(benzyloxycarbonylamino)hexanamido)phenyl)methyl)-2-(2-azidoacetamido)-2-deoxy-3,4,6-tri-O-acetyl-D-mannopyranoside A2. To a mixture of compound 1.1 (50 mg, 0.155 mmol) and compound 2.2 (45.8 mg, 0.118 mmol) in DCE (7 mL) at 0 °C under N2 was added dropwise BF3·Et2O (300 mg, 0.985 mmol). After stirring at 0 °C for 10 min and then at room temperature for 2 h, the reaction mixture was purified by reverse-phase flash chromatography (eluting with ACN in H2O) and further purified by reverse-phase prep-HPLC to give compound A2 (17 mg) in 10% yield. 1 H NMR (400 MHz, DMSO-d6) δ 10.24 - 10.06 (m, 1H), 9.01 (d, J = 20.6 Hz, 1H), 8.43 - 8.05 (m, 1H), 7.81 (t, J = 5.3 Hz, 1H), 7.74 - 7.54 (m, 3H), 7.53 - 6.95 (m, 8H), 5.96 - 5.76 (m, 1H), 5.34 - 4.85 (m, 4H), 4.68 - 4.41 (m, 1H), 4.27 - 4.02 (m, 3H), 4.02 - 3.69 (m, 7H), 2.99 (d, J = 5.7 Hz, 2H), 2.12 - 1.86 (m, 9H), 1.76 (s, 3H), 1.62 (s, 2H), 1.46 - 1.26 (m, 4H); MS(ESI) m / z: 878.5 [M+H] + . Example 3 1-O-(1-(thiazol-5-yl)-1-(4-(6-acetamido-2(S)-(benzyloxycarbonylamino)hexanamido)phenyl)methyl)-2-(2-azidoacetamido)-2-deoxy-3,4,6-tri-O-acetyl-D-mannopyranoside Preparation of A3

[0258] Compound A3 was prepared as shown in Scheme 3. Scheme 3

[0259] Preparation of 1-O-(2,2,2-trifluoro-N-(2-methoxyphenyl)ethanimidoyl)-2-(2-azidoacetamido)-2-deoxy-3,4,6-tri-O-acetyl-D-mannopyranoside 3.1. Compound 3.1 was prepared in a manner similar to that described for compound 4.1 in Example 4. 1 H NMR (500 MHz, CDCl3) δ 7.13 - 7.05 (m, 1H), 6.94 - 6.85 (m, 2H), 6.84 - 6.76 (m, 1H), 6.62 (dd, J = 62.7, 9.2 Hz, 1H), 6.29 - 6.00 (m, 1H), 5.44 - 5.14 (m, 2H), 5.13 - 4.83 (m, 2H), 4.28 (dd, J = 12.5, 4.0 Hz, 1H), 4.20 - 4.00 (m, 3H), 3.83 - 3.73 (m, 3H), 2.26 - 1.81 (m, 9H).

[0260] Preparation of (2-chlorothiazol-5-yl)(4-nitrophenyl)methanol 3.2. Under N2, n-BuLi (1 M, in hexane, 99.4 mL, 99.4 mmol) was added dropwise to a solution of 2-chlorothiazole (11.9 g, 99.4 mmol) in THF (150 mL) at -78 °C. After stirring the mixture at -78 °C for 1 h, 4-nitrobenzaldehyde (15 g, 99.4 mmol) was added portionwise at -78 °C. The reaction mixture was heated to room temperature and stirred overnight. The reaction was quenched with NH4Cl (a.q.), and then the reaction mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give a crude product, which was purified by silica gel column chromatography (eluting with EtOAc in PE) to give compound 3.2 (16 g) in 60% yield. 1 H NMR (400 MHz, DMSO-d6) δ 8.24 (d, J = 8.8 Hz, 2H), 7.71 (d, J = 8.8 Hz, 2H), 7.54 (s, 1H), 6.89 (d, J = 4.4 Hz, 1H), 6.19 (d, J = 4.4 Hz, 1H); MS (ESI) m / z: 270.9 [M + H] + 。

[0261] (4-Aminophenyl)(2-chlorothiazol-5-yl)methanol 3.3 Preparation. At room temperature, Fe (16.5 g, 295 mmol) and NH4Cl (15.9 g, 295 mmol) were added to a suspension of compound 3.2 (10 g, 36.9 mmol) in EtOH (80 mL) and H2O (16 mL). After stirring at 55 °C for 2 h, the reaction mixture was filtered, diluted with NH4Cl (a.q.), and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product, which was purified by silica gel column chromatography (eluted with EtOAc in PE) to give compound 3.3 (7 g) in 60% yield. MS (ESI) m / z: 240.9 [M+H] + 。

[0262] (4-Aminophenyl)(thiazol-5-yl)methanol 3.4 Preparation. 10% Pd / C (1.40 g) and K2CO3 (4.03 g, 29.2 mmol) were added to a solution of compound 3.3 (7 g, 29.2 mmol) in EtOH (70 mL) at 55 °C. After stirring overnight under H2, the reaction mixture was filtered and concentrated under reduced pressure to obtain the crude product, which was purified by silica gel column chromatography (eluted with MeOH in DCM) to give compound 3.4 (4.5 g) in 75% yield. 1 H NMR (400 MHz, DMSO-d6) δ 8.93 (s, 1H), 7.60 (s, 1H), 7.03 (d, J = 8.4 Hz, 2H), 6.52 (d, J = 8.4 Hz, 2H), 6.03 (d, J = 4.4 Hz, 1H), 5.83 (d, J = 4.4 Hz, 1H), 5.03 (s, 2H); MS (ESI) m / z: 207.0 [M+H] + 。

[0263] Preparation of benzyl ((2S)-6-acetamido-1-((4-(hydroxy(thiazol-5-yl)methyl)phenyl)amino)-1-oxohexan-2-yl)carbamate 3.5. Compound 3.1 (7.02 g, 21.8 mmol), HOPO (2.66 g, 24 mmol), EDCI (4.58 g, 24.0 mmol) and DIPEA (8.44 g, 65.4 mmol) were added to a solution of compound 3.4 (4.5 g, 21.8 mmol) in DMF (45 mL) at room temperature. After stirring at room temperature for 16 h, the reaction was quenched with NH4Cl (a.q.) and the reaction mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure to give the crude product, which was purified by reverse-phase flash chromatography (eluting with ACN in H2O) to give compound 3.5 (3.1 g) in 28% yield. 1 HNMR (400 MHz, DMSO-d6) δ 10.03 (s, 1H), 8.98 (s, 1H), 8.11 (t, J = 1.6 Hz, 1H), 7.55 (s, 1H), 7.54 - 7.35 (m, 3H), 7.35 - 7.32 (m, 7H), 5.99 (s, 1H), 5.02 (s, 2H), 4.13 - 4.11 (s, 1H), 2.99 (t, J = 2.4 Hz, 2H), 1.76 (s, 3H), 1.65 - 1.37 (m, 2H), 1.36 - 1.26 (m, 4H); MS (ESI) m / z: 511.7 [M+H] + 。

[0264] Preparation of 1-O-(1-(thiazol-5-yl)-1-(4-(6-acetamido-2(S)-(benzyloxycarbonylamino)hexanamido)phenyl)methyl)-2-(2-azidoacetamido)-2-deoxy-3,4,6-tri-O-acetyl-D-mannopyranoside A3. To a mixture of compound 3.5 (86.5 mg, 0.17 mmol) and molecular sieve (150 mg) in anhydrous 1,4-dioxane (3 mL) at room temperature and N2 was added TfOH (102 mg, 0.68 mmol), and then a solution of compound 3.1 (300 mg, 0.51 mmol) in anhydrous 1,4-dioxane (1.5 mL) was added dropwise at 0 °C over 30 min. After stirring at room temperature and N2 for 12 h, the reaction mixture was purified by reverse-phase prep-HPLC to give compound A3 (61 mg) in 40% yield. 11H NMR (400 MHz, DMSO-d6) δ 10.27 (s, 1H), 10.13 (d, J = 4.4 Hz, 1H), 8.62 - 8.27 (m, 2H), 7.71 - 7.55 (m, 2H), 7.48 - 7.16 (m, 7H), 6.31 (dd, J = 8.4, 4.0 Hz, 1H), 6.11 (d, J = 3.6 Hz, 1H), 5.25 - 4.94 (m, 4H), 4.86 - 4.73 (m, 1H), 4.52 - 4.46 (m, 2H), 4.29 (t, J = 8.0 Hz, 1H), 4.20 - 4.03 (m, 1H), 3.90 - 3.59 (m, 2H), 3.51 - 3.45 (m, 2H), 3.02 - 2.95 (m, 2H), 2.22 - 2.07 (m, 6H), 2.06 - 1.93 (m, 3H), 1.77 (s, 3H), 1.70 - 1.56 (m, 2H), 1.46 - 1.26 (m, 4H); MS (ESI) m / z: 881.3 [M+H] + 。 Example 4 1 - O - (1 - (thiophen-2-yl)-1-(4-(6-acetamido-2(S)-(benzyloxycarbonylamino)hexanamido)phenyl)methyl)-2-(2-azidoacetamido)-2-deoxy-3,4,6-tri-O-acetyl-D-mannopyranoside Preparation of A4

[0265] Compound A4 was prepared as shown in Scheme 4.

[0266] Preparation of 1 - O-(2,2,2-trifluoro-N-phenylethanimidoyl)-2-(2-azidoacetamido)-2-deoxy-3,4,6-tri-O-acetyl-D-mannopyranoside 4.1. K2CO3 (1.60 g, 12.0 mmol) was added to a mixture of compound 1.1 (2.32 g, 6 mmol) and molecular sieve in THF (30 mL), and then 2,2,2-trifluoro-N-phenylethanimidoyl chloride (2.4 g, 12 mmol) in THF (30 mL) was added under N2. After stirring the mixture at room temperature for 2 h, DBU (30 drops) was added, and the reaction mixture was stirred at room temperature for 1 h. Then the reaction mixture was filtered and concentrated under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography (eluting with EtOAc in PE) to give compound 4.1 (1.8 g) in 51% yield. 11H NMR (400 MHz, DMSO-d6) δ 8.60 - 8.48 (m, 1H), 7.38 - 7.34 (m, 2H), 7.16 - 7.12 (m, 1H), 6.88 (d, J = 7.2 Hz, 1H), 5.29 - 4.75 (m, 3H), 4.25 - 4.19 (m, 1H), 4.08 - 3.85 (m, 4H), 2.08 - 1.94 (m, 9H).

[0267] Preparation of (4-nitrophenyl)(thiophen-2-yl)methanol 4.2. Under N2, n-BuLi (1 mol / L in hexane, 69.8 mL, 69.8 mmol) was added dropwise to a solution of 2-bromothiophene (10.8 g, 66.5 mmol) in THF (100 mL) at -78 °C. After stirring the mixture at -78 °C for 1 h, 4-nitrobenzaldehyde (10 g, 66.2 mmol) was added portionwise at -78 °C, and the reaction mixture was heated to room temperature and stirred overnight. Then, the reaction was quenched with NH4Cl (a.q.) and the reaction mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product, which was purified by silica gel column chromatography (eluting with EtOAc in PE) to give compound 4.2 (10 g) in a yield of 64%.

[0268] Preparation of (4-aminophenyl)(thiophen-2-yl)methanol 4.3. At 0 °C, NiCl2·6H2O (10.1 g, 42.6 mmol) was added to a suspension of compound 4.2 (10 g, 42.6 mmol) in MeOH (100 mL), and then NaBH4 (4.84 g, 128 mmol) was added. After stirring at 0 °C for 2 h, the reaction mixture was filtered, diluted with NH4Cl (a.q.), and then extracted with EtOAc. The organic layers were combined, washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product, which was purified by reverse-phase flash chromatography (eluting with ACN in H2O) to give compound 4.3 (6.5 g) in a yield of 75%.

[0269] Preparation of benzyl ((2S)-6-acetamido-1-((4-(hydroxy(thiophen-2-yl)methyl)phenyl)amino)-1-oxohexan-2-yl)carbamate 4.4. Compound 4.4 was prepared in a manner similar to that described for compound 3.5 in Example 3. MS (ESI) m / z: 532.3 [M+Na] + 。

[0270] Preparation of 1-O-(1-(thiophen-2-yl)-1-(4-(6-acetamido-2(S)-(benzyloxycarbonylamino)hexanamido)phenyl)methyl)-2-(2-azidoacetamido)-2-deoxy-3,4,6-tri-O-acetyl-D-mannopyranoside A4. TMSI (110 mg, 0.55 mmol) was added to a mixture of compound 4.1 (461 mg, 0.825 mmol), compound 4.4 (140 mg, 0.28 mmol), triphenylphosphine oxide (306 mg, 1.10 mmol) and molecular sieve (400 mg) in anhydrous DCM (12.0 mL). After stirring at room temperature for 12 h, the reaction mixture was filtered and concentrated under reduced pressure to obtain a crude product, which was purified by reverse phase prep-HPLC to give compound A4 (21 mg) in 8% yield. 1 H NMR (400 MHz, DMSO-d6) δ 10.01 (d, J = 9.6 Hz, 1H), 7.79 (m, 1H), 7.54 (m, 3H), 7.43 - 7.11 (m, 8H), 6.95 - 6.87 (m, 1H), 6.73 (dd, J = 60.4, 2.8 Hz, 1H), 6.07 (dd, J = 180.4, 3.2 Hz, 1H), 5.22 - 5.02 (m, 4H), 4.91 - 4.81 (m, 1H), 4.35 - 4.23 (m, 2H), 4.17 - 4.03 (m, 3H), 3.95 - 3.89 (m, 1H), 3.04 - 2.76 (m, 4H), 2.11 - 2.01 (m, 3H), 1.99 - 1.95 (m, 6H), 1.76 (s, 3H), 1.63 - 1.60 (m, 2H), 1.38 - 1.26 (m, 4H); MS (ESI) m / z: 902.4 [M+Na] + . Example 5 Preparation of 1-O-(1-(2-methylpyrazol-3-yl)-1-(4-(6-acetamido-2(S)-(benzyloxycarbonylamino)hexanamido)phenyl)methyl)-2-(2-azidoacetamido)-2-deoxy-3,4,6-tri-O-acetyl-D-mannopyranoside A8

[0271] Compound A8 was prepared as shown in Scheme 5.

[0272] (1-Methyl-1H-pyrazol-5-yl)(4-nitrophenyl)methanone 5.1 Preparation. Under N2, n-BuLi (2.5 M, 53.6 mL, 134 mmol) in THF was added dropwise to a solution of 1-methyl-1H-pyrazole (10 g, 122 mmol) and TMEDA (14.4 g, 122 mmol) in THF (200 mL) at -70 °C. After stirring the mixture at -70 °C for 1 h, 4-nitrobenzaldehyde (18.4 g, 122 mmol) was added portionwise at -70 °C. The reaction mixture was heated to room temperature and stirred overnight. Then, the reaction was quenched with saturated NH4Cl (aq.) and extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give a crude product, which was purified by silica gel column chromatography (eluting with EtOAc in PE) to afford compound 5.1 (6 g) in 21% yield. MS (ESI) m / z: 232.0 [M+H] + .

[0273] (4-Aminophenyl)(1-methyl-1H-pyrazol-5-yl)methanone 5.2 Preparation. Compound 5.2 was prepared in a manner similar to that described for compound 3.3 in Example 3. 1 H NMR (400 MHz, DMSO-d6) δ 7.65 (d, J = 8.8 Hz, 2H), 7.53 (d, J = 2.0 Hz, 1H), 6.67 - 6.61 (m, 3H), 6.26 (brs, 2H), 3.97 (s, 3H); MS (ESI) m / z: 202.0 [M+H] + .

[0274] (4-Aminophenyl)(1-methyl-1H-pyrazol-5-yl)methanol 5.3 Preparation. NaBH4 (0.75 g, 19.9 mmol) was added portionwise to a solution of compound 5.2 (2 g, 9.95 mmol) in MeOH (35 mL) at 0 °C. After stirring overnight at room temperature, the reaction was quenched with saturated NH4Cl (aq.) and the reaction mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to give a crude product, which was purified by silica gel column chromatography (eluting with EtOAc in PE) to afford compound 5.3 (1.38 g) in 68% yield. 1HNMR (400 MHz, DMSO-d6) δ 7.24 (s, 1H), 6.98 (d, J = 8.4 Hz, 2H), 6.52 (d, J = 8.4 Hz, 2H), 5.93 (s, 1H), 5.70 (d, J = 4.8 Hz, 1H), 5.63 (d, J = 4.8 Hz, 1H), 5.00 (s, 2H), 3.66 (s, 3H); MS (ESI) m / z: 204.0 [M+H] + 。

[0275] Preparation of benzyl ((2S)-6-acetamido-1-((4-(hydroxy(1-methyl-1H-pyrazol-5-yl)methyl)phenyl)amino)-1-oxohexan-2-yl)carbamate 5.4. Compound 5.4 was prepared in a manner similar to that described for compound 1.7 in Example 1. 1 H NMR (400 MHz, DMSO-d6) δ 10.02 (s, 1H), 7.79 (s, 1H), 7.55 (m, 3H), 7.43 - 7.10 (m, 8H), 6.01 (d, J = 4.8 Hz, 1H), 5.89 (s, 1H), 5.80 (d, J = 4.8 Hz, 1H), 5.03 (s, 2H), 4.20 - 4.05 (m, 1H), 3.72 (s, 3H), 3.10 - 2.90 (m, 2H), 1.76 (s, 3H), 1.70 - 1.52 (m, 2H), 1.39 - 1.29 (m, 4H); MS (ESI) m / z: 508.3 [M+H] + 。

[0276] Preparation of 1-O-(1-(2-methylpyrazol-3-yl)-1-(4-(6-acetamido-2(S)-(benzyloxycarbonylamino)hexanamido)phenyl)methyl)-2-(2-azidoacetamido)-2-deoxy-3,4,6-tri-O-acetyl-D-mannopyranoside A8. Compound A8 was prepared in a manner similar to that described for compound A1 in Example 1. 11H NMR (400 MHz, DMSO-d6) δ 10.13 - 10.02 (m, 1H), 8.96 - 8.70 (m, 2H), 7.79 (t, J = 5.6 Hz, 1H), 7.65 - 7.56 (m, 3H), 7.35 - 7.25 (m, 7H), 6.93 (dd, J = 2.8 Hz, 2.8 Hz, 1H), 6.45 - 5.8 (m, 2H), 5.34 - 5.11 (m, 2H), 5.02 (s, 2H), 4.39 - 4.36 (m, 1H), 4.24 - 3.71 (m, 9H), 2.99 (d, J = 5.6 Hz, 2H), 2.11 - 1.88 (m, 9H), 1.76 (s, 3H), 1.63 - 1.28 (m, 6H); MS (ESI) m / z: 878.4 [M + H] + 。 Example 6 Preparation of 1-O-(1-(2-methylpyrazol-3-yl)-1-(4-(6-acetamido-2(S)-(benzyloxycarbonylamino)hexanamido)phenyl)methyl)-2-(2-azidoacetamido)-2-deoxy-3,4-di-O-acetyl-6-O-tetrahydropyran-4-ylcarbonyl-D-mannopyranoside A9

[0277] Compound A9 was prepared as shown in Scheme 6.

[0278] Preparation of 2-(2-azidoacetamido)-2-deoxy-1,3,4-tri-O-acetyl-6-O-tetrahydropyran-4-ylcarbonyl-D-mannopyranoside 6.2. EDCI (7.42 g, 38.7 mmol), DMAP (0.32 g, 2.50 mmol) and DIPEA (5 g, 38.7 mmol) were added to a solution of 2-(2-azidoacetamido)-2-deoxy-1,3,4-tri-O-acetyl-D-mannopyranoside 6.1 (5 g, 12.9 mmol) and oxane-4-carboxylic acid (3.36 g, 25.8 mmol) in anhydrous DCM (120 mL) at 0 °C. After stirring overnight at room temperature, the reaction mixture was concentrated under reduced pressure to give a crude product, which was purified by silica gel column chromatography (eluting with EtOAc in PE) to give compound 6.2 (6.12 g) in 95% yield. MS (ESI) m / z: 523.2 [M + Na] + 。

[0279] Preparation of 2-(2-azidoacetamido)-2-deoxy-3,4-di-O-acetyl-6-O-tetrahydropyran-4-ylcarbonyl-D-mannopyranoside 6.3. At room temperature, (NH4)2CO3 (1.15 g, 12 mmol) was added to a solution of compound 6.2 (2 g, 4 mmol) in anhydrous THF / MeOH (1:1, 16 mL). After stirring at room temperature for 5 h, the reaction mixture was concentrated under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography (eluted with EtOAc in TBME) to give compound 6.3 (1.02 g) in a yield of 56%. MS (ESI) m / z: 459.1 [M+H] + .

[0280] Preparation of 1-O-(2,2,2-trifluoro-N-(2-methoxyphenyl)ethanimidoyl)-2-(2-azidoacetamido)-2-deoxy-3,4-di-O-acetyl-6-O-tetrahydropyran-4-ylcarbonyl-D-mannopyranoside 6.4. Under N2, a mixture of compound 6.3 (300 mg, 0.65 mmol), molecular sieve (300 mg) and K2CO3 (181 mg, 1.31 mmol) in anhydrous THF (10 mL) was stirred at room temperature for 15 min. Then DBU (100 mg, 0.65 mmol) and (Z)-2,2,2-trifluoro-N-(4-methoxyphenyl)ethanimidoyl chloride (311 mg, 1.31 mmol) were added dropwise. After stirring at room temperature for 2 h, the reaction mixture was concentrated under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography (eluted with EtOAc in PE) to give compound 6.4 (300 mg) in a yield of 62%.

[0281] Preparation of 1-O-(1-(2-methylpyrazol-3-yl)-1-(4-(6-acetamido-2(S)-(benzyloxycarbonylamino)hexanamido)phenyl)methyl)-2-(2-azidoacetamido)-2-deoxy-3,4-di-O-acetyl-6-O-tetrahydropyran-4-ylcarbonyl-D-mannopyranoside A9. Compound A9 was prepared in a manner similar to that described for compound A3 in Example 3. 11H NMR (400 MHz, DMSO-d6) δ 8.66 (d, J = 4.8 Hz, 1H), 7.90 (t, J = 5.2 Hz, 1H), 7.70 - 7.51 (m, 2H), 7.45 - 7.14 (m, 8H), 7.01 - 6.85 (m, 1H), 6.32 (t, J = 8.4 Hz, 1H), 6.09 (s, 1H), 6.01 - 5.68 (m, 1H), 5.42 - 5.22 (m, 1H), 5.20 - 5.07 (m, 2H), 5.06 - 4.98 (m, 2H), 4.54 - 4.38 (m, 1H), 4.35 - 4.16 (m, 3H), 4.14 - 4.02 (m, 4H), 3.94 - 3.77 (m, 6H), 3.43 - 3.20 (m, 2H), 3.08 - 2.91 (m, 2H), 2.19 - 1.90 (m, 7H), 1.78 (s, 3H), 1.75 - 1.55 (m, 5H), 1.50 - 1.26 (m, 7H); MS (ESI) m / z: 948.4 [M+H] + 。

[0282] The following compounds were prepared similarly according to the synthetic procedures or methodologies exemplified herein.

[0283] 1-O-(1-(Thiophen-3-yl)-1-(4-(6-acetamido-2(S)-(benzyloxycarbonylamino)hexanamido)phenyl)methyl)-2-(2-azidoacetamido)-2-deoxy-3,4,6-tri-O-acetyl-D-mannopyranoside A5. 1 1H NMR (400 MHz, DMSO-d6) δ 10.03 (s, 1H), 7.79 (t, J = 5.4 Hz, 1H), 7.56 - 7.53 (m, 3H), 7.40 - 7.14 (m, 8H), 6.90 - 6.87 (m, 1H), 6.73 (dd, J = 60.8, 3.2 Hz, 1H), 6.07 (dd, J = 181.2, 3.2 Hz, 1H), 5.36 - 4.98 (m, 4H), 4.89 - 4.81 (m, 1H), 4.35 - 4.24 (m, 2H), 4.16 - 4.02 (m, 3H), 3.92 (t, J = 11.2 Hz, 1H), 3.06 - 2.74 (m, 4H), 2.06 (d, J = 30.8 Hz, 3H), 2.00 - 1.91 (m, 6H), 1.76 (s, 3H), 1.61 - 1.578 (m, 2H), 1.38 - 1.294 (m, 4H); MS (ESI) m / z: 902.3 [M+Na] + 。

[0284] 1-O-(1-(Pyridin-3-yl)-1-(4-(6-acetamido-2(S)-(benzyloxycarbonyl)amino)hexanamido)phenyl)methyl)-2-(2-azidoacetamido)-2-deoxy-3,4,6-tri-O-acetyl-D-mannopyranoside A6. 1 H NMR (400 MHz, DMSO-d6) δ 10.10 (s, 1H), 9.19 - 9.13 (m, 2H), 8.57 (dd, J = 18.0, 8.4 Hz, 2H), 8.25 - 8.10 (m, 1H), 7.67 - 7.11 (m, 10H), 6.41 (dd, J = 16.0, 9.6 Hz, 1H), 6.00 (d, J = 8.8 Hz, 1H), 5.22 - 5.19 (m, 1H), 5.08 (s, 1H), 5.02 (s, 2H), 4.68 - 4.60 (m, 3H), 4.40 - 4.36 (m, 1H), 4.12 - 4.02 (m, 1H), 3.7 - 3.73 (m, 1H), 3.51 - 3.49 (m, 2H), 2.99 (t, J = 4.8 Hz, 2H), 2.26 - 2.12 (m, 6H), 2.05 - 1.97 (m, 3H), 1.77 (d, J = 1.2 Hz, 3H), 1.68 - 1.52 (m, 2H), 1.42 - 1.26 (m, 4H); MS (ESI) m / z: 875.3 [M+H] + 。

[0285] 1-O-(1-(Pyridin-4-yl)-1-(4-(6-acetamido-2(S)-(benzyloxycarbonylamino)hexanamido)phenyl)methyl)-2-(2-azidoacetamido)-2-deoxy-3,4,6-tri-O-acetyl-D-mannopyranoside A7. 11H NMR (400 MHz, DMSO-d6) δ 10.08 (s, 1H), 9.08 (t, J = 6.2 Hz, 2H), 8.52 (d, J = 8.4 Hz, 1H), 8.17 (t, J = 7.0 Hz, 2H), 7.80 (t, J = 5.4 Hz, 1H), 7.603 - 7.538 (m, 3H), 7.352 - 6.891 (m, 7H), 6.29 (dd, J = 9.2, 3.2 Hz, 1H), 6.01 (d, J = 11.6 Hz, 1H), 5.24 - 5.16 (m, 1H), 5.07 - 5.02 (m, 3H), 4.77 - 4.52 (m, 3H), 4.38 - 4.32 (m, 1H), 4.11 - 4.05 (m, 1H), 3.67 (m, 2H), 2.99 - 2.96 (m, 2H), 2.20 - 1.97 (m, 5H), 1.96–1.76 (m, 4H), 1.75 (s, 3H), 1.67 - 1.51 (m, 2H), 1.37 - 1.32 (m, 4H); MS (ESI) m / z: 875.3 [M+H] + 。

[0286] 1-O-(1-(2-Methylpyrazol-3-yl)-1-(4-(6-acetamido-2(S)-(benzyloxycarbonylamino)hexanamido)phenyl)methyl)-2-(2-azidoacetamido)-2-deoxy-3,4-di-O-acetyl-6-O-(1-methylpiperidin-4-yl)carbonyl-D-mannopyranoside A10。 11H NMR (400 MHz, DMSO-d6) δ 8.68 (d, J = 8.4 Hz, 1H), 8.12 (d, J = 19.6 Hz, 1H), 7.85 (t, J = 6.0 Hz, 1H), 7.62 (dd, J = 32.4, 8.0 Hz, 3H), 7.43 - 7.10 (m, 8H), 6.92 (d, J = 12.4 Hz, 1H), 6.31 (t, J = 9.2 Hz, 1H), 6.09 (d, J = 3.6 Hz, 1H), 5.31 - 5.23 (m, 1H), 5.19 - 5.09 (m, 2H), 5.07 - 4.97 (m, 2H), 4.51 - 4.38 (m, 1H), 4.34 - 4.18 (m, 2H), 4.07 (d, J = 10.8 Hz, 4H), 3.96 - 3.86 (m, 1H), 3.83 - 3.70 (m, 2H), 3.19 - 2.91 (m, 5H), 2.16 - 2.00 (m, 7H), 1.95 - 1.80 (m, 3H), 1.77 (s, 3H), 1.71 - 1.52 (m, 5H), 1.45 - 1.24 (m, 5H); MS (ESI) m / z: 961.4 [M+H] + 。

[0287] 1-O-(1-(2-Methylpyrazol-3-yl)-1-(4-(6-acetamido-2(S)-(benzyloxycarbonylamino)hexanamido)phenyl)methyl)-2-(2-azidoacetamido)-2-deoxy-3,4-di-O-acetyl-6-O-(pyrrolidin-1-ylacetyl)-D-mannopyranoside A11。 11H NMR (400 MHz, DMSO-d6) δ 10.12 (d, J = 45.2 Hz, 1H), 8.66 (dd, J = 10.4, 2.8 Hz, 1H), 7.61 (dd, J = 32.8, 8.0 Hz, 2H), 7.45 - 7.10 (m, 8H), 6.91 (dd, J = 27.6, 2.8 Hz, 1H), 6.44 - 6.24 (m, 1H), 6.09 (d, J = 6.8 Hz, 1H), 5.37 - 5.24 (m, 1H), 5.20 - 5.07 (m, 2H), 5.06 - 4.96 (m, 2H), 4.68 - 4.55 (m, 1H), 4.47 (d, J = 12.4 Hz, 1H), 4.39 - 4.03 (m, 8H), 3.90 - 3.70 (m, 3H), 3.17 - 2.93 (m, 4H), 2.19 - 2.06 (m, 6H), 2.05 - 1.87 (m, 4H), 1.81 - 1.75 (m, 3H), 1.70 - 1.55 (m, 2H), 1.44 - 1.26 (m, 5H); MS (ESI) m / z: 947.6 [M+H] + 。

[0288] 1-O-(1-(2-Methylpyrazol-3-yl)-1-(4-(6-acetamido-2(S)-(benzyloxycarbonylamino)hexanamido)phenyl)methyl)-2-(2-azidoacetamido)-2-deoxy-3,4-di-O-acetyl-6-O-(pyridin-3-ylacetyl)-D-mannopyranoside A12。 11H NMR (400 MHz, DMSO-d6) δ 10.14 (d, J = 5.6 Hz, 1H), 8.71 - 8.44 (m, 4H), 7.78 (dd, J = 17.4, 7.8 Hz, 1H), 7.70 - 7.53 (m, 2H), 7.47 (dd, J = 13.0, 8.0 Hz, 1H), 7.41 - 7.11 (m, 9H), 6.92 (dd, J = 33.0, 3.1 Hz, 1H), 6.31 (dd, J = 14.4, 7.0 Hz, 1H), 6.11 (d, J = 5.0 Hz, 1H), 5.28 (dd, J = 8.8, 3.8 Hz, 1H), 5.13 (dd, J = 12.0, 5.6 Hz, 2H), 5.02 (s, 2H), 4.55 - 4.40 (m, 1H), 4.36 - 4.17 (m, 3H), 4.16 - 3.97 (m, 4H), 3.95 - 3.75 (m, 2H), 3.71 (s, 1H), 2.98 (t, J = 5.3 Hz, 2H), 2.20 - 2.06 (m, 6H), 1.77 (s, 3H), 1.66 - 1.53 (m, 2H), 1.46 - 1.26 (m, 4H); MS (ESI) m / z: 955.4 [M+H] + 。

[0289] 1-O-(1-(2-Methylpyrazol-3-yl)-1-(4-(6-acetamido-2(S)-(benzyloxycarbonylamino)hexanamido)phenyl)methyl)-2-(2-azidoacetamido)-2-deoxy-3,4-di-O-acetyl-6-O-(pyridin-3-ylcarbonyl)-D-mannopyranoside A13 11H NMR (400 MHz, DMSO-d6) δ 10.22 - 9.48 (m, 1H), 9.18 - 9.04 (m, 1H), 8.89 - 8.81 (m, 1H), 8.74 - 8.66 (m, 1H), 8.38 - 8.16 (m, 2H), 7.67 - 7.49 (m, 3H), 7.42 - 7.10 (m, 8H), 7.00 - 6.30 (m, 2H), 6.14 - 5.73 (m, 1H), 5.55 - 5.23 (m, 2H), 5.22 - 5.10 (m, 1H), 5.05 - 4.98 (m, 2H), 4.78 - 4.36 (m, 3H), 4.36 - 4.20 (m, 1H), 4.14 - 4.03 (m, 3H), 3.98 - 3.88 (m, 1H), 3.84 - 3.69 (m, 2H), 2.99 (s, 2H), 2.15 - 2.07 (m, 4H), 2.05 - 1.89 (m, 2H), 1.76 (s, 3H), 1.69 - 1.53 (m, 2H), 1.44 - 1.26 (m, 4H); MS (ESI) m / z: 941.3 [M+H] + 。

[0290] 1-O-(1-(2-Methylpyrazol-3-yl)-1-(4-(2(S),6-diethylacetamidocaproamido)phenyl)methyl)-2-(2-azidoacetamido)-2-deoxy-3,4,6-tri-O-acetyl-D-mannopyranoside A14 1 1H NMR (400 MHz, DMSO-d6) δ 10.12 (s, 1H), 8.69 - 8.66 (m, 2H), 8.11 (d, J = 7.2 Hz, 1H), 7.79 (d, J = 5.6 Hz, 1H), 7.64 (d, J = 8.4 Hz, 2H), 7.33 (d, J = 8.4 Hz, 2H), 6.93 (dd, J = 22 Hz, 2.8 Hz, 1H), 6.34 (dd, J = 13.2 Hz, 4.0 Hz, 1H), 6.12 (s, 1H), 5.29 - 5.12 (m, 3H), 4.33 - 4.12 (m, 4H), 4.08 - 4.04 (m, 3H), 3.95 - 3.67 (m, 2H), 3.02 - 2.97 (m, 2H), 2.11 - 2.02 (m, 6H), 1.99 - 1.86 (m, 6H), 1.76 (s, 3H), 1.70 - 1.20 (m, 6H); MS (ESI) m / z: 786.6 [M+H] + 。

[0291] 1-O-(1-(thiazol-2-yl)-1-(4-(2(S),6-diethylamidohexanamido)phenyl)methyl)-2-(2-azidoacetamido)-2-deoxy-3,4,6-tri-O-acetyl-D-mannopyranoside A15. 1 H NMR(400MHz, DMSO-d6) δ8.69 - 8.63(m, 1H), 8.51 - 8.35(m, 2H), 8.15 - 8.00(m, 1H), 7.85 - 7.66(m, 3H), 7.42 - 7.32(m, 3H), 6.50 - 6.29(m, 1H), 6.08 - 5.73(m, 1H), 5.19 - 4.95(m, 2H), 4.70 - 4.26(m, 3H), 4.15 - 3.68(m, 4H), 2.99 - 2.98(m, 2H), 2.33 - 1.76(m, 15H), 1.65 - 1.55(m, 2H), 1.41 - 1.18(m, 4H); MS(ESI) m / z: 789.4[M + H] + 。

[0292] 1-O-(1-(thiazol-5-yl)-1-(4-(2(S),6-diethylamidohexanamido)phenyl)methyl)-2-(2-azidoacetamido)-2-deoxy-3,4,6-tri-O-acetyl-D-mannopyranoside A16. 1 H NMR(400MHz, DMSO-d6) δ10.26(s, 1H), 10.10(d, J = 4.2Hz, 1H), 8.56 - 8.43(m, 1H), 8.35(d, J = 11.6Hz, 1H), 8.11(d, J = 7.4Hz, 1H), 7.79(s, 1H), 7.64(d, J = 8.4Hz, 2H), 7.38(t, J = 7.4Hz, 2H), 7.12 - 7.07(m, 1H), 6.31(d, J = 7.2Hz, 1H), 6.11(s, 1H), 5.18 - 5.12(m, 1H), 5.06 - 5.03(m, 1H), 4.81(d, J = 9.2Hz, 1H), 4.47(t, J = 8.6Hz, 2H), 4.33 - 4.27(m, 2H), 3.84 - 3.65(m, 1H), 2.99 - 2.98(m, 2H), 2.13(s, 6H), 2.00(s, 3H), 1.86(s, 3H), 1.76(s, 3H), 1.65 - 1.55(m, 2H), 1.38 - 1.24(m, 4H); MS(ESI) m / z: 789.5[M + H] + 。

[0293] 1-O-(1-(2-Methylpyrazol-3-yl)-1-(4-(2(S),6-diethylamidohexanamido)phenyl)methyl)-2-(2-azidoacetamido)-2-deoxy-3,4-di-O-acetyl-6-O-(pyridin-3-ylacetyl)-D-mannopyranoside A17. 1 H NMR(400MHz, DMSO-d6)δ8.65 - 8.46(m, 4H), 7.80(dd, J = 17.6, 8.0Hz, 1H), 7.66(d, J = 8.8Hz, 2H), 7.52 - 7.24(m, 4H), 6.92(dd, J = 31.6, 3.2Hz, 1H), 6.31(dd, J = 14.4, 7.2Hz, 1H), 6.10(d, J = 4.4Hz, 1H), 5.28(dd, J = 8.8, 4.0Hz, 1H), 5.19 - 5.05(m, 2H), 4.53 - 4.41(m, 1H), 4.33 - 4.23(m, 4H), 4.04(d, J = 19.2Hz, 3H), 3.95 - 3.82(m, 2H), 3.78(d, J = 16.0Hz, 2H), 3.71(d, J = 1.6Hz, 1H), 2.99(t, J = 6.4Hz, 2H), 2.13 - 2.06(m, 5H), 2.04 - 1.97(m, 1H), 1.86(s, 3H), 1.77(s, 3H), 1.61 - 1.55(m, 2H), 1.37 - 1.29(m, 4H); MS(ESI)m / z: 863.3[M + H] + 。

[0294] 1-O-(1-(2-Methylpyrazol-3-yl)-1-(4-(2(S),6-diethylamidohexanamido)phenyl)methyl)-2-(2-azidoacetamido)-2-deoxy-3,4-di-O-acetyl-6-O-(1-methylpiperidin-4-ylcarbonyl)-D-mannopyranoside A18. 11H NMR (400 MHz, DMSO-d6) δ 10.17 (s, 1H), 8.46 - 8.13 (m, 1H), 7.92 - 7.84 (m, 1H), 7.65 (d, J = 8.4 Hz, 2H), 7.44 - 7.38 (m, 1H), 7.32 (d, J = 6.4 Hz, 2H), 6.17 (d, J = 3.6 Hz, 1H), 5.91 (d, J = 6.0 Hz, 1H), 5.25 - 5.10 (m, 2H), 4.82 (d, J = 47.6 Hz, 1H), 4.53 - 4.41 (m, 1H), 4.36 - 4.27 (m, 1H), 4.26 - 3.99 (m, 2H), 3.98 - 3.78 (m, 4H), 3.71 (d, J = 14.4 Hz, 3H), 3.50 - 3.38 (m, 2H), 3.06 - 2.91 (m, 4H), 2.77 (s, 3H), 2.39 - 2.33 (m, 1H), 2.06 - 1.78 (m, 12H), 1.74 - 1.54 (m, 4H), 1.43 - 1.28 (m, 6H); MS (ESI) m / z: 869.4 [M+H] + 。

[0295] 1-O-(1-(1-Methylimidazol-4-yl)-1-(4-(6-acetamido-2(S)-(benzyloxycarbonylamino)hexanamido)phenyl)methyl)-2-deoxy-D-mannopyranoside A19 1 1H NMR (300 MHz, DMSO-d6) δ 10.09 - 9.92 (m, 1H), 7.85 - 7.7 (m, 2H), 7.66 - 7.47 (m, 4H), 7.39 - 7.12 (m, 3H), 7.53 - 6.95 (m, 7H), 7.01 - 6.76 (m, 1H), 5.83 - 5.52 (m, 1H), 5.03 (s, 2H), 4.92 - 4.65 (m, 3H), 4.55 - 4.27 (m, 1H), 4.19 - 4.03 (br, 2H), 3.89 - 3.67 (m, 3H), 3.62 - 3.40 (m, 4H), 3.09 - 2.97 (m, 2H), 1.76 (s, 3H), 1.65 (br, 2H), 1.46 - 1.22 (m, 4H); MS (ESI) m / z: 752.2 [M+H] + 。 Example B1 Flow cytometry analysis of cell labeling

[0296] Cells (2.0×10 5Cells / mL, 2 mL) were seeded in 6-well culture plates and allowed to adhere overnight at 37 °C. After washing three times with PBS, the cells were incubated with azide (25 μM) at 37 °C for 48 h. After washing three times with PBS, the cells were incubated with DBCO-biotin (50 μM) in 500 μL of serum-free DMEM at 37 °C for 1 h. The cells were washed three times with PBS and then incubated with streptavidin-Cy5 (5 μg / mL) in 500 μL of serum-free DMEM at 37 °C for 1 h. The cells were washed three times with PBS and then 300 μL of 1× trypsin / EDTA was added for digestion. The lifted cells were transferred to a 1.5 mL EP tube, centrifuged at 1000 rpm for 3 min, 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, and then flow cytometry was performed.

[0297] Flow cytometry was used to characterize the labeling efficiency of the compounds provided herein. After the cells were labeled 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 the analysis. The results were expressed as the mean fluorescence of live cells and compared with PBS as a negative control and with Ac4ManNAz (AAM) as a positive control, Ac4ManNAz (AAM, CAS: 361154-30-5). The results are summarized in Tables 1 and 2. Table 1. Labeling efficiency of monosaccharides in A549 cells Compound# PBS% AAM% A1 103 27 A2 250 37 A4 83 28 A5 130 44 A9 197 31 A10 166 26 A12 165 17 A13 180 21 A14 620 66 A15 318 50 A16 136 30 A17 161 19 A18 104 10 Table 2. Labeling efficiency of monosaccharide A8 in cell lines Cancer type Cell line PBS% AAM% Lung A549 196 28 Breast MDA-MB-231 209 31 Ovary OVCAR3 132 24 Example B2 LCMS analysis of cell labeling

[0298] The labeling efficiency of azide compounds was determined using LCMS. After the cells were labeled with azide compounds, the cells 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 the protein content-cell number standard curve. Azido sialic acid (N3-SA) was cleaved from glycoproteins in the lysate by incubation with acetic acid at 80 °C for 1 h and then derivatized with DBCO reagent as shown in the protocol below. The cycloaddition product was quantified by LCMS to obtain the number of N3-SA in the cell lysate. N3-SA / cell was calculated as n(N3-SA) / cell number.

[0299] Briefly, cells (2.0×10 5 cells / mL, 2 mL) were seeded in a 6-well culture plate and allowed to adhere overnight at 37 °C. After washing three times with PBS, the cells were incubated with azide (25 μM) at 37 °C for 48 h. After washing three times with PBS, the cells were lysed with RIPA (200 μL) at 4 °C for 0.5 h. 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), mixed with glacial acetic acid (14 μL), and incubated at 80 °C for 1 h. The suspension was centrifuged at 15000 rpm for 5 min, 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 h. The mixture was centrifuged at 15000 rpm for 5 min, and the supernatant (180 μL) was transferred to a sample vial. The formed cycloaddition product was quantified by LC-MS using a standard calibration curve. Example B3 Compound stability study in biological matrices

[0300] The compound was dissolved in DMSO as a 1 mg / mL stock solution. An ACN solution of the compound (100 μg / mL) was prepared from the stock solution, and 10 μL of it was added to biological matrix (90 μL) such that the final concentration of the compound was 10 μg / mL. At 37 °C, the mixture of the compound in the biological matrix was incubated for 0 h, 0.5 h, 1 h, or 4 h. At each time point, ACN (900 μL) was added to the mixture. After centrifuging the mixture at 15000 rpm for 5 min, the supernatant was mixed with an equal volume of H2O (1% TFA) and then analyzed by LC-MS / MS. The results are summarized in Table 3, where Cbz-AAM is (2R,3S,4R,5S)-6-((4-((S)-6-acetamido-2-(((benzyloxy)carbonyl)amino)hexanamido)phenyl)(phenyl)methoxy)-2-(acetoxymethyl)-5-(2-azidoacetamido)tetrahydro-2H-pyran-3,4-diyl diacetate. Table 3. Compound stability in mouse and human plasma *****

[0301] The above-described embodiments are provided to give those of ordinary skill in the art a complete disclosure and description of how to make and use the claimed embodiments, and are not intended to limit the scope of the disclosure herein. Modifications that are obvious to those skilled in the art should fall within the scope of the following claims. All publications, patents, and patent applications cited in this specification are incorporated herein by reference as if each such publication, patent, or patent application was specifically and individually indicated to be incorporated herein by reference.

Claims

1. A compound of formula (I): or its enantiomers, mixtures of enantiomers, diastereomers, mixtures of two or more diastereomers, tautomers, mixtures of two or more tautomers, or isotopic variants; or its pharmaceutically acceptable salts, solvates, hydrates or prodrugs; wherein: R 1 is (i) hydrogen or deuterium; or (ii) C 1-20 alkyl, C 1-20 heteroalkyl, C 2-20 alkenyl, C 2-20 alkynyl, C 3-20 cycloalkyl, C 6-20 aryl, C 7-20 aralkyl, heteroaryl or heterocyclic group; R 2 is a heteroaryl; R 3 Each independently is (i) deuterium, cyano, halogen or nitro; (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 heterocyclic group; 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 , –OR 1a , –OC(O)R 1a , –OC(O)OR 1a , –OC(O)NR 1b R 1c , –OC(O)SR 1a , –OC(NR 1a )NR 1b R 1c , –OC(S)R 1a , –OC(S)OR 1a , –OC(S)NR 1b R 1c , –OS(O)R 1a , –OS(O)2R 1a , –OS(O)NR 1b R 1c , –OS(O)2NR 1b R 1c , –NR 1b R 1c , –NR 1a C(O)R 1d , –NR 1a C(O)OR 1d , –NR 1a C(O)NR 1b R 1c , –NR 1a C(O)SR 1d , –NR 1a C(NR 1d )NR 1b R 1c 、 –NR 1a C(S)R 1d 、 –NR 1a C(S)OR 1d 、 –NR 1a C(S)NR 1b R 1c 、 –NR 1a S(O)R 1d 、 –N=S(O)R 1a R 1d 、 –NR 1a S(O)2R 1d 、 –NR 1a S(O)NR 1b R 1c 、 –NR 1a S(O)2NR 1b R 1c 、 –SR 1a 、 –S(O)R 1a 、 –S(O)2R 1a 、 –S(O)NR 1b R 1c or –S(O)2NR 1b R 1c ; R 4 and R 6 are each independently (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 heterocyclic group; 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 5 is 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 heterocyclic group; R 7 and R 8 each independently is (i) a halogen; or (ii) –OR 1a 、–OC(O)R 1a 、–OC(O)OR 1a or –OC(O)NR 1b R 1c ; and R 9 is (i) hydrogen; or (ii) –C(O)R 1a 、–C(O)OR 1a or –C(O)NR 1b R 1c ; or R 7 and R 8 or R 8 and R 9 are joined together to form a lactone ring; A is a key, O or N(R 1b ); E is hydrogen, azido, halogen, isocyano, –C=C(R 1a )R 1a , –C≡CR 1a , –C(O)R 1a or –SH; L 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 aralkyl, heteroaryl or heterocyclic group; R 1a , R 1b , R 1c and R 1d are independently hydrogen, deuterium, 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; and m is an integer of 0, 1, 2, 3 or 4; Among them, alkyl, alkylene, heteroalkyl, heteroalkylene, alkenyl, alkenylene, alkynyl, alkynylene, cycloalkyl, cycloalkylene, aryl, arylene, aralkyl, aralkylene, heteroaryl, heteroarylene, heterocyclic group and heterocycloalkylene are each optionally substituted by one or more (in one embodiment, by one, two, three or four) substituents Q, where Q is independently selected from: (a) deuterium, cyano, halogen, 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 heterocyclic group, each of which is further optionally substituted by one or more (in one embodiment, by one, two, three or four) substituents Q a ; 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)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)2R a , –S(O)NR b R c and –S(O)2NR b R c , where R a , R b , R c and R d are each independently (i) hydrogen or deuterium; (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, each of which is optionally substituted by one or more (in one embodiment, by one, two, three or four) substituents Q a or (iii) R b and R c Together with the N atom to which they are attached, form a heterocyclic group, which is optionally substituted by one or more (in one embodiment, by one, two, three or four) substituents Q a substituted; Among them, Q a are each independently selected from: (a) deuterium, cyano, halogen, 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 heterocyclic group; 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)2NR 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 ; wherein, R e 、 R f 、 R g and R h are each 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 heterocyclic group; or (iii) R f and R g together with the N atom to which they are attached form a heterocyclic group.

2. The compound according to claim 1, wherein R 7 is (i) a halogen; or (ii) –OR 1a , –OC(O)R 1a , –OC(O)OR 1a or –OC(O)NR 1b R 1c .

3. The compound according to claim 1 or 2, wherein R 7 is a halogen.

4. The compound according to any one of claims 1 - 3, wherein R 7 is fluorine.

5. The compound according to any one of claims 1-4, wherein R 8 is (i) a halogen; or (ii) –OR 1a , –OC(O)R 1a , –OC(O)OR 1a or –OC(O)NR 1b R 1c .

6. The compound according to any one of claims 1-5, wherein R 8 is a halogen.

7. The compound according to any one of claims 1-6, wherein R 8 is fluorine.

8. The compound according to any one of claims 1, 2 and 5, wherein the compound has the structure of formula (II): or its enantiomers, mixtures of enantiomers, diastereomers, mixtures of two or more diastereomers, tautomers, mixtures of two or more tautomers, or isotopic variants; or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof; wherein, R 7a and R 8a each independently is hydrogen, –C(O)R 1a –C(O)OR 1a or –C(O)NR 1b R 1c 。 9. The compound according to any one of claims 1-8, wherein, R 1 is hydrogen.

10. The compound according to any one of claims 1-9, wherein, R 2 is a monocyclic heteroaryl group, which is optionally substituted by one or more substituents Q.

11. The compound according to any one of claims 1-10, wherein, R 2 is a 5- or 6-membered heteroaryl, each optionally substituted with one or more substituents Q.

12. The compound according to any one of claims 1-11, wherein, R 2 is thiophenyl, pyrazolyl, imidazolyl, thiazolyl or pyridyl, each optionally substituted by one or more substituents Q.

13. The compound according to any one of claims 1-12, wherein R 2 is a pyrazolyl group, which is optionally substituted by one or more substituents Q.

14. A compound according to any one of claims 1-13, wherein, R 2 is thiophen-2-yl, thiophen-3-yl, 2-methylpyrazol-3-yl, imidazol-4-yl, 1-methylimidazol-4-yl, thiazol-2-yl, thiazol-5-yl, pyridin-3-yl or pyridin-4-yl.

15. The compound according to any one of claims 8 - 11, wherein the compound has the structure of formula (IV): or its enantiomers, mixtures of enantiomers, diastereomers, mixtures of two or more diastereomers, tautomers, mixtures of two or more tautomers, or isotopic variants; or its pharmaceutically acceptable salts, solvates, hydrates or prodrugs; wherein: U is a bond, N or CR 2a ; and each of V, X, Y and Z is independently N, O, S, CR 2a or NR 2b ; provided that at least one of U, V, X, Y and Z is not CR 2a ; R 2a Each is independently (i) hydrogen, deuterium, cyano, halogen or nitro; (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 heterocyclic group, each optionally substituted by one or more substituents Q; 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 , –OR 1a , –OC(O)R 1a , –OC(O)OR 1a , –OC(O)NR 1b R 1c , –OC(O)SR 1a , –OC(NR 1a )NR 1b R 1c , –OC(S)R 1a , –OC(S)OR 1a , –OC(S)NR 1b R 1c , –OS(O)R 1a , –OS(O)2R 1a , –OS(O)NR 1b R 1c , –OS(O)2NR 1b R 1c , –NR 1b R 1c , –NR 1a C(O)R 1d , –NR 1a C(O)OR 1d , –NR 1a C(O)NR 1b R 1c , –NR 1a C(O)SR 1d , –NR 1a C(NR 1d )NR 1b R 1c 、–NR 1a C(S)R 1d 、–NR 1a C(S)OR 1d 、–NR 1a C(S)NR 1b R 1c 、–NR 1a S(O)R 1d 、–N=S(O)R 1a R 1d 、–NR 1a S(O)2R 1d 、–NR 1a S(O)NR 1b R 1c 、–NR 1a S(O)2NR 1b R 1c 、–SR 1a 、–S(O)R 1a 、–S(O)2R 1a 、–S(O)NR 1b R 1c 或–S(O)2NR 1b R 1c ;以及 R 2b Each independently 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 heterocyclic group, each optionally substituted by one or more substituents Q; 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 or –S(O)2NR 1b R 1c .

16. The compound according to any one of claims 1-15, wherein, R 5 is C 1-6 alkyl, C 7-15 arylalkyl or heterocyclic group, each optionally substituted by one or more substituents Q.

17. The compound according to any one of claims 1-16, wherein, R 5 is C 1-6 alkyl, which is optionally substituted by one or more substituents Q.

18. The compound according to any one of claims 1-17, wherein R 5 is C 1-6 alkyl, optionally substituted by one, two or three substituents; and wherein each substituent is independently (i) C 1-6 alkyl, C 6-14 aryl or heteroaryl, each optionally substituted by one or more substituents Q; or (ii) –C(O)OR 1a , –C(O)NR 1b R 1c , –C(NR 1a )NR 1b R 1c , –OR 1a , –NR 1b R 1c or –SR 1a .

19. The compound according to any one of claims 1-18, wherein, R 5 is C 1-6 alkyl, optionally substituted with one or two substituents, where each substituent is independently methyl, phenyl, 4-hydroxyphenyl, imidazol-4-yl, indol-3-yl, amino, acetamido, benzamido, benzyloxycarbonylamino, tert-butoxycarbonylamino, 9-fluorenylmethoxycarbonylamino, aminocarbonyl, carboxyl, guanidino, hydroxy, mercapto or methylthio.

20. The compound according to any one of claims 1-16, wherein, R 5 is aminomethyl, 1-amino-ethyl, 1-amino-2-carboxyethyl, 1-amino-2-aminocarbonylethyl, 1-amino-2-mercaptoethyl, 1-amino-2-hydroxyethyl, 1-amino-2-(imidazol-4-yl)ethyl, 1-amino-2-(indol-3-yl)ethyl, 1-amino-2-methylpropyl, 1-amino-3-carboxypropyl, 1-amino-3-aminocarbonylpropyl, 1-amino-2-hydroxy-propyl, 1-amino-3-methylthiopropyl, 1-amino-2-methylbutyl, 1-amino-3-methylbutyl, 1-amino-4-guanidinobutyl, 1,4-diaminobutyl, 1,5-diaminopentyl, 1-amino-2-phenylethyl, 1-amino-2-(4-hydroxyphenyl)ethyl or pyrrolidin-2-yl, wherein the amino groups are each independently and optionally protected by an amino protecting group.

21. The compound according to claim 20, wherein The amino protecting group is independently –C(O)R a or –C(O)OR a .

22. The compound according to claim 20 or 21, wherein The amino protecting groups are each independently acetyl, benzoyl, Boc, Cbz or Fmoc.

23. The compound according to any one of claims 1-22, wherein R 5 is 1,5 - diethylamidopentyl or 5 - acetamido - 1 - (benzyloxycarbonylamino)pentyl.

24. The compound according to any one of claims 15 - 18, wherein the compound has the structure of formula (V): or its enantiomers, mixtures of enantiomers, diastereomers, mixtures of two or more diastereomers, tautomers, mixtures of two or more tautomers, or isotopic variants; or pharmaceutically acceptable salts, solvates, hydrates or prodrugs thereof; wherein, R 5a , R 5b , R 5c and R 5d are each independently (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, each optionally substituted with one or more substituents Q; 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.

25. The compound according to claim 24, wherein the compound has the structure of formula (VI): or its enantiomers, mixtures of enantiomers, diastereomers, mixtures of two or more diastereomers, tautomers, mixtures of two or more tautomers, or isotopic variants; or its pharmaceutically acceptable salts, solvates, hydrates or prodrugs.

26. The compound according to claim 24, wherein the compound has the structure of formula (VII): or its enantiomers, mixtures of enantiomers, diastereomers, mixtures of two or more diastereomers, tautomers, mixtures of two or more tautomers, or isotopic variants; or its pharmaceutically acceptable salts, solvates, hydrates or prodrugs.

27. The compound according to claim 24, wherein the compound has the structure of formula (VIII): or its enantiomers, mixtures of enantiomers, diastereomers, mixtures of two or more diastereomers, tautomers, mixtures of two or more tautomers, or isotopic variants; or its pharmaceutically acceptable salts, solvates, hydrates or prodrugs.

28. The compound according to claim 24 or 25, wherein the compound has the structure of formula (IX): or its enantiomers, mixtures of enantiomers, diastereomers, mixtures of two or more diastereomers, tautomers, mixtures of two or more tautomers, or isotopic variants; or its pharmaceutically acceptable salts, solvates, hydrates or prodrugs.

29. The compound according to claim 24 or 26, wherein the compound has the structure of formula (X): or its enantiomers, mixtures of enantiomers, diastereomers, mixtures of two or more diastereomers, tautomers, mixtures of two or more tautomers, or isotopic variants; or its pharmaceutically acceptable salts, solvates, hydrates or prodrugs.

30. The compound according to any one of claims 24 - 29, wherein, R 5a is hydrogen, –C(O)R 1a or –C(O)OR 1a 。 31. A compound according to any one of claims 24 - 30, wherein, R 5a is an amino protecting group.

32. A compound according to any one of claims 24 - 31, wherein, R 5a is –C(O)R 1a or –C(O)OR 1a as an amino protecting group.

33. The compound according to any one of claims 24 - 32, wherein, R 5a is acetyl, benzoyl, Boc, Cbz or Fmoc.

34. The compound according to any one of claims 24-33, wherein, R 5a is an acetyl group or Cbz.

35. The compound according to any one of claims 24 - 34, wherein, R 5b is hydrogen.

36. A compound according to any one of claims 24 - 35, wherein, R 5c is hydrogen, –C(O)R 1a or –C(O)OR 1a 。 37. A compound according to any one of claims 24 - 36, wherein, R 5c is an amino protecting group.

38. A compound according to any one of claims 24 - 37, wherein, R 5c is –C(O)R 1a or –C(O)OR 1a as an amino protecting group.

39. A compound according to any one of claims 24 - 38, wherein, R 5c is acetyl, benzoyl, Boc, Cbz or Fmoc.

40. A compound according to any one of claims 24 - 39, wherein, R 5c is an acetyl group or Cbz.

41. A compound according to any one of claims 24 - 40, wherein, R 5d is hydrogen.

42. A compound according to any one of claims 15 - 41, wherein, U is a bond.

43. A compound according to any one of claims 15 - 41, wherein, U is CR 2a or CH.

44. A compound according to any one of claims 15 - 42, wherein, V is N, S, CR 2a or NR 2b .

45. A compound according to any one of claims 15 - 43, wherein, V is N.

46. The compound according to any one of claims 15 - 43, wherein, V is S.

47. A compound according to any one of claims 15 - 43, wherein, V is CR 2a or CH.

48. A compound according to any one of claims 15 - 43, wherein, V is NR 2b , NH or N(CH3).

49. A compound according to any one of claims 15 - 48, wherein, X is N, S, CR 2a or NR 2b .

50. A compound according to any one of claims 15 - 49, wherein, X is N.

51. A compound according to any one of claims 15 - 49, wherein, X is S.

52. The compound according to any one of claims 15 - 49, wherein, X is CR 2a or CH.

53. A compound according to any one of claims 15 - 49, wherein, X is NR 2b , NH or N(CH3).

54. A compound according to any one of claims 15 - 53, wherein, Y is N, S, CR 2a or NR 2b .

55. The compound according to any one of claims 15 - 54, wherein, Y is N.

56. A compound according to any one of claims 15 - 54, wherein, Y is S.

57. A compound according to any one of claims 15 - 54, wherein, Y is CR 2a or CH.

58. A compound according to any one of claims 15 - 54, wherein Y is NR 2b , NH or N(CH3).

59. The compound according to any one of claims 15-58, wherein, Z is N, S, CR 2a or NR 2b .

60. The compound according to any one of claims 15 - 59, wherein, Z is N.

61. A compound according to any one of claims 15 - 59, wherein, Z is S.

62. The compound according to any one of claims 15 - 59, wherein, Z is CR 2a or CH.

63. A compound according to any one of claims 15 - 59, wherein, Z is NR 2b , NH or N(CH3).

64. A compound according to any one of claims 15 - 41, wherein, U is a bond; V is S; and X, Y, and Z are each independently CR 2a ; or, wherein, U is a bond; V is S; and X, Y, and Z are each CH.

65. A compound according to any one of claims 15 - 41, wherein, U is a bond; V, Y, and Z are each independently CR 2a ; and X is S; or, wherein, U is a bond; V, Y, and Z are each CH; and X is S.

66. The compound according to any one of claims 15 - 41, wherein, U is a bond; V is NR 2b , X is N; and Y and Z are each independently CR 2a ; or, wherein, U is a bond; V is N(CH3); X is N; and Y and Z are each CH.

67. A compound according to any one of claims 15 - 41, wherein, U is a bond; V is N; X and Z are each independently CR 2a ; and Y is NR 2b ; or, wherein, U is a bond; V is N; X and Z are each CH; and Y is NH or N(CH3).

68. The compound according to any one of claims 15 - 41, wherein, U is a bond; V is S; X and Z are each independently CR 2a ; and Y is N; or, wherein, U is a bond; V is S; X and Z are each CH; and Y is N.

69. A compound according to any one of claims 15 - 41, wherein, U is a bond; V is S; X and Y are each independently CR 2a ; and Z is N; or, wherein, U is a bond; V is S; X and Y are each CH; and Z is N.

70. The compound according to any one of claims 15 - 41, wherein, U, X, Y, and Z are each independently CR 2a ; and V is N; or, wherein, U, X, Y, and Z are each CH; and V is N.

71. A compound according to any one of claims 15 - 41, wherein, U, V, Y, and Z are each independently CR 2a ; and X is N; or, wherein, U, V, Y, and Z are each CH; and X is N.

72. The compound according to any one of claims 1-71, wherein, R 4 is hydrogen.

73. The compound according to any one of claims 1 - 72, wherein, R 6 is hydrogen.

74. A compound according to any one of claims 1 - 73, wherein, R 9 is hydrogen or –C(O)R 1a .

75. The compound according to any one of claims 1 - 74, wherein, R 9 is –C(O)–C 1-6 alkyl, which is optionally substituted with one or more substituents Q.

76. The compound according to any one of claims 1-75, wherein, R 9 is an acetyl group, a propionyl group or a butyryl group.

77. The compound according to any one of claims 1-76, wherein, R 9 is an acetyl group.

78. The compound according to any one of claims 8-77, wherein, R 7a is hydrogen or –C(O)R 1a .

79. A compound according to any one of claims 8 - 78, wherein, R 7a is –C(O)–C 1-6 alkyl, which is optionally substituted with one or more substituents Q.

80. The compound according to any one of claims 8 - 79, wherein, R 7a is an acetyl group, a propionyl group or a butyryl group.

81. A compound according to any one of claims 8 - 80, wherein, R 7a is an acetyl group.

82. The compound according to any one of claims 8-81, wherein, R 8a is hydrogen or –C(O)R 1a .

83. A compound according to any one of claims 8 - 82, wherein, R 8a is –C(O)–C 1-6 alkyl, which is optionally substituted with one or more substituents Q.

84. A compound according to any one of claims 8 - 83, wherein, R 8a is an acetyl group, a propionyl group or a butyryl group.

85. The compound according to any one of claims 8-84, wherein, R 8a is an acetyl group.

86. The compound according to any one of claims 1-85, wherein, A is a key or O.

87. A compound according to any one of claims 1 - 86, wherein, A is a key.

88. A compound according to any one of claims 1 - 87, wherein, E is hydrogen, azido, fluoro, iodo, isocyano, –C=CH2, –C≡C, –C(O)CCH3 or –SH.

89. A compound according to any one of claims 1 - 88, wherein, E is an azido group.

90. The compound according to any one of claims 1-89, wherein, L is C 1-6 an alkylene group, which is optionally substituted by one or more substituents Q.

91. The compound according to any one of claims 1-90, wherein, L is methylene, ethane-1,2-diyl, propane-1,2-diyl or butane-1,4-diyl, each optionally substituted by one or more substituents Q.

92. The compound according to any one of claims 1-91, wherein, L is methylene.

93. The compound according to any one of claims 1 - 92, wherein, m is the integer 0.

94. The compound according to claim 1, wherein The compound is: 1-O-(1-(imidazol-4-yl)-1-(4-(6-acetamido-2(S)-(benzyloxycarbonylamino)hexanamido)phenyl)methyl)-2-(2-azidoacetamido)-2-deoxy-3,4,6-tri-O-acetyl-D-mannopyranoside A1; 1-O-(1-(1-methylimidazol-4-yl)-1-(4-(6-acetamido-2(S)-(benzyloxycarbonylamino)hexanamido)phenyl)methyl)-2-(2-azidoacetamido)-2-deoxy-3,4,6-tri-O-acetyl-D-mannopyranoside A2; 1-O-(1-(thiazol-5-yl)-1-(4-(6-acetamido-2(S)-(benzyloxycarbonylamino)hexanamido)phenyl)methyl)-2-(2-azidoacetamido)-2-deoxy-3,4,6-tri-O-acetyl-D-mannopyranoside A3; 1-O-(1-(thiophen-2-yl)-1-(4-(6-acetamido-2(S)-(benzyloxycarbonylamino)hexanamido)phenyl)methyl)-2-(2-azidoacetamido)-2-deoxy-3,4,6-tri-O-acetyl-D-mannopyranoside A4; 1-O-(1-(thiophen-3-yl)-1-(4-(6-acetamido-2(S)-(benzyloxycarbonylamino)hexanamido)phenyl)methyl)-2-(2-azidoacetamido)-2-deoxy-3,4,6-tri-O-acetyl-D-mannopyranoside A5; 1-O-(1-(pyridin-3-yl)-1-(4-(6-acetamido-2(S)-(benzyloxycarbonyl)amino)hexanamido)phenyl)methyl)-2-(2-azidoacetamido)-2-deoxy-3,4,6-tri-O-acetyl-D-mannopyranoside A6; 1-O-(1-(pyridin-4-yl)-1-(4-(6-acetamido-2(S)-(benzyloxycarbonylamino)hexanamido)phenyl)methyl)-2-(2-azidoacetamido)-2-deoxy-3,4,6-tri-O-acetyl-D-mannopyranoside A7; 1-O-(1-(2-methylpyrazol-3-yl)-1-(4-(6-acetamido-2(S)-(benzyloxycarbonylamino)hexanamido)phenyl)methyl)-2-(2-azidoacetamido)-2-deoxy-3,4,6-tri-O-acetyl-D-mannopyranoside A8; 1-O-(1-(2-Methylpyrazol-3-yl)-1-(4-(6-acetamido-2(S)-(benzyloxycarbonylamino)hexanamido)phenyl)methyl)-2-(2-azidoacetamido)-2-deoxy-3,4-di-O-acetyl-6-O-tetrahydropyran-4-ylcarbonyl-D-mannopyranoside A9; 1-O-(1-(2-Methylpyrazol-3-yl)-1-(4-(6-acetamido-2(S)-(benzyloxycarbonylamino)hexanamido)phenyl)methyl)-2-(2-azidoacetamido)-2-deoxy-3,4-di-O-acetyl-6-O-(1-methylpiperidin-4-yl)carbonyl-D-mannopyranoside A10; 1-O-(1-(2-Methylpyrazol-3-yl)-1-(4-(6-acetamido-2(S)-(benzyloxycarbonylamino)hexanamido)phenyl)methyl)-2-(2-azidoacetamido)-2-deoxy-3,4-di-O-acetyl-6-O-(pyrrolidin-1-ylacetyl)-D-mannopyranoside A11; 1-O-(1-(2-Methylpyrazol-3-yl)-1-(4-(6-acetamido-2(S)-(benzyloxycarbonylamino)hexanamido)phenyl)methyl)-2-(2-azidoacetamido)-2-deoxy-3,4-di-O-acetyl-6-O-(pyridin-3-ylacetyl)-D-mannopyranoside A12; 1-O-(1-(2-Methylpyrazol-3-yl)-1-(4-(6-acetamido-2(S)-(benzyloxycarbonylamino)hexanamido)phenyl)methyl)-2-(2-azidoacetamido)-2-deoxy-3,4-di-O-acetyl-6-O-(pyridin-3-ylcarbonyl)-D-mannopyranoside A13; 1-O-(1-(2-Methylpyrazol-3-yl)-1-(4-(2(S),6-diethylamidohexanamido)phenyl)-methyl)-2-(2-azidoacetamido)-2-deoxy-3,4,6-tri-O-acetyl-D-mannopyranoside A14; 1-O-(1-(Thiazol-2-yl)-1-(4-(2(S),6-diethylamidohexanamido)phenyl)methyl)-2-(2-azidoacetamido)-2-deoxy-3,4,6-tri-O-acetyl-D-mannopyranoside A15; 1-O-(1-(Thiazol-5-yl)-1-(4-(2(S),6-diethylamidohexanamido)phenyl)methyl)-2-(2-azidoacetamido)-2-deoxy-3,4,6-tri-O-acetyl-D-mannopyranoside A16; 1-O-(1-(2-Methylpyrazol-3-yl)-1-(4-(2(S),6-diethylamidohexanamido)phenyl)methyl)-2-(2-azidoacetamido)-2-deoxy-3,4-di-O-acetyl-6-O-(pyridin-3-ylacetyl)-D-mannopyranoside A17; 1-O-(1-(2-methylpyrazol-3-yl)-1-(4-(2(S),6-diethylacetamidocaproamido)phenyl)methyl)-2-(2-azidoacetamido)-2-deoxy-3,4-di-O-acetyl-6-O-(1-methylpiperidin-4-ylcarbonyl)-D-mannopyranoside A18; or 1-O-(1-(1-methylimidazol-4-yl)-1-(4-(6-acetamido-2(S)-(benzyloxycarbonylamino)caproamido)phenyl)methyl)-2-deoxy-D-mannopyranoside A19; 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.

95. A pharmaceutical composition, the pharmaceutical composition comprising: a compound according to any one of claims 1-94, 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, a pharmaceutically acceptable excipient.

96. The pharmaceutical composition according to claim 95, wherein, The composition is in a single dosage form.

97. The pharmaceutical composition according to claim 95 or 96, wherein, The composition is in an oral, parenteral or intravenous dosage form.

98. The pharmaceutical composition according to claim 97, wherein, The composition is formulated into an oral dosage form.

99. The pharmaceutical composition according to claim 98, wherein, The oral dosage form is a tablet or a capsule.

100. A method for labeling cells in a subject with an azide group, the method comprising administering to a subject in need thereof an effective amount of a compound according to any one of claims 1-94 or a pharmaceutical composition according to any one of claims 95-99.

101. The method according to claim 100, wherein, The subject is a human.

102. A method for labeling cells with an azide group, the method comprising contacting the cells with an effective amount of a compound according to any one of claims 1-94 or a pharmaceutical composition according to any one of claims 95-99.

103. The method according to any one of claims 100 - 102, wherein The cells are cancer cells.

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