Functionalized monosaccharide capable of being activated by ALDH, pharmaceutical composition and diagnostic and therapeutic application

Abstract

Provided herein are monosaccharides that can be activated by ALDH, e.g., compounds of formula (A) and pharmaceutical compositions thereof. Also provided herein are methods of their use in cell labeling for diagnostic and / or therapeutic applications.

Description

Cross-reference to related applications

[0001] This application claims the benefit of priority to U.S. Provisional Application No. 63 / 519,834, filed August 15, 2023, the disclosure of which is incorporated herein by reference in its entirety. Technical Field

[0002] This article provides monosaccharides that can be activated by ALDH and pharmaceutical compositions thereof. It also provides methods for using them as cell markers for diagnostic and / or therapeutic applications. Background Technology

[0003] Glycosylation is an enzymatic process responsible for attaching glycans to glycosyl receptors (e.g., cell surface proteins). Reily et al., Nat. Rev. Nephrol. 2019, 15, 346-66. Glycosylation is essential for both physiological and pathological cellular function (ibid.). Alterations in glycosylation have been identified in almost every type of cancer and have significant implications for 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, 354, 78-89; Reily et al., Nat. Rev. Nephrol. 2019, 15, 346-66.

[0004] Metabolic glycoengineering is a technique that introduces non-natural sugars into cytoglycans. (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 cellular carbohydrate metabolism, tagging cells with chemical reporter molecules (as above). The chemical reporter molecules expressed on the cell surface (e.g., azides) can then be used for targeted drug delivery or in vivo imaging via bioorthogonal chemistry. Laughlin et al., Science 2008, 320, 664-7; Sletten and Bertozzi, Acc. Chem. Res. 2011, 44, 666-76; Wang et al., Nat. Chem. Biol. 2017, 13, 415; Wang and Mooney, Nat. Chem. 2020, 12, 1102-14.

[0005] Aldehyde dehydrogenase 1A1 (ALDH1A1) is an evolutionarily conserved intracellular enzyme that is typically overexpressed in tumorigenic cancer stem-like cells (CSCs), a subset of cancer cells capable of self-renewal and differentiation, and promoting drug resistance, metastasis, and recurrence. (Dagogo-Jack and Shaw, Nat. Rev. Clin. Oncol. 2018, 15, 81-94). As an oncogenic factor, ALDH1A1 plays a crucial role in promoting DNA repair and inducing drug resistance. (Ginestier et al., Cell Stem Cell 2007, 1, 555-67). Overexpression of ALDH1A1 in CSCs of breast, colon, lung, ovarian, and prostate cancers is associated with poor prognosis. Li et al., Lab. Invest. 2010, 90, 234-44; Landen et al., Mol. Cancer Ther. 2010, 9, 3186-99; Kahlert et al., Ann. Surg. Oncol. 2012, 19, 4193-201; Huang et al., Cancer Lett. 2013, 328, 144-51; Liu et al., BMC Cancer 2014, 14, 444. It is generally believed that targeted therapies capable of eliminating CSCs may contribute to more effective cancer treatment. Batlle and Clevers, Nat. Med, 2017, 23, 1124-34. However, there are more than 18 aldehyde dehydrogenase isoforms in humans, many of which have similar substrate ranges to ALDH1A1. Vasiliou and Nebert, Hum. Genomics 2005, 2, 138-43. Therefore, selectively targeting ALDH1A1 without affecting other ALDH isoforms commonly found in normal tissues is challenging.

[0006] Despite advances in cancer diagnosis and treatment, cancer remains a significant public health problem globally. Wang and Mooney, Nat. Chem. 2020, 12, 1102-14. It is estimated that in 2023, there will be 1,958,310 new cancer diagnoses and 609,820 cancer deaths in the United States alone. Cancer Facts & Figures 2023. Therefore, there is a need for effective methods and therapies for cancer diagnosis and treatment. Batlle and Clevers, Nat. Med, 2017, 23, 1124-34; Bargahi et al., Biol. Proced. Online 2022, 24, 5. Summary of the Invention

[0007] This article provides compounds of formula (A): 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 1 It is hydrogen or deuterium; R 2 and R 3 Each is independently (i) hydrogen, deuterium, cyano, halogen, or nitro; (ii) C 1-10 Alkyl, C 1-10 Heteroalkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 3-10 cycloalkyl, C 6-14 Aryl, C 7-15 Aryl, heteroaryl, or heterocyclic; 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 R1c –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 –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 5 Each is independently (i) hydrogen; (ii) C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, C 6-14 Aryl, C 7-15 Aryl, heteroaryl, or heterocyclic; 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)R1a –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 ; R 6 and R 7 Each independently is (i) halogen; or (ii) –OR 1a –OC(O)R 1a –OC(O)OR 1a Or –OC(O)NR 1b R 1c And R 8 For (i) hydrogen; or (ii) –C(O)R 1a –C(O)OR 1a Or –C(O)NR 1b R 1c ; or R 6 and R 7 Or R 7 and R 8 They connect together to form a lactone ring; A represents a bond, O, or N (R). 1b ); E represents hydrogen, azide, halogen, isocyanate, or –C=C(R). 1a )R 1a –C≡CR 1a , , , –C(O)R 1a Or –SH; L is C 1-6 Alkylene, C 1-6 Heteroalkyl, C 2-6 imidene group, C 2-6 Ethyne group, C 3-10 Cycloalkylene, C 6-14 Alpha-aryl, C 7-15 arylene alkyl groups, heteroarylene alkyl groups, or heterocyclic alkyl groups; and R 1a R 1b R 1c and R 1d Each is independently hydrogen, deuterium, and C. 1-30 Alkyl, C 1-30 Heteroalkyl, C 2-30 alkenyl, C 2-30alkynyl group, C 3-30 cycloalkyl, C 6-30 Aryl, C 7-30 Aryl, heteroaryl, or heterocyclic groups; Wherein, alkyl, alkylene, heteroalkyl, heteroalkylene, alkenyl, alkenylene, ynyl, ynylene, cycloalkyl, cycloalkylene, aryl, arylene, arylalkylene, heteroaryl, heteroaryl, heteroaryl, heterocyclic and heterocyclic are each optionally substituted by one or more (in one embodiment, by one, two, three or four) substituents Q, wherein each 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 group, C 3-10 cycloalkyl, C 6-14 Aryl, C 7-15 Aryl, heteroaryl, and heterocyclic groups, each optionally further substituented by one or more (in one embodiment, by one, two, three, or four) substituents Q. a Substitution; 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 Rc –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 –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 Each is independently (i) hydrogen or deuterium; (ii) C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, C 6-14 Aryl, C 7-15 Aryl, heteroaryl, or heterocyclic groups, each optionally substituted with one or more (in one embodiment, one, two, three, or four) substituents Q. a Replace; or (iii) Rb and R c Together with the N atoms to which they are attached, they form heterocyclic groups, which are optionally substituents Q by one or more (in one embodiment, by one, two, three, or four) substituents. a replace; Among them, Q a Each 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 group, C 3-10 cycloalkyl, C 6-14 Aryl, C 7-15 Aryl alkyl, heteroaryl and heterocyclic groups; 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 eC(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 Among them, R e R f R g and R h Each is independently (i) hydrogen or deuterium; (ii) C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, C 6-14 Aryl, C 7-15 Aryl, heteroaryl, or heterocyclic; or (iii) R f and R g Together with the N atoms they are attached to, they form heterocyclic groups.

[0008] This article also provides compounds 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 pharmaceutically acceptable salts, solvates, hydrates, or prodrugs thereof; wherein: R 1 It is hydrogen or deuterium; R 2 and R 3 Each is independently (i) hydrogen, deuterium, cyano, halogen, or nitro; (ii) C 1-10 Alkyl, C 1-10 Heteroalkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 3-10 cycloalkyl, C 6-14 Aryl, C 7-15 Aryl, heteroaryl, or heterocyclic; 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 1aC(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 –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 5 Each is independently (i) hydrogen; (ii) C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, C 6-14 Aryl, C 7-15 Aryl, heteroaryl, or heterocyclic; 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 –S(O)R 1a –S(O)2R 1a –S(O)NR 1b R 1c Or –S(O)2NR 1b R 1c ; R 6 and R 7 Each independently is (i) halogen; or (ii) –OR 1a –OC(O)R 1a –OC(O)OR 1a Or –OC(O)NR 1b R 1c And R 8 For (i) hydrogen; or (ii) –C(O)R 1a –C(O)OR 1a Or –C(O)NR 1b R 1c ; or R 6 and R 7 Or R 7 and R 8 They connect together to form a lactone ring; A represents a bond, O, or N (R). 1b ); E represents hydrogen, azide, halogen, isocyanate, or –C=C(R). 1a )R 1a –C≡CR 1a , , , –C(O)R 1a Or –SH; L is C 1-6 Alkylene, C 1-6 Heteroalkyl, C 2-6 imidene group, C 2-6 Ethyne group, C 3-10 Cycloalkylene, C 6-14 Alpha-aryl, C 7-15 arylene alkyl groups, heteroarylene alkyl groups, or heterocyclic alkyl groups; and R 1a R 1b R 1c and R 1d Each is independently hydrogen, deuterium, and C. 1-30 Alkyl, C 1-30 Heteroalkyl, C 2-30 alkenyl, C 2-30 alkynyl group, C 3-30 cycloalkyl, C 6-30 Aryl, C 7-30Aryl, heteroaryl, or heterocyclic groups; Wherein, alkyl, alkylene, heteroalkyl, heteroalkylene, alkenyl, alkenylene, ynyl, ynylene, cycloalkyl, cycloalkylene, aryl, arylene, arylalkylene, heteroaryl, heteroaryl, heteroaryl, heterocyclic and heterocyclic are each optionally substituted by one or more (in one embodiment, by one, two, three or four) substituents Q, wherein each 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 group, C 3-10 cycloalkyl, C 6-14 Aryl, C 7-15 Aryl, heteroaryl, and heterocyclic groups, each optionally further substituented by one or more (in one embodiment, by one, two, three, or four) substituents Q. a Substitution; 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 –NRb 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 –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 Each is independently (i) hydrogen or deuterium; (ii) C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, C 6-14 Aryl, C 7-15 Aryl, heteroaryl, or heterocyclic groups, each optionally substituted with one or more (in one embodiment, one, two, three, or four) substituents Q. a Replace; or (iii) R b and R cTogether with the N atoms to which they are attached, they form heterocyclic groups, which are optionally substituents Q by one or more (in one embodiment, by one, two, three, or four) substituents. a replace; Among them, Q a Each 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 group, C 3-10 cycloalkyl, C 6-14 Aryl, C 7-15 Aryl alkyl, heteroaryl and heterocyclic groups; 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 –NRe 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 Among them, R e R f R g and R h Each is independently (i) hydrogen or deuterium; (ii) C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, C 6-14 Aryl, C 7-15 Aryl, heteroaryl, or heterocyclic; or (iii) R f and R g Together with the N atoms they are attached to, they form heterocyclic groups.

[0009] Additionally, this document provides pharmaceutical compositions comprising a compound of formula (A) or 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.

[0010] Furthermore, this article provides a method for labeling cells in a subject with a functional group (e.g., an azide group), the method comprising administering to a subject in need an effective amount of a compound of formula (A) or 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.

[0011] This article provides a method for labeling cells with a functional group (e.g., an azide group), the method comprising contacting the cells with an effective amount of a compound of formula (A) or 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, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0012] This article provides N-((3S,4R,5S,6R)-2-amino-4,5-dihydroxy-6-(hydroxymethyl)-tetrahydro-2H-pyran-3-yl)-2-azidoacetamide C1; (Z)-N-((3S,4R,5S,6R)-3-(2-azidoacetamido)-4,5-dihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)-2-ethyl-4-oxobut-2-enamide C2; ​​or (Z)-3-(((3S,4R,5S,6R)-3-(2-azidoacetamido)-4,5-dihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)carbamoyl)pent-2-enoic acid C3. Attached Figure Description

[0013] Figure 1The metabolic glycoengineering process of AAMCHO A1 is demonstrated. After internalization into the cell, AAMCHO A1 is first hydrolyzed to AM-CHO by intracellular esterases (step 1). The aldehyde group on AAMCHO A1 is then enzymatically converted to a carboxylic acid group by intracellular ALDH1A1 (step 2), allowing the generated maleyl monoamide to spontaneously self-cyclize and release a C1 amine-substituted azide sugar (AM-NH2) and an anhydride byproduct (step 3). AM-NH2 is then rapidly hydrolyzed to generate the metabolically active sugar AM (step 4), which is further processed through a series of cellular biosynthetic pathways (steps 6-9) to express the azide group on the cell surface glycoprotein.

[0014] Figure 2 The degradation kinetics of AAMCHO A1 in the presence of ALDH1A1 were shown.

[0015] Figure 3 The degradation of AAMCHO A1 after incubation with different ALDH isoforms for 30 min was shown. Statistical comparisons were performed between each group and the enzyme-free control group. Numerical data are expressed as mean ± SD (0.01 < *P ≤ 0.05; and ****P ≤ 0.0001). DEAB (4-diethylaminobenzaldehyde) is an ALDH1A1 inhibitor.

[0016] Figure 4 The timeline for in vivo cell marker studies is shown. Mice were subcutaneously inoculated with CSCs or non-CSCs in the left and right flanks, respectively, followed by intravenous injection of AAMCHO A1 on days 7–9, and intravenous injection of DBCO-Cy5 on day 10.

[0017] Figure 5 The mean Cy5 fluorescence intensity of tumor tissue 24 hours after DBCO-Cy5 injection is shown. Numerical data are expressed as mean ± SD.

[0018] Figure 6 The quantitative results of azide-labeled sialic acid (Neu5NAz) extracted from different tissues are presented. Numerical data are expressed as mean ± SD (0.01 < *P ≤ 0.05; 0.001 < **P ≤ 0.01; and 0.0001 < ***P ≤ 0.001). Detailed Implementation

[0019] To facilitate understanding of the disclosures presented herein, several terms are defined below.

[0020] 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.

[0021] 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, for example, when referring to a mammalian subject, such as a human subject. In one embodiment, the subject is a human.

[0022] The term "contacting" refers to bringing a therapeutic agent and a biomolecule (e.g., a protein, enzyme, RNA, or DNA), cell, or tissue together, so that such contact induces physiological and / or chemical effects. Contact can occur in vitro, ex vivo, or in vivo. In one embodiment, the therapeutic agent is contacted with a biomolecule in vitro to determine the effect of the therapeutic agent on the biomolecule. In another embodiment, the 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, cell, or tissue includes administering the therapeutic agent to a subject having the biomolecule, cell, or tissue to be contacted.

[0023] The term "therapeutic effective amount" or "effective amount" means, when administered, an amount of compound sufficient to prevent the development of one or more symptoms of the treated disorder, disease, or condition, or to alleviate, to some extent, one or more symptoms of the treated disorder, disease, or condition. The term "therapeutic effective amount" or "effective amount" also means an amount of compound sufficient to elicit a biological or medical response in a biomolecule (e.g., a protein, enzyme, RNA, or DNA), cell, tissue, system, animal, or human that is being sought by researchers, veterinarians, physicians, or clinicians.

[0024] The terms “pharmaceutically acceptable carrier,” “pharmaceuticalally acceptable excipient,” “physiologically acceptable carrier,” or “physiologically acceptable excipient” refer to pharmaceutically acceptable materials, compositions, or media (e.g., liquid or solid fillers, diluents, solvents, or encapsulating materials). In one embodiment, each component is “pharmaceutically acceptable” in the sense of compatibility with other components of the pharmaceutical formulation and is suitable for contact with the tissues or organs of a subject (e.g., a human) without excessive toxicity, irritation, allergic reactions, immunogenicity, or other problems or complications, and is commensurate with a reasonable benefit / risk ratio. See, for example, 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.

[0025] The terms "about" or "approximately" refer to an acceptable error for a particular value as determined by those skilled in the art, depending in part on how the value is measured or determined. In some embodiments, the terms "about" or "approximately" mean within one, two, or three standard deviations. In some embodiments, the terms "about" or "approximately" mean 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.

[0026] The term "alkyl" refers to a straight-chain or branched saturated monovalent hydrocarbon group, wherein the alkyl group is optionally substituted by one or more substituents Q as described herein. For example, C 1-6 Alkyl groups refer to straight-chain saturated monovalent hydrocarbon groups with 1 to 6 carbon atoms or branched saturated monovalent hydrocarbon groups with 3 to 6 carbon atoms. In some embodiments, the alkyl group has 1 to 30 carbon atoms. 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 1-6A straight-chain saturated monovalent hydrocarbon group of carbon atoms, or 3 to 30 (C) atoms. 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 Branched monovalent hydrocarbon groups of carbon atoms. As used in this article, straight-chain C 1-6 and branch C 3-6 Alkyl groups are also called "lower alkyl groups". Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl (including all isomers, such as n-propyl and isopropyl), butyl (including all isomers, such as n-butyl, isobutyl, sec-butyl and tert-butyl), pentyl (including all isomers, such as n-pentyl, isopentyl, sec-pentyl, neopentyl and tert-pentyl), and hexyl (including all isomers, such as n-hexyl, isohexyl and sec-hexyl).

[0027] The terms "alkylene" and "alkanediyl" are used interchangeably herein when referring to a straight-chain or branched saturated divalent hydrocarbon group, wherein the alkanediyl group is optionally substituted with one or more substituents Q as described herein. For example, C 1-6 Alkidine refers to a straight-chain saturated divalent hydrocarbon group with 1 to 6 carbon atoms or a branched saturated divalent hydrocarbon group with 3 to 6 carbon atoms. In some embodiments, the alkidine group has 1 to 30 carbon atoms. 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 A straight-chain saturated divalent hydrocarbon group of carbon atoms, or 3 to 30 (C) atoms. 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 Branched saturated divalent hydrocarbon groups of carbon atoms. As used in this article, straight-chain C 1-6 and branch C 3-6Alkidine groups are also called "lower alkylidines". Examples of alkylidine groups include, but are not limited to, methanediyl, ethanediyl (including all isomers, such as ethane-1,1-diyl and ethane-1,2-diyl), propanediyl (including all isomers, such as propane-1,1-diyl, propane-1,2-diyl and propane-1,3-diyl), and butanediyl (including all isomers, such as butane-1,1-diyl, butane-1,2 ... Diyl, butane-1,3-diyl, and butane-1,4-diyl), pentanediyl (including all isomers, e.g., pentane-1,1-diyl, pentane-1,2-diyl, pentane-1,3-diyl, and pentane-1,5-diyl), and hexanediyl (including all isomers, e.g., hexane-1,1-diyl, hexane-1,2-diyl, hexane-1,3-diyl, and hexane-1,6-diyl). Examples of substituted alkyldiyl 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–, and –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)–.

[0028] The term "heteroalkyl" refers to a straight-chain or branched saturated monovalent hydrocarbon group containing one or more heteroatoms on its main chain, each heteroatom being independently selected from O, S, and N. Heteroalkyl groups are optionally substituted with one or more substituents Q as described herein. For example, C 1-6 Heteroalkyl groups refer to straight-chain saturated monovalent hydrocarbon groups with 1 to 6 carbon atoms or branched saturated monovalent hydrocarbon groups with 3 to 6 carbon atoms. In some embodiments, the heteroalkyl group has 1 to 30 carbon atoms. 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 A straight-chain saturated monovalent hydrocarbon group of carbon atoms, or 3 to 30 (C) atoms. 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 Branched monovalent hydrocarbon groups of carbon atoms. As used in this article, straight-chain C 1-6 and branch C 3-6Heteroalkyl groups are also called "lower heteroalkyl groups". 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.

[0029] The terms "heteroalkylene" and "heteroalkyldiyl" are used interchangeably herein when referring to a straight-chain or branched saturated divalent hydrocarbon group containing one or more heteroatoms independently selected from O, S, and N on its main chain. Heteroalkyleneenes may optionally be substituted with one or more substituents Q as described herein. For example, C 1-6 Heteroalkyl groups refer to straight-chain saturated divalent hydrocarbon groups with 1 to 6 carbon atoms or branched saturated divalent hydrocarbon groups with 3 to 6 carbon atoms. In some embodiments, the heteroalkyl group has 1 to 30 carbon atoms. 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 A straight-chain saturated divalent hydrocarbon group of carbon atoms, or 3 to 30 (C) atoms. 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 Branched saturated divalent hydrocarbon groups of carbon atoms. As used in this article, straight-chain C 1-6 and branch C 3-6 Heteroalkyl groups are also called "lower heteroalkyl groups". Examples of heteroalkyl groups include, but are not limited to, –CH2O–, –CH2CH2O–, –CH2CH2CH2O–, –(CH2)4O–, –(CH2)5O–, –(CH2)6O–, –(CH2)7O–, –(CH2)8O–, –(CH2)9O–, and –(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–, and –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(C H2CH2O)5–, –CH2NHC(O)CH2–, –CH2CH2C(O)NH–, –CH2N(CH3)–, –(CH2)2N(CH3)–, –(CH2)3N(CH3)–, or –(CH2)4N(CH3)–.

[0030] The term "alkenyl" refers to a straight-chain or branched 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 group is optionally substituted with one or more substituents Q as described herein. As will be understood by those skilled in the art, the term "alkenyl" includes groups having a "cis" or "trans" configuration or a mixture thereof, or groups having a "Z" or "E" configuration or a mixture thereof. For example, C 2-6 Alkenyl groups refer to straight-chain unsaturated monovalent hydrocarbon groups with 2 to 6 carbon atoms or branched unsaturated monovalent hydrocarbon groups with 3 to 6 carbon atoms. In some embodiments, the alkenyl group has 2 to 30 carbon atoms. 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 A straight-chain monovalent hydrocarbon group consisting of 3 to 30 carbon atoms. 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 a carbon atom. Examples of alkenyl groups include, but are not limited to, vinyl, propenyl (including all isomers, such as propen-1-yl, propen-2-yl, and allyl) and butenyl (including all isomers, such as buten-1-yl, buten-2-yl, buten-3-yl, and 2-buten-1-yl).

[0031] The terms “alkenyl” and “alkendiyl” 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. Alkendiyl groups are optionally substituted with one or more substituents Q as described herein. As will be understood by those skilled in the art, the term “alkendiyl” includes groups having a “cis” or “trans” configuration or a mixture thereof, or groups having a “Z” or “E” configuration or a mixture thereof. For example, C 2-6 An alkenediyl group refers to a straight-chain unsaturated divalent hydrocarbon group with 2 to 6 carbon atoms or a branched unsaturated divalent hydrocarbon group with 3 to 6 carbon atoms. In some embodiments, the alkenediyl group has 2 to 30 carbon atoms. 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 A straight-chain divalent hydrocarbon group of carbon atoms, or 3 to 30 (C) atoms. 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 A branched divalent hydrocarbon group consisting of a carbon atom. Examples of alkylene groups include, but are not limited to, ethylenediyl (including all isomers, e.g., ethylene-1,1-diyl and ethylene-1,2-diyl), propylenediyl (including all isomers, e.g., 1-propylene-1,1-diyl, 1-propylene-1,2-diyl and 1-propylene-1,3-diyl), and butendiyl (including all isomers, e.g., 1-buten-1,1-diyl, 1-buten-1,2-diyl and 1-buten- 1,4-diyl), pentenidyl (including all isomers, e.g., 1-penten-1,1-diyl, 1-penten-1,2-diyl and 1-penten-1,5-diyl) and hexenidyl (including all isomers, e.g., 1-hexen-1,1-diyl, 1-hexen-1,2-diyl, 1-hexen-1,3-diyl, 1-hexen-1,4-diyl, 1-hexen-1,5-diyl and 1-hexen-1,6-diyl).

[0032] The term "alkynyl" refers to a straight-chain or branched 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 a carbon-carbon double bond. The alkynyl group may optionally be substituted by one or more substituents Q as described herein. For example, C 2-6 An alkynyl group refers to a straight-chain unsaturated monovalent hydrocarbon group with 2 to 6 carbon atoms or a branched unsaturated monovalent hydrocarbon group with 4 to 6 carbon atoms. In some embodiments, the alkynyl group has 2 to 30 carbon atoms. 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 A straight-chain monovalent hydrocarbon group consisting of carbon atoms, or 4 to 30 (C) atoms. 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 A branched monovalent hydrocarbon group of a carbon atom. Examples of alkynyl groups include, but are not limited to, ethynyl (-C≡CH), propynyl (including all isomers, e.g., 1-propynyl (-C≡CCH3) and propynyl (-CH2C≡CH), butynyl (including all isomers, e.g., 1-butyn-1-yl and 2-butyn-1-yl), penynyl (including all isomers, e.g., 1-pentyn-1-yl and 1-methyl-2-butyn-1-yl), and hexynyl (including all isomers, e.g., 1-hexyn-1-yl and 2-hexyn-1-yl).

[0033] The terms "ynynyl" and "acetylide" 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 triple bonds. The ynynyl group does not contain a carbon-carbon double bond. The acetylide may optionally be substituted by one or more substituents Q as described herein. For example, C 2-6 A diacetyl group refers to a straight-chain unsaturated divalent hydrocarbon group with 2 to 6 carbon atoms or a branched unsaturated divalent hydrocarbon group with 4 to 6 carbon atoms. In some embodiments, the diacetyl group has 2 to 30 carbon atoms. 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 A straight-chain divalent hydrocarbon group of carbon atoms, or 4 to 30 (C) atoms. 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 A branched divalent hydrocarbon group of a carbon atom. Examples of ynyl groups include, but are not limited to, ethynyl, propynyl (including all isomers, e.g., 1-propyn-1,3-diyl and 1-propyn-3,3-diyl), butynyl (including all isomers, e.g., 1-butyn-1,3-diyl, 1-butyn-1,4-diyl and 2-butyn-1,1-diyl), pentyneyl (including all isomers, e.g., 1-pentyn-1,3-diyl, 1-pentyn-1,4-diyl and 2-pentyn-1,1-diyl), and hexynyl (including all isomers, e.g., 1-hexyn-1,3-diyl, 1-hexyn-1,4-diyl and 2-hexyn-1,1-diyl).

[0034] 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 group is a saturated or unsaturated but non-aromatic, and / or bridged or non-bridged, and / or fused bicyclic group. In some embodiments, the cycloalkyl group has 3 to 20 (C) atoms. 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 atom. In one embodiment, the cycloalkyl group is monocyclic. In another embodiment, the cycloalkyl group is bicyclic. In yet another embodiment, the cycloalkyl group is tricyclic. In still another embodiment, the cycloalkyl group 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.

[0035] The terms "cycloalkylene" and "cycloalkyl dieryl" are used interchangeably herein when referring to cyclic divalent hydrocarbon groups, which may optionally be substituted with one or more substituents Q as described herein. In one embodiment, the cycloalkyl dieryl group may be a saturated or unsaturated but non-aromatic, and / or bridged, and / or non-bridged, and / or fused bicyclic group. In some embodiments, the cycloalkyl dieryl group has 3 to 30 (C) atoms. 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 cycloalkanediyl groups include, but are not limited to, cyclopropanediyl (including all isomers, e.g., cyclopropane-1,1-diyl and cyclopropane-1,2-diyl), cyclobutanediyl (including all isomers, e.g., cyclobutane-1,1-diyl, cyclobutane-1,2-diyl and cyclobutane-1,3-diyl), cyclopentanediyl (including all isomers, e.g., cyclopentane-1,1-diyl, cyclopentane-1,2-diyl and cyclopentane-1,3-diyl), and cyclohexanediyl (including all isomers, e.g., cyclohexane-1,1-diyl, cyclohexane-1,3-diyl). 2-Diyl, cyclohexane-1,3-diyl and cyclohexane-1,4-diyl), cycloheptanediyl (including all isomers, e.g. cycloheptane-1,1-diyl, cycloheptane-1,2-diyl, cycloheptane-1,3-diyl and cycloheptane-1,4-diyl), decahydronaphthyl (including all isomers, e.g. decahydronaphthyl-1,1-diyl, decahydronaphthyl-1,2-diyl and decahydronaphthyl-1,8-diyl), and adamantanediyl (including all isomers, e.g. adamantane-1,2-diyl, adamantane-1,3-diyl and adamantane-1,8-diyl).

[0036] The term "aryl" refers to a monovalent monocyclic aromatic hydrocarbon group and / or a monovalent polycyclic aromatic hydrocarbon group containing at least one aromatic carbide ring. In some embodiments, the aryl group has 6 to 30 (C) rings. 6-30 ), 6 to 20 (C) 6-20 ), 6 to 15 (C) 6-15 ) or 6 to 10 (C 6-10 A ring carbon atom. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, fluorenyl, azulenyl, anthraceneyl, phenanthryl, pyrene, biphenyl, and terphenyl. The aryl group also refers to a bicyclic or tricyclic carbocyclic ring, where one ring is aromatic and the others may be saturated, partially unsaturated, or aromatic, such as dihydronaphthyl, indenyl, indenyl, or tetrahydronaphthyl (tetrahydronaphthyl). In one embodiment, the aryl group is monocyclic. In another embodiment, the aryl group is bicyclic. In yet another embodiment, the aryl group is tricyclic. In still another embodiment, the aryl group is polycyclic. In some embodiments, the aryl group is optionally substituted by one or more substituents Q as described herein.

[0037] The terms "arylene" and "aryl" 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 some embodiments, the arylene group has 6 to 30 (C) rings. 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 isomers, e.g., phenyl-1,2-diyl, phenyl-1,3-diyl, and phenyl-1,4-diyl), naphthylene (including all isomers, e.g., naphth-1,2-diyl, naphth-1,3-diyl, and naphth-1,8-diyl), fluorene (including all isomers, e.g., fluorene-1,2-diyl, fluorene-1,3-diyl, and fluorene-1,8-diyl), azulene (including all isomers, e.g., azulene-1,2-diyl, azulene-1,3-diyl, and azulene-1,8-diyl), and anthracene (including all isomers, e.g., anthracene-1,2-diyl...). , anthracene-1,3-diyl and anthracene-1,8-diyl), phenanthrene- (including all isomers, e.g., phenanthrene-1,2-diyl, phenanthrene-1,3-diyl and phenanthrene-1,8-diyl), pyrene- (including all isomers, e.g., pyrene-1,2-diyl, pyrene-1,3-diyl and pyrene-1,8-diyl), biphenyl- (including all isomers, e.g., biphenyl-2,3-diyl, biphenyl-3,4'-diyl and biphenyl-4,4'-diyl), and terphenyl- (including all isomers, e.g., terphenyl-2,3-diyl, terphenyl-3,4'-diyl and terphenyl-4,4'-diyl). Arylidene also refers to bicyclic or tricyclic carbocyclic rings, where one ring is aromatic and the others can be saturated, partially unsaturated, or aromatic. Examples include dihydronaphthylene (including all isomers, such as dihydronaphth-1,2-diyl and dihydronaphth-1,8-diyl), indenylene (including all isomers, such as indene-1,2-diyl, indene-1,5-diyl and indene-1,7-diyl), indenmanylene (including all isomers, such as indman-1,2-diyl, indman-1,5-diyl and indman-1,7-diyl), or tetrahydronaphthylene (including all isomers, such as tetrahydronaphth-1,2-diyl, tetrahydronaphth-1,5-diyl and tetrahydronaphth-1,8-diyl). In some embodiments, the aryl group is optionally substituted with one or more substituents Q as described herein.

[0038] The term "aralkyl" or "arylalkyl" refers to a monovalent alkyl group substituted with one or more aryl groups. In some embodiments, the aralkyl group has 7 to 30 (C) groups. 7-30 ), 7 to 20 (C) 7-20 ) or 7 to 16 (C 7-16 The aralkyl group includes, but is not limited to, benzyl, phenethyl (including all isomers, e.g., 1-phenethyl and 2-phenethyl), and phenylpropyl (including all isomers, e.g., 1-phenylpropyl, 2-phenylpropyl, and 3-phenylpropyl). In some embodiments, the aralkyl group is optionally substituted with one or more substituents Q as described herein.

[0039] The term "arylene alkyl" or "arylene alkylene" refers to a divalent alkyl group substituted with one or more aryl groups. In some embodiments, the arylene alkylene group has 7 to 30 (C) groups. 7-30 ), 7 to 20 (C) 7-20 ) or 7 to 16 (C 7-16 The carbon atom. Examples of arylene alkyl groups include, but are not limited to, benzylene (including all isomers, e.g., phenylmethyldiyl), phenylethylene (including all isomers, e.g., 2-phenyl-ethyl-1,1-diyl and 2-phenyl-ethyl-1,2-diyl), and phenylpropylene (including all isomers, e.g., 3-phenyl-prop-1,1-diyl, 3-phenyl-prop-1,2-diyl and 3-phenyl-prop-1,3-diyl). In some embodiments, the arylene alkyl group is optionally substituted with one or more substituents Q as described herein.

[0040] The term "heteroaryl" refers to a monovalent monocyclic aromatic group or a monovalent polycyclic aromatic group containing at least one aromatic ring, wherein the at least one aromatic ring contains one or more heteroatoms, each independently selected from O, S, and N. For heteroaryl groups containing heterocyclic and non-aromatic heterocycles, the heteroaryl group is not bonded to the rest of the molecule through its non-aromatic heterocycle. 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 four or less, and each ring contains at least one carbon atom. In some 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, furanyl, imidazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridinyl, pyrimidinyl, pyrroleyl, thiadiazolyl, thiazolyl, thiophene, tetrazolyl, triazinyl, and triazolyl. In another embodiment, the heteroaryl group is bicyclic.Examples of bicyclic heteroaryl groups include, but are not limited to, benzofuranyl, benzimidazolyl, benzoisoxazolyl, benzopyranyl, benzothiadiazolyl, benzothiazolyl, benzothiophenyl, benzotriazolyl, benzoxazolyl, furanopyridyl (including all isomers, such as 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), imidazolyl, and others. Pyridyl (including all isomers, e.g., imidazo[1,2-a]pyridyl, imidazo[4,5-b]pyridyl, and imidazo[4,5-c]pyridyl), imidazothiazolyl (including all isomers, e.g., imidazo[2,1-b]thiazolyl and imidazo[4,5-d]thiazolyl), indazole, indolizinyl, indole, isobenzofuranyl, isobenzothiophenyl (i.e., benzo[c]thiophenyl), isoindolyl, isoquinolinyl, naphthidyl (including all isomers) Formulas, such as 1,5-naphthidyl, 1,6-naphthidyl, 1,7-naphthidyl and 1,8-naphthidyl), oxazolopyridyl (including all isomers, such as oxazolo[4,5-b]pyridyl, oxazolo[4,5-c]pyridyl, oxazolo[5,4-b]pyridyl and oxazolo[5,4-c]pyridyl), phthalazinyl, pteridylyl, purinyl, pyrrolopyridyl (including all isomers, such as pyrrolo[2,3-b]pyridyl, pyrrolo[2,3-c]pyridyl, pyrrolo[3, [2-b]pyridinyl and pyrrolo[3,2-c]pyridinyl), quinolinyl, quinoxalinyl, quinazolinyl, thiadiazo[3,4-d]pyrimidinyl (including all isomers, e.g., [1,2,5]thiadiazo[3,4-d]pyrimidinyl and [1,2,3]thiadiazo[4,5-d]pyrimidinyl), and thieno[2,3-b]pyridinyl, thieno[2,3-c]pyridinyl, thieno[3,2-b]pyridinyl, and thieno[3,2-c]pyridinyl. In yet another embodiment, the heteroaryl group is tricyclic. Examples of tricyclic heteroaryl groups include, but are not limited to, acridinel, benzoindolyl, carbazolyl, dibenzofuranyl, perimidinyl, phenanthrolinel, phenanthidinel (including all isomers, e.g., 1,5-phenanthrolinel, 1,6-phenanthrolinel, 1,7-phenanthrolinel, 1,9-phenanthrolinel, and 2,10-phenanthrolinel), phenarsazinyl, phenazinyl, phenthiazinyl, phenoxazinyl, and xanthonyl. In some embodiments, the heteroaryl group is optionally substituted with one or more substituents Q as described herein.

[0041] The terms "heteroaryl" and "heteroaryl diaryl" 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 the at least one aromatic ring contains one or more heteroatoms, each heteroatom independently selected from O, S, and N. For a heteroaryl group containing a heterocyclic and non-aromatic heterocycle, the heteroaryl group is not bonded to the remainder of the molecule through its non-aromatic heterocycle. 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 four or less, and each ring contains at least one carbon atom. In some embodiments, the heteroaryl group has 5 to 20, 5 to 15, or 5 to 10 ring atoms. Examples of monocyclic heteroaryl groups include, but are not limited to, furanyl, imidazole, isothiazolyl, isoxazolyl, oxadiazole, oxazolyl, pyrazinyl, pyrazole, pyridazinyl, pyridine, pyrimidine, pyrroleyl, thiadiazole, thiazolyl, thiophene, tetrazolyl, triazineyl, and triazoleyl.Examples of bicyclic heteroaryl groups include, but are not limited to, benzofurandiyl, benzimidazolediyl, benzisoxazolediyl, benzopyrandiyl, benzothiadiazolediyl, benzothiazoldiyl, benzothiophenediyl, benzotriazolediyl, benzoxazolediyl, furanopyridindiyl (including all isomers, such as furano[2,3-b]pyridindiyl, furano[2,3-c]pyridindiyl, furano[3,2-b]pyridindiyl, furano[3,2-c]pyridindiyl, furano[3,4-b]pyridindiyl and furano[3,4-c]pyridindiyl). ), imidazopyridinyl (including all isomers, e.g., imidazo[1,2-a]pyridinyl, imidazo[4,5-b]pyridinyl and imidazo[4,5-c]pyridinyl), imidazothiazolediyl (including all isomers, e.g., imidazo[2,1-b]thiazolediyl and imidazo[4,5-d]thiazolediyl), indazolediyl, indenediyl, indolediyl, isobenzofurandiyl, isobenzothiophenediyl (i.e., benzo[c]thiophenediyl), isoindolediyl, isoquinolinediyl, naphthidinediyl (including all isomers, e.g.) 1,5-Naphthodiyl, 1,6-Naphthodiyl, 1,7-Naphthodiyl and 1,8-Naphthodiyl), oxazolopyridinyl (including all isomers, e.g. oxazolo[4,5-b]pyridinyl, oxazolo[4,5-c]pyridinyl, oxazolo[5,4-b]pyridinyl and oxazolo[5,4-c]pyridinyl), phthalazinyl, pteridinediyl, purinediyl, pyrrolopyridinyl (including all isomers, e.g. pyrrolo[2,3-b]pyridinyl, pyrrolo[2,3-c]pyridinyl, pyrrolo[3,2-b]pyridinyl, pyrrolo[3,2-b]pyridinyl, pyrrolo[4,5-b]pyridinyl, pyrrolo[4,5-c]pyridinyl, pyrrolo[4,5-c]pyridinyl, pyrrolo[5,4-b]pyridinyl, pyrrolo[5,4-c]pyridinyl, pyrrolo[3,2-b]pyridinyl, pyrrolo[4,5-b]pyridinyl, pyrrolo[4,5-c ...b]pyridinyl, pyrrolo[4,5-c]pyridinyl, pyrrolo[4,5-b] [-b]pyridinidyl and pyrrolo[3,2-c]pyridinidyl), quinolineidyl, quinoxalolineidyl, quinazolineidyl, thiadiazo[3,4-d]pyrimidineidyl (including all isomers, e.g., [1,2,5]thiadiazo[3,4-d]pyrimidineidyl and [1,2,3]thiadiazo[4,5-d]pyrimidineidyl), and thieno[2,3-b]pyridinidyl, thieno[2,3-c]pyridinidyl, thieno[3,2-b]pyridinidyl and thieno[3,2-c]pyridinidyl). Examples of tricyclic heteroaryl groups include, but are not limited to, acridinediyl, benzoindolyl, carbazolediyl, dibenzofurandiyl, piridinediyl, phenanthrolinediyl (including all isomers, e.g., 1,5-phenanthrolinediyl, 1,6-phenanthrolinediyl, 1,7-phenanthrolinediyl, 1,9-phenanthrolinediyl and 2,10-phenanthrolinediyl), phenidinediyl, phenpyrazinediyl, phenazinediyl, phenothiazinediyl, phenotoxazinediyl and xanthondiyl. In some embodiments, the heteroaryl group is optionally substituted with one or more substituents Q as described herein.

[0042] The term "heterocyclic group" or "heterocyclic" refers to a monovalent monocyclic non-aromatic ring system or a monovalent polycyclic ring system containing at least one non-aromatic ring, wherein one or more of the non-aromatic ring atoms are heteroatoms, each independently selected from O, S, and N; and the remaining ring atoms are carbon atoms. For heterocyclic groups containing heteroaromatic and non-aromatic heterocycles, the heterocyclic group is not bonded to the rest of the molecule via a heteroaromatic ring. In some embodiments, the heterocyclic group or heterocyclic group has 3 to 20, 3 to 15, 3 to 10, 3 to 8, 4 to 7, or 5 to 6 ring atoms. In some embodiments, the heterocyclic group is a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may be fused or bridged, and wherein nitrogen or sulfur atoms may optionally be oxidized, 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 causes the formation of a stable compound. Examples of heterocyclic groups and heterocyclic compounds include, but are not limited to, aziridine, benzodioxane, benzo-m-dioxacyclopentenyl, benzofuranone, chromanyl, decahydroisoquinolinyl, dihydrobenzofuranyl, dihydrobenzoisothiazolyl, dihydrobenzoisooxazinyl (including all isomers, e.g., 1,4-dihydrobenzo[d][1,3]oxazinyl, 3,4-dihydrobenzo[c][1,2]oxazinyl and 3,4-dihydrobenzo[d][1,2]oxazinyl), dihydrobenzothiophenyl, dihydroisobenzofuranyl, dihydrobenzo[c]thiophenyl, dihydrofuranyl, dihydroisoindolyl, dihydropyranyl, dihydropyrazolyl, dihydropyrazolyl, dihydropyrazolyl The heterocyclic groups include azinoyl, dihydropyridyl, dihydropyrimidinyl, dihydropyrroleyl, dioxolanecycloyl, 1,4-dithiaalkyl, furanoneyl, imidazoalkyl, imidazolinyl, dihydroindolyl, isochromyl, isodihydroindolyl, isothiazolyl, isoxazolyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, oxazolidinoneyl, oxazolyl, ethylene oxide, piperazinyl, piperidinyl, 4-piperidinoneyl, pyrazolyl, pyrazolyl, pyrroleyl, pyrrolinyl, quininecycloyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydropyranyl, tetrahydrothiophenyl, thiomorpholinyl, thiazoalkyl, thiochromyl, tetrahydroquinolinyl, and 1,3,5-trithiaalkyl. In some embodiments, the heterocyclic group is optionally substituted with one or more substituents Q as described herein.

[0043] The term "hypoheterocyclic 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 hypoheterocyclic group containing a heteroaromatic ring and a non-aromatic heterocycle, the hypoheterocyclic group has at least one bond to the rest of the molecule through its non-aromatic heterocycle. In some embodiments, the hypoheterocyclic group has 3 to 20, 3 to 15, 3 to 10, 3 to 8, 4 to 7, or 5 to 6 ring atoms. In some embodiments, the hypoheterocyclic group is a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may be fused or bridged, and wherein nitrogen or sulfur atoms may optionally be oxidized, nitrogen atoms may optionally be quaternized, and some rings may be partially or fully saturated or aromatic. The hypoheterocyclic group may be attached to the main structure at any heteroatom or carbon atom that causes the formation of a stable compound. Examples of such heterocyclic groups include, but are not limited to, aziridine diel, benzodioxane diel, benzo-m-dioxane diel, benzofuranone diel, chromanyl diel, decahydroisoquinoline diel, dihydrobenzofuran diel, dihydrobenzoisothiazol diel, and dihydrobenzoisooxazine diel (including all isomers, such as 1,4-dihydrobenzo[d][1,3]oxazine diel, 3,4-dioxazine diel, etc.). (Hydrobenzo[c][1,2]oxazinediyl and 3,4-dihydrobenzo[d][1,2]oxazinediyl), dihydrobenzothiophenediyl, dihydroisobenzofurandiyl, dihydrobenzo[c]thiophenediyl, dihydrofurandiyl, dihydroisoindolediyl, dihydropyrandiyl, dihydropyrazoldiyl, dihydropyrazinediyl, dihydropyridinediyl, dihydropyrimidinediyl, dihydropyrrolediyl, dioxolanediyl) (dioxolandiyl), 1,4-dithiandiyl, furanone diyl, imidazoline diyl, imidazoline diyl, dihydroindole diyl, isochoran diyl, isodihydroindole diyl, isothiazolidine diyl, isoxazolidine diyl, morpholine diyl, octahydroindole diyl, octahydroisoindole diyl, oxazolidinediyl, oxazolidinediyl, ethylene oxide diyl, piperazine diyl, piperidine diyl, 4-piperidinone diyl, pyrazolidine diyl, pyrazolidine diyl, pyrrolidine diyl, pyrrolidine diyl, quinine diyl, tetrahydrofuran diyl, tetrahydroisoquinoline diyl, tetrahydropyran diyl, tetrahydrothiophene diyl, thiomorpholine diyl, thiazoline diyl, thiochroman diyl, tetrahydroquinoline diyl, and 1,3,5-trithiazoline diyl. In some embodiments, the heterocyclic group is optionally substituted with one or more substituents Q as described herein.

[0044] The terms “halogen,” “halogen,” or “halogenated” refer to fluorine, chlorine, bromine, and / or iodine.

[0045] The term "optionally substituted with" means that a group or substituent (e.g., alkyl, alkylene, heteroalkyl, heteroalkylene, alkenyl, alkenylene, ynylene, cycloalkyl, cycloalkylene, aryl, arylene, aralkyl, arylene, heteroaryl, heteroaryl, heteroaryl, heterocyclic or heterocyclic group) may be substituted by one or more (in one embodiment, by 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 group, C 3-10 cycloalkyl, C 6-14 Aryl, C 7-15 Aryl, heteroaryl, and heterocyclic groups, each optionally further substituented by one or more (in one embodiment, by one, two, three, or four) substituents Q. a Substitution; 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 –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 Each is independently (i) hydrogen or deuterium; (ii) C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, C 6-14 Aryl, C 7-15 Aryl, heteroaryl, or heterocyclic groups, each optionally substituted with one or more (in one embodiment, one, two, three, or four) substituents Q. a Replace; or (iii) R b and R cTogether with the N atoms to which they are attached, they form a heterocyclic group, which is optionally substituent by one or more (in one embodiment, by one, two, three, or four) Q substituents. a Substitution. As used herein, all groups that can be substituted are “optionally substituted”.

[0046] In one implementation, Q a Each 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 group, C 3-10 cycloalkyl, C 6-14 Aryl, C 7-15 Aryl alkyl, heteroaryl and heterocyclic groups; 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 –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 Among them, R e R f R g and R h Each is independently (i) hydrogen or deuterium; (ii) C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, C 6-14 Aryl, C 7-15 Aryl, heteroaryl, or heterocyclic; or (iii) R f and R g Together with the N atoms they are attached to, they form heterocyclic groups.

[0047] In some embodiments, "optically active" and "enantiomerically active" refer to a collection of molecules having an enantiomer 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 some embodiments, based on the total weight of the enantiomer mixture under discussion, the optically active compound comprises about 95% or more of one enantiomer and about 5% or less of other enantiomers. In some embodiments, based on the total weight of the enantiomer mixture under discussion, the optically active compound comprises about 98% or more of one enantiomer and about 2% or less of other enantiomers. In some embodiments, based on the total weight of the enantiomer mixture under discussion, the optically active compound comprises about 99% or more of one enantiomer and about 1% or less of other enantiomers.

[0048] In describing optically active compounds, the prefixes R and S are used to indicate the absolute configuration of the compound around its chiral center. (+) and (-) are used to indicate the optical activity of the compound, i.e., the direction in which the optically active compound rotates the plane of polarization. The (-) prefix indicates that the compound is levorotatory, meaning it rotates the plane of polarization to the left or counterclockwise. The (+) prefix indicates that the compound is dextrorotatory, meaning it rotates the plane of polarization to the right or clockwise. However, the signs (+) and (-) for optical activity are independent of the absolute configurations R and S of the compound.

[0049] The term "isotope-enriched" refers to a compound that contains an unnatural proportion of isotopes at one or more atoms constituting such a compound. In some embodiments, the isotope-enriched compound contains one or more isotopes in unnatural proportions, 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 some embodiments, the isotope-enriched compound is in a stable form, i.e., non-radioactive. In some embodiments, the isotope-enriched compound contains one or more isotopes in non-natural proportions, including but not limited to hydrogen (I). 1 H), deuterium ( 2 H), carbon-12 ( 12 C), Carbon-13 ( 13 C) Nitrogen-14 ( 14 N), nitrogen-15 ( 15 N), Oxygen-16 ( 16 O), Oxygen-17 ( 17 O), Oxygen-18 ( 18 O), Fluorine-17 ( 17 F), Phosphorus-31 ( 31 P), sulfur-32 ( 32 S), sulfur-33 ( 33 S), sulfur-34 ( 34 S), sulfur-36 ( 36 S), Chlorine-35 ( 35 Cl), Chlorine-37 ( 37 Cl), Bromine-79 ( 79 Br), bromine-81 ( 81 Br) and iodine-127 127 I). In some embodiments, the isotope-enriched compound is in an unstable form, i.e., radioactive. In some embodiments, the isotope-enriched compound contains one or more isotopes in non-natural proportions, including but not limited to tritium (I). 3 H), carbon-11 (11 C), Carbon-14 ( 14 C) Nitrogen-13 ( 13 N), Oxygen-14 ( 14 O), Oxygen-15 ( 15 O), Fluorine-18 ( 18 F), Phosphorus-32 ( 32 P), Phosphorus-33 ( 33 P), sulfur-35 ( 35 S), Chlorine-36 ( 36 Cl), Iodine-123 ( 123 I), iodine-125( 125 I), iodine-129( 129 I) and Iodine-131 131 I). It should be understood that in the compounds provided herein, any hydrogen can be, where feasible, in accordance with the judgment of a person skilled in the art. 2 H (as an example); or any carbon can be H (as an example); or any carbon can be 13 C (as an example); or any nitrogen can be C. 15 N (as an example); or any oxygen can be 18 O (as an example).

[0050] The term "isotope enrichment" refers to the substitution of a less common isotope of an element (e.g., D for deuterium or hydrogen-2) at a given position in a molecule for a more common isotope of that element (e.g., D for protium or hydrogen-1). 1 The percentage of H) incorporated. As used herein, when an atom at a particular position in a molecule is designated as a particular, less common isotope, it should be understood that the abundance of that isotope at that position is substantially greater than its natural abundance.

[0051] The term "isotope enrichment factor" refers to the ratio between the isotope abundance in an isotope-enriched compound and the natural abundance of a particular isotope.

[0052] The term "hydrogen" or the symbol "H" refers to the composition of naturally occurring hydrogen isotopes, including protium at its natural abundance. 1 H), deuterium ( 2 H or D) and tritium ( 3 Protium is the most common hydrogen isotope, with a natural abundance of over 99.98%. Deuterium is a less common hydrogen isotope, with a natural abundance of approximately 0.0156%.

[0053] The term "deuterium enrichment" refers to the percentage of deuterium replacing 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 specified position. Since the natural distribution of deuterium is on average about 0.0156%, the deuterium enrichment at any position in a compound synthesized using non-enriched starting materials is on average about 0.0156%. As used herein, when a specific position in an isotopically enriched compound is designated as containing deuterium, it should be understood that the abundance of deuterium at that position in said compound is substantially greater than its natural abundance (0.0156%).

[0054] The term "carbon" or the symbol "C" refers to the composition of naturally occurring carbon isotopes, including carbon-12 at their natural abundance. 12 C) and carbon-13 ( 13 C). Carbon-12 is the most common carbon isotope, with a natural abundance of over 98.89%. Carbon-13 is a less common carbon isotope, with a natural abundance of approximately 1.11%.

[0055] The term "carbon-13 enrichment" or " 13 "C enrichment" refers to the percentage of carbon-13 that replaces 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 specified position. Because the natural distribution of carbon-13 is on average about 1.11%, the carbon-13 enrichment at any position in compounds synthesized using non-enriched starting materials is on average about 1.11%. As used herein, when a specific position in an isotopically enriched compound is designated as having carbon-13, it should be understood that the abundance of carbon-13 at that position in said compound is substantially greater than its natural abundance (1.11%).

[0056] The terms “substantially pure” and “substantially homogeneous” mean, when referring to a substance, that it is sufficiently homogeneous to appear free of easily detectable impurities as determined by standard analytical methods used by those skilled 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 that it is sufficiently pure such that further purification will not detectably alter the physical, chemical, biological, and / or pharmacological properties (e.g., enzymatic and biological activities) of the substance. In some 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 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 specific position in an isotopically enriched molecule is designated as a particular, less common isotope, a molecule containing an isotope other than the designated one at the specified position is an impurity relative to the isotopically enriched compound. Therefore, for a deuterated compound having an atom designated as deuterium at a specific position, a compound containing protium at the same position is an impurity.

[0057] The term "solvate" refers to a complex or aggregate formed of one or more solute molecules (e.g., compounds provided herein) and one or more solvent molecules (present in stoichiometric or non-stoichiometric form). Suitable solvents include, but are not limited to, water, methanol, ethanol, n-propanol, isopropanol, and acetic acid. In some embodiments, the solvent is pharmaceutically acceptable. In one embodiment, the complex or aggregate is in a crystalline form. In another embodiment, the complex or aggregate is in a non-crystalline form. When the solvent is water, the solvate is a hydrate. Examples of hydrates include, but are not limited to, hemihydrates, monohydrates, dihydrates, trihydrates, tetrahydrates, and pentahydrates.

[0058] For the divalent groups described herein, the orientation of the divalent groups 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)-.

[0059] The phrase “enantiomer, mixture of enantiomers, diastereomers, mixture of two or more diastereomers, tautomers, mixture of two or more tautomers or isotopic variants; or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof” has the same meaning as the following phrases: “(i) an enantiomer, mixture of enantiomers, diastereomers, mixture of two or more diastereomers, tautomers, mixture of two or more tautomers or isotopic variant of the compound mentioned herein; (ii) a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof of the compound mentioned herein; or (iii) a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof of an enantiomer, mixture of enantiomers, diastereomers, mixture of two or more diastereomers, tautomers, mixture of two or more tautomers or isotopic variant of the compound mentioned herein.” compound

[0060] In one embodiment, a compound of formula (A) is provided herein: 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 1 It is hydrogen or deuterium; R 2 and R 3 Each is independently (i) hydrogen, deuterium, cyano, halogen, or nitro; (ii) C 1-10 Alkyl, C 1-10 Heteroalkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 3-10 cycloalkyl, C 6-14 Aryl, C 7-15 Aryl, heteroaryl, or heterocyclic; 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)R1a 、 –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 、 –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 R1c ; R 4 and R 5 Each is independently (i) hydrogen; (ii) C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, C 6-14 Aryl, C 7-15 Aryl, heteroaryl, or heterocyclic; 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 ; R 6 and R 7 Each independently is (i) halogen; or (ii) –OR 1a –OC(O)R 1a –OC(O)OR 1a Or –OC(O)NR 1b R 1c And R 8 For (i) hydrogen; or (ii) –C(O)R 1a –C(O)OR 1a Or –C(O)NR 1b R 1c ; or R 6 and R 7 Or R 7 and R 8 They connect together to form a lactone ring; A represents a bond, O, or N (R). 1b ); E represents hydrogen, azide, halogen, isocyanate, or –C=C(R). 1a )R 1a –C≡CR 1a , , , –C(O)R 1a Or –SH; L is C 1-6 Alkylene, C 1-6 Heteroalkyl, C 2-6 imidene group, C 2-6 Ethyne group, C 3-10 Cycloalkylene, C 6-14 Alpha-aryl, C 7-15 arylene alkyl groups, heteroarylene alkyl groups, or heterocyclic alkyl groups; and R 1a R 1b R 1c and R 1d Each is independently hydrogen, deuterium, and C. 1-30 Alkyl, C 1-30 Heteroalkyl, C 2-30 alkenyl, C 2-30 alkynyl group, C 3-30 cycloalkyl, C 6-30 Aryl, C 7-30 Aryl, heteroaryl, or heterocyclic groups; Wherein, alkyl, alkylene, heteroalkyl, heteroalkylene, alkenyl, alkenylene, ynyl, ynylene, cycloalkyl, cycloalkylene, aryl, arylene, arylalkylene, heteroaryl, heteroaryl, heteroaryl, heterocyclic and heterocyclic are each optionally substituted by one or more (in one embodiment, by one, two, three or four) substituents Q, wherein each 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 group, C 3-10 cycloalkyl, C 6-14 Aryl, C 7-15 Aryl, heteroaryl, and heterocyclic groups, each optionally further substituented by one or more (in one embodiment, by one, two, three, or four) substituents Q. a Substitution; 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 –ORa 、–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 、–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 Each is independently (i) hydrogen or deuterium; (ii) C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, C 6-14 Aryl, C 7-15 Aryl, heteroaryl, or heterocyclic groups, each optionally substituted with one or more (in one embodiment, one, two, three, or four) substituents Q. a Replace; or (iii) R b and R c Together with the N atoms to which they are attached, they form heterocyclic groups, which are optionally substituents Q by one or more (in one embodiment, by one, two, three, or four) substituents. a replace; Among them, Q a Each 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 group, C 3-10 cycloalkyl, C 6-14 Aryl, C 7-15 Aryl alkyl, heteroaryl and heterocyclic groups; 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 )NRf 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 [[ID=3​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​R g and R h Each is independently (i) hydrogen or deuterium; (ii) C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, C 6-14 Aryl, C 7-15 Aryl, heteroaryl, or heterocyclic; or (iii) R f and R g Together with the N atoms they are attached to, they form heterocyclic groups.

[0061] In some implementations, in equation (A), R 6 It is a halogen. In some embodiments, in formula (A), R... 6 It is fluorine. In some embodiments, in formula (A), R... 6 For –OR 1a , where R 1a As defined herein. In some implementations, in equation (A), R 6 It is a hydroxyl group. In some embodiments, in formula (A), R... 6 For –OC(O)R 1a , where R 1a As defined herein. In some implementations, in equation (A), R 6 –OC(O)OR 1a , where R 1a As defined herein. In some implementations, in equation (A), R 6 For –OC(O)NR 1b R 1c , where R 1b and R 1c Each as defined in this article.

[0062] In some implementations, in equation (A), R 7 It is a halogen. In some embodiments, in formula (A), R... 7 It is fluorine. In some embodiments, in formula (A), R... 7 For –OR 1a , where R 1a As defined herein. In some implementations, in equation (A), R 7 It is a hydroxyl group. In some embodiments, in formula (A), R... 7 For –OC(O)R 1a , where R 1a As defined herein. In some implementations, in equation (A), R 7 –OC(O)OR 1a, where R 1a As defined herein. In some implementations, in equation (A), R 7 For –OC(O)NR 1b R 1c , where R 1b and R 1c Each as defined in this article.

[0063] In another embodiment, compounds of formula (I) are provided herein: 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 1 It is hydrogen or deuterium; R 2 and R 3 Each is independently (i) hydrogen, deuterium, cyano, halogen, or nitro; (ii) C 1-10 Alkyl, C 1-10 Heteroalkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 3-10 cycloalkyl, C 6-14 Aryl, C 7-15 Aryl, heteroaryl, or heterocyclic; 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)NR1b 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 –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 5 Each is independently (i) hydrogen; (ii) C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, C 6-14 Aryl, C 7-15Aryl, heteroaryl, or heterocyclic; 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 ; R 6 and R 7 Each independently is (i) halogen; or (ii) –OR 1a –OC(O)R 1a –OC(O)OR 1a Or –OC(O)NR 1b R 1c And R 8 For (i) hydrogen; or (ii) –C(O)R 1a –C(O)OR 1a Or –C(O)NR 1b R 1c ; or R 6 and R 7 Or R 7 and R 8 They connect together to form a lactone ring; A represents a bond, O, or N (R). 1b ); E represents hydrogen, azide, halogen, isocyanate, or –C=C(R). 1a )R 1a –C≡CR 1a , , , –C(O)R 1a Or –SH; L is C 1-6 Alkylene, C 1-6 Heteroalkyl, C 2-6 imidene group, C 2-6 Ethyne group, C 3-10 Cycloalkylene, C 6-14 Alpha-aryl, C7-15 arylene alkyl groups, heteroarylene alkyl groups, or heterocyclic alkyl groups; and R 1a R 1b R 1c and R 1d Each is independently hydrogen, deuterium, and C. 1-30 Alkyl, C 1-30 Heteroalkyl, C 2-30 alkenyl, C 2-30 alkynyl group, C 3-30 cycloalkyl, C 6-30 Aryl, C 7-30 Aryl, heteroaryl, or heterocyclic groups; Wherein, alkyl, alkylene, heteroalkyl, heteroalkylene, alkenyl, alkenylene, ynyl, ynylene, cycloalkyl, cycloalkylene, aryl, arylene, arylalkylene, heteroaryl, heteroaryl, heteroaryl, heterocyclic and heterocyclic are each optionally substituted by one or more (in one embodiment, by one, two, three or four) substituents Q, wherein each 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 group, C 3-10 cycloalkyl, C 6-14 Aryl, C 7-15 Aryl, heteroaryl, and heterocyclic groups, each optionally further substituented by one or more (in one embodiment, by one, two, three, or four) substituents Q. a Substitution; 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)Ra –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 –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 Each is independently (i) hydrogen or deuterium; (ii) C 1-6 Alkyl, C1-6 Heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, C 6-14 Aryl, C 7-15 Aryl, heteroaryl, or heterocyclic groups, each optionally substituted with one or more (in one embodiment, one, two, three, or four) substituents Q. a Replace; or (iii) R b and R c Together with the N atoms to which they are attached, they form heterocyclic groups, which are optionally substituents Q by one or more (in one embodiment, by one, two, three, or four) substituents. a replace; Among them, Q a Each 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 group, C 3-10 cycloalkyl, C 6-14 Aryl, C 7-15 Aryl alkyl, heteroaryl and heterocyclic groups; 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)2Re –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 Among them, R e R f R g and R h Each is independently (i) hydrogen or deuterium; (ii) C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, C 6-14 Aryl, C 7-15 Aryl, heteroaryl, or heterocyclic; or (iii) Rf and R g Together with the N atoms they are attached to, they form heterocyclic groups.

[0064] In some implementations, in equation (I), R 6 It is a halogen. In some embodiments, in formula (I), R... 6 It is fluorine. In some embodiments, in formula (I), R... 6 For –OR 1a , where R 1a As defined herein. In some implementations, in equation (I), R 6 It is a hydroxyl group. In some embodiments, in formula (I), R... 6 For –OC(O)R 1a , where R 1a As defined herein. In some implementations, in equation (I), R 6 –OC(O)OR 1a , where R 1a As defined herein. In some implementations, in equation (I), R 6 For –OC(O)NR 1b R 1c , where R 1b and R 1c Each as defined in this article.

[0065] In some implementations, in equation (I), R 7 It is a halogen. In some embodiments, in formula (I), R... 7 It is fluorine. In some embodiments, in formula (I), R... 7 For –OR 1a , where R 1a As defined herein. In some implementations, in equation (I), R 7 It is a hydroxyl group. In some embodiments, in formula (I), R... 7 For –OC(O)R 1a , where R 1a As defined herein. In some implementations, in equation (I), R 7 –OC(O)OR 1a , where R 1a As defined herein. In some implementations, in equation (I), R 7 For –OC(O)NR 1b R 1c , where R 1b and R 1c Each as defined in this article.

[0066] In yet another embodiment, compounds of formula (II) are provided herein: 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 6a and R 7a Each is independently (i) hydrogen; or (ii) –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 8 R 1a R 1b R 1c A, E, and L are each as defined in this document.

[0067] In some implementations, in formula (A), formula (I), or formula (II), E is... Azide, fluorine, iodine, isocyanate, –C=CH2, –C≡CH , , , –C(O)CH3 or –SH. In some embodiments, in formula (A), formula (I) or formula (II) In this context, E stands for azide group (–N3).

[0068] In some embodiments, in formula (I) or formula (II), E is an azide group, Fluorine, iodine, isocyanate, –C=CH2, –C≡CH , , , –C(O)CH3 or –SH. In some embodiments, in formula (I) or formula (II), E is an azide group (–N3).

[0069] In yet another embodiment, compounds of formula (III) are provided herein: 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 1 R 2 R 3 R 4 R 5 R 8 R 6a R 7a A and L are each as defined in this article.

[0070] In some embodiments, A is a bond or O in formula (A) and any one of formulas (I) to (III). In some embodiments, A is a bond in formula (A) and any one of formulas (I) to (III). In some embodiments, A is O in formula (A) and any one of formulas (I) to (III).

[0071] In some embodiments, A is a bond or O in any of equations (I) to (III). In some embodiments, A is a bond in any of equations (I) to (III). In some embodiments, A is O in any of equations (I) to (III).

[0072] In yet another embodiment, compounds of formula (IV) are provided herein: 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 1 R 2 R 3 R 4 R 5 R 8 R 6a R 7a L and L are as defined in this article.

[0073] In some implementations, L is C in equation (A) and any of equations (I) to (IV). 1-6The alkylene group is optionally substituted with one or more substituents Q. In some embodiments, in formula (A) and any of formulas (I) to (IV), L is methanediyl, ethanediyl, propanediyl, or butanediyl, each optionally substituted with one or more substituents Q. In some embodiments, in formula (A) and any of formulas (I) to (IV), L is methanediyl, ethane-1,2-diyl, propane-1,2-diyl, or butane-1,4-diyl, each optionally substituted with one or more substituents Q. In some embodiments, in formula (A) and any of formulas (I) to (IV), L is methanediyl.

[0074] In some implementations, L is C in any of equations (I) to (IV). 1-6 Alkylene, optionally substituted with one or more substituents Q. In some embodiments, in any of formulas (I) to (IV), L is methanediyl, ethanediyl, propanediyl, or butanediyl, each optionally substituted with one or more substituents Q. In some embodiments, in any of formulas (I) to (IV), L is methanediyl, ethane-1,2-diyl, propane-1,2-diyl, or butane-1,4-diyl, each optionally substituted with one or more substituents Q. In some embodiments, in any of formulas (I) to (IV), L is methanediyl.

[0075] In yet another embodiment, compounds of formula (V) are provided herein: 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 1 R 2 R 3 R 4 R 5 R 8 R 6a and R 7a Each as defined in this article.

[0076] In yet another embodiment, compounds of formula (VI) are provided herein: 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, R1 R 2 R 3 R 4 R 5 R 8 R 6a and R 7a Each as defined in this article.

[0077] In yet another embodiment, the present document provides compounds 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 pharmaceutically acceptable salts, solvates, hydrates, or prodrugs thereof; wherein, R 1 R 2 R 3 R 4 R 5 R 8 R 6a and R 7a Each as defined in this article.

[0078] In some implementations, in any of equations (II) to (VII), R 6a For hydrogen or –C(O)R 1a , where R 1a As defined herein. In some implementations, in any of equations (II) to (VII), R 6a It is hydrogen. In some embodiments, in any of formulas (II) to (VII), R 6a For –C(O)R 1a , where R 1a As defined herein. In some implementations, in any of equations (II) to (VII), R 6a –C(O)–C 1-6 Alkyl group, optionally substituted with one or more substituents Q. In some embodiments, R in any of formulas (II) to (VII) 6a It is acetyl, propionyl, or butyryl. In some embodiments, R in any of formulas (II) to (VII) 6a It is an acetyl group.

[0079] In some implementations, in any of equations (II) to (VII), R 7a For hydrogen or –C(O)R 1a , where R 1aAs defined herein. In some implementations, in any of equations (II) to (VII), R 7a It is hydrogen. In some embodiments, in any of formulas (II) to (VII), R 7a For –C(O)R 1a , where R 1a As defined herein. In some implementations, in any of equations (II) to (VII), R 7a –C(O)–C 1-6 Alkyl group, optionally substituted with one or more substituents Q. In some embodiments, R in any of formulas (II) to (VII) 7a It is acetyl, propionyl, or butyryl. In some embodiments, R in any of formulas (II) to (VII) 7a It is an acetyl group.

[0080] In some implementations, in equation (A) and any of equations (I) to (VII), R 1 It is hydrogen. In some embodiments, in formula (A) and any of formulas (I) to (VII), R 1 It is deuterium.

[0081] In some implementations, in equation (A) and any of equations (I) to (VII), R 2 (i) hydrogen or deuterium; or (ii) C 1-10 Alkyl, C 1-10 Heteroalkyl or C 2-10 Alkenyl groups, each optionally substituted with one or more substituents Q. In some embodiments, in formula (A) and any of formulas (I) to (VII), R 2 It is hydrogen. In some embodiments, in formula (A) and any of formulas (I) to (VII), R 2 For deuterium. In some embodiments, in equation (A) and any of equations (I) to (VII), R 2 C 1-10 Alkyl group, optionally substituted with one or more substituents Q. In some embodiments, R in formula (A) and any of formulas (I) to (VII) 2 C 1-10 Heteroalkyl, optionally substituted with one or more substituents Q. In some embodiments, in formula (A) and any of formulas (I) to (VII), R 2 C 1-10 The alkenyl group is optionally substituted with one or more substituents Q.

[0082] In some implementations, in equation (A) and any of equations (I) to (VII), R 3 (i) hydrogen or deuterium; or (ii) C 1-10 Alkyl, C 1-10 Heteroalkyl or C 2-10 Alkenyl groups, each optionally substituted with one or more substituents Q. In some embodiments, in formula (A) and any of formulas (I) to (VII), R 3 It is hydrogen. In some embodiments, in formula (A) and any of formulas (I) to (VII), R 3 For deuterium. In some embodiments, in equation (A) and any of equations (I) to (VII), R 3 C 1-10 Alkyl group, optionally substituted with one or more substituents Q. In some embodiments, R in formula (A) and any of formulas (I) to (VII) 3 It is methyl, ethyl, propyl, or butyl, each optionally substituted with one or more substituents Q. In some embodiments, in formula (A) and any of formulas (I) to (VII), R 3 C 1-10 Heteroalkyl, optionally substituted with one or more substituents Q. In some embodiments, in formula (A) and any of formulas (I) to (VII), R 2 C 2-10 The alkenyl group is optionally substituted with one or more substituents Q.

[0083] In some implementations, in equation (A) and any of equations (I) to (VII), R 4 It is hydrogen.

[0084] In some implementations, in equation (A) and any of equations (I) to (VII), R 5 It is hydrogen.

[0085] In some implementations, in equation (A) and any of equations (I) to (VII), R 8 For hydrogen or –C(O)R 1a , where R 1a As defined herein. In some embodiments, in equation (A) and any of equations (I) through (VII), R 8 It is hydrogen. In some embodiments, in formula (A) and any of formulas (I) to (VII), R 8 For –C(O)R 1a , where R 1aAs defined herein. In some embodiments, in equation (A) and any of equations (I) through (VII), R 8 –C(O)–C 1-6 Alkyl group, optionally substituted with one or more substituents Q. In some embodiments, R in formula (A) and any of formulas (I) to (VII) 8 It is acetyl, propionyl, or butyryl. In some embodiments, in formula (A) and any of formulas (I) to (VII), R 8 It is an acetyl group.

[0086] In some implementations, in any of equations (I) to (VII), R 1 It is hydrogen. In some embodiments, in any of formulas (I) to (VII), R 1 It is deuterium.

[0087] In some implementations, in any of equations (I) to (VII), R 2 (i) hydrogen or deuterium; or (ii) C 1-10 Alkyl, C 1-10 Heteroalkyl or C 2-10 Alkenyl groups, each optionally substituted with one or more substituents Q. In some embodiments, in any of formulas (I) to (VII), R 2 It is hydrogen. In some embodiments, in any of formulas (I) to (VII), R 2 For deuterium. In some embodiments, in any of equations (I) to (VII), R 2 C 1-10 Alkyl group, optionally substituted with one or more substituents Q. In some embodiments, R in any of formulas (I) to (VII) 2 C 1-10 Heteroalkyl groups, optionally substituted with one or more substituents Q. In some embodiments, R in any of formulas (I) to (VII) 2 C 1-10 The alkenyl group is optionally substituted with one or more substituents Q.

[0088] In some implementations, in any of equations (I) to (VII), R 3 (i) hydrogen or deuterium; or (ii) C 1-10 Alkyl, C 1-10 Heteroalkyl or C 2-10 Alkenyl groups, each optionally substituted with one or more substituents Q. In some embodiments, in any of formulas (I) to (VII), R 3It is hydrogen. In some embodiments, in any of formulas (I) to (VII), R 3 For deuterium. In some embodiments, in any of equations (I) to (VII), R 3 C 1-10 Alkyl group, optionally substituted with one or more substituents Q. In some embodiments, R in any of formulas (I) to (VII) 3 It is methyl, ethyl, propyl, or butyl, each optionally substituted with one or more substituents Q. In some embodiments, in any of formulas (I) to (VII), R 3 C 1-10 Heteroalkyl groups, optionally substituted with one or more substituents Q. In some embodiments, R in any of formulas (I) to (VII) 2 C 2-10 The alkenyl group is optionally substituted with one or more substituents Q.

[0089] In some implementations, in any of equations (I) to (VII), R 4 It is hydrogen.

[0090] In some implementations, in any of equations (I) to (VII), R 5 It is hydrogen.

[0091] In some implementations, in any of equations (I) to (VII), R 8 For hydrogen or –C(O)R 1a , where R 1a As defined herein. In some implementations, in any of equations (I) to (VII), R 8 It is hydrogen. In some embodiments, in any of formulas (I) to (VII), R 8 For –C(O)R 1a , where R 1a As defined herein. In some implementations, in any of equations (I) to (VII), R 8 –C(O)–C 1-6 Alkyl group, optionally substituted with one or more substituents Q. In some embodiments, R in any of formulas (I) to (VII) 8 It is acetyl, propionyl, or butyryl. In some embodiments, R is in any of formulas (I) to (VII). 8 It is an acetyl group.

[0092] The group R in the formulas (including formula (A) and formulas (I) to (VII)) described herein 1 R2 R 3 R 4 R 5 R 6 R 7 R 8 R 6a R 7a A, E, and L are further defined in the embodiments described herein. All combinations of embodiments provided herein for these groups are within the scope of this disclosure.

[0093] In some implementations, R 1 It is hydrogen. In some embodiments, R 1 It is deuterium.

[0094] In some implementations, R 2 It is hydrogen. In some embodiments, R 2 For deuterium. In some implementations, R 2 It is cyano. In some embodiments, R 2 It is a halogen. In some embodiments, R 2 It is fluorine. In some embodiments, R 2 It is chlorine. In some embodiments, R 2 It is nitro. In some embodiments, R 2 C 1-10 Alkyl group, optionally substituted with one or more substituents Q. In some embodiments, R 2 It is methyl, ethyl, propyl, or butyl. In some embodiments, R 2 It is methyl. In some embodiments, R 2 C 1-10 Heteroalkyl groups, optionally substituted with one or more substituents Q. In some embodiments, R 2 It is trifluoromethyl. In some embodiments, R 2 C 2-10 The alkenyl group is optionally substituted with one or more substituents Q. In some embodiments, R 2 C 2-10 The alkynyl group is optionally substituted with one or more substituents Q. In some embodiments, R 2 C 3-10 Cycloalkyl, optionally substituted with one or more substituents Q. In some embodiments, R 2 C 6-14 The aryl group is optionally substituted with one or more substituents Q. In some embodiments, R 2 C 7-15 Aryl alkyl group, optionally substituted with one or more substituents Q. In some embodiments, R 2It is a heteroaryl group, optionally substituted with one or more substituents Q. In some embodiments, R 2 It is a heterocyclic group, which is optionally substituted by one or more substituents Q.

[0095] In some implementations, R 2 For –C(O)R 1a , where R 1a As defined herein. In some implementations, R 2 -C(O)OR 1a , where R 1a As defined herein. In some implementations, R 2 For –C(O)NR 1b R 1c , where R 1b and R 1c Each as defined herein. In some implementations, R 2 –C(O)SR 1a , where R 1a As defined herein. In some implementations, R 2 For –C(NR) 1a )NR 1b R 1c , where R 1a R 1b and R 1c Each as defined herein. In some implementations, R 2 For –C(S)R 1a , where R 1a As defined herein. In some implementations, R 2 For –C(S)OR 1a , where R 1a As defined herein. In some implementations, R 2 For –C(S)NR 1b R 1c , where R 1b and R 1c Each as defined herein. In some implementations, R 2 For –OR 1a , where R 1a As defined herein. In some implementations, R 2 For –OC(O)R 1a , where R 1a As defined herein. In some implementations, R 2 –OC(O)OR 1a , where R 1a As defined herein. In some implementations, R 2 For –OC(O)NR1b R 1c , where R 1b and R 1c Each as defined herein. In some implementations, R 2 For –OC(S)R 1a , where R 1a As defined herein. In some implementations, R 2 For –OC(NR) 1a )NR 1b R 1c , where R 1a R 1b and R 1c Each as defined herein. In some implementations, R 2 For –OC(S)R 1a , where R 1a As defined herein. In some implementations, R 2 –OC(S)OR 1a , where R 1a As defined herein. In some implementations, R 2 For –OC(S)NR 1b R 1c , where R 1b and R 1c Each as defined herein. In some implementations, R 2 For –OS(O)R 1a , where R 1a As defined herein. In some implementations, R 2 For –OS(O)2R 1a , where R 1a As defined herein. In some implementations, R 2 For –OS(O)NR 1b R 1c , where R 1b and R 1c Each as defined herein. In some implementations, R 2 For –OS(O)2NR 1b R 1c , where R 1b and R 1c Each as defined herein. In some implementations, R 2 For –NR 1b R 1c , where R 1b and R 1c Each as defined herein. In some implementations, R 2 For –NR 1a C(O)R 1d, where R 1a and R 1d Each as defined herein. In some implementations, R 2 For –NR 1a C(O)OR 1d , where R 1a and R 1d Each as defined herein. In some implementations, R 2 For –NR 1a C(O)NR 1b R 1c , where R 1a R 1b and R 1c Each as defined herein. In some implementations, R 2 For –NR 1a C(O)SR 1d , where R 1a and R 1d Each as defined herein. In some implementations, R 2 For –NR 1a C(NR 1d )NR 1b R 1c , where R 1a R 1b R 1c and R 1d Each as defined herein. In some implementations, R 2 For –NR 1a C(S)R 1d , where R 1a and R 1d Each as defined herein. In some implementations, R 2 For –NR 1a C(S)OR 1d , where R 1a and R 1d Each as defined herein. In some implementations, R 2 For –NR 1a C(S)NR 1b R 1c , where R 1a R 1b and R 1c Each as defined herein. In some implementations, R 2 For –NR 1a S(O)R 1d , where R 1a and R 1d Each as defined herein. In some implementations, R 2 For –NR1a S(O)2R 1d , where R 1a and R 1d Each as defined herein. In some implementations, R 2 For –NR 1a S(O)NR 1b R 1c , where R 1a R 1b and R 1c Each as defined herein. In some implementations, R 2 For –NR 1a S(O)2NR 1b R 1c , where R 1a R 1b and R 1c Each as defined herein. In some implementations, R 2 For –SR 1a , where R 1a As defined herein. In some implementations, R 2 For –S(O)R 1a , where R 1a As defined herein. In some implementations, R 2 is –S(O)2R 1a , where R 1a As defined herein. In some implementations, R 2 For –S(O)NR 1b R 1c , where R 1b and R 1c Each as defined herein. In some implementations, R 2 For –S(O)2NR 1b R 1c , where R 1b and R 1c Each as defined in this article.

[0096] In some implementations, R 3 It is hydrogen. In some embodiments, R 3 For deuterium. In some implementations, R 3 It is cyano. In some embodiments, R 3 It is a halogen. In some embodiments, R 3 It is fluorine. In some embodiments, R 3 It is chlorine. In some embodiments, R 3 It is nitro. In some embodiments, R 3 C 1-10Alkyl group, optionally substituted with one or more substituents Q. In some embodiments, R 3 It is methyl, ethyl, propyl, or butyl. In some embodiments, R 3 It is methyl. In some embodiments, R 3 C 1-10 Heteroalkyl groups, optionally substituted with one or more substituents Q. In some embodiments, R 3 It is trifluoromethyl. In some embodiments, R 3 C 2-10 The alkenyl group is optionally substituted with one or more substituents Q. In some embodiments, R 3 C 2-10 The alkynyl group is optionally substituted with one or more substituents Q. In some embodiments, R 3 C 3-10 Cycloalkyl, optionally substituted with one or more substituents Q. In some embodiments, R 3 C 6-14 The aryl group is optionally substituted with one or more substituents Q. In some embodiments, R 3 C 7-15 Aryl alkyl group, optionally substituted with one or more substituents Q. In some embodiments, R 3 It is a heteroaryl group, optionally substituted with one or more substituents Q. In some embodiments, R 3 It is a heterocyclic group, which is optionally substituted by one or more substituents Q.

[0097] In some implementations, R 3 For –C(O)R 1a , where R 1a As defined herein. In some implementations, R 3 -C(O)OR 1a , where R 1a As defined herein. In some implementations, R 3 For –C(O)NR 1b R 1c , where R 1b and R 1c Each as defined herein. In some implementations, R 3 –C(O)SR 1a , where R 1a As defined herein. In some implementations, R 3 For –C(NR) 1a )NR 1b R 1c , where R 1a R 1b and R1c Each as defined herein. In some implementations, R 3 For –C(S)R 1a , where R 1a As defined herein. In some implementations, R 3 For –C(S)OR 1a , where R 1a As defined herein. In some implementations, R 3 For –C(S)NR 1b R 1c , where R 1b and R 1c Each as defined herein. In some implementations, R 3 For –OR 1a , where R 1a As defined herein. In some implementations, R 3 For –OC(O)R 1a , where R 1a As defined herein. In some implementations, R 3 –OC(O)OR 1a , where R 1a As defined herein. In some implementations, R 3 For –OC(O)NR 1b R 1c , where R 1b and R 1c Each as defined herein. In some implementations, R 3 For –OC(S)R 1a , where R 1a As defined herein. In some implementations, R 3 For –OC(NR) 1a )NR 1b R 1c , where R 1a R 1b and R 1c Each as defined herein. In some implementations, R 3 For –OC(S)R 1a , where R 1a As defined herein. In some implementations, R 3 –OC(S)OR 1a , where R 1a As defined herein. In some implementations, R 3 For –OC(S)NR 1b R 1c , where R 1b and R 1cEach as defined herein. In some implementations, R 3 For –OS(O)R 1a , where R 1a As defined herein. In some implementations, R 3 For –OS(O)2R 1a , where R 1a As defined herein. In some implementations, R 3 For –OS(O)NR 1b R 1c , where R 1b and R 1c Each as defined herein. In some implementations, R 3 For –OS(O)2NR 1b R 1c , where R 1b and R 1c Each as defined herein. In some implementations, R 3 For –NR 1b R 1c , where R 1b and R 1c Each as defined herein. In some implementations, R 3 For –NR 1a C(O)R 1d , where R 1a and R 1d Each as defined herein. In some implementations, R 3 For –NR 1a C(O)OR 1d , where R 1a and R 1d Each as defined herein. In some implementations, R 3 For –NR 1a C(O)NR 1b R 1c , where R 1a R 1b and R 1c Each as defined herein. In some implementations, R 3 For –NR 1a C(O)SR 1d , where R 1a and R 1d Each as defined herein. In some implementations, R 3 For –NR 1a C(NR 1d )NR 1b R 1c , where R 1a R 1b R1c and R 1d Each as defined herein. In some implementations, R 3 For –NR 1a C(S)R 1d , where R 1a and R 1d Each as defined herein. In some implementations, R 3 For –NR 1a C(S)OR 1d , where R 1a and R 1d Each as defined herein. In some implementations, R 3 For –NR 1a C(S)NR 1b R 1c , where R 1a R 1b and R 1c Each as defined herein. In some implementations, R 3 For –NR 1a S(O)R 1d , where R 1a and R 1d Each as defined herein. In some implementations, R 3 For –NR 1a S(O)2R 1d , where R 1a and R 1d Each as defined herein. In some implementations, R 3 For –NR 1a S(O)NR 1b R 1c , where R 1a R 1b and R 1c Each as defined herein. In some implementations, R 3 For –NR 1a S(O)2NR 1b R 1c , where R 1a R 1b and R 1c Each as defined herein. In some implementations, R 3 For –SR 1a , where R 1a As defined herein. In some implementations, R 3 For –S(O)R 1a , where R 1a As defined herein. In some implementations, R 3 is –S(O)2R1a , where R 1a As defined herein. In some implementations, R 3 For –S(O)NR 1b R 1c , where R 1b and R 1c Each as defined herein. In some implementations, R 3 For –S(O)2NR 1b R 1c , where R 1b and R 1c Each as defined in this article.

[0098] In some implementations, R 4 It is hydrogen. In some embodiments, R 4 C 1-6 Alkyl group, optionally substituted with one or more substituents Q. In some embodiments, R 4 It is a methyl group, optionally substituted with one or more substituents Q. In some embodiments, R 4 C 1-6 Heteroalkyl groups, optionally substituted with one or more substituents Q. In some embodiments, R 4 C 2-6 The alkenyl group is optionally substituted with one or more substituents Q. In some embodiments, R 4 C 2-6 The alkynyl group is optionally substituted with one or more substituents Q. In some embodiments, R 4 C 3-10 Cycloalkyl, optionally substituted with one or more substituents Q. In some embodiments, R 4 C 6-14 The aryl group is optionally substituted with one or more substituents Q. In some embodiments, R 4 C 7-15 Aryl alkyl group, optionally substituted with one or more substituents Q. In some embodiments, R 4 It is a heteroaryl group, optionally substituted with one or more substituents Q. In some embodiments, R 4 It is a heterocyclic group, which is optionally substituted by one or more substituents Q.

[0099] In some implementations, R 4 For –C(O)R 1a , where R 1a As defined herein. In some implementations, R 4 -C(O)OR 1a , where R 1aAs defined herein. In some implementations, R 4 For –C(O)NR 1b R 1c , where R 1b and R 1c Each as defined herein. In some implementations, R 4 –C(O)SR 1a , where R 1a As defined herein. In some implementations, R 4 For –C(NR) 1a )NR 1b R 1c , where R 1a R 1b and R 1c Each as defined herein. In some implementations, R 4 For –C(S)R 1a , where R 1a As defined herein. In some implementations, R 4 For –C(S)OR 1a , where R 1a As defined herein. In some implementations, R 4 For –C(S)NR 1b R 1c , where R 1b and R 1c Each as defined herein. In some implementations, R 4 For –S(O)R 1a , where R 1a As defined herein. In some implementations, R 4 is –S(O)2R 1a , where R 1a As defined herein. In some implementations, R 4 For –S(O)NR 1b R 1c , where R 1b and R 1c Each as defined herein. In some implementations, R 4 For –S(O)2NR 1b R 1c , where R 1b and R 1c Each as defined in this article.

[0100] In some implementations, R 5 It is hydrogen. In some embodiments, R 5 C 1-6 Alkyl group, optionally substituted with one or more substituents Q. In some embodiments, R5 It is a methyl group, optionally substituted with one or more substituents Q. In some embodiments, R 5 C 1-6 Heteroalkyl groups, optionally substituted with one or more substituents Q. In some embodiments, R 5 C 2-6 The alkenyl group is optionally substituted with one or more substituents Q. In some embodiments, R 5 C 2-6 The alkynyl group is optionally substituted with one or more substituents Q. In some embodiments, R 5 C 3-10 Cycloalkyl, optionally substituted with one or more substituents Q. In some embodiments, R 5 C 6-14 The aryl group is optionally substituted with one or more substituents Q. In some embodiments, R 5 C 7-15 Aryl alkyl group, optionally substituted with one or more substituents Q. In some embodiments, R 5 It is a heteroaryl group, optionally substituted with one or more substituents Q. In some embodiments, R 5 It is a heterocyclic group, which is optionally substituted by one or more substituents Q.

[0101] In some implementations, R 5 For –C(O)R 1a , where R 1a As defined herein. In some implementations, R 5 -C(O)OR 1a , where R 1a As defined herein. In some implementations, R 5 For –C(O)NR 1b R 1c , where R 1b and R 1c Each as defined herein. In some implementations, R 5 –C(O)SR 1a , where R 1a As defined herein. In some implementations, R 5 For –C(NR) 1a )NR 1b R 1c , where R 1a R 1b and R 1c Each as defined herein. In some implementations, R 5 For –C(S)R 1a , where R 1aAs defined herein. In some implementations, R 5 For –C(S)OR 1a , where R 1a As defined herein. In some implementations, R 5 For –C(S)NR 1b R 1c , where R 1b and R 1c Each as defined herein. In some implementations, R 5 For –S(O)R 1a , where R 1a As defined herein. In some implementations, R 5 is –S(O)2R 1a , where R 1a As defined herein. In some implementations, R 5 For –S(O)NR 1b R 1c , where R 1b and R 1c Each as defined herein. In some implementations, R 5 For –S(O)2NR 1b R 1c , where R 1b and R 1c Each as defined in this article.

[0102] In some implementations, R 6 It is a halogen. In some embodiments, R 6 It is fluorine. In some embodiments, R 6 For –OR 1a , where R 1a As defined herein. In some implementations, R 6 It is a hydroxyl group. In some embodiments, R 6 For –OC(O)R 1a , where R 1a As defined herein. In some implementations, R 6 –OC(O)–C 1-6 Alkyl group, optionally substituted with one or more substituents Q. In some embodiments, R 6 It is an acetyloxy, propionyloxy, or butyryloxy group, each optionally substituted with one or more substituents Q. In some embodiments, R 6 It is an acetyloxy group. In some embodiments, R 6 –OC(O)–C 1-6 Heteroalkyl groups, optionally substituted with one or more substituents Q. In some embodiments, R 6–OC(O)–C 2-6 The alkenyl group is optionally substituted with one or more substituents Q. In some embodiments, R 6 –OC(O)–C 2-6 The alkynyl group is optionally substituted with one or more substituents Q. In some embodiments, R 6 –OC(O)–C 3-10 Cycloalkyl, optionally substituted with one or more substituents Q. In some embodiments, R 6 –OC(O)–C 6-14 The aryl group is optionally substituted with one or more substituents Q. In some embodiments, R 6 R is a benzoyloxy group, which is optionally substituted with one or more substituents Q. In some embodiments, R 6 –OC(O)–(Double-ring C 6-14 Aryl group, optionally substituted with one or more substituents Q. In some embodiments, R 6 –OC(O)–C 7-15 Aryl alkyl group, optionally substituted with one or more substituents Q. In some embodiments, R 6 It is –OC(O)-heteroaryl, which is optionally substituted by one or more substituents Q. In some embodiments, R 6 It is –OC(O)– (monocyclic heteroaryl), which is optionally substituted by one or more substituents Q. In some embodiments, R 6 It is –OC(O)– (5- or 6-membered heteroaryl), each optionally substituted with one or more substituents Q. In some embodiments, R 6 It is –OC(O)– (bicyclic heteroaryl), which is optionally substituted by one or more substituents Q. In some embodiments, R 6 It is –OC(O)–(5,5-, 5,6-, or 6,6-fused heteroaryl), each optionally substituted with one or more substituents Q. In some embodiments, R 6 It is a –OC(O)- heterocyclic group, which is optionally substituted by one or more substituents Q. In some embodiments, R 6 It is a –OC(O)- monocyclic heterocyclic group, which is optionally substituted by one or more substituents Q. In some embodiments, R 6 It is –OC(O)– (3-, 4-, 5-, 6-, or 7-membered heterocyclic group), each optionally substituted with one or more substituents Q. In some embodiments, R 6 It is an –OC(O)- bicyclic heterocyclic group, which is optionally substituted by one or more substituents Q. In some embodiments, R 6It is –OC(O)– (bridged ring, fused or spirocyclic heterocyclic group), each optionally substituted with one or more substituents Q. In some embodiments, R 6 –OC(O)OR 1a , where R 1a As defined herein. In some implementations, R 6 For –OC(O)NR 1b R 1c , where R 1b and R 1c Each as defined in this article.

[0103] In some implementations, R 7 It is a halogen. In some embodiments, R 7 It is fluorine. In some embodiments, R 7 For –OR 1a , where R 1a As defined herein. In some implementations, R 7 It is a hydroxyl group. In some embodiments, R 7 For –OC(O)R 1a , where R 1a As defined herein. In some implementations, R 7 –OC(O)–C 1-6 Alkyl group, optionally substituted with one or more substituents Q. In some embodiments, R 7 It is an acetyloxy, propionyloxy, or butyryloxy group, each optionally substituted with one or more substituents Q. In some embodiments, R 7 It is an acetyloxy group. In some embodiments, R 7 –OC(O)–C 1-6 Heteroalkyl groups, optionally substituted with one or more substituents Q. In some embodiments, R 7 –OC(O)–C 2-6 The alkenyl group is optionally substituted with one or more substituents Q. In some embodiments, R 7 –OC(O)–C 2-6 The alkynyl group is optionally substituted with one or more substituents Q. In some embodiments, R 7 –OC(O)–C 3-10 Cycloalkyl, optionally substituted with one or more substituents Q. In some embodiments, R 7 –OC(O)–C 6-14 The aryl group is optionally substituted with one or more substituents Q. In some embodiments, R 7 R is a benzoyloxy group, which is optionally substituted with one or more substituents Q. In some embodiments, R7 –OC(O)–(Double-ring C 8-14 Aryl group, optionally substituted with one or more substituents Q. In some embodiments, R 7 –OC(O)–C 7-15 Aryl alkyl group, optionally substituted with one or more substituents Q. In some embodiments, R 7 It is –OC(O)-heteroaryl, which is optionally substituted by one or more substituents Q. In some embodiments, R 7 It is –OC(O)– (monocyclic heteroaryl), which is optionally substituted by one or more substituents Q. In some embodiments, R 7 It is –OC(O)– (5- or 6-membered heteroaryl), each optionally substituted with one or more substituents Q. In some embodiments, R 7 It is –OC(O)– (bicyclic heteroaryl), which is optionally substituted by one or more substituents Q. In some embodiments, R 7 It is –OC(O)–(5,5-, 5,6-, or 6,6-fused heteroaryl), each optionally substituted with one or more substituents Q. In some embodiments, R 7 It is a –OC(O)- heterocyclic group, which is optionally substituted by one or more substituents Q. In some embodiments, R 7 It is a –OC(O)- monocyclic heterocyclic group, which is optionally substituted by one or more substituents Q. In some embodiments, R 7 It is –OC(O)– (3-, 4-, 5-, 6-, or 7-membered heterocyclic group), each optionally substituted with one or more substituents Q. In some embodiments, R 7 It is an –OC(O)- bicyclic heterocyclic group, which is optionally substituted by one or more substituents Q. In some embodiments, R 7 It is –OC(O)– (bridged ring, fused or spirocyclic heterocyclic group), each optionally substituted with one or more substituents Q. In some embodiments, R 7 –OC(O)OR 1a , where R 1a As defined herein. In some implementations, R 7 For –OC(O)NR 1b R 1c , where R 1b and R 1c Each as defined in this article.

[0104] In some implementations, R 8 It is hydrogen. In some embodiments, R 8 For –C(O)R 1a , where R 1aAs defined herein. In some implementations, R 8 –C(O)–C 1-30 Alkyl group, optionally substituted with one or more substituents Q. In some embodiments, R 8 It is acetyl, propionyl, or butyryl, each optionally substituted by one or more substituents Q. In some embodiments, R 8 It is an acetyl group. In some embodiments, R 8 –C(O)–C 1-6 Heteroalkyl groups, optionally substituted with one or more substituents Q. In some embodiments, R 8 –C(O)–C 2-6 The alkenyl group is optionally substituted with one or more substituents Q. In some embodiments, R 8 –C(O)–C 2-6 The alkynyl group is optionally substituted with one or more substituents Q. In some embodiments, R 8 –C(O)–C 3-10 Cycloalkyl, optionally substituted with one or more substituents Q. In some embodiments, R 8 –C(O)–C 6-14 The aryl group is optionally substituted with one or more substituents Q. In some embodiments, R 8 R is benzoyl, which is optionally substituted with one or more substituents Q. In some embodiments, R 8 –C(O)–(bicyclic C) 8-14 Aryl group, optionally substituted with one or more substituents Q. In some embodiments, R 8 –C(O)–C 7-15 Aryl alkyl group, optionally substituted with one or more substituents Q. In some embodiments, R 8 It is a –C(O)-heteroaryl group, which is optionally substituted by one or more substituents Q. In some embodiments, R 8 It is –C(O)– (monocyclic heteroaryl), which is optionally substituted by one or more substituents Q. In some embodiments, R 8 It is –C(O)– (5- or 6-membered heteroaryl), each optionally substituted with one or more substituents Q. In some embodiments, R 8 It is –C(O)– (bicyclic heteroaryl), which is optionally substituted by one or more substituents Q. In some embodiments, R 8 It is –C(O)–(5,5-, 5,6-, or 6,6-fused heteroaryl), each optionally substituted with one or more substituents Q. In some embodiments, R 8It is a –C(O)– heterocyclic group, which is optionally substituted by one or more substituents Q. In some embodiments, R 8 It is a –C(O)– monocyclic heterocyclic group, which is optionally substituted by one or more substituents Q. In some embodiments, R 8 It is –C(O)– (3-, 4-, 5-, 6-, or 7-membered heterocyclic group), each optionally substituted with one or more substituents Q. In some embodiments, R 8 It is a –C(O)– bicyclic heterocyclic group, which is optionally substituted by one or more substituents Q. In some embodiments, R 8 It is –C(O)– (bridged ring, fused or spirocyclic heterocyclic group), each of which is optionally substituted by one or more substituents Q.

[0105] In some implementations, R 6 and R 7 They connect together to form a lactone ring. In some embodiments, R 6 and R 7 They connect together to form a 5-membered lactone ring. In some embodiments, R 6 and R 7 They connect together to form a 6-membered lactone ring.

[0106] In some implementations, R 7 and R 8 They are linked together to form a lactone ring, which is optionally substituted with one or more substituents Q. In some embodiments, R 7 and R 8 They are linked together to form a 5-membered lactone ring, which is optionally substituted with one or more substituents Q. In some embodiments, R 7 and R 8 They are linked together to form a 6-membered lactone ring, which is optionally substituted with one or more substituents Q.

[0107] In some implementations, R 6a It is hydrogen. In some embodiments, R 6a For –C(O)R 1a , where R 1a As defined herein. In some implementations, R 6a –C(O)–C 1-6 Alkyl group, optionally substituted with one or more substituents Q. In some embodiments, R 6a It is acetyl, propionyl, or butyryl, each optionally substituted by one or more substituents Q. In some embodiments, R 6a It is an acetyl group. In some embodiments, R 6a –C(O)–C 1-6Heteroalkyl groups, optionally substituted with one or more substituents Q. In some embodiments, R 6a –C(O)–C 2-6 The alkenyl group is optionally substituted with one or more substituents Q. In some embodiments, R 6a –C(O)–C 2-6 The alkynyl group is optionally substituted with one or more substituents Q. In some embodiments, R 6a –C(O)–C 3-10 Cycloalkyl, optionally substituted with one or more substituents Q. In some embodiments, R 6a –C(O)–C 6-14 The aryl group is optionally substituted with one or more substituents Q. In some embodiments, R 6a R is benzoyl, which is optionally substituted with one or more substituents Q. In some embodiments, R 6a –C(O)–(bicyclic C) 8-14 Aryl group, optionally substituted with one or more substituents Q. In some embodiments, R 6a –C(O)–C 7-15 Aryl alkyl group, optionally substituted with one or more substituents Q. In some embodiments, R 6a It is a –C(O)-heteroaryl group, which is optionally substituted by one or more substituents Q. In some embodiments, R 6a It is –C(O)– (monocyclic heteroaryl), which is optionally substituted by one or more substituents Q. In some embodiments, R 6a It is –C(O)– (5- or 6-membered heteroaryl), each optionally substituted with one or more substituents Q. In some embodiments, R 6a It is –C(O)– (bicyclic heteroaryl), which is optionally substituted by one or more substituents Q. In some embodiments, R 6a It is –C(O)–(5,5-, 5,6-, or 6,6-fused heteroaryl), each optionally substituted with one or more substituents Q. In some embodiments, R 6a It is a –C(O)– heterocyclic group, which is optionally substituted by one or more substituents Q. In some embodiments, R 6a It is a –C(O)– monocyclic heterocyclic group, which is optionally substituted by one or more substituents Q. In some embodiments, R 6a It is –C(O)– (3-, 4-, 5-, 6-, or 7-membered heterocyclic group), each optionally substituted with one or more substituents Q. In some embodiments, R 6a It is a –C(O)– bicyclic heterocyclic group, which is optionally substituted by one or more substituents Q. In some embodiments, R 6aIt is –C(O)– (bridged ring, fused or spirocyclic heterocyclic group), each of which is optionally substituted by one or more substituents Q.

[0108] In some implementations, R 7a It is hydrogen. In some embodiments, R 7a For –C(O)R 1a , where R 1a As defined herein. In some implementations, R 7a –C(O)–C 1-6 Alkyl group, optionally substituted with one or more substituents Q. In some embodiments, R 7a It is acetyl, propionyl, or butyryl, each optionally substituted by one or more substituents Q. In some embodiments, R 7a It is an acetyl group. In some embodiments, R 7a –C(O)–C 1-6 Heteroalkyl groups, optionally substituted with one or more substituents Q. In some embodiments, R 7a –C(O)–C 2-6 The alkenyl group is optionally substituted with one or more substituents Q. In some embodiments, R 7a –C(O)–C 2-6 The alkynyl group is optionally substituted with one or more substituents Q. In some embodiments, R 7a –C(O)–C 3-10 Cycloalkyl, optionally substituted with one or more substituents Q. In some embodiments, R 7a –C(O)–C 6-14 The aryl group is optionally substituted with one or more substituents Q. In some embodiments, R 7a R is benzoyl, which is optionally substituted with one or more substituents Q. In some embodiments, R 7a –C(O)–(bicyclic C) 8-14 Aryl group, optionally substituted with one or more substituents Q. In some embodiments, R 7a –C(O)–C 7-15 Aryl alkyl group, optionally substituted with one or more substituents Q. In some embodiments, R 7a It is a –C(O)-heteroaryl group, which is optionally substituted by one or more substituents Q. In some embodiments, R 7a It is –C(O)– (monocyclic heteroaryl), which is optionally substituted by one or more substituents Q. In some embodiments, R 7a It is –C(O)– (5- or 6-membered heteroaryl), each optionally substituted with one or more substituents Q. In some embodiments, R 7aIt is –C(O)– (bicyclic heteroaryl), which is optionally substituted by one or more substituents Q. In some embodiments, R 7a It is –C(O)–(5,5-, 5,6-, or 6,6-fused heteroaryl), each optionally substituted with one or more substituents Q. In some embodiments, R 7a It is a –C(O)– heterocyclic group, which is optionally substituted by one or more substituents Q. In some embodiments, R 7a It is a –C(O)– monocyclic heterocyclic group, which is optionally substituted by one or more substituents Q. In some embodiments, R 7a It is –C(O)– (3-, 4-, 5-, 6-, or 7-membered heterocyclic group), each optionally substituted with one or more substituents Q. In some embodiments, R 7a It is a –C(O)– bicyclic heterocyclic group, which is optionally substituted by one or more substituents Q. In some embodiments, R 7a It is –C(O)– (bridged ring, fused or spirocyclic heterocyclic group), each of which is optionally substituted by one or more substituents Q.

[0109] In some implementations, A is a key. In some implementations, A is O. In some implementations, A is N(R) 1b ), where R 1b As defined herein. In some implementations, A is N(H).

[0110] In some embodiments, E is hydrogen. In some embodiments, E is an azide group. In some embodiments, E is a halogen. In some embodiments, E is fluorine, chlorine, bromine, or iodine. In some embodiments, E is fluorine. In some embodiments, E is chlorine. In some embodiments, E is bromine. In some embodiments, E is iodine. In some embodiments, E is isocyanate (–NC). In some embodiments, E is –C=C(R) 1a )R 1a , where R 1a Each is as defined herein. In some implementations, E is –C=CH2. In some implementations, E is –C≡CR. 1a , where R 1a As defined herein. In some implementations, E is –C≡CH. In In some implementations, E is , where R 1a As defined herein. In some implementations, E is... In some implementations, E is... In some implementations, E is... In some implementations, E is... , where R1a As defined herein. In some implementations, E is... In some implementations, E is –C(O)R 1a , Among them, R 1a As defined herein. In some implementations, E is –C(O)CH3. In some implementations, E is –SH.

[0111] In some implementations, L is C 1-6 The alkylene group is optionally substituted with one or more substituents Q. In some embodiments, L is methanediyl, ethanediyl, propanediyl, or butanediyl, each optionally substituted with one or more substituents Q. In some embodiments, L is methanediyl, ethane-1,2-diyl, propane-1,2-diyl, or butane-1,4-diyl, each optionally substituted with one or more substituents Q. In some embodiments, L is C 1-6 Heteroalkyl, optionally substituted with one or more substituents Q. In some embodiments, L is C. 2-6 The alkenyl group is optionally substituted with one or more substituents Q. In some embodiments, L is C. 2-6 The ynylene group is optionally substituted with one or more substituents Q. In some embodiments, L is C. 3-10 Cycloalkylene, optionally substituted with one or more substituents Q. In some embodiments, L is C. 6-14 The aryl group is optionally substituted with one or more substituents Q. In some embodiments, L is C. 7-15 The arylene alkyl group is optionally substituted with one or more substituents Q. In some embodiments, L is a heteroarylene alkyl group, optionally substituted with one or more substituents Q. In some embodiments, L is a heterocyclic alkyl group, optionally substituted with one or more substituents Q.

[0112] In one embodiment, this document provides (2R,3S,4R,5S)-2-(acetoxymethyl)-5-(2-azidoacetamido)-6-((Z)-2-ethyl-4-oxobut-2-enamido)tetrahydro-2H-pyran-3,4-dimethyldiacetate A1; 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.

[0113] In another embodiment, this document provides (2R,3S,4R,5S)-2-(acetoxymethyl)-5-(2-azidoacetamido)-6-((E)-2,3-dimethyl-4-oxobut-2-enamido)tetrahydro-2H-pyran-3,4-dimethyldiacetate A2; 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.

[0114] In yet another embodiment, this document provides N-((3S,4R,5S,6R)-2-amino-4,5-dihydroxy-6-(hydroxymethyl)-tetrahydro-2H-pyran-3-yl)-2-azidoacetamide C1, the structure of which is... for .

[0115] In yet another embodiment, this document provides (Z)-N-((3S,4R,5S,6R)-3-(2-azidoacetamido)-4,5-dihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)-2-ethyl-4-oxo Butyl-2-enamide C2, its structure is .

[0116] In yet another embodiment, this document provides (Z)-3-(((3S,4R,5S,6R)-3-(2-azidoacetamido)-4,5-dihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)carbamoyl) Pentyl-2-enoic acid C3, its structure is .

[0117] In another embodiment, this document provides (2R,3S,4R,5S)-2-(acetoxymethyl)-6-amino-5-(2-azidoacetamido)-tetrahydro-2H-pyran-3,4-dimethyldiacetate, the structure of which Structure .

[0118] In some embodiments, the compounds provided herein are isolated or purified. In some embodiments, the compounds provided herein have a purity of at least about 90%, at least about 95%, at least about 98%, at least about 99%, or at least about 99.5% by weight. In some embodiments, the compounds provided herein have a purity of at least about 90% by weight. In some embodiments, the compounds provided herein have a purity of at least about 95% by weight. In some embodiments, the compounds provided herein have a purity of at least about 98% by weight. In some embodiments, the compounds provided herein have a purity of at least about 99% by weight. In some embodiments, the compounds provided herein have a purity of at least about 99.5% by weight.

[0119] The compounds provided herein are intended to include all possible stereoisomers unless a specific stereochemistry is specified. In the case of compounds containing 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 manifest as proton tautomerism in compounds containing, for example, imino, ketone, or oxime groups; or as so-called valence tautomerism in compounds containing aromatic moieties. Thus, a single compound may exhibit more than one isomer type.

[0120] The compounds described herein may be enantiomerically pure, for example, a single enantiomer or a single diastereomer, or a mixture of stereoisomers, such as a mixture of enantiomers, for example, a racemic mixture of two enantiomers; or a mixture of two or more diastereomers. Therefore, those skilled in the art will recognize that, for compounds undergoing epimerization in vivo, the administration of the compound in its (R) form is equivalent to the administration of the compound in its (S) form. Conventional techniques for the preparation / separation of single enantiomers include synthesis from suitable optically pure precursors, asymmetric synthesis from achiral starting materials, or resolution of mixtures of enantiomers, such as chiral chromatography, recrystallization, resolution, diastereomer salt formation, or derivatization into diastereomer adducts followed by separation.

[0121] When the compounds provided herein contain an acidic or basic moiety, 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 ed.; Stahl and Wermuth; John Wiley & Sons, 2011. In some embodiments, the pharmaceutically acceptable salts of the compounds provided herein are solvates. In some embodiments, the pharmaceutically acceptable salts of the compounds provided herein are hydrates.

[0122] Suitable acids for preparing 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, decanoic acid, hexanoic acid, caprylic acid, cinnamic acid, citric acid, and cyclamic acid. Cyclohexanesulfonic acid, dodecyl sulfate, ethane-1,2-disulfonic acid, ethanesulfonic acid, 2-hydroxy-ethanesulfonic acid, formic acid, fumaric acid, galactosic acid, gentian acid, glucoheponic acid, D-gluconic acid, D-glucuronic acid, L-glutamic acid, α-oxoglutarate, glycolic acid, hippuric acid, hydrobromic 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, primordic acid (acid), perchloric acid, phosphoric acid, L-pyroglutamic acid, gluconic acid, salicylic acid, 4-aminosalicylic acid, sebacic acid, stearic acid, succinic acid, sulfuric acid, tannic acid, (+)-L-tartaric acid, thiocyanate, p-toluenesulfonic acid, undecenoic acid, and valeric acid.

[0123] Suitable bases for preparing 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, quaternary, aliphatic, and aromatic amines, including but not limited to L-arginine, phenethylbenzylamine, benzathine, choline, deanol, diethanolamine, diethylamine, dimethylamine, dipropylamine, diisopropylamine, 2-(diethylamino)ethanol, and ethanolamine. Ethylamine, ethylenediamine, isopropylamine, N-methylglucosamine, hydrabamine, 1H-imidazolium, L-lysine, morpholine, 4-(2-hydroxyethyl)-morpholine, methylamine, piperidine, piperazine, propylamine, pyrrolidine, 1-(2-hydroxyethyl)-pyrrolidine, pyridine, quinine ring, quinoline, isoquinoline, triethanolamine, trimethylamine, triethylamine, N-methyl-D-glucosamine, 2-amino-2-(hydroxymethyl)-1,3-propanediol, and thiamethoxam.

[0124] The compounds provided herein can also be provided as prodrugs, which are functional derivatives of the compounds and readily converted into the parent compound in vivo. Prodrugs are often useful because, in some cases, they may be more readily administered than the parent compound. For example, they may be bioavailable when administered orally, whereas the parent compound is not. Prodrugs may also have increased solubility in pharmaceutical compositions compared to the parent compound. Prodrugs can be converted into the parent drug through various mechanisms, including enzymatic processes and metabolic hydrolysis. Pharmaceutical Composition

[0125] In one embodiment, this document provides pharmaceutical compositions comprising compounds provided herein, such as compounds of formula (A) or (I), or their enantiomers, mixtures of enantiomers, diastereomers, mixtures of two or more diastereomers, tautomers, mixtures of two or more tautomers, or isotopic variants; or their pharmaceutically acceptable salts, solvates, hydrates, or prodrugs; and pharmaceutically acceptable excipients.

[0126] The pharmaceutical compositions described herein can be formulated into various dosage forms, including but not limited to those for oral, parenteral, and topical administration. The pharmaceutical compositions can also be formulated into modulated-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, ibid.; Modified-Release Drug Delivery Technology, 2nd ed.; Rathbone et al.; Drugs and the Pharmaceutical Sciences 184; CRC Press; Boca Raton; FL, 2008.

[0127] In one embodiment, the pharmaceutical composition provided herein is formulated in a dosage form for oral administration. In another embodiment, the pharmaceutical composition provided herein is formulated in a dosage form for parenteral administration. In yet another embodiment, the pharmaceutical composition provided herein is formulated in a dosage form for intravenous administration. In yet another embodiment, the pharmaceutical composition provided herein is formulated in a dosage form for intramuscular administration. In yet another embodiment, the pharmaceutical composition provided herein is formulated in a dosage form for subcutaneous administration. In still another embodiment, the pharmaceutical composition provided herein is formulated in a dosage form for topical administration.

[0128] The pharmaceutical compositions described herein may be provided in single-dosage forms or multiple-dosage forms. As used herein, a single-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 compound described herein) and the desired pharmaceutical excipients, sufficient to produce the desired therapeutic effect. Examples of single-dosage forms include, but are not limited to, ampoules, syringes, and individually packaged tablets and capsules. A single-dosage form may be administered in part or in multiples thereof. Multiple-dosage forms are multiple identical single-dosage forms packaged in a single container and administered in separate single-dosage forms. Examples of multiple-dosage forms include, but are not limited to, vials, tablet or capsule vials, or pints or gallons.

[0129] The pharmaceutical compositions described herein may be administered once or at multiple time intervals. It should be understood that the precise dosage and duration of treatment may vary depending on the age, weight, and condition of the subject being treated, and may be determined empirically using known testing protocols or by extrapolation from in vivo or in vitro testing or diagnostic data. It should be further understood that, for any given individual, the specific dosage regimen should be adjusted over time based on the subject's needs and the professional judgment of the person administering or supervising the administration of the pharmaceutical composition. A. Oral administration

[0130] The pharmaceutical compositions described 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, tongue, and sublingual administration. Suitable oral dosage forms include, but are not limited to, tablets, fastmelts, chewable tablets, capsules, pills, strips, troches, tablets, pastils, capsules, pellets, medicated chewing gum, powders, effervescent or non-effervescent powders or granules, oral mists, solutions, emulsions, suspensions, wafers, granule powders, elixirs, and syrups. In addition to the active ingredient, the pharmaceutical compositions may contain one or more pharmaceutically acceptable carriers or excipients, including but not limited to binders, fillers, diluents, disintegrants, wetting agents, lubricants, flow aids, colorants, dye migration inhibitors, sweeteners, flavoring agents, emulsifiers, suspending and dispersing agents, preservatives, solvents, non-aqueous liquids, organic acids, and carbon dioxide sources.

[0131] Binders or granulators impart binding properties to tablets to ensure they remain intact after compression. Suitable binders or granulators include, but are not limited to, starches, such as corn starch, potato starch, and pregelatinized starches (e.g., STARCH 1500). ® Gelatin; sugars, such as sucrose, glucose, dextrose, molasses, and lactose; natural and synthetic gums, such as gum arabic, alginic acid, alginate, carrageenan (Irish moss) extract, Panwar gum, Ghatti gum, isabgol shell mucus, carboxymethyl cellulose, methyl cellulose, polyvinylpyrrolidone (PVP), VEEGUM ® Larch arabinogalactan, powdered tragacanth gum, and guar gum; cellulose, such as ethyl cellulose, cellulose acetate, calcium carboxymethyl cellulose, sodium carboxymethyl cellulose, methyl cellulose, hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC), and hydroxypropyl methyl cellulose (HPMC); and microcrystalline cellulose, such as AVICEL. ® PH-101, AVICEL ® PH-103, AVICEL ® PH-105 and AVICEL ®RC-581. Suitable fillers include, but are not limited to, talc, calcium carbonate, microcrystalline cellulose, powdered cellulose, dextrin, kaolin, mannitol, silica, sorbitol, starch, and pregelatinized starch. The amount of binder or filler in the pharmaceutical compositions provided herein varies depending on the type of formulation and is readily discernible to those skilled in the art. The binder or filler may be present in the pharmaceutical compositions provided herein in amounts of about 50% to about 99% by weight.

[0132] 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 quantities, can impart the property of allowing some compressed tablets to disintegrate in the mouth through 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 those skilled in the art.

[0133] Suitable disintegrants include, but are not limited to, agar; bentonite; cellulose, such as methylcellulose and carboxymethylcellulose; wood products; natural sponges; cation exchange resins; alginate; gums, such as guar gum and VEEGUM® HV; citrus pulp; cross-linked cellulose, such as cross-linked carboxymethylcellulose; cross-linked polymers, such as cross-linked povidone; cross-linked starch; calcium carbonate; microcrystalline cellulose, such as sodium hydroxymethyl starch; potassium polacrilin; starches, such as corn starch, potato starch, cassava starch, and pregelatinized starch; clay; and alginate. The amount of disintegrant in the pharmaceutical compositions provided herein varies depending on the type of formulation and is readily discernible to those skilled in the art. The pharmaceutical compositions provided herein may contain about 0.5% to about 15% or about 1% to about 5% by weight of disintegrant.

[0134] Suitable lubricants include, but are not limited to, calcium stearate; magnesium stearate; mineral oil; light mineral oil; glycerin; sorbitol; mannitol; glycols, such as glyceryl behenate and polyethylene glycol (PEG); stearic acid; sodium lauryl sulfate; talc; hydrogenated vegetable oils, such as peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, and soybean oil; zinc stearate; ethyl oleate; ethyl laurylate; agar; starch; phycocyanin; and silica or silica gel, such as AEROSIL. ® 200 and CAB-O-SIL ® The amount of lubricant in the pharmaceutical compositions provided herein varies depending on the type of formulation and is readily discernible to those skilled in the art. The pharmaceutical compositions provided herein may contain from about 0.1 to about 5% by weight of lubricant.

[0135] Suitable flow aids include, but are not limited to, colloidal silica and CAB-O-SIL. ® And asbestos-free talc. Suitable colorants include, but are not limited to, any approved, certified water-soluble FD&C dyes and water-insoluble FD&C dyes suspended on alumina hydrates, as well as lakes. A lake is a combination of water-soluble dyes adsorbed onto the hydrated oxides of heavy metals to produce an insoluble form of the dye. Suitable flavorings include, but are not limited to, natural flavorings extracted from plants (e.g., fruits), and synthetic hybrids 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, glycerin, 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 (TWEEN). ® 20) Polyoxyethylene dehydrated sorbitan monooleate 80 (TWEEN) ® 80) and triethanolamine oleate. Suitable suspending and dispersing agents include, but are not limited to, sodium carboxymethyl cellulose, pectin, tragacanth gum, and VEEGUM. ® Suitable preservatives include, but are not limited to, glycerin, methylparaben and propylparaben, benzoic acid additives, 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, glycerin, 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.

[0136] It should be understood that many carriers and excipients can perform several functions, even in the same formulation.

[0137] The pharmaceutical compositions for oral administration described herein are available as compressed tablets, tablet formulations, chewable tablets, rapidly dissolving tablets, multiple compressed tablets, enteric-coated tablets, sugar-coated tablets, or film-coated tablets. Enteric-coated tablets are compressed tablets coated with a substance that resists 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 sugar, which can beneficially cover unpleasant tastes or odors and protect the tablet from oxidation. Film-coated tablets are compressed tablets covered by a thin layer or film of 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. Multiple compression tablets are compressed tablets made through more than one compression cycle, including layered tablets and compressed coated tablets or dry coated tablets.

[0138] Tablet dosage forms can be prepared from active ingredients in powder, crystalline, or granular form, alone or in combination with one or more carriers or excipients described herein, including binders, disintegrants, controlled-release polymers, lubricants, diluents, and / or colorants. Flavoring agents and sweeteners are particularly suitable for forming chewable tablets and lozenges.

[0139] The pharmaceutical compositions for oral administration provided herein are available as soft capsules or hard capsules, which may be made from gelatin, methylcellulose, starch, or calcium alginate. Hard gelatin capsules, also known as dry-filled capsules (DFC), consist of two parts, one sliding over the other, thereby completely encapsulating the active ingredient. Soft elastic capsules (SEC) are soft, spherical shells, such as gelatin shells, which are plasticized by the addition of glycerol, sorbitol, or similar polyols. Soft gelatin shells may contain preservatives to prevent microbial growth. Suitable preservatives are those described herein, including methylparaben and propylparaben, as well as sorbic acid. The liquid, semi-solid, and solid dosage forms provided herein may 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 may be prepared as described in U.S. Patent Nos. 4,328,245, 4,409,239, and 4,410,545. As is known to those skilled in the art, capsules may also be coated to alter or maintain the solubility of the active ingredient.

[0140] The pharmaceutical compositions for oral administration described herein are available in liquid and semi-solid dosage forms, including emulsions, solutions, suspensions, elixirs, and syrups. Emulsions are two-phase systems in which one liquid is dispersed in droplets within another liquid; they may be oil-in-water or water-in-oil. Emulsions may include pharmaceutically acceptable non-aqueous liquids or solvents, emulsifiers, and preservatives. Suspensions may include pharmaceutically acceptable suspending agents and preservatives. Aqueous alcoholic solutions may include pharmaceutically acceptable acetals, such as di(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. Emulsions are clarifying, sweetening, and hydroalcoholic solutions. Syrups are concentrated aqueous solutions of sugars (e.g., sucrose) and may also contain preservatives. For liquid dosage forms, for example, solutions in polyethylene glycol may be diluted with a sufficient amount of a pharmaceutically acceptable liquid carrier (e.g., water) to facilitate measurement for administration.

[0141] Other useful liquid and semi-solid dosage forms include, but are not limited to, formulations containing active ingredients and dialkylated monoalkylene glycols or polyalkylene glycols, 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, and polyethylene glycol-750-dimethyl ether, wherein 350, 550, and 750 refer to the approximate average molecular weight of polyethylene glycol. These dosage forms may 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.

[0142] The pharmaceutical compositions for oral administration described herein may also be provided in the form of liposomes, micelles, microspheres, or nanosystems. Micellar dosage forms may be prepared as described in U.S. Patent No. 6,350,458.

[0143] The pharmaceutical compositions provided herein for oral administration may be provided as non-effervescent or effervescent granules and powders for reconfiguration into liquid dosage forms. Pharmaceutically acceptable carriers and excipients for non-effervescent granules or powders may include diluents, sweeteners, and wetting agents. Pharmaceutically acceptable carriers and excipients for effervescent granules or powders may include organic acids and carbon dioxide sources.

[0144] Colorants and flavorings may be used in all dosage forms described herein.

[0145] The pharmaceutical compositions provided herein for oral administration can be formulated as immediate-release or modulated-release dosage forms, including delayed-release, sustained-release, pulsatile-release, controlled-release, targeted-release, and programmed-release forms. B. Parenteral administration

[0146] The pharmaceutical compositions described herein can be administered parenterally via injection, infusion, or implantation for local or systemic administration. As used herein, parenteral administration includes intravenous, intra-arterial, intraperitoneal, intrathecal, intraventricular, intraurethral, ​​intrasternal, intracranial, intramuscular, intrasynovial, intravesical, and subcutaneous administration.

[0147] The pharmaceutical compositions for parenteral administration described herein are suitable for formulation into any dosage form suitable for parenteral administration (including, but not limited to, solutions, suspensions, emulsions, micelles, liposomes, microspheres, and nanosystems) and in a solid form suitable for forming a solution or suspension in a liquid prior to injection. Such dosage forms can be prepared according to conventional methods known to those skilled in the art of pharmaceutical science. See, for example, Remington: The Science and Practice of Pharmacy, ibid.

[0148] The pharmaceutical compositions provided herein for parenteral administration may 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 that inhibit 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, lyophilizing agents, thickeners, pH adjusters and inactive gases.

[0149] Suitable aqueous media include, but are not limited to, water, saline, physiological saline or phosphate-buffered saline (PBS), sodium chloride injection, Ringer's solution, isotonic dextran injection, sterile water injection, dextran and lactated Ringer's solution. Suitable non-aqueous media include, but are not limited to, plant-derived fixed oils, 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 seed oil. Suitable water-miscible media include, but are not limited to, ethanol, 1,3-butanediol, liquid polyethylene glycol (e.g., polyethylene glycol 300 and polyethylene glycol 400), propylene glycol, glycerol, N-methyl-2-pyrrolidone, N,N-dimethylacetamide, and dimethyl sulfoxide.

[0150] Suitable antimicrobial agents or preservatives include, but are not limited to, phenols, cresols, mercury, benzyl alcohol, chlorobutanol, methylparaben and propylparaben, thimerosal, benzalkonium chloride (e.g., benzyl chloride), methylparaben and propylparaben, and sorbic acid. Suitable isotonic agents include, but are not limited to, sodium chloride, glycerol, and dextran. Suitable buffers include, but are not limited to, phosphates and citrates. Suitable antioxidants include those described herein, such as bisulfites and sodium metabisulfite. Suitable local anesthetics include, but are not limited to, procaine hydrochloride. Suitable suspending and dispersing agents include, for example, sodium carboxymethyl cellulose, hydroxypropyl methylcellulose, and polyvinylpyrrolidone. Suitable emulsifiers include, for example, polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan monooleate 80, and triethanolamine oleate. Suitable masking 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 (CAPTISOL). ® ).

[0151] When the pharmaceutical compositions provided herein are formulated for multiple-dose administration, the multiple-dose parenteral formulation must contain an antimicrobial agent at an antibacterial or antifungal concentration. As is known and practiced in the art, all parenteral formulations must be sterile.

[0152] 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, dried soluble product (including lyophilized powder and subcutaneous tablets), reconstituted with a medium prior to use. In yet another embodiment, the pharmaceutical composition is provided as a ready-to-use sterile suspension. In still another embodiment, the pharmaceutical composition is provided as a sterile, dried insoluble product, reconstituted with a medium prior to use. In yet another embodiment, the pharmaceutical composition is provided as a ready-to-use sterile emulsion.

[0153] The pharmaceutical compositions provided herein for parenteral administration can be formulated as immediate-release or modulated-release dosage forms, including delayed-release, sustained-release, pulsatile-release, controlled-release, targeted-release, and programmed-release forms.

[0154] The pharmaceutical compositions provided herein for parenteral administration can be formulated as suspensions, solids, semi-solids, or thixotropic liquids for administration as implantable storage devices. In one embodiment, the pharmaceutical compositions provided herein are dispersed in a solid internal matrix surrounded by an external polymer membrane that is insoluble in body fluids but allows the active ingredient in the pharmaceutical composition to diffuse through.

[0155] 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, polyisobutylene, 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, crosslinked polyvinyl alcohol, and crosslinked partially hydrolyzed polyvinyl acetate.

[0156] Suitable external polymer films 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, vinyl chloride and vinyl acetate, vinylidene chloride, copolymers of ethylene and propylene, ionomer polyethylene terephthalate, butyl rubber, epichlorohydrin rubber, ethylene / vinyl alcohol copolymer, ethylene / vinyl acetate / vinyl alcohol terpolymer, and ethylene / ethyleneoxyethanol copolymer. C. Local application

[0157] The pharmaceutical compositions described herein may be administered topically to the skin, orifices, or mucous membranes. As used herein, topical administration includes administration to the dermis (inner), conjunctiva, cornea, eye, eye, ear, transdermal, nose, vagina, urethra, respiratory tract, and rectum.

[0158] The pharmaceutical compositions described herein can be formulated into any dosage form suitable for local 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. Topical formulations of the pharmaceutical compositions described herein may also include liposomes, micelles, microspheres, and nanosystems.

[0159] Pharmaceutically acceptable carriers and excipients suitable for use in topical formulations include, but are not limited to, aqueous media, water-miscible media, non-aqueous media, antimicrobial agents or preservatives that inhibit microbial growth, stabilizers, solubilizers, isotonic agents, buffers, antioxidants, local anesthetics, suspending and dispersing agents, wetting agents or emulsifiers, complexing agents, masking agents or chelating agents, penetration enhancers, cryoprotectants, lyophilization protectants, thickeners and inactive gases.

[0160] The pharmaceutical composition can also be administered topically via electroporation, iontophoresis, ultrasound permeation, ultrasound-enhanced permeation, or microneedle or needle-free injection (e.g., POWDERJECT™ and BIOJECT™).

[0161] The pharmaceutical compositions described herein are available in ointment, cream, and gel forms. Suitable ointment carriers include oily or hydrocarbon carriers, including lard, benzoic acid lard, olive oil, cottonseed oil, and other oils, and white petrolatum; emulsifiable or absorbable carriers, such as hydrophilic petrolatum, hydroxystearin sulfate, and anhydrous lanolin; water-removable carriers, such as hydrophilic ointments; water-soluble ointment carriers, including polyethylene glycol of varying molecular weights; and emulsion carriers, water-in-oil (W / O) emulsions or oil-in-water (O / W) emulsions, including cetyl alcohol, glyceryl monostearate, lanolin, and stearic acid. See, for example, Remington: The Science and Practice of Pharmacy, ibid. These carriers have emollient effects but typically require the addition of antioxidants and preservatives.

[0162] Suitable cream bases can be oil-in-water or water-in-oil. Suitable cream media can be washable and contain an oil phase, an emulsifier, and an aqueous phase. The oil phase, also known as the "internal" phase, typically includes petrolatum and fatty alcohols (e.g., cetyl alcohol or stearyl alcohol). The aqueous phase usually (but not necessarily) exceeds the oil phase in volume and typically contains a wetting agent. Emulsifiers in cream formulations can be nonionic surfactants, anionic surfactants, cationic surfactants, or amphoteric surfactants.

[0163] The gel is a semi-solid, suspension-type system. Single-phase gels contain organic macromolecules that are substantially uniformly distributed in a liquid carrier. Suitable gelling agents include, but are not limited to, cross-linked acrylic polymers, such as carbomers, carboxylated polyalkylene compounds, and CARBOPOL. ® Hydrophilic polymers, such as polyethylene oxide, polyethylene oxide-polypropylene 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 gum tragali 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 grinding, mechanical mixing, and / or stirring.

[0164] The pharmaceutical compositions described herein may be administered rectally, urethra, vaginally, or pervadermally in the form of suppositories, uterine pessaries, probes, wet dressings or 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 processes as described in Remington: The Science and Practice of Pharmacy (ibid.).

[0165] Rectal, urethral, ​​and vaginal suppositories are solid objects intended for insertion into bodily orifices. They 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 matrices or mediators, such as hardening agents that, when formulated with the active ingredient, produce a melting point close to body temperature; and antioxidants as described herein, including bisulfites and sodium metabisulfite. Suitable mediators include, but are not limited to, cocoa butter (cocoa soybean oil), glycerin-gelatin, carbowax (polyethylene glycol), cetyl wax, paraffin wax, white and yellow waxes, and appropriate mixtures of mono, di, and triglycerides of fatty acids, as well as hydrogels, such as polyvinyl alcohol, hydroxyethyl methacrylate, and polyacrylic acid. Combinations of various mediators may also be used. Rectal and vaginal suppositories can be prepared by compression or molding. The typical weight of a rectal and vaginal suppository is about 2 to about 3 g.

[0166] The pharmaceutical compositions described herein can be administered ocularly in the form of solutions, suspensions, ointments, emulsions, gel-forming solutions, powders for use with solutions, gels, ocular inserts, and implants.

[0167] The pharmaceutical compositions provided herein can be administered intranasally or by inhalation to the respiratory tract. The pharmaceutical compositions may be provided in the form of aerosols or solutions for delivery alone or in combination with a suitable propellant (e.g., 1,1,1,2-tetrafluoroethane or 1,1,1,2,3,3,3-heptafluoropropane) using a pressurized container, pump, nebulizer, nebulizer (e.g., a nebulizer that uses electrohydrodynamics to generate a fine mist), or nebulizer. The pharmaceutical compositions may also be provided alone or in combination with an inert carrier (e.g., lactose or phospholipids) as a dry powder for inhalation; and as nasal drops. For intranasal use, the powder may include a bioadhesive (including chitosan or cyclodextrin).

[0168] Formulate solutions or suspensions for use in pressurized containers, pumps, sprayers, nebulizers, or nebulized inhalers, containing ethanol, aqueous ethanol, or suitable alternative reagents for dispersing, dissolving, or delaying the release of active ingredients; propellants as solvents; and / or surfactants, such as sorbitan trioleate, oleic acid, or oligolactic acid.

[0169] The pharmaceutical compositions provided herein can be micronized to a size suitable for delivery by inhalation, for example, about 50 micrometers or less, or about 10 micrometers or less. Particles of such size can be prepared using pulverization methods known to those skilled in the art, such as helical jet milling, fluidized bed jet milling, supercritical fluid treatment to form nanoparticles, high-pressure homogenization, or spray drying.

[0170] Capsules, blister packs, and cartridges for use in inhalers or blowpipes may be formulated as a mixture of powders containing: the pharmaceutical composition described herein; a suitable powder matrix (e.g., lactose or starch); and a performance modifier (e.g., L-leucine, mannitol, or magnesium stearate). Lactose may be anhydrous or in monohydrate form. Other suitable excipients or carriers include, but are not limited to, dextran, glucose, maltose, sorbitol, xylitol, fructose, sucrose, and trehalose. The pharmaceutical compositions described herein for inhalation / intranasal administration may further include suitable flavoring agents, such as menthol and levonorgestrel; and / or sweeteners, such as saccharin and sodium saccharin.

[0171] The pharmaceutical compositions provided herein for local administration can be formulated for immediate or modulated release, including delayed release, sustained release, pulsatile release, controlled release, targeted release, and programmed release. D. Adjustment

[0172] The pharmaceutical compositions provided herein can be formulated into modulated-release dosage forms. As used herein, the term "modulated-release" refers to a dosage form in which the release rate or site of the active ingredient differs from that of an immediate-release dosage form when administered via the same route. Modulated-release dosage forms include, but are not limited to, delayed-release, extended-release, sustained-release, pulsatile-release, controlled-release, accelerated-release, rapid-release, targeted-release, programmed-release, and gastric-retention dosage forms. Various modulated-release devices and methods known to those skilled in the art can be used to prepare pharmaceutical compositions in modulated-release dosage forms, including but not limited to matrix-controlled release devices, osmotic-controlled release devices, multi-particle controlled-release devices, ion-exchange resins, enteric coatings, multilayer coatings, microspheres, liposomes, and combinations thereof. The release rate of the active ingredient can also be altered by changing the particle size and polymorphism of the active ingredient. 1. Matrix-controlled release device

[0173] The drug compositions of the modulated-release formulations provided herein can be made using matrix-controlled release devices known to those skilled in the art. See, for example, Takada et al., Encyclopedia of Controlled Drug Delivery, ed. Mathiowitz; Wiley, 1999; Vol. 2.

[0174] In some embodiments, the pharmaceutical compositions of the modulated-release formulations 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, such as polysaccharides and proteins.

[0175] Materials that can be used to form erosive matrices include, but are not limited to, chitin, chitosan, dextran, and pullulan; agar, gum arabic, gum karaya, locust bean gum, tragacanth gum, carrageenan, Ghatti gum, guar gum, xanthan gum, and stearin; starches, such as dextrin and maltodextrin; hydrophilic colloids, such as pectin; phospholipids, such as lecithin; alginate; propylene glycol alginate; gelatin; collagen; and cellulose materials, such as ethyl cellulose (EC), methyl ethyl cellulose (MEC), carboxymethyl cellulose (CMC), CMEC, hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC), cellulose acetate (CA), cellulose propionate (CP), cellulose butyrate (CB), cellulose acetate butyrate (CAB), CAP, CAT, hydroxypropyl methyl cellulose (HPMC), HPMCP, HPMCAS, and hydroxypropyl methyl cellulose acetate trimellitate. Trimellitate (HPMCAT) and ethyl hydroxyethyl cellulose (EHEC); polyvinylpyrrolidone; polyvinyl alcohol; polyvinyl acetate; fatty acid glycerides; polyacrylamide; polyacrylic acid; copolymers of ethyl acrylic acid or methacrylic acid (EUDRAGIT®); 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 acid derivatives, such as homopolymers and copolymers of butyl methacrylate, methyl methacrylate, ethyl methacrylate, ethyl methacrylate, (2-dimethylaminoethyl) methacrylate and (trimethylaminoethyl) methacrylate chlorides.

[0176] In some embodiments, the pharmaceutical compositions provided herein are formulated using a non-erodible matrix device. The active ingredient is dissolved or dispersed in an inert matrix and, upon administration, is released primarily through diffusion from the inert matrix. Materials suitable for use as non-corrosive matrix devices include, but are not limited to, insoluble plastics, such as polyethylene, polypropylene, polyisoprene, polyisobutylene, polybutadiene, polymethyl methacrylate, polybutyl methacrylate, chlorinated polyethylene, polyvinyl chloride, methyl acrylate-methyl methacrylate copolymer, ethylene-vinyl acetate copolymer, ethylene / propylene copolymer, ethylene / ethyl acrylate copolymer, vinyl chloride and vinyl acetate, vinylidene chloride, copolymers of ethylene and propylene, ionomer-type 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 copolymers; hydrophilic polymers, such as ethyl cellulose, cellulose acetate, crosslinked povidone and crosslinked partially hydrolyzed polyvinyl acetate; and aliphatic compounds, such as carnauba wax, microcrystalline wax and triglycerides.

[0177] In matrix-controlled release systems, the desired release kinetics can be controlled, for example, by the type of polymer used, polymer viscosity, particle size of the polymer and / or active ingredient, ratio of active ingredient to polymer, and other excipients or carriers in the composition.

[0178] The drug compositions of the modulated-release formulations 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. Osmosis-controlled release device

[0179] The modified-release formulations of pharmaceutical compositions described herein can be fabricated using osmotic controlled-release devices, including but not limited to single-chamber systems, two-chamber systems, asymmetric membrane technology (AMT), and extruding core systems (ECS). Typically, such devices have at least two components: (a) a core containing the active ingredient; and (b) a semi-permeable membrane having at least one delivery port encapsulating the core. The semi-permeable membrane controls the flow of water from the aqueous environment of use into the core, thereby releasing the drug by extrusion through the delivery port.

[0180] In addition to the active ingredient, the core of the permeation device optionally includes a permeabilizing agent, which generates the driving force for transporting water from the environment to the core of the device. One type of permeabilizing agent is a water-swellable hydrophilic polymer, also known as a "permeation polymer" or "hydrogel". Suitable water-swellable hydrophilic polymers as penetrants include, but are not limited to, hydrophilic vinyl and acrylic polymers, polysaccharides (e.g., calcium alginate), polyethylene oxide (PEO), polyethylene glycol (PEG), polypropylene glycol (PPG), poly(2-hydroxyethyl methacrylate), poly(acrylic) acid, poly(methacrylic) acid, polyvinylpyrrolidone (PVP), crosslinked PVP, polyvinyl alcohol (PVA), PVA / PVP copolymers, PVA / PVP copolymers with hydrophobic monomers (e.g., methyl methacrylate and vinyl acetate), hydrophilic polyurethanes containing large PEO blocks, crosslinked sodium carboxymethyl cellulose, carrageenan, hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC), hydroxypropyl methyl cellulose (HPMC), carboxymethyl cellulose (CMC) and carboxyethyl cellulose (CEC), sodium alginate, polycarbophil, gelatin, xanthan gum and sodium starch hydroxyacetate.

[0181] Another type of permeabilizer is the osmogen, which can absorb moisture to affect the osmotic pressure gradient across the surrounding coating barrier. Suitable osmogens include, but are not limited to, inorganic salts, such as magnesium sulfate, magnesium chloride, calcium chloride, sodium chloride, lithium chloride, potassium sulfate, potassium phosphate, sodium carbonate, sodium sulfite, lithium sulfate, potassium chloride, and sodium sulfate; sugars, such as dextrose, fructose, glucose, inositol, lactose, maltose, mannitol, raffinose, sorbitol, sucrose, trehalose, and xylitol; organic acids, such as ascorbic acid, benzoic acid, fumaric acid, citric acid, maleic acid, sebacic acid, sorbic acid, adipic acid, edetic acid, glutamic acid, p-toluenesulfonic acid, succinic acid, and tartaric acid; urea; and mixtures thereof.

[0182] The rate at which the active ingredient is initially delivered from the dosage form can be influenced by using penetrants with different dissolution rates. For example, amorphous sugars (e.g., mannogem) can be used. ™ EZ (Extra-Zone) can provide faster delivery during the initial hours, rapidly producing the desired therapeutic effect, and gradually and continuously release the remaining amount to maintain the desired level of therapeutic or preventative effect over the delayed period. In this case, the active ingredient is released at a rate that replaces the amount of active ingredient metabolized and excreted.

[0183] 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 promote stability or processing.

[0184] Materials used to form semipermeable membranes include various grades of acrylic, vinyl, ether, polyamide, polyester, and cellulose derivatives that are water-permeable and water-insoluble at physiologically relevant pH levels, or readily become water-insoluble through chemical changes (e.g., crosslinking). Examples of suitable polymers for coating formation include plasticized, unplasticized, and reinforced cellulose acetate (CA), cellulose diacetate, cellulose triacetate, CA propionate, cellulose nitrate, cellulose acetate butyrate (CAB), CA ethyl carbamate, CAP, CA methyl carbamate, CA succinate, cellulose acetate trimellitate (CAT), CA dimethylaminoacetic acid, CA ethyl carbonate, CA chloroacetic acid, CA ethyl oxalate, CA methyl sulfonate, CA butyl sulfonate, CA p-toluenesulfonate, acetic agar, amyl starch triacetate, and β-glucanacetic acid. Esters, β-glucan triacetate, acetaldehyde dimethyl acetate, locust bean gum triacetate, hydroxylated ethylene-vinyl acetate, EC, PEG, PPG, PEG / PPG copolymer, PVP, HEC, HPC, CMC, CMEC, HPMC, HPMC, HPMCP, HPMCS, HPMCT, 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, polyethylene halides, polyethylene esters and ethers, natural waxes and synthetic waxes.

[0185] Semipermeable membranes can also be hydrophobic microporous membranes, wherein the pores are essentially filled with gas and are not wetted by aqueous media, but are permeable to water vapor, as disclosed in U.S. Patent No. 5,798,119. Such hydrophobic but water vapor-permeable membranes are typically composed of hydrophobic polymers, such as polyolefins, polyethylene, polypropylene, polytetrafluoroethylene, polyacrylic acid derivatives, polyethers, polysulfones, polyethersulfones, polystyrene, polyethylene halides, polyvinylidene fluoride, polyethylene esters and ethers, natural waxes, and synthetic waxes.

[0186] Delivery ports on a semipermeable membrane can be formed after coating by mechanical or laser drilling. Delivery ports can also be formed in situ by eroding a plug with a water-soluble material or by rupturing a thinner portion of the membrane in a notch in the core. Furthermore, 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.

[0187] The total amount and release rate of the active ingredient released can be largely adjusted by the thickness and porosity of the semipermeable membrane, the composition of the core, and the number, size, and location of the delivery ports.

[0188] In pharmaceutical compositions of osmotic controlled release formulations, additional conventional excipients or carriers, as described herein, may be included to enhance the performance or processing of the formulation.

[0189] Osmotic controlled-release dosage forms can be prepared using conventional methods and techniques known to those skilled in the art. See, for example, Remington: The Science and Practice of Pharmacy, ibid.; 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.

[0190] In some embodiments, the pharmaceutical compositions provided herein are formulated as AMT controlled-release dosage forms comprising an asymmetric permeation membrane coated with a core containing the active ingredient and other pharmaceutically acceptable excipients or carriers. See, for example, U.S. Patent Nos. 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.

[0191] In some embodiments, the pharmaceutical compositions provided herein are formulated as ESC controlled-release dosage forms comprising a permeable membrane coated with a core containing an active ingredient, hydroxyethyl cellulose, and other pharmaceutically acceptable excipients or carriers. 3. Multi-particle controlled release device

[0192] The pharmaceutical compositions described herein in the controlled-release formulation can be fabricated as multi-particulate controlled-release devices, comprising various particles, granules, or pellets with diameters 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-particulate formulations can be manufactured by methods known to those skilled in the art, including wet and dry granulation, extrusion / spheronization, roller-compaction, melt coagulation, and spray-coating seed cores. See, for example, Multiparticulate Oral Drug Delivery; ed. Ghebre-Sellassie; Drugs and the Pharmaceutical Sciences 65; CRC Press: 1994; and Pharmaceutical Palletization Technology; ed. Ghebre-Sellassie; Drugs and the Pharmaceutical Sciences 37; CRC Press: 1989.

[0193] Other excipients or carriers as described herein may be mixed with the pharmaceutical composition to aid in processing and the formation of multiparticles. The resulting particles may themselves constitute a multiparticle device or may be coated with various film-forming materials (e.g., enteric polymers, water-swellable and water-soluble polymers). The multiparticles may be further processed into capsules or tablets. 4. Targeted delivery

[0194] The pharmaceutical compositions described herein can also be formulated to target specific tissues, receptors, or other regions of the body of the subject to be treated, including delivery systems based on liposomes, resealed erythrocytes, and antibodies. 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. How to use

[0195] In one embodiment, this document provides a method for labeling cells in a subject with a functional group (e.g., an azide group), the method comprising administering to a subject in need an effective amount of a compound provided herein, such as a compound of formula (A) or (I), or an enantiomer, mixture of enantiomers, diastereomers, mixture of two or more diastereomers, tautomers, mixture of two or more tautomers, or isotopic variants thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0196] In another embodiment, this document provides a method for labeling cell surfaces in a subject with a functional group (e.g., an azide group), the method comprising administering to a subject in need an effective amount of a compound provided herein, such as a compound of formula (A) or (I), or an enantiomer, mixture of enantiomers, diastereomers, mixture of two or more diastereomers, tautomers, mixture of two or more tautomers, or isotopic variants thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

[0197] In some embodiments, the functional group is a group used for click chemistry.

[0198] In some embodiments, the cells are aldehyde dehydrogenase (ALDH) overexpressing cells. In some embodiments, the cells are aldehyde dehydrogenase 1A1 (ALDHA1) overexpressing cells.

[0199] In some embodiments, the cells are cancer cells. In some embodiments, the cells are ALDH-overexpressing cancer cells. In some embodiments, the cells are ALDHA1-overexpressing cancer cells. In some embodiments, the cells are cancer stem cell-like cells (CSCs).

[0200] In some embodiments, the subject is a mammal. In some embodiments, the subject is a human.

[0201] In some embodiments, the effective amount of the compound provided herein ranges from about 0.1 to about 100 mg / kg / day, about 0.1 to about 50 mg / kg / day, about 0.1 to about 25 mg / kg / day, about 0.1 to about 20 mg / kg / day, about 0.1 to about 15 mg / kg / day, about 0.1 to about 10 mg / kg / day, or about 0.1 to about 5 mg / kg / day. In one embodiment, 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.

[0202] In some embodiments, the effective amount of the compound 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 compound provided herein ranges from about 1 to about 1000 mg per day. In another embodiment, the effective amount of the compound provided herein ranges from about 1 to about 500 mg per day. In yet another embodiment, the effective amount of the compound provided herein ranges from about 1 to about 200 mg per day. In still another embodiment, the effective amount of the compound provided herein ranges from about 1 to about 100 mg per day.

[0203] Depending on the disorder, disease, or condition to be treated and the condition of the subject, the compounds described herein may be administered via the following routes of administration: oral, parenteral (e.g., intramuscular, intraperitoneal, intravenous, CIV, intracisional injection or infusion, subcutaneous injection, or implantation), inhalation, nasal, vaginal, rectal, sublingual, or topical (e.g., transdermal or external). The compounds described herein may be formulated with pharmaceutically acceptable excipients, carriers, adjuvants, or mediators to appropriate dose units suitable for each route of administration.

[0204] In one embodiment, the compound provided herein is administered orally. In another embodiment, the compound provided herein is administered parenterally. In yet another embodiment, the compound provided herein is administered intravenously. In yet another embodiment, the compound provided herein is administered intramuscularly. In yet another embodiment, the compound provided herein is administered subcutaneously. In yet another embodiment, the compound provided herein is administered topically. In still another embodiment, the compound provided herein is administered by local infusion.

[0205] The compounds described herein may be delivered as a single dose, such as a single bolus injection, or an oral tablet or pill; or over time, such as by continuous infusion or by multiple bolus injections over time. If necessary, the compounds described herein may be administered repeatedly, for example, until the subject achieves disease stability or resolution, or until the subject experiences disease progression or unacceptable toxicity.

[0206] The compounds described herein may be administered once daily (QD) or divided into multiple daily doses, such as twice daily (BID) and three times daily (TID). Furthermore, administration may be continuous, i.e., daily or intermittent. The terms “intermittent” or “intermittently” as used herein are intended to indicate stopping and starting at regular or irregular intervals. For example, intermittent administration of the compounds described herein may be one to six days per week, cyclical administration (e.g., daily administration for two to eight consecutive weeks, followed by a rest period of up to one week without administration), or administration every other day.

[0207] The compounds described herein may also be used in combination or in combination with therapeutic agents for the treatment and / or prevention of the conditions, disorders or diseases described herein.

[0208] As used herein, the term "combination" includes the use of more than one therapy (e.g., one or more prophylactic and / or therapeutic agents). However, the use of the term "combination" does not limit the order in which therapies (e.g., prophylactic and / or therapeutic agents) are administered to subjects with a condition, disorder, or disease. A first therapy (e.g., a prophylactic or therapeutic agent, such as the compounds provided herein) may be administered to the subject 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 prior to, 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 prior to), during, 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 prior to), during, or after), during, or after, the administration of a second therapy (e.g., a prophylactic or therapeutic agent). Triple therapy is also considered herein.

[0209] The routes of administration for the compounds provided herein are unrelated to the routes of administration for the second therapy. In one embodiment, the compounds provided herein are administered orally. In another embodiment, the compounds provided herein are administered intravenously. In yet 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 may be administered orally, parenterally, intraperitoneally, intravenously, intra-arterially, transdermally, sublingually, intramuscularly, rectally, buccally, intranasally, via liposomes, by inhalation, vaginally, intraocularly, topically via catheter or stent, subcutaneously, intra-fat, intra-articularly, 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).

[0210] In one embodiment, this document provides a method for labeling cells with a functional group (e.g., an azide group), the method comprising contacting the cells with an effective amount of a compound provided herein, such as a compound of formula (A) or (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.

[0211] In another embodiment, this document provides a method for labeling cell surfaces with functional groups (e.g., azido groups), the method comprising contacting cells with an effective amount of a compound provided herein, such as a compound of formula (A) or (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.

[0212] In some embodiments, the functional group is a group used for click chemistry.

[0213] In some embodiments, the cells are aldehyde dehydrogenase (ALDH) overexpressing cells. In some embodiments, the cells are aldehyde dehydrogenase 1A1 (ALDHA1) overexpressing cells.

[0214] In some embodiments, the cells are cancer cells. In some embodiments, the cells are ALDH-overexpressing cancer cells. In some embodiments, the cells are ALDHA1-overexpressing cancer cells. In some embodiments, the cells are cancer stem cell-like cells (CSCs).

[0215] The compounds described herein may also be provided as articles of manufacture 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 method of administration and treatment.

[0216] In some embodiments, this document provides a kit that, when used by a medical practitioner, simplifies the administration of an appropriate amount of the compound provided herein as the active ingredient to a subject. In some embodiments, the kit provided herein includes a container and a dosage form of the compound provided herein.

[0217] The kits provided herein may further include devices for administering the active ingredient. Examples of such devices include, but are not limited to, syringes, needle-free injector droppers, patches, and inhalers. The kits provided herein may also include condoms for administering the active ingredient.

[0218] The kits provided herein may further include pharmaceutically acceptable media for administering 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 media in which the active ingredient is dissolved to form a particulate-free, sterile solution suitable for parenteral administration. Examples of pharmaceutically acceptable media include, but are not limited to: aqueous media, including but not limited to water for injection (USP), sodium chloride injection, Ringer's solution, dextran injection, dextran and sodium chloride injection, and lactated Ringer's solution; water-miscible media, including but not limited to ethanol, polyethylene glycol, and polypropylene glycol; and non-aqueous media, including but not limited to corn oil, cottonseed oil, peanut oil, sesame oil, ethyl oleate, isopropyl myristate, and benzyl benzoate.

[0219] This disclosure will be further understood through the following non-limiting examples. Example

[0220] As used herein, the symbols and conventions used in these methods, schemes and embodiments, whether or not specific abbreviations are specifically defined, are consistent with those used in contemporary scientific literature (e.g., the Journal of the American Chemical Society, the Journal of Medicinal Chemistry, or the 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 (micromolar); mmol (millimole); min (minute); h (hour); Ac (acetyl); Ac2O (acetic anhydride); ACN (acetonitrile); DCM (dichloromethane); DIEA (N,N-diisopropylethylamine); DMAP (4-dimethylaminopyridine); DMF (dimethylformamide); DMSO (dimethyl sulfoxide); EtOAc (ethyl acetate); EtOH (ethanol); HATU (azirbenztriazole tetramethylurea hexafluorophosphate); MeOH (methanol); NaOMe (sodium methoxide); PE (petroleum ether); Ph (phenyl); TEA (triethylamine); TFA (trifluoroacetic acid); THF (tetrahydrofuran); TMSN3 (azidotrimethylsilane); HRMS (high-resolution mass spectrometry); MS (mass spectrometry); NMR (nuclear magnetic resonance); and prep-HPLC (preparative high-performance liquid chromatography).

[0221] For all the following embodiments, standard processing and purification methods known to those skilled in the art can be utilized. Unless otherwise stated, all temperatures are expressed in °C (degrees Celsius). Unless otherwise stated, all reactions are carried out at room temperature. The synthetic methodologies described herein are intended to illustrate applicable chemical methods through specific examples and do not indicate the scope of this disclosure. Example 1 Preparation of (2R,3S,4R,5S)-2-(acetoxymethyl)-5-(2-azidoacetamido)-6-((Z)-2-ethyl-4-oxobut-2-enamido)tetrahydro-2H-pyran-3,4-dimethyldiacetate A1

[0222] Compound A1 was prepared according to Scheme 1.

[0223] Preparation of 1,3,4,6-tetra-O-acetyl-N-azidoacetyl-D-mannosamine (Ac4ManAz) 1.2. 0.5N NaOMe in MeOH (18.6 mL, 9.28 mmol) was added dropwise to a solution of D-mannosamine hydrochloride 1.1 (2 g, 9.28 mmol) in MeOH (10 mL) at 0 °C. After stirring the mixture at room temperature for 30 min, TEA (0.94 g, 9.28 mmol) and chloroacetic anhydride (1.90 g, 11.1 mmol, 95%) were added at 0 °C. The reaction mixture was then stirred overnight at room temperature, followed by the addition of H2O (3 mL) and NaN3 (2.41 g, 37.1 mmol). After stirring overnight at 65 °C, the reaction mixture was filtered, concentrated, and resuspended in pyridine (15 mL). DMAP (114 mg, 0.93 mmol) and Ac₂O (7.58 g, 7 mL, 74.2 mmol) were added at 0 °C. The reaction mixture was stirred overnight at room temperature and then quenched with MeOH. After concentration, the resulting residue was dissolved in EtOAc (50 mL) and washed successively with 1 M HCl, brine, and saturated NaHCO₃ aqueous solution. The organic layer was dried over anhydrous Na₂SO₄, filtered, concentrated, and purified by column chromatography (SiO₂, EtOAc / hexane) to give compound 1.2 (2.6 g), a mixture of terminal isomers (α:β ratio: 43:57), in 65% yield. 1H NMR (500 MHz, CDCl3) δ 6.64 (d, J =9.5 Hz, 1H), 6.56 (d, J = 8.0 Hz, 1H), 6.04 (d, J = 1.5 Hz, 1H), 5.89 (d, J =1.5 Hz, 1H), 5.34 (dd, J = 10.5, 4.5 Hz, 1H), 5.22 (t, J = 10.0 Hz, 1H), 5.16 (t, J = 9.5 Hz, 1H), 5.06 (dd, J = 9.5, 3.5 Hz, 1H), 4.73 (ddd, J = 9.5, 3.5,1.5 Hz, 1H), 4.62 (ddd, J = 9.0, 4.0, 2.0 Hz, 1H), 4.25 (dd, J = 7.5, 4.5 Hz,1H), 4.23 (dd, J = 7.5, 4.0 Hz, 1H), 4.15 (dd, J = 12.0, 2.0 Hz, 1H), 4.12-4.02 (m, 6H), 3.82 (ddd, J = 9.5, 4.5, 2.0 Hz, 1H), 2.18 (s, 3H), 2.11 (s,9H), 2.06 (s, 6H), 2.01 (s, 3H), 2.00 (s, 3H).

[0224] Preparation of 3,4,6-tri-O-acetyl-2-azidoacetamito-2-deoxy-D-mannopyranosyl azide 1.3. TMSN3 (642 mg, 740 μL, 5.58 mmol), SnCl4 (194 mg, 87 μL, 0.744 mmol), and AgClO4 (154 mg, 0.744 mmol) were added to a solution of compound 1.2 (1.6 g, 3.72 mmol) in DCM (16 mL) at 0 °C. After stirring overnight at room temperature, the reaction mixture was quenched with a saturated aqueous solution of NaHCO3, filtered through diatomaceous earth, and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, concentrated, and purified by column chromatography (SiO2, EtOAc / hexane) to give compound 1.3 (1.37 g) in 89% yield. 1H NMR (500 MHz, CDCl3) δ 6.61 (d, J =9.0 Hz, 1H), 5.36 (d, J = 1.5 Hz, 1H), 5.24 (dd, J = 10.0, 4.0 Hz, 1H), 5.12(t, J = 9.5 Hz, 1H), 4.50 (ddd, J = 9.0, 4.5, 2.0 Hz, 1H), 4.26 (dd, J =13.0, 5.5 Hz, 1H), 4.17-4.16 (m, 1H), 4.15-4.14 (m, 1H), 4.06 (d, J = 16.5Hz, 1H), 4.02 (d, J = 16.5 Hz, 1H), 2.11 (s, 3H), 2.05 (s, 3H), 1.98 (s, 3H);MS (ESI) m / z: 414.1 [M+H] + .

[0225] Preparation of (2R,3S,4R,5S)-2-(acetoxymethyl)-6-amino-5-(2-azidoacetamido)tetrahydro-2H-pyran-3,4-dimethyldiacetate 1.4. 1M P(CH3)3 in THF (484 μL, 0.484 mmol) was added dropwise to a solution of compound 1.3 (200 mg, 0.484 mmol) in THF (2 mL) at 0 °C. The reaction mixture was stirred at 0 °C for 30 min, then at room temperature for 5 min, and H2O (87 mg, 87 μL, 4.84 mmol) was added. The reaction mixture was stirred overnight at room temperature and then concentrated to give crude compound 1.4, which was used directly in the next step without further purification. MS (ESI) m / z: 388.1 [M+H] + 410.1 [M+Na] + .

[0226] Preparation of (2R,3S,4R,5S)-2-(acetoxymethyl)-5-(2-azidoacetamido)-6-(2-oxo-butamido)tetrahydro-2H-pyran-3,4-dimethyldiacetate 1.5. TEA (244 mg, 337 μL, 2.42 mmol) and oxalyl chloride (246 mg, 164 μL, 1.94 mmol) were added to a solution of 2-ketobutyric acid (247 mg, 2.42 mmol) in DCM (3 mL) at room temperature and under N2. After stirring for 30 min, the reaction mixture was concentrated to obtain crude acyl chloride. A solution of this crude acyl chloride in DCM (2 mL) was added dropwise to a solution of compound 1.4 and pyridine (154 mg, 157 μL, 1.94 mmol) in DCM (1 mL) at 0 °C. After stirring overnight at the same temperature, the reaction mixture was quenched with a saturated aqueous solution of NaHCO3 and extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, concentrated, and purified by column chromatography (SiO2, EtOAc / hexane) to give compound 1.5 (57 mg) in 25% yield. 1 H NMR (500 MHz, CDCl3) δ 7.61 (d, J = 9.2Hz, 1H), 6.66 (d, J = 9.8 Hz, 1H), 5.42 (d, J = 9.2 Hz, 1H), 5.22-5.04 (m,2H), 4.69 (dd, J = 9.7, 3.4 Hz, 1H), 4.24 (dd, J = 12.5, 4.3 Hz, 1H), 4.17(s, 2H), 4.14 (s, 1H), 3.82 (ddd, J = 9.7, 4.4, 2.2 Hz, 1H), 2.93 (q, J = 7.2Hz, 2H), 2.11 (s, 3H), 2.07 (s, 3H), 1.99 (s, 3H), 1.10 (t, J = 7.2 Hz, 3H); MS (ESI) m / z: 472.2 [M+H] + .

[0227] Preparation of (2R,3S,4R,5S)-2-(acetoxymethyl)-5-(2-azidoacetamido)-6-((Z)-2-ethyl-4-oxobut-2-enamido)tetrahydro-2H-pyran-3,4-dimethyldiacetate (AAMCHO) A1. A solution of (triphenylphosphine)acetaldehyde (147 mg, 0.484 mmol) in THF (500 μL) was added dropwise to a solution of compound 1.5 (57 mg, 0.121 mmol) in THF (200 μL) at 0 °C. After stirring at 0 °C for 30 min and then overnight at 45 °C, the reaction mixture was concentrated and resuspended in EtOH (2 mL), followed by the addition of anhydrous ZnCl2 (1312 mg, 0.968 mmol). The reaction mixture was stirred overnight, then filtered, washed with brine, dried over anhydrous Na2SO4, filtered, concentrated, and purified by column chromatography (SiO2, EtOAc / hexane) to give compound A1 (24 mg), a mixture of terminal isomers (1:3 α:β), in a yield of 39%. 1 H NMR (500 MHz, CDCl3) δ 9.70 (d, J = 7.7 Hz, 1H), 9.63 (d, J = 7.9 Hz, 1H), 7.03 (d, J = 8.9 Hz, 1H), 6.97 (d, J = 8.0 Hz, 2H), 6.94-6.80 (m, 2H), 6.58 (dt, J = 5.9, 1.9 Hz, 2H), 6.38 (dd, J = 15.2, 7.7 Hz, 1H), 6.27 (dd, J= 15.2, 7.8 Hz, 1H), 5.62-5.51 (m, 3H), 5.30-5.10 (m, 4H), 5.05 (q, J = 6.7Hz, 8H), 4.93-4.77 (m, 1H), 4.67 (s, 1H), 4.38-4.20 (m, 3H), 4.22-4.12 (m,1H), 4.06 (d, J = 7.8 Hz, 2H), 3.86 (d, J = 9.1 Hz, 3H), 2.58 (dd, J = 12.9,7.4 Hz, 1H), 2.30 (t, J = 6.8 Hz, 2H), 2.14 (s, 3H), 2.13 (s, 3H), 2.09 (s,3H), 2.04 (s, 3H), 2.02 (s, 3H), 2.00 (s, 2H), 1.16-1.13 (m, 4H); MS (ESI) m / z: 498.1 [M+H]+ . Example 2 Preparation of (2R,3S,4R,5S)-2-(acetoxymethyl)-5-(2-azidoacetamido)-6-((E)-2,3-dimethyl-4-oxobut-2-enamido)tetrahydro-2H-pyran-3,4-dimethyldiacetate A2 and N-((3S,4R,5S,6R)-2-amino-4,5-dihydroxy-6-(hydroxymethyl)-tetrahydro-2H-pyran-3-yl)-2-azidoacetamide C1

[0228] Compound A2 and compound C1 were prepared according to scheme 2.

[0229] Preparation of (E)-4-((tert-butyldimethylsilyl)oxy)-2,3-dimethylbut-2-enoate ethyl ester 2.2. NaH (3.78 g, 94.5 mmol, 60%) was added to a solution of 2-(diethoxyphosphoryl)propionate ethyl ester 2.1 (15 g, 63 mmol) in THF (200 mL) at 0 °C. The solution was stirred for 30 min, and then 1-((tert-butyldimethylsilyl)oxy)prop-2-one (11.9 g, 63 mmol) was added. After stirring at 0 °C for 2 h, the reaction mixture was diluted with H₂O (150 mL) and extracted with EtOAc (150 mL × 3). The combined organic layers were washed with brine (150 mL × 3), dried over anhydrous Na₂SO₄, filtered, concentrated, and purified by column chromatography (SiO₂, EtOAc / PE) to give compound 2.2 (16 g) in 93% yield. 1 H NMR (400 MHz, CDCl3)δ 4.48-4.07 (m, 4H), 1.96-1.81 (m, 3H), 1.81-1.75 (m, 3H), 1.28-1.22 (m, 3H), 0.87-0.83 (m, 9H), 0.04-0.01 (m, 6H); MS (ESI) m / z: 273.3 [M+H] + .

[0230] Preparation of (E)-4-((tert-butyldimethylsilyl)oxy)-2,3-dimethylbut-2-enoic acid 2.3. NaOMe (6.9 g, 129 mmol) was added to a solution of compound 2.2 (7 g, 25.7 mmol) in EtOH (100 mL) at room temperature. After stirring at 80 °C for 1 h, the reaction was quenched with H₂O (60 mL). The reaction mixture was acidified to pH 6 with 1 M HCl and then extracted with EtOAc (100 mL × 3). The combined organic layers were washed with brine (200 mL), dried over anhydrous Na₂SO₄, filtered, concentrated, and purified by column chromatography (SiO₂, EtOAc / PE) to give compound 2.3 (2.8 g) in 45% yield. 1 H NMR (400 MHz, DMSO-d6) δ 4.46 (s, 3H), 4.23 (s, 2H), 1.94 (d, J = 1.4 Hz, 3H), 1.83 (t, J =4.3 Hz, 8H), 1.80 (s, 3H), 0.92 (s, 12H), 0.90 (s, 9H), 0.12-0.09 (m, 6H),0.07 (d, J = 3.0 Hz, 8H); MS (ESI) m / z: 243.0 [MH] - .

[0231] Preparation of (2R,3S,4R,5S)-2-(acetoxymethyl)-5-(2-azidoacetamido)-6-((E)-4-((tert-butyldimethylsilyl)oxy)-2,3-dimethylbut-2-enamido)tetrahydro-2H-pyran-3,4-dimethyldiacetate 2.4. HATU (981 mg, 2.58 mmol) and DIEA (667 mg, 5.16 mmol) were added to a solution of compound 1.4 (1 g, 2.58 mmol) and compound 2.3 (631 mg, 2.58 mmol) in DMF (20 mL). After stirring at room temperature for 12 h, the reaction mixture was purified by reverse-phase preparative HPLC to give compound 2.4 (800 mg) in 50% yield. 1H NMR (400 MHz, CDCl3) δ 6.81-6.08 (m, 2H), 5.55 (t, J = 9.2 Hz, 1H), 5.20-5.01 (m, 2H), 4.75-4.57 (m, 1H), 4.33-4.14 (m, 3H), 4.14-4.12 (m, 2H), 4.08-4.01 (m, 1H), 3.88-3.73 (m, 1H), 2.10 (d, J = 4.8 Hz, 3H), 2.07-2.05 (m, 3H), 1.99 (d, J =2.0 Hz, 3H), 1.89-1.71 (m, 6H), 0.90 (s, 9H), 0.07 (s, 6H); MS (ESI) m / z:635.8 [M+Na] + .

[0232] Preparation of (2R,3S,4R,5S)-2-(acetoxymethyl)-5-(2-azidoacetamido)-6-((E)-4-hydroxy-2,3-dimethylbut-2-enamido)tetrahydro-2H-pyran-3,4-dimethyldiacetate 2.5. TFA (1.26 g, 13 mmol) was added to a solution of compound 2.4 (800 mg, 1.3 mmol) in DCM (10 mL). After stirring at room temperature for 3 h, the reaction mixture was purified by reversed-phase preparative HPLC to give compound 2.5 (400 mg) in 61% yield. 1 H NMR (400MHz, CDCl3) δ 6.73-6.29 (m, 2H), 5.57-5.35 (m, 2H), 5.22-5.11 (m, 2H), 4.70-4.60 (m, 1H), 4.34-4.20 (m, 2H), 4.19-4.13 (m, 3H), 4.10-4.00 (m, 2H), 2.16-2.01 (m, 12H), 1.87 (d, J = 8.4 Hz, 3H); MS (ESI) m / z: 499.9 [M+H] + .

[0233] Preparation of (2R,3S,4R,5S)-2-(acetoxymethyl)-5-(2-azidoacetamido)-6-((E)-2,3-dimethyl-4-oxobut-2-enamido)tetrahydro-2H-pyran-3,4-dimethyldiacetate A2. MnO2 (1.04 g, 12 mmol) was added to a solution of compound 2.5 (300 mg, 0.6 mmol) in DCM (10 mL). After stirring at room temperature for 12 h, the reaction mixture was filtered to give compound A2 (100 mg) in a yield of 33%. 1 H NMR (400 MHz, CDCl3) δ 10.18(s, 1H), 6.63 (d, J = 8.9 Hz, 1H), 6.50 (d, J = 8.6 Hz, 1H), 5.53 (d, J = 8.8Hz, 1H), 5.15 (d, J = 6.2 Hz, 2H), 4.69 (d, J = 9.0 Hz, 1H), 4.31 (dd, J =12.5, 4.4 Hz, 1H), 4.21-4.06 (m, 3H), 3.85 (s, 1H), 2.33 (s, 3H), 2.12 (s,3H), 2.07 (s, 3H), 2.01 (s, 3H), 1.80 (s, 3H); MS (ESI) m / z: 498.4 [M+H] + .

[0234] Preparation of N-((3S,4R,5S,6R)-2-amino-4,5-dihydroxy-6-(hydroxymethyl)-tetrahydro-2H-pyran-3-yl)-2-azidoacetamide C1. A solution of compound A2 (2 mg, 2.01 µmol) in acetone (0.2 mL) was added to 0.3 mL of 3% potassium permanganate ammonia solution at room temperature. After stirring for 16 h at room temperature, compound C1 was analyzed by MS. MS (ESI) m / z: 262.1 [M+H] + . Example 3 Preparation of (2R,3S,4R,5S)-2-(acetoxymethyl)-6-amino-5-(2-azidoacetamido)-tetrahydro-2H-pyran-3,4-dimethyldiacetate

[0235] The compound was prepared according to Scheme 3.

[0236] Ag₂O (2.8 mg, 12.1 µmol) was added to a solution of compound A₁ (2 mg, 4.02 µmol) in ACN (0.5 mL) at room temperature. After stirring at room temperature for 2 h, the compound was detected by MS. MS (ESI) m / z: 388.0 [M+H] + . Example B1 ALDH isotype selectivity

[0237] Activation of AAMCHO A1 was evaluated using 20 units of each ALDH isoform (including ALDH1A1, ALDH1A3, ALDH2, ALDH4A1, and ALDH5A1). All enzymatic reactions were performed at room temperature in 1 mL quartz cuvettes containing 2.5 mM NAD. + The assay was performed in 50 mM triethanolamine buffer (pH 7.4) with 5% v / v DMSO. AAMCHOA1 (1 µM) was added to the HPLC vial before measurement. At specified time points, aliquots (100 μL) were taken and quenched with MeOH (100 μL) and ACN (300 μL). The samples were then incubated at 37 °C with 10 mM DBCO-Cy5 (1 μL) for 1 h and detected by HPLC with a fluorescence detector (excitation: 650 nm, emission: 688 nm). DBCO-Cy5 was obtained from Click Chemistry Tools. All scans were performed in 50 mM TEA and 2.5 mM NAD. + The signal of AAMCHO A1 in (enzyme-free) samples was normalized. The results are shown in... Figure 2 and Figure 3 AAMCHO A1 was rapidly degraded by ALDH1A1. The formation of AM and 2-ethylmaleic anhydride was detected and quantified by HPLC-UV and LC-MS, respectively. The ALDH1A1 inhibitor DEAB significantly slowed the degradation of AAMCHO A1, while incubation with other ALDH isoforms (ALDH2, ALDH1A3, ALDH4A1, and ALDH5A1) resulted in limited degradation of AAMCHO A1. Example B2 In vivo cell markers

[0238] Mammospheres from MDA-MB-231 cells were prepared as previously described. Eirew et al., Nat. Med. 2008, 14, 1384-9; Shaw et al., J. Mammary Gland Biol. Neoplasia 2012, 17, 111-7; their respective publications are incorporated herein by reference in their entirety. For non-CSC cells, mammospheres were treated with 10% FBS and complete DMEM medium to induce differentiation for 36 h. Before in vivo seeding, CSC or non-CSC single-cell suspensions were prepared by gently treating mammospheres with trypsin and pipetting. CSC and non-CSC mammospheres were subcutaneously seeded in 50 μL of HBSS (10-1 cells in 50 μL of HBSS). 5 MDA-MB-231 xenograft tumor models were established in athymic nude mice using 10 cells per 100 cells. Starting from day 7 post-tumor inoculation, mice were intravenously injected daily with AAMCHO A1 (60 mg / kg), Ac4ManAz 1.2 (40 mg / kg), or PBS for three days. On day 10, DBCO-Cy5 (5 mg / kg) was injected intravenously to detect azide-labeled cells. Ac4ManAz was used as a positive control, and PBS as a negative control. Tumors and organs were removed from the mice 48 hours after DBCO-Cy5 injection for in vitro imaging. Fluorescence intensity of selected regions of interest (ROIs) was quantified using Bruker imaging software. Results are shown in [Figure number missing]. Figure 3 24 hours after DBCO-Cy5 injection, the inoculated CSCs showed significantly higher Cy5 fluorescence signals than non-CSCs. Ex vivo fluorescence imaging of CSC tumors showed a 2.5-fold increase in Cy5 fluorescence intensity compared to non-CSC tumors.

[0239] Twenty-four hours after the last injection of AAMCHO A1, Ac4ManAz 1.2, or PBS, tissue-bound azidosialic acid was extracted and derivatized by Cu(I)-catalyzed click reaction with coumarin-alkyne, followed by quantification by HPLC. Briefly, tissues were homogenized mechanically and then lysed using sonication with lysis buffer (50 mM Tris-HCl, 1% SDS, pH 7.4). Protein concentrations for each sample were quantified using a standard BCA protocol. The lysis buffer (90 µL) was mixed with acetic acid (10 µL) and heated at 80 °C for 3 h. The mixture was centrifuged at 10,000 rpm for 5 min. The supernatant was mixed with a freshly prepared reaction kit containing 7-ethynylcoumarin, tris-hydroxypropyltriazolylmethylamine, CuSO4, and ascorbic acid. The reaction mixture was shaken overnight at 37 °C and analyzed by HPLC equipped with a fluorescence detector (excitation: 328 nm, emission: 415 nm). The results are shown in Figure 4 Compared to non-CSC tumors and other tissues, AAMCHO A1 preferentially labeled CSC tumors. In contrast, the non-selective Ac4ManAz 1.2 similarly labeled both CSC and non-CSC tumors with azide groups and exhibited significant off-target labeling in other tissues. * * * * *

[0240] The embodiments described above are provided to give a complete disclosure and description of how to make and use the claimed implementations to those skilled in the art, 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 referenced in this specification are incorporated herein by reference, as each such publication, patent, or patent application expressly and separately designates as incorporated herein by reference.

Claims

1. A compound of formula (A): 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 1 It is hydrogen or deuterium; R 2 and R 3 Each is independently (i) hydrogen, deuterium, cyano, halogen, or nitro; (ii) C 1-10 Alkyl, C 1-10 Heteroalkyl, C 2-10 alkenyl, C 2-10 alkynyl group, C 3-10 cycloalkyl, C 6-14 Aryl, C 7-15 Aryl, heteroaryl, or heterocyclic; 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 、 –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 5 Each is independently (i) hydrogen; (ii) C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, C 6-14 Aryl, C 7-15 Aryl, heteroaryl, or heterocyclic; 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 ; R 6 and R 7 Each is independently a halogen; or (ii) –OR 1a –OC(O)R 1a –OC(O)OR 1a Or –OC(O)NR 1b R 1c And R 8 For (i) hydrogen; or (ii) –C(O)R 1a –C(O)OR 1a Or –C(O)NR 1b R 1c ; or R 6 and R 7 Or R 7 and R 8 They connect together to form a lactone ring; A represents a bond, O, or N (R). 1b ); E represents hydrogen, azide, halogen, isocyanate, or –C=C(R). 1a )R 1a –C≡CR 1a , , , –C(O)R 1a Or –SH; L is C 1-6 Alkylene, C 1-6 Heteroalkyl, C 2-6 imidene group, C 2-6 Ethyne group, C 3-10 Cycloalkylene, C 6-14 Alpha-aryl, C 7-15 arylene alkyl groups, heteroarylene alkyl groups, or heterocyclic alkyl groups; and R 1a R 1b R 1c and R 1d Each is independently hydrogen, deuterium, and C. 1-30 Alkyl, C 1-30 Heteroalkyl, C 2-30 alkenyl, C 2-30 alkynyl group, C 3-30 cycloalkyl, C 6-30 Aryl, C 7-30 Aryl, heteroaryl, or heterocyclic groups; In this embodiment, alkyl, alkylene, heteroalkyl, heteroalkylene, alkenyl, alkenylene, ynyl, ynylene, cycloalkyl, cycloalkylene, aryl, arylene, arylalkylene, heteroalkylene, heteroalkylene, heteroalkylene, heterocyclic, and heterocyclic are each optionally substituted by one or more substituents Q. In one embodiment, they are substituted by one, two, three, or four substituents Q, wherein each 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 group, C 3-10 cycloalkyl, C 6-14 Aryl, C 7-15 Aryl, heteroaryl, and heterocyclic groups, each optionally further substituent Q by one or more substituents. a In one embodiment, substitution occurs by one, two, three, or four substituents Q. a Substitution; 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 –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 Each is independently (i) hydrogen or deuterium; (ii) C 1-6 Alkyl, C 1-6 Heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, C 6-14 Aryl, C 7-15 Aryl, heteroaryl, or heterocyclic groups, each optionally substituent Q a In one embodiment, substitution occurs by one, two, three, or four substituents Q. a Replace; or (iii) R b and R c Together with the N atoms to which they are attached, they form a heterocyclic group, which is optionally substituent by one or more Q substituents. a In one embodiment, substitution occurs by one, two, three, or four substituents Q. a replace; Among them, Q a Each 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 group, C 3-10 cycloalkyl, C 6-14 Aryl, C 7-15 Aryl alkyl groups, heteroaryl groups, and heterocyclic groups; 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 Among them, R e R f R g and R h Each is independently (i) hydrogen or deuterium; (ii) C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, C 6-14 Aryl, C 7-15 Aryl, heteroaryl, or heterocyclic; or (iii) R f and R g Together with the N atoms they are attached to, they form heterocyclic groups.

2. The compound according to claim 1, wherein, R 6 For (i) 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 6 It is a halogen.

4. The compound according to any one of claims 1 to 3, wherein, R 6 It is fluorine.

5. The compound according to any one of claims 1 to 4, wherein, R 7 For (i) 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 to 5, wherein, R 7 It is a halogen.

7. The compound according to any one of claims 1 to 6, wherein, R 7 It 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 its pharmaceutically acceptable salts, solvates, hydrates, or prodrugs; wherein... R 6a and R 7a Each is independently 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 to 8, wherein, E represents hydrogen, azide, fluorine, iodine, isocyanate, –C=CH2, –C≡CH. , , , –C(O)CCH3 or –SH.

10. The compound according to any one of claims 1 to 9, wherein, E stands for azide group.

11. The compound according to any one of claims 8 to 10, wherein the compound has the structure of formula (III): 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.

12. The compound according to any one of claims 1 to 11, wherein, A represents a bond or O.

13. The compound according to any one of claims 1 to 12, wherein, A is the key.

14. The compound according to any one of claims 8 to 13, 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 pharmaceutically acceptable salts, solvates, hydrates, or prodrugs thereof.

15. The compound according to any one of claims 1 to 14, wherein, L is C 1-6 Alkylene, which is optionally substituted with one or more substituents Q.

16. The compound according to any one of claims 1 to 15, wherein, L is methanediyl, ethanediyl, propanediyl, or butanediyl, each optionally substituted by one or more substituents Q.

17. The compound according to any one of claims 1 to 16, wherein, L is methanediyl, ethane-1,2-diyl, propane-1,2-diyl, or butane-1,4-diyl, each optionally substituted by one or more substituents Q.

18. The compound according to any one of claims 1 to 17, wherein, L stands for methanediyl.

19. The compound according to any one of claims 8 to 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.

20. The compound according to any one of claims 8 to 19, 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 pharmaceutically acceptable salts, solvates, hydrates, or prodrugs thereof.

21. The compound according to any one of claims 8 to 19, 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 pharmaceutically acceptable salts, solvates, hydrates, or prodrugs thereof.

22. The compound according to any one of claims 8 to 21, wherein, R 6a For hydrogen or –C(O)R 1a .

23. The compound according to any one of claims 8 to 22, wherein, R 6a –C(O)–C 1-6 Alkyl group, which is optionally substituted with one or more substituents Q.

24. The compound according to any one of claims 8 to 23, wherein, R 6a It can be acetyl, propionyl, or butyryl.

25. The compound according to any one of claims 8 to 24, wherein, R 6a It is an acetyl group.

26. The compound according to any one of claims 8 to 25, wherein, R 7a For hydrogen or –C(O)R 1a .

27. The compound according to any one of claims 8 to 26, wherein, R 7a –C(O)–C 1-6 Alkyl group, which is optionally substituted with one or more substituents Q.

28. The compound according to any one of claims 8 to 27, wherein, R 7a It can be acetyl, propionyl, or butyryl.

29. The compound according to any one of claims 8 to 28, wherein, R 7a It is an acetyl group.

30. The compound according to any one of claims 1 to 29, wherein, R 1 It is hydrogen.

31. The compound according to any one of claims 1 to 29, wherein, R 2 (i) hydrogen or deuterium; or (ii) C 1-10 Alkyl, C 1-10 Heteroalkyl or C 1-10 Alkenyl groups, each optionally substituted by one or more substituents Q.

32. The compound according to any one of claims 1 to 31, wherein, R 2 It is hydrogen.

33. The compound according to any one of claims 1 to 32, wherein, R 3 (i) hydrogen or deuterium; or (ii) C 1-10 Alkyl, C 1-10 Heteroalkyl or C 1-10 Alkenyl groups, each optionally substituted by one or more substituents Q.

34. The compound according to any one of claims 1 to 33, wherein, R 3 It is hydrogen.

35. The compound according to any one of claims 1 to 33, wherein, R 3 C 1-10 Alkyl group, which is optionally substituted with one or more substituents Q.

36. The compound according to any one of claims 1 to 33 and 35, wherein, R 3 It is methyl, ethyl, propyl, or butyl, each optionally substituted by one or more substituents Q.

37. The compound according to any one of claims 1 to 33, 35 and 36, wherein, R 3 It is an ethyl group, which may optionally be substituted with one or more substituents Q.

38. The compound according to any one of claims 1 to 33, wherein, R 3 C 1-10 Heteroalkyl groups, which are optionally substituted with one or more substituents Q.

39. The compound according to any one of claims 1 to 33, wherein, R 3 C 2-10 The alkenyl group is optionally substituted with one or more substituents Q.

40. The compound according to any one of claims 1 to 39, wherein, R 4 It is hydrogen.

41. The compound according to any one of claims 1 to 40, wherein, R 5 It is hydrogen.

42. The compound according to any one of claims 8 to 41, wherein, R 8 For hydrogen or –C(O)R 1a .

43. The compound according to any one of claims 8 to 42, wherein, R 8 –C(O)–C 1-6 Alkyl group, which is optionally substituted with one or more substituents Q.

44. The compound according to any one of claims 8 to 43, wherein, R 8 It can be acetyl, propionyl, or butyryl.

45. The compound according to any one of claims 8 to 44, wherein, R 8 It is an acetyl group.

46. ​​The compound according to claim 1, wherein, The compound is (2R,3S,4R,5S)-2-(acetoxymethyl)-5-(2-azidoacetamido)-6-((Z)-2-ethyl-4-oxobut-2-enamido)tetrahydro-2H-pyran-3,4-dimethyldiacetate A1 or (2R,3S,4R,5S)-2-(acetoxymethyl)-5-(2-azidoacetamido)-6-((E)-2,3-dimethyl-4-oxobut-2-enamido)tetrahydro-2H-pyran-3,4-dimethyldiacetate A2; 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.

47. A pharmaceutical composition comprising the compound of any one of claims 1 to 46, 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.

48. The pharmaceutical composition according to claim 47, wherein, The composition is in a single dosage form.

49. The pharmaceutical composition according to claim 47 or 48, wherein, The composition is available in oral, parenteral, or intravenous dosage forms.

50. The pharmaceutical composition according to claim 49, wherein, The composition is formulated into an oral dosage form.

51. The pharmaceutical composition according to claim 50, wherein, The oral dosage form is a tablet or a capsule.

52. A method for labeling cells in a subject with a functional group, the method comprising administering to a subject in need an effective amount of a compound according to any one of claims 1 to 46 or a pharmaceutical composition according to any one of claims 47 to 51.

53. The method according to claim 52, wherein, The subjects were humans.

54. A method for labeling cells with functional groups, the method comprising contacting the cells with an effective amount of a compound according to any one of claims 1 to 46 or a pharmaceutical composition according to any one of claims 47 to 51.

55. The method according to any one of claims 52 to 54, wherein, The cells in question are ALDH1A1 overexpressing cells.

56. The method according to any one of claims 52 to 55, wherein, The cells in question are cancer cells.

57. The method according to any one of claims 52 to 55, wherein, The cells in question are cancer stem cell-like cells.

58. The method according to any one of claims 52 to 57, wherein, The functional group is an azide group.

59. A compound comprising: N-((3S,4R,5S,6R)-2-amino-4,5-dihydroxy-6-(hydroxymethyl)-tetrahydro-2H-pyran-3-yl)-2-azidoacetamide C1; (Z)-N-((3S,4R,5S,6R)-3-(2-azidoacetamido)-4,5-dihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)-2-ethyl-4-oxobut-2-enamide C2; ​​or (Z)-3-(((3S,4R,5S,6R)-3-(2-azidoacetamido)-4,5-dihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yl)carbamoyl)pent-2-enoic acid C3.

60. A compound of the following: (2R,3S,4R,5S)-2-(acetoxymethyl)-6-amino-5-(2-azidoacetamido)tetrahydro-2H-pyran-3,4-dimethyldiacetate.

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